Electrical and mechanical support in advanced heart failure. Rationale and feasibility of a combined management strategy.
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Adult↗
Biomedical subjects
T F Lüscher
Publications and source records attributed to T F Lüscher.
Endothelial dysfunction, hypertension and atherosclerosis. A review of the effects of lacidipine.
Lacidipine, a third generation dihydropyridine calcium antagonist, has demonstrated pronounced anti-atherosclerotic activity in preclinical studies. The drug can act at several stages within the atherosclerotic process, utilising its antihypertensive and antioxidant properties to protect hypertensive animals against mortality and vascular damage, to reduce cholesterol levels from the vessel wall of hypercholesterolaemic animals, and to reduce the progression of existing atherosclerotic lesions. The clinical benefit of lacidipine in atherosclerosis has recently been confirmed in humans in a large, multicentre, comparative, 4-year clinical trial involving patients with mild to moderate hypertension. The European Lacidipine Study on Atherosclerosis (ELSA) showed that lacidipine was able to slow the progression of atherosclerosis, measured as carotid intimato-media thickness, by 40% compared with atenolol (p = 0.0073). Although further comparative trials are needed, based on the results of ELSA, lacidipine is likely to become a promising therapeutic agent for atherosclerosis.
Animals↗
Vasopeptidase inhibitors: a new therapeutic concept in cardiovascular disease?
The cardiovascular system is regulated by hemodynamic and neurohumoral mechanisms. These regulatory systems play a key role in modulating cardiac function, vascular tone, and structure. Although neurohumoral systems are essential in vascular homeostasis, they become maladaptive in disease states such as hypertension, coronary disease, and heart failure. The clinical success of ACE inhibitors has led to efforts to block other humoral systems. Neutral endopeptidase (NEP) is an endothelial cell surface zinc metallopeptidase with similar structure and catalytic site. NEP is the major enzymatic pathway for degradation of natriuretic peptides, a secondary enzymatic pathway for degradation of kinins, and adrenomedullin. The natriuretic peptides can be viewed as endogenous inhibitors of the renin angiotensin system. Inhibition of NEP increases levels of atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) of myocardial cell origin, and C-type natriuretic peptide (CNP) of endothelial cell origin as well as bradykinin and adrenomedullin. By simultaneously inhibiting the renin-angiotensin-aldosterone system and potentiating the natriuretic peptide and kinin systems, vasopeptidase inhibitors reduce vasoconstriction, enhance vasodilation, improve sodium/water balance, and, in turn, decrease peripheral vascular resistance and blood pressure and improve local blood flow. Within the blood vessel wall, this leads to a reduction of vasoconstrictor and proliferative mediators such as angiotensin II and increased local levels of bradykinin (and, in turn, nitric oxide) and natriuretic peptides. Preliminary clinical experiences with vasopeptidase inhibitors are encouraging. Thus, the combined inhibition of ACE and neutral endopeptidase is a new and promising approach to treat patients with hypertension, atherosclerosis, or heart failure.
Angiotensin-Converting Enzyme Inhibitors↗
Thrombin suppresses endothelial nitric oxide synthase and upregulates endothelin-converting enzyme-1 expression by distinct pathways: role of Rho/ROCK and mitogen-activated protein kinase.
