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This study aimed to evaluate the risk of sustained life-threatening ventricular tachyarrhythmias (VTAs) after hospitalization for heart failure (HHF).HHF is common among patients with an implantable cardioverter-defibrillator (ICD).We analyzed all 5,511 ICD patients enrolled in the landmark MADIT (Multicenter Automatic Defibrillator Implantation Trial) and RAID (Ranolazine in High-Risk Patients With Implanted Cardioverter-Defibrillator) trials. Multivariate Cox regression was used to evaluate the association of in-trial HHF occurrence with the risk of subsequent VTA and the composite end point of VTA or cardiac death.Mean age was 64 ± 11 years, 23% were women, 62% were ischemic, and 40% had cardiac resynchronization therapy with defibrillators. The 3-year cumulative rate of VTA subsequent to HHF was significantly higher than the corresponding rate without HHF (44% vs. 24%, respectively; p 0.001). After multivariable adjustment, time-dependent HHF was shown to be associated with a 79% increased risk for VTA and a 2.9-fold increased risk for VTA/cardiac death (p 0.001 for both). In-trial development of atrial tachyarrhythmia (ATA) was also identified as an independent risk factor for the VTA and VTA/cardiac death end points (hazard ratio [HR]: 1.59 and 1.43, respectively; p ≤ 0.001 for both) but did not affect the association of HHF with VTA. Subgroup analysis demonstrated that the association of HHF with the risk of subsequent VTA was maintained among risk subsets categorized by age, sex, history of ATA, and implantation indication, but was significantly more pronounced among patients with nonischemic versus ischemic cardiomyopathy (HR: 2.54 and 1.43, respectively; p for interaction = 0.017).HHF is a powerful risk factor for subsequent VTA in patients implanted with an ICD. These data may be used for improved risk stratification in this population.

Low systolic blood pressure (SBP) was previously suggested to be a marker for heart failure and mortality in patients with low left ventricular ejection fraction. We aimed to explore the association of SBP on risk of ventricular tachyarrhythmias (VTA) and atrial arrhythmias as well as appropriate and inappropriate Implantable Cardioverter Defibrillator (ICD) therapy. The study population comprised 1,481 of 1,500 (99%) patients enrolled in the Multicenter Automatic Defibrillator Implantation Trial – Reduce Inappropriate Therapy trial. Multivariate Cox proportional hazards regression modeling was used to identify the association of baseline SBP (recorded prior to ICD implantation) with the risk of VTA > 170 beats/min during follow-up (primary end point) and atrial arrhythmia, appropriate and inappropriate ICD therapy, hospitalization and death (secondary end points). SBP was dichotomized at 120 mm Hg (approximate mean and median) and was also assessed as a continuous measure. Multivariate analysis showed that each 10 mm Hg decrement in SBP was associated with corresponding 11% increased risk for VTA (p = 0.008). Low SBP (≤120 mm Hg) was associated with a significant 58% (p = 0.002) increased risk for VTA ≥170 beats/min; 53% (p = 0.019) increased risk for VTA ≥200 beats/min; and 65% (p = 0.001) increased risk for appropriate ICD therapy, as compared with SBP >120 mm Hg. Low SBP was not associated with increased risk of atrial arrhythmias, and inappropriate ICD therapy. In conclusion, in MADIT-RIT, SBP (≤120 mm Hg) predicted higher rates of VTA. These findings suggest that SBP may be utilized for VTA risk stratification in candidates for primary ICD therapy.

Background Alcohol septal ablation (ASA) in patients with hypertrophic cardiomyopathy (HCM) can lead to heart rhythm disturbances including complete heart block (CHB) and atrial and ventricular arrhythmias. Objective We aimed to evaluate the utility of long-term arrhythmia monitoring with an implantable cardiac monitor (ICM) after ASA. Methods Between February 2014 and March 2019, 56 patients with HCM undergoing ASA were enrolled in a prospective study and underwent ICM implantation. Kaplan-Meier survival analysis was used to assess the rate of ICM-detected arrhythmic events. Results The mean age was 59 ± 11 years, and 20 (36%) were women. The median (25th, 75th percentile) resting left ventricular outflow tract gradient obtained by echocardiography was 43 (22, 81) mm Hg. Greater than 1 septal perforating artery was injected in 48 patients (86%). The Kaplan-Meier cumulative rate of ICM-detected arrhythmic events at 18 months of follow-up was 71%, with an event rate of 43% occurring within 3 months of ASA. The cumulative rate of the ICM-detected first atrial fibrillation event at 18 months was 37%, and the corresponding rate of CHB was 19%. All atrial fibrillation and CHB events were actionable, leading to the initiation of anticoagulation and pacemaker implantation, respectively. No baseline demographic or procedural variables were identified as independent predictors of an increased risk of developing ICM-detected arrhythmic events. Conclusion After ASA, ICM is effective in capturing clinically actionable arrhythmic events in patients with HCM regardless of patient's baseline risk factors.

Background Implantable cardioverter-defibrillator (ICD) programming to novel settings can reduce the risk of inappropriate therapies. Objective The purpose of this study was to evaluate the impact of novel ICD programming after the first occurrence of ventricular tachycardia (VT). Methods In MADIT-RIT (Multicenter Automatic Defibrillator Implantation Trial–Reduce Inappropriate Therapy) patients who experienced a first occurrence of VT, the risk of subsequent inappropriate and appropriate ICD therapies and adverse cardiovascular events by ICD programming to Arm A (conventional: VT ≥170 bpm), Arm B (high rate: VT ≥200 bpm), or Arm C (duration delay: ≥60-second delay before therapy ≥170 bpm) was determined. Results Among 205 patients, ICD programming changes were made in 30 patients (15%) after they experienced a VT episode; 117 patients (57%) were programmed to Arm A settings and 88 patients (43%) to Arm B/C settings. At 15-month follow-up, the cumulative probability of inappropriate ICD therapy was significantly lower in Arm B/C compared to Arm A (9% vs 20%; log-rank P = .029 for overall difference). The rate of appropriate ICD therapy also was significantly lower in Arm B/C compared to Arm A (32% vs 64%; log-rank P = .001 for overall difference). Multivariate analysis showed that patients programmed to Arm B/C after the occurrence of VT had a 71% reduction (P = .02) in the risk of inappropriate ICD therapies and a 43% reduction (P = .02) in the risk of appropriate ICD therapies compared to Arm A. Conclusion The benefit of high-rate cutoff or duration delay settings in patients with an ICD is maintained after the first occurrence of VT.

