Antiarrhythmic and Anti-Inflammatory Effects of Sacubitril/Valsartan on Post-Myocardial Infarction Scar.

BACKGROUND: Sacubitril/valsartan (Sac/Val) is superior to angiotensin-converting enzyme inhibitors in reducing the risk of heart failure hospitalization and cardiovascular death, but its mechanistic data on myocardial scar after myocardial infarction (MI) are lacking. The objective of this work was to assess the effects of Sac/Val on inflammation, fibrosis, electrophysiological properties, and ventricular tachycardia inducibility in post-MI scar remodeling in swine. METHODS: After MI, 22 pigs were randomized to receive ß-blocker (BB; control, n=8) or BB+Sac/Val (Sac/Val, n=9). The systemic immune response was monitored. Cardiac magnetic resonance data were acquired at 2-day and 29-day post MI to assess ventricular remodeling. Programmed electrical stimulation and high-density mapping were performed at 30-day post MI to assess ventricular tachycardia inducibility. Myocardial samples were collected for histological analysis. RESULTS: Compared with BB, BB+Sac/Val reduced acute circulating leukocytes (P=0.009) and interleukin-12 levels (P=0.024) at 2-day post MI, decreased C-C chemokine receptor type 2 expression in monocytes (P=0.047) at 15-day post MI, and reduced scar mass (P=0.046) and border zone mass (P=0.043). It also lowered the number and mass of border zone corridors (P=0.009 and P=0.026, respectively), scar collagen I content (P=0.049), and collagen I/III ratio (P=0.040). Sac/Val reduced ventricular tachycardia inducibility (P=0.034) and the number of deceleration zones (P=0.016). CONCLUSIONS: After MI, compared with BB, BB+Sac/Val was associated with reduced acute systemic inflammatory markers, reduced total scar and border zone mass on late gadolinium-enhanced magnetic resonance imaging, and lower ventricular tachycardia inducibility.

Impact of preventive substrate catheter ablation on implantable cardioverter-defibrillator interventions in patients with ischaemic cardiomyopathy and infarct-related coronary chronic total occlusion.

AIMS: Primary prevention patients with ischaemic cardiomyopathy and chronic total occlusion of an infarct-related coronary artery (CTO) are at a particularly high risk of implantable cardioverter-defibrillator (ICD) therapy occurrence. The trial was designed to evaluate the efficacy of preventive CTO-related substrate ablation strategy in ischaemic cardiomyopathy patients undergoing primary prevention ICD implantation. METHODS AND RESULTS: The PREVENTIVE VT study was a prospective, multicentre, randomized trial including ischaemic patients with ejection fraction ≤40%, no documented ventricular arrhythmias (VAs), and evidence of scar related to the coronary CTO. Patients were randomly assigned 1:1 to a preventive substrate ablation before ICD implantation or standard therapy with ICD implantation only. The primary outcome was a composite of appropriate ICD therapy or unplanned hospitalization for VAs. Secondary outcomes included the primary outcome's components, the incidence of appropriate ICD therapies, cardiac hospitalization, electrical storm, and cardiovascular (CV) mortality. Sixty patients were included in the study. During the mean follow-up of 44.7 ± 20.7 months, the primary outcome occurred in 5 (16.7%) patients undergoing preventive substrate ablation and in 13 (43.3%) patients receiving only ICD [hazard ratio (HR): 0.33; 95% confidence interval (CI): 0.12-0.94; P = 0.037]. Patients in the preventive ablation group also had fewer appropriate ICD therapies (P = 0.039) and the electrical storms (Log-rank: P = 0.01). While preventive ablation also reduced cardiac hospitalizations (P = 0.006), it had no significant impact on CV mortality (P = 0.151). CONCLUSION: Preventive ablation of the coronary CTO-related substrate in patients undergoing primary ICD implantation is associated with the reduced risk of appropriate ICD therapy or unplanned hospitalization due to VAs.

Inhibition of IL-1 Ameliorates Cardiac Dysfunction and Arrhythmias in a Murine Model of Kawasaki Disease.

