G. Breithardt

Genotype-Phenotype Correlation in the Long-QT Syndrome Gene-Specific Triggers for Life-Threatening Arrhythmias

Background—The congenital long-QT syndrome (LQTS) is caused by mutations on several genes, all of which encode cardiac ion channels. The progressive understanding of the electrophysiological consequences of these mutations opens unforeseen possibilities for genotype-phenotype correlation studies. Preliminary observations suggested that the conditions (“triggers”) associated with cardiac events may in large part be gene specific. Methods and Results—We identified 670 LQTS patients of known genotype (LQT1, n=371; LQT2, n=234; LQT3, n=65) who had symptoms (syncope, cardiac arrest, sudden death) and examined whether 3 specific triggers (exercise, emotion, and sleep/rest without arousal) differed according to genotype. LQT1 patients experienced the majority of their events (62%) during exercise, and only 3% occurred during rest/sleep. These percentages were almost reversed among LQT2 and LQT3 patients, who were less likely to have events during exercise (13%) and more likely to have events during rest/sleep (29% and 39%). Lethal and nonlethal events followed the same pattern. Corrected QT interval did not differ among LQT1, LQT2, and LQT3 patients (498, 497, and 506 ms, respectively). The percent of patients who were free of recurrence with &bgr;-blocker therapy was higher and the death rate was lower among LQT1 patients (81% and 4%, respectively) than among LQT2 (59% and 4%, respectively) and LQT3 (50% and 17%, respectively) patients. Conclusions—Life-threatening arrhythmias in LQTS patients tend to occur under specific circumstances in a gene-specific manner. These data allow new insights into the mechanisms that relate the electrophysiological consequences of mutations on specific genes to clinical manifestations and offer the possibility of complementing traditional therapy with gene-specific approaches.

Systemic Inflammatory Parameters in Patients With Atherosclerosis of the Coronary and Peripheral Arteries

Plasma concentration of markers of inflammation are increased in patients with atherosclerosis. However, it is unclear whether the pattern and magnitude of this increase vary with the site and extent of disease. In 147 patients undergoing semiquantitative coronary angiography, we measured the acute-phase reactants C-reactive protein (CRP) or serum amyloid A (SAA); the proinflammatory cytokine interleukin 6 (IL-6); the active and total fractions of the anti-inflammatory cytokine transforming growth factor-beta (TGF-beta); the macrophage activation marker neopterin; and the infection marker procalcitonin. Compared with 62 patients without either coronary artery disease (CAD) or peripheral artery disease (PAD), 57 patients with CAD but no PAD showed greater median CRP (0. 4 versus 0.2 mg/dL, P=0.004) and IL-6 (3.8 versus 1.6 pg/mL, P=0. 007) levels and a lower level of active-TGF-beta (57 versus 100 ng/mL, P=0.038). Moreover, CRP, IL-6, and neopterin levels showed a positive and the active TGF-beta level a negative correlation with the extent of coronary atherosclerosis. Compared with these 57 patients with CAD alone, 15 patients with PAD and CAD had higher median levels of SAA (17 versus 7 mg/mL, P=0.008), IL-6 (12 versus 4 pg/mL, P=0.002), neopterin (14 versus 11 mg/dL, P=0.006), and total TGF-beta (11834 versus 6417 ng/L, P=0.001). However, these strong univariate associations of markers of inflammation and atherosclerosis were lost in multivariate analysis once age, sex, and high density lipoprotein cholesterol or fibrinogen were taken into account. Increased plasma levels of CRP, SAA, IL-6, TGF-beta, neopterin, and procalcitonin constitute an inflammatory signature of advanced atherosclerosis and are correlated with the extent of disease but do not provide discriminatory diagnostic power over and above established risk factors.

Dynamics of mitral regurgitant flow and orifice area. Physiologic application of the proximal flow convergence method: clinical data and experimental testing.

