[Etiologic diagnosis and therapy of pericarditis and pericardial effusion].
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Diagnosis, Differential↗
Biomedical subjects
M Flesch
Publications and source records attributed to M Flesch.
Cardiac angiotensin II receptors: studies on functional coupling in Sprague-Dawley rats and TGR(alphaMHC-hAT1) transgenic rats.
The renin-angiotensin system plays an important role in the pathogenesis of cardiac hypertrophy and chronic heart failure as angiotensin II has been shown to induce cardiac hypertrophy and fibrosis. Besides these structural alterations, functional effects on cardiomyocytes have been reported in different mammalian species. Angiotensin II is known to produce a positive inotropic effect in some species, and differences in atrial and ventricular myocardium have been described. So far, the molecular events which govern angiotensin II-mediated changes in cardiac contractility are not completely understood. In order to study the dependency of the angiotensin II-induced positive inotropic effect on receptor density, we examined the effect of angiotensin II on cardiac function in atria, papillary muscles and isolated ventricular cardiomyocytes from adult Sprague-Dawley rats and TGR(alphaMHC-hAT1) transgenic rats, which expressed the human angiotensin AT1 receptor (hAT1) specifically in the heart. In atrial myocardium from adult Sprague-Dawley rats, angiotensin II (30 micromol/l) produced an AT1-mediated positive inotropic effect (38.5% of control), whereas in papillary muscles and isolated ventricular myocytes, no inotropic response was observed. As shown by polymerase chain reaction (PCR) and radioligand binding, the human angiotensin AT1 receptor was exclusively expressed in transgenic animals, which markedly overexpressed the angiotensin AT1 receptor. However, in transgenic rats the positive inotropic effect in atrial preparations was similar to the controls, and neither in papillary muscles nor in isolated cardiomyocytes the increase in receptor density led to an inotropic effect induced by angiotensin II. These data suggest that the existence of functionally uncoupled receptors rather than the low density of receptors at the ventricular site is responsible for the inability of ventricular myocardium to respond to angiotensin II.
1-Sarcosine-8-Isoleucine Angiotensin II↗
Angiotensin receptor antagonism and angiotensin converting enzyme inhibition improve diastolic dysfunction and Ca(2+)-ATPase expression in the sarcoplasmic reticulum in hypertensive cardiomyopathy.
BACKGROUND: Hypertensive cardiomyopathy is a major risk factor for the development of chronic heart failure. OBJECTIVE: To investigate whether treatment with an angiotensin converting enzyme inhibitor (ACEI) or with an angiotensin type 1 receptor antagonist (AT1-RA) is sufficient to prevent the development of hypertensive cardiomyopathy and cardiac contractile dysfunction. Special emphasis was placed on the effects of both treatments on sarcoplasmic reticulum Ca(2+)-ATPase (SERCA 2a) gene expression as a major cause of impaired diastolic cardiac relaxation. METHODS AND RESULTS: Eight-week-old rats harboring the mouse renin 2d gene [TG(mREN2)27] were treated for 8 weeks with 100 mg/kg captopril (Cap) in their food and 100 mg/kg of the AT1-RA Bay 10-6734 (Bay) in their food. Untreated TG(mREN2)27 and Sprague-Dawley rats (SDR) were used as controls. Both treatment regimens normalized the left ventricular weight, which was increased significantly (P < 0.001) in TG(mREN2)27. Both treatments normalized the left ventricular end-systolic and end-diastolic pressures, which were significantly (P < 0.001) higher in TG(mREN2)27 than they were in SDR, and they improved the velocity of the decrease in pressure [P < 0.05, Bay and Cap versus TG(mREN2)27]. Decreased left ventricular SERCA 2a mRNA and protein levels and increased atrial natriuretic peptide messenger RNA levels were normalized by Bay and Cap treatments (P < 0.05, Bay and Cap versus TG(mREN2)27, by Northern and Western blotting). According to radioimmunoassay and an enzyme assay, respectively, Bay, but not Cap, increased plasma angiotensin I concentrations and the renin activity above normal levels (P < 0.05), whereas myocardial angiotensin II concentrations (determined by radioimmunoassay), which were significantly (P < 0.05) increased in TG(mREN2)27, were normalized equally by Bay and Cap. CONCLUSIONS: In renin-induced hypertensive cardiomyopathy, left ventricular diastolic dysfunction occurs at the stage of compensated myocardial hypertrophy. The decreased left ventricular relaxation velocity might be due to reduced SERCA 2a gene expression. In this model of hypertensive cardiomyopathy, AT1-RA and ACEI treatments are similarly effective at reducing the arterial pressure, preventing myocardial hypertrophy and diastolic contractile dysfunction. Normalization of SERCA 2a gene expression, either by AT1-RA or by ACEI treatment, might contribute to the improvement in diastolic function.
