Abstract P2026: Moderate Ethanol Consumption Causes Right Ventricular Hypertrophy And Pulmonary Hypertension Via The Pro-inflammatory Endothelin-interleukin Pathway

Abstract

The substantial increase in ethanol consumption since the Covid-19 pandemic has re-emphasized the need for extensive preclinical research on the cardiac and pulmonary effects of ethanol. Current knowledge is mostly based on ethanol effects on left ventricular (LV) function and blood pressure. Therefore, this preclinical study dealt with the effects of moderate ethanol consumption on right ventricular (RV) and pulmonary artery (PA) structure and function, and the implicated mechanisms in a pulmonary hypertension susceptible rat strain. Two groups of Sprague-Dawley (CD strain) male rats (n=7-8 each) received balanced liquid diet containing 5% ethanol (w/v) or pair-fed with isocaloric liquid diet for 8 weeks. This ethanol regimen resulted in clinically relevant blood ethanol concentration (39.8 + 1.9 mg/dL). Echocardiographic analysis showed progressive decreases in PA acceleration time/ejection time and increases in mean PA pressure (hallmarks of pulmonary hypertension) in ethanol-fed rats. Further, transthoracic echocardiography in long-axis orientation showed a significant increase in the RV internal diameter/left ventricular internal diameter during diastole (RVID-d/LVID-d), indicative of RV dilation in chronic ethanol-treated rats. Echocardiographic LV Mass/body weight and post-mortem Fulton’s index were higher in ethanol-fed rats, suggesting ethanol induced simultaneous LV and RV hypertrophy. Further, ethanol increased mean arterial pressure (measured at the end of the 8-weeks study). Ex vivo biochemical analyses showed upregulation of the vasoconstrictor/pro-inflammatory protein endothelin-1 (ET-1) and its downstream target IL-6 in the RV and lungs of ethanol-fed rats. Finally, ethanol reduced lung endothelin ETB receptor expression but had no effect on the ETA receptor, leading to higher ETA/ETB receptor ratio. Collectively, this study yields new insight into ethanol-evoked RV and pulmonary artery remodeling via the upregulation of the ET-1-IL-6 pathway.