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Biomedical subjects

B Maisch

Publications and source records attributed to B Maisch.

At least 181 records · Page 10Linked to original sources
PubMed1995

Left ventricular hemodynamic parameters in the course of acute experimental coxsackievirus B 3 myocarditis.

In susceptible DBA/2 mice coxsackievirus B 3-induced myocarditis leads to inflammatory and necrotic lesions in the myocardium 7-10 days after virus inoculation. The purpose of this study was to determine whether hemodynamic changes occur in murine coxsackievirus B 3 myocarditis and whether they are correlated to histological cardiac lesions throughout the infection. Left ventricular function was determined by open chest puncture of the left ventricle in the course of acute coxsackievirus B 3 infection. Histological cross sections of the heart were stained with hematoxylin/eosin and scored blindly for myocarditic lesions. Left ventricular function was preserved until day 7 post-virus inoculation Left ventricular systolic pressure, +dP/dtmax and -dP/dtmax and heart rate declined significantly from day 7 to day 10. The decrease in these parameters did not correlate with viral concentrations in the heart on the day of hemodynamic measurements. The decrease was related to histological changes on day 10, but not on day 7 of the infection. The data suggest (a) that a cumulative loss of cardiac myofibers, induced either by the virus and/or by immune reactions to the heart, is likely to lead to a late depression of cardiac function, and (b) that there is a weak and only temporary structure-function relationship in the heart in coxsackievirus B 3 myocarditis. Therefore, in addition to an analysis of histological changes, the measurement of cardiac function appears to be very important in order to completely evaluate the severity of myocarditis and the usefulness of any therapy.

Animals↗
PubMed1995

Hormonal regulation of cardiac fibroblast function.

In arterial hypertension or congestive heart failure, myocardial fibrosis is associated with an activated renin-angiotensin-aldosterone system (RAAS). This reactive fibrosis presents as an excessive accumulation of fibrillar collagen within the normal connective tissue structures of the myocardium in either ventricle, irrespective of its haemodynamic load. It therefore would appear that circulating (hormonal) and not haemodynamic factors are responsible for this adverse fibrous tissue response. The cardiac fibroblast expresses mRNA for types I and III collagens, the major fibrillar collagens in the heart, and for collagenase or matrix metalloproteinase 1 (MMP 1), the key enzyme for interstitial collagen degradation. Therefore, adult rat cardiac fibroblasts were cultured to ascertain whether the RAAS effector hormones angiotensin II (Ang II) or aldosterone (Aldo) directly stimulate collagen synthesis or inhibit MMP 1 production. Collagen synthesis, determined by 3H-proline incorporation and MMP 1 activity determined by degradation of 14C-collagen, were measured under serum-free conditions in confluent, quiescent fibroblasts after 24 h incubation with Ang II or Aldo over a wide range of concentrations (10(-11) -10(-6) M). In addition, collagen synthesis was measured after incubation with the mineralocorticoid, dexoycorticosterone (DOC), or the prostaglandin, PGE2. Collagen synthesis, normalized per total protein synthesis, increased significantly in a dose-dependent manner after incubation with either mineralocorticoid hormone, Aldo or DOC, or after incubation with Ang II compared with untreated control cells. In contrast, collagen synthesis was significantly decreased with PGE2 treatment. This increase in collagen synthesis in Ang II or mineralocorticoid-stimulated fibroblasts could be completely abolished by Ang II type 1 or mineralocorticoid receptor antagonists, respectively. (ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Directions in antihypertensive treatment--our future from the past.

Future directions in antihypertensive treatment will rely on our present experience with antihypertensive drugs, on new concepts of cardiovascular regulation and on novel antihypertensive agents. At present, we seek early detection of hypertension; treatment should focus on normalization of blood pressure, the reversal or prevention of left ventricular hypertrophy, associated coronary artery disease and on the prevention of, or reparation of, myocardial fibrosis and microangiopathy. Therefore, combination therapy is advisable in severe cases, and any monotherapy should focus on the pharmacological principles compatible with these goals. ACE inhibitors and calcium antagonists appear to meet these requirements. There are, in addition, novel drugs i.e. angiotensin II receptor antagonists and renin inhibitors, as well as therapeutic stimulation of endothelial nitric oxide by L-arginine, the inhibition of endothelin-1 mediated vasoconstriction, and potassium-channel openers. All are examined in this contribution to delineate the perspectives in antihypertensive therapy.

