Marcelo F. Di Carli

Impaired vasodilator function is an early manifestation of coronary artery disease and may precede angiographic stenosis. It is unknown whether noninvasive assessment of coronary vasodilator function in patients with suspected or known coronary artery disease carries incremental prognostic significance.A total of 2783 consecutive patients referred for rest/stress positron emission tomography were followed up for a median of 1.4 years (interquartile range, 0.7-3.2 years). The extent and severity of perfusion abnormalities were quantified by visual evaluation of myocardial perfusion images. Rest and stress myocardial blood flows were calculated with factor analysis and a 2-compartment kinetic model and were used to compute coronary flow reserve (coronary flow reserve equals stress divided by rest myocardial blood flow). The primary end point was cardiac death. Overall 3-year cardiac mortality was 8.0%. The lowest tertile of coronary flow reserve (<1.5) was associated with a 5.6-fold increase in the risk of cardiac death (95% confidence interval, 2.5-12.4; P<0.0001) compared with the highest tertile. Incorporation of coronary flow reserve into cardiac death risk assessment models resulted in an increase in the c index from 0.82 (95% confidence interval, 0.78-0.86) to 0.84 (95% confidence interval, 0.80-0.87; P=0.02) and in a net reclassification improvement of 0.098 (95% confidence interval, 0.025-0.180). Addition of coronary flow reserve resulted in correct reclassification of 34.8% of intermediate-risk patients (net reclassification improvement=0.487; 95% confidence interval, 0.262-0.731). Corresponding improvements in risk assessment for mortality from any cause were also demonstrated.Noninvasive quantitative assessment of coronary vasodilator function with positron emission tomography is a powerful, independent predictor of cardiac mortality in patients with known or suspected coronary artery disease and provides meaningful incremental risk stratification over clinical and gated myocardial perfusion imaging variables.

Accurate risk stratification is crucial for effective treatment planning after myocardial infarction (MI). Previous studies suggest that the peri-infarct border zone may be an important arrhythmogenic substrate. In this pilot study, we tested the hypothesis that the extent of the peri-infarct zone quantified by contrast-enhanced cardiac magnetic resonance (CMR) is an independent predictor of post-MI mortality.We studied 144 patients with documented coronary artery disease and abnormal myocardial delayed enhancement (MDE) consistent with MI. A computer-assisted, semiautomatic algorithm quantified the total infarct size and divided it into the core and peri-infarct regions based on signal-intensity thresholds (>3 SDs and 2 to 3 SDs above remote normal myocardium, respectively). The peri-infarct zone was normalized as a percentage of the total infarct size (%MDE(periphery)). After a median follow-up of 2.4 years, 29 (20%) patients died. Patients with an above-median %MDE(periphery) were at higher risk for death compared with those with a below-median %MDE(periphery) (28% versus 13%, log-rank P<0.01). Multivariable analysis showed that left ventricular systolic volume index and %MDE(periphery) were the strongest predictors of all-cause mortality (adjusted hazard ratio [HR] for %MDE(periphery), 1.45 per 10% increase; P=0.002) and cardiovascular mortality (adjusted HR, 1.51 per 10% increase; P=0.009). Similarly, after adjusting for age and left ventricular ejection fraction, %MDE(periphery) maintained strong and independent associations with all-cause mortality (adjusted HR, 1.42; P=0.005) and cardiovascular mortality (adjusted HR, 1.49; P=0.01).In patients with a prior MI, the extent of the peri-infarct zone characterized by CMR provides incremental prognostic value beyond left ventricular systolic volume index or ejection fraction. Infarct characteristics by CMR may prove to be a unique and valuable noninvasive predictor of post-MI mortality.

This study sought to relate imaging findings on positron emission tomography (PET) to adverse cardiac events in patients referred for evaluation of known or suspected cardiac sarcoidosis.Although cardiac PET is commonly used to evaluate patients with suspected cardiac sarcoidosis, the relationship between PET findings and clinical outcomes has not been reported.We studied 118 consecutive patients with no history of coronary artery disease, who were referred for PET, using [(18)F]fluorodeoxyglucose (FDG) to assess for inflammation and rubidium-82 to evaluate for perfusion defects (PD), following a high-fat/low-carbohydrate diet to suppress normal myocardial glucose uptake. Blind readings of PET data categorized cardiac findings as normal, positive PD or FDG, positive PD and FDG. Images were also used to identify whether findings of extra-cardiac sarcoidosis were present. Adverse events (AE)-death or sustained ventricular tachycardia (VT)-were ascertained by electronic medical records, defibrillator interrogation, patient questionnaires, and telephone interviews.Among the 118 patients (age 52 ± 11 years; 57% males; mean ejection fraction: 47 ± 16%), 47 (40%) had normal and 71 (60%) had abnormal cardiac PET findings. Over a median follow-up of 1.5 years, there were 31 (26%) adverse events (27 VT and 8 deaths). Cardiac PET findings were predictive of AE, and the presence of both a PD and abnormal FDG (29% of patients) was associated with hazard ratio of 3.9 (p < 0.01) and remained significant after adjusting for left ventricular ejection fraction (LVEF) and clinical criteria. Extra-cardiac FDG uptake (26% of patients) was not associated with AE.The presence of focal PD and FDG uptake on cardiac PET identifies patients at higher risk of death or VT. These findings offer prognostic value beyond Japanese Ministry of Health and Welfare clinical criteria, the presence of extra-cardiac sarcoidosis and LVEF.

Patients with coronary artery disease (CAD) and severe left ventricular (LV) dysfunction have a high but variable annual mortality and some may benefit from myocardial revascularization. This study aimed to evaluate the prognostic value of positron emission tomography (PET), and its interrelation with the choice of medical therapy or revascularization for predicting survival and improvement in symptoms of heart failure in patients with CAD and LV dysfunction. Ninety-three consecutive patients with angiographic CAD and a mean LV ejection fraction of 0.25 who underwent cardiac PET studies for assessment of hypoperfused yet viable myocardium (“mismatch pattern”) using N-13 ammonia and 18-F deoxyglucose were followed up for an average of 13.6 months. Fifty patients underwent medical treatment and 43 underwent revascularization. The Cox model analysis showed that the extent of mismatch had a negative effect (p = 0.02), whereas revascularization had a positive effect on survival (p = 0.04). The annual survival probability of patients with mismatch receiving medical therapy was lower than of those without mismatch (50 vs 92%, p = 0.007). Patients with mismatch who underwent revascularization had a higher survival rate than those treated medically (88 vs 50%, p = 0.03). The presence of mismatch also predicted improvement in heart failure symptoms after revascularization (p < 0.001). These results suggest that the presence of mismatch in patients with CAD and severe LV dysfunction is associated with poor annual survival with medical therapy. Revascularization in patients with PET mismatch appears to be associated with improved survival and heart failure symptoms.

Angiographic severity of coronary artery stenosis has historically been the primary guide to revascularization or medical management of coronary artery disease. However, physiologic severity defined by coronary pressure and/or flow has resurged into clinical prominence as a potential, fundamental change from anatomically to physiologically guided management. This review addresses clinical coronary physiology-pressure and flow-as clinical tools for treating patients. We clarify the basic concepts that hold true for whatever technology measures coronary physiology directly and reliably, here focusing on positron emission tomography and its interplay with intracoronary measurements.

Coronary microvascular dysfunction (CMD) is a prevalent and prognostically important finding in patients with symptoms suggestive of coronary artery disease. The relative extent to which CMD affects both sexes is largely unknown.We investigated 405 men and 813 women who were referred for evaluation of suspected coronary artery disease with no previous history of coronary artery disease and no visual evidence of coronary artery disease on rest/stress positron emission tomography myocardial perfusion imaging. Coronary flow reserve was quantified, and coronary flow reserve <2.0 was used to define the presence of CMD. Major adverse cardiac events, including cardiac death, nonfatal myocardial infarction, late revascularization, and hospitalization for heart failure, were assessed in a blinded fashion over a median follow-up of 1.3 years (interquartile range, 0.5-2.3 years). CMD was highly prevalent both in men and women (51% and 54%, respectively; Fisher exact test =0.39; equivalence P=0.0002). Regardless of sex, coronary flow reserve was a powerful incremental predictor of major adverse cardiac events (hazard ratio, 0.80 [95% confidence interval, 0.75-086] per 10% increase in coronary flow reserve; P<0.0001) and resulted in favorable net reclassification improvement (0.280 [95% confidence interval, 0.049-0.512]), after adjustment for clinical risk and ventricular function. In a subgroup (n=404; 307 women/97 men) without evidence of coronary artery calcification on gated computed tomography imaging, CMD was common in both sexes, despite normal stress perfusion imaging and no coronary artery calcification (44% of men versus 48% of women; Fisher exact test P=0.56; equivalence P=0.041).CMD is highly prevalent among at-risk individuals and is associated with adverse outcomes regardless of sex. The high prevalence of CMD in both sexes suggests that it may be a useful target for future therapeutic interventions.

Background Studies of patients with coronary artery disease and left ventricular dysfunction have shown that preoperative quantification of myocardial viability may be clinically useful to identify those patients who will benefit most from revascularization both functionally and prognostically. However, the relation between preoperative extent of viability and change in heart failure symptoms has not been documented carefully. We assessed the relation between the magnitude of improvement in heart failure symptoms after coronary artery bypass surgery (CABG) and the extent of myocardial viability as assessed by use of quantitative analysis of preoperative positron emission tomography (PET) images. Methods and Results We studied 36 patients with ischemic cardiomyopathy (mean left ventricular ejection fraction, 28±6%) undergoing CABG. Preoperative extent and severity of perfusion abnormalities and myocardial viability (flow-metabolism mismatch) were assessed by use of quantitative analysis of PET images with 13 N ammonia and fluorine-18-deoxyglucose. Each patient’s functional status was determined before and after CABG by use of a Specific Activity Scale. Mean perfusion defect size and severity were 63±13% and 33±12%, respectively. Total extent of a PET mismatch correlated linearly and significantly with percent improvement in functional status after CABG ( r =.87, P &lt;.0001). A blood flow–metabolism mismatch ≥18% was associated with a sensitivity of 76% and a specificity of 78% for predicting a change in functional status after revascularization. Patients with large mismatches (≥18%) achieved a significantly higher functional status compared with those with minimal or no PET mismatch (&lt;5%) (5.7±0.8 versus 4.9±0.7 metabolic equivalents, P =.009). This resulted in an improvement of 107% in patients with large mismatches compared with only 34% in patients with minimal or no PET mismatch. Conclusions In patients with ischemic cardiomyopathy, the magnitude of improvement in heart failure symptoms after CABG is related to the preoperative extent and magnitude of myocardial viability as assessed by use of PET imaging. Patients with large perfusion-metabolism mismatches exhibit the greatest clinical benefit after CABG.

Diabetes mellitus increases the risk of adverse cardiac outcomes and is considered a coronary artery disease (CAD) equivalent. We examined whether coronary vascular dysfunction, an early manifestation of CAD, accounts for increased risk among diabetics compared with nondiabetics.A total of 2783 consecutive patients (1172 diabetics and 1611 nondiabetics) underwent quantification of coronary flow reserve (CFR; CFR=stress divided by rest myocardial blood flow) by positron emission tomography and were followed up for a median of 1.4 years (quartile 1-3, 0.7-3.2 years). The primary end point was cardiac death. Impaired CFR (below the median) was associated with an adjusted 3.2- and 4.9-fold increase in the rate of cardiac death for diabetics and nondiabetics, respectively (P=0.0004). Addition of CFR to clinical and imaging risk models improved risk discrimination for both diabetics and nondiabetics (c index, 0.77-0.79, P=0.04; 0.82-0.85, P=0.03, respectively). Diabetic patients without known CAD with impaired CFR experienced a rate of cardiac death comparable to that for nondiabetic patients with known CAD (2.8%/y versus 2.0%/y; P=0.33). Conversely, diabetics without known CAD and preserved CFR had very low annualized cardiac mortality, which was similar to patients without known CAD or diabetes mellitus and normal stress perfusion and systolic function (0.3%/y versus 0.5%/y; P=0.65).Coronary vasodilator dysfunction is a powerful, independent correlate of cardiac mortality among both diabetics and nondiabetics and provides meaningful incremental risk stratification. Among diabetic patients without CAD, those with impaired CFR have event rates comparable to those of patients with prior CAD, whereas those with preserved CFR have event rates comparable to those of nondiabetics.

We sought to determine the differences in coronary microvascular function between patients with type 1 (insulin-deficient) and type 2 (insulin-resistant) diabetes mellitus (DM).Coronary vascular function is impaired in patients with DM. However, it is unclear whether the type and/or severity of this vascular dysfunction are similar in patients with type 1 and type 2 DM.We studied 35 young subjects with DM (18 with type 1 and 17 with type 2), who were free of overt cardiovascular complications, and 11 age-matched healthy controls. Positron emission tomography imaging was used to measure myocardial blood flow (MBF) at rest, during adenosine-induced hyperemia (reflecting primarily endothelium-independent vasodilation), and in response to cold pressor test (CPT) (reflecting primarily endothelium-dependent vasodilation).The two groups of diabetics were similar with respect to age and glycemic control. The duration of diabetes was longer and high-density lipoprotein cholesterol levels were higher in type 1 than in type 2 diabetics. Basal MBF was similar in the three groups studied. The increase (from baseline) in MBF with adenosine was similar in the subjects with type 1 (161 +/- 18%) and type 2 (185 +/- 19%) DM, but lower than in the controls (351 +/- 43%) (p < 0.001 for the comparison with both groups of diabetics). Similarly, the increase in MBF during the CPT was comparable in the subjects with type 1 (23 +/- 4%) and type 2 (19 +/- 3%) DM, but lower compared with the controls (66 +/- 12%) (p < 0.0001 for the comparison with both groups of diabetics). These differences persisted after adjusting for the duration of diabetes, insulin treatment, metabolic abnormalities, and autonomic neuropathy.These results demonstrate markedly reduced and similar endothelium-dependent and -independent coronary vasodilator function in subjects with both type 1 and type 2 DM. These results suggest a key role of chronic hyperglycemia in the pathogenesis of vascular dysfunction in diabetes.

Coronary microvascular disease (CMD) refers to the subset of disorders affecting the structure and function of the coronary microcirculation, is prevalent in patients across a broad spectrum of cardiovascular risk factors, and is associated with an increased risk of adverse events. Contemporary evidence supports that most patients with CMD also have macrovessel atherosclerosis, which has important implications for their prognosis and management. In this state-of-the-art review, the authors summarize the pathophysiology of CMD, provide an update of diagnostic testing strategies, and classify CMD into phenotypes according to severity and coexistence with atherosclerosis. They examine emerging data highlighting the significance of CMD in specific populations, including obesity and insulin resistance, myocardial injury and heart failure with preserved ejection fraction, and nonobstructive and obstructive coronary artery disease. Finally, they discuss the role of CMD as a potential target for novel interventions beyond conventional approaches, representing a new frontier in cardiovascular disease reduction.

Background— Coronary flow reserve (CFR), an integrated measure of focal, diffuse, and small-vessel coronary artery disease (CAD), identifies patients at risk for cardiac death. We sought to determine the association between CFR, angiographic CAD, and cardiovascular outcomes. Methods and Results— Consecutive patients (n=329) referred for invasive coronary angiography after stress testing with myocardial perfusion positron emission tomography were followed (median 3.1 years) for cardiovascular death and heart failure admission. The extent and severity of angiographic disease were estimated with the use of the CAD prognostic index, and CFR was measured noninvasively by positron emission tomography. A modest inverse correlation was seen between CFR and CAD prognostic index ( r =−0.26; P &lt;0.0001). After adjustment for clinical risk score, ejection fraction, global ischemia, and early revascularization, CFR and CAD prognostic index were independently associated with events (hazard ratio for unit decrease in CFR, 2.02; 95% confidence interval, 1.20–3.40; P =0.008; hazard ratio for 10-U increase in CAD prognostic index, 1.17; 95% confidence interval, 1.01–1.34; P =0.032). Subjects with low CFR experienced rates of events similar to those of subjects with high angiographic scores, and those with low CFR or high CAD prognostic index showed the highest risk of events ( P =0.001). There was a significant interaction ( P =0.039) between CFR and early revascularization by coronary artery bypass grafting, such that patients with low CFR who underwent coronary artery bypass grafting, but not percutaneous coronary intervention, experienced event rates comparable to those with preserved CFR, independently of revascularization. Conclusions— CFR was associated with outcomes independently of angiographic CAD and modified the effect of early revascularization. Diffuse atherosclerosis and associated microvascular dysfunction may contribute to the pathophysiology of cardiovascular death and heart failure, and impact the outcomes of revascularization.

Coronary microvascular ischaemia, cardiomyocyte injury and stiffness may play an important role in the pathophysiology of heart failure with preserved ejection fraction (HFpEF). To date, the relationship between coronary flow reserve (CFR), myocardial injury, diastolic dysfunction, and future HFpEF risk is unknown. Consecutive patients (n = 201) undergoing evaluation for suspected coronary artery disease (CAD) with stress myocardial perfusion positron emission tomography, serum troponin, and transthoracic echocardiography who did not have flow-limiting CAD or reduced left ventricular ejection fraction were identified. Patients were followed up (median 4.1 years) for cardiovascular death and hospitalization for non-fatal myocardial infarction or heart failure. Coronary flow reserve was quantified as stress/rest myocardial blood flow. Early diastolic flow (E) and relaxation (e′) velocities were obtained via transmitral and tissue Doppler, respectively. Patients with impaired CFR (<2, n = 108) demonstrated linearly decreasing e′ and increasing E/e′ consistent with worsening diastolic function (P for trend <0.0001). A detectable troponin was associated with diastolic dysfunction only in the presence of impaired CFR (interaction P = 0.002). In adjusted analyses, impaired CFR was independently associated with diastolic dysfunction (E/e′septal > 15, adjusted OR 2.58, 95%CI 1.22–5.48) and composite cardiovascular outcomes or HFpEF hospitalization alone (adjusted HR 2.47, 95%CI 1.09–5.62). Patients with both impaired CFR and diastolic dysfunction demonstrated >five-fold increased risk of HFpEF hospitalization (P < 0.001). In symptomatic patients without overt CAD, impaired CFR was independently associated with diastolic dysfunction and adverse events, especially HFpEF hospitalization. The presence of both coronary microvascular and diastolic dysfunctions was associated with a markedly increased risk of HFpEF events.

Abstract Aims To evaluate the diagnostic power of integrating the results of computed tomography angiography (CTA) and CT myocardial perfusion (CTP) to identify coronary artery disease (CAD) defined as a flow limiting coronary artery stenosis causing a perfusion defect by single photon emission computed tomography (SPECT). Methods and results We conducted a multicentre study to evaluate the accuracy of integrated CTA–CTP for the identification of patients with flow-limiting CAD defined by ≥50% stenosis by invasive coronary angiography (ICA) with a corresponding perfusion deficit on stress single photon emission computed tomography (SPECT/MPI). Sixteen centres enroled 381 patients who underwent combined CTA–CTP and SPECT/MPI prior to conventional coronary angiography. All four image modalities were analysed in blinded independent core laboratories. The prevalence of obstructive CAD defined by combined ICA–SPECT/MPI and ICA alone was 38 and 59%, respectively. The patient-based diagnostic accuracy defined by the area under the receiver operating characteristic curve (AUC) of integrated CTA–CTP for detecting or excluding flow-limiting CAD was 0.87 [95% confidence interval (CI): 0.84–0.91]. In patients without prior myocardial infarction, the AUC was 0.90 (95% CI: 0.87–0.94) and in patients without prior CAD the AUC for combined CTA–CTP was 0.93 (95% CI: 0.89–0.97). For the combination of a CTA stenosis ≥50% stenosis and a CTP perfusion deficit, the sensitivity, specificity, positive predictive, and negative predicative values (95% CI) were 80% (72–86), 74% (68–80), 65% (58–72), and 86% (80–90), respectively. For flow-limiting disease defined by ICA-SPECT/MPI, the accuracy of CTA was significantly increased by the addition of CTP at both the patient and vessel levels. Conclusions The combination of CTA and perfusion correctly identifies patients with flow limiting CAD defined as ≥50 stenosis by ICA causing a perfusion defect by SPECT/MPI.

