How cardiac cells die--necrosis, oncosis and apoptosis.
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Apoptosis↗
Biomedical subjects
B Maisch
Publications and source records attributed to B Maisch.
[Cell death in inflammatory heart muscle diseases--apoptosis or necrosis?].
Cell death can be induced by 2 different mechanisms: necrosis and apoptosis. Necrosis, on the one hand, is usually caused by unphysiological stress factors such as hyperthermia or hypoxia, apoptosis, on the other hand, is part of the normal organ development and controls for example immune responses. Morphologically, necrosis is characterized by swelling of cells and their organelles leading to the disruption of the cell membrane, which in turn causes an inflammatory reaction in the surrounding tissue. Morphological and biochemical criteria (Figure 1, Table 1) of apoptosis are the condensation of chromatin leading to the development of apoptotic bodies or membrane-enclosed vesicles containing oligonucleosomal DNA fragments. Important diagnostic tools of cell death (Table 2), such as the TUNEL test (Figure 2) or gel electrophoresis of extracted DNA (Figure 3) are based on the above mentioned biochemical characteristics, but a reliable differentiation of apoptotic versus necrotic processes is not always possible. Experimental studies in animals and studies in various diseases of the cardiovascular system were able to show that apoptosis in myocytes can be induced, an issue that has long been discussed controversially. Ischemia, reperfusion, and myocardial infarction were also shown to lead to apoptosis in cardiomyocytes, whereas cell destruction was caused mainly by necrosis. Several authors (Table 3) demonstrated apoptotic indices in cardiomyocytes of patients with dilatated cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy and patients with acute infarction from 0.25 to 35% by the use of the TUNEL test. Others were able to demonstrate an elevated expression of Fas-receptor in cells of atheroslerotic plaques in patients with atherosclerosis and high indices of apoptotic cardiomyocytes in patients with chronic heart failure. We investigated endomyocardial biopsies of patients with inflammatory cardiomyopathy, DCM without inflammatory reaction but the presence of adenoviral or cytomegaloviral genome and idiopathic DCM using the TUNEL test. The percentage of apoptotic cardiomyocytes in biopsies of patients with DCMi was 1.03 and in biopsies of patients with adenoviral genome 0.25, whereas in all other groups no apoptosis was found. If apoptosis plays a major role in myocardial diseases such as heart failure, arrhythmia and others, blocking this mechanism will have to be considered as a therapeutical strategy. Therefore, studies on the extent of apoptotic processes in diseased versus healthy cardiac tissue are of great importance.
Animals↗
Control of apoptosis of cardiovascular fibroblasts: a novel drug target.
Adequate control of survival or programmed cell death (apoptosis) of cardiovascular cells appears as an important drug target. While prevention of apoptotic death of cardiomyocytes has been assessed in detail, selective induction of apoptosis of vascular smooth muscle cells or fibroblasts could also be of relevance. Thus, induction of apoptosis of vascular smooth muscle cells by p65 NF-kappa B and Bcl-xL antisense oligonucleotides or p53 overexpression could be useful for limiting vascular lesions associated with restenosis. Although fibroblasts represent the majority of cardiac cells, few attempts were made to induce fibroblast apoptosis in disorders associated with excessive collagen deposition and fibrosis. It is hypothesized that early interference with fibroblast proliferation after myocardial infarction or inflammatory heart disease limits fibrosis which further impairs cardiac performance. A candidate approach could involve growth factor analogues which are known to induce fibroblast apoptosis when an incomplete growth stimulus persists.
Anticoagulants↗
[Therapy recommendation--"Viagra and NO donors"].
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Congresses as Topic↗
[Prospective evaluation of effect of carvedilol therapy on heart rate variability in patients with dilated cardiomyopathy].
