Heart failure enhanced pulmonary vein arrhythmogenesis and dysregulated sodium and calcium homeostasis with increased calcium sparks.
ABSTRACT Late sodium currents and intracellular Ca(2+) (Ca(2+) (i)) dynamics play an important role in arrhythmogenesis of pulmonary vein (PV) and heart failure (HF). It is not clear whether HF enhances PV arrhythmogenesis through modulation of Ca(2+) homeostasis and increased late sodium currents. The aim of this study was to investigate the sodium and calcium homeostasis in PV cardiomyocytes with HF. METHODS AND RESULTS: Whole-cell patch clamp was used to investigate the action potentials and ionic currents in isolated rabbit single PV cardiomyocytes with and without rapid pacing induced HF. The Ca(2+) (i) dynamics were evaluated through fluorescence and confocal microscopy. As compared to control PV cardiomyocytes (n = 18), HF PV cardiomyocytes (n = 13) had a higher incidence of delayed afterdepolarization (45% vs 13%, P < 0.05) and faster spontaneous activity (3.0 ± 0.2 vs 2.1 ± 0.2 Hz, P < 0.05). HF PV cardiomyocytes had increased late Na(+) currents, Na(+) /Ca(2+) exchanger currents, and transient inward currents, but had decreased Na(+) currents or L-type calcium currents. HF PV cardiomyocytes with pacemaker activity had larger Ca(2+) (i) transients (R410/485, 0.18 ± 0.04 vs 0.11 ± 0.02, P < 0.05), and sarcoplasmic reticulum Ca(2+) stores. Moreover, HF PV cardiomyocytes with pacemaker activity (n = 18) had higher incidence (95% vs 70%, P < 0.05), frequency (7.8 ± 3.1 vs 2.3 ± 1.2 spark/mm/s, P < 0.05), amplitude (F/F(0) , 3.2 ± 0.8 vs 1.9 ± 0.5, P < 0.05), and longer decay time (65 ± 3 vs 48 ± 4 ms, P < 0.05) of Ca(2+) sparks than control PV cardiomyocytes with pacemaker activity (n = 18). CONCLUSIONS: Dysregulated sodium and calcium homeostasis, and enhanced calcium sparks promote arrhythmogenesis of PV cardiomyocytes in HF, which may play an important role in the development of atrial fibrillation.
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ABSTRACT: During atrial fibrillation (AF) intracellular Ca(2+) signaling in atrial myocytes changes substantially. This 'remodeled' intracellular Ca(2+) homeostasis plays an important role in the development of the contractile dysfunction and the changes in atrial electrophysiology (contractile and electrical remodeling) that are characteristic of AF. Recent studies also show that unstable intracellular Ca(2+) signaling (i.e. increased Ca(2+) sparks and Ca(2+) waves) is present in atrial myocytes from AF patients and that it might contribute to cellular arrhythmogenic mechanisms that help maintain the arrhythmia. It is currently not well understood how and when unstable Ca(2+) signaling develops during the progression of AF, or if, in cases of structural heart disease, it even precedes the onset of AF. Current work therefore in particular aims to elucidate the molecular and sub-cellular mechanisms underlying the arrhythmogenic intracellular Ca(2+) signaling instability in AF. As treatment of AF remains difficult, the identification of novel targets for counteracting or preventing arrhythmogenic Ca(2+) signaling is an important part of AF research. It is therefore important to recognize which phase of AF is addressed in a specific research (and ultimately treatment) approach. Here we review and critique the distinct alterations in intracellular Ca(2+) signaling during the progression of AF from initial intracellular Ca(2+) overload to the remodeling process. We address Ca(2+) signaling after cardioversion of the arrhythmia and its potential role in the recurrence of AF. We propose that altered Ca(2+) signaling during AF progression consists of three phases 1.) Ca(2+) Overload, 2.) Remodeling, 3.) Steady State. Similarly, after AF termination three distinct phases of 'recovery' of intracellular Ca(2+) handling occur. 4.) Calcium Unloading, 5.) Reverse Remodeling and 6.) Full Recovery. While there is evidence that unstable Ca(2+) signaling is part of phases 1, 3 and 4, phase 2 (remodeling) appears to have a more stabilizing function on Ca(2+) signaling ('Ca(2+) silencing'). This has important implications for the timing and type of pharmacological intervention, especially for new compounds aimed at intracellular 'Ca(2+) stabilization'.Journal of Molecular and Cellular Cardiology 01/2013; · 5.15 Impact Factor
