Claus Weiss

Attenuated Progression of Coronary Artery Disease After 6 Years of Multifactorial Risk Intervention Role of Physical Exercise

BACKGROUND It was the aim of this study to assess the long-term effects of physical exercise and low-fat diet on the progression of coronary artery disease. At the beginning of the study, 113 male patients with coronary artery disease were randomized to an intervention group (n=56) or a control group (n=57); 90 patients (80%) could be reevaluated after 6 years. METHODS AND RESULTS Patients in the intervention group (n=40) showed a reduction in total serum cholesterol (6.03+/-1.03 versus 5.67+/-1.01 mmol/L; P<.03) and triglyceride levels (1.94+/-0.8 versus 1.6+/-0.89 mmol/L; P<.005) and maintained their initial body mass index (26+/-2 versus 27+/-2 kg/m2; P=NS), but results were not statistically different from the control group (n=50) (total serum cholesterol, 6.05+/-1.02 versus 5.79+/-0.88 mmol/L; triglycerides, 2.25+/-1.28 versus 1.85+/-0.96 mmol/L [both P=NS]; body mass index, 26+/-2 versus 28+/-3 kg/m2 [P<.0001]). In the intervention group, there was a significant 28% increase in physical work capacity (166+/-59 versus 212+/-89 W; P<.001), whereas values remained essentially unchanged in the control group (165+/-51 versus 170+/-60 W; P=NS; between groups, P<.05). In the intervention group, coronary stenoses progressed at a significantly slower rate than in the control group (P<.0001). Energy expenditure during exercise was assessed in a subgroup; patients with regression of coronary stenoses spent an average of 1784+/-384 kcal/wk (approximately 4 hours of moderate aerobic exercise per week). Multivariate regression analysis identified only physical work capacity as independently contributing to angiographic changes. CONCLUSIONS After 6 years of multifactorial risk intervention, there is significant and persistent improvement in lipoprotein levels and physical work capacity, which results in a significant retardation of disease progression. These beneficial effects appear to be largely due to chronic physical exercise.

Coagulation and thrombomodulin in response to exercise of different type and duration

PURPOSE The present study was conducted to evaluate the role of the duration of exercise and the impact of the exercise type for exercise-induced activation of coagulation. METHODS Eleven male triathletes were subjected to stepwise maximal (17 min) and 1-h maximal exercise in swimming, cycling, and running. Changes of hemostatic variable sand of plasma thrombomodulin, a marker of endothelial cell activation, were monitored. RESULTS Irrespective of the type of exercise, alterations in markers of thrombin (prothrombin fragment 1 + 2, thrombin-antithrombin III complexes) and fibrin formation (fibrinopeptide A) were more pronounced after 1-h exercise than after stepwise maximal exercise. Hemostatic parameters rose to the highest levels after running resulting in substantial fibrin formation as indicated by fibrinopeptide A increasing from 1.33 ng.mL-1 to 2.25 ng.mL (P < 0.05) after 1-h exercise testing. Significant changes of plasma thrombomodulin were detected exclusively after running with increases from 38.2 ng.mL-1 to 44.2 ng.mL-1 (1 h, P < 0.01). CONCLUSIONS The data demonstrated that prolonged exercise is necessary for exercise-induced activation of coagulation resulting in thrombin and fibrin formation and suggested that endothelial cell activation possibly due to mechanical factors associated with running might play a role.

