Repeat ablation of refractory ventricular arrhythmias in patients with nonischemic cardiomyopathy: Impact of midmyocardial substrate and role of adjunctive ablation techniques.

INTRODUCTION: Multiple ablations are often necessary to manage ventricular arrhythmias (VAs) in nonischemic cardiomyopathy (NICM) patients. We assessed characteristics and outcomes and role of adjunctive, nonstandard ablation in repeat VA ablation (RAbl) in NICM. METHODS AND RESULTS: Consecutive NICM patients undergoing RAbl were analyzed, with characteristics of the last VA ablations compared between those undergoing 1 versus multiple-repeat ablations (1-RAbl vs. >1RAbl), and between those with or without midmyocardial substrate (MMS). VA-free survival was compared. Eighty-eight patients underwent 124 RAbl, 26 with > 1RAbl, and 26 with MMS. 1-RAbl and > 1-RAbl groups were similar in age (57 ± 16 vs. 57 ± 17 years; P = 0.92), males (76% vs. 69%; P = 0.60), LVEF (40 ± 17% vs. 40 ± 18%; P = 0.96), and amiodarone use (31% vs. 46%, P = 0.22). One-year VA freedom between 1-RAbl vs. > 1RAbl was similar (82% vs. 80%; P = 0.81); adjunctive ablation was utilized more in >1RAbl (31% vs. 11%, P = 0.02), and complication rates were higher (27% vs. 7%, P = 0.01), most due to septal substrate and anticipated heart block. >1-RAbl patients had more MMS (62% vs. 16%, P < 0.01). Although MMS was associated with worse VA-free survival after 1-RAbl (43% vs. 69%, P = 0.01), when >1RAbl was performed, more often with nonstandard ablation, VA-free survival was comparable to non-MMS patients (85% vs. 81%; P = 0.69). More RAbls were required in MMS versus non-MMS patients (2.00 ± 0.98 vs. 1.16 ± 0.37; P < 0.001). CONCLUSION: For NICM patients with recurrent, refractory VAs despite previous ablation, effective arrhythmia control can safely be achieved with subsequent ablation, although >1 repeat procedure with adjunctive ablation is often required, especially with MMS.

Fibroblast growth factor-23 and incident atrial fibrillation: the Multi-Ethnic Study of Atherosclerosis (MESA) and the Cardiovascular Health Study (CHS).

BACKGROUND: Fibroblast growth factor-23 (FGF-23) is a hormone that promotes urinary phosphate excretion and regulates vitamin D metabolism. Circulating FGF-23 concentrations increase markedly in chronic kidney disease and are associated with increased risk of clinical cardiovascular events. FGF-23 may promote atrial fibrillation (AF) by inducing left ventricular hypertrophy and diastolic and left atrial dysfunction. METHODS AND RESULTS: We tested the associations of circulating FGF-23 concentration with incident AF among 6398 participants in the Multi-Ethnic Study of Atherosclerosis (MESA) and 1350 participants in the Cardiovascular Health Study (CHS), all free of clinical cardiovascular disease at baseline. Over a median of 7.7 and 8.0 years of follow-up, we observed 291 and 229 incident AF events in MESA and CHS, respectively. In multivariable Cox proportional hazards models, each 2-fold-higher FGF-23 concentration was associated with a 41% higher risk of incident AF in MESA (hazard ratio, 1.41; 95% confidence interval, 1.13-1.76; P=0.003) and a 30% higher risk of incident AF in CHS (hazard ratio, 1.30; 95% confidence interval, 1.05-1.61; P=0.016) after adjustment for potential confounding characteristics, including kidney disease. Serum phosphate concentration was significantly associated with incident AF in MESA (hazard ratio, 1.15 per 0.5 mg/dL; 95% confidence interval, 1.02-1.31; P=0.023) but not CHS. In MESA, an association of low estimated glomerular filtration rate with incident AF was partially attenuated by adjustment for FGF-23. CONCLUSION: Higher circulating FGF-23 concentration is associated with incident AF and may, in part, explain the link between chronic kidney disease and AF.

Risk of recurrent cardiac events after onset of menopause in women with congenital long-QT syndrome types 1 and 2.

