Assessment of absolute risk of life-threatening cardiac events in long QT syndrome patients.

Background: Risk stratification in long QT syndrome (LQTS) patients is important for optimizing patient care and informing clinical decision making. We developed a risk prediction algorithm with prediction of 5-year absolute risk of the first life-threatening arrhythmic event [defined as aborted cardiac arrest, sudden cardiac death, or appropriate implantable cardioverter defibrillator (ICD) shock] in LQTS patients, accounting for individual risk factors and their changes over time. Methods: Rochester-based LQTS Registry included the phenotypic cohort consisting of 1,509 LQTS patients with a QTc ≥ 470 ms, and the genotypic cohort including 1,288 patients with single LQT1, LQT2, or LQT3 mutation. We developed two separate risk prediction models which included pre-specified time-dependent covariates of beta-blocker use, syncope (never, syncope while off beta blockers, and syncope while on beta blockers), and sex by age < and ≥13 years, baseline QTc, and genotype (for the genotypic cohort only). Follow-up started from enrollment in the registry and was censored at patients' 50s birthday, date of death due to reasons other than sudden cardiac death, or last contact, whichever occurred first. The predictive models were externally validated in an independent cohort of 1,481 LQTS patients from Pavia, Italy. Results: In Rochester dataset, there were 77 endpoints in the phenotypic cohort during a median follow-up of 9.0 years, and 47 endpoints in the genotypic cohort during a median follow-up of 9.8 years. The time-dependent extension of Harrell's generalized C-statistics for the phenotypic model and genotypic model were 0.784 (95% CI: 0.740-0.827) and 0.785 (95% CI: 0.721-0.849), respectively, in the Rochester cohort. The C-statistics obtained from external validation in the Pavia cohort were 0.700 (95% CI: 0.610-0.790) and 0.711 (95% CI: 0.631-0.792) for the two models, respectively. Based on the above models, an online risk calculator estimating a 5-year risk of life-threatening arrhythmic events was developed. Conclusion: This study developed two risk prediction algorithms for phenotype and genotype positive LQTS patients separately. The estimated 5-year absolute risk can be used to quantify a LQTS patient's risk of developing life-threatening arrhythmic events and thus assisting in clinical decision making regarding prophylactic ICD therapy.

Temporal Trends Analysis of the Characteristics, Management, and Outcomes of Women With Acute Coronary Syndrome (ACS): ACS Israeli Survey Registry 2000-2016.

Background Cardiovascular disease remains a leading cause of death among women. Despite improvements in the management of patients with acute coronary syndrome (ACS), women with an ACS remain at higher risk. Methods and Results We performed a time-dependent analysis of the management and outcomes of women admitted with ACS who enrolled in the prospective biennial ACS Israeli Surveys between 2000 and 2016. Surveys were divided into 3 time periods (2000-2004, 2006-2010, and 2013-2016). Outcomes included 30-day major adverse cardiac events (death, myocardial infarction, stroke, unstable angina, stent thrombosis, urgent revascularization) and 1-year mortality. Overall, 3518 women were admitted with an ACS. Their mean age (70±12 years) was similar among the time periods. Over the time course of the study, more women were admitted with non-ST-elevation ACS (51.9%, 59.6%, and 66.1%, respectively; P<0.001), and statins and percutaneous coronary intervention were increasingly utilized (66%, 91%, 93%, and 42%, 60%, and 68%, respectively; P<0.001 for each). Among women with ST-segment-elevation myocardial infarction, more primary percutaneous coronary interventions were performed (48.5%, 84.7%, and 95.3%, respectively; P<0.001). The rate of 30-day major adverse cardiac events has significantly decreased over the years (24.6%, 18.6%, and 13.5%, respectively; P<0.001). However, 1-year mortality rates declined only from 2000 to 2004 (16.9%, 12.8%, and 12.3%; P=0.007 for the overall difference), and this change was not significant after propensity matching or multivariate analysis. Conclusions Over more than a decade, 30-day major adverse cardiac events have decreased among women with ACS. Advances in pharmacological treatments and an early invasive approach may have accounted for this improvement. However, the lack of further reduction in 1-year mortality rates among women suggests that more measures should be provided in this high-risk population.