The aim of the present study was to assess the effects of carvedilol therapy in addition to conventional heart failure therapy on heart rate variability (HRV) and on left ventricular function in 14 patients with mild to moderate heart failure due to idiopathic dilated cardiomyopathy (IDC). After a 3- to 4-week titration period, carvedilol was titrated up to 50mg daily, or the highest dose tolerated (at least 25mg daily). Maintenance treatment was then continued for 8 weeks. Digital 24-hour Holter recordings were obtained at baseline and after 8 weeks of carvedilol therapy. HRV for the entire 24-hour period was computed in the time domain using the Oxford Medilog Excel 2 analysis system. Measures of HRV included the mean of all coupling intervals between normal beats (RRm), the standard deviation of all normal RR intervals (SDNN), the square root of the mean of the squared differences between adjacent normal RR intervals (rMSSD), and the proportion of adjacent normal RR intervals differing >50 ms (pNN50). Additional treatment with carvedilol induced a significant increase in HRV: SDNN increased from 77+/-21 ms to 110+/-22 ms (p=0.001), rMSSD from 19+/-7 ms to 26+/-7 ms (p=0.02), and mean pNN50-value increased from 1.7+/-1.3% to 5.5+/-4.5% (p<0.01) under therapy with carvedilol. Mean heart rate on carvedilol calculated over 24 hours was 13 beats less than at baseline (75 bpm versus 88 bpm, p<0.01). After 2 months of additional treatment with carvedilol, both hemodynamic and clinical parameters improved: left ventricular ejection fraction increased from 24+/-7% to 30+/-10% (p<0.05), and New York Heart Association class decreased from 2.5+/-0.8 to 1.8+/-0.7 (p<0.05). In summary, eight weeks of additional carvedilol therapy induced a significant increase in HRV parameters related to parasympathetic activity in patients with IDC. Whether increased vagal tone may contribute to the protective effect of carvedilol has to be evaluated by further studies.
Adrenergic beta-Antagonists↗
Metabolic basis of high density lipoproteins and apolipoprotein A-I increase by HMG-CoA reductase inhibition in healthy subjects and a patient with coronary artery disease.
HMG-CoA reductase inhibitors, such as pravastatin, are widely used as lipid lowering drugs in hypercholesterolemia. Pravastatin does not only reduce the atherogenic low density lipoprotein (LDL)-cholesterol, but is also increasing high density lipoprotein (HDL)-cholesterol. However, the mechanism leading to an increase of HDL are unclear. Therefore, the effects of pravastatin on the in vivo kinetics of apolipoprotein (apo) A-I were studied in six normolipidemic subjects and in a patient with coronary artery disease (CAD) utilizing stable isotope tracer techniques. Two turnover studies were performed. The first turnover study was carried out before any drug treatment, the second study after 6 weeks of 40 mg pravastatin/day. Three times deuterium labeled L-leucine (3D-leucine) was given as a primed bolus constant infusion (bolus: 1340 microg/kg; infusion: 22 microg/kg per h), and tracer uptake into HDL apoA-I was determined by gas chromatography (GC)-mass-spectrometry (MS). In the healthy subjects HDL-cholesterol increased by 13% and apoA-I increased by 12% under pravastatin treatment. The HDL in the CAD patient decreased by 3% and apoA-I increased by 2%. Prior to drug treatment the mean apoA-I fractional synthetic rate (FSR) was 0.194 per day (S.D. +/- 0.02) and apoA-I production rate (PR) was 10.8 mg/kg per day (S.D. +/- 2.1). The CAD patient had a FSR of 0.219 per day and a PR of 10.6 mg/kg per day. After treatment with pravastatin the mean apoA-I FSR was 0.204 per day (S.D. +/- 0.02) and apoA-I PR was 12.5 mg/kg per day (S.D. +/- 1.5) in the healthy subjects. Despite only minor changes of HDL and apoA-I in the CAD patient, there were significant changes of FSR (0.267 per day) and PR (13.1 mg/kg per day) with pravastatin treatment. The in vivo kinetic data demonstrate an increased FSR of apoA-I. The increase in apoA-I is due to an increased PR of apoA-I. This study demonstrates increased production of HDL apoA-I as the metabolic cause of the increase in HDL and apoA-I levels under inhibition of HMG-CoA reductase in man.
Adult↗
Guidelines for the study of familial dilated cardiomyopathies. Collaborative Research Group of the European Human and Capital Mobility Project on Familial Dilated Cardiomyopathy.
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Cardiomyopathy, Dilated↗
Complications of third-generation implantable cardioverter defibrillator therapy.
