Kent R. Bailey

Approximately half of patients with overt congestive heart failure (CHF) have diastolic dysfunction without reduced ejection fraction (EF). Yet, the prevalence of diastolic dysfunction and its relation to systolic dysfunction and CHF in the community remain undefined.To determine the prevalence of CHF and preclinical diastolic dysfunction and systolic dysfunction in the community and determine if diastolic dysfunction is predictive of all-cause mortality.Cross-sectional survey of 2042 randomly selected residents of Olmsted County, Minnesota, aged 45 years or older from June 1997 through September 2000.Doppler echocardiographic assessment of systolic and diastolic function. Presence of CHF diagnosis by review of medical records with designation as validated CHF if Framingham criteria are satisfied. Subjects without a CHF diagnosis but with diastolic or systolic dysfunction were considered as having either preclinical diastolic or preclinical systolic dysfunction.The prevalence of validated CHF was 2.2% (95% confidence interval [CI], 1.6%-2.8%) with 44% having an EF higher than 50%. Overall, 20.8% (95% CI, 19.0%-22.7%) of the population had mild diastolic dysfunction, 6.6% (95% CI, 5.5%-7.8%) had moderate diastolic dysfunction, and 0.7% (95% CI, 0.3%-1.1%) had severe diastolic dysfunction with 5.6% (95% CI, 4.5%-6.7%) of the population having moderate or severe diastolic dysfunction with normal EF. The prevalence of any systolic dysfunction (EF < or =50%) was 6.0% (95% CI, 5.0%-7.1%) with moderate or severe systolic dysfunction (EF < or =40%) being present in 2.0% (95% CI, 1.4%-2.5%). CHF was much more common among those with systolic or diastolic dysfunction than in those with normal ventricular function. However, even among those with moderate or severe diastolic or systolic dysfunction, less than half had recognized CHF. In multivariate analysis, controlling for age, sex, and EF, mild diastolic dysfunction (hazard ratio, 8.31 [95% CI, 3.00-23.1], P<.001) and moderate or severe diastolic dysfunction (hazard ratio, 10.17 [95% CI, 3.28-31.0], P<.001) were predictive of all-cause mortality.In the community, systolic dysfunction is frequently present in individuals without recognized CHF. Furthermore, diastolic dysfunction as rigorously defined by comprehensive Doppler techniques is common, often not accompanied by recognized CHF, and associated with marked increases in all-cause mortality.

Limited data exist on trends in incidence of atrial fibrillation (AF). We assessed the community-based trends in AF incidence for 1980 to 2000 and provided prevalence projections to 2050.The adult residents of Olmsted County, Minnesota, who had ECG-confirmed first AF in the period 1980 to 2000 (n=4618) were identified. Trends in age-adjusted incidence were determined and used to construct model-based prevalence estimates. The age- and sex-adjusted incidence of AF per 1000 person-years was 3.04 (95% CI, 2.78 to 3.31) in 1980 and 3.68 (95% CI, 3.42 to 3.95) in 2000. According to Poisson regression with adjustment for age and sex, incidence of AF increased significantly (P=0.014), with a relative increase of 12.6% (95% CI, 2.1 to 23.1) over 21 years. The increase in age-adjusted AF incidence did not differ between men and women (P=0.84). According to the US population projections by the US Census Bureau, the number of persons with AF is projected to be 12.1 million by 2050, assuming no further increase in age-adjusted incidence of AF, but 15.9 million if the increase in incidence continues.The age-adjusted incidence of AF increased significantly in Olmsted County during 1980 to 2000. Whether or not this rate of increase continues, the projected number of persons with AF for the United States will exceed 10 million by 2050, underscoring the urgent need for primary prevention strategies against AF development.

Myocardial infarction (MI) can directly cause ischemic mitral regurgitation (IMR), which has been touted as an indicator of poor prognosis in acute and early phases after MI. However, in the chronic post-MI phase, prognostic implications of IMR presence and degree are poorly defined.We analyzed 303 patients with previous (>16 days) Q-wave MI by ECG who underwent transthoracic echocardiography: 194 with IMR quantitatively assessed in routine practice and 109 without IMR matched for baseline age (71+/-11 versus 70+/-9 years, P=0.20), sex, and ejection fraction (EF, 33+/-14% versus 34+/-11%, P=0.14). In IMR patients, regurgitant volume (RVol) and effective regurgitant orifice (ERO) area were 36+/-24 mL/beat and 21+/-12 mm(2), respectively. After 5 years, total mortality and cardiac mortality for patients with IMR (62+/-5% and 50+/-6%, respectively) were higher than for those without IMR (39+/-6% and 30+/-5%, respectively) (both P<0.001). In multivariate analysis, independently of all baseline characteristics, particularly age and EF, the adjusted relative risks of total and cardiac mortality associated with the presence of IMR (1.88, P=0.003 and 1.83, P=0.014, respectively) and quantified degree of IMR defined by RVol >/=30 mL (2.05, P=0.002 and 2.01, P=0.009) and by ERO >/=20 mm(2) (2.23, P=0.003 and 2.38, P=0.004) were high.In the chronic phase after MI, IMR presence is associated with excess mortality independently of baseline characteristics and degree of ventricular dysfunction. The mortality risk is related directly to the degree of IMR as defined by ERO and RVol. Therefore, IMR detection and quantification provide major information for risk stratification and clinical decision making in the chronic post-MI phase.

The risk for venous thromboembolism during pregnancy or postpartum is uncertain.To estimate the relative and absolute risk for deep venous thrombosis and pulmonary embolism during pregnancy and postpartum and to describe trends in incidence.Population-based inception cohort study using the resources of the Rochester Epidemiology Project.Olmsted County, Minnesota.Women with deep venous thrombosis or pulmonary embolism first diagnosed between 1966 and 1995, including women with venous thromboembolism during pregnancy or the postpartum period (defined as delivery of a newborn no more than 3 months before the deep venous thrombosis or pulmonary embolism event date, including delivery of a stillborn infant after the first trimester).The authors obtained yearly counts of live births in Olmsted County between 1966 and 1995 from the Minnesota Department of Health.The relative risk (standardized incidence ratio) for venous thromboembolism among pregnant or postpartum women was 4.29 (95% CI, 3.49 to 5.22;P < 0.001), and the overall incidence of venous thromboembolism (absolute risk) was 199.7 per 100,000 woman-years. The annual incidence was 5 times higher among postpartum women than pregnant women (511.2 vs. 95.8 per 100,000), and the incidence of deep venous thrombosis was 3 times higher than that of pulmonary embolism (151.8 vs. 47.9 per 100,000). Pulmonary embolism was relatively uncommon during pregnancy versus the postpartum period (10.6 vs. 159.7 per 100,000). Over the 30-year study period, the incidence of venous thromboembolism during pregnancy remained relatively constant whereas the postpartum incidence of pulmonary embolism decreased more than 2-fold.Because the Olmsted County population was 98% white and of non-Hispanic ethnicity, the results may not be generalizable to other ethnicities.Among pregnant women, the highest risk period for venous thromboembolism and pulmonary embolism in particular is during the postpartum period. Any prophylaxis against these events should be particularly targeted to postpartum women. Although the incidence of pulmonary embolism has decreased over time, the incidence of deep venous thrombosis remains unchanged, indicating the need to better identify pregnant women at increased risk.

Left ventricular (LV) diastolic dysfunction is prevalent in the community. Current assessment of diastolic function can be complex, involving Doppler evaluation of an array of hemodynamic data. The relation between left atrial (LA) volume and diastolic function, and between LA volume and cardiovascular risk and disease burden are not well known. In the present prospective study of 140 adults, mean age 58 +/- 19 years, referred for a clinically-indicated echocardiogram and in sinus rhythm, with no history of atrial arrhythmias or valvular heart disease, we determined the LA volume, LV diastolic function status, cardiovascular risk score (based on age, gender, history of systemic hypertension, diabetes mellitus, hyperlipidemia, and smoking), and cardiovascular disease burden (based on confirmed vascular disease, congestive heart failure, and transient ischemic attack or stroke). LA volume was found to correlate positively with age, body surface area, cardiovascular risk score, LV end-diastolic and end-systolic dimensions, LV mass, diastolic function grade, tissue Doppler E/E', tricuspid regurgitation velocity, and negatively with LV ejection fraction (all p <0.006). In a multivariate clinical model, LA volume indexed to body surface area (indexed LA volume) was independently associated with cardiovascular risk score (p <0.001), congestive heart failure (p = 0.014), vascular disease (p = 0.012), transient ischemic attack or stroke (p = 0.021), and history of smoking (p = 0.008). In a clinical and echocardiographic model, indexed LA volume was strongly associated with diastolic function grade (p <0.001), independent of LV ejection fraction, age, gender, and cardiovascular risk score. In patients without a history of atrial arrhythmias or valvular heart disease, LA volume expressed the severity of diastolic dysfunction and provided an index of cardiovascular risk and disease burden.

We wished to examine the effects of age and gender on plasma brain natriuretic peptide (BNP) concentration in a population-based study. Measurement of BNP concentration is approved for use in the diagnosis of heart failure and may aid in the detection of left ventricular dysfunction. Although BNP is approved for clinical use, there are few data regarding the range of BNP observed in persons without cardiovascular disease or cardiac dysfunction. These data are essential for the interpretation of BNP. In 2,042 randomly selected residents of Olmsted County, Minnesota, >44 years old, BNP (Shionogi and Biosite assays), Doppler echocardiography, and medical record review were performed. A normal subset of subjects (n = 767) in sinus rhythm without cardiovascular, renal, or pulmonary disease or diabetes; on no cardiovascular medications; and with normal systolic, diastolic, and valvular function was identified. Within the normal subset, the distribution of BNP differed by age, gender, and assay system. With both assays, BNP increased significantly with age and was significantly higher in women than men, leading to age-, gender-, and assay-specific reference ranges. Receiver operating characteristic analysis for the ability of BNP to detect an ejection fraction ≤40% was performed in each age/gender stratum in the entire cohort (n = 2,042) and confirmed that discriminatory values for BNP for detection of reduced ejection fraction were higher in women and older persons and were different between the two assays. Interpretation of BNP should include consideration of age-, gender-, and assay-specific partition values.

Data are limited regarding the classification and prognosis of patients with congestive heart failure (CHF) in the community.Using the resources of the Rochester Epidemiology Project, we evaluated all patients receiving a first diagnosis of CHF in Olmsted County, Minnesota, in 1991 (n=216). Among these patients, 88% were >/=65 years and 49% were >/=80 years of age. The prognosis of patients with a new diagnosis of CHF was poor; survival was 86+/-2% at 3 months, 76+/-3% at 1 year, and 35+/-3% at 5 years. Of the 216 patients, 137 (63%) had an assessment of ejection fraction. In these patients, systolic function was preserved (ejection fraction >/=50%) in 59 (43%) and reduced (ejection fraction <50%) in 78 (57%). Survival adjusted for age, sex, NYHA class, and coronary artery disease was not significantly different between patients with preserved and those with reduced systolic function (relative risk, 0.80; P=0.369). ACE inhibitors were used in only 44% of the total population with CHF.The present study reports the clinical characteristics and natural history of CHF as it presents in the community in the vasodilator era. CHF is a disease of the "very elderly," frequently occurs in the setting of normal ejection fraction, and has a poor prognosis, regardless of the level of systolic function. Diagnostic and therapeutic methods are underused in the community.

Echocardiographic assessment of right ventricular function remains difficult and challenging. However, there is considerable clinical need for a simple, reproducible, and reliable parameter of right ventricular function in patients with right-sided heart disease. The purpose of this study was to assess the clinical value of a Doppler-derived index, combining systolic and diastolic intervals of the right cycle, in assessing global right ventricular function in patients with primary pulmonary hypertension. The study population comprised 26 consecutive patients with primary pulmonary hypertension and 37 age-matched normal subjects. The sum of right ventricular isovolumetric contraction time and isovolumetric relaxation time was obtained by subtracting right ventricular ejection time from the interval between cessation and onset of the tricuspid inflow velocities with pulsed-wave Doppler echocardiography. An index of combined right ventricular systolic and diastolic function was obtained by dividing the sum of both isovolumetric intervals by ejection time. The index was compared with available parameters of systolic or diastolic function, clinical symptoms, and survival. Right ventricular isovolumetric contraction time and isovolumetric relaxation time were prolonged significantly in patients with primary pulmonary hypertension (85 +/- 41 msec and 135 +/- 43 msec) compared with normal subjects (38 +/- 7 msec and 49 +/- 9 msec, respectively; p < 0.001). Ejection time was shortened significantly in patients with pulmonary hypertension (241 +/- 43 msec versus normal [322 +/- 21 msec]; p < 0.001). However, the index was the single most powerful variable to discriminate patients with primary pulmonary hypertension from normal subjects (0.93 +/- 0.34 versus 0.28 +/- 0.04; p < 0.001) and was the strongest predictor of clinical status and survival. The index was not significantly affected by heart rate, right ventricular pressure, right ventricular dilation, or tricuspid regurgitation. It is well known that right ventricular systolic and diastolic dysfunction coexist in patients with primary pulmonary hypertension. This article reports the use of an easily obtainable Doppler-derived index that combines elements of systolic and diastolic function. This index appears to be a useful noninvasive means that correlates with symptoms and survival in patients with primary pulmonary hypertension.

Immediate angioplasty and the administration of a thrombolytic agent followed by conservative treatment are two approaches to the management of acute myocardial infarction, but these methods have not been compared prospectively.

This study assessed the long-term outcome of a large, asymptomatic population with hemodynamically significant aortic stenosis (AS).We identified 622 patients with isolated, asymptomatic AS and peak systolic velocity > or =4 m/s by Doppler echocardiography who did not undergo surgery at the initial evaluation and obtained follow-up (5.4+/-4.0 years) in all. Mean age (+/-SD) was 72+/-11 years; there were 384 (62%) men. The probability of remaining free of cardiac symptoms while unoperated was 82%, 67%, and 33% at 1, 2, and 5 years, respectively. Aortic valve area and left ventricular hypertrophy predicted symptom development. During follow-up, 352 (57%) patients were referred for aortic valve surgery and 265 (43%) patients died, including cardiac death in 117 (19%). The 1-, 2-, and 5-year probabilities of remaining free of surgery or cardiac death were 80%, 63%, and 25%, respectively. Multivariate predictors of all-cause mortality were age (hazard ratio [HR], 1.05; P<0.0001), chronic renal failure (HR, 2.41; P=0.004), inactivity (HR, 2.00; P=0.001), and aortic valve velocity (HR, 1.46; P=0.03). Sudden death without preceding symptoms occurred in 11 (4.1%) of 270 unoperated patients. Patients with peak velocity > or =4.5 m/s had a higher likelihood of developing symptoms (relative risk, 1.34) or having surgery or cardiac death (relative risk, 1.48).Most patients with asymptomatic, hemodynamically significant AS will develop symptoms within 5 years. Sudden death occurs in approximately 1%/y. Age, chronic renal failure, inactivity, and aortic valve velocity are independently predictive of all-cause mortality.

We sought to compare left atrial (LA) volume to LA area and diameter for the prediction of adverse cardiovascular outcomes. The incremental value of LA volume compared with LA area or diameter as a cardiovascular risk marker has not been evaluated prospectively for patients with sinus rhythm or atrial fibrillation (AF). Left atrial size was assessed with biplane LA volume, four-chamber LA area, and M-mode dimension for 423 patients (mean age 71 ± 8 years, 56% men) who were prospectively followed for development of first AF, congestive heart failure, stroke, transient ischemic attack, myocardial infarction, coronary revascularization, and cardiovascular death. Of the 317 subjects in sinus rhythm at baseline, 62 had 90 new events during a mean follow-up of 3.5 ± 2.3 years. All three LA size parameters were independently predictive of combined outcomes (all p < 0.0001). The overall performance for the prediction of cardiovascular events was greatest for LA volume (area under the receiver operator characteristic curve: indexed LA volume 0.71; LA area 0.64; LA diameter 0.59). A graded association between the degree of LA enlargement and risk of cardiovascular events was only evident for indexed LA volume. For subjects with AF, there was no association between LA size and cardiovascular events. Left atrial volume is a more robust marker of cardiovascular events than LA area or diameter in subjects with sinus rhythm. The predictive utility of LA size for cardiovascular events in AF was poor, irrespective of the method of LA size quantitation.

After acute myocardial infarction (AMI), diastolic function assessed by Doppler echocardiography provides important prognostic information that is incremental to systolic function. However, Doppler variables are affected by multiple factors and may change rapidly. In contrast, left atrial (LA) volume is less influenced by acute changes and reflects subacute or chronic diastolic function. This may be of importance when one assesses risk in patients with AMI.Three hundred fourteen patients with AMI who had a transthoracic echocardiogram with assessment of left ventricular (LV) systolic and diastolic function and measurement of LA volume during admission were identified. The LA volume was corrected for body surface area, and the population was divided according to LA volume index of 32 mL/m2 (2 SDs above normal). LA volume index was >32 mL/m2 in 142 (45%). The primary study end point was all-cause mortality. During follow-up of 15 (range 0 to 33) months, 46 patients (15%) died. LA volume index was a powerful predictor of mortality and remained an independent predictor (hazard ratio 1.05 per 1-mL/m2 change, 95% CI 1.03 to 1.06, P<0.001) after adjustment for clinical factors, LV systolic function, and Doppler-derived parameters of diastolic function.Increased LA volume index is a powerful predictor of mortality after AMI and provides prognostic information incremental to clinical data and conventional measures of LV systolic and diastolic function.

Mitral regurgitation due to flail leaflet is difficult to manage, because it is frequently asymptomatic yet carries a high risk of left ventricular dysfunction and because the natural history of the condition is poorly defined.We obtained clinical follow-up data through 1994-1995 in 229 patients with isolated mitral regurgitation due to flail leaflet; this condition was first diagnosed by echocardiography between 1980 and 1989.The 86 patients who were treated medically had a mortality rate significantly higher than expected (6.3 percent yearly, P=0.016 for the comparison with the expected rate in the U.S. population according to the 1990 census). Independent determinants of mortality were an older age, the presence of symptoms, and a lower ejection fraction. Patients who were even transiently in New York Heart Association functional class III or IV had a high mortality rate (34 percent yearly), but the rate was also notable (4.1 percent yearly) among those in class I or II. At 10 years, the mean (+/- SE) rates of heart failure, atrial fibrillation, and death or surgery were 63 +/- 8, 30 +/- 12, and 90 +/- 3 percent, respectively. In a multivariate analysis, surgical correction of mitral regurgitation (performed in 143 patients) was associated with a reduced mortality rate (hazard ratio, 0.29; 95 percent confidence interval, 0.15 to 0.56; P<0.001).When treated medically, mitral regurgitation due to flail leaflet is associated with excess mortality and high morbidity. Surgery is almost unavoidable within 10 years after the diagnosis and appears to be associated with an improved prognosis; this finding suggests that surgery should be considered early in the course of the disease.

The objective of this study was to determine whether diastolic dysfunction is associated with increased risk of nonvalvular atrial fibrillation (NVAF) in older adults with no history of atrial arrhythmia.Few data exist regarding the relationship between diastolic function and NVAF.The clinical and echocardiographic characteristics of patients age > or =65 years who had an echocardiogram performed between 1990 and 1998 were reviewed. Exclusion criteria were history of atrial arrhythmia, stroke, valvular or congenital heart disease, or pacemaker implantation. Patients were followed up in their medical records to the last clinical visit or death for documentation of first AF.Of 840 patients (39% men; mean [+/- SD] age, 75 +/- 7 years), 80 (9.5%) developed NVAF over a mean (+/- SD) follow-up of 4.1 +/- 2.7 years. Abnormal relaxation, pseudonormal, and restrictive left ventricular diastolic filling were associated with hazard ratios of 3.33 (95% confidence interval [CI], 1.5 to 7.4; p = 0.003), 4.84 (95% CI, 2.05 to 11.4; p < 0.001), and 5.26 (95% CI, 2.3 to 12.03; p < 0.001), respectively, when compared with normal diastolic function. After a number of adjustments, diastolic function profile remained incremental to history of congestive heart failure and previous myocardial infarction for prediction of NVAF. Age-adjusted Kaplan-Meier five-year risks of NVAF were 1%, 12%, 14%, and 21% for normal, abnormal relaxation, pseudonormal, and restrictive diastolic filling, respectively. CONCLUSIONS; The presence and severity of diastolic dysfunction are independently predictive of first documented NVAF in the elderly.

