ABSTRACT
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.
Subject(s)
Cardiomyopathy, Alcoholic/metabolism , Cardiomyopathy, Alcoholic/pathology , Cell Proliferation , Myocytes, Cardiac/metabolism , Myostatin/metabolism , Adult , Aged , Alcoholism/metabolism , Alcoholism/pathology , Chronic Disease , Female , Humans , Hypertension/metabolism , Hypertension/pathology , Male , Middle Aged , Myocardium/metabolism , Myocardium/pathology , Myocytes, Cardiac/pathology , Myostatin/biosynthesis , Up-Regulation/physiologyABSTRACT
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.
Subject(s)
Cardiomyopathy, Alcoholic/metabolism , Cell Proliferation/drug effects , Central Nervous System Depressants/adverse effects , Ethanol/adverse effects , Ki-67 Antigen/genetics , Telomerase/genetics , Adult , Aged , Alcoholics , Apoptosis , Cardiomyopathy, Alcoholic/epidemiology , Cardiomyopathy, Alcoholic/pathology , Female , Heart/drug effects , Heart/physiopathology , Heart Diseases/metabolism , Heart Diseases/pathology , Humans , Hypertension/pathology , Ki-67 Antigen/biosynthesis , Ki-67 Antigen/metabolism , Male , Middle Aged , Myocardium/metabolism , Myocardium/pathology , Myocytes, Cardiac/metabolism , Myocytes, Cardiac/pathology , Telomerase/biosynthesis , Telomerase/metabolism , Time Factors , Tissue DonorsSubject(s)
Anaphylaxis/chemically induced , Anti-Ulcer Agents/adverse effects , Benzimidazoles/adverse effects , Omeprazole/analogs & derivatives , Sulfoxides/adverse effects , 2-Pyridinylmethylsulfinylbenzimidazoles , Aged , Anti-Ulcer Agents/administration & dosage , Anti-Ulcer Agents/metabolism , Benzimidazoles/administration & dosage , Benzimidazoles/metabolism , Humans , Male , Omeprazole/administration & dosage , Omeprazole/adverse effects , Omeprazole/metabolism , Pantoprazole , Proton Pump Inhibitors , Sulfoxides/administration & dosage , Sulfoxides/metabolismABSTRACT
We report a case of electrocardiographic signature of the Brugada syndrome in a 39-year-old patient with an overdose of diphenhydramine. He was found unconscious and hypotensive. His serum potassium concentration was 8.3 mEq/L and the ECG revealed a coved-type ST-segment elevation in leads V2-V3. These repolarization abnormalities neither normalize with the correction of the hyperkalemia nor with an intravenous infusion of isoproterenol. When he regained consciousness, he was admitted the toxic ingestion of diphenhydramine and progressively the ECG normalized. A negative flecainide test confirmed that the transient ECG abnormalities were the consequence of the drug overdose and ruled out the Brugada syndrome.
Subject(s)
Diphenhydramine/poisoning , Electrocardiography , Adult , Death, Sudden, Cardiac/etiology , Drug Overdose , Humans , Male , Suicide, AttemptedABSTRACT
BACKGROUND: Excessive ethanol intake is one of the most frequent causes of acquired dilated cardiomyopathy in developed countries. The pathogenesis is multifactorial, with the antioxidant imbalance of cardiac muscle being a potential factor. The current study evaluates myocardial antioxidant status in ethanol consumers and its relation to cardiac damage. METHODS: The authors assessed superoxide dismutase, glutathione peroxidase, and glutathione reductase enzyme activities as well as the total antioxidant status capacity in myocardial samples obtained from organ donors with sudden death of traumatic or neurological origin. They studied 23 high-dose chronic alcohol consumers, 27 individuals with long-standing hypertension, and 11 healthy controls. Cardiomyopathy was defined according to standard functional and histological criteria. RESULTS: Patients with dilated cardiomyopathy, either of alcoholic or hypertensive origin, showed increased myocardial superoxide dismutase activities compared with patients without cardiomyopathy (p < 0.001, both) and controls (p < 0.05, both). Total antioxidant status capacity and the activity of glutathione peroxidase and glutathione reductase enzymes were similar in all groups. Superoxide dismutase activity was related to the presence of cardiac enlargement and the degree of cardiac histological damage. The amount and type of alcoholic beverages as well as the nutritional status of the patients were not related to myocardial antioxidant activity. CONCLUSIONS: The presence of dilated cardiomyopathy, of either alcoholic or hypertensive origin, is related to an increase in myocardial superoxide dismutase activity.