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Cardiovascular research 04/2013; · 5.80 Impact Factor
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Eduard Guasch,
Begoña Benito,
Xiaoyan Qi,
Carlo Cifelli,
Patrice Naud,
Yanfen Shi,
Alexandra Mighiu,
Jean-Claude Tardif,
Artavazd Tadevosyan,
Yu Chen,
Marc-Antoine Gillis,
Yu-Ki Iwasaki, Dobromir Dobrev,
Lluis Mont,
Scott Heximer,
Stanley Nattel
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ABSTRACT: OBJECTIVES: To assess mechanisms underlying atrial fibrillation (AF)-promotion by exercise-training in an animal model. BACKGROUND: High-level exercise-training promotes AF, but underlying mechanisms are unclear. METHODS: AF-susceptibility was assessed by programmed stimulation in rats after 8 (Ex8) and 16 weeks (Ex16) of daily 1-hour treadmill training, along with 4 (DEx4) and 8 weeks (DEx8) after exercise-cessation and time-matched sedentary (Sed) controls. Structural remodeling was evaluated by serial echocardiography and histopathology, autonomic nervous-system with pharmacological tools, acetylcholine-regulated K(+)-current (IKACh) with patch-clamp recording, mRNA-expression with qPCR and RGS4-function in knockout (KO)-mice. RESULTS: AF-inducibility increased after 16 weeks of training (e.g. AF>30 seconds in 64% Ex16 vs 15% Sed rats (p<0.01), and returned to baseline-levels rapidly with detraining. Atropine restored sinus rhythm in 5/5 Ex rats with AF sustained>15 minutes. Atrial dilation and fibrosis developed after 16-week training, and failed to fully-recover with exercise-cessation. Parasympathetic tone was increased in Ex16-rats, and normalized within 4 weeks of detraining. Baroreflex heart-rate responses to phenylephrine-induced blood-pressure elevation and IKACh sensitivity to carbachol were enhanced in Ex16, implicating both central and end-organ mechanisms in vagal-enhancement. Ex-rats showed unchanged cardiac adrenergic and cholinergic receptor and IKACh-subunit gene-expression, but significant mRNA-downregulation of IKACh-inhibiting RGS-proteins, at 16 weeks. RGS4 KO-mice showed significantly enhanced sensitivity to AF-induction in the presence of carbachol. CONCLUSIONS: Chronic endurance-exercise increases AF-susceptibility in rats, with autonomic changes, atrial dilation and fibrosis identified as potential contributors. Vagal promotion is particularly important, and occurs via augmented baroreflex-responsiveness and increased cardiomyocyte-sensitivity to cholinergic stimulation, possibly due to RGS-protein downregulation.
Journal of the American College of Cardiology 04/2013; · 14.16 Impact Factor
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Archiv für Experimentelle Pathologie und Pharmakologie 04/2013; · 2.65 Impact Factor
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ABSTRACT: Shortened action-potential duration (APD) and blunted APD rate adaptation are hallmarks of chronic atrial fibrillation (cAF). Basal and muscarinic (M)-receptor-activated inward-rectifier K(+) currents (IK1 and IK,ACh, respectively) contribute to regulation of human atrial APD and are subject to cAF-dependent remodeling. Intracellular Na(+) ([Na(+)]i) enhances IK,ACh in experimental models but the effect of Na(+)-dependent regulation of inward-rectifier K(+) currents on APD in human atrial myocytes is currently unknown. Here, we report a [Na(+)]i-dependent inhibition of outward IK1 in atrial myocytes from sinus rhythm (SR) or cAF patients. In contrast, IK,ACh activated by carbachol, a non-selective M-receptor agonist, increased with elevation of [Na(+)]i in SR. This [Na(+)]i-dependent IK,ACh regulation was absent in cAF. Including [Na(+)]i dependence of IK1 and IK,ACh in a recent computational model of the human atrial myocyte revealed that [Na(+)]i accumulation at fast rates inhibits IK1 and blunts physiological APD rate dependence in both groups. [Na(+)]i-dependent IK,ACh augmentation at fast rates increased APD rate dependence in SR, but not in cAF. These results identify impaired Na(+)-sensitivity of IK,ACh as one potential mechanism contributing to the blunted APD rate dependence in patients with cAF.
