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Cardiac allograft vasculopathy (CAV) is the leading cause of late allograft failure and mortality after heart transplantation. As current standards of diagnosis and treatment of CAV have significant limitations, understanding cell-specific responses may prove critical for developing improved detection strategies and novel therapeutics. This study is the first to successfully utilize human endomyocardial biopsy (EMB) samples to isolate large numbers of intact nuclei for single-nuclear transcriptomics. These data also lay the groundwork for ongoing experiments to study serial, routinely-collected EMB specimens after heart transplantation to identify novel biomarkers and pathways through which early CAV pathogenesis can be interrupted, thereby prolonging allograft survival.

Background: Heart failure is a prominent complication of type 2 diabetes mellitus (T2D). The goal of this study was to provide longitudinal data on cardiac structure and function (and cross-sectional comparison to normal-weight and obese controls without T2D) in individuals followed from adolescence with youth-onset T2D. Methods: In the TODAY study (Treatment Options for Type 2 Diabetes Mellitus in Adolescents and Youth), echocardiograms were performed at study years 4 to 5 and 9 to 10. Echocardiograms were also obtained at years 8 to 9 in a control population of age, race/ethnicity, and sex-matched normal-weight and obese individuals without diabetes mellitus. Study outcomes were measures of left ventricular structure and function. The cohort included 411 participants with T2D, 194 obese controls, and 51 normal-weight controls. Results: At follow-up, mean participant age was 23 years, 65% women, 20% non-Hispanic white, 35% non-Hispanic black, and 39% Hispanic. Ejection fraction was P P Conclusions: Adverse changes in cardiac structure and function changed significantly from adolescence to early adulthood in participants with youth-onset T2D. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT00081328.

Background: Staging criteria for heart failure (HF) range from stage 0 (without risk) to being at risk (stage A) to presence of cardiac structural/functional abnormalities (stage B) to symptomatic/end stage (stages C/D). There are limited data on the prevalence of these stages in early adulthood and predictors of HF stage and symptoms in middle age. Methods and Results: The CARDIA study (Coronary Artery Risk Development in Young Adults)—a cohort of generally healthy black and white men and women—collected phenotypic, echocardiographic, and outcomes data at the year 5 and year 30 examinations when participants were 22 to 37 and 47 to 62 years of age. Prevalence of HF stages was calculated and relationship of year 5 stage to year 30 classification and outcomes was assessed. At year 5, 2189 participants had complete data. Prevalence of HF stage A/B increased from 24% to 76% in black men, from 13% to 64% in white men, from 34% to 81% in black women, and from 13% to 56% in white women. Blacks were more likely to be in any stage or with morbidity at both time points because of higher risk factor prevalence. Of 33 participants with HF or HF deaths by year 30, 21 (64%) had been in stage A or B at year 5. Only 6 participants at year 5 in stage A (at risk) improved risk status at year 30. Conclusions: Risk for HF increased in participants from 1990 (age 22–37 years) to 2015 (age 47–62 years). Symptomatic HF or death from HF is associated with HF stage at 22 to 37 years of age. Blacks are disproportionately affected.

Background: We evaluated the diagnostic and prognostic value of quantification of myocardial flow reserve (MFR) with positron emission tomography (PET) in orthotopic heart transplant patients. Methods and Results: We retrospectively identified orthotopic heart transplant patients who underwent rubidium-82 cardiac PET imaging. The primary outcome was the composite of cardiovascular death, acute coronary syndrome, coronary revascularization, and heart failure hospitalization. Cox regression was used to evaluate the association of MFR with the primary outcome. The relationship of MFR and cardiac allograft vasculopathy severity in patients with angiography within 1 year of PET imaging was assessed using Spearman rank correlation and logistic regression. A total of 117 patients (median age, 60 years; 71% men) were identified. Twenty-one of 62 patients (34%) who underwent angiography before PET had cardiac allograft vasculopathy. The median time from orthotopic heart transplant to PET imaging was 6.4 years (median global MFR, 2.31). After a median of 1.4 years, 22 patients (19%) experienced the primary outcome. On an unadjusted basis, global MFR (hazard ratio, 0.22 per unit increase; 95% confidence interval, 0.09–0.50; P P =0.004) were associated with the primary outcome. Decreased MFR independently predicted the primary outcome after adjustment for other variables. In 42 patients who underwent angiography within 12 months of PET, MFR and stress myocardial blood flow were associated with moderate–severe cardiac allograft vasculopathy (International Society of Heart and Lung Transplantation grade 2–3). Conclusions: MFR assessed by cardiac rubidium-82 PET imaging is a predictor of cardiovascular events after orthotopic heart transplant and is associated with cardiac allograft vasculopathy severity.

