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Coronavirus disease 2019 (COVID-19) is a rapidly expanding global pandemic caused by severe acute respiratory syndrome coronavirus 2, resulting in significant morbidity and mortality. A substantial minority of patients hospitalized develop an acute COVID-19 cardiovascular syndrome, which can manifest with a variety of clinical presentations but often presents as an acute cardiac injury with cardiomyopathy, ventricular arrhythmias, and hemodynamic instability in the absence of obstructive coronary artery disease. The cause of this injury is uncertain but is suspected to be related to myocarditis, microvascular injury, systemic cytokine-mediated injury, or stress-related cardiomyopathy. Although histologically unproven, severe acute respiratory syndrome coronavirus 2 has the potential to directly replicate within cardiomyocytes and pericytes, leading to viral myocarditis. Systemically elevated cytokines are also known to be cardiotoxic and have the potential to result in profound myocardial injury. Prior experience with severe acute respiratory syndrome coronavirus 1 has helped expedite the evaluation of several promising therapies, including antiviral agents, interleukin-6 inhibitors, and convalescent serum. Management of acute COVID-19 cardiovascular syndrome should involve a multidisciplinary team including intensive care specialists, infectious disease specialists, and cardiologists. Priorities for managing acute COVID-19 cardiovascular syndrome include balancing the goals of minimizing healthcare staff exposure for testing that will not change clinical management with early recognition of the syndrome at a time point at which intervention may be most effective. This article aims to review the best available data on acute COVID-19 cardiovascular syndrome epidemiology, pathogenesis, diagnosis, and treatment. From these data, we propose a surveillance, diagnostic, and management strategy that balances potential patient risks and healthcare staff exposure with improvement in meaningful clinical outcomes.

Background: A malignant subphenotype of left ventricular hypertrophy (LVH) has been described, in which minimal elevations in cardiac biomarkers identify individuals with LVH at high risk for developing heart failure (HF). We tested the hypothesis that a higher prevalence of malignant LVH among blacks may contribute to racial disparities in HF risk. Methods: Participants (n=15 710) without prevalent cardiovascular disease were pooled from 3 population-based cohort studies, the ARIC Study (Atherosclerosis Risk in Communities), the DHS (Dallas Heart Study), and the MESA (Multi-Ethnic Study of Atherosclerosis). Participants were classified into 3 groups: those without ECG-LVH, those with ECG-LVH and normal biomarkers (hs-cTnT (high sensitivity cardiac troponin-T) Results: Over the 10-year follow-up period, HF occurred in 512 (3.3%) participants, with 5.2% in black men, 3.8% in white men, 3.2% in black women, and 2.2% in white women. The prevalence of malignant LVH was 3-fold higher among black men and women versus white men and women. Compared with participants without LVH, the adjusted hazard ratio for HF was 2.8 (95% CI, 2.1–3.5) in those with malignant LVH and 0.9 (95% CI, 0.6–1.5) in those with LVH and normal biomarkers, with similar findings in each race/sex subgroup. Mediation analyses indicated that 33% of excess hazard for HF among black men and 11% of the excess hazard among black women was explained by the higher prevalence of malignant LVH in blacks. Of black men who developed HF, 30.8% had malignant LVH at baseline, with a corresponding population attributable fraction of 0.21. The proportion of HF cases occurring among those with malignant LVH, and the corresponding population attributable fraction, were intermediate and similar among black women and white men and lowest among white women. Conclusions: A higher prevalence of malignant LVH may in part explain the higher risk of HF among blacks versus whites. Strategies to prevent development or attenuate risk associated with malignant LVH should be investigated as a strategy to lower HF risk and mitigate racial disparities.

Introduction: Cardiomyopathy is a common complication in muscular dystrophy (MD) patients, though the mechanism is not clear. Retrospective data from adults with Duchenne muscular dystrophy suggest they have reduced LV mass compared to adults with other forms of non-ischemic cardiomyopathy. This raises the question whether pathologic hypertrophy contributes to the development of neuromuscular-associated cardiomyopathies. In this study, we hypothesized that MD patients have lower LV mass and associated changes in cardiac function as compared to healthy individuals. Methods: Utilizing cardiac magnetic resonance imaging (cMRI) data, a retrospective study was undertaken to compare LV mass, structure, and function between adults with MD and healthy age-, sex-, weight-matched controls from the Dallas Heart Study (DHS). Types of MD included dystrophinopathies, facioscapulohumeral MD, Freidreich ataxia, limb-girdle MD, myotonic dystrophy, and other rare MD. Approximately 50% of the MD patients were able to ambulate. MD patients were stratified into normal and reduced LVEF, defined as < 62% on cMRI, for further comparison. Statistical analysis was done using a two-sample, two-tailed t-test. Results: There were 339 MD patients (221 male) of mean age 40 and 417 DHS patients (187 male) of mean age 42. MD patients had a significantly lower LV mass, LV mass index, and LVEF than DHS adults. They also had significantly higher absolute and indexed volumes. In those with normal LVEF, all variables except LVESVi were significantly different from DHS. In those with reduced LVEF, all variables were significantly different from DHS. The results are summarized in Table 1. Conclusions: Collectively, MD patients have a reduced LV mass compared to healthy adults. In addition, MD patients with normal LVEF have lower LV mass than those patients with reduced LV function. Whether this observed decrease in LV mass represents cardiac hypoplasia or atrophy warrants further investigation.

