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M Schlepper

Publications and source records attributed to M Schlepper.

At least 19 recordsLinked to original sources
PubMed2000

Increased expression of cytoskeletal, linkage, and extracellular proteins in failing human myocardium.

Experimental studies have shown that in hypertrophy and heart failure, accumulation of microtubules occurs that impedes sarcomere motion and contributes to decreased ventricular compliance. We tested the hypothesis that these changes are present in the failing human heart and that an entire complex of structural components, including cytoskeletal, linkage, and extracellular proteins, are involved in causing functional deterioration. In explanted human hearts failing because of dilated cardiomyopathy (ejection fraction </=20%), expression of alpha- and beta-tubulin, desmin, vinculin, fibronectin, and vimentin was determined by Northern and Western blot analysis and compared with normal myocardium from explants not used for transplantation. The mRNA for alpha- and beta-tubulin was increased to 2.4-fold (P<0.01) and 1.25-fold (NS), respectively; for desmin, 1.2-fold (P<0.05); for fibronectin, 5-fold (P<0.001); and for vimentin, 1.7-fold (P<0.05). Protein levels for alpha-tubulin increased 2.6-fold (P<0.02); for beta-tubulin, 1.2-fold (P<0.005); for desmin, 2.1-fold (P<0.001); for vinculin, 1.2-fold (P<0.005); for fibronectin, 2.9-fold (P<0.001); and for vimentin, 1.5-fold (P<0. 005). Confocal microscopy showed augmentation and disorganization of all proteins studied. In combination with the loss of myofilaments and sarcomeric skeleton previously reported, these changes suggest cardiomyocyte remodeling. Increased fibronectin and elevated interstitial cellularity (vimentin labeling) indicate progressive fibrosis. The present results suggest a causative role of cytoskeletal abnormalities and myofilament loss for intrinsic contractile and diastolic dysfunction in failing hearts.

Adult↗
PubMed1998

Assessment of myocardial viability: Dobutamine echocardiography and thallium-201 single-photon emission computed tomographic imaging predict the postoperative improvement of left ventricular function after bypass surgery.

The aim of this study was to evaluate the usefulness of dobutamine echocardiography and quantitative thallium-201 single photon emission computed tomography myocardial scintigraphy with reinjection in the detection of viable myocardium in patients with coronary artery disease and reduced left ventricular function, which will improve after aortocoronary bypass surgery. Forty-eight patients (47 men, aged 61 +/- 6 years) with angiographically documented reduced left ventricular function (ejection fraction 35 +/- 14, 63% with chronic transmural myocardial infarction) were examined by dobutamine two-dimensional echocardiography (before and during low dosage), 201Tl, and gated radionuclide ventriculography before and 3 +/- 2 months after aortocoronary bypass surgery. Four of 55 areas classified viable before operation were revascularized inadequately and discarded. Global left ventricular ejection fraction at rest rose from 35% +/- 14% before operation to 40% +/- 13% (p < 0.05) after operation. Stress-induced perfusion defects involved 40% +/- 19% of the left ventricle circumference after stress and showed a significant reduction of size to 23% +/- 14% (p < 0.01) at rest, 4 hours later, and after reinjection. This value fell to 16% +/- 12% (p < 0.05) 3 months after aortocoronary bypass surgery. We conclude that both dobutamine echocardiography (sensitivity 95%, specificity 80%, positive predictive value 87%, negative predictive value 88%) and 201Tl studies (sensitivity 87%, specificity 98%, positive predictive value 97%, negative predictive value 93%) are suitable and comparable accurate methods for predicting improvement in systolic function 3 months after revascularization in a selected population with a high prevalence of viable but hypokinetic or akinetic myocardium.

Aged↗
PubMed1998

The extracellular matrix in hibernating myocardium--a significant factor causing structural defects and cardiac dysfunction.

