Evaluation of myocyte proliferation in alcoholic cardiomyopathy: telomerase enzyme activity (TERT) compared with Ki-67 expression.

AIMS: Although the human heart was classically considered a terminal organ, recent studies have reported a myocyte proliferation response versus some aggressions. Excessive ethanol consumption induces development of cardiomyopathy (CMP) through myocyte apoptosis. We evaluated myocyte proliferation response in the heart of chronic alcoholic donors with telomerase activity (telomerase reverse transcriptase (TERT)) compared with Ki-67 nuclear expression. METHODS: Heart samples were prospectively obtained from organ donors on life support. We included donors with (1) high lifetime alcohol consumption (n = 15), (2) longstanding hypertension (n = 14), (3) other causes of CMP (valve, coronary or idiopathic) (n = 8) and (4) previously healthy donors (n = 6). Groups 2 and 3 were subdivided according to the presence of CMP. Evaluation comprised parameters of ethanol consumption, left ventricular function by chest X-ray and 2D echocardiography, and histology and immunohistochemical studies. Myocyte proliferation was evaluated using an assay for Ki-67 expression and measuring telomerase gene activity by real-time PCR. RESULTS: Forty-three donors were included in the study, 35 having CMP. Nuclear Ki-67 activity was low in healthy controls and significantly increased in the other groups, mainly in those with CMP. Alcoholics with CMP had a non-significantly lower proliferation response than the other CMP groups. No proliferation activity was detected with TERT in any case. CONCLUSION: Heart Ki-67 proliferation activity increases in organ donors with CMP, independently of its origin. Alcoholics presented non-significant lower myocyte proliferation capacity compared with the other groups of CMP. TERT activity was not a useful marker of proliferation in this model. Ki-67 is a better procedure to evaluate proliferation than TERT expression in alcohol-induced heart damage.

Increased myostatin activity and decreased myocyte proliferation in chronic alcoholic cardiomyopathy.

BACKGROUND: Apoptosis mediates in alcohol-induced heart damage leading to cardiomyopathy (CMP). Myocyte proliferation may compensate for myocyte loss. Myostatin is upregulated after cardiac damage and by alcohol consumption thereby decreasing myocyte renewal. We assess the potential role of alcohol in inducing myocyte apoptosis as well as in inhibiting myocyte proliferation. METHODS: Heart samples were obtained from organ donors, including 22 high alcohol consumers, 22 with hypertension, 8 with other causes of CMP, and 10 healthy donors. Evaluation included medical record with data on daily, recent and lifetime ethanol consumption, chest X-ray, left ventricular (LV) function assessed by two-dimensional echocardiography, and LV histology and immunohistochemistry. Apoptosis was evaluated by TUNEL, BAX, and BCL-2 assays. Myocyte proliferation was evaluated with Ki-67 assay. Myostatin activity was measured with a specific immunohistochemical assay. CMP was assessed by functional and histological criteria. RESULTS: Alcoholic and hypertensive donors with CMP showed higher apoptotic indices than did their partners without CMP. Myostatin activity was higher in alcoholics than in controls, mainly in those with CMP. The increase in myostatin expression in alcoholic CMP was higher than in other groups. The Ki-67 proliferation index increased in all groups with CMP compared to those without CMP, with alcoholics showing a lower increase in this proliferation response. CONCLUSIONS: Alcohol produces cardiac myocyte loss through apoptosis but also partially inhibits myocyte proliferation through myostatin up-regulation. The final result may suppose an imbalance in myocyte homeostasis, with a net loss in total ventricular myocyte mass and progressive ventricular dysfunction.

Molecular and cellular events in alcohol-induced muscle disease.

