Marked deterioration of mitochondrial function in failing cardiomyocytes exposed to hypoxic conditions
Sabbah HN, Gupta RC, and Singh-Gupta V. Marked deterioration of mitochondrial function in failing cardiomyocytes exposed to hypoxic conditions. Journal of the American College of Cardiology 2020; 75(11):697.
J Am Coll Cardiol
Background Clinical presentation of acute heart failure (HF) defined as new-onset or worsening of chronic HF, includes symptoms or signs of congestion and volume overload. Understanding the underlying pathophysiological mechanisms related to congestion is essential for offering better treatment to these patients. Congestion can cause dyspnea as well as hypoxia often at the organ level. We and others have shown that under normoxic (NX) conditions, cardiac mitochondria (MITO) are dysfunctional in HF leading to energy deprivation and contributing to progressive LV dysfunction. This study tested the hypothesis that exposure of failing cardiomyocytes to hypoxia (HX) elicits further worsening of MITO function. Methods Cardiomyocytes were isolated from the LV free wall of 4 normal (NL) dogs and 7 dogs with HF produced by intracoronary microembolizations (LV ejection fraction <30%). A standard collagenase-based enzymatic process was used for isolation that yielded ~70% viable rod-shaped cardiomyocytes that excluded trypan blue. Equal aliquots of cardiomyocytes from NL and HF dogs were incubated for 1 hour at 37°C under NX conditions (room air) and under HX conditions (95% N2 +5% CO2). At the end of incubation, MITO ADP-stimulated state-3 respiration (ADPresp) was measured using a Strathklein respirometer and MITO maximum rate of ATP synthesis (ATPsyn) was measured using the bioluminescent ApoSENSOR assay kit. Results Under NX conditions, ADPresp and ATPsyn in HF cardiomyocytes were decreased to levels down to only 40% of NL cardiomyocytes (ADPresp: 167±10 vs. 470±38 nAtom Oxygen/min/mg protein, p<0.05; ATPsyn: 19±1 vs. 46±1 RFU/µg protein, p<0.05). Exposure of HF cardiomyocytes to HX elicited a further decrease of ADPresp and ATPsyn to levels down to only 20% of NL (ADPresp: 111±14 nAtom Oxygen/min/mg protein; ATPsyn: 10±5 RFU/µg protein). Conclusion Exposure of failing cardiomyocytes to HX conditions, even for short periods of time, can deliver a crippling insult to MITO function that can potentially lead to a critical state of cardiac energy deprivation with adverse consequences on LV function.