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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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Xiaobin Luo,
Zhenwei Pan,
Hongli Shan,
Jiening Xiao,
Xuelin Sun,
Ning Wang,
Huixian Lin,
Ling Xiao,
Ange Maguy,
Xiao-Yan Qi, [......],
Yong Zhang,
Yunlong Bai,
Jing Ai,
Lihua Sun,
Hang Lu,
Xiao-Yan Luo,
Zhiguo Wang,
Yanjie Lu,
Baofeng Yang, Stanley Nattel
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ABSTRACT: Atrial fibrillation (AF) is a highly prevalent arrhythmia with pronounced morbidity and mortality. Inward-rectifier K+ current (IK1) is believed to be an important regulator of reentrant-spiral dynamics and a major component of AF-related electrical remodeling. MicroRNA-26 (miR-26) is predicted to target the gene encoding KIR2.1, KCNJ2. We found that miR-26 was downregulated in atrial samples from AF animals and patients and this downregulation was accompanied by upregulation of IK1/KIR2.1 protein. miR-26 overexpression suppressed expression of KCNJ2/KIR2.1. In contrast, miR-26 knockdown, inhibition, or binding-site mutation enhanced KCNJ2/KIR2.1 expression, establishing KCNJ2 as a miR-26 target. Knockdown of endogenous miR-26 promoted AF in mice, whereas adenovirus-mediated expression of miR-26 reduced AF vulnerability. Kcnj2-specific miR-masks eliminated miR-26-mediated reductions in Kcnj2, abolishing miR-26's protective effects, while coinjection of a Kcnj2-specific miR-mimic prevented miR-26 knockdown-associated AF in mice. Nuclear factor of activated T cells (NFAT), a known actor in AF-associated remodeling, was found to negatively regulate miR-26 transcription. Our results demonstrate that miR-26 controls the expression of KCNJ2 and suggest that this downregulation may promote AF.
The Journal of clinical investigation 04/2013; · 15.39 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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Kimberley Crespo,
Cristina Chauvet,
Annie Ménard,
Julie Roy,
Yanfen Shi,
Danielle Gelinas,
Francine Duval,
Nathalie L'heureux, Stanley Nattel,
Jean-Claude Tardif,
Alan Y Deng
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ABSTRACT: OBJECTIVES:: Diastolic dysfunction often represents the onset of diastolic heart failure (DHF). We previously showed in principle that diastolic function in Dahl salt-sensitive rats (DSS) can be genetically determined by quantitative trait loci (QTLs) that also modulate blood pressure (BP). METHODS:: We analyzed cardiac phenotypes of four 'single' congenic strains by echocardiography, in which a specific DSS chromosome segment was replaced by its normotensive Lewis homologue. RESULTS:: Two of the strains permanently lowered BP, and but attenuated diastolic dysfunction only in rats at 10 weeks of age, not at 15 weeks fed on a 2% NaCl diet starting from 8 weeks of age. We then combined multiple QTLs by integrating several 'single' congenic strains. As a result, BP was greatly reduced. Cardiac dysfunction and LV hypertrophy were continuously improved from 10 to 15 weeks, although the degree and timing of the improvement varied among different congenic combinations. CONCLUSION:: Distinct QTLs exist that simultaneously modulate BP and diastolic function. These QTLs, in combination, synergistically lowered BP and permanently alleviated or reversed diastolic dysfunction. The genes that are contained in the congenic strains affecting diastolic function are not known for their specific influence on BP. Novel long-term strategies of prognosis, diagnosis and therapy for hypertensive DHF appear from this work.
Journal of hypertension 02/2013; · 4.02 Impact Factor
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Europace 01/2013; · 1.98 Impact Factor
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ABSTRACT: Recently it has been shown that long-term intensive exercise practice is able to induce myocardial fibrosis in an animal model. Angiotensin II is a profibrotic hormone that could be involved in the cardiac remodeling resulting from endurance exercise.
This study examined the antifibrotic effect of losartan, an angiotensin II type 1 receptor antagonist, in an animal model of heart fibrosis induced by long-term intense exercise.
