Edward G. Lakatta

Resveratrol (3,5,4′-trihydroxystilbene) extends the lifespan of diverse species including Saccharomyces cerevisiae, Caenorhabditis elegans and Drosophila melanogaster. In these organisms, lifespan extension is dependent on Sir2, a conserved deacetylase proposed to underlie the beneficial effects of caloric restriction. Here we show that resveratrol shifts the physiology of middle-aged mice on a high-calorie diet towards that of mice on a standard diet and significantly increases their survival. Resveratrol produces changes associated with longer lifespan, including increased insulin sensitivity, reduced insulin-like growth factor-1 (IGF-I) levels, increased AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α) activity, increased mitochondrial number, and improved motor function. Parametric analysis of gene set enrichment revealed that resveratrol opposed the effects of the high-calorie diet in 144 out of 153 significantly altered pathways. These data show that improving general health in mammals using small molecules is an attainable goal, and point to new approaches for treating obesity-related disorders and diseases of ageing. You can have your cake and eat it. Fat, healthy and tipsy. Fountain of youth. These headlines and more greeted online publication of the Article 'Resveratrol improves health and survival of mice on a high-calorie diet'. What the paper does show is that consumption of resveratrol at doses achievable in humans (but not from red wine — the hundreds of bottles a day needed would have side effects) can reproduce many of the physiological effects of a low-calorie diet in mice, improving health and survival. Read the small print in this issue.

HomeCirculationVol. 107, No. 1Arterial and Cardiac Aging: Major Shareholders in Cardiovascular Disease Enterprises Free AccessReview ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessReview ArticlePDF/EPUBArterial and Cardiac Aging: Major Shareholders in Cardiovascular Disease EnterprisesPart I: Aging Arteries: A “Set Up” for Vascular Disease Edward G. Lakatta, MD and Daniel Levy, MD Edward G. LakattaEdward G. Lakatta From the Gerontology Research Center, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, Md; and the Framingham Heart Study, National Heart, Lung and Blood Institute, National Institutes of Health, Framingham, Mass. Search for more papers by this author and Daniel LevyDaniel Levy From the Gerontology Research Center, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, Md; and the Framingham Heart Study, National Heart, Lung and Blood Institute, National Institutes of Health, Framingham, Mass. Search for more papers by this author Originally published7 Jan 2003https://doi.org/10.1161/01.CIR.0000048892.83521.58Circulation. 2003;107:139–146The Demographic Imperative and the Risk of Vascular Diseases in Older PersonsOur population is aging; in the United States today there are 35 million people 65 years of age or older. That number will double by the year 2030 (Figure 1). Although epidemiological studies have discovered that lipid levels, diabetes, sedentary lifestyle, and genetic factors are risk factors for coronary disease, hypertension, congestive heart failure, and stroke, the quintessential cardiovascular diseases within our society, advancing age unequivocally confers the major risk. The incidence and prevalence of these diseases increase steeply with advancing age (Figure 2). Not only does clinically overt cardiovascular disease increase dramatically with aging, but so do subclinical or occult diseases, such as silent coronary atherosclerosis. Figure 3 (top) shows that a substantial percentage of older, community-dwelling, otherwise healthy volunteers have evidence of inducible ischemia during combined thallium/ECG treadmill stress testing, and their prognosis is poor compared with their counterparts without subclinical coronary disease (Figure 3, bottom). Download figureDownload PowerPointFigure 1. The demographic imperative. Numbers of persons 65 years of age or older (light bars) and 85 years of age or older in the United States from 1900 through 2030. Data taken from the US Census Bureau data with projections for 2030.Download figureDownload PowerPointFigure 2. A, Prevalence of hypertension, defined as systolic blood pressure ≥140, diastolic blood pressure ≥90, or current use of medication for purposes of treating high blood pressure. Data are based on National Health and Nutrition Examination Survey III (1988–1991) (Burt VL, Whelton P, Roccella EJ, et al. Prevalence of hypertension in the US adult population: results from the Third National Health and Nutrition Examination Survey, 1988-1991. Hypertension. 1995;25:305–313). B, Incidence of atherothrombotic stroke (per 1000 subjects per year) by age in men (light bars) and women (dark bars) from the Framingham Heart Study. Data from Wolf PA. Lewis A. Conner lecture: contributions of epidemiology to the prevention of stroke. Circulation. 1993;88:2471–24783. C, Incidence of coronary heart disease by age in men (light bars) and women (dark bars) from the Framingham Heart Study. Data from Kannel WB, Wolf PA, Garrison RJ, eds. Framingham Study: An Epidemiological Investigation of Cardiovascular Disease. Section 34. NIH Publication No.87–2703. Bethesda, Md: National Heart, Lung and Blood Institute; 1987.Download figureDownload PowerPointFigure 3. Top, The prevalence of silent ischemia in apparently healthy asymptomatic BLSA volunteer subjects. Silent ischemia is defined as both a positive thallium scan (TI-201) and a positive ECG during maximal exercise. N indicates the number of test performed. From Fleg JL, Gerstenblith G, Zonderman AB, et al. Prevalence and prognostic significance of exercise-induced silent myocardial ischemia detected by thallium scintigraphy and electrocardiography in asymptomatic volunteers Circulation 1990;81:428-436, and Fleg JL, et al, Gerontology Research Center, National Institute on Aging, Baltimore, Md, unpublished data. Bottom, The event free survival rates in those with a double positive (ECG + TI-201) is markedly reduced compared with all other volunteers tested. Within 5 years, 50% of those with a double-positive test for silent ischemia developed their initial clinical manifestation of coronary artery disease. Numbers in the lower part of the figure represent the number of subjects monitored during the follow-up period; lower numbers indicate all double positive test; top numbers, all others. Reprinted from Fleg JL, Gerstenblith G, Zonderman AB, et al. Prevalence and prognostic significance of exercise-induced silent myocardial ischemia detected by thallium scintigraphy and electrocardiography in asymptomatic volunteers Circulation 1990;81:428-436.Advancing Age: The Major Risk Factor for Vascular DiseaseThere are several possible explanations for the dominant effect of age on the likelihood for occurrence of these cardiovascular diseases. One is that aging is synonymous with disease; however, many people achieve “old age” without evidence of these diseases. Another explanation for the “epidemic” of cardiovascular disease in older persons is that other defined risk factors co-vary in number or severity with increasing age. A related, but distinct, idea is that increasing age contributes to an increased exposure time to these other age-dependent risk factors. According to this view, time indirectly confers an increased risk for the occurrence and increased severity and extent of pathophysiological manifestations of these diseases in older persons. A somewhat different view is that cardiovascular structure and function change with time because an “aging process,” and that, over time, this process alters the substrate on which specific pathophysiological disease mechanisms, such as those that have been linked to experimental atherosclerosis, become superimposed. According to this view, the enhanced risk for older persons to encounter the above diseases is due to age–disease interactions. In other words, age impacts the severity of disease manifestations for a given time at risk. Thus, age-associated changes in cardiovascular structure and function become “partners” with pathophysiological disease mechanisms to determine the threshold, severity, and prognosis of cardiovascular disease occurrence in older persons. Of course, the true interactions are more complex and involve age, multiple risk factors, and genetics. Whereas we have begun to understand some aspects of the former two, the latter most likely involves complex genetic traits that, by and large, remain elusive. With the sequencing of the human genome and the availability of high-throughput genotyping to detect polymorphic allele variation on a population-wide basis, however, breakthroughs may be on the horizon.To define why age (or an aging process × exposure time interaction) is so risky with respect to the aforementioned vascular diseases, the specific components of the risk associated with age must be identified. Two complimentary approaches have evolved. On the one hand, epidemiologists are searching for novel measures of “subclinical disease” (in addition to the more established risk factors that have already been well characterized) in large, unselected study cohorts composed of persons both with and without cardiovascular disease. In contrast, gerontologists are attempting to develop quantitative information on cardiovascular structure and function in apparently healthy individuals to define and target the specific characteristics of aging that render it such a major risk factor for cardiovascular disease, even in the absence of clinically apparent comorbidity. The latter approach consists of identifying and selecting community-dwelling individuals who do not have (or have not yet experienced) clinical disease and who do not have occult disease that can be detected by noninvasive methods. These individuals are then grouped by age and stratified according to the level of a given variable, which may include some of the novel measures of subclinical disease identified by the epidemiologists. If the variable is perceived as beneficial or deleterious with respect to cardiovascular structure or function, those with extreme measures are considered to be aging “successfully” or “unsuccessfully,” respectively. “Unsuccessful” aging in this context is not synonymous with having clinical disease, as individuals with defined overt or occult clinical disease have been excluded from consideration a priori. Instead, unsuccessful aging, ie, falling within the poorest category with respect to the measure viewed as deleterious, may be viewed as a risk factor for future clinical cardiovascular disease. In this regard, unsuccessful aging is a manifestation of the interaction of the vascular aging process and specific aspects of vascular disease pathophysiology. Thus, gerontologists and epidemiologists have become part of a joint effort in the quest to define why aging confers enormous risk for cardiovascular disease.The central thesis of this review is that quintessential clinical cardiovascular diseases of older persons and age-associated changes in cardiovascular structure and function, heretofore not defined as disease, become intertwined and interdependent. The role of specific age-associated changes in cardiovascular structure and function in this age–disease interaction has formerly been, and largely continues to be, unrecognized by those who shape medical policy. Thus, specific aspects of cardiovascular aging have remained outside the bailiwick of clinical cardiology, and, until recently, have not been considered in most epidemiological studies of cardiovascular disease. Our main goal is to promote a new research frontier by defining our current understanding of the age-associated changes in cardiac and vascular structure and function that occur in apparently healthy persons and how these are relate to the risk of subsequent cardiovascular disease occurrence. This goal is pursued in this and the additional two articles of this series that will occur in subsequent issues of Circulation1,2 to provoke thought regarding the new and important research efforts to design basic experiments that elucidate these mechanisms and clinical trials that evaluate strategies aimed at reducing or preventing those aspects of aging, such as age-associated increases in large vessel lumen, wall thickening, and stiffness, that occur in apparently healthy persons but confer risk for overt clinical cardiovascular disease.Age-Associated Changes in Vascular Structure and Function in Apparent HealthDuring the past 2 decades, a sustained effort has been ongoing to characterize the effects of aging on multiple aspects of cardiovascular structure and function in a single study population in the Baltimore Longitudinal Study on Aging (BLSA).3 These community-dwelling volunteers are rigorously screened to detect both clinical and occult cardiovascular disease and are characterized with respect to lifestyle (eg, diet and exercise habits) in an attempt to identify and clarify the interactions of these factors and those changes that result from aging.3 Perspectives gleaned from these studies, as well as relevant information regarding cardiovascular aging from other studies in humans and in animal models, are revisited here in the context of the findings of large epidemiological studies that have sought to define risk factors for cardiovascular disease morbidity and mortality.Age-Associated Changes Central Arterial Structure of HumansAge-associated changes in the arterial properties of individuals who are considered otherwise healthy may have relevance to the steep age-dependent increase in vascular diseases (Figure 4 and Figure 5). Cross-sectional studies in humans have found that wall thickening and dilatation are prominent structural changes that occur within large elastic arteries during aging.4 Postmortem studies indicate that the aortic wall thickening that occurs with aging consists mainly of intimal thickening, even in populations with a low incidence of atherosclerosis.5 Noninvasive measurements made within the context of several epidemiological studies indicate that the carotid wall intimal media (IM) thickness increases 2- to 3-fold between 20 and 90 years of age, which also is the case in BLSA individuals rigorously screened to exclude carotid or coronary arterial stenosis (Figure 4A). Note, however, the marked heterogeneity in IM thickness among individuals of a given age. Although arterial remodeling with aging in otherwise healthy humans occurs in the context of age-associated endothelial dysfunction,6 there is presently no detailed information regarding the factors involved in progressive IM thickening with aging in humans. Download figureDownload PowerPointFigure 4. A, The common carotid intimal medical thickness in healthy BLSA volunteers as a function of age. B, Common carotid intimal medial thickness as a function of age, stratified by coronary artery disease (CAD) classification. CAD 2 indicates that group in Figure 3 with double positive tests (see Figure 3 legend). Data for A is from Nagai Y, Metter J, Earley CJ, et al. Increased carotid artery intimal-medial thickness in asymptomatic older subjects with exercise-induced myocardial ischemia. Circulation 1998;98:1504-1509. B is reprinted from that same article. C, Common carotid intimal medial thickness predicts future cardiovascular events in Cardiovascular Health Study (CHS). D, Comparison of the associations of age- and sex-adjusted risk factors with the combined event of stroke or myocardial infarction in Cox proportional-hazards models in the CHS study. Note that intimal medical thickness is a potent risk factor for future cardiovascular events. Both C and D reprinted from O’Leary DH, Polack JF, Kronmal RA, et al. Carotid-artery intima and media thickness as a risk factor for myocardial infarction and stroke in older adults: Cardiovascular Health Study Collaborative Research Group. N Engl J Med 1999;340:14-22.Download figureDownload PowerPointFigure 5. A, Aortic pulse wave velocity as a function of age in healthy BLSA volunteer subjects. From Vaitkevicius PV, Fleg JL, Engel JH, et al. Effects of age and aerobic capacity on arterial stiffness in healthy adults. Circulation 1993;88:1456–1462. B, Reduced arterial elasticity in normotensive persons, independent of blood pressure, predicts the future development of hypertension. AADC, EP, YEM, and B are indices of elasticity as defined in sources. Reprinted from Liao D, Arnett DK, Tyroler HA, et al. Arterial stiffness and the development of hypertension: the ARIC Study. Hypertension 1999;34:201–206.Increased Intimal Thickening as a Risk Factor for AtherosclerosisIt has been argued that the age-associated increase in IM thickness in humans represents an early stage of atherosclerosis. Indeed, excessive IM thickening at a given age predicts the co-existence of silent coronary artery disease (CAD) (Figure 4B). Because silent CAD often progresses to overt clinical CAD, it is not surprising that increased IM thickness predicts future clinical cardiovascular disease events. A plethora of other epidemiological studies of individuals who were not initially screened to exclude the presence of occult cardiovascular disease have indicated that increased IM thickness is an independent predictor of future cardiovascular events. Note in Figure 4C that the degree of risk varies with degree of vascular thickening, and that the risk gradation among quintiles of IM thickening is non-linear, with the greatest risk occurring in the upper quintile. Thus, older persons in the upper quintile of IM thickness may be considered to have aged unsuccessfully or to have “subclinical” vascular disease. The potency of IM thickness as a risk factor in other individuals equals or exceeds that of most other, more “traditional” risk factors (Figure 4D). Note, however, in Figure 4B that the difference between older and younger persons without evidence of coronary disease far exceeds the difference between older persons free of coronary disease and those with disease. Similar IM thickening occurs with aging in non-human primates and rodents in the absence of atherosclerosis,2 and age-dependent IM thickening has also been documented in humans in the absence of atherosclerosis.5The subclinical disease of excessive IM thickening is not necessarily early atherosclerosis. Rather, subclinical IM thickening is strongly correlated with intrinsic arterial aging. Viewed in this way, the increase in IM thickness with aging is analogous to intimal hyperplasia in aortocoronary saphenous vein graphs that serves as the foundation for the later development of atherosclerosis.7 Age-associated endothelial dysfunction, arterial stiffening, and arterial pulse pressure widening can also be considered similarly (see below). Combinations of these processes occurring to varying degrees determine the overall vascular aging profile of a given individual. Worse combinations may lead to the most unsuccessful aging within a vessel wall. In humans in Western society, additional risk factors, including hypertension, smoking, dyslipidemia, diabetes, diet, and heretofore unidentified genetic factors, interact with vascular aging (as described above) to activate an atherosclerotic plaque. According to this view, atherosclerosis, which increases with aging, is not a specific disease but rather an interaction of atherosclerotic plaque with intrinsic features related to vascular aging modulated by atherosclerotic risk factors. Evidence in support of this view comes from studies in which an atherogenic diet resulting in the same elevation of plasma lipids caused markedly more severe atherosclerotic lesions in older versus younger rabbits and non-human primates.8,9 Hence, it is possible that atherosclerosis occurring at younger ages may be attributable not only to exaggerated traditional risk factors, but also to accelerated aging of the vascular wall. Of course, the traditional risk factors may themselves accelerate aging of the vascular wall.Studies in various populations with clinically defined vascular disease have demonstrated that pharmacological interventions, with or without lifestyle (diet, physical activity) interventions, can retard the progression of IM thickening.10–14 There have be no such studies in persons at high risk for cardiovascular events solely due to unsuccessful vascular aging.Increased Arterial StiffeningAge-associated increase in IM thickening is accompanied by both luminal dilatation and a reduction in compliance or distensibility, with an increase in vessel stiffness.2 Pulse wave velocity (PWV), a relatively convenient, noninvasive index of vascular stiffening, increases with age both in men and women (Figure 5A). PWV is determined in part by the intrinsic stress/strain relationship (stiffness) of the vascular wall and by the mean arterial pressure. Increased PWV has traditionally been linked to structural alterations in the vascular media, including increased collagen, reduced elastin ontent, elastin fractures, and calcification. Prominent age-associated increases in PWV have been demonstrated in populations with little or no atherosclerosis, indicating that vascular stiffening can occur independently of atherosclerosis.15 However, more recent data emerging from epidemiological studies indicate that increased large vessel stiffening also occurs in the context of atherosclerosis and diabetes.16,17 The link may be that stiffness is governed not only by the structural changes within the matrix, as noted above, but also by endothelial regulation of vascular smooth muscle tone and of other aspects of vascular wall structure/function. Abnormalities of the endothelium have been identified to occur early on in the pathophysiology of atherosclerosis, diabetes, and hypertension.18 Thus, there is evidence of a vicious cycle: altered mechanical properties of the vessel wall influence the development of atherosclerosis and the latter, via endothelial cell dysfunction and other mechanisms, influences vascular stiffness.As the walls of large arteries become stiffer, central systolic arterial pressure increases, diastolic arterial pressure decreases, and the pulse pressure increases for a given pattern of left ventricular ejection. A longitudinal study of a large population of relatively aged subjects has shown that elevated levels of pulse pressure are associated with progression of IM thickening and that IM thickening, in turn, is associated with widening of pulse pressure.19 Numerous additional recent studies have concurred that elevated pulse pressure is an independent risk factor for future cardiovascular events.16–30 Thus, an increased PWV reflects 3 potential risk factors: increased systolic pressure, widened pulse pressure, and altered vascular wall properties. Recent studies17,31–33 indicate that elevated pulse wave velocity and reduced total systemic compliance assessed by stroke volume/pulse pressure, over and above blood pressure, are independent predictors of cardiovascular events. This suggests that altered structure/function of the stiff vessel wall, in addition to the associated increase in systolic and pulse pressures, is a risk factor for future vascular events. It has been hypothesized that cross-links, due to nonenzymatic glycation, that increase with age and increase markedly in diabetes contribute to age- and disease-related increases in large artery stiffening. In this regard, a novel drug that breaks such cross-links has been shown to reduce indices of arterial stiffness measures in rodents, dogs, non-human primates, and humans.34–37In fact, recent studies have demonstrated that increased vascular stiffness precedes the development of hypertension (Figure 5B). This concept has been overshadowed by the idea that an increase in mean arterial pressure or peripheral resistance is the predominant cause of increased large artery stiffness. In other words, while the “secondary” increase in large artery stiffness is attributable to an increase in mean pressure that occurs in hypertension, evidence now exists that the “primary” increase in large artery stiffness that accompanies aging gives rise to an increase in large vessel stiffness that proceeds an elevation of arterial pressure. Figure 5B illustrates this point. Normotensive individuals who fall within the upper quintiles for measures of arterial stiffness are more likely to develop hypertension (Figure 5B). Observations such as this give rise to the notion that hypertension is in part a disease of the arterial wall. There are compensatory mechanisms to normalize blood pressure that fail with advancing age. For example, endothelial function becomes apparently altered at about the 6th decade (Figure 6A), a time when pulse pressure begins to appreciably elevate (Figure 6B). Thus, the altered endothelial function that occurs with aging may be a mechanism that not only permits arterial pulse pressure to rise but that also underlies the importance of pulse pressure as a risk factor for cardiovascular events, even when systolic pressure is accounted for. Download figureDownload PowerPointFigure 6. A, Endothelial (flow) mediated and non-endothelial (glyceryl trinitrate) induced arterial dilatation in apparently healthy persons. Note that the marked age-associated decline occurs about a decade later in females versus males. Reprinted from Celermajer DS, Sorensen KE, Spiegelhalter DJ, et al. Aging is associated with endothelial dysfunction in healthy men years before the age-related decline in women. J Am Coll Cardiol 1994;24:471–476. B, Pulse pressure in healthy BLSA individuals. Reprinted from Pearson JD, Morrell CH, Brant LJ, et al. Age-associated changes in blood pressure in a longitudinal study of healthy men and women. J Gerontol Med Sci. 1997;52:M177–M183. C, Tracking of systolic blood pressure with age in Framingham Heart Study subjects. Subjects were stratified in 4 groups according to their systolic blood pressure (SBP) in middle age: <120 mm Hg, 120 to 139 mm Hg, 140 to 159 mm Hg, and ≥160 mm Hg. D, Tracking of diastolic blood pressure (DBP) with age in Framingham Heart Study subjects (same grouping were used as in C). Both C and D adapted from Franklin SS, Gustin W IV, Wong ND, et al. Hemodynamic patterns of age-related changes in blood pressure: the Framingham Heart Study. Circulation 1997;96:308–315.Arterial PressureAs our definition of disease continues to evolve, we may find that many subjects who were formerly thought to be healthy are not. For example, systolic pressure ≥140 mm Hg is now considered to be hypertension, and hypertension is considered to be a disease. Individuals with a systolic pressure between 140 and 160 mm Hg, who a decade ago were thought to be free from disease, are now identified as being diseased. Larger studies have shown that individuals who manifest modest elevations in systolic and pulse pressures are more likely to develop clinical disease or die from it.38In addition to stroke volume, arterial pressure is determined by the interplay of peripheral resistance and central artery stiffness; the former raises both systolic and diastolic pressure to a similar degree, whereas the latter raises systolic but lowers diastolic pressure. Pulse pressure is a useful hemodynamic indicator of conduit artery vascular stiffness. Framingham investigators and others have reported an age-dependent rise in average systolic blood pressure across all adult age groups (Figure 6C). In contrast, average diastolic pressure was found to rise until 50 years of age, level off from ages 50 to 60, and decline thereafter (Figure 6D). The age-dependent changes in systolic, diastolic, and pulse pressure are consistent with the notion that in younger people, blood pressure is determined largely by peripheral vascular resistance, whereas in older individuals, it is determined to a greater extent by central conduit vessel stiffness.Owing to the decline in diastolic pressure in older men and women in whom systolic pressure is increasing, isolated systolic hypertension emerges as the most common form of hypertension in individuals over the age of 50.38 Isolated systolic hypertension, even when mild in severity (stage 1), is associated with an appreciable increase in cardiovascular disease risk.21,22 Based on long-term follow up of middle-aged and older subjects, however, Framingham researchers have found pulse pressure to be a better predictor of coronary disease risk than the systolic or diastolic pressure.23 When considered jointly with the systolic blood pressure in older subjects, diastolic blood pressure is inversely related to coronary risk. Consideration of the systolic and diastolic pressures jointly may be preferable to consideration of either value alone.21,23,39An emerging concept in the treatment of hypertension recognizes that progressive vascular damage can continue to occur even when arterial pressure is controlled. It is conceivable that drugs that retard or reverse age-associated vascular wall remodeling and increased stiffness will be preferable to those that lower pressure without affecting the vascular wall properties.SummaryThere is a growing body of evidence that increased large artery thickening and stiffness and endothelial dysfunction in apparently otherwise healthy older persons, along with the ensuing increase in systolic and pulse pressure that was formerly thought to be part of “normal” aging, precede clinical disease and predict a higher risk for developing clinical atherosclerosis, hypertension, and stroke (Table). Some of these vascular changes that occur with aging in normotensive humans, including endothelial dysfunction, have been observed in hypertensive patients at an earlier age and are more marked than in normotensive subjects. Such otherwise asymptomatic individuals might be considered to manifest unsuccessful vascular aging. When stated in this context, unsuccessful vascular aging becomes the risk factor for eventual clinical disease manifestations. Some epidemiologists will perceive the risk of unsuccessful vascular aging as synonymous with subclinical cardiovascular disease; however, evidence is mounting that subclinical vascular disease in older persons represents specific aspects of vascular aging and is not synonymous with low-grade atherosclerosis or hypertension. Rather, vascular aging and vascular disease are partners; each contributes specific components to what is presently referred to as “vascular disease.” Thus, what clinical medicine and epidemiology now refer to as vascular disease should be regarded as the “vascular aging–vascular disease interaction.” Aging blood vessels provide the milieu in which vascular diseases can flourish. If vascular aging is a risk factor for disease, then age-associated vascular changes represent a potential target for treatment and prevention. The vascular changes due to aging in persons who do not have a diagnosis of clinical cardiovascular disease have remained largely outside the bailiwick of clinical cardiology, however, and until recently have not been the focus of preventive measures. Relationship of Vascular Human Aging in Health to Vascular DiseasesAge-Associated ChangesPlausible MechanismsPossible Relation to Human DiseaseVSMC indicates vascu

Joel Hirschhorn and colleagues report results of a large-scale genome-wide association and replication study for obesity-related traits. The newly discovered loci are enriched for genes expressed in the central nervous system, and may thus contribute to weight gain by modulating food intake. Similar results are reported in a related study by Gudmar Thorleifsson and colleagues. Common variants at only two loci, FTO and MC4R, have been reproducibly associated with body mass index (BMI) in humans. To identify additional loci, we conducted meta-analysis of 15 genome-wide association studies for BMI (n > 32,000) and followed up top signals in 14 additional cohorts (n > 59,000). We strongly confirm FTO and MC4R and identify six additional loci (P < 5 × 10−8): TMEM18, KCTD15, GNPDA2, SH2B1, MTCH2 and NEGR1 (where a 45-kb deletion polymorphism is a candidate causal variant). Several of the likely causal genes are highly expressed or known to act in the central nervous system (CNS), emphasizing, as in rare monogenic forms of obesity, the role of the CNS in predisposition to obesity.

The obesity epidemic is responsible for a substantial economic burden in developed countries and is a major risk factor for type 2 diabetes and cardiovascular disease. The disease is the result not only of several environmental risk factors, but also of genetic predisposition. To take advantage of recent advances in gene-mapping technology, we executed a genome-wide association scan to identify genetic variants associated with obesity-related quantitative traits in the genetically isolated population of Sardinia. Initial analysis suggested that several SNPs in the FTO and PFKP genes were associated with increased BMI, hip circumference, and weight. Within the FTO gene, rs9930506 showed the strongest association with BMI (p = 8.6 ×10−7), hip circumference (p = 3.4 × 10−8), and weight (p = 9.1 × 10−7). In Sardinia, homozygotes for the rare “G” allele of this SNP (minor allele frequency = 0.46) were 1.3 BMI units heavier than homozygotes for the common “A” allele. Within the PFKP gene, rs6602024 showed very strong association with BMI (p = 4.9 × 10−6). Homozygotes for the rare “A” allele of this SNP (minor allele frequency = 0.12) were 1.8 BMI units heavier than homozygotes for the common “G” allele. To replicate our findings, we genotyped these two SNPs in the GenNet study. In European Americans (N = 1,496) and in Hispanic Americans (N = 839), we replicated significant association between rs9930506 in the FTO gene and BMI (p-value for meta-analysis of European American and Hispanic American follow-up samples, p = 0.001), weight (p = 0.001), and hip circumference (p = 0.0005). We did not replicate association between rs6602024 and obesity-related traits in the GenNet sample, although we found that in European Americans, Hispanic Americans, and African Americans, homozygotes for the rare “A” allele were, on average, 1.0–3.0 BMI units heavier than homozygotes for the more common “G” allele. In summary, we have completed a whole genome–association scan for three obesity-related quantitative traits and report that common genetic variants in the FTO gene are associated with substantial changes in BMI, hip circumference, and body weight. These changes could have a significant impact on the risk of obesity-related morbidity in the general population.

To identify genetic variants influencing plasma lipid concentrations, we first used genotype imputation and meta-analysis to combine three genome-wide scans totaling 8,816 individuals and comprising 6,068 individuals specific to our study (1,874 individuals from the FUSION study of type 2 diabetes and 4,184 individuals from the SardiNIA study of aging-associated variables) and 2,758 individuals from the Diabetes Genetics Initiative, reported in a companion study in this issue. We subsequently examined promising signals in 11,569 additional individuals. Overall, we identify strongly associated variants in eleven loci previously implicated in lipid metabolism (ABCA1, the APOA5-APOA4-APOC3-APOA1 and APOE-APOC clusters, APOB, CETP, GCKR, LDLR, LPL, LIPC, LIPG and PCSK9) and also in several newly identified loci (near MVK-MMAB and GALNT2, with variants primarily associated with high-density lipoprotein (HDL) cholesterol; near SORT1, with variants primarily associated with low-density lipoprotein (LDL) cholesterol; near TRIB1, MLXIPL and ANGPTL3, with variants primarily associated with triglycerides; and a locus encompassing several genes near NCAN, with variants strongly associated with both triglycerides and LDL cholesterol). Notably, the 11 independent variants associated with increased LDL cholesterol concentrations in our study also showed increased frequency in a sample of coronary artery disease cases versus controls.

