Mechanisms of Heart Failure Enhanced Atrial Fibrillation

• Main Authors: Shih-Lin Chang, 張世霖
• Other Authors: Shih-Ann Chen
• Format: Others
• Language: en_US
• Published: 2012
• Online Access: http://ndltd.ncl.edu.tw/handle/9qst6z

博士 === 國立陽明大學 === 臨床醫學研究所 === 100 === Background: Atrial fibrillation (AF) and heart failure (HF) often coexist and may predispose to each other, which can cause severe complications, such as cardiac dysfunction, stroke, and even mortality. HF predisposes to AF due to substrate remodeling. Pulmonary vein (PV) is an important source for the initiation and maintenance of AF. Sodium currents and intracellular Ca2+ (Ca2+i) dynamics play a critical role in arrhythmogenesis of PV and HF. It is not clear whether HF enhances AF through modulation of Ca2+ homeostasis and sodium currents. On the other hand, complex fractionated atrial electrogram (CFAE) and dominant frequency (DF) sites have been proposed as important regions for maintaining AF. However, the electrophysiological characteristics of CFAEs site is not fully elucidated. This study aimed to investigate the mechanism of HF enhanced AF. We try to examine the impact of HF on the electrical remodeling of the PVs and left atrium (LA), explore the sodium and calcium homeostasis in PV cardiomyocytes with HF, and understand the electrophysiology of CFAEs and DF areas in HF rabbits with AF. Methods: Two HF rabbit models were created for experiments—rapid ventricular pacing medel and ischemia model. The electrical activity was recorded in LAs and PVs from control rabbits and rabbits with rapid ventricular pacing-induced HF, using a multielectrode array system, and conventional microelectrodes. Whole-cell patch clamp was used to investigate the action potentials and ionic currents in isolated rabbit single PV cardiomyocytes. The Ca2+i dynamics were evaluated through fluorescence and confocal microscopy. To study the electrophysiology of CFAE, AF was induced by rapid atrial pacing in ischemic HF rabbits (4 weeks 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. Results: Compared with the control-PVs (n=21), the HF-PVs (n=13) had a higher incidence and frequency of rapid pacing-induced spontaneous activity (85% vs. 29%; 3.5±0.2 vs. 1.7±0.1 Hz, P<0.05) and high-frequency irregular rhythms (92% vs. 38%; 23±1 vs. 19±1 Hz, P<0.05), greater depolarized resting membrane potential (-59±1 vs. -70±2 mV), higher incidence of early afterdepolarizations (EAD, 50% vs. 6%, P<0.05) and delayed afterdepolarizations (DAD, 88% vs. 25%, P<0.05), and slower conduction velocity (38±2 vs. 63±2 cm/s, P<0.05). In comparison to the HF-LAs, the HF-PVs had a higher incidence and frequency of spontaneous activity and high-frequency irregular rhythms (92% vs. 46%; 23±1 vs. 20±1 Hz, P<0.05), and higher incidence of EADs and DADs, and those differences were not found between the control-LAs and control-PVs. The control-PVs with high-frequency irregular rhythms had a higher incidence of DADs and spontaneous activity as compared to those without it. As compared to control PV cardiomyocytes (n=18), HF-PV cardiomyocytes (n=13) had a higher incidence of DAD (45% versus 13%, P<0.05) and faster spontaneous activity (3.0±0.2 versus 2.1±0.2 Hz, P<0.05). HF-PV cardiomyocytes had increased late Na+ currents, Na+/Ca2+ exchanger (NCX), and transient inward currents, but had decreased Na+ currents or L-type calcium currents. HF PV cardiomyocytes with pacemaker activity had larger Ca2+i transients (R410/485, 0.18±0.04 vs. 0.11±0.02, P<0.05), and sarcoplasmic reticulum Ca2+ stores. Moreover, HF-PV cardiomyocytes with pacemaker activity (n=18) had higher incidence (95% versus 70%, P<0.05), frequency (7.8±3.1 versus. 2.3±1.2 spark/mm/sec, P<0.05), amplitude (F/F0, 3.2±0.8 versus 1.9±0.5, P<0.05), and longer decay time (65±3 versus. 48±4 ms, P<0.05) of Ca2+ sparks than control-PV cardiomyocytes with pacemaker activity (n=18). In ischemic HF induced AF, 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 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. Conclusion: The PVs possessed more arrhythmogenic properties than LA. HF contributed to an increased automaticity, triggered activity, and conduction disturbance in the PVs. Dysregulated sodium and calcium homeostasis, and enhanced calcium sparks promote arrhythmogenesis of PV cardiomyocytes in HF, which plays an important role in the development of AF. CFAE site with high DF had an arrhythmogenic property and distinctive electrophysiological characteristics compared to the other areas of LA in an HF rabbit model, which may contribute to the genesis of AF.