Wolfgang Kübler

Physical training in patients with stable chronic heart failure: Effects on cardiorespiratory fitness and ultrastructural abnormalities of leg muscles

OBJECTIVES The present study was designed to evaluate the effect of an ambulatory training program on ultrastructural morphology and the oxidative capacity of skeletal muscle and its relation to central and peripheral hemodynamic variables in patients with chronic heart failure. BACKGROUND Clinical evidence supports the hypothesis that exercise intolerance in patients with chronic heart failure is not only a consequence of low cardiac output, but is also a result of alterations in oxidative metabolism of skeletal muscle. METHODS Twenty-two patients were prospectively randomized either to a training group (mean [+/-SD] ejection fraction 26 +/- 9%, n = 12) participating in an ambulatory training program or to a physically inactive control group (ejection fraction 27 +/- 10%, n = 10). At baseline and after 6 months, patients underwent symptom-limited bicycle exercise testing, and central and peripheral hemodynamic variables were measured. Percutaneous needle biopsy samples of the vastus lateralis muscle were obtained at baseline and after 6 months. The ultrastructure of skeletal muscle was analyzed by ultrastructural morphometry. RESULTS After 6 months, patients in the training group achieved an increase in oxygen uptake at the ventilatory threshold of 23% (from 0.86 +/- 0.2 to 1.07 +/- 0.2 liters/min, p < 0.01 vs. control group) and at peak exercise of 31% (from 1.49 +/- 0.4 to 1.95 +/- 0.4 liters/min, p < 0.01 vs. control group). There was no significant change in oxygen uptake at the ventilatory threshold and at peak exercise in the control group. The total volume density of mitochondria and volume density of cytochrome c oxidase-positive mitochondria increased significantly by 19% (from 4.7 +/- 1.5 to 5.6 +/- 1.5 vol%, p < 0.05 vs. control group) and by 41% (from 2.2 +/- 1.0 to 3.1 +/- 1.0 vol%, p < 0.05 vs. control group) after 6 months of regular physical exercise. Cardiac output at rest and at submaximal exercise remained unchanged but increased during maximal symptom-limited exercise from 11.9 +/- 4.0 to 14.1 +/- 3.3 liters/min in the training group (p < 0.05 vs. baseline; p = NS vs. control group). Peak leg oxygen consumption increased significantly by 45% (from 510 +/- 172 to 740 +/- 254 ml/min, p < 0.01 vs. control group). Changes in cytochrome c oxidase-positive mitochondria were significantly related to changes in oxygen uptake at the ventilatory threshold (r = 0.82, p < 0.0001) and at peak exercise (r = 0.87, p < 0.0001). CONCLUSIONS Regular physical training increases maximal exercise tolerance and delays anaerobic metabolism during submaximal exercise in patients with stable chronic heart failure. Improved functional capacity is closely linked to an exercise-induced increase in the oxidative capacity of skeletal muscle.

The effect of aortic valve replacement on survival.

We retrospectively studied 252 operated and 47 unoperated patients with isolated aortic valve disease. Aortic valve replacement (AVR) was recommended to all patients based on clinical and hemodynamic data. Preoperative hemodynamic and angiographic data were similar in operated and unoperated cohorts. Seventy-one percent of patients received a Bjork-Shiley prosthesis. Operative mortality was 7% for the entire surgical series. For patients with predominant aortic stenosis (AS), survival at 3 years was 87% in operated and 21% in unoperated patients (p < 0.001). For patients with predominant aortic insufficiency (Al), the 5-year survival rate was 86% in operated and 87% in unoperated patients (NS). AVR improved long-term survival inpatients with AS who had normal or impaired left ventricular (LV) function.In patients with Al and normal LV function, survival was not improved after AVR, but those with LV dysfunction who were operated on tended to survive longer (NS). Long-term survival of unoperated patients with AI was better than that in unoperated patients with AS. We conclude that AVR improves long-term survival in patients with AS who have normal or abnormal LV function, and that AVR does not change long-term survival in patients with Al, although those with LV dysfunction tended to survive longer.