BACKGROUND: Kawasaki disease (KD) is an acute febrile illness and systemic vasculitis often associated with cardiac sequelae, including arrhythmias. Abundant evidence indicates a central role for IL (interleukin)-1 and TNFα (tumor necrosis factor-alpha) signaling in the formation of arterial lesions in KD. We aimed to investigate the mechanisms underlying the development of electrophysiological abnormalities in a murine model of KD vasculitis. METHODS: Lactobacillus casei cell wall extract-induced KD vasculitis model was used to investigate the therapeutic efficacy of clinically relevant IL-1Ra (IL-1 receptor antagonist) and TNFα neutralization. Echocardiography, in vivo electrophysiology, whole-heart optical mapping, and imaging were performed. RESULTS: KD vasculitis was associated with impaired ejection fraction, increased ventricular tachycardia, prolonged repolarization, and slowed conduction velocity. Since our transcriptomic analysis of human patients showed elevated levels of both IL-1ß and TNFα, we asked whether either cytokine was linked to the development of myocardial dysfunction. Remarkably, only inhibition of IL-1 signaling by IL-1Ra but not TNFα neutralization was able to prevent changes in ejection fraction and arrhythmias, whereas both IL-1Ra and TNFα neutralization significantly improved vasculitis and heart vessel inflammation. The treatment of L casei cell wall extract-injected mice with IL-1Ra also restored conduction velocity and improved the organization of Cx43 (connexin 43) at the intercalated disk. In contrast, in mice with gain of function of the IL-1 signaling pathway, L casei cell wall extract induced spontaneous ventricular tachycardia and premature deaths. CONCLUSIONS: Our results characterize the electrophysiological abnormalities associated with L casei cell wall extract-induced KD and show that IL-1Ra is more effective in preventing KD-induced myocardial dysfunction and arrhythmias than anti-TNFα therapy. These findings support the advancement of clinical trials using IL-1Ra in patients with KD.

Cardiac monoamine oxidase-A inhibition protects against catecholamine-induced ventricular arrhythmias via enhanced diastolic calcium control.

AIMS: A mechanistic link between depression and risk of arrhythmias could be attributed to altered catecholamine metabolism in the heart. Monoamine oxidase-A (MAO-A), a key enzyme involved in catecholamine metabolism and longstanding antidepressant target, is highly expressed in the myocardium. The present study aimed to elucidate the functional significance and underlying mechanisms of cardiac MAO-A in arrhythmogenesis. METHODS AND RESULTS: Analysis of the TriNetX database revealed that depressed patients treated with MAO inhibitors had a lower risk of arrhythmias compared with those treated with selective serotonin reuptake inhibitors. This effect was phenocopied in mice with cardiomyocyte-specific MAO-A deficiency (cMAO-Adef), which showed a significant reduction in both incidence and duration of catecholamine stress-induced ventricular tachycardia compared with wild-type mice. Additionally, cMAO-Adef cardiomyocytes exhibited altered Ca2+ handling under catecholamine stimulation, with increased diastolic Ca2+ reuptake, reduced diastolic Ca2+ leak, and diminished systolic Ca2+ release. Mechanistically, cMAO-Adef hearts had reduced catecholamine levels under sympathetic stress, along with reduced levels of reactive oxygen species and protein carbonylation, leading to decreased oxidation of Type II PKA and CaMKII. These changes potentiated phospholamban (PLB) phosphorylation, thereby enhancing diastolic Ca2+ reuptake, while reducing ryanodine receptor 2 (RyR2) phosphorylation to decrease diastolic Ca2+ leak. Consequently, cMAO-Adef hearts exhibited lower diastolic Ca2+ levels and fewer arrhythmogenic Ca2+ waves during sympathetic overstimulation. CONCLUSION: Cardiac MAO-A inhibition exerts an anti-arrhythmic effect by enhancing diastolic Ca2+ handling under catecholamine stress.

Lifetime exercise dose and ventricular arrhythmias in patients with mitral valve prolapse.