Heart Rate Variability for Risk Assessment of Myocardial Ischemia in Patients Without Known Coronary Artery Disease: The HRV-DETECT (Heart Rate Variability for the Detection of Myocardial Ischemia) Study.

Background Detecting significant coronary artery disease (CAD) in the general population is complex and relies on combined assessment of traditional CAD risk factors and noninvasive testing. We hypothesized that a CAD-specific heart rate variability (HRV) algorithm can be used to improve detection of subclinical or early ischemia in patients without known CAD. Methods and Results Between 2014 and 2018 we prospectively enrolled 1043 patients with low to intermediate pretest probability for CAD who were screened for myocardial ischemia in tertiary medical centers in the United States and Israel. Patients underwent 1-hour Holter testing, with immediate HRV analysis using the HeartTrends DyDx algorithm, followed by exercise stress echocardiography (n=612) or exercise myocardial perfusion imaging (n=431). The threshold for low HRV was identified using receiver operating characteristic analysis based on sensitivity and specificity. The primary end point was the presence of myocardial ischemia detected by exercise stress echocardiography or exercise myocardial perfusion imaging. The mean age of patients was 61 years and 38% were women. Myocardial ischemia was detected in 66 (6.3%) patients. After adjustment for CAD risk factors and exercise stress testing results, low HRV was independently associated with a significant 2-fold increased likelihood for myocardial ischemia (odds ratio, 2.00; 95% CI, 1.41-2.89 [P=0.01]). Adding HRV to traditional CAD risk factors significantly improved the pretest probability for myocardial ischemia. Conclusions Our data from a large prospective international clinical study show that short-term HRV testing can be used as a novel digital-health modality for enhanced risk assessment in low- to intermediate-risk individuals without known CAD. Clinical Trial Registration URL: http://www.ClinicalTrials.gov. Unique identifiers: NCT01657006, NCT02201017).

Characteristics and outcomes associated with 30-day readmissions following acute coronary syndrome 2000-2013: the Acute Coronary Syndrome Israeli Survey.

BACKGROUND: Readmissions following acute myocardial infarction are associated with poor outcomes and a heavy economic burden. There are few evidence-based data on the characteristics and outcomes of patients readmitted following acute coronary syndrome. We explored the incidence and outcomes of patients readmitted after an acute coronary syndrome in the past decade. METHODS: The study population comprised all acute coronary syndrome patients who were enrolled and prospectively followed up in the biennial Acute Coronary Syndrome Israeli Survey from 2000 to 2013. Multivariate analysis identified factors independently associated with readmission and long-term mortality. RESULTS: There were 13,010 study patients, of whom 556 (4.2%) had an unplanned readmission within 30 days of the index event. Stent thrombosis during the index hospitalisation (odds ratio (OR) 8.43; 95% confidence interval (CI) 4.11-16.07; P<0.001), female sex (OR 1.34; 95% CI 1.1-1.63; P=0.003), older age (>65 years; OR 1.28; 95% CI 1.06-1.55; P=0.011), and lack of dual-antiplatelet therapy (OR 1.52; 95% CI 1.25-1.86; P<0.001) were independently associated with readmission. Readmitted patients were less likely to have been treated with guideline-directed medical therapy during hospitalisation and at discharge, and were less likely to have undergone coronary angiography. A strong trend towards decline in readmission rates following acute coronary syndrome was observed between 2000 and 2013 (P<0.001). However, the association between readmission and poor long-term outcome was more pronounced among patients readmitted during more recent years (2008-2013). CONCLUSIONS: Patients readmitted to hospital following acute coronary syndrome comprise an undertreated, high-risk cohort. Our findings indicate that despite a significant decline in readmission rates following acute coronary syndrome over the past decade, readmission within 30 days following acute coronary syndrome still portends a grave outcome.

Sex Differences in Long-Term Outcomes With Cardiac Resynchronization Therapy in Mild Heart Failure Patients With Left Bundle Branch Block.

