Incidence Of Ventricular Tachyarrhythmias Research Articles

Cooling Down Inflammation in the Cardiovascular System via the Nicotinic Acetylcholine Receptor.

Inflammation is a major player in many cardiovascular diseases including hypertension, atherosclerosis, myocardial infarction, and heart failure. In many individuals, these conditions coexist and mutually exacerbate each other's progression. The pathophysiology of these diseases entails the active involvement of both innate and adaptive immune cells. Immune cells that possess the α7 subunit of the nicotinic acetylcholine receptor (α7-nAChR) on their surface, have the potential to be targeted through both pharmacological and electrical stimulation of the cholinergic system. The cholinergic system regulates the inflammatory response to various stressors in different organ systems via systematically suppressing spleen-derived monocytes and chemokines, and locally improving immune cell function. Research on the cardiovascular system has demonstrated the potential for atheroma plaque stabilization and regression as favorable outcomes. Smaller infarct size and reduced fibrosis have been associated with improved cardiac function and a decrease in adverse cardiac remodeling. Furthermore, enhanced electrical stability of the myocardium can lead to a reduction in the incidence of ventricular tachyarrhythmia. Additionally, improving mitochondrial dysfunction and decreasing oxidative stress can result in less myocardial tissue damage caused by reperfusion injury. Restoring baroreflex activity and reduction in renal damage can promote blood pressure regulation and help counteract hypertension. Thus, the present review highlights the potential of nicotinic acetylcholine receptor activation as a natural approach to alleviate the adverse consequences of inflammation in the cardiovascular system.

Fragmented QRS on 12-lead electrocardiogram predicts long-term prognosis in patients with cardiac sarcoidosis.

Fragmented QRS (fQRS) on a 12-lead electrocardiogram is a known marker of fatal arrhythmias or cardiac adverse events in ischemic and non-ischemic cardiomyopathy patients. Nonetheless, the association between fQRS and clinical outcomes in patients with cardiac sarcoidosis (CS) remains unclear. Herein, we investigated whether fQRS is associated with long-term clinical outcomes in CS patients. A total of 78 patients who received immunosuppressive therapy (IST) for clinically diagnosed CS were retrospectively examined. Patients were classified into two groups according to the presence (n = 19) or absence (n = 59) of fQRS on electrocardiogram before IST. The primary outcome was the composite event of all-cause death, ventricular tachyarrhythmias (VTs), and hospitalization for heart failure. Results of late gadolinium enhancement on cardiac magnetic resonance imaging were also analyzed. During a median follow-up period of 3.7years (interquartile range: 1.6-6.2years), the primary outcome occurred more frequently in patients with fQRS than in those without (47% vs. 13%, log-rank p = 0.002). Multivariable Cox regression analyses showed that fQRS was an independent determinant of the primary outcome. The incidence of VTs, within 12months of IST initiation, was comparable between the two groups; however, late-onset VTs, defined as those occurring ≥ 12months after IST initiation, occurred more frequently in the fQRS group (21% vs. 2%, log-rank p = 0.002). The scar zone and scar border zone were greater in patients with fQRS than in those without it. In conclusion, our analysis suggests that fQRS is an independent predictor of adverse events, particularly late-onset VTs, in patients with CS.

The Risk of Ventricular Tachyarrhythmias in Patients with Antimitochondrial Antibodies-Related Noncardiac Diseases

Antimitochondrial antibodies (AMA) are serum autoantibodies specific to primary biliary cholangitis and are linked to myopathy and myocardial damage; however, the presence of AMA as a risk factor for ventricular tachyarrhythmias (VTs) has remained unknown. This study aimed to elucidate whether the presence of AMA-related noncardiac diseases indicates VTs risk.This cohort study enrolled 1,613 patients (883 females) who underwent AMA testing to assess noncardiac diseases. The incidence of VTs and supraventricular tachyarrhythmias (SVTs) from a year before the AMA testing to the last visit of the follow-up were retrospectively investigated as primary and secondary objectives. Using propensity score matching, we extracted AMA-negative patients whose covariates were matched to those of 152 AMA-positive patients. In this propensity score-matched cohort, the incidence of VTs and SVTs in the AMA-positive patients were compared with that in AMA-negative patients.The AMA-positive patients had higher estimated cumulative incidence (log-rank, P = 0.013) and prevalence (5.9% versus 0.7%, P = 0.020) of VTs than the AMA-negative patients. The presence of AMA was an independent risk factor for VTs (hazard ratio, 4.02; 95% CI, 1.44-20.01; P = 0.005). Meanwhile, AMA were associated with atrial flutter and atrial tachycardia development. In AMA-positive patients, VTs were associated with male sex, underlying myopathy, high creatine kinase levels, presence of chronic heart failure or ischemic heart disease, left ventricular dysfunction, presence of SVTs, and the electrocardiographic parameters indicating atrial disorders.The presence of AMA-related noncardiac diseases is an independent risk factor for VTs.