Alcohol consumption induces a dose-dependent noxious effect on skeletal muscle, leading to progressive functional and structural damage of myocytes, with concomitant reductions in lean body mass. Nearly half of high-dose chronic alcohol consumers develop alcoholic skeletal myopathy. The pathogenic mechanisms that lie between alcohol intake and loss of muscle tissue involve multiple pathways, making the elucidation of the disease somewhat difficult. This review discusses the recent advances in basic and clinical research on the molecular and cellular events involved in the development of alcohol-induced muscle disease. The main areas of recent research interest on this field are as follows: (i) molecular mechanisms in alcohol exposed muscle in the rat model; (ii) gene expression changes in alcohol exposed muscle; (iii) the role of trace elements and oxidative stress in alcoholic myopathy; and (iv) the role of apoptosis and preapoptotic pathways in alcoholic myopathy. These aforementioned areas are crucial in understanding the pathogenesis of this disease. For example, there is overwhelming evidence that both chronic alcohol ingestion and acute alcohol intoxication impair the rate of protein synthesis of myofibrillar proteins, in particular, under both postabsorptive and postprandial conditions. Perturbations in gene expression are contributory factors to the development of alcoholic myopathy, as ethanol-induced alterations are detected in over 400 genes and the protein profile (i.e., the proteome) of muscle is also affected. There is supportive evidence that oxidative damage is involved in the pathogenesis of alcoholic myopathy. Increased lipid peroxidation is related to muscle fibre atrophy, and reduced serum levels of some antioxidants may be related to loss of muscle mass and muscle strength. Finally, ethanol induces skeletal muscle apoptosis and increases both pro- and antiapoptotic regulatory mechanisms.

Evidence of apoptosis in alcoholic cardiomyopathy.

Apoptosis is a mechanism of cell death implicated in the pathogenesis of alcohol-induced organ damage. Experimental studies have suggested alcohol-mediated apoptosis in the cardiac muscle, and there is evidence of skeletal muscle apoptosis in long-term high-dose alcohol consumers. The relation between skeletal and cardiac muscle damage in alcoholism led us to consider the pathogenic role of apoptosis in alcoholic dilated cardiomyopathy. We evaluated apoptosis in the hearts of individuals with long-term alcoholism (n = 19), of those with long-standing hypertension (n = 20), and of those with no known disease as control subjects (n = 7). Alcohol consumption measurement, heart function evaluation, and myocardial immunohistochemical and morphometric analysis were performed. Apoptosis was evaluated with deoxyribonucleotidyl transferase-mediated dUTP-biotin nick end-labeling assay, and BAX and BCL-2 expressions were used to detect induction of and protection from proapoptotic mechanisms, respectively. Hearts from patients with a history of alcoholism showed apoptotic indexes similar to those of organs from hypertensive donors. Subjects with structural heart damage of alcoholic or hypertensive origin showed higher apoptotic indexes in deoxyribonucleotidyl transferase-mediated dUTP-biotin nick end-labeling, BAX, and BCL-2 assays as compared with control subjects (P < .001 for all). Moreover, New York Heart Association class I alcoholic patients displayed higher BAX and BCL-2 expressions as compared with control subjects. We conclude that apoptosis is present to a similar degree in the heart muscle of high-dose alcohol consumers and long-standing hypertensive subjects and is related to structural damage. Proapoptotic mechanisms are activated in alcoholic patients without heart damage.

Metabolic effects of ethanol on primary cell cultures of rat skeletal muscle.

Individuals who have consumed alcohol chronically accumulate glycogen in their skeletal muscles. Changes in the energy balance caused by alcohol consumption might lead to alcoholic myopathy. Experimental models used in the past, such as with skeletal muscle biopsy samples of alcohol-dependent individuals or in animal models, do not distinguish between direct effects and indirect effects (i.e., alterations to the nervous or endocrine system) of alcohol. In the current study, we evaluated the direct effect of ethanol on skeletal muscle glycogen concentrations and related glycolytic pathways. We measured the changes in metabolite concentrations and enzyme activities of carbohydrate metabolism in primary cell cultures of rat skeletal muscle exposed to ethanol for two periods. The concentrations of glycolytic metabolites and the activities of several enzymes that regulate glucose and glycogen metabolism were measured. After a short exposure to ethanol (6 h), glucose metabolism slowed. After 48 h of exposure, glycogen accumulation was observed.