Introduction: Duchenne muscular dystrophy (DMD) is a rare X-linked neuromuscular disorder affecting 1:5,000 males that results in terminal injury to the skeletal muscle and the heart. Recent evidence suggests that DMD female carriers are also at increased risk of developing cardiomyopathy. Renin-angiotensin-aldosterone system (RAAS) antagonists reduce morbidity and mortality and inhibit adverse left ventricular remodeling in patients with heart failure with reduced ejection fraction. The benefit of RAAS inhibition in DMD carriers has not been studied to date. Hypothesis: We hypothesize that RAAS inhibition will improve left ventricular function and induce favorable left ventricular structural changes in DMD carriers over time. Methods: A retrospective, single-center cohort study was undertaken to compare cardiac magnetic resonance imaging (cMRI) parameters in DMD carriers at the time of RAAS inhibitor initiation and after treatment with RAAS inhibitors for at least 12 months. RAAS inhibitors included angiotensin converting enzyme inhibitors, angiotensin receptor blockers, or angiotensin receptor neprilysin inhibitors. Through EMR review, demographic data and cMRI parameters were collected retrospectively on 20 consecutive DMD carriers. Results: The average time elapsed between cMRIs was 39 months. Overall, left ventricular ejection fraction (LVEF) increased in DMD carriers over time, though the improvement in LVEF did not reach significance (57% + 8 vs 59% + 6, p=0.2). However, subgroup analysis of 16 DMD carriers with reduced LVEF (defined as LVEF + 6 vs 58% + 7; p= 0.004). DMD carriers with reduced LVEF additionally demonstrated a significant decrease in left ventricular end systolic volume index (LVESVi) after RAAS inhibition (38 + 10 vs 32 + 10 ml/m2; p= 0.013). Conclusions: DMD carriers with reduced LVEF showed significant improvement in LVEF and LVESVi following RAAS inhibition. Collectively, the data suggest that RAAS inhibition significantly improves left ventricular systolic function and significantly reduces maladaptive left ventricular remodeling and dilation in this population.

Among the estimated 6.2 million Americans living with heart failure (HF), ≈5%/y may progress to advanced, or stage D, disease. Advanced HF has a high morbidity and mortality, such that early recognition of this condition is important to optimize care. Delayed referral or lack of referral in patients who are likely to derive benefit from an advanced HF evaluation can have important adverse consequences for patients and their families. A 2-step process can be used by practitioners when considering referral of a patient with advanced HF for consideration of advanced therapies, focused on recognizing the clinical clues associated with stage D HF and assessing potential benefits of referral to an advanced HF center. Although patients are often referred to an advanced HF center to undergo evaluation for advanced therapies such as heart transplantation or implantation of a left ventricular assist device, there are other reasons to refer, including access to the infrastructure and multidisciplinary team of the advanced HF center that offers a broad range of expertise. The intent of this statement is to provide a framework for practitioners and health systems to help identify and refer patients with HF who are most likely to derive benefit from referral to an advanced HF center.

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Background: Obesity may contribute to adverse outcomes in coronavirus disease 2019 (COVID-19). However, studies of large, broadly generalizable patient populations are lacking, and the effect of body mass index (BMI) on COVID-19 outcomes— particularly in younger adults—remains uncertain. Methods: We analyzed data from patients hospitalized with COVID-19 at 88 US hospitals enrolled in the American Heart Association’s COVID-19 Cardiovascular Disease Registry with data collection through July 22, 2020. BMI was stratified by World Health Organization obesity class, with normal weight prespecified as the reference group. Results: Obesity, and, in particular, class III obesity, was overrepresented in the registry in comparison with the US population, with the largest differences among adults ≤50 years. Among 7606 patients, in-hospital death or mechanical ventilation occurred in 2109 (27.7%), in-hospital death in 1302 (17.1%), and mechanical ventilation in 1602 (21.1%). After multivariable adjustment, classes I to III obesity were associated with higher risks of in-hospital death or mechanical ventilation (odds ratio, 1.28 [95% CI, 1.09–1.51], 1.57 [1.29–1.91], 1.80 [1.47–2.20], respectively), and class III obesity was associated with a higher risk of in-hospital death (hazard ratio, 1.26 [95% CI, 1.00–1.58]). Overweight and class I to III obese individuals were at higher risk for mechanical ventilation (odds ratio, 1.28 [95% CI, 1.09–1.51], 1.54 [1.29–1.84], 1.88 [1.52–2.32], and 2.08 [1.68–2.58], respectively). Significant BMI by age interactions were seen for all primary end points ( P -interaction70 years. Severe obesity (BMI ≥40 kg/m 2 ) was associated with an increased risk of in-hospital death only in those ≤50 years (hazard ratio, 1.36 [1.01–1.84]). In adjusted analyses, higher BMI was associated with dialysis initiation and with venous thromboembolism but not with major adverse cardiac events. Conclusions: Obese patients are more likely to be hospitalized with COVID-19, and are at higher risk of in-hospital death or mechanical ventilation, in particular, if young (age ≤50 years). Obese patients are also at higher risk for venous thromboembolism and dialysis. These observations support clear public health messaging and rigorous adherence to COVID-19 prevention strategies in all obese individuals regardless of age.