Genetic risk factors for dilated cardiomyopathy

Aim. To study the diagnostic significance of genetic testing in patients with dilated cardiomyopathy (DCM), identify predictors of life-threatening ventricular tachyarrhythmias (VTAs) and assess adverse clinical outcomes in different genetic groups.Material and methods. The study included 126 unrelated patients with verified DCM as follows: 70 (55,6%) probands with criteria for familial DCM and 56 (44,4%) individuals with a probable hereditary component. All patients (age, 43,1±11,3 years; men, 92 (73%); left ventricular ejection fraction, 30,6±8,43%; left ventricular enddiastolic diameter, 68,3±8,36 mm; follow-up period — median, 49 months) receive a complex of diagnostic investigations, including genetic screening using nextgeneration sequencing, followed by verification of variants by the Sanger method.Results. Pathogenic and likely pathogenic genetic variants were found in 61 (48,4%) of 126 patients with DCM. The dominant mutations were titin-truncating variants (TTNtvs), identified in 16 individuals (12,7%), and variants of lamin A/C (LMNA), identified in 13 probands (10,3%). Mutations in the other 19 genes were found in 32 (25,4%) patients. The following primary endpoints were assessed: sudden cardiac death (SCD), episodes of VTA (sustained ventricular tachycardia/ventricular fibrillation) and appropriate shocks of implanted cardiac resynchronization therapy (CRT)/cardioverter defibrillators (CVD) devices. As a result of ROC analysis, the following independent risk factors for SCD were identified: mutations in the LMNA gene (AUC, 0,760; p=0,0001) and non-sustained ventricular tachycardia (cut-off heart rate ≥161 bpm: AUC, 0,788; p=0,0001). When comparing the phenotypes and genotypes of DCM, TTNtv genotype was associated with a lower prevalence of complete left bundle branch block (χ2=7,46; p=0,024), a lower need for CRT/CVD implantation (χ2=5,70; p=0,017) and more rare episodes of sustained ventricular tachycardia/ventricular fibrillation (χ2=30,1; p=0,0001) compared with LMNA carriers. Kaplan-Meier analysis showed the worst prognosis in carriers of LMNA mutations both in relation to life-threatening VTA (log rang χ2=88,5; p=0,0001) and in achieving all unfavorable outcomes (χ2=27,8; p=0,0001) compared with groups of genenegative individuals, carriers of TTNtv and other genotypes.Conclusion. The phenotypes of DCM with TTNtv did not significantly differ in the incidence of VTAs and adverse outcomes compared with the gene-negative group and other genotypes (with the exception of LMNA). The contribution of the associations of LMNA mutations with VTAs on prognosis was confirmed, which shows the important role of LMNA genotype diagnosis for SCD risk stratification in patients with DCM.

Cardiac mechanics as predictors of left ventricular reverse remodelling in patients with dilated non-ischemic cardiomyopathy

Abstract Background and purpose The appearance of left ventricular reverse remodelling (LVRR) is associated with a better prognosis in patients with dilated non-ischemic cardiomyopathy (DCM). Our aim was to identify cardiac imaging parameters, including speckle tracking by transthoracic echocardiography (TTE) and feature tracking by CMR, associated with LVRR in a prospective cohort of patients with DCM. Methods From 2014 to 2021, 182 patients with DCM and left ventricle ejection fraction (LVEF) <40% were prospectively evaluated in our hospital. LVRR was defined as an increase in LVEF ≥10 points or absolute LVEF ≥50%, associated with a reduction in left ventricular end- diastolic diameter ≥10%. Patients underwent multimodality imaging evaluation including CMR with a 1.5 Tesla scanner, and TTE. Cardiac mechanics, including global longitudinal strain (GLS), strain rate (SR) and mechanical dispersion (MD) were measured. Results Median age of our cohort was 62.3 (14.4) years, and 67.7% were male. Most patients (>90%) were treated with beta-blockers or RASS blockers, and 67% with mineralocorticoid receptor antagonists. 30% had cardiac resynchronization therapy (CRT) and 37% had ICD as primary prevention. Mean LVEF was 31.3%. During a mean follow-up period of 35.9 (35.4) months, 38.3% of patients had LVRR. Age and gender distribution were similar in both groups. Regarding cardiovascular risk factors and pharmacological treatment, no differences were found between patients with and without LVRR. Baseline CRT therapy was not associated with LVRR (22.6% vs 34.7%; p=0.249). However, there was a trend towards higher LVRR in those who received CRT during follow-up 18.8% vs 0%; p=0.069). Patients who experienced LVRR had lower basal LVEF (23.4% vs 29%; p<0.008), as well as poorer RV function, including lower RVEF (40.5% vs 51%; p=0.006) and lower TAPSE (16 mm vs 19 mm; p=0.021). Regarding cardiac mechanics, those patients with lower GLS (−9% vs −12%; p=0.001), and higher MD (73 mm vs 55 mm; p=0,050) had LVRR more frequently during follow-up. The presence of a left bundle branch block (LBBB) contraction pattern by strain was associated with higher rate of LVRR (83.3% vs 30.4%; p=0.011). The burden of fibrosis measured by LGE with CMR was not associated with LVRR (14% vs 12%; p=NS). Patients with LVRR had a lower cardiovascular mortality (3.3 vs 14.3%; p=0.117), lower mortality due to heart failure (0% vs 12.2%; p=0.046), less heart failure hospitalizations (20% vs 46.9%; p=0.016), and a lower incidence of ventricular tachyarrhythmias (3.3% vs 18.4%; p=0.051). Conclusions LVRR in patients with DCM receiving optimized medical therapy is associated with a better prognosis. Imaging parameters, including a lower basal LVEF, RVEF, GLS and higher MD, as well as LBBB echo pattern, were associated with a higher frequency of LVRR, and might help to identify patients who could benefit from CRT/and may be helpful to stratify patients's risk. Funding Acknowledgement Type of funding sources: None.

