High-resolution respirometry in human endomyocardial biopsies shows reduced ventricular oxidative capacity related to heart failure

Daniel Scheiber,Tomas Jelenik,Julia Szendroedi,Patrick Horn,Heinz-Peter Schultheiss,Malte Kelm,Diyar Saeed,Dirk Lassner,Elric Zweck,Udo Boeken,Michael Roden,Ralf Westenfeld

doi:10.1038/s12276-019-0214-6

Abstract

The lifetime risk of developing heart failure is approximately 20%, and survival rates remain poor. Myocardial mitochondrial function has been suggested to play a pivotal role in heart failure pathophysiology. Human studies on ex vivo mitochondrial function have mostly been limited to atrial tissue obtained during open heart surgery and have provided contradictory results. This study aimed at measuring myocardial mitochondrial function in transcatheter ventricular endomyocardial biopsies and assessing the relationship between oxidative capacity and heart function. We enrolled 40 heart failure patients undergoing ventricular assist device surgery or heart transplantation (34 males, age 57 ± 11 years, body mass index 26.6 ± 4.8 kg/m2) and 29 heart transplant recipients of comparable age and body mass index with normal left ventricular function undergoing surveillance biopsies (23 males, 57 ± 12 years, body mass index 26.2 ± 4.1 kg/m2). High-resolution respirometry was established in the myocardium to measure oxidative capacity ex vivo. The mitochondrial oxidative capacity was 90% higher in ventricular compared to atrial tissues (n = 11, p < 0.01) of explanted hearts. Respiration rates were comparable in ventricular samples of heart failure patients obtained during open heart surgery by standard tissue preparation or ex vivo endomyocardial biopsy (r = 0.9988, p < 0.0001, n = 8), and the mitochondrial oxidative capacity in samples from these patients remained stable for 8 h when stored in either of two common preservation buffers. The oxidative capacity was 44% lower in heart failure than in transplant recipients (67 ± 3 vs. 97 ± 5 pmol/[s mg], p < 0.0001) and correlated positively with heart function (r = 0.49, p < 0.01). High-resolution respirometry of ventricular tissue is feasible in transcatheter biopsies, facilitating clinical studies on myocardial mitochondrial function in patients not undergoing heart surgery.

Highlights

Heart failure (HF) is a rising medical and societal burden[1]
Cardiac function in HF patients was significantly impaired compared to HTX patients, with an approximately 60% lower left ventricular (LV) ejection fraction and an approximately 40% lower cardiac index
The mitochondrial oxidative capacity of LV tissue was reduced by 44% in HF compared to HTX patients and correlated positively with the cardiac index

Summary

Introduction

Due to the aging of the population and improved survival from acute cardiac diseases, HF prevalence is increasing steadily, with a 20% lifetime risk for the development of HF2, which has a poor prognosis. The pathophysiology of HF is complex, but growing evidence from both preclinical and clinical studies points to impaired mitochondrial function in HF3,4. Mitochondria appear to be a promising therapeutic target to improve cardiac function[5]. Current in vivo noninvasive measurement of heart energy metabolism relies on the relative concentrations of phosphorous metabolites and is restricted to selected clinical centers[6,7,8].

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