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ABSTRACT: Inadequacies in current therapies for atrial fibrillation have made new drug development crucial. Conventional antiarrhythmic drugs increase the risk of ventricular proarrhythmia. In drug development, the focus has been on favourable multichannel-blocking profiles, atrial-specific ion-channels, and novel non-channel targets (upstream therapy). Molecular modification of the highly effective multichannel blocker, amiodarone, to improve safety and tolerability has produced promising analogues such as dronedarone, although this drug seems less effective than does amiodarone. Vernakalant, an atrial-selective drug with reduced proarrhythmic risk, might be useful for cardioversion in atrial fibrillation. Ranolazine, another atrial-selective agent initially developed as an antianginal, has efficacy for atrial fibrillation and is being tested in prospective clinical trials. So-called upstream therapy with angiotensin-converting enzyme and angiotensin-receptor inhibitors, statins, or omega-3 fatty acids and fish oil that target atrial remodelling could be effective, but need further clinical validation. We focus on the basic and clinical pharmacology of newly emerging antiarrhythmic drugs and non-traditional approaches such as upstream therapy for atrial fibrillation.
The Lancet 03/2010; 375(9721):1212-23. · 38.28 Impact Factor
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Katrin Wittköpper,
Larissa Fabritz,
Stefan Neef,
Katharina R Ort,
Clemens Grefe,
Bernhard Unsöld,
Paulus Kirchhof,
Lars S Maier,
Gerd Hasenfuss, Dobromir Dobrev,
Thomas Eschenhagen,
Ali El-Armouche
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ABSTRACT: Phosphatase inhibitor-1 (I-1) is a distal amplifier element of beta-adrenergic signaling that functions by preventing dephosphorylation of downstream targets. I-1 is downregulated in human failing hearts, while overexpression of a constitutively active mutant form (I-1c) reverses contractile dysfunction in mouse failing hearts, suggesting that I-1c may be a candidate for gene therapy. We generated mice with conditional cardiomyocyte-restricted expression of I-1c (referred to herein as dTGI-1c mice) on an I-1-deficient background. Young adult dTGI-1c mice exhibited enhanced cardiac contractility but exaggerated contractile dysfunction and ventricular dilation upon catecholamine infusion. Telemetric ECG recordings revealed typical catecholamine-induced ventricular tachycardia and sudden death. Doxycycline feeding switched off expression of cardiomyocyte-restricted I-1c and reversed all abnormalities. Hearts from dTGI-1c mice showed hyperphosphorylation of phospholamban and the ryanodine receptor, and this was associated with an increased number of catecholamine-induced Ca2+ sparks in isolated myocytes. Aged dTGI-1c mice spontaneously developed a cardiomyopathic phenotype. These data were confirmed in a second independent transgenic mouse line, expressing a full-length I-1 mutant that could not be phosphorylated and thereby inactivated by PKC-alpha (I-1S67A). In conclusion, conditional expression of I-1c or I-1S67A enhanced steady-state phosphorylation of 2 key Ca2+-regulating sarcoplasmic reticulum enzymes. This was associated with increased contractile function in young animals but also with arrhythmias and cardiomyopathy after adrenergic stress and with aging. These data should be considered in the development of novel therapies for heart failure.
The Journal of clinical investigation 02/2010; 120(2):617-26. · 15.39 Impact Factor
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ABSTRACT: Although it is generally accepted that excitation-contraction coupling is defective in patients with atrial fibrillation, the underlying cellular mechanisms remain incompletely understood. Recent studies suggest that abnormal sarcoplasmic reticulum calcium "leak" via ryanodine receptors contributes to atrial arrhythmogenesis. Increased activity of the enzyme calmodulin kinase II (CaMKII) and, specifically, enhanced CaMKII phosphorylation of ryanodine receptors appear to play a critical role in the induction and perhaps maintenance of atrial fibrillation. In this review, we will summarize new insights into the role of enhanced CaMKII in sarcoplasmic reticulum calcium leak and atrial arrhythmogenesis during atrial fibrillation.