Male Wistar rats were randomly distributed into 4 experimental groups: Exercise, Exercise plus losartan, Sedentary and Sedentary plus losartan. Exercise groups were conditioned to run vigorously for 16 weeks. Losartan was orally administered daily before each training session (50 mg/kg/day). Time-matched sedentary rats served as controls. After euthanasia, heart hypertrophy was evaluated by histological studies; ventricular collagen deposition was quantified by histological and biochemical studies; and messenger RNA and protein expression of transforming growth factor-β1, fibronectin-1, matrix metalloproteinase-2, tissue inhibitor of metalloproteinase-1, procollagen-I and procollagen-III was evaluated in all 4 cardiac chambers. Daily intensive exercise caused hypertrophy in the left ventricular heart wall and originated collagen deposition in the right ventricle. Additionally long-term intensive exercise induced a significant increase in messenger RNA expression and protein synthesis of the major fibrotic markers in both atria and in the right ventricle. Losartan treatment was able to reduce all increases in messenger RNA expression and protein levels caused by exercise, although it could not completely reverse the heart hypertrophy.
Losartan treatment prevents the heart fibrosis induced by endurance exercise in training animals.
PLoS ONE 01/2013; 8(2):e55427. · 4.09 Impact Factor
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ABSTRACT: BACKGROUND: Previous studies have demonstrated that atrial regions contribute differently to atrial fibrillation (AF) substrate. Pulmonary vein and the surrounding left atrial junction (LA-PV junction) are crucial areas in AF substrates and important ablation targets. OBJECTIVES: In this study, we utilized a genome-wide approach to identify regional differences in the left atria of AF patients. METHODS: Paired LA-PV junction and left atrial appendage (LAA) specimens were obtained from 16 patients with persistent AF and 3 with sinus rhythm who underwent valvular surgery. The paired specimens were sent for microarray comparison. RESULTS: Of 54,675 expressed sequence tags, microarray analysis in AF patients revealed that 391 genes were differentially expressed between LA-PV junction and LAA, including genes related to arrhythmia, cell death, fibrosis, hypertrophy, and inflammation. Microarray and real time-polymerase chain reaction produced parallel results in analyzing the expression of particular genes. In both AF and sinus rhythm patients, LA-PV junction exhibited greater paired like homeodomain-2 (PITX2) and its target protein (short stature homeobox-2 [SHOX2]) expression than LAA, which might contribute to arrhythmogenesis. Five genes related to thrombogenesis were up-regulated in LAA of AF patients, which might implicate for the preferential thrombus formation in LAA. Genes related to fibrosis were highly expressed in LAA of AF patients, which was reflected by intense ultrastructural changes in this region. CONCLUSION: We took a genome-wide approach to investigate region-specific gene expression in the left atria. Our findings provide important information relevant to region-specific arrhythmogenesis and thrombogenesis in AF pathogenesis.
Heart rhythm: the official journal of the Heart Rhythm Society 11/2012; · 4.56 Impact Factor
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Kunihiro Nishida,
Katsuyoshi Chiba,
Yu-Ki Iwasaki,
Grigorios Katsouras,
Yan-Fen Shi,
Mark D Blostein,
Paul Khairy,
Peter G Guerra,
Marc Dubuc,
Jean-Claude Tardif,
Jean-François Tanguay, Stanley Nattel
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ABSTRACT: BACKGROUND: -The most important complication of atrial fibrillation (AF) is thromboembolic stroke. Although AF-related remodeling is considered important in atrial thrombogenesis, its role has never been directly tested. This study assessed effects of AF-related remodeling on the atrial thrombogenic milieu, using radiofrequency ablation (RFA) to create a quantifiable prothrombotic nidus. METHODS AND RESULTS: -We studied normal-control dogs (CTL, n=16) and 3 canine AF-models: 1. atrial-tachycardia (AT) remodeling (ATR; n=16) induced by atrial-tachypacing (400 bpm × 1 week, with atrioventricular-block and ventricular pacing at 80 bpm); 2. congestive heart failure (CHF, n=14) due to ventricular-tachypacing (240 bpm × 2 weeks); 3. chronic AF (CAF, n=8) induced by atrial-tachypacing (35±3 days) without atrioventricular-block. CAF-dogs were in AF for 13±1 days until sacrifice. After remodeling was established, RFA-lesions were created in both atria. Half the ATR and CHF dogs were subjected to atrial-tachypacing during 7-day post-RFA follow-up. Electrophysiological and echocardiographic studies were performed pre-RFA and 7 days post-RFA, then hearts were removed and atrial thrombi quantified by histomorphometry. Burst-pacing induced AF-duration was significantly greater in ATR, CHF, and CAF groups vs. CTL. Atrial effective refractory period shortened in ATR and CAF groups. Left-atrial diameter was significantly larger with CHF but not with ATR. Neither total thrombus volume nor thrombus volume per lesion differed significantly among groups. CONCLUSIONS: -None of the AF-substrates tested, including sustained AT/AF itself, enhanced post RFA atrial thrombus formation. Indices of electrical and structural remodeling did not predict post-RFA thrombogenic potential. Contrary to widely-held but previously-untested notions, we were unable to demonstrate prothrombotic effects of AF-related remodeling.