Angiotensin Induces Inflammatory Activation of Human Vascular Smooth Muscle Cells

Multiple data suggest that the renin-angiotensin system contributes to the pathogenesis of atherosclerosis. The atherogenic effect of the renin-angiotensin system can only in part be explained by the influence of its effector angiotensin II on blood pressure, smooth muscle cell (SMC) growth, or antifibrinolytic activity. Because chronic inflammation of the vessel wall is a hallmark of atherosclerosis, we hypothesized that angiotensin II may elicit inflammatory signals in vascular SMCs. Human vascular SMCs were stimulated with angiotensin. Inflammatory activation was assessed by determination of interleukin-6 (IL-6) release into the culture medium, detection of IL-6 mRNA by RT-PCR, and demonstration of activation of nuclear factor-kappaB in electrophoretic mobility shift assays. Angiotensin II concentration-dependently (1 nmol/L to 1 micromol/L) stimulated IL-6 production by SMCs via activation of the angiotensin II type 1 receptor (demonstrated by the inhibitory action of the receptor antagonist losartan). Angiotensin I increased IL-6 production by SMCs, too. This effect was inhibited by captopril and ramiprilat, suggesting conversion of angiotensin I to angiotensin II by angiotensin-converting enzyme in SMCs. Steady-state mRNA for IL-6 was augmented after stimulation with angiotensin II, suggesting regulation of angiotensin-induced IL-6 release at the pretranslational level. Moreover, the proinflammatory transcription factor nuclear factor-kappaB, which is necessary for transcription of most cytokine genes, was also activated by angiotensin II. Pyrrolidine dithiocarbamate suppressed angiotensin II-induced IL-6 release, a finding compatible with involvement of reactive oxygen species as second messengers in cytokine production mediated by angiotensin. The data demonstrate the ability of angiotensin to elicit an inflammatory response in human vascular SMCs by stimulation of cytokine production and activation of nuclear factor-kappaB. Inflammatory activation of the vessel wall by a dysregulated renin-angiotensin system may contribute to the pathogenesis of atherosclerosis.

Reduced coronary dilatory capacity and ultrastructural changes of the myocardium in patients with angina pectoris but normal coronary arteriograms.

Hemodynamic and metabolic studies were performed in 15 patients without heart disease (controls, group A), in 21 patients with typical stress-induced anginal pain but normal coronary and left ventricular angiograms (angina pectoris with normal arteriogram, group B), and in 10 patients with angiographically proved coronary artery disease (CAD, group C). Coronary dilatory capacity, determined by measuring total myocardial blood flow at rest and during maximal coronary vasodilatation (dipyridamole, 0.5 mg/kg i.v.), was markedly reduced in group B and C patients. In group B patients, left ventricular catheter biopsy specimens revealed no evidence of small-vessel disease, but did show histologic alterations of mitochondria. During atrial pacing, the control subjects showed no changes in myocardial lactate uptake, whereas in group B patients, myocardial lactate production occurred. In contrast to controls, patients in group B showed a significant decline in ejection fraction and circumferential fiber shortening during isometric exercise. These findings suggest that myocardial ischemia is the cause of angina pectoris in patients who have angina but normal coronary arteriograms.

Frequency and phenotypes of familial dilated cardiomyopathy

OBJECTIVES This prospective study was performed to analyze the frequency and clinical characteristics of idiopathic dilated cardiomyopathy (DCM). BACKGROUND Despite several previous reports on families with DCM, most cases are still believed to be sporadic, and specific clinical findings of the familial form are not well defined. METHODS In 445 consecutive patients with angiographically proven DCM, we obtained detailed family histories to construct pedigrees and examined 970 first- and second-degree family members. RESULTS Familial DCM was confirmed in 48 (10.8%) of the 445 index patients and was suspected in 108 (24.2%). The 156 patients with suspected or confirmed familial disease were younger at the time of diagnosis (p < 0.03) and more often revealed electrocardiographic changes (p = 0.0003) than patients with nonfamilial disease. Among the families of the 48 index patients with confirmed familial disease, five phenotypes of familial DCM could be identified: 1) DCM with muscular dystrophy; 2) juvenile DCM with a rapid progressive course in male relatives without muscular dystrophy; 3) DCM with segmental hypokinesia of the left ventricle; 4) DCM with conduction defects; and 5) DCM with sensorineural hearing loss. CONCLUSIONS Up to 35% of patients with DCM may have an inherited disorder. Distinct clinical phenotypes can be observed in some families, suggesting a common molecular cause of the disease.

