Neal A. Chatterjee

Atrioventricular nodal ablation in atrial fibrillation: a meta-analysis of biventricular vs. right ventricular pacing mode.

For patients with refractory atrial fibrillation (AF) undergoing atrioventricular nodal ablation (AVNA), initial single‐chamber right ventricular (RV)‐only pacing is standard. Given the deleterious effects of chronic RV‐only pacing, the impact of an initial biventricular (BiV) pacing strategy post‐ablation is of interest.

Reduced appropriate implantable cardioverter-defibrillator therapy after cardiac resynchronization therapy-induced left ventricular function recovery: a meta-analysis and systematic review

AIMS For patients undergoing cardiac resynchronization therapy (CRT) with implantable cardioverter-defibrillator (ICD; CRT-D), the effect of an improvement in left ventricular ejection fraction (LVEF) on appropriate ICD therapy may have significant implications regarding management at the time of ICD generator replacement. METHODS AND RESULTS We conducted a meta-analysis to determine the effect of LVEF recovery following CRT on the incidence of appropriate ICD therapy. A search of multiple electronic databases identified 709 reports, of which 6 retrospective cohort studies were included (n = 1740). In patients with post-CRT LVEF ≥35% (study n = 4), the pooled estimated rate of ICD therapy (5.5/100 person-years) was significantly lower than patients with post-CRT LVEF <35% [incidence rate difference (IRD): -6.5/100 person-years, 95% confidence interval (95% CI): -8.8 to -4.2, P < 0.001]. Similarly, patients with post-CRT LVEF ≥45% (study n = 4) demonstrated lower estimated rates of ICD therapy (2.3/100 person-years) compared with patients without such recovery (IRD: -5.8/100 person-years, 95% CI: -7.6 to -4.0, P < 0.001). Restricting analysis to studies discounting ICD therapies during LVEF recovery (study n = 3), patients with LVEF recovery (≥35 or ≥45%) had significantly lower rates of ICD therapy compared with patients without such recovery (P for both <0.001). Patients with primary prevention indication for ICD, regardless of LVEF recovery definition, had very low rates of ICD therapy (0.4 to 0.8/100-person years). CONCLUSION Recovery of LVEF post-CRT is associated with significantly reduced appropriate ICD therapy. Patients with improvement of LVEF ≥45% and those with primary prevention indication for ICD appear to be at lowest risk.

Racial Differences in Breast Cancer Stage at Diagnosis in the Mammography Era

OBJECTIVES We assessed racial differences in breast cancer mortality by stage at diagnosis, since mammography became available. METHODS We calculated adjusted odds of distant (versus local or regional) tumors for 143,249 White and 13,571 Black women aged 50 to 69 years, diagnosed with breast cancer between 1982 and 2007 and living in a Surveillance, Epidemiology, and End Results region. We compared linear trends in stage at diagnosis before and after 1998. RESULTS Distant-stage cancer was diagnosed in 5.8% of White and 10.2% of Black participants. The Black-White disparity in distant tumors narrowed until 1998 (1998 adjusted difference = 0.65%), before increasing. Between 1982 and 1997, the proportion of distant tumors decreased for Blacks (adjusted odds ratio [AOR]/y = 0.973; 95% confidence interval [CI] = 0.960, 0.987) and Whites (AOR/y = 0.978; 95% CI = 0.973, 0.983), with no racial differences (P = .47). From 1998 to 2007, the odds of distant versus local or regional tumors increased for Blacks (AOR/y = 1.036; 95% CI = 1.013, 1.060) and Whites (AOR/y = 1.011; 95% CI = 1.002, 1.021); the rate of increase was greater for Blacks than Whites (P = .04). CONCLUSIONS In the mammography era, racial disparities remain in stage at diagnosis.