AIMS: Patients with mitral valve prolapse (MVP) have high risk of life-threatening ventricular arrhythmias (VAs). Data on the impact of exercise on arrhythmic risk in these patients are lacking. We explored whether lifetime exercise dose was associated with severe VA and with established risk factors in patients with MVP. Furthermore, we explored the circumstances at the VA event. METHODS AND RESULTS: In this retrospective cohort study, we included patients with MVP and assessed lifetime exercise dose as metabolic equivalents of task (MET) hours/week. Severe VA was defined as sustained ventricular tachycardia or fibrillation, aborted cardiac arrest, and appropriate shock by a primary preventive implantable cardioverter defibrillator. We included 136 MVP patients (48 years [interquartile range (IQR) 35-59], 61% female), and 17 (13%) had previous severe VA. The lifetime exercise dose did not differ in patients with and without severe VA (17 MET h/week [IQR 9-27] vs. 14 MET h/week [IQR 6-31], P = 0.34). Lifetime exercise dose > 9.6 MET h/week was a borderline significant marker for severe VA (OR 3.38, 95% CI 0.92-12.40, P = 0.07), while not when adjusted for age (OR 2.63, 95% CI 0.66-10.56, P = 0.17). Ventricular arrhythmia events occurred most frequently during wakeful rest (53%), followed by exercise (29%) and sleep (12%). CONCLUSION: We found no clear association between moderate lifetime exercise dose and severe VA in patients with MVP. We cannot exclude an upper threshold for safe levels of exercise. Further studies are needed to explore exercise and risk of severe VA.

Optimizing electrophysiology studies to prevent sudden cardiac death after myocardial infarction.

AIMS: This study assessed associations of minimum final extrastimulus coupling interval utilized within electrophysiology study (EPS) after myocardial infarction (MI) and possible site of origin of induced ventricular tachycardia (VT) with long-term occurrence of spontaneous ventricular tachyarrhythmia and long-term survival. METHODS AND RESULTS: This prospective study recruited consecutive patients with left ventricular ejection fraction (LVEF) ≤ 40% who underwent EPS days 3-5 after MI between 2004 and 2017. Positive EPS was defined as sustained monomorphic VT cycle length ≥200 ms for ≥10 s or shorter duration if haemodynamic compromise occurred. Each of the four extrastimuli was shortened by 10 ms at a time, until it failed to capture the ventricle (ventricular refractoriness) or induced ventricular tachyarrhythmia. Outcomes included spontaneous ventricular tachyarrhythmia occurrence and all-cause mortality. Shorter coupling interval length of final extrastimulus that induced VT was associated with higher risk of spontaneous ventricular tachyarrhythmia (P < 0.001). Significantly higher rates of spontaneous ventricular tachyarrhythmia (65.2% vs. 23.2%; P < 0.001) were observed for final coupling interval at EPS <200 ms vs. >200 ms. Right bundle branch block (RBBB) morphology of induced VT, with possible site of origin from the left ventricle, was associated with all-cause mortality [hazard ratio (HR) 3.2, P = 0.044] and a composite of spontaneous ventricular tachyarrhythmia recurrence or mortality (HR 1.8, P = 0.043). CONCLUSION: Ventricular tachycardia induced with shorter coupling intervals was associated with higher risk of spontaneous ventricular tachyarrhythymia on follow-up, indicating that the final extrastimulus coupling interval at EPS early after MI should be determined by ventricular refractoriness. Induced VT with possible origin from left ventricle was associated with increased risk of spontaneous ventricular tachyarrhythmia recurrence or death.

Right ventricular function is a predictor for sustained ventricular tachycardia requiring anti-tachycardic pacing in arrhythmogenic ventricular cardiomyopathy: insight into transvenous vs. subcutaneous implantable cardioverter defibrillator insertion.

AIMS: Arrhythmogenic right ventricular cardiomyopathy (ARVC) patients develop ventricular arrhythmias (VAs) responsive to anti-tachycardia pacing (ATP). However, VA episodes have not been characterized in accordance with the device therapy, and with the emergence of the subcutaneous implantable cardioverter defibrillator (S-ICD), the appropriate device prescription in ARVC remains unclear. Study aim was to characterize VA events in ARVC patients during follow-up in accordance with device therapy and elicit if certain parameters are predictive of specific VA events. METHODS AND RESULTS: This was a retrospective single-centre study utilizing prospectively collated registry data of ARVC patients with ICDs. Forty-six patients were included [54.0 ± 12.1 years old and 20 (43.5%) secondary prevention devices]. During a follow-up of 12.1 ± 6.9 years, 31 (67.4%) patients had VA events [n = 2, 6.5% ventricular fibrillation (VF), n = 14], 45.2% VT falling in VF zone resulting in ICD shock(s), n = 10, 32.3% VT resulting in ATP, and n = 5, 16.1% patients had both VT resulting in ATP and ICD shock(s). Lead failure rates were high (11/46, 23.9%). ATP was successful in 34.5% of patients. Severely impaired right ventricular (RV) function was an independent predictor of VT resulting in ATP (hazard ratio 16.80, 95% confidence interval 3.74-75.2; P < 0.001) with a high predictive accuracy (area under the curve 0.88, 95%CI 0.76-1.00; P < 0.001). CONCLUSION: VA event rates are high in ARVC patients with a majority having VT falling in the VF zone resulting in ICD shock(s). S-ICDs could be of benefit in most patients with ARVC with the absence of severely impaired RV function which has the potential to avoid consequences of the high burden of lead failure.