Various intensities of leisure time physical activity in patients with coronary artery disease: Effects on cardiorespiratory fitness and progression of coronary atherosclerotic lesions☆

Abstract Objectives . This study was designed to define the effect of different levels of leisure time physical activity on cardiorespiratory fitness and progression of coronary atherosclerotic lesions in unselected patients with coronary artery disease. Background . It has been shown in various studies that regression of coronary atherosclerotic lesions can be achieved by means of lipid-lowering drugs, reduction of fat consumption and physical exercise. Methods . Patients were prospectively randomized either to an intervention group (n = 29) participating in regular physical exercise or to a control group (n = 33) receiving usual care. Energy expenditure in leisure time physical activity was estimated from standardized questionnaires and from participation in group exercise sessions. After 12 months of particiption, repeat coronary angiography was performed; coronary lesions were measured by digital image processing. Results . After 1 year, patients in the intervention group achieved an increase in oxygen uptake at a ventilatory threshold of 7% (p Conclusions . Measurable improvement in cardiorespiratory fitness requires ~1,400 kcal/week of leisure time physical activity; higher work loads are necessary to halt progression of coronary atherosclerotic lesions (1,533 ± 122 kcal/week), whereas regression of coronary lesions is observed only in patients expending an average of 2,200 kcal/week in leisure time physical activity, amounting to ~5 to 6 h/week of regular physical exercise.

Reduction of coronary reserve: a mechanism for angina pectoris in patients with arterial hypertension and normal coronary arteries.

The pathogenesis of angina pectoris in patients with left ventricular hypertrophy secondary to arterial hypertension and with normal coronary arteries remains uncertain. We measured coronary blood flow (argon method) in 12 control subjects and in 16 patients with arterial hypertension at rest and after intravenous administration of dipyridamole (0.5 mg/kg). In the patients with arterial hypertension, coronary blood flow response to dipyridamole was markedly reduced (p less than .001 as compared with control values). During coronary vasodilation there was a linear correlation between coronary resistance and left ventricular end-diastolic pressure (r = .67, p less than .001). Left ventricular catheter biopsy specimens did not reveal alterations in myocardial microvasculature. These findings suggest that reduction of coronary reserve may be an important contributor to the pathogenesis of angina pectoris in these patients.

Enzyme linked immuno assay of cardiac troponin T for the detection of acute myocardial infarction in patients

For the diagnosis of acute myocardial infarction (AMI) in patients circulating constituents of the contractile apparatus may be measured instead of cytosolic cardiac enzymes. The potential advantages of the use of myofibrillar cardiac proteins as marker proteins for AMI results from their expression as cardio-specific isoforms, their high intracellular concentration, and their continuous release from infarcting myocardium. While analyzing the specificity of polyclonal goat anti-human cardiac myosin light chains antisera a cardio-specific antibody fraction was identified which is directed against cardiac troponin T contaminations of the myosin light chains antigen. Using this antibody fraction a standardized enzyme immuno-assay for circulating troponin T was developed to detect AMI in patients. In this assay troponin T is bound on different epitopes by affinity purified goat anti-cardiac troponin T antibodies immobilized on polyvinyl chloride test tubes as well as horse raddish peroxidase labeled monoclonal anti-troponin T antibody in liquid phase. The assay procedure can be completed semiautomatically in 90 min with a detection limit of the assay of 0.5 ng/ml human or bovine cardiac troponin T. There is 1% crossreactivity with skeletal troponin T. In 26 healthy volunteers no cardiac troponin T was detectable in serum of 25 persons, while in 1 further volunteer 1 ng/ml troponin T was found. In the sera of all 50 patients with transmural AMI troponin T was elevated ranging from 7.2 to 110 ng/ml. In the mean troponin T remained elevated from three until 300 hours after onset of ischemic pain showing a biphasic serum concentration curve.(ABSTRACT TRUNCATED AT 250 WORDS)

Release of endogenous catecholamines in the ischemic myocardium of the rat. Part A: Locally mediated release.

