Howard Why

Clinical and prognostic significance of detection of enteroviral RNA in the myocardium of patients with myocarditis or dilated cardiomyopathy.

BACKGROUND Enteroviral RNA sequences have been demonstrated in the myocardium of patients with myocarditis or dilated cardiomyopathy from presentation to end-stage disease. The prognosis of heart muscle disease has not previously been evaluated in relation to the detection of enterovirus in myocardial biopsy tissue. METHODS AND RESULTS We studied 123 consecutive patients with heart muscle disease prospectively. Multiple endomyocardial biopsy samples taken from all patients during diagnostic cardiac catheterization were classified histologically and were examined for enteroviral RNA by use of an enterovirus group-specific hybridization probe. Three enterovirus-negative patients with cardiac amyloidosis were excluded from subsequent analysis. Enteroviral RNA sequences were detectable in 41 (34%) of the remaining 120 patients (group A), while 79 (66%) had no virus detected (group B). The groups did not differ significantly in age, sex, symptomatic presentation, or hemodynamic characteristics; duration of symptoms was significantly shorter in group A (7.8 +/- 9.6 versus 14.9 +/- 19.0 months, P < .05). At follow-up (mean, 25 months; range, 11 to 50 months), patients from group A had an increased mortality compared with those in group B (25% versus 4%, respectively; P = .02). Mortality was also statistically greater in patients with symptomatic cardiac failure (P = .02), those with elevated left ventricular end-diastolic pressures (P = .03), and those in New York Heart Association functional classes III and IV (P = .05). Multivariate regression analysis, however, showed that only the presence of enterovirus RNA and symptomatic heart failure were of independent prognostic value. CONCLUSIONS These data demonstrate that the detection of enterovirus RNA in the myocardium of patients with heart muscle disease at the time of initial investigation is associated with an adverse prognosis and that the presence of enterovirus RNA is an independent predictor of clinical outcome.

Alcohol and the heart: biochemical alterations

A considerable amount of attention has focused on the cardiovascular events associated with ethanol consumption. The available evidence suggests that moderate ethanol consumption is associated with reduced risk of coronary heart disease, i.e., vessel events. In contrast, this review is primarily concerned with ethanol and heart muscle damage. Clinical features of the consequences of prolonged and excessive ethanol consumption encompass defects in myocardial contractility and derangement of cellular architecture, including disarray of the contractile elements. Although the incidence of heart muscle abnormalities in alcohol misusers is generally higher than previously considered, the mechanisms are only just being elucidated. This process has been facilitated by laboratory based studies in which animals receive either a single dose of ethanol (acute studies) or a continuous supply of ethanol in their daily diets (chronic studies). Results from these models show that acute ethanol dosage causes a marked decrease in the synthesis of contractile proteins. This occurs in the absence of overt mitochondrial abnormalities: ATP concentrations are generally unaffected. Paradoxically, the synthesis of mitochondrial proteins is reduced. Use of metabolic inhibitors suggests that the deleterious effects of acetaldehyde contribute to these reductions in protein synthesis. In chronic studies, ethanol causes a reduction in the amount of contractile proteins, and two dimensional protein profiling implicates selective loss of individual myocardial proteins. The differential activities of lysosomal proteases may contribute to this patterned response. However, in chronic ethanol feeding, adaptive mechanisms also become important, as the synthesis of the myofibrillary proteins increases. Overall, the mechanisms inherent in these biochemical responses may contribute to the genesis of a distinct disease entity, alcoholic heart muscle disease.

Ethanol toxicity and cardiac protein synthesis in vivo

Long- and short-term alcohol consumption induce a variety of cardiovascular changes, including alterations in hemodynamic variables and tissue biochemistry. In many instances some of the perturbations may be considered as compensatory adjustments, and indeed, there is some controversy that moderate long-term consumption may cause alterations in plasma lipid profiles, conferring cardiovascular protection by reducing the incidence of coronary artery disease. In the long term, however, ethanol misuse may induce a specific disease entity, namely alcoholic heart muscle disease, and short-term ethanol exposure may also perturb tissue contractility and hemodynamic indices. The mechanisms of these changes are unknown, but central to many of the metabolic and functional disturbances are alterations in tissue protein synthesis, perhaps precipitated or exacerbated by free radial formation or by the formation of protein-acetaldehyde adducts. Methods for measuring protein synthesis in vivo are reviewed, and their application to elucidating the mechanisms involved in cardiac abnormalities is described, including the effects of ethanol. Our results demonstrate that the effects of alcohol toxicity also occur at the subcellular level, and the synthesis of mitochondrial proteins are reduced in vivo, perhaps even contribution to defects in energy generation, the normal function of which is required to maintain contractility.