Low plasma glutamine in combination with high glutamate levels indicate risk for loss of body cell mass in healthy individuals: the effect of N-acetyl-cysteine

Skeletal muscle catabolism, low plasma glutamine, and high venous glutamate levels are common among patients with cancer or human immunodeficiency virus infection. In addition, a high glycolytic activity is commonly found in muscle tissue of cachectic cancer patients, suggesting insufficient mitochondrial energy metabolism. We therefore investigated (a) whether an “anaerobic physical exercise” program causes similar changes in plasma amino acid levels, and (b) whether low plasma glutamine or high glutamate levels are risk factors for loss of body cell mass (BCM) in healthy human subjects, i.e., in the absence of a tumor or virus infection. Longitudinal measurements from healthy subjects over longer periods suggest that the age-related loss of BCM occur mainly during episodes with high venous glutamate levels, indicative of decreased muscular transport activity for glutamate. A significant increase in venous glutamate levels from 25 to about 40 μM was seen after a program of “anaerobic physical exercise.” This was associated with changes in T lymphocyte numbers. Under these conditions persons with low baseline levels of plasma glutamine, arginine, and cystine levels also showed a loss of BCM. This loss of BCM was correlated not only with the amino acid levels at baseline examination, but also with an increase in plasma glutamine, arginine, and cystine levels during the observation period, suggesting that a loss of BCM in healthy individuals terminates itself by adjusting these amino acids to higher levels that stabilize BCM. To test a possible regulatory role of cysteine in this context we determined the effect of N-acetyl-cysteine on BCM in a group of subjects with relatively low glutamine levels. The placebo group of this study showed a loss of BCM and an increase in body fat, suggesting that body protein had been converted into other forms of chemical energy. The decrease in mean BCM/body fat ratios was prevented by N-acetyl-cysteine, indicating that cysteine indeed plays a regulatory role in the physiological control of BCM.

Myocardial ischemia during physical exercise in patients with stable coronary artery disease: predictability and prevention.

AIMS We assessed whether exercise-induced myocardial ischemia during intensive group exercise sessions can be predicted in patients with coronary artery disease and stable angina pectoris. METHODS AND RESULTS Twenty-three patients underwent cardiac catheterization, 201-thallium scintigraphy, and exercise testing prior to participation in group training sessions. Heart rates and myocardial ischemia were documented by Holter monitoring. The individual training heart rate was calculated as a percentage of the maximal heart rate achieved during symptom-limited exercise testing. Myocardial ischemia occurred significantly more often during group exercise sessions (15 of 23 patients) than during treadmill testing (4 of 23 patients, P<0.001). Maximal heart rate (145+/-23 vs. 134+/-21 beats/min, P<0.004) and maximal plasma lactate concentrations (6.0+/-2.9 vs. 4.3+/-2.0 mmol/l, P<0.05) were significantly higher than during symptom-limited exercise testing. Ischemic episodes occurred significantly more often during jogging than during competitive ball games or interval training. Myocardial ischemia occurred in patients who exceeded their individual target training heart rates (43 of 44 episodes; P<0.001). Duration of ischemic episodes did not correlate with any marker obtained at the beginning of the study. CONCLUSION These data demonstrate that routine diagnostic procedures do not sufficiently identify patients at risk for exercise-induced myocardial ischemia. Ischemic events are only effectively prevented by choosing adequate types of exercise and, above all, by the strict adherence to individual target heart rates.

Activation of Coagulation and Fibrinolysis After Rehabilitative Exercise in Patients With Coronary Artery Disease

It has been suggested that blood coagulation be activated and fibrinolytic activity be impaired in patients with coronary artery disease (CAD). With regard to the activation of coagulation and fibrinolysis occurring during exercise in healthy individuals, we examined the hypothesis that rehabilitative exercise in patients with CAD might give rise to an exaggerated activation of coagulation. In 12 patients with angiographically documented CAD without myocardial infarction within the preceding 6 months (male, age 55+/-9 years [SD]) and in 12 healthy controls (male, 52+/-7 years), molecular markers of thrombin, fibrin, and plasmin formation were determined before and after a rehabilitative group exercise session lasting 1 hour. Resting levels of prothrombin fragment 1+2 were lower in patients with CAD (0.67+/-0.2 [SE] vs 1.04+/-0.2 nmol/L, p <0.001) and remained unchanged after exercise, whereas a significant increase was noted in controls (p <0.01). After exercise, plasma levels of thrombin-antithrombin III complexes and of fibrinopeptide A increased significantly in both groups, although there were more pronounced changes in controls. Exercise resulted in a marked generation of plasmin as indicated by plasmin-alpha2-antiplasmin complexes increasing 2.5-fold in patients (p <0.001) and threefold in controls (p <0.001). Repeated experiments in control subjects after administration of aspirin (day 1: 500 mg; days 2 to 5: 100 mg) documented that differences between groups could not be attributed to aspirin medication (100 mg/day) in patients with CAD. We concluded that rehabilitative exercise in patients with CAD beyond the immediate postinfarction period has no detrimental effects on thrombin, fibrin, and plasmin formation.