We studied left atrial volume (LAV) as an index of atrial size.Increased left atrial dimension (LAD) measured by M-mode echocardiography is a risk factor for atrial fibrillation, stroke, and death.A random sample of residents of Olmsted County, Minnesota, age > or =45 years (n = 2,042) underwent Doppler echocardiography with assessment of LAD and LAV. A subgroup of the population (n = 767) with no cardiovascular disease and normal systolic and diastolic function was used to develop reference ranges for LAD and LAV. In the total population, the prevalence of left atrial enlargement and the association between cardiovascular disease and left atrial size as determined by both indexes were assessed.In the normal subgroup, both indexes were associated with gender and body size, thus models controlling for body size were used to determine gender-specific reference ranges for LAD and LAV. In the total population, left atrial enlargement was common, with a prevalence of 18% (men) and 12% (women) using LAD/body surface area (BSA) and of 16% (men and women) using LAV/BSA. The agreement between the indexes was only fair (kappa = 0.53). Adjusting for age and gender, LAV/BSA was more strongly associated with the presence of cardiovascular diseases than LAD/BSA.We described a simple technique of measuring LAV, examined methods for indexing LAV, and described its normal range in a large, healthy reference cohort. Further, we find that in the community, left atrial enlargement is common and reflects the burden of cardiovascular disease.

To evaluate the contribution of left atrial (LA) volume in predicting atrial fibrillation (AF).In this retrospective cohort study, a random sample of 2200 adults was identified from all Olmsted County, Minnesota, residents who had undergone transthoracic echocardiographic assessment between 1990 and 1998 and were 65 years of age or older at the time of examination, were in sinus rhythm, and had no history of AF or other atrial arrhythmias, stroke, pacemaker, congenital heart disease, or valve surgery. The LA volume was measured off-line by using a biplane area-length method. Clinical characteristics and the outcome event of incident AF were determined by retrospective review of medical records. Echocardiographic data were retrieved from the laboratory database. From this cohort, 1655 patients in whom LA size data were available were followed from baseline echocardiogram until development of AF or death. The clinical and echocardiographic associations of AF, especially with respect to the role of LA volume in predicting AF, were determined.A total of 666 men and 989 women, mean +/- SD age of 75.2 +/- 7.3 years (range, 65-105 years), were followed for a mean +/- SD of 3.97 +/- 2.75 years (range, < 1.00-10.78 years); 189 (11.4%) developed AF. Cox model 5-year cumulative risks of AF by quartiles of LA volume were 3%, 12%, 15%, and 26%, respectively. With Cox proportional hazards multivariate models, logarithmic LA volume was an independent predictor of AF, incremental to clinical risk factors. After adjusting for age, sex, valvular heart disease, and hypertension, a 30% larger LA volume was associated with a 43% greater risk of AF, incremental to history of congestive heart failure (hazard ratio [HR], 1.887; 95% confidence interval [CI], 1.230-2.895; P = .004), myocardial infarction (HR, 1.751; 95% CI, 1.189-2.577; P = .004), and diabetes (HR, 1.734; 95% CI, 1.066-2.819; P = .03). Left atrial volume remained incremental to combined clinical risk factors and M-mode LA dimension for prediction of AF (P < .001).This study showed that a larger LA volume was associated with a higher risk of AF in older patients. The predictive value of LA volume was incremental to that of clinical risk profile and conventional M-mode LA dimension.

Background and objectives: Studies of the impact of systemic lupus erythematosus (SLE) and its pregnancy complications have yielded conflicting results. Major limitations of these studies relate to their small numbers of patients and retrospective designs. The aim of this study was to perform a systematic literature review of pregnancy outcomes in women with SLE and a meta-analysis of the association of lupus nephritis with adverse pregnancy outcomes. Design, setting, participants, &amp; measurements: We searched electronic databases from 1980 to 2009 and reviewed papers with validity criteria. Random-effects analytical methods were used to evaluate pregnancy complications rates. Results: Thirty-seven studies with 1842 patients and 2751 pregnancies were included. Maternal complications included lupus flare (25.6%), hypertension (16.3%), nephritis (16.1%), pre-eclampsia (7.6%), and eclampsia (0.8%). The induced abortion rate was 5.9%, and when excluded, fetal complications included spontaneous abortion (16.0%), stillbirth (3.6%), neonatal deaths (2.5%), and intrauterine growth retardation (12.7%). The unsuccessful pregnancy rate was 23.4%, and the premature birth rate was 39.4%. Meta-regression analysis showed statistically significant positive associations between premature birth rate and active nephritis and increased hypertension rates in subjects with active nephritis or a history of nephritis. History of nephritis was also associated with pre-eclampsia. Anti-phospholipid antibodies were associated with hypertension, premature birth, and an increased rate of induced abortion. Conclusions: In patients with SLE, both lupus nephritis and anti-phospholipid antibodies increase the risks for maternal hypertension and premature births. The presented evidence further supports timing of pregnancy relative to SLE activity and multispecialty care of these patients.

Atrial and brain natriuretic peptides (ANP and BNP) are produced by the heart, and their plasma concentrations are increased in human chronic congestive heart failure. Although separate studies have suggested that circulating levels of the biologically active C-terminal ANP, the biologically inactive N-terminal ANP, and BNP may have diagnostic utility in the detection of left ventricular systolic dysfunction or left ventricular hypertrophy, no studies have directly assessed the relative value of these peptides prospectively. We therefore designed this study to compare the relative ability of the different natriuretic peptides to detect abnormal left ventricular systolic and diastolic function and left ventricular hypertrophy. Using a prospective study design, we investigated 94 patients referred for cardiac catheterization and 15 age-matched normal subjects. The diagnostic abilities of elevated plasma C-terminal ANP, N-terminal ANP-(1-30), and BNP concentrations to identify systolic dysfunction (ejection fraction &lt;45%), diastolic dysfunction (time constant of left ventricular relaxation &gt;55 milliseconds, left ventricular end-diastolic pressure &gt;18 mm Hg), and left ventricular hypertrophy (left ventricular mass index &gt;120 g/m 2 ) were objectively compared by receiver operating characteristic analysis. The areas under the receiver operating characteristic curve of BNP for detecting each of these abnormalities ranged from 0.715 to 0.908 and were significantly greater than those of C-terminal ANP or N-terminal ANP-(1-30). The sensitivity and specificity of an elevated plasma BNP, which we defined as greater than the mean+3 SD of the 15 age-matched normal subjects, were 0.83 and 0.77, respectively, for detecting ejection fraction less than 45%, 0.85 and 0.70 for detecting the time constant of left ventricular relaxation greater than 55 milliseconds, 0.63 and 0.76 for detecting left ventricular end-diastolic pressure greater than 18 mm Hg, and 0.81 and 0.85 for detecting left ventricular mass index greater than 120 g/m 2 . The use of BNP and one other peptide increased sensitivity (0.90 to 0.96), albeit with lower specificity (0.56 to 0.71). An elevated plasma BNP was a more powerful marker of left ventricular systolic dysfunction, left ventricular diastolic dysfunction, and left ventricular hypertrophy than C-terminal ANP or N-terminal ANP-(1-30) in this population of patients with suspected cardiac disease. Measurement of BNP alone or in combination with C-terminal ANP or N-terminal ANP-(1-30) has potential utility for the detection of altered left ventricular structure and function in a patient population at risk for cardiovascular disease.

Left ventricular dysfunction is a frequent cause of death after successful surgical repair of mitral regurgitation. The role of preoperative echocardiographic left ventricular variables in the prediction of postoperative survival and thus their clinical implications remain uncertain.The survival of 409 patients operated on between 1980 and 1989 for pure, isolated, organic mitral regurgitation and with a preoperative echocardiogram (within 6 months of operation) was analyzed. The overall survival was 75% at 5 years (90% of expected), 58% at 10 years (88% of expected), and 44% at 12 years (73% of expected). Operative mortality was 6.6% and markedly improved from 1980 to 1984 (10.7%) to 1985 to 1989 (3.7%). Multivariate analysis showed that age (P = .0003), date of operation (P = .003), and functional class (P = .016) but not left ventricular function were predictors of operative mortality. In the most recent period (1985 to 1989), operative mortality was 12.3% in patients age 75 years or older and 1.1% in patients younger than 75 years. Late survival was analyzed in the operative survivors. Multivariate analysis showed that the most powerful predictor was echocardiographic ejection fraction (EF) (P = .0004), followed by age (P = .0031), creatinine level (P = .0062), systolic blood pressure (P = .0164), and presence of coronary artery disease (P = .0237). The late survival at 10 years was 32 +/- 12% for patients with EF < 50%, 53 +/- 9% for EF 50% to 60%, and 72 +/- 4% for EF > or = 60%. The hazard ratio compared with EF > or = 60% was 2.79 (95% confidence interval, 1.65 to 4.72) for EF < 50% and 1.81 (95% confidence interval, 1.11 to 2.95) for EF 50% to 60%. Echocardiographic EF remained the best predictor of late survival, even when combined with left ventricular angiographic variables. The survival of patients with EF > or = 60% was 100% of expected at 10 years but was better in patients in class I or II than in those in class III or IV (82 +/- 6% versus 59 +/- 6%, respectively, at 10 years; P = .0021). The preoperative predictors of operative and late mortality remained significant independent of the type of surgical correction performed in combined multivariate analyses.In organic mitral regurgitation, (1) operative mortality has markedly decreased recently, being at a low 1.1% in patients younger than 75 years, and is predicted by age and symptoms and not by left ventricular function, and (2) left ventricular EF measured by echocardiography is the most powerful predictor of late survival. These results suggest that surgical treatment should be considered early, even in the absence of severe symptoms, in patients with severe mitral regurgitation, before left ventricular dysfunction occurs.

BACKGROUND Virtually all natural history studies of Wolff-Parkinson-White (WPW) syndrome have been case series and, as such, have been constrained by referral biases, skewed age and sex distributions, or brief follow-up periods. The purpose of our study was to examine the natural history, the development of arrhythmias, and the incidence of sudden death in an entire cohort of pediatric and adult WPW patients from a community-based local population. METHODS AND RESULTS We identified 113 residents of Olmsted County, Minnesota, during the period 1953-1989 using the centralized records-linkage system provided by the Mayo Clinic and the Rochester Epidemiology Program Project. Medical records and ECGs were reviewed to confirm the diagnosis and to establish pathway location by ECG criteria. Follow-up, via record review and telephone interview, was complete in 95% of subjects through 1990. The incidence of newly diagnosed cases was approximately four per 100,000 per year. Preexcitation was not present on the initial ECG of 22% of the cohort. Approximately 50% of the population was asymptomatic at diagnosis, with 30% subsequently having symptoms related to arrhythmia at follow-up. Two sudden cardiac deaths (SCD) occurred over 1,338 patient-years of follow-up, yielding an overall SCD rate of 0.0015 (95% confidence interval, 0.0002-0.0054) per patient-year. No SCD occurred in patients asymptomatic at diagnosis. CONCLUSIONS The incidence of sudden death in a local community-based population is low and suggests that electrophysiological testing should not be performed routinely in asymptomatic patients with WPW syndrome. Nevertheless, young, asymptomatic patients, particularly those &lt; 40 years old, should return for medical follow-up should symptoms develop.

Dilated cardiomyopathy is an important cause of morbidity and mortality among patients with congestive heart failure. Hemodynamic and prognostic characterization are critical in guiding selection of medical and surgical therapies.A cohort of 102 patients with the clinical diagnosis of dilated cardiomyopathy who underwent echocardiographic examination between 1986 and 1990 was identified and followed up through July 1, 1991. Patients with moderate or severe symptoms had lower indices of systolic function and greater left atrial and right ventricular dilation. Mitral inflow Doppler signals were characterized by a restrictive left ventricular filling pattern. In multivariate logistic regression analysis, deceleration time, ejection fraction, and peak E velocity were independently associated with symptom status. Over a mean follow-up of 36 months, 35 patients died. Kaplan-Meier estimated survival at 1, 2, and 4 years was 84%, 73%, and 61%, respectively, and was significantly poorer than that of an age- and sex-matched population. The subgroup with an ejection fraction < 0.25 and deceleration time < 130 milliseconds had a 2-year survival of only 35%. The subgroup with ejection fraction < 0.25 and deceleration time > 130 milliseconds had an intermediate 2-year survival of 72%, whereas patients with an ejection fraction > or = 0.25 had 2-year survivals > or = 95% regardless of deceleration time. In multivariate analysis, ejection fraction and systolic blood pressure were independently predictive of subsequent mortality. Mitral deceleration time was significant in univariate analysis.In patients with the clinical diagnosis of dilated cardiomyopathy, markers of diastolic dysfunction correlated strongly with congestive symptoms, whereas variables of systolic function were the strongest predictors of survival. Consideration of both ejection fraction and deceleration time allowed identification of subgroups with divergent long-term prognoses.

The purpose of this study was to assess the mortality trends of atrial fibrillation (AF) in a community.Limited data exist regarding the mortality trends of patients diagnosed with first AF.A community-based cohort of adult residents of Olmsted County, Minnesota, who had electrocardiogram-confirmed first-documented AF in the years 1980 to 2000 were identified and followed to 2004 or death. The primary outcome was all-cause mortality.Of a total of 4,618 residents (mean age 73 +/- 14 years) diagnosed with first AF, 3,085 died during a mean follow-up of 5.3 +/- 5.0 years. Relative to the age- and gender-matched general Minnesota population, the mortality risk was increased (p < 0.0001) with a hazard ratio (HR) of 9.62 (95% confidence interval [CI] 8.93 to 10.32) within the first 4 months and 1.66 (95% CI 1.59 to 1.73) thereafter. Cox proportional hazards modeling showed no change in overall age- and gender-adjusted mortality (HR for the year 2000 vs. 1980: 0.99; 95% CI 0.86 to 1.13; p = 0.84), even after adjustment for comorbidities. In secondary analyses, no changes in mortality were seen for early (within first 4 months) or late (after 4 months) mortality for the entire group or within the subgroup of patients who did not have cardiovascular disease at baseline.In this cohort of patients newly diagnosed with AF, mortality risk was high, especially within the first 4 months. There was no evidence for any significant changes over the 21 years in terms of overall mortality, early or late mortality, or mortality among patients without pre-existing cardiovascular disease.

The outcome of mitral valve prolapse (MVP) is controversial, with marked discrepancies in reported complication rates.We conducted a community study of all Olmsted County, Minn, residents first diagnosed with asymptomatic MVP between 1989 and 1998 (N=833). Diagnosis, motivated by auscultatory findings (n=557) or incidental (n=276), was always confirmed by echocardiography with the use of current criteria. End points analyzed during 4581 person-years of follow-up were mortality (n=96, 19+/-2% at 10 years), cardiovascular morbidity (n=171), and MVP-related events (n=109, 20+/-2% at 10 years). The most frequent primary risk factors for cardiovascular mortality were mitral regurgitation from moderate to severe (P=0.002, n=131) and, less frequently, ejection fraction <50% (P=0.003, n=31). Secondary risk factors independently predictive of cardiovascular morbidity were slight mitral regurgitation, left atrium > or =40 mm, flail leaflet, atrial fibrillation, and age > or =50 years (all P<0.01). Patients with only 0 or 1 secondary risk factor (n=430) had excellent outcome, with 10-year mortality of 5+/-2% (P=0.17 versus expected), cardiovascular morbidity of 0.5%/y, and MVP-related events of 0.2%/y. Patients with > or =2 secondary risk factors (n=250) had mortality similar to expected (P=0.20) but high cardiovascular morbidity (6.2%/y, P<0.01) and notable MVP-related events (1.7%/y, P<0.01). Patients with primary risk factors (n=153) showed excess 10-year mortality (45+/-9%, P=0.01 versus expected), high morbidity (18.5%/y, P<0.01), and high MVP-related events (15%/y, P<0.01).Natural history of asymptomatic MVP in the community is widely heterogeneous and may be severe. Clinical and echocardiographic characteristics allow separation of the majority of patients with excellent prognosis from subsets of patients displaying, during follow-up, high morbidity or even excess mortality as direct a consequence of MVP.

The outcome of aortic regurgitation conservatively followed in clinical practice is poorly defined.Long-term outcome of 246 patients with severe or moderately severe aortic regurgitation diagnosed by color Doppler echocardiography was analyzed. With conservative management, mortality rate was higher than expected (at 10 years, 34+/-5%, P<0. 001) and morbidity was high (10-year rates of 47+/-6% for heart failure and 62+/-4% for aortic valve surgery). At 10 years, 75+/-3% of patients had died or had surgery and 83+/-3% had had cardiovascular events. In multivariate analysis, predictors of survival were age (P<0.001), functional class (P<0.001), comorbidity index (P=0.033), atrial fibrillation (P=0.002), and left ventricular end-systolic diameter corrected for body surface area (P=0.025). Ejection fraction was also an independent predictor of overall survival, including postoperative follow-up of surgically treated patients (P<0.001). High risk during conservative treatment, with mortality rate in excess of that expected, was noted among patients with severe, even transient, symptoms (24.6% yearly, P<0.001) but also in those with mild (class II) symptoms (6.3% yearly, P=0.02) and in asymptomatic patients with left ventricular ejection fraction <55% (5.8% yearly, P=0.03) or with end-systolic diameter normalized to body surface area >/=25 mm/m2 (7.8% yearly, P=0.004). Surgery performed during follow-up was independently associated with reduced cardiovascular mortality (adjusted hazard ratio, 0.54; P=0.048).Patients diagnosed with severe aortic regurgitation in clinical practice incur excess mortality and high morbidity, underscoring the serious prognosis of the disease. Surgery, which reduces cardiac mortality rates, should be considered promptly in high-risk patients.

To compare the incidence of congestive heart failure and the survival in patients with congestive heart failure in Rochester, Minn, in 1981 with that observed in 1991.Population-based, descriptive epidemiological study with ecological and individual level comparisons over time. Olmsted County, Minnesota, where the Rochester Epidemiology Project provides passive surveillance of the population for health outcomes. All 248 patients fulfilled the Framingham criteria, 107 patients presenting with the new onset of congestive heart failure in 1981 and 141 patients in 1991. The community inpatient and outpatient medical records of all incident cases were reviewed to evaluate the presenting characteristics of patients at diagnosis.The incidence of congestive heart failure after adjustment for age and sex to the US population was not significantly different in the 1991 cohort compared with that in 1981 (3.0 per 1000 person-years; 95% confidence interval, 2.5-3.5 vs 2.8 per 1000 person-years; 95% confidence interval, 2.2-3.3; P = .55). The survival of patients with new diagnosis of congestive heart failure was similar in the 2 cohorts (P = .53). Survival adjusted for age, sex, and New York Heart Association functional class was not significantly different in patients with congestive heart failure in 1981 and 1991 (relative risk, 0.907; P = .55).These data suggest that recent advances in management of cardiovascular disease, as used in the community, had not yet impacted incidence or survival of patients with congestive heart failure in the community during the 10-year study period. This highlights the need to continue efforts to ensure that advances in diagnosis and therapy are incorporated into the care of patients with congestive heart failure in the community.

