Circulating Antibodies to Cardiac Protein—Acetaldehyde Adducts in Alcoholic Heart Muscle Disease

Harcombe, Alun; Ramsay, Laura; Kenna, J G; Koskinas, John; Why, Howard; Richardson, Peter J.; Weissberg, PL; Alexander, Graham J.

doi:10.1042/cs0880263

Cited by 42 publications

(21 citation statements)

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“…1) ACA is known to disrupt cellular functions by producing ACA-protein adducts even at very low concentration. Patients with alcoholic cardiomyopathy possess circulating antibodies to cardiac ACA-protein adducts (10). Protein adducts are polypeptides bound with other molecules (usually reactive biochemicals), which either render the protein inoperative or immunogenic.…”

Section: Discussionmentioning

confidence: 99%

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Overexpression of alcohol dehydrogenase exacerbates ethanol-induced contractile defect in cardiac myocytes

Duan¹,

McFadden²,

Borgerding

et al. 2002

American Journal of Physiology-Heart and Circulatory Physiology

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. Overexpression of alcohol dehydrogenase exacerbates ethanol-induced contractile defect in cardiac myocytes. Am J Physiol Heart Circ Physiol 282: H1216-H1222, 2002. First published December 13, 2001; 10.1152/ajpheart.00780.2001.-Alcoholic cardiomyopathy is characterized by impaired ventricular function although its toxic mechanism is unclear. This study examined the impact of cardiac overexpression of alcohol dehydrogenase (ADH), which oxidizes ethanol into acetaldehyde (ACA), on ethanol-induced cardiac contractile defect. Mechanical and intracellular Ca 2ϩ properties were evaluated in ventricular myocytes from ADH transgenic and wild-type (FVB) mice. ACA production was assessed by gas chromatography. ADH myocytes exhibited similar mechanical properties but a higher efficiency to convert ACA compared with FVB myocytes. Acute exposure to ethanol depressed cell shortening and intracellular Ca 2ϩ in the FVB group with maximal inhibitions of 23.3% and 23.4%, respectively. Strikingly, the ethanol-induced depression on cell shortening and intracellular Ca 2ϩ was significantly augmented in the ADH group, with maximal inhibitions of 43.7% and 40.6%, respectively. Pretreatment with the ADH inhibitor 4-methylpyrazole (4-MP) or the aldehyde dehydrogenase inhibitor cyanamide prevented or augmented the ethanol-induced inhibition, respectively, in the ADH but not the FVB group. The ADH transgene also substantiated the ethanol-induced inhibition of maximal velocity of shortening/relengthening and unmasked an ethanol-induced prolongation of the duration of shortening/relengthening, which was abolished by 4-MP. These data suggest that elevated cardiac ACA exposure due to enhanced ADH expression may play an important role in the development of alcoholic cardiomyopathy. transgene; acetaldehyde; shortening; intracellular calcium ion transient CHRONIC ALCOHOLISM causes heart muscle damage leading to the onset of alcoholic cardiomyopathy, which accounts for ϳ33% of dilated cardiomyopathy (6). The incidence of cardiomyopathy is increased up to 50% in patients with chronic alcoholism, and a high proportion of these patients die from cardiac disease. Alcoholic cardiomyopathy is manifested by cardiomegaly, disruptions of the myofibrillary architecture, reduced myocardial contractility, decreased ejection volumes, and enhanced risk of stroke and hypertension (21,27). Clinical studies indicate that alcoholic cardiomyopathy can be reversed by abstinence from alcohol before its progression beyond a certain, as yet poorly defined, point of severity. Diagnosis of alcoholic cardiomyopathy is often made on the basis of deteriorating cardiac function, increased heart size, and a history of alcohol abuse (31). Although several hypotheses have been postulated for the development of alcoholic cardiomyopathy, including direct and indirect cardiotoxicity of alcohol (22) and accumulation of fatty acid ethyl esters (13), no hypothesis has received convincing and consistent clinical and experimental support to be fully validated.Acetaldehyde (ACA), the...

