Martin Schlepper

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.

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.

Analysis of re-entry mechanisms in the three patients with concealed Wolff-Parkinson-White syndrome.

Three patients with recurring attacks of supraventricular tachycardia and no electrocardiographic evidence of the Wolff-Parkinson-White syndrome (WPW syndrome) were studied using intracardiac recordings and atrial stimulation. The findings are interpreted as evidence of a concealed WPW syndrome. In all patients there was antegrade block of the anomalous atrioventricular (A-V) pathway while retrograde conduction was unimpaired and allowed the initiation of the observed reciprocating tachycardias. The diagnosis was based on the assumption that the ventricular myocardium was an essential link in the re-entry circuit. The three most important findings to support this assumption are: 1) retrograde conduction time, measured by the Q-A′ interval (Q in ECG to atrial echo), and the rate of tachycardia were dependent on the mode of intraventricular conduction; 2) the first Q-A′ interval of the tachycardia was independent of the A-H interval (initiation of atrial impulse to first activation of the His bundle) of the initiating premature atrial depolarization(PAD); 3) there was retrograde conduction following a ventricular premature beat during tachycardia at a time when the A-V node and/or the bundle of His would be refractory.

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/mm 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. Additional arrhythmia detection algorithms such as rate stability and rate onset may contribute to a significant enhancement in the specificity of lCD therapy.

Echocardiographic imaging of the left ventricle by peripheral intravenous injection of echo contrast agent

With the use of a new echo contrast agent (ECA) that consists of a suspension with microbubbles (100% less than 3.9 micron in a moving system), we were able to opacify the left ventricle by peripheral intravenous injection in 124 of 130 patients (95%) without shunt connection. In 12 patients with aortic valve disease we measured the opacification of the right and left ventricles videodensitometrically by means of increasing doses. Dose 1 (8.7 ml ECA) and dose 4 (50 ml ECA) led to no significant difference in intensity in the right ventricle (168 +/- 32 vs 184 +/- 16 units, respectively; p greater than 0.05); however, opacification of the left ventricle was significantly more evident after dose 4 (60 +/- 60 vs 88 +/- 62 units, respectively; p less than 0.05). On the basis of the farthest distance reached by the regurgitant microbubbles from the aortic valve, the severity of regurgitation was graded on a four-point scale; the results were compared with those of aortography. A significant correlation (r = 0.98, n = 9) was found between ECA grading and aortography in the evaluation of the severity of aortic insufficiency. In addition, flow characteristics in patients with mitral stenosis, aortic insufficiency, and the regurgitation jet in incompetent aortic prosthesis in connection with diastolic inflow over the mitral valve were described. Moreover, it was possible to differentiate between inflow of ECA into the left atrium via an atrial septal defect and across the pulmonary vascular bed. No adverse effects were reported by the patients. Left ventricular end-diastolic volume index, end-systolic volume index, stroke volume index, and ejection fraction were determined before and after intravenous injection of increasing doses of ECA by means of the area-length method of Sandler and Dodge. Even after dose 4 we observed no significant changes in left ventricular function. The values before and after injection were in the range of intra- and interobserver reproducibility. Only three patients reported a slight taste sensation. In nine patients with a history of allergies there were no side effects.

Ultrastructural alterations during ischemia and reperfusion in human hearts during cardiac surgery

Abstract Needle biopsies taken from human hearts during cardiac surgery were investigated with the electron microscope. Cardiac tissue obtained before induction of ischemia was compared with tissue removed at the end of the ischemic period during total cardiopulmonary bypass with mild cardiac hypothermia and elective cardiac arrest (cardioplegia) and with tissue obtained after onset of coronary reperfusion. Ischemia led to changes in mitochondrial, nuclear, and vascular structures. The mitochondrial changes consisted of: loss of dense matrix granules, clearing of the matrix, fragmentation of cristae, appearance of amorphous densities, vacuolation and formation of myelin figures. The nuclear changes were: swelling of the nucleus, margination of chromatin, clumping of chromatin and, later, shrinkage of the nucleus. Study of reperfused tissue showed that amorphous densities, vacuolation and formation of myelin figures in mitochondria and nuclear shrinkage are probably irreversible. A good correlation was found between the duration of ischemia and the degree of ultrastructural damage. The degree of damage and the recovery upon reperfusion also correlated well. Full reversibility of ischemic changes was noted up to 40 min of ischemia. Between 40 and 60 min a number of cells appeared irreversibly damaged. The proportion of irreversibly damaged cells increased markedly with ischemia times exceeding 60 min.

