Impact of Cardiac Resynchronization Therapy on Global and Cardiac Metabolism and Cardiac Mitochondrial Function

Abstract

Cardiac resynchronization therapy (CRT) is one of the most effective therapies for heart failure with reduced ejection fraction (HFrEF), resulting in an improved quality of life, and a decrease in both heart failure hospitalization and mortality. 1À7 Although the macroscopic reverse remodeling response after CRT is well-described, its effects on the molecular and cellular levels remain relatively poorly understood. 8 Animal and limited human studies suggest that CRT improves ion channel signaling, calcium handling, myofilament function, redox balance , and mitochondrial function. 9À17 Mitochondrial and metabolic alterations in heart failure have gained increasing interest as a potential (blood pressure neutral) therapeutic target. However, human studies describing these alterations are limited, and the effects of targeted interventions on metabolic remodeling have only been reported in patients with end-stage heart failure with an indication for left ventricular (LV) assist device implantation. 18,19 Our goal was to specifically investigate the mitochondrial and metabolic alterations in patients with heart failure before and after CRT. Our analysis uses targeted metabolomics combined with nuclear medicine techniques to try and assess substrate use and the efficacy of oxidative phosphorylation (with the end product being the inner mitochondrial membrane potential). By specifically sampling of coronary sinus (CS) blood during CS cannulation and comparing with peripheral blood, we aim to understand the difference between cardiac versus the global metabolome in heart failure. Methods Study Population and Clinical Data Patients were enrolled prospectively in a single heart failure clinic (ZOL Genk, Belgium), between October 2016 and July 2018. Patients selected for this prospective cohort study had an indication for CRT, which for this study was defined as (I) symptomatic (New York Heart Association functional classes IIÀIV) heart failure with a LV ejection fraction (LVEF) of less than 35%, (II) QRS duration of more than 130 msec if left bundle branch block morphology or of more than 150 msec if right bundle branch block morphology , and (III) optimal medical heart failure therapy. 20 Patients with significant comorbidities that might also influence cardiac metabolism, were excluded; a detailed description of exclusion criteria is presented in the Supplementary Methods. Before CRT implantation, patients underwent a detailed, protocol-driven clinical evaluation consisting of medical history evaluation, physical examination, 12-lead electrocardio-gram, 2-and 3-dimensional echocardiography, and cardiopulmonary exercise testing. A detailed description on echocardiography and cardiopulmonary exercise testing protocol is presented in the Supplementary Methods. After CRT implantation, all patients underwent echocardiographic device optimization the subsequent day and were included in remote telemonitoring. Patients remained in regular follow-up in a dedicated CRT clinic with systematic follow-up after 6 weeks, 6 months, and every 9 months thereafter. At 6 months after CRT implantation, physical examination, 12-lead electrocar-diogram, 2-and 3-dimensional echocardiography, and cardio-pulmonary exercise testing studies were repeated. The study was approved by the local ethical committee and all patients provided a written informed consent. The study was conducted according to the principle of good clinical practice and the declaration of Helsinki. This article was drafted according to the STROBE-guidelines for observational studies.