We aimed to assess the predictors of new supraventricular tachycardia (SVT) and the association of new SVT with subsequent clinical outcomes among mild heart failure (HF) patients.The study population comprised patients enrolled in MADIT-CRT, after exclusion of patients with atrial arrhythmias before enrollment (N = 325). Multivariate analysis was used to identify predictors of new-onset SVT and the association of time-dependent development of SVT with subsequent ventricular tachyarrhythmic events (VTEs), HF-hospitalizations, and death. SVT burden was categorized into three groups based on the number of episodes per patient; (a) Low10, (b) Intermediate ≥10 but20, and (c) High ≥20. During mean follow up of 3.4 ± 1.1 years, 41(3%) subjects developed new SVT. African American race, diastolic blood pressure (DBP)80 mmHg and prior non sustained ventricular arrhythmia were independent predictors for SVT. Multivariate analysis showed that the development of time-dependent SVT was associated with a4-fold increased risk for VTEs (HR = 4.3; 95% CI: 1.6-11.7; P = .004) and with a6-fold increased risk for all-cause mortality (HR = 6.5; 95% CI: 2.3-18.7; P .001), but not with HF hospitalizations (HR = 2.2; 95% CI: 0.7-7.2; P = .17). Intermediate, and high SVT-burden were each independent risk factors for death when compared with Low burden (HR = 9.1; P = .03, and HR = 19.4; P .001; respectively).In patients with mild HF, the development of new-onset SVT after device implantation is related to distinct baseline clinical and epidemiologic characteristics and is associated with a significant increase in subsequent adverse outcomes, including VTEs and death.

Objectives This study sought to determine the association of cardiomyopathy etiology with the likelihood of ventricular arrhythmias, appropriate implantable cardioverter-defibrillator (ICD) therapy, and mortality. Background There are conflicting data on the benefit of primary prevention ICD therapy in patients with ischemic versus nonischemic cardiomyopathy (ICM/NICM). Methods The study population comprised 4803 patients with ICM (n = 3,106) or NICM (n = 1,697) with a primary prevention ICD enrolled in 5 randomized trials conducted between 1997 and 2017. The primary end point was sustained ventricular tachycardia (VT) ≥200 beats/min or ventricular fibrillation (VF). Secondary end points included appropriate ICD therapy and all-cause mortality. Differences in cause-specific mortality, including noncardiac, sudden cardiac, and non-sudden cardiac death, were also examined. Results Patients with ICM were significantly older and had more comorbid conditions, whereas those with NICM had a more advanced heart failure class at enrollment and were more often prescribed medical or cardiac resynchronization therapy for heart failure. Multivariate analysis showed that ICM versus NICM had a similar risk of VT/VF events (HR: 0.98 [95% CI: 0.79-1.20]) and appropriate ICD therapy (HR: 1.03 [95% CI: 0.87-1.22]), whereas the risk of all-cause mortality was 1.8-fold higher among ICM versus NICM patients (HR: 1.84 [95% CI: 1.42-2.38]), dominated by non-sudden cardiac mortality. Conclusions Combined data from 5 landmark ICD clinical trials show that ICM patients experience a similar risk of life-threatening ventricular arrhythmic events but have an increased risk of all-cause mortality, dominated by non-sudden cardiac death, compared with NICM patients.

Aims To validate the utility of CHA2DS2-VASc score to predict the annual risk of stroke in patients admitted with acute heart failure, comparing those with preserved ejection fraction (HF-presEF) and reduced ejection fraction (HF-redEF). Methods and results We investigated 2922 patients with known atrial fibrillation who were admitted to the Sheba Medical Center for acute decompensated heart failure (HF). Anticoagulation therapy was prescribed based on CHA2DS2-VASc score or physician’s discretion. Subjects were divided into four pre-specified groups based on HF type and median CHA2DS2-VASc score: HF-presEF with CHA2DS2-VASc Conclusion Our key finding is that the CHA2DS2-VASc score is a valid and powerful predictor of subsequent stroke among patients admitted with acute heart failure decompensation regardless of heart failure type.

Clinical and experimental data support a critical role for inflammation in cardiovascular disease. The purpose of the current study was to examine the relation between an inflammatory marker, neutrophil-to-lymphocyte ratio (NLR), and incident atrial fibrillation (AF) in asymptomatic adults. We investigated 21,118 self-referred men and women who were annually screened in a tertiary medical center. All subjects were free of AF at baseline and had their serum NLR calculated at the first annual visit. Subjects were divided into 2 groups based on their baseline NLR: Low (2.83; n = 17,524) and high (≥2.83; n = 3,594; Upper Sextile). The primary endpoint was new onset AF during follow-up. Mean age of study population was 48 ± 10 years and 72% were men. A total of 563 (2.7%) incident events occurred during an average follow-up of 7.5 ± 5 years. Unadjusted Cox regression analysis demonstrated that each 1 unit increase in NLR was associated with a significant 14% increase in risk of occurrence of a first AF event (95% confidence interval 1.06 to 1.23, p0.001) and 20% increased risk of death. Kaplan-Meier's survival analysis showed that the cumulative probability of incident AF was significantly higher among subjects with high NLR compared with low NLR group (p = 0.006). Interaction analysis with adjustment to clinical parameters showed that NLR-related risk was age-dependent, such that in the younger age-group (=50 years) high NLR group had two folds increased risk for AF event compared with low NLR group (95% confidence interval 1.08 to 3.51; p = 0.027) whereas among older subjects the rate of events was similar between both NLR groups (p = NS; p for interaction = 0.024). In conclusion, our findings suggest that high NLR is associated with increased risk of new onset AF. This finding is more pronounced among young adults.

