Showing papers by "Niels Voigt published in 2012"
TL;DR: Enhanced SR Ca2+ leak through CaMKII-hyperphosphorylated RyR2, in combination with larger INCX for a given SR Ca 2+ release and increased diastolic [Ca2+]i-voltage coupling gain, causes AF-promoting atrial delayed afterdepolarizations/triggered activity in cAF patients.
Abstract: Background—Delayed afterdepolarizations (DADs) carried by Na+-Ca2+-exchange current (INCX) in response to sarcoplasmic reticulum (SR) Ca2+ leak can promote atrial fibrillation (AF). The mechanisms leading to delayed afterdepolarizations in AF patients have not been defined. Methods and Results—Protein levels (Western blot), membrane currents and action potentials (patch clamp), and [Ca2+]i (Fluo-3) were measured in right atrial samples from 76 sinus rhythm (control) and 72 chronic AF (cAF) patients. Diastolic [Ca2+]i and SR Ca2+ content (integrated INCX during caffeine-induced Ca2+ transient) were unchanged, whereas diastolic SR Ca2+ leak, estimated by blocking ryanodine receptors (RyR2) with tetracaine, was ≈50% higher in cAF versus control. Single-channel recordings from atrial RyR2 reconstituted into lipid bilayers revealed enhanced open probability in cAF samples, providing a molecular basis for increased SR Ca2+ leak. Calmodulin expression (60%), Ca2+/calmodulin-dependent protein kinase-II (CaMKII) a...
525 citations
TL;DR: TRPC3 channels regulate cardiac fibroblast proliferation and differentiation, likely by controlling the Ca2+ influx that activates extracellular signal-regulated kinase signaling and is a novel potential therapeutic target.
Abstract: Background—Fibroblast proliferation and differentiation are central in atrial fibrillation (AF)–promoting remodeling. Here, we investigated fibroblast regulation by Ca2+-permeable transient receptor potential canonical-3 (TRPC3) channels. Methods and Results—Freshly isolated rat cardiac fibroblasts abundantly expressed TRPC3 and had appreciable nonselective cation currents (INSC) sensitive to a selective TPRC3 channel blocker, pyrazole-3 (3 μmol/L). Pyrazole-3 suppressed angiotensin II–induced Ca2+ influx, proliferation, and α-smooth muscle actin protein expression in fibroblasts. Ca2+ removal and TRPC3 blockade suppressed extracellular signal-regulated kinase phosphorylation, and extracellular signal-regulated kinase phosphorylation inhibition reduced fibroblast proliferation. TRPC3 expression was upregulated in atria from AF patients, goats with electrically maintained AF, and dogs with tachypacing-induced heart failure. TRPC3 knockdown (based on short hairpin RNA [shRNA]) decreased canine atrial fibrob...
222 citations
TL;DR: The results suggest that increased CaMKII phosphorylation of RyR2 plays a role in the development of pathological sarcoplasmic reticulum Ca2+ leak and HF development in nonischemic forms of HF such as transverse aortic constriction in mice.
Abstract: Rationale: Increased activity of Ca 2+ /calmodulin-dependent protein kinase II (CaMKII) is thought to promote heart failure (HF) progression. However, the importance of CaMKII phosphorylation of ryanodine receptors (RyR2) in HF development and associated diastolic sarcoplasmic reticulum Ca 2+ leak is unclear. Objective: Determine the role of CaMKII phosphorylation of RyR2 in patients and mice with nonischemic and ischemic forms of HF. Methods and Results: Phosphorylation of the primary CaMKII site S2814 on RyR2 was increased in patients with nonischemic, but not with ischemic, HF. Knock-in mice with an inactivated S2814 phosphorylation site were relatively protected from HF development after transverse aortic constriction compared with wild-type littermates. After transverse aortic constriction, S2814A mice did not exhibit pulmonary congestion and had reduced levels of atrial natriuretic factor. Cardiomyocytes from S2814A mice exhibited significantly lower sarcoplasmic reticulum Ca 2+ leak and improved sarcoplasmic reticulum Ca 2+ loading compared with wild-type mice after transverse aortic constriction. Interestingly, these protective effects on cardiac contractility were not observed in S2814A mice after experimental myocardial infarction. Conclusions: Our results suggest that increased CaMKII phosphorylation of RyR2 plays a role in the development of pathological sarcoplasmic reticulum Ca 2+ leak and HF development in nonischemic forms of HF such as transverse aortic constriction in mice.