Effects of alcohol on skeletal and cardiac muscle.

The acute and chronic toxic effects of alcohol on skeletal and cardiac muscle are clinically important. Muscle weakness and atrophy are the main manifestations of skeletal myopathy, and arrhythmias and progressive left-ventricular dysfunction are those of cardiomyopathy. Most patients remain asymptomatic from these effects for a long time. Myocyte atrophy and death are the main pathological findings. A clear dose-related effect has been established with ethanol consumption, with gender and some specific gene polymorphisms being factors of increased susceptibility to alcohol-induced muscle damage. Pathogenic mechanisms are pleiotropic, the most relevant being disturbances in carbohydrate, protein, and energy cell turnover, signal transduction, and induction of apoptosis and gene dysregulation. Ethanol abstinence is the only effective treatment, although controlled drinking is useful in patients who do not achieve abstinence. Persistent high-dose consumption results in deterioration of muscle and heart function, with a high mortality due to arrhythmias and progression of heart failure.

Decreased tumor necrosis factor-induced adhesion of human monocytes to endothelial cells after moderate alcohol consumption.

BACKGROUND: Moderate alcohol consumption protects against ischemic heart disease, possibly through an antiinflammatory effect. However, little is known about the mechanisms by which alcohol may interfere in the development of atherosclerosis. OBJECTIVE: We analyzed the effects of 2 alcoholic beverages with high (red wine) or low (gin) polyphenolic content on human monocyte adhesion to an endothelial cell line (Ea.hy926). DESIGN: This was a randomized, crossover trial with 8 healthy men. After a washout period, the subjects received 30 g ethanol/d as red wine or gin for 28 d. Before and after each intervention, a dietary survey and laboratory analysis were performed. Adhesion of human monocytes to endothelial cells was measured in basal and stimulated [by tumor necrosis factor alpha (TNF-alpha)] conditions. Adhesion molecules involved in monocyte-endothelium interactions were determined on the cell surface. RESULTS: The mean expression of very late activation antigen 4 on monocytes significantly decreased after red wine intake [by 18% (95% CI: 33%, 3%); P = 0.022]. Monocyte adhesion significantly increased after TNF-alpha stimulation of endothelial cells. This increase, however, was 39% less (95% CI: 48%, 35%; P = 0.049) after gin intake than after the respective washout period and was nearly abolished by red wine intake [96% less than after the respective washout period (95% CI: 142%, 76%); P < 0.001]. The reduction after red wine intake was significantly different from that after gin intake (P = 0.014). CONCLUSIONS: TNF-alpha-induced adhesion of monocytes to endothelial cells was virtually abolished after red wine consumption but was only partially reduced after gin consumption. This effect may be due to the down-regulation of adhesion molecules on the monocyte surface.

Different effects of red wine and gin consumption on inflammatory biomarkers of atherosclerosis: a prospective randomized crossover trial. Effects of wine on inflammatory markers.

BACKGROUND: No intervention studies have explored the anti-inflammatory effects of different alcoholic beverages on markers of atherosclerosis. We embarked on a randomized, crossover, single-blinded trial to evaluate the effects of wine and gin on inflammatory biomarkers of atherosclerosis. METHODS AND RESULTS: Forty healthy men (mean age, 37.6 years) consumed 30 g ethanol per day as either wine or gin for 28 days. Before and after each intervention, we measured the expression of lymphocyte function-associated antigen 1 (LFA-1), Mac-1, very late activation antigen 4 (VLA-4), and monocyte chemoattractant protein (MCP-1) in monocytes, as well as the soluble vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), interleukin-1alpha (IL-1alpha), C-reactive protein (hs-CRP) and fibrinogen. After either gin or wine consumption, plasma fibrinogen decreased by 5 and 9%, respectively, and cytokine IL-1alpha by 23 and 21%. The expression of LFA-1 (-27%), Mac-1 (-27%), VLA-4 (-32%) and MCP-1 (-46%) decreased significantly after wine, but not after gin. Wine reduced the serum concentrations of hs-CRP (-21%), VCAM-1 (-17%) and ICAM-1 (-9%). CONCLUSIONS: Both wine and gin showed anti-inflammatory effects by reducing plasma fibrinogen and IL-1alpha levels. However, wine had the additional effect of decreasing hs-CRP, as well as monocyte and endothelial adhesion molecules.