Journal of Molecular and Cellular Cardiology 03/2013; · 5.17 Impact Factor
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Kristin Dawson,
Reza Wakili,
Balázs Ordög,
Sebastian Clauss,
Yu Chen,
Yuki Iwasaki,
Niels Voigt,
Xiao Yan Qi,
Moritz F Sinner, Dobromir Dobrev,
Stefan Kääb,
Stanley Nattel
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ABSTRACT: BACKGROUND: Congestive heart failure (CHF) causes atrial fibrotic remodeling, a substrate for atrial fibrillation (AF)-maintenance. MicroRNA (miR)-29 targets extracellular-matrix (ECM) proteins. Here, we studied miR29b-changes in patients with AF and/or CHF and in a CHF related AF animal model, and assessed its potential role in controlling atrial fibrous-tissue production. METHODS AND RESULTS: Control dogs were compared with dogs subjected to ventricular tachypacing for 24 hours, 1 week or 2 weeks to induce CHF. Atrial miR29b-expression decreased within 24 hours in both whole atrial-tissue and atrial fibroblasts (-87%***, -92%*** vs. control respectively; ***P<0.001), and remained decreased throughout the time-course. Expression of miR29b ECM target-genes collagen-1A1 (COL1A1), collagen-3A1 (COL3A1), and fibrillin increased significantly in CHF-fibroblasts. Lentivirus-mediated miR29b knockdown in canine atrial fibroblasts (-68%**, **P<0.01) enhanced COL1A1, COL3A1 and fibrillin mRNA expression by 28%**, 19%* (*P<0.05) and 20%* respectively versus empty-virus-infected fibroblasts and increased COL1A1 protein expression by 90%*. In contrast, 3-fold overexpression of miR29b decreased COL1A1, COL3A1 and fibrillin mRNA by 65%***, 62%*** and 61%*** respectively versus scrambled control and COL1A1 protein by 60%*. MiR29b plasma-levels were decreased in patients with CHF or AF (by 53%***, 54%*** respectively) and were further decreased in patients with both AF and CHF (by 84%***). MiR29b-expression was also reduced in the atria of chronic-AF patients (by 54%* vs. sinus rhythm). Adenoasssociated-viral mediated knockdown of miR29b in mice significantly increased atrial COL1A1 mRNA-expression and cardiac-tissue collagen-content. CONCLUSIONS: MiR29 likely plays a role in atrial fibrotic remodeling, and might have value as a biomarker and/or therapeutic target.
Circulation 03/2013; · 14.74 Impact Factor
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ABSTRACT: The implantable cardioverter-defibrillator significantly improves survival in patients with malignant ventricular arrhythmias but does not target the underlying pathological substrate responsible for arrhythmic events. A significant proportion of defibrillator recipients experience multiple ventricular tachycardia/fibrillation episodes over a short period of time, termed electrical storm (ES). The current therapeutic strategy for ES is complex and unsatisfactory because simultaneous administration of several medications and additional invasive procedures are often required to control ES. Moreover, this treatment does not favorably influence the long-term outcome. Clearly, improved ES therapies are necessary and desirable, but a lack of understanding of the pathophysiological mechanisms underlying ES has hindered the development of more effective, rationally based therapeutic approaches. This paper reviews emerging experimental and clinical findings that provide insights into the pathophysiology of ES and discusses mechanism-based innovative therapeutic strategies.
Archiv für Kreislaufforschung 03/2013; 108(2):336. · 7.35 Impact Factor
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ABSTRACT: Intravenous vernakalant has recently been approved in Europe as an atrial-selective antiarrhythmic drug for the conversion of recent-onset atrial fibrillation (AF). It inhibits atrial-selective K(+) currents (IK,ACh and IKur) and causes rate-dependent atrial-predominant Na(+) channel block, with only a small inhibitory effect on the rapid delayed rectifier K(+) current (IKr) in the ventricle. Due to its atrial-selective properties, vernakalant prolongs the effective refractory period of the atria with minimal effects on the ventricles, being associated with a low proarrhythmic risk for torsades de pointes arrhythmias. Five pivotal clinical trials consistently demonstrated that vernakalant rapidly terminates AF with stable maintenance of sinus rhythm for up to 24 hours. A head-to-head comparative trial showed that the 90-minute conversion rate of vernakalant was substantially higher than that of amiodarone. Initially, a longer-acting oral formulation of vernakalant was shown to be effective and safe in preventing AF recurrence after cardioversion in a Phase IIb study. However, the clinical studies testing oral vernakalant for maintenance of sinus rhythm after AF cardioversion were prematurely halted for undisclosed reasons. This review article provides an update on the safety and efficacy of intravenous vernakalant for the rapid cardioversion of AF.