An imbalance of nitric oxide and endothelin plays an important role in cardiovascular disease. Thrombin exerts profound effects on endothelial function. The present study investigated the molecular mechanisms by which thrombin regulates endothelial nitric oxide synthase (eNOS) and endothelin-converting enzyme (ECE)-1 expression in human endothelial cells. Incubation of human umbilical vein endothelial cells with thrombin (0.01 to 4 U/mL) for 15 to 24 hours markedly downregulated eNOS and increased ECE-1 protein level in a dose-dependent manner. Thrombin also decreased eNOS mRNA and increased ECE-1 mRNA level. In mRNA stability assay, thrombin shortened the half-life of eNOS mRNA but not that of ECE-1 mRNA. Activation of protease-activated receptor 1 by the agonist (SFLLRN, 10 to 100 micromol/L) had no effect on eNOS expression but increased ECE-1 level as thrombin. Thrombin activated Rho A and extracellular signal-regulated kinase (ERK)1 and ERK2. Inhibition of Rho A by C3 exoenzyme (20 microgram/mL) and ROCK by Y-27632 (10 micromol/L) prevented the downregulation of eNOS expression by thrombin. Y-27632 also prevented the reduction in NOS activity induced by prolonged incubation with thrombin. On the other hand, inhibition of ERK1 and ERK2 activation by PD98059 (50 micromol/L) prevented the upregulation of ECE-1 expression by thrombin as well as the increase in ECE activity and ET-1 accumulation in the medium. Treatment of rat aorta with thrombin overnight impaired endothelium-dependent relaxations but not endothelium-independent relaxations. Thus, thrombin suppresses eNOS and upregulates ECE-1 expression via Rho/ROCK and ERK pathway, respectively. These effects of thrombin may be important for endothelial dysfunction in cardiovascular disease, particularly during acute coronary episodes.
Animals↗
Endothelin 1 type a receptor antagonism prevents vascular dysfunction and hypertension induced by 11beta-hydroxysteroid dehydrogenase inhibition: role of nitric oxide.
BACKGROUND: The enzyme 11beta-hydroxysteroid dehydrogenase (11beta-HSD) prevents inappropriate activation of the nonselective mineralocorticoid receptors by glucocorticoids. Renal activity of 11beta-HSD is decreased in patients with apparent mineralocorticoid excess (SAME), licorice-induced hypertension, and essential hypertension. Although expressed in vascular cells, the role of 11beta-HSD in the regulation of vascular tone remains to be determined. METHODS AND RESULTS: lycyrrhizic acid (GA; 50 mg/kg IP, twice daily for 7 days) caused a significant inhibition of 11beta-HSD activity and induced hypertension in Wistar-Kyoto rats (157 versus 127 mm Hg in controls; P<0.01). After 11beta-HSD inhibition, aortic endothelial nitric oxide (NO) synthase (eNOS) protein content, nitrate tissue levels, and acetylcholine-induced release of NO were blunted (all P<0.05 versus controls). In contrast, vascular prepro-endothelin (ET)-1 gene expression, ET-1 protein levels, and vascular reactivity to ET-1 were enhanced by GA treatment (P<0.05 versus controls). Chronic ET(A) receptor blockade with LU135252 (50 mg. kg(-1). d(-1)) normalized blood pressure, ET-1 tissue content, vascular reactivity to ET-1, vascular eNOS protein content, and nitrate tissue levels and improved NO-mediated endothelial function in GA-treated rats (P<0.05 to 0.01 versus untreated and verapamil-treated controls). In human endothelial cells, GA increased production of ET-1 in the presence of corticosterone, which indicates that activation of the vascular ET-1 system by 11beta-HSD inhibition can occur independently of changes in blood pressure but is dependent on the presence of glucocorticoids. CONCLUSIONS: Chronic ET(A) receptor blockade normalizes blood pressure, prevents upregulation of vascular ET-1, and improves endothelial dysfunction in 11beta-HSD inhibitor-induced hypertension and may emerge as a novel therapeutic approach in cardiovascular disease associated with reduced 11beta-HSD activity.
11-beta-Hydroxysteroid Dehydrogenases↗
Assessment of myocardial perfusion in coronary artery disease by magnetic resonance: a comparison with positron emission tomography and coronary angiography.
