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Toxic mechanisms of the heart: a review
1Division of Pharmacology and Toxicology, College of Pharmacy, University of Texas, Austin 78712.
Abstract:
Toxic injury is one of the many ways by which the functional integrity of the heart may become compromised. Any of the subcellular elements may be the target of toxic injury, including all of the various membranes and organelles. Understanding the mechanisms underlying cardiotoxicity may lead to treatment of the toxicity or to its prevention. Doxorubicin and its analogs are very important cancer chemotherapeutic agents that can cause cardiotoxicity. Other agents which are cardiotoxic and which have profound public health implications include the alkaloid emetine in ipecac syrup, cocaine, and ethyl alcohol. The most important cardiotoxic mechanisms proposed for doxorubicin include oxidative stress with its resultant damage to myocardial elements, changes in calcium homeostasis, decreased ability to produce ATP, and systemic release of cardiotoxic humoral mediators from tissue mast cells. Each of the first 3 mechanisms can lead to each of the other 2, and the causal relationships between all of these mechanisms are not clear. New evidence suggests that doxorubicinol, one of the metabolites of doxorubicin may be the moiety responsible for cardiotoxicity. Several other potential mechanisms also have been proposed for doxorubicin. Emetine in ipecac syrup is the first aid treatment of choice for many acute toxic oral ingestions and the alkaloid, itself, is used to treat amebiasis. Cardiotoxicity occurs following chronic exposure, such as occurs therapeutically in amebiasis and with ipecac abuse by bulemics. A number of mechanisms are proposed for emetine cardiotoxicity, but the current mechanistic literature is quite scarce. Cocaine abuse recently has caught the public interest, in particular because of the drug-related sudden deaths of certain athletes. Cocaine can cause hypertension, arrhythmias, and reduced coronary blood flow, each of which can contribute to its lethality. However, it may be possible that cocaine sudden death episodes are more related to hyperthermia and convulsive seizures, rather than to cardiovascular toxicity. Chronic alcohol use leads to dilated cardiomyopathy and failure as part of the general physical degeneration that occurs with alcoholism. Several mechanisms are proposed for the cardiomyopathy, but only 2 things seem clear. The cardiotoxicity is due to an intrinsic effect of alcohol, rather than to malnutrition or co-toxicity, and abstinence is the only effective treatment for the cardiomyopathy. Recent articles indicate that very moderate use of alcohol may be beneficial and protect against cardiovascular-related morbidity. One explanation for these findings seems to be that the non-drinking groups, against whom the moderate drinking comparisons were made, were enriched in former drinkers with significant alcohol-related cardiovascular pathology.
Insights
Understanding cardiotoxicity from drugs like doxorubicin, emetine, cocaine, and alcohol is crucial for prevention and treatment. Research explores mechanisms including oxidative stress and calcium imbalance, with metabolites potentially driving doxorubicin
Area of Science:
- Cardiology
- Toxicology
- Pharmacology
Background:
- Cardiotoxicity compromises heart function through various subcellular injury mechanisms.
- Understanding these mechanisms is key for developing treatments and preventative strategies.
- Several common agents, including doxorubicin, emetine, cocaine, and alcohol, are known cardiotoxins.
Purpose of the Study:
- To review and elucidate the proposed mechanisms of cardiotoxicity induced by doxorubicin, emetine, cocaine, and alcohol.
- To highlight the public health implications of these cardiotoxic agents.
- To discuss current understanding and gaps in knowledge regarding cardiotoxicity mechanisms.
Main Methods:
- Review of proposed cardiotoxic mechanisms for doxorubicin, including oxidative stress, calcium homeostasis, ATP production, and mast cell mediators.
- Examination of proposed mechanisms for emetine cardiotoxicity, noting the scarcity of current literature.
- Analysis of cocaine's cardiovascular effects (hypertension, arrhythmias, reduced coronary blood flow) and potential alternative causes of sudden death.
- Discussion of alcohol's role in dilated cardiomyopathy, distinguishing intrinsic effects from malnutrition and noting abstinence as the primary treatment.
- Consideration of recent findings on moderate alcohol consumption and cardiovascular health.
Main Results:
- Doxorubicin cardiotoxicity may involve oxidative stress, altered calcium homeostasis, reduced ATP production, and mast cell mediators, with doxorubicinol suggested as a key metabolite.
- Emetine cardiotoxicity mechanisms are not well-defined due to limited research.
- Cocaine can induce hypertension, arrhythmias, and reduced coronary blood flow, but hyperthermia and seizures may also contribute to sudden death.
- Alcohol's cardiotoxicity is an intrinsic effect leading to dilated cardiomyopathy, with abstinence being the only effective treatment.
- Moderate alcohol consumption may offer cardiovascular protection, potentially due to confounding factors in comparison groups.
Conclusions:
- Cardiotoxicity results from diverse mechanisms influenced by various agents, necessitating further research into specific pathways.
- Doxorubicin's cardiotoxic effects are complex, with metabolites playing a potential role.
- The cardiovascular risks of cocaine and alcohol are significant, requiring targeted prevention and treatment strategies.
- Abstinence is critical for alcohol-induced cardiomyopathy, while moderate alcohol use may have complex cardiovascular implications.