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

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

The driving force of the Na+/Ca2+-exchanger during metabolic inhibition.

Objective Metabolic inhibition causes a decline in mechanical performance and, if prolonged, myocardial contracture and cell death. The decline in mechanical performance is mainly due to altered intracellular calcium handling, which is under control of the Na+/Ca2+-exchanger (NCX) The driving force of the Na+/Ca2+-exchanger (DGncx) determines the activity of NCX. The aim of this study was to describe the relation between DGncx and calcium homeostasis during metabolic inhibition.Methods In left ventricular rabbit myocytes, during metabolic inhibition (2 mM sodiumcyanide), sodium ([Na+]i), calcium ([Ca2+]i) and action potentials were determined with SBFI, indo-1 and the patch clamp technique. Changes of dGncx were calculated.Results During metabolic inhibition: The first 8 minutes [Na+]i remained constant, systolic calcium decreased from 532±28 to 82±13 nM, diastolic calcium decreased from 121±12 to 36±10 nM and the sarcoplasmic reticulum (SR) calcium content was depleted for 85±3%. After 8 minutes [Na+]i and diastolic calcium started to increase to 30±1.3 mM and 500±31 nM after 30 minutes respectively. The action potential duration shortened biphasically. In the first 5 minutes it shortened from 225±12 to 153±11 ms and remained almost constant until it shortened again after 10 minutes. After 14 minutes action potential and calcium transients disappeared due to unexcitability of the myocytes. This resulted in an increased of the time average of dGncx from 6.2±0.2 to 7.7±0.3 kJ/mol during the first 3 minutes, where after it decreased and became negative after about 15 minutes.Conclusions Metabolic inhibition caused an early increase of Gncx caused by shortening of the action potential. The increase of dGncx contributed to decrease of diastolic calcium, calcium transient amplitude, SR calcium content and contractility. The increase of diastolic calcium started after dGncx became lower than under aerobic conditions

SR calcium handling and calcium after-transients in a rabbit model of heart failure

Objective: After-depolarization associated arrhythmias are frequently observed in heart failure and associated with spontaneous calcium release from sarcoplasmic reticulum (SR), calcium after-transients. We hypothesize that disturbed SR calcium handling underlies calcium after-transients in heart failure (HF). Methods: We measured the stimulation rate dependence (0.2-3 Hz) of diastolic calcium, calcium transient amplitude and SR calcium content in left ventricular myocytes isolated from hearts of rabbits with pressure and volume overload-induced HF and age-matched control animals. Cytosolic calcium was measured with indo-1. In some experiments, delayed after-depolarizations (DADS) were monitored with the voltage sensitive dye di-4-Annepps. SR calcium content was estimated from the response to rapid cooling (RC). After-transients were elicited in the presence of norepinephrine (100 nmol/1) after cessation of burst pacing. Results: With increasing stimulation rate (0.2-3.0 Hz): (1) steady state diastolic [Ca](i) increased from 102 to 174 nmol/1 in HF and from 44 to 103 nmol/l in control, (2) calcium transient amplitudes decreased from 310 to 254 nmol/1 in HF and increased from 186 to 429 nmol/1 in control; (3) SR calcium content decreased from 1.25 to 1.09 mmol/l in HF and increased from 1.51 to 2.48 mmol/l in control, (4) in HF and control, the end diastolic SR membrane calcium gradient decreased by about 30%; at any stimulation rate, the magnitude of gradient in HF was one-third of control, (5) systolic depletion of SR was 85% in HF and 60% in control. In HF, noradrenaline (100 nmol/1) increased SR calcium content and SR membrane gradient by 40% versus about 7% in control. Calcium after-transients were observed in 14 out of 18 HF rabbits, and none in eight control animals and were associated with DADs. Calcium after-transients were associated with a 35% decrease in SR calcium content. The frequency of occurrence of calcium after-transients was related to diastolic calcium. Conclusions: in HF, diastolic calcium is increased and both SR calcium content and SR membrane calcium gradient are decreased in a stimulation rate-dependent manner. In HF, beta-adrenergic stimulation can partly restore the SR calcium content and SR membrane gradient at higher stimulation rates in a meta-stable condition; upon transition to low stimulation rates, the SR membrane can no longer maintain this high unbalanced SR calcium load at increased diastolic calcium, the magnitude of which is causally related to the occurrence of calcium after-transients. (C) 2003 European Society of Cardiology. Published by Elsevier Science B.V. All rights reserve