[Implantable cardioverter-defibrillator explosion after gunshot: when the device protects not only from arrhythmic death]. / Esplosione di defibrillatore impiantabile in seguito a colpo d'arma da fuoco: quando il defibrillatore non previene soltanto la morte aritmica.

A 70-year-old man presented to the emergency department with accidental gunshot wound at left hemithorax and left shoulder/arm. Initial clinical assessment showed stable vital signs and an implantable cardioverter-defibrillator (ICD) protruding outside from large wound in the infraclavicular region. The ICD, previously implanted for secondary prevention of ventricular tachycardia, appeared burned and the battery was exploded. Urgent chest computed tomography scan was performed with evidence of left humeral fracture without significant arterial injury. The ICD generator was disconnected from passive fixation leads and removed. The patient was stabilized and the humeral fracture was fixed. Then lead extraction was successfully performed in a hybrid operating room with cardiac surgery standby. The patient was discharged in good clinical conditions after reimplantation of a novel ICD in the right infraclavicular region.Emerging technologies are promising in making lead extraction safer and more accessible for patients worldwide. This case report provides the most up-to-date indications and procedural approaches for lead extraction and insights on the future trends in this field.

Preventive substrate ablation in chronic post-myocardial infarction patients with high-risk scar characteristics for ventricular arrhythmias: rationale and design of PREVENT-VT study.

BACKGROUND: Recent studies showed that an early strategy for ventricular tachycardia (VT) ablation resulted in reduction of VT episodes or mortality. Cardiac magnetic resonance (CMR)-derived border zone channel (BZC) mass has proved to be a strong non-invasive predictor of VT in post-myocardial infarction (MI). CMR-guided VT substrate ablation proved to be safe and effective for reducing sudden cardiac death (SCD) and VA occurrence. METHODS: PREVENT-VT is a prospective, randomized, multicenter, and controlled trial designed to evaluate the safety and efficacy of prophylactic CMR-guided VT substrate ablation in chronic post-MI patients with CMR-derived arrhythmogenic scar characteristics. Chronic post-MI patients with late gadolinium enhancement (LGE) CMR will be evaluated. CMR images will be post-processed and the BZC mass measured: patients with a BZC mass > 5.15 g will be eligible. Consecutive patients will be enrolled at 3 centers and randomized on a 1:1 basis to undergo a VT substrate ablation (ABLATE arm) or optimal medical treatment (OMT arm). Primary prevention ICD will be implanted following guideline recommendations, while non-ICD candidates will be implanted with an implantable cardiac monitor (ICM). The primary endpoint is a composite outcome of sudden cardiac death (SCD) or sustained monomorphic VT, either treated by an ICD or documented with ICM. Secondary endpoints are procedural safety and efficiency outcomes of CMR-guided ablation. DISCUSSION: In some patients, the first VA episode causes SCD or severe neurological damage. The aim of the PREVENT-VT is to evaluate whether primary preventive substrate ablation may be a safe and effective prophylactic therapy for reducing SCD and VA occurrence in patients with previous MI and high-risk scar characteristics based on CMR. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04675073, registered on January 1, 2021.

Echocardiographic Predictors of Ventricular Tachyarrhythmias in Patients With Cardioverter-Defibrillator Implanted for Primary Prevention of Sudden Cardiac Death. Results From a two-Year Prospective Follow-up Study.