Neutrophil function in peripheral arterial occlusive disease: the effects of prostaglandin E1

The role of polymorph nuclear neutrophils (PMN) in limb ischemia and reperfusion has been recognized only in recent years. The present study aimed to investigate the systemic and local (in femoral venous blood) effects of intra-arterially or intravenously applied prostaglandin E1 (PGE1) on systemic and ischemia-induced local changes in neutrophil function. Thirty patients with intermittent claudication were randomly assigned to intra-arterial or intravenous infusion of prostaglandin E1 (10 mgIAor15 mg IV over 30 min). Prior to infusion femoral arterial and venous blood samples were obtained from the predominantly affected leg under resting conditions and immediately after a 3-min period of ischemia induced by suprasystolic thigh compression. After 24 h additional blood samples were obtained at baseline, following infusion of prostaglandin E1, and again after another 3-min period of ischemia following the prostaglandin E1 infusion. Intra-arterially administered prostaglandin E1 caused an increase in the PMN count by 3.5 ± 2% (p,0.05) and a decrease in free oxygen radical production by 13 ± 8% (p,0.05) measured by whole blood chemiluminescence. Additionally, a trend for lower PMN filterabilities (9 ± 12%, NS) was observed. Intra-arterially infused prostaglandin E1 significantly reduced the ischemia-induced decrease in neutrophil filterability (arterial and venous blood difference after ischemia - control: 22 ± 17% (p,0.05); IA PGE1:8 ± 11% (NS), each compared to baseline). Intravenously administered prostaglandin E1 showed similar systemic effects as the intra-arterial application, but did not affect the ischemia-induced changes in neutrophil filterability. In conclusion, prostaglandin E1 reduces PMN activation in patients with peripheral arterial occlusive disease.

Prognostic significance of glucocorticoid receptor determination in patients with chronic lymphocytic leukemia and immunocytoma--lack of a positive correlation between receptor levels and clinical responsiveness.

Glucocorticoid receptors (GR) have been suggested to have prognostic significance in patients with CLL treated with chemotherapy containing glucocorticoid. In this study, the GR levels in 65 patients with advanced CLL and immunocytoma (clinical stages III and IV according to Rai) were determined by means of a whole cell assay. The median GR-level was 1,920 bs/c with a range from 0 to 9591. The patients were subsequently treated according to a prospective, randomized trial with either a combination of chlorambucil and prednisolone, or with prednimustine. No significant difference in receptor levels was found between responders (median = 1940 bs/c; n = 47) and nonresponders (median = 1950 bs/c; n = 14). To assess the influence of receptor content on prognosis we have analyzed the relationship between GR content and survival time and duration of response. There was no significant difference in duration of response and in survival between those patients with high (greater than 1920 bs/c) and those with low GR levels (less than 1920 bs/c) (log-rank test). Our data suggest that determination of GR provides no reliable indicator for clinical response to regimens with glucocorticoid as a component in patients with CLL and immunocytoma.

Fibrinolytic response to exercise in women using third-generation oral contraceptives.