Atrioventricular Nodal Ablation in Atrial Fibrillation: A Meta-analysis and Systematic Review

Background— In the treatment of patients with refractory atrial fibrillation (AF), the safety and efficacy of atrioventricular nodal ablation (AVNA) versus pharmacotherapy alone remains unclear. Additionally, the impact of AVNA in patients with reduced systolic function is of growing interest. Methods and Results— A total of 5 randomized or prospective trials were included for efficacy review (314 patients), 11 studies for effectiveness review (810 patients), and 47 studies for safety review (5632 patients). All-cause mortality was similar between AVNA and medical therapy (3.1% versus 3.3%; relative risk ratio, 1.05; 95% confidence interval [CI], 0.29–3.85). There was no significant difference in exercise duration or ejection fraction (EF) with AVNA relative to pharmacotherapy. In subgroup analysis, patients with baseline systolic dysfunction (116 patients; mean EF, 44%) showed significant relative improvement in EF after AVNA (+4% greater; 95% CI, 3.11–4.89). In pooled observational analysis, AVNA was also associated with significant improvement in EF only in patients with systolic dysfunction (+7.44%; 95% CI, 5.4–9.5). The incidence of procedure-related mortality (0.27%) and malignant arrhythmia (0.57%) was low. At mean follow-up of 26.5 months, the incidence of sudden cardiac death after AVNA was 2.1%. There was significant heterogeneity in quality-of-life scales used; compared with pharmacotherapy, AVNA was associated with significant improvement in several symptoms (palpitations, dyspnea). Conclusions— In the management of refractory AF, AVNA is associated with improvement in symptoms and quality of life, with a low incidence of procedure morbidity. In patients with reduced systolic function, AVNA demonstrates small but significantly improved echocardiographic outcomes relative to medical therapy alone.Background— In the treatment of patients with refractory atrial fibrillation (AF), the safety and efficacy of atrioventricular nodal ablation (AVNA) versus pharmacotherapy alone remains unclear. Additionally, the impact of AVNA in patients with reduced systolic function is of growing interest. Methods and Results— A total of 5 randomized or prospective trials were included for efficacy review (314 patients), 11 studies for effectiveness review (810 patients), and 47 studies for safety review (5632 patients). All-cause mortality was similar between AVNA and medical therapy (3.1% versus 3.3%; relative risk ratio, 1.05; 95% confidence interval [CI], 0.29–3.85). There was no significant difference in exercise duration or ejection fraction (EF) with AVNA relative to pharmacotherapy. In subgroup analysis, patients with baseline systolic dysfunction (116 patients; mean EF, 44%) showed significant relative improvement in EF after AVNA (+4% greater; 95% CI, 3.11–4.89). In pooled observational analysis, AVNA was also associated with significant improvement in EF only in patients with systolic dysfunction (+7.44%; 95% CI, 5.4–9.5). The incidence of procedure-related mortality (0.27%) and malignant arrhythmia (0.57%) was low. At mean follow-up of 26.5 months, the incidence of sudden cardiac death after AVNA was 2.1%. There was significant heterogeneity in quality-of-life scales used; compared with pharmacotherapy, AVNA was associated with significant improvement in several symptoms (palpitations, dyspnea). Conclusions— In the management of refractory AF, AVNA is associated with improvement in symptoms and quality of life, with a low incidence of procedure morbidity. In patients with reduced systolic function, AVNA demonstrates small but significantly improved echocardiographic outcomes relative to medical therapy alone.

Novel Interventional Therapies to Modulate the Autonomic Tone in Heart Failure.