Recently, we described chronic intracellular degeneration accompanied by fibrosis as typical structural features of hibernating myocardium and we concluded that cellular degeneration as a sign of the incomplete adaptation to the reduced blood flow is characteristic of hibernation. This study has been extended by analyzing the composition of the extracellular matrix proteins of the diseased myocardium. Areas of hibernating myocardium were identified in 38 patients by angiography, multigated radionuclide ventriculography, thallium scintigraphy with reinjection and low-dose dobutamine echocardiography. These areas were biopsied at cardiac surgery and were studied by electron microscopic and immunofluorescence techniques. Electron microscopy showed an enlarged extracellular space containing numerous particles of cellular debris, macrophages, fibroblasts, homogeneous matrix material and collagen fibrils. The basement membrane of the cardiomyocytes was thickened by an augmentation of laminin, fibronectin and collagen VI, but these proteins also were present in the matrix itself. Collagen fibrils were numerous and macrophages (CD68) and fibroblasts (vimentin) were increased. In situ hybridization showed an increase in mRNA for laminin, fibronectin and collagen. This observation is consistent with the conclusion that fibrotic scar formation was occurring continuously. It is postulated that fibrosis is the consequence of myocyte loss due to chronic underperfusion in the hibernating tissue. This will further injure myocytes so that a vicious cycle is established that leads to progressive loss of structural integrity and functional capacity. Since these changes are progressive, revascularization should be performed at the earliest time point possible in patients with areas of hibernating myocardium.

Aged↗
PubMed1997

Hibernating myocardium: an incomplete adaptation to ischemia.

BACKGROUND: We tested the hypothesis that hibernating myocardium represents an incomplete adaptation to a reduced myocardial oxygen supply. METHODS AND RESULTS: In 38 patients, areas of hibernating myocardium were identified by angiography, multigated radionuclide ventriculography, thallium scintigraphy with reinjection, and low-dose dobutamine echocardiography. Biopsies removed at cardiac surgery showed structural degeneration characterized by a reduced protein and mRNA expression and disorganization of the contractile and cytoskeletal proteins myosin, actin, desmin, titin, alpha-actinin, and vinculin by electron microscopy, immunohistochemistry, and in situ hybridization. Additionally, an increased amount of extracellular matrix proteins resulting in a significant degree of reparative fibrosis was present. Dedifferentiation, ie, expression of fetal proteins, was absent. Apoptosis indicating suicidal cell death was found by the terminal deoxynucleotidyl transferase end-labeling method and electron microscopy. Radionuclide ventriculography showed improvement of regional function at 3 months postoperatively compared with preoperative values (mean values, 23.5% and 48%, respectively), and the echocardiographic wall-motion score index decreased from 3.4 to 1.8. The degree of severity of the morphological changes (three stages) correlated well with the extent of postoperative functional recovery: more advanced clinical improvement was observed in patients with slight and moderate morphological degeneration (stages 1 and 2), but recovery was only partial in severe degeneration (stage 3). CONCLUSIONS: Cellular degeneration rather than adaptation is present in hibernating myocardium. The consequence is progressive diminution of the chance for complete structural and functional recovery after restoration of blood flow. The practical consequence from this study should be early revascularization in patients showing areas of hibernating myocardium.

Adaptation, Physiological↗
PubMed1997

Clinical predictors of defibrillation energy requirements.

In implantable cardioverter-defibrillator therapy with endocardial lead systems, certain clinical variables are associated with defibrillation energy requirements. Because of the weak correlation coefficients, these variables cannot predict defibrillation thresholds in individual patients.

Age Factors↗
PubMed1997

Effect of the addition of an abdominal hot can cardioverter/defibrillator pulse generator on the defibrillation energy requirements in a single-lead endocardial defibrillation system.

