Substrate Mapping And Early Warning On Ventricular Arrhythmias

Backgrounds:Ventricular arrhythmias, including premature ventricular contractions (PVCs) and ventricular tachycardia (VT), in the absence of structural heart disease were known as idiopathic ventricular arrhythmias (IVAs), and the majority of them were IVAs originating from outflow tract (OT-IVAs) and idiopathic left ventricular tachycardia (ILVT). IVAs were previously considered "benign", however, recent studies have shown that it could result in a left ventricular dilatation or reversible cardiomyopathy in certain advance cases:For medically refractory patients, radiofrequency catheter ablation (RFCA) had become a recommended therapeutic option with high success rate and low complication risk. However, there were inherent limitations in the process of traditional mapping (activation and pace mapping). Recently, the abnormal potentials have been recorded at the target ablation sites in IVAs clinically, which was considered as arrhythmogenic substrate. And the substrate mapping and research have become a hot topic in clinical electrophysiology study.Objectives:The present study was performed under the guidance of three-dimensional electroanatomic mapping system (EAM) and traditional mapping which was to determine the relationship between the IVAs and substrate systemically. The purposes were:(1) to clarify the electrophysiological characteristics of diastolic potential (DP) and its role in guiding ablation in IVAs from the right ventricular outflow tract (RVOT-IVAs);(2) to investigate the significance of pre-potential (PP) and late potential (LP) in predicting the target ablation site of IVAs from the aortic sinus cusp (ASC-IVAs);(3) to demonstrate the variation of the electroanatomic substrate (left ventricular conduction system, LVCS and slow conduction zone, SCZ) in ILVT.Methods:Between May2009and Oct2012, patients undergoing catheter ablation of monomorphic RVOT-IVAs, ASC-IVAs and ILVT in Fuwai hospital were included prospectively. The echocardiogram, thallium scintigraphy and/or coronary angiography as well as magnetic resonance imaging were performed to exclude structural heart disease, and antiarrhythmic drugs were stopped for at least5half-life times before operation. During the process, a quadripolar electrode catheter was placed in the right ventricular apex for pacing (another one was placed in His-bundle area in ILVT patients), and surface electrogram and intracardiac electrograms were displayed on the multichannel oscilloscopic recorder (Filtered at50-500Hz) simultaneously. After the geometry of the RVOT (RVOT-IVAs study), RVOT and ASC (ASC-IVAs study) and left ventricular (ILVT study) during sinus rhythm or during IVAs were reconstructed by systematic sampling, the abnormal potentials (DP, PP, LP and LVCS) were tagged on them. After that, traditional mapping (activation mapping and pace mapping) were performed in RVOT-IVAs and ASC-IVAs patients. When the earliest ventricular activation preceding the onset of QRS and/or an average template-matching score (TM score) was≥90%were obtained, a radiofrequency application was delivered. In ILVT patients, the crossover junction area with LVCS and DP was recognized as the marker of ablation, after performing the entrainment study with a cycle length of10-20ms shorter than ILVT cycle length. Radiofrequency energy was delivered in a temperature-controlled mode with different parameters according to the location of ablation. If IVAs were accelerated or abolished within30seconds, the application was continued for120seconds. If not. the energy application was terminated and the catheter was repositioned for a repeat attempt. Successful ablation criterion was that spontaneous IVAs were abolished and not inducible even under isoproterenol infusion for at least30min.Control groups were included:RVOT-IVAs controls:10subjects with atrioventricular nodal reentrant tachycardia (AVNRT); ASC-IVAs controls:10subjects with RVOT-IVAs and10subjects with atrioventricular reentrant tachycardia mediated by a left-side accessory pathway (AVRT-L); and ILVT controls:26subjects with AVRT-L. After ablated the clinical arrhythmias successfully, EVM was performed focused on different region of the endocardium according to design of study. Abnormal potentials were also tagged and analyzed.Results:In the study of RVOT-IVAs substrate mapping,30consecutive patients with RVOT-IVAs and10controls with AVNRT were studied. DP was recorded in all patients in the vicinity of the target site, with the area of1.4±0.3cm2, the maximal amplitude of0.3±0.1mV and the distance to pulmonary valve of1.4±0.3cm, which could still be recorded after