Trends in cardiovascular medicine 01/2010; 20(1):30-4. · 4.37 Impact Factor
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ABSTRACT: Vagal nerve stimulation can promote atrial fibrillation (AF) that requires activation of the acetylcholine (ACh)-gated potassium current I(K,ACh). In chronic AF (cAF), I(K,ACh) shows strong activity despite the absence of ACh or analogous pharmacological stimulation. This receptor-independent, constitutive I(K,ACh) activity is suggested to represent an atrial-selective anti-AF therapeutic target, but the underlying molecular mechanisms are unknown. This chapter provides an overview of the voltage-clamp techniques that can be used to study constitutive I(K,ACh) activity in atrial myocytes and summarizes briefly the current knowledge about the potential underlying mechanism(s) of constitutive I(K,ACh) activity in diseased heart.
Methods in enzymology 01/2010; 484:653-75. · 1.90 Impact Factor
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ABSTRACT: Atrial fibrillation (AF) is the most common arrhythmia in clinical practice. A variety of animal models have been used to study the pathophysiology of AF, including molecular basis, ion-current determinants, anatomical features, and macroscopic mechanisms. In addition, animal models play a key role in the development of new therapeutic approaches, whether drug-based, molecular therapeutics, or device-related. This article discusses the various types of animal models that have been used for AF research, reviews the principle mechanisms governing atrial arrhythmias in each model, and provides some guidelines for model selection for various purposes.
Europace 10/2009; 12(2):160-72. · 1.98 Impact Factor
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ABSTRACT: Inward rectifier potassium currents I(K1) and acetylcholine activated I(K,ACh) are implicated in atrial fibrillation (AF) pathophysiology. In chronic AF (cAF), I(K,ACh) develops a receptor-independent, constitutively active component that together with increased I(K1) is considered to support maintenance of AF. Here, we tested whether class I (propafenone, flecainide) and class III (dofetilide, AVE0118) antiarrhythmic drugs inhibit atrial I(K1) and I(K,ACh) in patients with and without cAF. I(K1) and I(K,ACh) were measured with voltage clamp technique in atrial myocytes from 58 sinus rhythm (SR) and 35 cAF patients. The M-receptor agonist carbachol (CCh; 2 microM) was employed to activate I(K,ACh). In SR, basal current was not affected by either drug indicating no effect of these compounds on I(K1). In contrast, all tested drugs inhibited CCh-activated I(K,ACh) in a concentration-dependent manner. In cAF, basal current was confirmed to be larger than in SR (at -80 mV, -15.2 +/- 1.2 pA/pF, n = 88/35 vs. -6.5 +/- 0.4 pA/pF, n = 194/58 [myocytes/patients]; P < 0.05), whereas CCh-activated I(K,ACh) was smaller (-4.1 +/- 0.5 pA/pF vs. -9.5 +/- 0.6 pA/pF; P < 0.05). In cAF, receptor-independent constitutive I(K,ACh) contributes to increased basal current, which was reduced by flecainide and AVE0118 only. This may be due to inhibition of constitutively active I(K,ACh) channels. In cAF, all tested drugs reduced CCh-activated I(K,ACh). We conclude that in cAF, flecainide and AVE0118 reduce receptor-independent, constitutively active I(K,ACh), suggesting that they may block I(K,ACh) channels, whereas propafenone and dofetilide likely inhibit M-receptors. The efficacy of flecainide to terminate AF may in part result from blockade of I(K,ACh).
Archiv für Experimentelle Pathologie und Pharmakologie 09/2009; 381(3):251-9. · 2.65 Impact Factor
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Dobromir Dobrev
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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 moderate efficacy and increase the risk of life-threatening antiarrhythmias, making novel drug development crucial. Newer antiarrhythmic drugs like dronedarone and possibly vernakalant are efficient and may have less proarrhythmic potential. Emerging evidence suggests that abnormal intracellular Ca(2+) signaling is the key contributor to focal firing, substrate evolution, and atrial remodeling during AF. Accordingly, identification of the underlying atrial Ca(2+)-handling abnormalities is expected to discover novel mechanistically based therapeutic targets. This article reviews the molecular mechanisms of altered Ca(2+) signaling in AF and discusses the potential value of novel approaches targeting atrial Ca(2+)-handling abnormalities.
