Possible therapeutic targets in cardiac myocyte apoptosis.

Since Kerr described programmed cell death (apoptosis) as a process distinct from necrosis, there have been many studies of apoptosis in disease, especially of immunological origin. Because cardiac myocytes are terminally differentiated cells, they have typically been assumed to die exclusively by necrosis. However, during the last decade this view has been challenged by several studies demonstrating that a significant number of cardiac myocytes undergo apoptosis in myocardial infarction, heart failure, myocarditis, arrhythmogenic right ventricular dysplasia, and immune rejection after cardiac transplantation, as well as in other conditions of stress. These are potentially relevant observations, because apoptosis--unlike necrosis--can be blocked or reversed at early stages. Specific inhibition of this process may confer a considerable degree of cardioprotection, but requires a thorough understanding of the underlying mechanisms. Recent progress includes a better understanding of the importance of mitochondria-initiated events in cardiac myocyte apoptosis, of factors inducing apoptosis in heart failure and during hypoxia, and of the dual pro-apoptotic and anti-apoptotic effects of hypertrophic stimuli such as beta-adrenoceptor agonists, angiotensin converting enzyme inhibitors, nitric oxide and calcineurin. The investigation of cytoprotective and apoptotic signal transduction pathways has revealed important new insights into the roles of the mitogen-activated protein kinases p38, extracellular signal regulated kinase and c-Jun N-terminal kinase in cardiac cell fate. Our present review focuses on the intracellular signal transduction pathways of cardiac myocyte apoptosis and the possibility of specific inhibition of the process.

Plasma endotoxin level of healthy donors.

The plasma level of endotoxin was determined in 116 healthy blood donors. After a routine physical and laboratory investigations the endotoxin level was determined with Limulus amebocyte lysate assay (LAL-test) by the chromogenic kinetic method of Bio-Whittaker Co. (USA). Its sensitivity was 0.005-50 EU/ml. The plasma level of endotoxin in most of the healthy donors was less than 1 EU/ml (in the range of 0.01-1.0 EU/ml), but always measurable. The average +/- S.D. was 0.128 +/- 0.215 EU/ml. Because of the high standard deviation and high range of values, the data were distributed into two groups with the means of 0.05 +/- 0.022 EU/ml and 0.294 +/- 0.186 EU/ml. The difference between the groups was significant (p < 0.001). In conclusion, endotoxin can be measured in plasma of healthy individuals.

[Molecular regulation of myocardial apoptosis]. / A szívizom apoptosisának molekuláris szabályozása.

Since apoptosis was described as a process distinct from necrosis, there have been many studies of programmed cell death in diseases, especially immunological diseases. Because cardiac myocytes are terminally differentiated cells, they have typically been assumed to die exclusively by necrosis. However, during the last six to seven years this view has been challenged by several studies demonstrating that a significant number of myocytes undergo apoptosis in myocardial infarction, heart failure, myocarditis, arrhythmogen right ventricular dysplasia, and immune rejection after cardiac transplantation, as well as in other conditions of stress. These are potentially very important observations, because apoptosis--unlike necrosis--can be blocked or reversed at early stages. The tracking of cytoprotective and apoptotic signal transduction pathways has proceeded rapidly with important new insights into the roles of mitochondria-dependent pathway, Bcl-2 protein family, p38 mitogen-activated protein kinase, extracellular signal-regulated kinase and c-Jun N-terminal kinase in cell fate. New studies have demonstrated that specific inhibition of apoptosis and activation of cytoprotective mechanisms, based on the better understanding of the intracellular signaling pathways, can significantly protect cardiac myocytes. This review will assess progress in cardiac myocyte apoptosis research and report on the current status of anti-apoptotic therapy in acute and chronic heart diseases.

[The role of myocardial apoptosis in the development of heart failure]. / A myocardialis apoptosis szerepe a szívelégtelenség kialakulásában.

Heart failure can result from a variety of causes, including volume or pressure overload and contractile disturbances of the myocardium. Loss of myocytes is an important mechanism in the development of cardiac failure. In general, myocyte death resulting in progressive deterioration of myocardial function is attributed to necrosis, but recently the involvement of programmed cell death (mainly apoptosis) has been suggested. The authors review the possible role of myocardial apoptosis in developing of heart failure. Subcellular genetic regulatory processes as well as the pharmacological susceptibility of programmed cell death are also discussed. In heart failure, significant amount of cardiac myocytes undergoes apoptosis, that unlike necrosis can be prevented. Specific inhibition of this process could mean a considerable part of cardioprotection after thorough understanding of the underlying cellular mechanisms.