During the last decade, several case series and small reports have indicated that pulmonary vein isolation (PVI) in combination with renal denervation (RDN) may increase the rate of atrial fibrillation (AF) freedom in patients with hypertension. We aimed to provide a contemporary systematic overview on the techniques, and the efficacy/safety of RDN on AF recurrence, and the current landscape of ongoing investigation. The recent Evaluate Renal Denervation in Addition to Catheter Ablation to Eliminate Atrial Fibrillation (ERADICATE-AF) trial has demonstrated convincingly that among patients with paroxysmal AF and poorly controlled (but not “resistant”) hypertension, RDN added to catheter ablation, compared with catheter ablation alone, significantly increased the likelihood of freedom from AF at 12 months. RDN has proven to be a unique, effective and safe interventional therapy for the management of AF. Future investigation will likely focus on confirming current findings; expanding the population of eligible patients (eg., non-hypertensives, well controlled hypertensives); determining long-term maintenance of effect and therapeutics.

Background We aimed to provide personalized risk estimates for cardiac events (CEs) and life‐threatening events in women with either type 1 or type 2 long QT. Methods and Results The prognostic model was derived from the Rochester Long QT Syndrome Registry, comprising 767 women with type 1 long QT (n=404) and type 2 long QT (n=363) from age 15 through 60 years. The risk prediction model included the following variables: genotype/mutation location, QTc‐specific thresholds, history of syncope, and β‐blocker therapy. A model was developed with the end point of CEs (syncope, aborted cardiac arrest, or long QT syndrome–related sudden cardiac death), and was applied with the end point of life‐threatening events (aborted cardiac arrest, sudden cardiac death, or appropriate defibrillator shocks). External validation was performed with data from the Mayo Clinic Genetic Heart Rhythm Clinic (N=467; type 1 long QT [n=286] and type 2 long QT [n=181]). The cumulative follow‐up duration among the 767 enrolled women was 22 243 patient‐years, during which 323 patients (42%) experienced ≥1 CE. Based on genotype‐phenotype data, we identified 3 risk groups with 10‐year projected rates of CEs ranging from 15%, 29%, to 51%. The corresponding 10‐year projected rates of life‐threatening events were 2%, 5%, and 14%. C statistics for the prediction model for the 2 respective end points were 0.68 (95% CI 0.65–0.71) and 0.71 (95% CI 0.66–0.76). Corresponding C statistics for the model in the external validation Mayo Clinic cohort were 0.65 (95% CI 0.60–0.70) and 0.77 (95% CI 0.70–0.84). Conclusions This is the first risk prediction model that provides absolute risk estimates for CEs and life‐threatening events in women with type 1 or type 2 long QT based on personalized genotype‐phenotype data. The projected risk estimates can be used to guide female‐specific management in long QT syndrome.

Background: Long-term morbidity and mortality data among ischemic heart disease (IHD) patients of different ethnicities are conflicting. We sought to determine the independent association of ethnicity and all-cause mortality over two decades of follow-up of Israeli patients.Methods: Our study comprised 15,524 patients including 958 (6%) Arab patients who had been previously enrolled in the Bezafibrate Infarction Prevention (BIP) registry between February 1, 1990, and October 31, 1992, and subsequently followed-up for long-term mortality. We compared clinical characteristics and outcomes of Israeli Arabs and Jews. Propensity score matching (PSM) (1:2 ratios) was used for validation.Results: Arab patients were significantly younger (56 ± 7 years vs. 60 ± 7 years; p < 0.001; respectively), and had more cardiovascular disease (CVD) risk factors. Kaplan-Meier survival analysis showed that all-cause mortality was significantly higher among Arab patients (67 vs. 61%; log-rank p < 0.001). Multivariate adjusted analysis showed that mortality risk was 49% greater (HR 1.49; 95% CI: 1.37–1.62; p < 0.001) among Arabs.Conclusions: Arab ethnicity is independently associated with an increased 20-year all-cause mortality among patients with established IHD.

There are conflicting data on the impact of implantable cardioverter-defibrillator (ICD) shocks on subsequent mortality.The aim of this study was to determine whether the arrhythmic substrate leading to ICD therapy or the therapy itself increases mortality.The study cohort included 5,516 ICD recipients who were enrolled in 5 landmark ICD trials (MADIT-II, MADIT-RISK, MADIT-CRT, MADIT-RIT, RAID). The authors evaluated the association of device therapy with subsequent mortality in 4 separate time-dependent models: model I, type of ICD therapy; model II, type of arrhythmia for which ICD therapy was delivered; model III, combined assessment of all arrhythmia and therapy types during follow-up; and model IV, incremental risk associated with repeated ICD shocks.When analyzed by the type of ICD therapy (model I), a first appropriate ICD shock was associated with increased risk of subsequent mortality with or without concomitant occurrence of inappropriate shock during follow-up (hazard ratio [HR]: 2.78 and 2.31; p 0.001 and p = 0.12), whereas inappropriate shock alone was not associated with mortality risk (HR: 1.23; p = 0.42). Similarly, ICD therapy for ventricular tachycardia (VT) ≥200 beats/min or ventricular fibrillation (VF) (model II) was associated with increased risk of death with or without concomitant therapy for VT 200 beats/min (HRs: 2.25 and 2.62; both p 0.001), whereas appropriate therapy for VT 200 beats/min or inappropriate therapy (regardless of etiology) did not reach statistical significance (all p0.10). Combined assessment of all therapy and arrhythmia types during follow-up (model III) showed that appropriate ICD shocks for VF, shocks for fast VT (≥200 beats/min) without prior antitachycardia pacing (ATP), as well as shocks for fast VT delivered after failed ATP, were associated with the highest risk of subsequent death (HR: all2.8; p 0.001). Finally, 2 or more ICD appropriate shocks were not associated with incremental risk to the first appropriate ICD shock (model IV).The combined data from 5 landmark ICD trials suggest that the underlying arrhythmic substrate rather than the ICD therapy is the more important determinant of mortality in ICD recipients.