Vascular Health and Risk Management 01/2013; 9:165-75.
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ABSTRACT: Atrial fibrillation (AF) is the most prevalent cardiac arrhythmia and has a significant impact on morbidity and mortality. Current antiarrhythmic drugs for AF suffer from limited safety and efficacy, probably because they were not designed based on specific pathological mechanisms. Recent research has provided important insights into the mechanisms contributing to AF and highlighted several potential novel antiarrhythmic strategies. In this review, we highlight the main pathological mechanisms of AF, discuss traditional and novel aspects of atrial antiarrhythmic drugs in relation to these pathological mechanisms, and present potential novel therapeutic approaches including structure-based modulation of atrial-specific cardiac ion channels, restoring abnormal Ca(2+) handling in AF and targeting atrial remodeling.
Future Cardiology 01/2013; 9(1):71-88.
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Heart rhythm: the official journal of the Heart Rhythm Society 12/2012; · 4.56 Impact Factor
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ABSTRACT: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is caused by mutations in the genes encoding the cardiac ryanodine receptor channel (RyR2) or the major sarcoplasmic reticulum (SR) Ca(2+) buffer calsequestrin-2 (Casq2) (Leenhardt et al., 2012). Traditionally, CPVT has been described as a bi-directional or polymorphic ventricular arrhythmia occurring during conditions of increased sympathetic tone, which may originate from ectopic activity due to abnormal (sub)cellular Ca(2+) handling (Leenhardt et al., 2012). Recent studies, however, have suggested that CPVT mutations in RyR2 are also associated with atrial arrhythmias. In this edition of Acta Physiologica, King et al. (King et al., 2012) show for the first time that atria from mice homozygous for the CPVT-associated mutation P2328S in RyR2 (RyR2(S/S) ) have a reduced conduction velocity (CV) and lower maximum rates of action potential (AP) upstroke velocity compared to wild-type (WT) mice. Moreover, these parameters correlated strongly with arrhythmia susceptibility suggesting a potential novel arrhythmogenic mechanism due to RyR2 mutations. © 2012 The Authors Acta Physiologica © 2012 Scandinavian Physiological Society.
Acta Physiologica 11/2012; · 3.09 Impact Factor
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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.
Europace 11/2012; 14 Suppl 5:v97-v105. · 1.98 Impact Factor
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Masahide Harada,
Xiaobin Luo,
Xiao Yan Qi,
Artavazd Tadevosyan,
Ange Maguy,
Balazs Ordog,
Jonathan Ledoux,
Takeshi Kato,
Patrice Naud,
Niels Voigt,
Yanfen Shi,
Kaichiro Kamiya,
Toyoaki Murohara,
Itsuo Kodama,
Jean-Claude Tardif,
Ulrich Schotten,
David R Van Wagoner, Dobromir Dobrev,
Stanley Nattel
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ABSTRACT: Fibroblast proliferation and differentiation are central in atrial fibrillation (AF)-promoting remodeling. Here, we investigated fibroblast regulation by Ca(2+)-permeable transient receptor potential canonical-3 (TRPC3) channels.
Freshly isolated rat cardiac fibroblasts abundantly expressed TRPC3 and had appreciable nonselective cation currents (I(NSC)) sensitive to a selective TPRC3 channel blocker, pyrazole-3 (3 μmol/L). Pyrazole-3 suppressed angiotensin II-induced Ca(2+) influx, proliferation, and α-smooth muscle actin protein expression in fibroblasts. Ca(2+) 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 fibroblast proliferation. In left atrial fibroblasts freshly isolated from dogs kept in AF for 1 week by atrial tachypacing, TRPC3 protein expression, currents, extracellular signal-regulated kinase phosphorylation, and extracellular matrix gene expression were all significantly increased. In cultured left atrial fibroblasts from AF dogs, proliferation rates, α-smooth muscle actin expression, and extracellular signal-regulated kinase phosphorylation were increased and were suppressed by pyrazole-3. MicroRNA-26 was downregulated in canine AF atria; experimental microRNA-26 knockdown reproduced AF-induced TRPC3 upregulation and fibroblast activation. MicroRNA-26 has NFAT (nuclear factor of activated T cells) binding sites in the 5' promoter region. NFAT activation increased in AF fibroblasts, and NFAT negatively regulated microRNA-26 transcription. In vivo pyrazole-3 administration suppressed AF while decreasing fibroblast proliferation and extracellular matrix gene expression.
