Martin Borggrefe

Genetic basis and molecular mechanism for idiopathic ventricular fibrillation

Ventricular fibrillation causes more than 300, 000 sudden deaths each year in the USA alone,. In approximately 5–12% of these cases, there are no demonstrable cardiac or non-cardiac causes to account for the episode, which is therefore classified as idiopathic ventricular fibrillation (IVF). A distinct group of IVF patients has been found to present with a characteristic electrocardiographic pattern. Because of the small size of most pedigrees and the high incidence of sudden death, however, molecular genetic studies of IVF have not yet been done. Because IVF causes cardiac rhythm disturbance, we investigated whether malfunction of ion channels could cause the disorder by studying mutations in the cardiac sodium channel gene SCN5A. We have now identified a missense mutation, a splice-donor mutation, and a frameshift mutation in the coding region of SCN5A in three IVF families. We show that sodium channels with the missense mutation recover from inactivation more rapidly than normal and that the frameshift mutation causes the sodium channel to be non-functional. Our results indicate that mutations in cardiac ion-channel genes contribute to the risk of developing IVF.

Efficacy of antiarrhythmic drugs in patients with arrhythmogenic right ventricular disease. Results in patients with inducible and noninducible ventricular tachycardia

BackgroundVentricular tachyarrhythmias are the major clinical manifestation of arrhythmogenic right ventricular disease. Although antiarrhythmic therapy has been widely advocated, there is only limited information available on the efficacy of antiarrhythmic drugs in these patients. Methods and ResultsThe short and long-term efficacies of various antiarrhythmic agents were retrospectively and prospectively analyzed in 81 patients (mean age, 39±14 years; range, 16–68 years; 61.7% males) with arrhythmogenic right ventricular disease. In 42 patients with inducible ventricular tachycardia during programmed ventricular stimulation, the following efficacy rates were obtained: class Ia and lb drugs (n = 18), 5.6%; class Ic drugs (n = 25), 12%; β-blockers (n = 8), 0%; sotalol (n = 38), 68.4%; amiodarone (n = 13), 15.4%; verapamil (n = 5), 0%; and drug combinations (n = 26), 15.4%. Only one of the 10 patients not responding to sotalol was treated effectively by amiodarone, whereas the remaining nine patients proved to be drug refractory toward all other drugs tested (3.8±2.3 drugs, including amiodarone in five cases) and underwent nonpharmacological therapy. During a follow-up of 34±25 months, three of the 31 patients (9.7%) discharged on pharmacological therapy had nonfatal recurrences of ventricular tachycardia after 0.5, 51, and 63 months, respectively. In 39 patients with noninducible ventricular tachycardia during programmed ventricular stimulation, the following efficacy rates were observed: class Ia and Ib drugs (n = 16), 0%; class Ic agents (n = 23), 17.4%; β-blockers (n = 7), 28.6%; sotalol (n = 35), 82.8%; amiodarone (n = 4), 25%; verapamil (n = 24), 50%; and drug combinations (n = 11), 9.1%. During a follow-up of 14±13 months, four of 33 patients (12.1%) discharged on antiarrhythmic drugs had nonfatal relapses of their clinical ventricular arrhythmia. ConclusionsThus, in arrhythmogenic right ventricular disease, sotalol proved to be highly effective in patients with inducible as well as noninducible ventricular tachycardia. Patients with inducible ventricular tachycardia not responding to sotalol are likely to not respond to other antiarrhythmic drugs and should be considered for nonpharmacological therapy without further drug testing. Amiodarone did not prove to be more effective than sotalol and may not be an alternative because of frequent side effects during long-term therapy, especially in young patients. Verapamil and β-blockers were effective in a considerable number of patients with noninducible ventricular tachycardia and may be a therapeutic alternative in this subgroup. Class I agents appear to be rarely effective in the treatment of both inducible and noninducible ventricular tachycardia in arrhythmogenic right ventricular disease.