Introduction Cardiac resynchronization therapy (CRT) may be pro‐arrhythmic in patients with non‐left bundle branch block (non‐LBBB). We hypothesized that combined assessment of risk factors (RF) for ventricular tachyarrhythmias (VTAs) can be used to stratify non‐LBBB patients for CRT implantation. Methods The study comprised 412 non‐LBBB patients from MADIT‐CRT randomized to CRT‐D (n = 215) versus ICD only (n = 197). Best‐subset regression analysis was performed to identify RF associated with increased VTA risk in CRT‐D patients without LBBB. The primary end point was first occurrence of sustained VTA during follow‐up. Secondary end points included VTA/death and appropriate shock. Results Four RFs were associated with increased VTA risk: blood urea nitrogen >25mg/dl, ejection fraction

Hypertensive heart disease (HHD) is a major cause of global morbidity and mortality. Understanding its current burden among various countries and populations is crucial for formulating effective strategies for preventing and managing HHD. This study aimed to use the estimates from the Global Burden of Disease Study 2017 to describe the prevalence, mortality, and disability-adjusted life years for HHD for 195 countries and territories from 1990 to 2017. Worldwide, the age-standardized prevalence rate of HHD in 2017 was 217.9 (95% uncertainty interval [UI], 184.1–254.1) per 100 000 people, an increase of 7.4% (95% UI, 5.0–9.7) from 1990. The global age-standardized mortality and disability-adjusted life year rates of HHD were 12.3 (95% UI, 9.0–13.2) and 209.4 (95% UI, 160.5–226.3) per 100 000 people, a decrease of −19.3% (95% UI, −29.7 to −8.1) and −24.0% (95% UI, −31.0 to −13.7) from 1990, respectively. The global age-standardized prevalence rate of HHD was higher in females and increased with age. Between 1990 and 2017, Bolivia (51.3% [95% UI, 29.6–84.5]) and Maldives (32.3% [95% UI, 22.9–43.8]) showed the greatest increases in age-standardized prevalence rates. Generally, a negative association was found between the age-standardized disability-adjusted life year rates and Sociodemographic index at the regional and national levels. Our results suggest that HHD is a major public health challenge worldwide with an increasing prevalence rate over the past decades. Efforts to improve public awareness and management of high blood pressure and HHD, especially for vulnerable populations, were necessary.

The role of cardiovascular implantable electronic device (CIED)-derived activity to predict implantable cardioverter-defibrillator (ICD) therapy or death is not known.We aimed to assess CIED-derived activity to predict clinical outcomes.In 1500 patients enrolled in MADIT-RIT, CIED-derived patient activity was acquired daily, then averaged for the first 30 days following randomization to predict inappropriate/appropriate therapy or death. Kaplan-Meier analysis and Cox proportional regression models were used to evaluate inappropriate/appropriate therapy, heart failure, or death by 30-day CIED-derived patient activity quintiles.There were 1463 patients with CIED activity data (98%). Patients in the highest quintile (Q5) of activity (more active) had the highest rate of inappropriate therapy, 21% at 2 years, as compared to 7%-11% in the other 4 quintiles (P.001), a 1.75 times higher risk (95% confidence interval [CI]: 1.23-2.50, P = .002). However, patients in the lowest quintile of activity (Q1, 1 hour/day) had the highest risk of mortality, 15% in 2 years, as compared to Q2-3 (1-2 hours/day, 8%-7% mortality), and Q4-5 (2 hours/day, 2%-3% mortality) (P.001). Patients with the lowest level of activity (Q1) had a 2.02 times higher risk of mortality (95% CI: 1.21-3.38, P = .007), and they had an 82% higher risk of heart failure hospitalization (95% CI: 1.28-2.57, P = .001).High CIED-derived 30-day median patient activity predicted inappropriate therapy, while low patient activity predicted mortality and heart failure in ICD and cardiac resynchronization therapy with defibrillator patients enrolled in MADIT-RIT. Device-derived activity assessment could serve as a useful predictor of outcomes.

Introduction: Statins may reduce risk for ventricular tachyarrhythmia (VTA) in patients with implantable cardioverter defibrillator (ICD). Ranolazine was shown to increase plasma concentrations of statin. Objective: To evaluate the effect of statin on recurrent VTA, and to explore the interaction with both Ranolizine and cardiomyopathy (CMP) origin. Methods: The Andersen-Gill extension of the Cox proportional hazards regression was used to assess the association between statin treatment and the risk for recurrent VTA among 1012 ICD patients enrolled in the Ranolazine Implantable Cardioverter-Defibrillator Trial (RAID). Interaction-term analysis with ranolazine and ischemic status were performed. Number of events was limited to a maximum of 10 VTA events per patient to avoid any patients having an undue influence on model estimates. Results: A total of 740 (73%) RAID patients were treated with statins. Multivariable analysis showed that statin use was associated with an overall 30% reduction in the risk for recurrent VTA (HR=0.70; ponly among patients with non-ischemic CMP (HR=0.53 [95%CI 0.41-0.69]; p Conclusion: Our findings suggest that treatment with statin (regardless if with or without ranolazine) is highly effective in reducing VTA burden in non-ischemic ICD recipients.

Introduction: The Wearable Cardioverter Defibrillator (WCD) is utilized in patients with assumed but not yet confirmed risk for sudden cardiac death (SCD). Many of these patients also present with a history of atrial fibrillation (AF). However, the rate of WCD-detected ventricular or atrial arrhythmia events in this specific high-risk cohort is not well understood. Methods: In WEARIT-II, the cumulative probability of any sustained or non-sustained VT/VF (WCD-treated and non-treated), and atrial/supraventricular arrhythmias during WCD use was assessed using the Kaplan-Meier method, with comparisons by the log-rank test. The incidence of ventricular and atrial arrhythmia events were expressed as events per 100 patient-years, and were analyzed by negative binomial regression. Results: The WEARIT-II trial enrolled 2000 patients, 557 (28%) of whom had AF prior to enrollment. The cumulative probability of any sustained or non-sustained WCD-detected VT/VF during WCD use was significantly higher among patients with a history of AF than in patients without AF (6% vs. 3%, p=0.001, Figure). Similarly, the recurrent rate of any sustained or non-sustained VT/VF was significantly higher in patients with prior AF vs. no prior AF (131.5 events per 100 patient-years vs. 22.7 events per 100 patient-years, p=0.001). Patients with prior AF also had a significantly higher burden of WCD-detected atrial arrhythmias/SVT (64 events per 100 patient-years vs 13.7 events per 100 patient-years, p Conclusions: Our results demonstrate that patients with a history of AF wearing the WCD for risk assessment have a higher incidence of ventricular arrhythmias that may facilitate the decision making for ICD implantation.