Arrhythmia in Cardiomyopathy: Sex and Gender Differences.

There is emerging evidence for important sex differences in cardiac arrhythmias. In this up-to-date review, we summarise the differences in incidence, aetiology, treatment and prevention of ventricular arrhythmias (VAs) and sudden cardiac death (SCD) in women versus men, in the context of ischaemic and nonischaemic cardiomyopathies. The incidence of ventricular tachyarrhythmia and SCD is significantly lower in women than in men with ischaemic cardiomyopathy, whereas sex differences in nonischaemic cardiomyopathy are less clear. Women who receive a primary prevention implantable cardioverter-defibrillator (ICD) are less likely to receive appropriate activations, compared to men; however, such findings are limited by under-representation of women. Women with ischaemic cardiomyopathy have significantly lower incidence of VA and SCD compared to men and may not derive the same benefit from a primary prevention ICD. However, further clinical ICD studies are needed that ensure adequate female participation, in order to examine sex differences in outcomes in both ischaemic and nonischaemic cardiomyopathies.

Effects of Apparent Temperature on the Incidence of Ventricular Tachyarrhythmias in Patients With an Implantable Cardioverter-Defibrillator: Differential Association Between Patients With and Without Electrical Storm.

Background: Electrical storm (ES) has profound psychological effects and is associated with a higher mortality in patients with implantable cardioverter–defibrillator (ICD). Assessing the incidence and features of ES, is vital. Previous studies have shown winter peaks for ventricular tachyarrhythmia (VTA) in ICD patients. However, the effects of heat with a high relative humidity remain unclear. Thus, this study aimed to assess the nonlinear and lagged effects of apparent temperature [or heat index (HI)] on VTA among patients with and without ES after ICD implantation.Methods: Of 626 consecutive patients who had ICDs implanted from January 2004 to June 2017 at our hospital, 172 who experienced sustained VTAs in ICD recording were analyzed, and their clinical records were abstracted to assess the association between VTA incidence and HI by time-stratified case-crossover analysis. Cubic splines were used for the nonlinear effect of HI, with adjustment for air pollutant concentrations.Results: A significant seasonal effect for ES patients was noted. Apparent temperature, but not ambient temperature, was associated with VTA occurrences. The low and high HI thresholds for VTA incidence were <15° and >30°C, respectively, with a percentage change in odds ratios of 1.06 and 0.37, respectively, per 1°C. Lagged effects could only be demonstrated in ES patients, which lasted longer for low HI (in the next 4 days) than high HI (in the next 1 day).Conclusion: VTA occurrence in ICD patients was strongly associated with low HI and moderately associated with high HI. Lagged effects of HI on VTA were noted in patients with ES. Furthermore, patients with ES were more vulnerable to heat stress than those without ES. Patients with ICD implantation, particularly in those with ES, should avoid exposure to low and high HI to reduce the risk of VTAs, improve quality of life and possibly reduce mortality.

Ventricular tachyarrhythmia detection by implantable loop recording in patients with heart failure and preserved ejection fraction: the VIP-HF study.

