Exercise-Induced Genomic and Transcriptomic Changes in Heart Failure

Abstract

Cardiorespiratory test (CPX) directly measures cardiorespiratory fitness (CF). CF refers to the ability to supply oxygen to skeletal muscles during sustained exercise and is measured by peak oxygen uptake (VO2) per kg/min body weight. We postulate that impaired CF is associated with pro-inflammatory mechanisms in heart failure (HF). CPX-induced cell free mitochondria DNA (cf-mtDNA) release mediates a pro-inflammatory pattern in HF patients evaluated for heart transplantation. We hypothesize that CPX-induced cf-mtDNA release induces, in healthy individuals, a tightly regulated anti-inflammatory pattern, which is altered in chronic HF. This CPX-induced pattern can aid in clinical management of HF. 16 HF patients and 4 healthy volunteers (HV) underwent CPX using a standardized bicycle ergometer ramp protocol until their individual peak VO2 was reached. Participants were divided into 3 groups: HV (n=4), HF1 (n=7, VO2 >14 mL/kg/min) and HF2 (n=9, VO2 ≤14 mL/kg/min). Blood samples were collected at 3 time points: 30 min before exercise (TP1), at peak VO2 uptake (TP2), and 1 hour post-exercise (TP3) for genomic and transcriptomic analysis using statistical testing (ANOVA). Numbers of cf-mtDNA fragments showed a trend towards an increase in HF within 1h after peak VO2 and decrease in HV (Fig. 1). Time series analysis yielded 11 differentially expressed peripheral blood mononuclear cell transcripts that were more similar between TP2 and TP3 than at TP1 (Fig. 2). The gene expression profile in HF2 was markedly different at all time points from HF1 and HV. CPX allows to study exercise-induced mechanisms of inflammation in HF.