The goal of this study was to determine whether aortic pulse wave velocity (aPWV) improves prediction of cardiovascular disease (CVD) events beyond conventional risk factors. Several studies have shown that aPWV may be a useful risk factor for predicting CVD, but they have been underpowered to examine whether this is true for different subgroups. We undertook a systematic review and obtained individual participant data from 16 studies. Study-specific associations of aPWV with CVD outcomes were determined using Cox proportional hazard models and random effect models to estimate pooled effects. Of 17,635 participants, a total of 1,785 (10%) had a CVD event. The pooled age- and sex-adjusted hazard ratios (HRs) per 1-SD change in loge aPWV were 1.35 (95% confidence interval [CI]: 1.22 to 1.50; p < 0.001) for coronary heart disease, 1.54 (95% CI: 1.34 to 1.78; p < 0.001) for stroke, and 1.45 (95% CI: 1.30 to 1.61; p < 0.001) for CVD. Associations stratified according to sex, diabetes, and hypertension were similar but decreased with age (1.89, 1.77, 1.36, and 1.23 for age ≤50, 51 to 60, 61 to 70, and >70 years, respectively; pinteraction <0.001). After adjusting for conventional risk factors, aPWV remained a predictor of coronary heart disease (HR: 1.23 [95% CI: 1.11 to 1.35]; p < 0.001), stroke (HR: 1.28 [95% CI: 1.16 to 1.42]; p < 0.001), and CVD events (HR: 1.30 [95% CI: 1.18 to 1.43]; p < 0.001). Reclassification indices showed that the addition of aPWV improved risk prediction (13% for 10-year CVD risk for intermediate risk) for some subgroups. Consideration of aPWV improves model fit and reclassifies risk for future CVD events in models that include standard risk factors. aPWV may enable better identification of high-risk populations that might benefit from more aggressive CVD risk factor management.

Blood low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol and triglyceride levels are risk factors for cardiovascular disease. To dissect the polygenic basis of these traits, we conducted genome-wide association screens in 19,840 individuals and replication in up to 20,623 individuals. We identified 30 distinct loci associated with lipoprotein concentrations (each with P < 5 x 10(-8)), including 11 loci that reached genome-wide significance for the first time. The 11 newly defined loci include common variants associated with LDL cholesterol near ABCG8, MAFB, HNF1A and TIMD4; with HDL cholesterol near ANGPTL4, FADS1-FADS2-FADS3, HNF4A, LCAT, PLTP and TTC39B; and with triglycerides near AMAC1L2, FADS1-FADS2-FADS3 and PLTP. The proportion of individuals exceeding clinical cut points for high LDL cholesterol, low HDL cholesterol and high triglycerides varied according to an allelic dosage score (P < 10(-15) for each trend). These results suggest that the cumulative effect of multiple common variants contributes to polygenic dyslipidemia.

Background— Aging results in vascular stiffening and an increase in the velocity of the pressure wave as it travels down the aorta. Increased aortic pulse wave velocity (aPWV) has been associated with mortality in clinical but not general populations. The objective of this investigation was to determine whether aPWV is associated with total and cardiovascular (CV) mortality and CV events in a community-dwelling sample of older adults. Methods and Results— aPWV was measured at baseline in 2488 participants from the Health, Aging and Body Composition (Health ABC) study. Vital status, cause of death and coronary heart disease (CHD), stroke, and congestive heart failure were determined from medical records. Over 4.6 years, 265 deaths occurred, 111 as a result of cardiovascular causes. There were 341 CHD events, 94 stroke events, and 181 cases of congestive heart failure. Results are presented by quartiles because of a threshold effect between the first and second aPWV quartiles. Higher aPWV was associated with both total mortality (relative risk, 1.5, 1.6, and 1.7 for aPWV quartiles 2, 3, and 4 versus 1; P =0.019) and cardiovascular mortality (relative risk, 2.1, 3.0, and 2.3 for quartiles 2, 3, and 4 versus 1; P =0.004). aPWV quartile was also significantly associated with CHD ( P =0.007) and stroke ( P =0.001). These associations remained after adjustment for age, gender, race, systolic blood pressure, known CV disease, and other variables related to events. Conclusions— Among generally healthy, community-dwelling older adults, aPWV, a marker of arterial stiffness, is associated with higher CV mortality, CHD, and stroke.

HomeHypertensionVol. 66, No. 3Recommendations for Improving and Standardizing Vascular Research on Arterial Stiffness Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissionsDownload Articles + Supplements ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toSupplemental MaterialFree AccessResearch ArticlePDF/EPUBRecommendations for Improving and Standardizing Vascular Research on Arterial StiffnessA Scientific Statement From the American Heart Association Raymond R. Townsend, MD, FAHA, Chair, Ian B. Wilkinson, MD, DM, FRCP, FAHA, Vice Chair, Ernesto L. Schiffrin, MD, PhD, FAHA, Vice Chair, Alberto P. Avolio, BE, PhD, Julio A. Chirinos, MD, PhD, FAHA, John R. Cockcroft, FRCP, Kevin S. Heffernan, PhD, Edward G. Lakatta, MD, Carmel M. McEniery, PhD, Gary F. Mitchell, MD, Samer S. Najjar, MD, Wilmer W. Nichols, PhD, Elaine M. Urbina, MD, MS, FAHA, Thomas Weber, MD and Raymond R. TownsendRaymond R. Townsend Search for more papers by this author , Ian B. WilkinsonIan B. Wilkinson Search for more papers by this author , Ernesto L. SchiffrinErnesto L. Schiffrin Search for more papers by this author , Alberto P. AvolioAlberto P. Avolio Search for more papers by this author , Julio A. ChirinosJulio A. Chirinos Search for more papers by this author , John R. CockcroftJohn R. Cockcroft Search for more papers by this author , Kevin S. HeffernanKevin S. Heffernan Search for more papers by this author , Edward G. LakattaEdward G. Lakatta Search for more papers by this author , Carmel M. McEnieryCarmel M. McEniery Search for more papers by this author , Gary F. MitchellGary F. Mitchell Search for more papers by this author , Samer S. NajjarSamer S. Najjar Search for more papers by this author , Wilmer W. NicholsWilmer W. Nichols Search for more papers by this author , Elaine M. UrbinaElaine M. Urbina Search for more papers by this author , Thomas WeberThomas Weber Search for more papers by this author and Search for more papers by this author and on behalf of the American Heart Association Council on Hypertension Originally published9 Jul 2015https://doi.org/10.1161/HYP.0000000000000033Hypertension. 2015;66:698–722Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: January 1, 2015: Previous Version 1 Much has been published in the past 20 years on the use of measurements of arterial stiffness in animal and human research studies. This summary statement was commissioned by the American Heart Association to address issues concerning the nomenclature, methodologies, utility, limitations, and gaps in knowledge in this rapidly evolving field. The following represents an executive version of the larger online-only Data Supplement and is intended to give the reader a sense of why arterial stiffness is important, how it is measured, the situations in which it has been useful, its limitations, and questions that remain to be addressed in this field. Throughout the document, pulse-wave velocity (PWV; measured in meters per second) and variations such as carotid-femoral PWV (cfPWV; measured in meters per second) are used. PWV without modification is used in the general sense of arterial stiffness. The addition of lowercase modifiers such as “cf” is used when speaking of specific segments of the arterial circulation.The ability to measure arterial stiffness has been present for many years, but the measurement was invasive in the early times. The improvement in technologies to enable repeated, minimal-risk, reproducible measures of this aspect of circulatory physiology led to its incorporation into longitudinal cohort studies spanning a variety of clinical populations, including those at extreme cardiovascular risk (patients on dialysis), those with comorbidities such as diabetes mellitus (DM) and hypertension, healthy elders, and general populations.In the ≈3 decades of clinical use of PWV measures in humans, we have learned much about the importance of this parameter. PWV has proven to have independent predictive utility when evaluated in conjunction with standard risk factors for death and cardiovascular disease (CVD). However, the field of arterial stiffness investigation, which has exploded over the past 20 years, has proliferated without logistical guidance for clinical and translational research investigators. This summary statement, commissioned by the American Heart Association Council on Hypertension, represents an effort to provide such guidance, drawing on the expertise of experienced clinical and basic science investigators in Europe, Australia, and the United States. Recommendations made in this statement are assumed to refer to the research aspect of arterial stiffness investigations, unless accompanied by language that emphasizes clinical use as well, and are based on the grid shown in Table 1.Table 1. Applying Classification of Recommendations and Level of EvidenceTable 1. Applying Classification of Recommendations and Level of EvidenceSection 1. What Is Arterial Stiffness?Recommendation1.1.It is reasonable to measure arterial stiffness clinically by determining PWV (Class IIa; Levelof Evidence A).1Arterial stiffness is a concept that refers to the material properties of the arterial wall, which in turn has functional consequences for the artery because it affects the manner in which pressure, blood flow, and arterial diameter change with each heartbeat. In addition to the passive mechanical properties of the load-bearing structures, arterial stiffness can be modulated by functional components related to cellular processes in which wall stiffness can be affected by endothelial function through modulation of smooth muscle tone or by alterations in the integrity of the extracellular matrix. As developed in this summary statement, stiffness is measured in different kinds of arteries (muscular, elastic) and in cross section, longitudinally along the vessel, or in both directions. Often, arterial stiffness is assessed as the velocity of pulse-wave travel in a defined segment such as the aorta. However, the research questions addressed by investigations of arterial stiffness are not restricted to this use, and stiffness has been measured in most named large arteries in humans.2 Arterial stiffness is also estimated by measuring pressure or diameter in a vessel and applying 1 or several of the now extensive formulas to the data to derive a value that reflects this inherent property of all arteries.3Surrogate Measures of Arterial Stiffness and What Is Not Technically StiffnessArterial stiffness is often determined by measuring the velocity of pulse-wave travel in a segment of vessel.1 This is a valid measure, justified by equations such as the Moens-Korteweg and Bramwell Hill equations with which these measures agree.3 Other methods to measure arterial stiffness include the assessment of arterial compliance or distensibility or measures of characteristic impedance (relating pressure changes to flow changes). When arterial geometry (size and wall thickness) is known, it can be used to compute the arterial wall elastic modulus, a direct expression of the stiffness of the wall. Confusion arises when measures such as systolic pressure augmentation, which compares the first and second systolic peaks in the central aortic waveform and is sometimes reported as an augmentation index (AIx), are presented as “stiffness” parameters. Such measures are the result of several factors, including, but not limited to, arterial stiffness (described further in the Section 4).4The Arterial Wall and StiffnessArterial stiffness refers to the material properties of the arterial wall, which in turn affect the manner in which pressure, blood flow, and arterial diameter change with each heartbeat. The pressure load of each heartbeat in large conduit arteries is borne mainly by the elastin and collagen components, with less contribution from smooth muscle in the muscular arteries. Because of the anatomic arrangement of the elastin and collagen fibers, elastin engages at low distention (hence at low pressure) and collagen at higher distention (and pressure).5 The contribution of elastin and collagen to wall stiffness along the aorta varies as distance from the aortic valve increases to optimize the reservoir function of the aorta.Arterial stiffness is a major determinant of vascular impedance. Impedance relates the change in arterial pressure to the change in blood flow. Flow is determined by the presence of a pressure gradient. The relationships between time, pressure, and flow are such that local wave velocity becomes a determinant of the instantaneous relationship between pressure and flow. For elastic conduits, wave velocity is related to the stiffness of the wall, so changes in stiffness will modulate the pressure/flow relationships. The need to buffer each stroke volume and to adapt to changes in flow requires an optimal balance in the elastic and inelastic elements in the wall. Disease, aging, and other exposures typically reduce the elastic component and promote the inelastic (collagen) component such that arterial stiffness generally increases with age in most people.Changes in arterial stiffness fall into passive and active categories. Passive categories relate to arterial wall fiber elements that are stretched and recoil with each heartbeat and to heart rate (higher heart rates can be associated with increased arterial stiffness6). Active categories include endothelial function as it relates to nitric oxide and endothelin and vascular smooth muscle in which higher resting tone is associated with increased arterial stiffness.7 Inflammation, oxidative stress, and turnover in the extracellular matrix of the vessel wall are additional active contributors to arterial stiffness.8 In addition, sympathetic tone and genetic polymorphisms appear to regulate arterial stiffness in some vascular beds. The degree of the passive and active (functional) effects on wall stiffness depends on the type of artery: A greater degree of functional effects would be manifest in more muscular arteries (eg, carotid, iliac) compared with larger nonmuscular conduit arteries (eg, aorta).Section 2: Devices Used to Measure PWVRecommendations2.1.Arterial stiffness should be determined noninvasively by measurement of cfPWV (Class I; Level of Evidence A).9,102.2.PWVs measured in other vascular segments such as ankle-brachial or the determination of the cardiac-ankle vascular stiffness index is useful in cardiovascular outcome predictions in Asian populations, but longitudinal studies in the United States and Europe by these methods are lacking (Class I; Level of Evidence B).11,122.3.Single-point estimates of PWV are not recommended because there is a lack of evidence of cardiovascular outcome prediction in longitudinal studies. Measurement of PWV in other arterial segments such as carotid-radial is not recommended because it does not predict outcomes (Class III; Level of Evidence B).13Measurements of PWV are undertaken with several methodologies, some of which require sophisticated equipment (magnetic resonance imaging [MRI]) and software. These fall into 4 categories:Devices that use a probe or tonometer to record the pulse wave with a transducerDevices using cuffs placed around the limbs or the neck that record arrival of the pulse wave oscillometricallyUltrasonography approachesMRI-based approachesDevices Using a Probe or a Tonometer to Measure PWVA number of devices based on this technology are available and have been used extensively in published research. Tonometry-based techniques (eg, the SphygmoCor device, AtCor Medical, West Ryde, NSW, Australia) use a piezoelectric Millar tonometer that is placed at any 2 sites where a pulse is detectable. Only 1 tonometer is attached to the unit, so PWV measurements require 2 sequential 10- to 20-second readings, gated to the ECG, to be taken. The average transit time (TT) is then derived with the R wave of the ECG used as a reference point, and PWV is calculated from the inputted distance measurement. The SphygmoCor device has been used in the Anglo-Cardiff Collaborative Study of arterial stiffness14 and the Chronic Renal Insufficiency Cohort (CRIC) study of chronic kidney disease,15 as well as in other cohorts and intervention studies. Newer versions of this device use a cuff and tonometer system to record simultaneous pressure waves.16 Published reproducibility of the PWV with the SphygmoCor, as judged by Bland-Altman plot analysis, is good.17Mechanotransducer-based techniques (eg, Complior, ALAM Medical, Vincennes, France) use similar principles but allow simultaneous measurement between sites with distention sensors. The Complior software provides an online pulse-wave recording and automatic calculation of the PWV.18 This device has been used extensively in epidemiologic studies in Europe and has provided much of the early outcome data relating PWV to CVD risk. The published reproducibility of the PWV with the Complior, as judged by Bland-Altman plot analysis, is good.19Other tonometry-based devices (eg, PulsePen, DiaTecne, Milan, Italy) use an ECG signal and a handheld tonometer (similar to the SphygmoCor) to perform cfPWV measures. The PulsePen has been used in the Predictive Values of Blood Pressure and Arterial Stiffness in Institutionalized Very Aged Population (PARTAGE) study conducted in elderly patients in France and Italy.20 The reproducibility of the PulsePen, as judged by Bland-Altman plot analysis, is good.21Still other tonometry-based devices (eg, those used by Cardiovascular Engineering, Inc, Norwood, MA) use a custom device to measure PWV with tonometric methods. The system uses the foot-to-foot measure of carotid and femoral pressure waveforms, with distance measures to the carotid artery site and femoral artery site calculated from the sternal notch. The ECG QRS complex is used as the timing onset point, and the elapsed time to the carotid pressure waveform foot and the femoral pressure waveform foot is calculated and divided into the distance measurement. This system has been used in the Framingham22 and Reykjavik23 studies, as well as other cohorts and intervention trials. Reproducibility of the PWV by this method is reportedly good (Gary F. Mitchell, MD, Cardiovascular Engineering, Inc, Norwood, MA; personal communication, June 1, 2015).Devices Using Cuffs Placed Around the Limbs or the Neck That Record Pulse-Wave Arrival OscillometricallyOscillometry-based devices (eg, VP1000, Omron Healthcare, Kyoto, Japan) rely on 4 oscillometric cuffs placed on both arms (brachial) and ankles to calculate brachial-ankle PWV (baPWV; measured in meters per second). It also provides an ankle-brachial index (ratio of systolic pressure in the ankle to that of the brachial artery; a marker of peripheral arterial disease when this ratio is <0.9). Newer models (eg, VP2000) have additional probes that can be secured in place (with straps) that detect carotid and femoral pulses simultaneously (ie, both probes capture the same pulse wave) by tonometry. ECG leads are attached, as is a phonocardiographic microphone (whether the measurements are being done by oscillometry or tonometry). The subject’s age, height, and sex are entered into the software, and the distance estimate is calculated with the use of statistical norms (based on Japanese individuals). The Omron device has been used in prospective observational studies, mainly in Asia, and for independently predicting loss of kidney function,24 CVD,25 and all-cause death.26 Published reproducibility of the PWV with the VP1000, as judged by Bland-Altman plot analysis, is good.27Cuff-based devices (eg, Mobil-O-Graph, IEM, Stolberg, Germany) capture brachial blood pressure (BP) and brachial waveforms (casual and at 24 hours) to estimate central aortic pressures and to estimate cfPWV.28,29 The Mobil-O-Graph 24-hour pulse-wave analysis ambulatory BP measurement device uses a proprietary algorithm to obtain conventional brachial BP readings, after which the brachial cuff is inflated to the diastolic BP level and held constant for ≈10 seconds to record the pulse waves. Subsequently, central pressure curves are obtained with the use of a transfer function. To estimate aortic PWV, several parameters from pulse-wave analysis, along with wave separation analysis, are combined in a proprietary mathematical model incorporating age, systolic pressure, and aortic characteristic impedance.30 The Mobil-O-Graph aortic PWV values have been validated by direct intra-arterial measurement in the catheterization laboratory.31 Reproducibility of the Mobil-O-Graph, as judged by Bland-Altman plot analysis, is good.32Some cuff-based devices (eg, Vasera, Fukuda Denshi, Tokyo, Japan) use cuffs on all 4 limbs and gate the timing for the pulse-wave arrival at the ankle relative to the heart using phonocardiography through a small microphone taped onto the chest.33 In addition to the cardio-ankle vascular index, which is derived from the cardio-ankle PWV, it provides an ankle-brachial index. This device has been used mainly in Japan for longitudinal studies of dialysis patients11 and in community studies of cognitive decline.34 Reproducibility of the Vasera, as judged by Bland-Altman plot analysis, is good.35Ultrasonographic ApproachesUltrasonography can be used to assess vessel distention and derived stiffness indexes or flow waveforms to calculate PWV. Distention waveforms can be assessed with ultrasound transducers at a variety of locations, but often the carotid and femoral sites are used. Although some parts of the aorta itself are assessable, measurements in the thoracic aorta are technically challenging. An average change in cross-sectional area of a vessel can be derived from the distention waveform with dedicated software (eg, ARTLAB, ESAOTE, Genoa, Italy). Using a value for the pulse pressure (PP), the operator can determine distention and compliance. Brachial artery pressure often is used rather than local PP, which may introduce inaccuracies, as may any delay between distention and BP assessment. Pulse-wave speed (c) and other indexes of elasticity such as incremental elastic modulus can also be derived, as discussed earlier. It is worth noting that most ultrasonographic systems and software produce a time-averaged waveform, and mathematically, this will yield different values for stiffness indexes compared with calculating distention beat by beat and then averaging.In addition, ultrasonography is used to assess local (cross-sectional) distensibility of vessels such as the carotid artery. B-mode ultrasonography, video analysis, and echo-tracking methodologies are commonly used approaches.36,37 The online-only Data Supplement (Section 6) has more discussion of this aspect and device comparisons (Table 6.4 in the online-only Data Supplement).Doppler ultrasonography may be used to record flow waveforms from accessible sites from which PWV can be estimated in a manner similar to PWV based on pressure waveforms. Waveforms may be recorded either sequentially with ECG gating or simultaneously.38 Typically, 1 ultrasound transducer is clamped to the left side of the neck to insonate the site of the left subclavian artery or carotid artery, and the second transducer is secured on the abdomen, insonating the abdominal aorta above the bifurcation. Distance is measured from the suprasternal notch (SSN) to the location of the second transducer. This can be challenging because the angle of insonation makes it difficult to reliably determine where the abdominal aorta is being interrogated in most (obese) people. The foot of the flow wave from each of the recording sites is used, and the time elapsed in milliseconds is calculated. There is no set duration of recording, but averaging several beats (commonly 5–10 beats) is beneficial to increase the accuracy of the measurement.39 Identifying the foot of the flow wave can be more challenging than identifying the foot of a pressure wave. However, such techniques have shown independent predictive value for cardiovascular outcomes and death in longitudinal studies of diabetics,39 the healthy elderly,40 and a general population.41 Published reproducibility of ultrasonography-based PWV, as judged by Bland-Altman plot analyses, is good.42,43MRI-Based ApproachesMRI can be applied in much the same way as ultrasonography to determine distention-based indexes or PWV. It has the advantage of being able to assess almost any vessel and providing more accurate distance and area estimates (Vessels can always be “cut” in a perpendicular manner). However, these advantages are offset by poorer time and spatial resolution and cost.Phase-contrast MRI (PC-MRI) can be used to acquire blood flow velocity maps along any given anatomic plane. When the gradient direction is applied exactly perpendicular to the cross-sectional vessel plane (“through-plane” velocity encoding), flow can be measured through the vessel cross section. Such an approach can be used to compute the time delay between the onset of flow in the ascending and descending thoracic aorta, which can be simultaneously interrogated in cross section in a properly prescribed anatomic plane. Alternatively, the gradient direction can be prescribed in plane with the vessel flow axis, allowing the acquisition of a velocity map along the length of the vessel. This approach allows the measurement of the spatiotemporal flow profile along the length of the vessel, thus allowing the computation of PWV. This approach can be easily applied to the thoracic aorta in the “candy-cane” plane.PC-MRI sequences require a user-defined velocity-encoding sensitivity, which should be as low as possible to minimize noise during the acquisition yet higher than peak flow velocity in the region of interest to avoid aliasing. Although velocity-encoding sensitivity should be tailored to individual measurements, a velocity-encoding sensitivity of 130 to 150 cm/s allows adequate interrogation of thoracic aortic flow in most cases. PC-MRI data are acquired over several cardiac cycles, and consistent cardiac timing in each cycle is assumed. Adequate PC-MRI flow measurements require careful attention to technical details, including the recognition and minimization of sources of error such as phase-offset errors caused by inhomogeneities of the magnetic field environment (short-term eddy currents),44,45 signal loss resulting from turbulent flow, partial volume averaging resulting from limited spatial resolution, and signal misregistration caused by in-plane movement of the aorta and pulsatile flow artifacts. The temporal resolution of PC-MRI flow measurements should be maximized, which requires data collection over multiple cardiac cycles. This is usually achieved by prolonged (several minutes) acquisitions during free breathing. Various alternative techniques have been proposed for fast, real-time assessments of PWV.46–49 More research is needed into the optimal algorithm to measure the time delay between the foot of the flow waves with PC-MRI.A second approach to measure arterial stiffness with MRI involves the assessment of arterial distention, which can be paired with pressure measurements to obtain local arterial compliance and distensibility. Steady-state free-precession techniques provide high contrast between the arterial lumen and arterial wall and allow automatic segmentation of aortic lumen throughout the cardiac cycle. Such approaches can be used to assess ascending aortic properties as long as simultaneous (or quasi-simultaneous) central pressure recordings are performed. Unfortunately, tonometric arterial pressure recordings are difficult within the MRI suite because available tonometry systems are not MRI compatible. Good reproducibility of PWV by PC-MRI has been reported, with intraclass correlation coefficients of ≈0.90.50Many of the devices reviewed in this section can also be used to capture waveforms for central aortic pressure-wave analysis. Section 4 in this executive summary and Section 4 in the online-only Data Supplement provide greater detail.Regardless of the approach used, it is critical to include an accurate measurement of BP at the time of stiffness measurement because mean arterial pressure (MAP) is an important determinant of stiffness (Section 7 and Recommendation 7.1). Reproducibility is generally good, and most devices and approaches have been in use for at least a decade. Other approaches to measuring arterial stiffness are covered in Section 2 in the online-only Data Supplement.Section 3. Why Is Arterial Stiffness Important?Recommendation3.1.It is reasonable to measure arterial stiffness to provide incremental information beyond standard CVD risk factors in the prediction of future CVD events (Class IIa; Level of Evidence A).10Arterial Stiffness as a Predictor of Future Cardiovascular RiskStiffening of the central arteries has a number of adverse hemodynamic consequences, including a widening of PP, a decrease in shear stress rate, and an increase in the transmission of pulsatile flow into the microcirculation. These effects have a number of detrimental consequences that may, in part, explain mechanistically why stiffness is a predictor of risk. Numerous studies involving various disease-specific and community-based cohorts have demonstrated that higher cfPWV is associated with increased risk for a first or recurrent major CVD event.9,10 Consideration of cfPWV substantively reclassifies risk in individuals at intermediate risk for CVD, suggesting that consideration of cfPWV provides novel and clinically relevant information beyond that provided by standard risk factors.10,22 In addition, small studies have demonstrated that persistent elevation of cfPWV during treatment for hypertension or CVD is associated with high risk for an adverse outcome in those with established disease.51,52 The added benefit of cfPWV in risk prediction models may be a manifestation of the relatively modest relation between cfPWV and standard risk factors other than age and BP.53 In a recent individual-participant meta-analysis, higher cfPWV was shown to be associated with increased risk for coronary heart disease, stroke, and composite cardiovascular events. Importantly, relative risk was strongest in younger individuals, in whom an opportunity exists for early identification, lifestyle modification, and possible mitigation or prevention of further potentially irreversible deterioration of aortic structure and function.10HypertensionThe association between arterial stiffness and hypertension is well established.54–58 There is a widely held belief that increased aortic stiffness in hypertensive individuals is largely a manifestation of long-standing hypertension-related damage that stiffens the large arteries. A recent analysis from the Framingham Heart Study found that higher arterial stiffness, as assessed by cfPWV, was associated with BP progression and incident hypertension 7 years later.54 However, higher BP at an initial examination was not associated with progressive aortic stiffening, suggesting that aortic stiffness is a cause rather than a consequence of hypertension in middle-aged and older individuals. These results and several additional studies provide strong evidence in support of the hypothesis that arterial stiffness represents a cause rather than a consequence of hypertension and underscore the importance of better defining the pathogenesis of aortic stiffening.55–58High aortic stiffness is associated with increased BP lability.59–61 A stiffened vasculature is less able to buffer short-term alterations in flow. Increased aortic stiffness is also associated with impaired baroreceptor sensitivity.59,62–64 Together, these limitations may result in potentially marked alterations in BP as cardiac output changes during normal daily activities such as changes in posture and physical exertion.65Cardiac DiseaseExcessive arterial stiffness represents a compound insult on the heart. Aortic stiffening increases left ventricular (LV) systolic load, which contributes to ventricular remodeling and reduced mechanical efficiency. This leads to an increase in myocardial oxygen demand,66 compounded by a reduction in diastolic coronary perfusion as PP widens and diastolic BP decreases with aortic stiffening.67 Arterial stiffening may be associated with impaired measures of LV diastolic function,68,69 which may increase cardiac filling pressure and further limits coronary perfusion. Finally, arterial stiffness is associated with atherosclerosis,70–73 which may further impair ventricular perfusion, possibly leading to catastrophic reductions in ventricular function during ischemia.67Arterial stiffness is associated with diastolic dysfunction and diastolic heart failure resulting from direct effects of abnormal load and loading sequence on myocyte contraction and relaxation and indirectly through ventricular hypertrophy.69,74–78 Diastolic dysfunction increases filling pressures and thus may increase load on the atria, which will contribute to atrial hypertrophy and fibrosis and ultimately to atrial fibrillation.79 Arterial stiffness is independently associated with an increased risk of heart failure80 and is increased in patients with established heart failure regardless of whether LV function is preserved or impaired.81–83Peripheral Vascular FunctionArterial stiffness (arteriosclerosis) is associated with atherosclerosis, although the association is not strong and the 2 processes should be viewed as distinct pathophysiological entities. Aortic stiffening may increase the risk for development of atherosclerosis as a result of atherogenic hemodynamic stresses associated with a stiffened aorta, including increased pressure pulsatility and

