A common base change in the promoter region of the human endothelial NO-synthase (NOS3) gene.
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Base Sequence↗
Biomedical subjects
F X Kleber
Publications and source records attributed to F X Kleber.
Dyspnea in heart failure. Introduction.
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Dyspnea↗
Exertional hyperpnea in patients with chronic heart failure is a reversible cause of exercise intolerance.
BACKGROUND: Hyperpnea in chronic heart failure occurs even in the absence of considerable impairment of lung function. It is caused by altered respiratory pattern with rapid shallow breathing and ventilation-perfusion mismatch, so far thought to be irreversible. OBJECTIVES: To test the underlying pathophysiologic disorders and the reversibility of this hyperpnea, i.e., the increased ventilatory response to exercise and its impact on exercise tolerance, 17 patients with chronic heart failure were evaluated before and 4 weeks after adjustment of heart failure therapy with diuretics and ACE inhibitors, and results were compared with normal volunteers. METHODS: Ventilatory response to exercise was measured during treadmill exercise by calculation of the slope of the linear relation between minute ventilation (VE) and carbon dioxide output (VCO2) and compared to NYHA class, oxygen consumption at the gas exchange anaerobic threshold (VO2 AT), maximal oxygen uptake (VO2 max) and ventilation of physiological dead space. RESULTS: VE vs VCO2 slope was related to severity of heart failure (NYHA class). Elevation of VE vs VCO2 slope was strongly correlated to elevated ventilation of physiologic dead space. Patients were divided into responders (significant decrease of VE vs VCO2 slope of at least 5 l/l I CO2) and nonresponders (decrease of VE vs VCO2 slope less than 5 I or increase). Responders revealed an increase of VO2 AT (7.4 +/- 2.6 to 11.7 +/- 2.1 ml O2/kg/min; p = 0.01) and VO2 max (11.2 +/- 2.8 to 17.4 +/- 5.3; p = 0.005), while nonresponders showed a non significant decrease of oxygen consumption (VO2 AT 9.6 +/- 3.7 to 9.0 +/- 3.7; peak VO2 14.6 +/- 6.1 to 14.4 +/- 6.4), despite adjusted heart failure therapy. CONCLUSION: Exercise hyperpnea in heart failure is mainly caused by ventilation of excess physiologic dead space and strongly contributes to severity of symptoms. Ventilatory response to exercise can be improved by adjustment of heart failure therapy in a considerable proportion of patients. Improvement is associated with an increase in aerobic capacity. Ventilation-perfusion mismatch is a major and modifiable factor determining exercise tolerance in patients with chronic heart failure.
Carbon Dioxide↗
Angioscopic evaluation of atherosclerotic plaques: validation by histomorphologic analysis and association with stable and unstable coronary syndromes.
OBJECTIVES: We validated coronary angioscopic observations with histologic assessment of material removed by atherectomy. BACKGROUND: Up to now, angioscopic findings have been primarily descriptive, and the clinical significance still needs to be substantiated. The proposed Ermenoville classification is relevant but has not yet been validated by histomorphologic analysis. METHODS: We compared angioscopic findings in patients with different coronary syndromes and used atherosclerotic material retrieved by directional coronary atherectomy to validate the angioscopic observations. Coronary angioscopy was performed in 63 patients (56 men, 7 women) with stable (26 patients) and unstable angina (37 patients) before and after directional coronary atherectomy. The identity of atherectomized material was confirmed by ex vivo visualization with the angioscope and by postatherectomy angioscopy. Angioscopic and histologic findings could be compared in 44 of 63 patients. RESULTS: Angioscopic findings were grouped into gray-white and yellow lesions (gray-yellow, deep yellow, yellow-red or yellow-pink). We found that patients with unstable angina had predominantly yellow lesions (89%). In patients with stable angina, gray-white (43%) or yellow (57%) lesions were similarly distributed. Ruptured yellow plaques and red or pink thrombi were identified in 11% of patients with stable angina and 39% of patients with unstable or early postmyocardial infarction angina. Histologically, gray-white lesions represented fibrous plaque without degeneration in 64% and with degeneration in 36% of patients. Gray-yellow lesions were associated predominantly with degenerated plaque (64%) and, to a lesser extent, with fibrous plaque (14%) or atheroma (14%). Deep yellow and yellow-red lesions represented either atheroma (53%) or degenerated plaque (42%). CONCLUSIONS: Our study establishes a histomorphologic basis for classification and interpretation of angioscopic findings. Yellow plaque color is closely related to degenerated plaque or atheroma and is associated with unstable coronary syndromes.