Antihypertensive Agents↗
PubMed1995

The renin-angiotensin-aldosterone system and myocardial collagen matrix remodelling in congestive heart failure.

In chronic heart failure, various regulatory systems including the Frank-Starling mechanism, the neuro-hormonal response, cardiac growth and peripheral oxygen delivery may be operative. Recently, the inter-relationship of the renin-angiotensin-aldosterone system (RAAS) and cardiac growth has drawn clinical interest. In the pressure-or volume-overloaded heart, the development of myocyte growth is primarily dependent on ventricular loading. Non-myocyte cell growth involving cardiac fibroblasts may also occur but this is not primarily regulated by the haemodynamic load. Cardiac fibroblast activation is responsible for the accumulation of fibrillar type I and type III collagens within the interstitium and adventitia of intramyocardial coronary arteries. In addition to relaxation abnormalities due to impairment of sarcoplasmic Ca(2+)-ATPase activity, this remodelling of the cardiac interstitium represents a major determinant of pathological hypertrophy in that it accounts for abnormal myocardial stiffness, leading to ventricular diastolic and systolic dysfunction and ultimately the progression of symptomatic heart failure. The effector hormones of the RAAS, angiotensin II (AngII) and aldosterone (Aldo), appear to be primarily involved in promoting the adverse structural remodelling of the myocardial collagen matrix. In cultured adult cardiac fibroblasts, AngII and Aldo have been shown to stimulate collagen synthesis while AngII additionally inhibits matrix metalloproteinase I activity, which is the key enzyme for degradation of fibrillar collagen in the cardiac interstitium, leading to excessive collagen accumulation. These findings may serve as rationale as to why angiotensin converting enzyme inhibition or blockade of the RAAS represents such remedial therapy beyond the effect of simply unloading the heart in patients with congestive heart failure.

Adult↗
PubMed1995

Immunosuppressive treatment for myocarditis and dilated cardiomyopathy.

This overview examines the immunological rationale for immunosuppressive and immunomodulating therapy in man and experimental animals. The controversy of whether immunosuppressive treatment is beneficial in myocarditis will continue even after the Myocarditis Treatment Trials has been published. It is known that in viral heart disease immunosuppressive drugs should be avoided, but in autoreactive forms of myocarditis with proven humoral and cellular effector mechanisms they may be used in controlled randomized trials to validate or refute their benefit. Immunomodulating factors, e.g. immunostimulatory or antiviral substances such as ribaverin, the interleukins and interferons have demonstrated some effect in experimental animal myocarditis but proof of their benefit in man is still lacking. Hyperimmunoglobulin therapy appears to be of particular interest because it incurs few side effects and has positive results in cytomegalovirus-associated myopericarditis in man and suspected myocarditis in children.

Adjuvants, Immunologic↗
PubMed1995

The European Study of Epidemiology and Treatment of Cardiac Inflammatory Disease (ESETCID).

Diagnosis of myocarditis has improved with the application of new techniques such as immunohistochemistry, polymerase chain reaction, in situ hybridization and Southern blot in endomyocardial biopsies. Treatment of inflammatory heart disease is still difficult and not yet validated by a study with patient numbers sufficient to allow statistical analysis. The European Study of Epidemiology and Treatment of Cardiac Inflammatory Disease (ESETCID) addresses problems of aetiology, pathogenesis and specific treatment of myocarditis. It is the first multicentre, double-blind placebo-controlled randomized study, apart from the Myocarditis Treatment Trial, to discriminate between different forms of myocarditis. Patients with cytomegalovirus-induced myocarditis are treated by hyperimmunoglobulin compared to placebo. Patients with enterovirus-positive myocarditis will receive interferon alpha vs placebo. Patients with virus-negative myocarditis, which is considered autoimmune, will be treated with immunosuppression compared to placebo. The primary endpoint of this study is an improvement in ejection fraction of more than 5%. This trial may give a better understanding of the course of myocarditis, leading to more specific treatment which may in turn reduce the number of patients with post-myocardial heart muscle disease who require heart transplantation as a final therapeutic remedy.

