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Heart failure is known to be a complication of insulin-dependent (IDDM) and noninsulin-dependent diabetes mellitus (NIDDM) even in the absence of coronary heart disease or hypertension. The mechanisms leading to diabetic cardiomyopathy are unknown. The aim of the study was to characterize structural and functional alterations in hyperinsulinemic Zucker diabetic fatty (ZDF) rats treated with or without insulin. Diabetic animals showed a twofold increase in cardiomyocyte volume with increased left ventricular ANP but not BNP mRNA levels in spite of a reduced plasma renin activity (PRA) 2 months after onset of diabetes compared to nondiabetic littermates. These changes were associated with an increase in left ventricular performance as assessed by echocardiography. Insulin treatment led to a significant increase in body weight (BW), total heart weight, myocardial protein content, and left ventricular mass (LVM). Perivascular fibrosis and laminin thickness were significantly augmented in diabetic rat myocardium irrespective of insulin treatment, whereas interstitial collagen I and fibronectin were similarly found in diabetic and control myocardium. Initial stages of diabetic cardiomyopathy in hyperinsulinemic rats are characterized by cardiomyocyte hypertrophy and enhanced cardiac contractility. It is suggested that hyperinsulinemia may be involved in cardiac hypertrophy.

Background: Left ventricular hypertrophy involves growth of cardiomyocytes, as well as remodeling of extracellular matrix proteins (ECMPs). Several metabolic abnormalities may be triggered secondary to hyperglycemia in diabetes. The effects of combined supravalvular aortic banding and diabetes mellitus on the rat heart were investigated in order to detect possible synergistic effects of these two conditions. Moreover, this study focused on the impact of beta-adrenoceptor blockade with carvedilol (C) on the expression of ECMPs. Methods: Sixty male Wistar rats were allocated to six groups: control (CON), CON+C, streptozotocin (65 mg/kg iv)-induced diabetes (D), D+C, aortic stenosis (AS)+D and AS+D+C. Follow-up was 6 weeks. Results: Relative left ventricular weight was elevated and body weight was decreased in D, AS+D and AS+D+C rats (P

Experimental studies suggest a reduced neointimal tissue proliferation in vascular stainless steel stents coated with gold. This prospective multicenter trial evaluated the impact of gold coating on neointimal tissue proliferation in patients undergoing elective stent implantation. The primary end point was the in-stent tissue proliferation measured by intravascular ultrasound at 6 months comparing stents of identical design with or without gold coating (Inflow). Two hundred four patients were randomized to receive uncoated (group A, n = 101) or coated (group B, n = 103) stents. Baseline parameters did not differ between the groups. Stent length and balloon size were comparable, whereas inflation pressure was slightly higher in group A (14 +/- 3 vs 13 +/- 3 atm, p = 0.013). Procedural success was similar (A, 97%; B, 96%). The acute angiographic result was better for group B (remaining stenosis 4 +/- 12% vs 10 +/- 11%, p = 0.002). Six-month examinations revealed more neointimal proliferation in group B. By ultrasound, the neointimal volume within the stent was 47 +/- 25 versus 41 +/- 23 mm(3) (p = 0.04), with a ratio of neointimal volume-to-stent volume of 0.45 +/- 0.12 versus 0.40 +/- 0.12 (p = 0.003). The angiographic minimal luminal diameter was smaller in group B (1.47 +/- 0.57 vs 1.69 +/- 0.70 mm, p = 0.04), with a higher late luminal loss of 1.17 +/- 0.51 versus 0.82 +/- 0.56 mm (p = 0.001). Thus, gold coating of the tested stent type resulted in more neointimal tissue proliferation.

Background/Aims: Published data regarding the effects of common cardiovascular diseases, i.e. aortic stenosis on renal regulation of major vasoconstrictive (renin, endothelins) and vasodilatory systems (NO) are controversial. Therefore we aimed to evaluate the effects of chronic aortic stenosis on the renal renin-angiotensin, endothelin and NO systems. Methods: Experimental supravalvular aortic stenosis was induced by using silver clips with a 0.6 mm internal diameter on the ascending aorta of weanling rats. Renal endothelin-1 (ET-1), endothelin-3 (ET-3), renin, AT1a, AT1b, eNOS, and bNOS gene expression were assessed by RNase protection assay. Results: Renal renin gene expression increased twofold in rats with aortic stenosis. In contrast, renal ET-1, ET-3, eNOS, bNOS, and AT1a, AT1b gene expression were unchanged in rats with aortic stenosis. Conclusion: Our study demonstrates that in rats with severe experimental supravalvular aortic stenosis only renal renin gene expression is stimulated. This contrasts with severe heart failure where endothelins and NO synthases are also upregulated. Different patterns of regulation of renal vasoactive mediators may be of importance for the extent of the renal impairment associated with aortic stenosis, and may be correlated with the severity of congestive heart failure.

Background Published data regarding effects of growth hormone (GH) on the renin system are controversial. The aim of this study therefore was to evaluate the effects of GH on the renin system in normal rats and rats with myocardial infarction (MI). Methods Normal rats received 2, 5, or 10 IU GH/kg/day or vehicle subcutaneously for 4 weeks. Furthermore rats with MI were randomized to receive 2 IU GH/kg/day or vehicle for 4 weeks. Subdivision into MI groups (mild, moderate, and large) was by histological determination of infarct size. Renal renin gene expression was assessed by RNAase protection assay and plasma renin activity by radioimmunoassay. In addition, isolated mouse juxtaglomerular cells were exposed to GH for 20 h, and renin secretion rates were assessed. Results GH treatment in normal rats for 4 weeks increased body weight, and kidney weight to body weight ratio, but did not affect renin secretion and renal renin gene expression. In rats with large MI, renal renin gene expression increased about fourfold, but was unchanged in rats with small and moderate MI as compared to normal rats. In rats with MI, body weight decreased and this decrease was partially reversed by GH treatment. GH treatment did not change renal renin gene expression, and renin secretion in rats with MI. Renin secretion of isolated juxtaglomerular cells was unaffected by GH. Conclusions Our study demonstrates that GH treatment has no significant effect on renin secretion and on renal renin gene expression in normal rats and in rats with stimulated renin system due to MI in vivo. In isolated juxtaglomerular cells in vitro, renin secretion was also unaffected by GH.