The use of oral contraceptives (OC) is associated with an increased risk of thrombosis, suggesting OC exert procoagulant and/or antifibrinolytic effects. Given that physical exercise physiologically leads to an activation of blood coagulation and fibrinolysis, this study tested the hypothesis that OC might compromise the fibrinolytic response to exercise. Fibrinolytic variables were measured in 10 women (24 ± 2 years) using OC (a formulation containing 30 μg ethinylestradiol and 150 μg desogestrel) and in 11 women without OC (mean ± SD, 27 ± 3 years) before, during and after a 1-h run on a treadmill at a velocity corresponding to an oxygen demand of 75–80% of maximum (anaerobic threshold). Exercise testing gave rise to considerable increases of tissue-type plasminogen activator antigen by seven-fold to eight-fold in women taking and not taking OC alike. In the presence of unchanged plasma levels of plasminogen activator inhibitor-1, exercise-induced release of tissue-type plasminogen activator led to enhanced plasmin formation with respect to plasmin–antiplasmin complexes, rising by (mean ± standard error) 701 ± 77 ng/ml (P < 0.001) in women using OC and by 695 ± 117 ng/ml (P < 0.001 versus baseline; NS versus OC users) in controls. The fibrinolytic response to intensive physical exercise is preserved in women using OC and is similar to women not using OC.

Decrease in soluble CD8 antigen levels in splenectomized patients as an index for reduced suppressor/cytotoxic cell activity.

To investigate the effect of splenectomy on lymphocyte subpopulations we monitored changes in serum concentrations of soluble suppressor/cytotoxic (sCD8) and soluble helper/inducer (sCD4) antigen in 11 splenectomized patients. Indications for splenectomy were hereditary spherocytosis in 2, idiopathic thrombocytopenic purpura in 2, gastric carcinoma in 4, Hodgkins disease in 2 and pancreatitis in 1 patient. Lymphocyte subpopulations were also analyzed by means of conventional immunophenotyping with monoclonal antibodies to CD4 and CD8. We consistently found an early postoperative drop of sCD8 and sCD4 levels within the first week after splenectomy, paralleling changes in the percentages of CD4+ and CD8+ lymphocytes. While alterations of lymphocyte subsets in the peripheral blood were completely reversible and sCD4 levels returned to preoperative values, sCD8 concentrations remained suppressed even 3 months after splenectomy. SCD8 levels at the nadir and those 3 months after splenectomy were significantly lower than preoperative values (P = 0.003, P = 0.149 respectively). Since sCD8 levels reflect suppressor/cytotoxic cell activity, we suggest that suppressor cell activity is reduced in splenectomized patients.

Exercise-induced hemostatic activation in patients with dilated cardiomyopathy in sinus rhythm.

Abnormalities of baseline hemostatic variables have been related to a hypercoagulable state in patients with chronic heart failure (CHF). Given that physical exercise leads to an activation of coagulation physiologically, this study addressed the question of whether the exercise-induced hemostatic activation is enhanced in patients with CHF. Ten patients with dilated cardiomyopathy (ejection fraction < 40%) and 10 healthy individuals (matched for sex, age and body mass index) were subjected to a maximal exercise test on a bicycle ergometer. Healthy subjects performed a second exercise test at a submaximal intensity level, in which oxygen consumption (VO2) was adjusted to the peak oxygen consumption (VO2peak) of the corresponding patient. Exercise testing had only marginal effects on markers of thrombin formation in patients and healthy individuals alike. In patients with CHF, exercise-induced changes in fibrinopeptide A, an index of fibrin formation, paralleled those observed in controls after submaximal exercise whereas most pronounced changes occurred in healthy subjects after maximal exercise. Plasmin–antiplasmin complexes increased almost three-fold with maximal exercise in both groups, thus indicating a marked formation of plasmin. Maximal physical exercise does not induce an exaggerated formation of thrombin and fibrin in CHF patients. The fibrinolytic response to exercise in terms of plasmin formation is not compromised in patients with dilated cardiomyopathy.