Effects of alcohol withdrawal on 24 hour ambulatory blood pressure among alcohol-dependent patients.

BACKGROUND: Although epidemiologic studies have reported an association between alcohol intake and high blood pressure (BP), the results of intervention studies have shown inconsistent results. We embarked on a study to determine whether different subgroups of alcohol-dependent patients may be identified in relation to the effect of alcohol on BP. METHODS: Fifty alcohol-dependent men (mean age, 41.4 years) received 0.4 g of ethanol per kilogram of body weight every 4 hr in 200 ml of orange juice during 24 hr and the same amount of orange juice without ethanol during another 24 hr. Twenty-four hour ambulatory BP monitoring was performed during ethanol and orange juice intakes, as was hormonal and biochemical analysis. RESULTS: Thirty-five (75%) alcohol-dependent men were normotensive and 15 (30%) hypertensive. Eighteen (51%) normotensive and 12 (80%) hypertensive subjects showed a significant decrease in 24 hr mean BP after ethanol withdrawal (mean decrease of 8.4 mm Hg [95% confidence interval, -11.2 to -5.7] and 12.5 mm Hg [confidence interval, -16.2 to -8.8], respectively) and were considered as sensitive to alcohol. The remaining alcohol-dependent subjects were considered as resistant to alcohol. Normotensive subjects sensitive to ethanol showed a significantly greater left ventricular mass and a significantly lower ejection fraction than those normotensive patients whose BP did not change after ethanol withdrawal (both p < 0.01). CONCLUSIONS: More than three fourths of the hypertensive and more than half of the normotensive alcohol-dependent patients showed sensitivity to the pressor effects of ethanol. Impairment also was observed in heart function in normotensive patients sensitive to the pressor effects of ethanol.

Evidence of apoptosis in chronic alcoholic skeletal myopathy.

Apoptosis is a common mechanism of programmed cell death that has been implicated in the pathogenesis of alcohol-induced organ damage. Experimental studies have suggested alcohol-mediated apoptosis in cardiac muscle. The relationship between skeletal and cardiac muscle damage in alcoholism led us to consider the possible role of apoptosis in the pathogenesis of skeletal myopathy. We prospectively evaluated apoptosis in skeletal muscle biopsies of 30 consecutively selected male high-dose well-nourished chronic alcohol consumers and 12 nonalcoholic controls. Alcohol consumption, evaluation of muscle strength by myometry, and deltoid muscle biopsy with immunohistochemical and morphometric analysis were performed. Apoptosis was assessed by TUNEL, BAX, and BCL-2 immunohistochemical assays. Chronic alcoholics compared with controls showed a significantly higher apoptotic index in TUNEL (2.35% +/- 0.25% versus 0.18% +/- 0.03%, P < 0.001), BAX (9.16% +/- 2.00% versus 0.66% +/- 0.22%, P < 0.001), and BCL-2 muscle assays (8.08% +/- 0.20% versus 0.83% +/- 0.20%, P = 0.001), respectively. In addition, these apoptotic indexes were higher in alcoholics with skeletal myopathy compared with in those without skeletal myopathy (3.04% +/- 0.36% versus 1.65% +/- 0.26%, P = 0.004 for TUNEL; 17.00% +/- 2.78% versus 1.33% +/- 0.22%, P < 0.001 for BAX; and 15.13% +/- 3.2% versus 1.03% +/- 0.33%, P < 0.001 for BCL-2 assays, respectively). We conclude that apoptosis is present in the skeletal muscle of high-dose alcohol consumers, mainly in those affected by myopathy. However, the specific pathogenic mechanism of apoptosis in chronic skeletal myopathy in alcoholics remains to be elucidated.