AimsThe primary aim of the VIP‐HF study was to examine the incidence of sustained ventricular tachyarrhythmias (VTs) in heart failure (HF) with mid‐range (HFmrEF) or preserved ejection fraction (HFpEF). Secondary aims were to examine the incidence of non‐sustained VTs, bradyarrhythmias, HF hospitalizations and mortality.Methods and resultsThis was an investigator‐initiated, prospective, multicentre, observational study of patients with HF and left ventricular ejection fraction (LVEF) >40%. Patients underwent extensive phenotyping, after which an implantable loop recorder was implanted. We enrolled 113 of the planned 250 patients [mean age 73 ± 8 years, 51% women, New York Heart Association class II/III 54%/46%, median N‐terminal pro B‐type natriuretic peptide 1367 (710–2452) pg/mL and mean LVEF 54 ± 6%; 75% had LVEF >50%]. Eighteen percent had non‐sustained VTs and 37% had atrial fibrillation on Holter monitoring. During a median follow‐up of 657 (219–748) days, the primary endpoint of sustained VT was observed in one patient. The incidence of the primary endpoint was 0.6 (95% confidence interval 0.2–3.5) per 100 person‐years. The incidence of the secondary endpoint of non‐sustained VT was 11.5 (7.1–18.7) per 100 person‐years. Five patients developed bradyarrhythmias [3.2 (1.4–7.5) per 100 person‐years], three were implanted with a pacemaker. In total, 23 patients (20%) were hospitalized for HF [16.3 (10.9–24.4) per 100 person‐years]. Fourteen patients (12%) died [8.7 (5.2–14.7) per 100 person‐years]; 10 due to cardiovascular causes, and four sudden deaths, one with implantable loop recorder‐confirmed bradyarrhythmias as terminal event, three others undetermined.ConclusionDespite the lower than expected number of included patients, the incidence of sustained VTs in HFmrEF/HFpEF was low. Clinically relevant bradyarrhythmias were more often observed than expected.

Temporal Occurrence of Arrhythmic Complications After Alcohol Septal Ablation.

The temporal occurrence of arrhythmic complications after alcohol septal ablation (ASA) is unclear. As a result, the appropriate time to monitor patients after ASA is controversial. The purpose of this study is to determine the temporal occurrence of complete heart block (CHB) and ventricular tachyarrhythmia (VT) after ASA to better understand when patients can be safely discharged. Consecutive patients treated with ASA for hypertrophic cardiomyopathy from 2003 to 2019 at a tertiary referral center were reviewed retrospectively. The incidence and timing of CHB or sustained VT within 30 days post-ASA were assessed. A total of 243 patients were included in this study. Mean maximal septal thickness was 19.0±3.9 mm, and total volume of ethanol injected was 1.7±0.6 mL. CHB occurred in 59 (24.3%) patients, including transient CHB in 33 (13.6%) and permanent in 26 (10.7%). The initial episode of CHB occurred within 24 hours post-ASA in 51 (21.0%) patients, between 24 and 48 hours in 3 (1.2%), between 48 and 72 hours in 3 (1.2%), and after 72 hours in 2 (0.8%). New permanent pacemaker was placed in 46 (18.3%). Presence of baseline bundle branch block and age ≥70 were significantly associated with CHB but not CHB presenting after 24 hours. VT occurred in 3 (1.2%) patients, including 1 (0.4%) within 24 hours, 1 (0.4%) between 24 and 48 hours, and 1 (0.4%) after 72 hours. VT required cardioversion in 2 patients and new implantable cardioverter-defibrillator placement in 2. The incidence of CHB or VT presenting after 72 hours post-ASA was low. These findings suggest that timely discharge of patients without evidence of early conduction disturbances after ASA can be considered as a potentially safe management strategy, especially in patients without preexisting conduction abnormalities.

Effects of Temperature and Humidity (Heat Index) on the Incidence of Ventricular Tachyarrhythmias in Patients with an Implantable Cardioverter Defibrillator

Effects of Temperature and Humidity (Heat Index) on the Incidence of Ventricular Tachyarrhythmias in Patients with an Implantable Cardioverter Defibrillator

4178Insulin treatment is associated with increased risk of device-treated ventricular tachyarrhythmia in patients with diabetes and heart failure