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ABSTRACT: BACKGROUND: Obesity is an important risk factor for atrial fibrillation (AF) and heart failure (HF). The effects of epicardial fat on atrial electrophysiology were not clear. This study was to evaluate whether HF may modulate the effects of epicardial fat on atrial electrophysiology. METHODS: Conventional microelectrodes recording was used to record the action potential in left (LA) and right (RA) atria of healthy (control) rabbits before and after application of epicardial fat from control or HF (ventricular pacing of 360-400bpm for 4weeks) rabbits. Adipokine profiles were checked in epicardial fat of control and HF rabbits. RESULTS: The LA 90% of AP duration was prolonged by control epicardial fat (from 77±6 to 87±7ms, p<0.05, n=7), and by HF epicardial fat (from 78±3 to 98±4ms, p<0.001, n=9). However, control or HF epicardial fat did not change the AP morphology in RA. HF epicardial fat increased the contractility in LA (61±11 vs. 35±6mg, p=0.001), but not in RA. Control fat did not change the LA or RA contractility. Moreover, control and HF epicardial fat induced early and delayed afterdepolarizations in LA and RA, but only HF epicardial fat provoked spontaneous activity and burst firing in LA (n=3/9, 33.3% vs. n=0/7, 0%, n=0/9, 0%, p<0.05). Compared to control fat, HF epicardial fat, had lower resistin, C-reactive protein and serum amyloid A, but similar interluekin-6, leptin, monocyte chemotactic protein-1, adiponectin and adipsin. CONCLUSIONS: HF epicardial fat increases atrial arrhythmogenesis, which may contribute to the higher atrial arrhythmia in obesity.International journal of cardiology 05/2012; · 6.18 Impact Factor
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ABSTRACT: BACKGROUND: It is unclear whether atrial substrate with complex fractionated electrograms (CFAEs) is related to arrhythmogenesis. This study aimed to investigate the electrophysiology in CFAE and high dominant frequency (DF) areas. METHODS AND RESULTS: Atrial fibrillation (AF) was induced by rapid atrial pacing in heart failure (HF) rabbits (4weeks after coronary artery ligation). Real-time substrate mapping, multielectrode array, and monophasic action potential recordings were used to study areas of CFAE and DF. Conventional microelectrode and western blot were used to record the action potentials (APs) and protein expression in isolated tissue preparations. CFAE site with high DF had the most depolarized resting membrane potential, highest incidence of early and delayed afterdepolarizations, and steepest maxima slope of 90% of AP duration (APD90) restitution curve (RC) compared to CFAE site with low DF or non-CFAE sites. CFAE site with high DF exhibited the slowest conduction velocity and shortest wavelength than the other areas. Upregulation of the Na+-Ca2+ exchanger (NCX), apamin-sensitive small-conductance Ca2+-activated K+ channel type 2 (SK2) and sarcoplasmic reticulum Ca2+-ATPase, and downregulation of the Kir2.1 were found at CFAE site with high DF compared to that observed in the 3 other areas. Inhibition of the NCX and SK channels prolonged the APD90, flattened the maximum slope of RC, and suppressed AF. CONCLUSIONS: CFAE site with high DF had an arrhythmogenic property differing significantly from the other areas of LA in an HF rabbit model, which may contribute to the genesis of AF.International journal of cardiology 02/2013; · 6.18 Impact Factor