Objectives To evaluate the prevalence and prognostic impact of non-cardiac comorbidities in patients with heart failure (HF) with preserved ejection fraction (HFpEF) versus heart failure with reduced ejection fraction (HFrEF). Background There is paucity of information on the comparative prognostic significance of comorbidities between HFpEF and HFrEF patients. Methods In a national ambulatory cohort of Veterans with HF, we compared the comorbidity burden of 15 non-cardiac comorbidities and the impact of these comorbidities on hospitalization and mortality between HFpEF and HFrEF patients. Results The cohort consisted of 2,843 HFpEF and 6,599 HFrEF patients with 2 year follow-up. Compared to HFrEF, HFpEF patients were older and had higher prevalence of chronic obstructive pulmonary disease (COPD), diabetes, hypertension, psychiatric disorders, anemia, obesity, peptic ulcer disease and cancer, but lower prevalence of chronic kidney disease. HFpEF patients had lower HF hospitalization, higher non-HF hospitalization and similar overall hospitalization, compared with HFrEF patients (p<0.001, p<0.001, p=0.19, respectively). Increasing number of non-cardiac comorbidities was associated with higher risk of all-cause admissions (p<0.001). Comorbidities had similar impact on mortality in HFpEF vs. HFrEF patients except for COPD, which was associated with a higher hazard (1.62 [95% CI 1.36-1.92] vs. 1.23 [95% CI 1.11, 1.37], respectively; p=0.01 for interaction) in HFpEF patients. Conclusions There is a higher non-cardiac comorbidity burden associated with higher non-HF hospitalizations in HFpEF compared to HFrEF patients. However, individually, most comorbidities have similar impact on mortality in both groups. Aggressive management of comorbidities may have an overall greater prognostic impact in HFpEF compared to HFrEF.

Objectives To study the role of junctophilin 2 (JPH2) in atrial fibrillation (AF). Background JPH2 is believed to have an important role in sarcoplasmic reticulum (SR) Ca2+ handling and modulation of ryanodine receptor Ca2+ channels (RyR2). Whereas defective RyR2-mediated Ca2+ release contributes to the pathogenesis of AF, nothing is known about the potential role of JPH2 in atrial arrhythmias. Methods Screening 203 unrelated hypertrophic cardiomyopathy patients uncovered a novel JPH2 missense mutation (E169K) in 2 patients with juvenile-onset paroxysmal AF (pAF). Pseudo-knockin (PKI) mouse models were generated to determine the molecular defects underlying the development of AF caused by this JPH2 mutation. Results PKI mice expressing E169K mutant JPH2 exhibited a higher incidence of inducible AF compared with wildtype (WT)-PKI mice, while A399S-PKI mice expressing a HCM-linked JPH2 mutation not associated with atrial arrhythmias were not significantly different from WT-PKI. E169K-PKI but not A399A-PKI atrial cardiomyocytes showed an increased incidence of abnormal SR Ca2+ release events. These changes were attributed to reduced binding of E169KJPH2 to RyR2. Atrial JPH2 levels in WT-JPH2 transgenic, nontransgenic, and JPH2 knockdown mice correlated negatively with the incidence of pacing-induced AF. Ca2+ spark frequency in atrial myocytes and the open probability of single RyR2 channels from JPH2 knockdown mice was significantly reduced by a small JPH2-mimicking oligopeptide. Moreover, patients with pAF had reduced atrial JPH2 levels per RyR2 channel compared to sinus rhythm patients, and an increased frequency of spontaneous Ca2+ release events. Conclusions Our data suggest a novel mechanism by which reduced JPH2-mediated stabilization of RyR2 due to loss-of-function mutation or reduced JPH2:RyR2 ratios can promote SR Ca2+ leak and atrial arrhythmias, representing a potential novel therapeutic target for AF.

SUMMARY Atria and ventricles exhibit distinct molecular profiles that produce structural and functional differences between the two cardiac compartments. However, factors that determine these differences remain largely undefined. Cardiomyocyte-specific COUP-TFII ablation produces ventricularized atria that exhibit ventricle-like action potentials, increased cardiomyocyte size, and development of extensive T-tubules. Changes in atrial characteristics are accompanied by alterations of 2584 genes, in which 81% of them were differentially expressed between atria and ventricles, suggesting that a major function of myocardial COUP-TFII is to determine the atrial identity. Chromatin immunoprecipitation assays using E13.5 atria identified classic atrial-ventricular identity genes Tbx5, Hey2, Irx4, MLC2v, MLC2a and MLC1a, among many other cardiac genes, as potential COUP-TFII direct targets. Collectively, our results reveal that COUP-TFII confers the atrial identity through direct binding and modulating expression of a broad spectrum of genes that have an impact on atrial development and function.

Background The progression of atrial fibrillation (AF) from paroxysmal to persistent forms remains a major clinical challenge. Abnormal sarcoplasmic reticulum (SR) Ca2+-leak via the ryanodine receptor (RyR2) has been observed as a source of ectopic activity in various AF models. However, its potential role in progression to long-lasting spontaneous AF (sAF) has never been tested. This study tested the hypothesis that enhanced RyR2-mediated Ca2+-release underlies the development of a substrate for sAF and to understand the underlying mechanisms. Methods and Results CREM-IbΔC-X transgenic (CREM)-mice developed age-dependent progression from spontaneous atrial ectopy to paroxysmal and eventually long-lasting AF. The development of sAF in CREM-mice was preceded by enhanced diastolic Ca2+-release, atrial enlargement and marked conduction abnormalities. Genetic inhibition of CaMKII-mediated RyR2-S2814 phosphorylation in CREM-mice normalized open probability of RyR2-channels and SR Ca2+-release, delayed the development of spontaneous atrial ectopy, fully prevented sAF, suppressed atrial dilation and forestalled atrial conduction-abnormalities. Hyperactive RyR2-channels directly stimulated the Ca2+-dependent hypertrophic pathway NFAT/Rcan1-4, suggesting a role for the NFAT/Rcan1-4 system in the development of a substrate for long-lasting AF in CREM mice. Conclusions RyR2-mediated SR Ca2+-leak directly underlies the development of a substrate for sAF in CREM-mice, the first demonstration of a molecular mechanism underlying AF-progression and sAF substrate development in an experimental model. Our work demonstrates that the role of abnormal diastolic Ca2+ release in AF may not be restricted to the generation of atrial ectopy, but extends to the development of atrial remodeling underlying the AF substrate.