AIMS: The effects of a cardioverter/defibrillator system with an electrically active generator can, applied without recourse to thoracotomy, have not been investigated in the abdominal position in humans. The purpose of this acute clinical study was to evaluate the defibrillation efficacy of an abdominally positioned hot can electrode in connection with a single lead endocardial defibrillation system. PATIENTS AND METHODS: Thirty consecutive patients undergoing implantation of a cardioverter/defibrillator or pulse generator replacement were enrolled in this study Each patient received an integrated, tripolar single-lead system. This was tested using an asymmetrical biphasic defibrillation waveform with constant energy delivery. Defibrillation energy, peak voltage, peak current and impedance were compared between two electrode configurations: (A) in this configuration the distal right ventricular coil was negative and the proximal coil positive; (B) in this configuration the distal right ventricular coil was negative and the proximal coil and the abdominal hot can (65 ccm), as common anode, were positive. Defibrillation threshold testing started at 15 J with stepwise energy reduction (10 J, 8 J, 5 J and 3 J) until defibrillation was ineffective. RESULTS: Compared to the single-lead configuration, the abdominal hot can configuration revealed at 17.5% reduction in defibrillation energy requirements (8.6 J +/- 4.3 J vs 10.43 J +/- 3.9 J; P = 0.041), a 15.7% reduction in peak voltage (308.6 V +/- 63 V vs 365.3 V +/- 68 V; P = 0.003), and a 21.6% reduction in impedance (41.1 omega +/- 6.3 omega vs 52.4 omega +/- 6.6 omega; P < 0.001). Peak current showed a significant increase during hot can testing of 8.2% (7.2 A +/- 1.8 A vs 7.8 A +/- 2.2 A; P = 0.16). CONCLUSION: An abdominally placed hot can pulse generator lowered defibrillation energy requirements in patients with an endocardial defibrillation lead system.

Abdominal Muscles↗
PubMed1996

[Hemodynamic and humoral effects of parenteral therapy with intravenously administered ACE inhibitor quinaprilat in patients with advanced heart failure].

The hemodynamic and neurohumoral effects of single and multiple doses of intravenous quinaprilat were assessed and compared with placebo in a double-blind design. The study group included 50 patients aged between 33 and 76 years with NYHA Class III and IV heart failure. The patients were randomized into three treatment groups to receive low (0.5 and 1.0 mg), medium (1.0 and 2.5 mg), or high (5.0 and 10.0 mg) intravenous doses of quinaprilat or placebo on day 1, and, based on the responses, q6h on two further days. The hemodynamic parameters were determined by right-heart catheterization. Quinaprilat is the active metabolite of quinapril, an ACE inhibitor with high affinity for the angiotensin converting enzyme, which is formulated for oral application. Compared with placebo, single and multiple doses of quinaprilat increased cardiac index by 25% (p < 0.05) and simultaneously decreased both peripheral vascular resistance by 25% (p < 0.05) and left ventricular filling pressures by 33% (p < 0.05). There was a dose-related decrease in mean right atrial pressure by 47% (p < 0.05) without significant heart rate changes (-3-5 bpm). The mean artery pressure showed a dose-related maximum decrease of 4-9 mm Hg 45-60 min after single-dose quinaprilat and of 7-10 mm Hg (p < 0.05) after repetitive dosing. Maximum changes were observed 15-90 min after drug application. The hemodynamic changes after multiple-dose quinaprilat were similar to those observed following single doses and generally persisted during the total observation period of 6 h. Compared with placebo, quinaprilat reduced ACE activity and angiotensin II and aldosterone concentrations, and increased plasma renin activity. There were no significant changes with regard to plasma catecholamines and the atrial natriuretic factor, although a slight decrease could be observed. The study results obtained in patients with advanced heart failure support both the safety and favorable hemodynamic and neurohumoral effects of intravenous quinaprilat over an observation period of 3 days.

Adult↗
PubMed1996

[Acute effects of enoximone after intracoronary administration on hemodynamics, myocardial perfusion and regional wall motion].

The influence of intracoronary enoximone at a dose of 0.075 mg/ kg/10 min on global and regional wall motion and myocardial perfusion (Group I, n = 10) as well as on diastolic LV function (Group II, n = 8) during pacing-induced ischemia was investigated in 18 patients with significant LAD stenoses. The hemodynamic parameters were determined by left heart catheterization, the systolic and diastolic left ventricular function by echocardiography including Doppler technique, and myocardial perfusion analysis was done after intracoronary application of contrast medium. Enoximone did not change either heart rate (79 +/- 9 vs 80 +/- 9 min-1) or blood pressure (LVSP: 159 +/- 7 vs 162 +/- 5 mm Hg) at rest. In the postpacing ischemic period after enoximone, LVEDP fell from a mean of 28.9 to 18.4 mm Hg (p < 0.001), dp/dtmax increased from 1050 to 1369 mm Hg/s (p < 0.001) and regional EF from 47% to 58% (p < 0.01), while global EF remained unchanged (45% vs 47%). ST-segment depression was reduced significantly from 2.3 to 1.5 mm (p < 0.01). Enoximone induced an increase in myocardial perfusion by 129% (p < 0.001) in the stenosis-dependent myocardial areas with shortening of the wash-out half-life time of the echo contrast medium from a mean of 14 s to 5 s (p < 0.001). The isovolumetric relaxation was shortened by 13% (p < 0.05), the E wave by 5%, and dp/dtmin increased by 17% (p < 0.01). In summary, intracoronary application of enoximone led to an improvement in both systolic and diastolic LV function without concomitant peripheral effect due to regression of myocardial ischemia.