Angiotensin I↗
Effects of the novel T-type calcium channel antagonist mibefradil on human myocardial contractility in comparison with nifedipine and verapamil.
Mibefradil (Ro 40-5967) is a novel nondihydropyridine calcium antagonist. The aim of our study was to compare the negative inotropic effects of the well-known 1,4-dihydropyridine nifedipine and the phenylalkylamine verapamil with those of mibefradil. Isometric force of contraction in response to these substances was determined in isolated, electrically driven left ventricular papillary muscle strips from failing human hearts (1 Hz, 37 degrees C). The hearts were obtained during cardiac transplantation (n = 9) and mitral valve-replacement operations (n = 9). The calcium antagonists studied significantly (p < 0.05) depressed basal force of contraction in a concentration-dependent manner. The effect started at concentrations > 0.001 microM for nifedipine and > 0.01 microM for verapamil, but only at concentrations > 10 microM for mibefradil. Only in the presence of nifedipine and verapamil was a significant rightward shift of the inotropic concentration--response curves to calcium and a depression of the maximal effects of calcium observed. With respect of the relation between the therapeutic active plasma concentration in vivo and the negative intropic potency in vitro, it became evident that the difference between therapeutically beneficial concentrations and potentially hazardous cardiodepressant activity increases from nifedipine to mibefradil. We conclude that this new generation of calcium antagonists, almost lacking cardiodepressant effects, could lead to a greater therapeutic index and greater safety in the treatment of cardiovascular diseases.
Benzimidazoles↗
Contractile systolic and diastolic dysfunction in renin-induced hypertensive cardiomyopathy.
The present study investigated whether functional, molecular, and biochemical alterations occurring in chronic heart failure can already be detected in compensated hypertensive cardiac hypertrophy. Force of contraction (isolated papillary muscle strip preparations), sarcoplasmic reticulum (SR) protein and myosin heavy chain isoform expression (Northern and Western blot analysis), myocardial fibrosis (collagen stains, hydroxyproline quantification), myocardial renin mRNA (RT-PCR), and angiotensin II levels and plasma aldosterone concentrations (radioimmunoassay) were studied in hypertrophied myocardium from transgenic rats harboring the mouse Ren-2d gene. Contraction and relaxation velocities of isolated papillary muscle strips were significantly reduced in cardiac hypertrophy. The beta-/alpha-myosin heavy chain ratio was significantly increased in the hypertrophied left ventricles, whereas SR Ca2+-ATPase (SERCA 2a) and phospholamban mRNA and protein levels were significantly decreased. The decrease in SERCA 2a was more pronounced than the decrease in phospholamban levels. There was no increased myocardial fibrosis. Left ventricular myocardial renin mRNA and angiotensin II concentrations, as well as plasma aldosterone levels, were higher in transgenic than in control rats. In hypertensive cardiac hypertrophy, myosin heavy chain isoform shift and reduction of SR protein levels are related to systolic and diastolic dysfunction, respectively. These alterations precede the development of myocardial fibrosis. Increased myocardial renin mRNA and angiotensin II concentrations suggest that an activated tissue renin-angiotensin system might contribute to these alterations. Since the alterations in compensated cardiac hypertrophy apparently precede those in chronic heart failure, they might accelerate the transition from hypertrophy to failure and could therefore be targets for pharmacological interventions.