Hemodynamic and neurohumoral effects of moxonidine in patients with essential hypertension

SummaryThe hemodynamic and neurohumoral effects of a single oral dose (0.4 mg) of the novel centrally acting antihypertensive agent moxonidine were investigated over 4 hours in ten patients with essential hypertension (WHO I-II). Pulmonary pressure indices and cardiac output were determined both at rest and during ergometric exercise by means of Swan-Ganz catheterization. Blood pressure was measured by sphygmomanometry and in the brachial artery. Moxonidine induced a significant fall in blood pressure over the 4-hour observation period from 176/105 mmHg to 158/95 mmHg (p<0.01), accompanied by a decrease in systemic vascular resistance from 1695 to 1427 dyn.sec/cm5 (p<0.01). Cardiac output remained unchanged, while heart rate increased slightly from 69 to 75 beats/min (p<0.01). No significant changes were recorded for either pulmonary artery pressure or pulmonary vascular resistance. Plasma levels of noradrenaline (337 vs. 224 pg/ml) and renin (2.6 vs 2.0 ng/ml/hr) activity fell significantly after moxonidine (p<0.05), both at rest and during exercise. Although aldosterone plasma levels fell slightly, levels of angiotensin II and ANF remained unchanged.Moxonidine has favorable effects on hemodynamics and the neurohumoral system in patients with essential hypertension and is well tolerated at the dose administered.

Thrombotic complications with pacemakers

To analyze thrombotic complications, we performed brachial phlebographies in 100 consecutive patients (group 1), about 44 months after permanent pacemakers had been installed. Thirty-nine patients showed thrombotic lesions in the veins used to pass the stimulation electrode into the right ventricle. In 10 patients the medical history and in 12 patients clinical symptoms and signs indicated an impairment of venous flow. Fifteen of the 39 patients showed complete occlusion of one venous segment; collateral vessel formation was found dependent on the site and the extent of the occlusion. In the remaining 24 patients only partial occlusion without collateralization was demonstrated. Group 2 comprised 12 patients in whom the pacing lead originally inserted via right-sided veins had been severed and the free distal end left unsecured intraluminally when the second electrode was inserted via the left-sided cephalic vein. In all these patients phlebography about 19 months later revealed thrombotic complications, while 11 presented with clinical symptoms and signs. The incidence of thrombotic complications including segmental occlusion after the application of permanent pacer leads is only one-third of patients with segmental occlusion symptoms. However, since severed leads produce severe symptomatic complications in almost all cases their removal is mandatory.

Effect of Biphasic Waveform Pulse on Endocardial Defibrillation Efficacy in Humans

Several clinical studies have proved increased defibrillation efficacy for implantable cardioverter defibrillators with biphasic pulse waveforms compared to monophasic pulse waveforms. This difference in defibrillation efficacy depends on the type of defibrillation lead system used. The influence of biphasic defibrillation pulse waveforms on the defibrillation efficacy of purely endocardial defibrillation lead systems has not yet been sufficiently examined, we, therefore studied 30 consecutive patients with drug refractory ventricular tachyarrhythmias during the implantation of a cardioverter defibrillator. After implanting an endocardial “integrated” sensing/defibrillation lead we performed a prospective randomized comparison of the defibrillation efficacy of monophasic and biphasic defibrillation waveform pulses. For endocardial defibrillation with the biphasic waveform the mean defibrillation threshold was 12.5 ± 4.9 joules and for the monophasic waveform 22.2 ± 5.6 joules (P < 0.0001). There was a decrease in the required defibrillation energy of biphasic defibrillation in 29/30 patients. Thus considering purely endocardial defibrillation a statistically significant and clinically relevant increase in defibrillation efficacy can be demonstrated for biphasic defibrillation waveform pulses.

Effectiveness of nicorandil (SG-75), a new long-acting drug with nitroglycerin effects, in patients with coronary artery disease: improved left ventricular function and regional wall motion and abolition of pacing-induced angina.

Summary Nicorandil (SG-75; SG), 2-nicotinamidoethyl nitrate, is a new antianginal drag with coronary dilatory properties, according to investigations conducted in Japan. In nine patients with coronary artery disease and with reproducible pacing-induced myocardial ischemia, the effect of SG, 20 mg sublingually, was studied, i.e., changes in heart rate, arterial pressure, angiographic left ventricular (LV) ejection parameters, contractility, LV function, LV work, myocardial oxygen consumption, cardiac efficiency, and regional wall motion for the following hemodynamic phases were investigated at the 7th and 14th min after SG, the immediate postpacing phase without medication, and the postpacing phase under the influence of SG. There was no change as compared with control values (p > 0.05) in the 7th and 14th min after SG application and without stress. In the 15th and 16th min post-SG (serum level control), under equipotent pacing stress, myocardial ischemia could no longer be elicited, as, however, had been the case in the postpacing period without medication. In addition, percentile parameter changes (p < 0.05) comparing the postpacing phase, with SG, with the postpacing phase, without medication, were as follows: ejection fraction, +21%; cardiac index, +37%; stroke work index, +48%; LV work, +52%; cardiac efficiency, +60%; and regional wall motion, improved. “Protection from ischemia” and improved hemodynamics under SG influence were probably mainly due to a decrease in preload (left ventricular end-diastolic pressure, by −41%) and afterload (systemic vascular resistance, by −29%). These parameter changes correspond to alterations that could have been expected theoretically also after nitroglycerin given under similar conditions. Because, in addition, no untoward effects, either subjective or objective, could be elicited during or after application of SG, this seems to be a promising drug for antianginal therapy of the future.