Regional myocardial sympathetic dysinnervation in arrhythmogenic right ventricular cardiomyopathy. An analysis using 123I-meta-iodobenzylguanidine scintigraphy.

BackgroundIn patients with arrhythmogenic right ventricular cardiomyopathy (ARVC), the frequent provocation of ventricular tachycardia during exercise, the sensitivity toward catecholamines, and the response toward antiarrhythmic drug regimen with antiadrenergic properties suggest an involvement of the sympathetic nervous system in arrhythmogenesis. Methods and ResultsTo analyze the presence, extent, and location of impaired myocardial sympathetic innervation in ARVC, 123I–meta-iodobenzylguanidine (123I-MIBG) scintigraphy was performed in 48 patients with ARVC. For comparison, 9 patients with idiopathic ventricular tachycardia and a control group of 7 patients without heart disease were investigated. In patients with ARVC, the clinical sustained (n=25; 52%) or nonsustained (n=23; 48%) ventricular tachycardia originated in the right ventricular outflow tract in 38 patients (79%), whereas in the remaining 10 patients (21%), the site of origin was the apical (n=5) or inferior (n=5) right ventricle. In 33 patients (69%), nonsustained or sustained ventricular tachycardia was provocable by exercise (n=28 of 48; 58%) and/or by isoproterenol infusion (n= 16 of 37; 43%), whereas programmed ventricular stimulation induced sustained or nonsustained ventricular tachycardia in 16 patients each (33% each). With I MIBG scintigraphy, the right ventricle was not visible in any patient. No areas of intense 11I-MIBG uptake (“hot spots”) were observed. All patients of the control group and 7 of 9 patients (78%) with idiopathic ventricular tachycardia showed a uniform tracer uptake in the left ventricle. In contrast, only 8 of 48 ARVC patients (17%) showed a homogeneous distribution of 123I-MIBG uptake, whereas 40 patients (83%) demonstrated regional reductions or defects of tracer uptake. In 3 of 48 patients (6%), the defect area was < 15%; in 21 patients (44%), it was 15% to 30%; and in 16 patients (33%), it was >30% of the polar map area of the left ventricle (mean, 23±15%; range, 0% to 57%). In 38 of 40 patients (95%) with an abnormal 123I-MIBG scan, reduced tracer uptake was located in the basal posteroseptal left ventricle, involving the adjacent lateral wall in 10, the anterior wall in 2, and the apex in 12 patients. Only 2 patients demonstrated isolated defects of the anterior or lateral wall; one involved the apex. Perfusion abnormalities in the areas of 123I-MIBG defects were excluded by stress/redistribution 201Tl single-photon emission computed tomography scintigraphy and by normal coronary angiograms in all patients. Abnormalities in 123I-MIBG scintigraphy in patients with ARVC correlated with the site of origin of ventricular tachycardia, demonstrating a regionally reduced tracer uptake in 36 of 38 patients (95%) with right ventricular outflow tract tachycardia compared with only 4 of 10 patients (40%) with other right ventricular origins of tachycardia. There was no correlation between the results of 123I-MIBG scintigraphy and the extent of right ventricular contraction abnormalities, right ventricular ejection fraction, biopsy results, coronary anatomy, or left ventricular involvement in ARVC. ConclusionsIn patients with ARVC, regional abnormalities of sympathetic innervation are frequent and can be demonstrated by 123I-MIBG scintigraphy. Sympathetic denervation appears to be the underlying mechanism of reduced 123I-MIBG uptake and may be related to frequent provocation of ventricular arrhythmias by exercise or catecholamine exposure in ARVC. Therefore, in patients with ARVC, the noninvasive detection of localized sympathetic denervation by 123I-MIBG imaging may have implications for the early diagnosis and for the choice of antiarrhythmic drugs in the treatment of arrhythmias.