Introduction: Amyloid cardiomyopathy (ACM) is recognized increasingly as a cause of advanced heart failure. There are limited data describing clinical outcomes for ACM patients who receive durable mechanical circulatory support (MCS). Methods: This analysis included adult patients in the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) with a primary diagnosis of dilated cardiomyopathy (DCM, N=19,921), non-amyloid restrictive cardiomyopathy (RCM, N=248), or ACM (N=48) who received durable MCS of any type or strategy from 2005-2017. We compared baseline characteristics and adverse events for the 3 groups. The primary endpoint was death with heart transplantation as a competing risk with follow-up censored at device explantation. Results: Patients with ACM (N=48) were older (61 y [IQR 55-69] versus 58 y [IQR 49-66] for DCM and 55 y [IQR 46-62] for non-amyloid RCM, P Conclusion: Compared to DCM or non-amyloid RCM patients, those with durable MCS for ACM have the highest risk of early adverse events and lowest survival. These data highlight concerns with durable MCS for ACM.

Introduction: Left Ventricular Assist Devices (LVAD) decrease cardiac mechanical work and metabolic demand and may decrease cardiomyocyte oxidative stress, followed by cell cycle re-entry and cell regeneration. We tested whether LVAD long-term support is associated with myocardial regeneration. Methods: Viability fluorodeoxyglucose (18FDG) - positron-emission tomography scans were performed >3 months after LVAD implantation and every 6 months thereafter. 4 patients aged 18-70 with end-stage non-ischemic (NICM, n=3) or ischemic cardiomyopathy (ICM, n=1) were included. Low metabolic activity myocardial regions of interest (ROI) at Results: LV ejection fraction ranged 0-35% at baseline. Two patients (LVAD speed 2660 rotations per minute - RPM, output 3.4-4.1 and 5.6-5.9 liters per minute (LPM), respectively) underwent 2 scans before cardiac transplantation, exhibiting borderline increased global signal (1-4%) and significantly increased 18FDG signal in the baseline low-intensity ROI on the follow-up scan (67.7, 75.7%). The other 2 patients (LVAD parameters: 5600 RPM/ 4.6-5.8 LPM; 9200 RPM/ 4.3-4.8 LPM) exhibited decreased global 18FDG signal (10-16%) and increased signal in the co-registered baseline low-intensity ROIs (1.7-21.5%) (Figure). Conclusions: LVAD long-term support is associated with a global decrease in myocardial 18FDG uptake signal over time, and with increased viability signal in baseline low-intensity ROIs, suggestive of myocardial regeneration in metabolically inactive regions. Future research is required to identify patient subgroups that are most likely to exhibit high regeneration potential upon long-term LVAD support.

Background: Duchenne muscular dystrophy (DMD) is an X-linked neuromuscular disorder characterized by progressive muscle degeneration. The leading cause of death is complications from the development of DMD-associated cardiomyopathy. The majority of DMD patients have skeletal abnormalities that limit the quality of echocardiograms (ECHO). Although cardiac magnetic resonance imaging (cMRI) is the gold standard cardiac imaging tool, the vast majority of DMD patients are evaluated by ECHO rather than cMRI. We hypothesized that when compared to ECHO, cMRI more accurately assesses cardiac function and provides more valuable data for the diagnosis of DMD-associated cardiomyopathy. Methods: We undertook a retrospective study of 20 DMD patients referred to the UT Southwestern Adult Neuromuscular Cardiomyopathy Clinic who had undergone both an ECHO and cMRI within 15 months of each other. We assessed the proportion of studies demonstrating reduced left ventricular (LV) function [cMRI LVEF Results: Amongst these patients, 10% of cMRIs and 85% of ECHOs were technically difficult. By cMRI, 30% of the studies were normal (LVEF 64±2 %), while 70% showed reduced function (LVEF: 44±12%). By ECHO, 75% of the studies were normal (FS 32±5), while 25% showed reduced function (FS: 15±8). Of the patients with truly reduced function by cMRI, 64% were considered normal by ECHO. Finally, 61% of cMRI studies showed LGE (50% with normal LVEF and 67% with reduced LVEF). Conclusions: In summary, cMRI is superior to ECHO in assessing cardiac function in DMD. ECHO underestimates left ventricular dysfunction, likely due to the poor quality of studies obtained in this patient population. In addition, cMRI identifies LGE, a marker associated with increased mortality, irrespective of cardiac function. Earlier utilization of cMRI will expedite the diagnosis of DMD-associated cardiomyopathy and enable the cardiologist to initiate aggressive guideline-directed medical therapy at an earlier age.