To determine the incidence of complications of third-generation implantable cardioverter defibrillator (ICD) therapy, 144 patients were prospectively studied who underwent first implant of third-generation devices (i.e., ICD systems with biphasic shocks, ECG storage capability, and nonthoracotomy lead systems). During 21 +/- 15 months of follow-up, 41 (28%) patients had one or more complications. No patient died perioperatively (30 days) and no ICD infection was observed during follow-up. Complications included bleeding or pocket hematoma (hemoglobin drop > 2 g/dL) in 5 (3%) patients, prolonged reversible ischemic neurological deficit in 1 (1%) patient, postoperative deep venous thrombosis of leg in 1 (1%) patient, pneumothorax in 2 (1%) patients, difficulty to defibrillate ventricular fibrillation intraoperatively in 2 (1%) patients, generator malfunction in 1 (1%) patient, arthritis of the shoulder in 3 (2%) patients, and allergic reaction to prophylactic antibiotics in 2 (1%) patients. A total of seven lead related complications were observed in six (4%) patients including endocardial lead migration in four (3%) patients. Twenty-three (16%) patients received inappropriate shocks for supraventricular tachyarrhythmias (n = 13), non-sustained ventricular tachycardia (VT) (n = 7), or myopotential oversensing (n = 3). We conclude that serious complications such as perioperative death or ICD infection are rare in patients with third-generation ICDs. Lead-related problems and inappropriate shocks during follow-up are the most frequent complications of third-generation ICD therapy. Recognition of these complications should promote advances in ICD technology and management strategies to avoid their recurrence.
Defibrillators, Implantable↗
Risk of interference between pacemakers and security systems.
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Electromagnetic Fields↗
Transient QT prolongation with torsades de pointes tachycardia after ablation of permanent junctional reciprocating tachycardia.
INTRODUCTION: Catheter ablation with radiofrequency energy is a curative therapy in patients with permanent junctional reciprocating tachycardia (PJRT). METHODS AND RESULTS: For the first time, we report a case of transient QT prolongation with torsades de pointes tachycardia 18 hours after successful radiofrequency energy ablation of PJRT in a 25-year-old woman with tachycardia-induced cardiomyopathy. Of note, the torsades de pointes occurred in the absence of bradycardia, electrolyte disturbances, or QT-prolonging drugs. This patient initially was thought to have a hereditary long QT syndrome that was unmasked by PJRT ablation. Therefore, the patient received an implantable defibrillator in addition to beta-blocker therapy, which was discontinued 6 months later. Surprisingly, the QT interval completely normalized within 1 week after PJRT ablation, and the patient remained free of arrhythmias during a follow-up period of 4.5 years. CONCLUSION: Patients with incessant tachyarrhythmias should undergo ECG monitoring for at least 24 hours following successful radiofrequency catheter ablation because transient QT prolongation with torsades de pointes may occur even in the absence of bradycardia, QT-prolonging drugs, or electrolyte disturbances.
Adult↗
Radiotelemetric characterization of overweight-associated rises in blood pressure and heart rate.
We addressed the hypothesis that hypercaloric diets induce hyperkinetic hypertension irrespective of day-night cycle and locomotor activity that is associated with altered cardiac myosin isozymes. Normotensive rats with implanted radiotelemetry pressure transducers were fed increasing amounts of coconut fat (8, 16, and 24%, each for 2 wk) corresponding to 20-47% of total calories from fat. Thereafter, increasing amounts of sucrose (16, 32, and 50%) and fructose (50%) were added to the 24% fat diet corresponding to 13-40% of total calories from sugar. In contrast to the fat diets, the 32% and 50% sucrose diets as well as the 50% fructose diets increased (P < 0.05) blood pressure (systolic maximum +13 mmHg, diastolic maximum +4 mmHg, mean maximum +7 mmHg) and heart rate (maximum +50 beats/min) irrespective of the day-night cycle and the unaltered locomotor activity. Furthermore, body weight increased (P < 0.05) during the 32% and 50% sucrose feedings. The increased blood pressure and heart rate normalized after rats were fed a regular chow. We concluded that an excessive caloric intake results in hyperkinetic hypertension that increases the myosin V(1) proportion.