BACKGROUND: Monitoring contrast medium wash-in kinetics in hyperemic myocardium by magnetic resonance (MR) allows for the detection of stenosed coronary arteries. In this prospective study, the quality of a multislice MR approach with respect to the detection and sizing of compromised myocardium was determined and compared with positron emission tomography (PET) and quantitative coronary angiography. METHODS AND RESULTS: A total of 48 patients and healthy subjects were studied by MR using a multislice hybrid echo-planar pulse sequence for monitoring the myocardial first pass kinetics of gadolinium-diethylenetriamine pentaacetic acid bismethylamide (Omniscan; 0.1 mmol/kg injected at 3 mL/s IV) during hyperemia (dipyridamole 0.56 mg/kg). Signal intensity upslope as a measure of myocardial perfusion was calculated in 32 sectors per heart from pixelwise parametric maps in the subendocardial layer and for full wall thickness. Before coronary angiography, coronary flow reserve (hyperemia induced by dipyridamole 0.56 mg/kg) was determined in corresponding sectors by (13)N-ammonia PET. Receiver-operator characteristic analysis of subendocardial upslope data revealed a sensitivity and specificity of 91% and 94%, respectively, for the detection of coronary artery disease as defined by PET (mean coronary flow reserve minus 2SD of controls) and a sensitivity and specificity of 87% and 85%, respectively, in comparison with quantitative coronary angiography (diameter stenosis >/=50%). The number of pathological sectors per patient on PET and MR studies correlated linearly (slope, 0.94; r=0.76; P<0.0001). CONCLUSIONS: The presented MR approach reliably identifies patients with coronary artery stenoses and provides information on the amount of compromised myocardium, even when perfusion abnormalities are confined to the subendocardial layer. This modality may qualify for its clinical application in the management of coronary artery disease.
Adult↗
[Cost effectiveness of clopidogrel in secondary cardiovascular prevention: a cost-effectiveness analysis based on the Caprie Study].
As a result of medical progress each year numerous new therapies are introduced to the medical community, and each of them must prove its usefulness in two arenas. Firstly, does the new therapy improve outcomes relative to conventional therapy? If this test is passed, the second question is: are the improved outcomes worth the extra costs? Controlled clinical trials answer the first question and economic analysis, the second. The CARPIE-Study has proven, that Clopidogrel, a new antiplatelet drug, was superior in secondary prevention of cardiovascular events to aspirin. On the basis of this study we conducted a cost-effectiveness analysis from the perspective of Swiss third party payers. The following costs were included in the analysis: treatment costs of aspirin and clopidogrel, myocardial infarction, ischaemic stroke and primary non-fatal intracranial haemorrhage. For the calculation of the years of life gained the DEALE-method was applied. The net costs of treating 1000 patients, i.e. incremental drug costs less savings of treatment costs, are Fr. 1.5 Mio. The intervention with Clopidogrel lead to an additional gain of 63 life years in compared to aspirin. At additional yearly cost of Fr. 722.--per patient the analysis yield a cost-effectiveness of CHF 24,164 (nominal) Fr. 22,837 (discounted) per additional year of live saved. The results suggest that the cost-effectiveness of Clopidogrel in secondary prevention lie well within the range of other preventive cardiovascular interventions. Therefore, from an economic perspective the use of Clopidogrel in secondary prevention of major cardiovascular events in patients with atherosclerotic vascular disease is justifiable.
Adult↗
Endothelin and cardiac arrhythmias: do endothelin antagonists have a therapeutic potential as antiarrhythmic drugs?
Endothelin-1 (ET-1), the predominant isoform of the ET peptide family and a potent vasoconstrictor, has been shown to aggravate ischemia-induced ventricular arrhythmias. However, there is also evidence that ET-1 may have a direct arrhythmogenic action that is not solely attributable to myocardial ischemia. Proposed mechanisms for the arrhythmogenic effects of ET-1 are prolongation or increased dispersion of monophasic action potential duration, QT prolongation, development of early afterdepolarizations, acidosis, and augmentation of cellular injury. As for an ionic basis for the observed electrophysiologic effects, ET-induced Ca(2+) release from intracellular stores, generation of inositol triphosphate, inhibition of delayed rectifier K(+) current, and stimulation of the Na(+)/H(+) exchanger may be involved. Recently, some studies have shown that ET receptor antagonists, which promise to be powerful tools in cardiovascular medicine, may also demonstrate antiarrhythmic properties. This review describes the current state of knowledge on the interactions between the ET system and cardiac arrhythmias, and discusses the therapeutic potential of ET antagonists as antiarrhythmic drugs.
Action Potentials↗
Effects of blood pressure and glucose on endothelial function.