HomeCirculationVol. 107, No. 2Arterial and Cardiac Aging: Major Shareholders in Cardiovascular Disease Enterprises Free AccessReview ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessReview ArticlePDF/EPUBArterial and Cardiac Aging: Major Shareholders in Cardiovascular Disease EnterprisesPart II: The Aging Heart in Health: Links to Heart Disease Edward G. Lakatta, MD and Daniel Levy, MD Edward G. LakattaEdward G. Lakatta From the Gerontology Research Center, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, Md; and the Framingham Heart Study, National Heart, Lung and Blood Institute, National Institutes of Health, Framingham, Mass. Search for more papers by this author and Daniel LevyDaniel Levy From the Gerontology Research Center, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, Md; and the Framingham Heart Study, National Heart, Lung and Blood Institute, National Institutes of Health, Framingham, Mass. Search for more papers by this author Originally published21 Jan 2003https://doi.org/10.1161/01.CIR.0000048893.62841.F7Circulation. 2003;107:346–354A Trilogy of Heart Disease Manifestations Emerges With Advancing AgeThe preceding article in this series1 reviewed evidence as to why age-associated changes in the central arterial system are risky with respect to vascular disease. In a similar vane, the focus of this article is on the potential link between age-associated changes in the heart and clinical cardiac disease outcomes.Left ventricular hypertrophy, heart failure, and atrial fibrillation increase dramatically with age (Figure 1). The prevalence of left ventricular hypertrophy (LVH) also increases with rising blood pressure and body mass index, a measure of obesity.2–4 Whether identified by electrocardiography or echocardiography, left ventricular hypertrophy has been shown to be associated with increased risk for coronary heart disease, sudden death, stroke, and overall cardiovascular disease.4,5Download figureDownload PowerPointFigure 1. A, Prevalence of echocardiographic left ventricular hypertrophy (LVH) in women according to baseline age and systolic blood pressure. B, Prevalence of echocardiographic LVH in men according to baseline age and systolic blood pressure. Both A and B are reprinted from Levy D, Anderson KM, Savage DD, et al. Echocardiographically detected left ventricular hypertrophy: prevalence and risk factors: the Framingham Heart Study. Ann Intern Med. 1988;108:7–13. C, Prevalence of heart failure by age in Framingham Heart Study men (light bars) and women (dark bars). Reprinted from Ho KK, Pinsky JL, Kannel WB, et al. The epidemiology of heart failure: the Framingham Study. J Am Coll Cardiol 1993;22:6A–13A. D, Prevalence of AF by age in subjects from the Framingham Heart Study. Reprinted from Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation as an independent risk factor for stroke: the Framingham Study. Stroke. 1991;22:983–988.It has been increasingly appreciated that the development of heart failure with apparently preserved systolic function, as evidenced by a “normal” ejection fraction, occurs in about one-third to one-half of older patients with heart failure.6–9 In a patient with heart failure, a diagnosis of diastolic heart failure can be inferred, largely by exclusion, when other comorbidities that masquerade as heart failure are ruled out and left ventricular ejection fraction is intact.10Atrial fibrillation (AF) is detected in approximately 3% to 4% of healthy volunteers over age 60 years who are rigorously screened to exclude clinical coronary artery disease; this is a rate 10-fold higher than in the general adult population.11,12 In the Framingham population, a history of AF without identifiable cause (so-called “lone” AF) was present 16.8% of men and 6.0% of women with AF at a mean age of about 70 years.12 During long-term follow-up, individuals with lone AF suffered over 4 times as many strokes as control subjects, although their rates of coronary events or congestive heart failure were similar to those of controls. The proportion of AF cases that occur in the absence of an identifiable cause differs between studies. These differences are due to differences in characteristics of subjects and the rigor with which underlying causes are sought.Age-Associated Changes in Cardiac Structure and Function in Persons Without a Heart Disease DiagnosisThere is a continuum of expression of cardiac structural and functional alterations that occurs with age in healthy humans, and these age-associated cardiac changes seem to have relevance to the steep increases in LVH, chronic heart failure, and AF seen with increasing age.Cardiac StructureCross-sectional studies of subjects without hypertension or clinically apparent cardiovascular disease indicate that left ventricular (LV) wall thickness, measured via M-mode echocardiography, increases progressively with age in both sexes (Figure 2A). In older hospitalized patients without apparent cardiovascular disease, in whom overall LV mass was not increased, cardiac myocyte enlargement was observed at autopsy, along with an decrease in the estimated myocyte number that was greater in males than in females.13 An increase in the amount (focal increases) and a change in the physical properties of collagen (purportedly due to nonenzymatic cross-linking) also occur within the myocardium with aging. The cardiac myocyte-to-collagen ratio in the older heart either remains constant or increases, however, because of an increase in myocyte size. Download figureDownload PowerPointFigure 2. A, Left ventricular posterior wall thickness, measured by M-mode echocardiography, increases with age in healthy men and women in the BLSA. Reprinted from reference 33. B, Age-associated reduction in the early diastolic left ventricular filling measured via Doppler sonography in healthy volunteers in the BLSA. Reprinted from reference 16 and supplemented with measurements in additional BLSA volunteer subjects. The atrial contribution to filling is increased with aging. Reprinted from reference 16. D, The E/A decline with aging in healthy volunteers in the BLSA is identical to that participants of the Framingham Study. Reprinted from references 15 and 16.Left Ventricular Diastolic FunctionThe LV early diastolic filling rate progressively slows after the age of 20 years,14–16 so that by 80 years the rate is reduced, on average, up to 50% (Figure 2B). Structural (fibrous) changes within the LV myocardium or residual myofilament Ca2+ activation from the preceding systole (see below) are putative mechanisms for a reduced early diastolic LV filling rate. Despite the slowing of left ventricular filling early in diastole, more filling occurs in late diastole, due, in part, to a more vigorous atrial contraction (Figure 2C), which produces an exaggerated A wave. The augmented atrial contraction is accompanied by atrial hypertrophy and enlargement and on auscultation is manifested as a fourth heart sound (atrial gallop). Multiple regression analyses indicate that age is the major determinant of the E:A ratio; hence, the age-associated decrease in the Doppler transmittal E:A ratio is identical in healthy Baltimore Longitudinal Study on Aging (BLSA) participant and in Framingham Study participants15,16 (Figure 2D).Despite the age-associated changes in the diastolic filling pattern in older, healthy persons, their left ventricular end-diastolic volume index (end-diastolic volume normalized for body surface area [EDVI]) in the supine position is not compromised and does not substantially differ from their younger counterparts.17,18 Altered responses of cardiac volumes to postural maneuvers are associated with aging. Assumption of the sitting position from the supine position reduces EDVI in younger persons to a greater extent than in older ones.17 During short-term submaximal seated cycle exercise, EDVI increases equivalently at all ages, but during exhaustive exercise, EDVI drops to the seated rest level in younger men but remains elevated in older men.17 Thus, the average, acute, dynamic EDV reserve during the postural change and during graded upright exercise is moderately greater at 85 years of age versus 20 years of age. This does not support the widely held concept that LV filling is compromised in the older, “healthy” heart. In fact, during vigorous exercise, despite a reduction in the LV early diastolic filling rate,14 the LV at end diastole in healthy older persons is not reduced, but rather is greater in older than in younger men; in women, although EDV during exhaustive exercise is similar at older and younger ages, the change in EDV from rest to exercise significantly increases with age.17 Whether the capacity for further acute dilation of the LV of older persons is compromised has not been determined.Left Ventricular Systolic FunctionThe LV ejection fraction (EF), the most commonly used clinical measure of LV systolic performance, is preserved during aging (Figure 3A). The average value of EF is approximately 65%, and very few healthy, sedentary, community-dwelling older individuals highly screened to exclude clinical and occult coronary disease have an EF <50%,17 a value indicative of impaired LV systolic function.10 The maximum EF, which is achieved during exhaustive upright exercise, decreases with age in healthy persons rigorously screened to exclude latent coronary disease (Figure 3B). Note that the heterogeneity in maximum EF increases with age. The age-associated failure to augment EF with exercise is due to a remarkable age-associated deficit in the ability to reduce end-systolic volume index (ESVI); the acute ESV reserve (Figure 3C) at age 85 is only about one-fifth of that at age 20, and there is a similar age-associated loss of EF reserve. Download figureDownload PowerPointFigure 3. Ejection fraction at rest (A) and during exhaustive exercise (B), the change in end-systolic volume between rest and exhaustive exercise (C), and the stroke volume at maximum exercise (D) in healthy men and women in the BLSA. The average maximum ejection fraction and change in end-systolic volume index are markedly reduced in older persons. Note, however, that the heterogeneity in reserve function among individuals increases with age. Reprinted from reference 17.The net result of the age-associated changes in EDV and ESV regulation during exercise is that the stroke volume index (SVI) is preserved in these older persons over a wide range of performance demand (Figure 3D) because of a greater use of the Frank Starling mechanism.17 Although healthy older persons use the Frank Starling mechanism during vigorous exercise, this mechanism is deficient because of an inability to appropriately reduce the ESV. Hence, although EDV increases to a greater extent during vigorous exercise in older versus younger persons, SV does not (Figure 3D).Heart Rate and Cardiac OutputIn the supine position at rest, the heart rate (HR) in healthy men does not change with age.17 With assumption of the seated position from the supine position, HR increases slightly, but significantly less in older than in younger men.18 The maximum heart rate during exhaustive, dynamic exercise decreases with age, and the magnitude of this age-associated reduction in peak HR is about 30% between 20 and 85 years of age (Figure 4A). The reduction in HR response to exercise is the reason why the maximum acute cardiac output reserve in healthy volunteers decreases, on average, by about 30% between ages 20 and 85 years (Figure 4B). Healthy individuals at the older end of the age range can augment their cardiac index 2.5-fold over seated rest, whereas those at the younger end of the age spectrum can increase their cardiac index 3.5-fold. Download figureDownload PowerPointFigure 4. Maximum exercise, heart rate (A), cardiac index (B), and LV contractility index (C) in men and women in the BLSA who had been prescreened to exclude clinical and occult cardiovascular disease. Reprinted from reference 17.Mechanisms That Underlie Deficient Cardiovascular Regulation With Aging in Otherwise Healthy HumansDeficits in Sympathetic Modulation of Heart Rate and LV ContractilityA deficit in maximal intrinsic contractility of older persons might be expected because HR is a determinant of the myocardial contractile state (via the Bowditch phenomenon). The most reliable estimate of overall contractility is the slope of the ESP:ESV relationship as measured from pressure-volume loops obtained across a range of EDVs at rest. However, this has not been measured during exercise in a homogeneous, healthy study population of a broad age range, and by convention, this index cannot be assessed during exercise. A single point, depicting ESP:ESV ratio during exhaustive exercise (Figure 3D) as a crude “contractility” index suggests an age-associated decline in myocardial contractile reserve that is nearly identical to the defect in ESV regulation. Additional supporting evidence for a reduced LV contractile reserve that occurs with aging comes from studies in which the LV of older but not younger healthy men in the BLSA dilates at end diastole in response to a given increase in afterload in the presence of β-adrenergic blockade.20Sympathetic modulation of the cardiovascular system increases HR and contractility and redistributes blood to working muscles and skin to dissipate heat. All of the factors that have been identified to play a role in deficient cardiovascular regulation with aging, including HR (and thus filling time), afterload (both cardiac and vascular), myocardial contractility, and redistribution of blood flow, exhibit a deficient sympathetic modulatory component.Elaboration of CatecholaminesDuring any perturbation from the supine basal state, apparent deficits in sympathetic modulation of these functions with aging occur in the context of exaggerated plasma levels of norepinephrine and epinephrine (see reference 21 for review) due to an increased spillover into the circulation, and, to a lesser extent, to a reduced plasma clearance in older versus younger persons. It has been suggested that deficient norepinephrine re-uptake at nerve endings is the primary mechanism for its increased spillover in older persons; the degree of spillover differs among body organs, but within the heart it increases with age.22 During prolonged exercise, however, diminished neurotransmitter re-uptake might also be associated with depletion, reduced release, and spillover.23 Thus, depending on the duration of the stress, enhanced or deficient neurotransmitter release might be a basis for apparent impairment of sympathetic cardiovascular regulation that occurs with aging.Impaired Responses to β-Adrenergic Receptor StimulationThe age-associated increase in neurotransmitter spillover into the circulation during acute stress implies a greater cellular receptor occupancy by these substances, which leads to desensitization of post-receptor signaling. Multiple lines of evidence support the idea that the efficiency of post-synaptic β-adrenergic signaling declines with aging (see 21 for review). One line of evidence stems from the observation that acute β-adrenergic receptor blockade changes the exercise hemodynamic profile of younger persons to resemble that of older individuals. Significant β-blockade-induced LV dilatation occurs only in younger subjects (Figure 5A); the HR reduction during exercise in the presence of acute β-adrenergic blockade is greater in younger subjects than in older subjects (Figure 5B), as are the age-associated deficits in LV early diastolic filling rate, both at rest and during exercise (Figure 5C). It has also been observed that the age-associated increase in impedance during exercise in old dogs is also abolished by acute β-adrenergic blockade in old dogs.24 The second type of evidence for a diminished efficacy of synaptic β-adrenergic receptor signaling is that cardiovascular responses at rest to β-adrenergic agonist infusions decrease with age (see reference 21 for review). Download figureDownload PowerPointFigure 5. A, Stroke volume index as a function of end diastolic volume index at rest (R) and during graded cycle workloads in the upright seated position in healthy men from the BLSA in the presence and absence (dashed line) of β-adrenergic blockade. R indicates seated rest; 1 to 4 or 5, graded submaximal workloads on cycle ergometer; and max, maximum effort. Stroke volume end-diastolic functions with symbols are those measured in the absence of propranolol; dashed and solid line functions without symbols are the stroke volume versus end diastolic function measured in the presence of propranolol. Note that in the absence of propranolol, the SV versus EDV relation in older persons (▴) is shifted rightward in relation to that in younger ones (•). This indicates that the LV of older persons in the sitting position operates from a greater preload both at rest and during submaximal and max exercise compared with that of younger patients. Propranolol markedly shifts to the SV-EDV relationship in younger per-sons (solid line without points) rightward, but does not markedly offset the curve in older persons (dashed line without points). Thus, with respect to this assessment of ventricular function curve, β-adrenergic blockade with propranolol makes younger men seem like older ones. The abolition of the age-associated differences in the LV function curve after propranolol are accompanied by a reduction or abolition of the age-associated reduction in HR, which, at the maximum, is shown in B. Note, however, that β-adrenergic blockade in younger individuals (A) causes SVI to increase to a greater extent than during β-blockade in older subjects, suggesting that mechanisms other than deficient β-adrenergic regulation compromise LV ejection. One potential mechanism is an age-associated decrease in the maximum intrinsic myocardial contractility. Another likely mechanism is enhanced vascular afterload, due to the structural changes in compliance arteries noted above, and possibly also to impaired vasorelaxation during exercise. Reprinted from Fleg JL, Schulman S, O’Connor F, et al. Effects of acute β-adrenergic receptor blockade on age-associated changes in cardiovascular performance during dynamic exercise. Panels A and B reprinted from Ref 19. B, Peak exercise heart rate in the same subjects as in A in the presence and absence of acute β-adrenergic blockade by propranolol. C, The age-associated reduction in peak LV diastolic filling rate at max exercise in healthy subjects from the BLSA is abolished during exercise in the presence of β-adrenergic blockade with propranolol. Solid bars indicate age <40 years; light bars, age >60 years. Reprinted from reference 14.Left Ventricular Afterload and Vascular-Ventricular Load MatchingCardiac afterload has two components, one of which is generated by the heart itself and the other of which is generated by the vasculature. The cardiac component of afterload during exercise can be expected to increase slightly with age because the heart size increases in older persons throughout the cardiac cycle during exercise.17 The vascular load on the heart has 4 components: conduit artery compliance characteristics, reflected pulse waves, inertance, and resistance. There is considerable evidence to indicate that each becomes altered during aging and that at rest, the vascular load on the LV increases with age. Increased vascular loading on the heart is a likely cause of the increase in LV wall thickness associated with aging (Figure 2). Studies in large populations with a broad age range demonstrate that arterial pressure, which varies with vascular loading, is a major determinant of LV mass, and that the relative impact of age and arterial pressure on LV wall thickness varies with the manner in which study subjects are screened with respect to hypertension.25 The increase in LV wall thickness with aging reduces the expected increase in cardiac afterload because of increased LV volume in older persons during stress.17Optimal and efficient ejection of blood from the heart occurs when ventricular and vascular loads are matched. It has been suggested that the precise cardiac and vascular load matching that is characteristic in younger persons is preserved at older ages, at least at rest, because the increased vascular stiffness in older persons at rest is matched by increased resting ventricular stiffness.26 Note that in this context, “stiffness” refers to time varying cardiac elastance throughout the cardiac cycle due to combined effects of contractile and structural properties. During exercise, however, a mismatch in loading occurs in older individuals because of a failure of LV elastance to increase in proportion to the increase in vascular elastance.27 Such LV arterial-ventricular load mismatching in older persons during exercise may be a mechanism for the deficit in the acute LVEF reserve that accompanies advancing age in many persons.Acute reduction in both cardiac and vascular components of LV afterload has been achieved pharmacologically by administration of sodium nitroprusside (SNP) infusions in older, healthy BLSA volunteers. A reduction in resting mean arterial pressure of about 12% by SNP abolishes the greater carotid pulse pressure and heart size and augments exercise LVEF28 in these older subjects to levels observed in younger persons. The effect of physical conditioning to reduce vascular afterload is similar to the effect of conditioning to improve LV ejection in older persons.29Heart RhythmBeat-to-beat fluctuation of HR, commonly known as HR variability, declines steadily with age (Figure 6A). Reduced HR variability is an indicator of cardiac autonomic regulation commonly found in older people and has been linked to increased risk for morbid and fatal outcomes.30Download figureDownload PowerPointFigure 6. A, Heart rate variability, as determined by the standard deviation of normal RR intervals, shown as a function of age and resting heart rate in Framingham Heart Study subjects. The separate lines represent age groups 35, 45, 55, 65, and 75 years of age. Reprinted from reference 30. B, Prevalence of exercise-induced supraventricular tachycardia (SVT) as a function of age and sex during the initial treadmill exercise test in 1383 apparently healthy volunteers from the BLSA. The numbers above each bar represent the number of subjects in each age decade. The prevalence of exercise-induced SVT increased strikingly with age in men (P<0.001) and less strikingly in women (P=0.09). Reprinted from reference 34. C, Prevalence of frequent or repetitive ventricular ectopic beats induced by maximal treadmill exercise as a function of age and sex in 1160 apparently healthy volunteers from the BLSA who were tested between 1974 and 1986. The numbers above each bar represent the number of subjects tested in each decade. Only the first test within this period is counted for each subject. A highly significant increase in prevalence with age was seen in men but not in women. Reprinted from reference 35.An increase in the prevalence and complexity of both supraventricular and ventricular arrhythmias, whether detected by resting ECG, ambulatory monitoring, or exercise testing, occurs in otherwise healthy older patients but not in younger persons. Isolated atrial premature beats (APBs) appear on resting ECG in 5% to 10% of subjects older than 60 years and are generally not associated with heart disease. Isolated APBs were detected at rest in 6% of healthy BLSA volunteers who were older than 60 years, in 39% during exercise testing, and in 88% during ambulatory 24-hour monitoring.31 Over a 10-year mean follow-up period, isolated APBs, even if frequent, were not predictive of increased cardiac risk in these individuals.32Short bursts of paroxysmal supraventricular tachycardia (PSVT) are observed in 1% to 2% of apparently healthy individuals older than 65 years who were rigorously screened to exclude disease. Twenty-four-hour ambulatory monitoring studies have demonstrated short runs of this PSVT (usually 3 to 5 beats) in 13% to 50% of clinically healthy older subjects.11,31 Although the presence of nonsustained PSVT did not predict an increase in risk of a future coronary event in BLSA subjects, 15% of those with PSVT later developed de novo AF, compared with fewer than 1% of subjects without PSVT. The incidence of PSVT during exercise, typically asymptomatic 3 to 5 beat salvos, increases with age, from nil in the youngest age group to about 10% in the ninth decade (Figure 6B). Although those individuals with exercise-induced PSVT were not at a greater risk for coronary events over a multi-year follow-up, 10% developed a spontaneous atrial tachyarrhythmia compared with only 2% of the control group. Thus, PSVT at rest or induced by exercise is an early clue that some healthy individuals are at an increased risk for future AF. Another risk factor for AF may be the increase in left atrial size that accompanies advancing age in otherwise healthy persons.33Limited data available in older subjects without apparent heart disease support a marked age-associated increase in the prevalence and complexity of ventricular ectopy (VE), both at rest and during exercise, at least in men. A steep increase in the prevalence of VE with advancing age occurs in both those clinically free of heart disease and in unselected populations. In healthy BLSA volunteers with a normal ST-segment response to treadmill exercise, isolated VE occurred at rest in 8.6% of men over the age 60 years compared with only 0.5% in those 20- to 40-years-old. Interestingly, in women, the prevalence of VE at rest was not age-related. Among 98 carefully screened asymptomatic BLSA participants older than 60 years, 35% had multiform VE, 11% had ventricular couplets, and 4% had short runs of ventricular tachycardia on 24-hour monitoring31; all occurred substantially more commonly in older subjects than in healthy younger subjects. Neither the prevalence nor the complexity of resting VE was a determinant of future coronary events over a 10-year mean follow-up period.32 Isolated VE during or after maximal treadmill exercise increased in prevalence 5-fold, from 11% to 57% between the third and ninth decades in apparently healthy BLSA volunteers (Figure 6C).In summary, when cardiovascular function in healthy, adult, volunteer, community-dwelling subjects, ranging in age from 20 to 85 years, is assessed, increased LV wall thickness, alterations in the diastolic filling pattern, impaired LV ejection and HR reserve capacity, and altered heart rhythm are the most dramatic changes in cardiac function that occur with aging in healthy persons. Although these age-associated changes do not result in clinical heart disease per se, they do compromise the cardiac reserve capacity and affect the threshold for symptoms and signs, as well as the severity and prognosis of heart failure secondary to any given disease-related challenge. This is true for both systolic and diastolic heart failure. Thus, age-associated changes in the heart structure and function that occur in the absence of a clinical diagnosis of heart disease explain the increased risk for the 3 clinical conditions depicted in Figure 1: LVH, AF, and congestive heart failure, all of which occur at markedly higher rates in older persons than in younger persons. The 3 cardiac diagnoses become interrelated in older persons in part because of this link with age-associated cardiac changes. An age-dependent increase in left ventricular mass increases the stiffness of the left ventricle and promotes an increase in end diastolic filling pressure, which is an important contributor to diastolic heart failure in older persons. In addition, increased diastolic filling pressure results in left atrial dilation, which predisposes the heart to AF. AF, with associated tachycardia and loss of atrioventricular coupling, reduces diastolic filling time and eliminates atrial systolic contribution to left ventricular filling, thereby compounding the predisposition to diastolic heart failure.The age-associated changes in cardiac properties described herein, as well as changes in vascular structure and function that accompany aging, which are the forms of topics discussed in the initial article in this series,1 alter the substrate on which cardiovascular disease is superimposed (Figure 7) in several ways, and thus alter the occurrence, presentation, and manifestations of heart disease in older persons. Age-associated changes in cardiovascular structure and function may lower the threshold for results in clinically significant signs and symptoms of disease (Table). For example, a mild degree of ischemia-induced relaxation abnormalities that may not induce clinical symptoms in a younger patient may cause dyspnea in an older one, who, by virtue of age alone, has preexisting slowed and delayed early diastolic relaxation. Similarly, a progressive decline in LV compliance with age may go unnoticed for many years (ie, subclinical diastolic dysfunction), but with the occurrence of an acute stress, the subclinical dysfunction can become acutely manifest as overt heart failure. A classic example is the development of AF with the loss of atrial contraction, coupled with abbreviated diastolic filling time due to tachycardia, which can precipitate pulmonary edema in a matter of minutes when the structural and functional milieu is present, as it is in the aging heart. Download figureDownload PowerPointFigure 7. Changes in the vasculature and heart associated with aging in health may also be construed as risk factors for cardiovascular disease, l

E vidence supporting the hypothesis that age-associated changes in cardiovascular structure/function are implicated in the markedly increased risk for cardiovascular disease in older persons has been presented in the preceding 2 articles in this series. 1,2It follows that therapies to prevent or delay cardiovascular changes that accompany aging may reduce the risk for age-associated cardiovascular diseases.Understanding the nature and effectiveness of such therapies, however, requires an understanding of heart and arterial aging at the cellular and molecular levels.Fortunately, many of the age-associated changes in cardiac and arterial structure or function that have been observed in humans also occur across a wide range of other species.Insights gained from cellular and molecular studies in these animal models may hold clues that will assist in directing future efforts toward developing novel therapies for age-associated arterial and cardiac structural and functional remodeling in humans. Vascular AgingAge-associated remodeling of the walls of large arteries of rodents (Table 1) and nonhuman primates is quite similar to that observed in humans and includes luminal dilation, intimal and medial thickening (Figure 1), vascular stiffening, and endothelial dysfunction.

The ability of older persons to function independently is dependent largely on the maintenance of sufficient aerobic capacity and strength to perform daily activities. Although peak aerobic capacity is widely recognized to decline with age, its rate of decline has been estimated primarily from cross-sectional studies that may provide misleading, overly optimistic estimates of aging changes.To determine longitudinal rate of change in aerobic capacity and the influence of age, gender, and physical activity on these changes, we performed serial measurements of peak treadmill oxygen consumption (peak VO2) in 375 women and 435 men ages 21 to 87 years from the Baltimore Longitudinal Study of Aging, a community-dwelling cohort free of clinical heart disease, over a median follow-up period of 7.9 years. A linear mixed-effects regression model was used to calculate the predicted longitudinal 10-year rate of change in peak VO2, expressed in milliliters per minute, for each age decade from the 20s through the 70s after adjustment for self-reported leisure-time physical activity. A longitudinal decline in peak VO2 was observed in each of the 6 age decades in both sexes; however, the rate of decline accelerated from 3% to 6% per 10 years in the 20s and 30s to >20% per 10 years in the 70s and beyond. The rate of decline for each decade was larger in men than in women from the 40s onward. Similar longitudinal rates of decline prevailed when peak VO2 was indexed per kilogram of body weight or per kilogram of fat-free mass and in all quartiles of self-reported leisure-time physical activity. When the components of peak VO2 were examined, the rate of longitudinal decline of the oxygen pulse (ie, the O2 utilization per heart beat) mirrored that of peak VO2, whereas the longitudinal rate of heart rate decline averaged only 4% to 6% per 10 years, and accelerated only minimally with age.The longitudinal rate of decline in peak VO2 in healthy adults is not constant across the age span in healthy persons, as assumed by cross-sectional studies, but accelerates markedly with each successive age decade, especially in men, regardless of physical activity habits. The accelerated rate of decline of peak aerobic capacity has substantial implications with regard to functional independence and quality of life, not only in healthy older persons, but particularly when disease-related deficits are superimposed.

