O2-sensing signal cascade: clamping of O2 respiration, reduced ATP utilization, and inducible fumarate respiration

These studies explore the consequences of activating the prolyl hydroxylase (PHD) O2-sensing pathway in spontaneously twitching neonatal cardiomyocytes. Full activation of the PHD pathway was achieved using the broad-spectrum PHD inhibitor (PHI) dimethyloxaloylglycine (DMOG). PHI treatment of cardiomyocytes caused an 85% decrease in O2 consumption and a 300% increase in lactic acid production under basal conditions. This indicates a ∼75% decrease in ATP turnover rate, inasmuch as the increased ATP generation by glycolysis is inadequate to compensate for the lower respiration. To determine the extent to which decreased ATP turnover underlies the suppressed O2 consumption, mitochondria were uncoupled with 2,4-dinitrophenol. We were surprised to find that 2,4-dinitrophenol failed to increase O2 consumption by PHI-treated cells, indicating that electron transport chain activity, rather than ATP turnover rate, limits respiration in PHI-treated cardiomyocytes. Silencing of hypoxia-inducible factor-1α (HIF-1α) expression restored the ability of uncoupled PHI-treated myocytes to increase O2 consumption; however, basal O2 uptake rates remained low because of the unabated suppression of cellular ATP consumption. Thus it appears that respiration is actively “clamped” through an HIF-dependent mechanism, whereas HIF-independent mechanisms are responsible for downregulation of ATP consumption. In addition, we find that PHD pathway activation enables mitochondria to utilize fumarate as a terminal electron acceptor when cytochrome c oxidase is inactive. The source of fumarate for this unusual respiration is derived from aspartate via the purine nucleotide cycle. In sum, these studies show that the O2-sensing pathway is sufficient to actively “clamp” O2 consumption and independently suppress cellular ATP consumption. The PHD pathway also enables the mitochondria to utilize fumarate for respiration

Desmin loss and mitochondrial damage precede left ventricular systolic failure in volume overload heart failure

Heart failure due to chronic volume overload (VO) in rats and humans is characterized by disorganization of the cardiomyocyte desmin/mitochondrial network. Here, we tested the hypothesis that desmin breakdown is an early and continuous process throughout VO. Male Sprague-Dawley rats had aortocaval fistula (ACF) or sham surgery and were examined 24 h and 4 and 12 wk later. Desmin/mitochondrial ultrastructure was examined by transmission electron microscopy (TEM) and immunohistochemistry (IHC). Protein and kinome analysis were performed in isolated cardiomyocytes, and desmin cleavage was assessed by mass spectrometry in left ventricular (LV) tissue. Echocardiography demonstrated a 40% decrease in the LV mass-tovolume ratio with spherical remodeling at 4 wk with ACF and LV systolic dysfunction at 12 wk. Starting at 24 h and continuing to 4 and 12 wk, with ACF there is TEM evidence of extensive mitochondrial clustering, IHC evidence of disorganization associated with desmin breakdown, and desmin protein cleavage verified by Western blot analysis and mass spectrometry. IHC results revealed that ACF cardiomyocytes at 4 and 12 wk had perinuclear translocation of \uce\ub1B-crystallin from the Z disk with increased \uce\ub1, \uce\ub2-unsaturated aldehyde 4-hydroxynonelal. Use of protein markers with verification by TUNEL staining and kinome analysis revealed an absence of cardiomyocyte apoptosis at 4 and 12 wk of ACF. Significant increases in protein indicators of mitophagy were countered by a sixfold increase in p62/sequestosome-1, which is indicative of an inability to complete autophagy. An early and continuous disruption of the desmin/mitochondrial architecture, accompanied by oxidative stress and inhibition of apoptosis and mitophagy, suggests its causal role in LV dilatation and systolic dysfunction in VO. NEW & NOTEWORTHY This study provides new evidence of early onset (24 h) and continuous (4-12 wk) desmin misarrangement and disruption of the normal sarcomeric and mitochondrial architecture throughout the progression of volume overload heart failure, suggesting a causal link between desmin cleavage and mitochondrial disorganization and damage

RATIONALE AND DESIGN OF THE PROACTIVE-HF TRIAL FOR MANAGING NYHA CLASS III HEART FAILURE PATIENTS WITH THE COMBINED CORDELLA(TM) PULMONARY ARTERY SENSOR AND THE CORDELLA(TM) HEART FAILURE SYSTEM

BACKGROUND: Optimizing guideline-directed medical therapy (GDMT) and monitoring congestion in heart failure (HF) patients are key to disease management and preventing hospitalizations. A pulmonary artery pressure (PAP)-guided HF management system providing access to body weight, blood pressure, heart rate, blood oxygen saturation, PAP, and symptoms, may provide new insights into the effects of patient engagement and comprehensive care for remote GDMT titration and congestion management. METHODS: The PROACTIVE-HF study was originally approved in 2018 as a prospective, randomized, controlled, single-blind, multi-center trial to evaluate the safety and effectiveness of the Cordella(TM) PAP Sensor in HF patients with New York Heart Association (NYHA) functional class III symptoms. Since then, robust clinical evidence supporting PAP-guided HF management has emerged, making clinical equipoise and enrolling patients into a standard-of-care control arm challenging. Therefore, PROACTIVE-HF was changed to a single-arm trial in 2021 with pre-specified safety and effectiveness endpoints to provide evidence for a similar risk-benefit profile as the CardioMEMS(TM) HF System. CONCLUSION: The single-arm PROACTIVE-HF trial is expected to further demonstrate the benefits of PAP-guided HF management in NYHA class III patients. The addition of vital signs, patient engagement and self-reported symptoms may provide new insights into remote GDMT titration and congestion management