Heart failure (HF) represents a significant and expanding public health burden associated with increasing prevalence and exponential growth in related health care costs. Contemporary advances in both pharmacological and nonpharmacological therapies have often been restricted in application and benefit. Given the critical role of the autonomic nervous system (ANS) in maintaining cardiovascular homeostasis in the failing heart, there has been increasing interest in the role of ANS modulation as a therapeutic modality in HF. In this review, we highlight the anatomy of the ANS and its role in the pathophysiology of HF, as well as metrics of its assessment. Given the limitations associated with pharmacological ANS modulation, including lack of specificity and medication intolerance, we focus in this review on contemporary nonpharmacological ANS modulation therapies. For each therapy-vagal nerve stimulation, carotid baroreceptor stimulation, spinal cord stimulation, and renal denervation-we review the rationale for modulation, pre-clinical and clinical assessments, as well as procedural considerations and limitations. We conclude by commenting on novel technologies and strategies for ANS modulation on the horizon.

What Is the Prognostic Significance of Pulmonary Hypertension in Heart Failure

Increased left ventricular filling pressure is a hallmark of heart failure (HF) caused by left ventricular dysfunction (LVD). Within the closed hemodynamic system, increased LV filling pressure results in elevated pressures in the left atrium and pulmonary venous vasculature. When pulmonary hypertension (PH, defined by mean pulmonary artery pressure [mPAP] >25 mm Hg) is associated with an abnormally elevated pulmonary capillary wedge pressure (PCWP >15 mm Hg) or left ventricular end-diastolic pressure (LVEDP >18 mm Hg),1 it has been variably termed World Health Organization (WHO) Group 2 PH,1 pulmonary venous hypertension,2 “postcapillary PH,”3 or “passive PH.”4 Article see p 644 Patients with LVD also have a propensity to develop a precapillary pulmonary arterial contribution to PH, reflected by an increased transpulmonary gradient (TPG, defined as mPAP-PCWP that exceeds 12 to 15 mm Hg) or an elevated pulmonary vascular resistance (PVR, defined as TPG/cardiac output that exceeds 2.5 to 3 Wood units [WU]).5,6 This type of PH, which is “out of proportion” to underlying left-sided disease in the setting of normalized volume status, has been termed “mixed PH,” given both precapillary and postcapillary contributions to elevated PAP.7 PH in HF can be simplistically organized along 2 sequential dyads: (1) the presence or absence of a significant precapillary contribution to elevated PAP (ie, mixed PH as opposed to purely passive PH) and (2) if present, the relative fixed (ie, nonreversible with lowering left-sided filling pressures) or reactive (ie, reversible with reduction of left-sided filling pressures) character of the precapillary contribution to PH (Figure). Figure. Diagnostic framework for pulmonary hypertension in heart failure (HF). mPAP indicates mean pulmonary artery pressure; PCWP, pulmonary capillary wedge pressure; PVR, pulmonary vascular resistance; and PH, pulmonary hypertension. There are no widely established cut-points to define PVR and transpulmonary …

Genetic Obesity and the Risk of Atrial Fibrillation- Causal Estimates from Mendelian Randomization