Introduction: Duchenne muscular dystrophy (DMD) is an X-linked neuromuscular disorder. DMD-associated cardiomyopathy is the primary mode of premature death in the majority of male DMD patients, but the prevalence of cardiomyopathy and its clinical significance in female DMD carriers is less well characterized. Hypothesis: We hypothesized that a significant proportion of DMD carriers develop maladaptive left ventricular (LV) structural remodeling and cardiomyopathy over time. Methods: A cross-sectional study was undertaken comparing cardiac magnetic resonance imaging (cMRI) and cardiopulmonary stress test (CPX) parameters between DMD carriers and healthy age- and sex-matched controls from the Dallas Heart Study (DHS). Demographic data, cMRI parameters, and CPX parameters were collected retrospectively on 30 consecutive DMD carriers and 26 control DHS subjects. Results: Overall, DMD carriers had a significantly lower LVEF compared to DHS controls (58+8% vs 70+7%, p< 0.0001). The overall prevalence of reduced LVEF in DMD carriers (defined as LVEF 2 vs 58+7, p< 0.0001; 31+10 ml/m 2 vs 17+5, p< 0.0001; respectively). LV concentricity was also significantly lower among all DMD carriers compared to DHS controls (3.10+0.65 g/mL 0.67 vs 3.73+0.79, p =0.002). LV concentricity was significantly lower in DMD carriers with reduced EF compared to controls (3.09+0.51 g/mL 0.67 vs 3.73+0.79, p = 0.012), while DMD carriers with preserved EF also had reduced concentricity compared to controls (3.12+0.86 vs 3.73+0.79, p = 0.054). Finally, peak VO 2 was lower in DMD carriers compared to DHS controls (23+6 ml/kg/min vs 25+4, p =0.076), though this difference did not reach statistical significance. Conclusions: Collectively, the data suggest that middle-aged female DMD carriers are at greater risk of developing left ventricular systolic dysfunction and cardiomyopathy associated with decreased exercise capacity. A possible mechanism driving the development of this cardiomyopathy is progressive, maladaptive left ventricular dilatation and cardiac atrophy.

Background: Muscular dystrophies (MD) are genetic disorders that cause progressive peripheral skeletal myopathies. The majority of MD patients will develop atrial and ventricular arrhythmias and/or an associated cardiomyopathy with a high degree of morbidity and mortality. However, it remains unknown the degree of atrial remodeling that may also occur in MD patients. We hypothesize maladaptive atrial remodeling occurs in MD patients. Methods: Utilizing the UT Southwestern Cardiomyopathy Clinic, MD [total: 79 patients (34 females, 45 males)] and non-ischemic cardiomyopathy (NICM) [total: 81 patients (29 females, 52 males)] patients were identified who underwent a cardiac MRI (cMRI) between 2011 and 2015. A matched, healthy control cohort from the Dallas Heart Study (DHS) [total: 101 patients (40 females, 61 males)] were identified. Most MD patients had Duchenne/Becker MD, Limb-Girdle MD or myotonic MD. Two blinded, independent readers made volumetric measurements from cMRIs to assess right atrial (RA) and left atrial (LA) dimensions with low inter-reader variability. A third independent investigator analyzed the RA and LA data with aggregate data presented in the Table. The statistical significance of the data (p Results: Analysis of the cMRI data revealed significant differences in both the structure and function of the RA and the LA between MD and NICM patients. In addition, the data revealed significant differences in the LA but not the RA emptying fraction in MD patients as compared to the DHS patients. Conclusion: Collectively, the data suggests MD patients develop significant maladaptive remodeling of the LA but not the RA, predisposing these patients to atrial arrhythmias. Investigation into differences in atrial remodeling as a function of gender and the type of MD need to be explored.

Introduction: Although patient-reported outcomes are increasingly emphasized, symptoms may be discordant to objective parameters of heart failure severity. The frequency of such discordance, associated characteristics, and its influence on clinical outcomes is unknown. Methods: This is a post-hoc analysis of the HF-ACTION trial (N=2062). Participants were divided by median baseline values for Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ, subjective measure) and V E /VCO 2 slope (objective measure) into 4 groups: “concordant-lower severity” (high KCCQ, low V E /VCO 2 slope), “concordant-higher severity” (low KCCQ, high V E /VCO 2 slope), “symptom magnifier” (low KCCQ, V E /VCO 2 slope), and “symptom minimizer” (high KCCQ, V E /VCO 2 slope). Baseline characteristics were compared, and the relationship between group and clinical outcomes over a median follow-up of 442 days was assessed in adjusted Cox models. Results: Discordance of patient-reported and objective illness severity was common (46%). Depression was more prevalent among symptom magnifiers (N=480) versus concordant-lower severity (N=566) and symptom minimizer (N=465) groups (30%, 18%, 14%, respectively; P Conclusion: A high rate of discordance was observed between patient-reported and objective heart failure severity. Depression was associated with symptom magnification. Hospitalization was influenced by patient-reported severity but mortality tracked more closely with objective data, highlighting potential limitations of static patient-reported outcomes for risk stratification.

