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Alcohol Effects on Cardiac Function

Jason D. Gardner, Alan J. Mouton

10.1002/cphy.c140046

Source: Volume 5, Issue 2, April 2015

Published online: March 2015

Full Article on Wiley Online Library



ABSTRACT

The consumption of ethanol can have both beneficial and detrimental effects on the function of the heart and cardiovascular system, depending on the amount consumed. Low‐to‐moderate amounts of ethanol intake are associated with improvements in cardiac function and vascular health. On the other hand, ethanol chronically consumed in large amounts acts as a toxin to the heart and vasculature. The cardiac injury produced by chronic alcohol abuse can progress to heart failure and eventual death. Furthermore, alcohol abuse may exacerbate preexisting heart conditions, such as hypertension and cardiomyopathy. This article focuses on the molecular mechanisms and pathophysiology of both the beneficial and detrimental cardiac effects of alcohol. © 2015 American Physiological Society. Compr Physiol 5:791‐802, 2015.

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Figure 1. Figure 1. J‐shaped curve for association of alcohol intake and risk of cardiovascular disease. Low‐to‐moderate alcohol intake is associated with a decreased relative risk of cardiovascular disease, whereas high alcohol is associated with an increased risk.
Figure 2. Figure 2. Mechanisms of alcohol‐induced cardioprotection. Low‐to‐moderate alcohol consumption leads to increased high‐density lipoprotein (HDL), adiponectin, and insulin sensitivity. Increased HDL protects the endothelium against oxidative damage, prevents endothelial inflammation, and removes fat from infiltrating macrophages to prevent foam cell formation. Adiponectin has effects similar to HDL on the endothelium, and also improves insulin sensitivity. Improved insulin sensitivity protects against hyperglycemia and hyperinsulinemia, reducing the toxic effects of excess glucose and insulin on the vasculature. Low‐to‐moderate alcohol use increases endothelial‐derived nitric oxide, resulting in vasodilation, and decreases clotting factors and platelet aggregation, reducing risk of thrombolytic events. These levels of alcohol intake are also associated with reduced cardiac oxidative stress (* indicates direct cardiac effects).
Figure 3. Figure 3. Ethanol metabolism. Ethanol is primarily metabolized by the liver, but some metabolism also takes place in other tissues, including the vascular endothelium and heart. Ethanol is oxidized to acetaldehyde in the cytosol by alcohol dehydrogenase (ADH), coupled to reduction of NAD+ to NADH. During chronic alcohol abuse, ethanol is also metabolized by the inducible enzyme CYP2E1, which also produces oxidative stress. Acetaldehyde is then oxidized by mitochondrial aldehyde dehydrogenase 2 (ALDH2) to acetate, coupled to oxidation of NAD+ to NADH. Acetate then enters the Krebs cycle for energy production.
Figure 4. Figure 4. Mechanisms of alcoholic cardiomyopathy. Chronic alcohol abuse causes increased cardiac oxidative and nitrative stress, which is central to the development of cardiomyocyte apoptosis, mitochondrial dysfunction, decreased protein synthesis, and E‐C coupling dysfunction. Chronic alcohol abuse also leads to increased sympathetic nervous system (SNS) activity, which forms a positive feedback loop with the renin‐angiotensin‐aldosterone system (RAAS). Chronic SNS and RAAS activation produces fibrosis, while also causing hypertension, which increases the workload of the heart, exacerbating adverse cardiac hypertrophy and extracellular matrix alterations. Chronic alcohol abuse also damages the endothelium, adversely affecting vascular function and causing vascular smooth muscle cell (VSMC) contraction, which further contributes to alcohol‐induced hypertension and cardiac overload.
Figure 5. Figure 5. Mechanism of alcohol‐induced cardiac fibrosis. Alcohol activates cardiac fibroblasts and promotes their transition to myofibroblasts via a transforming growth factor beta1 (TGF‐B1) dependent mechanism. NADPH oxidases (NOXs) are necessary for fibroblast transformation, and represent another potential mechanism of alcoholic fibrosis, as alcohol is known to increases NOX expression and activity in many tissues. Myofibroblasts secrete excess collagen types I and III. Myofibroblasts also secrete matrix metalloproteinases (MMPs), which are inhibited by TIMPs. Alcohol increases TIMP expression relative to MMPs, resulting in decreased collagen degradation and excess collagen deposition.