Angiotensin II↗
Acute effects of nitric oxide and cyclic GMP on human myocardial contractility.
Evidence that the activity of nitric oxide synthase and the generation of nitric oxide (NO) within the myocardium are enhanced in several cardiovascular disorders is increasing. Findings whether NO exerts a direct effect on cardiac contractility are contradictory. Therefore, the direct effect of the NO donor sodium nitroprusside (SNP) on isometric force of contraction of human atrial and ventricular myocardium was investigated, and the question was addressed whether the effects of NO on cardiac contractility are mediated via cGMP. Experiments were performed on isolated electrically driven (1 Hz, 37 degrees C) human right atrial trabecula and left ventricular papillary muscle preparations from nonfailing and terminally failing hearts. SNP led to a concentration-dependent decrease of force of contraction (FOC) with a maximum effect at 100 micromol/l. In atrial trabecula, SNP (100 micromol/l) caused an acute decrease in basal FOC as well as in FOC after application of isoprenaline or IBMX by 12.5 +/- 5% (P < .05), 16.6 +/- 3.7% (P < .05) and 18.3 +/- 4.2% (P < .05), respectively. The negative inotropic effects could be attenuated by the guanylyl cyclase inhibitor methylene blue. In papillary muscle preparations, NO release caused a maximum decrease in basal and in isoprenaline-enhanced FOC of 11.0 +/- 1.9% (P < .05) and 23.6 +/- 1.5% (P < .05), respectively. In the presence of isoprenaline, the reduction of FOC was less pronounced in failing than in nonfailing papillary muscles. 8-bromo-cGMP caused a 38.2 +/- 5.2% decrease in atrial trabecula contractility. Both SNP and 8-bromo-cGMP caused a shortening of the contractile twitch with a premature onset of relaxation. As determined by radioimmunoassay, exposure of atrial trabecula to SNP (100 micromol) led to a 6-fold increase in myocardial cGMP concentrations, which could be attenuated by methylene blue. In conclusion, NO exerts a negative inotropic effect on human atrial and ventricular myocardium which seems to be mediated via generation of cGMP. The release of NO within the myocardium in a variety of cardiovascular disorders might explain decreases in cardiac contractility. The control of NO release could be an important target for future therapeutical interventions in these pathological conditions.
Cyclic GMP↗
Evidence for functional relevance of an enhanced expression of the Na(+)-Ca2+ exchanger in failing human myocardium.
BACKGROUND: The present study aimed at investigating the expression of the Na(+)-Ca2+ exchanger and its functional role in human failing myocardium. METHODS AND RESULTS: Na(+)-Ca2+ exchanger mRNA and protein levels were examined in nonfailing (NF, n = 8) and failing human myocardium (New York Heart Association functional class IV) with idiopathic dilated cardiomyopathy (DCM, n = 8) or ischemic heart disease (ICM, n = 6). The inotropic effect of the Na+ channel activator BDF 9148 was determined in electrically driven left ventricular papillary muscle strip preparations (1 Hz, 37 degrees C) from nonfailing (n = 8) and failing (n = 8) human hearts. Na(+)-Ca2+ exchanger mRNA levels were significantly increased, by 79% (P < .001) in DCM and by 58% (P < .01) in ICM compared with NF; protein levels increased by 36% (P < .001) and by 20% (P < .05), respectively. BDF 9148 increased the force of contraction concentration dependently, with a similar maximal effect in NYHA class IV and NF, but was more potent in NYHA class IV as demonstrated by a significantly smaller (P < .01) EC50 value (NYHA class IV, 0.18 [0.16 to 0.22] mumol/L; NF, 1.65 [1.3 to 3.0] mumol/L). In NYHA class IV, BDF 9148 (0.1 mumol/L) restored the positive force-frequency relationship and reduced the frequency-dependent increase in diastolic tension in relation to force of contraction. CONCLUSIONS: The increased expression of the Na(+)-Ca2+ exchanger is a possible explanation for the increased inotropic potency of the Na+ channel activator BDF 9148 in failing human myocardium. The increase in exchanger molecules could be of functional relevance for the modulation of cardiac contractility by agents that increase the intracellular Na+ concentration. Enhancement of Na(+)-Ca2+ exchanger activity might be a powerful mechanism for increasing cardiac contractility in chronic heart failure.