BACKGROUND: Women with congenital long-QT syndrome experience an increased risk for cardiac events after the onset of adolescence that is more pronounced among carriers of the LQT2 genotype. We hypothesized that the hormonal changes associated with menopause may affect clinical risk in this population. METHODS AND RESULTS: We used a repeated-events analysis to evaluate the risk for recurrent syncope during the menopause transition and postmenopausal periods (5 years before and after the age at onset of menopause, respectively) among 282 LQT1 (n=151) and LQT2 (n=131) women enrolled in the Long-QT Syndrome Registry. Multivariate analysis showed that the risk for recurrent syncope (n=150) among LQT2 women was significantly increased during both menopause transition (hazard ratio, 3.38; P=0.005) and the postmenopausal period (hazard ratio, 8.10; P<0.001) compared with the reproductive period. The risk increase was evident among women who did or did not receive estrogen therapy. In contrast, among LQT1 women, the onset of menopause was associated with a reduction in the risk for recurrent syncope (hazard ratio, 0.19; P=0.05; P=0.02 for genotype-by-menopause interaction). Only 22 women (8%) experienced aborted cardiac arrest or sudden cardiac death during follow-up. The frequency of aborted cardiac arrest/sudden cardiac death showed a similar genotype-specific association with the onset of menopause. CONCLUSIONS: The onset of menopause is associated with a significant increase in the risk of cardiac events (dominated by recurrent episodes of syncope) in LQT2 women, suggesting that careful follow-up and continued long-term therapy are warranted in this population.

Polymorphisms in the paraoxonase and endothelial nitric oxide synthase genes and the risk of early-onset myocardial infarction.

In young patients, the accumulative burden of traditional cardiovascular risk factors may not be as significant as in an older population. Genetic risk factors were suggested to have a role in the early development of myocardial infarction (MI). However, data about the association between polymorphisms in heart disease-related genes and the early onset of a first MI are limited. In the present study, age at onset of a first MI was related to individual single-nucleotide polymorphisms in each of 18 prespecified candidate genes in a cohort of 814 patients enrolled in the Thrombogenic Factors and Recurrent Coronary Events (THROMBO) Study. Multivariate regression analysis showed in patients who had the high-risk genotypes of paraoxonase 1 (PON1) Q192R and endothelial nitric oxide synthase (eNOS) E298D that ages at onset of a first MI were 1.8 (p = 0.02) and 3.5 years (p = 0.02) earlier than in noncarriers of the genotypes, respectively. Consistently, high-risk genotypes of the PON1 Q192R and eNOS E298D polymorphisms were significantly associated with onset of a first MI at age <50 years (adjusted odds ratio 1.70, p = 0.005, adjusted odds ratio 2.15, p = 0.01, respectively). In conclusion, our findings suggest that high-risk genotypes of the PON1 Q192R and eNOS E298D polymorphisms are independently associated with a significantly earlier occurrence of coronary events.

Atrial Fibrillation in Heart Failure US Ambulatory Cardiology Practices and the Potential for Uptake of Catheter Ablation: An National Cardiovascular Data Registry (NCDR®) Research to Practice (R2P) Project.

BACKGROUND: Atrial fibrillation (AF) and heart failure with reduced ejection fraction frequently coexist. The AATAC (Ablation versus Amiodarone for Treatment of persistent Atrial fibrillation in patients with Congestive heart failure and an implantable device) trial suggests that catheter ablation may benefit these patients. However, applicability to contemporary ambulatory cardiology practice is unknown. METHODS AND RESULTS: Using the outpatient National Cardiovascular Data Registry® Practice Innovation and Clinical Excellence Registry, we identified participants meeting AATAC enrollment criteria between 2013 and 2014. Treatment with medications and procedures was assessed at registry inclusion. From 164 166 patients with AF and heart failure, 8483 (7%) patients potentially met AATAC inclusion criteria. Eligible subjects, compared to AATAC trial participants, were older (mean age, 71.2±11.4 years) and had greater comorbidity (coronary artery disease 79.2%, hypertension 82.4%, and diabetes mellitus 31.8%). AF was predominantly paroxysmal (65.5%), rather than persistent/permanent (16.7%) or new onset (17.8%), whereas all patients in the AATAC trial had persistent AF. Commonly used atrioventricular-nodal blocking agents were carvedilol (71.2%), digoxin (31.9%), and metoprolol (27.1%). Rhythm control with anti-arrhythmic drugs was reported in 29.0% of AATAC eligible patients (predominantly amiodarone [24.6%]) and 9.3% had undergone catheter ablation. Patients who underwent ablation were more likely to be younger and have less comorbidities than those who did not. CONCLUSIONS: Among the contemporary ambulatory AF/heart failure with reduced ejection fraction population, treatment is predominantly rate control with few catheter ablations. Application of AATAC findings has the potential to markedly increase the use of catheter ablation in this population, although significant differences in clinical profiles might influence ablation outcomes in practice.