Abstract Background It is debated whether insulin use is associated with a pro-arrhythmic effect. There is paucity of studies investigating this aspect in patients with heart failure (HF), where use of insulin is associated with an increased mortality risk. Purpose We aimed to investigate whether patients receiving insulin had higher risk of device-treated ventricular tachyarrhythmia (VTA) in a population of HF patients with medically treated diabetes and primary prevention implantable cardioverter defibrillator (ICD) or cardiac resynchronization therapy with defibrillator (CRT-D). Methods Information on ICD/CRT-D implantation and therapy, comorbidities, diabetes, diabetes-related complications and medication were obtained through Danish nationwide registers. From 2007 through 2016 we identified all primary prevention ICD/CRT-D implantations in HF patients with diabetes, defined as treatment with antidiabetic medication within one year prior to implantation. Patients were divided into two groups; Insulin treated vs. non-insulin treated patients. Endpoints of interest were VTA, defined as appropriate ICD therapy, and all-cause mortality. Cumulative incidence curves and adjusted Cox proportional Hazards regression analyses were used to assess risk of outcomes. Adjustment variables included age, gender, ischemic heart disease (IHD), left ventricular ejection fraction (LVEF), ICD vs. CRT-D, diuretic use (as a proxy for severity of HF), prior VTA and diabetes-related complications, identified from diagnosis codes for diabetic nephro-, retino-, and neuropathy, multiple diabetic complications and unspecified diabetic complications. Results We identified 1240 patients with HF and diabetes with a primary prevention ICD/CRT-D. The majority of patients had type 2 diabetes (94%). Of these 479 patients (39%) were treated with insulin and 761 (61%) were not. Patients were primarily male (85%) with mean age of 66.9±8.3 years, mean LVEF of 25.6±7.5%, 42% had CRT-D and 58% ICD, without differences between the groups. The insulin-treated group had a higher occurrence of diabetes-related complications (81% vs. 42%, p&lt;0.01) and IHD (95% vs. 90%, p&lt;0.01). During a mean follow-up of 3.1±2.1 years, 74 insulin treated patients (16%) and 86 non-insulin treated patients (11%) experienced VTA (p=0.034), with higher 5-year cumulative incidence of VTA in the insulin group. Insulin treatment was associated with significantly increased risk of VTA (HR = 1.45; 95% CI [1.04–2.03], p=0.031) and all-cause mortality (HR=1.27; 95% CI [1.03–1.58], p=0.027), as compared with non-insulin treated patients. Figure 1 Conclusion In HF patients with diabetes implanted with a primary prevention ICD/CRT-D, treatment with insulin was associated with a significant 45% increased risk of device-treated ventricular tachyarrhythmias and 27% increased risk of all-cause mortality. These findings support further clinical trials to evaluate the safety of insulin in patients with HF and type 2 diabetes.

Potent immunomodulation and angiogenic effects of mesenchymal stem cells versus cardiomyocytes derived from pluripotent stem cells for treatment of heart failure

BackgroundOptimal cell type as cell-based therapies for heart failure (HF) remains unclear. We sought to compare the safety and efficacy of direct intramyocardial transplantation of human embryonic stem cell-derived cardiomyocytes (hESC-CMs) and human induced pluripotent stem cell-derived mesenchymal stem cells (hiPSC-MSCs) in a porcine model of HF.MethodsEight weeks after induction of HF with myocardial infarction (MI) and rapid pacing, animals with impaired left ventricular ejection fraction (LVEF) were randomly assigned to receive direct intramyocardial injection of saline (MI group), 2 × 108 hESC-CMs (hESC-CM group), or 2 × 108 hiPSC-MSCs (hiPSC-MSC group). The hearts were harvested for immunohistochemical evaluation after serial echocardiography and hemodynamic evaluation and ventricular tachyarrhythmia (VT) induction by in vivo programmed electrical stimulation.ResultsAt 8 weeks post-transplantation, LVEF, left ventricular maximal positive pressure derivative, and end systolic pressure-volume relationship were significantly higher in the hiPSC-MSC group but not in the hESC-CM group compared with the MI group. The incidence of early spontaneous ventricular tachyarrhythmia (VT) episodes was higher in the hESC-CM group but the incidence of inducible VT was similar among the different groups. Histological examination showed no tumor formation but hiPSC-MSCs exhibited a stronger survival capacity by activating regulatory T cells and reducing the inflammatory cells. In vitro study showed that hiPSC-MSCs were insensitive to pro-inflammatory interferon-gamma-induced human leukocyte antigen class II expression compared with hESC-CMs. Moreover, hiPSC-MSCs also significantly enhanced angiogenesis compared with other groups via increasing expression of distinct angiogenic factors.ConclusionsOur results demonstrate that transplantation of hiPSC-MSCs is safe and does not increase proarrhythmia or tumor formation and superior to hESC-CMs for the improvement of cardiac function in HF. This is due to their immunomodulation that improves in vivo survival and enhanced angiogenesis via paracrine effects.

Intra-tracheal gene delivery of aerosolized SERCA2a to the lung suppresses ventricular arrhythmias in a model of pulmonary arterial hypertension

