Jeffrey J. Goldberger

Clinical neurocardiology defining the value of neuroscience‐based cardiovascular therapeutics

The autonomic nervous system regulates all aspects of normal cardiac function, and is recognized to play a critical role in the pathophysiology of many cardiovascular diseases. As such, the value of neuroscience‐based cardiovascular therapeutics is increasingly evident. This White Paper reviews the current state of understanding of human cardiac neuroanatomy, neurophysiology, pathophysiology in specific disease conditions, autonomic testing, risk stratification, and neuromodulatory strategies to mitigate the progression of cardiovascular diseases.

Methods of assessment of the post-exercise cardiac autonomic recovery: A methodological review

The analysis of post-exercise cardiac autonomic recovery is a practical clinical tool for the assessment of cardiovascular health. A reduced heart rate recovery - an indicator of autonomic dysfunction - has been found in a broad range of cardiovascular diseases and has been associated with increased risks of both cardiac and all-cause mortality. For this reason, over the last several years, non-invasive methods for the assessment of cardiac autonomic recovery after exercise - either based on heart rate recovery or heart rate variability indices - have been proposed. However, for the proper implementation of such methods in daily clinical practice, the discussion of their clinical validity, physiologic meaning, mathematical formulation and reproducibility should be better addressed. Therefore, the aim of this methodological review is to present some of the most employed methods of post-exercise cardiac autonomic recovery in the literature and comprehensively discuss their strengths and weaknesses.

Sudden Cardiac Arrest Risk Assessment: Population Science and the Individual Risk Mandate

Importance High-resolution stratification of risk of sudden cardiac arrest (SCA) in individual patients is a tool that is necessary for achieving effective and efficient application of data generated by population-based research. This concept is at the core of initiatives for merging cost effectiveness with maximized clinical efficiency and individual patient treatment. Observations For this review, we analyzed data on sudden cardiac death and SCA available from population studies that included large longitudinal and cross-sectional databases, observational cohort studies, and randomized clinical trials. In the context of population science, we treated clinical trials as small, scientifically rigid population studies that generate outcomes focused on defined segments of the population. Application of probabilistic outcomes from these available sources to individual patients generally and patients at risk for SCA and sudden cardiac death in particular is limited by the diversity of the study population based on inclusion criteria and/or the absence of uniformly large effect sizes. Limited information is available on the requirements for defining small high-risk density subgroups that would lead to identification of individuals at a sufficiently high probability of SCA to have a significant effect on clinical decision making. Conclusions and Relevance Synthesis of available population and clinical science data demonstrates the limitations for prediction and prevention of SCA and sudden cardiac death and provides justification for a research mandate for improving risk prediction at the level of individual patients. This leads to suggested approaches to new data generation and required research funding to address this large public health burden.

Repolarization Heterogeneity: Beyond the QT Interval

Research over the past 2 decades has suggested that significant differences exist in the action potentials of endocardial, epicardial, and mid‐myocardial (M) cells that comprise the ventricular myocardium. Relative differences in the time course of repolarization of these 3 cell types, referred to

β-blocker dosage and outcomes after acute coronary syndrome

Background Although &bgr;‐blockers increase survival in acute coronary syndrome (ACS) patients, the doses used in trials were higher than doses used in practice, and recent data do not support an advantage of higher doses. We hypothesized that rates of major adverse cardiac events (MACE), all‐cause death, myocardial infarction, and stroke are equivalent for patients on low‐dose and high‐dose &bgr;‐blocker. Methods Patients admitted to Intermountain Healthcare with ACS and diagnosed with ≥70% coronary stenosis between 1994 and 2013 were studied (N = 7,834). We classified low dose as ≤25% and high dose as ≥50% of an equivalent daily dose of 200 mg of metoprolol. Multivariate analyses were used to test association between low‐dose versus high‐dose &bgr;‐blocker dosage and MACE at 0‐6 months and 6‐24 months. Results A total of 5,287 ACS subjects were discharged on &bgr;‐blockers (87% low dose, 12% high dose, and 1% intermediate dose). The 6‐month MACE outcomes rates for the &bgr;‐blocker dosage (low versus high) were not equivalent (P = .18) (hazard ratio [HR] = 0.76; 95% CI, 0.52‐1.10). However, subjects on low‐dose &bgr;‐blocker therapy did have a significantly decreased risk of myocardial infarction for 0‐6 months (HR = 0.53; 95% CI, 0.33‐0.86). The rates of MACE events during the 6‐24 months after presentation with ACS were equivalent for the 2 doses (P = .009; HR = 1.03 [95% CI, 0.70‐1.50]). Conclusions In ACS patients, rates of MACE for high‐dose and low‐dose &bgr;‐blocker doses are similar. These findings question the importance of achieving a high dose of &bgr;‐blocker in ACS patients and highlight the need for further investigation of this clinical question.

Chapter 103 – Impact of Nontraditional Antiarrhythmic Drugs on Sudden Cardiac Death

Although the mortality from coronary artery disease has declined in the United States, sudden cardiac death remains a major clinical problem with at least 300,000 deaths occurring annually. Strategies to decrease the incidence of sudden death include the prevention of underlying structural heart disease, identification of hereditary syndromes that predispose persons to sudden death, improvements in resuscitation of patients who experience a cardiac arrest (secondary prevention), or identification of patients at high risk for sudden death and appropriate intervention.

