[Typical laboratory constellation of a non-ST-segment elevation myocardial infarction in polymyositis]. / Typische laborkonstellation eines nicht ST-hebungsinfarkts bei polymyositis.

HISTORY AND ADMISSION FINDINGS: a 80-year-old women was admitted with a hypertensive crisis. Laboratory tests showed elevated cardiac enzymes (CK, CK-MB and troponin T). She was treated for suspected non-ST segment elevation myocardial infarction. INVESTIGATIONS: a cardiovascular examination, which included echocardiography, coronary angiography and magnetic resonance imaging, excluded a cardiac cause of the laboratory reults. After complete assessment the patient was found to have long-standing polymyosits positive for Mi-2 antibodies. This had caused troponin T elevation from the release of regenerating muscles after chronic inflammatory damage. Troponin I, however, is truly cardiomyocyte specific and distinguishes between cardiac and non cardiac origin of CK, CK-MB and troponin T. TREATMENT AND COURSE: prednisone medication was started with a single dose of 50mg, then gradually reduced. Follow-up examination merely revealed minimally active polymyositis. CONCLUSION: troponin I should be measured in patients with inflammatory myositis/myopathies in order to diagnose and assess cardiac involvement.

The PPAR-gamma agonist rosiglitazone facilitates Akt rephosphorylation and inhibits apoptosis in cardiomyocytes during hypoxia/reoxygenation.

BACKGROUND AND AIM: Results on the cardiovascular effects of PPAR-gamma agonists are conflicting. On one hand, it was suggested that the PPAR-gamma agonist rosiglitazone may increase the risk of cardiovascular events. On the other hand, PPAR-gamma agonists reduce myocardial infarct size and improve myocardial function during ischemia/reperfusion in animal studies in vivo. However, the mechanism of this effect is unclear, and it is open if PPAR-gamma agonists have a direct effect on cardiac myocyte survival in ischemia/reperfusion. The aim of this study was to determine the effect of the PPAR-gamma agonist rosiglitazone on hypoxia/reoxygenation-induced apoptosis of isolated cardiomyocytes. METHODS: Isolated rat cardiac myocytes were pretreated with rosiglitazone or vehicle for 30 min before they were subjected to hypoxia for 4 h followed by different times of reoxygenation (5 min to 12 h). Apoptosis was determined by in situ hybridization for DNA fragmentation (TUNEL) as well as detection of cytoplasmic accumulation of histone-associated DNA fragments by enzyme-linked immunosorbent assay (ELISA). Activation of apoptosis regulating intracellular signalling pathways was studied by immunoblotting using phosphospecific antibodies. RESULTS: Rosiglitazone significantly reduced apoptosis of isolated cardiomyocytes subjected to hypoxia/reoxygenation, independently determined with two methods. After 4 h of hypoxia and 12 h of reoxygenation, 34 +/- 3.6% of the vehicle treated cardiac myocytes stained positive for DNA fragmentation in the TUNEL staining. Rosiglitazone treatment reduced this effect by 23% (p < 0.01). Even more pronounced, cytoplasmic accumulation of histone-associated DNA fragments detected by ELISA was reduced by 35% (p < 0.05) in the presence of rosiglitazone. This inhibition of hypoxia/reoxygenation-induced apoptosis was associated with an increased reoxygenation-induced rephosphorylation of the protein kinase Akt, a crucial mediator of cardiomyocyte survival in ischemia/reperfusion of the heart. This effect was reversed by GW-9662, an irreversible PPAR-gamma antagonist. However, rosiglitazone did not alter phosphorylation of the MAP kinases ERK1/2 and c-Jun N-terminal kinase (JNK). CONCLUSION: It can be concluded that cardiac myocytes are direct targets of PPAR-gamma agonists promoting its survival in ischemia/reperfusion, at least in part by facilitating Akt rephosphorylation. This effect may be of clinical relevance inhibiting the reperfusion-induced injury in patients suffering from myocardial infarction or undergoing cardiac surgery.

[Characteristics of patients with coronary ectasias with and without stenotic coronary artery disease]. / Charakterisierung der dilatativen Koronaropathie bei Patienten mit und ohne stenosierende koronare Herzkrankheit.

