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

Nana Liu,Shijie Li,Jielin Pu,Shu Zhang,Min Zheng,Cui Hong Hou,Zhouying Liu,Hui Bai

doi:10.1038/s41598-017-11211-2

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.

Highlights

As the only effective therapy for bradycardia, millions of permanent cardiac pacemakers are implanted worldwide every year
We hypothesize that genetic mechanism plays an important role in the development of newly-onset heart failure (HF) in certain in third degree atrioventricular block (III AVB) patients and long-term Right ventricular apical (RVA) pacing may accelerate the deterioration of cardiac structure and function
We investigated the genetic background of III AVB patients with RVA pacing induced cardiomyopathy and explored the pathogenic mechanism with transfected neonatal rat cardiomyocytes (NRCMs)

Summary

Introduction

As the only effective therapy for bradycardia, millions of permanent cardiac pacemakers are implanted worldwide every year. Basic Characteristics Age (years) Male, n (%) Hypertension Hypercholesterol Diabetes Mellitus Coronary artery disease History of AF, n (%) Etiologies None, n (%) Cardiac surgery Cardiomyopathies, n (%) HCM RCM LVNC Rheumatic heart disease Myocardial infarction Viral myocarditis RFA Congenital third degree AVB Baseline LVEF (%) Baseline LVEDD (mm) Baseline HR (bpm) Pacing mode, n (%) DDD VDD VVI Mean percentage of ventricular pacing, (%). We hypothesize that genetic mechanism plays an important role in the development of newly-onset HF in certain III AVB patients and long-term RVA pacing may accelerate the deterioration of cardiac structure and function. To evaluate this hypothesis, we investigated the genetic background of III AVB patients with RVA pacing induced cardiomyopathy and explored the pathogenic mechanism with transfected neonatal rat cardiomyocytes (NRCMs)

Methods

Results

Conclusion