Adult↗
Functional relevance of an enhanced expression of the Na(+)-Ca2+ exchanger in the failing human heart.
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Calcium↗
Sarcoplasmic reticulum Ca2+ATPase and phospholamban mRNA and protein levels in end-stage heart failure due to ischemic or dilated cardiomyopathy.
Abnormalities in intracellular Ca2+ handling play a crucial role in the pathogenesis of heart failure. The reduced capacity of failing human myocardium to restore low resting Ca2+ levels during diastole has been explained by the impairment of Ca2+ uptake into the sarcoplasmic reticulum (SR) via the SR Ca2+ATPase. It is unclear whether Ca2+ATPase function, protein levels, and mRNA steady-state levels correspond to one other, and whether the cause of heart failure, namely idiopathic dilated or ischemic cardiomyopathy, produces different changes. The present study examined SR Ca2+ATPase activity and both mRNA and protein levels of SR Ca2+ATPase, phospholamban, and Gi alpha 2 in left ventricular myocardium from eight nonfailing hearts, from eight hearts of patients with idiopathic dilated cardiomyopathy (DCM), and from six hearts from patients with ischemic cardiomyopathy (ICM). Compared to nonfailing myocardium, the activity of the SR Ca2+ATPase was significantly reduced in failing myocardium from patients with DCM (36%, P < 0.01) and from patients with ICM (37%, P < 0.001). Significantly lower levels of SR Ca2+ATPase mRNA levels (55% and -56%, P < 0.001 for DCM and ICM, respectively) and phospholamban mRNA (45%, P < 0.001 for DCM; 31%, P < 0.05 for ICM) were observed in failing than in nonfailing myocardium. In contrast, no significant changes were observed at the level of proteins, Gi alpha 2 mRNA and protein levels were both significantly increased in failing myocardium. There were no differences between idiopathic dilated and ischemic cardiomyopathy concerning the examined parameter. It is concluded that reduced SR Ca2+ATPase activity contributes to an altered intracellular Ca2+ handling by the SR in both dilated and ischemic cardiomyopathic hearts. However, changes in SR Ca2+ATPase and phospholamban steady-state protein levels do not contribute to these alterations. The dissociation between protein and mRNA levels provides evidence for a posttranscriptional or post-translational regulation of these proteins. The observed alterations are not dependent on the underlying cause of end-stage heart failure.
Calcium↗
Role of G-proteins in altered beta-adrenergic responsiveness in the failing and hypertrophied myocardium.
In the heart and other tissues, beta-adrenergic desensitization occurs during treatment with catecholamines. In heart failure, a strong sympathetic activation has been observed and is the cause of beta-adrenergic desensitization in this condition. On the receptor level, there is a downregulation of beta 1-adrenergic receptors as well as an uncoupling of beta 2-adrenoceptors. The latter mechanism has been related to an increased activity and gene expression of beta-ARK2 in failing myocardium leading to phosphorylation and uncoupling of receptors. In addition, an increase of inhibitory G-protein alpha-subunits (Gi alpha) has been suggested to be causally linked to adenylyl cyclase desensitization in heart failure. In contrast, the catalytic subunit of adenylyl cyclase, stimulatory G-protein alpha-subunits and beta gamma-subunits have been observed to be unchanged. Recently, evidence has been raised that increases of Gi alpha also depress adenylyl cyclase in compensated cardiac hypertrophy in monogenic and polygenic as well as in secondary hypertension. These increases of Gi alpha can suppress adenylyl cyclase in the absence of beta-adrenergic receptor downregulation. Since cardiac hypertrophy in pressure overload is a strong predictor of cardiac failure these observations indicate that adenylyl cyclase desensitization by Gi alpha could be a pathophysiologically relevant mechanism to contribute to the progression from compensated cardiac hypertrophy to heart failure.
Animals↗
Changes in beta-adrenoceptors and G-proteins during the transition from cardiac hypertrophy to heart failure.