Abnormalities of Cardiac Sympathetic Innervation in Arrhythmogenic Right Ventricular Cardiomyopathy Quantitative Assessment of Presynaptic Norepinephrine Reuptake and Postsynaptic β-Adrenergic Receptor Density With Positron Emission Tomography

BACKGROUNDnThe frequent provocation of ventricular tachycardia by stress or catecholamines and the efficacy of antiarrhythmic drugs with antiadrenergic properties suggest an involvement of the cardiac adrenergic system in arrhythmogenesis in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC). Previous studies demonstrated abnormalities of the presynaptic uptake-1 assessed by (123)I-MIBG-single-photon emission computed tomography.nnnMETHODS AND RESULTSnThis study investigated neuronal reuptake of norepinephrine (uptake-1) and beta-adrenergic receptor density in 8 patients with ARVC and 29 age-matched control subjects. All subjects underwent positron emission tomography with the volume of distribution (V(d)) of [(11)C]hydroxyephedrine ((11)C-HED) used to assess presynaptic norepinephrine reuptake, the maximum binding capacity (B(max)) of [(11)C]CGP-12177 ((11)C-CGP-12177) to assess postsynaptic beta-adrenergic receptor density, and [(15)O]H(2)O for quantification of myocardial blood flow. Patients with ARVC demonstrated a highly significant global reduction in postsynaptic beta-adrenergic receptor density compared with that in control subjects (B(max) of (11)C-CGP-12177: 5.9+/-1.3 vs 10.2+/-2.9 pmol/g tissue, P<0.0007), whereas the presynaptic uptake-1 tended toward reduction only (V(d) of (11)C-HED: 59.1+/-25.2 vs 71.0+/-18.8 mL/g tissue, NS). There were no differences in myocardial blood flow between the groups, and plasma norepinephrine was within normal limits in patients and control subjects.nnnCONCLUSIONSnThe findings demonstrate a significant reduction of myocardial beta-adrenergic receptor density in patients with ARVC. This may result from a secondary downregulation after increased local synaptic norepinephrine levels caused by increased firing rates of the efferent neurons or as the result of impaired presynaptic catecholamine reuptake. These findings give new insights into the pathophysiology of arrhythmogenesis in ARVC, with potential impact on diagnostic evaluation and therapeutic management.

Ventricular vulnerability assessed by programmed ventricular stimulation in patients with and without late potentials.