The American College of Cardiology Foundation (ACCF), along with key specialty and subspecialty societies, conducted an appropriate use review of common clinical scenarios where cardiac radionuclide imaging (RNI) is frequently considered. This document is a revision of the original Single-Photon Emission Computed Tomography Myocardial Perfusion Imaging (SPECT MPI) Appropriateness Criteria, published 4 years earlier, written to reflect changes in test utilization and new clinical data, and to clarify RNI use where omissions or lack of clarity existed in the original criteria. This is in keeping with the commitment to revise and refine appropriate use criteria (AUC) on a frequent basis. The indications for this review were drawn from common applications or anticipated uses, as well as from current clinical practice guidelines. Sixty-seven clinical scenarios were developed by a writing group and scored by a separate technical panel on a scale of 1 to 9 to designate appropriate use, inappropriate use, or uncertain use. In general, use of cardiac RNI for diagnosis and risk assessment in intermediate- and high-risk patients with coronary artery disease (CAD) was viewed favorably, while testing in low-risk patients, routine repeat testing, and general screening in certain clinical scenarios were viewed less favorably. Additionally, use for perioperative testing was found to be inappropriate except for high selected groups of patients. It is anticipated that these results will have a significant impact on physician decision making, test performance, and reimbursement policy, and will help guide future research.

Although the value of coronary artery calcium (CAC) for atherosclerosis screening is gaining acceptance, its efficacy in predicting flow-limiting coronary artery disease remains controversial, and its incremental prognostic value over myocardial perfusion is not well established.We evaluated 695 consecutive intermediate-risk patients undergoing combined rest-stress rubidium 82 positron emission tomography (PET) perfusion imaging and CAC scoring on a hybrid PET-computed tomography (CT) scanner. The frequency of abnormal scans among patients with a CAC score > or = 400 was higher than that in patients with a CAC score of 1 to 399 (48.5% versus 21.7%, P<0.001). Multivariate logistic regression supported the concept of a threshold CAC score > or = 400 governing this relationship (odds ratio 2.91, P<0.001); however, the frequency of ischemia among patients with no CAC was 16.0%, and its absence only afforded a negative predictive value of 84.0%. Risk-adjusted survival analysis demonstrated a stepwise increase in event rates (death and myocardial infarction) with increasing CAC scores in patients with and without ischemia on PET myocardial perfusion imaging. Among patients with normal PET myocardial perfusion imaging, the annualized event rate in patients with no CAC was lower than in those with a CAC score > or = 1000 (2.6% versus 12.3%, respectively). Likewise, in patients with ischemia on PET myocardial perfusion imaging, the annualized event rate in those with no CAC was lower than among patients with a CAC score > or = 1000 (8.2% versus 22.1%).Although increasing CAC content is generally predictive of a higher likelihood of ischemia, its absence does not completely eliminate the possibility of flow-limiting coronary artery disease. Importantly, a stepwise increase occurs in the risk of adverse events with increasing CAC scores in patients with and without ischemia on PET myocardial perfusion imaging.

Successful autologous skeletal myoblast transplantation into infarcted myocardium in a variety of animal models has demonstrated improvement in cardiac function. We evaluated the safety and feasibility of transplanting autologous myoblasts into infarcted myocardium of patients undergoing concurrent coronary artery bypass grafting (CABG) or left ventricular assist device (LVAD) implantation. In addition, we sought to gain preliminary information on graft survival and any associated changes in cardiac function.Thirty patients with a history of ischemic cardiomyopathy participated in a phase I, nonrandomized, multicenter pilot study of autologous skeletal myoblast transplantation concurrent with CABG or LVAD implantation. Twenty-four patients with a history of previous myocardial infarction and a left ventricular ejection fraction <40% were enrolled in the CABG arm. In a second arm, 6 patients underwent LVAD implantation as a bridge to heart transplantation, and patients donated their explanted native hearts for testing at the time of heart transplantation. Myoblasts were successfully transplanted in all patients without any acute injection-related complications or significant long-term, unexpected adverse events. Follow-up positron emission tomography scans showed new areas of glucose uptake within the infarct scar in CABG patients. Echocardiography measured an average change in left ventricular ejection fraction from 28% to 35% at 1 year and of 36% at 2 years. Histological evaluation in 4 of 6 patients who underwent heart transplantation documented survival and engraftment of the skeletal myoblasts within the infarcted myocardium.These results demonstrate the survival, feasibility, and safety of autologous myoblast transplantation and suggest that this modality offers a potential therapeutic treatment for end-stage heart disease.

Background— The contribution of plaque extent to predict cardiovascular events among patients with nonobstructive and obstructive coronary artery disease (CAD) is not well defined. Our objective was to evaluate the prognostic value of plaque extent detected by coronary computed tomography angiography. Methods and Results— All consecutive patients without prior CAD referred for coronary computed tomography angiography to evaluate for CAD were included. Examination findings were classified as normal, nonobstructive (&lt;50% stenosis), or obstructive (≥50%). Based on the number of segments with disease, extent of CAD was classified as nonextensive (≤4 segments) or extensive (&gt;4 segments). The cohort included 3242 patients followed for the primary outcome of cardiovascular death or myocardial infarction for a median of 3.6 (2.1–5.0) years. In a multivariable analysis, the presence of extensive nonobstructive CAD (hazard ratio, 3.1; 95% confidence interval, 1.5–6.4), nonextensive obstructive (hazard ratio, 3.0; 95% confidence interval, 1.3–6.9), and extensive obstructive CAD (hazard ratio, 3.9; 95% confidence interval, 2.2–7.2) were associated with an increased rate of events, whereas nonextensive, nonobstructive CAD was not. The addition of plaque extent to a model that included clinical probability as well as the presence and severity of CAD improved risk prediction. Conclusions— Among patients with nonobstructive CAD, those with extensive plaque experienced a higher rate of cardiovascular death or myocardial infarction, comparable with those who have nonextensive disease. Even among patients with obstructive CAD, greater extent of nonobstructive plaque was associated with higher event rate. Our findings suggest that regardless of whether obstructive or nonobstructive disease is present, the extent of plaque detected by coronary computed tomography angiography enhances risk assessment.

This study investigated the regulation of glucose uptake in cells that participate in atherogenesis by stimuli relevant to this process, to gain mechanistic insight into the origin of the (18)fluorine-labeled 2-deoxy-D-glucose (FdG) uptake signals observed clinically.Patient studies suggest that positron emission tomography (PET) using FdG can detect "active" atherosclerotic plaques, yet the mechanism giving rise to FdG signals remains unknown.We exposed cells to conditions thought to operate in atheroma and determined rates of glucose uptake.Hypoxia, but not pro-inflammatory cytokines, potently stimulated glucose uptake in human macrophages and foam cells. Statins attenuated this process in vitro, suggesting that these agents have a direct effect on human macrophages. Immunohistochemical study of human plaques revealed abundant expression of proteins regulating glucose utilization, predominantly in macrophage-rich regions of the plaques-regions previously proved hypoxic. Smooth-muscle cells and endothelial cells markedly increased rates of glucose uptake when exposed to pro-inflammatory cytokines.Glucose uptake and, probably, FdG uptake signals in atheroma may reflect hypoxia-stimulated macrophages rather than mere inflammatory burden. Cytokine-activated smooth-muscle cells also may contribute to the FdG signal.

The field of nuclear cardiology is witnessing growing interest in the use of cardiac PET for the evaluation of patients with coronary artery disease (CAD). The available evidence suggests that myocardial perfusion PET provides an accurate means for diagnosing obstructive CAD, which appears superior to SPECT especially in the obese and in those undergoing pharmacologic stress. The ability to record changes in left ventricular function from rest to peak stress and to quantify myocardial perfusion (in mL/min/g of tissue) provides an added advantage over SPECT for evaluating multivessel CAD. There is growing and consistent evidence that gated myocardial perfusion PET also provides clinically useful risk stratification. Although the introduction of hybrid PET/CT technology offers the exciting possibility of assessing the extent of anatomic CAD (CT coronary angiography) and its functional consequences (ischemic burden) in the same setting, there are technical challenges in the implementation of CT-based transmission imaging for attenuation correction. Nonetheless, this integrated platform for assessing anatomy and biology offers a great potential for translating advances in molecularly targeted imaging into humans.

C ardiac computed tomography (CT) and positron emis- sion tomography (PET) are emerging as powerful noninvasive imaging tools for the evaluation of atherosclerosis in patients with known or suspected coronary artery disease (CAD).Unlike invasive coronary angiography, CT coronary angiography (CTA) not only assesses disease within the coronary lumen but can also provide direct qualitative and quantitative information about nonobstructive atherosclerotic plaque burden within the vessel wall.Thus, it is possible that CTA-based patient evaluation may provide more clinically relevant information on which to base risk assessments compared with conventional "lumenography."On the other hand, PET is rapidly growing as a powerful and efficient alternative to conventional single-photon emission CT (SPECT) imaging to evaluate regional myocardial perfusion and metabolism in patients with CAD.In addition, PET scanners are now being converted to hybrid PET/CT devices, which, in the setting of CAD, offer the potential for a comprehensive noninvasive cardiac evaluation of anatomy and function.This review will discuss current and potential future applications of cardiovascular CT, PET, and hybrid PET/CT, with a particular focus on ischemic heart disease.

This investigation sought to study the incremental value of gated rubidium (Rb)-82 positron emission tomography (PET) myocardial perfusion imaging (MPI) over clinical variables for predicting survival and future cardiac events.The prognostic value of Rb-82 PET-MPI and left ventricular ejection fraction (LVEF) reserve (stress minus rest LVEF) is not well defined.1,432 consecutive patients undergoing gated rest/vasodilator stress rubidium-82 PET were followed up for at least 1 year. Of these, rest and peak stress LVEF and LVEF reserve were available in 985 patients. Cardiac events (CE) including cardiac death or nonfatal myocardial infarction and all-cause death were assessed.Over a mean follow-up of 1.7 +/- 0.7 years, 83 (5.8%) CE and 140 (9.7%) all-cause death were observed. There was an increase in risk for both end points with an increasing percentage of abnormal and ischemic myocardium. With normal, mild, moderate, or severely ischemic scans, the observed annualized rates of CE were 0.7%, 5.5%, 5%, and 11% and of all-cause death were 3.3%, 7.2%, 6.9%, and 12.5%, respectively. In 985 patients with peak stress gated data, the observed annualized rates of CE (2.1% vs. 5.3%, p < 0.001) and all-cause death (4.3% vs. 9.2%, p < 0.001) were higher in patients with an LVEF reserve <0% compared with those with an LVEF reserve >or=0%. On Cox proportional hazards analysis, after consideration of clinical, historical, and rest LVEF information, stress PET results and LVEF reserve yielded incremental prognostic value with respect to both CE and all-cause death.Vasodilator stress Rb-82 PET-MPI provides incremental prognostic value to historical/clinical variables and rest LVEF to predict survival free of CE and all-cause death. An increasing percentage of ischemia on PET-MPI is associated with an increase in the risk of CE and all-cause death. Left ventricular ejection fraction reserve provides significant independent and incremental value to Rb-82 MPI for predicting the risk of future adverse events.

82 Rb cardiac PET allows the assessment of myocardial perfusion with a column generator in clinics that lack a cyclotron.There is evidence that the quantitation of myocardial blood flow (MBF) and coronary flow reserve (CFR) with dynamic 82 Rb PET is feasible.The objectives of this study were to determine the accuracy and reproducibility of MBF estimates from dynamic 82 Rb PET by using our methodology for generalized factor analysis (generalized factor analysis of dynamic sequences [GFADS]) and compartment analysis.Methods: Reproducibility was evaluated in 22 subjects undergoing dynamic rest and dipyridamole stress 82 Rb PET studies at a 2-wk interval.The inter-and intraobserver variability of MBF quantitation with dynamic 82 Rb PET was assessed with 4 repeated estimations by each of 4 observers.Accuracy was evaluated in 20 subjects undergoing dynamic rest and dipyridamole stress PET studies with 82 Rb and 13 Nammonia, respectively.The left ventricular and right ventricular blood pool and left ventricular tissue time-activity curves were estimated by GFADS.MBF was estimated by fitting the blood pool and tissue time-activity curves to a 2-compartment kinetic model for 82 Rb and to a 3-compartment model for 13 N-ammonia.CFR was estimated as the ratio of peak MBF to baseline MBF.Results: The reproducibility of the MBF estimates in repeated 82 Rb studies was very good at rest and during peak stress (R 2 5 0.935), as was the reproducibility of the CFR estimates (R 2 5 0.841).The slope of the correlation line was very close to one for the estimation of MBF (0.986) and CFR (0.960) in repeated 82 Rb studies.The intraobserver reliability was less than 3% for the estimation of MBF at rest and during peak stress as well as for the estimation of CFR.The interobserver reliabilities were 0.950 at rest and 0.975 at peak stress.The correlation between myocardial flow estimates obtained at rest and those obtained during peak stress in 82 Rb and 13 N-ammonia studies was very good (R 2 5 0.857).Bland-Altman plots comparing CFR estimated with 82 Rb and CFR estimated with 13 N-ammonia revealed an underestimation of CFR with 82 Rb compared with 13 N-ammonia; the underestimation was within 61.96 SD.Conclusion: MBF quantitation with GFADS and dynamic 82 Rb PET demonstrated excellent reproducibility as well as intra-and interobserver reliability.The accuracy of the absolute quantitation of MBF with factor and compartment analyses and dynamic 82 Rb PET was very good, compared with that achieved with 13 N-ammonia, for MBF of up to 2.5 mL/g/min.

Background: Cardiovascular disease (CVD) fatality rates are higher for women than for men, yet obstructive coronary artery disease (CAD) is less prevalent in women. Coronary flow reserve (CFR), an integrated measure of large- and small-vessel CAD and myocardial ischemia, identifies patients at risk for CVD death, but is not routinely measured in clinical practice. We sought to investigate the impact of sex, CFR, and angiographic CAD severity on adverse cardiovascular events. Methods: Consecutive patients (n=329, 43% women) referred for invasive coronary angiography after stress testing with myocardial perfusion positron emission tomography and with left ventricular ejection fraction &gt;40% were followed (median, 3.0 years) for a composite end point of major adverse cardiovascular events, including cardiovascular death and hospitalization for nonfatal myocardial infarction or heart failure. The extent and severity of angiographic CAD were estimated by using the CAD prognostic index, and CFR was quantified by using positron emission tomography. Results: Although women in comparison with men had lower pretest clinical scores, rates of prior myocardial infarction, and burden of angiographic CAD ( P &lt;0.001), they demonstrated greater risk of CVD events, even after adjustment for traditional risk factors, imaging findings, and early revascularization (adjusted hazard ratio, 2.05; 95% confidence interval, 1.05–4.02; P =0.03). Impaired CFR was similarly present among women and men, but in patients with low CFR (&lt;1.6, n=163), women showed a higher frequency of nonobstructive CAD, whereas men showed a higher frequency of severely obstructive CAD ( P =0.002). After also adjusting for CFR, the effect of sex on outcomes was no longer significant. When stratified by sex and CFR, only women with severely impaired CFR demonstrated significantly increased adjusted risk of CVD events ( P &lt;0.0001, P for interaction=0.04). Conclusions: Women referred for coronary angiography had a significantly lower burden of obstructive CAD in comparison with men but were not protected from CVD events. Excess cardiovascular risk in women was independently associated with impaired CFR, representing a hidden biological risk, and a phenotype less amenable to revascularization. Impaired CFR, particularly absent severely obstructive CAD, may represent a novel target for CVD risk reduction.

The aim of the study was to systematically review and perform a meta-analysis of randomized, controlled trials of coronary computed tomography angiography (CCTA) versus usual care (UC) triage of acute chest pain in the emergency department (ED). CCTA allows rapid evaluation of patients presenting to the ED with acute chest pain syndromes; however, the impact of such testing on patient management and downstream testing has emerged as a concern. We systematically searched for randomized, controlled trials of CCTA in the ED and performed a meta-analysis of clinical outcomes. Four randomized, controlled trials were included, with 1,869 patients undergoing CCTA and 1,397 undergoing UC. There were no deaths and no difference in the incidence of myocardial infarction, post-discharge ED visits, or rehospitalizations. Four studies reported decreased length of stay with CCTA and 3 reported cost savings; 8.4% of patients undergoing CCTA versus 6.3% of those receiving UC underwent invasive coronary angiography (ICA), whereas 4.6% of patients undergoing CCTA versus 2.6% of those receiving UC underwent coronary revascularization. The odds ratio of ICA for CCTA patients versus UC patients was 1.36 (95% confidence interval [CI]: 1.03 to 1.80, p = 0.030), and for revascularization, it was 1.81 (95% CI: 1.20 to 2.72, p = 0.004). The absolute increase in ICA after CCTA was 21 per 1,000 CCTA patients (95% CI: 1.8 to 44.9), and the number needed to scan was 48. The absolute increase in revascularization after CCTA was 20 per 1,000 patients (95% CI: 5.0 to 41.4); the number needed to scan was 50. Both percutaneous coronary intervention and coronary artery bypass graft surgery independently contributed to the significant increase in revascularization. Compared with UC, the use of CCTA in the ED is associated with decreased ED cost and length of stay but increased ICA and revascularization.

Myocardial perfusion imaging has limited sensitivity for the detection of high-risk coronary artery disease (CAD). We tested the hypothesis that a normal coronary flow reserve (CFR) would be helpful for excluding the presence of high-risk CAD on angiography.We studied 290 consecutive patients undergoing (82)Rb PET within 180 d of invasive coronary angiography. High-risk CAD on angiography was defined as 2-vessel disease (≥ 70% stenosis), including the proximal left anterior descending artery; 3-vessel disease; or left main CAD (≥ 50% stenosis). Patients with prior Q wave myocardial infarction, elevated troponin levels between studies, prior coronary artery bypass grafting, a left ventricular ejection fraction of less than 40%, or severe valvular heart disease were excluded.Fifty-five patients (19%) had high-risk CAD on angiography. As expected, the trade-off between the sensitivity and the specificity of the CFR for identifying high-risk CAD varied substantially depending on the cutoff selected. In multivariable analysis, a binary CFR of less than or equal to 1.93 provided incremental diagnostic information for the identification of high-risk CAD beyond the model with the Duke clinical risk score (>25%), percentage of left ventricular ischemia (>10%), transient ischemic dilation index (>1.07), and change in the left ventricular ejection fraction during stress (<2) (P = 0.0009). In patients with normal or slightly to moderately abnormal results on perfusion scans (<10% of left ventricular mass) during stress (n = 136), a preserved CFR (>1.93) excluded high-risk CAD with a high sensitivity (86%) and a high negative predictive value (97%).A normal CFR has a high negative predictive value for excluding high-risk CAD on angiography. Although an abnormal CFR increases the probability of significant obstructive CAD, it cannot reliably distinguish significant epicardial stenosis from nonobstructive, diffuse atherosclerosis or microvascular dysfunction.

Myocardial perfusion imaging (MPI) is well established in the diagnosis and workup of patients with known or suspected coronary artery disease (CAD); however, it can underestimate the extent of obstructive CAD. Quantification of myocardial perfusion reserve with PET can assist in the diagnosis of multivessel CAD. We evaluated the feasibility of dynamic tomographic SPECT imaging and quantification of a retention index to describe global and regional myocardial perfusion reserve using a dedicated solid-state cardiac camera.Ninety-five consecutive patients (64 men and 31 women; median age, 67 y) underwent dynamic SPECT imaging with (99m)Tc-sestamibi at rest and at peak vasodilator stress, followed by standard gated MPI. The dynamic images were reconstructed into 60-70 frames, 3-6 s/frame, using ordered-subsets expectation maximization with 4 iterations and 32 subsets. Factor analysis was used to estimate blood-pool time-activity curves, used as input functions in a 2-compartment kinetic model. K1 values ((99m)Tc-sestamibi uptake) were calculated for the stress and rest images, and K2 values ((99m)Tc-sestamibi washout) were set to zero. Myocardial perfusion reserve (MPR) index was calculated as the ratio of the stress and rest K1 values. Standard MPI was evaluated semiquantitatively, and total perfusion deficit (TPD) of at least 5% was defined as abnormal.Global MPR index was higher in patients with normal MPI (n = 51) than in patients with abnormal MPI (1.61 [interquartile range (IQR), 1.33-2.03] vs. 1.27 [IQR, 1.12-1.61], P = 0.0002). By multivariable regression analysis, global MPR index was associated with global stress TPD, age, and smoking. Regional MPR index was associated with the same variables and with regional stress TPD. Sixteen patients undergoing invasive coronary angiography had 20 vessels with stenosis of at least 50%. The MPR index was 1.11 (IQR, 1.01-1.21) versus 1.30 (IQR, 1.12-1.67) in territories supplied by obstructed and nonobstructed arteries, respectively (P = 0.02). MPR index showed a stepwise reduction with increasing extent of obstructive CAD (P = 0.02).Dynamic tomographic imaging and quantification of a retention index describing global and regional perfusion reserve are feasible using a solid-state camera. Preliminary results show that the MPR index is lower in patients with perfusion defects and in regions supplied by obstructed coronary arteries. Further studies are needed to establish the clinical role of this technique as an aid to semiquantitative analysis of MPI.