TRPC3 channels regulate cardiac fibroblast proliferation and differentiation, likely by controlling the Ca(2+) influx that activates extracellular signal-regulated kinase signaling. AF increases TRPC3 channel expression by causing NFAT-mediated downregulation of microRNA-26 and causes TRPC3-dependent enhancement of fibroblast proliferation and differentiation. In vivo, TRPC3 blockade prevents AF substrate development in a dog model of electrically maintained AF. TRPC3 likely plays an important role in AF by promoting fibroblast pathophysiology and is a novel potential therapeutic target.
Circulation 09/2012; 126(17):2051-64. · 14.74 Impact Factor
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ABSTRACT: Large-conductance, calcium- and voltage-gated potassium (BK) channels play an important role in cellular excitability by controlling membrane potential and calcium influx. The stress axis regulated exon (STREX) at splice site 2 inverts BK channel regulation by protein kinase A (PKA) from stimulatory to inhibitory. Here we show that palmitoylation of STREX controls BK channel regulation also by protein kinase C (PKC). In contrast to the 50% decrease of maximal channel activity by PKC in the insertless (ZERO) splice variant, STREX channels were completely resistant to PKC. STREX channel mutants in which Ser(700), located between the two regulatory domains of K(+) conductance (RCK) immediately downstream of the STREX insert, was replaced by the phosphomimetic amino acid glutamate (S700E) showed a ∼50% decrease in maximal channel activity, whereas the S700A mutant retained its normal activity. BK channel inhibition by PKC, however, was effectively established when the palmitoylation-mediated membrane-anchor of the STREX insert was removed by either pharmacological inhibition of palmitoyl transferases or site-directed mutagenesis. These findings suggest that STREX confers a conformation on BK channels where PKC fails to phosphorylate and to inhibit channel activity. Importantly, PKA which inhibits channel activity by disassembling the STREX insert from the plasma membrane, allows PKC to further suppress the channel gating independent from voltage and calcium. Our results present an important example for the cross-talk between ion channel palmitoylation and phosphorylation in regulation of cellular excitability.
Journal of Biological Chemistry 07/2012; 287(38):32161-71. · 4.77 Impact Factor
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Journal of Molecular and Cellular Cardiology 06/2012; 53(3):320-2. · 5.17 Impact Factor
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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.
Wiener Medizinische Wochenschrift 06/2012; 162(13-14):287-91.
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Jonathan L Respress,
Ralph J van Oort,
Na Li,
Natale Rolim,
Sayali S Dixit,
Angela deAlmeida,
Niels Voigt,
William S Lawrence,
Darlene G Skapura,
Kristine Skårdal,
Ulrik Wisløff,
Thomas Wieland,
Xun Ai,
Steven M Pogwizd, Dobromir Dobrev,
Xander H T Wehrens
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ABSTRACT: 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.
Determine the role of CaMKII phosphorylation of RyR2 in patients and mice with nonischemic and ischemic forms of HF.
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.
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.
Circulation Research 04/2012; 110(11):1474-83. · 9.49 Impact Factor
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ABSTRACT: Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia, and its prevalence is increasing with the ageing of the population. Presently available treatment options are far from optimal and new insights into underlying mechanisms are needed to improve therapy. A variety of recent lines of research are converging to reveal important and relatively underappreciated multidimensional roles of cellular Ca(2+) content, distribution, and handling in AF pathophysiology. The objective of the present paper is to review the participation of changes in cell Ca(2+) and related processes in the mechanisms that lead to AF initiation and maintenance, and to consider the relevance of new knowledge in this area to therapeutic innovation. We first review the involvement of Ca(2+)-related functions in the principal arrhythmia mechanisms underlying AF: focal ectopic activity due to afterdepolarizations and re-entrant mechanisms. The detailed molecular pathophysiology of focal ectopic and re-entrant activity is then discussed in relationship to the participation of cell Ca(2+) changes and related Ca(2+)-handling and Ca(2+)-sensitive signalling systems. We then go on to consider the participation of Ca(2+)-related functions in electrical and structural remodelling processes leading to the AF substrate. Finally, we consider the implications for development of new arrhythmia management approaches and future research and development.
