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Aims CONCERT‐HF is an NHLBI‐sponsored, double‐blind, placebo‐controlled, Phase II trial designed to determine whether treatment with autologous bone marrow‐derived mesenchymal stromal cells (MSCs) and c‐kit positive cardiac cells (CPCs), given alone or in combination, is feasible, safe, and beneficial in patients with heart failure (HF) caused by ischaemic cardiomyopathy. Methods and results Patients were randomized (1:1:1:1) to transendocardial injection of MSCs combined with CPCs, MSCs alone, CPCs alone, or placebo, and followed for 12 months. Seven centres enrolled 125 participants with left ventricular ejection fraction of 28.6 ± 6.1% and scar size 19.4 ± 5.8%, in New York Heart Association class II or III. The proportion of major adverse cardiac events (MACE) was significantly decreased by CPCs alone (−22% vs. placebo, P = 0.043). Quality of life (Minnesota Living with Heart Failure Questionnaire score) was significantly improved by MSCs alone (P = 0.050) and MSCs + CPCs (P = 0.023) vs. placebo. Left ventricular ejection fraction, left ventricular volumes, scar size, 6‐min walking distance, and peak oxygen consumption did not differ significantly among groups. Conclusions This is the first multicentre trial assessing CPCs and a combination of two cell types from different tissues in HF patients. The results show that treatment is safe and feasible. Even with maximal guideline‐directed therapy, both CPCs and MSCs were associated with improved clinical outcomes (MACE and quality of life, respectively) in ischaemic HF without affecting left ventricular function or structure, suggesting possible systemic or paracrine cellular mechanisms. Combining MSCs with CPCs was associated with improvement in both these outcomes. These results suggest potential important beneficial effects of CPCs and MSCs and support further investigation in HF patients.

Endothelial dysfunction is characterized by nitric oxide dysregulation and an altered redox state. Oxidative stress and inflammatory markers prevail, thus promoting atherogenesis and hypertension, important risk factors for the development and progression of heart failure. There has been a reemerging interest in the role that endothelial dysfunction plays in the failing circulation. Accordingly, patients with heart failure are being clinically assessed for endothelial dysfunction via various methods, including flow-mediated vasodilation, peripheral arterial tonometry, quantification of circulating endothelial progenitor cells, and early and late endothelial progenitor cell outgrowth measurements. Although the mechanisms underlying endothelial dysfunction are intimately related to cardiovascular disease and heart failure, it remains unclear whether targeting endothelial dysfunction is a feasible strategy for ameliorating heart failure progression. This review focuses on the pathophysiology of endothelial dysfunction, the mechanisms linking endothelial dysfunction and heart failure, and the various diagnostic methods currently used to measure endothelial function, ultimately highlighting the therapeutic implications of targeting endothelial dysfunction for the treatment of heart failure.

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Therapies for heart failure with preserved ejection fraction (HFpEF) are lacking. Growth hormone-releasing hormone agonists (GHRH-As) have salutary effects in ischemic and nonischemic heart failure animal models. Accordingly, we hypothesized that GHRH-A treatment ameliorates chronic kidney disease (CKD)-induced HFpEF in a large-animal model. Female Yorkshire pigs (n = 16) underwent 5/6 nephrectomy via renal artery embolization and 12 wk later were randomized to receive daily subcutaneous injections of GHRH-A (MR-409; n = 8; 30 µg/kg) or placebo (n = 8) for 4 to 6 wk. Renal and cardiac structure and function were serially assessed postembolization. Animals with 5/6 nephrectomy exhibited CKD (elevated blood urea nitrogen [BUN] and creatinine) and faithfully recapitulated the hemodynamic features of HFpEF. HFpEF was demonstrated at 12 wk by maintenance of ejection fraction associated with increased left ventricular mass, relative wall thickness, end-diastolic pressure (EDP), end-diastolic pressure/end-diastolic volume (EDP/EDV) ratio, and tau, the time constant of isovolumic diastolic relaxation. After 4 to 6 wk of treatment, the GHRH-A group exhibited normalization of EDP (P = 0.03), reduced EDP/EDV ratio (P = 0.018), and a reduction in myocardial pro-brain natriuretic peptide protein abundance. GHRH-A increased cardiomyocyte [Ca2+] transient amplitude (P = 0.009). Improvement of the diastolic function was also evidenced by increased abundance of titin isoforms and their ratio (P = 0.0022). GHRH-A exerted a beneficial effect on diastolic function in a CKD large-animal model as demonstrated by improving hemodynamic, structural, and molecular characteristics of HFpEF. These findings have important therapeutic implications for the HFpEF syndrome.