The aim of this study was to examine the effects of both angiotensin II type I receptor antagonism using losartan (LOS) and beta-receptor blockade by metoprolol (MP) in isoproterenol-induced cardiac injury in the rat. Two weeks after isoproterenol (ISO) application, 90 ISO and 30 control (CTRL) rats were examined. ISO rats were treated for two weeks with either LOS, MP, or vehicle (n = 30 each group). Compared to CTRL, ISO induced left ventricular hypertrophy (LVH), fibrosis, and overexpression of extracellular matrix proteins. LOS significantly attenuated these changes. MP only reduced LVH, but exerted no effect on structural alterations. LV end-diastolic and mean right atrial pressures were significantly increased in the ISO group and normalized in the LOS and MP group. Mean aortic blood flow velocity was significantly decreased in the ISO group and unaltered in the LOS and MP group versus CTRL. Blood pressure was decreased in ISO and LOS rats. MP treatment had no effect on blood pressure, but significantly lowered heart rate. Isoproterenol induced mild heart failure. Losartan and metoprolol applications in ISO-treated rats were highly effective in attenuating hemodynamic alterations and LVH. Early application of losartan 24 hours after isoproterenol-induced cardiac injury revealed significant beneficial effects on myocardial structure.

Left ventricular hypertrophy (LVH) is characterized by remodeling of both myocyte and interstitial compartments of the heart. The aim of this investigation was to study the effects of angiotensin converting enzyme (ACE) inhibition on alterations in the composition of the interstitium in chronic pressure-overload hypertrophy.LVH was induced in weanling rats by banding the ascending aorta. Animals with aortic banding received either vehicle (n = 20), hydralazine (20 mg/kg per day, n = 20), or the ACE inhibitor ramipril (10 mg/kg per day, n = 20) during weeks 6-12 after banding.Compared with sham-operated, untreated rats (n = 20), aortic-banded vehicle and hydralazine-treated rats displayed substantially increased left ventricular weights and myocyte diameters whereas ramipril significantly blunted the hypertrophic response at the myocyte level (each P0.001) as well as the increase in left ventricular weight (each P0.01). In addition, image analysis revealed a significant induction of perivascular and interstitial tissue accumulation in vehicle- and hydralazine-treated rats (2.5-fold, each P0.0001). In contrast, ramipril-treated rats displayed attenuated interstitial and perivascular fibrosis, both being significantly diminished compared with vehicle- and hydralazine-treated rats (each P0.001). Further, vehicle- and hydralazine-treated rats were characterized by elevated steady-state messenger (m)RNA levels of fibronectin (2.7- and 2.8-fold, P0.005), collagen I (2.0- and 1.8-fold, P0.0005), collagen III (both 2.2-fold, P0.001) and laminin B (1.6- and 1.6-fold, P0.005). In parallel, the corresponding immunohistochemical signals were markedly enhanced in these groups. In comparison, ramipril significantly blunted the induction of collagen I and III, laminin B and fibronectin at both the mRNA and protein levels. These morphological and molecular differences between the hydralazine and ramipril groups could not be attributed to differences in left ventricular-pressures, which were markedly elevated in all aortic stenosis rats (1.9-fold, each P0.001 versus sham). In fact, given that ramipril but not hydralazine blunted the hypertrophic response to pressure overload, the echocardiographic measurements revealed that left ventricular systolic wall stress was higher in the ramipril group (70 +/- 1 versus 34 +/- 0.7 kdyn/cm2; P0.02).ACE inhibition may limit both myocyte and interstitial remodeling despite ongoing cardiac pressure overload.

To test the hypothesis that elevated plasma levels of natriuretic peptides may serve to identify patients with left ventricular (LV) dysfunction, we assessed the predictive diagnostic value of natriuretic peptide levels, in addition to clinical and electro-cardiographic risk factors, as noninvasive indicators of cardiac dysfunction. Plasma levels of atrial natriuretic peptide (cANP) (99-126), N-terminal fragment of proANP (nANP) (26-55), nANP(80-96), brain natriuretic peptide (BNP-32), proBNP(22-46), and C-type natriuretic peptide (CNP-22) were measured in 211 subjects before cardiac catheterization. The strongest correlations with parameters of LV function were found for nANP(80-96) (up to r = -0.55, p < 0.0001), whereas there was no significant correlation with proBNP(22-46) or CNP-22. In patients with LV ejection fractions (LVEF) < or = 45% (n = 38) nANP(26-55), nANP(80-96), cANP(99-126), and BNP-32 were significantly increased (p < 0.001). Partition values for elevated versus normal natriuretic peptide levels were obtained from normal controls and used to separate subjects with and without LV dysfunction. Receiver operating characteristic analysis for LVEF < or = 45% indicated a significantly better diagnostic accuracy for high levels of nANP(80-96), nANP(22-56), cANP(99-126), and BNP-32 than for proBNP and CNP-22. Multivariate analysis by logistic regression identified Q waves and bundle branch block in the electrocardiogram as well as elevated plasma levels of cANP, nANP(80-96), and nANP(26-55) as the strongest independent predictors of low ejection fractions. The relative risk of LV dysfunction was raised up to tenfold in subjects with high natriuretic peptide levels (p < 0.001). The addition of nANP(80-96) and nANP(26-55) to the combination of clinical and electrocardiographic risk factors did not further improve the diagnostic sensitivity for the detection of LVEF < or = 45%, but it markedly increased the overall accuracy (59% to 81%, p < 0.001) and specificity (55% to 81%, p < 0.001). Among natriuretic peptides, elevated nANP(80-96) and nANP(26-55) levels have the strongest impact on the detection of LV dysfunction. They add to the diagnostic information contained in clinical and electrocardiographic factors. Plasma levels alone or in combination with clinical factors seem to be of value for a refined identification of abnormal LV function in the individual patient.