Effects of lisinopril and amlodipine on antioxidant status in experimental hypertension

The objective of this investigation was to compare changes in antioxidant status (together with other metabolites relevant to hypertension) in plasma and cardiac tissue from spontaneously hypertensive rats (SHR) and normotensive Wistar Kyoto rats (WKY), following 8 weeks of treatment with lisinopril (angiotensin converting enzyme inhibitor) or amlodipine (Ca(2+) channel antagonist) respectively. There was no significant difference in the levels of total antioxidant capacity, retinol, urea, albumin or triglyceride in plasma from SHR or WKY rats, with or without lisinopril or amlodipine treatment. However in SHR rats, levels of alpha-tocopherol were substantially reduced in both plasma (-54% WKY, P<0.01) and cardiac tissue (-43% WKY, P<0.05). Treatment with lisinopril ameliorated reduced levels of plasma alpha-tocopherol in SHR rats, but not in cardiac tissue. Amlodipine treatment had no effect on alpha-tocopherol levels in plasma or cardiac tissue in SHR rats. In SHR rats total cholesterol levels were significantly lower thanWKY controls (-36%, P<0.001). This effect was reversed in lisinopril treated SHR rats (+27%, P<0.01). Plasma high density lipoprotein (HDL) and low density lipoprotein (LDL) cholesterol were reduced in untreated SHR rats (P<0.025) when compared to WKY controls; neither lisinopril nor amlodipine treatment significantly altered these parameters. These findings suggest possible alternative mechanisms of action for lisinopril, and reinforce its use in hypertensive patients or patients with left ventricular hypertrophy.

Protein synthesis in the heart in vivo, its measurement and patho-physiological alterations

Changes in cardiac protein composition occur in a variety of patho-physiological situations and are usually accompanied by modifications in protein synthesis. Although adjustments in protein synthesis during starvation may be adaptive, the alterations in protein synthesis seen in response to ethanol ingestion may be pathological and an important step in the genesis of alcoholic heart muscle disease. The alterations in heart muscle in hypertension are initially adaptive but in the long term they are deleterious, and involve both transcription and translation. While adequate methods exist for quantifying the amount of mRNA for contractile and non-contractile proteins, such studies of gene-expression provide no dynamic information on the rate at which tissue proteins are lost or accrued. This can only be determined by measuring the rate of protein turnover, i.e. either protein synthesis or protein breakdown. Techniques for directly determining the rates of protein breakdown are limited or involve surgical procedures. Methods for measuring the rate of protein synthesis are described, and are illustrated by their application to the investigation of starvation and ethanol toxicity. In particular, attention is focused on the fact that reliable rates of protein synthesis are obtained only if the specific radioactivity of the precursor at the site of protein synthesis (aminoacyl-tRNA) is assessed.

Substance Misuse and Tissue Pathology with Special Reference to the Heart

Common drugs of misuse include alcohol, nicotine (and tobacco products), cannabis, cocaine and, to a certain extent, caffeine. Other lesser used drugs include amphetamines, opiates, sedatives/hypnotics, phencyclidines, hallucinogens and anabolic steroids. In Europe there are many millions of drug misusers and, similarly, the extent of drug misuse in North America is staggering. Thus, in the UK there are between 1 and 3 million alcohol abusers and a third of the adult population smoke tobacco products. The biomedical implications of this prevalence are considerable. In comparison with psychomotor, neuropsychiatric and cognitive reports on the above substances, investigations into organ damage are comparatively limited. This particularly relates to the biochemical mechanisms responsible for tissue specific lesions. It is a truism that virtually every single tissue system or organ in the mammalian body is adversely affected to some degree by one or more of the above drugs of misuse. At the extreme, there is organ failure and death. At the very least, there may arise compensatory mechanisms, that may be considered to be either adaptive or destructive but, nevertheless, impair organ function.