Two-dimensional and Doppler echocardiography was performed prospectively in 100 patients with aortic stenosis who were undergoing clinically indicated cardiac catheterization. The purpose of this study procedure was to determine various Doppler variables predictive of the severity of aortic stenosis and to compare Doppler- and catheterization-derived aortic valve areas. Doppler-derived mean gradient correlated well with corresponding gradient by catheterization (r = 0.86). Peak Doppler aortic flow velocity greater than or equal to 4.5 m/s and Doppler-derived mean aortic gradient greater than or equal to 50 mm Hg were specific (93 and 94%, respectively) for severe aortic stenosis (defined as catheterization-derived aortic valve area less than or equal to 0.75 cm2) but were not sensitive (44 and 48%, respectively). Doppler-derived aortic valve area calculated by the continuity equation correlated well with catheterization-derived aortic valve area calculated by the Gorlin equation when either the time-velocity integral ratio (r = 0.83) or the peak flow velocity ratio (r = 0.80) between the left ventricular outflow tract and the aortic valve was used in the continuity equation. A velocity ratio of less than or equal to 0.25 alone was sensitive (92%) in detecting severe aortic stenosis. Therefore, use of various Doppler-derived values allows reliable noninvasive estimation of the severity of aortic stenosis.

Surgical correction of mitral regurgitation in patients with no or mild symptoms remains controversial, particularly because the impact of preoperative symptoms on postoperative outcome is unknown.The long-term outcome of 478 patients with organic mitral regurgitation (199 in NYHA functional class I/II and 279 in class III/IV before surgery) operated on between 1984 and 1991 was analyzed. In patients in NYHA class I/II before surgery compared with those in class III/IV, postoperative long-term survival was higher (at 10 years, 76+/-5% versus 48+/-4%, P<0.0001), with lower operative mortality (0.5% versus 5.4%, P=0.003) and better late survival (P<0.0001). Comparison of observed and expected survival showed identical curves in patients in class I/II before surgery (P=0.18), whereas excess mortality was observed in patients in class III/IV before surgery (P<0.0001). Excess mortality associated with severe symptoms was also confirmed in all subgroups (all P<0.003) and in multivariate analysis (P=0.0036; adjusted hazard ratio [95% CI], 1.81 [1.21 to 2.70]).In patients with organic mitral regurgitation, preoperative functional class III/IV symptoms are associated with excess short- and long-term postoperative mortality independently of all baseline characteristics. These data should lead to consideration of surgical correction of severe organic mitral regurgitation when no or minimal symptoms are present in patients at low operative risk, especially if repair is feasible.

We attempted to determine the accuracy and pitfalls of calculating the mitral regurgitant orifice area with the proximal isovelocity surface area method in a clinical series that included patients with valvular prolapse and eccentric jets. The effective regurgitant orifice area, a measure of lesion severity of mitral regurgitation, can be calculated by the proximal isovelocity surface area method, the accuracy and pitfalls of which have not been established. In 119 consecutive patients with isolated mitral regurgitation, effective regurgitant orifice area was measured by the proximal isovelocity surface area method and compared with measurements simultaneously obtained by quantitative Doppler and quantitative two-dimensional echocardiography. The effective mitral regurgitant orifice area measured by the proximal isovelocity surface area method tended to be overestimated compared with that measured by quantitative Doppler and quantitative two-dimensional echocardiography (38 ± 39 vs. 36 ± 33 mm2[p = 0.09] and 34 ± 32 mm2[p = 0.02], respectively). Overestimation was limited to patients with prolapse (61 ± 43 vs. 56 ± 35 mm2[p = 0.05] and 54 ± 34 mm2[p = 0.014]) and was restricted to patients with nonoptimal flow convergence (n = 7; 137 ± 35 vs. 84 ± 34 mm2[p = 0.002] and 79 ± 33 mm2[p = 0.002]). In patients with optimal flow convergence (n = 112), excellent correlations with both reference methods were obtained (r = 0.97, SEE 6 mm2and r = 0.97, SEE 7 mm2, p < 0.0001). In calculating the mitral effective regurgitant orifice area with the proximal isovelocity surface area method, the observed pitfall (overestimation due to nonoptimal flow convergence) is rare. Otherwise, the method is reliable and can be used clinically in large numbers of patients.

Transesophageal echocardiography (TEE) is the diagnostic modality of choice for visualizing the left atrial appendage (LAA). This study defined the morphology of the LAA in normal autopsy specimen hearts and considered the implications of these findings for TEE studies.Five hundred normal autopsy hearts were reviewed (25 male and 25 female subjects from each decade for 10 decades). LAA length, width, orifice size, and number of lobes were recorded. Number of lobes was compared between sexes with the rank sum test and regressed against age. Mean length, width, and orifice size increased with age, up to age 20 years, in both sexes. Rates were significantly different between sexes for LAA size (P=.011) and width (P=.006). After age 20, statistically significant but clinically insignificant age-related changes were observed. Fifty-four percent of LAAs had two lobes (range, 1 to 4), with no age or sex differences. Lobes exist in different planes of the heart. Most pectinate muscles were > or = 1 mm in width. Pectinate muscles < 1 mm (2.6% of cases) were seen in only the first and last decades.Age- and sex-related differences in LAA dimensions exist. These differences and the existence of multilobed appendages are important in the accurate TEE evaluation of LAA. Because lobes exist in different planes, imaging must be done in multiple planes to visualize the entire LAA.

We sought to determine if echocardiography enhances prediction of first age-related cardiovascular events.Whether echocardiographic assessment improves risk stratification for first cardiovascular events is not well known.This retrospective cohort study included randomly selected residents of Olmsted County, Minnesota, age >/=65 years, who had >/=1 transthoracic echocardiograms at the Mayo Clinic between 1990 and 1998, in sinus rhythm, without valvular or congenital heart disease, and followed through medical records for first myocardial infarction (MI), coronary revascularization, atrial fibrillation (AF), congestive heart failure (CHF), transient ischemic attack (TIA), stroke, or cardiovascular death. Patients were excluded if they had any of these events before the baseline echocardiogram.Of 1,160 patients (age 75 +/- 7 years; 746 women) followed for a mean of 3.8 +/- 2.7 years, 333 (29%) first events occurred (70 AF, 67 coronary revascularization procedures, 65 CHF, 48 MI, 38 stroke, 25 TIA, and 20 cardiovascular deaths). In a multivariate model, age (p < 0.001), male gender (p < 0.001), diabetes mellitus (p = 0.005), systemic hypertension (p < 0.001), left atrial volume/body surface area >/=32 ml/m(2) (p = 0.003), left ventricular (LV) mass/height >/=120 g/m (p = 0.014), LV systolic dysfunction (p < 0.001), and LV diastolic dysfunction (p = 0.029) were independent predictors. A risk-scoring algorithm was developed and validated for the prediction of first events. The five-year event-free survival was 90%, 74%, and 50% for low-, medium-, and high-risk groups, respectively.Echocardiography enhanced prediction of first cardiovascular events in this referral-based elderly cohort. Its role in risk stratification for primary prevention of these events in the community warrants further investigations.

This study attempted to determine the incidence, prognosis and predictability of postoperative left ventricular dysfunction in patients undergoing correction of mitral regurgitation.Left ventricular function in patients with mitral regurgitation is altered by loading conditions and is difficult to assess. Predictive value of preoperative variables on postoperative left ventricular function and the role of echocardiography are uncertain.In 266 patients undergoing correction of mitral regurgitation between 1980 and 1989, left ventricular function was echocardiographically assessed preoperatively (within 6 months) and postoperatively (within 1 year).After correction of mitral regurgitation, left ventricular ejection fraction decreased significantly ([mean +/- SD] 50% +/- 14% vs. 58% +/- 13%, p < 0.0001). Postoperative left ventricular dysfunction (ejection fraction < 50%) was frequent (41% of patients) and carried a poor prognosis (at 8 years survival, 38% +/- 9% vs. 69% +/- 8%, p < 0.0001). Four preoperative echocardiographic variables showed good correlation with postoperative ejection fraction: preoperative ejection fraction (r = -0.70), systolic diameter (r = -0.63), diameter/thickness ratio (r = -0.64) and end-systolic wall stress (r = -0.62) (all p < 0.0001). With multivariate analysis, ejection fraction (p = 0.0001) and systolic diameter (p = 0.0005) were independent predictors of postoperative ejection fraction, and angiographic variables provided no incremental predictive power. In addition to echocardiographic variables, recent regurgitation, functional class and coronary artery disease were also independent predictors of postoperative ejection fraction.After surgical correction of mitral regurgitation, left ventricular dysfunction is frequent and carries a poor prognosis. Postoperative ejection fraction can be predicted by echocardiographic preoperative ejection fraction and systolic diameter. Recent onset of regurgitation, mild or no symptoms, and absence of coronary artery disease are independent and favorable predictors of postoperative ejection fraction. These results should lead to consideration of surgical correction at an earlier stage.

The Animal Models for Protecting Ischemic Myocardium Study was undertaken for the purpose of developing reproducible animal models that could be used to assess interventions designed to limit infarct size. This paper describes the results obtained in an unconscious dog model and in a conscious dog model, developed in three participating laboratories. The unconscious dog model, involving reperfusion after 3 hours of ischemia in open-chest dogs, was intended to determine whether therapy followed by early reperfusion would limit infarct size more than reperfusion alone. The conscious dog model used chronically instrumented dogs and permanent coronary occlusion to better mimic myocardial infarction in man. In both models, the proximal circumflex artery was occluded, and the primary experimental endpoint was infarct size, as measured by histological techniques 3 days after the initial occlusion. Infarct size was analyzed in relation to baseline variables including the anatomic area at risk, collateral blood flow to the subepicardial zone of ischemia and hemodynamic determinants of myocardial metabolic demand. Most of the variation in infarct size in control dogs could be related to variation in the area at risk, collateral blood flow, and rate pressure product. Using multivariate analysis and groups of 15 dogs, an intervention that limited infarct size by 10-13% of the area at risk would have been detected 50% of the time. Larger treatment effects would be detected more readily, and smaller effects often would be missed, unless group sizes were larger. Two drugs, verapamil and ibuprofen, were evaluated in both models, with experimental group sizes averaging 13 and 20 dogs, in the unconscious and conscious models, respectively. Three of 15 verapamil-treated dogs in the unconscious model study had much smaller infarcts than expected from baseline parameters. With these exceptions, neither drug limited infarct size in either model.

A general linear regression model for the usual least squares estimated rate of change (slope) on censoring time is described as an approximation to account for informative right censoring in estimating and comparing changes of a continuous variable in two groups. Two noniterative estimators for the group slope means, the linear minimum variance unbiased (LMVUB) estimator and the linear minimum mean squared error (LMMSE) estimator, are proposed under this conditional model. In realistic situations, we illustrate that the LMVUB and LMMSE estimators, derived under a simple linear regression model, are quite competitive compared to the pseudo maximum likelihood estimator (PMLE) derived by modeling the censoring probabilities. Generalizations to polynomial response curves and general linear models are also described.

The study was done to define the incidence, determinants and prognostic implications of onset of atrial fibrillation (AF) during follow-up of mitral regurgitation (MR) initially in sinus rhythm.The rates and clinical implications of AF in MR are undefined.We analyzed the occurrence of AF under conservative management in two populations of patients with degenerative MR in sinus rhythm at diagnosis: 1) 360 patients (65 +/- 13 years, 74% men) with MR due to flail leaflets; and 2) 89 residents of Olmsted County, Minnesota (67 +/- 17 years, 56% men) with grade 3 or 4 MR due to simple mitral valve prolapse (MVP) diagnosed echocardiographically.In patients with MR due to flail leaflets, AF rates at 5 and 10 years were 18 +/- 3% and 48 +/- 6%, respectively, and the linearized rate was 5.0 +/- 0.7% per year. Development of AF during follow-up was independently associated with high risk of cardiac death or heart failure (adjusted risk ratio 2.23, p = 0.025). The AF rate at 10 years was higher in patients >or=65 years (75 +/- 10% vs. 24 +/- 6%, p < 0.0001) and in those with baseline left atrial (LA) dimension >or=50 mm (67 +/- 8% vs. 37 +/- 9%, p < 0.001). In multivariate analysis, independent baseline predictors of AF were age and LA diameter (both p < 0.01). In patients with MR due to MVP, similar rates of AF (41 +/- 7% vs. 44 +/- 6% at nine years, p > 0.50) and predictors of AF (age and LA dimension, both p < 0.006) were noted.In patients with degenerative MR in sinus rhythm at diagnosis, the incidence of AF occurring under conservative management is high and similar whether the cause of MR is flail leaflet or simple MVP. After onset of AF, an increased cardiac mortality and morbidity are both observed under conservative management. The risk of AF increases with advancing age and larger LA dimension. These data suggest that the clinical management of MR should take into account the high incidence, excess risk, and predictors of AF.

The natural history of asymptomatic, hemodynamically significant, valvular aortic stenosis in adults was documented. Of 471 patients with aortic stenosis identified by Doppler echocardiography (peak systolic flow velocity ≥4 m/s) from January 1994 through August 1987, 143 were asymptomatic and had isolated valvular aortic stenosis. Thirty patients underwent aortic valve intervention within 3 months (group 1); the remaining 113 patients did not have an intervention within 3 months (group 2). Follow-up information was available for all patients; the mean duration of follow-up study was 20 months (range 6 to 48). Three cardiac events occurred in the 30 group 1 patients after operation (two deaths, one reoperation). Among the 113 group 2 patients, three had cardiac death presumed to be a result of the aortic stenosis; all three developed symptoms at least 3 months before death. The actuarial probability of remaining free of symptoms of angina, dyspnea or syncope for group 2 was 86% at 1 year and 62% at 2 years. For this group, the 1 and 2 year probabilities of remaining free of cardiac events, including aortic valve intervention or cardiac death, were 93% and 74%, respectively. Of all clinical and echocardiographic variables (group 2), only Doppler flow velocity (p = 0.004) and ejection fraction (p = 0.01) were independent predictors of subsequent cardiac events. Among the 44 patients (groups 1 and 2) with a flow velocity ≥4.5 m/s, the relative risk of sustaining a cardiac event (by Cox regression analysis) was 4.9 (p = 0.004). Patients with asymptomatic, hemodynamically significant aortic stenosis are at significant risk for cardiac events within 2 years. However, during the time they remain asymptomatic, the risk of sudden death is low. The asymptomatic patient may be treated medically but requires careful follow-up evaluation for the development of symptoms.

<h3>OBJECTIVE</h3> To evaluate consecutive therapeutic echocardiographically (echo)-guided pericardiocenteses performed at Mayo Clinic, Rochester, Minn, from 1979 to 2000 and to determine whether patient profiles, practice patterns, and outcomes have changed over time. <h3>Patients and Methods</h3> Consecutive echo-guided pericardiocenteses performed between February 1, 1979, and January 31, 2000, for treatment of clinically significant pericardial effusions were identified in the Mayo Clinic Echocardiographic-guided Pericardiocentesis Registry. The medical records of these patients were examined, and a follow-up survey was conducted. Clinical profiles, echocardiographic findings, procedural details, and outcomes were determined for 3 periods: February 1, 1979, through January 31, 1986; February 1, 1986, through January 31, 1993; and February 1, 1993, through January 31, 2000. <h3>Results</h3> During the 21-year study period, 1127 therapeutic echo-guided pericardiocenteses were performed in 977 patients. The mean ± SD age at pericardiocentesis increased from 49±14 years in period 1 to 57±14 years in period 3. in recent years, cardiothoracic surgery replaced malignancy as the leading cause of an effusion requiring pericardiocentesis and together with malignancy and perforation from catheter-based procedures accounted for nearly 70% of all pericardiocenteses performed. The procedural success rate was 97% overall, with a total complication rate of 4.7% (major, 1.2%; minor, 3.5%). These rates did not change significantly over time. The use of a pericardial catheter for extended drainage increased from 23% in period 1 to 75% in period 3 (P<.001), whereas rates of effusion recurrence and pericardial surgery decreased significantly <i>(P</i><.001). <h3>Conclusions</h3> The profile of patients presenting with clinically significant pericardial effusion has changed over time. Increasing numbers of older patients and those who have undergone cardiothoracic surgery or catheter-based procedures develop effusions that can be rapidly, safely, and effectively managed with echo-guided pericardiocentesis. Extended drainage with use of a pericardial catheter has become standard practice, and concomitantly, recurrence rates and need for surgical management have decreased considerably.

BACKGROUND We have previously characterized the left ventricular diastolic filling abnormalities in cardiac amyloidosis by Doppler methods. The various filling patterns were shown to be related to the degree of cardiac amyloid infiltration. The purpose of this study was to determine the value of Doppler diastolic filling variables for assessing prognosis in cardiac amyloidosis. METHODS AND RESULTS We performed pulsed-wave Doppler studies of the left ventricular inflow and obtained clinical follow-up data in 63 consecutive patients with biopsy-proven systemic amyloidosis. All patients had typical echocardiographic features of cardiac involvement. The patients were subdivided into two groups according to deceleration time: Group 1 (33 patients) had a deceleration time of 150 msec or less, indicative of restrictive physiology, and group 2 (30 patients) had a deceleration time of more than 150 msec. Of the 63 patients, 32 (51%) died during a mean follow-up period of 18 +/- 12 months. Of these deaths, 25 (78%) were cardiac deaths, and 19 of the 25 patients (76%) were from group 1. The 1-year probability of survival in group 1 was significantly less than that in group 2 (49% versus 92%, p less than 0.001). Bivariate analysis revealed that the combination of the Doppler variables of shortened deceleration time and increased early diastolic filling velocity to atrial filling velocity ratio were stronger predictors of cardiac death than were the two-dimensional echocardiographic variables of mean left ventricular wall thickness and fractional shortening. CONCLUSIONS Doppler-derived left ventricular diastolic filling variables are important predictors of survival in cardiac amyloidosis.

Sixty-four patients with primary systemic amyloidosis—53 with two-dimensional echocardiographic features of cardiac involvement (Group I) and 11 without cardiac involvement (Group II)—underwent Doppler echocardiographic assessment of left ventricular diastolic function. Pulsed wave Doppler recordings of left ventricular inflow velocities and pulmonary vein flow velocities with respiratory monitoring in these patients were compared with findings in a normal group. Patients in Group I showed striking abnormalities of left ventricular diastolic filling when classified into subgroups by mean left ventricular wall thickness: early >12 but <15 mm; advanced ≥15 mm. In early amyloidosis, relaxation was abnormal, with decreased peak early velocity (75 ± 20 versus 86 ± 16 cm/s; p < 0.01), increased late velocity (71 ± 22 versus 56 ± 13 cm/s; p < 0.01), decreased early to late velocity ratio (1.2 ± 0.6 versus 1.6 ± 0.5; p < 0.01) and prolonged isovolumic relaxation time (87 ± 15 versus 73 ± 13 ms; p < 0.01) compared with normal values. In advanced amyloidosis, there was a restrictive filling pattern with a markedly shortened deceleration time (148 ± 50 versus 199 ± 32 ms; p < 0.001), decreased pulmonary vein peak systolic flow velocity (34 ± 16 versus 54 ± 2 cm/s; p < 0.01) and increased diastolic flow velocity (55 ± 20 versus 44 ± 12 cm/s; p < 0.01) compared with normal values. Group II and the subgroup with early amyloidosis had similar flow velocity patterns. Thus, this study documents that in cardiac amyloidosis, a spectrum of diastolic filling abnormalities exists; the restrictive filling pattern is seen only in the advanced stages.

We sought to summarize and critically appraise the literature on the epidemiology of infective endocarditis (IE) in the general population. We retrieved population-based IE surveys by searching MEDLINE and EMBASE. Two reviewers independently extracted relevant data. We performed a metaregression to determine if temporal trends of IE characteristics exist. Fifteen population-based investigations with 2,371 IE cases from seven countries (Denmark, France, Italy, the Netherlands, Sweden, United Kingdom, and United States) from 1969 to 2000 were eligible. Different case definitions and procedures were used to capture all IE cases, including census of existing diagnoses, record-linkage system, and direct contact survey. In the unadjusted regression, there was a decline in the proportion of IE patients with underlying rheumatic heart disease (RHD; 12%; 95% confidence interval [CI], − 21 to − 3%; p = 0.01) and an increase in the proportion of patients undergoing valve surgery (9%; 95% CI, 3 to 16%) per decade. After adjusting for country, the decline in IE cases with underlying RHD became nonsignificant, but the proportions of IE patients undergoing valve surgery increased 7% per decade (95% CI, − 4 to 14%; p = 0.06), and those with underlying prosthetic valve increased 7% per decade (95% CI, − 1 to 16%; p = 0.07). There were no significant temporal trends in the causative organisms. Evidence from well-planned, representative IE epidemiologic surveys is scarce in many countries. Available studies suggest a changing distribution of underlying valvular heart disease in patients with IE and an increase in its surgical treatment.