Hypertension and diabetes mellitus are associated with accelerated atherosclerosis and an increased prevalence of cardiovascular disease. Loss of the modulatory role of the endothelium can be considered the link between these conditions and cardiovascular disease. Substantial evidence suggests that vasodilation mediated by endothelium-derived nitric oxide (NO) is impaired in animal models and in patients with hypertension and diabetes mellitus. NO is a principal factor involved in the anti-atherosclerotic properties of the endothelium. Therefore, the pathogenesis of hypertensive and diabetic vascular disease may involve a reduced bioavailability of endothelium-derived NO. Inactivation of NO by reactive oxygen species is an important common mechanism by which endothelial dysfunction may occur. This review summarizes experimental and clinical evidence for impaired NO-mediated vasodilation in the presence of high blood pressure and hyperglycemia. A better understanding of the mechanisms leading to endothelial dysfunction may unmask new preventive strategies to reduce cardiovascular morbidity and mortality in these conditions.
Animals↗
Vasopeptidase inhibition and endothelial function in hypertension.
Vasopeptidase inhibitors are a new class of drugs capable of inhibiting both angiotensin-converting enzyme and neutral endopeptidase 24.11. This involves simultaneous inhibition with a single molecule of two key enzymes, ACE and NEP, which are both involved in the regulation of cardiovascular homeostasis in many ways. This includes metabolism of several vasoactive peptides and their clearance from the circulation, therefore contributing to neurohumoral modulation, which might have therapeutic advantages in the prevention of endothelial dysfunction in hypertension.
Angiotensin-Converting Enzyme Inhibitors↗
Endothelin receptor antagonists in congestive heart failure: a new therapeutic principle for the future?
Congestive heart failure (CHF) is characterized by impaired left ventricular function, increased peripheral and pulmonary vascular resistance and reduced exercise tolerance and dyspnea. Thus, mediators involved in the control of myocardial function and vascular tone may be involved in its pathophysiology. The family of endothelins (ET) consists of four closely related peptides, ET-1, ET-2, ET-3 and ET-4, which cause vasoconstriction, cell proliferation and myocardial effects through activation of ETA receptors. In contrast, endothelial ETB receptors mediate vasodilation via release of nitric oxide and prostacyclin. In addition, ETB receptors in the lung are a major pathway for the clearance of ET-1 from plasma. Thus, infusion of an ETA-receptor antagonist into the brachial artery in healthy humans leads to vasodilation, whereas infusion of an ETB-receptor antagonist causes vasoconstriction. Endothelin-1 plasma levels are elevated in CHF and correlate both with hemodynamic severity and symptoms. Plasma levels of ET-1 and its precursor, big ET-1, are strong independent predictors of death after myocardial infarction as well as in CHF. Endothelin-1 contributes to increased systemic and pulmonary vascular resistance, vascular dysfunction, myocardial ischemia and renal impairment in CHF. Selective ETA, as well as combined ETA/B-receptor antagonists, have been studied in patients with CHF, and their use has shown impressive hemodynamic improvement (i.e., reduced peripheral vascular and pulmonary resistance as well as increased cardiac output). These results indicate that ET-receptor antagonists, indeed, have a potential to improve hemodynamics, symptoms and, potentially, prognosis in patients with CHF, which still carries a high mortality.
Antihypertensive Agents↗
Endothelium-dependent vasoactive modulation in the ophthalmic circulation.
The vascular endothelium is strategically located between the circulating blood and the vascular smooth muscle cells. Different agonists or stimuli transported by the circulating blood can trigger the endothelium to release potent relaxing (nitric oxide, prostacyclin, endothelium-derived hyperpolarizing factor) or contracting factors (endothelin, cycloxygenase products). These endothelium-derived vasoactive factors can modulate blood flow locally. Heterogeneity exists from one vascular bed to the other, or even between vessels, in the agonists able to stimulate the release of endothelium-derived vasoactive factors. In the ophthalmic circulation, nitric oxide and endothelin are strong vasoactive modulators. In many vascular diseases that are of importance in ophthalmology (hypercholesterolemia, arteriosclerosis, hypertension, diabetes, vasospastic syndrome, ischemia and reperfusion, etc) the function of the endothelium can be impaired. There exist different drugs that can modulate the vasoactive function of the vascular endothelium. In other words, it appears that the vascular endothelium plays an important role in both the physiology and pathophysiology of the regulation of blood flow. The modulation of this regulatory system by different drugs might open new therapeutical approaches to treat vascular disorders in ophthalmology.
