Molecular ablation of ventricular tachycardia after myocardial infarction.
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ABSTRACT:
SUBMITTER: Sasano T
PROVIDER: S-EPMC1783685 | biostudies-literature | 2006 Nov
REPOSITORIES: biostudies-literature
Publications
Molecular ablation of ventricular tachycardia after myocardial infarction.
Sasano Tetsuo T McDonald Amy D AD Kikuchi Kan K Donahue J Kevin JK
Nature medicine 20061029 11
Ventricular tachycardia is a common and lethal complication after myocardial infarction. Here we show that focal transfer of a gene encoding a dominant-negative version of the KCNH2 potassium channel (KCNH2-G628S) to the infarct scar border eliminated all ventricular arrhythmias in a porcine model. No proarrhythmia or other negative effects were discernable. Our results demonstrate the potential viability of gene therapy for ablation of ventricular arrhythmias. ...[more]
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Project description:ObjectivesThe aim of this study was to evaluate the links between connexin43 (Cx43) expression, myocardial conduction velocity, and ventricular tachycardia in a model of healed myocardial infarction.BackgroundPost-infarction ventricular arrhythmias frequently cause sudden death. Impaired myocardial conduction has previously been linked to ventricular arrhythmias. Altered connexin expression is a potential source of conduction slowing identified in healed scar border tissues. The functional effect of increasing border-zone Cx43 has not been previously evaluated.MethodsTwenty-five Yorkshire pigs underwent anterior infarction by transient left anterior descending coronary artery occlusion, followed by weekly testing for arrhythmia inducibility. Twenty animals with reproducibly inducible sustained monomorphic ventricular tachycardia were randomized 2:1:1 to receive AdCx43, Adβgal, or no gene transfer. One week later, animals underwent follow-up electrophysiologic study and tissue assessment for several functional and molecular measures.ResultsAnimals receiving AdCx43 had less electrogram fractionation and faster conduction velocity in the anterior-septal border zone. Only 40% of AdCx43 animals remained inducible for ventricular tachycardia, while 100% of controls were inducible after gene transfer. AdCx43 animals had 2-fold higher Cx43 protein levels in the anterior-septal infarct border, with similar percents of phosphorylated and intercalated disk-localized Cx43 compared with controls.ConclusionsThese data mechanistically link Cx43 expression to slow conduction and arrhythmia susceptibility in the healed scar border zone. Targeted manipulation of Cx43 levels improved conduction velocity and reduced ventricular tachycardia susceptibility. Cx43 gene transfer represents a novel treatment strategy for post-infarction arrhythmias.
| S-EPMC3578694 | biostudies-literature
Project description:Arrhythmias originating in scarred ventricular myocardium are a major cause of death, but the underlying mechanism allowing these rhythms to exist remains unknown. This gap in knowledge critically limits identification of at-risk patients and treatment once arrhythmias become manifest. Here we show that potassium voltage-gated channel subfamily E regulatory subunits 3 and 4 (KCNE3, KCNE4) are uniquely upregulated at arrhythmia sites within scarred myocardium. Ventricular arrhythmias occur in areas with a distinctive cardiomyocyte repolarization pattern, where myocyte tracts with short repolarization times connect to myocytes tracts with long repolarization times. We found this unique pattern of repolarization heterogeneity only in ventricular arrhythmia circuits. In contrast, conduction abnormalities were ubiquitous within scar. These repolarization heterogeneities are consistent with known functional effects of KCNE3 and KCNE4 on the slow delayed-rectifier potassium current. We observed repolarization heterogeneity using conventional cardiac electrophysiologic techniques that could potentially translate to identification of at-risk patients. The neutralization of the repolarization heterogeneities could represent a potential strategy for the elimination of ventricular arrhythmia circuits.