BACKGROUND: Previous studies have shown conflicting results regarding the benefit of cardiac resynchronization therapy (CRT) by sex and QRS duration. METHODS AND RESULTS: In the Multicenter Automatic Defibrillator Implantation Trial With Cardiac Resynchronization Therapy (MADIT-CRT), we evaluated long-term clinical outcome of heart failure (HF) or death, death, and HF alone by sex and QRS duration (dichotomized at 150 ms) in left bundle-branch block patients with CRT with defibrillator backup (CRT-D) versus implantable cardioverter-defibrillator (ICD) only. There were 394 women (31%) and 887 men with left bundle-branch block. During the median follow-up of 5.6 years, women derived greater clinical benefit from CRT-D compared with implantable cardioverter-defibrillator only, with a significant 71% reduction in HF or death (hazard ratio [HR] 0.29, P<0.001) and a 77% reduction in HF alone (HR 0.23, P<0.001) compared with men, who had a 41% reduction in HF or death (HR 0.59, P<0.001) and a 50% reduction in HF alone (HR 0.50, P<0.001) (all sex-by-treatment interaction P<0.05). Men and women had similar reduction in long-term mortality with CRT-D versus implantable cardioverter-defibrillator only (men: HR 0.70, P=0.03; women: HR 0.59, P=0.04). The incremental benefit of CRT-D in women for HF or death and HF alone was consistent with QRS <150 or >150 ms. CONCLUSIONS: During long-term follow-up of mild HF patients with left ventricular dysfunction and wide QRS, both women and men with left bundle-branch block derived sustained benefit from CRT-D versus implantable cardioverter-defibrillator only, with significant reduction in HF or death, HF alone, and all-cause mortality regardless of QRS duration. There is an incremental benefit with CRT-D in women for the end points of HF or death and HF alone. CLINICAL TRIAL REGISTRATION: URL: https://clinicaltrials.gov/. Unique identifiers: NCT00180271, NCT01294449, and NCT02060110.

Congenital long QT syndromes: prevalence, pathophysiology and management.

Long QT syndrome is a genetic disorder associated with life threatening ventricular arrhythmias and sudden death. This inherited arrhythmic disorder exhibits genetic heterogeneity, incomplete penetrance, and variable expressivity. During the past two decades there have been major advancements in understanding the genotype-phenotype correlations in LQTS. This genotype-phenotype relationship can lead to improved management of LQTS. However, development of genotype-specific or mutation-specific management strategies is very challenging. This review describes the pathophysiology of LQTS, genotype-phenotype correlations, and focuses on the management of LQTS. In general, the treatment of LQTS consists of lifestyle modifications, medical therapy with beta-blockers, device and surgical therapy. We further summarize current data on the efficacy of pharmacological treatment options for the three most prevalent LQTS variants including beta-blockers in LQT1, LQT2 and LQT3, sodium channel blockers and ranolazine for LQT3, potassium supplementation and spironolactone for LQT2, and possibly sex hormone-based therapy for LQT2.

Sex differences in implantable cardioverter-defibrillator implantation indications and outcomes: lessons from the Nationwide Israeli-ICD Registry.

AIMS: Implantable cardioverter-defibrillators (ICDs) improve survival in certain high arrhythmic risk populations. However, there are sex differences regarding both the utilization and the benefit of these devices. Using a prospective national ICD registry, we aim to compare the indications for ICD implantation as well as outcomes in implanted women vs. men. METHODS AND RESULTS: All subjects implanted with an ICD or cardiac resynchronization therapy with a defibrillator (CRTD) in Israel between July 2010 and February 2013 were included. A total of 3544 subjects constructed the baseline cohort, of whom 615 (17%) were women. Women had the same age (64 years) and rate of secondary prevention indication (26%) as men. However, women were more likely than men to have significant heart failure symptoms (52 vs. 45%), QRS > 120 ms (41 vs. 36%), and a higher rate of non-ischaemic cardiomyopathy (54 vs. 21%, all P values <0.05). Using multivariate analysis, women were more likely to undergo CRTD implantation (odds ratio = 1.8, P < 0.01). Follow-up data were available for 1518 subjects with a mean follow-up of 12 months. During follow-up, there were no significant differences among genders in the rate of any single or the combined outcomes of appropriate device therapies, heart failure admissions, or death. First-year re-intervention rate was double among women (5.6 vs. 3.0%, P < 0.01). CONCLUSION: In real-world setting, women implanted with an ICD differ significantly from men in their baseline characteristics and in the use of CRTD devices. These, however, did not translate into outcome differences.