Cardiovascular regulatory mechanisms in advanced age.E G LakattaE G LakattaLaboratory of Cardiovascular Science, National Institute on Aging, Baltimore, Maryland.Published Online:01 Apr 1993https://doi.org/10.1152/physrev.1993.73.2.413MoreSectionsPDF (16 MB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInWeChat Previous Back to Top Next Download PDF FiguresReferencesRelatedInformation Cited ByCardiac transmembrane ion channels and action potentials: cellular physiology and arrhythmogenic behaviorAndrás Varró, Jakub Tomek, Norbert Nagy, László Virág, Elisa Passini, Blanca Rodriguez, and István Baczkó,28 May 2021 | Physiological Reviews, Vol. 101, No. 3Heat therapy: mechanistic underpinnings and applications to cardiovascular healthVienna E. Brunt and Christopher T. 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Lakatta15 May 2014 | American Journal of Physiology-Heart and Circulatory Physiology, Vol. 306, No. 10Exercise, Vascular Stiffness, and Tissue TransglutaminaseJournal of the American Heart Association, Vol. 3, No. 2Altered ventricular torsion and transmural patterns of myocyte relaxation precede heart failure in aging F344 ratsStuart G. Campbell, Premi Haynes, W. Kelsey Snapp, Kristofer E. Nava, and Kenneth S. Campbell1 September 2013 | American Journal of Physiology-Heart and Circulatory Physiology, Vol. 305, No. 5Caloric restriction: powerful protection for the aging heart and vasculatureEdward P. Weiss, and Luigi Fontana1 October 2011 | American Journal of Physiology-Heart and Circulatory Physiology, Vol. 301, No. 4Genetic influence on electrocardiogram time intervals and heart rate in aging miceShuqin Xing, Shirng-Wreng Tsaih, Rong Yuan, Karen L. Svenson, Linda M. Jorgenson, Milly So, Beverly J. Paigen, and Ron Korstanje1 June 2009 | American Journal of Physiology-Heart and Circulatory Physiology, Vol. 296, No. 6Long-Term Treatment with a Chinese Herbal Formula, Sheng-Mai-San, Improves Cardiac Contractile Function in Aged Rats: The Role of Ca 2+ HomeostasisRejuvenation Research, Vol. 11, No. 6Arginase and vascular agingLakshmi Santhanam, David W. Christianson, Daniel Nyhan, and Dan E. Berkowitz1 November 2008 | Journal of Applied Physiology, Vol. 105, No. 5Arterial-ventricular coupling: mechanistic insights into cardiovascular performance at rest and during exercisePaul D. Chantler, Edward G. Lakatta, and Samer S. Najjar1 October 2008 | Journal of Applied Physiology, Vol. 105, No. 4QT Dispersion and Left Ventricular Hypertrophy in Elderly Hypertensive and Normotensive Patients27 May 2008 | Angiology, Vol. 59, No. 5Cardiac dysfunction in aging conscious rats: altered cardiac cytoskeletal proteins as a potential mechanismSamuel C. Lieber*, Hongyu Qiu*, Li Chen, You-Tang Shen, Chull Hong, William C. Hunter, Nadine Aubry, Stephen F. Vatner, and Dorothy E. Vatner1 August 2008 | American Journal of Physiology-Heart and Circulatory Physiology, Vol. 295, No. 2Regulation of middle cerebral artery blood velocity during dynamic exercise in humans: influence of agingJames P. Fisher, Shigehiko Ogoh, Colin N. Young, Peter B. Raven, and Paul J. Fadel1 July 2008 | Journal of Applied Physiology, Vol. 105, No. 1Fluid pressure modulates L-type Ca2+ channel via enhancement of Ca2+-induced Ca2+ release in rat ventricular myocytesSunwoo Lee*, Joon-Chul Kim*, Yuhua Li, Min-Jeong Son, and Sun-Hee Woo1 April 2008 | American Journal of Physiology-Cell Physiology, Vol. 294, No. 4Invasive Physiology: Clinical Cardiovascular Pathophysiology and Diastolic DysfunctionHeat Shock Proteins in Cardiovascular Stress7 August 2008 | Clinical medicine. Cardiology, Vol. 2Effects of aging on adipose resistance artery vasoconstriction: possible implications for orthostatic blood pressure regulationMichael W. Ramsey, Bradley J. Behnke, Rhonda D. Prisby, and Michael D. Delp1 November 2007 | Journal of Applied Physiology, Vol. 103, No. 5Age-related changes in lamin A/C expression in cardiomyocytesJonathan Afilalo, Igal A. Sebag, Lorraine E. Chalifour, Daniel Rivas, Rahima Akter, Kamal Sharma, and Gustavo Duque1 September 2007 | American Journal of Physiology-Heart and Circulatory Physiology, Vol. 293, No. 3G protein-coupled receptor systems and their lipid environment in health disorders during agingBiochimica et Biophysica Acta (BBA) - Biomembranes, Vol. 1768, No. 4Association of mitochondrial SOD deficiency with salt-sensitive hypertension and accelerated renal senescenceBernardo Rodriguez-Iturbe, Lili Sepassi, Yasmir Quiroz, Zhenmin Ni, and Nosratola D. Vaziri1 January 2007 | Journal of Applied Physiology, Vol. 102, No. 1The Telomere–Telomerase Axis and the HeartAntioxidants & Redox Signaling, Vol. 8, No. 11-12Contactless magnetocardiographic mapping in anesthetized Wistar rats: evidence of age-related changes of cardiac electrical activityDonatella Brisinda, Maria Emiliana Caristo, and Riccardo Fenici1 July 2006 | American Journal of Physiology-Heart and Circulatory Physiology, Vol. 291, No. 1Maturational and Adaptive Modulation of Left Ventricular Torsional BiomechanicsCirculation, Vol. 113, No. 21CREB expression in cardiac fibroblasts and CREM expression in ventricular myocytesBiochemical and Biophysical Research Communications, Vol. 334, No. 4Cardiovascular aging and psychometric performances: correlations in a group of ultraseptagenarian elderlyArchives of Gerontology and Geriatrics, Vol. 40, No. 1Left ventricular pressure-volume relationship in a rat model of advanced aging-associated heart failurePál Pacher, Jon G. Mabley, Lucas Liaudet, Oleg V. Evgenov, Anita Marton, György Haskó, Márk Kollai, and Csaba Szabó1 November 2004 | American Journal of Physiology-Heart and Circulatory Physiology, Vol. 287, No. 5Absence of left ventricular and arterial adaptations to exercise in octogenariansRobert J. Spina, Timothy E. Meyer, Linda R. Peterson, Dennis T. Villareal, Morton R. Rinder, and Ali A. Ehsani1 November 2004 | Journal of Applied Physiology, Vol. 97, No. 5Autonomic receptor systems in the failing and aging human heart: similarities and differencesEuropean Journal of Pharmacology, Vol. 500, No. 1-3Effects of aging on the cardiac remodeling induced by chronic high-altitude hypoxia in ratC. Chouabe, E. Ricci, J. Amsellem, S. Blaineau, Y. Dalmaz, R. Favier, J.-M. Pequignot, and R. Bonvallet1 September 2004 | American Journal of Physiology-Heart and Circulatory Physiology, Vol. 287, No. 3Effects of multivitamins and low-dose folic acid supplements on flow-mediated vasodilation and plasma homocysteine levels in older adultsAmerican Heart Journal, Vol. 148, No. 3Age and Gender Affect Ventricular-Vascular Coupling During Aerobic ExerciseJournal of the American College of Cardiology, Vol. 44, No. 3Aminoguanidine prevents age-related deterioration in left ventricular-arterial coupling in Fisher 344 ratsBritish Journal of Pharmacology, Vol. 142, No. 7Physical activity and older adults: a review of health benefits and the effectiveness of interventionsJournal of Sports Sciences, Vol. 22, No. 8Age-associated cardiovascular changes are the substrate for poor prognosis with myocardial infarction**Editorials published in the Journal of the American College of Cardiologyreflect the views of the authors and do not necessarily represent the views of JACCor the American College of Cardiology.Journal of the American College of Cardiology, Vol. 44, No. 1Perioperative risk assessment in elderly and high-risk patients1 1No competing interests declared.Journal of the American College of Surgeons, Vol. 199, No. 1Beyond Bowditch: the convergence of cardiac chronotropy and inotropyCell Calcium, Vol. 35, No. 6Thioredoxin, a redox-regulating protein, is expressed in spontaneous myocarditis in inbred strains of miceInternational Journal of Cardiology, Vol. 95, No. 2-3Long-term endurance training does not prevent the age-related decrease in left ventricular relaxation propertiesActa Physiologica Scandinavica, Vol. 181, No. 2Influence d'une activité physique sur les capacités posturales de personnes âgées : effets du temps de pratiqueAnnales de Réadaptation et de Médecine Physique, Vol. 47, No. 4Cardiac Stem Cell and Myocyte Aging, Heart Failure, and Insulin-Like Growth Factor-1 OverexpressionCirculation Research, Vol. 94, No. 4Echocardiographic assessment of age-associated changes in systolic and diastolic function of the female F344 rat heartMarvin O. Boluyt, Kimber Converso, Hyun Seok Hwang, Agdas Mikkor, and Mark W. Russell1 February 2004 | Journal of Applied Physiology, Vol. 96, No. 2Selective reductions of cardiac autonomic responses to light bicycle exercise with aging in healthy humansAutonomic Neuroscience, Vol. 110, No. 1Influence of age and run training on cardiac Na+/Ca2+ exchangeLisa C. Mace, Bradley M. Palmer, David A. Brown, Korinne N. Jew, Joshua M. Lynch, Jason M. Glunt, Todd A. Parsons, Joseph Y. Cheung, and Russell L. Moore1 November 2003 | Journal of Applied Physiology, Vol. 95, No. 5Age and gender effects on heart rate activation associated with periodic leg movements in patients with restless legs syndromeClinical Neurophysiology, Vol. 114, No. 11Molecular mechanisms of reduced β-adrenergic signaling in the aged heart as revealed by genomic profilingJames G. Dobson, John Fray, Jack L. Leonard, and Richard E. Pratt17 October 2003 | Physiological Genomics, Vol. 15, No. 2Senescence and Death of Primitive Cells and Myocytes Lead to Premature Cardiac Aging and Heart FailureCirculation Research, Vol. 93, No. 7In vitro cellular aging is associated with enhanced proliferative capacity, G1 cell cycle modulation, and matrix metalloproteinase-9 regulation in mouse aortic smooth muscle cellsArchives of Biochemistry and Biophysics, Vol. 418, No. 1Unchanged G-protein-coupled receptor kinase activity in the aging human heartJournal of the American College of Cardiology, Vol. 42, No. 8Gonadectomy of adult male rats reduces contractility of isolated cardiac myocytesKish L. Golden, James D. Marsh, Yang Jiang, Tiane Brown, and Jerome Moulden1 September 2003 | American Journal of Physiology-Endocrinology and Metabolism, Vol. 285, No. 3Ca2+ transients of cardiomyocytes from senescent mice peak late and decay slowlyCell Calcium, Vol. 34, No. 3Cardiovascular aging and anesthetic implicationsJournal of Cardiothoracic and Vascular Anesthesia, Vol. 17, No. 4Cardiovascular aging and heart failure11 August 2003 | European Journal of Heart Failure, Vol. 5, No. 4Hemodynamics induced after acute reduction of proximal thoracic aorta complianceEuropean Journal of Vascular and Endovascular Surgery, Vol. 26, No. 2Short-term Training Effects on Left Ventricular Diastolic Function and Oxygen Uptake in Older and Younger MenClinical Journal of Sport Medicine, Vol. 13, No. 4Cardiac and thoracic vascular surgeryBest Practice & Research Clinical Anaesthesiology, Vol. 17, No. 2Chronological age modifies the microscopic remodeling process in viable cardiac tissue after infarctionUltrasound in Medicine & Biology, Vol. 29, No. 5Differential response of cardiac fibroblasts from young adult and senescent rats to ANG IIK. Shivakumar, David E. Dostal, Kenneth Boheler, Kenneth M. Baker, and Edward G. Lakatta1 April 2003 | American Journal of Physiology-Heart and Circulatory Physiology, Vol. 284, No. 4Pulse pressure/stroke index and left ventricular geometry and functionJournal of Hypertension, Vol. 21, No. 4Socioeconomic status and hemodynamic recovery from mental stressPsychophysiology, Vol. 40, No. 2Impact of aging on substrate metabolism by the human heartJournal of the American College of Cardiology, Vol. 41, No. 2Endothelial cells maintain a reduced redox environment even as mitochondrial function declinesRicarda Carlisle, Carol Ann Rhoads, Tak Yee Aw, and Lynn Harrison1 December 2002 | American Journal of Physiology-Cell Physiology, Vol. 283, No. 6Is age an independent determinant of mortality in cardiac surgery as suggested by the EuroSCORE?7 October 2002 | BMC Surgery, Vol. 2, No. 1Use of cardiovascular medications in the elderlyInternational Journal of Cardiology, Vol. 85, No. 2-3Age-dependent changes of cardiac neuronal noradrenaline reuptake transporter (uptake1) in the human heartJournal of the American College of Cardiology, Vol. 40, No. 8Oxidative Stress, Mitochondrial DNA Mutation, and Impairment of Antioxidant Enzymes in Aging29 November 2016 | Experimental Biology and Medicine, Vol. 227, No. 9Hemodynamic and autonomic correlates of postexercise hypotension in patients with mild hypertensionJacopo M. Legramante, Alberto Galante, Michele Massaro, Antonio Attanasio, Gianfranco Raimondi, Fabio Pigozzi, and Ferdinando Iellamo1 April 2002 | American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, Vol. 282, No. 4Overview of cardiovascular agingCardiovascular ageing in health sets the stage for cardiovascular diseaseHeart, Lung and Circulation, Vol. 11, No. 2Nitric oxide and cGMP protein kinase activity in aged ventricular myocytesQihang Zhang, Bruno Molino, Lin Yan, Todd Haim, Yakir Vaks, Peter M. Scholz, and Harvey R. Weiss1 December 2001 | American Journal of Physiology-Heart and Circulatory Physiology, Vol. 281, No. 6Diminished α1-adrenergic-mediated contraction and translocation of PKC in senescent rat heartD. H. Korzick, D. A. Holiman, M. O. Boluyt, M. H. Laughlin, and E. G. Lakatta1 August 2001 | American Journal of Physiology-Heart and Circulatory Physiology, Vol. 281, No. 2Age-Associated Cardiac Dysfunction in Drosophila melanogasterCirculation Research, Vol. 88, No. 10Heart AgingCirculation Research, Vol. 88, No. 10Upregulation of the Nitric Oxide-cGMP Pathway in Aged MyocardiumCirculation Research, Vol. 88, No. 5Changes in uncoupling protein-2 and -3 expression in aging rat skeletal muscle, liver, and heartRocco Barazzoni, and K. Sreekumaran Nair1 March 2001 | American Journal of Physiology-Endocrinology and Metabolism, Vol. 280, No. 3Upregulation of the Nitric Oxide–cGMP Pathway in Aged MyocardiumCirculation Research, Vol. 88, No. 1Heat Shock Proteins and Cardiovascular PathophysiologyLuc H. E. H. Snoeckx, Richard N. Cornelussen, Frans A. Van Nieuwenhoven, Robert S. Reneman, and Ger J. Van der Vusse10 January 2001 | Physiological Reviews, Vol. 81, No. 4Aging and baroreflex control of RSNA and heart rate in ratsM. C. Irigoyen, E. D. Moreira, A. Werner, F. Ida, M. D. Pires, I. A. Cestari, and E. M. Krieger1 November 2000 | American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, Vol. 279, No. 5The aged cardiovascular risk patientBritish Journal of Anaesthesia, Vol. 85, No. 5Human ageing and the sympathoadrenal system1 November 2000 | The Journal of Physiology, Vol. 528, No. 3Effects of aging on single cardiac myocyte function in Fischer 344 x Brown Norway ratsPhilip A. Wahr, Daniel E. Michele, and Joseph M. Metzger1 August 2000 | American Journal of Physiology-Heart and Circulatory Physiology, Vol. 279, No. 2QT dispersion and hypertensive heart disease in the elderlyJournal of Hypertension, Vol. 18, No. 4Age-related changes in A1-adenosine receptor-mediated bradycardiaAndrea K. Hinschen, Roselyn B. Rose'Meyer, and John P. Headrick1 March 2000 | American Journal of Physiology-Heart and Circulatory Physiology, Vol. 278, No. 3Redox Regulation of Cardiac Muscle Calcium SignalingAntioxidants & Redox Signaling, Vol. 2, No. 1Restoration of Diastolic Function in Senescent Rat Hearts Through Adenoviral Gene Transfer of Sarcoplasmic Reticulum Ca 2+ -ATPaseCirculation, Vol. 101, No. 7Influence of Age on Contractile Response to Insulin-Like Growth Factor 1 in Ventricular Myocytes From Spontaneously Hypertensive RatsHypertension, Vol. 34, No. 6Hemodynamic effects of unloading the old heartAmit Nussbacher, Gary Gerstenblith, Frances C. O'connor, Lewis C. Becker, David A. Kass, Steven P. Schulman, Jerome L. Fleg, and Edward G. Lakatta1 November 1999 | American Journal of Physiology-Heart and Circulatory Physiology, Vol. 277, No. 5Impaired lusitropy-frequency in the aging mouse: role of Ca2+-handling proteins and effects of isoproterenolChee Chew Lim, Ronglih Liao, Niraj Varma, and Carl S. Apstein1 November 1999 | American Journal of Physiology-Heart and Circulatory Physiology, Vol. 277, No. 5Pharmacologic agents on cardiovascular mass, coronary dynamics and collagen in aged spontaneously hypertensive ratsJournal of Hypertension, Vol. 17, No. 8How to assess sympathetic activity in humansJournal of Hypertension, Vol. 17, No. 6Aging-dependent depression in the kinetics of force development in rat skinned myocardiumDaniel P. Fitzsimons, Jitandrakumar R. Patel, and Richard L. Moss1 May 1999 | American Journal of Physiology-Heart and Circulatory Physiology, Vol. 276, No. 5Special Problems in the ElderlyChest, Vol. 115, No. 5Age, splanchnic vasoconstriction, and heat stress during tiltingChristopher T. Minson, Stacey L. Wladkowski, James A. Pawelczyk, and W. Larry Kenney1 January 1999 | American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, Vol. 276, No. 1Molecular Mechanisms of Myocardial RemodelingBERNARD SWYNGHEDAUW1 January 1999 | Physiological Reviews, Vol. 79, No. 1Prolonged L-Arginine on Cardiovascular Mass and Myocardial Hemodynamics and Collagen in Aged Spontaneously Hypertensive Rats and Normal RatsHypertension, Vol. 33, No. 1Effects of aging on sarcoplasmic reticulum Ca2+-cycling proteins and their phosphorylation in rat myocardiumA. Xu, and N. Narayanan1 December 1998 | American Journal of Physiology-Heart and Circulatory Physiology, Vol. 275, No. 6Ventricular Myocytes Are Not Terminally Differentiated in the Adult Mammalian HeartCirculation Research, Vol. 83, No. 1Assessment of prevalence of left ventricular hypertrophy in hypertensionJournal of Hypertension, Vol. 16, No. 6Age alters the cardiovascular response to direct passive heatingChristopher T. Minson, Stacey L. Wladkowski, Anthony F. Cardell, James A. Pawelczyk, and W. Larry Kenney1 April 1998 | Journal of Applied Physiology, Vol. 84, No. 4β-Adrenergic-mediated improvement in left ventricular function by exercise training in older menRobert J. Spina, Michael J. Turner, and Ali A. Ehsani1 February 1998 | American Journal of Physiology-Heart and Circulatory Physiology, Vol. 274, No. 2Alterations in myocardial signal transduction due to aging and chronic dynamic exerciseDavid A. Roth, Cynthia D. White, Deborah A. Podolin, and Robert S. Mazzeo1 January 1998 | Journal of Applied Physiology, Vol. 84, No. 1Regulation of blood volume during training in post-menopausal womenMedicine &amp Science in Sports &amp Exercise, Vol. 30, No. 1Left ventricular function and remodeling after myocardial infarction in aging ratsThomas E. Raya, Mohamed Gaballa, Peter Anderson, and Steven Goldman1 December 1997 | American Journal of Physiology-Heart and Circulatory Physiology, Vol. 273, No. 6Age and cardiac output during cycle exercise in thermoneutral and warm environmentsMedicine &amp Science in Sports &amp Exercise, Vol. 29, No. 1Stress Testing for Coronary Artery Disease in the ElderlyClinics in Geriatric Medicine, Vol. 12, No. 1Molecular and cellular biology of the senescent hypertrophied and failing heartThe American Journal of Cardiology, Vol. 76, No. 13Magnesium cardioplegia reduces cytosolic and nuclear calcium and DNA fragmentation in the senescent myocardiumThe Annals of Thoracic Surgery, Vol. 58, No. 4Activation of angiotensinogen and angiotensin-converting enzyme gene expression in the left ventricle of senescent rats.Circulation, Vol. 90, No. 3Aging differentially modifies arterial sensitivity to endothelin-1 and 5-hydroxytryptamine: Studies in dog coronary arteries and rat arterial mesenteric bedPeptides, Vol. 15, No. 8High-frequency ultrasonic detection of protein crosslinking in myocardial tissue More from this issue > Volume 73Issue 2April 1993Pages 413-67 Copyright & PermissionsCopyright © 1993 by American Physiological Societyhttps://doi.org/10.1152/physrev.1993.73.2.413PubMed8475195History Published online 1 April 1993 Published in print 1 April 1993 Metrics

To identify previously unknown genetic loci associated with fasting glucose concentrations, we examined the leading association signals in ten genome-wide association scans involving a total of 36,610 individuals of European descent. Variants in the gene encoding melatonin receptor 1B (MTNR1B) were consistently associated with fasting glucose across all ten studies. The strongest signal was observed at rs10830963, where each G allele (frequency 0.30 in HapMap CEU) was associated with an increase of 0.07 (95% CI = 0.06-0.08) mmol/l in fasting glucose levels (P = 3.2 x 10(-50)) and reduced beta-cell function as measured by homeostasis model assessment (HOMA-B, P = 1.1 x 10(-15)). The same allele was associated with an increased risk of type 2 diabetes (odds ratio = 1.09 (1.05-1.12), per G allele P = 3.3 x 10(-7)) in a meta-analysis of 13 case-control studies totaling 18,236 cases and 64,453 controls. Our analyses also confirm previous associations of fasting glucose with variants at the G6PC2 (rs560887, P = 1.1 x 10(-57)) and GCK (rs4607517, P = 1.0 x 10(-25)) loci.

In quiescent cells, mitochondria are the primary source of reactive oxygen species (ROS), which are generated by leakiness of the electron transport chain (ETC). High levels of ROS can trigger cell death, whereas lower levels drive diverse and important cellular functions. We show here by employing a newly developed mitochondrial matrix-targeted superoxide indicator, that individual mitochondria undergo spontaneous bursts of superoxide generation, termed “superoxide flashes.” Superoxide flashes occur randomly in space and time, exhibit all-or-none properties, and provide a vital source of superoxide production across many different cell types. Individual flashes are triggered by transient openings of the mitochondrial permeability transition pore stimulating superoxide production by the ETC. Furthermore, we observe a flurry of superoxide flash activity during reoxygenation of cardiomyocytes after hypoxia, which is inhibited by the cardioprotective compound adenosine. We propose that superoxide flashes could serve as a valuable biomarker for a wide variety of oxidative stress-related diseases.

Arterial stiffening with increased pulse pressure is a leading risk factor for cardiovascular disease in the elderly. We tested whether ALT-711, a novel nonenzymatic breaker of advanced glycation end-product crosslinks, selectively improves arterial compliance and lowers pulse pressure in older individuals with vascular stiffening.Nine US centers recruited and randomly assigned subjects with resting arterial pulse pressures >60 mm Hg and systolic pressures >140 mm Hg to once-daily ALT-711 (210 mg; n=62) or placebo (n=31) for 56 days. Preexisting antihypertensive treatment (90% of subjects) was continued during the study. Morning upright blood pressure, stroke volume, cardiac output, systemic vascular resistance, total arterial compliance, carotid-femoral pulse wave velocity, and drug tolerability were assessed. ALT-711 netted a greater decline in pulse pressures than placebo (-5.3 versus -0.6 mm Hg at day 56; P=0.034 for treatment effect by repeated-measures ANOVA). Systolic pressure declined in both groups, but diastolic pressure fell less with ALT-711 (P=0.056). Mean pressure declined similarly in both groups (-4 mm Hg; P<0.01 for each group, P=0.34 for treatment effect). Total arterial compliance rose 15% in ALT-711-treated subjects versus no change with placebo (P=0.015 versus ALT-711), an effect that did not depend on reduced mean pressure. Pulse wave velocity declined 8% with ALT-711 (P<0.05 at day 56, P=0.08 for treatment effect). Systemic arterial resistance, cardiac output, and heart rate did not significantly change in either group.ALT-711 improves total arterial compliance in aged humans with vascular stiffening, and it may provide a novel therapeutic approach for this abnormality, which occurs with aging, diabetes, and isolated systolic hypertension.

To assess the effect of age on cardiac volumes and function in the absence of overt or occult coronary disease, we performed serial gated blood pool scans at rest and during progressive upright bicycle exercise to exhaustion in 61 participants in the Baltimore Longitudinal Study of Aging. The subjects ranged in age from 25 to 79 years and were free of cardiac disease according to their histories and results of physical, resting and stress electrocardiographic, and stress thallium scintigraphic examinations. Absolute left ventricular volumes were obtained at each workload. There were no age-related changes in cardiac output, end-diastolic or end-systolic volumes, or ejection fraction at rest. During vigorous exercise (125 W), cardiac output was not related to age (cardiac output [1/min] = 16.02 + 0.03 [age]; r = .12, p = .46). However, there was an age-related increase in end-diastolic volume (end-diastolic volume [ml] = 86.30 + 1.48 [age]; r = .47, p = .003) and stroke volume (stroke volume [ml] = 85.52 + 0.80 [age]; r = .37, p = .02), and an age-related decrease in heart rate (heart rate [beats/min] = 184.66 - 0.70 [age]; r = -.50, p = .002). The dependence of the age-related increase in stroke volume on diastolic filling was emphasized by the fact that at this high workload end-systolic volume was higher (end-systolic volume [ml] = 3.09 + 0.65 [age]; r = .45, p = .003) and ejection fraction lower (ejection fraction = 88.48 - 0.18 [age]; r = -.33, p = .04) with increasing age. These findings indicate that although aging does not limit cardiac output per se in healthy community-dwelling subjects, the hemodynamic profile accompanying exercise is altered by age and can be explained by an age-related diminution in the cardiovascular response to beta-adrenergic stimulation.

Age is the dominant risk factor for cardiovascular diseases. However, until recently, convincing mechanistic or molecular explanations for the increased cardiovascular risks conferred by aging have been elusive. Aging is associated with alterations in a number of structural and functional properties of large arteries, including diameter, wall thickness, wall stiffness, and endothelial function. Emerging evidence indicates that these age-associated changes are also accelerated in the presence of cardiovascular diseases, and that these changes are themselves risk factors for the appearance or progression of these diseases. In this review, the evidence demonstrating that arterial aging is accelerated in cardiovascular diseases and that accelerated arterial aging is a risk factor for adverse cardiovascular outcomes is briefly reviewed, and selected advances in vascular biology that provide insights into the mechanisms that may underlie the increased risks conferred by arterial aging are summarized. Remarkably, a host of biochemical, enzymatic, and cellular alterations that are operative in accelerated arterial aging have also been implicated in the pathogenesis and progression of arterial diseases. These vascular alterations are thus putative candidates that could be targeted by interventions aimed at attenuating arterial aging, similar to the lifestyle and pharmacological interventions that have already been proven effective. Therefore, the notion that aging is a chronological process and that its risky components cannot be modulated is no longer tenable. It is our hope that a greater appreciation of the links between arterial aging and cardiovascular diseases will stimulate further investigation into strategies aimed at preventing or retarding arterial aging.

A progressive decline in maximal O2 consumption (VO2max) expressed traditionally as per kilogram body weight generally occurs with advancing age. To investigate the extent to which this decline could be attributable to the age-associated loss of metabolically active tissue, i.e., muscle, we measured 24-h urinary creatinine excretion, an index of muscle mass, in 184 healthy nonobese volunteers, ages 22-87 yr, from the Baltimore Longitudinal Study of Aging who had achieved a true VO2max during graded treadmill exercise. A positive correlation was found between VO2max and creatinine excretion in both men (r = 0.64, P less than 0.001) and women (r = 0.47, P less than 0.001). As anticipated, VO2max showed a strong negative linear relationship with age in both men and women. Creatinine excretion also declined with age in men and women. When VO2max was normalized for creatinine excretion, the variance in the VO2max decline attributable to age declined from 60 to 14% in men and from 50 to 8% in women. Thus comparing the standard age regression of VO2max per kilogram body weight with that in which VO2max is normalized per milligram creatinine excretion, the decline in VO2max between a hypothetical 30 yr old and a 70 yr old was reduced from 39 to 18% in men and from 30 to 14% in women. We conclude that in both sexes, a large portion of the age-associated decline in VO2max in non-endurance-trained individuals is explicable by the loss of muscle mass, which is observed with advancing age.

Abstract: Ion channels on the surface membrane of sinoatrial nodal pacemaker cells (SANCs) are the proximal cause of an action potential. Each individual channel type has been thoroughly characterized under voltage clamp, and the ensemble of the ion channel currents reconstructed in silico generates rhythmic action potentials. Thus, this ensemble can be envisioned as a surface “membrane clock” (M clock). Localized subsarcolemmal Ca 2+ releases are generated by the sarcoplasmic reticulum via ryanodine receptors during late diastolic depolarization and are referred to as an intracellular “Ca 2+ clock,” because their spontaneous occurrence is periodic during voltage clamp or in detergent-permeabilized SANCs, and in silico as well. In spontaneously firing SANCs, the M and Ca 2+ clocks do not operate in isolation but work together via numerous interactions modulated by membrane voltage, subsarcolemmal Ca 2+ , and protein kinase A and CaMKII-dependent protein phosphorylation. Through these interactions, the 2 subsystem clocks become mutually entrained to form a robust, stable, coupled-clock system that drives normal cardiac pacemaker cell automaticity. G protein–coupled receptors signaling creates pacemaker flexibility, ie, effects changes in the rhythmic action potential firing rate, by impacting on these very same factors that regulate robust basal coupled-clock system function. This review examines evidence that forms the basis of this coupled-clock system concept in cardiac SANCs.