Background: It is suggested that the integration of maximal myocardial blood flow (MBF) and coronary flow reserve (CFR), termed coronary flow capacity, allows for comprehensive evaluation of patients with known or suspected stable coronary artery disease. Because management decisions are predicated on clinical risk, we sought to determine the independent and integrated value of maximal MBF and CFR for predicting cardiovascular death. Methods: MBF and CFR were quantified in 4029 consecutive patients (median age 66 years, 50.5% women) referred for rest/stress myocardial perfusion positron emission tomography scans from January 2006 to December 2013. The primary outcome was cardiovascular mortality. Maximal MBF &lt;1.8 mL·g −1 ·min −1 and CFR&lt;2 were considered impaired. Four patient groups were identified based on the concordant or discordant impairment of maximal MBF or CFR. Association of maximal MBF and CFR with cardiovascular death was assessed using Cox and Poisson regression analyses. Results: A total of 392 (9.7%) cardiovascular deaths occurred over a median follow-up of 5.6 years. CFR was a stronger predictor of cardiovascular mortality than maximal MBF beyond traditional cardiovascular risk factors, left ventricular ejection fraction, myocardial scar and ischemia, rate-pressure product, type of radiotracer or stress agent used, and revascularization after scan (adjusted hazard ratio, 1.79; 95% confidence interval [CI], 1.38–2.31; P &lt;0.001 per unit decrease in CFR after adjustment for maximal MBF and clinical covariates; and adjusted hazard ratio, 1.03; 95% CI, 0.84–1.27; P =0.8 per unit decrease in maximal MBF after adjustment for CFR and clinical covariates). In univariable analyses, patients with concordant impairment of CFR and maximal MBF had high cardiovascular mortality of 3.3% (95% CI, 2.9–3.7) per year. Patients with impaired CFR but preserved maximal MBF had an intermediate cardiovascular mortality of 1.7% (95% CI, 1.3–2.1) per year. These patients were predominantly women (70%). Patients with preserved CFR but impaired maximal MBF had low cardiovascular mortality of 0.9% (95% CI, 0.6–1.6) per year. Patients with concordantly preserved CFR and maximal MBF had the lowest cardiovascular mortality of 0.4% (95 CI, 0.3–0.6) per year. In multivariable analysis, the cardiovascular mortality risk gradient across the 4 concordant or discordant categories was independently driven by impaired CFR irrespective of impairment in maximal MBF. Conclusions: CFR is a stronger predictor of cardiovascular mortality than maximal MBF. Concordant and discordant categories based on integrating CFR and maximal MBF identify unique prognostic phenotypes of patients with known or suspected coronary artery disease.

The primary objective of this multicenter registry was to study the prognostic value of positron emission tomography (PET) myocardial perfusion imaging (MPI) and the improved classification of risk in a large cohort of patients with suspected or known coronary artery disease (CAD). Limited prognostic data are available for MPI with PET. A total of 7,061 patients from 4 centers underwent a clinically indicated rest/stress rubidium-82 PET MPI, with a median follow-up of 2.2 years. The primary outcome of this study was cardiac death (n = 169), and the secondary outcome was all-cause death (n = 570). Net reclassification improvement (NRI) and integrated discrimination analyses were performed. Risk-adjusted hazard of cardiac death increased with each 10% myocardium abnormal with mildly, moderately, or severely abnormal stress PET (hazard ratio [HR]: 2.3 [95% CI: 1.4 to 3.8; p = 0.001], HR: 4.2 [95% CI: 2.3 to 7.5; p < 0.001], and HR: 4.9 [95% CI: 2.5 to 9.6; p < 0.0001], respectively [normal MPI: referent]). Addition of percent myocardium ischemic and percent myocardium scarred to clinical information (age, female sex, body mass index, history of hypertension, diabetes, dyslipidemia, smoking, angina, beta-blocker use, prior revascularization, and resting heart rate) improved the model performance (C-statistic 0.805 [95% CI: 0.772 to 0.838] to 0.839 [95% CI: 0.809 to 0.869]) and risk reclassification for cardiac death (NRI 0.116 [95% CI: 0.021 to 0.210]), with smaller improvements in risk assessment for all-cause death. In patients with known or suspected CAD, the extent and severity of ischemia and scar on PET MPI provided powerful and incremental risk estimates of cardiac death and all-cause death compared with traditional coronary risk factors.

Background— Although cardiac magnetic resonance (CMR) and positron emission tomography (PET) detect different pathological attributes of cardiac sarcoidosis (CS), the complementary value of these tests has not been evaluated. Our objective was to determine the value of combining CMR and PET in assessing the likelihood of CS and guiding patient management. Methods and Results— In this retrospective study, we included 107 consecutive patients referred for evaluation of CS by both CMR and PET. Two experienced readers blinded to all clinical data reviewed CMR and PET images and categorized the likelihood of CS as no (&lt;10%), possible (10%–50%), probable (50%–90%), or highly probable(&gt;90%) based on predefined criteria. Patient management after imaging was assessed for all patients and across categories of increasing CS likelihood. A final clinical diagnosis for each patient was assigned based on a subsequent review of all available imaging, clinical, and pathological data. Among 107 patients (age, 55±11 years; left ventricular ejection fraction, 43±16%), 91 (85%) had late gadolinium enhancement, whereas 82 (76%) had abnormal F18-fluorodeoxyglucose uptake on PET, suggesting active inflammation. Among the 91 patients with positive late gadolinium enhancement, 60 (66%) had abnormal F18-fluorodeoxyglucose uptake. When PET data were added to CMR, 48 (45%) patients were reclassified as having a higher or lower likelihood of CS, most of them (80%) being correctly reclassified when compared with the final diagnosis. Changes in immunosuppressive therapies were significantly more likely among patients with highly probable CS. Conclusions— Among patients with suspected CS, combining CMR and PET provides complementary value for estimating the likelihood of CS and guiding patient management.

Sarcoidosis is a systemic disorder of unknown etiology whose clinical presentation is characterized by the heterogeneous contributions of nonnecrotizing granulomatous inflammation and concomitant fibrosis. Cardiac involvement portends an adverse prognosis and may account for approximately 25% of

Preamble……2 I.Introduction……2 II.Goals……2 III.Definitions……3 IV. Common clinical applications……3 V. Qualifications and responsibilities of personnel (in the United States)……3 1. Physicians……3 1. SPECT/CT cardiac radionuclide imaging……3 2

Background 3D printing is a promising technique that may have applications in medicine, and there is expanding interest in the use of patient-specific 3D models to guide surgical interventions. Objective To determine the feasibility of using cardiac CT to print individual models of the aortic root complex for transcatheter aortic valve replacement (TAVR) planning as well as to determine the ability to predict paravalvular aortic regurgitation (PAR). Methods This retrospective study included 16 patients (9 with PAR identified on blinded interpretation of post-procedure trans-thoracic echocardiography and 7 age, sex, and valve size-matched controls with no PAR). 3D printed models of the aortic root were created from pre-TAVR cardiac computed tomography data. These models were fitted with printed valves and predictions regarding post-implant PAR were made using a light transmission test. Results Aortic root 3D models were highly accurate, with excellent agreement between annulus measurements made on 3D models and those made on corresponding 2D data (mean difference of −0.34 mm, 95% limits of agreement: ± 1.3 mm). The 3D printed valve models were within 0.1 mm of their designed dimensions. Examination of the fit of valves within patient-specific aortic root models correctly predicted PAR in 6 of 9 patients (6 true positive, 3 false negative) and absence of PAR in 5 of 7 patients (5 true negative, 2 false positive). Conclusions Pre-TAVR 3D-printing based on cardiac CT provides a unique patient-specific method to assess the physical interplay of the aortic root and implanted valves. With additional optimization, 3D models may complement traditional techniques used for predicting which patients are more likely to develop PAR.

Individuals with cardiac sarcoidosis have an increased risk of ventricular arrhythmia and death. Several small cohort studies have evaluated the ability of late gadolinium enhancement (LGE) by cardiac magnetic resonance imaging (MRI) to predict adverse cardiovascular events. However, studies have yielded inconsistent results, and some analyses were underpowered. Therefore, we sought to systematically review and perform meta-analysis of the prognostic value of cardiac MRI for patients with known or suspected cardiac sarcoidosis.We systematically searched for cohort studies of patients with known sarcoidosis with suspected cardiac involvement who underwent cardiac MRI with LGE with at least 12 months of either prospective or retrospective follow-up data regarding post-MRI adverse cardiovascular outcomes. We identified 7 studies of 694 subjects (mean age 53; 42% men).One hundred and ninety-nine patients (29%) were LGE positive. All-cause mortality occurred in 19 LGE-positive versus 17 LGE-negative subjects (annualized incidence, 3.1% versus 0.6%). The pooled relative risk was 3.38 (95% confidence interval, 1.07-10.7; P=0.04). Cardiovascular mortality occurred in 10 LGE-positive versus 2 LGE-negative subjects (annualized incidence, 1.9% versus 0.3%; relative risk 10.7 [95% confidence interval, 1.34-86.3]; P=0.03). Ventricular arrhythmia occurred in 41 LGE-positive versus 0 LGE-negative subjects (annualized incidence, 5.9% versus 0%; relative risk 19.5 [95% confidence interval, 2.68-143]; P=0.003). A combined end point of death or ventricular arrhythmia occurred in 64 LGE-positive versus 18 LGE-negative subjects (annualized incidence, 8.8% versus 0.6%; relative risk 6.20 [95% confidence interval, 2.47-15.6]; P<0.001). There was no significant heterogeneity for any outcomes.LGE is associated with future cardiovascular death and ventricular arrhythmia among patients referred to MRI for known or suspected cardiac sarcoidosis.

The purpose of this study was to test the hypothesis that coronary microvascular function is impaired in subjects with cardiac amyloidosis.Effort angina is common in subjects with cardiac amyloidosis, even in the absence of epicardial coronary artery disease (CAD).Thirty-one subjects were prospectively enrolled in this study, including 21 subjects with definite cardiac amyloidosis without epicardial CAD and 10 subjects with hypertensive left ventricular hypertrophy (LVH). All subjects underwent rest and vasodilator stress N-13 ammonia positron emission tomography and 2-dimensional echocardiography. Global left ventricular myocardial blood flow (MBF) was quantified at rest and during peak hyperemia, and coronary flow reserve (CFR) was computed (peak stress MBF/rest MBF) adjusting for rest rate pressure product.Compared with the LVH group, the amyloid group showed lower rest MBF (0.59 ± 0.15 ml/g/min vs. 0.88 ± 0.23 ml/g/min; p = 0.004), stress MBF (0.85 ± 0.29 ml/g/min vs. 1.85 ± 0.45 ml/g/min; p < 0.0001), and CFR (1.19 ± 0.38 vs. 2.23 ± 0.88; p < 0.0001) and higher minimal coronary vascular resistance (111 ± 40 ml/g/min/mm Hg vs. 70 ± 19 ml/g/min/mm Hg; p = 0.004). Of note, almost all subjects with amyloidosis (>95%) had significantly reduced peak stress MBF (<1.3 ml/g/min). In multivariable linear regression analyses, a diagnosis of amyloidosis, increased left ventricular mass, and age were the only independent predictors of impaired coronary vasodilator function.Coronary microvascular dysfunction is highly prevalent in subjects with cardiac amyloidosis, even in the absence of epicardial CAD, and may explain their anginal symptoms. Further study is required to understand whether specific therapy directed at amyloidosis may improve coronary vasomotion in amyloidosis.

Radionuclide myocardial perfusion imaging (MPI) is among the most commonly performed diagnostic tests in cardiology. Although the diagnostic and prognostic applications of radionuclide MPI are supported by a wealth of observational and clinical trial data, its performance is limited by two

Despite significant progress in primary prevention, the rate of MI has not declined in young adults. The purpose of this study was to evaluate statin eligibility based on the 2013 American College of Cardiology/American Heart Association guidelines for treatment of blood cholesterol and 2016 U.S. Preventive Services Task Force recommendations for statin use in primary prevention in a cohort of adults who experienced a first-time myocardial infarction (MI) at a young age. The YOUNG-MI registry is a retrospective cohort from 2 large academic centers, which includes patients who experienced an MI at age ≤50 years. Diagnosis of type 1 MI was adjudicated by study physicians. Pooled cohort risk equations were used to estimate atherosclerotic cardiovascular disease risk score based on data available prior to MI or at the time of presentation. Of 1,685 patients meeting inclusion criteria, 210 (12.5%) were on statin therapy prior to MI and were excluded. Among the remaining 1,475 individuals, the median age was 45 years, there were 294 (20%) women, and 846 (57%) had ST-segment elevation MI. At least 1 cardiovascular risk factor was present in 1,225 (83%) patients. The median 10-year atherosclerotic cardiovascular disease risk score of the cohort was 4.8% (interquartile range: 2.8% to 8.0%). Only 724 (49%) and 430 (29%) would have met criteria for statin eligibility per the 2013 American College of Cardiology/American Heart Association guidelines and 2016 U.S. Preventive Services Task Force recommendations, respectively. This finding was even more pronounced in women, in whom 184 (63%) were not eligible for statins by either guideline, compared with 549 (46%) men (p < 0.001). The vast majority of adults who present with an MI at a young age would not have met current guideline-based treatment thresholds for statin therapy prior to their MI. These findings highlight the need for better risk assessment tools among young adults.

This article is being jointly published in the Journal of Nuclear Cardiology and The Journal of Nuclear Medicine.

Background Cardiac amyloidosis is a substantially underdiagnosed disease, and contemporary estimates of the epidemiology of amyloidosis are lacking. This study aims to determine the incidence and prevalence of cardiac amyloidosis among Medicare beneficiaries from 2000 to 2012. Methods and Results Medicare beneficiaries were counted in the prevalence cohort in each year they had (1) ≥1 principal or secondary International Classification of Diseases, Ninth Revision code for amyloidosis and (2) ≥1 principal or secondary International Classification of Diseases, Ninth Revision code for heart failure or cardiomyopathy within 2 years after the systemic amyloidosis code. A beneficiary was counted in the incidence cohort only during the first year in which they met criteria. Primary outcomes included the prevalence and incidence of hospitalizations for cardiac amyloidosis. There were 4746 incident cases of cardiac amyloidosis in 2012 and 15 737 prevalent cases in 2012. There was also a significant increase in the prevalence rate (8 to 17 per 100 000 person-years) and incidence rate (18 to 55 per 100 000 person-years) from 2000 to 2012, most notable after 2006. Incidence and prevalence increased substantially more among men, the elderly, and in blacks. Conclusions The incidence and prevalence rates of cardiac amyloidosis are higher than previously thought. The incidence and prevalence rates of cardiac amyloidosis among hospitalized patients have increased since 2000, particularly among specific patient subgroups and after 2006, suggesting improved amyloidosis awareness and higher diagnostic rates with noninvasive imaging. In light of these trends, cardiac amyloidosis should be considered during the initial work up of patients ≥65 years old hospitalized with heart failure.

Left ventricular (LV) hypertrophy (LVH) is a growth in left myocardial mass mainly caused by increased cardiomyocyte size. LVH can be a physiological adaptation to physical exercise or a pathological condition either primary, i.e. genetic, or secondary to LV overload. Patients with both primary and secondary LVH have evidence of coronary microvascular dysfunction (CMD). The latter is mainly due to capillary rarefaction and adverse remodelling of intramural coronary arterioles due to medial wall thickening with an increased wall/lumen ratio. An important feature of this phenomenon is the diffuse nature of this remodelling, which generally affects the coronary microvessels in the whole of the left ventricle. Patients with LVH secondary to arterial hypertension can develop both heart failure with preserved ejection fraction (HFpEF) and heart failure with reduced ejection fraction (HFrEF). These patients can develop HFrEF via a 'direct pathway' with an interval myocardial infarction and also in its absence. On the other hand, patients can develop HFpEF that can then progress to HFrEF with or without interval myocardial infarction. A similar evolution towards LV dysfunction and both HFpEF and HFrEF can occur in patients with hypertrophic cardiomyopathy, the most common genetic cardiomyopathy with a phenotype characterized by massive LVH. In this review article, we will discuss both the experimental and clinical studies explaining the mechanisms responsible for CMD in LVH as well as the evidence linking CMD with HFpEF and HFrEF.

Our purpose was to evaluate the long-term benefit of myocardial viability assessment for stratifying risk and selecting patients with low ejection fraction for coronary artery bypass grafting and to determine the relation between the severity of anginal symptoms, the amount of ischemic myocardium, and clinical outcome.We studied 93 consecutive patients with severe coronary artery disease and low ejection fraction (median, 25%) who underwent positron emission tomography to delineate the extent of perfusion-metabolism mismatch (reflecting hibernating myocardium) for potential myocardial revascularization. Median follow-up was 4 years (range, 0 to 6.2 years).Fifty patients received medical therapy, and 43 patients underwent bypass grafting. In Cox survival models, heart failure class, prior myocardial infarction, and positron emission tomographic mismatch were the best predictors of survival. Patients with positron emission tomographic mismatch receiving bypass grafting had improved 4-year survival compared with those on medical therapy (75% versus 30%; P =.007) and a significant improvement in angina and heart failure symptoms. In patients without positron emission tomographic mismatch, bypass grafting tended to improve survival and symptoms only in those patients with severe angina (100% versus 60%; P =.085), whereas no survival advantage was apparent in patients with minimal or no anginal symptoms (63% versus 52%; P =.462).Patients with low ejection fraction and evidence of viable myocardium by positron emission tomography have improved survival and symptoms with coronary bypass grafting compared with medical therapy. In patients without evidence of viability, survival and symptom improvement with bypass grafting are apparent only among those patients with severe angina.

Our objective was to determine the accuracy of rubidium-82 myocardial perfusion positron emission tomography-computed tomography (PET-CT) imaging for detecting obstructive coronary artery disease (CAD). Hybrid PET-CT is a new noninvasive imaging modality for evaluating patients with known or suspected CAD. We evaluated 64 consecutive patients with suspected CAD undergoing rest-stress rubidium-82 cardiac PET-CT (CT was only used for attenuation correction) and coronary angiography within 7 days (range 1 to 180 days). Patients with known CAD, previous myocardial infarction, or revascularization were excluded. Thirty-eight patients with a low likelihood for CAD were also studied. Obstructive CAD was defined as ≥70% diameter stenosis on angiography. The mean age of the patients was 62 ± 15 years, with a body mass index of 31 ± 8 kg/m2. Chest pain and/or dyspnea were the predominant reasons for evaluation. Stress perfusion defects were detected in 41 of 44 patients with obstructive CAD (sensitivity 93%, 95% confidence interval [CI] 87 to 99). The specificity of PET-CT was 83% (48 of 58, 95% CI 71 to 91), and its overall diagnostic accuracy was 87% (95% CI 79 to 93). All patients with a low likelihood for CAD showed normal scans, for a normalcy rate of 100% (38 of 38, 95% CI 91 to 100). The sensitivity for detecting CAD in patients with single and multivessel (≥2 vessels) disease was 92% (22 of 24, 95% CI 74 to 99) and 95% (19 of 20, 95% CI 74 to 99), respectively. Myocardial perfusion PET-CT affords high sensitivity and overall accuracy for detecting CAD, including patients with single-vessel disease, women, and obese patients.