Late potentials can be recorded noninvasively with the averaging technique in about one-third of patients with coronary heart disease in whom ventricular tachyarrhythmias have not been previously documented. The prognostic significance of these findings has not yet been established. Therefore, the presence or absence of late potentials was correlated to the results of programmed ventricular stimulation (single and double premature stimuli during sinus rhythm and a paced ventricular rhythm, cycle lengths 500, 430, 370, and 330 msec) in 110 male patients (age 52 + 5.9 years, mean SD). The end of the stimulation protocol was reached as soon as 4 or more ventricular echo beats (defined as an abnormal response) were induced. Late potentials were recorded in 40 patients (36.4%). The duration of late potentials was less than 20 msec in 12 patients, between 20 and 39 msec in 16 patients, and 40 msec or more in another 12 patients. In those patients with late potentials, four or more consecutive ventricular echo beats (repetitive ventricular response) were recorded more frequently (63%) than in those without (33%). The incidence of abnormal responses increased from 42% in those with late potentials of less than 20 msec to 56% in those with late potentials of between 20 to 39 msec and to 92% in those with late potentials of 40 msec or more. There was a significant correlation between left ventricular function and presence and duration of late potentials (X2 = 12.96; p < .0115) and between left ventricular function and the results of programmed ventricular stimulation (X2 = 16.24; p < .0003). In contrast, late potentials and the results of programmed ventricular stimulation were less closely associated (X2 = 5.49; p < .0643). In conclusion, late potentials proved to be a noninvasive indicator of abnormal left ventricular function, indicating an increase in ventricular vulnerability in patients that were free of symptomatic ventricular tachyarrhythmias. The predictive value of both late potentials and repetitive ventricular responses alone or in combination with regard to the occurrence of ventricular tachycardia or sudden death is still to be established. Circulation 68, No. 2, 275-281, 1983. IT HAS RECENTLY become possible to record electrical activity originating from abnormally conducting myocardium from the body surface with high-gain amplification and the averaging technique.1 16 These signals, which result from delayed ventricular activation (late potentials), have been recorded in patients with documented ventricular tachycardia. In a pilot study in postmyocardial infarction patients, we were able to show that the presence of late potentials predicted subsequent occurrence of ventricular tachycardia. 5 However, late potentials can also be recorded in about From the Medical Hospital B (Cardiology), University of Dusseldorf. Supported by the Johann A. Wiulfing Stiftung and the Sonderforschungsbereich 30 (Kardiologie) of the Deutsche Forschungsgemeinschaft. Address for correspondence: Prof. Dr. G. Breithardt, Medizinische Klinik B, Universitat Dusseldorf, Moorenstrasse 5, D-4000 Dusseldorf, Germany. Received July 23, 1982; revision accepted April 25, 1983. one-third of patients without previously documented ventricular tachycardia, especially those with left ventricular akinesia or dyskinesia.3 The significance of these findings with respect to predicting the development of ventricular tachycardia has not yet been established. The purpose of this study was to correlate the presence of late potentials to the results of programmed ventricular stimulation in a group of patients in whom ventricular tachycardia has not been previously documented to get more insight into the mechanisms and potential prognostic value of late potentials in these patients. Patients and methods. One hundred ten male patients (mean age + SD 52 + 5.9 years) without previously documented tachycardia or fibrillation and without a history of resuscitation or syncope were studied. The findings in 27 patients concerning the noninvasive recording of late potentials have been included in a previous report.3 All patients were informed about the Vol. 68, No. 2, August 1983 275 by guest on July 14, 2011 http://circ.ahajournals.org/ Downloaded from

Potential Benefit From Implantable Cardioverter-Defibrillator Therapy in Patients With and Without Heart Failure

BACKGROUNDnWhether patients with heart failure derive a benefit from therapy with implantable cardioverter-defibrillators (ICDs) has been questioned. The purpose of this study was to investigate whether New York Heart Association (NYHA) functional class had an impact on the potential benefit from ICD therapy as assessed from data stored in the memory of ICDs.nnnMETHODS AND RESULTSnBetween 1989 and 1996, 603 patients (77% men; 59% with coronary artery disease and 16% with dilated cardiomyopathy; age, 57+/-13 years; ejection fraction, 44+/-18%) were treated with an ICD with extended memory function (storage of electrograms and/or RR intervals from treated episodes) in combination with endocardial lead systems. The stages of heart failure (NYHA functional class I through III) at implantation were correlated with overall mortality and the recurrence of fast ventricular tachyarrhythmias (>240 bpm) during follow-up. The potential benefit of the device was estimated as the difference between overall mortality and the hypothetical death rate had the device not been implanted. The latter was based on the recurrence of fast and, without termination by the devices, presumably fatal ventricular tachyarrhythmias. In the overall group, a significant difference between hypothetical death rate and overall mortality was observed (13.9%, 23.5%, and 26.6% at 1, 3, and 5 years, respectively) that suggested a benefit from ICD implantation. In patients in NYHA class I, the estimated benefit, which increased over time, was 15.2%, 29.2%, and 35.6% after 1, 3, and 5 years, respectively. In patients in NYHA class II or III, the estimated benefit increased until the third year (21.8% and 21.9%, respectively) and then remained constant until the fifth year (22.9% and 23.8%, respectively). Even those patients in NYHA class III with a history of decompensated heart failure benefited from ICD implantation.nnnCONCLUSIONSnAnalysis of stored ECG data suggests that in patients with a history of ventricular tachycardia or ventricular fibrillation, ICD therapy may lead to a prolongation of life in NYHA classes I through III. The initial benefit is greatest in patients in NYHA class II and class III, but the estimated benefit might persist longest for patients in NYHA class I.