Aging represents a convergence of declining cardioprotective systems and increasing disease processes that is fertile ground for the development of heart failure. Fifty percent of all heart failure diagnoses and 90% of all heart failure deaths occur in individuals older than 70. This article discusses the microscopic and macroscopic changes in cardiovascular structure, function, protective systems, and disease associated with aging. In addition to outlining important clinical considerations and conditions in older persons, the link between normal aging and the elevated risk for development of stage B heart failure is explained and potential therapeutic pathways are highlighted.

Echocardiograms were performed on 105 male participants in the National Institutes on Aging's volunteer Longitudinal Study Program. All subjects (25--84 years of age) were physically active and had no evidence of hypertension or cardiovascular disease. Measurements were made of the initial diastolic (E-F) slope of the anterior mitral valve leaflet, the aortic and left ventricular cavity dimensions, and the thickness of the posterior left ventricular wall. Fractional shortening of the minor semi-axis of the left ventricle and the velocity of circumferential fiber shortening were also determined. It was found that increasing age correlated with a decrease mitral valve E-F slope and increased aortic root diameter and left ventricular wall thickness. Aging did not affect left ventricular cavity dimension, fractional shortening of the minor semi-axis, and velocity of circumferential fiber shortening. These findings suggest that aging in the normal male is associated with altered left ventricular diastolic filling, increased aortic root diameter and left ventricle hypertrophy but little change in contractile ability in the resting state.

In family studies, phenotypic similarities between relatives yield information on the overall contribution of genes to trait variation. Large samples are important for these family studies, especially when comparing heritability between subgroups such as young and old, or males and females. We recruited a cohort of 6,148 participants, aged 14–102 y, from four clustered towns in Sardinia. The cohort includes 34,469 relative pairs. To extract genetic information, we implemented software for variance components heritability analysis, designed to handle large pedigrees, analyze multiple traits simultaneously, and model heterogeneity. Here, we report heritability analyses for 98 quantitative traits, focusing on facets of personality and cardiovascular function. We also summarize results of bivariate analyses for all pairs of traits and of heterogeneity analyses for each trait. We found a significant genetic component for every trait. On average, genetic effects explained 40% of the variance for 38 blood tests, 51% for five anthropometric measures, 25% for 20 measures of cardiovascular function, and 19% for 35 personality traits. Four traits showed significant evidence for an X-linked component. Bivariate analyses suggested overlapping genetic determinants for many traits, including multiple personality facets and several traits related to the metabolic syndrome; but we found no evidence for shared genetic determinants that might underlie the reported association of some personality traits and cardiovascular risk factors. Models allowing for heterogeneity suggested that, in this cohort, the genetic variance was typically larger in females and in younger individuals, but interesting exceptions were observed. For example, narrow heritability of blood pressure was approximately 26% in individuals more than 42 y old, but only approximately 8% in younger individuals. Despite the heterogeneity in effect sizes, the same loci appear to contribute to variance in young and old, and in males and females. In summary, we find significant evidence for heritability of many medically important traits, including cardiovascular function and personality. Evidence for heterogeneity by age and sex suggests that models allowing for these differences will be important in mapping quantitative traits.

To examine whether age differentially modifies the physiological response to exercise in men and women, we performed gated radionuclide ventriculography with measurement of left ventricular volumes at rest and during peak upright cycle exercise in 200 rigorously screened healthy sedentary volunteers (121 men and 79 women) aged 22–86 yr from the Baltimore Longitudinal Study of Aging. At rest in the sitting position, age-associated declines in heart rate (HR) and increases in systolic blood pressure occurred in both sexes. Whereas resting cardiac index (CI) and total systemic vascular resistance (TSVR) in men did not vary with age, in women resting CI decreased 16% and TSVR increased 46% over the six-decade age span. Men, but not women, demonstrated an age-associated increase of approximately 20% in sitting end-diastolic volume index (EDVI), end-systolic volume index (ESVI), and stroke volume index over this age span. Peak cycle work rate declined with age approximately 40% in both sexes, but at any age it was greater in men than in women even after normalization for body weight. At peak effort, ejection fraction (EF), HR, and CI were reduced similarly with age while ESVI and TSVR were increased in both sexes; EDVI increased 35% with age and stroke work index (SWI) rose 19% in men, but neither was related to age in women; and stroke volume index did not vary with age in either sex. When hemodynamics were expressed as the change from rest to peak effort as an index of cardiovascular reserve function, both sexes demonstrated age-associated increases in EDVI and ESVI and reductions in EF, HR, and CI. However, the exercise-induced reduction in ESVI and the increases in EF, CI, and SWI from rest were greater in men than in women. Thus, age and gender each have a significant impact on the cardiac response to exhaustive upright cycle exercise.

The purpose of this study was to identify cardiovascular features of patients with heart failure with preserved ejection fraction (HFpEF) that differ from those in individuals with hypertensive left ventricular hypertrophy (HLVH) of similar age, gender, and racial background but without failure.Heart failure with preserved ejection fraction often develops in HLVH patients and involves multiple abnormalities. Clarification of changes most specific to HFpEF may help elucidate underlying pathophysiology.A cross-sectional study comparing HFpEF patients (n = 37), HLVH subjects without HF (n = 40), and normotensive control subjects without LVH (n = 56). All subjects had an EF of >50%, sinus rhythm, and insignificant valvular or active ischemic disease, and groups were matched for age, gender, and ethnicity. Comprehensive echo-Doppler and pressure analysis was performed.The HFpEF patients were predominantly African-American women with hypertension, LVH, and obesity. They had vascular and systolic-ventricular stiffening and abnormal diastolic function compared with the control subjects. However, most of these parameters either individually or combined were similarly abnormal in the HLVH group and poorly distinguished between these groups. The HFpEF group had quantitatively greater concentric LVH and estimated mean pulmonary artery wedge pressure (20 mm Hg vs. 16 mm Hg) and shorter isovolumic relaxation time than the HLVH group. They also had left atrial dilation/dysfunction unlike in HLVH and greater total epicardial volume. The product of LV mass index and maximal left atrial (LA) volume best identified HFpEF patients (84% sensitivity, 82% specificity).In an urban, principally African American, cohort, HFpEF patients share many abnormalities of systolic, diastolic, and vascular function with nonfailing HLVH subjects but display accentuated LVH and LA dilation/failure. These latter factors may help clarify pathophysiology and define an important HFpEF population for clinical trials.

This study sought to evaluate whether pulse wave velocity (PWV), a noninvasive index of arterial stiffness, is a predictor of the longitudinal changes in systolic blood pressure (SBP) and of incident hypertension.Although arterial stiffness is believed to underlie, in part, the age-associated changes in SBP, particularly at older ages, few longitudinal studies in humans have examined the relationship between arterial stiffness and blood pressure.Pulse wave velocity was measured at baseline in 449 normotensive or untreated hypertensive volunteers (age 53 +/- 17 years). Repeated measurements of blood pressure were performed during an average follow-up of 4.9 +/- 2.5 years.After adjusting for covariates including age, body mass index, and mean arterial pressure, linear mixed effects regression models showed that PWV was an independent determinant of the longitudinal increase in SBP (p = 0.003 for the interaction term with time). In a subset of 306 subjects who were normotensive at baseline, hypertension developed in 105 (34%) during a median follow-up of 4.3 years (range 2 to 12 years). By stepwise Cox proportional hazards models, PWV was an independent predictor of incident hypertension (hazard ratio 1.10 per 1 m/s increase in PWV, 95% confidence interval 1.00 to 1.30, p = 0.03) in individuals with a follow-up duration greater than the median.Pulse wave velocity is an independent predictor of the longitudinal increase in SBP and of incident hypertension. This suggests that PWV could help identify normotensive individuals who should be targeted for the implementation of interventions aimed at preventing or delaying the progression of subclinical arterial stiffening and the onset of hypertension.

We sought to evaluate whether the clustering of multiple components of the metabolic syndrome (MS) has a greater impact on these vascular parameters than individual components of MS. Intima-media thickness (IMT) and vascular stiffness have been shown to be independent predictors of adverse cardiovascular events. The MS is defined as the clustering of three or more of the cardiovascular risk factors of dysglycemia, hypertension, dyslipidemia, and obesity. Carotid IMT and stiffness were derived via B-mode ultrasonography in 471 participants from the Baltimore Longitudinal Study on Aging, who were without clinical cardiovascular disease and not receiving antihypertensive therapy. The MS conferred a disproportionate increase in carotid IMT (+16%, p < 0.0001) and stiffness (+32%, p < 0.0001), compared with control subjects. Multiple regression models, which included age, gender, smoking, low-density lipoprotein, as well as each individual component of MS as continuous variables, showed that MS was an independent determinant of both IMT (p = 0.002) and stiffness (p = 0.012). The MS was associated with a greater prevalence of subjects whose values were in the highest quartiles of IMT, stiffness, or both. Even after taking into account each individual component of MS, the clustering of at least three of these components is independently associated with increased IMT and stiffness. This suggests that the components of MS interact to synergistically impact vascular thickness and stiffness. Future studies should examine whether the excess cardiovascular risk associated with MS is partly mediated through the amplified alterations in these vascular properties.

Background —Despite limiting elastic recoil and late vascular remodeling after angioplasty, coronary stents remain vulnerable to restenosis, caused primarily by neointimal hyperplasia. Paclitaxel, a microtubule-stabilizing drug, has been shown to inhibit vascular smooth muscle cell migration and proliferation contributing to neointimal hyperplasia. We tested whether paclitaxel-coated coronary stents are effective at preventing neointimal proliferation in a porcine model of restenosis. Methods and Results —Palmaz-Schatz stents were dip-coated with paclitaxel (0, 0.2, 15, or 187 μg/stent) by immersion in ethanolic paclitaxel and evaporation of the solvent. Stents were deployed with mild oversizing in the left anterior descending coronary artery (LAD) of 41 minipigs. The treatment effect was assessed 4 weeks after stent implantation. The angiographic late loss index (mean luminal diameter) decreased with increasing paclitaxel dose ( P &lt;0.0028 by ANOVA), declining by 84.3% (from 0.352 to 0.055, P &lt;0.05) at the highest level tested (187 μg/stent versus control). Accompanying this change, the neointimal area decreased (by 39.5%, high-dose versus control; P &lt;0.05) with increasing dose ( P &lt;0.040 by ANOVA), whereas the luminal area increased (by 90.4%, high-dose versus control; P &lt;0.05) with escalating dose ( P &lt;0.0004 by ANOVA). Inflammatory cells were seen infrequently, and there were no cases of aneurysm or thrombosis. Conclusions —Paclitaxel-coated coronary stents produced a significant dose-dependent inhibition of neointimal hyperplasia and luminal encroachment in the pig LAD 28 days after implantation; later effects require further study. These results demonstrate the potential therapeutic benefit of paclitaxel-coated coronary stents in the prevention and treatment of human coronary restenosis.

The electrocardiographic PR interval (or PQ interval) reflects atrial and atrioventricular nodal conduction, disturbances of which increase risk of atrial fibrillation. We report a meta-analysis of genome-wide association studies for PR interval from seven population-based European studies in the CHARGE Consortium: AGES, ARIC, CHS, FHS, KORA, Rotterdam Study, and SardiNIA (N = 28,517). We identified nine loci associated with PR interval at P < 5 x 10(-8). At the 3p22.2 locus, we observed two independent associations in voltage-gated sodium channel genes, SCN10A and SCN5A. Six of the loci were near cardiac developmental genes, including CAV1-CAV2, NKX2-5 (CSX1), SOX5, WNT11, MEIS1, and TBX5-TBX3, providing pathophysiologically interesting candidate genes. Five of the loci, SCN5A, SCN10A, NKX2-5, CAV1-CAV2, and SOX5, were also associated with atrial fibrillation (N = 5,741 cases, P < 0.0056). This suggests a role for common variation in ion channel and developmental genes in atrial and atrioventricular conduction as well as in susceptibility to atrial fibrillation.

One of the major conceptual advances in our understanding of the pathogenesis of age-associated cardiovascular diseases has been the insight that age-related oxidative stress may promote vascular inflammation even in the absence of traditional risk factors associated with atherogenesis (e.g., hypertension or metabolic diseases). In the present review we summarize recent experimental data suggesting that mitochondrial production of reactive oxygen species, innate immunity, the local TNF-alpha-converting enzyme (TACE)-TNF-alpha, and the renin-angiotensin system may underlie NF-kappaB induction and endothelial activation in aged arteries. The theme that emerges from this review is that multiple proinflammatory pathways converge on NF-kappaB in the aged arterial wall, and that the transcriptional activity of NF-kappaB is regulated by multiple nuclear factors during aging, including nuclear enzymes poly(ADP-ribose) polymerase (PARP-1) and SIRT-1. We also discuss the possibility that nucleophosmin (NPM or nuclear phosphoprotein B23), a known modulator of the cellular oxidative stress response, may also regulate NF-kappaB activity in endothelial cells.

Objective To examine the relationship between brachial and central carotid pressures and target organ indices at baseline and their association with future mortality. Methods We examined, cross-sectionally and longitudinally, the relations of baseline systolic and pulse pressures in central (calibrated tonometric carotid pulse) and peripheral (brachial, mercury sphygmomanometer) arteries to baseline left ventricular mass, carotid intima-media thickness, estimated glomerular filtration rate, and 10-year all-cause and cardiovascular mortality in 1272 participants (47% women aged 30–79 years) from a community of homogeneous Chinese. Results Left ventricular mass was more strongly related to central and peripheral systolic pressures than pulse pressures. Intima-media thickness and glomerular filtration rate were more strongly related to central pressures than peripheral pressures. A total of 130 participants died, 37 from cardiovascular causes. In univariate analysis, all four blood pressure variables significantly predicted all-cause and cardiovascular mortality. Each blood pressure variable was entered into the multivariate models, both individually and jointly with another blood pressure variable. After adjustment for age, sex, heart rate, BMI, current smoking, glucose, ratio of total cholesterol to high-density lipoprotein cholesterol, carotid–femoral pulse wave velocity, left ventricular mass, intima-media thickness, and glomerular filtration rate, only central systolic pressure consistently and independently predicted cardiovascular mortality (hazards ratio, 1.30 per 10 mmHg). No significant sex interactions were observed in all analyses. Conclusion Systolic and pulse pressures relate differently to different target organs. Central systolic pressure is more valuable than other blood pressure variables in predicting cardiovascular mortality.

Arne Pfeufer, Aravinda Chakravarti and colleagues from the QTSCD consortium report genetic associations influencing the QT interval duration, a measure of cardiac repolarization which is a risk factor for sudden cardiac death, in five genome-wide association studies. The QT interval, a measure of cardiac repolarization, predisposes to ventricular arrhythmias and sudden cardiac death (SCD) when prolonged or shortened. A common variant in NOS1AP is known to influence repolarization. We analyze genome-wide data from five population-based cohorts (ARIC, KORA, SardiNIA, GenNOVA and HNR) with a total of 15,842 individuals of European ancestry, to confirm the NOS1AP association and identify nine additional loci at P < 5 × 10−8. Four loci map near the monogenic long-QT syndrome genes KCNQ1, KCNH2, SCN5A and KCNJ2. Two other loci include ATP1B1 and PLN, genes with established electrophysiological function, whereas three map to RNF207, near LITAF and within NDRG4-GINS3-SETD6-CNOT1, respectively, all of which have not previously been implicated in cardiac electrophysiology. These results, together with an accompanying paper from the QTGEN consortium, identify new candidate genes for ventricular arrhythmias and SCD.

We present the AGEMAP (Atlas of Gene Expression in Mouse Aging Project) gene expression database, which is a resource that catalogs changes in gene expression as a function of age in mice. The AGEMAP database includes expression changes for 8,932 genes in 16 tissues as a function of age. We found great heterogeneity in the amount of transcriptional changes with age in different tissues. Some tissues displayed large transcriptional differences in old mice, suggesting that these tissues may contribute strongly to organismal decline. Other tissues showed few or no changes in expression with age, indicating strong levels of homeostasis throughout life. Based on the pattern of age-related transcriptional changes, we found that tissues could be classified into one of three aging processes: (1) a pattern common to neural tissues, (2) a pattern for vascular tissues, and (3) a pattern for steroid-responsive tissues. We observed that different tissues age in a coordinated fashion in individual mice, such that certain mice exhibit rapid aging, whereas others exhibit slow aging for multiple tissues. Finally, we compared the transcriptional profiles for aging in mice to those from humans, flies, and worms. We found that genes involved in the electron transport chain show common age regulation in all four species, indicating that these genes may be exceptionally good markers of aging. However, we saw no overall correlation of age regulation between mice and humans, suggesting that aging processes in mice and humans may be fundamentally different.

Recent studies have shown that chronic beta-adrenergic receptor (beta-AR) stimulation alters cardiac myocyte survival in a receptor subtype-specific manner. We examined the effect of selective beta(1)- and beta(2)-AR subtype stimulation on apoptosis induced by hypoxia or H(2)O(2) in rat neonatal cardiac myocytes. Although neither beta(1)- nor beta(2)-AR stimulation had any significant effect on the basal level of apoptosis, selective beta(2)-AR stimulation protected myocytes from apoptosis. beta(2)-AR stimulation markedly increased mitogen-activated protein kinase/extracellular signal-regulated protein kinase (MAPK/ERK) activation as well as phosphatidylinositol-3'-kinase (PI-3K) activity and Akt/protein kinase B phosphorylation. beta(1)-AR stimulation also markedly increased MAPK/ERK activation but only minimally activated PI-3K and Akt. Pretreatment with pertussis toxin blocked beta(2)-AR-mediated protection from apoptosis as well as the beta(2)-AR-stimulated changes in MAPK/ERK, PI-3K, and Akt/protein kinase B. The selective PI-3K inhibitor, LY 294002, also blocked beta(2)-AR-mediated protection, whereas inhibition of MAPK/ERK activation at an inhibitor concentration that blocked agonist-induced activation but not the basal level of activation had no effect on beta(2)-AR-mediated protection. These findings demonstrate that beta(2)-ARs activate a PI-3K-dependent, pertussis toxin-sensitive signaling pathway in cardiac myocytes that is required for protection from apoptosis-inducing stimuli often associated with ischemic stress.

-Transgenic mouse models have been developed to manipulate beta-adrenergic receptor (betaAR) signal transduction. Although several of these models have altered betaAR subtypes, the specific functional sequelae of betaAR stimulation in murine heart, particularly those of beta2-adrenergic receptor (beta2AR) stimulation, have not been characterized. In the present study, we investigated effects of beta2AR stimulation on contraction, [Ca2+]i transient, and L-type Ca2+ currents (ICa) in single ventricular myocytes isolated from transgenic mice overexpressing human beta2AR (TG4 mice) and wild-type (WT) littermates. Baseline contractility of TG4 heart cells was increased by 3-fold relative to WT controls as a result of the presence of spontaneous beta2AR activation. In contrast, beta2AR stimulation by zinterol or isoproterenol plus a selective beta1-adrenergic receptor (beta1AR) antagonist CGP 20712A failed to enhance the contractility in TG4 myocytes, and more surprisingly, beta2AR stimulation was also ineffective in increasing contractility in WT myocytes. Pertussis toxin (PTX) treatment fully rescued the ICa, [Ca2+]i, and contractile responses to beta2AR agonists in both WT and TG4 cells. The PTX-rescued murine cardiac beta2AR response is mediated by cAMP-dependent mechanisms, because it was totally blocked by the inhibitory cAMP analog Rp-cAMPS. These results suggest that PTX-sensitive G proteins are responsible for the unresponsiveness of mouse heart to agonist-induced beta2AR stimulation. This was further corroborated by an increased incorporation of the photoreactive GTP analog [gamma-32P]GTP azidoanilide into alpha subunits of Gi2 and Gi3 after beta2AR stimulation by zinterol or isoproterenol plus the beta1AR blocker CGP 20712A. This effect to activate Gi proteins was abolished by a selective beta2AR blocker ICI 118,551 or by PTX treatment. Thus, we conclude that (1) beta2ARs in murine cardiac myocytes couple to concurrent Gs and Gi signaling, resulting in null inotropic response, unless the Gi signaling is inhibited; (2) as a special case, the lack of cardiac contractile response to beta2AR agonists in TG4 mice is not due to a saturation of cell contractility or of the cAMP signaling cascade but rather to an activation of beta2AR-coupled Gi proteins; and (3) spontaneous beta2AR activation may differ from agonist-stimulated beta2AR signaling.

The value of increased arterial wave reflection, usually assessed by the transit time-dependent augmentation index and augmented pressure (Pa), in the prediction of cardiovascular events may have been underestimated. We investigated whether the transit time-independent measures of reflected wave magnitude predict cardiovascular outcomes independent of arterial stiffness indexed by carotid-femoral pulse wave velocity. A total of 1272 participants (47% women; mean age: 52+/-13 years; range: 30 to 79 years) from a community-based survey were studied. Carotid pressure waveforms derived by tonometry were decomposed into their forward wave amplitudes, backward wave amplitudes (Pb), and a reflection index (=[Pb/(forward wave amplitude+Pb)]), in addition to augmentation index, Pa, and reflected wave transit time. During a median follow-up of 15 years, 225 deaths occurred (17.6%), including 64 cardiovascular origins (5%). In univariate Cox proportional hazard regression analysis, pulse wave velocity, Pa, and Pb predicted all-cause and cardiovascular mortality in both men and women, whereas augmentation index, reflected wave transit time, and reflection index were predictive only in men. In multivariate analysis accounting for age, height, and heart rate, Pb predicted cardiovascular mortality in both men and women, whereas Pa was predictive only in men. Per 1-SD increment (6 mm Hg), Pb predicted 15-year cardiovascular mortality independent of brachial but not central pressure, pulse wave velocity, augmentation index, Pa, and conventional cardiovascular risk factors with hazard ratios of approximately 1.60 (all P<0.05). In conclusion, Pb, a transit time-independent measure of reflected wave magnitude, predicted long-term cardiovascular mortality in men and women independent of arterial stiffness.

Carotid-femoral pulse wave velocity (PWV), a marker of arterial stiffness, is an established independent cardiovascular risk factor. Little information is available on the pattern and determinants of the longitudinal change in PWV with aging. Such information is crucial to elucidating mechanisms underlying arterial stiffness and the design of interventions to retard it. Between 1988 and 2013, we collected 2 to 9 serial measures of PWV in 354 men and 423 women of the Baltimore Longitudinal Study of Aging, who were 21 to 94 years of age and free of clinically significant cardiovascular disease. Rates of PWV increase accelerated with advancing age in men more than women, leading to sex differences in PWV after the age of 50 years. In both sexes, not only systolic blood pressure (SBP) ≥140 mm Hg but also SBP of 120 to 139 mm Hg was associated with steeper rates of PWV increase compared with SBP&lt;120 mm Hg. Furthermore, there was a dose-dependent effect of SBP in men with marked acceleration in PWV rate of increase with age at SBP ≥140 mm Hg compared with SBP of 120 to 139 mm Hg. Except for waist circumference in women, no other traditional cardiovascular risk factors predicted longitudinal PWV increase. In conclusion, the steeper longitudinal increase of PWV in men than women led to the sex difference that expanded with advancing age. Age and SBP are the main longitudinal determinants of PWV, and the effect of SBP on PWV trajectories exists even in the prehypertensive range.

The role of cGMP in myocardial contraction is not established. Recent reports suggest that nitric oxide, released by endothelial cells or within myocytes, modifies myocardial contraction by raising cGMP. We studied the effects of 8-bromo-cGMP (8bcGMP, 50 mumol/L) on contraction (cell shortening) and simultaneous intracellular Ca2+ transients (indo 1 fluorescence ratio) in intact adult rat ventricular myocytes (0.5 Hz and 25 degrees C) 8bcGMP reduced myocyte twitch amplitude and time to peak shortening (-19.6 +/- 4.2% and -17.6 +/- 1.3%, respectively) and increased steady-state diastolic cell length (+0.6 +/- 0.1 microns, mean +/- SEM, n = 8; all P < .05) but had no effect on shortening velocity, systolic or diastolic fluorescence ratio, or time to peak fluorescence ratio (all P = NS). In 7 of 13 myocytes, this negative inotropic effect was preceded by a transient positive inotropic effect, with small increases in twitch amplitude, shortening velocity, and cytosolic Ca2+ transient. Analysis of 8bcGMP effects on both the dynamic and steady-state relation between cell shortening and intracellular Ca2+ (during twitch contraction and tetanic contraction, respectively) indicated reduction in the myofilament response to Ca2+ in all cases. These 8bcGMP effects were inhibited by KT5823 (1 mumol/L), an inhibitor of cGMP-dependent protein kinase, or by the presence of isoproterenol (3 nmol/L). 8bcGMP had no effect on cytosolic pH in cells (n = 4) loaded with the fluorescent probe carboxyseminaphthorhodafluor-1. These data indicate that cGMP may modulate myocardial relaxation and diastolic tone by reducing the relative myofilament response to Ca2+, probably via cGMP-dependent protein kinase.

The effect of advanced age on the response of active tension, maximal rate of tension development (dT/dt), and contraction duration to catecholamines and to calcium was evaluated in isometric trabeculae carneae from young adult (6-month-old), middle-aged (12-month-old), and aged (25-month-old) rats. Control values were not age dependent except for that for contraction duration which was prolonged in the aged group. At a norepinephrine concentration of 8 times 10-5M, dT/dt increased to 163.8 plus or minus 5.3% of control in the young adult group and to 125.9 plus or minus 6.3% of control in the aged group (P smaller than 0.001). Active tension increased to 121.3 plus or minus 4.0% of control in the young adult muscles but did not increase in the aged muscles (P smaller than 0.01). Contraction duration shortened proportionately in both age groups. Similar results were obtained with isoproterenol. In contrast to the response to catecholamines, there was no age difference in the response of active tension and dT/dt to increasing concentrations of calcium. It is concluded that the intrinsic inotropic response to catecholamines is diminished in the aged myocardium. This finding does not appear to result from differences in tachyphylaxis, tissue uptake of catecholamines, or the ability of the contractile proteins to respond to increasing concentrations of calcium but instead may result from a decreased ability of catecholamines to increase the intracellular calcium available for contraction.

Understanding the performance of the left ventricle (LV) requires not only examining the properties of the LV itself, but also investigating the modulating effects of the arterial system on left ventricular performance. The interaction of the LV with the arterial system, termed arterial-ventricular coupling (E A /E LV ), is a central determinant of cardiovascular performance and cardiac energetics. E A /E LV can be indexed by the ratio of effective arterial elastance (E A ; a measure of the net arterial load exerted on the left ventricle) to left ventricular end-systolic elastance (E LV ; a load-independent measure of left ventricular chamber performance). At rest, in healthy individuals, E A /E LV is maintained within a narrow range, which allows the cardiovascular system to optimize energetic efficiency at the expense of mechanical efficacy. During exercise, an acute mismatch between the arterial and ventricular systems occurs, due to a disproportionate increase in E LV (from an average of 4.3 to 13.2, and 4.7 to 15.5 mmHg·ml −1 ·m −2 in men and women, respectively) vs. E A (from an average of 2.3 to 3.2, and 2.3 to 2.9 mmHg·ml −1 ·m −2 in men and women, respectively), to ensure that sufficient cardiac performance is achieved to meet the increased energetic requirements of the body. As a result E A /E LV decreases from an average of 0.58 to 0.34, and 0.52 to 0.27 in men and women, respectively. In this review, we provide an overview of the concept of E A /E LV , and examine the effects of age, hypertension, and heart failure on E A /E LV and its components (E A and E LV ) in men and women. We discuss these effects both at rest and during exercise and highlight the mechanistic insights that can be derived from studying E A /E LV .

High serum uric acid levels elevate pro-inflammatory-state gout crystal arthropathy and place individuals at high risk for cardiovascular morbidity and mortality. Genome-wide scans in the genetically isolated Sardinian population identified variants associated with serum uric acid levels as a quantitative trait. They mapped within GLUT9, a Chromosome 4 glucose transporter gene predominantly expressed in liver and kidney. SNP rs6855911 showed the strongest association (p = 1.84 x 10(-16)), along with eight others (p = 7.75 x 10(-16) to 6.05 x 10(-11)). Individuals homozygous for the rare allele of rs6855911 (minor allele frequency = 0.26) had 0.6 mg/dl less uric acid than those homozygous for the common allele; the results were replicated in an unrelated cohort from Tuscany. Our results suggest that polymorphisms in GLUT9 could affect glucose metabolism and uric acid synthesis and/or renal reabsorption, influencing serum uric acid levels over a wide range of values.