| S-EPMC8837660 | biostudies-literature
Project description:BackgroundJ-waves and fragmented QRS (fQRS) on surface ECGs have been associated with the occurrence of ventricular tachyarrhythmias. Whether these non-invasive parameters can also predict ventricular tachycardia (VT) recurrence after radiofrequency catheter ablation (RFCA) is unknown. Of interest, patients with a wide QRS-complex have been excluded from clinical studies on J-waves, although a J-wave like pattern has been described for wide QRS.MethodsWe retrospectively included 168 patients (67 ± 10 years; 146 men) who underwent RFCA of post-infarct VT. J-wave pattern were defined as J-point elevation ≥ 0.1 mV in at least two leads irrespective of QRS width. fQRS was defined as various RSR` pattern in patients with narrow QRS and more than two R wave in those with wide QRS. The primary endpoint was VT recurrence after RFCA up to 24 months.ResultsJ-wave pattern and fQRS were present in 27 and 28 patients, respectively. Overlap of J-wave pattern and fQRS was observed in nine. During a median follow-up of 20 (interquartile range 9-24) months, 46 (27%) patients had VT recurrence. Kaplan-Meier curves revealed that both J-wave pattern and fQRS were associated with VT recurrence. Multivariate Cox regression analysis demonstrated that the presence of J-wave pattern (hazard ratio [HR] 2.84; 95% confidence interval [CI] 1.45-5.58; P = .002) and greater number of induced VT (HR 1.29; 95% CI 1.15-1.45; P < .001) were the independent predictors of VT recurrence.ConclusionsA J-wave pattern-but not fQRS-is independently associated with an increased risk of post-infarct VT recurrence after RFCA irrespective of QRS width. This simple non-invasive parameter may identify patients who require additional treatment.
| S-EPMC8252510 | biostudies-literature
Project description:BackgroundThe optimal timing of catheter ablation for the treatment of ventricular tachycardia (VT) in patients with ischemic cardiomyopathy remains unclear. Studies examining the impact of early preventive ablation of VT on rates of implantable cardioverter-defibrillator (ICD) therapies and mortality have been limited by small sample size.ObjectivesTo conduct a meta-analysis of randomized controlled trials (RCTs) comparing initial catheter ablation and ICD implantation (preventive ablation arm) vs ICD implantation alone (deferred ablation arm) in patients with ischemic cardiomyopathy and VT.MethodsThe primary endpoint was the incidence of appropriate ICD therapy during follow-up. Secondary endpoints included appropriate ICD shock, VT storm, procedural complications, and mortality. Sensitivity analysis, meta-regression, and evaluation of bias were performed.ResultsFour RCTs (n = 505) fulfilled inclusion criteria. During follow-up (mean >22 months for all RCTs), preventive ablation was associated with a significant reduction in ICD therapies (odds ratio [95% confidence interval]: 0.53 [0.36-0.78]). The occurrence of ICD shocks and VT storm were also significantly reduced in the preventive ablation group. Among patients with left ventricular ejection fraction (LVEF) >30%, preventive ablation was associated with marked reduction in ICD therapy when compared to deferred ablation (odds ratio [95% confidence interval]: 0.37 [0.19-0.72]). Overall, there was no difference in mortality between treatment groups.ConclusionsPreventive catheter ablation in patients with ischemic cardiomyopathy decreases ICD therapies, ICD shocks, and VT storm without increasing complications, particularly in patients with LVEF >30%. However, early preventive ablation is not associated with any benefit in mortality.
| S-EPMC8183888 | biostudies-literature
Project description:AimsComplexity of the ventricular tachycardia (VT) substrate and the size and thickness of infarction area border zones differ based on location of myocardial infarctions (MIs). These differences may translate into heterogeneity in the effectiveness of treatments. This study aims to examine the influence of infarct location on the effectiveness of VT ablation in comparison with escalated pharmacological therapy in patients with prior MI and antiarrhythmic drug (AAD)-refractory VT.Methods and resultsVANISH trial participants were categorized based on the presence or absence of an inferior MI scar. Inverse probability of treatment weighted Cox models were calculated for each subgroup. Of 259 randomized patients (median age 69.8 years, 7.0% women), 135 had an inferior MI and 124 had a non-inferior MI. Among patients with an inferior MI, no statistically significant difference in the composite primary outcome of all-cause mortality, appropriate implantable cardioverter-defibrillator (ICD) shock, and VT storm was detected between treatment arms [adjusted hazard ratio (aHR) 0.80, 95% confidence interval (CI) 0.51-1.20]. In contrast, patients with non-inferior MIs had a statistically significant reduction in the incidence of the primary outcome with ablation (aHR 0.48, 95% CI 0.27-0.86). In a sensitivity analysis of anterior MI patients (n = 83), a trend towards a reduction in the primary outcome with ablation was detected (aHR 0.50, 95% CI 0.23-1.09).ConclusionThe effectiveness of VT ablation versus escalated AADs varies based on the location of the MI. Patients with MI scars located only in non-inferior regions of the ventricles derive greater benefit from VT ablation in comparison to escalation of AADs in reducing VT-related events.
