PCSK9 inhibition attenuates alcohol-induced cardiovascular dysfunction and links hepatic lipid accumulation to impaired myocardial contractile reserve.

Excessive alcohol consumption accelerates cardiovascular aging by promoting oxidative stress, inflammation, lipid dysregulation, fibrotic remodeling, and loss of ventricular-vascular reserve. PCSK9, a key regulator of cholesterol metabolism, has emerged as a mediator of age-related cardiovascular dysfunction and alcohol-associated liver and neurovascular injury. We investigated whether PCSK9 inhibition protects against alcohol-induced cardiovascular dysfunction and associated cardiac-hepatic injury in rats. Male Sprague-Dawley rats were assigned to pair-fed control or 35% ethanol liquid diet groups and treated weekly with subcutaneous alirocumab, 50 mg/kg, or vehicle for 6 weeks. Blood alcohol and cholesterol levels were measured; cardiac function was assessed by echocardiography and invasive pressure-volume analysis; and myocardial, vascular, and hepatic injury markers were quantified. Alirocumab reduced total cholesterol in both pair-fed and ethanol-fed rats without altering blood alcohol levels. Chronic ethanol exposure impaired systolic performance, myocardial contractile reserve, diastolic relaxation, and ventricular-arterial coupling, as reflected by reduced stroke volume, cardiac output, ejection fraction, fractional area change, dP/dtmax, stroke work, ESPVR slope, PRSW, and dP/dtmax-EDV, together with abnormalities in TauWeiss and dP/dtmin. PCSK9 inhibition markedly attenuated these functional deficits. Alirocumab also reduced ethanol-induced myocardial and vascular malondialdehyde accumulation and suppressed myocardial induction of NOX4, LOX1, iNOS, TNF-α, ANP, and profibrotic markers. Ethanol increased myocardial fibrosis, hepatic triglyceride accumulation, perilipin-2 staining, and mild hepatic fibrotic remodeling, all of which were attenuated by alirocumab. Liver triglyceride content correlated inversely with ESPVR slope and PRSW. These findings identify PCSK9 as a potential therapeutic target for alcohol-related cardiovascular dysfunction and associated cardiac-hepatic injury.