Archiv für Experimentelle Pathologie und Pharmakologie 09/2009; 381(3):195-206. · 2.65 Impact Factor
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Mihail G Chelu,
Satyam Sarma,
Subeena Sood,
Sufen Wang,
Ralph J van Oort,
Darlene G Skapura,
Na Li,
Marco Santonastasi,
Frank Ulrich Müller,
Wilhelm Schmitz,
Ulrich Schotten,
Mark E Anderson,
Miguel Valderrábano, Dobromir Dobrev,
Xander H T Wehrens
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ABSTRACT: A trial fibrillation (AF), the most common human cardiac arrhythmia, is associated with abnormal intracellular Ca2+ handling. Diastolic Ca2+ release from the sarcoplasmic reticulum via "leaky" ryanodine receptors (RyR2s) is hypothesized to contribute to arrhythmogenesis in AF, but the molecular mechanisms are incompletely understood. Here, we have shown that mice with a genetic gain-of-function defect in Ryr2 (which we termed Ryr2R176Q/+ mice) did not exhibit spontaneous AF but that rapid atrial pacing unmasked an increased vulnerability to AF in these mice compared with wild-type mice. Rapid atrial pacing resulted in increased Ca2+/calmodulin-dependent protein kinase II (CaMKII) phosphorylation of RyR2, while both pharmacologic and genetic inhibition of CaMKII prevented AF inducibility in Ryr2R176Q/+ mice. This result suggests that AF requires both an arrhythmogenic substrate (e.g., RyR2 mutation) and enhanced CaMKII activity. Increased CaMKII phosphorylation of RyR2 was observed in atrial biopsies from mice with atrial enlargement and spontaneous AF, goats with lone AF, and patients with chronic AF. Genetic inhibition of CaMKII phosphorylation of RyR2 in Ryr2S2814A knockin mice reduced AF inducibility in a vagotonic AF model. Together, these findings suggest that increased RyR2-dependent Ca2+ leakage due to enhanced CaMKII activity is an important downstream effect of CaMKII in individuals susceptible to AF induction.
The Journal of clinical investigation 08/2009; 119(7):1940-51. · 15.39 Impact Factor
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Andreas Goette,
Alicja Bukowska, Dobromir Dobrev,
Jan Pfeiffenberger,
Henning Morawietz,
Denis Strugala,
Ingrid Wiswedel,
Friedrich-Wilhelm Röhl,
Carmen Wolke,
Sybille Bergmann,
Peter Bramlage,
Ursula Ravens,
Uwe Lendeckel
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ABSTRACT: Patients with paroxysmal atrial fibrillation (AF) often present with typical angina pectoris and mildly elevated levels of cardiac troponin (non ST-segment elevation myocardial infarction) during an arrhythmic event. However, in a large proportion of these patients, significant coronary artery disease is excluded by coronary angiography. Here we explored the potential underlying mechanism of these events.
A total of 14 pigs were studied using a closed chest, rapid atrial pacing (RAP) model. In five pigs RAP was performed for 7 h (600 b.p.m.; n = 5), in five animals RAP was performed in the presence of angiotensin-II type-1-receptor (AT(1)-receptor) inhibitor irbesartan (RAP+Irb), and four pigs were instrumented without intervention (Sham). One-factor analysis of variance was performed to assess differences between and within the three groups. Simultaneous measurements of fractional flow reserve (FFR) and coronary flow reserve (CFR) before, during, and after RAP demonstrated unchanged FFR (P = 0.327), but decreased CFR during RAP (RAP: 67.7 +/- 7.2%, sham: 97.2 +/- 2.8%, RAP+Irb: 93.2 +/- 3.3; P = 0.0013) indicating abnormal left ventricular (LV) microcirculation. Alterations in microcirculatory blood flow were accompanied by elevated ventricular expression of NADPH oxidase subunit Nox2 (P = 0.039), lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1, P = 0.004), and F(2)-isoprostane levels (P = 0.008) suggesting RAP-related oxidative stress. Plasma concentrations of cardiac troponin-I (cTn-I) increased in RAP (RAP: 613.3 +/- 125.8 pmol/L vs. sham: 82.5 +/- 12.5 pmol/L; P = 0.013), whereas protein levels of eNOS and LV function remained unchanged. RAP+Irb prevented the increase of Nox2, LOX-1, and F(2)-isoprostanes, and abolished the impairment of microvascular blood flow.
