Is the implantable defibrillator indicated in patients with hypertrophic cardiomyopathy and aborted sudden death?
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Arrhythmias, Cardiac↗
Biomedical subjects
G Breithardt
Publications and source records attributed to G Breithardt.
Cardiac sympathetic innervation in patients with idiopathic right ventricular outflow tract tachycardia.
OBJECTIVES: This study investigated the neuronal reuptake of norepinephrine (uptake-1) and the beta-adrenoceptor density in patients with idiopathic right ventricular outflow tract tachycardia (RVO-VT). BACKGROUND: Clinical findings, such as the inducibility of ventricular tachycardia by stress or catecholamine infusion, and the therapeutic efficacy of antiarrhythmic drugs with antiadrenergic properties suggest abnormalities of cardiac sympathetic innervation in patients with idiopathic RVO-VT. METHODS: Eight patients with idiopathic RVO-VT and a total of 29 age-matched control subjects were investigated by positron emission tomography using [11C]hydroxyephedrine (HED) (volume of distribution of [11C]HED) to assess presynaptic norepinephrine reuptake; [11C]CGP 12177 (maximal binding capacity of [11C]CGP 12177) to measure postsynaptic beta-adrenoceptor density; and oxygen-15-labeled water for quantification of myocardial blood flow (MBF). RESULTS: Both myocardial catecholamine reuptake and beta-adrenoceptor density were significantly reduced in patients with idiopathic RVO-VT. The volume of distribution of [11C]HED in patients with RVO-VT was (mean +/- SD) 41.0 +/- 13.5 versus 71.0 +/- 18.8 ml/g in control subjects (p < 0.002). The maximal binding capacity of the beta-adrenoceptor antagonist [11C] CGP 12177 was 6.8 +/- 1.2 pmol/g in patients with RVO-VT versus 10.2 +/- 2.9 pmol/g in control subjects (p < 0.004). There were no significant differences in MBF at rest (0.98 +/- 0.14 vs. 0.97 +/- 0.24 ml/min per g, p = NS) between patients with RVO-VT and control subjects. CONCLUSIONS: The findings of the present study suggest that myocardial beta-adrenoceptor downregulation in patients with RVO-VT occurs subsequently to increased local synaptic catecholamine levels caused by impaired catecholamine reuptake.
Adult↗
Atrial fibrillation: current knowledge and recommendations for management. Working Group on Arrhythmias of the European Society of Cardiology.
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Aged↗
Drug-related torsades de pointes in the isolated rabbit heart: comparison of clofilium, d,l-sotalol, and erythromycin.
Torsades de pointes is a potentially life-threatening form of polymorphic ventricular tachyarrhythmia typically seen in the presence of repolarization-prolonging agents. We investigated this particular form of tachyarrhythmia in the isolated, perfused rabbit heart. The experimental model was designed to reproduce conditions that are clinically known to be associated with an increased propensity to the development of torsades de pointes. The class III agent clofilium (1 microM) and d,l-sotalol (10 microM), as well as the antibiotic erythromycin (30-150 microM) were infused in the presence of either normal (5.88 mM) or low (1.5 mM) potassium concentration in sinus-driven or atrioventricular (AV)-blocked hearts. Ventricular tachyarrhythmias spontaneously emerged in the clofilium-, d,l-sotalol-, and erythromycin-treated AV-blocked hearts. The episodes showed typical features of torsades de pointes found in humans. They developed within 4-12 min after the onset of infusion, were normally nonsustained, and only rarely degenerated into ventricular fibrillation. Electrical stimulation at cycle lengths <600 ms and perfusion with MgSO4 suppressed arrhythmic activity. In the d,l-sotalol- and erythromycin-treated hearts, torsades de pointes occurred only in the presence of hypokalemia and bradycardia, whereas, in the presence of clofilium, bradycardia alone caused torsades de pointes. Monophasic action-potential recordings demonstrated early afterdepolarizations in endocardial and epicardial recordings. Thus the isolated AV-blocked rabbit heart represents a model for studying drug-related torsades de pointes and its mechanism.