BACKGROUND AND OBJECTIVE: The term "coronary ectasia" describes the dilatation of one or more coronary artery segments with the signs of an impaired coronary blood flow. The prevalence, clinical significance and necessity of treatment of such a lesion is unclear. PATIENTS AND METHODS: Diagnostic coronary angiographies of 7101 patients (2131 women and 4970 men) were retrospectively evaluated for the presence of dilated coronary segments. Prevalence, age- and gender distribution, cardiovascular risk factors, clinical symptoms, CRP-concentrations, prevalence of myocardial infarction as well as the coronary morphology of patients with coronary ectasia were studied. The occurrence of myocardial infarction in this group was compared to that in a control group consisting of patients with stenotic coronary artery disease. RESULTS: The prevalence of coronary ecstasy was 1.4 % (women: 0.56 %; men: 1.79 %), mean age of patients was 63.5 +/- 10.5 years. The right coronary artery was most frequently involved (RCA: 97 %, LAD: 30 %, RCX: 23 %, LCA: 35 %). In patients with one-vessel disease the right coronary artery was exclusively affected. In 85.1 % the dilatation of coronary segments was associated with stenotic coronary artery disease. 73.3 % of the patients with coronary ectasias suffered from angina, 33.7 % CCS (Canadian Cardiovascular Society) class III and IV. Angina in patients with coronary ecstasy did not differ from that of patients with stenotic coronary artery disease only. Patients with coronary ectasias had a higher incidence of myocardial infarction than patients with stenotic coronary heart disease (p < 0.001). CONCLUSION: Coronary ectasia is a relatively rare entity and often associated with stenosis. Angina is a common symptom. Patients with coronary ectasias seem to suffer more frequently from myocardial infarctions than patients with only stenotic coronary heart disease.

[Systolic heart failure in the elderly]. / Die systolische Herzinsuffizienz des Alteren.

Aging is associated with changes in cardiac and vascular structure, promoting the development of heart failure. An increase in vascular stiffness leads to an increase of systolic arterial pressure and pulse wave velocity. This augments the afterload of the heart, which contributes to cardiac hypertrophy and neuroendocrine activation in the elderly. On the molecular level the age-associated changes in the sympathetic nervous system are similar to alterations that can be found in congestive heart failure. Therapy of systolic heart failure does not differ between the elderly and younger patients. All drugs which have shown to improve the prognosis of younger patients are indicated in the elderly as well. This holds true for ACE-inhibitors or angiotensin receptor antagonists, betablockers and aldosterone antagonists. However, comorbidities as well as changes in the pharmacokinetics and pharmacodynamics might require a cautious initiation of the therapy, an individual adjustment of the dosage and a thoroughly monitoring of the elderly patients.

Congenital dyserythropoietic anemia type III associated with congenital atrioseptal defect has led to severe cardiac problems in a 32-year-old patient.

We report the case of a 32-year-old woman who was admitted at hospital because of ortho-dyspnea, arrhythmia, and paleness. Clinical examination showed continuous arrhythmia, systolic heart murmur, enlargement of spleen and liver, and pathologic hematological parameters, thus indicating an intravasal hemolysis (elevated HBDH, bilirubin, and reticulocytes; reduced hemoglobin and haptoglobin levels), and bone-marrow-smears showed a typical cytomorphology of CDA III. The patient's diagnosis was heart failure caused by mitral valve insufficiency due to congenital atrioseptal defect associated with congenital dyserythropoietic anemia type III (CDA III).

Effects of endotoxin on human myocardial contractility involvement of nitric oxide and peroxynitrite.