| S-EPMC9282915 | biostudies-literature
Project description:Electrical storm (ES) is a life threatening clinical situation. Though a few clinical pointers exist, the occurrence of ES in a patient with remote myocardial infarction (MI) is generally unpredictable. Genetic markers for this entity have not been studied. In the present study, we carried out genetic screening in patients with remote myocardial infarction presenting with ES by next generation sequencing and identified 25 rare variants in 19 genes predominantly in RYR2, SCN5A, KCNJ11, KCNE1 and KCNH2, CACNA1B, CACNA1C, CACNA1D and desmosomal genes - DSP and DSG2 that could potentially be implicated in electrical storm. These genes have been previously reported to be associated with inherited syndromes of Sudden Cardiac Death. The present study suggests that the genetic architecture in patients with remote MI and ES of unstable ventricular tachycardia may be similar to that of Ion channelopathies. Identification of these variants may identify post MI patients who are predisposed to develop electrical storm and help in risk stratification.
| S-EPMC5986548 | biostudies-literature
Project description:BackgroundRecent advances have enabled noninvasive mapping of cardiac arrhythmias with electrocardiographic imaging and noninvasive delivery of precise ablative radiation with stereotactic body radiation therapy (SBRT). We combined these techniques to perform catheter-free, electrophysiology-guided, noninvasive cardiac radioablation for ventricular tachycardia.MethodsWe targeted arrhythmogenic scar regions by combining anatomical imaging with noninvasive electrocardiographic imaging during ventricular tachycardia that was induced by means of an implantable cardioverter-defibrillator (ICD). SBRT simulation, planning, and treatments were performed with the use of standard techniques. Patients were treated with a single fraction of 25 Gy while awake. Efficacy was assessed by counting episodes of ventricular tachycardia, as recorded by ICDs. Safety was assessed by means of serial cardiac and thoracic imaging.ResultsFrom April through November 2015, five patients with high-risk, refractory ventricular tachycardia underwent treatment. The mean noninvasive ablation time was 14 minutes (range, 11 to 18). During the 3 months before treatment, the patients had a combined history of 6577 episodes of ventricular tachycardia. During a 6-week postablation "blanking period" (when arrhythmias may occur owing to postablation inflammation), there were 680 episodes of ventricular tachycardia. After the 6-week blanking period, there were 4 episodes of ventricular tachycardia over the next 46 patient-months, for a reduction from baseline of 99.9%. A reduction in episodes of ventricular tachycardia occurred in all five patients. The mean left ventricular ejection fraction did not decrease with treatment. At 3 months, adjacent lung showed opacities consistent with mild inflammatory changes, which had resolved by 1 year.ConclusionsIn five patients with refractory ventricular tachycardia, noninvasive treatment with electrophysiology-guided cardiac radioablation markedly reduced the burden of ventricular tachycardia. (Funded by Barnes-Jewish Hospital Foundation and others.).
| S-EPMC5764179 | biostudies-literature
Project description:Data on relative safety, efficacy, and role of different percutaneous left ventricular assist devices for hemodynamic support during the ventricular tachycardia (VT) ablation procedure are limited.We performed a multicenter, observational study from a prospective registry including all consecutive patients (N=66) undergoing VT ablation with a percutaneous left ventricular assist devices in 6 centers in the United States. Patients with intra-aortic balloon pump (IABP group; N=22) were compared with patients with either an Impella or a TandemHeart device (non-IABP group; N=44). There were no significant differences in the baseline characteristics between both the groups. In non-IABP group (1) more patients could undergo entrainment/activation mapping (82% versus 59%; P=0.046), (2) more number of unstable VTs could be mapped and ablated per patient (1.05±0.78 versus 0.32±0.48; P<0.001), (3) more number of VTs could be terminated by ablation (1.59±1.0 versus 0.91±0.81; P=0.007), and (4) fewer VTs were terminated with rescue shocks (1.9±2.2 versus 3.0±1.5; P=0.049) when compared with IABP group. Complications of the procedure trended to be more in the non-IABP group when compared with those in the IABP group (32% versus 14%; P=0.143). Intermediate term outcomes (mortality and VT recurrence) during 12±5-month follow-up were not different between both groups. Left ventricular ejection fraction ?15% was a strong and independent predictor of in-hospital mortality (53% versus 4%; P<0.001).Impella and TandemHeart use in VT ablation facilitates extensive activation mapping of several unstable VTs and requires fewer rescue shocks during the procedure when compared with using IABP.