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Animals↗
[T3 hyperthyroidism with metastatic follicular thyroid carcinoma in substitution therapy].
This case report shows the anamnesis of a female patient with follicular Thyroidglandular-Ca. in an advanced stage with multiple metastases in the skeletal system, lungs and hilar lymph nodes. In addition, the patient showed a T3 hyperthyroidism with clinical symptoms but normal to low level of T4. After exclusion of hormone producing metastases as a reason for the hyperthyroidism, the most likely explanation would be an increased 5'-deiodination from T4 to T3.
Adenocarcinoma, Follicular↗
Effects of angiotensin II and angiotensin-converting enzyme inhibitors on human myocardium.
Human myocardial angiotensin II receptors and the angiotensin AT1 and AT2 receptor subtypes were characterised using the partial angiotensin II receptor agonist [125I][Sar1,IIe8]angiotensin II and the selective antagonists losartan (2-n-butyl-4-chloro-5-hydroxymethyl-1-[2'((1H-tetrazol-5-yl)biphen yl-4-yl)- methyl]imidazole) and PD 123177 (1-[(4-amino-3-methylphenyl)methyl]-5-(diphenyl-acetyl)- 4,5,6,7-tetrahydro-1H-imidazol[4,5-c]pyridine-6-carboxylic acid). The density of angiotensin II receptors was higher in atrial than in ventricular myocardium. Angiotensin AT2 receptors were predominant in atria and ventricles (80-85% of total angiotensin II receptors). Only in isolated, electrically driven atrial trabeculae but not in ventricular preparations, angiotensin II did produce a concentration-dependent positive inotropic effect, which was antagonized exclusively by the angiotensin AT1 receptor antagonist losartan and which amounted to about 20% of the positive inotropic effect of milrinone and isoprenaline. The application of the angiotensin-converting enzyme inhibitors captopril, enalaprilat and ramiprilat had no inotropic effect in either tissue. It is concluded that angiotensin AT1 receptors exclusively mediate direct positive inotropic effects in atrial myocardium. Since angiotensin-converting enzyme inhibitors do not produce any inotropic effect, tonic regulation of basal force of contraction by angiotensin II does not occur.
Adolescent↗
Unchanged protein levels of SERCA II and phospholamban but reduced Ca2+ uptake and Ca(2+)-ATPase activity of cardiac sarcoplasmic reticulum from dilated cardiomyopathy patients compared with patients with nonfailing hearts.
BACKGROUND: The aim of the present study was to investigate whether Ca2+ uptake into the sarcoplasmic reticulum (SR) is altered in failing human myocardium resulting from dilated cardiomyopathy. METHODS AND RESULTS: Ca(2+)-ATPase (SERCA II) activity and Ca(2+)-dependent 45Ca2+ uptake (oxalate supported, steady state) in isolated vesicles from the SR (VSR) and in crude membrane preparations (CSR) (free Ca2+, 0.01 to 100 mumol/L) from nonfailing (donor hearts, n = 13) and terminally failing (heart transplants, dilated cardiomyopathy, n = 17) human myocardium were studied. In the same hearts, protein levels (Western blot analysis) and mRNA levels (Northern blot analysis) of SERCA II and phospholamban were measured. Increasing concentrations of Ca2+ were followed by an increased Ca(2+)-ATPase activity and Ca2+ uptake. Ca2+ uptake activity and Ca(2+)-ATPase activity in CSR preparations from failing myocardium were significantly reduced compared with nonfailing hearts (Ca(2+)-ATPase, 163 +/- 8 and 125 +/- 7 nmol ATP/mg protein per minute for nonfailing tissue and failing tissue in New York Heart Association [NYHA] class IV, respectively; Ca2+ uptake, 7.1 +/- 0.8 and 3.5 +/- 0.3 nmol/mg protein per minute in CSR from nonfailing and NYHA class IV hearts, respectively P < .05). In contrast, no significant difference was measured in VSR. In the same preparations (CSR and VSR), both SERCA II and phospholamban levels (Western blot technique with monoclonal antibodies) were unchanged in failing compared with nonfailing tissue. mRNA expression relative to GAPDH mRNA for SERCA IIa and for phospholamban was significantly reduced in failing human myocardium (P < .05). CONCLUSIONS: These findings provide evidence that in failing human myocardium caused by dilated cardiomyopathy, protein levels of SERCA II and phospholamban are unchanged even though mRNA levels for SERCA II and phospholamban and the SERCA II function are reduced compared with nonfailing myocardium.
