Abstract 17533: Metabolic Manipulation of Carbohydrate Oxidation in a Porcine Right Ventricle Exposed to Pressure Overloading Stress

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Abstract

Introduction: The right ventricle (RV) exposed to sub-acute or chronic pressure overload exhibits hypertrophy and decompensates when exposed to stress. RV maladaptation leading to decreased function typically occurs after surgical palliation of complex congenital heart diseases in early infancy.

Hypothesis: Impaired ability to increase myocardial oxidative flux through pyruvate dehydrogenase (PDH) leads to RV dysfunction when exposed to stress; direct PDH stimulation can improve RV function.

Methods: We used infant male Yorkshire piglets (13.2 ± 0.7 kg, n = 19) to assess substrate fractional contribution to the citric acid cycle after pulmonary artery banding (PAB) through left thoracotomy (pressure overloading RV, n = 5) compared with sham (Control, n = 4). Carbon 13 labeled glucose and lactate, oxidative substrate tracers for citric acid cycle, were infused into right coronary artery on 7-10 days after PAB. We performed NMR and GCMS metabolic analysis on RV tissue in order to map flux to the citric acid cycle. We then assessed substrate utilization under stress by atrial pacing (~80% increase in heart rate) and RV pressure overload (n = 10) with (n = 5) receiving dichloroacetate (DCA), a PDH agonist.

Results: RV systolic pressure (34 ± 2 mmHg) and RV free wall thickness (47 ± 1 mm) on 7-10 days after PAB were significantly elevated compared to Control pigs (22 ± 3 mmHg, 36 ± 2 mm). Both glucose and lactate oxidations in PAB group were > 2-fold higher than in Control. Hemodynamic parameters except RV systolic pressure were similar between Control and PAB groups. Pigs with atrial pacing stress after PAB showed lower lactate and glucose oxidation rate and higher anaerobic lactate flux in RV tissue compared with PAB without atrial pacing. Intracoronary DCA infusion attenuated the RV impairment in PDH flux and produced higher rate-pressure product in response to increased work-load by pacing.

Conclusions: The immature hypertrophied RV relies on carbohydrate oxidation to meet contractile energy requirements. However, the RV shows limited ability to increase PDH flux in response to stress leading to energy supply/utilization imbalance and decreased function. Direct activation PDH activation increases energy supply and preserves RV function during stress.

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