Animals↗
Elevation of the pacing threshold: a side effect in a patient with pacemaker undergoing therapy with doxorubicin and vincristine.
A 56-year-old female patient with an IgG plasmocytoma first diagnosed 5 years before underwent 3 cycles of chemotherapy according to the VAD scheme. A VVI pacemaker had been implanted 3 years earlier. After each cycle, the output of the pacemaker had to be increased as the pacing threshold had increased, resulting in a slow pulse. This case demonstrates that patients with a pacemaker that undergo chemotherapy with cardiotoxic agents must be followed carefully.
Antineoplastic Combined Chemotherapy Protocols↗
Semi-automated rapid isoelectric focusing of apolipoproteins C from human plasma using Phastsystem and immunofixation.
Apolipoproteins (apo) C-I, C-II, and C-III play crucial roles in intravascular lipid metabolism. Whereas apo C-II is an obligate cofactor for lipoprotein lipase, apo C-III was shown to inhibit its action. Apo C-I can be a potent cofactor of human lecithin:cholesterol acyltransferase. Structural mutants and deficiencies of apo C-II lead to hypertriglyceridemia. A similar phenotype is associated with apo C-III mutants and is inducible by overexpression of human apo C-III in transgenic animals. No structural variant has so far been reported for apo C-I. The present paper describes a rapid semi-automated procedure for isoelectric focusing analysis of these C-apolipoproteins from whole plasma or serum and their visualization by immunofixation and silver staining. The procedure allows detection of charged variants of C-apolipoproteins. As applied to 295 patients with coronary heart disease and 85 controls, it also serves to detect deficiency syndromes of these apolipoproteins. The procedure provides reliable, easy and quick analysis of C-apolipoproteins applicable as a routine or screening procedure not restricted to specialized laboratories.
Acrylic Resins↗
Association of mutations in the apolipoprotein B gene with hypercholesterolemia and the risk of ischemic heart disease.
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Apolipoproteins B↗
[Sources of interference for cardiac pacemakers. Technical improvements of pacemakers--risks in the medical realm].
Such new technologies are associated with potential problems for patients with pacemakers which have not yet been adequately investigated. External sources of interference may inhibit or, in the case of dual chamber devices, trigger, the pacemaker, change its program or cause thermal damage to electrode tips leading to elevation of the stimulation threshold, or may destroy both hardware and software components. To prevent such problems, protective measures such as screening, sensitivity filters, asynchronous stimulation, and the bipolar electrodes have been developed. Detection by the pacemaker of a constant source of interference automatically activates an anti-interference circuit providing a fixed stimulating frequency. In contrast, interference by a pulsed or strongly amplitude-modulated signal can inhibit pacemaker function for a lengthy period and thus cause symptoms and possibly syncope.
Contraindications↗
[Classification of cardiomyopathies according to the WHO/ISFC Task Force--more questions than answers?].
The most recent WHO/ISFC classification of cardiomyopathies (1995) describes as cardiomyopathies all heart muscle diseases, which demonstrate a disturbance of cardiac function. It distinguishes primarily according to hemodynamic criteria the following 5 forms: 1. dilated (DCM), 2. hypertrophic (HCM), 3. restrictive (RCM) from 4. arrhythmogenic right ventricular (ARVCM) and assembles in 5. non-classified cardiomyopathies (NKCM) the non-classifiable forms. When compared to the 18-year-old former classification several points have been altered: 1. ARVCM has been introduced as a new entity. 2. The new term ischemic cardiomyopathy has been reserved for the remodeling process of the non-infarcted myocardium and does not mean hemodynamic alterations of an infarcted area (aneurysm), of stunned or hibernating myocardium. Hypertensive cardiomyopathy corresponds to left ventricular hypertrophy in hypertensive patients, valvular cardiomyopathy identifies cardiomegaly, which cannot sufficiently be explained by the valvular dysfunction (stenoses or insufficiency) alone. For the first time the term inflammatory cardiomyopathy has been used and defined as acute or chronic myocarditis associated with cardiac dysfunction, for which etiological and pathogenetic factors, e.g. viral or microbial infection or autoimmune processes have been made responsible. Two ISFC task forces have just recently clarified in consensus conferences the immunohistopathological criteria for chronic myocarditis or dilated cardiomyopathy with inflammation (DCMi: > 14 lymphocytes or macrophages/mm3) and set standards for molecular and virological diagnoses in endomyocardial biopsies.