Aim      To compare variables of transthoracic EchoCG for determining echocardiographic predictors and their prognostic role in the development of persistent paroxysmal ventricular tachyarrhythmias (VT) in patients with ischemic CHF who had been implanted with a cardioverter defibrillator (CD) for primary prevention of sudden cardiac death.Material and methods  This single-site prospective study included 176 patients with CHF of ischemic origin aged 58.7±7.4 years with a left ventricular ejection fraction (LV EF) of 30 % [25; 34] % who had been implanted with CD. The follow-up duration was 24 months. The primary endpoint was a newly developed persistent paroxysm of VT (duration ≥30 sec) detected in the "monitored" VT area or a VT paroxysm that required electric treatment. The echocardiographic picture was evaluated by 28 variables. Statistical analysis was performed with the c2, Fisher's, and Mann-Whitney tests, and the one-factor logistic regression (LR). Prognostic models were developed with a multifactorial LR. The model accuracy was evaluated by 4 metrics: area under the ROC (AUC), sensitivity, specificity, and diagnostic efficacy.Results The primary endpoint was observed in 60 (34 %) patients. Mean time to a persistent VT episode was 19.2±0.8 months (95 % confident interval (CI): 17.5-20.8). Superior-inferior dimensions of the right and left atria (RA and LA, respectively) and the left atrial volume (LAv) were independent predictors for VT. The odds of VT development in patients of the study cohort increased with RAl ≥4.5 cm (odds ratio (OR), 1.6; 95 % CI: 1.4-1.9; р=0.03), LAl ≥5.5 cm (OR, 2.5; 95 % CI: 1.01-6.1; р=0.04), LAv ≥95 ml (OR, 3.2; 95 % CI: 1.3-17.5; р=0.01). A comprehensive analysis of echocardiographic variables proved the prognostic potential of LAv that was linearly associated with the development of VT. The metrics of the best prognostic model were AUC 0.7±0.07 with 95 % CI: 0.54-0.83; specificity, 20.9 %; sensitivity, 95.7 %; and diagnostic efficacy, 47 %.Conclusion      This study allowed evaluation of capabilities of transthoracic EchoCG for predicting the probability of VT in patients with CHF of ischemic origin and reduced LV EF. It was shown that linear and volumetric atrial dimensions could be used for stratification of risk of VT and for determining the tactics for primary prevention of sudden cardiac death in this patient category.

Effects of obesity on arrhythmic events and survival in patients with an implantable cardioverter defibrillator.

Background    Studies have shown that increased body weight and obesity may be associated with an increased risk of arrhythmic events. The aim of this study was to evaluate the effect of obesity on the risk of arrhythmic events, hospitalization, and death in patients who received implantable cardioverter defibrillator (ICD) therapy for primary or secondary prevention.Material and Methods    A single-center, prospective, observational study was conducted. Patients with body mass index (BMI) <30 kg / m2 were classified as non-obese, and patients with BMI ≥30 kg / m2 were classified as obese. The primary endpoints were arrhythmic events and device interventions. The secondary endpoints were all-cause mortality, cardiac mortality, cardiac rehospitalization, and a composite endpoint of mortality and hospitalization.Results    Among a total of 340 patients, 78.2 % were male, and 22.1 % were obese. The mean age was 60.9 yrs. Ventricular tachycardia (VT) was more frequent in non-obese patients (HR 0.57, [CI] 0.38-0.87, p=0.009). All-cause mortality and cardiac mortality in all patients tended to be more frequent in non-obese (HR 2.71, [CI] 0.93-7.93, p= 0.069 for all-cause mortality; HR 3.29, [CI] 0.97-11.17, p=0.056 for cardiac mortality). In the subgroup analysis, VT, all-cause mortality, and cardiac mortality were more common for non-obese patients in primary prevention and ischemic heart failure (HF) groups.Conclusion    While VT was more frequent in non-obese patients, VF, ICD appropriate shock, inappropriate shock, and antitachycardia pacing were similar in obese and non-obese patients. All-cause mortality and cardiac mortality were more frequent in non-obese patients.

Impact of coronavirus disease 19 outbreak on arrhythmic events and mortality among implantable cardioverter defibrillator patients followed up by remote monitoring: a single center study from the Veneto region of Italy.