The effect of recombinant hirudin and the dosage of heparin on acute platelet-thrombus deposition during carotid angioplasty in anesthetized pigs was prospectively assessed. Fifty-five animals (mean weight, 33.9 kg) were randomized to one of six heparin dosages: heparin boluses of 35, 50, 100, 150, 200, or 250 units/kg followed by a continuous infusion of 35, 50, 100, 150, 200, or 250 units/kg/hr, respectively. Another five pigs received a bolus of 1 mg/kg hirudin (recombinant desulphatohirudin), a specific thrombin inhibitor, followed by an infusion of 1 mg/kg/hr. Bilateral carotid angioplasty was performed in all pigs 20 minutes after starting the infusion; they were sacrificed 57 +/- 12 minutes after the procedure. Deep medial arterial injury was present in approximately 75% of the dilated segments, and subendothelial injury in the remaining 25%. Mean log of number of platelets and molecules of fibrinogen per centimeter squared of deep injury in segments from all the animals treated with heparin were 4.74 +/- 1.03 and 5.02 +/- 0.64, respectively. A regression analysis showed an inverse correlation of the log of platelet deposition with the heparin group (r = -0.56, p = 0.0001) with administered total units of heparin (r = -0.55, p = 0.0003) and with mean plasma heparin concentration (r = -0.55, p = 0.0004) in deeply injured arteries. Similar inverse relations were obtained for fibrinogen. In contrast, the deposition of platelets and fibrinogen in subendothelial injury was very low and independent of the heparin administered.(ABSTRACT TRUNCATED AT 250 WORDS)

Left atrial (LA) volume is a barometer of diastolic dysfunction. Whether it predicts congestive heart failure (CHF) in patients with preserved left ventricular (LV) systolic function is not known. Olmsted County, Minnesota, residents aged ≥65 years referred for transthoracic echocardiography from 1990 to 1998, who were in sinus rhythm without a history of CHF were followed in the medical records to 2003 (mean follow-up duration 4.3 ± 2.7 years). Of the 1,495 patients identified, 1,375 (92%) with LV ejection fractions ≥50% (mean age 75 ± 7 years; 59% women) constituted the study population, 138 (10%) of whom developed CHF. Baseline LA volume ≥32 ml/m2 was an independent predictor of first CHF (p <0.001). Of the 138 patients who had first CHF, ejection fractions were assessed within 4 weeks of diagnosis in 98 subjects, 74 (76%) of whom had ejection fractions remaining at ≥50%, with a mean increase in LA volume of 8 ± 10 ml/m2 (p <0.001) from baseline. The age-adjusted CHF-free survival rates for LA volume tertiles (<28, 28 to ≤37, and >37 ml/m2) were 95%, 91%, and 83%, respectively (p <0.001). In conclusion, LA volume independently predicted first CHF in an elderly cohort with well-preserved LV systolic function. Left atrial (LA) volume is a barometer of diastolic dysfunction. Whether it predicts congestive heart failure (CHF) in patients with preserved left ventricular (LV) systolic function is not known. Olmsted County, Minnesota, residents aged ≥65 years referred for transthoracic echocardiography from 1990 to 1998, who were in sinus rhythm without a history of CHF were followed in the medical records to 2003 (mean follow-up duration 4.3 ± 2.7 years). Of the 1,495 patients identified, 1,375 (92%) with LV ejection fractions ≥50% (mean age 75 ± 7 years; 59% women) constituted the study population, 138 (10%) of whom developed CHF. Baseline LA volume ≥32 ml/m2 was an independent predictor of first CHF (p <0.001). Of the 138 patients who had first CHF, ejection fractions were assessed within 4 weeks of diagnosis in 98 subjects, 74 (76%) of whom had ejection fractions remaining at ≥50%, with a mean increase in LA volume of 8 ± 10 ml/m2 (p <0.001) from baseline. The age-adjusted CHF-free survival rates for LA volume tertiles (<28, 28 to ≤37, and >37 ml/m2) were 95%, 91%, and 83%, respectively (p <0.001). In conclusion, LA volume independently predicted first CHF in an elderly cohort with well-preserved LV systolic function.

The measurement of multiple protein biomarkers may refine risk stratification in clinical settings. This concept has stimulated development of multiplexed immunoassay platforms that provide multiple, parallel protein measurements on the same specimen.We provide an overview of antibody-based multiplexed immunoassay platforms and discuss technical and operational challenges. Multiplexed immunoassays use traditional immunoassay principles in which high-affinity capture ligands are immobilized in parallel arrays in either planar format or on microspheres in suspension. Development of multiplexed immunoassays requires rigorous validation of assay configuration and analytical performance to minimize assay imprecision and inaccuracy. Challenges associated with multiplex configuration include selection and immobilization of capture ligands, calibration, interference between antibodies and proteins and assay diluents, and compatibility of assay limits of quantification. We discuss potential solutions to these challenges. Criteria for assessing analytical multiplex assay performance include the range of linearity, analytical specificity, recovery, and comparison to a quality reference method. Quality control materials are not well developed for multiplexed protein immunoassays, and algorithms for interpreting multiplex quality control data are needed.Technical and operational challenges have hindered implementation of multiplexed assays in clinical settings. Formal procedures that guide multiplex assay configuration, analytical validation, and quality control are needed before broad application of multiplexed arrays can occur in the in vitro diagnostic market.

<h3>Importance</h3> After percutaneous coronary intervention (PCI), patients with<i>CYP2C19*2</i>or<i>*3</i>loss-of-function (LOF) variants treated with clopidogrel have increased risk of ischemic events. Whether genotype-guided selection of oral P2Y12 inhibitor therapy improves ischemic outcomes is unknown. <h3>Objective</h3> To determine the effect of a genotype-guided oral P2Y12 inhibitor strategy on ischemic outcomes in<i>CYP2C19</i>LOF carriers after PCI. <h3>Design, Setting, and Participants</h3> Open-label randomized clinical trial of 5302 patients undergoing PCI for acute coronary syndromes (ACS) or stable coronary artery disease (CAD). Patients were enrolled at 40 centers in the US, Canada, South Korea, and Mexico from May 2013 through October 2018; final date of follow-up was October 2019. <h3>Interventions</h3> Patients randomized to the genotype-guided group (n = 2652) underwent point-of-care genotyping.<i>CYP2C19</i>LOF carriers were prescribed ticagrelor and noncarriers clopidogrel. Patients randomized to the conventional group (n = 2650) were prescribed clopidogrel and underwent genotyping after 12 months. <h3>Main Outcomes and Measures</h3> The primary end point was a composite of cardiovascular death, myocardial infarction, stroke, stent thrombosis, and severe recurrent ischemia at 12 months. A secondary end point was major or minor bleeding at 12 months. The primary analysis was in patients with<i>CYP2C19</i>LOF variants, and secondary analysis included all randomized patients. The trial had 85% power to detect a minimum hazard ratio of 0.50. <h3>Results</h3> Among 5302 patients randomized (median age, 62 years; 25% women), 82% had ACS and 18% had stable CAD; 94% completed the trial. Of 1849 with<i>CYP2C19</i>LOF variants, 764 of 903 (85%) assigned to genotype-guided therapy received ticagrelor, and 932 of 946 (99%) assigned to conventional therapy received clopidogrel. The primary end point occurred in 35 of 903<i>CYP2C19</i>LOF carriers (4.0%) in the genotype-guided therapy group and 54 of 946 (5.9%) in the conventional therapy group at 12 months (hazard ratio [HR], 0.66 [95% CI, 0.43-1.02];<i>P</i> = .06). None of the 11 prespecified secondary end points showed significant differences, including major or minor bleeding in<i>CYP2C19</i>LOF carriers in the genotype-guided group (1.9%) vs the conventional therapy group (1.6%) at 12 months (HR, 1.22 [95% CI, 0.60-2.51];<i>P</i> = .58). Among all randomized patients, the primary end point occurred in 113 of 2641 (4.4%) in the genotype-guided group and 135 of 2635 (5.3%) in the conventional group (HR, 0.84 [95% CI, 0.65-1.07];<i>P</i> = .16). <h3>Conclusions and Relevance</h3> Among<i>CYP2C19</i>LOF carriers with ACS and stable CAD undergoing PCI, genotype-guided selection of an oral P2Y12 inhibitor, compared with conventional clopidogrel therapy without point-of-care genotyping, resulted in no statistically significant difference in a composite end point of cardiovascular death, myocardial infarction, stroke, stent thrombosis, and severe recurrent ischemia based on the prespecified analysis plan and the treatment effect that the study was powered to detect at 12 months. <h3>Trial Registration</h3> ClinicalTrials.gov Identifier:NCT01742117

Giant cell myocarditis (GCM) is a rare and highly lethal disorder. The only multicenter case series with treatment data lacked cardiac function assessments and had a retrospective design. We conducted a prospective, multicenter study of immunosuppression including cyclosporine and steroids for acute, microscopically-confirmed GCM. From June 1999 to June 2005 in a standard protocol, 11 subjects received high dose steroids and cyclosporine, and 9 subjects received muromonab-CD3. In these, 7 of 11 were women, the mean age was 60 ± 15 years, and the mean time from symptom onset to presentation was 27 ± 33 days. During 1 year of treatment, 1 subject died of respiratory complications on day 178, and 2 subjects received heart transplantations on days 2 and 27, respectively. Serial endomyocardial biopsies revealed that after 4 weeks of treatment the degree of necrosis, cellular inflammation, and giant cells decreased (p = 0.001). One patient who completed the trial subsequently died of a fatal GCM recurrence after withdrawal of immunosuppression. Her case demonstrates for the first time that there is a risk of recurrent, sometimes fatal, GCM after cessation of immunosuppression. In conclusion, this prospective study of immunosuppression for GCM confirms retrospective case reports that such therapy improves long-term survival. Additionally, withdrawal of immunosuppression can be associated with fatal GCM recurrence. Giant cell myocarditis (GCM) is a rare and highly lethal disorder. The only multicenter case series with treatment data lacked cardiac function assessments and had a retrospective design. We conducted a prospective, multicenter study of immunosuppression including cyclosporine and steroids for acute, microscopically-confirmed GCM. From June 1999 to June 2005 in a standard protocol, 11 subjects received high dose steroids and cyclosporine, and 9 subjects received muromonab-CD3. In these, 7 of 11 were women, the mean age was 60 ± 15 years, and the mean time from symptom onset to presentation was 27 ± 33 days. During 1 year of treatment, 1 subject died of respiratory complications on day 178, and 2 subjects received heart transplantations on days 2 and 27, respectively. Serial endomyocardial biopsies revealed that after 4 weeks of treatment the degree of necrosis, cellular inflammation, and giant cells decreased (p = 0.001). One patient who completed the trial subsequently died of a fatal GCM recurrence after withdrawal of immunosuppression. Her case demonstrates for the first time that there is a risk of recurrent, sometimes fatal, GCM after cessation of immunosuppression. In conclusion, this prospective study of immunosuppression for GCM confirms retrospective case reports that such therapy improves long-term survival. Additionally, withdrawal of immunosuppression can be associated with fatal GCM recurrence.

Obesity has been shown to be a risk factor for first atrial fibrillation (AF), but whether it is associated with progression from paroxysmal to permanent AF is unknown.In this longitudinal cohort study, Olmsted County, MN residents confirmed to have developed paroxysmal AF during 1980-2000 were identified and followed passively to 2006. The interrelationships of body mass index (BMI), left atrial (LA) size, and progression to permanent AF were analysed. Of a total of 3248 patients (mean age 71 +/- 15 years; 54% men) diagnosed with paroxysmal AF, 557 (17%) progressed to permanent AF (unadjusted incidence, 36/1000 person-years) over a median follow-up period of 5.1 years (interquartile range 1.2-9.4). Adjusting for age and sex, BMI independently predicted the progression to permanent AF (hazard ratio, HR 1.04, CI 1.03-1.06; P < 0.0001). Compared with normal BMI (18.5-24.9 kg/m(2)), obesity (30-34.9 kg/m(2)) and severe obesity (>or=35 kg/m(2)) were associated with increased risk for progression [HR 1.54 (CI 1.2-2.0; P = 0.0004) and 1.87 (CI 1.4-2.5; P < 0.0001, respectively)]. BMI remained highly significant even after multiple adjustments. In the subgroup with echocardiographic assessment (n = 744), LA volume was incremental to BMI for independent prediction of progression after multiple adjustments, and did not weaken the association between BMI and progression to permanent AF (HR 1.04; CI 1.02-1.05; P < 0.0001).There was a graded risk relationship between BMI and progression from paroxysmal to permanent AF. This relationship was not weakened by LA volume, which was independent of and incremental to BMI for the prediction of progression to permanent AF.

Fuchs's corneal dystrophy (FCD) is a leading cause of corneal transplantation and affects 5% of persons in the United States who are over the age of 40 years. Clinically visible deposits called guttae develop under the corneal endothelium in patients with FCD. A loss of endothelial cells and deposition of an abnormal extracellular matrix are observed microscopically. In advanced disease, the cornea swells and becomes cloudy because the remaining endothelial cells are not sufficient to keep the cornea dehydrated and clear. Although rare genetic variation that contributes to both early-onset and typical late-onset forms of FCD has been identified, to our knowledge, no common variants have been reported.

Genome-wide association studies (GWASs) have identified many SNPs underlying variations in plasma-lipid levels. We explore whether additional loci associated with plasma-lipid phenotypes, such as high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), and triglycerides (TGs), can be identified by a dense gene-centric approach. Our meta-analysis of 32 studies in 66,240 individuals of European ancestry was based on the custom ∼50,000 SNP genotyping array (the ITMAT-Broad-CARe array) covering ∼2,000 candidate genes. SNP-lipid associations were replicated either in a cohort comprising an additional 24,736 samples or within the Global Lipid Genetic Consortium. We identified four, six, ten, and four unreported SNPs in established lipid genes for HDL-C, LDL-C, TC, and TGs, respectively. We also identified several lipid-related SNPs in previously unreported genes: DGAT2, HCAR2, GPIHBP1, PPARG, and FTO for HDL-C; SOCS3, APOH, SPTY2D1, BRCA2, and VLDLR for LDL-C; SOCS3, UGT1A1, BRCA2, UBE3B, FCGR2A, CHUK, and INSIG2 for TC; and SERPINF2, C4B, GCK, GATA4, INSR, and LPAL2 for TGs. The proportion of explained phenotypic variance in the subset of studies providing individual-level data was 9.9% for HDL-C, 9.5% for LDL-C, 10.3% for TC, and 8.0% for TGs. This large meta-analysis of lipid phenotypes with the use of a dense gene-centric approach identified multiple SNPs not previously described in established lipid genes and several previously unknown loci. The explained phenotypic variance from this approach was comparable to that from a meta-analysis of GWAS data, suggesting that a focused genotyping approach can further increase the understanding of heritability of plasma lipids. Genome-wide association studies (GWASs) have identified many SNPs underlying variations in plasma-lipid levels. We explore whether additional loci associated with plasma-lipid phenotypes, such as high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), and triglycerides (TGs), can be identified by a dense gene-centric approach. Our meta-analysis of 32 studies in 66,240 individuals of European ancestry was based on the custom ∼50,000 SNP genotyping array (the ITMAT-Broad-CARe array) covering ∼2,000 candidate genes. SNP-lipid associations were replicated either in a cohort comprising an additional 24,736 samples or within the Global Lipid Genetic Consortium. We identified four, six, ten, and four unreported SNPs in established lipid genes for HDL-C, LDL-C, TC, and TGs, respectively. We also identified several lipid-related SNPs in previously unreported genes: DGAT2, HCAR2, GPIHBP1, PPARG, and FTO for HDL-C; SOCS3, APOH, SPTY2D1, BRCA2, and VLDLR for LDL-C; SOCS3, UGT1A1, BRCA2, UBE3B, FCGR2A, CHUK, and INSIG2 for TC; and SERPINF2, C4B, GCK, GATA4, INSR, and LPAL2 for TGs. The proportion of explained phenotypic variance in the subset of studies providing individual-level data was 9.9% for HDL-C, 9.5% for LDL-C, 10.3% for TC, and 8.0% for TGs. This large meta-analysis of lipid phenotypes with the use of a dense gene-centric approach identified multiple SNPs not previously described in established lipid genes and several previously unknown loci. The explained phenotypic variance from this approach was comparable to that from a meta-analysis of GWAS data, suggesting that a focused genotyping approach can further increase the understanding of heritability of plasma lipids.

Background— Whether knowledge of genetic risk for coronary heart disease (CHD) affects health-related outcomes is unknown. We investigated whether incorporating a genetic risk score (GRS) in CHD risk estimates lowers low-density lipoprotein cholesterol (LDL-C) levels. Methods and Results— Participants (n=203, 45–65 years of age, at intermediate risk for CHD, and not on statins) were randomly assigned to receive their 10-year probability of CHD based either on a conventional risk score (CRS) or CRS + GRS ( + GRS). Participants in the + GRS group were stratified as having high or average/low GRS. Risk was disclosed by a genetic counselor followed by shared decision making regarding statin therapy with a physician. We compared the primary end point of LDL-C levels at 6 months and assessed whether any differences were attributable to changes in dietary fat intake, physical activity levels, or statin use. Participants (mean age, 59.4±5 years; 48% men; mean 10-year CHD risk, 8.5±4.1%) were allocated to receive either CRS (n=100) or + GRS (n=103). At the end of the study period, the + GRS group had a lower LDL-C than the CRS group (96.5±32.7 versus 105.9±33.3 mg/dL; P =0.04). Participants with high GRS had lower LDL-C levels (92.3±32.9 mg/dL) than CRS participants ( P =0.02) but not participants with low GRS (100.9±32.2 mg/dL; P =0.18). Statins were initiated more often in the + GRS group than in the CRS group (39% versus 22%, P &lt;0.01). No significant differences in dietary fat intake and physical activity levels were noted. Conclusions— Disclosure of CHD risk estimates that incorporated genetic risk information led to lower LDL-C levels than disclosure of CHD risk based on conventional risk factors alone. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT01936675.

Key Points VTE recurrence risk in patients with cancer can be stratified by cancer type, stage, stage progression, and presence of leg paresis. Patients with cancer at high VTE recurrence risk should be considered for secondary prophylaxis.

Background: Cardiomyocytes are resistant to radiation. However, cardiac radiation exposure causes coronary microvascular endothelial inflammation, a perturbation implicated in the pathogenesis of heart failure (HF) and particularly HF with preserved ejection fraction (HFpEF). Radiotherapy for breast cancer results in variable cardiac radiation exposure and may increase the risk of HF. Methods: We conducted a population-based case-control study of incident HF in 170 female residents of Olmsted County, Minnesota (59 cases and 111 controls), who underwent contemporary (1998–2013) radiotherapy for breast cancer with computed tomography–assisted radiotherapy planning. Controls were matched to cases for age, tumor side, chemotherapy use, diabetes mellitus, and hypertension. Mean cardiac radiation dose (MCRD) in each patient was calculated from the patient’s computed tomography images and radiotherapy plan. Results: Mean age at radiotherapy was 69±9 years. Of HF cases, 38 (64%) had EF≥50% (HFpEF), 18 (31%) had EF&lt;50% (HF with reduced EF), and 3 (5%) did not have EF measured. The EF was ≥40% in 50 of the 56 HF cases (89%) with an EF measurement. The mean interval from radiotherapy to HF was 5.8±3.4 years. The odds of HF was higher in patients with a history of ischemic heart disease or atrial fibrillation. The MCRD was 2.5 Gy (range, 0.2–13.1 Gy) and higher in cases (3.3±2.7 Gy) than controls (2.1±2.0 Gy; P =0.004). The odds ratio (95% confidence interval) for HF per log MCRD was 9.1 (3.4–24.4) for any HF, 16.9 (3.9–73.7) for HFpEF, and 3.17 (0.8–13.0) for HF with reduced EF. The increased odds of any HF or HFpEF with increasing MCRD remained significant after adjustment for HF risk factors and in sensitivity analyses matching by cancer stage rather than tumor side. Only 18.6% of patients experienced new or recurrent ischemic events between radiotherapy and the onset of HF. Conclusions: The relative risk of HFpEF increases with increasing cardiac radiation exposure during contemporary conformal breast cancer radiotherapy. These data emphasize the importance of radiotherapy techniques that limit MCRD during breast cancer treatment. Moreover, these data provide further support for the importance of coronary microvascular compromise in the pathophysiology of HFpEF.

