Chronic Alcohol Exposure Attenuates Compensatory Hypertrophy and Remodeling and Accelerates Cardiac Dysfunction in a Rat Model of Volume Overload
Authors: Mouton Alan , Ninh Van K , El Hajj Elia C , El Hajj Milad C , Gilpin Nicholas W , Gardner Jason D 
Published: November 2023

Chronic alcohol (EtOH) consumption leads to a form of dilated cardiomyopathy (DCM) known as alcoholic cardiomyopathy (ACM), which involves chamber dilation, interstitial fibrosis, and reduced ejection fraction (EF). Volume overload (VO) induced heart failure also produces a DCM phenotype. As both of these types of cardiac insults produce similar phenotypes, we hypothesized that chronic alcohol consumption would exacerbate VO‐induced cardiac dysfunction and remodeling. For this study, adult male Sprague‐Dawley rats were exposed to EtOH vapor inhalation for 2 weeks (14hr ON/10hr OFF) at a level sufficient to achieve blood alcohol levels (BALs) of ~200mg/dl prior to aortocaval fistula surgery to induce VO. Control animals received sham surgery. Following surgery rats were exposed to EtOH vapor daily for 8 weeks. All rats had undetectable BALs at the time of functional measurements and during tissue collection. Echocardiography was performed weekly to track left ventricular (LV) end‐diastolic diameter (EDD), end‐systolic diameter (ESD), posterior wall thickness at diastole (PWT), and fractional shortening (%FS). Eccentricity index (EI) for eccentric remodeling was calculated by EI=(2 × LV posterior wall thickness at diastole)/EDD. Diastolic wall stress was calculated based on measurements for end‐diastolic volume (EDV), end‐diastolic pressure (EDP), and PWT. LV catheterization was performed to generate LV pressure‐volume loops. Protein expression of collagen I and III, and alpha‐ and beta‐myosin heavy chains (α‐ and β‐MHC) was determined by Western blot. LV expression of atrial and brain natriuretic peptides (ANP and BNP) was determined by quantitative PCR. Collagen I cross‐linking was determined by Western blot analysis of the insoluble LV collagen fraction. VO led to increases in EDD and ESD, and decreases in %FS, which EtOH did not affect. However, EtOH prevented VO‐induced increases in PWT, which led to decreased EI in the VO+EtOH group. The VO+EtOH group also had significantly elevated EDP. Collectively, these changes led to significantly elevated diastolic wall stress in the VO + EtOH group, a hallmark sign of transition from compensatory hypertrophy to decompensated heart failure. Interestingly, EtOH either partially or completely prevented compensatory increases in LV hypertrophy markers collagen I, ANP, and BNP, and also prevented collagen I cross‐linking. EtOH also increased the expression of collagen III in the VO+EtOH group, and prevented compensatory increases in the collagen I/III ratio due to VO. The VO+EtOH group also had increased expression of β‐MHC, suggesting a transition to the fetal cardiac phenotype. We conclude that by blocking compensatory hypertrophy during the progression of VO‐induced cardiac remodeling, EtOH may accelerate the transition to heart failure.

Support or Funding Information

NIH/NIAAA 1R21AA022690‐01A1 (Gardner)

American Heart Association Predoctoral Fellowship 15PRE25090092, Greater Southeast Affiliate (Mouton)