Animals↗
Endothelin A receptor antagonists in congestive heart failure: blocking the beast while leaving the beauty untouched?
Congestive heart failure (CHF) is a disease process characterized by impaired left ventricular function, increased peripheral and pulmonary vascular resistance and reduced exercise tolerance and dyspnea. Thus, mediators involved in the control of myocardial function and vascular tone may be involved in its pathophysiology. The family of endothelins (ET) consists of four closely related peptides, ET-1, ET-2, ET-3, and ET-4, which cause vasoconstriction, cell proliferation, and myocardial effects through activation of ET(A) receptors. In contrast, endothelial ET(B) receptors mediate vasodilation via release of nitric oxide and prostacyclin. In addition, ET(B) receptors in the lung are a major pathway for the clearance of ET-1 from plasma. Thus, infusion of an ET(A) receptor antagonist into the brachial artery in healthy humans leads to vasodilation whereas infusion of an ET(B) receptor antagonist causes vasoconstriction. ET-1 plasma levels are elevated in CHF and correlate both with the hemodynamic severity and with symptoms. Plasma levels of ET-1 and its precursor, big ET-1, are strong independent predictors of death in patients after myocardial infarction and with CHF. ET-1 contributes to increased systemic and pulmonary vascular resistance, vascular dysfunction, myocardial ischemia, and renal impairment in CHF. Selective ET(A) as well as combined ET(A/B) receptor antagonists have been studied in patients with CHF showing impressive hemodynamic improvements (i.e. reduced peripheral vascular and pulmonary resistance as well as increased cardiac output). These results indicate that ET receptor antagonists indeed have a potential to improve hemodynamics, symptoms, and potentially prognosis of CHF which still carries a high mortality.
Coronary Circulation↗
Pacing in magnetic resonance imaging environment: clinical and technical considerations on compatibility.
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Animals↗
Predictors of long-term survival after valve replacement for chronic aortic regurgitation; is M-mode echocardiography sufficient?
AIMS: The clinical importance of pre-operative and follow-up echocardiographic studies in patients operated on for chronic severe aortic valve regurgitation is still a matter of debate. The prognostic significance of M-mode echocardiography has never been directly compared with clinical and angiographic data. METHODS AND RESULTS: Univariate and multivariate analyses of cumulative survival were performed for clinical, echocardiographic and angiographic data of 125 patients operated on between 1975 and 1983, and followed for 13.3+/-6.4 years. Ten and 20 year survival rates were 77% and 48%, respectively. Age, NYHA class, angiographic volumes, ejection fraction, as well as M-mode echocardiographic end-systolic dimension and shortening fraction were the main pre-operative prognostic parameters for long-term survival. In a multivariate analysis the angiographic end-systolic volume index, age and preoperative NYHA class were independent pre-operative prognostic variables of long-term survival. A postoperative reduction in end-diastolic dimension of >20% predicted a significantly better late survival (74% vs 44% after 20 years, P<0.001). CONCLUSIONS: Age, pre-operative NYHA class and left ventricular systolic function are the main determinants of long-term survival after valve replacement for chronic aortic regurgitation. Despite a slightly lower predictive value of echocardiography when compared to angiography, it appeared sufficient for everyday clinical decision making for valve replacement. Echocardiography within 6 months postoperatively is able to detect recovery of left ventricular function, and enables additional risk-stratification, regardless of pre-operative findings.
Adolescent↗
Influence of aldosterone vs. endothelin receptor antagonism on renovascular function in liquorice-induced hypertension.