C ardiac sympathetic signals play an important role in the regulation of myocardial perfusion. We hypothesized that sympathetically mediated myocardial blood flow would be impaired in diabetics with autonomic neuropathy.We studied 28 diabetics (43+/-7 years old) and 11 age-matched healthy volunteers. PET was used to delineate cardiac sympathetic innervation with [(11)C]hydroxyephedrine ([(11)C]HED) and to measure myocardial blood flow at rest, during hyperemia, and in response to sympathetic stimulation by cold pressor testing. The response to cardiac autonomic reflex tests was also evaluated. Using ultrasonography, we also measured brachial artery reactivity during reactive hyperemia (endothelium-dependent dilation) and after sublingual nitroglycerin (endothelium-independent dilation). Based on [(11)C]HED PET, 13 of 28 diabetics had sympathetic-nerve dysfunction (SND). Basal flow was regionally homogeneous and similar in the diabetic and normal subjects. During hyperemia, the increase in flow was greater in the normal subjects (284+/-88%) than in the diabetics with SND (187+/-80%, P=0.084) and without SND (177+/-72%, P=0.028). However, the increase in flow in response to cold was lower in the diabetics with SND (14+/-10%) than in those without SND (31+/-12%) (P=0.015) and the normal subjects (48+/-24%) (P<0.001). The flow response to cold was related to the myocardial uptake of [(11)C]HED (P<0.001). Flow-mediated brachial artery dilation was impaired in the diabetics compared with the normal subjects, but it was similar in the diabetics with and without SND.Diabetic autonomic neuropathy is associated with an impaired vasodilator response of coronary resistance vessels to increased sympathetic stimulation, which is related to the degree of SND.

The role of cardiac sympathetic nerves in regulating coronary blood flow is controversial. We sought to determine the degree to which cardiac efferent sympathetic signals modulate coronary blood flow. The heterogeneous sympathetic reinnervation in transplanted hearts provides a model for studying the vasomotor responses to adrenergic stimulation in reinnervated and denervated coronary territories of the same heart.We studied 14 cardiac-transplant recipients who had normal coronary arteries and no evidence of rejection and 8 normal subjects. We used positron-emission tomography with [(11)C]hydroxyephedrine, an analogue of norepinephrine, to delineate sympathetic innervation. Using [(13)N]ammonia, we measured myocardial blood flow at rest, during adenosine-induced hyperemia, and in response to sympathetic stimulation induced by cold pressor testing.In the transplant recipients, the uptake of [(11)C]hydroxyephedrine was greater in the territory served by the left anterior descending artery (0.15+/-0.01) than in those served by the right coronary artery (0.07+/-0.01, P<0.001) or the circumflex artery (0.09+/-0.01, P<0.001). The basal flow was similar in all three regions, as was the percent increase in flow during hyperemia. However, the increase in flow in response to cold pressor testing was higher in the territory of the left anterior descending artery (46+/-10 percent) than in those of the right coronary artery (16+/-5 percent, P=0.01) or the circumflex artery (23+/-6 percent, P=0.06), although the changes in hemodynamics and levels of circulating catecholamines were similar. No such regional differences were observed in the normal subjects.Increases in coronary blood flow in response to sympathetic stimulation correlated with the regional norepinephrine content in the cardiac sympathetic-nerve terminals. These findings suggest that cardiac adrenergic signals play an important part in regulating myocardial blood flow.

We sought to determine whether right ventricular (RV) function late after myocardial infarction (MI) impacts long-term prognosis. Right ventricular failure predicts early mortality in patients with acute MI. The prognostic impact of RV function late after MI is not well defined. Accordingly, we determined whether RV dysfunction late after MI influences survival beyond traditional risk predictors, including patient age, left ventricular ejection fraction (LVEF), and infarct size. We studied 147 consecutive patients >30 days after MI (mean age of infarct 6.7 ± 8.2 years) who were referred for contrast-enhanced cardiovascular magnetic resonance imaging. We assessed hazard ratios for death by RV ejection fraction (RVEF). The association of RVEF with mortality adjusted to traditional risk predictors was examined by using multivariable Cox proportional hazards regression models. A total of 26 deaths occurred during a median follow-up of 17 months (range 6 to 53 months). By univariable analysis, RVEF <40% was strongly associated with mortality (unadjusted hazard ratio 4.02; p = 0.0007). By multivariable analysis that adjusted for patient age, left ventricular (LV) infarct size, and LVEF, RVEF <40% remained a significant independent predictor of mortality (adjusted hazard ratio 2.86; p = 0.03). Right ventricular ejection fraction quantified late after MI is an important predictor of prognosis adjusted for patient age, LV infarct size, and LVEF. Accordingly, evaluation of RVEF using cardiovascular magnetic resonance imaging can improve risk-stratification and potentially refine patient management after MI.

This study examined short-term cardiac catheterization rates and medication changes after cardiac imaging. Noninvasive cardiac imaging is widely used in coronary artery disease, but its effects on subsequent patient management are unclear. We assessed the 90-day post-test rates of catheterization and medication changes in a prospective registry of 1,703 patients without a documented history of coronary artery disease and an intermediate to high likelihood of coronary artery disease undergoing cardiac single-photon emission computed tomography, positron emission tomography, or 64-slice coronary computed tomography angiography. Baseline medication use was relatively infrequent. At 90 days, 9.6% of patients underwent catheterization. The rates of catheterization and medication changes increased in proportion to test abnormality findings. Among patients with the most severe test result findings, 38% to 61% were not referred to catheterization, 20% to 30% were not receiving aspirin, 35% to 44% were not receiving a beta-blocker, and 20% to 25% were not receiving a lipid-lowering agent at 90 days after the index test. Risk-adjusted analyses revealed that compared with stress single-photon emission computed tomography or positron emission tomography, changes in aspirin and lipid-lowering agent use was greater after computed tomography angiography, as was the 90-day catheterization referral rate in the setting of normal/nonobstructive and mildly abnormal test results. Overall, noninvasive testing had only a modest impact on clinical management of patients referred for clinical testing. Although post-imaging use of cardiac catheterization and medical therapy increased in proportion to the degree of abnormality findings, the frequency of catheterization and medication change suggests possible undertreatment of higher risk patients. Patients were more likely to undergo cardiac catheterization after computed tomography angiography than after single-photon emission computed tomography or positron emission tomography after normal/nonobstructive and mildly abnormal study findings. (Study of Perfusion and Anatomy's Role in Coronary Artery [CAD] [SPARC]; NCT00321399)

Rationale: Myeloid cell content in atherosclerotic plaques associates with rupture and thrombosis. Thus, imaging of lesional monocytes and macrophages could serve as a biomarker of disease progression and therapeutic intervention. Objective: To noninvasively assess plaque inflammation with dextran nanoparticle (DNP)-facilitated hybrid positron emission tomography/magnetic resonance imaging (PET/MRI). Methods and Results: Using clinically approved building blocks, we systematically developed 13-nm polymeric nanoparticles consisting of cross-linked short chain dextrans, which were modified with desferoxamine for zirconium-89 radiolabeling ( 89 Zr-DNP) and a near-infrared fluorochrome (VT680) for microscopic and cellular validation. Flow cytometry of cells isolated from excised aortas showed DNP uptake predominantly in monocytes and macrophages (76.7%) and lower signal originating from other leukocytes, such as neutrophils and lymphocytes (11.8% and 0.7%, P &lt;0.05 versus monocytes and macrophages). DNP colocalized with the myeloid cell marker CD11b on immunohistochemistry. PET/MRI revealed high uptake of 89 Zr-DNP in the aortic root of apolipoprotein E knock out (ApoE −/− ) mice (standard uptake value, ApoE −/− mice versus wild-type controls, 1.9±0.28 versus 1.3±0.03; P &lt;0.05), corroborated by ex vivo scintillation counting and autoradiography. Therapeutic silencing of the monocyte-recruiting receptor C-C chemokine receptor type 2 with short-interfering RNA decreased 89 Zr-DNP plaque signal ( P &lt;0.05) and inflammatory gene expression ( P &lt;0.05). Conclusions: Hybrid PET/MRI with a 13-nm DNP enables noninvasive assessment of inflammation in experimental atherosclerotic plaques and reports on therapeutic efficacy of anti-inflammatory therapy.

Minimally elevated serum cardiac troponin reflects myocardial injury and is associated with increased mortality, even absent coronary artery disease (CAD). We sought to investigate the relationship between low-level troponin elevation and impaired coronary flow reserve (CFR), an integrated measure of coronary vasomotor function, and to assess their contributions to adverse outcomes in patients without overt CAD.Consecutive patients (n=761) undergoing evaluation for suspected CAD with troponin before stress myocardial perfusion positron emission tomography were followed up (median, 2.8 years) for major adverse cardiovascular events, including cardiovascular death, nonfatal myocardial infarction, or late revascularization. Patients with flow-limiting CAD, left ventricular ejection fraction <40%, or revascularization within 60 days of imaging were excluded. CFR was quantified from stress/rest myocardial blood flow with the use of positron emission tomography. Compared with patients with negative troponin, those with at least 1 positive troponin (n=97) had higher pretest clinical scores, more renal dysfunction, and lower left ventricular ejection fraction and CFR. In adjusted analysis, impaired CFR remained independently associated with positive troponin (odds ratio, 2.18; 95% confidence interval, 1.37-3.47; P=0.001), and both impaired CFR and positive troponin were independently associated with major adverse cardiovascular events (hazard ratio, 2.25; 95% confidence interval, 1.31-3.86; P=0.003; and hazard ratio, 2.42; 95% confidence interval, 1.34-4.40; P=0.004, respectively). Impaired CFR and positive troponin identified patients at highest risk of major adverse cardiovascular events (log-rank P<0.0001), with a significant interaction (P<0.007) seen between CFR and troponin.In patients without overt CAD, impaired CFR was independently associated with minimally elevated troponin and major adverse cardiovascular events. Impaired CFR, here reflecting microvascular dysfunction, modified the effect of a positive troponin on adverse outcomes.

Our aim was to determine the value of vasodilator left ventricular ejection fraction (LVEF) reserve (stress ejection fraction - rest ejection fraction) in evaluating the magnitude of myocardium at risk and the anatomic extent of underlying severe coronary artery disease (CAD).We studied 510 consecutive patients with suspected CAD undergoing gated rest and vasodilator stress (82)Rb PET/CT. Patients were categorized as having no perfusion abnormalities, mild, moderate, or severe reversible perfusion defects. In a subgroup of 68 patients with coronary angiography, patients were categorized as having 0-vessel, 1-vessel, 2-vessel, or left main/3-vessel disease.Patients without coronary risk factors who comprised our control group as well as patients with coronary risk factors and normal perfusion demonstrated a high LVEF reserve (7% +/- 7% and 5% +/- 6%, respectively). The mean LVEF reserve was negative (-0.2% +/- 8%) in patients with severe reversible defects and in patients with 3-vessel (-6% +/- 8%) and left main (-8% +/- 5%) disease. Among the clinical and scintigraphic variables studied, male sex, rest ejection fraction, and increasing magnitude of myocardium at risk predicted a lower LVEF reserve, whereas LVEF reserve was the only independent predictor of left main/3-vessel disease (P = 0.008). An LVEF reserve of more than +5% had a positive predictive value of only 41% but a negative predictive value of 97% for excluding severe left main/3-vessel CAD.During (82)Rb PET/CT, LVEF increases with vasodilator stress in patients without significant stress-induced perfusion defects or severe left main/3-vessel CAD. A high LVEF reserve appears to be an excellent tool to exclude left main/3-vessel CAD noninvasively.

Substance abuse is increasingly prevalent among young adults, but data on cardiovascular outcomes remain limited.The objectives of this study were to assess the prevalence of cocaine and marijuana use in adults with their first myocardial infarction (MI) at ≤50 years and to determine its association with long-term outcomes.The study retrospectively analyzed records of patients presenting with a type 1 MI at ≤50 years at 2 academic hospitals from 2000 to 2016. Substance abuse was determined by review of records for either patient-reported substance abuse during the week before MI or substance detection on toxicology screen. Vital status was identified by the Social Security Administration's Death Master File. Cause of death was adjudicated using electronic health records and death certificates. Cox modeling was performed for survival free from all-cause and cardiovascular death.A total of 2,097 patients had type 1 MI (mean age 44.0 ± 5.1 years, 19.3% female, 73% white), with median follow-up of 11.2 years (interquartile range: 7.3 to 14.2 years). Use of cocaine and/or marijuana was present in 224 (10.7%) patients; cocaine in 99 (4.7%) patients, and marijuana in 125 (6.0%). Individuals with substance use had significantly lower rates of diabetes (14.7% vs. 20.4%; p = 0.05) and hyperlipidemia (45.7% vs. 60.8%; p < 0.001), but they were significantly more likely to use tobacco (70.3% vs. 49.1%; p < 0.001). The use of cocaine and/or marijuana was associated with significantly higher cardiovascular mortality (hazard ratio: 2.22; 95% confidence interval: 1.27 to 3.70; p = 0.005) and all-cause mortality (hazard ratio: 1.99; 95% confidence interval: 1.35 to 2.97; p = 0.001) after adjusting for baseline covariates.Cocaine and/or marijuana use is present in 10% of patients with an MI at age ≤50 years and is associated with worse all-cause and cardiovascular mortality. These findings reinforce current recommendations for substance use screening among young adults with an MI, and they highlight the need for counseling to prevent future adverse events.

The major aim of this study is to test the hypothesis that stress cardiac magnetic resonance (CMR) imaging can provide robust prognostic value in women presenting with suspected ischemia, to the same extent as in men. Compelling evidence indicates that women with coronary artery disease (CAD) experience worse outcomes than men owing to a lack of early diagnosis and management. Numerous clinical studies have shown that stress CMR detects evidence of myocardial ischemia and infarction at high accuracy. Compared to nuclear scintigraphy, CMR is free of ionizing radiation, has high spatial resolution for imaging small hearts, and overcomes breast attenuation artifacts, which are substantial advantages when imaging women for CAD. We performed stress CMR in 405 patients (168 women, mean age 58 ± 14 years) referred for ischemia assessment. CMR techniques included cine cardiac function, perfusion imaging during vasodilating stress, and late gadolinium enhancement imaging. All patients were followed for major adverse cardiac events (MACE). At a median follow-up of 30 months, MACE occurred in 36 patients (9%) including 21 cardiac deaths and 15 acute myocardial infarctions. In women, CMR evidence of ischemia (ISCHEMIA) demonstrated strong association with MACE (unadjusted hazard ratio: 49.9, p < 0.0001). While women with ISCHEMIA(+) had an annual MACE rate of 15%, women with ISCHEMIA(−) had very low annual MACE rate (0.3%), which was not statistically different from the low annual MACE rate in men with ISCHEMIA(−) (1.1%). CMR myocardial ischemia score was the strongest multivariable predictor of MACE in this cohort, for both women and men, indicating robust cardiac prognostication regardless of sex. In addition to avoiding exposure to ionizing radiation, stress CMR myocardial perfusion imaging is an effective and robust risk-stratifying tool for patients of either sex presenting with possible ischemia.

This study sought to evaluate whether impaired vasodilator function, an early manifestation of coronary artery disease, which precedes angiographic stenosis, accounts for increased risk among patients with moderate to severe renal dysfunction.Patients with renal dysfunction are at increased risk of adverse cardiac outcomes, even in the absence of overt myocardial ischemia or infarction.We included 866 consecutive patients with moderate to severe renal dysfunction referred for rest and stress myocardial perfusion positron emission tomography and followed them for a median of 1.28 years (interquartile range: 0.64 to 2.34). Regional myocardial perfusion abnormalities were assessed by semiquantitative visual analysis of positron emission tomography images. Rest and stress myocardial blood flow were calculated using factor analysis and a 2-compartment kinetic model; they were also used to compute coronary flow reserve (stress/rest myocardial blood flow). The primary endpoint was cardiac death.Overall, 3-year cardiac mortality was 16.2%. After adjusting for clinical risk, left ventricular ejection fraction, as well as the magnitude of scar and/or ischemia, coronary flow reserve below the median (<1.5) was associated with a 2.1-fold increase in the risk of cardiac death (95% confidence interval [CI]: 1.3 to 3.5, p = 0.004). Incorporation of coronary flow reserve into cardiac death risk assessment models resulted in an increase in the C-index from 0.75 to 0.77 (p = 0.05) and in a net reclassification improvement of 0.142 (95% CI: 0.076 to 0.219). Among patients at intermediate risk based on all data other than coronary flow reserve, the net reclassification improvement was 0.489 (95% CI: 0.192 to 0.836). Corresponding improvements in risk assessment for mortality from any cause were also demonstrated.The presence of coronary vascular dysfunction in patients with moderate to severe renal dysfunction, as assessed by positron emission tomography, is a powerful, independent predictor of cardiac mortality and provides meaningful incremental risk stratification over conventional markers of clinical risk.

Background— Limited data exist on how noninvasive testing options compare for evaluating patients with suspected stable coronary artery disease. In this study, we have performed a meta-analysis of randomized controlled trials comparing the use of coronary computed tomographic angiography (CTA) with usual care. Methods and Results— We systematically searched databases for randomized clinical trials comparing coronary CTA with usual care for the evaluation of stable chest pain with follow-up for cardiovascular outcomes. The primary outcomes were myocardial infarction and all-cause mortality. We identified 4 randomized clinical trials, including a total of 7403 patients undergoing coronary CTA and 7414 patients undergoing usual care with various functional testing approaches. When compared with usual care, the use of coronary CTA was associated with a significant reduction in the annual rate of myocardial infarction (rate ratio, 0.69; 95% confidence interval, 0.49–0.98; P =0.038), but no difference was found in all-cause mortality. There was a trend toward more invasive coronary angiographies among patients undergoing coronary CTA (odds ratio, 1.33; 95% confidence interval, 0.95–1.84; P =0.09) and higher use of coronary revascularizations (odds ratio, 1.77; 95% confidence interval, 1.14–2.75). Significant heterogeneity for invasive coronary angiography and revascularization was noted, which was attributable to the Scottish Computed Tomography of the HEART (SCOT-HEART) study. We found no difference in the rate of admission for cardiac chest pain (rate ratio, 1.21; 95% confidence interval, 0.95–1.54). Conclusions— In comparison to usual care, an initial investigation of suspected stable coronary artery disease using coronary CTA resulted in a significant reduction in myocardial infarction, an increased incidence of coronary revascularization, and no effect in all-cause mortality. Future studies should further define whether the potential reduction in myocardial infarction identified justifies the increased resource utilization associated with coronary CTA.

Besides body mass index (BMI), other discriminators of cardiovascular risk are needed in obese patients, who may or may not undergo consideration for bariatric surgery. Coronary microvascular dysfunction (CMD), defined as impaired coronary flow reserve (CFR) in the absence of flow-limiting coronary artery disease, identifies patients at risk for adverse events independently of traditional risk factors. The study sought to investigate the relationship among obesity, CMD, and adverse outcomes. Consecutive patients undergoing evaluation for coronary artery disease with cardiac stress positron emission tomography demonstrating normal perfusion (N = 827) were followed for median 5.6 years for events, including death and hospitalization for myocardial infarction or heart failure. An inverted independent J-shaped relationship was observed between BMI and CFR, such that in obese patients CFR decreased linearly with increasing BMI (adjusted p < 0.0001). In adjusted analyses, CFR but not BMI remained independently associated with events (for a 1-U decrease in CFR, adjusted hazard ratio: 1.95; 95% confidence interval: 1.41 to 2.69; p < 0.001; for a 10-U increase in BMI, adjusted hazard ratio: 1.20; 95% confidence interval: 0.95 to 1.50; p = 0.125) and improved model discrimination (C-index 0.71 to 0.74). In obese patients, individuals with impaired CFR demonstrated a higher adjusted rate of events (5.7% vs. 2.6%; p = 0.002), even in those not currently meeting indications for bariatric surgery (6.4% vs. 2.6%; p = 0.04). In patients referred for testing, CMD was independently associated with elevated BMI and adverse outcomes, and was a better discriminator of risk than BMI and traditional risk factors. CFR may facilitate management of obese patients beyond currently used markers of risk.

(18)F-florbetapir is a promising imaging biomarker for cardiac light chain amyloidosis (AL) and transthyretin amyloidosis (ATTR). Our aim, using human autopsy myocardial specimens, was to test the hypothesis that (18)F-florbetapir binds specifically to myocardial AL and ATTR amyloid deposits.We studied myocardial sections from 30 subjects with autopsy-documented AL (n=10), ATTR (n=10), and nonamyloid controls (n=10) using (18)F-florbetapir and cold florbetapir compound and digital autoradiography. Total and nonspecific binding of (18)F-florbetapir was determined using the maximum signal intensity values. Specific binding of (18)F-florbetapir was calculated by subtracting nonspecific from total binding measurements (in decays per minute/mm(2), DPM mm(2)) and was compared with cardiac structure and function on echocardiography and the histological extent of amyloid deposits. Diffuse or focally increased (18)F-florbetapir uptake was noted in all AL and ATTR samples and in none of the control samples. Compared with control samples, mean (18)F-florbetapir-specific uptake was significantly higher in the amyloid samples (0.94±0.43 versus 2.00±0.58 DPM/mm(2); P<0.001), and in the AL compared with the ATTR samples (2.48±0.40 versus 1.52±0.22 DPM/mm(2); P<0.001). The samples from subjects with atypical echocardiographic features of amyloidosis showed quantitatively more intense (18)F-florbetapir-specific uptake compared with control samples (1.50±0.17 versus 0.94±0.43 DPM/mm(2); P=0.004), despite smaller amyloid extent than in subjects with typical echocardiograms.(18)F-florbetapir specifically binds to myocardial AL and ATTR deposits in humans and offers the potential to screen for the 2 most common types of myocardial amyloid.