Outcomes Among Older Patients Receiving Implantable Cardioverter-Defibrillators for Secondary Prevention: From the NCDR ICD Registry.

BACKGROUND: Clinical trials of implantable cardioverter-defibrillators (ICDs) for secondary prevention of sudden cardiac death were conducted nearly 2 decades ago and enrolled few older patients. OBJECTIVES: This study assessed morbidity and mortality of older patients receiving ICDs for secondary prevention in contemporary clinical practice. METHODS: We identified 12,420 Medicare beneficiaries from the National Cardiovascular Data Registry ICD Registry undergoing first-time secondary prevention ICD implantation between 2006 and 2009 in 956 U.S. hospitals. Risks of death, hospitalization, and admission to a skilled nursing facility (SNF) were assessed over 2 years in age strata (65 to 69, 70 to 74, 75 to 79, and ≥80 years of age) using Medicare claims. The adjusted association between age and outcomes was evaluated using multivariable models. RESULTS: The mean age was 75 years at the time of implantation; 25.3% were <70 years of age and 25.7% were ≥80 years of age. Overall, the risk of death at 2 years was 21.8%, ranging from 14.7% among those <70 years of age to 28.9% among those ≥80 years of age (adjusted risk ratio [aRR]: 2.01; 95% confidence interval [CI]: 1.85 to 2.33; p for trend <0.001). The cumulative incidence of hospitalizations was 65.4%, ranging from 60.5% in those <70 years of age to 71.5% in those ≥80 years of age (aRR: 1.27; 95% CI: 1.19 to 1.36; p for trend <0.001). The cumulative incidence of admission to a SNF ranged from 13.1% among those <70 years of age to 31.9% among those ≥80 years of age (aRR: 2.67; 95% CI: 2.37 to 3.01; p for trend <0.001); SNF admission risk was highest in the first 30 days. CONCLUSIONS: Almost 4 in 5 older patients receiving a secondary prevention ICD survives at least 2 years. High hospitalization and SNF admission rates, particularly among the oldest patients, identify substantial care needs after device implantation.

eGFR and Albuminuria in Relation to Risk of Incident Atrial Fibrillation: A Meta-Analysis of the Jackson Heart Study, the Multi-Ethnic Study of Atherosclerosis, and the Cardiovascular Health Study.

BACKGROUND AND OBJECTIVES: The incidence of atrial fibrillation is high in ESRD, but limited data are available on the incidence of atrial fibrillation across a broad range of kidney function. Thus, we examined the association of eGFR and urine albumin-to-creatinine ratio with risk of incident atrial fibrillation. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We meta-analyzed three prospective cohorts: the Jackson Heart Study, the Multi-Ethnic Study of Atherosclerosis, and the Cardiovascular Health Study. Cox regression models were performed examining the association of eGFR and urine albumin-to-creatinine ratio with incident atrial fibrillation adjusting for demographics and comorbidity. In additional analyses, we adjusted for measures of subclinical cardiovascular disease (by electrocardiogram and cardiac imaging) and interim heart failure and myocardial infarction events. RESULTS: In the meta-analyzed study population of 16,769 participants without prevalent atrial fibrillation, across categories of decreasing eGFR (eGFR>90 [reference], 60-89, 45-59, 30-44, and <30 ml/min per 1.73 m2), there was a stepwise increase in the adjusted risk of incident atrial fibrillation: hazard ratios (95% confidence intervals) were 1.00, 1.09 (0.97 to 1.24), 1.17 (1.00 to 1.38), 1.59 (1.28 to 1.98), and 2.03 (1.40 to 2.96), respectively. There was a stepwise increase in the adjusted risk of incident atrial fibrillation across categories of increasing urine albumin-to-creatinine ratio (urine albumin-to-creatinine ratio <15 [reference], 15-29, 30-299, and ≥300 mg/g): hazard ratios (95% confidence intervals) were 1.00, 1.04 (0.83 to 1.30), 1.47 (1.20 to 1.79), and 1.76 (1.18 to 2.62), respectively. The associations were consistent after adjustment for subclinical cardiovascular disease measures and interim heart failure and myocardial infarction events. CONCLUSIONS: In this meta-analysis of three cohorts, reduced eGFR and elevated urine albumin-to-creatinine ratio were significantly associated with greater risk of incident atrial fibrillation, highlighting the need for further studies to understand mechanisms linking kidney disease with atrial fibrillation.