The accumulation of endogenous catecholamines within the extracellular space of the ischemic myocardium has been studied in the isolated perfused (Langendorff) heart of the rat subjected to various periods of complete ischemia, with subsequent collection of the reperfusate. Catecholamines and deaminated metabolites were measured by radioenzymatic methods, or high pressure liquid chromatography. Ischemic periods of less than 10 minutes are not associated with an increased overflow of catecholamines or metabolites. Longer periods of ischemia are accompanied by the overflow of noradrenaline and its deaminated metabolite 3,4-dihydroxyphenylgly-col. This overflow increases with lengthening of the preceding ischemic period (10 minutes: 2.5 ± 0.6, 20 minutes: 209.8 ± 17.2, 60 minutes: 1270.5 ± 148.1 pmol noradrenaline/g heart). Noradrenaline concentration is highest during the first minute of reperfusion, suggesting that the noradrenaline detected during reperfusion is released into the extracellular space of the myocardium during ischemia and is subsequently eluted. Experiments with variation of extracellular calcium concentration and with neuronal uptake (uptakei) blocking agents suggest that different mechanisms of catecholamine release are acting during the course of ischemia. A calcium-independent carrier-mediated efflux of noradrenaline from the nerve terminals is of major importance, using the same carrier as is normally responsible for transporting noradrenaline from the synaptic clefts into the neuronal varicosities. Thus, various uptake1-blocking agents diminish the noradrenaline overflow following ischemic periods of between 10 and 40 minutes. The noradrenaline overflow following longer periods of ischemia is unaffected by uptake]-blocking agents, and additional noradrenaline release at this time is probably consequent upon dissolution of cell membranes. Overflow of adrenaline and dopamine occurs to a minor degree (less than 5% of the corresponding noradrenaline overflow), and only after ischemic periods of more than 15 minutes.

Circulating Vascular Cell Adhesion Molecule-1 Correlates With the Extent of Human Atherosclerosis in Contrast to Circulating Intercellular Adhesion Molecule-1, E-Selectin, P-Selectin, and Thrombomodulin

Secondary prevention of atherosclerosis, especially before the onset of symptoms, appears desirable and could be possible with a serum marker detecting atherosclerosis. Circulating, shedded forms of adhesion molecules may serve as such because their expression is upregulated in atherosclerotic plaques. In 52 patients with peripheral arterial vascular disease (Fontaine class IIa, 7 patients; class IIb, 29 patients; and class III, 16 patients), the extent of atherosclerosis was evaluated on the basis of angiograms of a large portion of the arterial system. The area diseased by atherosclerosis was determined by the percentage of vessel wall irregularities of the following calculated segments: aorta (distal from the kidney arteries), common iliac artery, external iliac artery, common femoral artery, lateral circumflex femoral artery, and popliteal artery. The maximal surface area that could exhibit atherosclerotic changes was 250 cm2. The serum concentration of circulating vascular cell adhesion molecule-1 (VCAM-1) correlated with the extent of atherosclerosis (r = .8, P < .001). In contrast, circulating intercellular adhesion molecule-1, E-selectin, P-selectin, and thrombomodulin (as markers for endothelial cell damage) did not correlate with the extent of atherosclerosis. Furthermore, circulating VCAM-1 could be used to indicate stages of atherosclerosis with a high degree of statistical significance. The potential bias of factors such as age, diabetes mellitus, hypercholesterolemia, arterial hypertension, renal failure, and history of myocardial infarction on the correlation of circulating VCAM-1 with the extent of atherosclerosis could be excluded by multivariate analysis. These findings suggest an important role of VCAM-1 in atherosclerosis and may serve as the basis for further evaluation of circulating VCAM-1 as a potential serum marker for atherosclerosis.