Follicular thyroid carcinomas (FTC) characteristically spread via blood vessels, while papillary thyroid carcinomas (PTC) predominantly metastasize to lymph nodes. This different behavior of cancer cells originating from one organ was investigated by layering multicellular tumor spheroids (MCTS) consisting of various kinds of human thyroid cells onto confluent monolayers of human venous endothelial cells (HEC). The MCTS and HEC were cocultured in an incubation chamber fixed under a microscope, and the behavior of the cells was investigated. In this way significant differences between FTC, PTC, and follicular adenoma cells (FTA) were observed regarding their in vitro behavior upon interaction with HEC. FTC cells required 20 min for adhesion and another hour until they migrated out of a spheroid, whereas PTC- and FTA-MCTS were adhesive after 2 h or later, and their cells did not start migration until 5 h of incubation. Furthermore, one FTC-spheroid triggered about 100 endothelial cells to enter the replication cycle, while no spheroid consisting of either PTC or FTA cells induced more than 20 endothelial cells to start proliferation. During these processes, the cells of the MCTS and the endothelial cells contacted each other directly and remained viable. The results show that FTC cells interact faster and more intensively with human endothelial cells than PTC and FTA cells. Thus the study suggests that an enhanced capability of the FTC cells to interact with venous endothelial cells might favor the clinically observed hematogenous spreading of follicular thyroid carcinomas.

To test the efficacy of exogenous prostaglandins for vasodilator therapy in heart failure, we studied the hemodynamic, hormonal, and renal effects of prostaglandin E2 (1.5-150 ng/kg/min) in six conscious dogs before and after induction of heart failure by right ventricular pacing (250 beats/min, 10 days). In healthy dogs, PGE2 decreased the mean arterial pressure (MAP) by a reduction in total peripheral resistance (TPR), increased cardiac output (CO), stroke volume (SV), and heart rate with no effect on right atrial pressure (RAP). Plasma levels of renin (PRC) and norepinephrine (NE) were increased at the highest dosage. Renal plasma flow (RPF) and sodium excretion (UNaV) were augmented without a change in the glomerular filtration rate (GFR) and urine flow (UF). In dogs with heart failure, PGE2 lowered the MAP and TPR and elevated the CO and SV without an effect on the RAP, PRC, and NE. The RPF and GFR were not changed, but the increase in UNaV was preserved and UF significantly augmented. In experimental heart failure, PGE2 increases the CO due to arteriolar dilation and afterload reduction without inducing further neurohumoral activation and exerts potent natriuretic and diuretic action. Therefore, PGE2 may have beneficial effects in heart failure therapy.

Candoxatril is a novel, orally active inhibitor of neutral endopeptidase EC 3.4.24.11, the enzyme that degrades atrial natriuretic peptide (ANP). The acute and chronic (10 days treatment) hemodynamic and hormonal effects of candoxatril (150 mg twice daily) in 12 patients with moderately severe congestive heart failure were investigated in a randomized, placebo-controlled, double-blind study. On study day 1, candoxatril acutely increased plasma ANP levels, suppressed aldosterone and decreased right atrial and pulmonary capillary wedge pressures. After 10 days of treatment, basal ANP was increased and basal aldosterone was decreased. Body weight was reduced, most likely reflecting chronic natriuretic or diuretic effects, or both, and there was a trend toward increased cardiac index and reduced preload values. On study day 10, the acute effects of candoxatril were similar to those on day 1 (i.e., ANP was further increased, aldosterone was suppressed, and right and left ventricular filling pressures were decreased). Thus, candoxatril may offer a new and effective therapeutic approach in the treatment of heart failure.

The role of endothelium-derived nitric oxide (EDRF/NO) for control of systemic and regional vascular resistances and for regulation of neurohumoral systems was investigated by studying the effects of the inhibitor of EDRF/NO-synthesis NG-nitro-L-arginine (L-NNA; 5 mg/kg) in six conscious dogs. L-NNA increased mean arterial pressure by an increase in total peripheral resistance, increased renal vascular, and total pulmonary resistances and reflexly decreased heart rate and cardiac output. Renal plasma flow, urine flow, and urinary sodium excretion were reduced, glomerular filtration rate was not affected. These changes were reversed by additional treatment with L-arginine (150 mg/kg). Plasma concentrations of renin, norepinephrine, vasopressin, and atrial natriuretic peptide were not changed by L-NNA. Our conclusions were that basal release of EDRF/NO plays an important physiologic role for control of systemic and regional vascular resistances, thereby controlling blood pressure, organ blood flow, and function. Neurohumoral systems are not affected by the inhibition of EDRF/NO synthesis and do not contribute to the observed vasoconstriction.

purpose: We conducted a double-blind, placebo-controlled trial to determine whether the administration of acetylsalicylic acid has adverse effects on renal function in patients with moderate chronic congestive heart failure with and without stimulation of the renin system. patients and methods: Forty patients were randomly assigned to one of the following four groups: Group 1, low sodium diet and placebo; Group 2, low sodium diet and acetylsalicylic acid; Group 3, normal sodium diet and placebo; or Group 4, normal sodium diet and acetylsalicylic acid. Patients were studied over 8 days. After Day 5, patients in Groups 2 and 4 received acetylsalicylic acid (500 mg three times a day). The low sodium diet consisted of 13.6 mmol of sodium per day and the normal sodium diet consisted of 136 mmol of sodium per day. results: The low sodium diet resulted in a highly significant increase in the plasma renin (2p = 0.0001), aldosterone (2p = 0.0006), and urinary prostaglandin E 2 (2p = 0.01) concentrations and the renal potassium excretion (2p = 0.0009), whereas renal sodium excretion was significantly reduced (2p = 0.0001). Severe sodium depletion led to a reduction of the glomerular filtration rate (2p = 0.007), which was independent from cyclooxygenase inhibition. In patients on the low sodium diet, acetylsalicylic acid reduced the elevated urinary prostaglandin E 2 levels to normal values without changing the renal sodium excretion rate. In patients with a normal sodium intake, acetylsalicylic acid significantly reduced the renal sodium excretion rate by 29% (2p = 0.04). conclusion: We conclude that severe sodium depletion has adverse effects on kidney function in patients with heart failure due to a reduction in the glomerular filtration rate. Administration of acetylsalicylic acid in doses that reduce the synthesis of renal prostaglandin E 2 significantly reduces renal sodium excretion.