Objective: The platelet phenotype in certain patients and clinical contexts may differ from healthy conditions. We evaluated platelet activation through specific receptors in healthy men and women, comparing this to patients presenting with ST-segment-elevation myocardial infarction and non-ST-segment-elevation myocardial infarction. Approach and Results: We identified independent predictors of platelet activation through certain receptors and a murine MI model further explored these findings. Platelets from healthy women and female mice are more reactive through PARs (protease-activated receptors) compared with platelets from men and male mice. Multivariate regression analyses revealed male sex and non-ST-segment-elevation myocardial infarction as independent predictors of enhanced PAR1 activation in human platelets. Platelet PAR1 signaling decreased in women and increased in men during MI which was the opposite of what was observed during healthy conditions. This trend was also observed in male and female mice in which thrombin-mediated platelet calcium mobilization was augmented coincident with platelet activation in males and attenuated in females at the time of MI. Conclusions: Sex-specific signaling in platelets seems to be a cross-species phenomenon. The divergent platelet phenotype in males and females at the time of MI suggests a sex-specific antiplatelet drug regimen should be prospectively evaluated.

Cardiac resynchronization therapy-defibrillator (CRT-D) may reduce the incidence of first ventricular tachyarrhythmia (VTA) in patients with heart failure (HF) and left bundle branch block (LBBB).The purpose of this study was to assess the effect of CRT-D on VTA burden in LBBB patients.We included 1281 patients with LBBB from MADIT-CRT (Multicenter Automatic Defibrillator Implantation Trial-Cardiac Resynchronization Therapy). VTA was defined as any treated or monitored sustained ventricular tachycardia (VT ≥180 bpm) or ventricular fibrillation (VF). Life-threatening VTA was defined as VT ≥200 bpm or VF. VTA recurrence was assessed using the Andersen-Gill model.During a mean follow-up of 2.5 years, 964 VTA episodes occurred in 264 patients (21%). The VTA rate per 100 person-years was significantly lower in the CRT-D group compared with the implantable cardioverter-defibrillator (ICD) group (20 vs 34; P .01). Multivariate analysis demonstrated that CRT-D treatment was associated with a 32% risk reduction for VTA recurrence (hazard ratio 0.68; 95% confidence interval 0.57-0.82; P.001), 57% risk reduction for recurrent life-threatening VTA, 54% risk reduction for recurrent appropriate ICD shocks, and 25% risk reduction for the combined endpoint of VTA and death. The effect of CRT-D on VTA burden was consistent among all tested subgroups but was more pronounced among patients in New York Heart Association functional class I. Landmark analysis showed that at 2 years, the cumulative probability of death subsequent to year one was highest (16%) among patients who had ≥2 VTA events during their first year.In patients with LBBB and HF, early intervention with CRT-D reduces mortality, VTA burden, and frequency of multiple appropriate ICD shocks. VTA burden is a powerful predictor of subsequent mortality.

Background Following cryptogenic stroke, guidelines recommend cardiac monitoring for occult atrial fibrillation (AF). We aimed to evaluate predictors of AF during long‐term implantable cardiac monitoring. Methods and Results We studied 293 consecutive patients who underwent implantable cardiac monitor implant (Medtronic LINQ) following hospitalization for cryptogenic stroke at the University of Rochester Medical Center from January 2013 to September 2018. Multivariable Cox proportional hazards regression modeling was used to identify predictors of AF during long‐term monitoring. At 36 months of follow‐up, the cumulative rate of implantable cardiac monitor–detected AF events was 32% in the total study population. Multivariable analysis identified age ≥70 years as the most powerful predictor of the development of AF events during follow‐up (hazard ratio, 2.28 [95% CI, 1.39–3.76]; P =0.001). Replacing age with the CHA 2 DS 2 ‐VASc (congestive heart failure, hypertension, age, diabetes mellitus, stroke, vascular disease, age, sex category) score resulted in a weaker association, for which each 1‐point increment in the CHA 2 DS 2 ‐VASC score was associated with an 18% increased risk of developing AF (95% CI, 1.00–1.38; P =0.047). Consistent results were shown using Kaplan–Meier analysis by age and by the CHA 2 DS 2 VASc score. Conclusions Cryptogenic stroke patients continue to develop AF episodes during 36 months of implantable cardiac monitoring following the index event. Age is the most powerful predictor of occult AF in this population.

Aims The benefit of prophylactic implantable cardioverter-defibrillator (ICD) is not uniform due to differences in the risk of life-threatening ventricular tachycardia (VT)/ventricular fibrillation (VF) and non-arrhythmic mortality. We aimed to develop an ICD benefit prediction score that integrates the competing risks. Methods and results The study population comprised all 4531 patients enrolled in the MADIT trials. Best-subsets Fine and Gray regression analysis was used to develop prognostic models for VT (≥200 b.p.m.)/VF vs. non-arrhythmic mortality (defined as death without prior sustained VT/VF). Eight predictors of VT/VF (male, age 75 b.p.m., systolic blood pressure Conclusions We propose the novel MADIT-ICD benefit score that predicts the likelihood of prophylactic ICD benefit through personalized assessment of the risk of VT/VF weighed against the risk of non-arrhythmic mortality.

Background: Mild heart failure (HF) patients without left bundle branch block (LBBB) did not derive a significant reduction in risk of a HF event/death in the MADIT-CRT trial (Multicenter Automatic Defibrillator Implantation Trial With Cardiac Resynchronization Therapy). However, the efficacy of CRT with a defibrillator (CRT-D) may be modified after the development of the first hospitalization for HF (HHF). We aimed to study the effect of CRT-D on long-term risk of recurrent HHF in patients without LBBB in MADIT-CRT. Methods: Data on recurring HHF were collected for 1818 subjects. The CRT-D versus implantable cardioverter-defibrillator-only risk for first and subsequent HHF was assessed by QRS morphology in on-treatment analysis using Cox proportional hazards regression modeling. Results: During long-term follow-up, 412 patients had ≥1 HHF and 333 had ≥2 HHF. Multivariate analysis revealed that in LBBB patients, CRT-D, compared with implantable cardioverter-defibrillator, was associated with a significant reduction in risk of first and subsequent HHF (first: hazard ratio, 0.41 [95% CI, 0.31–0.54], P P P =0.808). However, after occurrence of a first HHF, CRT-D therapy was associated with a pronounced 44% reduction in risk of subsequent HHF (hazard ratio, 0.56 [95% CI, 0.32–0.97], P =0.039). Patients without LBBB with ≥1 HHF during the first year of follow-up demonstrated increasing dyssynchrony at 1 year compared with those who had no HHF ( P =0.016). Conclusions: In MADIT-CRT, we show a beneficial effect of CRT-D in patients without LBBB subsequent to development of a first HHF, possibly due to increased dyssynchrony associated with HF progression. Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT00180271, NCT01294449, and NCT02060110.