Reduced coronary flow reserve (CFR), an indicator of coronary microvascular dysfunction, is seen in type 2 diabetes mellitus (T2DM) and predicts cardiac mortality. Since aldosterone plays a key role in vascular injury, the aim of this study was to determine whether mineralocorticoid receptor (MR) blockade improves CFR in individuals with T2DM. Sixty-four men and women with well-controlled diabetes on chronic ACE inhibition (enalapril 20 mg/day) were randomized to add-on therapy of spironolactone 25 mg, hydrochlorothiazide (HCTZ) 12.5 mg, or placebo for 6 months. CFR was assessed by cardiac positron emission tomography at baseline and at the end of treatment. There were significant and similar decreases in systolic blood pressure with spironolactone and HCTZ but not with placebo. CFR improved with treatment in the spironolactone group as compared with the HCTZ group and with the combined HCTZ and placebo groups. The increase in CFR with spironolactone remained significant after controlling for baseline CFR, change in BMI, race, and statin use. Treatment with spironolactone improved coronary microvascular function, raising the possibility that MR blockade could have beneficial effects in preventing cardiovascular disease in patients with T2DM.

The purpose of this study was to quantify the effects of coronary atherosclerosis morphology and extent on myocardial flow reserve (MFR).Although the relationship between coronary stenosis and myocardial perfusion is well established, little is known about the contribution of other anatomic descriptors of atherosclerosis burden to this relationship.We evaluated the relationship between atherosclerosis plaque burden, morphology, and composition and regional MFR (MFR(regional)) in 73 consecutive patients undergoing Rubidium-82 positron emission tomography and coronary computed tomography angiography for the evaluation of known or suspected coronary artery disease.Atherosclerosis was seen in 51 of 73 patients and in 107 of 209 assessable coronary arteries. On a per-vessel basis, the percentage diameter stenosis (p = 0.02) or summed stenosis score (p = 0.002), integrating stenoses in series, was the best predictor of MFR(regional). Importantly, MFR(regional) varied widely within each coronary stenosis category, even in vessels with nonobstructive plaques (n = 169), 38% of which had abnormal MFR(regional) (<2.0). Total plaque length, composition, and remodeling index were not associated with lower MFR. On a per-patient basis, the modified Duke CAD (coronary artery disease) index (p = 0.04) and the number of segments with mixed plaque (p = 0.01) were the best predictors of low MFR(global).Computed tomography angiography descriptors of atherosclerosis had only a modest effect on downstream MFR. On a per-patient basis, the extent and severity of atherosclerosis as assessed by the modified Duke CAD index and the number of coronary segments with mixed plaque were associated with decreased MFR.

Patients with left ventricular systolic dysfunction frequently show abnormal coronary vascular function, even in the absence of overt coronary artery disease. Moreover, the severity of vascular dysfunction might be related to the aetiology of cardiomyopathy.We sought to determine the incremental value of assessing coronary vascular dysfunction among patients with ischaemic (ICM) and non-ischaemic (NICM) cardiomyopathy at risk for adverse cardiovascular outcomes.Coronary flow reserve (CFR, stress/rest myocardial blood flow) was quantified in 510 consecutive patients with rest left ventricular ejection fraction (LVEF) ≤45% referred for rest/stress myocardial perfusion PET imaging. The primary end point was a composite of major adverse cardiovascular events (MACE) including cardiac death, heart failure hospitalization, late revascularization, and aborted sudden cardiac death.Median follow-up was 8.2 months. Cox proportional hazards model was used to adjust for clinical variables. The annualized MACE rate was 26.3%. Patients in the lowest two tertiles of CFR (CFR ≤ 1.65) experienced higher MACE rates than those in the highest tertile (32.6 vs. 15.5% per year, respectively, P = 0.004), irrespective of aetiology of cardiomyopathy.Impaired coronary vascular function, as assessed by reduced CFR by PET imaging, is common in patients with both ischaemic and non-ischaemic cardiomyopathy and is associated with MACE.

Alzheimer's disease (AD) is the most common cause of dementia. Neuroinflammation appears to play an important role in AD pathogenesis. Ligands of the 18 kDa translocator protein (TSPO), a marker for activated microglia, have been used as positron emission tomography (PET) tracers to reflect neuroinflammation in humans and mouse models. Here, we used the novel TSPO-targeted PET tracer (18)F-GE180 (flutriciclamide) to investigate differences in neuroinflammation between young and old WT and APP/PS1dE9 transgenic (Tg) mice. In vivo PET scans revealed an overt age-dependent elevation in whole-brain uptake of (18)F-GE180 in both WT and Tg mice, and a significant increase in whole-brain uptake of (18)F-GE180 (peak-uptake and retention) in old Tg mice compared with young Tg mice and all WT mice. Similarly, the (18)F-GE180 binding potential in hippocampus was highest to lowest in old Tg > old WT > young Tg > young WT mice using MRI coregistration. Ex vivo PET and autoradiography analysis further confirmed our in vivo PET results: enhanced uptake and specific binding (SUV75%) of (18)F-GE180 in hippocampus and cortex was highest in old Tg mice followed by old WT, young Tg, and finally young WT mice. (18)F-GE180 specificity was confirmed by an in vivo cold tracer competition study. We also examined (18)F-GE180 metabolites in 4-month-old WT mice and found that, although total radioactivity declined over 2 h, of the remaining radioactivity, ∼90% was due to parent (18)F-GE180. In conclusion, (18)F-GE180 PET scans may be useful for longitudinal monitoring of neuroinflammation during AD progression and treatment.Microglial activation, a player in Alzheimer's disease (AD) pathogenesis, is thought to reflect neuroinflammation. Using in vivo microPET imaging with a novel TSPO radioligand, (18)F-GE180, we detected significantly enhanced neuroinflammation during normal aging in WT mice and in response to AD-associated pathology in APP/PS1dE9 Tg mice, an AD mouse model. Increased uptake and specific binding of (18)F-GE180 in whole brain and hippocampus were confirmed by ex vivo PET and autoradiography. The binding specificity and stability of (18)F-GE180 was further confirmed by a cold tracer competition study and a metabolite study, respectively. Therefore, (18)F-GE180 PET imaging may be useful for longitudinal monitoring of neuroinflammation during AD progression and treatment and may also be useful for other neurodegenerative diseases.

This study sought to evaluate the interrelation of atherosclerotic burden, as assessed by coronary artery calcium (CAC) score and coronary vascular function, as assessed by quantitative estimates of coronary flow reserve (CFR), with respect to prediction of clinical outcomes.The contribution of coronary vascular dysfunction, atherosclerotic burden, and the 2 combined to cardiac events is unknown.A total of 901 consecutive patients underwent (82)Rubidium myocardial perfusion imaging (MPI) positron emission tomography (PET) and CAC scan. All patients had normal MPI. The primary endpoint was a composite of major adverse cardiac events (MACE) including cardiac death, nonfatal myocardial infarction, late revascularization, and admission for heart failure.At baseline, CFR decreased (2.15 ± 0.72, 2.02 ± 0.65, and 1.88 ± 0.64, p < 0.0001) with increasing levels of CAC (0, 1 to 399, and ≥400). Over a median of 1.53 years (interquartile range: 0.77 to 2.44), there were 57 MACE. Annual risk-adjusted MACE rates were higher for patients with CFR <2.0 compared with ≥2.0 (1.9 vs. 5.5%/year, p = 0.0007) but were only borderline associated with CAC (3.1%, 3.4%, and 6.2%/year for CAC of 0, 1 to 399, and ≥400, respectively; p = 0.09). Annualized adjusted MACE was increased in the presence of impaired CFR even among patients with CAC = 0 (1.4% vs. 5.2%, p = 0.03). Cox proportional hazards analysis revealed that CFR improved model fit, risk discrimination, and risk reclassification over clinical risk, whereas CAC only modestly improved model fit without improving risk discrimination or reclassification.In symptomatic patients with normal MPI, global CFR but not CAC provides significant incremental risk stratification over clinical risk score for prediction of major adverse cardiac events.

Background— Coronary computed tomographic angiography (CCTA) is an accurate test for the identification of coronary artery disease (CAD), yet the impact of CCTA results on subsequent medical therapy and risk factors has not been widely reported. Methods and Results— We identified consecutive patients aged &gt;18 years without prior CAD who underwent CCTA from 2004 to 2011 and had complete data on medications before and after CCTA. CCTA results were categorized as no CAD, &lt;50% stenosis, and ≥50% stenosis. Based on the number of involved segments, extent of disease was categorized as nonextensive (≤4 segments) or extensive CAD (&gt;4 segments). Electronic medical records and patient interviews were reviewed blinded to CCTA findings to assess initiation of aspirin and intensification of lipid-lowering therapies. Survival analysis was performed to evaluate intensification of lipid therapy as a predictor of cardiovascular death or nonfatal myocardial infarction. Among 2839 patients with mean follow-up of 3.6 years, the odds of physician intensification of lipid-lowering therapy significantly increased for those with nonobstructive CAD (odds ratio, 3.6; 95% confidence interval, 2.9–4.9; P &lt;0.001) and obstructive CAD (odds ratio, 5.6; 95% confidence interval, 4.3–7.3; P &lt;0.001). Low-density lipoprotein cholesterol levels declined significantly in association with intensification of lipid-lowering therapy after CCTA in all patient subgroups. In a hypothesis-generating analysis, among patients with nonobstructive but extensive CAD, statin use after CCTA was associated with a reduction in cardiovascular death or myocardial infarction (hazards ratio, 0.18; 95% confidence interval, 0.05–0.66; P =0.01). Conclusions— Abnormal CCTA findings are associated with downstream intensification in statin and aspirin therapy. In particular, CCTA may lead to increased use of prognostically beneficial therapies in patients identified as having extensive, nonobstructive CAD.

AimsThe impact of coronary computed tomographic angiography (CTA) on management of anomalous origin of the coronary artery arising from the opposite sinus (ACAOS) remains uncertain. We examined the prevalence, anatomical characterization, and outcomes of ACAOS patients undergoing CTA.

Cardiac amyloidosis, once considered untreatable, is now gaining well-deserved attention due to advances in imaging and the recent approval of targeted breakthrough therapies. In this paper, we discuss the role of radionuclide imaging in the evaluation and management of patients with the most common form of amyloidosis-cardiac transthyretin amyloidosis (ATTR). We provide a comprehensive summary of the literature interspersed with our institutional experience as appropriate, to deliver our perspective.

Cardiac allograft vasculopathy (CAV) is a leading cause of death in orthotopic heart transplant (OHT) survivors. Effective non-invasive screening methods are needed. Our aim was to investigate the added diagnostic and prognostic value of myocardial blood flow (MBF) to standard myocardial perfusion imaging (MPI) with positron emission tomography (PET) for CAV detection. We studied 94 OHT recipients (prognostic cohort), including 66 who underwent invasive coronary angiography and PET within 1 year (diagnostic cohort). The ISHLT classification was used as standard definition for CAV. Positron emission tomography evaluation included semiquantitative MPI, quantitative MBF (mL/min/g), and left ventricular ejection fraction (LVEF). A PET CAV severity score (on a scale of 0–3) was modelled on the ISHLT criteria. Patients were followed for a median of 2.3 years for the occurrence of major adverse events (death, re-transplantation, acute coronary syndrome, and hospitalization for heart failure). Sensitivity, specificity, positive, and negative predictive value of semiquantitative PET perfusion alone for detecting moderate-severe CAV were 83% [52–98], 82% [69–91], 50% [27–73], and 96% [85–99], respectively {receiver operating characteristic (ROC area: 0.82 [0.70–0.95])}. These values improved to 83% [52–98], 93% [82–98], 71% [42–92], and 96% [97–99], respectively, when LVEF and stress MBF were added (ROC area: 0.88 [0.76–0.99]; P = 0.01). There were 20 major adverse events during follow-up. The annualized event rate was 5%, 9%, and 25% in patients with normal, mildly, and moderate-to-severely abnormal PET CAV grading (P < 0.001), respectively. Multiparametric cardiac PET evaluation including quantification of MBF provides improved detection and gradation of CAV severity over standard myocardial perfusion assessment and is predictive of major adverse events.

The quantification of myocardial blood flow (MBF) and myocardial flow reserve (MFR) using PET with (82)Rb in patients with known or suspected coronary artery disease has been demonstrated to have substantial prognostic and diagnostic value. However, multiple methods for estimation of an image-derived input function and several models for the nonlinear first-pass extraction of (82)Rb by myocardium have been used. We sought to compare the differences in these methods and models and their impact on prognostic assessment in a large clinical dataset.Consecutive patients (n = 2,783) underwent clinically indicated rest-stress myocardial perfusion PET with (82)Rb. The input function was derived using a region of interest (ROI) semiautomatically placed in the region of the mitral valve, factor analysis, and a hybrid method that creates an ROI from factor analysis. We used 5 commonly used extraction models for (82)Rb to estimate MBF and MFR. Pearson correlations, bias, and Cohen κ were computed for the various measures. The relationship between MFR/stress MBF and annual rate of cardiac mortality was estimated with spline fits using Poisson regression. Finally, incremental value was assessed with the net reclassification improvement using Cox proportional hazards regression.Correlations between MFR or stress MBF measures made with the same input function derivation method were generally high, regardless of extraction model used (Pearson r > 0.90). However, correlations between measures derived with the ROI method and other methods were only moderate (Pearson r = 0.42-0.62). Importantly, substantial biases were seen for most combinations. We saw that the relationship between cardiac mortality and stress MBF was variable depending on the input function method and extraction model, whereas the relationship between MFR and risk was highly consistent. Net reclassification improvement was comparable for most methods and models for MFR but was highly variable for stress MBF.Although both stress MBF and MFR can improve prognostic assessment, MFR is substantially more consistent, regardless of choice of input function derivation method and extraction model used.

There are sex differences in presentation, treatment, and outcomes of myocardial infarction (MI) but less is known about these differences in a younger patient population. The objective of this study was to investigate sex differences among individuals who experience their first MI at a young age.Consecutive patients presenting to two large academic medical centres with a Type 1 MI at ≤50 years of age between 2000 and 2016 were included. Cause of death was adjudicated using electronic health records and death certificates. In total, 2097 individuals (404 female, 19%) had an MI (mean age 44 ± 5.1 years, 73% white). Risk factor profiles were similar between men and women, although women were more likely to have diabetes (23.7% vs. 18.9%, P = 0.028). Women were less likely to undergo invasive coronary angiography (93.5% vs. 96.7%, P = 0.003) and coronary revascularization (82.1% vs. 92.6%, P < 0.001). Women were significantly more likely to have MI with non-obstructive coronary disease on angiography (10.2% vs. 4.2%, P < 0.001). They were less likely to be discharged with aspirin (92.2% vs. 95.0%, P = 0.027), beta-blockers (86.6% vs. 90.3%, P = 0.033), angiotensin-converting enzyme inhibitors/angiotensin-receptor blockers (53.4% vs. 63.7%, P < 0.001), and statins (82.4% vs. 88.4%, P < 0.001). There was no significant difference in in-hospital mortality; however, women who survived to hospital discharge experienced a higher all-cause mortality rate (adjusted HR = 1.63, P = 0.01; median follow-up 11.2 years) with no significant difference in cardiovascular mortality (adjusted HR = 1.14, P = 0.61).Women who experienced their first MI under the age of 50 were less likely to undergo coronary revascularization or be treated with guideline-directed medical therapies. Women who survived hospitalization experienced similar cardiovascular mortality with significantly higher all-cause mortality than men. A better understanding of the mechanisms underlying these differences is warranted.

Background Despite significant progress in primary prevention, the rate of myocardial infarction has not decreased in young adults. We sought to compare the risk factor profiles and outcomes between individuals who experienced a first myocardial infarction at a very young (≤40 years) and a young (age 41-50 years) age. Methods We evaluated all patients ≤50 years of age admitted with a Type 1 myocardial infarction to 2 large academic hospitals from 2000 to 2016. Risk factors were determined by review of electronic medical records. The primary outcomes of interest were all-cause and cardiovascular mortality. Results Among 2097 consecutive young patients with myocardial infarction, 431 (20.5%) were ≤40 years of age. When compared with their older counterparts, very young patients had similar risk profiles, with the exception of greater substance abuse (17.9% vs 9.3%, P < .001) and less hypertension (37.9% vs 50.9%, P < .001). Spontaneous coronary artery dissection was more prevalent in very young patients (3.1% vs 1.1%, P = .003). Over a median follow-up of 11.2 years, very young myocardial infarction patients had a similar risk of all-cause and cardiovascular mortality. Conclusions Despite being, on average, 10 years younger and having a lower prevalence of hypertension, very young myocardial infarction patients had similar 1-year and long-term outcomes when compared with those aged 41 to 50 years at the time of their index infarction. Our findings suggest the need for aggressive secondary prevention measures in very young patients who experience a myocardial infarction.

Hodgkin lymphoma (HL) survivors treated with thoracic radiation therapy (RT) have impaired exercise tolerance and increased cardiovascular mortality. The purpose of this study was to evaluate the prevalence of autonomic dysfunction and its implications on exercise capacity and mortality in long-term survivors of HL. Exercise parameters in 263 HL survivors referred for exercise treadmill testing at a median interval of 19 years after RT were compared with 526 age-, sex-, and cardiovascular risk score–matched control subjects. Within the RT cohort, the presence of autonomic dysfunction, defined by an elevated resting heart rate (HR) (≥80 beats/min) and abnormal heart rate recovery (HRR) at 1 min (≤12 beats/min if active cool-down, or ≤18 beats/min if passive recovery), was correlated with exercise capacity and all-cause mortality over a median follow-up of 3 years. RT was associated with elevated resting HR and abnormal HRR after adjusting for age, sex, cardiovascular risk factors, medications, and indication for exercise treadmill testing: odds ratio: 3.96 (95% confidence interval [CI]: 2.52 to 6.23) and odds ratio: 5.32 (95% CI: 2.94 to 9.65), respectively. Prevalence of autonomic dysfunction increased with radiation dose and time from RT. Both elevated resting HR and abnormal HRR were associated with reduced exercise capacity in RT patients. Abnormal HRR was also associated with increased all-cause mortality (age-adjusted hazard ratio: 4.60 [95% CI: 1.62 to 13.02]). Thoracic RT is associated with autonomic dysfunction, as measured by elevated resting HR and abnormal HRR. These abnormalities are associated with impaired exercise tolerance, and abnormal HRR predicts increased all-cause mortality in RT patients.

Purpose To compare the prognostic importance (time to major adverse cardiovascular event [MACE]) of combined computed tomography (CT) angiography and CT myocardial stress perfusion imaging with that of combined invasive coronary angiography (ICA) and stress single photon emission CT myocardial perfusion imaging. Materials and Methods This study was approved by all institutional review boards, and written informed consent was obtained. Between November 2009 and July 2011, 381 participants clinically referred for ICA and aged 45–85 years were enrolled in the Combined Noninvasive Coronary Angiography and Myocardial Perfusion Imaging Using 320-Detector Row Computed Tomography (CORE320) prospective multicenter diagnostic study. All images were analyzed in blinded independent core laboratories, and a panel of physicians adjudicated all adverse events. MACE was defined as revascularization (>30 days after index ICA), myocardial infarction, or cardiac death; hospitalization for chest pain or congestive heart failure; or arrhythmia. Late MACE was defined similarly, except for patients who underwent revascularization within the first 182 days after ICA, who were excluded. Comparisons of 2-year survival (time to MACE) used standard Kaplan-Meier curves and restricted mean survival times bootstrapped with 2000 replicates. Results An MACE (49 revascularizations, five myocardial infarctions, one cardiac death, nine hospitalizations for chest pain or congestive heart failure, and one arrhythmia) occurred in 51 of 379 patients (13.5%). The 2-year MACE-free rates for combined CT angiography and CT perfusion findings were 94% negative for coronary artery disease (CAD) versus 82% positive for CAD and were similar to combined ICA and single photon emission CT findings (93% negative for CAD vs 77% positive for CAD, P < .001 for both). Event-free rates for CT angiography and CT perfusion versus ICA and single photon emission CT for either positive or negative results were not significantly different for MACE or late MACE (P > .05 for all). The area under the receiver operating characteristic curve (AUC) for combined CT angiography and CT perfusion (AUC = 68; 95% confidence interval [CI]: 62, 75) was similar (P = .36) to that for combined ICA and single photon emission CT (AUC = 71; 95% CI: 65, 79) in the identification of MACE at 2-year follow-up. Conclusion Combined CT angiography and CT perfusion enables similar prediction of 2-year MACE, late MACE, and event-free survival similar to that enabled by ICA and single photon emission CT. © RSNA, 2017 Online supplemental material is available for this article.