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Beta-blockers are established drugs in heart failure with reduced ejection fraction, but their role in heart failure with preserved ejection fraction (HFpEF) is not established. Hence, we undertook a meta-analysis to evaluate the efficacy of beta-blockers on mortality and morbidity in HFpEF patients. A systematic search using PubMed, Embase, Scopus and Cochrane databases was performed to identify all relevant studies on beta-blockers and HFpEF. A random-effects model was performed to assess the role of beta-blockers on all-cause mortality and HF hospitalization. Overall 15 observational studies and two randomized control trial involving a total of 27,099 patients were included in the analysis. In the observational studies, beta-blocker therapy was associated with lower all-cause mortality [RR 0.81 (0.72-0.90), p < 0.001], but not HF hospitalization [RR 0.79 (0.57-1.10), p < 0.001]. However, in the two RCTs, the use of beta-blocker was not associated with all-cause mortality [RR 0.94 (0.67-1.32), p = 0.72] or HF hospitalization [0.90 (0.54-1.49), p = 0.68]. The results were consistent by geographic region (USA vs. rest of world) and ejection fraction subgroups. Subgroup analysis revealed that the beneficial survival effect of beta-blocker was limited to studies with mean age <75 years. Observational studies showed a significant benefit from the use of beta-blockers for all-cause mortality, but not for HF hospitalization. Beta-blockers in the two RCTs were not associated with significant reduction in all-cause mortality or HF hospitalization; however, both the trials were not adequately powered and had high loss to follow-up rates. Further large sampled well-conducted randomized trials are warranted to confirm the effects of beta-blockers on mortality and hospitalization.

BACKGROUND Although obesity is an independent risk factor for heart failure (HF), once HF is established, obesity is associated with lower mortality. It is unclear if the weight loss due to advanced HF leads to this paradoxical finding. OBJECTIVES We sought to evaluate the prognostic impact of pre-morbid obesity in patients with HF. METHODS In the Atherosclerosis Risk in Communities (ARIC) study, we used body mass index (BMI) measured ≥6 months before incident HF (pre-morbid BMI) to evaluate the association of overweight (BMI 25 to <30 kg/m2) and obesity (≥30 kg/m2) compared to normal BMI (18.5 to <25 kg/m2) with mortality after incident HF. RESULTS Among 1,487 patients with incident HF, 35% were overweight and 47% were obese by pre-morbid BMI measured 4.3 ± 3.1 years before HF diagnosis. Over 10-year follow-up after incident HF, 43% of patients died. After adjustment for demographics and comorbidities, being premorbidly overweight (hazard ratio [HR]: 0.72; 95% confidence interval [CI[]: 0.58 to 0.90; p = 0.004) or obese (HR: 0.70; 95% CI: 0.56 to 0.87; p = 0.001) had a protective association with survival compared to normal BMI. The protective effect of overweight and obesity was consistent across subgroups based on a history of cancer, smoking, and diabetes. CONCLUSIONS Our results, for the first time, demonstrate that individuals who were overweight or obese before HF development have lower mortality once they have HF compared with normal BMI individuals. Thus, weight loss due to advanced HF may not completely explain the protective effect of higher BMI in HF patients.

Background Ventricular tachycardia (VT) is the second most common cause of death in patients with Duchenne muscular dystrophy (DMD). Recent studies have implicated enhanced sarcoplasmic reticulum (SR) Ca2+ leak via ryanodine receptors (RyR2) as a cause of VT in the mdx mouse model of DMD. However, the signaling mechanisms underlying induction of SR Ca2+ leak and VT are poorly understood. Objective To test whether enhanced CaMKII phosphorylation of RyR2 underlies SR Ca2+ leak and induction of VT in mdx mice. Methods Programmed electrical stimulation (PES) was performed on anesthetized mice, and confocal imaging of calcium release events in isolated ventricular myocytes. Results PES revealed inducible VT in mdx mice, which was inhibited by CaMKII inhibition or mutation S2814A in RyR2. Myocytes from mdx mice exhibited more Ca2+ sparks and Ca2+ waves compared with wild type (WT) mice, in particular at faster pacing rates. Arrhythmogenic Ca2+ waves were inhibited by CaMKII but not PKA inhibition. Moreover, mutation S2814A but not S2808A in RyR2 suppressed spontaneous Ca2+ waves in myocytes from mdx mice. Conclusion CaMKII blockade and genetic inhibition of RyR2-S2814 phosphorylation prevent VT induction in a mouse model of DMD. In ventricular myocytes from mdx mice, spontaneous Ca2+ sparks and Ca2+ waves can be suppressed by CaMKII inhibition or mutation S2814A in RyR2. Thus, inhibition of CaMKII-induced SR Ca2+ leak might be a new strategy to prevent arrhythmias in patients with DMD without heart failure.