Calcium dynamics in the failing heart: restoration by β-adrenergic receptor blockade

Abstract

Changes in calcium (Ca2+) regulation contribute to loss of contractile function in dilated cardiomyopathy. Clinical treatment using β-adrenergic receptor antagonists (β-blockers) slows deterioration of cardiac function in end-stage heart failure patients; however, the effects of β-blocker treatment on Ca2+ dynamics in the failing heart are unknown. To address this issue, tropomodulin-overexpressing transgenic (TOT) mice, which suffer from dilated cardiomyopathy, were treated with a nonselective β-receptor blocker (5 mg · kg-1 · day-1 propranolol) for 2 wk. Ca2+ dynamics in isolated cardiomyocytes of TOT mice significantly improved after treatment compared with untreated TOT mice. Frequency-dependent diastolic and Ca2+ transient amplitudes were returned to normal in propranolol-treated TOT mice and but not in untreated TOT mice. Ca2+ kinetic measurements of time to peak and time decay of the caffeine-induced Ca2+ transient to 50% relaxation were also normalized. Immunoblot analysis of untreated TOT heart samples showed a 3.6-fold reduction of sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA), whereas Na+/Ca2+ exchanger (NCX) concentrations were increased 2.6-fold relative to nontransgenic samples. Propranolol treatment of TOT mice reversed the alterations in SERCA and NCX protein levels but not potassium channels. Although restoration of Ca2+ dynamics occurred within 2 wk of β-blockade treatment, evidence of functional improvement in cardiac contractility assessed by echocardiography took 10 wk to materialize. These results demonstrate that β-adrenergic blockade restores Ca2+ dynamics and normalizes expression of Ca2+-handling proteins, eventually leading to improved hemodynamic function in cardiomyopathic hearts.

Dissociation between cardiomyocyte function and remodeling with β-adrenergic receptor blockade in isolated canine mitral regurgitation

“…This may be due to increased myofibrillar content, as previously reported by Carabello and coworkers (18). In addition, ␤ 1 -RB improved Ca 2ϩ transients, a finding that is consistent with studies in chronic dilated cardiomyopathy in humans (6) and in tropomodulin-overexpressing transgenic mice (12), where ␤ 1 -RB restored Ca 2ϩ handling and improved Ca 2ϩ transients in cardiomyocytes from failing hearts. Interestingly, Iso-induced Ca 2ϩ transients did not differ from normal in untreated and ␤ 1 -RB-treated MR dogs.…”

Cardiomyocyte Apoptosis Triggered by RAFTK/pyk2 via Src Kinase Is Antagonized by Paxillin

“…We found overexpression of WT RAFTK/pyk2 caused dramatic changes in myofibril organization consistent with a role in reorganization of focal adhesions and cytoskeleton and demonstrated that RAFTK/pyk2 is activated in dilated cardiomyopathy (7). Chronic elevation of intracellular calcium in cardiomyocytes of failing hearts (8,9) is presumably responsible for RAFTK/pyk2 activation, which then leads to redistribution and altered phosphorylation of paxillin (7).…”

“…The precipitating stimulus of chronically impaired calcium handling promotes maladaptive remodeling via activation of calcium-dependent signaling cascades (4,5) with chronic elevation of calcium influx leading to hypertrophy and heart failure in transgenic mice (6). Earlier work from our group demonstrated activation of related adhesion focal tyrosine kinase (RAFTK, also known as pyk2) signaling in cultured cardiomyocytes treated with ionomycin (7) as well as a murine model of dilated cardiomyopathy exhibiting chronic elevation of intracellular calcium levels (8,9). Concurrent with RAFTK/pyk2 activation, heart samples from cardiomyopathic mice showed enhanced paxillin phosphorylation (7).…”

CaMKII-Dependent Diastolic SR Ca 2+ Leak and Elevated Diastolic Ca 2+ Levels in Right Atrial Myocardium of Patients With Atrial Fibrillation

“…With respect to established pharmacological treatments in AF, our results might explain a part of the antiarrhythmic effect of ␤-blockers, which work upstream of CaMKII and which have been shown to reduce hyperphosphorylation of the RyR2 and reduce SR Ca 2ϩ leak. 45,46 Sources of Funding …”