Background: Current strategies for cardiovascular disease (CVD) risk assessment among adults without known CVD are limited by suboptimal performance and a narrow focus on only atherosclerotic CVD (ASCVD). We hypothesized that a strategy combining promising biomarkers across multiple different testing modalities would improve global and atherosclerotic CVD risk assessment among individuals without known CVD. Methods: We included participants from MESA (Multi-Ethnic Study of Atherosclerosis) (n=6621) and the Dallas Heart Study (n=2202) who were free from CVD and underwent measurement of left ventricular hypertrophy by ECG, coronary artery calcium, N-terminal pro B-type natriuretic peptide, high-sensitivity cardiac troponin T, and high-sensitivity C-reactive protein. Associations of test results with the global composite CVD outcome (CVD death, myocardial infarction, stroke, coronary or peripheral revascularization, incident heart failure, or atrial fibrillation) and ASCVD (fatal or nonfatal myocardial infarction or stroke) were assessed over >10 years of follow-up. Multivariable analyses for the primary global CVD end point adjusted for traditional risk factors plus statin use and creatinine (base model). Results: Each test result was independently associated with global composite CVD events in MESA after adjustment for the components of the base model and the other test results ( P P =0.001), significant integrated discrimination improvement (0.07, 95% confidence interval [CI] 0.06–0.08, P P =0.003) were observed, and the model was well calibrated (χ 2 =12.2, P =0.20). Using a simple integer score counting the number of abnormal tests, compared with those with a score of 0, global CVD risk was increased among participants with a score of 1 (adjusted hazard ratio, 1.9; 95% CI, 1.4–2.6), 2 (hazard ratio, 3.2; 95% CI, 2.3–4.4), 3 (hazard ratio, 4.7; 95% CI, 3.4–6.5), and ≥4 (hazard ratio, 7.5; 95% CI, 5.2–10.6). Findings replicated in the Dallas Health Study were similar for the ASCVD outcome. Conclusions: Among adults without known CVD, a novel multimodality testing strategy using left ventricular hypertrophy by ECG, coronary artery calcium, N-terminal pro B-type natriuretic peptide, high-sensitivity cardiac troponin T, and high-sensitivity C-reactive protein significantly improved global CVD and ASCVD risk assessment.

Background: Outcome trials in patients with type 2 diabetes mellitus have demonstrated reduced hospitalizations for heart failure (HF) with sodium-glucose co-transporter-2 inhibitors. However, few of these patients had HF, and those that did were not well-characterized. Thus, the effects of sodium-glucose co-transporter-2 inhibitors in patients with established HF with reduced ejection fraction, including those with and without type 2 diabetes mellitus, remain unknown. Methods: DEFINE-HF (Dapagliflozin Effects on Biomarkers, Symptoms and Functional Status in Patients with HF with Reduced Ejection Fraction) was an investigator-initiated, multi-center, randomized controlled trial of HF patients with left ventricular ejection fraction ≤40%, New York Heart Association (NYHA) class II-III, estimated glomerular filtration rate ≥30 mL/min/1.73m 2 , and elevated natriuretic peptides. In total, 263 patients were randomized to dapagliflozin 10 mg daily or placebo for 12 weeks. Dual primary outcomes were (1) mean NT-proBNP (N-terminal pro b-type natriuretic peptide) and (2) proportion of patients with ≥5-point increase in HF disease-specific health status on the Kansas City Cardiomyopathy Questionnaire overall summary score, or a ≥20% decrease in NT-proBNP. Results: Patient characteristics reflected stable, chronic HF with reduced ejection fraction with high use of optimal medical therapy. There was no significant difference in average 6- and 12-week adjusted NT-proBNP with dapagliflozin versus placebo (1133 pg/dL (95% CI 1036–1238) vs 1191 pg/dL (95% CI 1089–1304), P =0.43). For the second dual-primary outcome of a meaningful improvement in Kansas City Cardiomyopathy Questionnaire overall summary score or NT-proBNP, 61.5% of dapagliflozin-treated patients met this end point versus 50.4% with placebo (adjusted OR 1.8, 95% CI 1.03-3.06, nominal P =0.039). This was attributable to both higher proportions of patients with ≥5-point improvement in Kansas City Cardiomyopathy Questionnaire overall summary score (42.9 vs 32.5%, adjusted OR 1.73, 95% CI 0.98–3.05), and ≥20% reduction in NT-proBNP (44.0 vs 29.4%, adjusted OR 1.9, 95% CI 1.1–3.3) by 12 weeks. Results were consistent among patients with or without type 2 diabetes mellitus, and other prespecified subgroups (all P values for interaction=NS). Conclusions: In patients with heart failure and reduced ejection fraction, use of dapagliflozin over 12 weeks did not affect mean NT-proBNP but increased the proportion of patients experiencing clinically meaningful improvements in HF-related health status or natriuretic peptides. Benefits of dapagliflozin on clinically meaningful HF measures appear to extend to patients without type 2 diabetes mellitus. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT 02653482.