It has been hypothesized that a decreased activity of vagal afferents might contribute to the activation of neurohumoral systems in congestive heart failure. Therefore, we studied the effects of vagal nerve blockade by local anesthesia on neurohormones in six conscious dogs before and after induction of heart failure by rapid right ventricular pacing (250 beats/min, 10 days). In healthy dogs, vagal blockade significantly increased plasma vasopressin levels (from 1.5 +/- .6 to 13.7 +/- 10.5 pg/ml, p less than 0.02), without significantly affecting plasma catecholamines and renin. After 10 days of pacing, mean arterial pressure and cardiac output were decreased, right atrial and pulmonary arterial pressures and plasma levels of norepinephrine, dopamine, and atrial natriuretic peptide were increased. In this state, vagal blockade significantly increased plasma renin activity (from 1.52 +/- .43 to 3.18 +/- .54 ngAI/ml/h, p less than 0.02) and plasma vasopressin (from 4.2 +/- 3.3 to 89.1 +/- 54.9 pg/ml, p less than 0.02), this increase being significantly higher than in healthy dogs. We conclude that in these dogs with low cardiac output state, which resembles early heart failure, vagal afferent activity is increased and effectively suppresses renin and vasopressin. This does not exclude the possibility that in later stages of heart failure vagal afferent dysfunction may develop, resulting in neurohumoral disinhibition.

Left ventricular hypertrophy (LVH) is accompanied by progressive accumulations of extracellular matrix proteins. They are produced predominantly by cardiac fibroblasts that surround the cardiac myocytes. The aim of this study was to emphasize the role of a combined approach using both in vivo and in vitro studies to elucidate the effects of carvedilol on cardiac remodeling. We therefore used an established model of supravalvular aortic banding and cardiac fibroblasts. LVH was induced by banding of the ascending aorta. Male Wistar rats were allocated to four groups: sham-operated, sham+carvedilol, aortic stenosis (AS), and AS+carvedilol. Treatment time was four weeks. Fibroblasts were isolated from the entire left ventricle of sham and AS rats. Carvedilol/metoprolol/prazosin were added (0.1, 1.0 and 10 microM; 24 h). In addition, interferon- gamma was applied for 24 h (10, 100 and 1000 IU). AS rats revealed increased LV weights (+27%) and cardiomyocyte widths as compared to sham-operated rats (1.6-fold, P

Study objective – The aim was to test the hypothesis that endothelium dependent vasomotor control is impaired in heart failure. Design and subjects – The haemodynamic effects of NG-nitro-L-arginine (NNA), an inhibitor of nitric oxide synthesis, were studied in five dogs with and without pacing induced heart failure. Main results – In healthy dogs, NNA increased total peripheral resistance and arterial pressure, decreasing cardiac output and heart rate. These effects were partially reversed by L-arginine. In dogs with heart failure, NNA did not change any haemodynamic variable. However, L-arginine decreased total peripheral resistance. Conclusions – These findings support a physiological role for endothelium derived nitric oxide in control of vascular resistance and are in agreement with the hypothesis that endothelium dependent vasomotion may be impaired in heart failure.

Beranek suggests that growth hormone rather prevents than reduces interstitial fibrosis in non-infarcted areas following experimental myocardial infarction in rats. We appreciate his thorough reading of our paper and his important contribution on the possible mechanisms of growth hormone on myocardial structure. Indeed, we agree that Fig. 3B (showing the non-infarcted area of the left ventricle in an untreated rat), visualizes reactive as well as reparative fibrosis [1]. His …

Objectives: Growth hormone (GH) causes cardiomyocyte hypertrophy without development of fibrosis in the normal rat heart. The aim of this study was to evaluate the effects of GH on cardiac remodeling following experimental myocardial infarction (MI). Methods: Following ligation of the left coronary artery or sham operation, rats were randomized to receive 2 IU GH/kg/day or vehicle for four weeks ( n =140). Extracellular matrix proteins were assessed in the non-infarcted myocardium of the posterior wall using immunohistochemistry and automatic image analysis. In addition, cardiomyocyte size was measured. Results: Compared to sham, vehicle-treated rats with moderate (20–40%) and large (>40%) infarct size showed left ventricular (LV)-dilatation, reduced fractional shortening as well as increases in LV end-diastolic and right atrial pressures, LV/body weight (BW) ratio and LV posterior wall thickness. Compared to vehicle-treated MI-rats, treatment with GH considerably increased fractional shortening and attenuated LV-dilatation. Vehicle-treated MI-rats displayed progressive increases in cardiomyocyte width and deposition of collagen I, compared to sham rats. Treatment with GH nearly doubled the increase in cardiomyocyte width and reduced collagen I accumulation by 50%. Conclusions: Our study demonstrates that GH, given early after large MI, elicits a unique pattern of structural effects characterized by enhanced cardiomyocyte hypertrophy and reduced adaptive fibrosis. This attenuation of pathological remodeling translates into a significant improvement in systolic and diastolic LV-function.

Einzelstudien, Megatrials und Metaanalysen sind die Grundlage fur Therapieempfehlungen der nationalen und internationalen Fachgesellschaften und damit auch die Basis fur unsere Therapieentscheidungen bei Patienten mit KHK. Die Therapie verfolgt im Wesentlichen folgende Ziele: Verbesserung der Symptomatik, d.h. Vermeidung von Angina pectoris Anfallen und/oder Steigerung der Belastbarkeit Revaskularisierung von Myokardarealen mit eingeschrankter Perfusion chirurgisch interventionell Verbesserung der Prognose Kontrolle modifizierbarer Risikofaktoren zur Progressionshemmung.

Die Behandlung von Patienten mit koronarer Herzerkrankung (KHK) wird in weiten Teilen gemeinsam von ambulant und klinisch tatigen Arzten getragen. Aus praktischer Sicht wendet sich ein Patient mit thorakalen Beschwerden allerdings zunachst an den Hausarzt, der damit zur Schaltstelle fur die weitere Planung von Diagnostik und Therapie wird. In Anbetracht der breiten Palette moglicher Ursachen einer thorakalen Symptomatik kommt dem Primararzt die wichtige Funktion zu, die adaquaten diagnostischen Schritte zeitgerecht einzuleiten oder, bei Verdacht auf Myokardinfarkt bzw. akutes Koronarsyndrom, eine rasche Klinikeinweisung vorzunehmen.

