Claus Bossaller

Comparison of clinical benefits of Clopidogrel therapy in patients with acute coronary syndromes taking Atorvastatin versus other statin therapies

In clinical practice, we found no significant difference between atorvastatin therapy or other statin therapies in the clinical outcomes of patients with acute coronary syndromes receiving clopidogrel therapy. In patients receiving atorvastatin therapy, clopidogrel therapy was associated with a significant decrease in mortality and stroke during univariate analysis and a moderate trend of reduced mortality and stroke without statistical significance in the multivariate analysis.

Ciclosporin A inhibits endothelium-dependent vasodilatation and vascular prostacyclin production

Aortic rings dissected from rats treated with ciclosporin A (30 mg/kg per day for five days) showed reduced relaxation induced by the endothelium-dependent vasodilator acetylcholine, but unchanged responses induced by glyceryl trinitrate. After eight weeks of ciclosporin A treatment, the relaxation induced by both acetylcholine and glyceryl trinitrate was inhibited. In addition, phenylephrine-induced contractions were slightly enhanced and vascular prostacyclin production was reduced by more than 80%. These effects may participate in the hypertensive and thrombo-embolic complications associated with the clinical use of ciclosporin A.

Endothelial and vascular smooth muscle function after chronic treatment with cyclosporin A

We wished to characterize the altered reactivity of vascular smooth muscle and endothelial cells in rat aorta during chronic treatment with cyclosporin. Male adult rats were treated orally for 6 weeks with either cyclosporin A (30 mg/kg/day in 1 ml olive oil, n = 9) or with vehicle alone (n = 10). Rings of isolated thoracic aorta were mounted in organ chambers to measure the change in isometric force in response to smooth muscle-contracting drugs and endothelium-dependent and independent vasodilators. Contractions to potassium chloride (20–80 mM) were markedly reduced in cyclosporin-treated rats. Contractions to phenylephrine (10-10-10-6 M) were reduced at high concentrations (≥10-7 M); those to endothelin-1 (10-10-10-7 M) were not significantly altered. In contrast, contractions to angiotensin II (All 10-9-10-6 M) were significantly augmented. Endothelium-dependent relaxations to acetylcholine (ACh 10-8-10-5 M) or ADP (10-7-10-5 M) were reduced in cyclosporin-treated rats; endothelium-independent relaxations to SIN-1 (10∼7-10∼5 M) and atrial natiuretic peptide (ANP 10-10-10-7 M) remained unaffected. Thus, chronic treatment with cyclosporin affects both endothelium-dependent vasodilation and vascular smooth muscle contraction in rat aorta depending on the stimulus applied. The enhanced response to AH and the reduced release of endothelium-derived relaxing factor (EDRF) may contribute to augmented vascular tone and further damage to the arterial wall.

Local Potentiation of Bradykinin-Induced Vasodilation by Converting-Enzyme Inhibition in Isolated Coronary Arteries

The interaction of angiotensin-converting enzyme (ACE) inhibitors and bradykinin was investigated in isolated bovine and human coronary arteries. Rings with and without endothelium were mounted in organ chambers for measurement of isometric force. The effects of the ACE inhibitors lisinopril, enalaprilat, fosinoprilat, ramiprilat, and captopril were determined during sub-maximal stimulation with bradykinin or other vasodilators. Lisinopril and captopril alone did not affect vascular tone; however, in rings with endothelium partially relaxed with bradykinin (≥10-10 M), all ACE inhibitors caused further relaxations. Lisinopril did not affect bradykinin concentrations in the incubation medium. Mechanical removal of the endothelium or incubation with nitro-L-ar-ginine or the bradykinin2-receptor antagonist Hoe 140 prevented the relaxations to bradykinin and lisinopril. Other vasodilators including acetylcholine, adenosine diphosphate, substance P, or SIN-1 did not prime the rings to respond to ACE inhibitors. Endothelium-dependent relaxations to lisinopril were also observed in human coronary arteries treated with bradykinin (≥10-7 M). Thus, ACE inhibitors potentiate endothelium-dependent relaxations to submaximal concentrations of bradykinin in bovine and human coronary arteries. This local mechanism occurs regardless of elevated bradykinin concentrations in the blood and reduced angiotensin II generation.