Animals↗
Divergent effect of acute ventricular dilatation on the electrophysiologic characteristics of d,l-sotalol and flecainide in the isolated rabbit heart.
INTRODUCTION: The interaction between acute ventricular dilatation (AVD) as one aspect of ventricular dysfunction and Class I and III antiarrhythmic drugs is uncertain. We therefore investigated the effects of AVD on the electrophysiologic properties of d,l-sotalol and flecainide. METHODS AND RESULTS: The isolated rabbit heart was used as a model of AVD. The ventricular size and, therefore, the diastolic pressure were modified by sudden volume changes of a fluid-filled balloon placed in the left ventricle. Pacing was performed alternately using epi- and endocardial monophasic action potential (MAP)-pacing catheters at cycle lengths from 1,000 to 300 msec. d,l-Sotalol (10 microM) resulted in a significant (P < 0.05) lengthening of refractoriness (+13.5% +/- 3.1%), MAP duration (+14.9% +/- 3.2%), and QT interval (+15.5% +/- 4.1%) (mean +/- SEM at 1,000 msec). These effects had a reverse rate-dependence. AVD to a diastolic pressure of 30 mmHg reduced refractoriness and left ventricular MAP duration. In comparison with the control group with the same extent of AVD, d,l-sotalol still led to a significant prolongation of repolarization for all cycle lengths except 300 msec, so that its effects were not absolutely but relatively preserved. In contrast, flecainide (2 microM) had no significant effects on refractoriness or MAP duration. It led to a significant, rate-dependent increase of pacing thresholds (+47.6% +/- 8.2%), prolongation of QRS (+48.8% +/- 5.6%), and conduction time (+78.6% +/- 8.6%) (mean +/- SEM at 300 msec). In the flecainide group, AVD significantly increased the normal rate-dependent prolongation of QRS (+16.7% +/- 5.5%) and conduction time (+17.1% +/- 4.3%). CONCLUSION: Our data demonstrate that, during AVD, the Class III effect of d,l-sotalol is preserved, whereas flecainide's effect of slowing conduction is exaggerated. This may contribute to flecainide-related proarrhythmia in certain clinical situations.
Action Potentials↗
Failure to confirm ferritin and caeruloplasmin as risk factors for the angiographic extent of coronary arteriosclerosis.
BACKGROUND: It has been suggested that iron overload, as assessed by increased serum ferritin concentration, may be a risk factor for coronary artery disease (CAD). Recent studies have reported conflicting data on the role of ferritin and other parameters of oxidative metabolism in CAD. OBJECTIVE: The aim of this study was to assess the relation between the extent of CAD and parameters of oxidation. METHODS: We studied 275 patients (208 men aged 55.1 +/- 9.6 years and 67 women aged 54.6 +/- 10.0 years) who underwent coronary angiography or percutaneous transluminal coronary angioplasty for the first time. The parameters assessed were: iron, ferritin, transferrin, copper, caeruloplasmin and lipid. Cinefilms were assessed by the use of three scores: (1) Vessel score: 0-3 points; 1 point for each of the three main coronary arteries with a stenosis >70%. (2) Stenosis score: 0-32 points; the coronary artery tree was divided into eight segments that were scored 1-4 points per segment with respect to the maximal degree of stenosis. (3) Extent score: 0-100 points; extent of diffuse coronary lesions in each segment in relation to the length of the vessel. Multiple regression analyses were used to evaluate the results. RESULTS: Total cholesterol and low-density lipoprotein cholesterol (P < 0.001) in women, low-density lipoprotein cholesterol (P < 0.05) in men, and patient age showed a significant correlation with all three scores, but none of the parameters of oxidative metabolism (iron, transferrin, ferritin, copper, caeruloplasmin) correlated significantly with any of the three scores. CONCLUSION: This study demonstrated a correlation between lipoproteins and the angiographic extent of CAD, but did not confirm a role for serum ferritin and other oxidative parameters as risk factors for the extent of CAD.