BACKGROUND We aimed to characterize the hourly, daily, and seasonally variations in the detection of new atrial fibrillation (AF) in heart failure patients implanted with a defibrillator. METHODS In 1309 patients enrolled in MADIT-RIT without AF at baseline, atrial arrhythmia data were analyzed from device interrogations. The circadian, weekly, and seasonal distribution of device detected AF was evaluated. The morning period was defined as 06:00-11:59, afternoon as 12:00-16:59, evening as 17:00-22:59, and the nighttime as 23:00-05:59. RESULTS During 17 months of follow-up, 66 (5%) patients developed new device-detected AF. AF patients were less likely to have ischemic cardiomyopathy and were more likely to have received an implantable cardioverter defibrillator rather than a cardiac resynchronization therapy with defibrillator. The highest number of AF occurred during the evening hours (25 patients [38%]) followed by a second peak in AF detection during the afternoon hours (21 patients [32%]). Importantly during the nighttime, new AF occurred only in three patients (4%). In comparison with the nighttime period, the odds ratio (OR) of developing AF during the evening time period was 8.5-fold higher (95% CI 7.3-9.7, P

OBJECTIVE To evaluate the efficacy and safety of periprocedural beta-blocker (BB) discontinuation among patients undergoing transcatheter aortic valve replacement (TAVR) and high degree atrioventricular block (HD-AVB) and/or atrial fibrillation (AF). METHODS The study population comprised 743 consecutive patients who underwent TAVR between 2009 and 2017 in two high-volume tertiary centers. All patients received chronic BB therapy, and were divided into two groups: (1) BB continuation and (2) BB discontinued 24 hr prior to the procedure. The primary endpoint was the development of composite brady and tachy-arrhytmic events (including HD-AVB and/or NOAF) following the procedure. RESULTS Among 743 study patients, 366 (49%) continued BB prior to the procedure and in 377 (51%) chronic BB therapy was discontinued. The rate of the composite periprocedural arrhythmic event was significantly higher among patients who stopped BB (20% vs. 13%, respectively, P = 0.018). Consistently, multivariate analysis showed that discontinuation of BB was associated with two-fold (P = 0.003) increase in the risk for periprocedural arrhythmic events (OR = 2.0; 95% CI 1.24-3.23; P = 0.004). The association between BB discontinuation and periprocedural arrhythmic events was consistent for the separate endpoints for HDAV and NOAF. Furthermore, the need for permanent pacemaker was significantly higher among patients who discontinued BB (20% vs. 13%; P = 0.018, respectively). CONCLUSIONS Among patients undergoing TAVR who receive chronic BB therapy, BB discontinuation prior to the procedure is independently associated with a significant increase in the rate of adverse arrhythmic events, including HDAVB, NOAF, and the need for pacemaker implantation.

Limited, contradictory data exist regarding the effect of hyperkalemia on both short- and long-term all-cause mortality among hospitalized patients with heart failure (HF).We analyzed 4,031 patients who were enrolled in the Heart Failure Survey in Israel. The study patients were grouped into 3 different potassium (K) categories. Multivariate analysis was used to determine the association of potassium levels as well as 1- and 10-year all-cause mortality.A total of 3,349 patients (83%) had K5mEq/L, whereas 461 patients (11%) had serum K ≥ 5mEq/L but≤ 5.5mEq/L and 221 patients (6%) had K5.5mEq/L. Survival analysis showed that 1-year mortality rates were significantly higher among patients with K5.5mEq/L (40%) and those with serum K ≥ 5mEq/L but ≤ 5.5mEq/L (34%) compared to those with K5mEq/L (27%); (all log rank P0.01). Similarly, 10-year mortality rates among those with K5.5mEq/L were 92%, whereas among those with serum K ≥ 5mEq/L but ≤ 5.5mEq/L rates were 88%, and in those with K5mEq/L rates were 82%; (all log rank P0.001). Consistently, multivariate analysis showed that compared to patients with K5mEq/L, patients with K5.5mEq/L had an independently 51% and 31% higher mortality risk at 1 year and 10 years, respectively (1-year hazard ratio = 1.51, 95% CI: 1.04-2.2; 10-years hazard ratio = 1.31, 95% CI: 1.035-1.66), whereas patients with serum K ≥ 5mEq/L but ≤ 5.5mEq/L had comparable adjusted mortality risk to patients with K5mEq/L at 1 and 10 years.Among hospitalized patients with HF, admission K5.5mEq/L was independently associated with increased short- and long-term mortality, whereas serum K ≥ 5mEq/L but ≤ 5.5mEq/L was not independently associated with worse outcomes.

BACKGROUND Data on the association between AF and fitness are conflicting. OBJECTIVES The aim of this analysis was to investigate the association between fitness, obesity and incidence of atrial fibrillation (AF) among apparently healthy non-athlete adults. METHODS We investigated 20 410 self-referred subjects who were annually screened in a tertiary medical centre. All subjects were free of AF and completed maximal exercise stress test according to the Bruce protocol at baseline. Fitness was categorised into age- and sex-specific quintiles (Q) according to the treadmill time. Subjects were categorised to low (Q1-Q2) and high fitness (Q3-5) groups. The primary end point was new-onset AF during follow-up. RESULTS Mean age was 48 ± 10 years and 72% were men. A total of 463 (2.3%) events occurred during an average follow-up of 8 ± 5 years corresponding to an AF event rate of 0.3% per person year. Univariate and multivariate models showed that AF risk was similar in both fitness groups. However, AF event rate was 0.55% per person year among high fitness obese subjects, compared with 0.31% for low fitness obese subjects (P