The medical profession should play a central role in evaluating the evidence related to drugs, …

Jonathan L. Halperin, MD, FACC, FAHA, Chair Glenn N. Levine, MD, FACC, FAHA, Chair-Elect Sana M. Al-Khatib, MD, MHS, FACC, FAHA Kim K. Birtcher, PharmD, MS, AACC Biykem Bozkurt, MD, PhD, FACC, FAHA Ralph G. Brindis, MD, MPH, MACC Joaquin E. Cigarroa, MD, FACC Lesley H. Curtis, PhD, FAHA

Introduction: Obesity is linked to an adverse cardiac structural phenotype in cross-sectional studies. However, the effects of longitudinal changes in generalized and central adiposity on left ventricular (LV) remodeling are unknown. Methods: Participants without baseline cardiovascular disease or LV dysfunction in the Dallas Heart Study underwent assessment of body composition and cardiac structure by MRI at baseline and then 7 years later. Associations between change in weight and waist circumference with alterations in structure and function were assessed using multivariable linear regression. Results: The study cohort (n=1262) had a mean age of 44 years and was 43% (545 of 1262) male, 44% (556 of 1262) African-American, and 36% (460 of 1262) obese at baseline. At 7 years follow-up, 7% (85 of 1262) had >10% weight loss, 8% (108 of 1262) had 5-10% weight loss, 44% (551 of 1262) had 10% weight gain. Those who gained >10% weight were younger, had lower BMI and LV mass at baseline, and had greater increases in blood pressure, glucose, triglycerides, LDL cholesterol, and hs-CRP over follow-up. In multivariable models adjusted for age, sex, race, and baseline and interim development of comorbidities, 1-standard deviation increases in body weight and waist circumference over follow-up were significantly associated with higher LV mass, LV wall thickness, and concentricity; but minimally or not significantly associated with LV end-diastolic volume or ejection fraction (EF) (Table). Conclusion: Increases in generalized and central adiposity are characterized primarily by concentric remodeling, with a more modest impact on LV volume and EF. These results support the notion that the development of specific obesity patterns may impact cardiac remodeling with potential implications for the development of cardiac hypertrophy and heart failure.

Introduction: A recent study in clinic patients found serum activity of the anti-oxidative, anti-inflammatory HDL-associated enzyme paraoxonase 1 (PON1) inversely associated with plasma brain natriuretic peptide (BNP), a marker of heart failure, and predictive of cardiovascular events. We tested whether PON1 protects from hypertensive heart disease in a population sample. Methods: The Dallas Heart Study measured blood biomarkers at baseline in a population sample of 3480 subjects. Left ventricular mass and ejection fraction were measured by cardiac MRI. Serum PON1 activity was measured by the standard arylesterase enzymatic assay. Incident deaths and causes of death were ascertained for 9 years from baseline through the National Death Index where ICD-9 codes I10 –I13.1 indicated hypertensive heart disease. Multivariable models controlled for age, sex, race, cystatin-C, LDL, HDL, high sensitivity C-reactive protein and uncontrolled hypertension. Preliminary mechanistic studies explored effect modification of 34 biomarkers by PON1. Results: In a general linear model PON1 activity was independently associated inversely with log Pro-BNP (standardized r = -0.11, s.e. 0.015, Pinteraction < 0.001, Fig.). Conclusions: The findings suggest that PON1, a component of HDL, may protect from hypertensive heart disease by mitigating cardiac remodeling.

Introduction: In patients with advanced heart failure, shortness of breath while bending forwards, e.g. when putting on their shoes, is a recently described symptom termed “bendopnea”. Hypothesis: Whether bendopnea is associated with well validated markers of heart failure severity measured by cardiopulmonary exercise (CPX) testing, such as peak VO2 or VE/VCO2 slope, is not known. Methods: Bendopnea was assessed prior to a CPX in a prospective study of 95 subjects with systolic HF who were referred for functional evaluation. Standard CPX techniques were used including measurement of peak VO2 and VE/VCO2 slope. Multivariable linear regression analysis was performed to adjust the associations of bendopnea and CPX parameters for potential confounders. Results: The study cohort was predominantly male (72%), nonischemic cardiomyopathy (54%), NYHA class 3 or 4 (86%), with a mean age of 55 ± 14 years and LVEF 26 ± 4%. Bendopnea was present in 30 of 95 (31.5%) subjects. The association of bendopnea with key CPX parameters (Table) is shown. Peak VO2 was similar in both groups but patients with bendopnea had a higher VE/VCO2 slope (35.28 ± 2.72 vs 30.31 ± 6.41, P< 0.001) and trended towards having a lower oxygen pulse. The association of bendopnea with VE/VCO2 slope persisted in multivariable analysis. Conclusions: Bendopnea was independently associated with elevated VE/VCO2 slope in advanced HF patients. These data suggest that bendopnea is a marker of HF disease severity.