Temporal trends in management of hypertension among Israeli adults, 2002-2010: lesson from the Acute Coronary Syndromes Israeli Survey (ACSIS).

Our aim was to evaluate trends in blood pressure (BP) management and BP levels among patients admitted with acute coronary syndromes (ACS) over the past decade. The study population comprised 7658 ACS patients enrolled in the Acute Coronary Syndromes Israeli Survey (ACSIS) between 2002 and 2010. We compared patients' characteristics, admission systolic BP levels, and antihypertensive therapy between those hospitalized during the early (years: 2002-2004) and late (years: 2008-2010) periods. Among 7658 study participants, 4421 (58%) were hypertensive. Hypertensive patients presenting from 2008 to 2010 tended to exhibit lower BP levels (P < .001). The use of angiotensin converting enzyme inhibitors (ACEi)/angiotensin receptor blockers (ARB) and beta-blockers has increased over the years (P < .001 for both), whereas the use of diuretics and calcium antagonists has remained stable (P = .77 for both). The use of diuretics tended to increase in hypertensive subjects without prior cardiovascular disease (P = .05). In addition, the late period was characterized by a significant increase in the use of two or more antihypertensive agents (combination therapy) compared with the early period (57% vs 50%; P < .001). BP levels decreased among Israeli hypertensive patients presenting with ACS between 2002 and 2010, possibly due to increased use of ACEi/ARB, and combination therapies during this time period.

Risk stratification for implantable cardioverter defibrillator therapy: the role of the wearable cardioverter-defibrillator.

The benefit of implantable cardioverter-defibrillator (ICD) therapy depends upon appropriate evaluation of a persisting risk of sudden death and estimation of the patient's overall survival. Assessment of a stable and unchangeable arrhythmogenic substrate is often difficult. Structural abnormality and ventricular dysfunction, the two major risk parameters, may recover, and heart failure symptoms can improve so that ICD therapy may not be indicated. Risk stratification can take time while the patient continues to be at high risk of arrhythmic death, and patients may need temporary bridging by a defibrillator in cases of interrupted ICD therapy. The wearable cardioverter-defibrillator (WCD) combines a long-term electrocardiogram (ECG)-monitoring system with an external automatic defibrillator. The LIfeVest® (ZOLL, Pittsburgh, PA, USA) is composed of a garment, containing two defibrillation patch electrodes on the back, and an elastic belt with a front-defibrillation patch electrode and four non-adhesive ECG electrodes, connected to a monitoring and defibrillation unit. The WCD is a safe and effective tool to terminate ventricular tachycardia/ventricular fibrillation events, unless a conscious patient withholds shock delivery. It may be used in patients in the early phase after acute myocardial infarction with poor left ventricular function, after acute coronary revascularization procedures (percutaneous coronary intervention or coronary artery bypass grafting) and reduced left ventricular ejection fraction (≤35%), in patients with acute heart failure in non-ischaemic cardiomyopathy of uncertain aetiology and prognosis. The WCD may be helpful in subjects with syncope of assumed tachyarrhythmia origin or in patients with inherited arrhythmia syndromes. The WCD may replace ICD implantation in patients waiting for heart transplantation or who need a ventricular-assist device. This review describes the technical details and characteristics of the WCD, discusses its various potential applications, and reports the currently available experience with the wearable defibrillator.

In silico cardiac risk assessment in patients with long QT syndrome: type 1: clinical predictability of cardiac models.