Common genetic variation in CYP2C19 (cytochrome P450, family 2, subfamily C, polypeptide 19) *2 and *3 alleles leads to a loss of functional protein, and carriers of these loss-of-function alleles when treated with clopidogrel have significantly reduced clopidogrel active metabolite levels and high on-treatment platelet reactivity resulting in increased risk of major adverse cardiovascular events, especially after percutaneous coronary intervention. The Food and Drug Administration has issued a black box warning advising practitioners to consider alternative treatment in CYP2C19 poor metabolizers who might receive clopidogrel and to identify such patients by genotyping. However, routine clinical use of genotyping for CYP2C19 loss-of-function alleles in patients undergoing percutaneous coronary intervention is not recommended by clinical guidelines because of lack of prospective evidence. To address this critical gap, TAILOR-PCI (Tailored Antiplatelet Initiation to Lessen Outcomes due to Decreased Clopidogrel Response After Percutaneous Coronary Intervention) is a large, pragmatic, randomized trial comparing point-of-care genotype-guided antiplatelet therapy with routine care to determine whether identifying CYP2C19 loss-of-function allele patients prospectively and prescribing alternative antiplatelet therapy is beneficial.

The aim of this study was to examine the effect of CYP2C19 genotype on clinical outcomes in patients with coronary artery disease (CAD) who predominantly underwent percutaneous coronary intervention (PCI), comparing those treated with ticagrelor or prasugrel versus clopidogrel.The effect of CYP2C19 genotype on treatment outcomes with ticagrelor or prasugrel compared with clopidogrel is unclear.Databases through February 19, 2020, were searched for studies reporting the effect of CYP2C19 genotype on ischemic outcomes during ticagrelor or prasugrel versus clopidogrel treatment. Study eligibility required outcomes reported for CYP2C19 genotype status and clopidogrel and alternative P2Y12 inhibitors in patients with CAD with at least 50% undergoing PCI. The primary analysis consisted of randomized controlled trials (RCTs). A secondary analysis was conducted by adding non-RCTs to the primary analysis. The primary outcome was a composite of cardiovascular death, myocardial infarction, stroke, stent thrombosis, and severe recurrent ischemia. Meta-analysis was conducted to compare the 2 drug regimens and test interaction with CYP2C19 genotype.Of 1,335 studies identified, 7 RCTs were included (15,949 patients, mean age 62 years; 77% had PCI, 98% had acute coronary syndromes). Statistical heterogeneity was minimal, and risk for bias was low. Ticagrelor and prasugrel compared with clopidogrel resulted in a significant reduction in ischemic events (relative risk: 0.70; 95% confidence interval: 0.59 to 0.83) in CYP2C19 loss-of-function carriers but not in noncarriers (relative risk: 1.0; 95% confidence interval: 0.80 to 1.25). The test of interaction on the basis of CYP2C19 genotype status was statistically significant (p = 0.013), suggesting that CYP2C19 genotype modified the effect. An additional 4 observational studies were found, and adding them to the analysis provided the same conclusions (p value of the test of interaction <0.001).The effect of ticagrelor or prasugrel compared with clopidogrel in reducing ischemic events in patients with CAD who predominantly undergo PCI is based primarily on the presence of CYP2C19 loss-of-function carrier status. These results support genetic testing prior to prescribing P2Y12 inhibitor therapy.

Early identification of patients with symptomless left-ventricular dysfunction and early pharmacologic intrervention may have an impact on the outlook of patients with heart failure. Atrial natriuretic peptide (ANP) is a cardiac hormone that is released as a C-terminal (C-ANP) and an N-terminal peptide (N-ANP). Since N-ANP has reduced clearance rates compared with C-ANP, N-ANP circulates at higher concentrations. Based on the known increased concentration of C-ANP in symptomatic congestive heart failure, our study was designed to evaluate prospectively N-ANP profile and left-ventricular function in subjects with symptomless and symptomatic heart failure, and the role of plasma N-ANP as a marker for early identification of patients with heart failure.180 patients who were referred for rest and exercise radionuclide angiography for evaluation of left-ventricular function were studied. Blood was taken for measurement of C-AN P and N-AN P before angiography. Patients were grouped according to New York Heart Association (NYHA) heart failure classification and left-ventricular function. Mean (SD) plasma N-ANP concentration in patients with symptomless left-ventricular dysfunction (NYHA class I, n=70) was 243 (256) pmol/L (range 27-922 pmol/L), and was higher (p<0·001) than in 25 control subjects (28 [13] pmol/L). A plasma N-ANP concentration above 54 pmol/L (mean±1·96SD of the control group) had a sensitivity of 90% and a specificity of 92% for detection of patients with symptomless left-ventricular dysfunction.We have shown that plasma N-ANP concentrations are significantly increased in patients with symptomless left-ventricular dysfunction and that this peptide can serve as a marker for diagnosis of such patients.

We studied the rate of thromboembolism in patients undergoing bioprosthetic replacement of the aortic or mitral valve, or both, at serial intervals after operation and the effects of anticoagulant or antiplatelet treatment and risk factors.Thromboembolism appears to occur early after operation, but the incidence, timing and risk factors for thromboembolism and the role, timing, adequacy, effectiveness, duration and risk of anticoagulation and antiplatelet agents are uncertain.The rate of thromboembolism was studied at three time intervals after operation (1 to 10, 11 to 90 and > 90 days) in 816 patients who underwent bioprosthetic replacement of the aortic or mitral valve, or both, at the Mayo Clinic from January 1975 to December 1982. The effect of antithrombotic therapy (warfarin, aspirin or dipyridamole, alone or in combination) was evaluated.Median follow-up of surviving patients was 8.6 years. The rate of thromboembolism (%/year) decreased significantly (p < 0.01) at each time interval after operation (1 to 10, 11 to 90 and > 90 days) for mitral valve replacement (55%, 10% and 2.4%/year, respectively) and over the first time interval for aortic valve replacement (41%, 3.6% and 1.9%/year, respectively). During the first 10 days, 52% to 70% of prothrombin time ratios were low (< 1.5 x control). Patients with mitral valve replacement who received anticoagulation had a lower rate of thromboembolism for the entire follow-up period (2.5%/year with vs. 3.9%/year without anticoagulation, p = 0.05). Of 112 patients with a first thromboembolic episode, permanent disability occurred in 38% and death in 4%. Risk factors for emboli were lack of anticoagulation, mitral valve location, history of thromboembolism and increasing age. Only 10% of aortic, 44% of mitral and 17% of double valve recipients had anticoagulation at the time of an event. Patients with bleeding episodes (2.3%/year) were older and usually underwent anticoagulation. Blood transfusions were required in 60 of 111 patients (1.2%/year), and 13 patients (0.3%/year) died.Thromboembolic risk was especially high for aortic and mitral valve replacement for 90 days after operation, and overall was increased with lack of anticoagulation, mitral valve location, previous thromboembolism and increasing age. Anticoagulation reduced thromboemboli and appears to be indicated in all patients as early as possible for 3 months and thereafter in those with risk factors, but needs prospective testing.

Aortic valve replacement for aortic stenosis (AS) carries an increased risk in the presence of left ventricular (LV) systolic dysfunction. Few data are available on the outcome of such patients.Between 1985 and 1992, 154 consecutive patients (107 men and 47 women) with LV systolic dysfunction (ejection fraction [EF] < or = 35%) underwent aortic valve replacement for AS. The mean preoperative characteristics included EF, 27 +/- 6%; aortic valve mean gradient, 44 +/- 18 mm Hg; aortic valve area, 0.6 +/- 0.2 cm2; and cardiac output, 4.1 +/- 1.5 L/min. Simultaneous coronary artery bypass graft surgery was performed in 78 patients (51%). Perioperative (30-day) mortality was 9% (14 of 154 patients). Fifty patients died during follow-up. Coronary artery disease (P = .002) and a reduced preoperative cardiac output (P = .03) were significantly related to reduced overall survival rate by multivariate analysis. Postoperative improvement occurred in most patients; 88% were New York Heart Association class III or IV before surgery versus 7% after surgery. Postoperative EF was assessed in 76% of survivors; 76% of these demonstrated improvement. By multivariate analysis, change in EF was inversely related to coronary disease (P = .002) and preoperative aortic valve area (P = .03).Despite LV dysfunction, the risk of aortic valve replacement for AS was acceptable and related to coronary artery disease and mean aortic gradient, and long-term survival was related to coronary disease and cardiac output. Improvement in symptoms and EF occurred in most patients.

Quantitation of valvular regurgitation remains a challenge. The accuracy of quantitative Doppler is controversial, and its ability to measure regurgitant volume is unknown; therefore, it is not widely used.In 120 patients (20 without regurgitation, 19 with aortic regurgitation, and 81 with mitral regurgitation), the stroke volume through the mitral annulus and left ventricular outflow tract were measured using pulsed-wave Doppler concurrently with left ventricular stroke volume calculated using left ventricular volumes measured by two-dimensional echocardiography Simpson's biapical method. Regurgitant volume and fraction were thus computed using Doppler or ventricular methods. In normal patients there were good correlations between Doppler and left ventricular measurements of stroke volume. Doppler regurgitant volume and fraction were 4.4 +/- 4.4 mL and 5.3 +/- 4.5%, respectively. In patients with aortic regurgitation, there were good correlations between Doppler and left ventricular measurements of stroke volume, regurgitant volume, and regurgitant fraction (r = 0.97, r = 0.95, and r = 0.93, respectively; p < 0.0001). In patients with mitral regurgitation, despite good correlations between Doppler and ventricular methods for stroke volume, regurgitant volume, and regurgitant fraction (r = 0.94, r = 0.93, and r = 0.94, respectively; p < 0.001), these variables were overestimated by Doppler. However, in the last 54 patients compared with the first 27, overestimation decreased significantly for regurgitant volume (5 +/- 10 mL versus 18 +/- 27 mL, p < 0.05) and regurgitant fraction (3.3 +/- 6.7% versus 6.2 +/- 6.8%, p = 0.05).Quantitative Doppler can be performed in large numbers of patients in a clinical laboratory. Its potential limitation was identified as overestimation of mitral regurgitation, which is overcome with increased experience. Its achieved accuracy in mitral and aortic regurgitation allows measurement not only of regurgitant fraction but most importantly of regurgitant volume.

To determine standard left ventricular Doppler measurements in a large reference group of various ages to reflect the senescence process.We prospectively studied the influence of aging on left ventricular diastolic filling by performing Doppler echocardiography in 117 normal healthy volunteers.Transthoracic pulsed-wave Doppler echocardiographic studies of pulmonary venous flow and left ventricular inflow were done in the 53 male and 64 female study subjects. For analysis, the study subjects were arbitrarily classified into two groups: those younger than 50 years of age (group 1; N = 61) and those 50 years old or older (group 2; N = 56).A striking difference was found in pulmonary venous flow and left ventricular inflow between group 1 and group 2 subjects. Group 2 had increased pulmonary venous peak systolic flow velocity (71 +/- 9 versus 48 +/- 9 cm/s), decreased peak diastolic flow velocity (38 +/- 9 versus 50 +/- 10 cm/s), increased peak atrial reversal flow velocity (23 +/- 4 versus 19 +/- 4 cm/s), and increased percentage of forward flow in systole (65 +/- 7 versus 55 +/- 8%) in comparison with group 1. In group 2, peak early filling velocity (62 +/- 14 versus 72 +/- 14 cm/s) and ratio of early filling to atrial filling (1.1 +/- 0.3 versus 1.9 +/- 0.6) were lower and peak atrial filling velocity (59 +/- 14 versus 40 +/- 10 cm/s) was higher than in group 1. Deceleration time (210 +/- 36 versus 179 +/- 20 ms) and isovolumic relaxation time (90 +/- 17 versus 76 +/- 11 ms) were prolonged in group 2 in comparison with group 1.This study confirms the major influence of the aging process on left ventricular diastolic function in a large series of normal subjects. This physiologic factor should be considered in Doppler assessment of left ventricular diastolic filling in future studies.

The purpose of this study was to determine the feasibility, relation to other methods and significance of the effective regurgitant orifice area measurement.Assessment of the severity of valvular regurgitation (effective regurgitant orifice area) has not been implemented in clinical practice but can be made by Doppler echocardiography.Effective regurgitant orifice area was calculated by Doppler echocardiography as the ratio of regurgitant volume/regurgitant jet time-velocity integral and compared with color flow Doppler mapping, angiography, surgical classification, regurgitant fraction and variables of volume overload.In 210 consecutive patients examined prospectively, feasibility improved from the early to the late experience (65% to 95%). Effective regurgitant orifice area was 28 +/- 23 mm2 (mean +/- SD) for aortic regurgitation (32 patients), 22 +/- 13 mm2 for ischemic/functional mitral regurgitation (50 patients) and 41 +/- 32 mm2 for organic mitral regurgitation (82 patients). Significant correlations were found between effective regurgitant orifice and mitral jet area by color flow Doppler mapping (r = 0.68 and r = 0.63, p < 0.0001, respectively) and angiographic grade (r = 0.77, p = 0.0004). Effective regurgitant orifice area in surgically determined moderate and severe lesions was markedly different in mitral regurgitation (35 +/- 12 and 75 +/- 33 mm2, respectively, p = 0.009) and in aortic regurgitation (21 +/- 8 and 38 +/- 5 mm2, respectively, p = 0.08). Strong correlations were found between effective regurgitant orifice area and variables reflecting volume overload. A logarithmic regression was found between effective regurgitant orifice area and regurgitant fraction, underlining the complementarity of these indexes.Calculation of effective regurgitant orifice area is a noninvasive Doppler development of an old hemodynamic concept, allowing assessment of the lesion severity of valvular regurgitation. Feasibility is excellent with experience. Effective regurgitant orifice area is an important and clinically significant index of regurgitation severity. It brings additive information to other quantitative indexes and its measurement should be implemented in the comprehensive assessment of valvular regurgitation.

We sought to assess the incidence and determinants of sudden death (SUD) in mitral regurgitation due to flail leaflet (MR-FL).Sudden death is a catastrophic complication of MR-FL. Its incidence and predictability are undefined.The occurrence of SUD was analyzed in 348 patients (age 67 +/- 12 years) with MR-FL diagnosed echocardiographically from 1980 through 1994.During a mean follow-up of 48 +/- 41 months, 99 deaths occurred under medical treatment. Sudden death occurred in 25 patients, three of whom were resuscitated. The sudden death rates at five and 10 years were 8.6 +/- 2% and 18.8 +/- 4%, respectively, and the linearized rate was 1.8% per year. By multivariate analysis, the independent baseline predictors of SUD were New York Heart Association (NYHA) functional class (p = 0.006), ejection fraction (p = 0.0001) and atrial fibrillation (p = 0.059). The yearly linearized rate of sudden death was 1% in patients in functional class I, 3.1% in class II and 7.8% in classes III and IV. However, of 25 patients who had SUD, at baseline, 10 (40%) were in functional class I, 9 (36%) were in class II and only 6 (24%) in class III or IV. In five patients (20%), no evidence of risk factors developed until SUD. In patients with an ejection fraction > or =60% and sinus rhythm, the linearized rate of SUD was not different in functional classes I and II (0.8% per year). Surgical correction of MR (n = 186) was independently associated with a reduced incidence of SUD (adjusted hazard ratio [95% confidence interval] 0.29 [0.11 to 0.72], p = 0.007).Sudden death is relatively common in patients with MR-FL who are conservatively managed. Patients with severe symptoms, atrial fibrillation and reduced systolic function are at higher risk, but notable rates of SUD have been observed without these risk factors. Correction of MR appears to be associated with a reduced incidence of SUD, warranting early consideration of surgical repair.

157 caucasian male patients undergoing vascular surgery for atherosclerosis and a matched control group of patients with high cholesterol levels were screened for antibodies to cytomegalovirus (CMV) and herpes simplex virus type 1 (HSV1) and type 2 (HSV2), indicative of persistent infection. The prevalence of CMV antibodies was higher in the surgical group than in the control group (90% and 74%, respectively), and a significantly greater percentage (p<0.001) of surgical cases than controls had high titres of CMV antibodies (57% and 26%, respectively). Small but not significant differences in antibodies to HSV1 were observed, and there were no differences in HSV2 antibody titres. For each virus there was no correlation between antibody titre and blood levels of total cholesterol or triglycerides. It is suggested that periodically activated virus may have a role in the pathogenesis of atherosclerosis.

Objectives. This study sought to analyze the determinants of pulmonary hypertension in patients with left ventricular dysfunction. Background. Pulmonary hypertension in patients with left ventricular dysfunction is a predictor of poor outcome. The independent role of cardiac functional abnormalities in the genesis of pulmonary hypertension is unclear. Methods. In 102 consecutive patients with primary left ventricular dysfunction (ejection fraction <50%), systolic pulmonary artery pressure was prospectively measured by Doppler echocardiography (using tricuspid regurgitant velocity), and left ventricular systolic and diastolic function, functional mitral regurgitation, cardiac output and left atrial volume were quantified. Results. Systolic pulmonary artery pressure was elevated in patients with left ventricular dysfunction (51 ± 14 mm Hg [mean ± SD]), but the range was wide (23 to 87 mm Hg). Of the numerous variables correlating significantly with systolic pulmonary artery pressure, the strongest were mitral deceleration time (r = −0.61, p = 0.0001; odds ratio of pulmonary pressure ≥50 mm Hg [95% confidence interval] if <150 ms, 48.8 [14.8 to 161]) and mitral effective regurgitant orifice (r = 0.50, p = 0.0001; odds ratio [95% confidence interval] if ≥20 mm2, 5.9 [2.3 to 15.5]). In multivariate analysis, these two variables were the strongest predictors of systolic pulmonary artery pressure in association with age (p = 0.005). Ejection fraction or end-systolic volume was not an independent predictor of pulmonary artery pressure. Conclusions. Pulmonary hypertension is frequent and highly variable in patients with left ventricular dysfunction. It is not independently related to the degree of left ventricular systolic dysfunction but is strongly associated with diastolic dysfunction (shorter mitral deceleration time) and the degree of functional mitral regurgitation (larger effective regurgitant orifice). These results emphasize the importance of assessing diastolic function and quantifying mitral regurgitation in patients with left ventricular dysfunction. (J Am Coll Cardiol 1997;29:153–9)>

To determine the clinical importance of left atrial (LA) volume in the prediction of first ischemic stroke.This retrospective cohort study included randomly selected residents of Olmsted County, Minnesota, aged 65 years or older, who had undergone transthoracic echocardiography at least once at the Mayo Clinic in Rochester, Minn, between January 1, 1990, and December 31, 1998, were in sinus rhythm, and had no history of stroke, transient ischemic attack, atrial fibrillation, or valvular heart disease. Patients were monitored through medical records for first ischemic stroke or death.Of 1554 residents (59% women) aged 75+/-7 years, 92 (6%) had experienced at least 1 ischemic stroke over 4.3+/-2.7 years (incident stroke rate, 1.4 per 100 person-years). Left atrial volume of 32 mL/m2 or greater (hazard ratio [HR], 1.63; confidence interval [CI], 1.08-2.46) was independent of age (HR, 1.04; CI, 1.02-1.07), diabetes (HR, 1.91; CI, 1.07-3.41), myocardial infarction (HR, 1.64; CI, 1.01-2.64), and hyperlipidemia (HR, 1.55; CI, 1.01-2.37) for the prediction of first ischemic stroke. When quartiles of LA dimension were plotted against quartiles of indexed LA volume, a stepwise increase in risk with each quartile increment was evident only for indexed LA volume. Also, an LA volume of 32 mL/m2 or greater was associated with an increased mortality risk (HR, 1.30; CI, 1.09-1.56), independent of age, sex, and stroke status.In our elderly cohort with no prior atrial fibrillation, LA volume was independently predictive of first ischemic stroke, incremental to age, diabetes, myocardial infarction, and hyperlipidemia. It was also an independent predictor of death.