Adult↗
Role of anticoagulant therapy in atrial fibrillation.
Atrial fibrillation belongs to the group of cardiovascular diseases that most frequently predispose to arterial thromboembolic events. Within the last years, the AFASAK, BAATAF, SPAF I, SPINAF, and CAFA trials have consistently demonstrated a significant, approximately 70%, risk reduction for stroke on oral anticoagulation in patients with nonrheumatic atrial fibrillation. This benefit by far outweighed the slight increase in annual major hemorrhage. Recently, additional trials (SPAF II, EAFT, SPAF III, and others) have shed further light on important questions concerning risk factors, secondary prophylaxis, the optimal intensity of anticoagulation, and the role of aspirin and other antiplatelet drugs. The main results of these studies are discussed in this review. The majority of patients with atrial fibrillation are > 65 years of age and have other clinical or echocardiographic risk factors. In these patients, adjusted-dose warfarin with target international normalized ratios (INRs) 2.0 to 3.0 is effective and safe. The risk of stroke rises with INR values < 2.0, whereas INR values > 3.0 result in an increase in intracerebral hemorrhages, especially in the very elderly. In contrast, no anticoagulation seems warranted in younger atrial fibrillation patients < 60 years of age without any clinical or echocardiographic risk factor. An overview of all randomized trials that compared aspirin with placebo and/or adjusted-dose warfarin indicates that adjusted-dose warfarin is approximately 50% more effective than aspirin for primary and secondary prevention of stroke, at least in patients with atrial fibrillation who have clinical risk factors. Therefore, oral anticoagulation clearly is the therapy of choice for prevention of thromboembolism in patients with atrial fibrillation.
Anticoagulants↗
Selection and outcome of ventricular assist device patients: the Muenster experience.
BACKGROUND: Because the number of patients on the waiting list for transplantation is increasing and the stagnation in the number of organs donated has led to a more restrictive listing for transplantation, an increased fraction of patients needs to be bridged mechanically. We examined the hypothesis that selection of these patients with regard to urgency status is critical in determining outcome. METHODS: A cohort of 631 patients referred for transplantation to our center between January 1, 1990, and December 31, 1996, was analyzed. Two hundred ninety-seven patients were listed for transplantation and 157 were given transplantation. Forty-one patients had to undergo ventricular assist device implantation (n=34, Novacor; n=6, TCI Heartmate; n=1, Medos), 39 for bridging to transplantation and 2 for permanent support. Initial transplantation evaluation data were analyzed in 3 subgroups (elective bridging, urgent bridging, emergency bridging) and compared with another and with other patients referred for transplantation, specifically those who did not have to be bridged on the waiting list. RESULTS: Patients who underwent elective or urgent assist device bridging were younger and more compromised than the rest of patients accepted on the waiting list (higher functional class, lower mean arterial pressure, lower cardiac index, lower serum sodium, higher pulmonary capillary wedge pressure). In the elective group, overall survival including perioperative mortality rate was better than in the urgent/emergency group and at least as good as in patients who were stable on the waiting list and did not undergo heart transplantation during follow-up. This should prompt cardiologists and cardiac surgeons to consider assist device implantation earlier.
Adult↗
Philosophy of antiarrhythmic approaches to ventricular tachyarrhythmias close to the 21st century.
The scientific basis and the reasoning underlying the changes in antiarrhythmic approaches to ventricular arrhythmias during recent decades are discussed. The early enthusiasm in the use of antiarrhythmic drugs in patients after myocardial infarction to prevent sudden cardiac death was severely affected by the results of the Cardiac Arrhythmia Suppression Trial (CAST) which show an increased mortality of patients on sodium-channel antagonist antiarrhythmic drugs. A transient euphoria for drugs that prolong repolarization received criticism after premature termination of the Survival With Oral D-sotalol-trial (SWORD). Recently, attention has focused on the use of the implantable cardioverter defibrillator in both secondary and primary prevention of sudden death. In contrast, catheter ablation, although very useful in supraventricular tachycardia, still plays a limited role in the management of ventricular tachyarrhythmias in the presence of organic heart disease.