Metabolic syndrome (MetS) remains a controversial entity. Specific clusters of MetS components - rather than MetS per se - are associated with accelerated arterial ageing and with cardiovascular (CV) events. To investigate whether the distribution of clusters of MetS components differed cross-culturally, we studied 34,821 subjects from 12 cohorts from 10 European countries and one cohort from the USA in the MARE (Metabolic syndrome and Arteries REsearch) Consortium.In accordance with the ATP III criteria, MetS was defined as an alteration three or more of the following five components: elevated glucose (G), fasting glucose ≥110 mg/dl; low HDL cholesterol, < 40mg/dl for men or <50 mg/dl for women; high triglycerides (T), ≥150 mg/dl; elevated blood pressure (B), ≥130/≥85 mmHg; abdominal obesity (W), waist circumference >102 cm for men or >88 cm for women.MetS had a 24.3% prevalence (8468 subjects: 23.9% in men vs. 24.6% in women, p < 0.001) with an age-associated increase in its prevalence in all the cohorts. The age-adjusted prevalence of the clusters of MetS components previously associated with greater arterial and CV burden differed across countries (p < 0.0001) and in men and women (p < 0.0001). In details, the cluster TBW was observed in 12% of the subjects with MetS, but was far more common in the cohorts from the UK (32.3%), Sardinia in Italy (19.6%), and Germany (18.5%) and less prevalent in the cohorts from Sweden (1.2%), Spain (2.6%), and the USA (2.5%). The cluster GBW accounted for 12.7% of subjects with MetS with higher occurrence in Southern Europe (Italy, Spain, and Portugal: 31.4, 18.4, and 17.1% respectively) and in Belgium (20.4%), than in Northern Europe (Germany, Sweden, and Lithuania: 7.6, 9.4, and 9.6% respectively).The analysis of the distribution of MetS suggested that what follows under the common definition of MetS is not a unique entity rather a constellation of cluster of MetS components, likely selectively risky for CV disease, whose occurrence differs across countries.

Heart rate (HR) variability (HRV; beat-to-beat changes in the R-wave to R-wave interval) has attracted considerable attention during the past 30+ years (PubMed currently lists >17 000 publications). Clinically, a decrease in HRV is correlated to higher morbidity and mortality in diverse conditions, from heart disease to fetal distress. It is usually attributed to fluctuation in cardiac autonomic nerve activity. We calculated HRV parameters from a variety of cardiac preparations (including humans, living animals, Langendorff-perfused heart, and single sinoatrial nodal cell) in diverse species, combining this with data from previously published articles. We show that regardless of conditions, there is a universal exponential decay-like relationship between HRV and HR. Using 2 biophysical models, we develop a theory for this and confirm that HRV is primarily dependent on HR and cannot be used in any simple way to assess autonomic nerve activity to the heart. We suggest that the correlation between a change in HRV and altered morbidity and mortality is substantially attributable to the concurrent change in HR. This calls for re-evaluation of the findings from many articles that have not adjusted properly or at all for HR differences when comparing HRV in multiple circumstances.

The processes underlying the initiation of the heartbeat, whether due to intracellular metabolism or surface membrane events, have always been a major focus of cardiac research. Dr. Lakatta is the founder and Director of the Laboratory of Cardiovascular Science, National Institute on Aging, National Institutes of Health. He also holds adjunct appointments as Professor, Department of Physiology, University of Maryland School of Medicine, and Professor, Cardiology Division, Johns Hopkins School of Medicine. Dr. Lakatta received his M.D., Magna cum laude, at Georgetown University School of Medicine. Following an internship and residency in Medicine at Strong Memorial Hospital, University of Rochester, Rochester, N.Y., he trained in basic research for 2 years at the NIH. Subsequently, he completed his cardiology fellowship at Georgetown and Johns Hopkins University Schools of Medicine. This was followed by a year of basic research training in the Department of Physiology, University College and the Cardiothoracic Institute, London England. Dr. Lakatta is recognized both nationally and internationally as an expert in cardiovascular research. He has authored over 300 original publications in top peer-reviewed cardiovascular journals, written over 200 invited reviews/book chapters, and delivered over 300 invited lectures. He is a member of multiple scholarly societies and journal editorial boards. Dr. Lakatta has made a sustained 30-plus-year commitment to a broad-based research career. His studies range from molecules to humans, including translation of novel findings into the clinical realm. The overall goals of his research program are 1) to identify age associated changes that occur within the cardiovascular system and to determine the mechanisms for these changes; 2) to determine how aging of the heart and vasculature interacts with chronic disease states to enhance the risk for CV diseases in older persons; 3) to study basic mechanisms in excitation–contraction coupling and how these are modulated by surface receptor signaling pathways in cardiac cells; 4) to elucidate mechanisms of pacemaker activity in sinoatrial nodal cells; 5) to elucidate mechanisms that govern cardiac and vascular cell survival; 6) to establish the potentials and limitations of new therapeutic approaches such as changes in lifestyle, novel pharmacologic aging or gene or stem cell transfer techniques in aging or disease states. Based upon his accomplishments, he has received several awards, among which has been election into the American Society for Clinical Research and the Association of American Physicians. Dr. Lakatta has also been elected as a fellow in the APS Cardiovascular Section, a fellow of the American Heart Association (F.A.H.A.) and is an Inaugural Fellow of the Council on Basic Cardiovascular Sciences of the American Heart Association and a Life Member of the International Society of Heart Research. He is the recipient of the Eli Lilly Award in Medical Science, the Paul Dudley White Award in Cardiology, the Allied Signal Achievement Award in Aging, the Novartis Prize in Gerontology, the Irving Wright Award of Distinction of the American Federation for Aging Research (AFAR), Distinguished Service Medals, Public Health Service, National Institute of Health, National Institute on Aging and an Honorary Degree from the Universite D'Auvergne in Clermont, France. In 1994 he chaired the Gordon Conference on Cardiac Regulatory Mechanisms, and was the Chairman of the Scientific Program Committee of the International Society for Heart Research (ISHR) World Congress in 1998 and 2004. Dr. DiFrancesco received his Ph.D., Magna cum Laude, at the University of Milano, Faculty of Science, after which he received a research fellowship at the Institute of Physiology in the same Faculty, until in 1976 he joined the Laboratory of Physiology of the University of Cambridge, and shortly later the Physiological Laboratory of the University of Oxford, UK, where he trained as a postdoc in cardiac electrophysiology in Denis Noble's laboratory until 1979. Present research in his laboratory is focused mainly on basic and clinically-relevant aspects of the properties of the “pacemaker" (funny) current, which he first described in 1979 with Hilary Brown and Susan Noble while visiting Denis Noble's laboratory in Oxford. As well as in Oxford, Dario DiFrancesco spent research time early in his career in several internationally renowned laboratories including Cambridge UK, Homburg-Saar, Paris Orsay, Tours, Stony Brook, New York Columbia University. In the course of their activity since the early 80s, the group he heads in Milano has established research collaborations with several laboratories worldwide. Following decades of basic studies, in recent years the interest in “funny" channels has grown because of their relevance to clinical use as well as to the fundamentals of cardiac physiology. The main research projects now in progress in Dr. DiFrancesco's laboratory include: 1) production, starting from different sources of stem-cell derived cardiomyocytes, of spontaneously active cell agglomerates characterized by constitutive expression of HCN4 channels, with the aim of generating substrates useful for development of “biological" pacemakers; 2) investigation of molecular features of f-channel block by pure heart rate-reducing molecules such as ivabradine, to improve knowledge of how to exploit f-channel properties for pharmacological control of heart rate; 3) HCN4 channel screening of patients with inheritable forms of arrhythmias such as bradycardia, Inappropriate Sinus Tachycardia, Sick Sinus Syndrome and others, in the search for arrhythmia-associated channel mutations; 4) generation of conditional, cardiac-specific HCN4 knock-out mice, with the aim of characterizing the function of f-channels in an animal model in vivo. Dr. DiFrancesco is a member of Italian and international scientific societies, including the Physiological Society of UK, the American Physiological Society and the American Biophysical Society. He is a member of the “Academia Europaea" and in 1994 was awarded the triennial International Prize for Cardiac Electrophysiology “Professeur Pierre Rijlant" by the Royal Academy of Medicine of Belgium. Recently he received the 2008 "Grand Prix Scientifique" for Cardiovascular Research by the Fondation Lefoulon-Delalande – Institut de France, awarded by the French Academy of Sciences for the “très remarquables travaux de recherches qui ont conduit à la découverte des canaux ioniques impliqués dans la régulation du rythme cardiaque". He has authored some 150 peer-reviewed articles and has received over 150 invitations to speak at congresses/named lectures/seminars worldwide.

Acute ST-segment elevation myocardial infarction (STEMI) is a leading cause of morbidity and mortality. In experimental models of MI, erythropoietin reduces infarct size and improves left ventricular (LV) function.To evaluate the safety and efficacy of a single intravenous bolus of epoetin alfa in patients with STEMI.A prospective, randomized, double-blind, placebo-controlled trial with a dose-escalation safety phase and a single dose (60,000 U of epoetin alfa) efficacy phase; the Reduction of Infarct Expansion and Ventricular Remodeling With Erythropoietin After Large Myocardial Infarction (REVEAL) trial was conducted at 28 US sites between October 2006 and February 2010, and included 222 patients with STEMI who underwent successful percutaneous coronary intervention (PCI) as a primary or rescue reperfusion strategy.Participants were randomly assigned to treatment with intravenous epoetin alfa or matching saline placebo administered within 4 hours of reperfusion.Infarct size, expressed as percentage of LV mass, assessed by cardiac magnetic resonance (CMR) imaging performed 2 to 6 days after study medication administration (first CMR) and again 12 ± 2 weeks later (second CMR).In the efficacy cohort, the infarct size did not differ between groups on either the first CMR scan (n = 136; 15.8% LV mass [95% confidence interval {CI}, 13.3-18.2% LV mass] for the epoetin alfa group vs 15.0% LV mass [95% CI, 12.6-17.3% LV mass] for the placebo group; P = .67) or on the second CMR scan (n = 124; 10.6% LV mass [95% CI, 8.4-12.8% LV mass] vs 10.4% LV mass [95% CI, 8.5-12.3% LV mass], respectively; P = .89). In a prespecified analysis of patients aged 70 years or older (n = 21), the mean infarct size within the first week (first CMR) was larger in the epoetin alfa group (19.9% LV mass; 95% CI, 14.0-25.7% LV mass) than in the placebo group (11.7% LV mass; 95% CI, 7.2-16.1% LV mass) (P = .03). In the safety cohort, of the 125 patients who received epoetin alfa, the composite outcome of death, MI, stroke, or stent thrombosis occurred in 5 (4.0%; 95% CI, 1.31%-9.09%) but in none of the 97 who received placebo (P = .04).In patients with STEMI who had successful reperfusion with primary or rescue PCI, a single intravenous bolus of epoetin alfa within 4 hours of PCI did not reduce infarct size and was associated with higher rates of adverse cardiovascular events. Subgroup analyses raised concerns about an increase in infarct size among older patients.clinicaltrials.gov Identifier: NCT00378352.

Carotid intima media thickness (cIMT) and plaque determined by ultrasonography are established measures of subclinical atherosclerosis that each predicts future cardiovascular disease events. We conducted a meta-analysis of genome-wide association data in 31,211 participants of European ancestry from nine large studies in the setting of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. We then sought additional evidence to support our findings among 11,273 individuals using data from seven additional studies. In the combined meta-analysis, we identified three genomic regions associated with common carotid intima media thickness and two different regions associated with the presence of carotid plaque (P < 5 × 10(-8)). The associated SNPs mapped in or near genes related to cellular signaling, lipid metabolism and blood pressure homeostasis, and two of the regions were associated with coronary artery disease (P < 0.006) in the Coronary Artery Disease Genome-Wide Replication and Meta-Analysis (CARDIoGRAM) consortium. Our findings may provide new insight into pathways leading to subclinical atherosclerosis and subsequent cardiovascular events.

Central arterial wall stiffening, driven by a chronic inflammatory milieu, accompanies arterial diseases, the leading cause of cardiovascular (CV) morbidity and mortality in Western society. An increase in central arterial wall stiffening, measured as an increase in aortic pulse wave velocity (PWV), is a major risk factor for clinical CV disease events. However, no specific therapies to reduce PWV are presently available. In rhesus monkeys, a 2 year diet high in fat and sucrose (HFS) increases not only body weight and cholesterol, but also induces prominent central arterial wall stiffening and increases PWV and inflammation. The observed loss of endothelial cell integrity, lipid and macrophage infiltration, and calcification of the arterial wall were driven by genomic and proteomic signatures of oxidative stress and inflammation. Resveratrol prevented the HFS-induced arterial wall inflammation and the accompanying increase in PWV. Dietary resveratrol may hold promise as a therapy to ameliorate increases in PWV.

"Inside every old person is a young person wondering what happened." So, what is aging? Aging is a manifestation of progressive, time-dependent failure of molecular mechanisms that create disorder within a system of DNA and its environment (nuclear, cytosolic, tissue, organ, organism, other organisms, society, terra firma, atmosphere, universe). Continuous signaling, transmitted with different kinetics across each of these environments, confers a "mutual enslavement" that creates ordered functions among the components within the system. Accrual of this molecular disorder over time, i.e. during aging, causes progressive changes in the structure and function of the heart and arteries that are quite similar in humans, non-human primates, rabbits and rats that compromise cardiovascular reserve function, and confer a marked risk for incident cardiovascular disease. Nearly all aspects of signaling within the DNA environment system within the heart and arteries become disordered with advancing age: Signals change, as does sensing of the signals, transmission of signals and responses to signals, impaired cell renewal, changes in the proteome due to alterations in genomic transcription, mRNA translation, and proteostasis. The density of some molecules becomes reduced, and post-translational modifications, e.g. oxidation and nitration phosphorylation, lead to altered misfolding and disordered molecular interactions. The stoichiometry and kinetics of enzymatic and those reactions which underlie crucial cardiac and vascular cell functions and robust reserve mechanisms that remove damaged organelles and proteins deteriorate. The CV cells generate an inflammatory defense in an attempt to limit the molecular disorder. The resultant proinflammatory milieu is not executed by "professional" inflammatory cells (i.e. white blood cells), however, but by activation of renin-angiotensin-aldosterone endothelin signaling cascades that leads to endothelial and vascular smooth muscle and cardiac cells' phenotype shifts, resulting in production of inflammatory cytokines. Progressive molecular disorder within the heart and arteries over time leads to an excessive allostatic load on the CV system, that results in an increase and "overshoot" in the inflammatory defense signaling. This age-associated molecular disorder-induced inflammation that accrues in the heart and arteries does not, itself, cause clinical signs or symptoms of CVD. Clinical signs and symptoms of these CVDs begin to emerge, however, when the age-associated inflammation in the heart and arteries exceeds a threshold. Thus, an emerging school of thought is that accelerated age-associated alterations within the heart and arteries, per se, ought to be considered to be a type of CVD, because the molecular disorder and the inflammatory milieu it creates within the heart and arteries with advancing age are the roots of the pathophysiology of most cardiovascular diseases, e.g. athersclerosis and hypertension. Because many effects of aging on the CV system can be delayed or attenuated by changes in lifestyle, e.g. diet and exercise, or by presently available drugs, e.g. those that suppress Ang II signaling, CV aging is a promising frontier in preventive cardiology that is not only ripe for, but also in dire need of attention! There is an urgency to incorporate the concept of cardiovascular aging as a disease into clinical medicine. But, sadly, the reality of the age-associated molecular disorder within the heart and ateries has, for the most part, been kept outside of mainstream clinical medicine. This article is part of a Special Issue entitled CV Aging.

Arterial aging is the major contributing factor to increases in the incidence and prevalence of cardiovascular disease, due mainly to the presence of chronic, low-grade, 'sterile' arterial inflammation. Inflammatory signaling driven by the angiotensin II cascade perpetrates adverse age-associated arterial structural and functional remodeling. The aged artery is characterized by endothelial disruption, enhanced vascular smooth muscle cell (VMSC) migration and proliferation, extracellular matrix (ECM) deposition, elastin fracture, and matrix calcification/amyloidosis/glycation. Importantly, the molecular mechanisms of arterial aging are also relevant to the pathogenesis of hypertension and atherosclerosis. Age-associated arterial proinflammation is to some extent mutable, and interventions to suppress or delay it may have the potential to ameliorate or retard age-associated arterial diseases.

Rationale: Lipid overload-induced heart dysfunction is characterized by cardiomyocyte death, myocardial remodeling, and compromised contractility, but the impact of excessive lipid supply on cardiac function remains poorly understood. Objective: To investigate the regulation and function of the mitochondrial fission protein Drp1 (dynamin-related protein 1) in lipid overload-induced cardiomyocyte death and heart dysfunction. Methods and Results: Mice fed a high-fat diet (HFD) developed signs of obesity and type II diabetes mellitus, including hyperlipidemia, hyperglycemia, hyperinsulinemia, and hypertension. HFD for 18 weeks also induced heart hypertrophy, fibrosis, myocardial insulin resistance, and cardiomyocyte death. HFD stimulated mitochondrial fission in mouse hearts. Furthermore, HFD increased the protein level, phosphorylation (at the activating serine 616 sites), oligomerization, mitochondrial translocation, and GTPase activity of Drp1 in mouse hearts, indicating that Drp1 was activated. Monkeys fed a diet high in fat and cholesterol for 2.5 years also exhibited myocardial damage and Drp1 activation in the heart. Interestingly, HFD decreased nicotinamide adenine dinucleotide (oxidized) levels and increased Drp1 acetylation in the heart. In adult cardiomyocytes, palmitate increased Drp1 acetylation, phosphorylation, and protein levels, and these increases were abolished by restoration of the decreased nicotinamide adenine dinucleotide (oxidized) level. Proteomics analysis and in vitro screening revealed that Drp1 acetylation at lysine 642 (K642) was increased by HFD in mouse hearts and by palmitate incubation in cardiomyocytes. The nonacetylated Drp1 mutation (K642R) attenuated palmitate-induced Drp1 activation, its interaction with voltage-dependent anion channel 1, mitochondrial fission, contractile dysfunction, and cardiomyocyte death. Conclusions: These findings uncover a novel mechanism that contributes to lipid overload-induced heart hypertrophy and dysfunction. Excessive lipid supply created an intracellular environment that facilitated Drp1 acetylation, which, in turn, increased its activity and mitochondrial translocation, resulting in cardiomyocyte dysfunction and death. Thus, Drp1 may be a critical mediator of lipid overload-induced heart dysfunction as well as a potential target for therapy.

The central arteries stiffen with age, causing hemodynamic alterations that have been associated with cardiovascular events. Changes in body fat with age may be related to aortic stiffening. The association between vascular stiffness and body fat was evaluated in 2488 older adults (mean age, 74 years; 52% female; 40% black) enrolled in the Study of Health, Aging, and Body Composition (Health ABC), a prospective study of changes in weight and body composition. Clinical sites were located in Pittsburgh, Pa, and Memphis, Tenn. Aortic pulse wave velocity was used as an indirect measure of aortic stiffness. A faster pulse wave velocity indicates a stiffer aorta. Body fat measures were evaluated with dual energy x-ray absorptiometry and computed tomography. Independent of age and blood pressure, pulse wave velocity was positively associated with weight, abdominal circumference, abdominal subcutaneous fat, abdominal visceral fat, thigh fat area, and total fat ( P &lt;0.001 for all). The strongest association was with abdominal visceral fat. Elevated pulse wave velocity was also positively associated with history of diabetes and higher levels of glucose, insulin, and hemoglobin A1c ( P &lt;0.001 for all). In multivariate analysis, independent positive associations with pulse wave velocity were found for age, systolic blood pressure, heart rate, abdominal visceral fat, smoking, hemoglobin A1c, and history of hypertension. The association between pulse wave velocity and abdominal visceral fat was consistent across tertiles of body weight. Among older adults, higher levels of visceral fat are associated with greater aortic stiffness as measured by pulse wave velocity.

The rate of spontaneous diastolic depolarization (DD) of sinoatrial nodal cells (SANCs) that triggers recurrent action potentials (APs) is a fundamental aspect of the heart's pacemaker. Here, in experiments on isolated SANCs, using confocal microscopy combined with a patch clamp technique, we show that ryanodine receptor Ca(2+) release during the DD produces a localized subsarcolemmal Ca(2+) increase that spreads in a wavelike manner by Ca(2+)-induced Ca(2+) release and produces an inward current via the Na(+)-Ca(2+) exchanger (NCX). Ryanodine, a blocker of the sarcoplasmic reticulum Ca(2+) release channel, in a dose-dependent manner reduces the SANC beating rate with an IC(50) of 2.6 micromol/L and abolishes the local Ca(2+) transients that precede the AP upstroke. In voltage-clamped cells in which the DD was simulated by voltage ramp, 3 micromol/L ryanodine decreased an inward current during the voltage ramp by 1.6+/-0.3 pA/pF (SEM, n=4) leaving the peak of L-type Ca(2+) current unchanged. Likewise, acute blockade of the NCX (via rapid substitution of bath Na(+) by Li(+)) abolished SANC beating and reduced the inward current to a similar extent (1.7+/-0.4 pA/pF, n=4), as did ryanodine. Thus, in addition to activation/inactivation of multiple ion channels, Ca(2+) activation of the NCX, because of localized sarcoplasmic reticulum Ca(2+) release, is a critical element in a chain of molecular interactions that permits the heartbeat to occur and determines its beating rate.

Myocyte cell loss is a prominent and important pathogenic feature of cardiac ischemia. We have used cultured neonatal rat cardiac myocytes exposed to prolonged hypoxia as an experimental system to identify critical factors involved in cardiomyocyte death. Exposure of myocytes to hypoxia for 48 h resulted in intranucleosomal cleavage of genomic DNA characteristic of apoptosis and was accompanied by increased p53 transactivating activity and protein accumulation. Expression of p21/WAF-1/CIP-1, a well-characterized target of p53 transactivation, also increased in response to hypoxia. Hypoxia did not cause DNA laddering or cell loss in cardiac fibroblasts. To determine whether the increase in p53 expression in myocytes was sufficient to induce apoptosis, normoxic cultures were infected with a replication-defective adenovirus expressing wild-type human p53 (AdCMV.p53). Infected cells expressed high intracellular levels of p53 protein and exhibited the morphological changes and genomic DNA fragmentation characteristic of apoptosis. In contrast, no genomic DNA fragmentation was observed in myocytes infected with the control virus lacking an insert (AdCMV.null) or in cardiac fibroblasts infected with AdCMV.p53. These results suggest that the intracellular signaling pathways activated by p53 might play a critical role in the regulation of hypoxia-induced apoptosis of cardiomyocytes.

The failing heart is characterized by impaired cardiac muscle function and increased interstitial fibrosis. Our purpose was to determine whether the functional impairment of the failing heart is associated with changes in levels of mRNA encoding proteins that modulate parameters of contraction and relaxation and whether the increased fibrosis observed in the failing heart is related to elevated expression of genes encoding extracellular matrix components. We studied hearts of 18- to 24-month-old spontaneously hypertensive rats with signs and symptoms of heart failure (SHR-F) or without evidence of failure (SHR-NF) and of age-matched normotensive Wistar-Kyoto (WKY) rats. Compared with WKY rats, SHR-NF exhibited left ventricular (LV) hypertrophy (2.2-fold) and right ventricular (RV) hypertrophy (1.5-fold), whereas SHR-F were characterized by comparable LV hypertrophy (2.1-fold) and augmented RV hypertrophy (2.4-fold; all P < .01). Total RNA was isolated from ventricles and subjected to Northern blot analysis. In SHR-F hearts, the level of alpha-myosin heavy chain mRNA was decreased in both ventricles to 1/3 and 1/5 of the SHR-NF and WKY values, respectively (both P < .01). Levels of beta-myosin heavy chain, alpha-cardiac actin, and myosin light chain-2 mRNAs were not significantly altered in hearts of SHR-NF or SHR-F. Levels of alpha-skeletal actin were twofold greater in SHR-NF hearts compared with WKY hearts and were intermediate in SHR-F hearts. Levels of atrial natriuretic factor (ANF) mRNA were elevated threefold in the LV of SHR-NF (P < .05) but were not significantly increased in the RV of SHR-NF compared with WKY rats. During the transition to failure (SHR-F versus SHR-NF), ANF mRNA levels increased an additional 1.6-fold in the LV and were elevated 4.7-fold in the RV (both P < .05). Levels of sarcoplasmic reticulum Ca(2+)-ATPase (SRCA) mRNA were maintained in the LV of hypertensive and failing hearts at levels not significantly different from WKY values. In contrast, the level of RV SRCA mRNA was 24% less in SHR-NF compared with WKY rats, and during the transition to failure, this difference was not significantly exacerbated (29% less than the WKY value). The levels of fibronectin and pro-alpha 1(I) and pro-alpha 1(III) collagen mRNAs were not significantly elevated in either ventricle of the SHR-NF group but were fourfold to fivefold higher in both ventricles of SHR-F (all P < .05).(ABSTRACT TRUNCATED AT 400 WORDS)

Erythropoietin (EPO), well known for its role in stimulation of erythropoiesis, has recently been shown to have a dramatic neuroprotective effect in animal models of cerebral ischemia, mechanical trauma of the nervous system, and excitotoxins, mainly by reducing apoptosis. We studied the effect of single systemic administration of recombinant human EPO (rhEPO) on left ventricular (LV) size and function in rats during 8 weeks after the induction of a myocardial infarction (MI) by permanent ligation of the left descending coronary artery. We found that an i.p. injection of 3,000 units/kg of rhEPO immediately after the coronary artery ligation resulted, 24 h later, in a 50% reduction of apoptosis in the myocardial area at risk. Eight weeks after the induction of MI, rats treated with rhEPO had an infarct size 15-25% of the size of that in untreated animals. The reduction in myocardial damage was accompanied by reductions in LV size and functional decline as measured by repeated echocardiography. Thus, a single dose of rhEPO administered around the time of acute, sustained coronary insufficiency merits consideration with respect to its therapeutic potential to limit the extent of resultant MI and contractile dysfunction.

Patients with chronic renal failure develop a “uremic” cardiomyopathy characterized by diastolic dysfunction, cardiac hypertrophy, and systemic oxidant stress. Patients with chronic renal failure are also known to have increases in the circulating concentrations of the cardiotonic steroid marinobufagenin (MBG). On this background, we hypothesized that elevations in circulating MBG may be involved in the cardiomyopathy. First, we observed that administration of MBG (10 μg/kg per day) for 4 weeks caused comparable increases in plasma MBG as partial nephrectomy at 4 weeks. MBG infusion caused increases in conscious blood pressure, cardiac weight, and the time constant for left ventricular relaxation similar to partial nephrectomy. Decreases in the expression of the cardiac sarcoplasmic reticulum ATPase, cardiac fibrosis, and systemic oxidant stress were observed with both MBG infusion and partial nephrectomy. Next, rats were actively immunized against a MBG-BSA conjugate or BSA control, and partial nephrectomy was subsequently performed. Immunization against MBG attenuated the cardiac hypertrophy, impairment of diastolic function, cardiac fibrosis, and systemic oxidant stress seen with partial nephrectomy without a significant effect on conscious blood pressure. These data suggest that the increased concentrations of MBG are important in the cardiac disease and oxidant stress state seen with renal failure.

The prevalence of the metabolic syndrome, a potent risk factor for cardiovascular diseases (CVDs), has not been adequately explored in older individuals. Moreover, two sets of criteria have been proposed for the definition of metabolic syndrome, one by the World Health Organization (WHO) and one by the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATPIII). We therefore investigated the prevalence of this syndrome in a subgroup of older participants from the Cardiovascular Health Study (CHS) who were free of CVD at baseline. We also compared the prognostic significance of the two definitions of the metabolic syndrome.A total of 2,175 subjects from the CHS who were free of CVD at baseline and not taking antihypertensive or lipid-lowering medications were studied. Prevalence of the metabolic syndrome was assessed with both the WHO and ATPIII criteria. The incidence of coronary or cerebrovascular disease was ascertained during a median follow-up time of 4.1 years.Prevalence of the metabolic syndrome was 28.1% by ATPIII criteria and 21.0% by WHO criteria. The two sets of criteria provided concordant classification for 80.6% of participants. Multivariate Cox propotional hazard models showed that the metabolic syndrome defined with the ATPIII criteria, but not with the WHO criteria, was an independent predictor of coronary or cerebrovascular events and was associated with a 38% increased risk (hazard ratio 1.38 [95% CI 1.06-1.79], P < 0.01).Prevalence of the metabolic syndrome in older individuals is approximately 21-28% (depending on the definition used). The two sets of criteria have 80% concordance in classifying subjects. As defined by the ATPIII criteria, the metabolic syndrome yields independent prognostic information, even after adjusting for traditional cardiovascular risk factors and the individual domains of the metabolic syndrome.