Angina Pectoris↗
The economics of cardiac failure.
Quality assurance and inclusion of prospective evaluation of costs of treatment in phase 3 and 4 pharmaceutical trials are becoming increasingly important. Not only high technology applications have to be investigated, but also relatively cheap but very common strategies for diagnostic work up and therapy. This may yield major savings. We are at the beginning of an era in which waste of resources may be reduced by scientific analysis with improvement in patient care and teaching achieved as a result.
Cost-Benefit Analysis↗
Current guidelines for the treatment of congestive heart failure.
Overt congestive heart failure (CHF) has a prevalence of 1% of the population. The predominant symptoms of patients with CHF are fatigue and dyspnoea. Fatigue is thought to result from changes in peripheral muscle metabolism secondary to decrease vasodilative capacity and physical inactivity. An increase of peripheral perfusion by vasodilator therapy and physical activity are therefore recommended. Beside overt decompensation, where dyspnoea results from acute pulmonary congestion due to backward failure, increased physiological dead space ventilation caused by pulmonary ventilation/perfusion mismatch accounts, to a large degree, for dyspnoea, and can be improved by vasodilator therapy. According to the pathophysiology of CHF, normalisation of loading conditions and myocardial inotropy are the parameters addressed by various pharmacological agents in order to alleviate symptoms and slow progression of the disease. Diuretics are rapidly acting and effective agents to improve congestion and decrease filling pressures. Digitalis improves haemodynamics and symptomatology by increasing inotropy and slowing resting heart rate in atrial fibrillation; however, prognostic effects have yet to be proved. The introduction of vasodilators has significantly improved the prognosis of the disease, and the administration of ACE inhibitors in particular has been shown to slow progression of CHF. This results in a substantial decrease in morbidity and mortality. The present article appraises the role of the currently used drugs in the treatment of CHF, considering effects on pathophysiology and clinical outcome and provides an approach to a differential drug regimen.
Adrenergic beta-Antagonists↗
[Percutaneous "high risk" angioplasty with prophylactic cardiopulmonary support. High risk PTCA with mechanical circulatory support].
With improved technology and development of several mechanical assist devices, the indications of percutaneous transluminal coronary revascularization have been extended. In 39 patients (30 men, mean age = 60.1 +/- 8.1 years) with angina pectoris or heart failure, with poor operative risk-benefit ratio and ejection fraction < 35% and/or target vessel supplying > 50% of the viable myocardium, we performed assisted percutaneous transluminal coronary revascularization. Intraortic balloon counterpulsation (n = 16), extracorporal circulation (n = 21), or hemopump (n = 2) were used for mechanical support. Complete 6-week follow up was possible in 27 patients. An improvement of left-ventricular function (patients with EF < or = 35% demonstrated an improvement: 27 +/- 7 vs 36 +/- 10%, p < 0.05), heart failure (patients with EF < or = 35% demonstrated an improvement of maximal oxygen uptake: 14 +/- 4 vs 17 +/- 4 ml/kg/min; p < 0.05) and a marked improvement of angina (23/38 demonstrated CCS-improvement of at least one class) was found. Hospital mortality was as low as 2.6%. Major postinterventional complications included nonfatal myocardial infarction (n = 2), fatal retroperitoneal bleeding (n = 1), pulmonary edema (n = 1), nonfatal ventricular fibrillation (n = 1), cerebrovascular event without residual (n = 1), and deep vein thrombosis (n = 4). In conclusion, assisted percutaneous revascularization was successful in a high risk subset of patients with increased surgical risk and/or poor ventricular function.
Aged↗
[Inflammatory mediators in patients with biventricular assist device systems].