| S-EPMC4329420 | biostudies-literature
Project description:OBJECTIVES:This study sought to characterize ventricular tachycardia (VT) ablation outcomes across nonischemic cardiomyopathy (NICM) etiologies and adjust these outcomes by patient-related comorbidities that could explain differences in arrhythmia recurrence rates. BACKGROUND:Outcomes of catheter ablation of VT in patients with NICM could be related to etiology of NICM. METHODS:Data from 2,075 patients with structural heart disease referred for catheter ablation of VT from 12 international centers was retrospectively analyzed. Patient characteristics and outcomes were noted for the 6 most common NICM etiologies. Multivariable Cox proportional hazards modeling was used to adjust for potential confounders. RESULTS:Of 780 NICM patients (57 ± 14 years of age, 18% women, left ventricular ejection fraction 37 ± 13%), underlying prevalence was 66% for dilated idiopathic cardiomyopathy (DICM), 13% for arrhythmogenic right ventricular cardiomyopathy (ARVC), 6% for valvular cardiomyopathy, 6% for myocarditis, 4% for hypertrophic cardiomyopathy, and 3% for sarcoidosis. One-year freedom from VT was 69%, and freedom from VT, heart transplantation, and death was 62%. On unadjusted competing risk analysis, VT ablation in ARVC demonstrated superior VT-free survival (82%) versus DICM (p ? 0.01). Valvular cardiomyopathy had the poorest unadjusted VT-free survival, at 47% (p < 0.01). After adjusting for comorbidities, including age, heart failure severity, ejection fraction, prior ablation, and antiarrhythmic medication use, myocarditis, ARVC, and DICM demonstrated similar outcomes, whereas hypertrophic cardiomyopathy, valvular cardiomyopathy, and sarcoidosis had the highest risk of VT recurrence. CONCLUSIONS:Catheter ablation of VT in NICM is effective. Etiology of NICM is a significant predictor of outcomes, with ARVC, myocarditis, and DICM having similar but superior outcomes to hypertrophic cardiomyopathy, valvular cardiomyopathy, and sarcoidosis, after adjusting for potential covariates.
| S-EPMC6242273 | biostudies-literature
Project description:Radiofrequency catheter ablation has become an established treatment for ventricular tachycardia. The exponential increase in procedures has provided further insights into mechanisms causing arrhythmias and identification of ablation targets with the development of new mapping strategies. Since the definition of criteria to identify myocardial dense scar, borderzone and normal myocardium, and the description of isolated late potentials, local abnormal ventricular activity and decrementing evoked potential mapping, substrate-guided ablation has progressively become the method of choice to guide procedures. Accordingly, a wide range of ablation strategies have been developed from scar homogenization to scar dechanneling or core isolation using increasingly complex and precise tools such as multipolar or omnipolar mapping catheters. Despite these advances long-term success rates for VT ablation have remained static and lower in nonischemic than ischemic heart disease because of the more patchy distribution of myocardial scar. Ablation aims to deliver an irreversible loss of cellular excitability by myocardial heating to a temperatures exceeding 50°C. Many indicators of ablation efficacy have been developed such as contact force, impedance drop, force-time integral and ablation index, mostly validated in atrial fibrillation ablation. In ventricular procedures there is limited data and ablation lesion parameters have been scarcely investigated. Since VT arrhythmia recurrence can be related to inadequate RF lesion formation, it seems reasonable to establish robust markers of ablation efficacy.
| S-EPMC7896466 | biostudies-literature