Preclinical systolic or diastolic dysfunction is associated with increased morbidity and mortality. We postulated that plasma brain natriuretic peptide (BNP) might serve as a biomarker for preclinical ventricular dysfunction (PCVD) but that the discriminatory values for BNP may vary with age and sex.We measured BNP, systolic and diastolic ventricular function, and clinical parameters in 2042 randomly selected residents of Olmsted County, Minn, aged 45 years or older. For preclinical systolic dysfunction, the areas under the receiver operating characteristics curve were higher for those with more severe (0.82 to 0.92) than any (0.51 to 0.74) systolic dysfunction and were similar in men and women and in younger and older persons. For preclinical diastolic dysfunction, the areas under the receiver operating characteristics curve were higher for those with moderate-to-severe (0.74 to 0.79) than any (0.52 to 0.68) diastolic dysfunction and were similar regardless of age or sex. Optimal discriminatory values of BNP varied with age and sex. Considering the prevalence of preclinical systolic or diastolic dysfunction and the predictive characteristics observed, using BNP to screen for PCVD would necessitate echo in 10% to 40% of those screened, with most confirmatory echocardiograms being negative, and would miss 10% to 60% of those affected.BNP is a suboptimal screening test for PCVD in the population.

Left ventricular filling pressures can be estimated reliably by combining mitral inflow early diastolic velocity (E) and annulus velocity (E'). An increased E/E' ratio reflects elevated filling pressures and may be useful in assessing an abnormal increase in filling pressures for patients with diastolic dysfunction. The purpose of this study was to evaluate the feasibility of supine bicycle exercise Doppler echocardiography for assessing left ventricular diastolic pressure during exercise. Mitral inflow and septal mitral annulus velocities were measured at rest and during supine bicycle exercise (25-W 3-minute increments) in 45 patients (19 men; mean age, 59 years) referred for evaluation of exertional dyspnea. None had echocardiographic or electrocardiographic evidence of myocardial ischemia with exercise. Patients were classified according to E/E' ratio at rest: 26 had E/E' < or = 10 at rest (group 1) and 19 had E/E' > 10 (group 2). For group 1, 17 had no increase in E/E' during exercise (group 1A) and 9 did (group 1B). For group 2, E/E' did not increase during exercise. Despite different responses of E/E', there was no significant difference in changes of mitral inflow indices (E, A, E/A, deceleration time) between groups. Although the percentage of dyspnea as a primary reason for stopping exercise was similar for the groups, exercise duration was significantly shorter for groups 1B (7.2 +/- 2.5 minutes) and 2 (7.1 +/- 3.3 minutes) than in group 1A (10.4 +/- 3.7 minutes, P = .0129). Diastolic stress echocardiography using a supine bicycle is technically feasible for demonstrating changes in E/E' (filling pressure) with exercise. Our preliminary results suggest the hemodynamic consequences of exercise-induced increase in diastolic filling pressure can be demonstrated noninvasively with exercise Doppler echocardiography.

We sought evidence of a change in the prevalence of atrial fibrillation (AF) over a 30-year period among residents of Rochester, Minnesota. Atrial fibrillation is increasingly encountered in clinical practice, but there is limited data on secular trends of AF over time. Within a longitudinal case-control study of ischemic stroke, the prevalence of AF and of selected comorbid conditions among incident stroke cases and age- and gender-matched controls between 1960 and 1989 was determined. The mean age ± standard deviation for the 1,871 stroke cases (45% men) and matched controls was 75 ± 11 years. For cases, age-adjusted estimates of AF prevalence for 1960 to 1969, 1970 to 1979, and 1980 to 1989 were 11%, 13%, and 16%, respectively, for men, and 13%, 16%, and 20% for women. For controls, the rates were 5%, 8%, and 12%, respectively, for men, and 4%, 6%, and 8% for women. Increasing AF prevalence was associated with increasing age (doubling of odds per decade of age in both cases and controls) and calendar time adjusted for age and gender (cases: odds ratio [OR] per 5 years 1.13, 95% confidence interval [CI], 1.05 to 1.22; controls: OR per 5 years 1.24, 95% CI 1.12 to 1.37). The rates of increase with calendar time were significant for cases (p = 0.001) and controls (p < 0.001) and comparable between the genders. The prevalence of AF increased significantly in ischemic stroke patients and their controls from 1960 to 1989 in Rochester, Minnesota, independent of age and gender. The rate of increase did not differ significantly between men and women.

Idiopathic restrictive cardiomyopathy is a poorly recognized entity of unknown cause characterized by nondilated, nonhypertrophied ventricles with diastolic dysfunction resulting in dilated atria and variable systolic function.Between 1979 and 1996, 94 patients (61% women) 10 to 90 years old (mean, 64 years) met strict morphological echocardiographic criteria for idiopathic restrictive cardiomyopathy, mainly dilated atria with nonhypertrophied, nondilated ventricles. None had known infiltrative disease, hypertension of >5 years' duration, or cardiac or systemic conditions associated with restrictive filling. Nineteen percent were in NYHA class I, 53% in class II, and 28% in class III or IV. Atrial fibrillation was noted in 74% of patients and systolic dysfunction in 16%. Follow-up (mean, 68 months) was complete for 93 patients (99%). At follow-up, 47 patients (50%) had died, 32 (68%) of cardiovascular causes. Four had heart transplantation. The death rate compared with actuarial statistics was significantly higher than expected (P<0.0001). Kaplan-Meier 5-year survival was 64%, compared with expected survival of 85%. Multivariate analysis using proportional hazards showed that the risk of death approximately doubles with male sex (hazard ratio [HR] = 2.1), left atrial dimension >60 mm (HR = 2.3), age >70 years (HR = 2.0), and each increment of NYHA class (HR = 2.0).Idiopathic restrictive cardiomyopathy or nondilated, nonhypertrophic ventricles with marked biatrial dilatation, as defined morphologically by echocardiography, affects predominantly elderly patients but can occur in any age group. Patients present with systemic and pulmonary venous congestion and atrial fibrillation and have a poor prognosis, particularly men >70 years old with higher NYHA class and left atrial dimension >60 mm.

Hypertrophic cardiomyopathy is a disease entity characterized by marked heterogeneity in morphology and natural history. Most of our knowledge of the natural history of this disorder derives from the study of hospital-based populations and is influenced by referral bias. Therefore, this population-based study was undertaken to examine the natural history of hypertrophic cardiomyopathy among unselected residents of Olmsted County, Minnesota.Patients with hypertrophic cardiomyopathy, confirmed by echocardiography, were identified by use of the resources of the Rochester Epidemiology Project. Patients with the echocardiographic features of hypertrophic cardiomyopathy but with long-standing hypertension requiring drug therapy were categorized as having hypertensive hypertrophic cardiomyopathy. Baseline clinical details and follow-up events were obtained by retrospective chart review. Thirty-seven patients were diagnosed with hypertrophic cardiomyopathy and 24 with hypertensive hypertrophic cardiomyopathy. Eight additional patients were first diagnosed at autopsy. The mean age of the 37 patients with hypertrophic cardiomyopathy was 59 +/- 20 years (range, 1 week to 92 years); the mean ventricular septal thickness was 17.5 +/- 3 mm. Follow-up was obtained for a median of 7.7 years (range, 45 days to 17.2 years). The 1- and 5-year survival rates were 95% and 92%, respectively; these rates did not differ from those of an age- and sex-matched population (P = NS). The annual risk of cardiac death was 0.7%. The mean age of patients with hypertensive hypertrophic cardiomyopathy was 79 +/- 8 years (range, 62 to 91 years), and the mean ventricular septal thickness was 19 +/- 2.5 mm. Follow-up was obtained for a median of 2.8 years (range, 4 days to 16.7 years). The 1- and 5-year survival rates were 75% and 43%, respectively, which differed sharply from the expected rates of 94% and 70% (P = .0028). The annual risk of cardiac death was 5%. Atrial fibrillation and evidence for myocardial infarction on ECG, use of digoxin and diuretics, and a high New York Heart Association functional class at presentation were all associated with decreased survival by multivariate analysis for both groups combined. A history of myocardial infarction, atrial fibrillation, and mitral annual calcification at presentation were associated with cardiac death.Hypertrophic cardiomyopathy is a more benign disease than previously reported from tertiary referral centers. Patients assessed as having hypertensive hypertrophic cardiomyopathy represent a subset at higher risk for cardiac and noncardiac death, with an overall decreased survival rate.

The aim of this prospective study was to evaluate the incremental value of left atrial (LA) function for the prediction of risk for first atrial fibrillation (AF) or atrial flutter. Maximum and minimum LA volumes were quantitated by echocardiography in 574 adults (mean age 74 ± 6 years, 52% men) without a history or evidence of atrial arrhythmia. During a mean follow-up period of 1.9 ± 1.2 years, 30 subjects (5.2%) developed electrocardiographically confirmed AF or atrial flutter. Subjects with new AF or atrial flutter had lower LA reservoir function, as measured by total LA emptying fraction (38% vs 49%, p <0.0001) and higher maximum LA volumes (47 vs 40 ml/m2, p = 0.005). An increase in age-adjusted risk for AF or atrial flutter was evident when the cohort was stratified according to medians of LA emptying fraction (≤49%: hazard ratio 6.5, p = 0.001) and LA volume (≥38 ml/m2: hazard ratio 2.0, p = 0.07), with the risk being highest for subjects with concomitant LA emptying fractions ≤49% and LA volume ≥38 ml/m2 (hazard ratio 9.3, p = 0.003). LA emptying fraction (p = 0.002) was associated with risk for first AF or atrial flutter after adjusting for baseline clinical risk factors for AF or atrial flutter, left ventricular ejection fraction, diastolic function grade, and LA volume. In conclusion, reduced LA reservoir function markedly increases the propensity for first AF or atrial flutter, independent of LA volume, left ventricular function, and clinical risk factors. The aim of this prospective study was to evaluate the incremental value of left atrial (LA) function for the prediction of risk for first atrial fibrillation (AF) or atrial flutter. Maximum and minimum LA volumes were quantitated by echocardiography in 574 adults (mean age 74 ± 6 years, 52% men) without a history or evidence of atrial arrhythmia. During a mean follow-up period of 1.9 ± 1.2 years, 30 subjects (5.2%) developed electrocardiographically confirmed AF or atrial flutter. Subjects with new AF or atrial flutter had lower LA reservoir function, as measured by total LA emptying fraction (38% vs 49%, p <0.0001) and higher maximum LA volumes (47 vs 40 ml/m2, p = 0.005). An increase in age-adjusted risk for AF or atrial flutter was evident when the cohort was stratified according to medians of LA emptying fraction (≤49%: hazard ratio 6.5, p = 0.001) and LA volume (≥38 ml/m2: hazard ratio 2.0, p = 0.07), with the risk being highest for subjects with concomitant LA emptying fractions ≤49% and LA volume ≥38 ml/m2 (hazard ratio 9.3, p = 0.003). LA emptying fraction (p = 0.002) was associated with risk for first AF or atrial flutter after adjusting for baseline clinical risk factors for AF or atrial flutter, left ventricular ejection fraction, diastolic function grade, and LA volume. In conclusion, reduced LA reservoir function markedly increases the propensity for first AF or atrial flutter, independent of LA volume, left ventricular function, and clinical risk factors.

The optimal timing for surgery in patients with mitral regurgitation is disputed. Because of the frequency of left ventricular dysfunction, which is difficult to predict, early surgery has been recommended, but its potential benefits have not been demonstrated.The outcomes of 221 patients (mean age, 65 +/- 13 years; 71% males) with flail leaflets diagnosed with two-dimensional echocardiography between 1980 and 1989 who were eligible for operation were analyzed. Group I comprised 63 patients who had early mitral valve surgery (within 1 month after diagnosis). Group II comprised 158 patients initially treated conservatively (80 of whom were operated on later). Group I patients were younger (P=.009), had more symptoms (P<.0001), and were more frequently in atrial fibrillation (P=.023) than group II patients. There was no difference in ejection fraction between the groups. The early surgery strategy was followed by an improved overall survival rate (P=.028) and a lower incidence of cardiovascular deaths (P=.025), congestive heart failure (P=.046), and new chronic atrial fibrillation (P=.032), as confirmed by multivariate analysis (adjusted risk ratios of 0.31, 0.18, 0.38, and 0.05, respectively; all P<.02).In patients with mitral regurgitation due to flail leaflets, the strategy of early surgery versus conservative management is associated with an improved long-term survival rate, decreased cardiac mortality, and decreased morbidity after diagnosis. This outcome advantage suggests that early surgery is a reasonable treatment option to be considered in low-risk candidates with repairable valves and severe mitral regurgitation.

BACKGROUND The implications of hypotension occurring during dobutamine stress echocardiography have not been elucidated. We observed in some patients that hyperdynamic left ventricular function developed during dobutamine stress echocardiography and hypothesized that intracavitary obstruction was occurring and might account for hypotension in some patients. METHODS AND RESULTS Fifty-seven consecutive patients undergoing dobutamine stress echocardiography underwent pulsed-wave and continuous-wave Doppler examination of the left ventricular cavity at rest and at peak dobutamine infusion. The development of an intraventricular gradient with dobutamine stress was defined as a late-peaking left ventricular Doppler velocity profile that exceeded basal velocity by at least 1 m/sec. During dobutamine stress testing, left ventricular outflow velocity or intracavitary velocity increased in all patients. Obstruction occurred in 12 patients (21%, group 1). Group 2 was the remaining 45 patients. Peak velocities in group 1 ranged from 2.0 to 5.0 m/sec (mean, 3.5 m/sec), and the mean increase from velocity at rest was 2.3 m/sec. The mean change in systolic blood pressure was significantly lower in patients in group 1 (-15 versus 4 mm Hg, p = 0.02). When the 18 patients with an ischemic response to stress testing (evidenced by new or worsening wall motion abnormalities) were excluded from analysis, systolic blood pressure response was still significantly different for the two groups (-19 versus 2 mm Hg, p = 0.03). CONCLUSIONS Dynamic left ventricular obstruction is a new observation; it may develop frequently in patients undergoing dobutamine stress echocardiography. Obstruction rather than ischemia may explain a decrease in blood pressure during dobutamine stress echocardiography.

We prospectively assessed the influence of aging on the prevalence of valvular regurgitation by using color flow imaging. One hundred eighteen healthy volunteers (21 to 82 years old) had a two-dimensional Doppler echocardiographic study that included color flow imaging to assess valvular regurgitation and that was semiquantitated by mapping the dimensions of the color flow regurgitant jet in orthogonal views. The subjects were divided into two groups: group 1 consisted of subjects who were younger than 50 years old (n = 61), and group 2 consisted of subjects who were at least 50 years old (n = 57). Mitral regurgitation was detected in 57 (48%) of the 118 subjects: 24 subjects (39%) in group 1 and 33 subjects (58%) in group 2. The severity of mitral regurgitation was trivial to mild. Aortic regurgitation was detected in 13 (11%) of the 118 subjects, all in group 2. The severity was trivial to mild. Tricuspid regurgitation was detected in 77 (65%) of the 118 subjects: 35 (57%) in group 1 and 42 (74%) in group 2. The severity was trivial to mild. Pulmonary regurgitation was detected in 24 (31%) of 78 subjects: nine (22%) in group 1 and 15 (41%) in group 2. The severity was trivial. These findings suggest that valvular regurgitation of a trivial or mild degree is a frequent finding in normal subjects and that it increases with age.

To determine levels of natriuretic peptides (NPs) in patients with end-stage renal disease (ESRD) and to examine the relationship of these cardiovascular peptides to left ventricular hypertrophy (LVH) and to cardiac mortality.One hundred twelve dialysis patients without clinical evidence of congestive heart failure underwent plasma measurement of NP concentrations and echocardiographic investigation for left ventricular mass index (LVMI).Plasma atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) concentrations correlated positively with LVMI and inversely with left ventricular ejection fraction, whereas C-type NP and Dendroaspis NP levels did not correlate with LVMI. In dialysis patients with LVH (LVMI >125 g/m2), plasma ANP and BNP concentrations were increased compared with those in dialysis patients without LVH (both P<001). In a subset of 15 dialysis patients without LVH or other concomitant diseases, plasma BNP concentrations were not significantly increased compared with those in 35 controls (mean +/- SD, 20.1+/-13.4 vs 13.5+/-9.6 pg/mL; P=.06), demonstrating that the BNP concentration was not increased by renal dysfunction alone. Furthermore, the BNP level was significantly higher in the 16 patients who died from cardiovascular causes compared with survivors (mean +/- SD, 129+/-13 vs 57+/-7 pg/mL; P<.003) and was significantly associated with greater risk of cardiovascular death in Cox regression analysis (P<.001), as was the ANP level (P=.002).Elevation of the plasma BNP concentration is more specifically related to LVH compared with the other NP levels in patients with ESRD independent of congestive heart failure. Thus, BNP serves as an important plasma biomarker for ventricular hypertrophy in dialysis patients with ESRD.

Left atrial (LA) size is an important predictor of cardiovascular events. Various methods of LA volume assessment exist, but their differences have not been defined. This prospective study included 631 patients (331 men; mean age of 68 ± 14 years) without a history of atrial arrhythmias, stroke, valvular heart disease, pacemaker implantation, or congenital heart disease. All underwent echocardiography with comprehensive diastolic function assessment and LA volume measurement by 3 commonly used methods: biplane area–length, biplane Simpson’s method, and the prolate-ellipsoid method. Mean LA volumes were 39 ± 14 ml/m2 by the area–length method, 38 ± 13 ml/m2 by the Simpson’s method, and 32 ± 14 ml/m2 by the prolate-ellipsoid method. In 92% of patients, the prolate measurement was smaller than the 2 biplane methods. Pairwise correlations (r) were 0.98 for area–length versus Simpson’s, 0.85 for prolate versus area–length, and 0.86 for prolate versus Simpson’s (all p values <0.001). For distinguishing normal (n = 62) from pseudonormal diastolic function (n = 240) using receiver-operating curve analysis, areas under the curves were 0.76, 0.78, and 0.75 for the area–length, Simpson’s, and prolate methods, respectively (all p values <0.001, no significant intermethod differences). In conclusion, our findings suggest that there are systematic differences among existing LA volume methods. Biplane area–length and Simpson’s methods compare closely, whereas the prolate-ellipsoid method generally yields smaller volumes. Left atrial (LA) size is an important predictor of cardiovascular events. Various methods of LA volume assessment exist, but their differences have not been defined. This prospective study included 631 patients (331 men; mean age of 68 ± 14 years) without a history of atrial arrhythmias, stroke, valvular heart disease, pacemaker implantation, or congenital heart disease. All underwent echocardiography with comprehensive diastolic function assessment and LA volume measurement by 3 commonly used methods: biplane area–length, biplane Simpson’s method, and the prolate-ellipsoid method. Mean LA volumes were 39 ± 14 ml/m2 by the area–length method, 38 ± 13 ml/m2 by the Simpson’s method, and 32 ± 14 ml/m2 by the prolate-ellipsoid method. In 92% of patients, the prolate measurement was smaller than the 2 biplane methods. Pairwise correlations (r) were 0.98 for area–length versus Simpson’s, 0.85 for prolate versus area–length, and 0.86 for prolate versus Simpson’s (all p values <0.001). For distinguishing normal (n = 62) from pseudonormal diastolic function (n = 240) using receiver-operating curve analysis, areas under the curves were 0.76, 0.78, and 0.75 for the area–length, Simpson’s, and prolate methods, respectively (all p values <0.001, no significant intermethod differences). In conclusion, our findings suggest that there are systematic differences among existing LA volume methods. Biplane area–length and Simpson’s methods compare closely, whereas the prolate-ellipsoid method generally yields smaller volumes.