BackgroundPulmonary arterial hypertension (PAH) results in right ventricular (RV) failure, electro-mechanical dysfunction and heightened risk of sudden cardiac death (SCD), although exact mechanisms and predisposing factors remain unclear. Because impaired chronotropic response to exercise is a strong predictor of early mortality in patients with PAH, we hypothesized that progressive elevation in heart rate can unmask ventricular tachyarrhythmias (VT) in a rodent model of monocrotaline (MCT)-induced PAH. We further hypothesized that intra-tracheal gene delivery of aerosolized AAV1.SERCA2a (AAV1.S2a), an approach which improves pulmonary vascular remodeling in PAH, can suppress VT in this model. ObjectiveTo determine the efficacy of pulmonary AAV1.S2a in reversing electrophysiological (EP) remodeling and suppressing VT in PAH. MethodsMale rats received subcutaneous injection of MCT (60 mg/kg) leading to advanced PAH. Three weeks following MCT, rats underwent intra-tracheal delivery of aerosolized AAV1.S2a (MCT + S2a, N = 8) or saline (MCT, N = 9). Age-matched rats served as controls (CTRL, N = 7). The EP substrate and risk of VT were determined using high-resolution optical action potential (AP) mapping ex vivo. The expression levels of key ion channel subunits, fibrosis markers and hypertrophy indices were measured by RT-PCR and histochemical analyses. ResultsOver 80% of MCT but none of the CTRL hearts were prone to sustained VT by rapid pacing (P < .01). Aerosolized gene delivery of AAV1.S2a to the lung suppressed the incidence of VT to <15% (P < .05). Investigation of the EP substrate revealed marked prolongation of AP duration (APD), increased APD heterogeneity, a reversal in the trans-epicardial APD gradient, and marked conduction slowing in untreated MCT compared to CTRL hearts. These myocardial EP changes coincided with major remodeling in the expression of K and Ca channel subunits, decreased expression of Cx43 and increased expression of pro-fibrotic and pro-hypertrophic markers. Intra-tracheal gene delivery of aerosolized AAV1 carrying S2a but not luciferase resulted in selective upregulation of the human isoform of SERCA2a in the lung but not the heart. This pulmonary intervention, in turn, ameliorated MCT-induced APD prolongation, reversed spatial APD heterogeneity, normalized myocardial conduction, and suppressed the incidence of pacing-induced VT. Comparison of the minimal conduction velocity (CV) generated at the fastest pacing rate before onset of VT or at the end of the protocol revealed significantly lower values in untreated compared to AAV1.S2a treated PAH and CTRL hearts. Reversal of EP remodeling by pulmonary AAV1.S2a gene delivery was accompanied by restored expression of key ion channel transcripts. Restored expression of Cx43 and collagen but not the pore-forming Na channel subunit Nav1.5 likely ameliorated VT by improving CV at rapid rates in PAH. ConclusionAerosolized AAV1.S2a gene delivery selectively to the lungs ameliorates myocardial EP remodeling and VT susceptibility at rapid heart rates. Our findings highlight for the first time the utility of a non-cardiac gene therapy approach for arrhythmia suppression.

Abstract 21353: Ccn5 Gene Therapy Suppresses Arrhythmias by Reversing Fibrosis in Mice With Chronic Angiotensin II Infusion

Background: Increased angiotensin II (ANG) levels elicit profibrotic effects which promote ventricular tachyarrhythmias (VT). Hypothesis: Gene delivery of the matricellular protein CCN5 ameliorates ANG related VT by reversing fibrosis. Methods: 8-10 wk old mice underwent ANG infusion (3mg/Kg/d) for 2wk after which they received 5E11 drp AAV9.CCN5 (ANGII+CCN5, n=8) or empty vector (ANGII, n=8) and were maintained for another 2wk. Optical mapping was performed in hearts that were challenged with right atrial (RA) burst trains (20Hz, 5-20 sec) to determine VT propensity. Fibrosis was assessed using trichrome staining. Results: VT was induced in 6/8 ANG, 2/8 ANG+CCN5, and 1/3 control hearts. A total of 34 trains elicited 13 VT episodes (38.4% rate) in ANG whereas 150 trains yielded only 6 episodes in ANG+CCN5 (4.0%). ANG increased the transepicardial APD gradient by causing selective APD prolongation on the RV side which was partially reversed by CCN5. No differences in the APD gradient were found between VT (+) and VT (-) hearts. Activation mapping revealed fixed lines of conduction block leading to onset of VT in ANG hearts. In contrast, RA trains caused shifting ventricular activation patterns that were normalized following the train in ANG+CCN5 (Fig). Extensive fibrotic lesions in ANG were reversed by CCN5 (Fig). Conclusions: Reversal of fibrosis by chronic CCN5 gene therapy suppresses the incidence of ANG related VT.

Incidence and predictors of sudden arrhythmic death or ventricular tachyarrhythmias after acute coronary syndrome: An asian perspective

Current data on the risk of sudden arrhythmic death (SAD) and ventricular tachyarrhythmias (VTs) after acute coronary syndrome (ACS) in the Asian population are limited. The purpose of this study was to investigate the incidence and predictors of SAD or VT after ACS in a contemporary cohort of Chinese patients in the era of early revascularization. Consecutive patients admitted to our unit for ACS from 2010 to 2015 were retrospectively reviewed. A total of 918 patients (74.8% male, mean age 65.9 ± 13.4 years) were included in the study. Of these patients, 864 (94.1%) survived to discharge. After a mean of 34.1 ± 21.8 months, 42 (4.9%) had SAD or VT. The event rate was 0.46% in month 1, 0.26% per month in the months 2 to 6, 0.15% per month in months 6 to 12, and 1.23% per year from the second year onward. In multivariate analysis, early VT (hazard ratio [HR] 5.78, 95% confidence interval [CI] 2.63-12.72, P < .01), left ventricular ejection fraction ≤35% (HR 1.96, 95% CI 1.03-3.73, P = .04), prior coronary artery disease (HR 2.50, 95% CI 1.29-4.82, P < .01), triple-vessel disease (HR 3.69, 95% CI 1.81-7.54, P < .01), and chronic kidney disease (HR 2.43, 95% CI 1.21-4.92, P = .01) independently predicted SAD or VT. This study reports the rate of SAD or VT among Asian patients after ACS in the era of early revascularization and optimal medical therapy. Aggressive preventive measures should be considered for patients with multiple risk factors for SAD or VT, especially in the initial period after ACS.

