Background: The prevalence and clinical significance of right ventricular (RV) systolic dysfunction (RVD) in patients with heart failure and preserved EF (HFpEF) are not well characterized. Methods and Results: Consecutive, prospectively identified HFpEF (Framingham HF criteria, EF ≥50%) patients (N=562) from Olmsted County, Minnesota underwent echocardiography at HF diagnosis and follow-up for cause specific mortality and HF hospitalization. RV function was categorized by tertiles of tricuspid annular plane systolic excursion (TAPSE) and by semi-quantitative (normal, mild RVD or moderate-severe RVD) 2D assessment. Whether RVD was defined by semi-quantitative assessment or TAPSE ≤ 15 mm, HFpEF patients with RVD were more likely to have atrial fibrillation, pacemakers and chronic diuretic therapy. At echo, patients with RVD had slightly lower LVEF, worse diastolic dysfunction, lower blood pressure and cardiac output, higher pulmonary artery systolic pressure (PASP), and more severe RV enlargement and tricuspid valve regurgitation. Adjusting for age, sex, PASP and comorbidities, the presence of any RVD by semi-quantitative assessment was associated with higher all-cause (hazard ratio (HR) = 1.35 (1.03-1.77; p=0.03)) and cardiovascular (HR=1.85 (1.20-2.80; p=0.006)) mortality and higher first (HR=1.99 (1.35-2.90; p=0.0006) and multiple (HR=1.81 (1.18-2.78; p=0.007) HF hospitalization rates. RVD defined by TAPSE values showed similar but weaker associations with mortality and HF hospitalizations. Conclusions: In the community, RVD is common in HFpEF patients, associated with clinical and echocardiographic evidence of more advanced HF and predictive of poorer outcomes.

Stimulation of beta-adrenergic receptors (betaARs) causes apoptosis in adult rat ventricular myocytes (ARVMs). The role of reactive oxygen species (ROS) in mediating betaAR-stimulated apoptosis is not known. Stimulation of betaARs with norepinephrine (10 micromol/L) in the presence of prazosin (100 nmol/L) for 24 hours increased the number of apoptotic myocytes as determined by TUNEL staining by 3.6- fold. The superoxide dismutase/catalase mimetics Mn(III)tetrakis(1-methyl-4-pyridyl)porphyrin pentachloride (MnTMPyP; 10 micromol/L) and Euk-134 decreased betaAR-stimulated apoptosis by 89+/-6% and 76+/-10%, respectively. Infection with an adenovirus expressing catalase decreased betaAR-stimulated apoptosis by 82+/-15%. The mitochondrial permeability transition pore inhibitor bongkrekic acid (50 micromol/L) decreased betaAR-stimulated apoptosis by 76+/-8%, and the caspase inhibitor zVAD-fmk (25 micromol/L) decreased betaAR-stimulated apoptosis by 62+/-11%. betaAR-stimulated cytochrome c release was inhibited by MnTMPyP. betaAR stimulation caused c-Jun NH2-terminal kinase (JNK) activation, which was abolished by MnTMPyP. Transfection with an adenovirus expressing dominant-negative JNK inhibited betaAR-stimulated apoptosis by 81+/-12%, and the JNK inhibitor SP600125 inhibited both betaAR-stimulated apoptosis and cytochrome c release. Thus, betaAR-stimulated apoptosis in ARVMs involves ROS/JNK-dependent activation of the mitochondrial death pathway.

Background The Wnt/β-catenin signaling pathway plays a central role during cardiac development and has been implicated in cardiac remodeling and aging. However, the role of Wnt modulators in this process is unknown. In the present study, we examined the role of the Wnt signaling inhibitor sFRP-1 in aged wildtype and sFRP-1 deficient mice. Methods and Results sFRP-1 gene deletion mice were grossly normal with no difference in mortality but developed abnormal cardiac structure and dysfunction with progressive age. Ventricular dilation and hypertrophy in addition to deterioration of cardiac function and massive cardiac fibrosis, all features present in dilated cardiomyopathy was observed in the aged sFRP-1 KO mice when aged. Loss of sFRP-1 led to increased expression of Wnt ligands (Wnt1, 3, 7b, 16) and Wnt target genes (Wisp1, Lef1) in aged hearts, which correlated with increased protein levels of β-Catenin. Cardiac fibroblasts lacking endogenous sFRP-1 showed increased αSMA expression, higher cell proliferation rates and increased collagen production consistent with the cardiac phenotype exhibited in aged sFRP-1 KO mice. The clinical relevance of these findings was supported by the demonstration of decreased sFRP-1 gene expression and increased Wisp-1 levels in the left ventricles of patients with ischemic dilated cardiomyopathy (ICM) and dilated cardiomyopathy (DCM). Conclusions This study identifies a novel role for sFRP-1 in age-related cardiac deterioration and fibrosis. Further exploration of this pathway will identify downstream molecules important in these processes and also suggest the potential use of Wnt signaling agents as therapeutic targets for age-related cardiovascular disorders in humans.

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