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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?

SUBMITTER: Liu N

PROVIDER: S-EPMC5587648 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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

Liu Nana N Zheng Min M Li Shijie S Bai Hui H Liu Zhouying Z Hou Cui Hong CH Zhang Shu S Pu Jielin J

Scientific reports 20170906 1

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 ...[more]

PMID: 28878402

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Project description:Background: Left bundle branch area pacing (LBBAP) is a novel pacing modality with stable pacing parameters and a narrow-paced QRS duration. We compared heart failure (HF) hospitalization events and echocardiographic measures between LBBAP and right ventricular pacing (RVP) in patients with atrioventricular block (AVB). Methods and Results: This multicenter observational study prospectively recruited consecutive AVB patients requiring ventricular pacing in five centers if they received LBBAP or RVP and had left ventricular ejection fraction (LVEF) >50%. Data on electrocardiogram, pacing parameters, echocardiographic measurements, device complications, and clinical outcomes were collected at baseline and during follow-up. The primary outcome was first episode hospitalization for HF or upgrade to biventricular pacing. LBBAP was successful in 235 of 246 patients (95.5%), while 120 patients received RVP. During a mean of 11.4 ± 2.7 months of follow-up, the ventricular pacing burden was comparable (83.9 ± 35.1 vs. 85.7 ± 30.0%), while the mean LVEF differed significantly (62.6 ± 4.6 vs. 57.8 ± 11.4%) between the LBBAP and RVP groups. Patients with LBBAP had significantly lower occurrences of HF hospitalization and upgrading to biventricular pacing than patients with RVP (2.6 vs. 10.8%, P <0.001), and differences in primary outcome between LBBAP and RVP were mainly observed in patients with ventricular pacing >40% or with baseline LVEF <60%. The primary outcome was independently associated with LBBAP (adjusted HR 0.14, 95% CI: 0.04-0.55), previous myocardial infarction (adjusted HR 6.82, 95% CI: 1.23-37.5), and baseline LVEF (adjusted HR 0.91, 95% CI: 0.86-0.96). Conclusion: Permanent LBBAP might reduce the risk of HF hospitalization or upgrade to biventricular pacing compared with RVP in AVB patients requiring a high burden of ventricular pacing. Clinical Trial Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03851315; URL: http://www.chictr.org.cn; Unique Identifier: ChiCTR2100043296.

Project description:Background: No medical therapies exist to treat right ventricular (RV) remodeling and RV failure (RVF), in large part because molecular pathways that are specifically activated in pathologic human RV remodeling remain poorly defined. Murine models have suggested involvement of Wnt signaling, but this has not been well-defined in human RVF. Methods: Using a candidate gene approach, we sought to identify genes specifically expressed in human pathologic RV remodeling by assessing the expression of 28 WNT-related genes in the RVs of three groups: explanted nonfailing donors (NF, n = 29), explanted dilated and ischemic cardiomyopathy, obtained at the time of cardiac transplantation, either with preserved RV function (pRV, n = 78) or with RVF (n = 35). Results: We identified the noncanonical WNT receptor ROR2 as transcriptionally strongly upregulated in RVF compared to pRV and NF (Benjamini-Hochberg adjusted P < 0.05). ROR2 protein expression correlated linearly to mRNA expression (R 2 = 0.41, P = 8.1 × 10-18) among all RVs, and to higher right atrial to pulmonary capillary wedge ratio in RVF (R 2 = 0.40, P = 3.0 × 10-5). Utilizing Masson's trichrome and ROR2 immunohistochemistry, we identified preferential ROR2 protein expression in fibrotic regions by both cardiomyocytes and noncardiomyocytes. We compared RVF with high and low ROR2 expression, and found that high ROR2 expression was associated with increased expression of the WNT5A/ROR2/Ca2+ responsive protease calpain-μ, cleavage of its target FLNA, and FLNA phosphorylation, another marker of activation downstream of ROR2. ROR2 protein expression as a continuous variable, correlated strongly to expression of calpain-μ (R 2 = 0.25), total FLNA (R 2 = 0.67), calpain cleaved FLNA (R 2 = 0.32) and FLNA phosphorylation (R 2 = 0.62, P < 0.05 for all). Conclusion: We demonstrate robust reactivation of a fetal WNT gene program, specifically its noncanonical arm, in human RVF characterized by activation of ROR2/calpain mediated cytoskeleton protein cleavage.

Dataset Information

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

Publications

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

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