Electrophysiological Consequences of Dyssynchronous Heart Failure and Its Restoration by Resynchronization Therapy

Abstract

Background-Cardiac resynchronization therapy (CRT) is widely applied in patients with heart failure and dyssynchronous contraction (DHF), but the electrophysiological consequences of CRT in heart failure remain largely unexplored. Methods and Results-Adult dogs underwent left bundle-branch ablation and either right atrial pacing (190 to 200 bpm) for 6 weeks (DHF) or 3 weeks of right atrial pacing followed by 3 weeks of resynchronization by biventricular pacing at the same pacing rate (CRT). Isolated left ventricular anterior and lateral myocytes from nonfailing (control), DHF, and CRT dogs were studied with the whole-cell patch clamp. Quantitative polymerase chain reaction and Western blots were performed to measure steady state mRNA and protein levels. DHF significantly reduced the inward rectifier K ϩ current (I K1 ), delayed rectifier K ϩ current (I K ), and transient outward K ϩ current (I to ) in both anterior and lateral cells. CRT partially restored the DHF-induced reduction of I K1 and I K but not I to , consistent with trends in the changes in steady state K ϩ channel mRNA and protein levels. DHF reduced the peak inward Ca 2ϩ current (I Ca ) density and slowed I Ca decay in lateral compared with anterior cells, whereas CRT restored peak I Ca amplitude but did not hasten decay in lateral cells. Calcium transient amplitudes were depressed and the decay was slowed in DHF, especially in lateral myocytes. CRT hastened the decay in both regions and increased the calcium transient amplitude in lateral but not anterior cells. No difference was found in Ca V 1.2 (␣1C) mRNA or protein expression, but reduced Ca V ␤2 mRNA was found in DHF cells. DHF reduced phospholamban, ryanodine receptor, and sarcoplasmic reticulum Ca 2ϩ ATPase and increased Na ϩ -Ca 2ϩ exchanger mRNA and protein. CRT did not restore the DHF-induced molecular remodeling, except for sarcoplasmic reticulum Ca 2ϩ ATPase. Action potential durations were significantly prolonged in DHF, especially in lateral cells, and CRT abbreviated action potential duration in lateral but not anterior cells. Early afterdepolarizations were more frequent in DHF than in control cells and were reduced with CRT. Conclusions-CRT partially restores DHF-induced ion channel remodeling and abnormal Ca 2ϩ homeostasis and attenuates the regional heterogeneity of action potential duration. The electrophysiological changes induced by CRT may suppress ventricular arrhythmias, contribute to the survival benefit of this therapy, and improve the mechanical performance of the heart.

Coupling of ventricular action potential duration and local strain patterns during reverse remodeling in responders and nonresponders to cardiac resynchronization therapy

“…19 In a canine model with LBBB ablation, cells isolated from the LV lateral wall after 6 weeks showed APD prolongation which was attenuated by CRT. 8 In humans several studies using body surface ECG measurements have reported repolarization changes during CRT. Braunschweig and colleagues found an initial increase in QT and JT interval followed by a sustained reduction in a group of responders.…”

“…11 While the mechanism underlying reverse electrical remodeling during CRT in heart failure is considered to be multifactorial a general consensus is that LV mechanics play an important role. [6][7][8][9][10] Canine models of myocardial dyssynchrony show APD changes with APD shortening in the early activated low strain regions and APD lengthening in the late activated high strain regions. 21,22 In humans, Kroon et al have recently demonstrated a good correlation between LV depolarization pattern and strain pattern in heart failure patients, 23 and our group has also found a similar correlation in heart failure patients with LBBB.…”

“…Such a relationship would be consistent with the interaction of dyssynchronous contraction with the electrophysiology being multifactorial resulting in ion channel remodeling involving stretch activated receptors, gap junctions via connexins, calcium handling, beta adrenergic responsiveness, mitochondrial function, fibrosis and other changes. [6][7][8][9][10] APD prolongation, particularly in the late activated lateral wall, is a consistent manifestation of heart failure and may contribute to the substrate for ventricular arrhythmias. Changes in all three strain patterns identified whether APD would lengthen or shorten during CRT with a high degree of sensitivity and specificity (Figure 4).…”

“…6 Several studies demonstrating the beneficial effects of CRT on LV remodeling have suggested that improvement of LV mechanical synchrony was the predominant mechanism, 7 while others have in addition focused on the molecular and cellular effects that it chronically induces. [8][9][10] Information in humans is limited. We have recently reported activation recovery interval (ARI), as a surrogate measure of APD, changes in heart failure patients during CRT.…”

Personalised Biophysical Model to Optimise Left Ventricle Pacing Location for Cardiac Resynchronisation Therapy Over Time

“…To improve the response rate of patients, the optimal location from which to pace the LV free wall has therefore received some interest. In earlier studies, it was found that the optimal location from which to pace the LV is in the non-ischemic, non-apical, postero-lateral/lateral regions of the LV epicardium, or the latest point of mechanical or electrical activation [4][5][6].The heart remodels in response to sustained pacing with regards to the anatomy, mechanics and electrophysiology properties [7,8]. New pacing catheter technologies such as multipole pacing (MPP) and multi-vein pacing (MVP) allow for the LV lead position to be altered post implant without further surgery.…”