European Heart Journal 04/2012; 33(15):1870-7. · 10.48 Impact Factor
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ABSTRACT: Atrial fibrillation is the most common type of cardiac arrhythmia, and is responsible for substantial morbidity and mortality in the general population. Current treatments have moderate efficacy and considerable risks, especially of pro-arrhythmia, highlighting the need for new therapeutic strategies. In recent years, substantial efforts have been invested in developing novel treatments that target the underlying molecular determinants of atrial fibrillation, and several new compounds are under development. This Review focuses on the mechanistic rationale for the development of new anti-atrial fibrillation drugs, on the molecular and structural motifs that they target and on the results obtained so far in experimental and clinical studies.
dressNature Reviews Drug Discovery 04/2012; 11(4):275-91. · 29.01 Impact Factor
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Niels Voigt,
Na Li,
Qiongling Wang,
Wei Wang,
Andrew W Trafford,
Issam Abu-Taha,
Qiang Sun,
Thomas Wieland,
Ursula Ravens,
Stanley Nattel,
Xander H T Wehrens, Dobromir Dobrev
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ABSTRACT: Delayed afterdepolarizations (DADs) carried by Na(+)-Ca(2+)-exchange current (I(NCX)) in response to sarcoplasmic reticulum (SR) Ca(2+) leak can promote atrial fibrillation (AF). The mechanisms leading to delayed afterdepolarizations in AF patients have not been defined.
Protein levels (Western blot), membrane currents and action potentials (patch clamp), and [Ca(2+)](i) (Fluo-3) were measured in right atrial samples from 76 sinus rhythm (control) and 72 chronic AF (cAF) patients. Diastolic [Ca(2+)](i) and SR Ca(2+) content (integrated I(NCX) during caffeine-induced Ca(2+) transient) were unchanged, whereas diastolic SR Ca(2+) 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 Ca(2+) leak. Calmodulin expression (60%), Ca(2+)/calmodulin-dependent protein kinase-II (CaMKII) autophosphorylation at Thr287 (87%), and RyR2 phosphorylation at Ser2808 (protein kinase A/CaMKII site, 236%) and Ser2814 (CaMKII site, 77%) were increased in cAF. The selective CaMKII blocker KN-93 decreased SR Ca(2+) leak, the frequency of spontaneous Ca(2+) release events, and RyR2 open probability in cAF, whereas protein kinase A inhibition with H-89 was ineffective. Knock-in mice with constitutively phosphorylated RyR2 at Ser2814 showed a higher incidence of Ca(2+) sparks and increased susceptibility to pacing-induced AF compared with controls. The relationship between [Ca(2+)](i) and I(NCX) density revealed I(NCX) upregulation in cAF. Spontaneous Ca(2+) release events accompanied by inward I(NCX) currents and delayed afterdepolarizations/triggered activity occurred more often and the sensitivity of resting membrane voltage to elevated [Ca(2+)](i) (diastolic [Ca(2+)](i)-voltage coupling gain) was higher in cAF compared with control.
Enhanced SR Ca(2+) leak through CaMKII-hyperphosphorylated RyR2, in combination with larger I(NCX) for a given SR Ca(2+) release and increased diastolic [Ca(2+)](i)-voltage coupling gain, causes AF-promoting atrial delayed afterdepolarizations/triggered activity in cAF patients.
Circulation 03/2012; 125(17):2059-70. · 14.74 Impact Factor
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ABSTRACT: During the last decades Ca(2+) 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 Ca(2+) 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 Ca(2+) cycling mechanisms in atrial cardiomyocytes and relates them to fundamental cellular proarrhythmic mechanisms involving Ca(2+) signaling abnormalities in the atrium during atrial fibrillation.
Advances in experimental medicine and biology 01/2012; 740:1175-91. · 1.09 Impact Factor