ablation except one. The areas with DP mainly located in the transitional-voltage zone (0.5-1.5mV). The target site was within the DP area in24patients (80.0%) and was on the borderline in the other6patients. There was no difference in the local activation time and TM score at the target site between patients with the target site within or on the border of the DP area (P>0.05). According to the intervals between ventricular activation and DP (V-DP) during sinus rhythm, DPs were characterized by decremental and/or automatic property, and the V-DP intervals during sinus rhythm were longer than those during IVAs (371±t57ms vs.268±64ms, P<0.001).In the predictive study of ASC-IVAs substrate mapping,29patients with ASC-IVAs and20controls (10patients with RVOT-IVAs and10patients with AVRT-L) were included. The incidence of PP and LP, the amplitude of LP before and after ablation and interval between QRS and LP (QRS-LP) after ablation were significantly greater than those of controls (P<0.05). In ASC-IVAs group, compared with unsuccessful ablation sites, the amplitude of PP at the target site was smaller (0.80±0.53mV vs.0.24±0.25mV, P-0.004) and the incidences of LP were higher (before ablation:79.3%vs.30.0%; after ablation:86.2%vs.20%, P<0.05). Besides, compared with before ablation, the amplitude of LP was obviously decreased (0.30±0.07mV vs.0.21±0.07mV, P=0.016) and QRS-LP was longer in21patients (117±28ms vs.138±31ms, P=0.026) at the target site after ablation. The sensitivity and specificity of prolonged QRS-LP for predicting target were72%and100%.In the study of substrate and possible reentrant mechanism in ILVT,20patients with ILVT and26controls AVRT-L were included. In ILVT group, LVCS was distinguished into3types:left bundle branch was divided into two discrete fascicles without interconnections, three separate fascicles and fanlike structure distribution over septum broadly. There was no statistical differences in the length of fascicles between patients and controls (P>0.05). SCZ was located at inferoposterior septum in17patients, at inferior apex in1patient and at posterior and mid-septal with2SCZs in2patients. At the crossover junction area with LVCS and DP, with the size of1.5±0.4cm2, could achieved concealed entertainment and/or ablation successfully. However, in controls, the length (16.1±3.3mm vs.20.4±4.7mm,P=.048) and size (1.8±0.3cm2vs.2.5±0.5cm2, P=0.006) of6subjects were significantly shorter and smaller than those of ILVT group. Conclusions:DP and its border region, located at the transitional-voltage zone, were associated with the target site of RVOT-IVAs, the decremental and/or automatic property suggested that it might originate from tissue with incomplete differentiation or migrate from the original atrioventricular node.Many patterns of abnormal potentials were recorded at the target site during ablation of ASC-IVAs. LP, which might the arrhythmogenic substrate of IVAs, has greater significance for guiding ablation than PP. The prolonged interval between QRS and LP might become a sensitive and specific maker for predicting successful ablation. The anatomy of the LVCS and SCZ is highly variable in ILVT, which made the reentrant mechanism complicated. The crossover junction area with LVCS and SCZ might be a marker of ablation.Although it was not involve the anatomical and histological research, and the clinical significance of arrhythmogenic substrate has not yet clear, the present have demonstrated the clinical value and reliability of substrate mapping in mapping and ablation of IVAs. Substrate mapping might provide a new mapping strategy in IVAs, especially in patients without spontaneous IVAs or patients with multiple failures of ablation. Background:Chronic heart failure (CHF) represented a major public health problem worldwide owing to high prevalence, poor prognosis and extreme expenditure. Despite of advances in understanding and management of patients with CHF, especially in CHF with reduced ejection fraction (CHF-rEF), the morbidity and mortality as well as re-hospitalization rates were still high. The5-year mortality was still>50%, but the current data of long-term prognosis of CHF-REF in China were still missing. In the dead, greater than half of the deaths were due to sustained ventricular tachycardia (VT) and ventricular fibrillation (VF) leading to sudden cardiac death (SCD). Therefore, prediction and prevention of SCD have been recognized as pivotal step toward improved outcomes. Several indicators have been recognized as potential predictors of SCD, such as hemodynamic status, electrophysiological parameters, biomarkers and inflammatory factors, but the sensitivity and specificity