There are limited data on the prevalence and treatment of familial hypercholesterolemia (FH) among U.S. adults who experience a myocardial infarction (MI) at a young age. This study aimed to evaluate the prevalence of clinically defined FH and examine the rates of statin utilization and low-density lipoprotein cholesterol (LDL-C) achieved 1-year post MI. The YOUNG-MI registry is a retrospective cohort study that includes patients who experience an MI at or below age 50 years between 2000 and 2016 at 2 academic centers. Probable or definite FH was defined by the Dutch Lipid Clinic criteria. Outcomes included the proportion of patients classified as probable or definite FH, use of lipid-lowering therapy, and LDL-C achieved 1-year post MI. The cohort consisted of 1,996 adults with a median age of 45 years; 19% were women, and 54% had ST-segment elevation MI. Probable/definite FH was present in 180 (9%) of whom 42.8% were not on statins prior to their MI. Of the 1,966 patients surviving until hospital discharge, 89.4% of FH patients and 89.9% of non-FH patients were discharged on statin therapy (p = 0.82). Among FH patients, 63.3% were discharged on high-intensity statin compared with 48.4% for non-FH patients (p < 0.001). At 1-year follow-up, the percent reduction in LDL-C among FH patients was −44.4% compared with −34.5% (p = 0.006) in non-FH patients. The proportion of patients with LDL-C ≥70 mg/dl was higher among FH patients (82.2%) compared with non-FH patients (64.5%; p < 0.001). Clinically defined FH was present in nearly 1 of 10 patients with MI at a young age. Only two-thirds of FH patients were discharged on high-intensity statin therapy, and the vast majority had elevated LDL-C at 1 year. These findings reinforce the need for more aggressive lipid-lowering therapy in young FH and non-FH patients post-MI.

This review provides an integrative and forward-looking perspective on the gamut of coronary physiology for the diagnosis and management of atherosclerosis. Because clinical events serve as the ultimate gold standard, the future of all diagnostic tests, including invasive fractional flow reserve and noninvasive coronary flow reserve, depends on their ability to improve patient outcomes. Given the prominent role of acute coronary syndromes and invasive procedures in cardiology, we practically consider 2 broad categories of patients with coronary disease: acute and stable. For patients with acute coronary disease, coronary physiology may potentially refine treatment of the culprit lesion. For both patients with stable and acute nonculprit disease, reducing hard endpoints with revascularization potentially occurs at the severe end of the focal physiological spectrum, an area under-represented in existing trials. Nonepicardial disease and diffuse atherosclerosis remain underexplored aspects of coronary physiology for testing of novel treatments.

Background Cardiac magnetic resonance imaging ( CMR ) provides useful information for characterizing cardiac masses, but there are limited data on whether CMR can accurately distinguish benign from malignant lesions. We aimed to describe the distribution and imaging characteristics of cardiac masses identified by CMR and to determine the diagnostic accuracy of CMR for distinguishing benign from malignant tumors. Methods and Results We examined consecutive patients referred for CMR between May 2008 and August 2013 to identify those with a cardiac mass. In patients for whom there was histological correlation, 2 investigators blinded to all data analyzed the CMR images to categorize the mass as benign or malignant. For benign masses, readers were also asked to specify the most likely diagnosis. Benign masses were defined as benign neoplastic or non‐neoplastic. Malignant masses were defined as primary cardiac or metastatic. Of 8069 patients (mean age: 58±16 years; 55% female) undergoing CMR , 145 (1.8%) had a cardiac mass. In most cases (142, 98%), there was a known cardiac mass before the CMR study. Among 145 patients with a cardiac mass, 93 (64%) had a known history of malignancy. Among 53 cases that had histological correlation, 25 (47%) were benign, 26 (49%) were metastatic, and 2 (4%) were malignant primary cardiac masses. Blinded readers correctly diagnosed 89% to 94% of the cases as benign versus malignant, with a 95% agreement rate (κ=0.83). Conclusions Although C MR can be highly effective in distinguishing benign from malignant lesions, pathology remains the gold standard in accurately determining the type of mass.

Cardiac amyloidosis is an underdiagnosed disease and is highly fatal when untreated. Early diagnosis and treatment with the emerging novel therapies significantly improve survival. A comprehensive analysis of amyloidosis-related mortality is critical to appreciate the nature and distribution of underdiagnosis and improve disease detection.To evaluate the temporal and regional trends in age-adjusted amyloidosis-related mortality among men and women of various races/ethnicities in the United States.In this observational cohort study, death certificate information from the Centers for Disease Control and Prevention's Wide-ranging ONline Data for Epidemiologic Research database and the National Vital Statistics System from 1979 to 2015 was analyzed. A total of 30 764 individuals in the United States with amyloidosis listed as the underlying cause of death and 26 591 individuals with amyloidosis listed as a contributing cause of death were analyzed.Region of residence.Age-adjusted mortality rate from amyloidosis per 1 000 000 population stratified by year, sex, race/ethnicity, and state and county of residence.Of the 30 764 individuals with amyloidosis listed as the underlying cause of death, 17 421 (56.6%) were men and 27 312 (88.8%) were 55 years or older. From 1979 to 2015, the reported overall mean age-adjusted mortality rate from amyloidosis as the underlying cause of death doubled from 1.77 to 3.96 per 1 000 000 population (2.32 to 5.43 in men and 1.35 to 2.80 in women). Black men had the highest mortality rate (12.36 per 1 000 000), followed by black women (6.48 per 1 000 000). Amyloidosis contributed to age-adjusted mortality rates as high as 31.73 per 1 000 000 in certain counties. Most southern states reported the lowest US mortality rates despite having the highest proportions of black individuals.The increased reported mortality over time and in proximity to amyloidosis centers more likely reflects an overall increase in disease diagnosis rather than increased lethality. The reported amyloidosis mortality is highly variable in different US regions. The lack of higher reported mortality rates in states with a greater proportion of black residents suggests underdiagnosis of amyloidosis, including cardiac forms of the disease, in many areas of the United States. Better understanding of the determinants of geographic and racial disparity in the reporting of amyloidosis deaths are warranted.

Background: Cardiac dysfunction and cardiovascular events are prevalent among patients with chronic kidney disease without overt obstructive coronary artery disease, but the mechanisms remain poorly understood. Coronary microvascular dysfunction has been proposed as a link between abnormal renal function and impairment of cardiac function and cardiovascular events. We aimed to investigate the relations between chronic kidney disease, coronary microvascular dysfunction, cardiac dysfunction, and adverse cardiovascular outcomes. Methods: Patients undergoing cardiac stress positron emission tomography, echocardiogram, and renal function ascertainment at Brigham and Women’s Hospital were studied longitudinally. Patients free of overt coronary (summed stress score &lt;3 and without a history of ischemic heart disease), valvular, and end-organ disease were followed up for the adverse composite outcome of death or hospitalization for myocardial infarction or heart failure. Coronary flow reserve (CFR) was determined from positron emission tomography. Echocardiograms were used to measure cardiac mechanics: diastolic (lateral and septal E/e’) and systolic (global longitudinal, radial, and circumferential strain). Image analyses and event adjudication were blinded. The associations between estimated glomerular filtration rate (eGFR), CFR, diastolic and systolic indices, and adverse cardiovascular outcomes were assessed in adjusted models and mediation analyses. Results: Of the 352 patients (median age, 65 years; 63% female; 22% black) studied, 35% had an eGFR &lt;60 mL·min −1 ·1.73 m −2 , a median left ventricular ejection fraction of 62%, and a median CFR of 1.8. eGFR and CFR were associated with diastolic and systolic indices, as well as future cardiovascular events (all P &lt;0.05). In multivariable models, CFR, but not eGFR, was independently associated with cardiac mechanics and cardiovascular events. The associations between eGFR, cardiac mechanics, and cardiovascular events were partly mediated via CFR. Conclusions: Coronary microvascular dysfunction, but not eGFR, was independently associated with abnormal cardiac mechanics and an increased risk of cardiovascular events. Coronary microvascular dysfunction may mediate the effect of chronic kidney disease on abnormal cardiac function and cardiovascular events in those without overt coronary artery disease.

The objective of this study was to determine the diagnostic performance of 15O-water positron emission tomography (PET) myocardial perfusion imaging to detect coronary artery disease (CAD) using the truth-standard of invasive coronary angiography (ICA) with fractional flow reserve (FFR) or instantaneous wave-Free Ratio (iFR) or coronary computed tomography angiogram (CCTA). 15O-water has a very high first-pass extraction that allows accurate quantification of myocardial blood flow and detection of flow-limiting CAD. However, the need for an on-site cyclotron and lack of automated production at the point of care and relatively complex image analysis protocol has limited its clinical use to date. The RAPID WATER FLOW study is an open-label, multicenter, prospective investigation of the accuracy of 15O-water PET to detect obstructive angiographic and physiologically significant stenosis in patients with suspected CAD. The study will include the use of an automated system for producing, dosing, and injecting 15O-water and enrolling approximately 215 individuals with suspected CAD at approximately 10 study sites in North America and Europe. The primary endpoint of the study is the diagnostic sensitivity and specificity of the 15O-water PET study using the truth-standard of ICA with FFR or iFR to determine flow-limiting stenosis, or CCTA to rule out CAD and incorporating a quantitative analytic platform developed for the 15O-water PET acquisitions. Sensitivity and specificity are to be considered positive if the lower bound of the 95% confidence interval is superior to the threshold of 60% for both, consistent with prior registration studies. Subgroup analyses include assessments of diagnostic sensitivity, specificity, and accuracy in female, obese, and diabetic individuals, as well as in those with multivessel disease. All enrolled individuals will be followed for adverse and serious adverse events for up to 32 hours after the index PET scan. The study will have >90% power (one-sided test, α = 0.025) to test the hypothesis that sensitivity and specificity of 15O-water PET are both >60%. The RAPID WATER FLOW study is a prospective, multicenter study to determine the diagnostic sensitivity and specificity of 15O-water PET as compared to ICA with FFR/iFR or CCTA. This study will introduce several novel aspects to imaging registration studies, including a more relevant truth standard incorporating invasive physiologic indexes, coronary CTA to qualify normal individuals for eligibility, and a more quantitative approach to image analysis than has been done in prior pivotal studies. Clinical-Trials.gov (#NCT05134012).

Body mass index (BMI) is a controversial marker of cardiovascular prognosis, especially in women. Coronary microvascular dysfunction (CMD) is prevalent in obese patients and a better discriminator of risk than BMI, but its association with body composition is unknown.The authors used a deep learning model for body composition analysis to investigate the relationship between CMD, skeletal muscle (SM), subcutaneous adipose tissue (SAT), and visceral adipose tissue (VAT), and their contribution to adverse outcomes in patients referred for evaluation of coronary artery disease.Consecutive patients (n = 400) with normal perfusion and preserved left ventricular ejection fraction on cardiac stress positron emission tomography were followed (median, 6.0 years) for major adverse events, including death and hospitalization for myocardial infarction or heart failure. Coronary flow reserve (CFR) was quantified as stress/rest myocardial blood flow from positron emission tomography. SM, SAT, and VAT cross-sectional areas were extracted from abdominal computed tomography at the third lumbar vertebra using a validated automated algorithm.Median age was 63, 71% were female, 50% non-White, and 50% obese. Compared with the nonobese, patients with obesity (BMI: 30.0-68.4 kg/m2) had higher SAT, VAT, and SM, and lower CFR (all P < 0.001). In adjusted analyses, decreased SM but not increased SAT or VAT was significantly associated with CMD (CFR <2; OR: 1.38; 95% CI: 1.08-1.75 per -10 cm2/m2 SM index; P < 0.01). Both lower CFR and SM, but not higher SAT or VAT, were independently associated with adverse events (HR: 1.83; 95% CI: 1.25-2.68 per -1 U CFR and HR: 1.53; 95% CI: 1.20-1.96 per -10 cm2/m2 SM index, respectively; P < 0.002 for both), especially heart failure hospitalization (HR: 2.36; 95% CI: 1.31-4.24 per -1 U CFR and HR: 1.87; 95% CI: 1.30-2.69 per -10 cm2/m2 SM index; P < 0.004 for both). There was a significant interaction between CFR and SM (adjusted P = 0.026), such that patients with CMD and sarcopenia demonstrated the highest rate of adverse events, especially among young, female, and obese patients (all P < 0.005).In a predominantly female cohort of patients without flow-limiting coronary artery disease, deficient muscularity, not excess adiposity, was independently associated with CMD and future adverse outcomes, especially heart failure. In patients with suspected ischemia and no obstructive coronary artery disease, characterization of lean body mass and coronary microvascular function may help to distinguish obese phenotypes at risk for cardiovascular events.

BACKGROUND Myocardial perfusion imaging (MPI) is one of the most common cardiac scans and is used for diagnosis of coronary artery disease and assessment of cardiovascular risk.However, the large majority of MPI patients have normal results.We evaluated whether unsupervised machine learning could identify unique phenotypes among patients with normal scans and whether those phenotypes were associated with risk of death or myocardial infarction.METHODS Patients from a large international multicenter MPI registry (10 sites) with normal perfusion by expert visual interpretation were included in this cohort analysis.The training population included 9849 patients, and external testing population 12,528 patients.Unsupervised cluster analysis was performed, with separate training and external testing cohorts, to identify clusters, with four distinct phenotypes.We evaluated the clinical and imaging features of clusters and their associations with death or myocardial infarction.FINDINGS Patients in Clusters 1 and 2 almost exclusively underwent exercise stress, while patients in Clusters 3 and 4 mostly required pharmacologic stress.In external testing, the risk for Cluster 4 patients (20.2% of population, unadjusted hazard ratio [HR] 6.17, 95% confidence interval [CI] 4.64-8.20)was higher than the risk associated with pharmacologic stress (HR 3.03, 95% CI 2.53-3.63),or previous myocardial infarction (HR 1.82, 95% CI 1.40-2.36).INTERPRETATION Unsupervised learning identified four distinct phenotypes of patients with normal perfusion scans, with a significant proportion of patients at very high risk of myocardial infarction or death.Our results suggest a potential role for patient phenotyping to improve risk stratification of patients with normal imaging results.FUNDING

Lipoprotein(a) [Lp(a)] is associated with an increased risk of atherosclerotic cardiovascular disease (ASCVD). However, whether the optimal Lp(a) threshold for risk assessment should differ based on baseline ASCVD status is unknown.The purpose of this study was to assess the association between Lp(a) and major adverse cardiovascular events (MACE) among patients with and without baseline ASCVD.We studied a retrospective cohort of patients with Lp(a) measured at 2 medical centers in Boston, Massachusetts, from 2000 to 2019. To assess the association of Lp(a) with incident MACE (nonfatal myocardial infarction [MI], nonfatal stroke, coronary revascularization, or cardiovascular mortality), Lp(a) percentile groups were generated with the reference group set at the first to 50th Lp(a) percentiles. Cox proportional hazards modeling was used to assess the association of Lp(a) percentile group with MACE.Overall, 16,419 individuals were analyzed with a median follow-up of 11.9 years. Among the 10,181 (62%) patients with baseline ASCVD, individuals in the 71st to 90th percentile group had a 21% increased hazard of MACE (adjusted HR: 1.21; P < 0.001), which was similar to that of individuals in the 91st to 100th group (adjusted HR: 1.26; P < 0.001). Among the 6,238 individuals without established ASCVD, there was a continuously higher hazard of MACE with increasing Lp(a), and individuals in the 91st to 100th Lp(a) percentile group had the highest relative risk with an adjusted HR of 1.93 (P < 0.001).In a large, contemporary U.S. cohort, elevated Lp(a) is independently associated with long-term MACE among individuals with and without baseline ASCVD. Our results suggest that the threshold for risk assessment may be different in primary vs secondary prevention cohorts.