Background: Observational studies have identified an association between body mass index (BMI) and incident atrial fibrillation (AF). Inferring causality from observational studies, however, is subject to residual confounding, reverse causation, and bias. The primary objective of this study was to evaluate the causal association between BMI and AF by using genetic predictors of BMI. Methods: We identified 51 646 individuals of European ancestry without AF at baseline from 7 prospective population-based cohorts initiated between 1987 and 2002 in the United States, Iceland, and the Netherlands with incident AF ascertained between 1987 and 2012. Cohort-specific mean follow-up ranged from 7.4 to 19.2 years, over which period there was a total of 4178 cases of incident AF. We performed a Mendelian randomization with instrumental variable analysis to estimate a cohort-specific causal hazard ratio for the association between BMI and AF. Two genetic instruments for BMI were used: FTO genotype (rs1558902) and a BMI gene score comprising 39 single-nucleotide polymorphisms identified by genome-wide association studies to be associated with BMI. Cohort-specific estimates were combined by random-effects, inverse variance–weighted meta-analysis. Results: In age- and sex-adjusted meta-analysis, both genetic instruments were significantly associated with BMI (FTO: 0.43 [95% confidence interval, 0.32–0.54] kg/m2 per A-allele, P<0.001; BMI gene score: 1.05 [95% confidence interval, 0.90–1.20] kg/m2 per 1-U increase, P<0.001) and incident AF (FTO, hazard ratio, 1.07 [1.02–1.11] per A-allele, P=0.004; BMI gene score, hazard ratio, 1.11 [1.05–1.18] per 1-U increase, P<0.001). Age- and sex-adjusted instrumental variable estimates for the causal association between BMI and incident AF were hazard ratio, 1.15 (1.04–1.26) per kg/m2, P=0.005 (FTO) and 1.11 (1.05–1.17) per kg/m2, P<0.001 (BMI gene score). Both of these estimates were consistent with the meta-analyzed estimate between observed BMI and AF (age- and sex-adjusted hazard ratio 1.05 [1.04–1.06] per kg/m2, P<0.001). Multivariable adjustment did not significantly change findings. Conclusions: Our data are consistent with a causal relationship between BMI and incident AF. These data support the possibility that public health initiatives targeting primordial prevention of obesity may reduce the incidence of AF.Background: Observational studies have identified an association between body mass index (BMI) and incident atrial fibrillation (AF). Inferring causality from observational studies, however, is subject to residual confounding, reverse causation, and bias. The primary objective of this study was to evaluate the causal association between BMI and AF by using genetic predictors of BMI. Methods: We identified 51 646 individuals of European ancestry without AF at baseline from 7 prospective population-based cohorts initiated between 1987 and 2002 in the United States, Iceland, and the Netherlands with incident AF ascertained between 1987 and 2012. Cohort-specific mean follow-up ranged from 7.4 to 19.2 years, over which period there was a total of 4178 cases of incident AF. We performed a Mendelian randomization with instrumental variable analysis to estimate a cohort-specific causal hazard ratio for the association between BMI and AF. Two genetic instruments for BMI were used: FTO genotype (rs1558902) and a BMI gene score comprising 39 single-nucleotide polymorphisms identified by genome-wide association studies to be associated with BMI. Cohort-specific estimates were combined by random-effects, inverse variance–weighted meta-analysis. Results: In age- and sex-adjusted meta-analysis, both genetic instruments were significantly associated with BMI ( FTO : 0.43 [95% confidence interval, 0.32–0.54] kg/m2 per A-allele, P <0.001; BMI gene score: 1.05 [95% confidence interval, 0.90–1.20] kg/m2 per 1-U increase, P <0.001) and incident AF ( FTO , hazard ratio, 1.07 [1.02–1.11] per A-allele, P =0.004; BMI gene score, hazard ratio, 1.11 [1.05–1.18] per 1-U increase, P <0.001). Age- and sex-adjusted instrumental variable estimates for the causal association between BMI and incident AF were hazard ratio, 1.15 (1.04–1.26) per kg/m2, P =0.005 ( FTO ) and 1.11 (1.05–1.17) per kg/m2, P <0.001 (BMI gene score). Both of these estimates were consistent with the meta-analyzed estimate between observed BMI and AF (age- and sex-adjusted hazard ratio 1.05 [1.04–1.06] per kg/m2, P <0.001). Multivariable adjustment did not significantly change findings. Conclusions: Our data are consistent with a causal relationship between BMI and incident AF. These data support the possibility that public health initiatives targeting primordial prevention of obesity may reduce the incidence of AF. # Clinical Perspective {#article-title-71}

National Trends in the Use of Cardiac Resynchronization Therapy With or Without Implantable Cardioverter-Defibrillator