Rapid atrial pacing induces AT(1)-receptor-mediated oxidative stress in LV myocardium that is accompanied by impaired microvascular blood flow and cTn-I release. These findings provide a plausible mechanism for the frequently observed cTn-I elevation accompanied with typical angina pectoris symptoms in patients with paroxysmal AF and normal (non-stenotic) coronary arteries.
European Heart Journal 04/2009; 30(11):1411-20. · 10.48 Impact Factor
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ABSTRACT: Patients with atrial fibrillation taking vitamin-K antagonists and undergoing invasive interventions or large surgery procedures are at highest risk of bleeding complications. Therefore, the temporary interruption of vitamin-K antagonists and bridging with heparin is a frequent clinical need, particularly in patients with high risk for stroke. The management of such patients is challenging because of the lack of randomized clinical trials assessing different periprocedural anticoagulation approaches and inconsistent recommendations from consensus groups. Recent non-randomized trials have helped to estimate the risks of thromboembolism and bleeding with "bridging" anticoagulation involving either low-molecular-weight heparin or intravenous unfractioned heparin. Nevertheless, there is still a clear need for randomized double-blinded controlled trials comparing efficacy and safety of the different "bridging" strategies, including unfractionated heparin and placebo comparators, in preventing thromboembolism for specific patients and procedures.
Cardiovascular Therapeutics 01/2009; 27(4):223-5. · 2.35 Impact Factor
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Günter Breithardt, Dobromir Dobrev,
Nicolas Doll,
Andreas Goette,
Boris Hoffmann,
Paulus Kirchhof,
Ilka Köster,
Karl-Heinz Kuck,
Angelika Leute,
Thomas Meinertz,
Michael Näbauer,
Michael Oeff,
Ursula Ravens,
Andreas Schuchert,
Claudia Sprenger,
Gerhard Steinbeck,
Stephan Willems
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ABSTRACT: The German Competence Network on Atrial Fibrillation (AFNET) is an interdisciplinary national research network funded by the Federal Ministry of Education and Research (BMBF) since 2003. The AFNET aims at improving treatment of atrial fibrillation (AF), the most frequent sustained arrhythmia of the heart. The AFNET has established a nationwide patient registry on manifestation, diagnostics, and therapy of AF in Germany. The data analyzed to date demonstrate that patients with AF are likely to have multiple comorbidities (hypertension, valvular heart disease, coronary artery disease, diabetes mellitus) and an advanced age. Regarding oral anticoagulation, guideline adherence is very high. Basic research has identified specific changes in atrial tissue during AF-induced remodeling providing the rationale for novel therapeutic interventions. Clinical trials are being carried out to optimize pharmacological and nonpharmacological treatments. The ANTIPAF trial is designed to prove that angiotensin II receptor blockers reduce the incidence of paroxysmal AF. The Flec-SL trial tests the efficacy of a short-term treatment with antiarrhythmic drugs after cardioversion. The Gap-AF trial investigates the impact of complete pulmonary vein (PV) isolation versus incomplete circumferential PV ablation on AF recurrences. The effect of preventive pacing on the recurrence of paroxysmal AF is studied in the BACE-PACE trial.