With 550 000 new cases diagnosed annually and $37 billion spent per year,1 heart failure (HF) with reduced ejection fraction is one of the largest contributors to disease burden and healthcare expenditure in the United States. Despite significant progress in the treatment of HF2,3 with medications, the prognosis of HF remains dismal, with a mortality rate of 42% at 5 years after diagnosis. Therefore, understanding the underlying molecular pathways in the transition from established cardiovascular disease to HF may spur the development of novel biomarkers and therapeutic targets. The heart responds to stressors such as hypoxia (in myocardial infarction [MI]), increased wall stress (in valvular heart disease), and neurohormonal/metabolic stress (in diabetes mellitus and hypertension) by cardiomyocyte hypertrophy and fibrosis. Although initially compensatory for increased wall stress or myocyte loss, the molecular pathways that underlie pathological hypertrophy are ultimately maladaptive, recapitulating further hypertrophy, contractile dysfunction, apoptosis, and fibrosis. The progression to HF is associated with a characteristic cascade of altered intracellular signaling and gene expression, representing a final common pathway to ultimate decompensation. The various signaling pathways that underlie pathological hypertrophy and the progression to HF have been the subject of intense investigation and are summarized in multiple review publications.4–9. More recently, considerable attention has been paid to microRNAs (miRNAs), a novel biological control mechanism with the ability to regulate entire molecular networks by complex feedback and feed-forward mechanisms. Several reviews have summarized recent findings implicating miRNAs in cardiac development and disease.10,11 In the past few years, the discovery of circulating miRNAs has led to their investigation as biomarkers and mediators of cell–cell communication. This review focuses on recent developments detailing the role of miRNAs in the pathogenesis of HF, their potential role as biomarkers, and their use as …

Background— Regenerative medicine, including cell therapy, is a promising strategy for recovery of the damaged myocardium. C-kit–positive cardiac stem cells (CSCs) have been shown to improve myocardial function after ischemic injury in animal models and in early clinical experience. We used a chronic large animal model of myocardial infarction with substantial reductions in left-ventricular (LV) ejection fraction and adverse remodeling to examine the effect of late autologous CSC intramyocardial injection on long-term cardiac structure and function. Methods and Results— Thoracotomy and ligation of the proximal left anterior descending artery, additional diagonal branches, and atrial biopsy for CSC culture were performed in canines. Baseline cardiac MRI was performed at 6 weeks postinfarct followed by repeat thoracotomy for randomization to intramyocardial injection of CSCs (n=13) or vehicle alone (n=6). At 30 weeks postmyocardial infarction, repeat MRI was performed. Data were analyzed using nonparametric tests (Wilcoxon signed-rank and rank-sum tests). In control animals, LV end-systolic volume and end-diastolic volume increased from 6 to 30 weeks (median and interquartile range, 51.3 mL [43.3–57.4] to 76.1 mL [72.0–82.4]; P =0.03 and 78.5 mL [69.7–86.1] to 99.2 mL [97.1–100.4]; P =0.03). Left-ventricular ejection fraction declined further (35.2% [27.9–38.7] to 26.4% [22.0–31.0]; P =0.12). In the cell-treated animals, this late adverse LV remodeling was attenuated (LV end-systolic volume, 42.6 mL [38.5–50.5] to 56.1 mL [50.3–63.0]; P =0.01 versus control). There was a nonsignificant attenuation in the increase in LV end-diastolic volume (64.8 mL [60.7–71.3] to 83.5 mL [74.7–90.8]; P =0.14 versus control) and LV ejection fraction change over time differed (30.5% [28.4–33.4] to 32.9% [28.6–36.9]; P =0.04 versus control). Conclusions— Intramyocardial injection of autologous CSCs in a late phase model of chronic infarction resulted in less increase in LV end-systolic volume and preservation of LV ejection fraction.

Background— Elevated resting pulmonary arterial pressure (PAP) in patients with left ventricular systolic dysfunction (LVSD) purports a poor prognosis. However, PAP response patterns to exercise in LVSD and their relationship to functional capacity and outcomes have not been characterized. Methods and Results— Sixty consecutive patients with LVSD (age 60±12 years, left ventricular ejection fraction 0.31±0.07, mean±SD) and 19 controls underwent maximum incremental cardiopulmonary exercise testing with simultaneous hemodynamic monitoring. During low-level exercise (30 W), LVSD subjects, compared with controls, had greater augmentation in mean PAPs (15±1 versus 5±1 mm Hg), transpulmonary gradients (5±1 versus 1±1 mm Hg), and effective pulmonary artery elastance (0.05±0.02 versus −0.03±0.01 mm Hg/mL, P P o 2 (10.6±2.6 versus 13.1±4.0 mL · kg −1 · min −1 , P =0.005), lower right ventricular stroke work index augmentation with exercise (5.7±3.8 versus 9.7±5.0 g/m 2 , P =0.002), and increased mortality (hazard ratio 8.1, 95% CI 2.7 to 23.8, P Conclusions— A steep increment in PAP during exercise and failure to augment PAP throughout exercise are associated with decreased exercise capacity and survival in patients with LVSD, and may therefore represent therapeutic targets. Clinical Trial Information— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00309790.