Ethanol or alcohol, is the most consumed drug in human history. At present, its consumption rates are still very high, with a widespread worldwide distribution, in a global uncontrolled scenario with easy access. This ethanol misuse at high consumption rates causes a variety of health problems, ethanol being the sixth most relevant factor of global burden of disease and responsible for 5.3% of all deaths
One of the characteristics that makes ethanol harmful is its systemic toxic effect on the human body. It has been described as having some kind of effect in all human body organs either in acute or chronic consumption.
The liver is the most affected organ, since ethanol is mostly metabolized there but central, and peripheral nervous systems; the heart and vascular system; endocrinological systems; nutrition; and muscular-skeletal systems are clearly affected. This multi-factorial effect is attributed to genetic factors and ethnic variability. The final damage is an equilibrium between the intensity of damaging effects and the possibility of defence, plasticity, regeneration, and adaptation for every specific organ. Thus, alcohol-dilated cardiomyopathy (ACM) is the result of dosage and individual predisposition. This article, specifically describe and discuss the global effects that ethanol exerts on the heart myocytes, the so-called alcoholic cardiomyopathy.
The first clinical recognition of ACM was performed by Hippocrates in Greece during the 4th century B.C. However, its modern clinical report was delayed until the 19th century, where specific ACM cases were clinically described in Germany and England. During the 20th century, the physiopathological basis for ACM was progressively established. At present, ACM is defined as a dilated cardiomyopathy of toxic origin with low left-ventricle ejection fraction, chamber dilatation, and progression to congestive heart failure. Excessive Ethyl consumption is one of the main causes of non-ischemic dilated cardiomyopathy (CMP), representing around one-third of cases.
Pathological Aspects of ACM
In the course of ethanol-induced cardiac damage, one of the more relevant findings is that ethanol exerts its deleterious effects on cardiac myocytes at multiples sites. This is because the ethanol molecule has a small size and is highly reactive, with many cell targets. In addition, ethanol has a widespread diffusion because of the potential for distribution though biological membranes, achieving targets not only in the membrane receptors and channels but also in endocellular particles and at the same nuclear compartment.
This induces a variety of effects, since more than 14 different sites in the myocyte can be affected by ethanol. Thus, ethanol enhances permeation in model membranes by interfering with plasma membrane composition and permeability, disturbing signaling mechanisms, and activating apoptosis, as well as disturbing L-Type Ca2+ channel activity, Na+/K+ ATPase channel activity, Na+/Ca2+ exchanger activity, and Na+and K+ channel currents. Specifically, ethanol disturbs the ryanodine Ca2+ release, the sarcomere Ca2+sensitivity, the excitation–contraction coupling and myofibrillary structure, and protein expression, decreasing heart contraction.
Prognosis of ACM
The natural course of ACM is mainly related to the degree of persistence in alcohol consumption and the individual biological adaptive response. Ethanol abstinence allows for recovery in the majority of cases, including in those with previous severe depression of LV EF. On the contrary, subjects who continue drinking at moderate to high doses (more than 60 g ethanol/day in men—equivalent to four standard drinks—and 40 g of ethanol/day in women—equivalent to 2.5 standard drinks—experience progressive functional and structural cardiac impairment, with repeated episodes of cardiac left or congestive failure, arrhythmias, and progression to death, with a mortality rate of 10%/year. Episodes of binge-drinking are highly damaging and should be especially avoided. In these subjects, mortality is related to episodes of sudden death and refractory congestive heart failure. In addition to the risk of other ethanol-mediated systemic diseases, liver cirrhosis is the main risk that is highly prevalent in ACM.
Treatment of ACM
The treatment of episodes of heart failure in ACM does not differ from that performed in idiopathic-dilated CMP. A decrease in cardiac preload with diuretics and post load with angiotensin-converting-enzyme inhibitors or beta blockage agents allows for an improvement in signs of acute heart failure. A reduction of dietary sodium intake is also necessary. Nutritional factors are relevant in ACM. A Mediterranean diet, based on monounsaturated fats from olive oil, fruits, vegetables, whole grains, and legumes/nuts, has been demonstrated to be beneficial for primary prevention of global cardiovascular events. However, since it includes moderate alcohol consumption of red wine, this aspect should be clearly avoided in subjects affected by ACM.
The exact mechanism by which an increased adherence to the traditional Mediterranean diet exerts its favourable effects is not known. However, its beneficial cardiovascular effect may be caused by different factors including lipid-lowering, protection against oxidative stress, inflammation and platelet aggregation, modification of hormones and growth factors, inhibition of nutrient-sensing pathways by specific amino acid restriction, and gut-microbiota-mediated production of metabolites influencing metabolic health.
They aim to control oxidative damage, myocyte hypertrophy, interstitial fibrosis, and persistent apoptosis. Pharmacological restoration of autophagy reflux by inhibition of soluble epoxide hydrolase has been described to ameliorate chronic ethanol-induced cardiac fibrosis in an in vivo swine model. In addition to these, stem-cell therapy tries to improve myocyte regeneration. However, these new strategies have not yet demonstrated their real effectiveness in clinical trials, require further evaluation, and are not approved for clinical use.
Discussion and Conclusions
Since ethanol consumption of the global population is not currently under control, the incidence of alcoholic cardiomyopathy is expected to be maintained in the future, especially in specific population groups, such as adolescents and young people. Therefore, efforts for the prevention, early detection, and specific treatment in this relevant disease should be established.
The direct dose-dependent effect between alcohol intake and development of ACM is clearly established, women being more sensitive than men to the toxic effects of ethanol on the heart. However, genetic polymorphisms, the use of other concomitant drugs (tobacco, cocaine), and the presence of other cardiac risk factors (hypertension, diabetes) may influence and worsen the natural course of ACM in each specific individual.
Heart remodelling is an adaptive mechanism, susceptible to being modified in ACM by the use of cardiomyokines and growth factors. Since ethanol is a drug with systemic toxic effects, the evaluation of global alcohol-related systemic damage is necessary in ACM. Control of other cardiac risk factors also allows for a better prognosis in ACM. Total abstention from alcohol is the preferred goal, although controlled drinking (with daily consumption < 60 g/day) still allows improvement. Binge drinking should be absolutely discouraged in ACM. Subjects with ACM who continue in high-dose ethanol consumption have a bad prognosis, with repeated episodes of heart failure and ventricular arrhythmias leading to a 10% increase in annual mortality rate. New strategies aiming to control apoptosis, autophagy and pathological heart remodelling, and increase myocyte regeneration may be promising in the near future. However, areas of uncertainty in this complex disease are still present and should be further explored.