Mitochondrial metabolic adaptation in right ventricular hypertrophy and failure

Area of Science:

• Cardiology
• Metabolic Research
• Pulmonary Hypertension

Background:

• Right ventricular failure (RVF) is a primary cause of mortality in pulmonary arterial hypertension (PAH).
• Patients with PAH exhibit varying responses to pulmonary hypertension, with some developing adaptive right ventricular hypertrophy (RVH) and others maladaptive RVH leading to RVF.
• The underlying mechanisms of RVF remain understudied, with current PAH therapies primarily targeting pulmonary vascular disease.

Purpose of the Study:

• To investigate the role of impaired mitochondrial metabolism in the pathogenesis of RVH and RVF.
• To explore the hypothesis that a vicious cycle of ischemia and transcription factor activation promotes a metabolic shift towards glycolysis in maladaptive RVH.
• To evaluate the potential of targeting mitochondrial metabolism as a therapeutic strategy for RVH and RVF.

Main Methods:

• Review of studies on animal models (rats with adaptive and maladaptive RVH) and human RVH.
• Analysis of metabolic shifts, including reduced glucose oxidation and increased glycolysis, in RVH.
• Examination of the effects of dichloroacetate (a pyruvate dehydrogenase kinase inhibitor) on RV function and metabolism in experimental RVH.

Main Results:

• Both adaptive and maladaptive RVH are associated with reduced glucose oxidation and increased glycolysis.
• Mitochondrial dysfunction and a shift towards less energy-efficient glycolytic metabolism may contribute to RVF.
• Dichloroacetate demonstrated beneficial effects on RV function and metabolism by improving glucose oxidation in experimental RVH.

Conclusions:

• Impaired mitochondrial metabolism plays a significant role in the development of RVH and RVF in PAH.
• Therapeutic interventions aimed at reducing ischemia or enhancing glucose oxidation, such as dichloroacetate, show promise for treating RVH and RVF.
• Targeting mitochondrial dysfunction represents a potential novel therapeutic avenue for RVF in PAH.