Elevated production of interleukin-6 is associated with a lower incidence of disease-related ischemic events in patients with giant-cell arteritis: angiogenic activity of interleukin-6 as a potential protective mechanism.

BACKGROUND: Patients with giant-cell arteritis (GCA) who develop a strong acute-phase response are at low risk of disease-related ischemic events. METHODS AND RESULTS: To assess the potential protective role of proinflammatory cytokines in the development of ischemic events in GCA, we measured tissue expression (66 individuals) and/or circulating levels (80 individuals) of interleukin (IL)-1beta, tumor necrosis factor-alpha (TNF-alpha), and IL-6 in patients with biopsy-proven GCA. Tissue expression was determined by quantitative real-time polymerase chain reaction and immunohistochemistry. Circulating cytokines were determined by enzyme-linked immunoassay. We found that patients with disease-related ischemic events had lower IL-6 mRNA levels (5.9+/-2.1 versus 27.6+/-7.8 relative units, P=0.013), lower IL-6 immunohistochemical expression scores (1.5+/-0.9 versus 2.7+/-1, P=0.001), and lower circulating levels of IL-6 (13.6+/-2.1 versus 24+/-2.4 pg/mL, P=0.002) than patients without ischemic complications. No significant differences were found for either IL-1beta or TNF-alpha. We subsequently investigated direct effects of IL-6 on vessel wall components. We found that IL-6 stimulates endothelial cell proliferation and differentiation into capillary-like structures and induces full angiogenic activity in both ex vivo (aortic ring) and in vivo (chick chorioallantoic membrane) assays. CONCLUSIONS: GCA patients with ischemic complications have lower tissue expression and circulating levels of IL-6 than patients with no ischemic events. IL-6 has relevant direct effects on vascular wall components that might be protective: IL-6 activates a functional program related to angiogenesis that may compensate for ischemia in patients with GCA.

Angiotensin-converting enzyme gene polymorphism is associated with vulnerability to alcoholic cardiomyopathy.

BACKGROUND: Chronic alcohol abuse has a dose-dependent toxic effect on the myocardium, leading to alcoholic cardiomyopathy. The fact that only a minority of persons with chronic alcoholism have this condition suggests the possibility of a genetic vulnerability. In this context, polymorphism of the angiotensin-converting enzyme (ACE) gene has been implicated in cardiac dysfunction. OBJECTIVE: To compare the ACE genotypes of alcoholic persons who have cardiomyopathy with those of comparable alcohol abusers who have normal cardiac function. DESIGN: Case-control study over a 2-year period. SETTING: An academic tertiary referral hospital in Barcelona, Spain. PATIENTS: 30 alcoholic men with symptomatic cardiomyopathy and 27 alcoholic men with normal cardiac function. MEASUREMENTS: Ethanol intake, cardiac status, left ventricular ejection fraction (LVEF), and ACE gene polymorphism. RESULTS: The DD ACE genotype was present in 57% of alcoholic persons with an LVEF less than 0.50 and in 7% of those with normal cardiac function. Compared with persons who had an I allele, the odds ratio for development of left ventricular dysfunction in alcoholic persons with the DD genotype was 16.4. CONCLUSIONS: Vulnerability to cardiomyopathy among chronic alcohol abusers is partially genetic and is related to presence of the ACE DD genotype. This finding demonstrates genetic susceptibility to alcohol-induced myocardial damage.

Tissue and serum angiogenic activity is associated with low prevalence of ischemic complications in patients with giant-cell arteritis.