Effect of Preinfarction Angina Pectoris on Outcome in Patients With Acute Myocardial Infarction Treated With Primary Angioplasty (Results from the Myocardial Infarction Registry (MIR))

Preinfarction angina is associated with better clinical outcome in patients with acute myocardial infarction (AMI) who receive intravenous thrombolysis. This has not been proved in patients with AMI treated with primary angioplasty. We analyzed the data of the prospective multicenter Myocardial Infarction Registry (MIR). Of 14,440 patients with AMI, 774 with a prehospital delay of < or =12 hours were treated with primary angioplasty. Five hundred thirty-two patients (68.7%) had preinfarction angina. Patients with preinfarction angina were slightly older than patients without (63 vs 62 years, p = 0.042), prehospital delay was 1 hour longer (180 vs 120 minutes, p = 0.001), and arterial hypertension was more prevalent (47.6% vs 32.2%, odds ratio [OR] 1.91, 95% confidence intervals [CI] 1.39 to 2.62). There was no significant difference in hospital mortality (5.6% vs 3.3%, OR 1.75, 95% CI 0.79 to 3.87), reinfarction, stroke, or the combined end point of death, reinfarction, or stroke between the 2 groups. Logistic regression analysis showed no association of preinfarction angina with the occurrence of either death (OR 2.21, 95% CI 0.91 to 6.08) or the combined end points (OR 1.10, 95% CI 0.55 to 2.31). There was also no significant difference in mortality (6% vs 5.1%, OR 1.19, 95% CI 0.56 to 2.52), reinfarction, stroke, postinfarction angina, or the combined end points between patients with preinfarction angina within 48 hours compared with patients with preinfarction angina between 49 hours and 4 weeks before the AMI. Thus, the MIR data showed no protective effects of preinfarction angina in patients with AMI treated with primary angioplasty.

Endothelium-dependent relaxations are augmented in rats chronically treated with the angiotensin-converting enzyme inhibitor enalapril

The study was designed to evaluate the effects of chronic inhibition of angiotensin-converting enzyme (ACE) on the reactivity of the endothelium and the smooth muscle to vasoconstrictor and vasodilator stimuli in normal rats. Male rats were treated orally for 6 weeks with enalapril (10 mg/kg/day, n = 10) or with placebo (n = 10). Endothelium-dependent relaxations to acetylcholine and adenosine diphosphate were augmented in aortic rings from rats treated with enalapril compared with controls, whereas the response to the endothelium-indepen-dent vasodilator SIN-1 were similar. Contractions induced by phenylephrine and angiotensin II remained unchanged. Thus, the results suggest that chronic ACE inhibition enhances the release of relaxing factors from the endothelium in normotensive rats.

Impact of Ramipril versus other angiotensin-converting enzyme inhibitors on outcome of unselected patients with ST-elevation Acute Myocardial Infarction

We examined the impact of treatment with ramipril versus other angiotensin-converting enzyme (ACE) inhibitors on clinical outcome in unselected patients of the prospective multicenter registry Maximal Individual Therapy of Acute Myocardial Infarction PLUS registry (MITRA PLUS). Of 14,608 consecutive patients with ST-elevation acute myocardial infarction, 4.7% received acute therapy with ramipril, 39.0% received other ACE inhibitor therapy, and 56.3% received no ACE inhibitor therapy. In a multivariate analysis, the treatment with ramipril compared with the treatment without ACE inhibitors was associated with a significantly lower hospital mortality and a lower rate of nonfatal major adverse coronary and cerebrovascular events. Compared with other generic ACE inhibitors, ramipril therapy was independently associated with a significantly lower hospital mortality (odds ratio [OR] 0.54, 95% confidence interval [CI] 0.32 to 0.90) and a lower rate of nonfatal major adverse coronary and cerebrovascular events (OR 0.65, 95% CI 0.46 to 0.93), but not with a lower rate of heart failure at discharge (OR 0.79, 95% CI 0.50 to 1.27).

