Genetic Mechanisms Contribute to the Development of Heart Failure in Patients with Atrioventricular Block and Right Ventricular Apical Pacing

Abstract

Right ventricular apical (RVA) pacing can lead to progressive left ventricular dysfunction and heart failure (HF), even in patients with normal cardiac structure and function. Our study conducted candidate gene screening and lentivirus transfected neonatal rat cardiomyocytes (NRCMs) to explore the genetic and pathogenic mechanisms of RVA pacing induced cardiomyopathy in third degree atrioventricular block (III AVB) patients. We followed 887 III AVB patients with baseline normal cardiac function and RVA pacing. After a median follow-up of 2.5 years, 10 patients (four males, mean age 47.6 ± 10.0 years) were diagnosed with RVA pacing induced HF with left ventricular ejection fraction (LVEF) reducing dramatically to 37.8 ± 7.1% (P < 0.05). Candidate genes sequencing found cardiomyopathy associated genetic variations in all ten HF patients and six SCN5A variations in 6 of 20 control patients. Transfected NRCMs of Lamin A/C mutations (R216C and L379F) disrupted Lamin A/C location on nucleus membrane and finally resulted in increased apoptotic rate after serum starvation. In conclusion, cardiomyopathy associated genetic variations play an essential role in occurrence of newly onset HF in the III AVB patients with RVA pacing. RVA pacing, serving as extra stimulator, might accelerate the deterioration of cardiac structure and function.

Identification of TTN as a novel candidate gene for atrioventricular block in a Chinese pedigree by whole-exome sequencing

“…4,5 AVB can result from various causes including ischemia, cardiomyopathy, fibrosis or drugs. 6–8 The prevalence of third degree AVB is about 0.04% as reported previously. 9…”

“…10–16 Besides, the structural protein TTN mutation (TTN p.Glu5365Asp;TTN p.Arg3067His; TTN p.Arg8985Cys) was reported previously to be detected among AVB patients. 6 TTN mutation was reported previously to be the genetic cause of cardiomyopathy, 17,18 one of the potential causes of AVB. Recently, TTN was identified as being associated with atrial and atrioventricular electrical activity though genome-wide association study.…”

The Specific Value of Upgrading to Left Bundle Branch Pacing in Patients with Pacing-Induced Cardiomyopathy or Non-Pacing-Induced Cardiomyopathy: A Retrospective Study

“…Cho (31,32). Moreover, Liu et al and Xu et al found that the expression of genetic genes was also associated with PICM (33,34). Of course, all these risk factors still need a better prediction model to help us further identify the PICM.…”

Pacing induced cardiomyopathy

“…For PICM, interventricular dyssynchrony results from high burden RV pacing, whereas in LBBB‐cardiomyopathy it results from native conduction system disease and in PVC‐induced cardiomyopathy, from the presence of high burden ventricular ectopic beats. Although other risk factors, such as the presence of concomitant atrial fibrillation or a favorable genetic milieu may increase the risk of DAC, the presence of dyssynchrony appears to be the primary culprit. For PVC‐induced cardiomyopathy, irregularity of ventricular rate likely provides an additional pathophysiologic insult beyond ventricular dyssynchrony. …”