Aims Patients with impaired renal function were shown to have an attenuated benefit from implantable cardioverter-defibrillator. However, there are limited data on the competing risk of ventricular arrhythmia events and death by renal function in patients without severe disease. Therefore, we aimed to assess the competing risk of ventricular arrhythmia events and death by renal function. Methods and results We analysed 1782 patients (99%) enrolled in Multicenter Automatic Defibrillator Implantation Trial–Cardiac Resynchronization Therapy (MADIT–CRT) with glomerular filtration rate (GFR) data available. Cumulative incidence function curves were used to display the rate of ventricular tachycardia (VT), ventricular fibrillation (VF), and the competing risk of death without experiencing VT/VF. Multivariable Fine and Gray regression models and recurrent event analysis were performed. There were 355 (20%) patients with GFR Conclusions We show, in a competing risk model, a lower risk of VT/VF events and a higher risk of mortality without an arrhythmic event in patients with moderate renal dysfunction in MADIT–CRT. These findings can be used for improved selection of patients for defibrillator therapy among CRT candidates. Clinical Trial Registration https://clinicaltrials.gov/ct2/show/NCT00180271.

Married patients have been shown to have a lower risk for adverse cardiovascular outcomes. However, the risk of heart failure (HF) or death in married versus unmarried patients with left ventricular (LV) dysfunction and an implantable cardioverter defibrillator (ICD), and the effect of cardiac resynchronization therapy with defibrillator (CRT-D) are unknown. In Multicenter Automatic Defibrillator Implantation Trial-Cardiac Resynchronization Therapy (MADIT-CRT), in patients with left bundle branch block, we evaluated long-term clinical outcomes of all-cause mortality or HF events in married (including common law status) compared with unmarried (single/divorced/widowed) patients with CRT-D versus an ICD-only. There were 937 married patients and 344 unmarried patients with left bundle branch block. Multivariate analysis showed that married patients had a 54% lower risk of all-cause mortality (hazard ratio [HR] 0.46, 95% confidence interval [CI] 0.30 to 0.71, p

Atrial tachyarrhythmias (ATAs) are common among heart failure (HF) patients.The purpose of this study was to assess predictors for the development of new ATA and its components (atrial fibrillation/flutter [AF], supraventricular tachycardia [SVT]), and their association with subsequent clinical outcomes.We assessed predictors for first and recurrent ATA, AF, and SVT among 1500 patients in MADIT-RIT (Multicenter Automatic Defibrillator Implantation Trial-Reduce Inappropriate Therapy). We also investigated the association of new ATA, AF, or SVT with subsequent ventricular arrhythmia (VA), adverse events (HF hospitalization, syncope, or death), or death by time-dependent analysis.During 17 months of follow-up, 286 patients (19%) developed new ATA, of whom 92 (6%) had AF and 194 (12%) had SVT. Younger age (≤65 years), diastolic blood pressure ≥72 mm Hg, heart rate ≥63 bpm, absence of diabetes, and prior atrial arrhythmia were independent predictors of ATA. Prior atrial arrhythmia was the only predictor of AF (hazard ratio 3.14; P.001). New ATA was associated with significantly increased risk for subsequent VA (HR 2.12; P.001), increased adverse events (HR 1.42; P.001), and death (HR 1.85; P = .038). New AF and new SVT were both independently associated with2-fold increased risk for the development of subsequent VA (HR 2.21; P = .012l and HR 2.15; P.001, respectively) and adverse events.Among MADIT-RIT patients, younger age, absence of diabetes, higher blood pressure, higher heart rate, and prior atrial arrhythmia predicted device-detected ATA. Both AF and SVT were associated with increased risk for subsequent VA and adverse events. Aggressive management should be considered in HF patients who develop new-onset, device-detected ATA to improve clinical outcomes.

Background Data are scarce regarding sex differences among patients with myocarditis and peri-myocarditis. Our aim was to define the sex differences in clinical characteristics as well as in-hospital outcomes in a cohort of consecutive patients hospitalized due to myocarditis and peri-myocarditis. Methods and results We analyzed data of 322 consecutive patients between January 2007 and October 2017 who were hospitalized with the diagnosis of myocarditis or peri-myocarditis at our medical center. Eighty-four percent of the patients were males. Both males as well as females had similar rates of chronic medical conditions. However, males were more likely to present with ST elevation (75% vs. 44%. P Variable Male (N=272) Female (N=50) P-value Age 36±14 45±17 Conclusions Male patients, which constitute the majority of patients. Admitted with myocarditis are younger, with higher troponin levels at admission, are more likely to present with ST elevation, and have a higher rate of ventricular arrythmias when compared to women. However, there are no differences in early as well as long term mortality rates between men and women.

Background Transcatheter aortic valve implantation (TAVI) for aortic stenosis (AS) risk assessment is still developing and mostly concerned with mortality in the periprocedural period. We therefore sought to develop and then validate a score to predict 1-year adverse outcome. Methods Patients that underwent TAVI for severe AS in the Israeli registry. Patients with unsuccessful/suboptimal implantation were excluded. The cohort was split to derivation/validation cohorts by a ratio of 70:30. The outcome was defined as 1-year composite of mortality, stroke, and no improvement in NYHA class (vs. baseline). Logistic regression was used to fit the prediction model. Results Out of 2,440 patients meeting inclusion criteria, 276 were excluded, leaving 2,160 patients for both cohorts. At 1 year, 299 (14%) patients experienced the adverse ("futile") outcome. The derived prediction model included mean aortic valve (AV) gradient, previous pacemaker, previous oncological disease, need for diuretics, baseline NYHA class, hemoglobin and creatinine levels, and nonfemoral access site. The model's area under the curve (AUC) was 0.69 in the derivation and 0.70 in the validation cohort. Performance of other scores in the validation cohort were lower (0.60 for STS, 0.55 for Euroscore2, 0.56 for TVT score, and 0.53 for TAVI2-score, p = .03). Based on three risk tiers, patients had a low risk (20/306, 7% futility), a medium risk (50/304, 17%), and high risk (18/37, 49%) for futility. Conclusions The TAVI futility risk model can be used to provide further insight regarding prediction measures and/or patients' outcomes outside of the periprocedural period (NCT02023060).