197 citations
TL;DR: Genetic inhibition of RyR2-S2814 phosphorylation prevents AF induction in FKBP12.6−/− mice by suppressing SR Ca2+ leak and DADs, which promote triggered activity.
Abstract: Rationale:Abnormal calcium release from sarcoplasmic reticulum (SR) is considered an important trigger of atrial fibrillation (AF). Whereas increased Ca2+/calmodulin-dependent protein kinase II (CaMKII) activity has been proposed to contribute to SR leak and AF induction, downstream targets of CaMKII remain controversial. Objective:To test the hypothesis that inhibition of CaMKII-phosphorylated type-2 ryanodine receptors (RyR2) prevents AF initiation in FKBP12.6-deficient (−/−) mice. Methods and Results:Mice lacking RyR2-stabilizing subunit FKBP12.6 had a higher incidence of spontaneous and pacing-induced AF compared with wild-type mice. Atrial myocytes from FKBP12.6−/− mice exhibited spontaneous Ca2+ waves (SCaWs) leading to Na+/Ca2+-exchanger activation and delayed afterdepolarizations (DADs). Mutation S2814A in RyR2, which inhibits CaMKII phosphorylation, reduced Ca2+ spark frequency, SR Ca2+ leak, and DADs in atrial myocytes from FKBP12.6−/−:S2814A mice compared with FKBP12.6−/− mice. Moreover, FKBP12...
133 citations
TL;DR: The causes, consequences, and therapeutic implications of altered atrial Ca2+ handling for AF pathophysiology are reviewed.
Abstract: Atrial fibrillation (AF) is the most prevalent sustained cardiac arrhythmia in the clinical setting. It is associated with substantial cardiovascular morbidity and mortality. Recent research has indicated that abnormal Ca(2+) handling plays a critical role in the induction and maintenance of AF, contributing to ectopic activity, AF-maintaining reentry circuits and related prothrombotic atrial hypocontractility. The AF-specific Ca(2+)-handling abnormalities may constitute viable therapeutic approaches to treat AF. Here, we review the causes, consequences, and therapeutic implications of altered atrial Ca(2+) handling for AF pathophysiology.
22 citations
TL;DR: The recent evidence for a role of cellular ectopic activity in human AF pathophysiology is reviewed, the molecular mechanisms underlying triggered activity inhuman atrial myocytes are discussed, and their relevance to the design of novel therapeutic options are considered.
Abstract: Atrial fibrillation (AF) is the most frequent arrhythmia and is associated with increased morbidity and mortality. Current drugs for AF treatment have limited efficacy and a substantial risk of proarrhythmic side effects, making novel drug development critical. Emerging evidence suggests that abnormal intracellular calcium (Ca(2+)) signalling is a key contributor to ectopic (triggered) electrical activity in human AF. Accordingly, atrial Ca(2+)-handling abnormalities underlying ectopic activity may constitute novel mechanism-based therapeutic approaches to treat AF. This article reviews the recent evidence for a role of cellular ectopic activity in human AF pathophysiology, discusses the molecular mechanisms underlying triggered activity in human atrial myocytes, and considers their relevance to the design of novel therapeutic options.
16 citations
TL;DR: Physiological Ca(2+) cycling mechanisms in atrial cardiomyocytes are described and fundamental cellular proarrhythmic mechanisms involving Ca( 2+) signaling abnormalities in the atrium during atrial fibrillation are related.
Abstract: During the last decades Ca2+ has been found to play a crucial role in cardiac arrhythmias associated with heart failure and a number of congenital arrhythmia syndromes. Recent studies demonstrated that altered atrial Ca2+ cycling may promote the initiation and maintenance of atrial fibrillation, the most common clinical arrhythmia that contributes significantly to population morbidity and mortality. This article describes physiological Ca2+ cycling mechanisms in atrial cardiomyocytes and relates them to fundamental cellular proarrhythmic mechanisms involving Ca2+ signaling abnormalities in the atrium during atrial fibrillation.
13 citations