BACKGROUND: The 2020 severe acute respiratory syndrome coronavirus 2 outbreak entailed reduced availability of traditional (in-office) cardiology consultations. Remote monitoring is an alternative way of caring that may potentially mitigate the negative effects of the epidemic to the care of cardiovascular diseases. We evaluated the outcome of implantable cardioverter defibrillator (ICD) carriers followed up remotely in 2020 (epidemic period) versus 2019 (control). METHODS: We included all patients with an ICD who remained remotely monitored from the beginning to the end of each year. The combined end point included: new-onset atrial fibrillation; sustained ventricular tachycardia >170 bpm without ICD intervention; appropriate ICD intervention (either shock or antitachycardia pacing); any-cause death. Multiple events in the same patients were counted separately if occurring ≥48 h apart. RESULTS: In 2020, 52 end points occurred in 37 of 366 (10%) ICD carriers [0.14/patient (95% confidence interval [CI] = 0.11-0.19)] versus 43 end points in 32 of 325 (10%) ICD carriers in 2019 [0.13/patient (95% CI = 0.10-0.18) P  = 0.75]. There was no difference between the distribution of any individual end point in 2020 versus 2019 although a nonsignificant mortality increase was observed (from 2.8% to 4.6%, P  = 0.19). The lowest weekly event rate occurred during the national lock down in spring 2020 but a similar trend occurred also in 2019 suggesting that the effect may not be linked to social distancing measures. CONCLUSIONS: We did not observe an increase in a combined end point including arrhythmic events and mortality in ICD carriers who were remotely monitored in 2020, compared to 2019, despite the negative impact of the coronavirus disease 2019 outbreak on the healthcare system.

Implantable defibrillators in primary prevention of genetic arrhythmias. A shocking choice?

Many previously unexplained life-threatening ventricular arrhythmias and sudden cardiac deaths (SCDs) in young individuals are now recognized to be genetic in nature and are ascribed to a growing number of distinct inherited arrhythmogenic diseases. These include hypertrophic cardiomyopathy, arrhythmogenic cardiomyopathy, long QT syndrome, Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia (VT), and short QT syndrome. Because of their lower frequency compared to coronary disease, risk factors for SCD are not very precise in patients with inherited arrhythmogenic diseases. As randomized studies are generally non-feasible and may even be ethically unjustifiable, especially in the presence of effective therapies, the risk assessment of malignant arrhythmic events such as SCD, cardiac arrest due to ventricular fibrillation (VF), appropriate implantable cardioverter defibrillator (ICD) interventions, or ICD therapy on fast VT/VF to guide ICD implantation is based on observational data and expert consensus. In this document, we review risk factors for SCD and indications for ICD implantation and additional therapies. What emerges is that, allowing for some important differences between cardiomyopathies and channelopathies, there is a growing and disquieting trend to create, and then use, semi-automated systems (risk scores, risk calculators, and, to some extent, even guidelines) which then dictate therapeutic choices. Their common denominator is a tendency to favour ICD implantation, sometime with reason, sometime without it. This contrasts with the time-honoured approach of selecting, among the available therapies, the best option (ICDs included) based on the clinical judgement for the specific patient and after having assessed the protection provided by optimal medical treatment.

Sex Differences in the Risk of First and Recurrent Ventricular Tachyarrhythmias Among Patients Receiving an Implantable Cardioverter-Defibrillator for Primary Prevention.