Autoimmune Diseases↗
PubMed1995

Left ventricular haemodynamics in murine viral myocarditis.

In susceptible DBA/2 mice infection with coxsackievirus B3 leads to severe inflammatory and necrotic lesions in the heart. There is a temporal discrepancy of peak concentrations of replicative virus in the heart and maximal cardiac inflammation. Aims of this study were, first, to determine whether haemodynamic changes occur in coxsackievirus B3-induced murine myocarditis and, second, the time frame in which those alterations may be apparent. By puncture of the left ventricle, pressures and the first derivative dp/dt as parameters of left ventricular function could be obtained on several days of the infection. Haematoxylin-eosin stains of cross-sections of the heart showed the course of inflammatory lesions in the heart; a plaque forming assay assessed virus titres in the heart. Cardiac concentrations of replicative virus peaked on day 3, inflammatory lesions in the heart were maximal on day 7. Left ventricular function was almost preserved until day 5 of the infection, then dropped significantly until day 10. The study suggests that either a cumulative virus-mediated destruction of the myofibres or virally triggered immune reactions to heart cells lead to impairment of left ventricular function.

Animals↗
PubMed1995

Cytomegalovirus-associated heart muscle disease.

Human cytomegalovirus (CMV) can persist in many organs after primary infection. Not only is it suspected to cause morbidity during reactivation in patients under immunosuppression, but it may also induce long-term latency by chronic disease, e.g. in the myocardium. Endomyocardial biopsies of 27 patients with active myocarditis, 35 patients with healing, 41 patients with healed and 25 patients with ongoing myocarditis according to the Dallas Criteria and 52 patients with dilated cardiomyopathy (DCM) and the biopsies of 25 healthy heart donors were studied for persisting CMV-DNA by polymerase chain reaction (PCR) and in-situ hybridization (ISH). CMV-DNA could be assessed in 5-14% of patients in the different stages of myocarditis and in 22% of patients with DCM. Although two biopsies of the control group showed a positive result, studies by in-situ hybridization demonstrated that in patients with heart muscle disease CMV persists in all cell types including myocytes, whereas in the controls it is only found in interstitial cells. CMV antigens could not be detected in the myocardium with our methods. It must be assumed that infection by CMV is more a persistent or latent than an active infection.

Adult↗
PubMed1995

Characterization of relevant membrane antigens by two-dimensional immunoblot and n-terminal sequence analysis in patients with myocarditis.

In myocarditis an antigen-specific immune response to cardiac epitopes has been demonstrated by several investigators. In 25 patients with histologically proven myocarditis, autoantibodies to cardiac tissue were observed in 65% by immunofluorescence assay. By immunoblot analysis 46% of sera reacted with cardiac tissue. These antibodies were preferentially directed against proteins with molecular weights of 43 and 67 kDa. Many of these antibodies have been demonstrated to be cytolytic to isolated cardiocytes in vitro. However, their corresponding antigens on heart muscle cells still remains unclear. To characterize the epitopes recognized by the autoantibodies, isoelectric focusing followed by SDS-PAGE was used to separate the complex mixture of proteins from human heart. Immunoblot analysis of antigens revealed proteins in the range of 30-67 kDa at isoelectric points of 6.5-8.5 to be of particular interest. Five of these proteins were identified by immunoblot analysis and two were identified by n-terminal sequence analysis (Edman Degradation) as creatine kinase and a sarcomeric isoenzyme. As creatine kinase is an intracellularly located enzyme, the pathogenetic role of the autoantibodies directed against it remains to be elucidated further.

Adult↗
PubMed1995

Comparative study on the effects of intracoronary nicorandil and nitroglycerin in ischaemic, reperfused porcine hearts.

