Genetic studies indicate that alcohol consumption may shorten lifespan [16,17,18,19,20,21]. Coupled with rising alcohol use among the aging population and their heightened risk of cardiovascular disease [22], this underscores the urgent need for a deeper understanding of alcohol’s effects on both normal and aging cardiovascular system. Despite these concerns, there are very few studies investigating the impact of chronic alcohol consumption on cardiovascular aging [39].

Our study, using a well-established rat model that closely resembles human cardiovascular aging, reveals that prolonged heavy drinking accelerates the primary aging processes in the heart and blood vessels. This acceleration occurs through mitochondrial dysfunction, increased oxidative and nitrative stress, inflammation, cell death, senescence, and dysregulation of lipid metabolism. These changes contribute to the development and progression of cardiovascular remodeling and dysfunction. Moreover, alcohol aggravates the existing uncoupling of the vascular and cardiac systems associated with aging, further diminishing the heart’s mechanical efficiency, and leading to a reduced cardiovascular reserve capacity.

Excessive chronic alcohol consumption can lead to the development of nonischemic dilated cardiomyopathy with myocardial fibrosis, known as alcoholic (more recently termed alcohol-associated) cardiomyopathy. This condition is characterized by the dilation of the left ventricle and impaired cardiac function [26, 40, 41]. Additionally, excessive alcohol intake impairs vascular function and structure both directly and indirectly. The detrimental effects of alcohol on the cardiovascular system are complex, involving mitochondrial dysfunction, oxidative and nitrative stress, chronic inflammation, parenchymal cell death, impaired protein synthesis and lipid metabolism, autonomic nervous system dysfunction, activation of the renin-angiotensin and sympathetic nervous systems, and hormonal imbalances, among other factors [26, 28, 40, 42, 43]. These pathological processes ultimately lead to cardiovascular dysfunction, pathological remodeling of the heart and vascular system, decreased cardiovascular reserve capacity, and eventually heart failure when the reserve capacity is exhausted.

Ethanol undergoes enzymatic transformation primarily through alcohol dehydrogenase (ADH) or Cytochrome P450 2E (CYP2E1), initially converting it into acetaldehyde. This acetaldehyde is subsequently transported into mitochondria, where aldehyde dehydrogenase metabolizes it into acetate and further into acetyl-CoA. This metabolic pathway results in the production of reactive oxygen species (ROS) such as superoxide, which leads to significant oxidative stress [44, 45]. In addition to mitochondrial impairment, various enzymes including NADPH oxidases and uncoupled inducible nitric oxide synthase (iNOS) can also contribute to ROS generation under pathological conditions. Superoxide can react with nitric oxide (NO) in a diffusion-limited manner, forming peroxynitrite, a reactive nitrogen species (RNS) [38]. Both ROS and RNS damage cellular components such as contractile proteins, enzymes, and mitochondria through oxidation and nitration processes, exacerbating stress signaling, cellular dysfunction, and ultimately leading to cell death in cardiomyocytes and endothelial cells [38].

Consistent with the importance of mitochondrial dysfunction and increased ROS/RNS generation in the pathology of alcohol-induced cardiomyopathy and vascular dysfunction we found decreased myocardial mitochondrial function (complex 1, 2 and 4 activities) and increased expression of angiotensin II receptor and its downstream effector ROS generating enzyme NADPH oxidase (gp91 and p22phox isoforms) in young rats exposed to chronic liquid alcohol diet. Similarly, there was an increased myocardial expression of the inducible nitric oxide synthase (iNOS) (Fig. 2), which could be a significant source of nitric oxide under pathological conditions and when uncoupled can also generate ROS. These alterations, akin to those observed in isolated vessels, were paralleled by elevated levels of lipid peroxidation and protein nitration in the cardiovascular system of young rats exposed to alcohol (Figs. 3 and 9).