SERCA2a upregulation ameliorates cellular alternans induced by metabolic inhibition.

Cardiac alternans has been associated with the incidence of ventricular tachyarrhythmias and sudden cardiac death. The aim of this study was to investigate the effect of impaired mitochondrial function in the genesis of cellular alternans and to examine whether modulating the sarcoplasmic reticulum (SR) Ca(2+)ameliorates the level of alternans. Cardiomyocytes isolated from control and doxycyline-induced sarco(endo)plasmic reticulum Ca(2+)-ATPase 2a (SERCA2a)-upregulated mice were loaded with two different Ca(2+)indicators to selectively measure mitochondrial and cytosolic Ca(2+)using a custom-made fluorescence photometry system. The degree of alternans was defined as the alternans ratio (AR) [1 - (small Ca(2+)intensity)/(large Ca(2+)intensity)]. Blocking of complex I and II, cytochrome-coxidase, F0F1synthase, α-ketoglutarate dehydrogenase of the electron transport chain, increased alternans in both control and SERCA2a mice (P< 0.01). Changes in AR in SERCA2a-upregulated mice were significantly less pronounced than those observed in control in seven of nine tested conditions (P< 0.04).N-acetyl-l-cysteine (NAC), rescued alternans in myocytes that were previously exposed to an oxidizing agent (P< 0.001). CGP, an antagonist of the mitochondrial Na(+)-Ca(2+)exchanger, had the most severe effect on AR. Exposure to cyclosporin A, a blocker of the mitochondrial permeability transition pore reduced CGP-induced alternans (P< 0.0001). The major findings of this study are that impairment of mitochondrial Ca(2+)cycling and energy production leads to a higher amplitude of alternans in both control and SERCA2a-upregulated mice, but changes in SERCA2a-upregulated mice are less severe, indicating that SERCA2a mice are more capable of sustaining electrical stability during stress. This suggests a relationship between sarcoplasmic Ca(2+)content and mitochondrial dysfunction during alternans, which may potentially help to understand changes in Ca(2+)signaling in myocytes from diseased hearts, leading to new therapeutic targets.

Impact of the right ventricular lead position on clinical outcome and on the incidence of ventricular tachyarrhythmias in patients with CRT-D

Data on the impact of right ventricular (RV) lead location on clinical outcome and ventricular tachyarrhythmias in cardiac resynchronization therapy with defibrillator (CRT-D) patients are limited. To evaluate the impact of different RV lead locations on clinical outcome in CRT-D patients enrolled in the Multicenter Automatic Defibrillator Implantation Trial-Cardiac Resynchronization Therapy trial. We investigated 742 of 1089 CRT-D patients (68%) with adjudicated RV lead location enrolled in the Multicenter Automatic Defibrillator Implantation Trial-Cardiac Resynchronization Therapy trial to evaluate the impact of RV lead location on cardiac events. The primary end point was heart failure or death; secondary end points included ventricular tachycardia (VT), ventricular fibrillation (VF), or death and VT or VF alone. Eighty-six patients had the RV lead positioned at the RV septal or right ventricular outflow tract region, combined as nonapical RV group, and 656 patients had apical RV lead location. There was no difference in the primary end point in patients with nonapical RV lead location versus those with apical RV lead location (hazard ratio [HR] 0.98; 95% confidence interval [CI] 0.54-1.80; P = .983). Echocardiographic response to CRT-D was comparable across RV lead location groups (P > .05 for left ventricular end-diastolic volume, left ventricular end-systolic volume, and left atrial volume percent change). However, nonapical RV lead location was associated with significantly higher risk of VT/VF/death (HR 2.45; 95% CI 1.36-4.41; P = .003) and VT/VF alone (HR 2.52; 95% CI 1.36-4.65; P = .002), predominantly in the first year after device implantation. Results were consistent in patients with left bundle branch block. In CRT-D patients, there is no benefit of nonapical RV lead location in clinical outcome or echocardiographic response. Moreover, nonapical RV lead location is associated with an increased risk of ventricular tachyarrhythmias, particularly in the first year after device implantation.