The direct cardioprotective properties of nitroglycerin and nicorandil were compared in regionally ischaemic (45 min), reperfused (24 h) porcine hearts. Intracoronary treatments, which were started 15 min prior to occlusion of the distal left anterior descending coronary artery (LAD), were continuously administered for 105 min. The following equi-hypotensive drug dosages were used in nine pigs each; nitroglycerin 6 micrograms.kg-1 x min before ischaemia and during 45 min of reperfusion, 0.6 microgram.kg-1 x min during ischaemia; nicorandil 5 micrograms.kg-1 x min before ischaemia and during 45 min of reperfusion, and 0.5 microgram.kg-1 x min during ischaemia. Nine control animals were treated with isotonic sodium hydrochloride solution (1 ml.min-1). Despite comparable effects on blood pressure, intracoronary nicorandil, in contrast to intracoronary nitroglycerin, did not increase heart rate. Although neither drug affected coronary blood flow significantly, nicorandil substantially reduced regional myocardial oxygen consumption before coronary artery occlusion (-37 +/- 22%, P = 0.003 vs control group, P = 0.01 vs nitroglycerin treatment). Infarct sizes (tetrazolium method) after 45 min of ischaemia and 24 h of reperfusion were significantly decreased by nicorandil (control group 76.9 +/- 19%, nicorandil group 49.3 +/- 24%, P = 0.012) whereas nitroglycerin exhibited a borderline effect (62.5 +/- 15%, P = 0.054). Both treatments resulted in improved regional systolic shortening of the reperfused segment at the end of the experiments but this was not significant. At these drug dosages the direct cardioprotective action of nicorandil is slightly superior to nitroglycerin. This may be ascribed to its K-channel opening property associated with reduced regional myocardial oxygen consumption before the onset of ischaemia.

Animals↗
PubMed1995

Effects of R56865, an Na(+)- and Ca(2+)-overload inhibitor, on myocardial injury in ischemic, reperfused porcine hearts.

The cardioprotective effect of R56865, an Na(+)- and Ca(2+)-overload inhibitor, was studied in 20 regionally ischemic reperfused (I/R) porcine hearts. Ten pigs were treated with a single intravenous (i.v.) injection of 0.4 mg/kg 15 min before occlusion of the distal left anterior descending coronary artery (LAD) for 45 min. Ten other animals served as controls. Infarct size (IS) was determined as percentage of infarcted (tetrazolium method) to ischemic (dye technique) myocardium after 24-h reperfusion. Regional systolic shortening (SS) was determined by sonomicrometry. Fifteen minutes after i.v. administration of R56865, a significant decrease in heart rate (HR) (from 83 +/- 15 to 74 +/- 16 beats/min), dP/dtmax (from 2,033 +/- 604 to 1,822 +/- 524 mm Hg/s), LAD blood flow (BF, from 17 +/- 7 to 14 +/- 7 ml/min), and calculated global myocardial O2 consumption (MVO2) (from 5.9 +/- 0.9 to 5.4 +/- 0.9 ml O2/min x 100 g) was observed. Although this investigational drug attenuated the increase in HR during early reperfusion, the incidence of ventricular fibrillation (VF) was not affected during either ischemia or reperfusion. R56865 reduced IS by 24% from 67.1 +/- 16% (control group) to 50.8 +/- 13%. In addition, this treatment improved systolic shortening after 24-h reperfusion from 6 +/- 8% (control group) to 15 +/- 9%. Our results support the concept that inhibition of intracellular Na(+)- and Ca(2+)-overload is a promising new principle in treatment of myocardial I/R.

Animals↗
PubMed1995

Invasive electrophysiological evaluation of patients with sleep apnoea-associated ventricular asystole-methods and preliminary results.

Twelve patients (aged 48 +/- 12 y) with ventricular asystole of >3 s due to complete atrioventricular (AV) block (n = 8), sinoatrial (SA) block or sinus node arrest (n = 3) or both (n = 1) associated with obstructive sleep apnoea underwent invasive electrophysiological evaluation of sinus node function and AV conduction properties before and after administration of atropine (0.02 mg kg-1). Ventricular asystole lasted for 5.9 +/- 2.8 s (range 3.1-13 s). Sinus node function was assessed by measurement of sinus node recovery time, sinoatrial conduction time, and the response of sinus rate to atropine. Parameters of AV-conduction assessment included AH- and HV-intervals, AV- and VA-Wenckebach periods, and effective refractory period of the AV node before and after atropine. Sinus node function was normal in 11 of the 12 study patients and moderately abnormal in 1 patient. AV-nodal function was normal in 8 patients and moderately abnormal in 4 patients. A slightly prolonged HV-interval (59-63 ms) was present in 6 patients. Intra- or infra His block was not observed in any patient. In conclusion, normal or only moderately abnormal electrophysiological findings in patients with sleep apnoea-associated ventricular asystole suggest that a neurally mediated cardioinhibitory reflex may cause ventricular asystole in these patients. This sleep apnoea-triggered 'vasovagal' reflex may unmask pre-existing mild to moderate structural abnormalities of the AV conduction system.