[Plasma endotoxin level in healthy blood donors]. / Egészséges véradók plazma endotoxin szintje.

The plasma level of endotoxin was determined in 116 healthy blood donors in this laboratory. After a routine physical and laboratory investigations the endotoxin level was determined with Limulus amebocyte lysate assay (LAL test) by the chromogenic kinetic method of Bio-Whittaker Co. (USA). Its sensitivity was 0.005-50 EU/ml. The plasma level of endotoxin in most of healthy donors was less than 1 EU/ml (in the range of 0.01-1.0 EU/ml), but always measurable. The average +/- S. D. was 0.128 +/- 0.215 EU/ml. Because of the high standard deviation and high range of values, the data were distributed to two groups with the means of 0.05 +/- 0.022 EU/ml and 0.294 +/- 0.186 EU/ml. The difference between the groups was significant found (p < 0.001). In conclusion, endotoxin can be measured in plasma of healthy individuals.

[Effect of acute alcohol intake on certain cardiovascular functions in healthy young males]. / Akut alkoholbevitel hatása egyes cardiovascularis funkciókra fiatal egészséges férfiakon.

.15, 0.25 and 0.5 g/kg alcohol in the form of 40% brandy in one week intervals was consumed by eight healthy, regularly trained young men volunteers. Blood alcohol level, blood pressure and ECG were registered before and 30, 60 and 90 min after, each alcohol consumption. The cardiac output was measured with a radiocirculographic method before and 45 min after alcohol consumption. The cardiac index, stroke volume, stroke index, and total peripheral resistance (TPR) were calculated. With increase of the alcohol dose the blood alcohol level increased, while cardiac output, cardiac index, stroke volume, stroke index, and the systolic blood pressure fell. The other parameters examined--heart rate, diastolic blood pressure, TPR among others--remained unchanged. The ECG was normal. The highest no effect alcohol dose was less than 0.15 g/kg (0.1, k/kg). It is concluded that, depending on the dose, alcohol has practically no effect on the majority of the heart-functions, however, in the range of 0.1 to 0.5 g/kg it has a depressive influence, i.e. lowers the pump-function of the heart and, at 0.5 g/kg the arterial blood pressure.

Identification of health damage due to alcohol abuse; importance of alterations in cardiac function and blood chemistries.

Like in any other disease, diagnosis of health damage caused by alcohol abuse can be established all the easier and sooner, the more results of medical examinations are taken into consideration simultaneously. Evidence is presented that a larger proportion (96.4%) of alcoholics suffer from compromised cardiac function (the classification function uses 6 variables out of the measured 21 than from disorders of liver function and the metabolism (87.7%) (the classification function uses 12 variables out of the 21). Taking into consideration all the 41 variables (using only 12) the power of discrimination is 99.2% (discriminant analysis).

Acute effects of low doses of alcohol on the cardiovascular system in young men.

.15, 0.25 and 0.5 g/kg alcohol in the form of 40% brandy in one week intervals was consumed by eight healthy, regularly trained young men volunteers. Blood alcohol level, blood pressure and ECG were registered before and 30, 60 and 90 min after, each alcohol consumption. The cardiac output was measured with a radiocirculographic method before and 45 min after alcohol consumption. The cardiac index, stroke volume, stroke index, and total peripherial resistance (TPR) were calculated. With increase of the alcohol dose the blood alcohol level increased, while cardiac output, cardiac index, stroke volume, stroke index, and the systolic blood pressure fell. The other parameters examined--heart rate, diastolic blood pressure, TPR among others--remained unchanged. The ECG was normal. The highest no effect alcohol dose was less than 0.15 g/kg (approximately 0.1 g/kg). It is concluded that, depending on the dose, alcohol has practically no effect on the majority of the heart-functions, however, in the range of 0.1 to 0.5 g/kg it has a depressive influence, i.e. lowers the pump-function of the heart and, at 0.5 g/kg the arterial blood pressure. Evaluation of the quantitative and qualitative relationships of dose-effect and dose-response of the human heart following acute alcohol consumption needs experiments with various doses in homogeneous groups as well as toxicological investigations in animals.