We analyzed the clinical characteristics and outcomes of 47 patients with severe pulmonary hypertension (PHT) and severe aortic valve stenosis (AS) from 1987 to 1999.The prognostic implications of severe pulmonary hypertension in patients with severe AS are poorly understood.The mean age of patients was 78 years (range 47 to 91 years), and 37 patients (79%) were in New York Heart Association (NYHA) functional class III or IV. Aortic valve replacement (AVR) was performed in 37 patients (79%) and 10 patients (21%) were treated conservatively.In the group that had AVR, there were six perioperative deaths (16%) and nine late deaths, resulting in a total mortality of 32%. In the conservatively treated group, there were eight deaths (80%) on follow-up. Severe PHT was an independent predictor of perioperative mortality. However, perioperative mortality was independent of the severity of left ventricular systolic dysfunction or concomitant coronary artery bypass grafting. Aortic valve replacement was associated with significant improvement in left ventricular ejection fraction, the severity of PHT and NYHA functional class. The difference between long-term survival of the operative survivors and the expected survival from life tables was not statistically significant.The prognosis for patients with AS and severe PHT treated conservatively without AVR is dismal. Although AVR is associated with higher than usual mortality, the potential benefits outweigh the risk of surgery.

The study objectives were 1) to assess the long-term outcome of patients with biopsy-proved lymphocytic myocarditis (Dallas criteria), and 2) to compare the outcome of these patients with that of patients with idiopathic dilated cardiomyopathy. Endomyocardial biopsy is frequently performed in patients presenting with dilated cardiomyopathy to identify lymphocytic myocarditis. Most previous studies of the natural history of myocarditis were performed before the establishment of the Dallas criteria. Thus, it is important to evaluate the prognostic value of positive endomyocardial biopsy findings in patients presenting with dilated cardiomyopathy, using standardized criteria for lymphocytic myocarditis. All endomyocardial biopsy results from the Mayo Clinic (October 1979 to April 1988) with a diagnosis of myocarditis were reclassified according to the Dallas criteria. Patients whose biopsy specimens showed borderline or lymphocytic myocarditis were included in the study group; those with systemic inflammatory diseases known to be associated with myocardial involvement were excluded. Study group survival was compared with that for a cohort of patients with idiopathic dilated cardiomyopathy seen at the Mayo Clinic from 1976 to 1987 who had endomyocardial biopsy findings negative for myocarditis. Biopsy specimens from 41 patients met the Dallas criteria for a diagnosis of myocarditis (n = 28) or borderline myocarditis (n = 13). Of these 41 patients, 9 were excluded because of the presence of systemic diseases known to be associated with myocarditis, and 5 patients were excluded because of lack of available follow-up data. The myocarditis study group therefore included 27 patients (10 with borderline myocarditis, 17 with myocarditis). Fifty-eight patients with a diagnosis of idiopathic dilated cardiomyopathy who underwent endomyocardial biopsy served as the comparison cohort. Ejection fraction was lower in patients with idiopathic dilated cardiomyopathy ([mean ± SD] 25 ± 11%) than in those with myocarditis (38 ± 19%, p = 0.001), even though a higher proportion of myocarditis group patients were in New York Heart Association functional class III or IV (63%) than patients in the dilated cardiomyopathy group (30%, p = 0.005). There was no difference in 5-year survival rate between the myocarditis and idiopathic dilated cardiomyopathy groups (56% vs. 54%, respectively). This study demonstrates that the long-term outcome of patients with biopsy-proved myocarditis seen in a referral setting is poor, although no different from that of patients with idiopathic dilated cardiomyopathy. With the current lack of proved effective treatment for lymphocytic myocarditis and no demonstration of survival benefit for patients with myocarditis, these data suggest that endomyocardial biopsy performed to exclude myocarditis is of limited prognostic value in the routine evaluation of dilated cardiomyopathy.

Coronary balloon angioplasty of chronic total occlusions is associated with relatively low success rates and a high incidence of restenosis. Whether there is long-term benefit in performing angioplasty of these lesions is unknown. The purpose of the present report was to analyze the long-term outcome of a large series of patients undergoing this procedure.A computerized database analysis of 354 consecutive patients (from 1979 to 1990) who underwent coronary angioplasty of a chronic total coronary occlusion was performed (mean age, 62.3 years). Initial technical success was achieved in 69%; in 66%, success was achieved without procedural death or need for coronary artery surgery. During hospitalization, six patients suffered myocardial infarction, nine required emergency bypass surgery, and nine patients died. During a mean follow-up period of 2.7 years, no difference was found in survival or freedom from myocardial infarction among 234 successfully dilated patients compared with 120 patients with a failed attempt. However, the use of coronary artery bypass surgery was significantly less after successful dilation (p less than 0.0001 versus failed attempt). No significant difference in the cumulative incidence of severe angina was observed between these two patient populations, with the majority remaining asymptomatic. Restenosis occurred in 59% of 69 patients who returned for follow-up angiography.Successful recanalization is achieved in the majority of patients undergoing angioplasty of chronic total occlusions and reduces the need for coronary artery bypass surgery. However, no major impact on either survival or incidence of myocardial infarction was noted after successful recanalization when patients with surgery were included.

This study was performed to define the rates and determinants of progression of organic mitral regurgitation (MR).Severe MR has major clinical consequences, but the rates and determinants of progression of the degree of regurgitation are unknown. Quantitative Doppler echocardiographic methods allow the quantitation of regurgitant volume (RVol), regurgitant fraction (RF) and effective regurgitant orifice (ERO) to define progression of MR.In a prospective study of MR progression, 74 patients had two quantitative Doppler echocardiographic examinations of MR (with at least two methods) 561 +/- 423 days apart without an intervening event.Progression of MR was observed, with increase in RVol (77 +/- 46 ml vs. 65 +/- 40 ml, p < 0.0001), RF (47 +/- 16% vs. 43% +/- 15%, p < 0.0001), and ERO (50 +/- 35 mm2 vs. 41 +/- 28 mm2, p < 0.0001). Annual rates (95% confidence interval) were, respectively, 7.4 ml/year (5.1, 9.7), 2.9%/year (1.9, 3.9) and 5.9 mm2/year (3.9, 7.8). However, wide individual variation was observed, and regression and progression of RVol >8 ml was found in 11% and 51%, respectively. In multivariate analysis, independent predictors of progression of RVol were progression of the lesions, particularly a new flail leaflet (p = 0.0003), and progression of mitral annulus diameter (p = 0.0001). Regression of MR was associated with marked changes in afterload, particularly decreased blood pressure (p = 0.008). No significant effect of treatment was detected.Organic MR tends to progress over time with increase in volume overload (RVol) due to increase in ERO. Progression of MR is variable and determined by progression of lesions or mitral annulus size. These data should help plan follow up of patients with organic MR and future intervention trials.

To evaluate consecutive therapeutic echocardiographically (echo)-guided pericardiocenteses performed at Mayo Clinic, Rochester, Minn, from 1979 to 2000 and to determine whether patient profiles, practice patterns, and outcomes have changed over time.Consecutive echo-guided pericardiocenteses performed between February 1, 1979, and January 31, 2000, for treatment of clinically significant pericardial effusions were identified in the Mayo Clinic Echocardiographic-guided Pericardiocentesis Registry. The medical records of these patients were examined, and a follow-up survey was conducted. Clinical profiles, echocardiographic findings, procedural details, and outcomes were determined for 3 periods: February 1, 1979, through January 31, 1986; February 1, 1986, through January 31, 1993; and February 1, 1993, through January 31, 2000.During the 21-year study period, 1127 therapeutic echo-guided pericardiocenteses were performed in 977 patients. The mean +/- SD age at pericardiocentesis increased from 49+/-14 years in period 1 to 57+/-14 years in period 3. In recent years, cardiothoracic surgery replaced malignancy as the leading cause of an effusion requiring pericardiocentesis and together with malignancy and perforation from catheter-based procedures accounted for nearly 70% of all pericardiocenteses performed. The procedural success rate was 97% overall, with a total complication rate of 4.7% (major, 1.2%; minor, 3.5%). These rates did not change significantly over time. The use of a pericardial catheter for extended drainage increased from 23% in period 1 to 75% in period 3 (P<.001), whereas rates of effusion recurrence and pericardial surgery decreased significantly (P<.001).The profile of patients presenting with clinically significant pericardial effusion has changed over time. Increasing numbers of older patients and those who have undergone cardiothoracic surgery or catheter-based procedures develop effusions that can be rapidly, safely, and effectively managed with echo-guided pericardiocentesis. Extended drainage with use of a pericardial catheter has become standard practice, and concomitantly, recurrence rates and need for surgical management have decreased considerably.

Objective— This study was undertaken to examine the association between bicuspid aortic valve (BAV) and aortic dilatation in the community. The association between BAV and aortic dilatation has been reported predominantly in retrospective studies in patients mostly with valvular dysfunction or selected surgical patients from tertiary referral centers. An independent association of BAV and aortic dilatation in a community-based study has not been demonstrated. Methods and Results— In a geographically defined population of Olmsted County, Minnesota, residents with BAV (n=44, age 35±13 years) without hemodynamically significant obstruction or regurgitation and matched controls with normal tricuspid aortic valves were identified by transthoracic echocardiography. The two groups were compared with respect to measurements of the aorta. The BAV and control groups differed with respect to size of the aortic anulus (23.2±2.4 versus 21.6±2.4 mm; P =0.002), aortic sinus (33.5±4.6 versus 30.3±4.1 mm; P =0.0001), and proximal ascending aorta (33.3±6.5 versus 27.9±3.6 mm; P =0.0001). There was no difference in the size of the aortic arch (24.2±3.6 versus 25.3±3.4 mm; P =0.16). These differences were maintained when the groups were stratified by sex and blood pressure. The relationship between bicuspid aortic valve and aortic dilatation was maintained when adjusting for factors related to fluid mechanics and hemodynamics such as systolic blood pressure, diastolic blood pressure, left ventricular ejection time, and peak aortic valve velocity. Conclusions— In a community-based study, BAV is associated with an alteration of aortic dimensions even in the absence of hemodynamically significant aortic valve stenosis or regurgitation.

To determine the influence of jet eccentricity and mechanism of mitral regurgitation, we examined 1) the relation between jet extent and severity of mitral regurgitation, and 2) the use of Doppler color flow imaging for quantitation of mitral regurgitation.Doppler color flow imaging is widely used to assess mitral regurgitation. However, whether, how and in which subgroups it can quantify regurgitation remain controversial.In 80 patients with mitral regurgitation, results of color flow Doppler studies obtained in two orthogonal apical views were prospectively compared with quantitative Doppler measurement of the regurgitant volume and the regurgitant fraction. Comparisons were made according to the eccentricity of the jet (group 1 eccentric jets, n = 29; group 2 central jets, n = 51); group 2 was subdivided according to the mechanism of mitral regurgitation (group 2a organic, n = 27; group 2b ischemic or functional, n = 24).Globally, weak correlations were found between regurgitant volume and jet area (r = 0.57) and regurgitant fraction and jet area/left atrial area ratio (r = 0.65). Groups 1 and 2 showed a correlation between regurgitant volume and jet area (r = 0.68 and r = 0.65, respectively, p < 0.0001), but the slope was steeper in group 2 than in group 1 (0.22 vs. 0.06, p < 0.0001). The same jet area corresponded to more severe regurgitation in group 1 than in group 2 (jet > or = 8 cm2, regurgitant volume 113 +/- 55 vs. 43 +/- 21 ml, p < 0.0001). Similarly, for comparable regurgitant volumes (24 +/- 22 vs. 29 +/- 11 ml, p = NS), group 2a had a smaller jet area than did group 2b (5.3 +/- 6 vs. 9.6 +/- 6 cm2, p < 0.02). Quantitation of regurgitation by Doppler color flow imaging was unreliable in group 1; in group 2b, the regression line between regurgitant fraction and jet area/left atrial area ratio was close to the identity line.Mitral regurgitant jet eccentricity and mechanism influence jet extent. The same regurgitant volume produces smaller jet areas for eccentric compared with central jets and for central organic compared with ischemic or functional regurgitation. Quantitation of regurgitation using Doppler color flow imaging is possible in ischemic or functional regurgitation but inappropriate in eccentric jets, where quantitative Doppler study should be recommended.

Objective The objective of this study was to examine whether podocyturia, which is the urinary excretion of viable podocytes (glomerular epithelial cells), is present in urinary sediments of patients with preeclampsia. We also aimed to compare the test characteristics of podocyturia to those angiogenic factors that have been shown to play an important role in the pathogenesis of preeclampsia (s-Flt-1, PlGF, and endoglin). Study Design Serum angiogenic factors were measured in 44 patients with preeclampsia and 23 normotensive control patients. In a patient subset (15 cases and 16 control patients), urinary proteinuria were identified and quantified on the basis of their expressions of podocyte-specific proteins. Results Urinary podocyte excretion occurred in all patients with preeclampsia. The positive predictive value for the diagnosis of preeclampsia was greater for podocyturia than for any of the measured angiogenic factors. Conclusion Podocyturia is a highly sensitive and specific marker for preeclampsia. It may contribute to the development of proteinuria in preeclampsia. The objective of this study was to examine whether podocyturia, which is the urinary excretion of viable podocytes (glomerular epithelial cells), is present in urinary sediments of patients with preeclampsia. We also aimed to compare the test characteristics of podocyturia to those angiogenic factors that have been shown to play an important role in the pathogenesis of preeclampsia (s-Flt-1, PlGF, and endoglin). Serum angiogenic factors were measured in 44 patients with preeclampsia and 23 normotensive control patients. In a patient subset (15 cases and 16 control patients), urinary proteinuria were identified and quantified on the basis of their expressions of podocyte-specific proteins. Urinary podocyte excretion occurred in all patients with preeclampsia. The positive predictive value for the diagnosis of preeclampsia was greater for podocyturia than for any of the measured angiogenic factors. Podocyturia is a highly sensitive and specific marker for preeclampsia. It may contribute to the development of proteinuria in preeclampsia.

The use of exercise echocardiography for the diagnosis of coronary artery disease (CAD) has been validated in pilot studies but is not documented in clinical practice and in women comparatively with men. The objectives of this study were to determine the effects of sex and of test verification bias on the diagnostic performance of exercise echocardiography.Three thousand six hundred seventy-nine consecutive patients (1714 women, 1965 men) who underwent an exercise echocardiographic study were studied; the observed sensitivity, specificity, and correct classification rate were calculated among 340 patients (244 men, 96 women) who underwent angiography; to study the effect of test verification bias, sensitivity and specificity were estimated for all patients who underwent exercise echocardiography including those not referred to angiography. In the angiographic group, the prevalence of CAD was 60% in women and 80% in men. The observed sensitivity and specificity of exercise echocardiography was 78% and 44% in men and 79% and 37% in women. After adjustment for test verification bias, the estimated sensitivity was lower in women (32% versus 42% in men), whereas specificity was similar in both sexes. The positive predictive value was lower in women (66%) compared with men (84%).In clinical practice, test verification bias results in a lower observed specificity and a higher sensitivity of exercise echocardiography. In women, positive predictive value and adjusted sensitivity are lower compared with that in men.

Objectives. We sought to determine the independent effect of preoperative symptoms on survival after surgical correction of aortic regurgitation (AR). Background. Aortic valve replacement for severe AR is recommended after New York Heart Association functional class III or IV symptoms develop. However, whether severe preoperative symptoms have a negative influence on postoperative survival remains controversial. Methods. Preoperative characteristics and postoperative survival in 161 patients with functional class I or II symptoms (group 1) were compared with those in 128 patients with class III or IV symptoms (group 2) undergoing surgical repair of severe isolated AR between 1980 and 1989. Results. Compared with group 1, group 2 patients were older (p < 0.0001), were more often female (p = 0.001) and more often had a history of hypertension (p = 0.001), diabetes mellitus (p = 0.029) or myocardial infarction (p = 0.005) and were more likely to require coronary artery bypass graft surgery (p < 0.0001). The operative mortality rate was higher in group 2 (7.8%) than in group 1 (1.2%, p = 0.005), and the 10-year postoperative survival rate was worse (45% ± 5% [group 2] vs. 78% ± 4% [group 1], p < 0.0001). Compared with age- and gender-matched control subjects, long-term postoperative survival was similar to that expected in group 1 (p = 0.14) but significantly worse in group 2 (p < 0.0001). On multivariate analysis, functional class III or IV symptoms were significant independent predictors of operative mortality (adjusted odds ratio 5.5, p = 0.036) and worse long-term postoperative survival (adjusted hazard ratio 1.81, p = 0.0091). Conclusions. In the setting of severe AR, preoperative functional class III or IV symptoms are independent risk factors for excess immediate and long-term postoperative mortality. The presence of class II symptoms should be a strong incentive to consider immediate surgical correction of severe AR.

The prognostic value of treadmill exercise testing (TMET) has been studied in selected populations. The generalizability of these data to different populations and to women is uncertain.A retrospective, population-based cohort study of all persons (1452 men and 741 women) who underwent TMET in years 1987 to 1989 in Olmsted County, Minnesota, was undertaken. Individuals were followed up for all-cause mortality and cardiac events (cardiac deaths, nonfatal myocardial infarction, or congestive heart failure). Sex-specific analyses were performed to determine whether the predictors of outcome and the magnitude of the associations were similar in both sexes. In men, 77 deaths and 106 cardiac events occurred during 8956 person-years of observation; in women, 46 deaths and 54 cardiac events occurred during 4801 person-years of follow-up. Exercise-induced angina, ECG changes, and workload achieved on the TMET were strongly associated with all-cause mortality and cardiac events in both sexes, and the strength of the association was similar. After adjustment, workload was the only TMET variable associated with outcome. A higher workload was associated with a reduction in the risk of cardiac events and of all-cause mortality; the protective effect of exercise capacity was strong and was similar in both sexes.In this population-based cohort, exercise capacity was the TMET variable that exhibited the strongest association with all-cause mortality and cardiac events. This protective effect of exercise capacity was observed in both sexes.

Studies correlating prosthetic valve gradients determined by continuous wave Doppler echocardiography with gradients obtained by cardiac catheterization have, to date, been limited to patients with mitral and tricuspid prostheses or have compared nonsimultaneous measurements. Simultaneous Doppler and catheter pressure gradients in 36 patients (mean age, 63 +/- 13 years) with 42 prosthetic valves (20 aortic, 20 mitral, one tricuspid, and one pulmonary) were studied. Catheter gradients were obtained using a dual-catheter technique. The simultaneous pressure tracings and Doppler flow velocity profiles were digitized at 10-msec intervals to derive the corresponding maximal and mean gradients. The correlation between the maximal Doppler gradient and the simultaneously measured maximal catheter gradient was 0.94 (SEE = 6), and that between the Doppler gradient and the simultaneously measured mean catheter gradient was 0.96 (SEE = 3). There were no significant differences in correlation between gradients for the 32 mechanical valves (maximal gradients: r = 0.95, SEE = 6; mean gradients: r = 0.96, SEE = 3) and the 10 bioprosthetic valves (maximal gradients: r = 0.89, SEE = 6; mean gradients: r = 0.93, SEE = 3). In patients with mitral prostheses, Doppler gradients correlated well with the corresponding catheter gradients obtained with direct measurement of left atrial pressure (maximal gradients: r = 0.96, SEE = 2; mean gradients: r = 0.97, SEE = 1.2). A close correlation between corresponding Doppler and catheter gradients also was found in patients with aortic prostheses (maximal gradients: r = 0.94, SEE = 6; mean gradients: r = 0.94, SEE = 3). Thus, continuous wave Doppler echocardiography can accurately predict the pressure gradient across prosthetic valves.