OBJECTIVES: The study was designed to assess the ability of computer-simulated electrocardiography parameters to predict clinical outcomes and to risk-stratify patients with long QT syndrome type 1 (LQT1). BACKGROUND: Although attempts have been made to correlate mutation-specific ion channel dysfunction with patient phenotype in long QT syndrome, these have been largely unsuccessful. Systems-level computational models can be used to predict consequences of complex changes in channel function to the overall heart rhythm. METHODS: A total of 633 LQT1-genotyped subjects with 34 mutations from multinational long QT syndrome registries were studied. Cellular electrophysiology function was determined for the mutations and introduced in a 1-dimensional transmural electrocardiography computer model. The mutation effect on transmural repolarization was determined for each mutation and related to the risk for cardiac events (syncope, aborted cardiac arrest, and sudden cardiac death) among patients. RESULTS: Multivariate analysis showed that mutation-specific transmural repolarization prolongation (TRP) was associated with an increased risk for cardiac events (35% per 10-ms increment [p < 0.0001]; ≥upper quartile hazard ratio: 2.80 [p < 0.0001]) and life-threatening events (aborted cardiac arrest/sudden cardiac death: 27% per 10-ms increment [p = 0.03]; ≥upper quartile hazard ratio: 2.24 [p = 0.002]) independently of patients' individual QT interval corrected for heart rate (QTc). Subgroup analysis showed that among patients with mild to moderate QTc duration (<500 ms), the risk associated with TRP was maintained (36% per 10 ms [p < 0.0001]), whereas the patient's individual QTc was not associated with a significant risk increase after adjustment for TRP. CONCLUSIONS: These findings suggest that simulated repolarization can be used to predict clinical outcomes and to improve risk stratification in patients with LQT1, with a more pronounced effect among patients with a lower-range QTc, in whom a patient's individual QTc may provide less incremental prognostic information.

Sex-related differences in patients' responses to heart failure therapy.

Men and women with heart failure display important differences in clinical characteristics that might affect their responses to pharmacological and nonpharmacological therapies. In women, heart failure is associated with a higher frequency of hypertension, nonischemic cardiomyopathy and left bundle branch block than in men. Subgroup analyses of data from randomized clinical trials suggest that these differences result in a differential response to heart failure therapies, including a somewhat better response to ß-blockers, a worse prognosis with digoxin therapy, and a lower survival benefit with implantable cardioverter-defibrillators in women. Importantly, female patients with heart failure also derive significantly greater improvements in cardiac volumes from cardiac resynchronization therapy than do male patients, and this treatment is associated with reduced risks of all-cause mortality and heart failure events among women with mild symptoms. These data suggest that sex-related differences might exist in response to both medical and device therapies for patients with heart failure.

Combined assessment of sex- and mutation-specific information for risk stratification in type 1 long QT syndrome.

BACKGROUND: Men and women with type 1 long QT syndrome (LQT1) exhibit time-dependent differences in the risk for cardiac events. OBJECTIVE: We hypothesized that sex-specific risk for LQT1 is related to the location and function of the disease-causing mutation in the KCNQ1 gene. METHODS: The risk for life-threatening cardiac events (comprising aborted cardiac arrest [ACA] or sudden cardiac death [SCD]) from birth through age 40 years was assessed among 1051 individuals with LQT1 (450 men and 601 women) by the location and function of the LQT1-causing mutation (prespecified as mutations in the intracellular domains linking the membrane-spanning segments [ie, S2-S3 and S4-S5 cytoplasmic loops] involved in adrenergic channel regulation vs other mutations). RESULTS: Multivariate analysis showed that during childhood (age group: 0-13 years) men had >2-fold (P < .003) increased risk for ACA/SCD than did women, whereas after the onset of adolescence the risk for ACA/SCD was similar between men and women (hazard ratio = 0.89 [P = .64]). The presence of cytoplasmic-loop mutations was associated with a 2.7-fold (P < .001) increased risk for ACA/SCD among women, but it did not affect the risk among men (hazard ratio 1.37; P = .26). Time-dependent syncope was associated with a more pronounced risk-increase among men than among women (hazard ratio 4.73 [P < .001] and 2.43 [P = .02], respectively), whereas a prolonged corrected QT interval (≥ 500 ms) was associated with a higher risk among women than among men. CONCLUSION: Our findings suggest that the combined assessment of clinical and mutation location/functional data can be used to identify sex-specific risk factors for life-threatening events for patients with LQT1.