OBJECTIVES: This study examined the effects of endotoxin on cardiac contractility in human myocardium. BACKGROUND: In animal myocardium, endotoxin and cytokine treatment led to enhanced inducible nitric oxide synthase (iNOS) expression and contractile dysfunction. Effects in human myocardium are unknown. METHODS: Left ventricular myocardial preparations from failing (n = 18) and nonfailing (n = 5) human hearts were incubated for 6 and 12 h in tyrode solution or in tyrode plus lipopolysaccharides (LPS), with LPS plus N(G)-mono-methyl-L-arginine (L-NMMA), with LPS plus hemoglobin or with LPS plus the superoxide scavenger 4,5-dihydroxy-1,3-benzene disulfonic acid (Tiron). Force of contraction in response to isoprenaline (0.001 to 3 micromol/liter) was determined in electrically stimulated muscle preparations. The iNOS mRNA expression was examined by in situ hybridization and by polymerase chain reaction. The cyclic guanosine monophosphate (cGMP) levels were determined by radioimmunoassay. RESULTS: Isoprenaline concentration dependently increased force of contraction. Six and 12 hours of LPS treatment of failing myocardium decreased maximum inotropic response to isoprenaline by 54% (p = 0.009) and by 69% (p = 0.0023), respectively. In nonfailing myocardium, 12 h of LPS treatment decreased maximum inotropic effect of isoprenaline by 66% (p < 0.001). The LPS effects were attenuated by L-NMMA, hemoglobin and also Tiron. The iNOS mRNA was expressed in all LPS-treated preparations but also in most control myocardial preparations. In situ hybridization revealed iNOS expression within cardiac myocytes. There was no increase in myocardial cGMP content in response to endotoxin. CONCLUSIONS: Endotoxin exposure of human myocardium leads to a depression of cardiac contractility, which is mediated by enhanced iNOS activity and release of nitric oxide (NO). Consecutive reaction of NO with superoxide and formation of peroxynitrite may contribute to the decrease in force of contraction.

Overexpression of the Na(+)-Ca2+ exchanger leads to enhanced inotropic responsiveness to Na(+)-channel agonist without sarcoplasmic reticulum protein changes in transgenic mice.

The present study investigated the influence of over-expression of the cardiac Na(+)-Ca2+ exchanger on myocardial force of contraction and alterations in sarcoplasmic reticulum (SR) Ca(2+)-handling proteins in a transgenic mouse model. Inotropic effects of Na+ channel agonist BDF 9148 and isoprenaline were determined in isolated electrically driven atria. Protein levels of key SR Ca(2+)-handling proteins were determined by Western blot analysis. Transgenic animals had no myocardial hypertrophy or failure. The positive inotropic effect of BDF 9148 was significantly more pronounced in myocardium for transgenic animals, whereas the inotropic response to isoprenaline was similar in both groups. Strong immunoreactivity of the transgene Na(+)-Ca2+ exchanger was detected in myocardium of transgenic animals. Protein levels of SR Ca(2+)-ATPase, phospholamban, and calsequestrin were unchanged. In conclusion, transgenic overexpression of the Na(+)-Ca2+ exchanger is accompanied by increased force development following Na+ channel agonist administration, even though Ca2+ proteins of the SR are unchanged.

Functional coupling of overexpressed beta 1-adrenoceptors in the myocardium of transgenic mice.

To assess functional and cellular effects of myocardial beta 1-adrenoceptor overexpression, alterations of the beta-adrenergic signal transduction pathway and contractile function in transgenic mice with atrial overexpression of the human beta 1-adrenoceptor were investigated. Radioligand binding experiments confirmed a 5- to 6-fold increase in beta-adrenoceptor density and a 2.7-fold increase in high-affinity binding sites in atria of transgenic mice. Dose-response curves for isoprenaline-induced force of contraction showed unchanged maximum effects but significantly increased pD2 values. Basal, MnCl2- and isoprenaline-stimulated adenylyl cyclase activities did not significantly differ, whereas the Gpp(NH)p and forskolin effect tends to be reduced in transgenic mice. The level of Gi alpha (pertussis toxin-catalyzed ADP-ribosylation) was unchanged, whereas the bioactivity of Gs alpha (reconstitution experiments into S49 cyc- cell membranes) was reduced by about 19% in the transgenic group. These results suggest that overexpressed beta 1-adrenoceptors act as functional spare receptors. In addition, increased beta 1-adrenoceptor density is associated with a decrease in Gs alpha-activity.

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.

Investigation of the negative inotropic effects of 17 beta-oestradiol in human isolated myocardial tissues.

