This fact has been assessed with echocardiographic monitoring in women consuming high doses of ethanol both in the subclinical period of disease 46 as well as in the clinical period when congestive heart failure appears 95. At the experimental level, some gender differences also are evident in functional proteomic analysis, with sex-dependent differences in structural and energy-producing myocardial proteins in a rat model of alcoholic cardiomyopathy 96. The biological reason for this gender difference is based on different ethanol absorption rates, distribution pattern, and metabolism in women compared to men 52. During pregnancy, ethanol consumption should be clearly discouraged because of the possibility of fetal alcohol syndrome or the development of other congenital heart diseases 97. The cardiovascular system is, after the liver and gastrointestinal system, the Alcoholics Anonymous second most affected system by global ethanol toxicity 1,33,34.

Nutritional factors

There is significant variation in the initial presentation of alcoholic cardiomyopathy with diastolic dysfunction possibly being the first indication. Ethanol exposure generates toxic metabolites, primarily acetaldehyde and ROS, which activate several cell signaling systems to alter cell function across many levels. Sudden cardiac death is a known occurrence of alcoholism that may be linked to an arrhythmogenic effect of alcohol. A diverse variety of arrhythmias appear early and may worsen the course of ACM, atrial fibrillation being the most frequent 60 and ventricular tachycardia the most deleterious 61. These arrhythmias are usually related to episodes of binge drinking 43,62 and are more frequent in established ACM than in subjects with normal cardiac function 52. In chronic alcoholics, arrhythmia may frequently appear in relation to episodes of ethanol abstinence because of the increased release of catecholamines and electrolyte deficiencies 19.

• Ethanol abstinence allows for recovery in the majority of cases, including in those with previous severe depression of LV EF 81,88,135.
• Later and progressively in the course of the disease, around 20% of women and 25% of men with excessive alcohol consumption develop exertion dyspnea and orthopnea, leading to episodes of left-ventricle heart failure 39,46,59.
• Thus, Nicolás et al73 studied the evolution of the ejection fraction in 55 patients with ACM according to their degree of withdrawal.
• Diastolic dysfunction, characterized by impaired left ventricular relaxation and reduced diastolic filling capacity, serves as an early indicator of ACM.

Quantity of Alcohol Intake in Cardiac Disease

• However, it has been evidenced that ACM may develop in the absence of protein or caloric malnutrition 38.
• Cardiac percussion and palpation reveal evidence of an enlarged heart with a laterally displaced and diffuse point of maximal impulse.
• The sub-group of patients in whom symptoms improved was made up of a larger proportion of non-drinkers (73%), compared to 25% in the group who did not improve, or 17% in the group whose condition worsened.
• 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 27,72,98.
• In experimental studies, acetaldehyde directly impairs cardiac contractile function 76, disrupts cardiac excitation–contraction coupling, and promotes oxidative damage and lipid peroxidation 20.

The findings were analysed taking into account the amount and chronicity of intake and they were compared with the same parameters measured in a control group of non-drinkers. A second set of studies that are quoted when addressing this topic are those conducted in individuals who started an alcohol withdrawal program21-24. In these studies, the authors estimated the amount and chronicity of alcohol intake and subsequently related the figures to a number of echocardiographic measurements and parameters. Although all of the studies reported an increase in left ventricular mass and volume, it cannot generally be stated that they provided the alcohol consumption dosage required to cause ACM. Along with signs of heart failure such as increased N-terminal pro-B-type natriuretic peptide, blood tests can provide hints suggesting chronic alcohol abuse.

• In the latter case, the association between acute alcohol consumption and arrhythmias has been referred to as “holiday heart syndrome”.
• Interestingly, many decades ago ACM was thought to arise due to nutritional deficiency, specifically thiamine (vitamin B12).
• In addition to the assessment of the status of the coronary arteries, cardiac catheterization may help obtain useful information regarding cardiac output, the degree of aortic or mitral valvular disease, and cardiac hemodynamics and filling pressures.
• The sarcomere complex is early affected by ethanol, decreasing the titin content, a protein that is responsible for sarcomere relaxation and LV distensibility 130.

Epidemiological studies

• Cardiac remodeling tries to compensate for this damage, establishing a balance between aggression and defense mechanisms.
• By inhibiting NOX2 (the most important superoxide-producing enzyme) with apocynin, they observed a decrease in ethanol- and acetaldehyde-induced superoxide levels.
• Since cardiac myocytes are excitable cells, and ethanol may easily damage this excitation–contraction mechanism, disruption of this coupling mechanism is involved in the ACM pathogenic process 19,58.
• 5 Many studies have shown this result, and it remains a topic of ongoing investigation and speculation.
• Finally, it is worth stressing that a large majority of studies on the physiopathology and prognosis of ACM were conducted some years ago, prior to the development of our current understanding regarding the role of genetics in DCM67.

Chronic alcohol exposure accelerates mitochondrial dysfunction and apoptosis across different organs including the heart, liver and pancreases 19,64,65,71. Studies reporting degradation of mitochondrial function have shown significant decreases in mitochondrial protein content both across the whole mitochondrial fraction as well as specific proteins critical for mitochondrial function 52,53,72. In part due to a decline if the production of mitochondrial proteins, but also a function of the degradation of mitochondrial DNA (mtDNA) 70,73,74. As a membrane delimited organelle, mitochondria possess their own genetic material that is used to encode 37 genes, 13 of which are proteins. Although a small number relative to the more than 1000 proteins localized to the mitochondria, high fidelity mtDNA is critical in the formation and stability of the complexes important for oxidative phosphorylation 69, 75-78.

2. Ethanol-induced Myocyte Apoptosis and Autophagy

The alcohol cardiomyopathy natural history and long-term prognosis studies of Gavazzi et al10 and Fauchier et al11 compared the evolution of ACM patients according to their degree of withdrawal. These authors found a relationship between the reduction or cessation of alcohol consumption and higher survival rates without a heart transplant. He divided this cohort into two groups according to the evolution of the ejection fraction during 36 mo in which no deaths were recorded. The 6 subjects who experienced a clear improvement in their ejection fraction had fully refrained from drinking. Conversely, the 3 subjects recording a less satisfactory evolution had persisted in their consumption of alcohol.