Circulation Arrhythmia and Electrophysiology 10/2012; · 6.46 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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A John Camm,
Sana M Al-Khatib,
Hugh Calkins,
Jonathan L Halperin,
Paulus Kirchhof,
Gregory Y H Lip, Stanley Nattel,
Jeremy Ruskin,
Amitava Banerjee,
Dan Blendea,
Eduard Guasch,
Matthew Needleman,
Irina Savelieva,
Juan Viles-Gonzalez,
Eric S Williams
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ABSTRACT: Atrial fibrillation (AF) represents a growing public health burden. It is a complex condition, involving a number of etiologic factors and arrhythmia mechanisms associated with atrial remodeling. Greater understanding of these mechanisms may improve therapy. Current AF classification schemes are limited by simplicity. A number of risk factors predict AF onset, and additional factors are being evaluated in registry studies. Doppler imaging and Holter monitoring in high-risk patients to predict the onset of AF and progression from paroxysmal to permanent AF are promising. There is a need for a novel multifactorial classification model encompassing AF duration, symptoms, markers of atrial remodeling, and a risk score for AF onset, persistence, progression, and complications to guide treatment and prognostication. Preventing AF onset with upstream therapy is of great interest, but current data are conflicting. More study is needed to optimize rhythm control with antiarrhythmic drugs and targeted ablation to specific patient populations at an earlier stage. There is little consensus on optimal rate control and no information relating to optimum rate control in specific populations. This article highlights new concepts in AF and directions for future research.
American heart journal 09/2012; 164(3):292-302.e1. · 4.65 Impact Factor
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ABSTRACT: Background- Atrial tissue fibrosis is often an important component of the atrial fibrillation (AF) substrate. Small noncoding microRNAs are important mediators in many cardiac remodeling paradigms. MicroRNA-21 (miR-21) has been suggested to be important in ventricular fibrotic remodeling by downregulating Sprouty-1, a protein that suppresses fibroblast proliferation. The present study examined the potential role of miR-21 in the atrial AF substrate resulting from experimental heart failure after myocardial infarction (MI). Methods and Results- Large MIs (based on echocardiographic left ventricular wall motion score index) were created by left anterior descending coronary artery ligation in rats. Changes induced by MI versus sham controls were first characterized with echocardiography, histology, biochemistry, and in vivo electrophysiology. Additional MI rats were then randomized to receive anti-miR-21 (KD21) or scrambled control sequence (Scr21) injections into the left atrial myocardium. Progressive left ventricular enlargement, hypocontractility, left atrial dilation, fibrosis, refractoriness prolongation, and AF promotion occurred in MI rats versus sham controls. Atrial tissues of MI rats showed upregulation of miR-21, along with dysregulation of the target genes Sprouty-1, collagen-1, and collagen-3. KD21 treatment reduced atrial miR-21 expression levels in MI rats to values in sham rats, decreased AF duration from 417 (69-1595; median [Q1-Q3]) seconds to 3 (2-16) seconds (8 weeks after MI; P<0.05), and reduced atrial fibrous tissue content from 14.4±1.8% (mean±SEM) to 4.9±1.2% (8 weeks after MI; P<0.05) versus Scr21 controls. Conclusions- MI-induced heart failure leads to AF-promoting atrial remodeling in rats. Atrial miR-21 knockdown suppresses atrial fibrosis and AF promotion, implicating miR-21 as an important signaling molecule for the AF substrate and pointing to miR-21 as a potential target for molecular interventions designed to prevent AF.