Figure 1. J‐shaped curve for association of alcohol intake and risk of cardiovascular disease. Low‐to‐moderate alcohol intake is associated with a decreased relative risk of cardiovascular disease, whereas high alcohol is associated with an increased risk.


Figure 2. Mechanisms of alcohol‐induced cardioprotection. Low‐to‐moderate alcohol consumption leads to increased high‐density lipoprotein (HDL), adiponectin, and insulin sensitivity. Increased HDL protects the endothelium against oxidative damage, prevents endothelial inflammation, and removes fat from infiltrating macrophages to prevent foam cell formation. Adiponectin has effects similar to HDL on the endothelium, and also improves insulin sensitivity. Improved insulin sensitivity protects against hyperglycemia and hyperinsulinemia, reducing the toxic effects of excess glucose and insulin on the vasculature. Low‐to‐moderate alcohol use increases endothelial‐derived nitric oxide, resulting in vasodilation, and decreases clotting factors and platelet aggregation, reducing risk of thrombolytic events. These levels of alcohol intake are also associated with reduced cardiac oxidative stress (* indicates direct cardiac effects).


Figure 3. Ethanol metabolism. Ethanol is primarily metabolized by the liver, but some metabolism also takes place in other tissues, including the vascular endothelium and heart. Ethanol is oxidized to acetaldehyde in the cytosol by alcohol dehydrogenase (ADH), coupled to reduction of NAD+ to NADH. During chronic alcohol abuse, ethanol is also metabolized by the inducible enzyme CYP2E1, which also produces oxidative stress. Acetaldehyde is then oxidized by mitochondrial aldehyde dehydrogenase 2 (ALDH2) to acetate, coupled to oxidation of NAD+ to NADH. Acetate then enters the Krebs cycle for energy production.


Figure 4. Mechanisms of alcoholic cardiomyopathy. Chronic alcohol abuse causes increased cardiac oxidative and nitrative stress, which is central to the development of cardiomyocyte apoptosis, mitochondrial dysfunction, decreased protein synthesis, and E‐C coupling dysfunction. Chronic alcohol abuse also leads to increased sympathetic nervous system (SNS) activity, which forms a positive feedback loop with the renin‐angiotensin‐aldosterone system (RAAS). Chronic SNS and RAAS activation produces fibrosis, while also causing hypertension, which increases the workload of the heart, exacerbating adverse cardiac hypertrophy and extracellular matrix alterations. Chronic alcohol abuse also damages the endothelium, adversely affecting vascular function and causing vascular smooth muscle cell (VSMC) contraction, which further contributes to alcohol‐induced hypertension and cardiac overload.


Figure 5. Mechanism of alcohol‐induced cardiac fibrosis. Alcohol activates cardiac fibroblasts and promotes their transition to myofibroblasts via a transforming growth factor beta1 (TGF‐B1) dependent mechanism. NADPH oxidases (NOXs) are necessary for fibroblast transformation, and represent another potential mechanism of alcoholic fibrosis, as alcohol is known to increases NOX expression and activity in many tissues. Myofibroblasts secrete excess collagen types I and III. Myofibroblasts also secrete matrix metalloproteinases (MMPs), which are inhibited by TIMPs. Alcohol increases TIMP expression relative to MMPs, resulting in decreased collagen degradation and excess collagen deposition.
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Article Title: Alcohol Effects on Cardiac Function
 

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Jason D. Gardner, Alan J. Mouton. Alcohol Effects on Cardiac Function. Compr Physiol 2015, 5: 791-802. doi: 10.1002/cphy.c140046