Adult↗
PubMed1996

[The new potassium channel blocker tedisamil and its hemodynamic, anti-ischemic and neurohumoral effect in patients with coronary heart disease].

Thirty-two patients with angiographically proven coronary artery disease and reproducible ST-segment depression in the exercise ECG took part in this open dose-finding study on the hemodynamic and anti-ischemic effects of tedisamil, using right heart catheterization and bicycle exercise testing. Tedisamil--a bispidine derivative--is a new potassium channel blocking agent with negative chronotropic (i.e., direct effects on sinus node automaticity) and class III antiarrhythmic properties. Four groups of 8 patients each received rising doses of 0.1, 0.2, 0.3, and 0.4 mg/kg BW tedisamil intravenously. Being well tolerated, tedisamil was found to be dose-linear with the dose of 0.3 mg/kg BW having the most favorable anti-ischemic effects accompanied by a significant decrease in heart rate at rest (-13%, p < 0.001) and maximum exercise (-9%, p < 0.05). There was a consecutive fall of CO (by 10%, p < 0.05), while stroke volume remained unaltered. Despite singular significant changes, PCWPm and RV-EF, as indirect parameters of ventricular function, showed different responses without a clear tendency. PAPm increased slightly in accordance with peripheral and pulmonary vascular resistance, being significant at 3.3 mm Hg (p < 0.05) only at the dose of 0.4 mg/kg BW. Mean arterial pressure demonstrated a slight increase at rest (9% at 0.4 mg/kg BW; p < 0.05). Plasma catecholamine levels fell in a dose-dependent way by a maximum of 115-150 pg/ml (p < 0.01) on treatment with 0.4 mg/kg BW. QTc was found significantly prolonged by 16% (p < 0.001) on 0.4 mg/kg BW. During treatment with 0.3 mg/kg BW, tedisamil produced a dose-dependent reduction of ST segment depression at a maximum of 42% (p < 0.001) as well as a decrease in myocardial oxygen consumption, pressure rate product, and plasma lactate concentrations. In conclusion, tedisamil lowered heart rate and showed favorable hemodynamic, anti-ischemic, and neurohumoral effects in patients with coronary artery disease.

Aged↗
PubMed1995

Determination of monoamine oxidase B activity by high-performance liquid chromatography with electrochemical detection.

A sensitive high-performance liquid chromatography method with electrochemical detection for measuring monoamine oxidase B activity in blood platelets is described. Dopamine is used as substrate and is incubated with isolated platelets and aldehyde dehydrogenase to convert dihydroxyphenylacetaldehyde to dihydroxyphenylacetic acid (DOPAC). The acid and the added internal standard hydrocaffeic acid are separated from dopamine and the incubation mixture by extraction with 5 ml of ethyl acetate-toluene (5:1, v/v). The organic phase is evaporated under nitrogen stream and the residue dissolved in 0.1 M citric acid. Dihydroxyphenylacetic acid and the internal standard dihydrocaffeic acid are then separated on a Eurosphere 100-C18 5 microns column. The mobile phase used was a mixture of sodium acetate, citric acid, and acetonitrile at pH 2.5. The standard curve was linear from 125 pg to 10 ng. Absolute recovery of DOPAC was 85 +/- 3.8% and of hydrocaffeic acid 87 +/- 4.1%. The method presented is sensitive (detection limit 8.0 pg of DOPAC injected) and reproducible (coefficient of variation 0.4-1%) with good accuracy (94-98%).

3,4-Dihydroxyphenylacetic Acid↗
PubMed1995

Effects of nicorandil on regional perfusion and left ventricular function.