We studied the plasma levels of TNF-alpha, IL-6, IL-8 and soluble adhesion molecules (sE-Selectin, sL-Selectin, sVCAM-1) immediately before and during mechanical circulatory support with a Biventricular Assist Device System (BVAD-"Berlin Heart") in comparison to patients with chronic heart failure (NYHA classes II/III) and patients with coronary artery disease with normal ventricular function. Additionally, the biocompatibility of the membranes used in the "Berlin Heart" was tested in vitro. IL-6 and IL-8 but not TNF-alpha could only be detected in patients with cardiogenic shock immediately before starting circulatory support. Furthermore, plasma concentrations of soluble adhesion molecules were statistically significantly elevated in patients with cardiogenic shock compared to patients with coronary artery disease. This picture of a systemic inflammatory response syndrome without significant level of TNF-alpha looks quite similar to that seen in patients following trauma and severe operations. During mechanical circulatory support plasma levels of cytokines and soluble adhesion molecules dropped to low levels in patients, who were successfully maintained on BVAD. By contrast, we have found persistently elevated levels of these mediators in patients with fatal outcome. This seems not to be the result of individual distinct response of blood cells to contact with the artificial surfaces of the device. In summary, our data suggest the development of a systemic inflammatory response syndrome may be due to hypoxia during cardiogenic shock. Persistence of systemic inflammation suggests failing of the mechanical support. Therefore, the monitoring of inflammatory mediators may be relevant as a prognostic marker in these patients (disappearance of peripheral hypoxia).
Adult↗
Socioeconomic aspects of ACE inhibition in the secondary prevention in cardiovascular diseases.
Cardiovascular diseases are the leading causes of morbidity and mortality in the industrialized world and have become a major economic burden. Therefore, not only ethical and medical but also economic reasons suggest more intense efforts in primary and secondary prevention of cardiovascular and, especially, coronary artery disease. The prevention of the progression of heart failure and of the risks inherent in left ventricular dysfunction, including development of heart failure, reinfarctions, and death, are major cornerstones in the ambitious but economically balanced use of our resources. Major trials in chronic heart failure as well as the angiotensin-converting enzyme inhibitor pooling project in heart failure of all major studies have shown almost uniformly a reduction in hospitalizations attributable to slowing of the progression of the disease. In the Munich Mild Heart Failure Trial (MHFT) socioeconomic analysis confirmed the high economic burden of progression to the end-stages of disease: Patients with progressive heart failure had a four- to fivefold increase in hospital costs. The blunting of the progressive course of heart failure was effective enough to offset the costs of drug treatment with captopril in an analysis extrapolating the results of the socioeconomic analysis to the total trial population. Favorable results in preventive treatment of patients with asymptomatic left ventricular dysfunction, hypertension, and diabetic nephropathy also suggest that part of the additional costs of medication is outweighed by fewer hospitalizations and interventions. Thus in many cardiovascular diseases angiotensin-converting enzyme inhibitors have a favorable cost-benefit ratio and can be recommended for broader use.
Angiotensin-Converting Enzyme Inhibitors↗
E-selectin polymorphism and atherosclerosis: an association study.
Adhesion molecules like the members of the selectin family participate in the interaction between leukocytes and the endothelium. They are also involved in the pathogenesis of atherosclerotic processes. To contribute to the analysis of the genetic background of atherosclerosis we searched for DNA polymorphisms in the genes encoding adhesion molecules especially E-selectin which seems to be expressed only in activated endothelium. An adenine to cytosine substitution for cDNA position 561 resulting in an amino acid exchange from serine to arginine (position 128) was detected in the epidermal growth factor like domain. A significantly higher mutation frequency (P = 0.02) was observed in 97 patients aged 50 years or less with angiographically proven severe atherosclerosis (allele frequency of arginine 0.155) compared with an unselected population (allele frequency of arginine 0.088) as well as in 40 patients aged 40 years or less (allele frequency of arginine 0.21, P = 0.0025). These data suggest that the 128-serine/arginine polymorphism is associated with a higher risk for early severe atherosclerosis.
Adult↗
[Ergospirometry in the evaluation of cardiovascular drugs].