Background— Candidates for cardiac resynchronization therapy (CRT) receive either a biventricular pacemaker or a biventricular pacemaker with an implantable cardioverter-defibrillator (CRT-D). Optimal device selection remains challenging because the benefit of implantable cardioverter-defibrillator therapy may not be uniform, particularly in patients at competing risk of nonsudden death. Methods and Results— In this serial cross-sectional study using the National Inpatient Sample database, we identified 311 086 admissions associated with CRT implant between 2006 to 2012. CRT-D was the most common device type (86.1%), including in patients ≥75 years of age with ≥5 Elixhauser comorbidities (75.5%). Multivariate predictors of CRT-D implant included demographic, clinical, and geographic factors: prior ventricular arrhythmia (rate ratio [RR], 1.14; 95% CI, 1.13–1.14), ischemic heart disease (RR, 1.11; 95% CI, 1.10–1.11), male sex (RR, 1.10; 95% CI, 1.09–1.10), black race (RR, 1.06; 95% CI: 1.04–1.07), and Northeast geographic region (RR, 1.06; 95% CI, 1.04–1.09). There was significant interhospital variation in the use of CRT-D (10–90 percentile range, 72.9%–98.0% CRT-D). Conclusions— The majority of patients in this contemporary US cohort underwent implantation of CRT-D. Predictors of CRT-D implant included demographic, clinical, and geographic factors. In patient subgroups predicted to have an attenuated benefit from implantable cardioverter-defibrillator therapy (older adults with multiple comorbidities), CRT-D remained the dominant device type. An improved understanding of the determinants of device selection may aid in decision making and ultimately better align patient risk with device benefit at the time of CRT implantation.

Pre-Capillary Pulmonary Hypertension and Right Ventricular Dilation Predict Clinical Outcome in Cardiac Resynchronization Therapy

OBJECTIVES This study examined the prognostic significance of pre- and post-capillary components of pulmonary hypertension (PH) in patients receiving cardiac resynchronization therapy (CRT). BACKGROUND PH is common in patients with left ventricular systolic dysfunction (LVSD) receiving CRT. The impact of PH subtype on clinical outcome in CRT is unknown. METHODS The study population consisted of 101 patients (average age 66 ± 13 years, left ventricular ejection fraction 0.23 ± 0.07, and New York Heart Association functional class 3.2 ± 0.4) who underwent right heart catheterization in the 6 months before CRT. PH was defined as a mean pulmonary artery pressure ≥25 mm Hg; a significant pre-capillary contribution to elevated mean pulmonary artery pressure was defined as a transpulmonary gradient (TPG) ≥12 mm Hg. Clinical endpoints were assessed at 2 years and included all-cause mortality and a composite of death, left ventricular assist device, or cardiac transplantation. RESULTS Patients with TPG ≥12 mm Hg were more likely to experience all-cause mortality (hazard ratio [HR]: 3.2; 95% confidence interval [CI]: 1.3 to 7.4; p = 0.009) and the composite outcome (HR: 3.0; 95% CI: 1.4 to 6.3; p = 0.004) compared with patients with TPG <12 mm Hg. After multivariate adjustment for hemodynamic, clinical, and echocardiographic variables, only TPG ≥12 mm Hg and baseline right ventricular (RV) dilation (RV end-diastolic dimension >42 mm) were associated with the composite clinical outcome (p = 0.05 and p = 0.04, respectively). CONCLUSIONS High TPG PH and RV dilation are independent predictors of adverse outcomes in patients with LVSD who are receiving CRT. RV pulmonary vascular dysfunction may be a therapeutic target in select patients receiving CRT.

Cardiac resynchronization therapy: past, present, and future.

Cardiac resynchronization therapy (CRT), or biventricular pacing, has become a standard therapeutic modality for patients with symptomatic heart failure (HF), depressed left ventricular (LV) function, and electrical dyssynchrony. Despite the overall success of CRT in improving morbidity and mortality in selected patients with HF, a significant minority demonstrates nonresponse. This review describes the electrical and physiologic rationale for biventricular pacing therapy, summarizes landmark clinical trials assessing CRT efficacy, highlights strategies to optimize the response to CRT, and frames future challenges in the use, delivery, and care of patients undergoing CRT.