Importance: Current guidelines for primary implantable cardioverter-defibrillator (ICD) therapy do not account for sex differences in arrhythmic risk in ICD candidates. Objective: To evaluate the association between sex and risk of ventricular tachyarrhythmia (VTA) and mortality. Design, Setting, and Participants: This cohort study compared differences in the risk of VTA and mortality between 4506 men and women enrolled in the 4 Multicenter Automatic Defibrillator Implantation Trials (MADIT) between July 1, 1997, and December 31, 2011. Data from prospective randomized controlled multicenter studies were analyzed retrospectively. Men and women with an ICD or cardiac resynchronization therapy defibrillator who were enrolled in all MADIT studies were included. Data were analyzed between January 10 and June 10, 2021. Exposures: ICD implant. Main Outcomes and Measures: The primary end point was sustained VTA, defined as ICD-recorded, treated or monitored VTA at least 170/min or ventricular fibrillation. Secondary VTA end points included VTA at least 200/min, appropriate ICD shocks, and appropriate antitachycardia pacing. All end points were included in a first and recurrent event analysis. Results: Of the 4506 study participants, 3431 were men (76%). Mean (SD) age of the cohort was 64 (12) years. For women vs men, the mean (SD) age (64 [12] years vs 64 [11] years) and left ventricular ejection fraction (24% vs 25%) were similar, but women exhibited a higher frequency of nonischemic cardiomyopathy (454 of 1075 women [42%] vs 2535 of 3431 men [74%]). Women had significantly lower 3-year cumulative probability of sustained VTA (16% vs 26%), fast VTA (9% vs 17%), and appropriate ICD shocks (7% vs 15%) compared with men (P < .001 for all). Multivariable analysis showed that female sex was independently associated with at least 40% lower risk of all first and recurrent VTA end points (P < .001 for all), including the primary end point (first event, HR = 60 [95% CI, 50-73], P < .001; recurrent event, HR = 49 [95% CI, 43-55], P < .001), after accounting for the competing risk of all-cause mortality and nonarrhythmic mortality. The lower VTA risk associated with female sex was consistent in risk subsets but was significantly more pronounced in patients with nonischemic cardiomyopathy (female vs male in the ischemic group: hazard ratio, 0.73 [95% CI, 0.56-0.95], P = .02; nonischemic group: hazard ratio, 0.50 [95% CI, 0.38-0.66], P < .001; P = .03 for interaction between female sex and cardiomyopathy). Conclusions and Relevance: Findings suggest that women display a significantly lower risk of first and recurrent life-threatening VTA events than men, and that it is more pronounced in patients with nonischemic cardiomyopathy, suggesting a need for sex-specific risk assessment for primary prevention ICD therapy.

Reduction in Ventricular Tachyarrhythmia Burden in Patients Enrolled in the RAID Trial.

BACKGROUND: The RAID (Ranolazine Implantable Cardioverter-Defibrillator) randomized placebo-controlled trial showed that ranolazine treatment was associated with reduction in recurrent ventricular tachycardia (VT) requiring appropriate implantable cardioverter-defibrillator (ICD) therapy. OBJECTIVES: This study aimed to identify groups of patients in whom ranolazine treatment would result in the highest reduction of ventricular tachyarrhythmia (VTA) burden. METHODS: Andersen-Gill analyses were performed to identify variables associated with risk for VTA burden among 1,012 patients enrolled in RAID. The primary endpoint was VTA burden defined as VTA episodes requiring appropriate treatment. RESULTS: Multivariate analysis identified 7 factors associated with increased VTA burden: history of VTA, age ≥65 years, New York Heart Association functional class ≥III, QRS complex (≥130 ms), low ejection fraction (<30%), atrial fibrillation (AF), and concomitant antiarrhythmic drug (AAD) therapy. The effect of ranolazine on VTA burden was seen among patients without concomitant AAD therapy (HR [HR]: 0.68; 95% CI: 0.55-0.84; P < 0.001), whereas no effect was seen among those who are concomitantly treated with other AADs (HR: 1.33; 95% CI: 0.90-1.96; P = 0.16); P = 0.003 for interaction. In patients with cardiac resynchronization therapy (CRT) ICDs, ranolazine treatment was associated with a 36% risk reduction for VTA recurrence (HR: 0.64; 95% CI: 0.47-0.86; P < 0.001), whereas among patients with ICDs without CRT no significant effect was noted (HR: 0.94; 95% CI: 0.74-1.18; P = 0.57); P = 0.047 for interaction. CONCLUSIONS: In patients with high risk for VTA, ranolazine is effective in reducing VTA burden, with significantly greater effect in CRT-treated patients, those without AF, and those not treated with concomitant AADs. In patients already on AADs or those with AF, the addition of ranolazine did not affect VTA burden. (Ranolazine Implantable Cardioverter-Defibrillator Trial [RAID]; NCT01215253).

Impact of synchronized left ventricular pacing rate on risk for ventricular tachyarrhythmias after cardiac resynchronization therapy in patients with heart failure.