Purpose The burden of atrial arrhythmias (AA) and ventricular tachycardia/fibrillation (VT/VF) during long-term continuous-flow (CF) LVAD support is not well described. Methods Our Arrhythmia Database included all implantable cardioverter-defibrillator interrogations completed from September 2015 to August 2019 for 101 consecutive CF-LVAD patients at a single center. Endpoints included first occurrence of any arrhythmia, AA, and VT/VF. Results Patients (mean age at LVAD implant 59±12 years, 83% male, 51% with ischemic cardiomyopathy, 60% with history of AA before LVAD implant, and 75% with history of VT/VF before LVAD implant) were supported by an LVAD for a median of 2.1 years before entering the Arrhythmia Database. Subsequent follow-up in the Database extended over >2 years. At 2.5 years from Arrhythmia Database entry (median of 4.5 years from LVAD implant), the cumulative rate of any arrhythmia was 74%, the rate of AA was 66%, and the rate of VT/VF was 47% (Figure). Conclusion Both atrial and ventricular arrhythmias remain common during long-term LVAD support (median >4 years). Our findings support the role of generator replacement of implantable devices for continued detection and treatment of arrhythmic events in LVAD patients.

Purpose The purpose of this study was to compare clinical characteristics and risk of readmissions by race among patients with left ventricular assist device (LVAD). Methods The study population included 349 patients implanted with LVADs at the University of Rochester Medical Center, NY from May 5, 2008 to September 19, 2018. Patients were stratified by race as White (N=304 [87%]) and Black (N=45 [13%]). The Anderson-Gill recurrent regression analysis was used to assess the independent association between race and recurrent readmissions during an average follow-up of 2.49 ± 2.19 years. Results Black patients displayed significant differences in the baseline clinical characteristics prior to LVAD implantation compared to White patients (Table 1), including a younger age and a lower frequency of ischemic etiology (10 (22%) vs 176 (58%), and a higher baseline serum creatinine. Kaplan-Meier survival analysis showed that mortality rates at 2- years of follow-up were non-significantly lower among Black patients as compared with White patients (14% vs. 25%, respectively; log-rank p-value = 0.163 for the overall difference). However, after multivariate adjustment, Black patients were shown to experience a significant 41% increased risk for recurrent admission after LVAD implantation (Hazard ratio 1.41, 95% CI; 1.05-1.90, p 0.022). Conclusion Black patient were younger than White patient with LVAD but remain at higher risk of readmissions following LVAD implant. These findings suggest the need for careful follow-up with appropriate interventions to reduce readmissions in Black patients who undergo LVAD implantation.

We have previously shown that a response score, including 7 baseline clinical and echocardiographic factors, can be used to predict CRT-D benefit among patients enrolled in MADIT-CRT over a median of 2.4 years. We aimed to evaluate the yield of the score for the assessment of the long-term clinical

We hypothesized that combined assessment of factors associated with increased risk for ventricular arrhythmic event (VTE) after cardiac resynchronization therapy (CRT) implantation can be used to identify non-LBBB patients in whom CRT implantation will not be pro-arrhythmic. We analyzed 412 non

We aimed to assess predictors of new supraventricular tachycardia (SVT) and the association with subsequent clinical outcomes among mild heart failure (HF) patients who receive primary prevention device therapy Study population comprised 1820 patients enrolled in MADIT-CRT, after exclusion of

Aims Heart failure patients with advanced chronic kidney disease (CKD) may experience an increased rate of non-arrhythmic mortality due to associated comorbidities. We aimed to evaluate the risk of mortality without appropriate implantable cardioverter-defibrillator (ICD) shocks in this high-risk population. Methods and results The study population comprised 3542 patients who received an ICD, were enrolled, and prospectively followed-up in the Israeli ICD registry. Study patients were categorized into two groups: those with advanced CKD [defined by a glomerular filtration rate of Conclusion Nearly one-half of ICD with advanced CKD die within 5 years without receiving an appropriate ICD shock. These findings stress the importance of appropriate patient selection for primary ICD implantation in this high-risk population.

BACKGROUND The impact of donor-recipient ethnic matching on heart transplantation (HT) has been poorly studied with inconclusive results. We aimed to investigate the impact of ethnic matching on HT outcomes in Israeli multiethnic patients. METHODS The study comprised 168 patients who underwent HT from 1990-2017. Patients and their donors were ethnically categorized to Jews and Arabs. Primary end points were all-cause in-hospital and late mortality; secondary end points included primary graft dysfunction (PGD), rejections, and vasculopathy. RESULTS Donor-recipient ethnic matching was found in 111 patients, while 57 were ethnically mismatched. Baseline characteristics were similar in both groups. Ethnic mismatching was associated with >7-fold (P = 0.018) increased risk for in-hospital mortality and >8-fold (P

BACKGROUND: Atrial fibrillation (AF) is associated with diminished cardiac function, and exercise tolerance. HYPOTHESIS: We sought to investigate the role of cardiac rehabilitation program (CR) in patients with AF. METHODS: The study included 2165 consecutive patients that participated in our CR program between the years 2009 to 2015. All were evaluated by a standard exercise stress test (EST) at baseline, and upon completion of at least 3 months of training. Participants were dichotomized according to baseline fitness and the degree of functional improvement. The combined primary end point was cardiac related hospitalization or all‐cause mortality. RESULTS: A total of 292 patients had history of AF, with a mean age of 68 ± 9 years old, 76% of which were males. The median predicted baseline fitness of AF patients was significantly lower compared to non‐AF patients (103% vs 122%, P < 0.001, respectively). Prominent improvement was achieved in the majority of the patients in both groups (64% among AF patients and 63% among those without AF). Median improvement in fitness between stress tests was significantly higher in patients with AF (124% vs 110%, P < 0.001, respectively). Among AF patients, high baseline fitness was associated with a lower event rates (HR 0.40; 95%CI 0.23‐0.70; P = 0.001). Moreover, prominent improvement during CR showed a protective effect (HR 0.83; 95% CI 0.69‐0.99; P = 0.04). CONCLUSION: In patients with AF participating in CR program, low fitness levels at baseline EST are associated with increased risk of total mortality or cardiovascular hospitalization during long‐term follow‐up. Improvement on follow‐up EST diminishes the risk.