In der Diagnostik der KHK haben Untersuchungen des Herzens unter physiologischem oder pharmakologischem Stres eine duale Funktion. Zunachst ist ein positiver Ischamienachweis mittels Belastungs-EKG, Stresechokardiographie oder Myokardszintigraphie ein deutlicher Hinweis fur das Vorliegen einer KHK. Dies wiederum erhartet die Indikation zur Durchfuhrung einer Herzkatheteruntersuchung, um Ausmas und Morphologie der KHK zu erfassen. Zum anderen erlaubt die Funktionsdiagnostik eine Abschatzung der hamo dynamischen Beeintrachtigung einer koronarangiograpisch oder durch abgelaufenen Infarkt bereits dokumentierten KHK.

Pathophysiologisch sind die klinischen Beschwerden des Koronarkranken auf eine unzureichende Deckung des myokardialen O2-Bedarfes zuruckzufuhren. In der Regel liegt dem wiederum eine koronare Minderperfusion bei atheroskleroti-scher und/oder thrombotischer Einengung eines oder mehrerer epikardialer Kranzgefase zugrunde.

Thorakale Beschwerden lassen differentialdiagnostisch neben der KHK auch an weitere kardiale und nicht-kardiale Erkrankungen denken. So ist eine Angina pectoris bei der Aortenstenose ein haufig angetroffenes Symptom, selbst wenn die Koronarmorphologie unauffallig ist. Auch eine dilatative oder hypertrophische Kardiomyopathie sowie eine hypertensive Herzerkrankung konnen belastungsinduziert ein thorakales Engegefuhl oder Schmerzen hervorrufen. Diese Erkrankungen sind allesamt durch eine Hypertrophie der Kardiomyozyten sowie eine Fibrosierung des Myokards charakterisiert, sodas auch in diesen Fallen, neben anderen Ursachen, eine Myokardischamie durch Beeintrachtigung der Diffusionswege zur Symptomatik beitragen kann.

Die bildgebenden Stresuntersuchungen bieten gegenuber dem Belastungs-EKG 5 wesentliche Vorteile. Erstens ist die Sensitivitat bei Vorliegen einer Myokardischamie hoher als beim Belastungs-EKG, zweitens ist die Befundinterpretation unabhangig von vorbestehenden EKG-Veranderungen, drittens ist die Lokalisier-barkeit der ischamischen Region genauer, viertens lassen sich Aussagen zur Vitalitat des Myokards machen und funftens kann die Grose des Myokardareals besser definiert werden, welches von einer Ischamie bedroht ist („area at risk“). In der Ischamiediagnostik kommen die bildgebenden Verfahren v. a. dann zum Einsatz, wenn das Belastungs-EKG keine verlasliche Beurteilung erlaubt, wobei diese neueren Verfahren qualitativ relativ geringe Unterschiede zeigen. In der Vitalitatsdiagnostik unterscheidet sich jedoch die Aussagekraft der Methoden (s. Ubersicht 9–1).

Das erste Gesprach zwischen Arzt und Patient dient zunachst zur Schaffung einer personlichen Vertrauensbasis. Zeichnet sich nach Schilderung der subjektiven Beschwerden der Verdacht auf das Vorliegen einer KHK ab, sollten zunachst 2 Fragen geklart werden.

Wenn anhand der Beschwerden und/oder bisher erhobener nichtinvasiver Befunde die Indikation zur Durchfuhrung der Herzkatheteruntersuchung gestellt wird, sollten im Vorfeld — falls die notwendige Zeit zur Verfugung steht — erganzende Masnahmen getroffen bzw. Untersuchungen durchgefuhrt werden. Sie haben folgende Ziele: optimale Information und Aufklarung des Patienten im Vorfeld, Verkurzung des Krankenhausaufenthaltes und Verringerung moglicher Komplikationen auf das Minimum.

To evaluate the feasibility and accuracy of multiplane transesophageal Doppler echocardiographic assessment of the severity of aortic stenosis in mechanically ventilated patients using modified transgastral views of the left ventricular outflow tract and the aortic valve.A prospective study comparing the results of transesophageal echocardiography (TEE) with transthoracic echocardiography (TTE) and cardiac catheterization.A university hospital.Twenty-eight American Society of Anesthesiologists class III and IV patients with aortic stenosis undergoing elective cardiac surgery for valve replacement.Intubated and mechanically ventilated patients with aortic stenosis undergoing cardiac surgery for valve replacement were studied by multiplane transesophageal Doppler echocardiography to determine transvalvular pressure gradients (Bernoulli formula) and valve areas (continuity equation). These findings were compared with the respective preoperative data from TTE and cardiac catheterization.In 25 of 28 patients (89%), adequate transgastral Doppler recordings of the aortic jet could be obtained. The TEE measurements correlated well with the respective data obtained by TTE (maximal pressure gradient: r=0.93, p0.0001, mean difference=5.9+/-5.8 mm Hg [mean+/-SD]; mean pressure gradient: r=0.91, p0.0001, mean difference=5.4+/-4.6 mm Hg; aortic valve area: r=0.97, p0.0001, mean difference=0.07+/-0.05 cm2) and cardiac catheterization (n=16) (maximal vs peak-to-peak pressure gradient: r=0.84, p0.0001, mean difference=10.9+/-8.8 mm Hg; mean pressure gradient: r=0.80, p0.0002, mean difference=9.7+/-5.9 mm Hg; aortic valve area: r=0.84, p0.0001, mean difference=0.1+/-0.08 cm2).Multiplane transesophageal Doppler echocardiography offers an alternative approach for assessing the severity of aortic stenosis in mechanically ventilated patients in whom conventional TTE is not feasible.