BACKGROUND: The adaptive cardiac resynchronization therapy (aCRT) algorithm automatically produces synchronized left ventricular pacing (sLVP) with intrinsic atrioventricular conduction to improve clinical outcomes. However, relationship between sLVP percentage and risk for ventricular tachyarrhythmia (VT/VF) remains unclear. This study aimed to evaluate the clinical impact of sLVP rate on VT/VF occurrence. METHODS: In total, 1,419 device interrogation data from 42 consecutive patients who underwent new aCRT device implantation were retrospectively analyzed. The primary endpoint was the first time VT/VF episode after aCRT device implantation. RESULTS: During a median follow-up of 34 months, 15 patients had VT/VF episodes. Patients were divided into a high sLVP (the average sLVP percentage of ≥ 51.5%, n = 27) or low sLVP group (< 51.5%, n = 15). The high sLVP group had a significantly lower VT/VF incidence (22% vs. 60%; p = 0.014) and an independent predictor for VT/VF occurrence on multivariate analysis (hazard ratio 0.21; p = 0.007). LV ejection fraction improvements after 6 months (12.3 ± 8.7% vs. 2.8 ± 10.3%; p = 0.004) and 12 months (13.8 ± 9.3% vs. 6.2 ± 11.1%; p = 0.030) were significantly greater in the high sLVP group than in the low sLVP group. Age, PR interval, and left atrial diameter were significantly associated with the sLVP rate after aCRT. CONCLUSIONS: Patients with high sLVP percentage after aCRT had lower long-term risk of VT/VF incidence with a favorable response to CRT. A synchronized pacing algorithm using intrinsic conduction may prevent malignant arrhythmias, as well as recover cardiac functions.

Comparison of Frequency of Ventricular Tachyarrhythmia in Men-Versus-Women in Patients with Implantable Cardioverter-Defibrillator for Primary Prevention.

Current guidelines do not account for possible sex differences in the risk of ventricular tachyarrhythmia (VTA). We sought to identify specific factors associated with increased risk for VTA in women implanted with a primary prevention implantable cardioverter-defibrillator (ICD). Our study cohort consisted of 4,506 patients with an ICD or cardiac resynchronization therapy-defibrillator who were enrolled in the 4 landmark MADIT studies - MADIT-II, MADIT-RISK, MADIT-CRT and MADIT-RIT (1,075 women [24%]). Fine and Gray regression models were used to identify female-specific risk factors for the primary end point of VTA, defined as ICD-recorded, treated, or monitored, sustained ventricular tachycardia ≥170 beats per minute or ventricular fibrillation. At 3.5 years of follow-up, the cumulative incidence of VTA was significantly lower in women than men (17% vs 26%, respectively; p <0.001 for the entire follow-up). Use of amiodarone at enrollment, Black race, and history of previous myocardial infarction without previous revascularization was found to be independent risk factors of VTA in women. Of these factors, only Black race was associated with a statistically significant risk increase in men. At 3.5 years, the cumulative incidence of VTA in women with one or more of these risk factors was 27% compared with 14% in women with none of the risk factors (hazard ratio [confidence interval] = 2.08 [1.49 to 2.91]). In conclusion, our study, comprising 4 landmark ICD clinical trials, shows that sex and race have the potential to be used for improved risk stratification of patients who are candidates for primary prevention ICD.

Biological substrate modification suppresses ventricular arrhythmias in a porcine model of chronic ischaemic cardiomyopathy.

AIMS: Cardiomyopathy patients are prone to ventricular arrhythmias (VA) and sudden cardiac death. Current therapies to prevent VA include radiofrequency ablation to destroy slowly conducting pathways of viable myocardium which support re-entry. Here, we tested the reverse concept, namely that boosting local tissue viability in zones of slow conduction might eliminate slow conduction and suppress VA in ischaemic cardiomyopathy. METHODS AND RESULTS: Exosomes are extracellular vesicles laden with bioactive cargo. Exosomes secreted by cardiosphere-derived cells (CDCEXO) reduce scar and improve heart function after intramyocardial delivery. In a VA-prone porcine model of ischaemic cardiomyopathy, we injected CDCEXO or vehicle into zones of delayed conduction defined by electroanatomic mapping. Up to 1-month post-injection, CDCEXO, but not the vehicle, decreased myocardial scar, suppressed slowly conducting electrical pathways, and inhibited VA induction by programmed electrical stimulation. In silico reconstruction of electrical activity based on magnetic resonance images accurately reproduced the suppression of VA inducibility by CDCEXO. Strong anti-fibrotic effects of CDCEXO, evident histologically and by proteomic analysis from pig hearts, were confirmed in a co-culture assay of cardiomyocytes and fibroblasts. CONCLUSION: Biological substrate modification by exosome injection may be worth developing as a non-destructive alternative to conventional ablation for the prevention of recurrent ventricular tachyarrhythmias.