Left ventricular function and regional perfusion were evaluated by two study designs in patient groups with stable ischemic coronary artery disease (CAD): (1) using conventional left ventricular angiographies and (2) applying myocardial contrast echocardiography. The aim of the studies was to establish the effects of sublingually or orally applied nicorandil (N) on pacing-induced myocardial ischemia (MIS). In the first angiographic study, in nine patients with ischemic CAD and with pacing-inducible MIS, the effect of N, 20 mg sublingually, on hemodynamics and regional wall motion (RWM) were studied. There were no parameter changes without MIS being induced when comparing measurements at the 7th and 14th minute after N application to control values (p > 0.05). In the 15th and 16th minutes after N, pacing-induced MIS could no longer be elicited but left ventricular pump function improved; comparing MIS with N versus MIS without N: ejection fraction improved by 21%, cardiac index by 37%, and RWM by 21%, while filling pressure fell by 41% and systemic vascular resistance fell by 29%. Thus, N-mediated "protection from ischemia" with rather improved hemodynamics and RWM corresponds with alterations that theoretically could have been expected after nitroglycerin given under the above conditions. In the second echocardiographic study, regional perfusion was assessed in 10 patients by intracoronary injection of a newly developed echo contrast medium (ECM) and measurement of ECM washout halftime (t1/2) over opacified myocardial regions of interest, which displayed wall motion abnormalities already at rest.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Programmable VT detection enhancements in implantable cardioverter defibrillator therapy.

This report describes the distribution of automatically measured values of enhanced arrhythmia detection parameters such as "rate stability" and "rate onset" in various forms of spontaneous arrhythmia episodes in patients treated with a new, third-generation, tiered therapy implantable cardioverter defibrillator (ICD). The study population consisted of 27 patients who received the Ventak PRxII cardioverter defibrillator, which provides extensive diagnostic options such as electrogram storage capabilities, and the ability to store measured values of additional arrhythmia detection parameters such as rate stability and rate onset during spontaneous arrhythmia episodes. During a follow-up period of 11.1 +/- 5.2 months, this device detected 264 arrhythmia episodes. The analysis of stored electrograms revealed 13 episodes of sinus tachycardia, 52 episodes of atrial tachyarrhythmias, and 201 episodes of monomorphic ventricular tachycardias (VTs). The mean measured values of rate stability and rate onset were: 2.2 +/- 0.9 msec, 0% in sinus tachycardias; 41.0 +/- 24.1 msec, 8.5% +/- 9.5% in atrial tachyarrhythmias; and 7.8 +/- 6.0 msec, 30.6% +/- 12.1% in monomorphic VTs. There was a wide zone of overlapping measured values for rate stability and rate onset in ventricular and nonventricular rhythms. No episode of VT showed a measured rate stability criterion > 35 msec. The subanalysis of arrhythmia episodes presenting with a heart rate < 160 beats/min revealed no episode of VT with a rate stability value > 24 msec. The calculated, rate dependent specificities for these programmed rate stability parameters in detecting VTs were 46.2% and 81.8%, respectively. The analysis of the rate onset algorithm revealed no comparable relationship between sensitivity and specificity in the detection of VTs.(ABSTRACT TRUNCATED AT 250 WORDS)

Arrhythmias, Cardiac↗
PubMed1995

Steady-state plasma kinetics of slow-release propafenone, its two isomers and its main metabolites.

Steady-state plasma kinetics of propafenone (CAS 54063-53-5), the S- and R-enantiomers, and the two main metabolites were investigated in a double-blind, placebo-controlled dose-finding study using a slow-release formulation of propafenone at three different dose regimens (2 x 225 mg, 2 x 325 mg, and 2 x 425 mg). The study included a total of 24 patients (18 m, 6 f) with symptomatic ventricular arrhythmia. Since statistically valuable data was limited by a considerable portion of undetectable plasma concentrations among patients having received verum, kinetics could be followed up only in a group of 14 patients (10 m, 4 f) over a period of 12 h under steady state conditions. All patients were phenotyped prior to the study by measuring the ratio of sparteine/dehydrosparteine and three poor metabolizers were identified. A detailed description of the analytical methods used is given. With the low dose, a mean plasma level of 87 +/- 16 ng propafenone per ml plasma was obtained, with the medium dose a level of 243 +/- 34 ng/ml and with the higher dose 334 +/- 71 ng/ml were reached. All three doses of the slow-release preparation resulted in a smoothened and thus therapeutically favorable plasma concentration curve, independently from phenotype. With regard to the two propafenone enantiomers, a preferential clearance of the R-form (S/R = 2.08 +/- 0.19) could be confirmed without observing a change in the S/R ratio with time.