Herz 01/2009; 33(8):548-55. · 0.92 Impact Factor
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Maura Greiser,
Hans-Ruprecht Neuberger,
Erik Harks,
Ali El-Armouche,
Peter Boknik,
Sunniva de Haan,
Fons Verheyen,
Sander Verheule,
Wilhelm Schmitz,
Ursula Ravens,
Stanley Nattel,
Maurits A Allessie, Dobromir Dobrev,
Ulrich Schotten
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ABSTRACT: Atrial dilatation is an independent risk factor for thromboembolism in patients with and without atrial fibrillation (AF). In many patients, atrial dilatation goes along with depressed contractile function of the dilated atria. While some mechanisms causing atrial contractile dysfunction in fibrillating atria have been addressed previously, the cellular and molecular mechanisms of atrial contractile remodeling in dilated atria are unknown. This study characterized in vivo atrial contractile function in a goat model of atrial dilatation and compared it to a goat model of AF. Differences in the underlying mechanisms were elucidated by studying contractile function, electrophysiology and sarcoplasmic reticulum (SR) Ca2+ load in atrial muscle bundles and by analyzing expression and phosphorylation levels of key Ca2+-handling proteins, myofilaments and the expression and activity of their upstream regulators. In 7 chronically instrumented, awake goats atrial contractile dysfunction was monitored during 3 weeks of progressive atrial dilatation after AV-node ablation (AV block goats (AVB)). In open chest experiments atrial work index (AWI) and refractoriness were measured (10 goats with AVB, 5 goats with ten days of AF induced by repetitive atrial burst pacing (AF), 10 controls). Isometric force of contraction (FC), transmembrane action potentials (APs) and rapid cooling contractures (RCC, a measure of SR Ca2+ load) were studied in right atrial muscle bundles. Total and phosphorylated Ca2+-handling and myofilament protein levels were quantified by Western blot. In AVB goats, atrial size increased by 18% (from 26.6+/-4.4 to 31.6+/-5.5 mm, n=7 p<0.01) while atrial fractional shortening (AFS) decreased (from 18.4+/-1.7 to 12.8+/-4.0% at 400 ms, n=7, p<0.01). In open chest experiments, AWI was reduced in AVB and in AF goats compared to controls (at 400 ms: 8.4+/-0.9, n=7, and 3.2+/-1.8, n=5, vs 18.9+/-5.3 mmxmmHg, n=7, respectively, p<0.05 vs control). FC of isolated right atrial muscle bundles was reduced in AVB (n=8) and in AF (n=5) goats compared to controls (n=9) (at 2 Hz: 2.3+/-0.5 and 0.7+/-0.2 vs 5.5+/-1.0 mN/mm2, respectively, p<0.05). APs were shorter in AF, but unchanged in AVB goats. RCCs were reduced in AVB and AF versus control (AVB, 3.4+/-0.5 and AF, 4.1+/-1.4 vs 12.2+/-3.2 mN/mm2, p<0.05). Protein levels of protein kinase A (PKA) phosphorylated phospholamban (PLB) were reduced in AVB (n=8) and AF (n=8) vs control (n=7) by 37.9+/-12.4% and 29.7+/-10.1%, respectively (p<0.01), whereas calmodulin-dependent protein kinase II (CaMKII) phosphorylated ryanodine channels (RyR2) were increased by 166+/-55% in AVB (n=8) and by 146+/-56% in AF (n=8) goats (p<0.01). PKA-phosphorylated myosin-binding protein-C and troponin-I were reduced exclusively in AVB goat atria (by 75+/-10% and 55+/-15%, respectively, n=8, p<0.05). Atrial dilatation developing during slow ventricular rhythm after complete AV block as well as AF-induced remodeling are associated with atrial contractile dysfunction. Both AVB and AF goat atria show decreased SR Ca2+ load, likely caused by PLB dephosphorylation and RYR2 hyperphosphorylation. While shorter APs further compromise contractility in AF goat atria, reduced myofilament phosphorylation may impair contractility in AVB goat atria. Thus, atrial hypocontractility appears to have distinct molecular contributors in different types of atrial remodeling.