In the evaluation of drugs intended to alleviate symptomatology and to improve exercise capacity in congestive heart failure, various pathophysiologic mechanisms including impairment of cardiac output, oxygenation of blood, muscle blood flow, and muscle metabolism have to be considered. In various forms of acute and chronic heart failure these mechanisms contribute more or less to impaired oxygen uptake. In acute forms of heart failure pulmonary congestion and its effects on airway resistance and lung capacity might be the predominating mechanisms of symptoms, while in chronic heart failure impedement of muscle blood flow and metabolic changes, comparable with deconditioning, are additional pathomechanisms. The increase in cardiac output and in muscle blood flow provided by some positive inotropic agents and by vasodilators after acute administration is often paralleled by a decrease in arteriovenous oxygen difference and does not lead to an improvement of oxygen uptake. However, chronic therapy with some vasodilators can lead to improvement in oxygen uptake, either due to training effects or due to flow dependent or direct effects on muscle metabolism. In pulmonary congestion a decrease of elevated filling pressures can acutely lead to some improvement of exercise capacity. Furthermore, chronic decrease in filling pressures by administration of diuretics, nitrates, ACE-inhibitors or dopaminergic drugs leads to long-term improvement in oxygen uptake. By comparing hemodynamic effects of acute and chronic drug therapy in CHF with their effects on exercise capacity, the chronic decrease of filling pressures seems to be the major hemodynamic variable leading to improvement of exercise capacity.(ABSTRACT TRUNCATED AT 250 WORDS)
Cardiotonic Agents↗
Long-term survival in the Munich Mild Heart Failure Trial (MHFT).
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Captopril↗
[Arterial hypertension and left ventricular dysfunction: pathophysiology, diagnosis and therapy].
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Antihypertensive Agents↗
Experiences with ACE inhibitors early after acute myocardial infarction. Rationale and design of the German Multicenter Study on the Effects of Captopril on Cardiopulmonary Exercise parameters post myocardial infarction (ECCE).
Left ventricular damage by necrosis of myocardial tissue can lead to compromise of left ventricular function, to left ventricular volume increase and ultimately to development of heart failure. This sequence in the pathophysiology has been shown to be blunted by ACE inhibitors. Volume increase, however, can also be helpful in restoring stroke volume and ameliorate elevation of filling pressures. Furthermore, very early institution of ACE inhibition has failed to improve short-term mortality after myocardial infarction in one large trial. The aim of the ECCE trial therefore is, to investigate the early effects of the ACE inhibitor captopril on compromise of exercise capacity, thought to be a first measurable sign of developing heart failure. The ECCE trial is a randomized, seven-center investigation, studying the effects of ACE inhibition on oxygen uptake in a double blind, placebo controlled design in a group of 204 patients. Sample size was calculated on the basis of a pilot trial. The study design and first not unblinded data of 104 patients are presented. The population consists of predominantly male patients with mostly first myocardial infarction. They were admitted to hospital within five hours of onset of chest pain. End-diastolic volumes were normal, but ejection fraction was moderately compromised. ACE inhibition was started after the first day, but within 72 hours of onset of chest pain. After four and after twelve weeks, oxygen uptake was considerably below expected values and one third of the patients had severe compromise of exercise capacity.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
[Significance of treatment of early forms and prevention of heart failure. Value of ACE inhibitors in therapy after myocardial infarct].
Myocardial infarction has become the most important condition causing congestive heart failure. Several treatment regimens compete with each other in the early and later post myocardial infarction phase focussing on different pathophysiologic mechanisms. In this review emphasis is put on absolute risks and absolute risk reductions in patients with left ventricular dysfunction after myocardial infarction. In the first year mortality is still as high as 10% and the major risks are sudden unexpected death, reinfarction, and congestive heart failure. In the following years sudden death and development of congestive heart failure become less prominent, while a considerable risk of reinfarction persists. Thrombolysis and beta-blockade are the most important drugs in the acute infarction phase leading to a marked reduction in one year mortality. In the first year after infarction beta-blockade has an established place in the prevention of sudden death; revascularization and aspirin are established in reinfarction prophylaxis. However, since most drugs lower 1 year mortality by 0.5 to 2% only, drugs like ACE inhibitors that influence more than one risk, i.e. sudden death and reinfarction as well as deterioration of pump dysfunction might play a more important role in the therapeutic strategy after myocardial infarction. A supplementation by one or two drugs aiming at the individually estimated leading risks might be the best choice in patients with left ventricular dysfunction today.
Angiotensin-Converting Enzyme Inhibitors↗
Treatment of chronic congestive heart failure.
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Angiotensin-Converting Enzyme Inhibitors↗
[The effect of captopril on the progression of heart insufficiency].
We conclude from our studies and data from the literature that ACE inhibitors belong to the proper basic therapy of cardiac failure because of their marked influence on progression and death by pump failure. The therapeutic gain per 100 patients treated for one year exceeds that of other medications used commonly for secondary prophylaxis.
Captopril↗