Hypertension remains a major public health problem associated with considerable morbidity and mortality. Hypertensive heart disease is a constellation of abnormalities that includes left ventricular hypertrophy (LVH), systolic and diastolic dysfunction, and their clinical manifestations including arrhythmias and symptomatic heart failure. The classic paradigm of hypertensive heart disease is that the left ventricular (LV) wall thickens in response to elevated blood pressure as a compensatory mechanism to minimize wall stress. Subsequently, after a series of poorly characterized events (“transition to failure”), the left ventricle dilates, and the LV ejection fraction (EF) declines (defined herein as “dilated cardiac failure”).1 The purpose of this review is to focus on the key steps in the progression of hypertensive heart disease (Figure 1), highlighting recent advances as well as some unresolved controversies. Figure 1. The 7 pathways in the progression from hypertension to heart failure. Hypertension progresses to concentric (thick-walled) LVH (cLVH; pathway 1). The direct pathway from hypertension to dilated cardiac failure (increased LV volume with reduced LVEF) can occur without (pathway 2) or with (pathway 3) an interval myocardial infarction (MI). Concentric hypertrophy progresses to dilated cardiac failure (transition to failure) most commonly via an interval myocardial infarction (pathway 4). Recent data suggest that it is not common for concentric hypertrophy to progress to dilated cardiac failure without interval myocardial infarction (pathway 5). Patients with concentric LVH can develop symptomatic heart failure with a preserved LVEF (pathway 6), and patients with dilated cardiac failure can develop symptomatic heart failure with reduced LVEF (pathway 7). The influences of other important modulators of the progression of hypertensive heart disease, including obesity, diabetes mellitus, age, environmental exposures, and genetic factors, are not shown to simplify the diagram. A thicker arrow depicts a more common pathway compared with a thinner arrow. Adapted from Drazner.2 Copyright 2005 …

Background— Current-generation left ventricular assist devices provide circulatory support that is minimally or entirely nonpulsatile and are associated with marked increases in muscle sympathetic nerve activity (MSNA), likely through a baroreceptor-mediated pathway. We sought to determine whether the restoration of pulsatile flow through modulations in pump speed would reduce MSNA through the arterial baroreceptor reflex. Methods and Results— Ten men and 3 women (54±14 years) with Heartmate II continuous-flow left ventricular assist devices underwent hemodynamic and sympathetic neural assessment. Beat-to-beat blood pressure, carotid ultrasonography at the level of the arterial baroreceptors, and MSNA via microneurography were continuously recorded to determine steady-state responses to step changes (200–400 revolutions per minute) in continuous-flow left ventricular assist device pump speed from a maximum of 10 480±315 revolutions per minute to a minimum of 8500±380 revolutions per minute. Reductions in pump speed led to increases in pulse pressure (high versus low speed: 17±7 versus 26±12 mm Hg; P P P P =0.037). Conclusions— Among subjects with continuous-flow left ventricular assist devices, the restoration of pulsatile flow through modulations in pump speed leads to increased distortion of the arterial baroreceptors with a subsequent decline in MSNA. Additional study is needed to determine whether reduction of MSNA in this setting leads to improved outcomes.

Background— The natriuretic peptide system contributes to blood pressure regulation. Atrial and brain natriuretic peptides are cleaved into smaller biologically active molecules by corin, a transmembrane serine protease expressed in cardiomyocytes. Method and Results— This genotype-phenotype genetic association study included replication samples and genomic control to correct for population stratification. Sequencing of the human corin gene identified 2 nonsynonymous, nonconservative single nucleotide polymorphisms (Q568P and T555I) in near-complete linkage disequilibrium, thus describing a single minor I555 (P568) corin gene allele. This allele was present in the heterozygote state in &12% of blacks but was extremely rare in whites (P =0.013). The corin I555 (P568) allele also was associated with higher systolic blood pressure in subjects not using antihypertensive medication in unadjusted (133.7±20.7 versus 129.4±17.4 mm Hg; P =0.029) and adjusted (132.5±1.6 versus 128.9±0.6 mm Hg; P =0.029) analyses. The independent association of the minor corin allele with increased risk for prevalent hypertension was confirmed in the Multi-Ethnic Study of Atherosclerosis (odds ratio, 1.50; 95% CI, 1.09 to 2.06; P =0.014). In addition, the association of the minor corin I555 (P568) allele with higher systolic blood pressure was confirmed in adjusted analysis in the Chicago Genetics of Hypertension Study (125.8±1.9 versus 121.4±0.7 mm Hg; P =0.03). Conclusions— The corin I555 (P568) allele is common in blacks and is associated with higher blood pressure and an increased risk for prevalent hypertension.

Background— In the setting of acute coronary syndromes (ACS), nonwhite patients are less likely to undergo invasive cardiac procedures and may have worse clinical outcomes than white patients. Whether the disparate outcomes exist independently of potential biases in treatment patterns remains unclear. Methods and Results— We examined the association between race and outcome in the Treat Angina with Aggrastat and Determine Cost of Therapy With an Invasive or Conservative Strategy–Thrombolysis in Myocardial Infarction 18 study (TACTICS-TIMI 18), a randomized trial of invasive versus conservative treatment strategy in patients with non–ST-elevation ACS. There were 1722 white and 461 nonwhite patients. After adjustment for differences in medical characteristics, nonwhite patients were at significantly increased risk for death, MI, or rehospitalization for ACS (hazard ratio [HR], 1.54; P =0.003). Rates of protocol-guided angiography and revascularization were similar in both groups. For non–protocol-guided care, however, we found significant disparities, with nonwhite patients less likely to be taking their cardiac medications at follow-up (odds ratio [OR], 0.59; P =0.0002), to undergo non–protocol-mandated angiography (OR, 0.40; P =0.03), to receive a stent if undergoing percutaneous coronary intervention (OR, 0.55; P =0.045), and to have less procedural success after percutaneous coronary intervention (acute gain, 1.40±0.83 versus 1.81±0.92 mm; P =0.004). Nonetheless, an invasive strategy was similarly efficacious in white (HR, 0.66; 95% CI, 0.50 to 0.88) and nonwhite (HR, 0.85; 95% CI, 0.52 to 1.39) patients ( P interaction =0.52), especially in those with troponin elevation or ST deviation. Conclusions— After adjustment for baseline characteristics, nonwhite patients had a significantly worse prognosis than white patients, regardless of treatment approach. In the absence of protocol guidance, important disparities emerged between the care given the 2 groups. An early invasive strategy is beneficial in and should be considered for all patients, regardless of race.