Implantable cardioverter defibrillator therapy in patients with arrhythmogenic right ventricular cardiomyopathy, long QT syndrome, or no structural heart disease

Recent technical developments in implantable cardioverter defibrillator (ICD) systems and reduced operative mortality and morbidity rates associated with ICD implantation have expanded the indications for ICD treatment of ventricular tachyarrhythmias. This review summarizes data regarding ICD therapy in patients with arrhythmogenic right ventricular cardiomyopathy, long QT syndrome, and idiopathic ventricular fibrillation and presents preliminary concepts for identification of patients who will benefit more from ICD therapy than from pharmacologic and other nonpharmacologic approaches. Recent studies suggest that ICD therapy may improve long-term prognosis by reliably terminating recurrences of life-threatening arrhythmias. Appropriate ICD therapies during mean follow-up periods of 12 to 36 months occurred in 30% of patients with idiopathic ventricular fibrillation to 50% of patients with arrhythmogenic right ventricular cardiomyopathy and long QT syndrome. At present no strict recommendations can be given for ICD implantation in these patients. However, at least in cardiac arrest survivors in whom the clinical arrhythmia is not reproducibly inducible during electrophysiologic study, ICD therapy appears to be superior to other treatment options with regard to long-term survival and thus should be considered as a first-line treatment. We are hopeful that continued study of long-term follow-up with and without ICD treatment and improved risk stratification will lead to better criteria for selection of treatment options.

A prospective randomized cross-over comparison of mono- and biphasic defibrillation using nonthoracotomy lead configurations in humans.

Biphasic Defibrillation with Nonthoracotomy Leads. Introduction: For current implantable defibrillators, the nonthoracotomy approach to implantation fails in a substantial number of patients. In a prospective randomized cross‐over study the defibrillation efficacy of a standard monophasic and a new biphasic waveform was compared for different lead configurations.

Results and Realistic Expectations with Transvenous Lead Systems

Since the implantable cardioverter defibrillator [ICD) was introduced by Mirowski in 1980, thousands of patients have received the device and frequently survived several episodes of otherwise sudden cardiac death. A higher efficacy in the prevention of sudden cardiac death than with any other therapeutic option could be demonstrated.^ The use of the ICD has increased significantly in North America. However, currently, especially in Europe and Japan, only a minority of patients who survive an episode of sudden cardiac death receive an ICD. Implantations in patients who are at risk of sudden cardiac death but have had no VT or VF, are still rare. Major obstacles to a widespread use of the device are the high costs of the device and the need for tboracotomy with a significant perioperative morbidity and mortality. Therefore an implantable unit resembling present pacemaker implantations with their low perioperative morbidity and mortality and short hospital stay would be desirable. Until recently ICDs had to be implanted like the first pacemakers in the 1960s using an epicardial approach for the leads and an abdominal pouch for the device. The size of present devices does not allow a pectoral implantation. Superior results of defibrillation efficacy with epicardial patches limited the use of transvenous leads. Problems arose when investigational nonthoracotomy lead systems were implanted in a small series of patients in 1987 (Fndotak^. CPI, St. Paul, MN^) and 1990 [DF electrode system, Teletronics, Englewood, CO^). These were

Autosomal recessive long-QT syndrome (Jervell Lange-Nielsen syndrome) is genetically heterogeneous

Jervell Lange-Nielsen syndrome (JLNS) is a recessive disorder with congenital deafness and long-QT syndrome (LQTS). Mutations in the potassium-channel gene KVLQT1 (LQTS 1) have been identified in JLNS and in autosomal-dominant LQTS as well. We performed haplotype analysis with microsatellite markers in a Lebanese family with JLNS, but failed to detect linkage at LQTS 1. Moreover, using this approach, we excluded two other ion-channel genes involved in autosomal-dominant LQTS, HERG (LQTS 2) and SCN5A (LQTS 3). Our findings indicate that JLNS is genetically heterogeneous and that, in this family, an unknown LQTS gene causes the disease.