Metabolic Alterations in End-Stage and Less Severe Heart Failure — Myocardial Carnitine Decrease

Severe tissue carnitine deficiency impairs fatty acid oxidation. In explanted hearts from patients with end stage heart failure a 57% carnitine decrease was found in comparison with healthy donor hearts (p less than 0.05). The reduction of myocardial carnitine levels affected all areas of the explanted hearts to a comparable extent. Carnitine decreases in patients with dilated cardiomyopathy or coronary artery disease were similar. Endomyocardial biopsies from patients with less severe heart failure due to cardiomyopathy (n = 28) or other myocardial diseases (n = 8) showed a 42% decrease of total myocardial carnitine (in nmol/mg non-collagen protein) in comparison with biopsies from patients with normal cardiac function (controls) (heart failure: 5.7, confidence interval 4.2-7.0; controls 9.3, confidence interval 7.6-12.0, p less than 0.005). Free myocardial carnitine in heart failure was also different from controls (heart failure: 4.2, confidence interval 3.7-5.3; controls 10.3, confidence interval 7.5-12.2, p less than 0.001). The decrease of free and total myocardial carnitine was comparable in dilated cardiomyopathy and heart failure due to other diseases. Alterations in myocardial carnitine content represent therefore non-specific biochemical markers in heart failure with yet unknown consequences for myocardial function.

Bradykinin degrading activity in cultured human endothelial cells

The role of angiotensin-converting enzyme (ACE), neutral endopeptidase 24.11 (NEP), and other peptidases in the endothelial degradation of bradykinin was investigated in cultured human umbilical vein endothelial cells (HUVEC). The major part of the kininase II activity on intact cells was attributed to ACE activity, the minor part to NEP activity. Amastatin, as aminopeptidase inhibitor, and DL-2-mercaptomethyl-3-guanidino-ethyl-thiopropionic acid (MGTA), an inhibitor of kininase I, did not affect endothelial kininase activity. The decline of the bradykinin concentrations in the supernatant of intact endothelial monolayer indicated a total kininase activity of 289 ± 27 fmol/min/dish. The calculated activity of ACE was 223 fmol/min/dish and the neutral endopeptidase activity was 51 fmol/min/dish. Thus, ACE and neutral endopeptidase are the main kininases in the degradation of bradykinin by intact endothelial cells. In contrast to the intact endothelial monolayers, in homogenates additional kininase activity was found which was not affected by either ACE and NEP inhibitors nor by amastatin and MGTA.

Degradation of Bradykinin by Neutral Endopeptidase (EC 3.4.24.11) in Cultured Human Endothelial Cells

The presence of neutral endopeptidase 24.11 was demonstrated in human umbilical vein endothelial cells by immunostaining. Enzymatic activity of neutral endopeptidase was determined as 0.167 +/- 0.02 mU/mg protein in the membrane fraction of human umbilical vein endothelial cells, using the fluorogenic peptide substrate, dansyl-D-Ala-Gly-Phe(pNO2)-Gly. No activity was found in the cytosolic fraction of endothelial cells. The role of this peptidase in the degradation of the endogenous vasodilator bradykinin was investigated by incubating human umbilical vein endothelial cell monolayers with bradykinin (10(-8) mol/l). The inhibitor of neutral endopeptidase, phosphoramidon (10(-8) mol/l), decreased the degradation of bradykinin in the supernatant of endothelial cells; the half-life of bradykinin was then increased from 29 +/- 1 to 46 +/- 2 minutes. The angiotensin-converting enzyme inhibitor, lisinopril (10(-8) mol/l), increased the half-life of bradykinin to 244 +/- 20 minutes; the combination of both inhibitors increased the half-life of bradykinin to 381 +/- 51 minutes. Inhibitors of aminopeptidase (amastatin) and carboxypeptidase (2-mercaptomethyl-3-guanidinoethyl-thiopropionic acid) caused no significant effect. The effect of phosphoramidon was small in comparison with that of lisinopril, but was pronounced in combination with lisinopril. Neutral endopeptidase activity is localized in the membranes of human endothelial cells and seems to be involved in the degradation of bradykinin by the vascular endothelium, particularly during angiotensin converting enzyme inhibition.