Right Heart Adaptation to Pressure and Volume Overload: Epidemiology, Animal Models, and Molecular Mechanisms

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Xiong, Ping Yu
Pulmonary Hypertension , Mitochondria , Right Heart Failure , Pyruvate Kinase
Background: Pulmonary hypertension (PH) is a syndrome in which an increase in mean pulmonary artery pressure>20 mmHg is associated with adverse pulmonary vascular remodeling, which results in right heart failure and death. The World Health Organization classified PH into 5 groups. The most common causes of PH are left heart diseases, which is classified as group 2 PH. Currently, there is no approved therapy for group 2 PH and treatments are largely supportive. The goal of my PhD work is to find effective therapeutic strategies for group 2 PH in preclinical rodent models. Methods & Results: A retrospective cohort study was done on patients (n=9289) who had a transthoracic echocardiography at the Kingston Health Sciences Centre. We found that although 44.1% patients had elevated pulmonary pressure [right ventricular systolic pressure (RVSP)>30mmHg], only 3.1% carried a clinical diagnosis of PH. The rate of hospitalization increased in direct proportion to RVSP. We studied the supra-coronary aortic banding (SAB) rat model of group 2 PH, a preclinical model of aortic stenosis or coarctation. SAB rats developed group 2 PH and a metabolic shift in the terminal stage of glycolysis in their LV and RV myocardium. Specifically, the expression of pyruvate kinase muscle isoform 2 (PKM2) to 1 (PKM1) ratio was significantly upregulated in the SAB vs. control myocardium. We then treated SAB rats with the PKM2 inhibitor, shikonin, in SAB rats. Shikonin restored PKM2/PKM1 ratio and improved RV function. Finally, we examined the role of RV ischemia in group 1 PH. SAB increases right coronary artery systolic perfusion pressure, which improved RV perfusion, restored the RV PKM2/PKM1 ratio and improved RV function. Conclusion: PH is common and portends adverse outcomes and yet is under-diagnosed by clinicians. Even mild elevation of pulmonary pressure (RVSP>30 mmHg) is associated with increased number of hospitalization and comorbidities. Elevated PKM2/PKM1 ratio is associated with RV dysfunction and failure in the SAB and MCT rat models of PH. Improving RV perfusion pressure and using PKM2 inhibitor, shikonin reduces PKM2/PKM1 ratio to normal level in MCT and SAB rats, respectively. Restoration of normal PKM2/PKM1 ratio is associated with reduced RV hypertrophy and improved RV function.
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