Faculty peer reviewed
Excessive consumption of ethanol (EtOH) has many deleterious effects on the human body. The heart is a target of damage from EtOH consumption, as chronic consumption of EtOH leads to decreased cardiac function and structural heart disease, including dilated cardiomyopathy.(1) The exact mechanism by which EtOH exerts its deleterious effects on the heart remains poorly understood and is an area of active research. This report will focus on some of the proposed mechanisms and some recent advances in the understanding of the pathogenesis of EtOH-induced cardiomyopathy.
The pathogenesis of alcoholic cardiomyopathy is likely multifactorial, and current evidence suggests a role for decreased excitation/contraction coupling, oxidative damage, and membrane destabilization in cardiac myocytes. However, the key initiating event is not known. Several theories have been put forth to explain the underlying pathogenesis of alcoholic cardiomyopathy. Two of the leading theories will be reviewed here.
The idea that apoptosis underlies the myocardial damage observed in alcoholic cardiomyopathy was first proposed in 2000 by Chen et al, based on the observation that several markers of apoptosis were observed to be elevated in many cardiac diseases.(2-4) A more recent study looked at the post-mortem hearts of 20 long-standing alcoholics and compared them to non-alcoholic controls and hearts from patients with hypertension but not alcoholism. Histological staining for apoptosis using terminal deoxynucleotidyl transferase d-UTP nick-end labeling (TUNEL), as well as staining for several markers of apoptosis, including Bcl-2 and activated caspase-3, revealed a significantly elevated level of apoptosis in the alcoholic and hypertensive hearts, as compared to control hearts.(5) The authors concluded that alcohol mediates its deleterious effects on the heart via induction of apoptosis. These studies failed, however, to identify any mechanistic connection between EtOH exposure and myocyte death.
Another theory has been termed the acetaldehyde toxicity theory by Cai et al.(6) The theory is based on the observation, made several decades ago in rats, that acute EtOH exposure can decrease cardiac contractility.(7) It was hypothesized then that the long-term effects of EtOH exposure on cardiac contractility could result from either chronic exposure to EtOH itself or from exposure to a toxic metabolite of EtOH, possibly acetaldehyde, which is metabolized from EtOH in the liver by the enzymes alcohol dehydrogenase and P450IIE1.(8)
To elucidate the exact effects of acetaldehyde on various cellular and physiological processes, Li and Ren recently conducted an elegant study using transgenic mice. These mice express a transgene coding for the human enzyme alcohol dehydrogenase.(9) By feeding these mice high levels of ethanol, they were able to simulate the high serum levels of acetaldehyde observed in human chronic alcoholics. The authors fed EtOH to transgenic and non-transgenic littermate control mice and analyzed these mice for insulin signaling in the heart, oxidative and endoplasmic reticulum (ER) stress in the heart, and overall cardiac function. Any differences between the two groups could then be attributed to increased exposure to acetaldehyde.
Interestingly, the authors found significant differences between the two groups of mice in all of the processes they tested. It had been known previously that chronic EtOH ingestion leads to impaired glucose tolerance and to cerebral dysfunction secondary to reduced insulin-receptor signaling. It was not clear, however, whether these effects were at all related to EtOH induced cardiomyopathy. This study provided evidence that these effects do indeed contribute to the pathogenesis of alcoholic cardiomyopathy. Chronic alcohol feeding led to glucose intolerance, dampened cardiac glucose uptake, cardiac hypertrophy, and contractile dysfunction in control mice. These effects were significantly exaggerated by the alcohol dehydrogenase transgene. Thus, acetaldehyde exposure directly mediates the toxicity of EtOH on the heart and may underlie the pathogenesis of alcohol-induced cardiomyopathy.
Although the above study did not directly address the role of acetaldehyde in the ER and oxidative stress, previous studies from Ren’s lab showed that acetaldehyde and ethanol both induced the generation of reactive oxygen species and resultant apoptosis in human cardiac myocytes.(10) This finding provides more evidence for the acetaldehyde toxicity theory, and in addition, explains some of the findings of Chen et al, mentioned above, that apoptosis underlies the pathogenesis of alcoholic cardiomyopathy. Thus, both theories of the pathogenesis of alcoholic cardiomyopathy can be seen as complementary, with the acetaldehyde toxicity theory underlying the ultimate apoptosis that may contribute significantly to cardiac dysfunction.
These studies provide a compelling explanation for the pathogenesis of alcoholic cardiomyopathy, but they do not offer an explanation for the reversibility of the disease observed clinically with EtOH abstinence. Several studies have demonstrated that even as little as 10 weeks of abstinence can improve cardiac function significantly in patients with alcoholic cardiomyopathy. (11-13) Given that the final cardiac insult from EtOH results in apoptosis, and that the cardiomyopathy can be reversible, perhaps myocyte regeneration from adult stem cells may play a significant role in restoration of cardiac function following abstinence from EtOH. This finding itself could be extremely exciting in the context of harnessing this reparative potential for the treatment of other cardiac diseases as well.
Charles Levine is a 4th year medical student at NYU School of Medicine.
Peer reviewed by Robert Donnino MD, NYU Division of Cardiology
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