Rapid development of transgenic and gene-targeted mice and acute genetic manipulation via gene transfer vector systems have provided powerful tools for cardiovascular research. To facilitate the phenotyping of genetically engineered murine models at the cellular and subcellular levels and to implement acute gene transfer techniques in single mouse cardiomyocytes, we have modified and improved current enzymatic methods to isolate a high yield of high-quality adult mouse myocytes (5.3 +/- 0.5 x 10(5) cells/left ventricle, 83.8 +/- 2.5% rod shaped). We have also developed a technique to culture these isolated myocytes while maintaining their morphological integrity for 2-3 days. The high percentage of viable myocytes after 1 day in culture (72.5 +/- 2.3%) permitted both physiological and biochemical characterization. The major functional aspects of these cells, including excitation-contraction coupling and receptor-mediated signaling, remained intact, but the contraction kinetics were significantly slowed. Furthermore, gene delivery via recombinant adenoviral infection was highly efficient and reproducible. In adult beta(1)/beta(2)-adrenergic receptor (AR) double-knockout mouse myocytes, adenovirus-directed expression of either beta(1)- or beta(2)-AR, which occurred in 100% of cells, rescued the functional response to beta-AR agonist stimulation. These techniques will permit novel experimental settings for cellular genetic physiology.

Local, rhythmic, subsarcolemmal Ca2+ releases (LCRs) from the sarcoplasmic reticulum (SR) during diastolic depolarization in sinoatrial nodal cells (SANC) occur even in the basal state and activate an inward Na(+)-Ca2+ exchanger current that affects spontaneous beating. Why SANC can generate spontaneous LCRs under basal conditions, whereas ventricular cells cannot, has not previously been explained. Here we show that a high basal cAMP level of isolated rabbit SANC and its attendant increase in protein kinase A (PKA)-dependent phosphorylation are obligatory for the occurrence of spontaneous, basal LCRs and for spontaneous beating. Gradations in basal PKA activity, indexed by gradations in phospholamban phosphorylation effected by a specific PKA inhibitory peptide were highly correlated with concomitant gradations in LCR spatiotemporal synchronization and phase, as well as beating rate. Higher levels of basal PKA inhibition abolish LCRs and spontaneous beating ceases. Stimulation of beta-adrenergic receptors extends the range of PKA-dependent control of LCRs and beating rate beyond that in the basal state. The link between SR Ca2+ cycling and beating rate is also present in vivo, as the regulation of beating rate by local beta-adrenergic receptor stimulation of the sinoatrial node in intact dogs is markedly blunted when SR Ca2+ cycling is disrupted by ryanodine. Thus, PKA-dependent phosphorylation of proteins that regulate cell Ca2+ balance and spontaneous SR Ca2+ cycling, ie, phospholamban and L-type Ca2+ channels (and likely others not measured in this study), controls the phase and size of LCRs and the resultant Na(+)-Ca2+ exchanger current and is crucial for both basal and reserve cardiac pacemaker function.

Determination of the calcium spark amplitude distribution is of critical importance for understanding the nature of elementary calcium release events in striated muscle. In the present study we show, on general theoretical grounds, that calcium sparks, as observed in confocal line scan images, should have a nonmodal, monotonic decreasing amplitude distribution, regardless of whether the underlying events are stereotyped. To test this prediction we developed, implemented, and verified an automated computer algorithm for objective detection and measurement of calcium sparks in raw image data. When the sensitivity and reliability of the algorithm were set appropriately, we observed highly left-skewed or monotonic decreasing amplitude distributions in skeletal muscle cells and cardiomyocytes, confirming the theoretical predictions. The previously reported modal or Gaussian distributions of sparks detected by eye must therefore be the result of subjective detection bias against small amplitude events. In addition, we discuss possible situations when a modal distribution might be observed.

Nonenzymatic glycosylation and cross-linking of proteins by glucose contributes to an age-associated increase in vascular and myocardial stiffness. Some recently sythesized thiazolium compounds selectively break these protein cross-links, reducing collagen stiffness. We investigated the effects of 3-phenacyl-4,5-dimethylthiazolium chloride (ALT-711) on arterial and left ventricular (LV) properties and their coupling in old, healthy, nondiabetic Macaca mulatta primates (age 21 +/- 3.6 years). Serial measurements of arterial stiffness indices [i.e., aortic pulse wave velocity (PWV) and augmentation (AGI) of carotid arterial pressure waveform] as well as echocardiographic determinations of LV structure and function were made before and for 39 weeks after 11 intramuscular injections of ALT-711 at 1.0 mg/kg body weight every other day. Heart rate, brachial blood pressure, and body weight were unchanged by the drug. PWV and AGI decreased to a nadir at 6 weeks [PWV to 74.2 +/- 4.4% of baseline (B), P = 0.007; AGI to 41 +/- 7.3% of B, P = 0.046], and thereafter gradually returned to baseline. Concomitant increases in LV end diastolic diameter to 116.7 +/- 2.7% of B, P = 0.02; stroke volume index (SV(index)) to 173.1 +/- 40.1% of B, P = 0.01; and systolic fractional shortening to 180 +/- 29.7% of B, P = 0.01 occurred after drug treatment. The LV end systolic pressure/SV(index), an estimate of total LV vascular load, decreased to 60 +/- 12.1% of B (P = 0.02). The LV end systolic diameter/SV(index), an estimate of arterio-ventricular coupling, was improved (decreased to 54.3 +/- 11% of B, P < 0.002). Thus, in healthy older primates without diabetes, ALT-711 improved both arterial and ventricular function and optimized ventriculo-vascular coupling. This previously unidentified cross-link breaker may be an effective pharmacological therapy to improve impaired cardiovascular function that occurs in the context of heart failure associated with aging, diabetes, or hypertension, conditions in which arterial and ventricular stiffness are increased.

Despite significant improvements in the primary success rate of the medical and surgical treatments for atherosclerotic disease, including angioplasty, bypass grafting, and endarterectomy, secondary failure due to late restenosis continues to occur in 30-50% of individuals. Restenosis and the later stages in atherosclerotic lesions are due to a complex series of fibroproliferative responses to vascular injury involving potent growth-regulatory molecules (such as platelet-derived growth factor and basic fibroblast growth factor) and resulting in vascular smooth muscle cell (VSMC) proliferation, migration, and neointimal accumulation. We show here, based on experiments with both taxol and deuterium oxide, that microtubules are necessary for VSMCs to undergo the multiple transformations contributing to the development of the neointimal fibroproliferative lesion. Taxol was found to interfere both with platelet-derived growth factor-stimulated VSMC migration and with VSMC migration and with VSMC proliferation, at nanomolar levels in vitro. In vivo, taxol prevented medial VSMC proliferation and the neointimal VSMC accumulation in the rat carotid artery after balloon dilatation and endothelial denudation injury. This effect occurred at plasma levels approximately two orders of magnitude lower than that used clinically to treat human malignancy (peak levels achieved in this model were approximately 50-60 nM). Taxol may therefore be of therapeutic value in preventing human restenosis with minimal toxicity.

The migration of vascular smooth muscle cells (VSMCs) from the tunica media to the neointima is a key event in the development and progression of many vascular diseases and a highly predictable consequence of mechanical injury to the blood vessel. In vivo, VSMCs are surrounded by and embedded in a variety of extracellular matrices (ECMs) that must be traversed during migration. One of the principal barriers to cell movement in the intact vessel is the basement membrane (BM) that surrounds each VSMC and separates the VSMC-containing medial cell layer from the endothelium. We have used a Boyden chamber to monitor the ability of VSMCs to degrade a BM barrier as they migrate toward a chemoattractant and to define the role of extracellular proteases in this process. We show that cultured VSMCs can migrate across a BM barrier and that this ability was dependent on the phenotypic state of the cell. VSMCs maintained in a proliferating or "synthetic" state readily migrated across a BM toward a chemoattractant, whereas the migration of serum-starved/differentiated VSMCs was suppressed by &gt; 80% (P &lt; .001). By use of a number of peptides that inhibit matrix metalloproteinase (MMP) activity, the migration of proliferating VSMCs across the BM barrier was inhibited by &gt; 80% (P &lt; .0001), whereas migration that occurred in the absence of the barrier was unaffected. Northern blotting and zymographic analyses indicated that 72-kD type IV collagenase (MMP2) was the principal MMP expressed and secreted by these cells. Accordingly, antisera capable of selectively neutralizing MMP2 activity also inhibited VSMC migration across the barrier without significantly affecting the migration of VSMCs in the absence of the barrier. Finally, MMP2 activity was also regulated by the phenotypic state of the cells in that MMP2 activity expressed by serum-starved/differentiated VSMCs was &lt; 5% of that measured in proliferating VSMCs. Extrapolating to the in vivo situation in which VSMCs reside in an ECM composed of various BM barriers, these results suggest that VSMC migration in vivo may be dependent on MMP2 activity. That activity, in turn, could be regulated by the phenotypic state of VSMCs and increase as these cells undergo the transition from a quiescent and differentiated state to that of a dedifferentiated, proliferating, and motile phenotype after injury to the vessel.

Although a silent ischemic electrocardiographic response to treadmill exercise in clinically healthy populations is associated with an increased likelihood of future coronary events (i.e., angina pectoris, myocardial infarction, or cardiac death), such a response has a low predictive value for future events because of the low prevalence of disease in asymptomatic populations. To examine whether detection of reduced regional perfusion by thallium scintigraphy improved the predictive value of exercise-induced ST segment depression, we performed maximal treadmill exercise electrocardiography (ECG) and thallium scintigraphy (201Tl) in 407 asymptomatic volunteers 40-96 years of age (mean = 60) from the Baltimore Longitudinal Study on Aging. The prevalence of exercise-induced silent ischemia, defined by concordant ST segment depression and a thallium perfusion defect, increased more than sevenfold from 2% in the fifth and sixth decades to 15% in the ninth decade. Over a mean follow-up period of 4.6 years, cardiac events developed in 9.8% of subjects and consisted of 20 cases of new angina pectoris, 13 myocardial infarctions, and seven deaths. Events occurred in 7% of individuals with both negative 201Tl and ECG, 8% of those with either test positive, and 48% of those in whom both tests were positive (p less than 0.001). By proportional hazards analysis, age, hypertension, exercise duration, and a concordant positive ECG and 201Tl result were independent predictors of coronary events. Furthermore, those with positive ECG and 201Tl had a 3.6-fold relative risk for subsequent coronary events, independent of conventional risk factors.(ABSTRACT TRUNCATED AT 250 WORDS)

Nitric oxide (NO) donors were recently shown to produce biphasic contractile effects in cardiac tissue, with augmentation at low NO levels and depression at high NO levels. We examined the subcellular mechanisms involved in the opposing effects of NO on cardiac contraction and investigated whether NO modulates contraction exclusively via guanylyl cyclase (GC) activation or whether some contribution occurs via cGMP/PKG-independent mechanisms, in indo 1-loaded adult cardiac myocytes. Whereas a high concentration of the NO donor S-nitroso-N-acetylpenicillamine (SNAP, 100 micromol/L) significantly attenuated contraction amplitude by 24.4+/-4.5% (without changing the Ca2+ transient or total cAMP), a low concentration of SNAP (1 micromol/L) significantly increased contraction amplitude (38+/-10%), Ca2+ transient (26+/-10%), and cAMP levels (from 6.2 to 8.5 pmol/mg of protein). The negative contractile response of 100 micromol/L SNAP was completely abolished in the presence of the specific blocker of PKG KT 5823 (1 micromol/L); the positive contractile response of 1 micromol/L SNAP persisted, despite the presence of the selective inhibitor of GC 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ, 10 micromol/L) alone, but was completely abolished in the presence of ODQ plus the specific inhibitory cAMP analog Rp-8-CPT-cAMPS (100 micromol/L), as well as by the NO scavenger oxyhemoglobin. Parallel experiments in cell suspensions showed significant increases in adenylyl cyclase (AC) activity at low concentrations (0.1 to 1 micromol/L) of SNAP (AC, 18% to 20% above basal activity). We conclude that NO can regulate both AC and GC in cardiac myocytes. High levels of NO induce large increases in cGMP and a negative inotropic effect mediated by a PKG-dependent reduction in myofilament responsiveness to Ca2+. Low levels of NO increase cAMP, at least in part, by a novel cGMP-independent activation of AC and induce a positive contractile response.

Studies in animal models demonstrate that angiotensin II and its downstream signaling molecules, that is, matrix metalloproteinases and monocyte chemoattractant protein-1, increase within the diffusely thickened intima of central arteries with aging. Whether such age-related changes occur within the human arterial wall is unknown. We harvested "grossly normal thoracic aortas" from 5 young (20+/-3 years) and 5 old white males (65+/-6 years) at necropsy, after death from traumatic causes. The intimae of older samples were markedly and diffusely thickened compared with younger intimae and contained increased levels of angiotensin-converting enzyme, angiotensin II, angiotensin II receptor type 1, matrix metalloproteinases 2/9, monocyte chemoattractant protein-1, and collagen I and III proteins. In situ activities of metalloproteinases 2/9 were also significantly enhanced within old, normal aortas. The thickened intima of older aortas also contained a 5-fold increase in the embryonic form of smooth muscle myosin heavy chain-labeled cells than that of younger aortas, and these fetal-type cells were colocalized with angiotensin II protein staining. The ability of isolated smooth muscle cells to invade an artificial basement membrane in response to a monocyte chemoattractant protein-1 gradient increased with age. Furthermore, angiotensin II increased the invasive capacity of young smooth muscle cells, and this effect was reduced by a metalloproteinase inhibitor or an angiotensin II receptor blocker. Thus, in the absence of lipid infiltration, the aged human aortic wall exhibits a proinflammatory profile that renders it a fertile substrate for the development of arterial disease, for example, atherosclerosis and hypertension.

To study matrix metalloproteinase 2 (MMP-2) effects on transforming growth factor-beta1 (TGF-beta1) activation status and downstream signaling during arterial aging.Western blotting and immunostaining showed that latent and activated TGF-beta1 are markedly increased within the aorta of aged Fisher 344 cross-bred Brown Norway (30 months of age) rats compared with adult (8 months of age) rats. Aortic TGF-beta1-type II receptor (TbetaRII), its downstream molecules p-similar to mad-mother against decapentaplegic (SMAD)2/3 and SMAD4, fibronectin, and collagen also increased with age. Moreover, TGF-beta1 staining is colocalized with that of activated MMP-2 within the aged arterial wall and vascular smooth muscle cell (VSMC) in vitro, and this physical association was confirmed by coimmunoprecipitation. Incubation of young aortic rings ex vivo or VSMCs in vitro with activated MMP-2 enhanced active TGF-beta1, collagen, and fibronectin expression to the level of untreated old counterparts, and this effect was abolished via inhibitors of MMP-2. Interestingly, in old untreated rings or VSMCs, the increased TGF-beta1, fibronectin, and collagen were also substantially reduced by inhibition of MMP-2.Active TGF-beta1, its receptor, and receptor-mediated signaling increase within the aortic wall with aging. TGF-beta1 activation is dependent, in part at least, by a concomitant age-associated increase in MMP-2 activity. Thus, MMP-2-activated TGF-beta1, and subsequently TbetaRII signaling, is a novel molecular mechanism for arterial aging.

Recent studies have added complexities to the conceptual framework of cardiac beta-adrenergic receptor (beta-AR) signal transduction. Whereas the classical linear G(s)-adenylyl cyclase-cAMP-protein kinase A (PKA) signaling cascade has been corroborated for beta(1)-AR stimulation, the beta(2)-AR signaling pathway bifurcates at the very first postreceptor step, the G protein level. In addition to G(s), beta(2)-AR couples to pertussis toxin-sensitive G(i) proteins, G(i2) and G(i3). The coupling of beta(2)-AR to G(i) proteins mediates, to a large extent, the differential actions of the beta-AR subtypes on cardiac Ca(2+) handling, contractility, cAMP accumulation, and PKA-mediated protein phosphorylation. The extent of G(i) coupling in ventricular myocytes appears to be the basis of the substantial species-to-species diversity in beta(2)-AR-mediated cardiac responses. There is an apparent dissociation of beta(2)-AR-induced augmentations of the intracellular Ca(2+) (Ca(i)) transient and contractility from cAMP production and PKA-dependent cytoplasmic protein phosphorylation. This can be largely explained by G(i)-dependent functional compartmentalization of the beta(2)-AR-directed cAMP/PKA signaling to the sarcolemmal microdomain. This compartmentalization allows the common second messenger, cAMP, to perform selective functions during beta-AR subtype stimulation. Emerging evidence also points to distinctly different roles of these beta-AR subtypes in modulating noncontractile cellular processes. These recent findings not only reveal the diversity and specificity of beta-AR and G protein interactions but also provide new insights for understanding the differential regulation and functionality of beta-AR subtypes in healthy and diseased hearts.

Background —Previous studies have shown an association between symptomatic coronary artery disease (CAD) and increased intimal-medial thickness of the common carotid artery (CCA IMT), a purported index of atherosclerosis. This study determines whether CCA IMT is increased in asymptomatic older subjects with an ischemic ST-segment response to treadmill exercise. Methods and Results —CCA IMT was measured by B-mode ultrasound in community-dwelling volunteers from the Baltimore Longitudinal Study of Aging, including 397 healthy subjects (age, 58.5±15.8 years) with normal ECG responses to maximum treadmill exercise, 72 asymptomatic subjects (age, 66.1±13.4 years) with exercise-induced horizontal or downsloping ST-segment depression ≥1 mm, and 38 subjects (age, 77.4±7.8 years) with clinically manifest CAD as diagnosed by medical history and resting ECG. Forty-three subjects with abnormal exercise ECGs also underwent exercise thallium scintigraphy. Exercise-induced ST-segment depression was associated with increased IMT ( P &lt;0.0001) independent of age and manifest CAD. After adjustment for age, IMT values progressively increased from healthy subjects to asymptomatic subjects with positive exercise ECG alone to those with concordant positive ECG and thallium scintigraphic findings who had virtually identical IMT to subjects with manifest CAD. Each 0.1-mm increase in IMT was associated with a 1.91-fold (95% CI, 1.46 to 2.50; P &lt;0.0001) increased risk for concordant positive exercise tests or manifest CAD, independent of other significant predictors of CAD. Conclusions —CCA IMT is increased in older subjects with asymptomatic myocardial ischemia as evidenced by exercise ECG alone or in combination with thallium scan. Carotid ultrasound may help to identify asymptomatic individuals with CAD.

To seek evidence that the nonhuman primate arterial wall, as it ages in the absence of atherosclerosis, exhibits alterations in pathways that are involved in the pathogenesis of experimental atherosclerosis, we assessed aortic matrix metalloproteinase-2 (MMP-2) and its regulators, ie, membrane type-1 of matrix metalloproteinase (MT1-MMP) and tissue inhibitor of matrix metalloproteinase-2 (TIMP-2), and the expression of angiotensin II (Ang II), angiotensin-converting enzyme (ACE), and chymase in young (6.4±0.7 years) and old (20.0±1.9 years) male monkeys. With advancing age, (1) the intimal thickness increased 3-fold and contained numerous vascular smooth muscle cells and matrix, but no inflammatory cells; (2) the intimal MMP-2 antibody–staining fraction increased by 80% ( P &lt;0.01); (3) in situ zymography showed that MMP-2 activity, mainly confined to the intima, increased 3-fold ( P &lt;0.01); (4) the MT1-MMP antibody–staining fraction increased by 150% ( P &lt;0.001), but the TIMP-2 antibody–staining fraction did not significantly change; (5) steady levels of the mRNA-staining fraction (via in situ hybridization) for MMP-2 increased 7-fold, for MT1-MMP increased 9-fold, and for TIMP-2 increased 2-fold (all P &lt;0.001); and (6) intimal Ang II and ACE immunofluorescence were increased 5-fold and 5.6-fold, respectively, and colocalized with MMP-2. Thus, age-associated arterial remodeling and the development and progression of experimental atherosclerosis in young animals share common mechanisms, ie, MMP-2 activation and increased Ang II signaling. This might explain, in part, the dramatically exaggerated prevalence and severity of vascular diseases with aging.

The effects of beta 2- and beta 1-adrenoceptor (beta 2AR and beta 1AR, respectively) agonists on the cytosolic Ca2+ (Cai) transient (indexed by the transient increase in indo-1 fluorescence ratio after excitation), twitch amplitude (measured via photodiode array), membrane potential, and L-type sarcolemmal Ca2+ current (ICa, measured by whole-cell patch electrode) were assessed in single rat ventricular myocytes. The selective beta 2AR agonist Zinterol increased the amplitudes of both the Cai transient and twitch in a concentration-dependent manner. Similar results were obtained when beta 2ARs were stimulated with isoproterenol in the presence of the selective beta 1AR antagonist CGP 20712A. beta 1AR stimulation induced by norepinephrine increased twitch amplitude to about the same extent as did beta 2AR stimulation. However, several striking differences between response to beta 1AR and beta 2AR stimulation were observed. beta 1AR stimulation had the potent effect of abbreviating the time course of the contraction and Cai transient, and beta 2AR stimulation did not reduce the time course of the Cai transient and had only a minor effect on the twitch duration. For a given increase in twitch amplitude, beta 1AR stimulation caused a greater increase in Cai transient, suggesting a diminished Cai-myofilament interaction. beta 1AR, but not beta 2AR, stimulation evoked spontaneous Cai oscillations, increased the diastolic indo fluorescence level, and caused a decline in resting cell length. beta 1AR and beta 2AR also differed in their effects on ICa. Whereas both beta 1AR and beta 2AR stimulation increased the peak ICa amplitude, beta 2AR stimulation markedly prolonged the ICa inactivation time. Accordingly, beta 2AR stimulation prolonged the action potential duration to a greater extent than did beta 1AR stimulation. 8-(4-Chlorophenylthio)cAMP mimicked the effects of beta 1AR stimulation by norepinephrine but not those due to beta 2AR stimulation. These results clearly indicate that both beta 2ARs and beta 1ARs functionally coexist in rat ventricular myocytes but that stimulation of these receptor subtypes elicits qualitatively different cell responses at the levels of ionic channels, the myofilaments, and sarcoplasmic reticulum.

The transition from compensated hypertrophy to failure in spontaneously hypertensive rats (SHR) of advanced age is associated with a marked increase in collagen, a reduction in myocyte mass, and a reduction in maximum Ca(2+)-activated myofibrillar force. We hypothesized that the reduction in myocyte mass and associated functional loss may be due to increased cell death by apoptosis. To test this hypothesis, we studied hearts from failing (SHR-F) and nonfailing SHR (SHR-NF) and age-matched Wistar-Kyoto rats (WKY). In addition, hearts from SHR-F that had been treated with an angiotensin-converting enzyme inhibitor (captopril) for an average of 27 days were also studied. Apoptotic cells were quantified in cross sections of myocardium by the terminal deoxynucleotidyltransferase- mediated 2'-deoxyuridine 5'-triphosphate nick end labeling technique. To identify the type of the cells undergoing apoptosis, sections were also stained for alpha-sarcomeric actin. Apoptotic cells were significantly increased in the SHR-F (38.92 +/- 12.79 vs. 8.05 +/- 3.98 cells/100,000 nuclei in SHR-NF; P &lt; 0.05 and vs. 2.21 +/- 1.4 cells/100,000 nuclei in WKY; P &lt; 0.01). Captopril treatment of SHR-F reduced the number of apoptotic cells to the level in SHR-NF (9.17 +/- 1.53 cells/100,000 nuclei; P &lt; 0.01 vs. SHR-F). Most apoptotic cells were of cardiac myocyte origin. There was no significant difference in Bcl-2 protein expressed by hearts among the three groups. WAF-1 mRNA levels were increased in both SHR groups vs. WKY; in SHR-F, the density of WAF-1 mRNA was higher than in SHR-NF. Thus increased numbers of apoptotic cells are present in failing SHR hearts, suggesting that apoptosis might be a mechanism involved in the reduction of myocyte mass that accompanies the transition from stable compensation to heart failure in this model. Administration of the angiotensin-converting enzyme inhibitor captopril, which ameliorates heart failure in this model, is associated with a reduction in the exaggerated apoptosis that accompanies heart failure.

Age-related changes in cardiovascular function and structure in healthy adult volunteer community dwelling subjects (from 20 to 85 years) is remarkable for changes in pump function [impaired left ventricular (LV) ejection reserve capacity manifest by a reduced ejection fraction and accompanied by diminished cardioacceleration, LV dilation at end diastole and an altered diastolic filling pattern] and increased vascular afterloading. There is also evidence for a reduction in the number of cardiac myocytes with advancing age. Subcellular changes with aging (best understood in rodents) include certain regulatory factors of excitation-contraction-relaxation coupling (i.e. calcium handling), modulation by adrenergic receptor (AR) stimulation, and changes in the generation and sensitivity to the damaging effects of ROS. Coordinated changes in gene expression and/or protein function with aging result in a prolonged action potential (AP), Ca(i) transient, and contraction. L-type Ca(2+) current (I(Ca)) inactivates more slowly, and outwardly-directed K(+) currents are reduced, and likely contribute to AP-prolongation. The rate of Ca(2+) sequestration by the sarcoplasmic reticulum (SR) decreases in the senescent myocardium, in part underlying the prolonged Ca(i) transient. An age-associated reduction in transcription of the SERCA2 gene, coding for the SR Ca(2+) pump, accounts in part for a decrease in the SR pump site density. The contractile response to both beta(1)-AR and beta(2)-AR stimulation diminishes with aging due to decreased adrenergic augmentation of I(Ca), and thus the Ca(i) transient, in senescent vs. young hearts. The age-associated reduction in the postsynaptic response of myocardial cells to beta(1)-AR stimulation appears to be due to multiple changes in molecular and biochemical receptor coupling and post-receptor mechanisms. An increased basal production of ROS is paralleled by increased ROS-sensitivity, markers of chronic ROS damage and mitochondrial functional decline. Overall, these changes lead to a diminished (but not necessarily exhausted) capacity of the heart to adapt to physiological or pathological stress with advancing age.

β₁- and β₂-adrenergic receptors (β₁AR and β₂AR) are co-expressed in numerous tissues where they play a central role in the responses of various organs to sympathetic stimulation. Although the two receptor subtypes share some signaling pathways, each has been shown to have specific signaling and regulatory properties. Given the recent recognition that many G protein-coupled receptors can form homo- and heterodimers, the present study was undertaken to determine whether the β₁AR and β₂AR can form dimers in cells and, if so, to investigate the potential functional consequences of such heterodimerization. Using co-immunoprecipitation and bioluminescence resonance energy transfer, we show that β₁AR and β₂AR can form heterodimers in HEK 293 cells co-expressing the two receptors. Functionally, β-adrenergic stimulated adenylyl cyclase activity was found to be identical in cells expressing β₁AR, β₂AR, or both receptors at similar levels, indicating that heterodimerization did not affect this signaling pathway. When considering ERK1/2 MAPK activity, a significant agonist-promoted activation was detected in β₂AR- but not β₁AR-expressing cells. Similarly to what was observed in cells expressing the β₁AR alone, no β-adrenergic stimulated ERK1/2 phosphorylation was observed in cells co-expressing the two receptors. A similar inhibition of agonist-promoted internalization of the β₂AR was observed upon co-expression of the β₁AR, which by itself internalized to a lesser extent. Taken together, our data suggest that heterodimerization between β₁AR and β₂AR inhibits the agonist-promoted internalization of the β₂AR and its ability to activate the ERK1/2 MAPK signaling pathway.

Background— Intermittent fasting (IF), a dietary regimen in which food is available only every other day, increases the life span and reduces the incidence of age-associated diseases in rodents. We have reported neuroprotective effects of IF against ischemic injury of the brain. In this study, we examined the effects of IF on ischemic injury of the heart in rats. Methods and Results— After 3 months of IF or regular every-day feeding (control) diets started in 2-month-old rats, myocardial infarction (MI) was induced by coronary artery ligation. Twenty-four hours after MI, its size in the IF group was 2-fold smaller, the number of apoptotic myocytes in the area at risk was 4-fold less, and the inflammatory response was significantly reduced compared with the control diet group. Serial echocardiography revealed that during 10 weeks after MI (with continuation of the IF regimen), the left ventricular (LV) remodeling and MI expansion that were observed in the control diet group were absent in the IF group. In a subgroup of animals with similar MI size at 1 week after MI, further observation revealed less remodeling, better LV function, and no MI expansion in the IF group compared with the control group. Conclusions— IF protects the heart from ischemic injury and attenuates post-MI cardiac remodeling, likely via antiapoptotic and antiinflammatory mechanisms.