Objective : High dosages of catecholamines induce cardiomyocyte necrosis and interstitial fibrosis in rats. We investigated whether this initial damage is followed by the development of heart failure and assessed the particular role of the renin–angiotensin system using ramipril. Methods and Results : Following the administration of 0 mg or 150 mg isoproterenol/kg 6 groups of Wistar rats were followed for 2 or 16 weeks: Sham, isoproterenol, isoproterenol+ramipril. Isoproterenol induced significant increases of echocardiographically measured left ventricular end-diastolic posterior wall thickness and dimension, whereas ramipril treatment significantly attenuated these changes. Left ventricular end-diastolic pressure was markedly increased in isoproterenol-treated rats and normalized following ramipril. Isoproterenol rats were further characterized by hormonal activations including transient elevations of plasma renin activity, aldosterone and cardiac angiotensin converting enzyme activity. Histomorphological characterization of isoproterenol-treated hearts demonstrated cardiomyocyte necrosis and reparative fibrosis. Ramipril treatment only slightly reduced the amount of necrosis as well as the expression of extracellular matrix proteins. Conclusions : In rats, a toxic dosage of isoproterenol caused characteristic myocardial damage that subsequently resulted in mild heart failure. Ramipril administration following isoproterenol was highly effective to attenuate hemodynamic and hormonal alterations as well as the development of left ventricular hypertrophy, but had only little influence on the expression of extracellular matrix proteins. Since angiotensin converting enzyme inhibition had no impact on the initial myocardial injury, the development of heart failure in this model seems to require functional integrity of the renin–angiotensin system.

Features of multicellular tumor spheroids (MCTS) differed depending on their types of cells. MCTS formed by 4000 human thyroid primary culture epithelial tumor cells displayed diameters between 0.31 and 0.33 mm within 2 days regardless of the stage of malignancy of the originating tumors. Their cellular composition reflected that of the originating tumor in regard to DNA content and the expression of cytokeratin, vimentin, as well as thyroglobulin. During the following 3 weeks, their sizes increased up to diameters of 0.42 mm when their cells had been derived from carcinomas, and MCTS originating from adenomas stopped growing within the next 2 days. After 8 days of incubation, proliferating cells were only found in carcinoma MCTS. The cells were randomly distributed over the total volume of the spheroids, which displayed irregular cell arrangements but not concentric cell layers and did not form necrotic centers.

A large family with congenital heart disease is described. The pattern of inheritance suggests an autosomal dominant trait with high penetration, although the morphologic phenotype is quite variable, including Ebstein's anomaly, cleft mitral leaflet, bicuspid aortic valve, and atrioventricular canal.

Objective: The role of the brain as a target for angiotensin converting enzyme (ACE) inhibitors in the treatment of heart failure and hypertension is unclear. To test the hypothesis that ACE inhibitors may modulate other central neuropeptide systems such as the central vasopressin system, we studied the effects of chronic treatment with the ACE inhibitor, quinapril, on ACE activity and on central vasopressin content in specific brain areas in rats. Methods: 22 rats were chronically treated with quinapril (6 mg·kg−1 BW per gavage daily for 6 weeks; untreated controls, n =14). ACE density in various brain regions was assessed by in vitro autoradiography using the specific ACE inhibitor, 125I-351A. Vasopressin content was determined in 19 brain areas (micropunch technique) known to be involved in cardiovascular regulation. Results: Following chronic quinapril treatment ACE was significantly decreased in the thalamus (−38%), hypothalamus (−37%), hypophysis (−35%), cerebellum (−36%), choroid plexus (−20%), and locus coeruleus (−35%). Additionally, a marked reduction in serum ACE activity (−97%) was observed. Plasma levels of vasopressin were significantly decreased after quinapril treatment (0.97[s.e.m. 0.11] vs. 1.63[0.24] pg·ml−1 in controls, P

We investigated whether multiplane transesophageal Doppler echocardiography using transgastral views allows determination of pressure gadients and valve areas in patients with aortic stenosis. This technique was feasible in 35 of 39 patients (90%), with highly significant correlations with results obtained from transthoracic Doppler echocardiography and cardiac catheterization, thus offering an alternative approach for quantification of aortic stenosis.

The aim of the present study was to investigate the functional regulation of the myocardial postreceptor adenylyl cyclase (AC) system in compensated left ventricular hypertrophy (LVH) and the effect of long-term angiotensin converting enzyme (ACE) inhibition.Pressure overload LVH was induced in rats by supravalvular aortic banding for 12 weeks. At 12 weeks left ventricular function and inner diameters were analyzed by echocardiography of anesthetized animals, and responsiveness to forskolin (systolic developed pressure) was determined in isolated perfused hearts. Functional activities of AC and the stimulatory G protein Gs were measured as well as mRNA expression (quantitative slot blot analyses) of AC type V, isoforms of Gs alpha and Gi alpha 2. G protein alpha-subunits were also quantified by immunoblotting. Rats were treated with ramipril (Ram, 10 mg/kg per day p.o.) during weeks 7 to 12 to induce regression of LVH or with vehicle (Veh, tap water).Pressure overload induced severe LVH (3.2 +/- 0.09 g/kg in Veh vs. 1.8 +/- 0.03 in sham; P0.05) which was significantly reduced by ramipril (2.7 +/- 0.09; P0.05 vs. Veh). In-vivo left ventricular function and diameters were unchanged in LVH. In contrast, in hearts with LVH, responsiveness of left ventricles to forskolin was attenuated and basal, GTP gamma S and forskolin as well as manganese chloride-stimulated adenylyl cyclase activity was significantly downregulated by approximately 40% (basal 20.8 +/- 1.9 pmol cAMP/mg per min vs. 34.0 +/- 2.2 in sham; P0.01). However, no significant changes of AC type V mRNA were found in hypertrophied left ventricles. Functional activity of the stimulatory G protein Gs was reduced in LVH (48 +/- 7 pmol cAMP/mg per min in Veh vs. 68 +/- 3 in sham), whereas mRNA expression of long and short Gs alpha-isoforms was not altered and that of Gi alpha 2 was only slightly increased in ramipril-treated animals. Western analysis showed no significant differences of Gs alpha or Gi alpha 2 subunits. Long-term blockade of the renin-angiotensin system had no effect on the activity of the adenylyl cyclase system.Functional desensitization of adenylyl cyclase and stimulatory G protein occurred in rat adaptive LVH prior to the onset of severe left ventricular dysfunction which was not restored by ACE-inhibitor treatment. The desensitization seems not to be mediated by significant changes of mRNA expression of AC type V or abundance of regulatory G proteins.