ROS/RNS through the activation of various stress signaling pathways and activation of transcription factors can also promote inflammation, cell death and senescence in the cardiovascular system. In line with this we found that chronic alcohol consumption in young rats enhanced myocardial macrophage infiltration and expression of various pro-inflammatory cytokines/chemokines (TNFα, ILβ, and MIP-1) (Fig. 4.), which was also accompanied by increased cell death (apoptotic and PARP dependent) and senescence (Fig. 5), but not myocardial fibrosis (Fig. 6). The predominant oxidative and nitrative stress driven pathology accompanied by modest myocardial inflammation, elevated serum triglyceride levels and absence of myocardial fibrosis in young rats on a chronic alcohol diet, and the associated impaired systolic function and endothelium-dependent vasorelaxation aligns well with previously reported findings in mouse models [28].

Consistent with the literature [3, 5, 46,47,48] we observed impaired mitochondrial function, heightened oxidative and nitrative stress, inflammation, cell death, senescence, and myocardial fibrosis in the hearts and/or vasculature of aging animals (Figs. 1, 2, 3, 4, 5, 6). Additionally, impaired lipid metabolism was evident, reflected by elevated serum LDL cholesterol levels. Chronic alcohol consumption in aging rats further aggravated these pathological processes (Figs. 1, 2, 3, 4, 5, 6).

Recent preclinical and clinical studies have highlighted a potential link between the development of metabolic dysfunction-associated steatohepatitis (MASH; formerly termed non-alcoholic steatohepatitis (NASH)) and cardiac dysfunction, including aging-related cardiac impairment [5, 12, 49]. Given that alcohol consumption is a known driver of alcohol related steatohepatitis (ASH) and that ALD worsens with aging, it is reasonable to hypothesize that ALD in aging may also contribute indirectly to cardiac dysfunction.

Research into alcohol-associated cardiomyopathy extensively explores cardiac performance using invasive, noninvasive, and in vitro methods [26, 39, 40, 43, 44, 50]. Yet, debates persist regarding the overall impact of ethanol consumption on cardiovascular function and disease, as it can be dose- and time-dependent, affecting not only the heart but also the vasculature, influencing either vasoconstriction or vasodilation [26]. Most studies investigating alcohol-induced cardiovascular function have relied on the use of conventional echocardiography. However, conventional echocardiographic measurements are dependent on loading conditions and heart rate and are often unreliable in conditions with significant vascular alterations, which occur during both acute [51] and chronic [28] alcohol consumption. Similar changes also occur during cardiovascular aging [52]. Therefore, to reliably investigate the effects of ethanol consumption on cardiovascular performance, a comprehensive analysis of cardiac and vascular function is required.

Thus, to determine the cardiovascular consequences of chronic alcohol consumption we utilized invasive hemodynamic examination and pressure–volume (P–V) analysis [31, 52, 53], a gold standard in complex hemodynamic measurements. P–V analysis enables the measurement of pre- and afterload, as well as heart rate-independent systolic contractility parameters, specific diastolic function, cardiac stiffness, and vascular parameters (elastance, total peripheral resistance, etc.). It also allows calculations of important mechanoenergetic parameters, such as ventriculo-arterial coupling (VAC) and mechanical efficiency. In addition to the P–V approach, we also investigated the vascular function in isolated aortic rings by evaluating the endothelial-dependent vasorelaxant response to acetylcholine.

We observed a significant reduction in systolic indices, including cardiac output, ejection fraction, + dP/dtmax, stroke work, Ees, PRSW, and + dP/dtmax-EDV, indicating left ventricular (LV) contractile dysfunction in both young and aging rats subjected to chronic ethanol consumption (Fig. 7). These detrimental effects of alcohol on systolic cardiac performance were notably more pronounced in aging animals. Aging animals in our study on a pair-fed diet exhibited characteristic functional changes (Fig. 7) similar to those previously described [5, 30, 34].

In addition to prominent systolic dysfunction, we noted a significant worsening of diastolic LV relaxation, evidenced by increased Taus and decreased dP/dtmin, in aging animals (Fig. 8). This was accompanied by increased LV stiffness, as measured by LVEDP and the slope of EDPVR. These pathological changes were further exacerbated by alcohol in aging rats and were consistent with the increased fibrosis observed in these groups.