Aims We sought to determine whether the incidence of and survival following congestive heart failure (CHF) in patients with atrial fibrillation (AF) have changed over time.Methods and results Olmsted County, Minnesota residents diagnosed with first AF during 1980-2000 were identified and followed in medical records to 2004.The trends of incidence and survival of CHF over time were assessed.Of the 3288 subjects (mean age 71 + 15 years) diagnosed with first AF and without CHF prior to or at AF diagnosis, 790 (24%) developed a first CHF during a mean follow-up of 6.1 + 5.2 years (unadjusted incidence, 44 per 1000 person years).Age-and sex-adjusted CHF incidence was unrelated to calendar year of AF diagnosis (P ¼ 0.86).The age-and sex-adjusted mortality risk following CHF was higher than that in patients without CHF (hazard ratio 3.4, 95% confidence interval 3.1-3.8,P , 0.0001).There were no detectable changes over time with respect to the absolute (P ¼ 0.94) or the relative (P ¼ 0.68) mortality risk after CHF diagnosis.Conclusion In this study spanning two decades, there appeared to have been no significant reduction in terms of the incidence and mortality risk of CHF following first AF diagnosis.

This study was performed to determine the accuracy and outcome implications of mitral regurgitant lesions assessed by echocardiography.In patients with mitral regurgitation (MR), valve repair is a major incentive to early surgery and is decided on the basis of the anatomic mitral lesions. These lesions can be observed easily with transesophageal echocardiography (TEE), but the accuracy and implications for outcome and clinical decision-making of these observations are unknown.In 248 consecutive patients operated on for MR, the anatomic lesions diagnosed with TEE were compared with those observed by the surgeon and those seen on 216 transthoracic echocardiographic (TTE) studies, and their relationship to postoperative outcome was determined.Compared with surgical diagnosis, the accuracy of TEE was high: 99% for cause and mechanism, presence of vegetations and prolapsed or flail segment, and 88% for ruptured chordae. Diagnostic accuracy was higher for TEE than TTE for all end points (p < 0.001), but the difference was of low magnitude (<10%) except for mediocre TTE imaging or flail leaflets (both p < 0.001). The type of mitral lesions identified by TEE (floppy valve, restricted motion, functional lesion) were determinants of valve repairability and postoperative outcome (operative mortality and long-term survival; all p < 0.001) independent of age, gender, ejection fraction and presence of coronary artery disease.Transesophageal echocardiography provides a highly accurate anatomic assessment of all types of MR lesions and has incremental diagnostic value if TTE is inconclusive. The functional anatomy of MR defined by TEE is strongly and independently predictive of valve repairability and postoperative outcome. Therefore, the mitral lesions assessed by echocardiography represent essential information for clinical decision making, particularly for the indication of early surgery for MR.

Human coronary artery restenosis after percutaneous revascularization is a response to mechanical injury. Smooth muscle cell proliferation is a major component of restenosis, resulting in obstructive neointimal hyperplasia. Because ionizing radiation inhibits cellular proliferation, this study tested in a porcine coronary injury model the hypothesis that the hyperplastic response to coronary artery injury would be attenuated by X-irradiation. Deep arterial injury was produced in 37 porcine left anterior descending coronary artery segments with overexpanded, percutaneously delivered tantalum wire coils. Three groups of pigs were irradiated with 300-kV X-rays after coil injury: Group I (n = 10), 400 cGy at 1 day; Group II (n = 10), 400 cGy at 1 day and 400 cGy at 4 days and Group III (n = 9), 800 cGy at 1 day. Eight pigs in the control group underwent identical injury but received no radiation. Treatment efficacy was histologically assessed by measuring neointimal thickness and percent area stenosis. Mean neointimal thickness in all irradiated groups was significantly higher than in the control groups and thickness was proportional to X-ray dose. X-irradiation delivered at these doses and times did not inhibit proliferative neointima. Rather, it accentuated the neointimal response to acute arterial injury and may have potentiated that injury.

Quantitative Doppler echocardiography and proximal flow convergence methods are validated techniques for quantifying mitral regurgitation. However, the clinical interpretation of the values calculated is hindered by the absence of calibration of ranges of severity in large numbers of patients.In 180 consecutive patients (men, 62%; mean age+/-SD, 66+/-11 years), the results of Doppler quantification of isolated mitral regurgitation were calibrated by use of left ventricular angiographic grading performed within 3 months in routine practice and without intervening events. The thresholds of the quantitative variables corresponding to the angiographic grades were identified by maximizing the sum of sensitivity and specificity and minimizing their difference. The mitral regurgitation grade by angiography was 2.7+/-1.3. The mean value and correlation with angiographic grades for effective regurgitant orifice were 43+/-37 mm and r=.79 (P<.0001); for regurgitant volume, 62+/-45 mL and r=.80 (P<.0001); and for regurgitant fraction, 45+/-17% and r=.78 (P<.0001). Despite some overlap, differences between mitral regurgitation grades were all significant (all P<.05). The thresholds for severe mitral regurgitation (grade 4) were 60 mL, 50%, and 40 mm2 for regurgitant volume, regurgitant fraction, and orifice, respectively.In routine practice in large numbers of patients in a clinical laboratory, Doppler echocardiographic quantification of mitral regurgitation shows highly significant correlation with qualitative angiographic grades. Despite an expected overlap between classes, the calibration by angiography of grading ranges for the quantitative variables provides a framework for their interpretation and allows the definition in clinical practice of thresholds for severe mitral regurgitation.

The objectives of this study were to determine the long-term outcome and the predictors of adverse events in patients originally diagnosed with lone atrial fibrillation (AF).This population-based historical cohort study comprised 46 residents of Olmsted County, MN, USA, with well-documented, clinically defined lone AF and a complete two-dimensional echocardiographic examination. The original echocardiographic videotape recordings were analysed in a blinded fashion for left atrial volume (LAV) and left ventricular ejection fraction. With 1296 person-years of follow-up, the median duration of AF was 27 (first quartile=24, third quartile=33) years. Twenty-three (50%) patients developed events. Cerebral infarction occurred in seven patients, myocardial infarction in 11, and congestive heart failure in 16. In a multivariable analysis, patients with indexed LAV >or=32 mL/m(2) had a significantly worse event-free survival (adjusted HR, 4.46; 95% CI, 1.56-12.74; P=0.005). All cerebral infarctions occurred in patients with an indexed LAV >32 mL/m(2).Patients originally diagnosed with benign lone AF follow divergent courses based on LAV. Those originally diagnosed with lone AF and normal sized atria had a benign clinical course throughout the long-term follow-up. Patients with increased LAV at diagnosis or later during the follow-up experienced adverse events.

We sought to assess the impact of contrast injection and harmonic imaging, on the measure by echocardiography of left ventricular (LV) remodeling.Left ventricular remodeling is a precursor of LV dysfunction, but the impact of contrast injection and harmonic imaging on the accuracy or reproducibility of echocardiography is unclear.We prospectively collected LV images by using simultaneous methods. Then, LV volumes were measured off-line, in blinded manner and in random order. The accuracy of echocardiography was determined in comparison to electron beam computed tomography (EBCT) in 26 patients. The reproducibility of echocardiography was assessed by three blinded observers with different training levels in 32 patients.End-diastolic volume (EDV), end-systolic volume (ESV), stroke volume (SV) and ejection fraction (EF), as measured by EBCT (195 +/- 55, 58 +/- 24 and 137 +/- 35 ml and 71 +/- 5%, respectively) and echocardiography with harmonic imaging and contrast injection (194 +/- 51, 55 +/- 20 and 140 +/- 35 ml and 72 +/- 4%, respectively), showed no differences (all p > 0.15) and excellent correlations (all r > 0.87). In contrast, echocardiography using harmonic imaging without contrast injection underestimated the EBCT results (all p < 0.01). Reproducibility was superior with rather than without contrast injection for intraobserver and interobserver variabilities (all p < 0.001). Values measured by different observers were different without contrast injection, but were similar with contrast injection (all p > 0.18). Consequently, intrinsic patient differences represented a larger and almost exclusive proportion of global variability with contrast injection for EDV (94 vs. 79%), ESV (93 vs. 82%), SV (87 vs. 53%) and EF (84 vs. 41%), as compared with harmonic imaging without contrast injection (all p < 0.005).For assessment of LV remodeling, echocardiography with harmonic imaging and contrast injection improved the accuracy and reproducibility, as compared with imaging without contrast injection. With contrast injection, variability was almost exclusively due to intrinsic patient differences. Therefore, when evaluation of LV remodeling is deemed important, assessment after contrast injection should be the preferred echocardiographic approach.

A spectrum of left ventricular diastolic filling abnormalities noted on Doppler echocardiography has been demonstrated in patients with cardiac amyloidosis. To determine how these filling abnormalities evolve over time and the significance of any change, serial pulsed wave Doppler studies of left ventricular inflow were performed over 12.6 ± 4.9 months in 41 consecutive patients (36 men and 15 women. mean age 59 ± 11 years) with typical two-dimensional echocardiographic features of cardiac involvement. The measurements were peak left ventricular inflow in early diastole (E) and atrial contraction (A) velocities, E/A ratio. deceleration time and isovolumetric relaxation time. Patients were classified by mean left ventricular wall thickness into an early group (<15 mm) of 24 patients and an advanced group (≥15 mm) of 17 patients. The total group showed an increased E/A ratio (1.7 ± 0.9 versus 1.4 ± 0.9, p = 0.009) and decreased deceleration time (164 ± 57 versus 174 ± 51 ms. p = 0.11) at follow up compared with baseline study. The early group showed significant changes in the E/A ratio (1.6 ± 1.0 versus 1.2 ± 0.7, p = 0.001) between the two studies. Seven patients (29%) in the early group showed a change from an abnormal relaxation or “normal” pattern to one of restriction, coincident with increased symptoms in six of these patients. Fifteen (88%) of the 17 patients in the advanced group did not show significant changes in the measures during the follow-up study, but these patients already showed a restrictive pattern. Thus, significant changes in serial left ventricular flow velocity variables occur during short-term follow-up evaluation, predominantly in the early group with cardiac amyloidosis.

The natural history of severe, symptomatic aortic stenosis has been well documented. However, the natural history of moderate aortic stenosis remains poorly understood. Therefore, a group of 66 patients was identified who had a diagnosis of moderate aortic stenosis at the time of cardiac catheterization (aortic valve area 0.7 to 1.2 cm2) and who did not have surgical therapy during the 1st 180 days after cardiac catheterization. During a mean follow-up period of 35 months, 14 patients died of causes attributed to aortic stenosis and 21 underwent aortic valve replacement. The estimated probability for remaining free of any complication of aortic stenosis at the end of the first 4 years was 59%. Symptomatic patients with decreased ejection fraction or hemodynamic evidence of left ventricular decompensation were at greater risk for these complications. It is concluded that patients with moderate aortic stenosis are at significant risk for the development of complications.

The objective of this study was to evaluate the incidence and correlates of sudden unexpected nontraumatic death among young adults in a well-surveyed population. The incidence and pathogenesis of sudden unexpected nontraumatic death in a young adult population (aged 20 to 40 years old) have not been well defined. All residents 20 to 40 years old from Olmsted County, Minnesota, who had nontraumatic sudden death between 1960 and 1989 were included. Histologic and gross cardiac specimens were examined. The incidence of sudden death was estimated based on the ratio of number of observed events to relative census data for the Olmsted County population from the last 3 decades. Statistical comparisons between age decades were obtained with the chi-square test. Incidence trends were tested using Poisson regression. Of the 54 subjects, 19 were women (4.1/10(5) population annually) and 35 were men (8.7/10(5) population annually). An increase in incidence of sudden death was evident in men. Causes of death included coronary artery disease, noncardiovascular disease, suspected primary arrhythmia, vascular disease, myocarditis, hypertrophic cardiomyopathy, and unknown causes. Gross and histologic features suggestive of right ventricular dysplasia were found in 9 subjects (17%), but 6 of these 9 had other established causes of death. Of the 27 sudden deaths between 1980 and 1989, 9 (33%) had a history of cocaine abuse. A trend in increasing incidence of sudden death in young men is noted. A high prevalence of cocaine abuse was observed in young adults who died suddenly. Histologic features of right ventricular dysplasia were prevalent but were not necessarily the primary cause of death.

Recently, balloon aortic valvuloplasty has been proposed for the treatment of severe aortic stenosis in elderly patients when aortic valve replacement has been declined or deferred. The natural history of these patients has not been clearly defined. Therefore, to develop a comparison cohort of patients with unoperated aortic stenosis, we reviewed the records of all Mayo Clinic patients in whom severe aortic stenosis had been diagnosed during the period 1978 through 1985 but no surgical procedure had been performed because the patient declined or the physician deferred this option. Among the 50 patients identified (36 men and 14 women; mean age 77 years, range 60 to 89 years), an operation was declined by 28 and deferred in 22. The diagnosis of aortic stenosis was established clinically by a cardiologist in all 50 patients and independently confirmed by echocardiography, Doppler ultrasonography, or catheterization in 47 of the 50. All patients were symptomatic. Follow-up was complete to September 1986 or death in all 50 patients. Actuarial survival at 1, 2, and 3 years was 57, 37, and 25%, respectively. Survival of age- and sex-matched control subjects was 93, 85, and 77%, respectively (P less than 0.0001 at each 1-year interval). At last follow-up, only 13 of the 50 patients (26%) were alive. A cardiac cause was cited for 36 of the 37 deaths. Because of the poor survival in this group of patients, evaluation of alternative nonsurgical therapeutic modalities such as balloon valvuloplasty is imperative when operative intervention is declined or deferred in elderly patients.

We sought to determine if newer Doppler diastolic function parameters are associated with age and to define age-stratified reference ranges for these parameters in a population-based setting.Although newer Doppler parameters aid in the evaluation of diastolic function and filling pressures, age-specific reference ranges are poorly described.Randomly selected residents of Olmsted County, Minn, age >/= 45 years were studied (n = 2042) prospectively. Those without a history of cardiovascular disease or abnormal 2-dimensional echocardiograms were selected. Measured parameters included the transmitral early (E) and late (A) filling velocities at rest and with Valsalva, A duration, pulmonary venous atrial reversal duration, lateral and septal early diastolic mitral annular velocities, E/lateral early diastolic mitral annular velocity, E/septal early diastolic mitral annular velocity, and the index of left ventricular myocardial performance.A total of 1012 subjects met the inclusion criteria. Both A duration (r = 0.18, P <.001) and pulmonary venous atrial reversal duration (r = 0.28, P <.001) were longer in older subjects, whereas their difference showed a marginal correlation with age (r = 0.07, P =.036). The E/A ratio at peak Valsalva correlated with age (r = -0.54, P <.001) whereas the change in E/A with Valsalva (corrected for E-A fusion) showed a marginal correlation with age (r = 0.08, P =.032). Both E/lateral early diastolic mitral annular velocity (r = 0.39, P <.001) and E/septal early diastolic mitral annular velocity (r = 0.27, P <.001) increased with age. Left ventricular myocardial performance showed a marginal correlation with age (r = 0.08, P =.014). Age specific reference ranges (median, 5th and 95th percentiles) for all parameters are provided.All newer Doppler diastolic function parameters showed a variable but significant correlation with age. Age-specific reference values will aid in the interpretation of diastolic function parameters.

The ability of exercise thallium-201 tomographic imaging to predict the presence of left main or 3-vessel coronary artery disease (CAD) was examined in 688 patients who underwent both exercise thallium-201 testing and coronary angiography. Significant differences existed for multiple variables between patients with (n = 196) and without (n = 492) severe left main or 3-vessel CAD. Logistic regression analysis identified 4 variables as independently predictive of left main or 3-vessel CAD. These variables were the magnitude of ST-segment depression with exercise, the number of visually abnormal short-axis thallium-201 segments, the presence or absence of diabetes mellitus, and the change in systolic blood pressure with exercise. Using these variables, patients were classified by nomograms into low-, intermediate- and high-probability groups. Patients at high probability (n = 205) had a 52% prevalence of 3-vessel or left main CAD, whereas those at low probability (n = 170) had only a 12% prevalence. Only 53 patients (29%) with 3-vessel or left main CAD had perfusion abnormalities in all 3 coronary territories. Clinical and exercise parameters provide important independent information in the identification of left main or 3-vessel CAD by exercise thallium-201 tomographic imaging, because thallium scintigraphy alone is suggestive of extensive CAD in few patients.

Left ventricular diastolic filling was characterized by transmitral pulsed-wave Doppler velocities in 62 patients with acute myocardial infarction, and diastolic filling variables were correlated with the presence of clinical heart failure. At the time of admission, 47 patients were free of heart failure and 15 patients were in Killip class II to IV. In the latter group of patients with heart failure, peak velocity of late filling wave caused by atrial contraction (A) was lower (0.48 versus 0.59 m/sec, p < 0.05), ratio of peak velocity of early rapid filling wave to peak velocity of late filling wave caused by atrial contraction (E/A) was higher (1.5 versus 1.1, p < 0.01), and deceleration time (136 versus 196 msec, p = 0.0001) was shorter when compared with the patients not in heart failure after acute myocardial infarction. Multivariate analysis showed that the deceleration time was a powerful independent predictor of presence of heart failure after controlling for systolic functional variables. Therefore, diastolic filling variables can complement systolic functional variables in the identification of the patients with postinfarction left ventricular failure.

This study sought to identify preoperative predictors of postoperative atrial fibrillation (POAF) among patients undergoing cardiac surgery. Postoperative atrial fibrillation is frequent after cardiac surgery and is associated with increased morbidity, mortality, prolonged hospital stay, and increased costs. Left atrial volume (LAV), a marker of chronically elevated left ventricular filling pressure, is a predictor of atrial fibrillation (AF) in the nonsurgical setting. A total of 205 patients (mean age 62 ± 16 years; 35% women) undergoing cardiac surgery were prospectively enrolled. Clinical risk factors were obtained by detailed medical record review and patient interview. Preoperative transthoracic echocardiograms were performed for assessment of LAV, left ventricular ejection fraction, and diastolic function. Follow-up was complete. Detection of POAF was based on documentation of AF episodes by continuous telemetry throughout hospitalization. Postoperative atrial fibrillation occurred in 84 patients (41.4%) at a median of 1.8 days after cardiac surgery. The LAV was significantly larger in patients in whom AF developed (49 ± 14 ml/m2vs. 39 ± 16 ml/m2, p = 0.0001). Patients with LAV >32 ml/m2had an almost five-fold increased risk of POAF, independently of age and clinical risk factors (adjusted hazard ratio 4.84, 95% confidence interval 1.93 to 12.17, p = 0.001). Age and LAV were the only independent predictors of POAF. The area under the receiver-operator characteristics curve to predict POAF was 0.729 for LAV and 0.768 for the combination of LAV and age (both p < 0.0001). The LAV is a strong and independent predictor of POAF. Risk stratification using LAV and age enables clinicians to identify high-risk patients before cardiac surgery.

Sinus venosus atrial septal defect (SVASD) differs from secundum atrial septal defect by its atrial septal location and its association with anomalous pulmonary venous connection (APVC). Data on long-term outcome after surgical repair are limited.We reviewed outcomes of 115 patients (mean age+/-SD 34+/-23 years) with SVASD who had repair from 1972 through 1996. APVC was present in 112 patients (97%). Early mortality was 0.9%. Complete follow-up was obtained for 108 patients (95%) at 144+/-99 months. Symptomatic improvement was noted in 83 patients (77%), and deterioration was noted in 17 patients (16%). At follow-up, 7 (6%) of 108 patients had sinus node dysfunction, a permanent pacemaker, or both, and 15 (14%) of 108 patients had atrial fibrillation. Older age at repair was predictive of postoperative atrial fibrillation (P=0.033). No reoperations were required during follow-up. Survival was not different from expected for an age- and sex-matched population. Clinical improvement was more common with older age at surgery (P=0.014). Older age at repair (P=0.008) and preoperative New York Heart Association class III or IV (P=0.038) were independent predictors of late mortality.Operation for SVASD is associated with low morbidity and mortality, and postoperative subjective clinical improvement occurs irrespective of age at surgery. Postoperative atrial fibrillation appears to be related to older age at operation. SVASD repair achieves survival similar to that of a matched population and should be considered whenever repair may impact survival or symptoms.