Journal Article↗
PubMed1995

[Cardiac structure-function relationship and the renin-angiotensin-aldosterone system in hypertensive heart disease].

Based on the epidemiologic data of the Framingham heart study, arterial hypertension and coronary artery disease are the most frequent etiologic factors for the development of heart failure. In the pressure overloaded heart, hypertrophic growth of the myocardium includes the enlargement of cardiac myocytes stimulated by ventricular loading. Non-myocyte cell growth involving cardiac fibroblasts may also occur but is not primarily regulated by the hemodynamic load. Cardiac fibroblast activation is responsible for the accumulation of fibrillar type I and type III collagens within the interstitium while vascular smooth muscle cell growth accounts for the medial thickening of resistance vessels. This remodeling of the cardiac interstitium represents a major determinant of pathological hypertrophy in that it accounts for abnormal myocardial stiffness and impaired coronary vasodilator reserve, leading to ventricular diastolic and systolic dysfunction and ultimately to the appearance of symptomatic heart failure. Several lines of evidence suggest that the renin-angiotensin-aldosterone system is involved in regulating the structural remodeling of the nonmyocyte compartment, including the cardioprotective effects of angiotensin converting enzyme (ACE) inhibition that was found to prevent myocardial fibrosis in the rat with renovascular hypertension. In rats with genetic hypertension, established left ventricular hypertrophy, abnormal diastolic stiffness due to interstitial fibrosis, and reduced coronary vasodilator reserve associated with medial wall thickening of intramyocardial resistance vessels, the ACE inhibitor lisinopril was able to restore myocardial structure and function to normal. These cardioreparative properties of ACE inhibition may be valuable in reversing left ventricular dysfunction in hypertensive heart disease.

Animals↗
PubMed1995

Pharmacological modulation of cardiac fibroblast function.

The cardiac interstitium is composed of nonmyocyte cells and a structural protein network which plays a dominant role in governing the structure, architecture, and mechanical behavior of the myocardium. The heterogeneity in myocardial structure, created by the altered behavior of nonmyocyte cells, particularly cardiac fibroblasts which are responsible for myocardial collagen metabolism and fibrous tissue accumulation, may largely explain the appearance of diastolic and/or systolic myocardial failure. Regulatory mechanisms that are related to the fibrous tissue response in various cardiovascular diseases, e.g., hypertensive heart disease, dilated cardiomyopathy or post myocardial infarction, are of primary clinical interest. A better understanding of the hitherto neglected role of cardiac fibroblasts in mediating an adverse structural remodeling of the myocardium will lead to specific pharmacologic agents that interfere with the fibrous tissue response. Several lines of evidence based on in vivo and in vitro studies suggest that circulating and tissue renin-angiotensin-aldosterone systems (RAAS) are involved in the structural remodeling of the nonmyocyte compartment, including the cardioprotective effects of angiotensin converting enzyme (ACE) inhibition or aldosterone receptor antagonism that was found to prevent myocardial fibrosis in the rat with renovascular or genetic hypertension. In cultured adult cardiac fibroblasts, an angiotensin (Ang)II- or aldosterone-mediated dose-dependent increase in collagen synthesis could be completely abolished by the use of AngII type 1 or mineralocorticoid receptor antagonists, respectively. Likewise, the AngII-mediated decrease in the activity of matrix metalloproteinase 1, the key enzyme for interstitial collagen degradation, could be antagonized by AngII receptor blockade.(ABSTRACT TRUNCATED AT 250 WORDS)

Aldosterone↗