Anti-Arrhythmia Agents↗
Introduction: changing trends in antiarrhythmic therapy: worldwide experience with class III agents.
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Anti-Arrhythmia Agents↗
Drugs versus devices in controlling ventricular tachycardia, ventricular fibrillation, and recurrent cardiac arrest.
Patients with symptomatic ventricular tachycardia, ventricular fibrillation, or aborted sudden cardiac death remain at high risk for arrhythmia recurrence. In recent years, strategies to treat these patients have changed. Concerns about the proarrhythmia risk and uncertain efficacy of class I agents have resulted in a shift in interest to non-class I antiarrhythmic drugs such as sotalol and amiodarone. Both drugs have class III antiarrhythmic properties (i.e., both lengthen repolarization and refractoriness); however, each also has its own additional electrophysiologic effects. Prospectively designed, randomized studies have shown that both sotalol and amiodarone have more potent antiarrhythmic actions than class I agents. However, even as the advantages of sotalol and amiodarone have been recognized, enthusiasm for nonpharmacologic modes of treatment, particularly the implantable cardioverter-defibrillator (ICD), has also markedly increased. The ICD has been shown to decrease dramatically the incidence of sudden death, which may lead to the reduction of total mortality. Whether patients with life-threatening ventricular tachyarrhythmias should be treated first with antiarrhythmic agents or with an ICD is an important question. The results of recent studies suggest that treatment with an ICD is more effective than electrophysiologically guided treatment with class I agents. However, results of prospectively designed randomized studies comparing the efficacy of the ICD with that of sotalol and amiodarone must become available before definitive recommendations can be made concerning the use of the ICD as first-line therapy in patients with ventricular tachycardia/ventricular fibrillation or aborted sudden cardiac death. In addition, there may be a significant role for the use of antiarrhythmic drugs in conjunction with ICDs.
Amiodarone↗
Antiarrhythmic therapy--future trends and forecast for the 21st century.
This article discusses recent changes in antiarrhythmic therapy, with a focus on nonpharmacologic therapy (electrode catheter ablation, implantable cardioverter-defibrillators [ICDs]), and puts them into perspective for the coming years. The treatment of supraventricular tachycardias and tachycardia involving accessory pathways is likely to remain the domain of catheter ablation. With promising new techniques under investigation, the spectrum of arrhythmias that can be cured will probably be expanded. Treatment of life-threatening ventricular arrhythmias is likely to remain the domain of the ICD in the foreseeable future. With the safety net of the ICD in place, new antiarrhythmic drugs or other forms of antiarrhythmic therapy can be developed and tested.
Anti-Arrhythmia Agents↗
Ischemic versus idiopathic cardiomyopathy: differing neurohumoral profiles despite comparable peak oxygen uptake.
OBJECTIVE: We tested the hypothesis that neurohormonal and immunological activation differs in ischemic and idiopathic dilated cardiomyopathy since recent intervention trials indicate that ischemic cardiomyopathy seems to carry a worse prognosis than idiopathic cardiomyopathy of comparable clinical severity. METHODS: In ten patients with ischemic cardiomyopathy undergoing spiroergometric evaluation venous levels of norepinephrine, epinephrine, renin, angiotensin, atrial natriuretic peptide as well as soluble interleukin-2-receptor were determined before, during and 10 min after exercise. Results were compared to sixteen patients with idiopathic cardiomyopathy with similar peak oxygen uptake (13.3+/-3 vs. 13.6+/-3 ml/kg/min; P=ns). RESULTS: In ischemic patients, norepinephrine, angiotensin, and interleukin-2 receptor levels were significantly higher before, during and after exercise. Interleukin-2-receptor levels correlated with angiotensin. CONCLUSIONS: We conclude that in ischemic as compared to idiopathic cardiomyopathy, a more pronounced activation of the sympathetic, renin-angiotensin and T-cell immune system is present at rest, during and after exercise. These data may contribute to explain differences in response to intervention and in prognosis. They warrant further investigation.