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Section: Discussionmentioning

confidence: 99%

“…Elevated levels of circulating ACA and antibodies to cardiac ACAprotein adducts have been found in alcoholics with alcoholic cardiomyopathy (10,12,18). Our laboratories have shown (1,24,25,26) that ACA may directly impair cardiac excitation-contraction (E-C) coupling and inhibit sarco(endo)plasmic reticulum (SR) Ca 2ϩ release function.…”

mentioning

confidence: 99%

Overexpression of alcohol dehydrogenase exacerbates ethanol-induced contractile defect in cardiac myocytes

Duan¹,

McFadden²,

Borgerding

et al. 2002

American Journal of Physiology-Heart and Circulatory Physiology

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“…Various mechanisms have been proposed to account for the changes in the heart muscle in alcoholism, including changes in the synthesis of contractile proteins (25,(42)(43)(44)(45) and the induction of autoantibodies due to the formation of acetaldehyde-protein adducts (46). The involvement of lipid peroxidation and hence free radical mediated damage has also been hypothesized in the pathogenesis of ACM.…”

Section: Clinical Features Of Alcoholic Cardiomyopathymentioning

confidence: 99%

Oxidants antioxidants and alcohol implications for skeletal and cardiac muscle

Preedy¹

1999

Front Biosci

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“…The b/g subunits ducts are the major causes leading to cardiac impairment. 33,34 On the other hand, in cirrhotic cardiomyopathy, diminished are tightly associated, functioning as a monomer. 44,45 The interaction between the activated receptor and G-proteins leads b-adrenergic receptor function, alteration in membrane physical properties, and perhaps hyperdynamic circulation with to guanine nucleotide exchanges.…”

Section: Cardiac Histology In Cirrhosismentioning

confidence: 99%

Cirrhotic Cardiomyopathy: Getting to the Heart of the Matter

1996

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can lead to liver dysfunction and damage. How unexpected In cirrhosis, cardiac contractile function has been exand gratifying, therefore, to find a voice as eloquent as the tensively documented to be abnormal. At baseline, carlate Chilean Nobel laureate's to not only extoll the many diac output is increased, and this is one of the charactervirtues of the liver, but also remind us that sometimes the istics of hyperdynamic circulation. However, when liver takes precedence over the heart, i.e., that liver failure cirrhotic patients are challenged by pharmacological or can also lead to cardiac dysfunction. physiological stress, ventricular hyporesponsiveness is It has been known for more than four decades that hepatic revealed. Similar patterns have been noted in cirrhotic cirrhosis is associated with a host of cardiovascular abnoranimal models. This phenomenon has been termed ''cirmalities. The initial studies in the early 1950s documented rhotic cardiomyopathy.'' Although alcohol abuse may the existence of hyperdynamic circulation in cirrhosis, manicontribute to some cases of cirrhotic cardiomyopathy, it has been clearly documented to occur even in the ab-fested by increased cardiac output and reduced systemic vassence of alcohol ingestion. Diminished myocardial b-ad-cular resistance. This latter phenomenon, the peripheral varenergic receptor signal transduction function, possibly sodilatation, continues to fascinate investigators even up to caused by a persistent elevation in norepinephrine con-the present, and recent studies have examined the possible tent, has been shown to play an important role. Alter-role of nitric oxide and other endothelium-dependent factors ation in cardiac plasma membrane properties due to im-in mediating the vasodilatation. The heart itself was not expaired lipid metabolism is also crucial. Other possible amined until about three decades ago, and around that time pathogenic factors are reviewed, including accumula-studies of cardiac contractile function in patients with alcotion of cardiodepressant substances caused by hepato-holic-induced liver disease started consistently showing that cellular insufficiency, and ventricular overload sec-despite the increased baseline cardiac output, when ventricuondary to increased blood volume and hyperdynamic lar contractile responses were tested under conditions of circulation. Because the cardiac reserve function is bor-pharmacological or physiological stress, the heart behaved derline in patients with cirrhosis, cardiovascular status abnormally in a blunted manner. For many years, this was should be carefully monitored, especially when patients ascribed to the well-known direct toxic effects of alcohol on undergo stresses such as liver transplantation or porto-cardiac muscle, i.e., as a manifestation of latent or subclinical systemic shunting procedures. (HEPATOLOGY 1996;24: alcoholic cardiomyopathy, and relegated to the scientific 451-459.)backwaters as a clinically insignificant curiosity. However, recently several studies have emerged in both ...

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Circulating Antibodies to Cardiac Protein—Acetaldehyde Adducts in Alcoholic Heart Muscle Disease

Cited by 42 publications

References 0 publications

Overexpression of alcohol dehydrogenase exacerbates ethanol-induced contractile defect in cardiac myocytes

Overexpression of alcohol dehydrogenase exacerbates ethanol-induced contractile defect in cardiac myocytes

Oxidants antioxidants and alcohol implications for skeletal and cardiac muscle

Cirrhotic Cardiomyopathy: Getting to the Heart of the Matter

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