Objective: In several forms of heart disease characterised by low cardiac output, activated neurohumoral systems including increased vasopressin plasma levels play a key role in the changes in cardiovascular function. The aim of this study was to test the hypothesis that under such conditions the central vasopressin system might also be altered, which could contribute to deranged cardiovascular control. Methods: Aortic stenosis was produced in 22 rats by placing a Silver clip (inner diameter 0.6 mm) on the ascending aorta. After 12 weeks, haemodynamic and hormonal measurements were performed, and vasopressin content was determined in 20 microdissected brain areas (micropunch technique). Twenty two sham operated rats served as controls. Results: Twelve weeks after placing the supravalvular clip, significant aortic stenosis was documented by left ventricular myocardial hypertrophy. Cardiac index was significantly reduced and the peripheral vascular resistance index was increased, while poststenotic aortic pressure was non-significantly decreased. Plasma renin concentration [6.8(SEM 0.9) ν 2.1(0.2) ngAI·ml−1·h−1in controls] and plasma vasopressin [32.9(12.5) ν 18.4(6.0) pg·ml−1] were significantly increased, while plasma and urinary noradrenaline remained unaltered. The vasopressin content was significantly altered in eight out of 20 brain areas investigated. Concerning the vasopressin producing hypothalamic nuclei, concentrations were increased in the paraventricular [7494(360) ν 4744(237) pg·mg−1 protein, P < 0.05] and suprachiasmatic [3613(170) ν 1784(197) pg·mg−1 protein, P < 0.01], but not in the supraoptic nuclei. Rats with aortic stenosis showed significantly raised vasopressin concentrations in the median eminence [25 186(1682) ν 37 367(1345) pg·mg−1 protein, P < 0.01], where the hormone is mainly concentrated in the hypothalamo-hypophysial tract. Vasopressin content was significantly decreased in locus coeruleus [49(5) ν 89(6) pg·mg−1 protein], which is known to be involved in modulation of sympathetic activity. Conclusions: As well as showing increased secretion of vasopressin into the blood with consecutive peripheral antidiuretic and vasoconstrictive effects, these data suggest an alteration in the central vasopressin system in aortic stenosis which might transmit cardiovascular effects by neuromodulation and neuroregulation.

Abstract Left ventricular hypertrophy in response to pressure overload may be modified by neurohumoral activation. To investigate the contribution of the renin-angiotensin system, we studied rats after banding of the ascending aorta that developed severe left ventricular hypertrophy associated with normal plasma renin but elevated cardiac angiotensin-converting enzyme (ACE) levels. Rats were treated with vehicle, ACE inhibitor (ramipril), angiotensin II type 1 receptor antagonist (losartan), or vasodilator (hydralazine) during weeks 7 through 12 after aortic banding. A significant regression of left ventricular mass index as determined by serial echocardiography was observed in ramipril- and losartan-treated groups during weeks 9 through 12 after banding, whereas hypertrophy further increased in vehicle- and hydralazine-treated groups. Twelve weeks after banding, relative left ventricular weights and myocyte widths were markedly increased in vehicle- and hydralazine-treated groups, whereas ramipril and losartan significantly reduced these parameters. In addition, molecular adaptations in left ventricular hypertrophy, such as upregulation of left ventricular atrial natriuretic peptide and downregulation of sarcoplasmic reticulum Ca 2+ -ATPase mRNA levels, were blunted by ramipril or losartan treatment. Hypertrophic regression was associated with reduced mortality in rats treated with ramipril (11%) and losartan (13%) versus hydralazine (20%) and vehicle (31%). Thus, the renin-angiotensin system may be involved in the maintenance of chronic left ventricular hypertrophy. Blockade of the system may result in regression of the hypertrophic phenotype and improve survival in rats despite persistent pressure overload.

Objective: The aim was to investigate the interrelation between pulsatile components (assessed by determination of aortic input impedance) and neurohormonal activation in chronic congestive heart failure. Methods: Aortic input impedance, plasma noradrenaline, renin, atrial natriuretic factor, and arginine vasopressin were measured in 20 patients with mild to moderate chronic congestive heart failure (coronary artery disease n=12, idiopathic dilated cardiomyopathy n=8). Results: Cardiac index [2.2(SEM 0.3) litre·min−1·m−2] and left ventricular ejection fraction [38(4)%] were reduced, and pulmonary wedge pressure was increased [21(2) mmHg]. Plasma concentrations of noradrenaline [462(62) pg·ml−1], renin [12(4) ng Al·ml·h−1], atrial natriuretic factor [408(64) pg·ml−1], and - to a slight degree - arginine vasopressin [1.1(0.3) pg·ml−1] were increased. Characteristic impedance Zc [80(6) dyne·s·cm−5) and relative oscillatory aortic input pressure power [10(1)%] - both reflecting the pulsatile components of left ventricular afterload - were within the normal range. There was no significant correlation between these variables and the degree of neurohormonal activation (r values: -0.05 to -0.35). Conclusions: The data show that in patients with mild to moderate chronic congestive heart failure there is no interrelationship between the degree of neurohormonal activation and pulsatile components of left ventricular afterload. This may indicate that in these stages of heart failure there are no trophic effects of stimulated neurohormonal systems on the physical properties of the great arteries.

We studied the role of the sympathetic nervous system and the renin angiotensin system for pressure induced left ventricular hypertrophy (LVH) in 135 rats with experimental supravalvular aortic stenosis (AS). We induced this condition by a silver clip on the ascending aorta, when body weight (BW) was 90 to 100 g. Sympathectomy by 6-OH-dopamine reduced LV norepinephrine content to less than 5%. The renin-angiotensin system was blocked by quinapril, which reduced serum angiotensin converting enzyme (ACE) activity to less than 5%. Aortic stenosis (LV peak systolic pressure 212 +/- 10 mm Hg) induced significant LVH with an increase of LV weight from 198 +/- 3 (sham) to 266 +/- 6 after 6 weeks and to 303 +/- 13 mg/100 g body weight after 12 weeks. Sympathectomy did not reduce LVH 6 weeks after induction of AS (260 +/- 6 mg/100 g body weight). Angiotensin converting enzyme inhibition initiated immediately after induction of AS did not alter the increase of LV mass after 6 weeks (250 +/- 7 mg/100 g body weight). Removing the silver clip 6 weeks after induction of AS resulted in a 90% regression of LVH after 6 more weeks. When ACE-inhibition was started after 6 weeks--ie, once LVH had developed--and maintained for another 6 weeks, an 80% regression of LVH was observed despite the persistent afterload elevation. Our findings of an afterload independent regression of LVH by ACE-inhibition emphasize an important role of the renin angiotensin system for the maintenance of pressure induced LVH.