The proximal flow convergence method, a quantitative color Doppler flow technique, has been validated recently for calculating regurgitant flow and orifice area. We investigated the potential of the method as a tool to study different pathophysiological mechanisms of mitral valve incompetence by assessing the time course of regurgitant flow and orifice area and analyzed the implications for quantification of mitral regurgitation. Methods and ResultsFifty-six consecutive patients with mitral regurgitation of different etiologies were studied. The instantaneous regurgitant flow rate Q(t) was computed from color M-mode recordings of the proximal flow convergence region and divided by the corresponding orifice velocity V(t) to obtain the instantaneous orifice area At). Regurgitant stroke volume (RSV) was obtained by integrating Q(t). Mean regurgitant flow rate Qm was calculated by RSV divided by regurgitation time. Peak-to-mean regurgitant flow rates Qp/Qm and orifice areas A(p)/Am were calculated to assess the phasic character of Qt)and A(t). In the first 24 patients (group 1), computation of Qm and RSV from the color Doppler recordings was compared with the conventional pulsed Doppler method (r = .94, SEE=29.4 mL/s and r = .95, SEE=9.7 mL) as well as with angiography (r,=.93 and r,=.94, P < .001). The temporal variation of Q(t) and A(t) was studied in the next 32 patients (group 2): In functional regurgitation in dilated cardiomyopathy (n= 12), there was a constant decrease in At) throughout systole with an increase during left ventricular relaxation; Ap/Am was 5.49±3.17. In mitral valve prolapse n=6), A(t) was small in early systole, increasing substantially in midsystole, and decreasing mildly during left ventricular relaxation; Ap/Am was 2.48±0.26. In rheumatic mitral regurgitation n= 14), a roughly constant regurgitant orifice area during most of systole was found in 4 patients. In the other patients there was significant variation of ASt) and the time of its maximum; Ap/Am was 1.81 ±0.56. ANOVA demonstrated that the differences in Ap/Am were related to the etiology of mitral regurgitation (P < .0001). To verify that the calculated variation in regurgitant orifice area during the cardiac cycle reflects an actual variation, the ability of the method to predict a constant orifice area throughout systole was tested experimentally in a canine model of mitral regurgitation. Five flow stages were produced by implanting fixed grommet orifices of different sizes into the anterior mitral leaflet. A constant regurgitant orifice area was correctly predicted throughout systole with a mean percent error of −1.8±4% (from −6.9% to ±5.8%); the standard deviation of the individual curves calculated at 10% intervals during systole averaged 13.3% (from 3.6% to 19.6%). In addition, functional mitral regurgitation caused by ventricular dysfunction was produced pharmacologically in five dogs, and the color M-mode recordings of the proximal flow convergence region were obtained with the transducer placed directly on the heart instead of the chest, thus ruling out a significant effect of translational motion on the observed flow pattern. The pattern of regurgitant flow variation was identical to that observed in patients. ConclusionsThe proximal flow convergence method demonstrates that regurgitant flow and orifice area vary throughout systole in distinct patterns characteristic of the underlying mechanism of mitral incompetence. Therefore, in addition to the potential of the method as a tool to quantify mitral regurgitation, it allows analysis of the pathophysiology of regurgitation in the individual patient, which may be helpful in clinical decision making. Calculating mitral regurgitant flow rate and volume from the time-varying proximal flow field (ie, without assuming a constant orifice area that would produce overestimation in individual patients) provides excellent agreement with independent techniques and agrees well with angiography.

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.

Relationship of Late Loss in Lumen Diameter to Coronary Restenosis in Sirolimus-Eluting Stents

Background—Observed rates of restenosis after drug-eluting stenting are low (<10%). Identification of a reliable and powerful angiographic end point will be useful in future trials. Methods and Results—Late loss (postprocedural minimum lumen diameter minus 8-month minimum lumen diameter) was measured in the angiographic cohorts of the SIRIUS (n=703) and E-SIRIUS (n=308) trials. Two techniques, the standard normal approximation and an optimized power transformation, were used to predict binary angiographic restenosis rates and compare them with observed restenosis rates. The mean in-stent late loss observed in the SIRIUS trial was 0.17±0.45 mm (sirolimus) versus 1.00±0.70 mm (control). If a normal distribution was assumed, late loss accurately estimated in-stent binary angiographic restenosis for the control arm (predicted 35.4% versus observed 35.4%) but underestimated it in the sirolimus arm (predicted 0.6% versus observed 3.2%). Power transformation improved the reliability of the estimate in the sirolimus arm (predicted 3.2% [CI 1.0% to 6.7%]) with similar improvements in the E-SIRIUS trial (predicted 4.0% [CI 1.2% to 7.0%] versus observed 3.9%). In the sirolimus-eluting stent arm, in-stent late loss correlated better with target-lesion revascularization than in-segment late loss (c-statistic=0.915 versus 0.665). Conclusions—Because distributions of late loss with a low mean are right-skewed, the use of a transformation improves the accuracy of predicting low binary restenosis rates. Late loss is monotonically correlated with the probability of restenosis and yields a more efficient estimate of the restenosis process in the era of lower binary restenosis rates.

