Metabolic Remodeling in Pulmonary Arterial Hypertension (PAH)

Pulmonary Arterial Hypertension Clinical Trial

Official title: Cardiac Metabolic Remodeling After Pulmonary Vasodilator Therapy in Pulmonary Arterial Hypertension: A Pilot Study

Status Recruiting

Clinical Trial Summary

Pulmonary arterial hypertension (PAH) is a progressive disease in which clinically relevant symptoms present a few years after the onset in rise of pulmonary arterial pressure. Increased PA pressure presents an overload on the right ventricle (RV), with RV failure being a common cause of mortality in PAH. Current therapeutic targets help reduce vascular resistance and RV afterload, however, RV dysfunction may continue to progress. Therefore, the reason for RV failure in PAH cannot be contributed to altered vascular hemodynamics alone but may be related to metabolic alterations and failure of adaptive mechanisms in the RV. Providing a better understanding of metabolic remodeling in RV failure may permit the development of RV-targeted pharmacological agents to maintain RV function despite increased pulmonary vascular pressures. This study will evaluate how cardiac metabolism changes in response to pulmonary vasodilator therapy in patients with pulmonary arterial hypertension.

Clinical Trial Description

PAH is a silent progressive disease of the pulmonary vasculature that often presents clinically later in the course of disease. Symptoms, including severe shortness of breath, present on average 2 years post onset as pulmonary arterial pressures rise due to elevated pulmonary vascular resistance (PVR). Elevated PVR causes right ventricular (RV) overload, metabolic shifts and myocardial remodeling resulting in impaired RV contractility, dysfunction, and subsequent RV failure. Right heart failure is a common cause of death in patients with PAH. Currently, all therapies for PAH target the pulmonary vasculature by improving pulmonary vasodilation and reducing vascular resistance. There is limited direct effect on the myocardium, although RV function generally improves with reduced afterload. However, despite reduction in PVR with vasodilators, the resting RV dysfunction may ultimately progress in patients with PAH. Thus, the reason for RV failure cannot be completely attributed to the changes in pulmonary vascular hemodynamics but may also be related to metabolic shifts and failure of compensatory mechanisms in the RV. A better understanding of how the RV myocardium remodels in RV failure from PAH and in response to pulmonary vasodilator therapy may allow for development of RV-targeted therapies to maintain RV function despite continually elevated afterload.

Currently, there are very few existing techniques to study cardiac metabolism in vivo. Nuclear medicine techniques (i.e., Positron Emission Tomography, PET, and Single Photon Emission Computer Tomography, SPECT) are limited in that they utilize radiolabeled tracers which cannot distinguish the tracer and its metabolic products and expose patients to ionizing radiation. Hyperpolarized (HP) magnetic resonance spectroscopic imaging (MRSI) of 13C-labeled species enables large-scale determination of cellular metabolism linked to pathophysiological mechanisms of disease without the use of ionizing radiation, and represents a unique and novel method to image real time in vivo cardiac metabolic substrate utilization coupled to cardiac function. Currently, the canonical HP compound utilized is 13C-pyruvate. The short-lived, non-radioactive, HP 13C-pyruvate metabolites are biologically analogous to their endogenous analogues and can reveal enzymatic activity (e.g., lactate dehydrogenase and pyruvate dehydrogenase) before and after interventions that are not readily answered by PET or any other imaging method. Importantly, HP MRSI has the potential to reveal metabolic mechanisms associated with cardiac disease states, understand the relationship of metabolism with contractile function, and may be a biomarker for determining therapeutic efficacy. These techniques will enable robust imaging of cardiac metabolism with quantitative measures derived from both the RV and LV. Measurement of downstream products of pyruvate metabolism, including lactate, alanine, and bicarbonate, will allow for real time activity assessment of lactate dehydrogenase (LDH), alanine aminotransferase (ALAT), pyruvate dehydrogenase (PDH), respectively. The measurement of these downstream products of metabolism; namely, bicarbonate and lactate, will permit the assessment of the relative contribution of oxidative metabolism and glycolysis. Since the imaging is performed on a clinical MRI system, metabolism can be studied simultaneously with classic parameters of cardiac function. ;

Related Conditions & MeSH terms

• Familial Primary Pulmonary Hypertension
• Hypertension
• Pulmonary Arterial Hypertension

• NCT number: NCT04968210
• Study type: Observational
• Source: University of Texas Southwestern Medical Center
• Contact: Kara Goss, MD
• Phone: 214/648-6868
• Email: Kara.Goss@UTSouthwestern.edu
• Status: Recruiting
• Start date: May 27, 2022
• Completion date: December 2024