Journal of Molecular and Cellular Cardiology 11/2008; 46(3):385-94. · 5.17 Impact Factor
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ABSTRACT: Cardiac action potentials (APs) are driven by ionic currents flowing through specific channels and exchangers across cardiomyocyte membranes. Once initiated by rapid Na(+) entry during phase 0, the AP time course is determined by the balance between inward depolarizing currents, carried mainly by Na(+) and Ca(2+), and outward repolarizing currents carried mainly by K(+). K(+) currents play a major role in repolarization. The loss of a K(+) current can impair repolarization, but there is a redundancy of K(+) currents so that when one K(+) current is dysfunctional, other K(+) currents increase to compensate, a phenomenon called 'repolarization reserve'. Repolarization reserve protects repolarization under conditions that increase inward current or reduce outward current, threatening the balance that governs AP duration. This protection comes at the expense of reduced repolarization reserve, potentially resulting in unexpectedly large AP prolongation and arrhythmogenesis, when an additional repolarization-suppressing intervention is superimposed. The critical role of appropriate repolarization is such that cardiac rhythm stability can be impaired with either abnormally slow or excessively rapid repolarization. In cardiac disease states such as heart failure and atrial fibrillation (AF), changes in ion channel properties appear as part of an adaptive response to maintain function in the face of disease-related stress on the cardiovascular system. However, if the stress is maintained the adaptive ion channel changes may themselves lead to dysfunction, in particular cardiac arrhythmias. The present article reviews ionic remodelling of cardiac repolarization, and focuses on how potentially adaptive repolarization changes with congestive heart failure and AF can have arrhythmogenic consequences.
Cardiovascular research 10/2008; 81(3):491-9. · 5.80 Impact Factor
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ABSTRACT: Atrial electrical and structural alterations (remodeling) have emerged as key elements in the development of the atrial fibrillation (AF) substrate. Evidence points to abnormalities in intracellular Ca (calcium) handling as crucial links in AF-initiating focal activity and in perpetuation by rapidly firing foci and reentry. This review focuses on the molecular basis of altered Ca handling in AF, with the goal of providing new insights into molecular effective antiarrhythmic therapy.
Journal of cardiovascular pharmacology 10/2008; 52(4):293-9. · 2.83 Impact Factor
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Ali El-Armouche,
Katrin Wittköpper,
Franziska Degenhardt,
Florian Weinberger,
Michael Didié,
Ivan Melnychenko,
Michael Grimm,
Micha Peeck,
Wolfram H Zimmermann,
Bernhard Unsöld,
Gerd Hasenfuss, Dobromir Dobrev,
Thomas Eschenhagen
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ABSTRACT: Phosphatase inhibitor-1 (I-1) is a conditional amplifier of beta-adrenergic signalling downstream of protein kinase A by inhibiting type-1 phosphatases only in its PKA-phosphorylated form. I-1 is downregulated in failing hearts and thus contributes to beta-adrenergic desensitization. It is unclear whether this should be viewed as a predominantly adverse or protective response.
We generated transgenic mice with cardiac-specific I-1 overexpression (I-1-TG) and evaluated cardiac function and responses to catecholamines in mice with targeted disruption of the I-1 gene (I-1-KO). Both groups were compared with their wild-type (WT) littermates. I-1-TG developed cardiac hypertrophy and mild dysfunction which was accompanied by a substantial compensatory increase in PP1 abundance and activity, confounding cause-effect relationships. I-1-KO had normal heart structure with mildly reduced sensitivity, but unchanged maximal contractile responses to beta-adrenergic stimulation, both in vitro and in vivo. Notably, I-1-KO were partially protected from lethal catecholamine-induced arrhythmias and from hypertrophy and dilation induced by a 7 day infusion with the beta-adrenergic agonist isoprenaline. Moreover, I-1-KO exhibited a partially preserved acute beta-adrenergic response after chronic isoprenaline, which was completely absent in similarly treated WT. At the molecular level, I-1-KO showed lower steady-state phosphorylation of the cardiac ryanodine receptor/Ca(2+) release channel and the sarcoplasmic reticulum (SR) Ca(2+)-ATPase-regulating protein phospholamban. These alterations may lower the propensity for diastolic Ca(2+) release and Ca(2+) uptake and thus stabilize the SR and account for the protection.
