Effects of chronic graded ethanol consumption on the metabolism, ultrastructure, and mechanical function of the rat heart

Abstract

Three sequential sets of ethanolic rats (E) and their matched controls (C) were fed regular chow containing standard vitamins with the ethanol group in each series also receiving a progressively greater alcohol intake for 3 to 6 months: E1 5%, E2 10%, and E3 25% ethanol. Electron microscopy showed swelling of mitochondria, transverse tubules and sarcoplasmic reticulum, dehiscence of intercalated discs and disintegration of myofibrils scattered throughout the ventricular myocardium in E1 and E2 as early as 7 wk after beginning 5% ethanol; in addition, there were clumping of mitochondria and supercontraction of myofibrils in E3. Concomitant with substructural abnormalities in E3, there were slight but significant depressions of cardiac myofibrillar ATPase activity and mitochondrial function. Cardiac catecholamines, hydroxyproline, and total bound glycerol were unchanged. Alteration of isometric contraction of isolated, supported left ventricular papillary muscles occurred initially in E2 and was clearly evident in E3 by significant reduction of duration of systolic active state (time from onset to peak tension), while total tension generated and peak rate of tension rise were not yet disturbed. Extra vitamin supplementation in additional rats drinking 25% ethanol minimally lessened decline in myofibrillar ATPase activity, but otherwise provided no protection. Thus, chronic daily ingestion of graded quantities of ethanol representing 10 to 30% of total calories in well-nourished animals exerted toxic effects on microstructure, metabolism and mechanics of the ventricle. These alterations are postulated to be pertinent to early pathogenesis of clinical alcoholic cardiomyopathy.

Chronic alcohol consumption disrupts myocardial protein balance and function in aged, but not adult, female F344 rats

“…This alcohol-induced decrement is in part mTOR-dependent as demonstrated by the reduced phosphorylation of mTOR, S6K1, S6, eIF4G, and 4E-BP1, the latter of which is responsible for the observed reduction in the assembly of the active eIF4E·eIF4G capbinding complex (72,73,77). These protein metabolic effects are also associated with a cardiac dysfunction after longer periods of alcohol consumption (14,35,64,66). However, in our current study, alcohol feeding for 20 wk did not alter the rate of global, myofibrillar, or sarcoplasmic protein synthesis in female F344 rats.…”

Mitochondrial dysfunction induced by fatty acid ethyl esters, myocardial metabolites of ethanol.

“…In 1917, it was shown that oxygen consumption is increased after even moderate ingestion of ethanol in some individuals (10). Over the past 20 yr, light and electron microscopic changes in mitochondrial structure and function have been documented in myocardium from animals (11,12) and human subjects (13,14) exposed to ethanol. After a lag period of ethanol exposure in vivo, mitochondria isolated from the heart exhibit impaired rates of oxygen consumption, diminished respiratory control, and reduced P/O ratios (15)(16)(17)(18).…”

“…Such changes could be due to alterations in mitochondrial function. Consumption of alcohol over several weeks leads to gross morphological changes in heart mitochondria in laboratory animals (11,12) and human subjects (13,14). Impairment of mitochondrial function has been noted as well and it includes diminished phosphate/oxygen ratios (P/O)' and respiratory control ratios (15)(16)(17)(18); these are changes that do not occur after exposure of mitochondria to ethanol in vitro.…”

Is the rat a suitable model for studying alcoholic cardiomyopathy? Hemodynamic studies at various stages of chronic alcohol ingestion

“…The results are controversial: some authors describe unequivocal cardiodepressant or histological effects (1,5,25,28,31,34,38,39), while others do not (17,40). Some workers find only slight cardiodepression (7,24), or only one out of several hemodynamic variables altered (33), or cardiodepression only after stress-test (27,35).…”