Adenosine Triphosphatases↗
Dose-dependent dissociation of ACE-inhibitor effects on blood pressure, cardiac hypertrophy, and beta-adrenergic signal transduction.
BACKGROUND: Dose-dependent effects of ACE inhibitors on blood pressure, cardiac hypertrophy, and beta-adrenergic signal transduction were examined in an animal model with beta-adrenergic desensitization, which has been identified in failing hearts and in hypertensive cardiac hypertrophy. It is unknown whether beneficial ACE-inhibitor effects are due to an unloading of the failing heart or a reduction of neuroendocrine activation with beta-adrenergic resensitization. METHODS AND RESULTS: Low-dose (LD, 1 mg/kg) and high-dose (HD, 25 mg/kg) fosinopril treatment was performed in spontaneously hypertensive rats (SHR) and control (WKY) rats. Myocardial norepinephrine concentrations, adenylyl cyclase activity, beta-adrenergic receptors (radioligand binding), Gs alpha (functional reconstitution), and Gi alpha (pertussis toxin labeling) were determined. Ventricular weights and blood pressures were measured. HD but not LD reduced blood pressure and left ventricular weights in SHR. Isoprenaline- and guanylylim-idodiphosphate-stimulated adenylyl cyclase activities as well as beta 1-adrenergic receptors were reduced in SHR. The catalyst and Gs alpha were unchanged, but Gi alpha and norepinephrine concentrations were increased. Both LD and HD treatments restored beta-adrenergic alteration. CONCLUSIONS: LD treatment with ACE inhibitors restored beta-adrenergic signal transduction defects independently of regression of cardiac hypertrophy. This could contribute to the effects of ACE inhibitors in patients, who are often treated with nonhypotensive doses.
Adenylyl Cyclases↗
[Nitric oxide as agent with cardio-depressive effect].
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Hemodynamics↗
Effects of TCV-116 and CV-11974 on angiotensin II-induced responses in vascular smooth muscle cells.
(+/-)-1-(Cyclohexyloxycarbonyloxy)ethyl 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H- benzimidazole-7-carboxylate (TCV-116, Candesartan) and its active metabolite 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H- benzimidazole-7-carboxylic acid (CV-11974) are specific nonpeptide angiotensin AT1 receptor antagonists. In the present study, the inhibitory potency of these two antagonists on the angiotensin II-induced responses in aortic vascular smooth muscle cells from Wystar Kyoto rats was investigated. The specific binding of 125I-angiotensin II to cells was inhibited by CV-11974 and TCV-116 with a half-maximal inhibitory concentration (IC50) of 3 x 10(-11) M and 1 x 10(-9) M, respectively. CV-11974 and TCV-116 inhibited the angiotensin II-induced increase in [3H]thymidine incorporation with an IC50 of 3 x 10(-10) and 5 x 10(-9) M, respectively. Both CV-11974 and TCV-116 (10(-7) M) completely blocked the angiotensin II-induced increase in c-fos mRNA. The inhibitory potency of the metabolite CV-11974 was about 30-100-fold higher than that of the prodrug TCV-116.
Angiotensin II↗
[Listeriosis in patients with malignant hemopathy. 3 cases in the same hospital ward].
During the listeriosis epidemic which occurred in France in the summer 1992, three patients with malignant haematopathies hospitalized in our service contracted the disease. Although the retrospective investigations were hindered by the variable incubation period and the impossibility of examining the foods eaten at the time of infection, there was a high probability that two of the patients had been infected by cooked ham and dairy products at home. The third patient was apparently infected in hospital with well-cooked food found to be contaminated. The hypothesis of coinfection has been raised.
Aged↗