Background— Cardiorespiratory fitness (fitness) is associated with cardiovascular disease (CVD) mortality. However, the extent to which fitness improves risk classification when added to traditional risk factors is unclear. Methods and Results— Fitness was measured by the Balke protocol in 66 371 subjects without prior CVD enrolled in the Cooper Center Longitudinal Study between 1970 and 2006; follow-up was extended through 2006. Cox proportional hazards models were used to estimate the risk of CVD mortality with a traditional risk factor model (age, sex, systolic blood pressure, diabetes mellitus, total cholesterol, and smoking) with and without the addition of fitness. The net reclassification improvement and integrated discrimination improvement were calculated at 10 and 25 years. Ten-year risk estimates for CVD mortality were categorized as P P Conclusions— A single measurement of fitness significantly improves classification of both short-term (10-year) and long-term (25-year) risk for CVD mortality when added to traditional risk factors.

Background— The prevalence and determinants of cardiac troponin T (cTnT) elevation in the general population are unknown, and the significance of minimally increased cTnT remains controversial. Our objective was to determine the prevalence and determinants of cTnT elevation in a large, representative sample of the general population. Methods and Results— cTnT was measured from stored plasma samples in 3557 subjects of the Dallas Heart Study, a population-based sample. cTnT elevation (≥0.01 μg/L) was correlated with clinical variables and cardiac MRI findings. The sample weight-adjusted prevalence of cTnT elevation in the general population was 0.7%. In univariable analyses, cTnT elevation was associated with older age, black race, male sex, coronary artery calcium by electron beam CT, a composite marker of congestive heart failure (CHF), left ventricular hypertrophy (LVH), diabetes mellitus (DM), and chronic kidney disease (CKD) ( P Conclusions— In the general population, cTnT elevation is rare in subjects without CHF, LVH, CKD, or DM, suggesting that the upper limit of normal for the immunoassay should be

Background— The association between higher body mass index (BMI) and lower B-type natriuretic peptide (BNP) level is thought to be mediated by expression of the natriuretic peptide clearance receptor (NPR-C) in adipose tissue. To explore this association, we tested 2 hypotheses: (1) that N-terminal (NT)-proBNP, which is not believed to bind NPR-C, would not be associated with BMI and (2) that lower BNP would be more closely associated with fat mass than with lean mass. Methods and Results— Measurements of BNP, NT-proBNP, and body composition by direct dual energy x-ray absorptiometry (DEXA) were performed in 2707 subjects from the Dallas Heart Study. The associations between obesity and low BNP (P Conclusions— In a large, population-based cohort, we confirm the previously described association between higher BMI and lower BNP and demonstrate a similar inverse association between BMI and NT-proBNP. Interestingly, both BNP and NT-proBNP are more closely associated with lean mass than with fat mass. These findings do not support the hypothesis that the lower BNP levels seen in obesity are driven by enhanced BNP clearance mediated via NPR-C.

Hypertensive heart disease is a major contributor to cardiovascular morbidity and mortality, especially in African Americans, in whom LV hypertrophy is 2 to 3-fold more common in the general population as compared with whites.1 In the classic paradigm of hypertensive heart disease, concentric hypertrophy (a nondilated, thick-walled left ventricle typically with a normal left ventricular ejection fraction [LVEF]) is a common precursor to LV failure (an increased LV volume with reduced LVEF).2 Although molecular triggers of this transition from concentric hypertrophy to failure have been the subject of intense investigation, there are no previous large, longitudinal cohort studies in humans demonstrating that this progression occurs frequently. The transition from concentric LV hypertrophy to failure has been well demonstrated in animal models including the spontaneously hypertensive rat,3 or after aortic banding4 or transgenic manipulation,5 and also in humans with aortic stenosis6 or familial hypertrophic cardiomyopathy.7 Whether this paradigm faithfully represents the natural history of hypertensive heart disease is not yet known (Figure). An alternative paradigm is that the LV response to elevated blood pressure is either hypertrophy or failure, with transition between the 2 uncommon in the absence of an interval cardiac injury. Potential pathways in progression of hypertensive heart disease. Hypertension can lead to concentric left ventricular hypertrophy (LVH), characterized by nondilated, thick-walled left ventricle (arrow, top left). After “transition to failure,” the LV is dilated with reduced LVEF. Coronary artery disease often via MI is a common contributor to this transition (first horizontal arrow). Whether concentric LVH commonly leads to low EF in absence of an interval MI or significant coronary artery disease is uncertain (second horizontal arrow). If LVH is not common precursor to LV …