Alterations in platelet bioenergetics in Group 2 PH-HFpEF patients

Abstract

Background Pulmonary hypertension (PH) is characterized by elevated pulmonary artery pressure but classified into subgroups based on disease etiology. It is established that systemic bioenergetic dysfunction contributes to the pathogenesis of pulmonary arterial hypertension classified as World Health Organization (WHO) Group 1. Consistent with this, we previously showed that platelets from Group 1 PH patients demonstrate increased glycolysis and enhanced maximal capacity for oxidative phosphorylation, which is due to increased fatty acid oxidation (FAO). However, it remains unclear whether identical mitochondrial alterations contribute to the pathology of other PH subgroups. The most prevalent subgroup of PH is WHO Group 2, which encompasses pulmonary venous hypertension secondary to left heart disease. Here, we hypothesized that platelets from Group 2 subjects show bioenergetic alteration compared to controls, and that these changes were similar to Group 1 PH patients. Method and results We isolated platelets from subjects with Group 2 PH and controls (n = 20) and measured platelet bioenergetics as well as hemodynamic parameters. We demonstrate that Group 2 PH platelets do not show a change in glycolytic rate but do demonstrate enhanced maximal capacity of respiration due at least partially to increased FAO. Moreover, this enhanced maximal capacity correlates negatively with right ventricular stroke work index and is not changed by administration of inhaled nitrite, a modulator of pulmonary hemodynamics. Conclusions These data demonstrate that Group 2 PH subjects have altered bioenergetic function though this alteration is not identical to that of Group 1 PH. The implications of this alteration for disease pathogenesis will be discussed.

Peripheral Blood Mononuclear Cells and Platelets Mitochondrial Dysfunction, Oxidative Stress, and Circulating mtDNA in Cardiovascular Diseases

“…On the other hand, Nguyen et al recently observed that the platelets of patients with pulmonary hypertension secondary to left heart diseases demonstrated an enhanced maximal respiratory capacity despite a normal basal oxygen consumption rate [45]. Increased fatty acid oxidation, together with the metabolic syndrome, likely contributed to this result.…”

Current Understanding of Circulating Biomarkers in Pulmonary Hypertension Due to Left Heart Disease

“…Unlike platelets from PAH patients, only an increase in maximal respiratory capacity, but not in glycolytic rate, was observed in platelets from PH-HFpEF patients relative to healthy controls. The enhancement of platelet maximal respiratory capacity was found to be associated with RV dysfunction, but not with mPAP or PVR in patients with PH-HFpEF ( 88 ). Whether or not a measurement of these factors can provide a method for distinguishing PH-LHD patient phenotypes, identifying at-risk subjects, and predicting PH-LHD patient outcomes requires additional research.…”

“…While this led the authors to conclude that high CRP levels may identify a unique HFpEF phenotype that is associated with comorbidity-driven systemic inflammation, CRP levels were not associated with PH or LV function in this study cohort ( 87 ). Lastly, platelets from patients with PH-HFpEF have also been shown to exhibit a distinct metabolic phenotype compared to patients with PAH ( 88 ). Unlike platelets from PAH patients, only an increase in maximal respiratory capacity, but not in glycolytic rate, was observed in platelets from PH-HFpEF patients relative to healthy controls.…”

The Biological Bases of Group 2 Pulmonary Hypertension

“…Whether mitochondrial dysregulation takes place in other PH forms is unknown, as well as the role of the mitochondria in PH-LHD. However, alterations in platelet bioenergetics, a known proxy of mitochondrial function changes, have been recently reported in PH-LHD [65]. These alterations are characterized by an increase in respiratory capacity, similar to PAH subjects, but not by an increase in glycolysis.…”

“…These alterations are characterized by an increase in respiratory capacity, similar to PAH subjects, but not by an increase in glycolysis. Further, nitrite has shown no effect on the mitochondrial respiration of platelets [65].…”