We investigated effects of the first orally active atriopeptidase inhibitor UK 79300 (Pfizer Clinical Research, UK) on left ventricular hydraulic load in patients with congestive heart failure NYHA II and III. In our study, 6 patients received 200 mg and 4 patients received 400 mg of UK 79300, and 4 patients received placebo (controls). Before and 90 min after oral administration of UK 79300 or placebo aortic input impedance was assessed to characterize left ventricular hydraulic load. Plasma levels of atrial natriuretic peptide (ANP) significantly increased by 126% after 200 mg and by 141% after 400 mg of UK 79300, but remained unchanged in control patients. Mean arterial pressure and flow, resistive term, characteristic impedance and oscillatory aortic input pressure power showed minor changes without statistical significance on an intergroup comparison. We conclude that acute atriopeptidase inhibition by UK 79300 effectively increases endogenous ANP levels up to 2.5-fold. However, these changes were not accompanied by significant effects on left ventricular hydraulic load.

To test the efficacy of exogenous prostaglandins for vasodilator therapy in heart failure, we studied the effects of the prostacyclin-derivative iloprost (1.5-150 ng/kg/min) in seven conscious dogs before and after induction of heart failure by right ventricular pacing (250/min. 10 days). In healthy dogs, iloprost (150 ng/kg/min) decreased mean arterial blood pressure (MAP) (-45%) by a decrease in total peripheral resistance (TPR) (-55%), and increased cardiac output (CO) (+24%) and heart rate (HR) (+20%) with no effect on right atrial and pulmonary arterial pressures (RAP, PAP). Plasma norepinephrine (NE) (+47%), renin (+351%), and aldosterone (+126%) were increased. Urine flow (-70%) and Na excretion (-53%) were decreased. Iloprost (15 ng/kg/min) increased renal blood flow (RBF) (+29%), but did not change glomerular filtration rate (GFR). In dogs with heart failure, iloprost decreased arterial BP (-31%), TPR (-42%) and pulmonary vascular resistance (-28%) and increased CO (+29%), with no change in RAP and PAP. Plasma NE (+34%), renin (+385%), and aldosterone (+146%) were increased. RBF was unchanged. GFR (-24%) and filtration fraction (FF) (-30%) were decreased, as was urine flow (-65%). In experimental heart failure, iloprost is a potent arteriolar dilator, increasing CO with no preload effect. These beneficial effects are limited, however, by further neurohumoral activation and deterioration of renal function.

In a randomized single-blind cross-over trial, the efficacy of digoxin, angiotensin-converting enzyme (ACE) inhibition by quinapril, and their combination on exercise tolerance, heart size (echocardiography), and neurohumoral systems was investigated in 19 outpatients with congestive heart failure (CHF) New York Heart Association functional class II and sinus rhythm. Baseline therapy consisted of 25 mg hydrochlorothiazide and remained unchanged. After treatment with quinapril, exercise tolerance significantly increased (606 vs. 644 s, 2 p less than 0.03) and left ventricular end-diastolic dimension (63 vs. 58 mm, 2 p less than 0.03), mean arterial blood pressure (MABP, 100 vs. 92 mm Hg, 2 p less than 0.03) and plasma norepinephrine (NE) levels (378 vs. 323 pg/ml, 2 p less than 0.03) were significantly reduced. Digoxin increased resting systolic blood pressure (SBP 133 vs. 142 mm Hg, 2 p less than 0.03). Combined administration of both drugs significantly increased fractional shortening (24 vs. 28%, 2 p less than 0.03), reflecting the positive inotropic action of digoxin in combination with afterload reduction. However, there was no further increase in exercise tolerance. Our data suggest that early administration of ACE inhibitors may be beneficial in patients with mild CHF and sinus rhythm, although the magnitude of improvement was less substantial than that reported for patients with more severe CHF.

The aim of the present study was to investigate the contribution of the renin angiotensin system to maintenance of pressure overload left ventricular hypertrophy (LVH). Rats with fixed ascending aortic stenosis were treated with either vehicle (VEH, n = 36), hydralazine (HYD, 20 mg/kg/d, n = 35). ramipril (RAM, 10 mg/kg/d, n = 35), or losartan (LOS, 40 mg/kg/d, n = 16) during weeks 6–12 after banding. We have previously demonstrated that compared to sham (n = 36), VEH and HYD rats were characterized by a 1.8–1.9-fold increase of left ventricular to body weight ratios (LV/BW). whereas those aortic stenosis rats treated with RAM or LOS displayed a blunted increase of LV/BW (14-fold; p l 0.05, each vs. HYD). We now extend these observations demonstrating that myocyte cross sectional widths were increased by 150% in VEH and HYD rats (p l 0.001, vs. sham), whereas ramipril and losartan treatment resulted in myocyte widths that were only mildly elevated (53% and 28%, respectively). Furthermore, VEH and HYD displayed a 14–15 fold increase of LV atrial natriuretic peptide (ANP) mRNA as well as a 44% decrease of sarcoplasmatic reticulum (SR) Ca2+-ATPase (p l 0.001, vs. sham). In contrast, alterations of ANP and SR-Ca2+-ATPase mRNA levels were significantly blunted by both RAM and LOS. The attenuation of LVH by RAM or LOS was not explained by blood pressure reduction that was similar in the HYD group. Finally, RAM and LOS decreased mortality (6 out of 51 animals; 11%)as compared to 20% in HYD and 31% in VEH groups (p l 0.05). In summary, blockade of the renin angiotensin system may promote regression of pressure overload LVH on the macro-, and microscopical, as well as the molecular level by mechanisms that are, in part, independent of hemodynamic drug effects. LVH regression may improve survival despite persisting pressure overload.