HomeCirculationVol. 117, No. 21Methods and Limitations of Assessing New Noninvasive Tests Free AccessReview ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessReview ArticlePDF/EPUBMethods and Limitations of Assessing New Noninvasive TestsPart II: Outcomes-Based Validation and Reliability Assessment of Noninvasive Testing Rory Hachamovitch and Marcelo F. Di Carli Rory HachamovitchRory Hachamovitch From the Divisions of Nuclear Medicine/Positron Emission Tomography and Cardiovascular Imaging, Departments of Radiology and Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Mass (M.F.D.). and Marcelo F. Di CarliMarcelo F. Di Carli From the Divisions of Nuclear Medicine/Positron Emission Tomography and Cardiovascular Imaging, Departments of Radiology and Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Mass (M.F.D.). Originally published27 May 2008https://doi.org/10.1161/CIRCULATIONAHA.107.714006Circulation. 2008;117:2793–2801Outcomes-based approaches are the preferred methodology for technology validation. As discussed in part I of this review, the difficulties of performing an unbiased diagnostic evaluation are increasingly appreciated.1 An outcomes-based approach is advantageous in that it mimics the clinical application of testing. By risk stratifying patients, the results of this approach can be applied directly to clinical practice.2 Nonetheless, outcomes-based technology validation is not without challenges and limitations. These issues include the need for multivariable modeling for observational data, end point selection, and limitations of estimating posttest risk. Finally, it is increasingly appreciated that the future “gold standard” for outcomes-based assessments will be demonstrating whether imaging can identify which therapeutic approach optimizes patient benefit rather than merely identifying risk.Outcomes-Based ValidationStudy DesignRequirements of imaging studies include a relevant study population, comparison with an appropriate control group, and follow-up for outcomes. Designing randomized controlled trials (RCTs) that address imaging questions is challenging. The RCT may utilize imaging results as inclusion criteria or the basis for therapeutic assignment. Randomization to strategies with versus without imaging is problematic. The use of imaging per se affects outcomes only if a therapy is triggered; hence, in these studies, therapy and imaging results must be linked.3,4 Comparisons of imaging methods/modalities must mandate that test results are acted on rather than “available to the physician” (thus, an emphasis on efficacy rather than effectiveness). Because observational studies are far more common, they will be our focus. Although limited by inherent design flaws (eg, selection biases, potentially spurious observations, missing covariates), patients in observational studies better represent those seen in practice.Patient SelectionUnlike diagnostic-based validation in which only patients referred to a gold standard after testing are included, in prognostic-based approaches all eligible patients are followed up at a preselected time point after testing to determine their status relative to the events of interest. The selection of the cohort for a given study can be challenging as issues of power (eg, increasing risk and event rates in patients with versus those without prior coronary artery disease), patient availability for follow-up, generalizability to other settings, and impact of posttest treatment and biases occur.Study end points should be clinically relevant, easily ascertainable, sensitive to the effects under evaluation, and verifiable. In prognostic studies, 2 end points predominate: cardiac death and all-cause death. The former is profoundly limited and susceptible to misclassification bias (for review, see Lauer et al5). Death certificates are often erroneous, and the gold standard (autopsy) is rarely performed. The mechanism of demise and the actual cause of death are often confused.5 Death in patients with coronary artery disease is usually assumed to be cardiac. Hence, the use of cardiac death as an end point has significant flaws and unacceptably high error rates.All-cause death is a “harder” end point, relatively unbiased, easily ascertained, and the most valid. However, this end point has limitations. Do studies modeling all-cause death in patients aged <55 years, in whom <20% to 25% of deaths are cardiac, have the same meaning as those with an older cohort? In patients undergoing preoperative evaluation, with more frequent and serious comorbidities, noncardiac mortality will likely be higher, obfuscating all-cause death rates. Therefore, we recommend all-cause death as a primary end point but cardiac death as a secondary end point. Because the social security death index is used to determine all-cause death, a “follow-up” study may not need to contact patients. This is potentially problematic because if the use of early revascularization is not known, its impact on outcomes cannot be determined.6Hard events, such as combined cardiac death and nonfatal myocardial infarction (MI), have the aforementioned limitations and those of MI verification2,5 (eg, nonblinding of ascertaining observers and defining and identifying MI) and thus lack rigor but may be helpful as secondary end points. Interestingly, predictors of these 2 events differ, and therefore a study’s relative proportions of MI and cardiac death will influence observed test performance.2,5 This differential prediction may aid posttest therapeutic decision making, but further investigation is necessary. However, because these 2 events are not independent, modeling of MI alone requires a more advanced Cox proportional hazards methodology.7Composite end points (eg, combined hard events, late revascularizations, catheterizations, hospitalizations) have numerous limitations. Although their use reduces needed sample size and accrual time, they assume risk homogeneity among the component events. The differential impact of treatment on each end point yields ambiguous and problematic results, including reduced power due to unaffected end points. Physician-influenced outcomes (catheterization, revascularization, hospitalization) are often more amenable to treatment than harder end points, and trials using these outcomes more frequently have positive results.A study of the prognostic value of computed tomographic angiography (CTA) in 100 patients used a composite end point of cardiac death, MI, unstable angina, and revascularization.8 Revascularizations represented 24 of 32 events that occurred. Although the authors concluded that CTA predicted the composite end point, CTA actually predicted revascularization—an end point it triggered—but predicted other end points questionably. Hence, a study reporting composite end points when one event predominates is potentially misleading. Although broadening the spectrum of events may enhance the value of the study, care must be exercised. The component events should be presented as secondary end points, with event rates for individual as well as combined end points reported.Test Performance MetricsPrognostic studies avoid reporting sensitivity, specificity, and predictive values and focus on aggregate and/or annualized event rates for the overall cohort and the subgroups with normal and abnormal test results. Risk stratification, evidenced by increasing event rates as a function of worsening test abnormalities (eg, small versus large myocardial perfusion abnormalities), requires demonstration. Historically, demonstration of “low” event rates after normal studies has been a mantra because it reassures physicians about the safety of managing these patients conservatively.2 Two standards for low risk are used: a hard event rate <1% per year and, more recently, a <1% cardiac death rate per year. The latter lends itself to comparisons of risks and benefits for revascularization as a therapeutic approach. Numerous stress imaging reports have claimed <1% hard event risk in normal studies2; stress cardiovascular magnetic resonance imaging, computed tomography, positron emission tomography (PET), and perfusion echocardiography will eventually require similar studies. However, these observational reports of unadjusted risk are limited, and no evidence suggests that this approach enhances patient outcomes. In addition, newer paradigms question the validity of fixed thresholds in defining “low risk.”2Multivariable Modeling and Risk- Adjustment TechniquesPrognostic imaging studies are commonly observational, compromised by multiple factors (eg, bias, confounding) that necessitate multivariable techniques to enhance validity and accuracy. (Multivariable is defined as the simultaneous modeling of multiple variables; multivariate is defined as the simultaneous consideration of multiple outcomes.) Several important concepts will be reviewed, and the reader will be referred to reviews in this area.7Briefly, multivariable models express the association between an end point (y) and a combination of factor(s) (x’s).7 Modeling may serve 2 purposes: descriptive (determining whether y is associated with 1 or more xs and assessing the effect of x on y after adjustment for other factors) and predictive (predicting the value of y at specific values of x).Types of ModelsThe first step in modeling is selecting a model form. Linear regression is used for continuous end points (eg, blood pressure, exercise tolerance), logistic for dichotomous end points (eg, disease presence), and Cox proportional hazards for survival analyses (survival analyses model time to event rather than the event occurrence). In specific situations, it may be advantageous to model survival with parametric survival or logistic models.Variable SelectionIdeally, candidate variable selection for model entry is based on clinical experience and judgment, the research question posed, and common sense.7 Importantly, the input to and findings of a model should make clinical sense. Known predictors or confounders merit inclusion, with extraneous variables ideally omitted. Variable selection based on univariate analysis (inclusion of independent predictors) is inappropriate because it wrongly rejects potentially important variables in the setting of uncontrolled confounders; avoiding this error depends on careful data analysis.7 Variable selection based on automated algorithms, including stepwise approaches, also has serious limitations, introducing numerous potential errors while including significant noise and failing to include >50% of actual predictors.7Different studies using similar cohorts and end points may identify different models and predictors. This is due to varying patient selection; the variables that were examined; the manner in which they were defined, collected, and coded; and the manner in which the modeling was performed and tested. It may also be due to inherent limitations of classic regression techniques.9Model Assumptions, Power, and OverfittingAll models are based on multiple assumptions that must be examined7 (Table). Unfortunately, the reader is at the mercy of the authors as to whether these were examined, and most published studies do not state whether this was done. Table. Assumptions Underlying Multivariable Survival Modeling7AssumptionDescriptionImportanceEF indicates ejection fraction; CPH, Cox proportional hazards.AdditivityThe magnitude of effect of each variable does not depend on the value of other variables (x has an additive relationship with y); violation necessitates use of interactionsInteractions indicate that the effect of one variable depends on the level of another; failure to specify significant interactions results in compromised model fit and inferences; if valid, interactions can reveal clinically important relationships but complicate model interpretation and may represent spurious findings (especially with overfitting)LinearityContinuous variables are related to the outcome in a linear fashion; violation requires variable transformationFor example, when modeling death, if EF is linear, it indicates that a 20% change in EF has identical risk ramifications whether EF changes from 20% to 40% or from 50% to 70%; uncorrected nonlinearity results in compromised model fit and invalid hypothesis testingCollinearityThe presence of independent variables that are highly interrelated (r>0.80–85); the regression coefficient of one variable depends on which other predictors are in the modelCollinearity results in biased calculated regression coefficients and invalid hypothesis testingProportional hazardsCPH requires the ratio of risk in the presence and absence of a variable to remain constant throughout the observed time (proportionality of risk over time); violation requires the use of either extended CPH models or parametric survival analysisUsing CPH, the 2 survival curves of a binary variable should remain roughly parallel over time and not cross; violations may lead to data misinterpretation; eg, if men have a high risk early after test but women’s risk increases several years later, CPH may indicate no gender-related risk differenceInteractions are a means of addressing issues relative to the additivity assumption, and they are also a source of significant clinical insight in the modeling process. For example, identification of a therapeutic benefit by means of multivariable modeling is often based on the presence of an interaction between therapy given and a metric of disease burden. The presence of this interaction identifies both the presence of a survival benefit with one treatment versus another but may also identify the threshold of disease burden at which a benefit may be present. As shown in Figure 1, the amount of ischemia present identifies whether revascularization or medical therapy is associated with greater benefit and a potential threshold at which the benefit occurs. Similarly, interactions can identify unique relationships between 2 variables. For example, the presence of greater risk in female than in male diabetics but greater risk in male than in female nondiabetics is characterized by an interaction between sex and diabetes mellitus. Download figureDownload PowerPointFigure 1. Relationship between percentage myocardium ischemic, treatment, and risk based on multivariable modeling. Rx indicates treatment; revasc, revascularization. Reprinted from Hachamovitch et al.14Similarly, the shape of a relationship, as revealed by demonstration of nonlinearity of a modeled variable, also yields significant insights. The likelihood of referral to revascularization after stress single photon emission computed tomography (SPECT) increases sharply in the lower range of ischemia but plateaus in the higher ranges, thereby permitting better understanding of physician utilization of stress SPECT results (Figure 2). Download figureDownload PowerPointFigure 2. Relationship between ischemia and probability of referral to revascularization (Revasc.) in patients with typical angina. From Hachamovitch et al.13Sample size methods exist for both RCTs and observational study designs based on estimates of the number of events needed rather than total population size. Nonetheless, these power calculations may be challenging when little or no previous data exist.7Overfitting (ie, fitting models with an excessive number of variables and complexity relative to the amount of data available) is ubiquitous because studies are often underpowered yet have numerous candidate variables for model entry. The minimum number of events necessary is expressed as the events per variable ratio (EPV). (EPV actually refers to events per degree of freedom [rather than per variable] as the former increases with continuous variables, interactions, and nonlinearity terms.) Generally, an EPV >10:1 is strongly recommended; an EPV of 20:1 is preferred.7 Careful review often reveals that articles that claim to observe the 10:1 EPV may not.6Modeling “sicker” or narrowly distributed cohorts increases error likelihoods and requires greater EPVs. Caution is recommended when overfitted models are interpreted because their reliability or calibration is questionable. When faced with excessive variables and insufficient events, data reduction techniques are available (eg, principal components analysis).7 These techniques can reduce complex, multidimensional data to lower dimension orders, yielding insights into the underlying structure of the data. Unlike variable elimination, these methods preserve information while permitting parsimonious modeling.7Conversely, “underfitted” models do not consider variables of likely importance. For example, when the incremental value of imaging over pretest information is determined, it is assumed that an optimized model of pre-SPECT data will be developed. A suboptimal model is often used in that predictors of known prognostic value (eg, exercise capacity, heart rate reserve, resting ECG) are not included, resulting in overestimation of the added value of imaging.Model Validation, Calibration, and DiscriminationAfter development, model performance is assessed. A model’s calibration (reliability) assesses agreement between observed and (model) predicted events across the range of predicted probabilities.7 Discrimination refers to a model’s ability to discern between patients with versus without the outcome. For example, when modeling risk, patients with events should have a high predicted probability, whereas patients without events should have a low predicted probability. Good discrimination and calibration do not necessarily coincide.7 Model validation is performed to ascertain whether the developed model will perform in populations other than those in whom it was developed. Model performance is often overestimated because models are derived and tested with the use of the same cohort.Model InterpretationUnderstanding the interpretation of multivariable models greatly enhances the amount of information these models yield. Separate statistics are generated for the overall model fit as well as for each variable in the model. Each variable also has a β coefficient. In Cox proportional hazards, the exponential (eβ) yields the hazard ratio; in logistic regression, the eβ yields the odds ratio. A change of >5% to 10% in the value of the β of the variable after the addition of another variable to a model indicates that the former variable is confounded by the latter.7A model’s conclusions can be misinterpreted. A study examining prognostic implications of different tracers may find variable “tracer used” to be statistically insignificant after risk adjustment, but if each site used only 1 tracer, whether the variable “tracer used” represents the tracer used or intersite differences is unclear. Other sources of intersite variability (patient mix, referral patterns, interpretation methods) must also be considered and adjusted for.Alternative ApproachesAlthough multivariable modeling has dominated statistical analyses, it is both limited and limiting, particularly in data sets with complex variables of unclear distribution and interrelationship.9 Several alternative approaches, although less commonly used, excel in classification problems such as clinical decision rules: artificial neural networks, Bayesian approaches, and decision tree–based approaches. Artificial neural networks have both advantages (ability to detect complex nonlinear relationships and all possible interactions) and disadvantages (“black box” character, greater computational burden, tendency for overfitting, empirical model development). These approaches are not universally accepted, and disagreement exists on whether they are equivalent,10 superior,9 or inferior11 to conventional techniques. Importantly, methodological flaws have compromised many studies utilizing artificial neural networks, suggesting that the enthusiasm surrounding this approach requires tempering.12Assessing the Prognostic Value of TestingApproaches to determining a test’s prognostic value have evolved significantly. Previously, demonstrations that imaging resulted in better predicted outcomes than clinical, historical, or stress testing data were adequate. The concept of incremental value—the obligation to show that a test predicted outcomes even after all other preimaging data were considered—changed this standard. This concept expanded through the 1990s, and a paradigm for validating testing emerged. This paradigm now includes the following components2: Statistical incremental value: ascertaining the statistical added value of a test over pretest information (incremental value based on an increase in C index or χ2 of a model incorporating pretest data);Predictive incremental value: demonstrating further (enhanced) risk stratification on the basis of the test results after considering initial risk stratification by pretest data; alternatively, measurement of risk reclassification by test results beyond initial preclinical risk determination;Economic incremental value: the reduction in the cost of a testing strategy after the inclusion of the test of interest;Therapeutic incremental value: the ability to identify which patients may benefit with a specific posttest therapeutic approach.13–15Prognostic test validation is based on multiple criteria and is defined by a body of evidence consisting of multiple, well-powered studies verifying the presence of these various measures of clinical value in diverse patient groups.Limitations of prognostic assessment are 3-fold: issues of the validity of the literature, issues of bias, and intrinsic limitations of risk as a clinical tool. A significant proportion of the supporting data for imaging is based on large databases from a limited number of centers whose data are predominantly from an era before the use of devices and medications currently considered standard of care (eg, stents, statins, clopidogrel), as well as the use of imaging techniques that may be outmoded. The generalizability of these data to other centers with different techniques, referral patterns, and expertise, using newer therapeutic approaches, is unclear. Importantly, the performance characteristics of imaging as performed in most private and community settings (the majority of studies performed) are undefined, suggesting the need for large-scale registries to assess the value of testing in practice.Prognostic Posttest Referral BiasesImaging results affect patient management, especially referral to revascularization.1 Because revascularization also affects risk, the association between test results and revascularization referral introduces a bias that lowers observed patients’ risk in proportion to their imaging results. To prevent underestimating risk, studies remove (censor) from prognostic analyses patients revascularized shortly after testing.2 Patients with revascularizations after this threshold are included in analyses (the revascularization likely results from worsening clinical status). Investigations of newer modalities (eg, CTA) must consider the impact of test results and patient management on outcomes and differentiate physician-driven outcomes (eg, revascularization) from risk-related outcomes (death).8Although censoring early revascularizations was well intended, selective removal of patients with greater test abnormalities results in relative underestimation of risk and flattening of the test abnormality–risk relationship2 in proportion to revascularization referral rates (treatment selection bias). Thus, for example, a greater observed risk reduction exists in patients with versus those without ischemia and in those with versus those without angina.Interestingly, of 2 data elements reported by a test (eg, ischemia and ejection fraction), if one (ischemia) but not the other (ejection fraction) triggers revascularization referral, the prognostic value of the latter relative to the former is overestimated if censoring occurs (a differential treatment selection bias; Figure 3). Initial gated SPECT studies reported that the incremental value of ejection fraction over perfusion data was such that perfusion data were no longer predictive.16 Cardiac mortality increased from 2.2% in mild to moderately abnormal results to 3.6% in severely abnormal results. However, with reduced left ventricular ejection fraction (<45%), the latter were at lower risk than the former (5.7% versus 9.2%).16 This counterintuitive result was caused by referrers predominantly using perfusion but not left ventricular ejection fraction data for revascularization decisions, thereby reducing the predictive power of perfusion with minimal impact on the value of the ejection fraction.2,14 Consequently, analysis of medically treated patients underestimated the value of ischemia relative to the value of the ejection fraction. More recently, a study modeling both medically treated and revascularized patients found that ejection fraction and perfusion added incrementally to each other for risk stratification.14 Therefore, inclusion of all patients in the analysis and modeling appears to at least partially correct this form of referral bias. Download figureDownload PowerPointFigure 3. Schematic representation of impact of selective treatment referral bias. Test A results (left), test B results (right), and abnormal tests (+) and normal tests (−) are shown. Four possible combinations are shown: top dark box, abnormal A with normal or abnormal B; bottom dark box, normal A with normal or abnormal B. In this example, revascularization referral is driven by the results of test A but not B. Thus, the combinations of test results shown at top (abnormal test A) will have high revascularization rates and subsequent decreases in risk. The test results in the bottom box (normal test A) will have low revascularization rates and thus little impact on event rates. Hence, the survival with abnormal test A will be underestimated relative to survival with abnormal test B (because the former are heavily revascularized and the latter less so). In studies comparing their prognostic value in medically treated patients, test B will appear to predict risk better than test A (unless additional adjustments are made).This differential treatment selection bias is probably common, occurring in any prognostic study of medically treated patients that compares variables with disparate associations with posttest revascularization; for example, even after risk adjustment, prognostic comparisons between patients with ischemic versus nonischemic abnormalities would be problematic because the former are more commonly revascularized than the latter, with a resulting impact on event rates. Similarly, comparing stress echocardiographic results (eg, left ventricular ejection fraction change) with pretest data (stress ECG response) will underestimate the incremental prognostic value of the former compared with the latter. Importantly, this bias will similarly impact analyses that include medically treated patients and exclude early revascularization patients.Estimating Posttest RiskPostimaging risk estimation is often suboptimal because of the failure to consider pretest information. For any imaging result, a range of posttest risk exists (Figure 4); for example, risk after moderate SPECT ischemia ranges from 2% to 10%, varying with patient characteristics. Similarly, after a coronary artery calcium score of zero, posttest risk varies with Framingham risk score17 (Figure 5). A coronary artery calcium value of zero with high Framingham risk score indicated greater risk than a low Framingham risk score with any coronary artery calcium value. Comparable risk variation after a normal SPECT occurs with underlying clinical risk,2 and both stress echocardiography and SPECT are associated with event rates >1% per year in higher-risk cohorts.2 Thus, postimaging risk is contextual, challenging the validity of a fixed risk threshold after a normal result as a benchmark in technology validation. Furthermore, meta-analyses comparing the prognostic value of these modalities must also adjust for cohort characteristics; for example, comparing risk after a normal result with 2 modalities with similar performance characteristics will reveal differing event rates if they are used in patients at different risks. Similarly, low risk after a normal result may occur with a mediocre test if a sufficiently low-risk cohort is tested. Alternative approaches to prognostically assess normal tests include indexing the event rates to the underlying risk of the overall population tested. A 0.5% per year event rate after a normal test has a different meaning in a cohort with a 3% per year overall risk and 60% abnormal test prevalence than a 2% per year overall event rate and 20% abnormal test prevalence. Expressing a relative risk of an abnormal versus normal imaging study may be helpful.2Download figureDownload PowerPointFigure 4. Relationship between percentageu myocardium ischemic and predicted cardiac death risk demonstrating variability in risk at any ischemia level due to the confounding effects of clinical and demographic data (diabetes mellitus [DM], age, or pharmacological stress). W indicates women; M, men. Reprinted from Berman et al.26 Reproduced with permission of the publisher. Copyright © 2007, The McGraw-Hill Companies.Download figureDownload PowerPointFigure 5. Relationship between Framingham risk score, calcium score, and risk of cardiac death or nonfatal MI. From Greenland et al.17 Copyright © 2004, American Medical Association. All rights reserved.Scores for Predicting Cardiovascular Risk and Potential BenefitPostimaging risk estimation necessitates inclusion of preimag

The aim of the current analysis was to compare sex differences in the prognostic accuracy of stress myocardial perfusion rubidum-82 (Rb-82) positron emission tomography (PET). The diagnostic evaluation of women presenting with suspected cardiac symptoms is challenging with reported reduced accuracy, attenuation artifact, and more recent concerns regarding radiation safety. Stress myocardial perfusion Rb-82 PET is a diagnostic alternative with improved image quality and radiation dosimetry. Currently, the prognostic accuracy of stress Rb-82 PET in women has not been established. A total of 6,037 women and men were enrolled in the PET Prognosis Multicenter Registry. Patients were followed for the occurrence of coronary artery disease (CAD) mortality, with a median follow-up of 2.2 years. Cox proportional hazards modeling was used to estimate CAD mortality. The net re-classification improvement index (NRI) was calculated. The 5-year CAD mortality was 3.7% for women and 6.0% for men (p < 0.0001). Unadjusted CAD mortality ranged from 0.9% to 12.9% for women (p < 0.0001) and from 1.5% to 17.4% for men (p < 0.0001) for 0% to ≥15% abnormal myocardium at stress. In multivariable models, the percentage of abnormal stress myocardium was independently predictive of CAD mortality in women and men. An interaction term of sex by the percentage of abnormal stress myocardium was nonsignificant (p = 0.39). The categorical NRI when Rb-82 PET data was added to a clinical risk model was 0.12 for women and 0.17 for men. Only 2 cardiac deaths were reported in women <55 years of age; accordingly the percentage of abnormal myocardium at stress was of borderline significance (p = 0.063), but it was highly significant for women ≥55 years of age (p < 0.0001), with an increased NRI of 0.21 (95% confidence interval: 0.09 to 0.34), including 17% of CAD deaths and 3.9% of CAD survivors that were correctly re-classified in this older female subset. Stress Rb-82 PET provides significant and clinically meaningful effective risk stratification of women and men, supporting this modality as an alternative to comparative imaging modalities. Rb-82 PET findings were particularly helpful at identifying high-risk, older women.