Regarding vascular indices, we observed an increase in total peripheral resistance (TPR) in aging animals, which was further exacerbated by chronic alcohol consumption (Fig. 10). Additionally, chronic alcohol consumption impaired endothelial-dependent vascular function in isolated aortic rings both in young and aging rats (Fig. 10). Our functional data align with in vitro findings, indicating that significant myocardial oxidative/nitrative stress and inflammation, combined with mitochondrial dysfunction, impaired lipid metabolism, increased cell death and senescence, leads to an energetic crisis. This crisis combined with remodeling (fibrosis) results in the observed impairments in cardiac contractility and diastolic relaxation.

We also employed P–V analysis to assess the mechanoenergetic parameters, such as ventriculo-arterial coupling (VAC) and efficiency. Ventriculo-arterial coupling is the ratio of Ees (end-systolic elastance) to Ea (arterial elastance) [54, 55]. Venticulo-arterial coupling is a critical determinant of cardiovascular health, reflecting the efficiency of the heart and vascular system working together [54, 55]. Disruption in this balance, observed in aging, hypertension, and heart failure, is linked to poor cardiovascular outcomes, and serves as a significant predictor of morbidity and mortality [54,55,56]. Mechanoenergetic efficiency (related to Ees, and the P–V area and calculated as the ratio of stroke work (SW) and pressure–volume area (PVA)) is an important measure of cardiac performance, reflecting how effectively the heart converts metabolic energy into mechanical work [57, 58]. In cardiovascular diseases such as heart failure, hypertension, ischemic heart disease, aging, and diabetes, reduced mechanoenergetic efficiency is common and is associated with increased morbidity and mortality [57, 59].

Chronic alcohol consumption both in young and aging animals significantly increased the ventriculo-arterial coupling ratio, indicating a mismatch (uncoupling) between the left ventricle’s contractility and the arterial system’s load, leading to inefficient stroke volume transmission, increased cardiac workload, reduced cardiac efficiency, and a higher risk of cardiovascular events. Consistently with arterio-ventricular uncoupling, we also found that chronic alcohol consumption in both young and aging rats reduced cardiac efficiency. This reduction suggests a decrease in metabolic efficiency, likely caused by mitochondrial disturbances and oxidative/nitrative stress observed in the hearts of the experimental animals. Understanding and assessing these parameters in subjects with alcohol use disorder can provide valuable insights into patient risk and guide therapeutic strategies to optimize cardiovascular function and improve patient outcomes.

Although the available literature is limited, evidence suggests that in the early stages of alcohol-associated cardiomyopathy, where cardiomyocyte death and fibrotic remodeling have not yet occurred, myocardial dysfunction may be reversible [60]. In such cases, complete alcohol abstinence can lead to significant improvements in cardiac function. However, in advanced stages, prolonged alcohol consumption results in irreversible structural damage, significantly limiting recovery even after cessation [60]. Regular exercise improves ventricular-arterial coupling in the elderly by reducing arterial stiffness and improving ventricular contractility, leading to more efficient energy transfer between the heart and arteries [61]. Given these benefits, it is plausible that combining alcohol abstinence with regular exercise could positively impact cardiovascular function in alcohol-associated cardiomyopathy by mitigating vascular stiffness, improving cardiac efficiency, and potentially slowing disease progression.

Collectively, our findings demonstrate that chronic alcohol consumption accelerates cardiovascular aging (Fig. 11). Additionally, we show that long-term drinking impairs the efficiency of the heart and vascular system, diminishing the heart’s ability to convert metabolic energy into mechanical work. This leads to a decreased cardiovascular reserve capacity and an increased risk of cardiovascular disease.

Effects of alcohol on cardiovascular aging and reserve capacity. A schematic illustration depicting the mechanisms by which alcohol promotes cardiovascular aging and reduces cardiovascular reserve capacity