A diet rich in unsaturated fatty acids prevents progression toward heart failure in a rabbit model of pressure and volume overload

Background-During heart failure (HF), cardiac metabolic substrate preference changes from fatty acid (FA) toward glucose oxidation. This change may cause progression toward heart failure. We hypothesize that a diet rich in FAs may prevent this process, and that dietary 3-FAs have an added antiarrhythmic effect based on action potential (AP) shortening in animals with HF. Methods and Results-Rabbits were fed a diet containing 1.25% (w/w) high oleic sunflower oil (HF-9, N 11), 1.25% fish oil (HF-3, N11), or no supplement (HF-control, N8). Subsequently, HF was induced by volume and pressure overload. After 4 months, HF-parameters were assessed, electrocardiograms were recorded, and blood and ventricular tissue were collected. Myocytes were isolated for patch clamp or intracellular Ca2-recordings to study electrophysiologic remodeling and arrhythmogenesis. Both the HF-9 and the HF-3 groups had larger myocardial FA oxidation capacity than HF control. The HF-3 group had significantly lower mean ( SEM) relative heart and lung weight (3.3-0.13 and 3.2-0.12 g kg 1, respectively) than HF control (4.8-0.30 and 4.5-0.23), and shorter QTc intervals (167-2.6 versus 182-6.4). The HF-9 also displayed a significantly reduced relative heart weight (3.6-0.26), but had similar QTc (179-4.3) compared with HF control. AP duration in the HF-3 group was 20% shorter due to increased Ito1 and IK1 and triggered activity, and Ca2-aftertransients were less than in the HF-9 group. Conclusions-Dietary unsaturated FAs started prior to induction of HF prevent hypertrophy and HF. In addition, fish oil FAs prevent HF-induced electrophysiologic remodeling and arrhythmias. © 2012 American Heart Association, Inc

RBM20 Mutations Induce an Arrhythmogenic Dilated Cardiomyopathy Related to Disturbed Calcium Handling

BACKGROUND: Mutations in RBM20 (RNA-binding motif protein 20) cause a clinically aggressive form of dilated cardiomyopathy, with an increased risk of malignant ventricular arrhythmias. RBM20 is a splicing factor that targets multiple pivotal cardiac genes, such as Titin (TTN) and CAMK2D (calcium/calmodulin-dependent kinase II delta). Aberrant TTN splicing is thought to be the main determinant of RBM20-induced dilated cardiomyopathy, but is not likely to explain the increased risk of arrhythmias. Here, we investigated the extent to which RBM20 mutation carriers have an increased risk of arrhythmias and explore the underlying molecular mechanism

Effects of dapagliflozin and gliclazide on the cardiorenal axis in people with type 2 diabetes

OBJECTIVES: There is a bidirectional relationship between cardiovascular and renal disease. The drug-class of SGLT2 inhibitors improves outcomes at both ends of this so called cardiorenal axis. We assessed the effects of SGLT2 inhibition and sulfonylurea treatment on systemic hemodynamic function and investigated whether SGLT2 inhibitor-induced changes in systemic hemodynamics correlate with changes in renal hemodynamics. METHODS: Forty-four people with type 2 diabetes were randomized to 12 weeks of dapagliflozin 10 mg/day or gliclazide 30 mg/day treatment. Systemic hemodynamic function, autonomic nervous system activity, and vascular stiffness were measured noninvasively, whereas renal hemodynamics, glomerular filtration rate (GFR) and effective renal plasma flow, were assessed with gold-standard urinary clearances of inulin or iohexol and para-aminohippuric acid, respectively. Correlation analyses were performed to assess relationships between dapagliflozin-induced changes in cardiovascular and renal variables. RESULTS: Dapagliflozin reduced stroke volume by 4%, cardiac output by 5%, vascular stiffness by 11%, and mean arterial pressure by 5% from baseline, without increasing heart rate or sympathetic activity, while simultaneously lowering glomerular filtration rate by 8%. Despite similar improvements in glycemic control by dapagliflozin and gliclazide (-0.5 ± 0.5 versus-0.7 ± 0.5%; P = 0.12), gliclazide did not affect any of these measurements. There was no clear association between the dapagliflozin-induced changes in cardiovascular and renal physiology. CONCLUSION: Dapagliflozin seemingly influences systemic and renal hemodynamics independently and beyond glucose lowering in people with type 2 diabetes.This clinical trial was registered at https://clinicalTrials.gov (ID: NCT02682563)

Orphan nuclear receptor Nur77 affects cardiomyocyte calcium homeostasis and adverse cardiac remodelling

Distinct stressors may induce heart failure. As compensation, β-adrenergic stimulation enhances myocardial contractility by elevating cardiomyocyte intracellular Ca2+ ([Ca2+]i). However, chronic β-adrenergic stimulation promotes adverse cardiac remodelling. Cardiac expression of nuclear receptor Nur77 is enhanced by β-adrenergic stimulation, but its role in cardiac remodelling is still unclear. We show high and rapid Nur77 upregulation in cardiomyocytes stimulated with β-adrenergic agonist isoproterenol. Nur77 knockdown in culture resulted in hypertrophic cardiomyocytes. Ventricular cardiomyocytes from Nur77-deficient (Nur77-KO) mice exhibited elevated diastolic and systolic [Ca2+]i and prolonged action potentials compared to wild type (WT). In vivo, these differences resulted in larger cardiomyocytes, increased expression of hypertrophic genes