were not satisfied so far. The susceptibility of SCD was a heritable trait, and it has been demonstrated that single nucleotide polymorphisms (SNPs) of NOSIAP were associated with risk of SCD in several independent populations. Cellular electrophysiological study showed that overexpression of NOSIAP resulted in up-regulation of the nNOS-NO signaling pathway, which might abbreviate the action potential duration (APD) via inhibition of L-type calcium current (Ica-)L and activation of delayed rectifier potassium current (Ikr).Objective:The purposes of this multicenter, prospective study were (1) to reveal the clinical characteristics, current treatment status and long-term prognosis; and (2) to investigate the association between genetic variations of NOS1AP and prognosis of patients with CHF-rEF in Chinese Han population. Methods:Consecutive patients with CHF-rEF referred from13hospitals in mainland China were recruited. The CHF-rEF was diagnosed based on medical history, symptoms, physical signs and echocardiography on admission. Enrolment criteria included:CHF caused by idiopathic dilated cardiomyopathy (DCM) or ischaemic cardiomyopathy (ICM); left ventricular ejection fraction (LVEF)≤45%in DCM or≤50%in ICM and in New York Heart Association (NYHA) classes II-IV. Patients were excluded if they had incomplete clinical data, malignancies, severe systemic disease, pregnancy, or unwillingness to participate. Subjects without structural heart disease were considered as control group, and divided into ward controls and community controls. Follow-up data were obtained by regular visits at outpatient clinics or telephone contact, and the endpoints included all cause death and SCD. The independent predictors of endpoints and difference of prognosis in DCM and ICM were determined using univariate and multivariate Cox regression analyses.Participants were genotyped for6SNPs of NOS1AP and the genetic associations with mortality as well as QTc interval were analyzed. Patients with failure of genotyping, sustained arrhythmias and pacemaker dependency and using medicine that might alter QT interval were excluded. For statistical analysis, univariate and multivariate Cox regression and multiple linear regression models were used.Results:A total of2154patients with CHF-rEF were enrolled and followed up successfully in this prospective study. ACEIs/ARBs, β-blockers, diuretics and aldosterone receptor antagonists were dominant prescribed drugs with the rates of65.97%,68.29%,74.37%and74.61%, respectively. After a median follow-up of52months,850(39.46%) patients died, of whom302(35.53%) were SCD. Unadjusted rates of all-cause mortality and SCD were higher in DCM than those in ICM (p<0.001for both), but were comparable after adjustment for co-variables (p=0.387and p=0.483respectively). The predictors for mortalities in DCM and ICM were different, however, co-morbidities (eg, hypertension), advanced NHYA class, VT/VF, prolonged QRS duration, decreased LVEF and high level of creatinine were independent predictors of mortalities in the entire cohort, and ACEIs/ARB, β-blockers and statins were associated with better prognosis. Survived from sustained VT/VF episodes had the highest predictive value for SCD (HR,4.230;95%CI,2.500-7.157; P<0.001). A total of1428patients with CHF-rEF and480control subjects were genotyped. During a median follow-up period of52months,467(32.70%) patients died, of whom169(36.19%) were SCD. The A allele of rs12567209was associated with greater risk of all-cause death and SCD (HR1.381,95%CI1.124-1.698, P=0.002and HR1.645,95%CI1.184-2.287, P=0.003). After adjusting for co-variables, significances remained (HR1.309,95%CI1.054-1.624, P=0.015and HR1.601,95%CI1.129-2.271, P=0.008). The A allele was also associated with a prolonged of QTc interval by4.04ms in the entire cohort (P=0.026).Conclusions:Despite under current standard therapies, patients with CHF-rEF still had a poor prognosis in China, especially in DCM. The co-morbidities, advanced NYHA class, decreased LVEF and VT/VF were identified as independent predictors of SCD. While use of ACEIs/ARB,β-blockers and statins were multivariate predictors for survival. Independent predictors for mortality might be identified according to different etiologies and it would be useful for the prognostication and treatment of those patients individually.The A allele of rs12567209in NOSIAP not only increased the risk of all-cause death and SCD in patients with CHF-rEF, but also associate with prolongation of QTc interval in Chinese Han population, which suggesting the prognostic values of rs12567209might be mediated by other mechanisms rather than ventricular repolarization.