While an age-associated diminution in myocardial contractile response to beta-adrenergic receptor (beta-AR) stimulation has been widely demonstrated to occur in the context of increased levels of plasma catecholamines, some critical mechanisms that govern beta-AR signaling must still be examined in aged hearts. Specifically, the contribution of beta-AR subtypes (beta1 versus beta2) to the overall reduction in contractile response with aging is unknown. Additionally, whether G protein-coupled receptor kinases (GRKs), which mediate receptor desensitization, or adenylyl cyclase inhibitory G proteins (Gi) are increased with aging has not been examined. Both these inhibitory mechanisms are upregulated in chronic heart failure, a condition also associated with diminished beta-AR responsiveness and increased circulatory catecholamines. In this study, the contractile responses to both beta1-AR and beta2-AR stimulation were examined in rat ventricular myocytes of a broad age range (2, 8, and 24 mo). A marked age-associated depression in contractile response to both beta-AR subtype stimulation was observed. This was associated with a nonselective reduction in the density of both beta-AR subtypes and a reduction in membrane adenylyl cyclase response to both beta-AR subtype agonists, NaF or forskolin. However, the age-associated diminutions in contractile responses to either beta1-AR or beta2-AR stimulation were not rescued by inhibiting Gi with pertussis toxin treatment. Further, the abundance or activity of beta-adrenergic receptor kinase, GRK5, or Gi did not significantly change with aging. Thus, we conclude that the positive inotropic effects of both beta1- and beta2-AR stimulation are markedly decreased with aging in rat ventricular myocytes and this is accompanied by decreases in both beta-AR subtype densities and a reduction in membrane adenylate cyclase activity. Neither GRKs nor Gi proteins appear to contribute to the age-associated reduction in cardiac beta-AR responsiveness.

Fluctuations in body weight as occur with aging make body weight an unreliable reference for normalizing heart weight. We compared heart weight normalized by tibial length, which remains constant after maturity, with that normalized by body weight in 5- to 28-mo-old male Wistar rats. When normalized by tibial length or body weight, relative to the 5-mo heart, the senescent left ventricle undergoes 17 vs. 38% hypertrophy, respectively, and the right ventricle undergoes 0 vs. 28% hypertrophy, respectively. Histological measurements in the 25- compared with the 5-mo-old left ventricles reveal 6% larger myocyte diameters and 12% larger cellular cross-sectional areas, indicating about 15% hypertrophy; this value agrees more closely with the estimates based on tibial length than with those based on body weight. To allow prediction of left ventricular weight in a living rat, a regression equation using body weight, age, and tibial length was derived. This enabled us to perform a longitudinal aging study that verified that the above results were not biased by selective survival. Thus, in conditions in which body weight changes, cardiac hypertrophy can be more accurately quantified by relating heart weight to tibial length than to body weight. This approach may have applicability for assessing relative sizes of other organs as well.

A technique that allows the continuous measurement of mitochondrial free Ca2+ ([Ca2+]m) in a single living cardiac myocyte is described. It involves the introduction of the fluorescent chelating agent indo-1 into the cell by exposure to the acetoxymethyl ester, followed by selective quenching of the fluorescence of indo-1 in the cytosol by Mn2+. The identity of the remaining fluorescence due to intramitochondrial indo-1 is established by its resistance to treatment of the cell with digitonin at concentrations that release cytosolic but not mitochondrial enzymes and by the finding that ruthenium red and carbonyl cyanide p-trifluoromethoxyphenylhydrazone prevent its response to elevated cytosolic free Ca2+ ([Ca2+]c). [Ca2+]m is found to be low (less than 100 nM) in unstimulated cells and to rise in procedures that chronically elevate [Ca2+]c, such as Na+ replacement. The gradient [Ca2+]m/[Ca2+]c is less than unity at values of [Ca2+]c of less than 500 nM but rapidly increases at higher values of [Ca2+]c. Although there is no detectable increase in [Ca2+]m during a single electrical stimulation, [Ca2+]m increases up to 600 nM as the pacing frequency is raised to 4 Hz in the presence of norepinephrine; this increase occurs over the course of many contractions. It is concluded that these findings are consistent with an increase in [Ca2+]m acting as a signal to increase dehydrogenase activity, and hence flux through oxidative phosphorylation, in response to increased work loads.

Although plasma norepinephrine (NE) increases with age in response to a variety of submaximal adrenergic stimuli, the effect of age on plasma catecholamine levels during maximal aerobic effort and during submaximal work at a fixed percent of peak O2 consumption (VO2) is unknown. We therefore measured NE, epinephrine (E), and VO2 at rest and during graded maximal treadmill exercise in 24 healthy male volunteers (ages 22-77 yr) from the Baltimore Longitudinal Study of Aging who were rigorously screened to exclude the presence of cardiovascular disease. At rest neither heart rate (HR) nor VO2 were age related. Resting NE (pg/ml) was not age related, but resting E (pg/ml) was higher in male subjects 68-77 yr old (group III) than in those aged 22-37 (group I) or 44-55 yr (group II), P less than 0.01. Maximal HR (beats/min) showed a strong inverse relationship to age (203.5 - 0.65 age, r = -0.80, P less than 0.001). Peak VO2 in milliliters per kilogram total body weight per minute decreased with age (47.7 - 0.23 age, r = -0.71, P less than 0.001). At maximal effort both NE (P less than 0.01) and E (P less than 0.05) were higher in group III than in either of the younger groups. At submaximal work levels NE and E also increased with age, and when normalized for relative effort at loads between 45 and 80% of peak VO2 both NE and E were higher in the group III male subjects, although statistical significance was reached for NE (P less than 0.01) but not for E (P = 0.09).(ABSTRACT TRUNCATED AT 250 WORDS)

Kinetic measurements of Ca+2 uptake in microsomal fractions from rat myocardium demonstrated significantly lower rates of oxalate-facilitated accumulation in preparations from aged (24 to 25 month) hearts as compared to those from young adult (6 to 8 month) hearts. The per cent decline in transport activity in microsomes from aged hearts varied with Ca2+ concentration decreasing from 57% at 0.33 μm Ca2+ to 24% at 1.21 μm Ca2+. Double-reciprocal plots of the dependence of the velocity of accumulation on Ca2+ concentration showed upward curvature in both age groups indicating the presence of multiple Ca2+ binding sites. Mechanical studies using muscles isolated from the same hearts used to prepare sarcoplasmic reticulum demonstrated prolonged contraction duration in aged myocardium in agreement with previous findings. The lower in vitro rates of Ca2+ accumulation in aged microsomes suggest a possible biochemical mechanism to account for the observed increase in the time-course of cardiac relaxation.

Isometric performance at 29degreesC was measured in left ventricular trabeculae carneae from young adult (6-mo) and aged (25-mo) rats (n equals 18 in each group). Active tension and maximal rate of tension development did not differ with age, but contraction duration was 255plus or minus6 ms in the young adult and 283plus or minus6 ms in the aged group (P less than0.001). Although catecholamine content per gram heart weight was less in the aged myocardium, additional experiments showed that neither 1 times 10-6 M propranolol nor pretreatment with 6-hydroxydopamine eliminated the age difference in contraction duration. To determine if this age difference resulted from a prolonged active state, electromechanical dissociation and the overshoot of contraction duration during recovery from hypoxia were measured. During paired stimulation greater mechanical refractoriness was found in aged muscles (P less than0.01), but intracellular action potential recordings showed no age difference in the electrical refractory period. On recovery from hypoxia, contraction duration overshoot was 117plus or minus 4percent of control in the young and 138plus or minus 4percent of control in the aged muscles (P less than0.01). The greater electromechanical dissociation and greater overshoot in contraction duration following hypoxia in aged myocardium suggests that prolonged contraction duration in aged myocardium results from a prolonged active state rather than changes in passive properties or myocardial catecholamine content.

Arterial stiffness has been associated with aging, hypertension, and diabetes; however, little data has been published examining risk factors associated with arterial stiffness in elderly individuals.Longitudinal associations were made between aortic stiffness and risk factors measured approximately 4 years earlier. Aortic pulse wave velocity (PWV), an established index of arterial stiffness, was measured in 356 participants (53.4% women, 25.3% African American), aged 70 to 96 years, from the Pittsburgh site of the Cardiovascular Health Study during 1996 to 1998.Mean aortic pulse wave velocity (850 cm/sec, range 365 to 1863) did not differ by ethnicity or sex. Increased aortic stiffness was positively associated with higher systolic blood pressure (SBP), age, fasting and 2-h postload glucose, fasting and 2-h insulin, triglycerides, waist circumference, body mass index, truncal fat, decreased physical activity, heart rate, and common carotid artery wall thickness (P < .05). After controlling for age and SBP, the strongest predictors of aortic stiffness in men were heart rate (P = .001) and 2-h glucose (P = .063). In women, PWV was positively associated with heart rate (P = .018), use of antihypertensive medication (P = .035), waist circumference (P = .030), and triglycerides (P = .081), and was negatively associated with physical activity (P = .111). Results were similar when the analysis was repeated in nondiabetic individuals and in those free of clinical or subclinical cardiovascular disease in 1992 to 1993.In these elderly participants, aortic stiffness was positively associated with risk factors associated with the insulin resistance syndrome, increased common carotid intima-media thickness, heart rate, and decreased physical activity measured several years earlier.

Cycling as a mode of travel provides an opportunity for many people to increase their levels of regular physical activity and contribute to their mental and physical health. Heart rate is often used as a means of measuring the intensity and energy expenditure of physical activity. However, heart rate is also linked to emotional factors such as anxiety and fear. Perceptions of risk due to external factors such as other road users and infrastructure may arouse such emotions in urban cyclists. The present study set out to investigate whether or not perceptions of risk among urban cyclists may lead to increased heart rates. Cyclists completed a test route in normal traffic conditions in Cork, Ireland and heart rates and self-reported risk ratings were recorded in real time. Evidence was found of a link between perceptions of risk and heart rates. This raises questions regarding the use of heart rate to estimate exercise intensity and energy expenditure during urban cycling. The perceptions of cyclists of their safety in relation to various road elements on familiar routes were also assessed, as well as specific events which they perceive to be high in risk. The results indicate that incidents involving car traffic and busy roads which offer no protection from interaction with car traffic are associated with greatest perceptions of risk.

Recent experimental studies have demonstrated that sinoatrial node cells (SANC) generate spontaneous, rhythmic, local subsarcolemmal Ca 2+ releases (Ca 2+ clock), which occur during late diastolic depolarization (DD) and interact with the classic sarcolemmal voltage oscillator (membrane clock) by activating Na + -Ca 2+ exchanger current ( I NCX ). This and other interactions between clocks, however, are not captured by existing essentially membrane-delimited cardiac pacemaker cell numerical models. Using wide-scale parametric analysis of classic formulations of membrane clock and Ca 2+ cycling, we have constructed and initially explored a prototype rabbit SANC model featuring both clocks. Our coupled oscillator system exhibits greater robustness and flexibility than membrane clock operating alone. Rhythmic spontaneous Ca 2+ releases of sarcoplasmic reticulum (SR)-based Ca 2+ clock ignite rhythmic action potentials via late DD I NCX over much broader ranges of membrane clock parameters [e.g., L-type Ca 2+ current ( I CaL ) and/or hyperpolarization-activated (“funny”) current ( I f ) conductances]. The system Ca 2+ clock includes SR and sarcolemmal Ca 2+ fluxes, which optimize cell Ca 2+ balance to increase amplitudes of both SR Ca 2+ release and late DD I NCX as SR Ca 2+ pumping rate increases, resulting in a broad pacemaker rate modulation (1.8–4.6 Hz). In contrast, the rate modulation range via membrane clock parameters is substantially smaller when Ca 2+ clock is unchanged or lacking. When Ca 2+ clock is disabled, the system parametric space for fail-safe SANC operation considerably shrinks: without rhythmic late DD I NCX ignition signals membrane clock substantially slows, becomes dysrhythmic, or halts. In conclusion, the Ca 2+ clock is a new critical dimension in SANC function. A synergism of the coupled function of Ca 2+ and membrane clocks confers fail-safe SANC operation at greatly varying rates.

Calcium entry through voltage-gated Ca2+ channels is critical in cardiac excitation-contraction coupling and calcium metabolism. In this report, we demonstrate both spatially resolved and temporally distinct effects of Ca2+/calmodulin-dependent protein kinase II (CaMKII) on L-type Ca2+ channel current (ICa) in rat cardiac myocytes. Either depolarization alone or calcium influx can increase the amplitude and slow the inactivation of ICa. The distinct voltage- and Ca(2+)-dependent effects persist with time constants of approximately 1.7 sec and 9 sec, respectively. Both effects are completely abolished by a specific peptide inhibitor of CaMKII. This CaMKII inhibitor also suppresses the prolongation of ICa induced by depolarizing holding potentials. Furthermore, using an antibody specific for the autophosphorylated (activated) CaMKII, we find that this kinase is localized close to sarcolemmal membranes and that the profile of CaMKII activation correlates qualitatively with the changes in ICa under various conditions. Therefore, we conclude that the action of CaMKII on ICa is dually regulated by membrane depolarization and by Ca2+ influx; the latter directly activates CaMKII, whereas the former likely promotes the interaction between constitutive CaMKII and the membrane-channel proteins. These regulatory mechanisms provide positive-feedback control of Ca2+ channels and are probably important in the regulation of cardiac contractility and other intracellular Ca(2+)-regulated processes.

To assess the efficacy of digitalis in patients with chronic clinically compensated congestive heart failure and normal sinus rhythm, we performed a double-blind crossover study with digoxin and placebo in 30 consecutive outpatients fulfilling these criteria; serum digoxin levels, clinical symptoms and signs, and objective indexes of cardiac function were monitored. No patient's clinical condition deteriorated during three months of placebo administration. Discontinuation of digoxin resulted in a small increase in echocardiographically determined resting left ventricular end-diastolic dimension (1.8 +/- 0.6 mm, p less than 0.001) and a similar decrease in velocity of circumferential fiber shortening (-0.08 +/- 0.04 circ/sec, p less than 0.05) from the corresponding values of 55.8 +/- 2.3 mm and 0.90 +/- 0.08 circ/sec during digitalis therapy. Resting left ventricular ejection time and pre-ejection period were prolonged by digoxin withdrawal. Maximal exercise capacity was unchanged. No clinical exacerbation of heart failure attributable to digitalis withdrawal occurred over a follow-up period averaging 19 months. The results indicate that long-term digoxin therapy has only a minor effect on cardiac performance that is without apparent clinical importance in a representative population of ambulatory patients treated with cardiac glycosides.

Studies have shown that the rise in intracellular ionized calcium, [Ca2+]i, in hypoxic myocardium is driven by an increase in sodium, [Na+]i, but the source of Na+ is not known.Inhibitors of the voltage-gated Na+ channel were used to investigate the effect of Na+ channel blockade on hypoxic Na+ loading, Na(+)-dependent Ca2+ loading, and reoxygenation hypercontracture in isolated adult rat cardiac myocytes. Single electrically stimulated (0.2 Hz) cells were loaded with either SBFI (to index [Na+]i) or indo-1 (to index [Ca2+]i) and exposed to glucose-free hypoxia (PO2 < 0.02 mm Hg). Both [Na+]i and [Ca2+]i increased during hypoxia when cells became inexcitable following ATP-depletion contracture. The hypoxic rise in [Na+]i and [Ca2+]i was significantly attenuated by 1 mumol/L R 56865. Tetrodotoxin (60 mumol/L), a selective Na(+)-channel blocker, also markedly reduced the rise in [Ca2+]i during hypoxia and reoxygenation. Reoxygenation-induced cellular hypercontracture was reduced from 83% (45 of 54 cells) under control conditions to 12% (4 of 32) in the presence of R 56865 (P < .05). Lidocaine reduced hypercontracture dose dependently with 13% of cells hypercontracting in 100 mumol/L lidocaine, 42% in 50 mumol/L lidocaine, and 93% in 25 mumol/L lidocaine. The Na(+)-H+ exchange blocker, ethylisopropylamiloride (10 mumol/L) was also effective, limiting hypercontracture to 12%. R 56865, lidocaine, and ethylisopropylamiloride were also effective in preventing hypercontracture in normoxic myocytes induced by 75 mumol/L veratridine, an agent that impairs Na+ channel inactivation. Ethylisopropylamiloride prevented the veratridine-induced rise in [Ca2+]i without affecting Na(+)-Ca2+ exchange, suggesting that amiloride derivatives can reduce Ca2+ loading by blocking Na+ entry through Na+ channels, an action that may in part underlie their ability to prevent hypoxic Na+ and Ca2+ loading.Na+ influx through the voltage-gated Na+ channel is an important route of hypoxic Na+ loading, Na(+)-dependent Ca2+ loading, and reoxygenation hypercontracture in isolated rat cardiac myocytes. Importantly, the Na+ channel appears to serve as a route for hypoxic Na+ influx after myocytes become inexcitable.

It has long been recognized that activation of sympathetic β-adrenoceptors (β-ARs) increases the spontaneous beating rate of sinoatrial nodal cells (SANCs); however, the specific links between stimulation of β-ARs and the resultant increase in firing rate remain an enigma. In the present study, we show that the positive chronotropic effect of β-AR stimulation is critically dependent on localized subsarcolemmal ryanodine receptor (RyR) Ca 2+ releases during diastolic depolarization (CRDD). Specifically, isoproterenol (ISO; 0.1 μmol/L) induces a 3-fold increase in the number of CRDDs per cycle; a shift to higher CRDD amplitudes (from 2.00±0.04 to 2.17±0.03 F/F 0 ; P &lt;0.05 [F and F 0 refer to peak and minimal fluorescence]); and an increase in spatial width (from 3.80±0.44 to 5.45±0.47 μm; P &lt;0.05). The net effect results in an augmentation of the amplitude of the local preaction potential subsarcolemmal Ca 2+ transient that, in turn, accelerates the diastolic depolarization rate, leading to an increase in SANC firing rate. When RyRs are disabled by ryanodine, β-AR stimulation fails to amplify subsarcolemmal Ca 2+ releases, fails to augment the diastolic depolarization rate, and fails to increase the SANC firing rate, despite preserved β-AR stimulation-induced augmentation of L-type Ca 2+ current amplitude. Thus, the RyR Ca 2+ release acts as a switchboard to link β-AR stimulation to an increase in SANC firing rate: recruitment of additional localized CRDDs and partial synchronization of their occurrence by β-AR stimulation lead to an increase in the heart rate.

Little is known concerning the molecular mechanisms responsible for changes in sarcoplasmic reticulum (SR) function during ontogenic development and aging except that the amount of SR Ca(2+)-ATPase mRNA varies in these conditions. The aim of the present work was to determine whether SR maturation requires expression of specific isoforms and synchronous accumulation of mRNAs encoding proteins located in SR. Thus, we have studied expression of SR Ca(2+)-ATPase and calsequestrin genes in the rat at different developmental stages from 14 fetal days to 24 months of age. Analysis of alternative splicing of the major Ca(2+)-ATPase gene expressed in heart by nuclease S1 mapping led us to conclude that the Ca(2+)-ATPase gene expressed in heart was not differentially spliced during ontogenic development and senescence. A single calsequestrin mRNA isoform was also detected in rat heart whatever the developmental stage. The amount of specific mRNA was then measured by dot blot and normalized to 18S ribosomal RNA or to myosin heavy chain mRNA. The amount of Ca(2+)-ATPase mRNA relative to 18S RNA increases substantially at the end of fetal life and in the early postnatal period (9.5 +/- 0.5% in the 14-15 day fetus versus 99 +/- 7% in the 4-day-old rat). A stable high level is observed during adulthood. In aged rats (24 months), Ca(2+)-ATPase mRNA represents only 44.6% the amount observed in young adults (1-2 months).(ABSTRACT TRUNCATED AT 250 WORDS)

-To characterize remodeling of elastic arteries with aging and to investigate its potential mechanisms, matrix metalloproteinase-2 (MMP-2), intracellular adhesive molecule-1 (ICAM-1), transforming growth factor-beta (TGF-beta), and fibronectin protein levels were measured in the aortas of young adult (6 months) and aged (30 months) Fischer 344XBN rats. At 30 versus 6 months, the thickness of the intima was 5-fold greater and contained marked increases in TGF-beta and ICAM-1, and fibronectin expression was enhanced throughout the aortic wall. Total MMP-2 protein (Western blot) of 30-month-old rats was increased 8-fold over that of 6-month-old rats (0.166+/-0.032 versus 0.020+/-0.006; P<0.01), and staining and activity were regionally localized to the intima, often near breaks in the internal elastic membrane and lamellae. Early passage, explanted smooth muscle cells (SMC) from aged aorta secreted more MMP-2 than those from young aorta; while basal MMP-2 production did not differ with age, after stimulation with cytokines (interleukin-1, tumor necrosis factor-alpha, or TGF-beta, 10 ng/mL each for 24 hours), MMP-2 production in SMC from 30-month-old rats increased to levels greater than those in 6-month-old rats. Thus, enhanced expression of TGF-beta, MMP-2, and ICAM-1 in the thickened vascular intima of aged rats may in part be produced by exaggerated SMC responses to cytokines and may have potential roles in intimal remodeling with aging.

The structure and function of arteries change throughout a lifetime. Age is the dominant risk factor for hypertension, coronary heart disease, congestive heart failure, and stroke. The cellular/molecular proinflammatory alterations that underlie arterial aging are novel putative candidates to be targeted by interventions aimed at attenuating arterial aging as a major risk factor for cardiovascular diseases. This review provides a landscape of central arterial aging and age-disease interactions, integrating perspectives that range from humans to molecules, with the goal that future therapies for cardiovascular diseases, such as hypertension, also will target the prevention or amelioration of unsuccessful arterial aging.

Increased arterial stiffness is an independent predictor of cardiovascular disease independent from blood pressure. Recent studies have shed new light on the importance of inflammation on the pathogenesis of arterial stiffness. Arterial stiffness is associated with the increased activity of angiotensin II, which results in increased NADPH oxidase activity, reduced NO bioavailability and increased production of reactive oxygen species. Angiotensin II signaling activates matrix metalloproteinases (MMPs) which degrade TGFβ precursors to produce active TGFβ, which then results in increased arterial fibrosis. Angiotensin II signaling also activates cytokines, including monocyte chemoattractant protein-1, TNF-α, interleukin-1, interleukin-17 and interleukin- 6. There is also ample clinical evidence that demonstrates the association of inflammation with increased arterial stiffness. Recent studies have shown that reductions in inflammation can reduce arterial stiffness. In patients with rheumatoid arthritis, increased aortic pulse wave velocity in patients was significantly reduced by anti tumor necrosis factor-α therapy. Among the major classes of anti hypertensive drugs, drugs that block the activation of the RAS system may be more effective in reducing the progression of arterial stiffness. Thus, there is rationale for targeting specific inflammatory pathways involved in arterial stiffness in the development of future drugs. Understanding the role of inflammation in the pathogenesis of arterial stiffness is important to understanding the complex puzzle that is the pathophysiology of arterial stiffening and may be important for future development of novel treatments.

Aging promotes oxidative stress in vascular endothelial and smooth muscle cells, which contribute to the development of cardiovascular diseases. NF-E2–related factor 2 (Nrf2) is a transcription factor, which is activated by reactive oxygen species in the vasculature of young animals, leading to adaptive upregulation of numerous reactive oxygen species detoxifying and antioxidant genes. The present study was designed to elucidate age-associated changes in the homeostatic role of Nrf2-driven free radical detoxification mechanisms in the vasculature of nonhuman primates. We found that carotid arteries of aged rhesus macaques (Macaca mulatta, age: ≥20 years) exhibit significant oxidative stress (as indicated by the increased 8-iso-PGF2α and 4-HNE content and decreased glutathione and ascorbate levels) as compared with vessels of young macaques (age: ∼10 years) that is associated with activation of the redox-sensitive proinflammatory transcription factor, nuclear factor-kappaB. However, age-related oxidative stress does not activate Nrf2 and does not induce Nrf2 target genes (NQO1, GCLC, and HMOX1). In cultured vascular smooth muscle cells (VSMCs) derived from young M mulatta, treatment with H2O2 and high glucose significantly increases transcriptional activity of Nrf2 and upregulates the expression of Nrf2 target genes. In contrast, in cultured vascular smooth muscle cells cells derived from aged macaques, H2O2– and high glucose–induced Nrf2 activity and Nrf2-driven gene expression are blunted. High glucose–induced H2O2 production was significantly increased in aged vascular smooth muscle cells compared with that in vascular smooth muscle cells from young M mulatta. Taken together, aging is associated with Nrf2 dysfunction in M mulatta arteries, which likely exacerbates age-related cellular oxidative stress, promoting nuclear factor-kappaB activation and vascular inflammation in aging.

Monophasic action potential (MAP) recording with non-suction, 'contact' electrode catheters has been shown possible and safe during clinical catheterization, but direct validation of this new technique is lacking. We therefore recorded these contact electrode MAPs simultaneously with transmembrane action potentials (TAPs) from closely adjacent sites in perfused and superfused rabbit septum preparations and performed a quantitative comparison between the two signals for duration and area at 30, 60 and 90% repolarization. To obtain a variety of action potential durations and configurations for the comparison, the rate and rhythm of stimulation and the extracellular calcium or potassium ion concentration were changed. With action potential duration at 90% repolarization made to vary from 150 to 513 ms, the mean absolute difference +/- SD between the simultaneous intra- and extracellular recordings was 5.4 +/- 11.3 ms and the linear correlation coefficient was r = 0.96 +/- 0.03. Similar agreement between the two types of recordings was found for measurements for area and at 60 and 30% repolarization levels. These data confirm that MAPs recorded with this clinically safe contact electrode technique can be used to measure accurately the repolarization time course of transmembrane action potentials.

The goal of this study was to examine the age-associated differences in ventricular-vascular coupling, defined by the ratio of arterial elastance (EaI) to left ventricular systolic elastance (ELVI), and its components, at rest and during exercise. Ejection fraction (EF) increases during exercise, but the EF reserve decreases with aging. Ejection fraction is inversely related to EaI/ELVI, an index of the interaction between arterial and ventricular properties, which is an important determinant of cardiac performance. Thus, age differences in EaI/ELVI during exercise, due to age differences in EaI, ELVI, or both, may help to explain the age deficit in EF reserve. We noninvasively characterized EaI/ELVI = end-systolic volume index (ESVI)/stroke volume index (SVI) and its two determinants EaI = end-systolic pressure/SVI, and ELVI = end-systolic pressure/ESVI, at rest and during exercise in 239 healthy men and women (age range, 21 to 87 years). Blood pressures were assessed with cuff sphygomanometry, and cardiac volumes with gated blood pool scintingraphy. Resting EaI/ELVI was not age related in men or women. In both sexes, EaI/ELVI decreased during exercise and declined to a lesser extent in older subjects. There were gender differences in the components of EaI/ELVI during exercise: EaI was greater in older versus young women (p = 0.01) but was unaffected by age in men. Left ventricular systolic elastance increased to a greater extent in young versus older subjects (p = 0.0001 for men, p = 0.07 for women). Age-associated differences in EaI/ELVI occur in both genders during exercise. Sub-optimal ventricular-vascular coupling helps to explain the age-associated blunting of maximal exercise EF, and its underlying mechanisms appear to differ between men and women.

Mitochondrial calcium overload has been suggested as a marker for irreversible injury in the ischemic heart. A new technique is used to measure dynamic changes in mitochondrial free calcium concentration ([Ca2+]m) in electrically stimulated (0.2 Hz) adult rat cardiac myocytes during exposure to anoxia and reoxygenation. Cells were incubated with indo-1 AM, which distributes in both the cytosol and mitochondria. After Mn2+ quenching of the cytosolic signal, cells were exposed to anoxia, and the residual fluorescence was monitored. [Ca2+]m averaged 94 +/- 3 nM (n = 16) at baseline, less than the baseline diastolic cytosolic free calcium concentration ([Ca2+]c, 124 +/- 4 nM, n = 12), which was measured in cells loaded with the pentapotassium salt of indo-1. [Ca2+]m and [Ca2+]c rose steadily only after the onset of ATP-depletion rigor contracture. At reoxygenation 35 minutes later, [Ca2+]c fell rapidly to preanoxic levels and then often showed a transient further rise. In contrast, [Ca2+]m showed only a slight transient fall and a secondary rise at reoxygenation. At reoxygenation, cells immediately either recovered, demonstrating partial relengthening and retaining their rectangular shape and response to stimulation, or they hypercontracted to rounded dysfunctional forms. Recovery occurred only in cells in which [Ca2+]m or [Ca2+]c remained below 250 nM before reoxygenation. Early during reoxygenation, [Ca2+]m remained higher in cells that hypercontracted (305 +/- 36 nM) than in cells that recovered (138 +/- 9 nM, p less than 0.05), whereas [Ca2+]c did not differ between the two groups (156 +/- 10 versus 128 +/- 10 nM, respectively; p = NS).(ABSTRACT TRUNCATED AT 250 WORDS)