Adult↗
Sequence-specific antiproliferative effects of antisense and end-capping-modified antisense oligodeoxynucleotides targeted against the 5'-terminus of basic-fibroblast-growth-factor mRNA in coronary smooth muscle cells.
Basic fibroblast growth factor (bFGF), a potent mitogen for arterial smooth muscle cells, has been shown to play a fundamental role in the pathogenesis of arteriosclerosis and restenosis by stimulating the proliferation of vascular smooth muscle cells. We found that partially phosphorothioate-modified 15-residue antisense oligodeoxynucleotides complementary to bFGF mRNA at 0.1-2.0 microM block growth and division of cultured human and bovine coronary smooth muscle cells in a dose-dependent manner. The effect is sequence specific at low (0.1-0.5 microM) nontoxic concentrations. It is associated with inhibition of expression of pericellular and intracellular bFGF, with a decreased de novo synthesis of bFGF and is partly reversible by the addition of exogenous (recombinant) bFGF. The antisense effect lasts 48-72 h and diminishes thereafter. If the antisense oligodeoxynucleotide medium is replaced by an oligonucleotide-free medium after 24 h, the [3H]thymidine incorporation rate returns to control levels. Under the same conditions, the corresponding sense oligodeoxynucleotide exerts negligible nonspecific inhibitory actions. The antiproliferative potency of the 15-residue antisense oligodeoxynucleotide is markedly enhanced by adding 3-4 nonbase-pairing guanosine residues at the 5'- and 3'-termini of the 15-residue antisense oligonucleotide. The data implicate bFGF in the process of smooth muscle cell proliferation and an effective and specific antiproliferative potency of bFGF-specific antisense oligonucleotides. The results point to possible new therapeutic strategies for the use of antisense methodology in the suppression of post-angioplasty restenosis.
Animals↗
Patients with valvular heart disease presenting with sustained ventricular tachyarrhythmias or syncope: results of programmed ventricular stimulation and long-term follow-up.
BACKGROUND: Programmed ventricular stimulation is commonly used to guide therapy in post-myocardial infarction patients with sustained monomorphic ventricular tachycardia (VT) or ventricular fibrillation (VF). In patients with valvular heart disease presenting with spontaneous VT, VF, or syncope, the usefulness of this technique is still unclear. The aim of the study was to analyze whether programmed ventricular stimulation was helpful in guiding therapy and determining prognosis in 97 patients with valvular heart disease presenting with VT (60%), VF (18%), or syncope (22%). METHODS AND RESULTS: Patients were classified as having either predominant ventricular pressure or volume overload or no significant pressure or volume overload. Overall, sustained VT or VF was inducible in 38 (39%) and 19 (20%) patients, respectively. Forty-six (47%) patients were discharged on antiarrhythmic drugs, 29 (30%) received an implantable cardioverter-defibrillator, and 22 (23%) remained without therapy. With serial drug testing, inducibility was completely or partially suppressed in 18 (19%) and 9 (9%) patients, respectively. During a mean follow-up of 51 months (n=97), 17 patients (18%) died (sudden death, n=7; heart failure, n=4; noncardiac causes, n=6). One-, 2- and 3-year event-free survival for sudden death, sustained VT, or VF was 77%, 68%, and 61%, respectively. Only inducibility of VT during baseline study (P<.0003) and left ventricular volume overload (P<.008) were significant predictors of arrhythmic events. Recurrence of arrhythmic events occurred in 56% and 56% of patients with complete or partial suppression of inducibility during serial drug testing as well as in 10 of 19 (53%) patients without a change in inducibility. CONCLUSIONS: Although programmed ventricular stimulation seems to predict adverse outcome, serial drug testing is unreliable in guiding therapy. The type of workload imposed on the ventricles influences outcome, being worse in patients with left ventricular volume overload. Therefore, implantation of a cardioverter-defibrillator should be considered early for the management of these patients.