Circulation Arrhythmia and Electrophysiology 08/2012; 5(5):1027-35. · 6.46 Impact Factor
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Circulation Arrhythmia and Electrophysiology 08/2012; 5(4):860-7. · 6.46 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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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: Obesity and obstructive sleep apnea (OSA) are risk factors for atrial fibrillation (AF), but the underlying mechanisms are poorly understood.
The purpose of this study was to assess the mechanisms underlying AF promotion by obesity and OSA in rat models.
Zucker obese rats (ORs) and lean rats (LRs) were intubated and ventilated with air and 2% isoflurane. OSA was mimicked by stopping the ventilator and closing the airway for 40 seconds. For nonobstructive control periods, the protocol was repeated with an open airway. Fifteen seconds after apnea onset, AF susceptibility was tested with 6 atrial burst pacing cycles (25 Hz, 3 seconds, 1-second intercycle pauses).
AF was not inducible in ORs or LRs at baseline or in nonobstructive control periods. AF was induced in 24 of 28 ORs (85.7%) vs 5 of 18 LRs (27.8%) during obstructive apnea (P <.001). Negative intrathoracic pressure generation (esophageal pressure monitoring) was substantial during obstructive apnea. Echocardiography showed left ventricular hypertrophy with diastolic dysfunction in ORs. Obstructive apnea caused acute left atrial (LA) dilation, increasing LA diameter significantly more in ORs than in LRs. To clarify AF mechanisms, 24 AF-inducible ORs were divided into 4 groups: saline (n = 5), pharmacologic autonomic blockade (n = 7), respiratory muscle paralysis with rocuronium (n = 6), and inferior vena cava (IVC) balloon occlusion to unload the LA (n = 6). Balloon catheter-induced IVC occlusion prevented LA distension during obstructive apnea, leading to 83.3% AF prevention (P <.05). Rocuronium also was protective (66.7%), but autonomic blockade had smaller effects (42.9% prevention).
Obesity and acute obstructive apnea interacted to promote AF in this model. Forced inspiration-induced acute LA distension related to diastolic dysfunction may be an important component of the arrhythmogenic substrate for AF during OSA episodes in obese patients.
Heart rhythm: the official journal of the Heart Rhythm Society 03/2012; 9(9):1409-16.e1. · 4.56 Impact Factor
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The Journal of Physiology 03/2012; 590(Pt 6):1311-2. · 4.72 Impact Factor
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ABSTRACT: Atrial fibrillation (AF) is the most common type of clinical arrhythmia. Currently available anti-AF drugs are limited by only moderate efficacy and an unfavorable safety profile. Thus, there is a recognized need for improved antiarrhythmic agents with actions that are selective for the fibrillating atrium. State-dependent Na(+)-channel blockade potentially allows for the development of drugs with maximal actions on fibrillating atrial tissue and minimal actions on ventricular tissue at resting heart rates. In this study, we applied a mathematical model of state-dependent Na(+)-channel blocking (class I antiarrhythmic drug) action, along with mathematical models of canine atrial and ventricular cardiomyocyte action potentials, AF, and ventricular proarrhythmia, to determine the relationship between their pharmacodynamic properties and atrial-selectivity, AF-selectivity (atrial Na(+)-channel block at AF rates versus ventricular block at resting rates), AF-termination effectiveness, and ventricular proarrhythmic properties. We found that drugs that target inactivated channels are AF-selective, whereas drugs that target activated channels are not. The most AF-selective drugs were associated with minimal ventricular proarrhythmic potential and terminated AF in 33% of simulations; slightly fewer AF-selective agents achieved termination rates of 100% with low ventricular proarrhythmic potential. Our results define properties associated with AF-selective actions of class-I antiarrhythmic drugs and support the idea that it may be possible to develop class I antiarrhythmic agents with optimized pharmacodynamic properties for AF treatment.
Biophysical Journal 03/2012; 102(5):951-60. · 3.65 Impact Factor