BACKGROUND: The enzyme 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2) provides mineralocorticoid receptor specificity for aldosterone by metabolizing glucocorticoids to their receptor inactive 11-dehydro derivatives. Inhibition of 11beta-HSD2 by liquorice-derived glycyrrhizic acid (GA) therefore results in sodium retention and hypertension. The present study investigated the effect of the aldosterone receptor antagonist spironolactone in comparison with the endothelin ET(A) receptor antagonist darusentan on renovascular endothelial function in liquorice-induced hypertension. METHODS: GA, a recognized inhibitor of 11beta-HSD2 was supplemented to the drinking water (3 g/l) of Wistar Kyoto rats over a period of 21 days. From day 8 to 21, spironolactone (5.8+/-0.6 mg/kg/day), darusentan (45.2+/-6.5 mg/kg/day), or placebo was added to chow (n=7 per group). After the animals were killed, vascular function of isolated renal artery segments was assessed by isometric tension recording. RESULTS: Relaxation of pre-constricted renal artery segments in response to acetylcholine (10(-10) to 10(-5) mol/l) was impaired by GA as compared with controls (12+/-4% vs 98+/-5% of norepinephrine 3x10(-7) mol/l), whereas endothelium independent relaxations were unaffected. Endothelin receptor antagonism improved renovascular endothelium-dependent relaxation (32+/-4%, P<0.05 vs placebo) whereas endothelium-dependent relaxation was completely normalized by aldosterone receptor antagonism (85+/-4%, P<0.01 vs placebo). CONCLUSIONS: In GA-induced hypertension, both aldosterone receptor antagonism and endothelin receptor antagonism normalize blood pressure and improve renovascular function and, thus, may represent a new therapeutic approach in cardiovascular disease associated with impaired 11beta-HSD2 activity.
Animals↗
Chronic vasopeptidase inhibition restores endothelin-converting enzyme activity and normalizes endothelin levels in salt-induced hypertension.
BACKGROUND: Vasopeptidase inhibition (VPI) represents a new therapeutic principle including both inhibition of angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP). The present study investigated the effect of the vasopeptidase inhibitor omapatrilat on endothelin-1 (ET-1)-mediated vascular function in salt-induced hypertension. METHODS: Dahl salt-sensitive rats (n=6/group) on standard or salt-enriched (4% NaCl) chow were treated for 8 weeks with either omapatrilat (36+/-4 mg/kg/day), captopril (94+/-2 mg/kg/day) or placebo. Aortic and renal artery segments were isolated and suspended in organ chambers for isometric tension recording. Functional endothelin-converting enzyme (ECE) activity was assessed in native segments and after preincubation with omapatrilat. Furthermore, vascular ECE protein levels as well as plasma and tissue ET-1 levels were determined. RESULTS: The increase in systolic blood pressure of salt-fed rats was prevented by omapatrilat and captopril to a comparable degree. In salt-induced hypertension, functional ECE activity (calculated as the ratio of the contraction to big ET-1 divided by the contraction to ET-1) in renal arteries (0.46+/-0.05) and in aorta (0.68+/-0.05) was reduced as compared with control animals (0.9+/-0.05 and 0.99+/-0.04, respectively; P<0.05). While omapatrilat in vitro blunted the response to big endothelin-1 (big ET-1) and diminished ECE activity further (P<0.01 vs native segments), chronic treatment with omapatrilat in vivo restored contractions to ET-1 (120+/-6%) and big ET-1 (98+/-9%) in renal arteries, and therefore normalized renovascular ECE activity. In addition, omapatrilat normalized plasma ET-1 concentrations (12.9+/-1.2 vs 16.6+/-1.4 pg/ml on high salt diet; P<0.05) and renovascular ECE protein levels. CONCLUSIONS: In salt-induced hypertension, vasopeptidase inhibition restores alterations in the endothelin system, such as renovascular ECE activity and responsiveness to ET-1 and big ET-1 with chronic but not acute in vitro application. Thus, the beneficial effects of vasopeptidase inhibition may reflect a resetting of cardiovascular control systems and therefore may be particularly suited to treat hypertension and heart failure.
Angiotensin-Converting Enzyme Inhibitors↗
Vasopeptidase inhibitors--concepts and evidence.
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Angioedema↗