Chronic kidney disease and cardiac remodelling in patients with mild heart failure: results from the REsynchronization reVErses Remodeling in Systolic Left vEntricular Dysfunction (REVERSE) study.

AIMS: Chronic kidney disease (CKD) is a risk factor for left ventricular hypertrophy (LVH) and heart failure. We evaluated the effect of CKD on left ventricular (LV) remodelling among patients with mild heart failure. METHODS AND RESULTS: REVERSE was a randomized, controlled trial evaluating cardiac resynchronization therapy (CRT) in patients with New York Heart Association (NYHA) class I/II heart failure. CKD was defined as an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m(2). We compared changes in LV function and size over the course of 12 months by CKD status using linear mixed models adjusted for demographics, co-morbidities, medications, cardiomyopathy aetiology, and CRT status. Finally, we evaluated the effect of CKD on cardiac remodelling among patients randomized to CRT on or off. CKD was associated with worsening LV function and dilation compared with the non-CKD group {adjusted, 12-month ß coefficients for the CKD group compared with the non-CKD referent group: LV ejection fraction (%) [-1.80, 95% confidence interval (CI) -3.36 to -0.24], LV end-systolic volume (mL) (14.16, 95% CI 3.96-24.36), LV end-diastolic volume (mL) (14.88, 95% CI 2.88-26.76), LV end-systolic diameter (cm) (0.36, 95% CI 0.12-0.48), LV end-diastolic diameter (cm) (0.24, 95% CI 0.012-0.36), mitral regurgitation (%) (3.12, 95% CI 0.48-5.76), and LV shape (0.036, 95% CI 0.012-0.060)}. In participants assigned to CRT, those without CKD had significantly greater improvements in LV structural parameters compared with the CKD group. CONCLUSIONS: In comparison with participants with normal kidney function, CKD is an independent risk factor for ventricular dysfunction and dilation. CRT improves LV function and structure to a lesser extent in patients with CKD than in those with normal kidney function.

Corrected QT variability in serial electrocardiograms in long QT syndrome: the importance of the maximum corrected QT for risk stratification.

OBJECTIVES: We evaluated the incremental prognostic information provided by multiple corrected QT (QTc) measurements on serial electrocardiograms (ECGs) in patients with the inherited long QT syndrome (LQTS). BACKGROUND: A baseline QTc of > or =500 ms has been shown to be associated with increased risk of cardiac events among LQTS patients. However, the value of QTc measurements on follow-up ECGs in risk assessment has not been determined. METHODS: The risk of a first LQTS-related cardiac event during adolescence was assessed in 375 patients enrolled in the International LQTS Registry for whom serial follow-up ECGs were recorded before age 10. RESULTS: The mean +/- SD difference between the minimum and maximum QTc values on serial ECGs recorded in study patients was 47 +/- 40 ms. The maximum QTc interval recorded before age 10 was the strongest predictor of cardiac events during adolescence (adjusted hazard ratio [HR] = 2.74; p < 0.001). Other follow-up QTc measures, including the baseline, the mean, and the most recent QTc interval recorded before age 10, were less significant risk factors. After adjusting for the maximum QTc value during follow-up, no significant association remained between the baseline QTc value and the risk of subsequent cardiac events (HR = 1.04; p = 0.91). CONCLUSIONS: In LQTS patients, there is a considerable variability in QTc measures in serial follow-up ECGs. The maximum QTc interval provides incremental prognostic information beyond the baseline measurement. We suggest that risk stratification in LQTS patients should include follow-up ECG data.