Cardiomyopathies↗
[Cardiotropic DNA viruses and bacteria in the pathogenesis of dilated cardiomyopathy with or without inflammation].
In the report of the 1995 WHO/ISFC task force on the definition and classification of cardiomyopathies a new entity within the dilated cardiomyopathies was introduced as "inflammatory cardiomyopathy". It is defined as myocarditis associated with cardiac dysfunction. Idiopathic, autoimmune and infectious forms of inflammatory cardiomyopathy are now recognized through this definition. Dilated cardiomyopathy with inflammation (DCMi, chronic myocarditis) was also defined by a recent ISFC task force as > 14 lymphocytes/macrophages/mm3. Enteroviruses, adenoviruses and cytomegaloviruses are considered as main etiopathogenetic factors in the pathogenesis of inflammatory heart disease and have been demonstrated as important trigger for inflammatory cardiac disease. They may also cause dilated cardiomyopathy by viral persistence or secondary immunopathogenesis due to antigenic or molecular mimicry. For the detection of viral persistence the investigation of endomyocardial biopsies in patients with cardiomyopathy by the use of polymerase chain reaction and southern blot analysis is an important step for the standardization of diagnostic criteria on virally induced inflammatory cardiomyopathy. Present studies indicate an incidence of cytomegalovirus-DNA in patients with inflammatory cardiomyopathy in 10%, adenoviral-DNA in 17% and borreliosis only in rare cases (< 1%). In dilated cardiomyopathy without inflammation the respective incidences were for cytomegalovirus 12%, 15% for adenovirus and only 0.5% of cases for borreliosis. In addition the results of immunohistochemical analysis and molecular biological investigations of endomyocardial biopsies may have implications for future therapeutic studies. Depending on the etiology of the disease, immunosuppression may have benefit for patients with virus-negative cardiomyopathy with inflammation in contrast to patients with cytomegalo-, adenovirus-DNA or enteroviral persistence, in whom immunomodulation with hyperimmunoglobulins or immunoglobulins may be a feasible therapeutic option. Patients with a positive PCR for Borrelia burgdorferi should be treated with 3rd generation cephalosporines and/or sublactam.
Biopsy↗
[Therapy of dilated cardiomyopathies with and without inflammation].
Diagnosis of inflammatory dilated cardiomyopathy relies on the histological and immunohistological examination of endomyocardial biopsies. Only with the demonstration of the etiological agents in the myocardium specific therapy can be attempted. Whereas the spontaneous course of endemic myocarditis with little hemodynamic impairment is fair, the prognosis of symptomatic myocarditis and dilated cardiomyopathy is poor, with complete restitution in 35% and a 10-year survival rate of 30%. Restriction of physical activity is a validated form of therapy with normalization of the heart size in 40 to 60%. Symptomatic medical therapy consists of digitalis, diuretics, ACE-inhibitors and vasodilators and betablocker therapy, where a reduction of mortality was demonstrated in clinical (sub)studies up to 60%. Specific forms of therapy in inflammatory cardiomyopathy rely on the demonstration or lack of viral persistence or signs of autoreactivity in the myocardial tissue. Immunosuppressive therapy in autoimmune forms improved cardiac function in up to 60% of the patients in controlled trials, when compared to controls (40%). The double-blind randomized myocarditis treatment trial, which unfortunately did not distinguish viral from autoimmune myocarditis could not demonstrate such a benefit, however. Depending on the etiology of the disease, immunomodulation with immunoglobulins or interferon or antiviral therapy with hyperimmunoglobulins are presently tested in clinical treatment trials (ESETCID) in patients with enterovirus-positive or cytomegalovirus-positive and adenovirus-positive chronic myocarditis. Specific therapies are aimed to avoid the progression of the disease which may ultimately lead to heart failure with a cardiac assist device or heart transplantation as ultimate therapeutic option.
Adjuvants, Immunologic↗