Cost-effectiveness of implanted defibrillators in young people with inherited cardiac arrhythmias.

BACKGROUND: The implanted cardioverter-defibrillator (ICD) has been shown to improve survival in adult patients with high risk acquired cardiac disease, with a cost-effectiveness ratio in the range of $30,000 to $185,000 per quality-adjusted-life-year saved. However, data on the benefit and cost-effectiveness of device therapy in high-risk patients with inherited cardiac disorders are limited. METHODS: We developed two separate computer-based analytical models to compare non-ICD with ICD therapy in patients (age range: 10-75 years) with long QT syndrome (LQTS) and hypertrophic cardiomyopathy (HCM). In each disease entity patients were stratified into low-risk (no known risk factors); high-risk (known risk factors [primary prevention]); and very high-risk (prior near-fatal events [secondary prevention]). Net costs were defined as the difference between costs resulting from treatment of the disease and savings due to gained productivity attributable to prevention of sudden cardiac death. Outcome was defined as costs per quality-adjusted life-years saved. RESULTS: In LQTS, defibrillator therapy was shown to be cost effective in high-risk male patients (incremental cost-effectiveness ratio [ICER]=$3328 per quality-adjusted-life-year saved), and cost saving in high-risk females (ICER=$7102 gained per quality-adjusted-life-year saved) and very high-risk males and females (ICER=$15,483 and 19,393 gained per quality-adjusted-life-year saved, respectively). In HCM, defibrillator therapy was cost saving in both male and female high-risk (ICER=$17,892 and $17,526 gained per quality-adjusted-life-year saved, respectively) and very high-risk (ICER $22,944 and $22,329 gained per quality-adjusted-life-year saved, respectively) patients. Defibrillator therapy was not shown to be cost effective in low-risk patients with either LQTS or HCM (ICER in the range of $400,000 to $600,000 lost per quality-adjusted-life-year saved). Sensitivity analyses were consistent with the results in each risk group. CONCLUSIONS: In appropriately selected patients with inherited cardiac disorders, early intervention with ICD therapy is cost-effective to cost saving due to added years of gained productivity when the lifespan of an individual at risk is considered.

Serologic testing for celiac disease in young adults--a cost-effect analysis.

In recent years, there has been a marked increase in the diagnostic workups for celiac disease among military personnel, thereby significantly increasing overall laboratory testing expenditures and burden. We evaluated the serologic testing procedure in symptomatic young adults, using a "cost-effect" approach. We evaluated the serologic screening policy for celiac disease among serologically tested military personnel. The study population was divided into subgroups according to the clinical presentation prior to screening: isolated (low-risk) and combined complaints (high-risk). Sensitivity, specificity, and predictive values of serologic markers for celiac disease were evaluated. Cost analyses were based on diagnostic expenditures. Cost-effect ratio is expressed as cost per newly diagnosed patients, and cost minimization as cost per screened individuals. Five hundred thirty-eight military personnel were serologically tested for celiac disease. Eight new cases of celiac were diagnosed, all of whom belonged to the high-risk subgroup and tested positive for at least two positive serologic tests (tTG + EMA or tTG + AGA IgG + EMA). EMA Ab measured the highest sensitivity, specificity, and predictive values. Average screening expenditure was U.S. $287 per patient. The lowest cost-effect and cost minimization ratios were achieved by implementing a two-step single-marker screening protocol for high-risk subjects and one-step follow-up for low-risk subjects. Among patient population of young adults, selective diagnostic workup could result in cost-minimization without risking quality of diagnosis. From a cost-effect perspective, implemented screening procedures need to be dependent on subgroup: low-risk, clinical follow-up; and high-risk, serological testing for EMA and, only if positive, possibly a small-bowel biopsy.