To assess the quality and validity of the included studies, we performed a critical appraisal using appropriate tools such as the Newcastle-Ottawa Scale for observational studies or the Cochrane Risk of Bias tool for clinical trials. This assessment allowed us to evaluate the methodological rigor of each study and determine its overall quality and potential impact on the literature review. Finally, we analyzed and presented the synthesized literature, along with relevant findings and conclusions from the included studies, in a coherent manner. We identified main themes and sub-themes to provide a comprehensive overview of the current state of knowledge regarding ACM.
International Patients
Acetaldehyde is produced at a lower quantity in the heart as compared to the liver, and systemic acetaldehyde does not achieve toxic heart concentrations 77. In addition, acetaldehyde is able to interact with proteins and produce protein-adduct compounds that are highly reactive and may induce additional inflammatory and immunologic heart damage 78. Therefore, because of its multiple actions, acetaldehyde may influence ACM pathogenesis in addition to ethanol effect itself 20,76,77. Diastolic dysfunction is the earliest sign of ACM and is usually seen in approximately 30% of patients with a history of chronic alcohol abuse with no evidence of systolic dysfunction nor left ventricle hypertrophy.
Symptoms
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 1. During the 20th century, the physiopathological basis for ACM was progressively established 6. 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 18,52,53. Excessive EtOH consumption is one of the main causes of non-ischemic dilated cardiomyopathy (CMP), representing around one-third of cases 30.
- At histological evaluation, dilatation, myofibrillar necrosis and fibrosis are typically present, with a reduction of myofibrils and giant mytochondria 3.
- New strategies are addressed to decrease myocyte hypertrophy and interstitial fibrosis and try to improve myocyte regeneration, minimizing ethanol-related cardiac damage.
- Indeed, the first account of the possible harmful effects of alcohol specifically on heart muscle was reported in the latter half of the 19th century.
- Besides, newer and better targeted therapies are required to be developed which will act on pathways involved in the loss of myocytes (apoptosis and necrosis) and cardiac fibrosis.
- All-cause mortality was assessed using Kaplan–Meier survival curves, and the risk factors were assessed using Cox regression.
The Effects of Ethanol on the Heart: Alcoholic Cardiomyopathy
It is unknown whether individual susceptibility would be related to increased vulnerability at the myocardial level and/or to impaired alcohol metabolism. One relevant question concerning ethanol cardiac toxicity is if ethanol itself or its active metabolite acetaldehyde causes cardiac damage 73,74. In fact, both molecules are directly cardiotoxic, decreasing structural protein synthesis and heart contractility and increasing oxidative and metabolic damage, leading to autophagy 20,75. In experimental studies, acetaldehyde directly impairs cardiac contractile function 76, disrupts cardiac excitation–contraction coupling, and promotes oxidative damage and alcoholic cardiomyopathy symptoms lipid peroxidation 20.
Organ-Specific Toxicologic Pathology
These mechanisms contribute to the development of oxidative stress, which is responsible for the onset of cardiomyopathies and ischemia-reperfusion injury. Electron microscopic studies (7,8) of biopsies from patients with alcohol-induced cardiomyopathy have shown evidence of damage to the myofibres, including separation of filaments and loss of striation. In animal studies, loss of contractile proteins and defects in myocardial protein synthesis may partly explain the altered contractility. These studies have demonstrated that acute alcohol ingestion directly reduces contractile protein synthesis in vivo by approximately 25%.
ACKNOWLEDGMENTS
The percentage of apoptotic myocytes in ACM is relatively low but, in combination with a persistent decrease in myocyte proliferation, they may contribute to an absolute cell loss and decreased cardiac contractility 52,115. Recent data favored a role for micro RNA, such as the involvement of miR-378a-5p in cardiomyocyte apoptosis and ACM development through ALDH2 gene suppression 120. Since myocardium requires a high energy supply to maintain persistent sarcomere contractions, it was supposed that alcohol could exert its damaging effect on the mitochondrial energy supply system, with the disruption of oxidative control mechanisms 26,100. In fact, mitochondrial structural changes have been described in chronic alcohol consumers, with swollen megamitochondria and the distortion of inner cristae 107,108. Functionally high ethanol produces disruptions in the myocyte oxidative pattern and decreases in Complex I, II, and IV of the mitochondrial respiratory chain 100,109,110.
Various studies have shown that alcohol exerts a negative inotropic effect on the myocardium. It is possible that changes in calcium hemostasis may contribute toward this phenomenon, because this divalent cation plays an integral part in transmembrane ion movement and muscle contraction (9). Some have also suggested that lipid peroxidation may play a role in the pathogenesis of alcoholic cardiomyopathy (10).
The first study, which specifically focused on the amount of alcohol necessary to cause ACM, was conducted by Koide et al20 in 1975. The authors examined the prevalence of cardiomegaly by means of chest x-rays and related it to alcohol consumption among a consecutive series of Japanese males of working age. They found that 2 of the 6 individuals (33%) whose alcohol consumption exceeded 125 mL/d had cardiomegaly.
- Specifically, ethanol disturbs the ryanodine Ca2+ release, the sarcomere Ca2+sensitivity 102,103, the excitation–contraction coupling and myofibrillary structure, and protein expression, decreasing heart contraction 86.
- While some consider that this toxin alone is able to cause such a disease18,19, others contend that it is just a trigger or an agent favouring DCM3,21,22.
- Many changes can be observed including premature atrial or ventricular contractions, supraventricular tachycardias, atrioventricular blocks, bundle branch blocks, QT prolongation, non-specific ST and T wave changes and abnormal Q waves.
- Individuals who completely quit alcohol generally have improved overall outcomes.
- Most heavy drinkers remain asymptomatic in the earlier stages of disease progression, and many never develop the familiar clinical manifestations that typify heart failure.
- Segmental wall motion abnormalities usually suggest myocardial injury; however, approximately 18% to 20% of patients with cocaine abuse manifest global hypokinesia.
Enlarged heart, in heart failure
- Abnormal heart sounds, murmurs, ECG abnormalities, and enlarged heart on chest x-ray may lead to the diagnosis.
- 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.
- Disrupted bioenergetics and oxidative phosphorylation indices and a change in the ultrastructure of the mitochondria may be the cause of such dysfunctions.
- It is therefore possible that patients with ACM could also harbour a genetic substrate that predisposes them to this form of cardiomyopathy.
Future studies with a strict classification of non-drinkers and drinkers will help clarify whether complete abstinence is mandatory for ACM patients. In the interim it seems appropriate to continue discouraging any alcohol consumption in these patients, as it would be difficult for them to maintain a limited alcohol intake considering their history of alcohol dependence and abuse. More specifically, atrial fibrillation with rapid ventricular response is a cause of arrhythmia-induced cardiomyopathy,61 which can potentially worsen LVEF in AC patients, on top of the direct toxic effect of ethanol, acetaldehyde damage, or the aforementioned genetic factors. Cardiac remodeling is a global process that myocardium establishes as a result of different aggressions 31,132. Heart myocytes are relatively resistant to the toxic effect of ethanol, developing a functional and structural compensatory mechanism able to minimize or repair the ethanol-induced myocyte damage 20,31,39. Structurally, hypertrophy of myocytes is seen in the early stages to avoid contractile depression 52,107,125.