NOT INTERMEDIATE BUT HIGH SIGNAL-INTENSITY LATE GADOLINIUM ENHANCEMENT IN CMRI PREDICTS MAJOR ADVERSE CARDIOVASCULAR EVENTS IN PATIENTS WITH HYPERTROPHIC CARDIOMYOPATHY: RESULT FROM LONGITUDINAL STUDY

Late gadolinium enhancement (LGE) using cardiac magnetic resonance has emerged as the gold-standard technique for imaging of myocardial fibrosis which associated with the incidence of ventricular tachyarrhythmia and may convey prognostic importance in hypertrophic cardiomyopathy (HCM). Intermediate

Overexpression of Kir2.1 channel in embryonic stem cell-derived cardiomyocytes attenuates posttransplantation proarrhythmic risk in myocardial infarction

Cellular replacement strategies using embryonic stem cell-derived cardiomyocytes (ESC-CMs) have been shown to improve left ventricular (LV) ejection fraction and prevent LV remodeling post-myocardial infarction (MI). Nonetheless, the immature electrical phenotypes of ESC-CMs may increase the risk of ventricular tachyarrhythmias (VTs) and sudden death. To investigate whether the forced expression of Kir2.1-encoded inward rectifying K(+) channels that are otherwise absent in ESC-CMs would attenuate their proarrhythmic risk after transplantation post-MI. Mouse ESC line stably transduced with a lentivirus (LentV)-based doxycycline (DOX)-inducible system coexpressing the transgenes Kir2.1 and a dsRed (LentV-THM-Kir2.1-GFP/LentV-TR-KRAB-dsRed) was differentiated into ESC-CMs with (DOX(+)) or without (DOX(-)) treatment with DOX. Detailed in vitro and in vivo assessments of LV function and cardiac electrophysiology were measured 4 weeks after transplantation. ESC-CM DOX(+) with atrial and ventricular phenotype exhibited more hyperpolarizing resting membrane potential than did ESC-CM DOX(-) (P< .05). Transplantations of ESC-CM DOX(-) and ESC-CM DOX(+) both significantly improved LV ejection fraction, LV end-systolic diameter, end-systolic pressure-volume relationship, and positive maximal and negative pressure derivative (P< .05) at 4 weeks compared with the MI group; however, the DOX(-) group (22 of 40, 55%) had a significantly higher early sudden death rate than the DOX(+) group (13 of 40, 32.5%; P = .036). Telemetry monitoring revealed that the DOX(-) group (6.09%±3.65%) had significantly more episodes of spontaneous VT compared with the DOX(+) group (0.92%±0.81%; P< .05). In vivo programmed electrical stimulation at 2 weeks resulted in a significantly higher incidence of inducible VT in the DOX(-) group (9 of 16, 56.25%) compared with the DOX(+) group (3 of 16, 18.75%; P = .031). Forced expression of Kir2.1 in ESC-CMs improves their electrical phenotypes and lowers the risk of inducible and spontaneous VT after post-MI transplantation.

Long-term follow-up of patients with cardiac sarcoidosis and implantable cardioverter-defibrillators

Ventricular tachyarrhythmias are an important cause of morbidity and mortality in cardiac sarcoidosis. To date, the prevalence and incidence of ventricular tachycardia/ventricular fibrillation (VT/VF) in this population remain unknown. To determine the prevalence and incidence of ventricular tachyarrhythmias in patients with cardiac sarcoidosis and to identify the clinical attributes associated with appropriate implantable cardioverter-defibrillator (ICD) therapies. We studied 45 patients with ICDs, biopsy-proven systemic sarcoidosis, and cardiac involvement, as evidenced by histopathology, cardiac magnetic resonance imaging, and/or (18)F-fluoro-2-deoxyglucose-positron emission tomography imaging. Device logs and medical records were retrospectively reviewed. Appropriate ICD therapies for VT/VF were observed in 37.8% of the patients with an incidence of 15% per year. Inappropriate ICD therapies occurred in 13.3% of the patients. Longer ICD follow-up (4.5 ± 3.1 years vs 1.5 ± 1.5 years; P = .001), depressed left ventricular ejection fraction (35.5% ± 15.5% vs 50.9% ± 15.5%; P = .002), and complete heart block (47.1% vs 17.9%; P = .048) were associated with appropriate ICD therapy. While there was no significant difference in the total number of shocks/antitachycardia pacing-terminated events between primary (n = 29) and secondary (n = 16) prevention groups, there was a trend toward more events in the secondary prevention arm after 2 years. Ventricular tachyarrhythmias requiring ICD therapy were common in patients with cardiac sarcoidosis, with an estimated incidence rate of 15% per year. Longer follow-up, left ventricular systolic dysfunction, and complete heart block were associated with VT/VF. Patients with primary prevention ICDs had high rates of appropriate ICD therapy but not as high as did secondary prevention patients. In the absence of reliable risk stratification techniques, consideration should be given to prophylactic ICD implantation in patients with cardiac sarcoidosis.