Taken together, loss of I-1 attenuates detrimental effects of catecholamines on the heart, suggesting I-1 downregulation in heart failure as a beneficial desensitization mechanism and I-1 inhibition as a potential novel strategy for heart failure treatment.
Cardiovascular research 09/2008; 80(3):396-406. · 5.80 Impact Factor
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ABSTRACT: Atrial tachycardia (AT) downregulates L-type Ca(2+) current (I(CaL)) and causes atrial fibrillation-promoting electric remodeling. This study assessed potential underlying signal transduction. Cultured adult canine atrial cardiomyocytes were paced at 0, 1, or 3 Hz (P0, P1, P3) for up to 24 hours. Cellular tachypacing (P3) mimicked effects of in vivo AT: decreased I(CaL) and transient outward current (I(to)), unchanged I(CaT), I(Kr), and I(Ks), and reduced action potential duration (APD). I(CaL) was unchanged in P3 at 2 and 8 hours but decreased by 55+/-6% at 24 hours. Tachypacing caused Ca(2+)(i) accumulation in P3 cells at 2 to 8 hours, but, by 24 hours, Ca(2+)i returned to baseline. Ca(v)1.2 mRNA expression was not altered at 2 hours but decreased significantly at 8 and 24 hours (32+/-4% and 48+/-4%, respectively) and protein expression was decreased (47+/-8%) at 24 hours only. Suppressing Ca(2+)(i) increases during tachypacing with the I(CaL) blocker nimodipine or the Ca(2+) chelator BAPTA-AM prevented I(CaL) downregulation. Calcineurin activity increased in P3 at 2 and 8 hours, respectively, returning to baseline at 24 hours. Nuclear factor of activated T cells (NFAT) nuclear translocation was enhanced in P3 cells. Ca(2+)-dependent signaling was probed with inhibitors of Ca(2+)/calmodulin (W-7), calcineurin (FK-506), and NFAT (INCA6): each prevented I(CaL) downregulation. Significant APD reductions ( approximately 30%) at 24 hours in P3 cells were prevented by nimodipine, BAPTA-AM, W-7, or FK-506. Thus, rapid atrial cardiomyocyte activation causes Ca(2+) loading, which activates the Ca(2+)-dependent calmodulin-calcineurin-NFAT system to cause transcriptional downregulation of I(CaL), restoring Ca(2+)i to normal at the cost of APD reduction. These studies elucidate for the first time the molecular feedback mechanisms underlying arrhythmogenic AT remodeling.
Circulation Research 09/2008; 103(8):845-54. · 9.49 Impact Factor
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Dobromir Dobrev
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ABSTRACT: Atrial fibrillation is the most frequent cardiac arrhythmia in clinical practice. Although much has been learned, the underlying mechanisms are incompletely understood. Clinically used antiarrhythmic drugs are limited in their efficacy to terminate atrial fibrillation or to maintain sinus rhythm and were associated with substantial toxicity including life-threatening ventricular arrhythmias. Novel therapeutic approaches suggest targeting of atrium-selective ion channels and pathology-specific alterations in atrial repolarisation and arrhythmogenesis as promising drug targets for patients with atrial fibrillation. This article focuses on novel aspects of altered atrial repolarisation and discusses atrium-selective (I(Kur), I(K,ACh)) and pathology-specific (I(K,ACh)) ion channels as potential targets for safe and effective treatment of atrial fibrillation.
Journal of Interventional Cardiac Electrophysiology 09/2008; 22(2):107-10. · 1.17 Impact Factor
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ABSTRACT: Although defective Ca(2+) homeostasis may contribute to arrhythmogenesis in atrial fibrillation (AF), the underlying molecular mechanisms remain poorly understood. Studies in patients with AF revealed that impaired diastolic closure of sarcoplasmic reticulum (SR) Ca(2+)-release channels (ryanodine receptors, RyR2) is associated with reduced levels of the RyR2-inhibitory subunit FKBP12.6.