BACKGROUND: Vascular inflammatory lesions from patients with giant-cell arteritis show a remarkable amount of neovascularization, but its clinical implications have never been investigated. METHODS AND RESULTS: To assess the clinical relevance of neovascularization in giant-cell arteritis, angiogenesis was measured in temporal artery sections from 31 patients with biopsy-proven giant-cell arteritis by staining endothelial cells with Ulex europaeus lectin. Angiogenesis was highly variable among these patients. Patients without ischemic complications had higher tissue angiogenesis scores than patients with ischemic events (5.69+/-0.6 versus 2.91+/-0.6, P=0.003). Angiogenesis was also more prominent in patients with a strong acute phase response (score: 5.31+/-0.6) compared with those with a weak systemic inflammatory reaction (2.30+/-0.44; P=0.0007). Serum angiogenic activity was studied in an additional series of 38 biopsy-proven patients. Sera from patients without ischemic events tended to be more active in stimulating human umbilical vein endothelial cell growth (optical density x1000, 270+/-15 versus 192+/-14, P=0.065) and differentiation into capillary-like structures (107+/-5 versus 84+/-8 relative units, P=0.0058) than patients with ischemic complications. Sera from patients without ischemic events had more in vivo full angiogenic activity tested in the chick chorioallantoic membrane than sera from patients with ischemic complications. CONCLUSION: Inflammation-induced angiogenic activity may play a compensatory role for ischemia in patients with giant-cell arteritis.

Muscle diseases in elders: a 10-year retrospective study.

BACKGROUND: Muscle complaints are frequent among older adults, but histological data in this setting are scarce. Our objective was to detect the major categories of muscle diseases in the elderly population based on histological study. METHODS: We reviewed all muscle biopsies performed in our hospital on patients older than the age of 65 during a 10-year period (1988-1997). As a control group, we included the next patient younger than 65 who underwent muscle biopsy after each elderly patient. We recorded demographic, clinical, and histological data of the patients, as well as the final diagnosis. Concordance between pre- and postbiopsy diagnosis was also analyzed. RESULTS: We included 239 muscle biopsies corresponding to elderly patients and 239 to controls. Compared with the control group, elderly patients more frequently exhibited type II fiber atrophy and were diagnosed with a specific myopathy. The latter was achieved in 86 cases (36%), idiopathic inflammatory myopathies and vasculitis being the most frequent diagnoses. Interestingly, in about one quarter of the elderly patients in whom a definite diagnosis of muscle disease was achieved, this diagnosis had not been clinically suspected prior to muscle biopsy. Overall, in 60 out of 239 elderly patients (25%), a specific therapeutic regimen could be instituted on the basis of the muscle biopsy results. CONCLUSIONS: Muscle diseases are not rare in elderly patients. Therefore, muscle biopsy constitutes a safe and useful tool for diagnosis because, if not performed, some potentially treatable diseases may be undiagnosed or misdiagnosed.

A strong initial systemic inflammatory response is associated with higher corticosteroid requirements and longer duration of therapy in patients with giant-cell arteritis.

OBJECTIVE: To assess whether the intensity of the initial systemic inflammatory response is able to predict response to therapy in patients with giant cell arteritis (GCA). METHODS: Retrospective review of 75 patients (49 women and 26 men) with biopsy-proven GCA who had regular followup and were treated according to uniform criteria. Four parameters were used to evaluate the baseline inflammatory response at diagnosis: fever, weight loss, erythrocyte sedimentation rate > or = 85 mm/hour, and hemoglobin < 110 gm/liter. Patients were considered to have a weak inflammatory response if they had 2 or fewer inflammatory parameters (group 1) and a strong inflammatory response if 3 or 4 parameters were present (group 2). Time required to achieve a maintenance dose of less than 10 mg prednisone/day was recorded and analyzed by the Kaplan-Meier survival analysis method. Tumor necrosis factor alpha (TNFalpha) and interleukin 6 (IL-6) serum levels were also determined in 62 patients and 15 controls. RESULTS: Forty patients had a weak (group 1) and 35 had a strong (group 2) initial inflammatory response. Patients in group 2 had significantly higher levels of circulating TNFalpha (31.9 +/- 16.8 versus 22.3 +/- 9 pg/ml; P = 0.01) and IL-6 (28.2 +/- 17.4 versus 16.6 +/- 13 pg/ml; P = 0.004) than patients in group 1. In group 1, 50% of patients required a median of 40 weeks (95% CI 37-43) to reach a maintenance dose of <10 mg, whereas in group 2 a median of 62 weeks (95% CI 42-82) was necessary (P = 0.0062). Patients in group 2 experienced more flares than patients in group 1 (P = 0.01) and received higher cumulative steroid doses (8.974 +/- 3.939 gm versus 6.893 +/- 3.075 gm; P = 0.01). CONCLUSION: GCA patients with a strong initial systemic inflammatory reaction have more elevated circulating levels of IL-6 and TNFalpha, have higher and more prolonged corticosteroid requirements, and experience more disease flares during corticosteroid therapy than patients with a weak systemic acute phase response.