Acetylation↗
PubMed1995

[Implantable cardioverter/defibrillators with endocardial electrode systems: long-term stability of the defibrillator's effectiveness].

The vast majority of cardioverter/defibrillator implantations is performed with non-thoracotomy lead systems. The temporal stability of defibrillation energy requirements is well established for epicardial defibrillation lead systems, but not for non-thoracotomy lead systems. The defibrillation energy requirements were reevaluated in 30 patients, 13 months after implantation of a cardioverter/defibrillator with a non-thoracotomy lead system. The study patients group consisted of 4 females and 26 males; mean age 60.1 +/- 10.5 years; mean left ventricular ejection fraction was 32.2 +/- 6.2%. Coronary artery disease was the underlying heart disease in 12 patients, dilated cardiomyopathy in 15 patients, and artificial valve replacement in 3 patients. There was no clinical progression in the underlying heart disease between defibrillator implantation and control measurements; left ventricular ejection fraction was unchanged (32.2 +/- 6.2 vs. 32.3 +/- 6.4%); no changes occurred regarding patients' clinical status. In 27/30 patients the defibrillation threshold at defibrillator implantation could be reconfirmed at control measurements. The mean defibrillation energy/requirements at implantation (14.4 +/- 4.8 Joules) were unchanged compared to control measurements (14.8 +/- 4.6 Joules). A temporal stability of defibrillation energy requirements could be established for the monophasic (n = 15; 18.0 +/- 4 vs. 18.1 +/- 3.4 Joules) as well as for the biphasic waveform (n = 15; 11.1 +/- 3.4 vs. 11.5 +/- 2.9 Joules). The results of intraoperative defibrillation thresholds measurements are predictive for chronic defibrillation energy requirements in patients with non-thoracotomy lead systems.

Aged↗
PubMed1995

[Incidence of intervention-related heart valve lesions after high-frequency catheter ablation of the left-side accessory atrioventricular conduction pathways].

The aim of this study was to evaluate the incidence of valve lesions after radiofrequency catheter ablation of accessory atrioventricular pathways using the retrograde transaortic approach. Patients who presented no preexisting detectable valve lesion prior to catheter ablation and who underwent a comparable echocardiographic examination prior to and after catheter ablation were included for data analysis. From January 1991 until May 1993, 113 patients underwent radiofrequency catheter ablation of a left-sided accessory atrioventricular pathways at our institution. Fifty-nine patients were included in this study. Five patients (8.4%) developed new valve lesions after radiofrequency catheter ablation. There were two cases (3.3%) of aortic regurgitation and four cases (6.7%) of mitral regurgitation. In the majority of cases only mild valve regurgitation was detected. A hemodynamically significant valve lesion was observed in a single patient (1.6%). We speculate that the new onset of valve lesions is mostly due to catheter manipulations rather than due to tissue injury related to radiofrequency current application. Echocardiographic examinations prior to and after radiofrequency catheter ablation of accessory pathways may contribute to a further reduction in intervention-related complications.

Adult↗
PubMed1995

[Clinical and morphologic findings in the "hibernating myocardium"].

From the clinical point of view, the diagnosis of "hibernating myocardium" is of predominant importance in patients with LV-dysfunction, because a prediction of a possible functional recovery allows to determine risk and outcome of an intervention. Alone or in combination, thalliumscintigraphy with reinjection and dobutamine echocardiography are suitable to detect "hibernating myocardium". In addition, morphological investigations of biopsies taken from hibernating regions permit the evaluation of structural changes. The spectrum of alterations is wide and at a certain degree of severity they are irreversible. The relation between clinical and morphological results provides further insight into the degree of injury and of functional recovery after adequate revascularization.

Biopsy↗