The objective of the present study was to test the hypothesis that Ca(2+) leak from the SR through RyR2 increases the propensity for AF in FKBP12.6-deficient (-/-) mice.
Surface electrocardiogram and intracardiac electrograms were recorded simultaneously in FKBP12.6-/- mice and wild-type (WT) littermates. Right atrial programmed stimulation was performed before and after injection of RyR2 antagonist tetracaine (0.5 mg/kg). Intracellular Ca(2+) transients were recorded in atrial myocytes from FKBP12.6-/- and WT mice.
FKBP12.6-/- mice had structurally normal atria and unaltered expression of key Ca(2+)-handling proteins. AF episodes were inducible in 81% of FKBP12.6-/-, but in only 7% of WT mice (P <.05), and were prevented by tetracaine in all FKBP12.6-/- mice. SR Ca(2+) leak in FKBP12.6-/- myocytes was 53% larger than in WT myocytes, and FKBP12.6-/- myocytes showed increased incidence of spontaneous SR Ca(2+) release events, which could be blocked by tetracaine.
The increased vulnerability to AF in FKBP12.6-/- mice substantiates the notion that defective SR Ca(2+) release caused by abnormal RyR2 and FKBP12.6 interactions may contribute to the initiation or maintenance of atrial fibrillation.
Heart rhythm: the official journal of the Heart Rhythm Society 07/2008; 5(7):1047-54. · 4.56 Impact Factor
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Cardiovascular Research 07/2008; 78(3):411-2. · 6.06 Impact Factor
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ABSTRACT: Congestive heart failure (CHF) is a common cause of atrial fibrillation. Focal sources of unknown mechanism have been described in CHF-related atrial fibrillation. The authors hypothesized that abnormal calcium (Ca(2+)) handling contributes to the CHF-related atrial arrhythmogenic substrate.
CHF was induced in dogs by ventricular tachypacing (240 bpm x2 weeks). Cellular Ca(2+)-handling properties and expression/phosphorylation status of key Ca(2+) handling and myofilament proteins were assessed in control and CHF atria. CHF decreased cell shortening but increased left atrial diastolic intracellular Ca(2+) concentration ([Ca(2+)](i)), [Ca(2+)](i) transient amplitude, and sarcoplasmic reticulum (SR) Ca(2+) load (caffeine-induced [Ca(2+)](i) release). SR Ca(2+) overload was associated with spontaneous Ca(2+) transient events and triggered ectopic activity, which was suppressed by the inhibition of SR Ca(2+) release (ryanodine) or Na(+)/Ca(2+) exchange. Mechanisms underlying abnormal SR Ca(2+) handling were then studied. CHF increased atrial action potential duration and action potential voltage clamp showed that CHF-like action potentials enhance Ca(2+)(i) loading. CHF increased calmodulin-dependent protein kinase II phosphorylation of phospholamban by 120%, potentially enhancing SR Ca(2+) uptake by reducing phospholamban inhibition of SR Ca(2+) ATPase, but it did not affect phosphorylation of SR Ca(2+)-release channels (RyR2). Total RyR2 and calsequestrin (main SR Ca(2+)-binding protein) expression were significantly reduced, by 65% and 15%, potentially contributing to SR dysfunction. CHF decreased expression of total and protein kinase A-phosphorylated myosin-binding protein C (a key contractile filament regulator) by 27% and 74%, potentially accounting for decreased contractility despite increased Ca(2+) transients. Complex phosphorylation changes were explained by enhanced calmodulin-dependent protein kinase IIdelta expression and function and type-1 protein-phosphatase activity but downregulated regulatory protein kinase A subunits.
CHF causes profound changes in Ca(2+)-handling and -regulatory proteins that produce atrial fibrillation-promoting atrial cardiomyocyte Ca(2+)-handling abnormalities, arrhythmogenic triggered activity, and contractile dysfunction.
Circulation Arrhythmia and Electrophysiology 06/2008; 1(2):93-102. · 6.46 Impact Factor