Silent cerebral white matter lesions in middle-aged essential hypertensive patients.

OBJECTIVE: Age, hypertension, diabetes mellitus and a history of cardiovascular disease are the most important factors related to the presence of cerebral white matter lesions (WML), which are a common finding in elderly people. This study investigates which factors related to hypertension per se are associated with the presence of WML in asymptomatic, middle-aged, never-treated essential hypertensive patients. METHODS: A total of 66 untreated essential hypertensive patients of both genders, aged 50-60 years, with neither diabetes mellitus nor evidence of cardiovascular disease, were studied. Hypertensive patients were classified into two groups according to the presence or absence of WML in brain magnetic resonance imaging (MRI). RESULTS: A total of 39 (59.1%) hypertensives showed no WML in brain MRI, and 27 (40.9%) exhibited the presence of WML. Compared with hypertensives without WML, patients with WML showed significantly higher values of both office and 24 h ambulatory blood pressure monitoring (ABPM) systolic, diastolic, mean and pulse pressure. No differences were observed in either the nocturnal fall of blood pressure, or in blood pressure variability, assessed by 24 h standard deviation, among hypertensives with WML. In contrast, the nocturnal decline of heart rate was significantly blunted in patients with WML, compared with those without WML. CONCLUSIONS: Cerebral white matter lesions are a common finding in asymptomatic middle-aged essential hypertensives. The severity of blood pressure elevation seems to be the most important factor related to the presence of WML. Neither the circadian rhythm nor the long-term variability of blood pressure were related to WML.

The effect of controlled drinking in alcoholic cardiomyopathy.

BACKGROUND: Cardiomyopathy is a potentially fatal complication of alcohol abuse. In alcoholic persons who develop cardiac dysfunction, abstinence is thought to be essential to halt further deterioration of cardiac contractility. Some evidence indicates that reducing alcohol intake may also be beneficial. OBJECTIVE: To evaluate the effect of moderate "controlled" drinking on cardiac function in patients with alcoholic cardiomyopathy. DESIGN: 4-year prospective cohort study. SETTING: A university hospital in Barcelona, Spain. PATIENTS: 55 alcoholic men with cardiomyopathy who had been drinking a minimum of 100 g of ethanol per day for at least 10 years. MEASUREMENTS: Evaluation of ethanol intake and nutrition, clinical assessment of cardiac status, and sequential echocardiography and radionuclide cardiac angiography. RESULTS: After the first year of evaluation, all patients with cardiomyopathy who abstained from alcoholic beverages demonstrated significant improvement in left ventricular function (average increase in left ventricular ejection fraction, 0.131 [95% CI, 0.069 to 0.193]). Patients who drank 20 to 60 g of ethanol per day showed a comparable mean improvement of 0.125 (CI, 0.082 to 0.168). In contrast, left ventricular ejection fraction deteriorated further in most patients who continued to abuse alcohol (>80 g/d). After 4 years, left ventricular ejection fraction had continued to improve in both abstinent patients and those who controlled their drinking. Ten patients who had continued to consume more than 80 g of ethanol per day died during the study. CONCLUSION: In patients with alcoholic cardiomyopathy, both abstinence and controlled drinking of up to 60 g of ethanol per day (four standard drinks) were comparably effective in promoting improvement in cardiac function.