Adolescent↗
Subendocardial and intramural temperature response during radiofrequency catheter ablation in chronic myocardial infarction and normal myocardium.
BACKGROUND: The ability of radiofrequency energy to extend across scar tissue is unknown. We investigated the effects of radiofrequency catheter ablation on intramural temperature in experimental chronic myocardial infarction. METHODS AND RESULTS: Myocardial infarction was induced in eight dogs by a transcatheter coronary artery occlusion-reperfusion technique. The dogs were reanesthetized after 15 to 24 days. Four additional dogs served as controls. The freshly excised preparations were cut and placed in a saline bath at 37 degrees C. Temperature-guided energy applications with a preselected catheter tip temperature of 80 degrees C were performed for 60 seconds with a 7F ablation catheter. Thermoelements were inserted into the ventricular muscle at depths of 2.5 to 3.0 mm ("subendocardial") and 5.5 to 6.0 mm ("intramural"). Surviving muscle fibers were interspersed among the transmural scar tissue. The maximal temperatures did not differ significantly between normal hearts and chronic infarctions at the subendocardial (64.5+/-6.4 degrees C versus 66.7+/-6.6 degrees C) or intramural thermo-element (51.9+/-5.7 degrees C versus 52.3+/-5.7 degrees C). The myocardial temperature rise was slow, and steady-state temperatures had not been reached after 60 seconds. The intramural temperatures in chronic infarctions measured 49.0+/-4.3 degrees C after 40 seconds of energy delivery and were still below the critical tissue temperature of 50 degrees C that is necessary to induce permanent myocardial damage. CONCLUSIONS: Temperature-guided radiofrequency ablation in a dog model of chronic myocardial infarction may induce tissue temperatures >50 degrees C at a depth of 5.5 to 6.0 mm. The intramural temperature rise was slow, indicating that long energy applications might be necessary if the arrhythmogenic substrate is subepicardial.
Animals↗
A simple method for the flow cytometric analysis of intracellular antigens in whole smooth muscle cells: quantification of cyclin-dependent kinase 2.
Flow cytometry has become a widely used technique for the quantitative analysis of antigens at the single cell level. In the past, several protocols have been published for the detection of cytoplasmic and nuclear antigens in various cell lines, especially blood cells or cells growing in fluid culture. The applicability of these protocols to cells growing in a monolayer, such as smooth muscle cells (SMC) is often restricted, although flow cytometry is of great interest in the fields of arteriosclerosis and cancer research. We here describe a simple and reproducible method for the flow cytometric analysis of intracellular antigens such as cyclin-dependent kinase 2 (Cdk2) in rat aortic SMC. The sensitivity of the method was analyzed under growth and growth-inhibitory conditions using lovastatin, a cholesterol-lowering compound with antiproliferative capacity. Various antigens (Ras-protein, protein kinase C-alpha (PKC-alpha), Ki-67/MIB-1) in rat and bovine SMC were detectable using this methodology which should have a wide range of applications.
Animals↗
Mortality trials with implantable defibrillators.
The continuing disappointing results from recent major studies with antiarrhythmic drugs combined with the continuing excellent outcomes with implantable cardioverter-defibrillators is making it exceedingly difficult, ethically, to conduct future randomized trials comparing the 2 treatment options. On the other hand, the high quality of stored Holter electrograms and the therapy history retrievable from current implantable cardioverter-defibrillators creates opportunities for needed trials on drug efficacy without this ethical dilemma.
Arrhythmias, Cardiac↗