Background— Studies have shown the feasibility of imaging plaques with 2-deoxy-2-[ 18 F]fluoroglucose (FDG) positron emission tomography and dynamic contrast–enhanced magnetic resonance imaging with inconsistent results. We sought to investigate the relationship between markers of inflammatory activation, plaque microvascularization, and vessel wall permeability in subjects with carotid plaques using a multimodality approach combining FDG positron emission tomography, dynamic contrast–enhanced magnetic resonance imaging, and histopathology. Methods and Results— Thirty-two subjects with carotid stenoses underwent noninvasive imaging with FDG positron emission tomography and dynamic contrast–enhanced magnetic resonance imaging, 46.9% (n=15) before carotid endarterectomy. We measured FDG uptake (target:background ratio [TBR]) by positron emission tomography and K trans (reflecting microvascular permeability and perfusion) by magnetic resonance imaging and correlated imaging with immunohistochemical markers of macrophage content (CD68), activated inflammatory cells (major histocompatibility complex class II), and microvessels (CD31) in plaque and control regions. TBR and K trans correlated significantly with tertiles of CD68 + ( P =0.009 and P =0.008, respectively), major histocompatibility complex class II + ( P =0.003 and P &lt;0.001, respectively), and CD31 + ( P =0.004 and P =0.008, respectively). Regions of plaques were associated with increased CD68 + ( P =0.002), major histocompatibility complex class II + ( P =0.002), CD31 + ( P =0.02), TBR ( P &lt;0.0001), and K trans ( P &lt;0.0001), as compared with those without plaques. Microvascularization correlated with macrophage content ( r s =0.52; P =0.007) and inflammatory activity ( r s =0.68; P =0.0001) and TBR correlated with K trans ( r s =0.53; P &lt;0.0001). In multivariable mixed linear regression modeling, TBR remained independently associated with K trans (β[SE], 2.68[0.47]; P &lt;0.0001). Conclusions— Plaque regions with active inflammation, as determined by macrophage content and major histocompatibility complex class II expression, showed increased FDG uptake, which correlated with increased K trans and microvascularization. The correlation between K trans and TBR was moderate, direct, highly significant, and independent of clinical symptoms and plaque luminal severity.

The metabolic syndrome affects 25% of the U.S. population and greatly increases the risk of diabetes and coronary artery disease (CAD). We tested the hypothesis that the metabolic syndrome is associated with impaired coronary vasodilator function, a marker of atherosclerotic disease activity.Four hundred sixty-two patients at risk for CAD, as defined by a low-density lipoprotein cholesterol ≥ 160 mg/dL with fewer than 2 coronary risk factors, a low-density lipoprotein cholesterol ≥ 130 mg/dL with 2 or more coronary risk factors, or with documented CAD were included. A subset of 234 individuals underwent repeated PET at 1 y. Myocardial blood flow (MBF) and vasodilator reserve were assessed by PET. Modified criteria of the National Cholesterol Education Program, Adult Treatment Panel III were used to characterize the metabolic syndrome.Adenosine- and cold-stimulated MBF were similar in patients with and without metabolic syndrome, whereas baseline MBF showed a stepwise increase with increasing features of the syndrome. Consequently, patients with metabolic syndrome showed a lower coronary flow reserve (CFR) (2.5 ± 1.0) than those without metabolic syndrome (3.0 ± 0.9, P = 0.004). Differences in CFR were no longer present after correcting rest flows for the rate-pressure product. Change in MBF and CFR at 1 y were not different across groups of patients with increasing features of the metabolic syndrome.Patients with metabolic syndrome demonstrate impaired CFR, which is related to the augmentation in resting coronary blood flow caused by hypertension. In high-risk individuals, peak adenosine- and cold-stimulated blood flows are impaired even in the absence of the metabolic syndrome.

Local plaque macrophage proliferation and monocyte production in hematopoietic organs promote progression of atherosclerosis. Therefore, noninvasive imaging of proliferation could serve as a biomarker and monitor therapeutic intervention.To explore (18)F-FLT positron emission tomography-computed tomography imaging of cell proliferation in atherosclerosis.(18)F-FLT positron emission tomography-computed tomography was performed in mice, rabbits, and humans with atherosclerosis. In apolipoprotein E knock out mice, increased (18)F-FLT signal was observed in atherosclerotic lesions, spleen, and bone marrow (standardized uptake values wild-type versus apolipoprotein E knock out mice, 0.05 ± 0.01 versus 0.17 ± 0.01, P<0.05 in aorta; 0.13 ± 0.01 versus 0.28 ± 0.02, P<0.05 in bone marrow; 0.06 ± 0.01 versus 0.22 ± 0.01, P<0.05 in spleen), corroborated by ex vivo scintillation counting and autoradiography. Flow cytometry confirmed significantly higher proliferation of macrophages in aortic lesions and hematopoietic stem and progenitor cells in the spleen and bone marrow in these mice. In addition, (18)F-FLT plaque signal correlated with the duration of high cholesterol diet (r(2)=0.33, P<0.05). Aortic (18)F-FLT uptake was reduced when cell proliferation was suppressed with fluorouracil in apolipoprotein E knock out mice (P<0.05). In rabbits, inflamed atherosclerotic vasculature with the highest (18)F-fluorodeoxyglucose uptake enriched (18)F-FLT. In patients with atherosclerosis, (18)F-FLT signal significantly increased in the inflamed carotid artery and in the aorta.(18)F-FLT positron emission tomography imaging may serve as an imaging biomarker for cell proliferation in plaque and hematopoietic activity in individuals with atherosclerosis.

Myocardial perfusion imaging (MPI) with PET has expanded significantly over the past decade. With the wider availability of PET scanners and the routine use of quantitative blood flow imaging, the clinical use of PET MPI is expected to increase further. PET MPI is a powerful tool to identify risk, to quantify risk, and to guide therapy in patients with known or suspected coronary artery disease. A large body of evidence supports the prognostic value of PET MPI and ejection fraction in intermediate- to high-risk subjects, in women, in obese individuals, and in post-coronary artery bypass grafting individuals. A normal perfusion study indicates low risk (<1% annualized rate of cardiac events of cardiac death and non-fatal myocardial infarction), while an abnormal study indicates high risk. With accurate risk stratification, high-quality images, and quantitation, PET MPI may transform the management of patients with known or suspected coronary artery disease.

Capillary rarefaction of the coronary microcirculation is a consistent phenotype in patients with dialysis-dependent ESRD (dd-ESRD) and may help explain their excess mortality. Global coronary flow reserve (CFR) assessed by positron emission tomography (PET) is a noninvasive, quantitative marker of myocardial perfusion and ischemia that integrates the hemodynamic effects of epicardial stenosis, diffuse atherosclerosis, and microvascular dysfunction. We tested whether global CFR provides risk stratification in patients with dd-ESRD. Consecutive patients with dd-ESRD clinically referred for myocardial perfusion PET imaging were retrospectively included, excluding patients with prior renal transplantation. Per-patient CFR was calculated as the ratio of stress to rest absolute myocardial blood flow. Multivariable Cox proportional hazards models, including age, overt cardiovascular disease, and myocardial scar/ischemia burden, were used to assess the independent association of global CFR with all-cause and cardiovascular mortality. The incremental value of global CFR was assessed with relative integrated discrimination index and net reclassification improvement. In 168 patients included, median global CFR was 1.4 (interquartile range, 1.2-1.8). During follow-up (median of 3 years), 36 patients died, including 21 cardiovascular deaths. Log-transformed global CFR independently associated with all-cause mortality (hazard ratio, 0.01 per 0.5-unit increase; 95% confidence interval, <0.01 to 0.14; P<0.001) and cardiovascular mortality (hazard ratio, 0.01 per 0.5-unit increase; 95% confidence interval, <0.01 to 0.15; P=0.002). For all-cause mortality, addition of global CFR resulted in risk reclassification in 27% of patients. Thus, global CFR may provide independent and incremental risk stratification for all-cause and cardiovascular mortality in patients with dd-ESRD.

The above position statement originally published containing errors in the author metadata; specifically, the Expert Content Reviewers—Andrew Einstein, Raymond Russell and James R. Corbett—were tagged as full authors of the paper. The article metadata has now been corrected to remove Drs. Einstein, Russell and Corbett from the author line, and the PubMed record has been updated accordingly.

This study sought to determine and compare the prognostic and incremental value of positron emission tomography (PET) in normal, overweight, and obese patients.Cardiac rubidium 82 (Rb-82) PET is increasingly being used for myocardial perfusion imaging (MPI). A strength of PET is its accurate attenuation correction, thereby potentially improving its diagnostic accuracy in obese patients. The prognostic value of PET in obese patients has not been well studied.A total of 7,061 patients who had undergone Rb-82 PET MPI were entered into a multicenter observational registry. All patients underwent pharmacologic Rb-82 PET and were followed for cardiac death and all-cause mortality. Based on body mass index (BMI), patients were categorized as normal (<25 kg/m(2)), overweight (25 to 29.9 kg/m(2)), or obese (≥30 kg/m(2)). Using a 17-segment model and 5-point scoring system, the percentage of abnormal myocardium was calculated for stress and rest patients categorized as normal (0%), mild (0.1% to 9.9%), moderate (10% to 19.9%), and severe (≥20%).A total of 6,037 patients were followed for cardiac death (median: 2.2 years) and the mean BMI was 30.5 ± 7.4 kg/m(2). A total of 169 cardiac deaths were observed. PET MPI demonstrated independent and incremental prognostic value over BMI. Normal PET MPI conferred an excellent prognosis with very low annual cardiac death rates in normal (0.38%), overweight (0.43%), and obese (0.15%) patients. As well, both moderately and severe obese patients with a normal PET MPI had excellent prognosis (0.20% and 0.10%, respectively). The net reclassification improvement of PET was 0.46 (95% confidence interval [CI]: 0.31 to 0.61), and appeared similar in the moderately and severe obese patients which were 0.44 (95% CI: 0.12 to 0.76) and 0.63 (95% CI: 0.27 to 0.98), respectively.Rb-82 PET has incremental prognostic value in all patients irrespective of BMI. In the obese population, where other modalities may have reduced diagnostic accuracy, cardiac PET appears to be a promising noninvasive modality with prognostic value.

Microvascular rarefaction is found in experimental uremia, but data from patients with chronic kidney disease (CKD) are limited. We therefore quantified absolute myocardial blood flow and coronary flow reserve (the ratio of peak to resting flow) from myocardial perfusion positron emission tomography scans at a single institution. Individuals were classified into standard CKD categories based on the estimated glomerular filtration rate. Associations of coronary flow reserve with CKD stage and cardiovascular mortality were analyzed in models adjusted for cardiovascular risk factors. The coronary flow reserve was significantly associated with CKD stage, declining in early CKD, but it did not differ significantly among individuals with stage 4, 5, and dialysis-dependent CKD. Flow reserve with preserved kidney function was 2.01, 2.06 in stage 1 CKD, 1.91 in stage 2, 1.68 in stage 3, 1.54 in stage 4, 1.66 in stage 5, and 1.55 in dialysis-dependent CKD. Coronary flow reserve was significantly associated with cardiovascular mortality in adjusted models (hazard ratio 0.76, 95% confidence interval: 0.63-0.92 per tertile of coronary flow reserve) without evidence of effect modification by CKD. Thus, coronary flow reserve is strongly associated with cardiovascular risk regardless of CKD severity and is low in early stage CKD without further decrement in stage 5 or dialysis-dependent CKD. This suggests that CKD physiology rather than the effects of dialysis is the primary driver of microvascular disease. Our findings highlight the potential contribution of microvascular dysfunction to cardiovascular risk in CKD and the need to define mechanisms linking low coronary flow reserve to mortality.

Background: The diagnostic yield of cardiac sarcoidosis (CS) by endomyocardial biopsy is limited. Fluorodeoxyglucose (FDG) positron emission tomography (PET) and cardiac magnetic resonance imaging (MRI) may facilitate noninvasive diagnosis, but the accuracy of this approach is not well defined. We aimed to correlate findings from FDG PET and cardiac MRI with histological findings from explanted hearts of patients who underwent cardiac transplantation. Methods: We analyzed the explanted heart histology for all patients who underwent cardiac transplant at our center from April 2008 to July 2018 and had pretransplant FDG PET (n=18) or cardiac MRI (n=31). The likelihood of CS based on FDG PET or cardiac MRI was categorized in a blinded fashion using a previously published method. RESULTS: Using a CS probable cutoff for FDG PET resulted in a sensitivity of 100.0% (95% CI, 54.1%–100.0%) and a specificity of 33.3% (95% CI, 9.9%–65.1%). Three of the 9 CS probable by FDG PET cases were found to be arrhythmogenic cardiomyopathy. The test characteristics of cardiac MRI are more challenging to comment on using our data as there was only one confirmed case of CS on post-transplant histological assessment. Of the 8 CS highly probable or probable cases by cardiac MRI, 3 were found to be dilated cardiomyopathy, and 2 were found to be end-stage hypertrophic cardiomyopathy. Conclusions: FDG PET and cardiac MRI can help facilitate the diagnosis of CS in patients with advanced heart failure with a high degree of sensitivity but lower specificity.

Immunoglobulin light-chain (AL) amyloidosis affects multiple systemic organs. However, determination of the precise extent of organ involvement remains challenging. Targeted amyloid imaging with 18F-florbetapir PET/CT offers the potential to detect AL deposits in multiple organs. The primary aim of this study was to determine the distribution and frequency of AL deposits in the various organs of subjects with systemic AL amyloidosis using 18F-florbetapir PET/CT. Methods: This prospective study included 40 subjects with biopsy-proven AL amyloidosis including active AL amyloidosis (n = 30) or AL amyloidosis in hematologic remission for more than 1 y (n = 10). All subjects underwent 18F-florbetapir PET/CT, skull base to below the kidney scan field, from 60 to 90 min after injection of radiotracer. Volume-of-interest measurements of SUVmax were obtained using Hermes software for the parotid gland, tongue, thyroid, lung, gastric wall, pancreas, spleen, kidney, muscle, abdominal fat, lower thoracic spine, vertebral body, and humeral head. Uptake in each organ was visually compared with that in spine bone marrow. An SUVmax of at least 2.5 was considered abnormal in all organs other than the liver. Results: Compared with the international consensus definition of organ involvement, 18F-florbetapir PET/CT identified amyloid deposits in substantially higher percentages of subjects for several organ systems, including parotid gland (50% vs. 3%), tongue (53% vs. 10%), and lung (35% vs. 10%). In several organ systems, including kidney (13% vs. 28%) and abdominal wall fat (10% vs. 13%), PET identified involvement in fewer subjects than did international consensus. Quantitative analysis of 18F-florbetapir PET/CT revealed more frequent organ involvement than did visual analysis in the tongue, thyroid, lung, pancreas, kidney, muscle, and humeral head. Extensive organ amyloid deposits were observed in active AL as well as in AL remission cohorts, and in both cardiac and noncardiac AL cohorts. Conclusion:18F-florbetapir PET/CT detected widespread organ amyloid deposition in subjects with both active AL and AL hematologic remission. In most instances, amyloid deposits in the various organs were not associated with clinical symptoms and, thus, were unrecognized. Early recognition of systemic organ involvement may help tailor treatment, and noninvasive monitoring of organ-level disease may guide management with novel fibril-resorbing therapies.

Type 2 myocardial infarction (MI) and myocardial injury are associated with increased short-term mortality. However, data regarding long-term mortality are lacking. This study compared long-term mortality among young adults with type 1 MI, type 2 MI, or myocardial injury. Adults age 50 years or younger who presented with troponin >99th percentile or the International Classification of Diseases code for MI over a 17-year period were identified. All cases were adjudicated as type 1 MI, type 2 MI, or myocardial injury based on the Fourth Universal Definition of MI. Cox proportional hazards models were constructed for survival free from all-cause and cardiovascular death. The cohort consisted of 3,829 patients (median age 44 years; 30% women); 55% had type 1 MI, 32% had type 2 MI, and 13% had myocardial injury. Over a median follow-up of 10.2 years, mortality was highest for myocardial injury (45.6%), followed by type 2 MI (34.2%) and type 1 MI (12%) (p < 0.001). In an adjusted model, type 2 MI was associated with higher all-cause (hazard ratio: 1.8; 95% confidence interval: 1.2 to 2.7; p = 0.004) and cardiovascular mortality (hazard ratio: 2.7; 95% confidence interval: 1.4 to 5.1; p = 0.003) compared with type 1 MI. Those with type 2 MI or myocardial injury were younger and had fewer cardiovascular risk factors but had more noncardiovascular comorbidities. They were significantly less likely to be prescribed cardiovascular medications at discharge. Young patients who experience a type 2 MI have higher long-term all-cause and cardiovascular mortality than those who experience type 1 MI, with nearly one-half of patients with myocardial injury and more than one-third of patients with type 2 MI dying within 10 years. These findings emphasize the need to provide more aggressive secondary prevention for patients who experience type 2 MI and myocardial injury.

The primary aims of this study were to determine the correlation between absolute quantitative 99mTc-pyrophosphate metrics and traditional measures of cardiac amyloid burden and to measure the intraobserver repeatability of the quantitative metrics. Methods: We studied 72 patients who underwent 99mTc-pyrophosphate SPECT/CT using a novel general-purpose cadmium-zinc-telluride-based SPECT/CT system. The clinical standard for these studies is visual grading (with grades of 0, 1, 2, and 3 indicating myocardial uptake absent, less than rib uptake, equal to rib uptake, or more than rib uptake, respectively). A visual grade of 2 or more was considered positive. For 72 patients, SUVmax, SUVmean, cardiac amyloid activity (CAA; i.e., SUVmean × left ventricular [LV] volume), and percentage injected dose (%ID) were calculated, and visual grading was performed. The correlation was determined between the 4 quantitative metrics or visual grades and the LV mass index (LVMI) (indexed to body surface area on echocardiography, 67 patients). For a subset of 11 patients, the correlation was determined between the visual or quantitative metrics and the extracellular volume (ECV) on cardiac MRI. Normal linear regression was used to compare the standardized association of each of the 4 quantitative metrics with LVMI, as a surrogate for amyloid burden. Receiver-operating-characteristic curve analysis was used to determine the diagnostic accuracy of quantitative metrics, using visual grading as the reference standard. The intraobserver repeatability of generating quantitative metrics was also determined. Results: All 4 quantitative metrics were highly accurate, with an area under the receiver-operating-characteristic curve of more than 0.96 for diagnosis of transthyretin cardiac amyloidosis. SUVmax, SUVmean, CAA, %ID, and visual grade were moderately positively correlated with LVMI (r = 0.485 for %ID) and strongly positively correlated, albeit in a small cohort, with ECV (r = 0.873, SUVmax). Intraobserver repeatability was excellent, with less than a 2% coefficient of variation for SUVmax, %ID, and CAA and 3.8% for SUVmean All 4 quantitative metrics had a standardized effect of more than 0.324 on LVMI; the largest standardized effect was 0.485, for %ID. Conclusion: In this first (to our knowledge) study of 99mTc-pyrophosphate cardiac imaging using a novel cadmium-zinc-telluride SPECT/CT scanner, SUVmax, SUVmean, CAA, and %ID measured by absolute quantitation of 99mTc-pyrophosphate were moderately correlated with LVMI and strongly correlated, albeit in a small cohort, with ECV. The intraobserver repeatability of generating the quantitative metrics was excellent.

Standard evaluation and management of the patient with suspected or proven cardiovascular complications of coronavirus disease-2019 (COVID-19), the disease caused by severe acute respiratory syndrome related-coronavirus-2 (SARS-CoV-2), is challenging. Routine history, physical examination, laboratory testing, electrocardiography, and plain x-ray imaging may often suffice for such patients, but given overlap between COVID-19 and typical cardiovascular diagnoses such as heart failure and acute myocardial infarction, need frequently arises for advanced imaging techniques to assist in differential diagnosis and management. This document provides guidance in several common scenarios among patients with confirmed or suspected COVID-19 infection and possible cardiovascular involvement, including chest discomfort with electrocardiographic changes, acute hemodynamic instability, newly recognized left ventricular dysfunction, as well as imaging during the subacute/chronic phase of COVID-19. For each, the authors consider the role of biomarker testing to guide imaging decision-making, provide differential diagnostic considerations, and offer general suggestions regarding application of various advanced imaging techniques.