1. The aim of the present study was to evaluate the effects of 17 beta-oestradiol in human myocardium. The effects of 17 beta-oestradiol, progesterone and testosterone on force of contraction were investigated in electrically driven isolated atrial trabeculae and ventricular papillary muscles from human hearts in the presence and absence of Bay K 8644, a calcium channel agonist. In addition, the effects of 17 beta-oestradiol, progesterone and testosterone on binding of [3H]-PN 200 110 were assessed in membranes prepared from human ventricular myocardium. 2. 17 beta-Oestradiol elicited a negative inotropic effect in atrial (IC50: 7.1 mumol 1(-1), confidence interval 3.8 to 13.4, n = 3) and ventricular preparations (IC50: 4.6 mumol 1(-1)), confidence interval 2.2 to 9.4, n = 3) as compared with solvent controls. There was no significant difference (P > 0.05) of IC50 values in the absence and presence of isoprenaline (0.0 mumol 1(-1)) in atrial (IC50: 10.8 mumol 1(-1), confidence interval 9.1 to 12.9, n = 6) and ventricular preparations (IC50: 9.4 mumol 1(-1), confidence interval 7.3 to 11.9, n = 8). 3. 17 beta-Oestradiol at 30 mumol 1(-1) induced a significant rightward shift of the concentration-response curves for the positive inotropic effect of Bay K 8644 in atrial preparations (EC50: 0.13 mumol 1(-1), confidence interval 0.08 to 0.19, n = 6; EC50 with 17 beta-oestradiol: 0.58 mumol 1(-1), confidence interval 0.33 to 0.83, n = 6, P < 0.05) and ventricular preparations (EC50: 0.07 mumol 1(-1), confidence interval 0.04 to 0.11, n = 8; EC50 with 17 beta-oestradiol: 0.3 mumol 1(-1), confidence interval 0.18 to 0.49, n = 8, P < 0.05). Testosterone, progesterone at 30 mumol 1(-1) and the solvent control had no significant effect on the concentration-response curves to Bay K 8644. 4. In membranes prepared from human ventricular myocardium the effect of 17 beta-oestradiol on binding of [3H]-PN 200 110, an antagonist at the 1,4 dihydropyridine binding site, was not different from that observed with progesterone, testosterone or solvent controls. 5. In myocardial membranes no specific oestrogen receptors were demonstrated by [3H]-oestradiol binding studies. 6. Thus, the calcium antagonistic property of 17 beta-oestradiol cannot be attributed to a direct interaction with 1, 4 dihydropyridine binding sites.

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.

Evidence against a role of nitric oxide in the indirect negative inotropic-effect of M-cholinoceptor stimulation in human ventricular myocardium.

Nitric oxide (NO) has been reported to mediate several effects in response to muscarinic cholinergic stimulation in cardiovascular tissues. Recently, an attenuation of guinea pig cardiac myocyte contraction by NO has been described. The aim of the present study was to determine whether the indirect negative inotropic effect of M-cholinoceptor stimulation in human myocardium is in part due to an effect of endogenous NO. Therefore, the effect of carbachol was studied under control conditions and during inhibition of NO-synthase by pretreatment with NG-monomethyl-L-arginine (NMMA). Functional experiments were performed in isolated, electrically driven (1 Hz, 37 degrees C) left ventricular papillary muscle strips of human myocardium. Since cytokines have been reported to be increased in the serum of patients with heart failure and could induce NO-synthase activity in failing myocardium, we compared samples from nonfailing and terminally failing (classified as NYHA IV) hearts. The indirect negative inotropic effect of carbachol (10 mumol/l) was studied in the presence of the beta-adrenoceptor agonist isoprenaline (0.03 mumol/l). After stimulation with isoprenaline, carbachol significantly (P < 0.05) reduced force of contraction. This effect was diminished in failing myocardium compared to nonfailing, probably due to the diminished inotropic response most likely due to the lower cAMP levels in response to beta-adrenoceptor stimulation in the former condition. Pretreatment with NMMA (100 mumol/l) altered the antiadrenergic effect of carbachol neither in nonfailing nor in failing preparations. Furthermore, inhibition of guanylyl cyclase, the target enzyme of NO, by preincubation with methylene blue (10 mumol/l) for 30 min had no effect on the carbachol-induced decrease in force of contraction.(ABSTRACT TRUNCATED AT 250 WORDS)