Radiofrequency Catheter Ablation of Sustained Ventricular Tachycardia in Idiopathic Dilated Cardiomyopathy

BACKGROUND The feasibility of radiofrequency (RF) catheter ablation for the treatment of sustained ventricular tachycardia (VT) in patients with coronary artery disease and remote myocardial infarction has recently been demonstrated. At present, therapeutic options for VT in patients with idiopathic dilated cardiomyopathy (DCM) include antiarrhythmic drugs and implantable cardioverter/defibrillators (ICD). The purpose of the present study was to investigate the feasibility of RF catheter ablation in patients with idiopathic DCM who could not be adequately treated by conventional treatment modalities because of incessant or frequent, recurrent VT. METHODS AND RESULTS RF current application for ablation of 9 VTs (mean cycle length, 402 +/- 78 ms) was attempted in 8 patients with idiopathic DCM (4 men, 4 women; mean age, 54 +/- 6 years; mean left ventricular ejection fraction, 30 +/- 9%). Inclusion criteria for ablation were incessant VT (n = 4) or frequent, recurrent VT reproducibly inducible with programmed electrical stimulation (n = 5). Three patients had suffered aborted sudden cardiac death, and 2 had experienced syncope. Two patients were artificially ventilated and catecholamine dependent for hemodynamic reasons at the time of attempted ablation. Potential target sites for RF current application were identified by detailed endocardial mapping during sinus rhythm, activation and entrainment mapping during VT, and pace mapping. After 7 +/- 5 RF pulses (range, 2 to 18 pulses; median, 6 pulses) applied with 32 +/- 7 W for 39 +/- 9 seconds, 6 of the 9 target VTs (67%) were rendered noninducible (4 of 4 incessant VTs and 2 of 5 chronic recurrent VTs). In 6 patients, VTs with ECG morphologies other than the target VTs were inducible after RF catheter ablation. Seven patients were on antiarrhythmic drugs during the ablation procedure and during the follow-up period of 8 +/- 5 months (range, 2 to 17 months). One patient received an ICD before RF ablation, 4 patients after RF ablation, and 1 patient after ablation of an incessant VT and before attempted ablation of frequent, recurrent VTs. One patient underwent heart transplantation 5 months after ablation in end-stage heart failure. There were no acute complications during the mapping and ablation procedure. During the follow-up period, 1 patient had been resuscitated from ventricular fibrillation 6 weeks after ablation and finally died of congestive heart failure 2 weeks later. No further episodes of incessant VT occurred in the patients who had undergone RF current application for ablation of incessant VT. A complete prevention of VT could be achieved in 2 of 8 patients, whereas in 5 patients, VT episodes were stored in the ICD devices during follow-up. CONCLUSIONS The results of the present study indicate that RF current application for ablation of VT in a select group of patients with idiopathic DCM is feasible. The efficacy of RF ablation may be high in patients presenting with incessant VT, whereas the success rate seems to be only moderate in patients with chronic recurrent VT. In all patients, additional treatment options, including antiarrhythmic drugs, ICDs, and/or heart transplantation, were applied after RF ablation, indicating that RF ablation for this indication may be an adjunctive and not a curative treatment option.

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.

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.

Heparin-Induced Overexpression of Basic Fibroblast Growth Factor, Basic Fibroblast Growth Factor Receptor, and Cell-Associated Proteoheparan Sulfate in Cultured Coronary Smooth Muscle Cells

Basic fibroblast growth factor (bFGF), a potent mitogen for arterial smooth muscle cells (SMCs), plays a pivotal role in the pathogenesis of arteriosclerosis and restenosis. Heparin in nanogram quantities may promote or even be required for binding of bFGF to its cognate receptor. Conversely, heparin in microgram doses is a strong inhibitor of arterial SMC replication in vitro and in vivo. Bovine coronary SMCs (cSMCs) express bFGF, bFGF receptor (FGF-R1), and cell membrane-integrated proteoheparan sulfate (HSPG). These three molecules are known to form a trimolecular complex that promotes signal transduction and mitogenesis. The bFGF synthesized by cSMCs is distributed to an intracellular and a pericellular compartment. Resting cultured cells retain about 80% of their bFGF intracellularly; 20% is found in the pericellular region. During proliferation, 70% to 80% of total bFGF is expressed in the pericellular compartment. Trypsinization generates soluble forms of the complex of bFGF with the ectodomains of the bFGF receptor and cell membrane-integrated HSPG in the pericellular compartment, thus allowing quantification of pericellular bFGF by a highly specific enzyme immunoassay. Standard heparin inhibits the proliferation of cSMCs by up to 80% in a concentration range between 10 and 100 micrograms/mL medium in a dose-dependent manner but increases the protein content of cSMCs compared with proliferating control cells. The heparin-induced increase in cellular protein content includes a 60% to 100% increase in the expression of pericellular bFGF, FGF-R1, and cell membrane-integrated HSPG. Thus, under heparin treatment, the heparan sulfate side chains of cell membrane-integrated HSPG incorporate more [35S]sulfate, and the proportion of [35S]heparan sulfate among total glycosaminoglycans increases from 36% to 52%. Fluorescence-activated cell sorting analysis and [3H]thymidine incorporation experiments provide evidence for multiple effects of heparin, including blocks at early and late checkpoints of the cell cycle in heparin-treated cells. These results indicate that heparin, despite its anti-proliferative potency, stimulates the expression of all components of the bFGF system even in coronary SMCs in which growth is inhibited.