Effects of transendocardial stem cell injection on ventricular proarrhythmia in patients with ischemic cardiomyopathy: Results from the POSEIDON and TAC-HFT trials

Transendocardial stem cell injection in patients with ischemic cardiomyopathy (ICM) improves left ventricular function and structure but has ill‐defined effects on ventricular arrhythmias. We hypothesized that mesenchymal stem cell (MSC) implantation is not proarrhythmic. Post hoc analyses were performed on ambulatory ECGs collected from the POSEIDON and TAC‐HFT trials. Eighty‐eight subjects (mean age 61 ± 10 years) with ICM (mean EF 32.2% ± 9.8%) received treatment with MSC (n = 48), Placebo (n = 21), or bone marrow mononuclear cells (BMC) (n = 19). Heart rate variability (HRV) and ventricular ectopy (VE) were evaluated over 12 months. VE did not change in any group following MSC implantation. However, in patients with ≥ 1 VE run (defined as ≥ 3 consecutive premature ventricular complexes in 24 hours) at baseline, there was a decrease in VE runs at 12 months in the MSC group (p = .01), but not in the placebo group (p = .07; intergroup comparison: p = .18). In a subset of the MSC group, HRV measures of standard deviation of normal intervals was 75 ± 30 msec at baseline and increased to 87 ± 32 msec (p =.02) at 12 months, and root mean square of intervals between successive complexes was 36 ± 30 msec and increased to 58.2 ± 50 msec (p = .01) at 12 months. In patients receiving MSCs, there was no evidence for ventricular proarrhythmia, manifested by sustained or nonsustained ventricular ectopy or worsened HRV. Signals of improvement in ventricular arrhythmias and HRV in the MSC group suggest a need for further studies of the antiarrhythmic potential of MSCs. Stem Cells Translational Medicine 2017;6:1366–1372

Ranolazine reduces atrial fibrillatory wave frequency.

Aims Antiarrhythmic medications for the treatment of atrial fibrillation (AF) have limited efficacy and rare but potentially life-threatening side effects. Ranolazine is an antianginal agent that may have antiarrhythmic activity in AF. Methods and results Using the Duke Enterprise Data Unified Content Explorer database, we analysed a cohort of AF patients on ranolazine. Patients served as their own historic control. Electrocardiograms (ECGs) were analysed before and after ranolazine initiation to determine the effect of ranolazine on dominant frequency (DF), f-wave amplitude, and organizational index (OI). We identified 15 patients with ECGs in AF before and after ranolazine. Ranolazine was associated with lower DF by an average of 10% (5.10 ± 0.74 vs. 5.79 ± 0.96 Hz, P = 0.04) but not with changes in OI (0.47 ± 0.11 vs. 0.50 ± 0.12, P = 0.71) or amplitude (0.47 ± 0.43 vs. 0.41 ± 0.40 mV, P = 0.82). Ranolazine was also associated with lower DF in patients (n = 10) not on concomitant antiarrhythmic therapy (5.25 ± 0.78 vs. 6.03 ± 0.79 Hz, P = 0.04). Conclusion Ranolazine is associated with lower AF DF but no change in OI or fibrillatory wave amplitude. Prospective trials are needed to evaluate ranolazines potential as a novel antiarrhythmic drug for AF.

Sudden Death in Patients With Coronary Heart Disease Without Severe Systolic Dysfunction

Importance The majority of sudden and/or arrhythmic deaths (SAD) in patients with coronary heart disease occur in those without severe systolic dysfunction, for whom strategies for sudden death prevention are lacking. Objective To provide contemporary estimates of SAD vs other competing causes of death in patients with coronary heart disease without severe systolic dysfunction to search for high-risk subgroups that might be targeted in future trials of SAD prevention. Design, Setting, and Participants This prospective observational cohort study included 135 clinical sites in the United States and Canada. A total of 5761 participants with coronary heart disease who did not qualify for primary prevention implantable cardioverter defibrillator therapy based on left ventricular ejection fraction (LVEF) of more than 35% or New York Heart Association (NYHA) heart failure class (LVEF >30%, NYHA I). Exposures Clinical risk factors measured at baseline including age, LVEF, and NYHA heart failure class. Main Outcomes and Measures Primary outcome of SAD, which is a composite of SAD and resuscitated ventricular fibrillation arrest. Results The mean (SD) age of the cohort was 64 (11) years. During a median of 3.9 years, the cumulative incidence of SAD and non-SAD was 2.1% and 7.7%, respectively. Sudden and/or arrhythmic death was the most common mode of cardiovascular death accounting for 114 of 202 cardiac deaths (56%), although noncardiac death was the primary mode of death in this population. The 4-year cumulative incidence of SAD was lowest in those with an LVEF of more than 60% (1.0%) and highest among those with LVEF of 30% to 40% (4.9%) and class III/IV heart failure (5.1%); however, the cumulative incidence of non-SAD was similarly elevated in these latter high-risk subgroups. Patients with a moderately reduced LVEF (40%-49%) were more likely to die of SAD, whereas those with class II heart failure and advancing age were more likely to die of non-SAD. The proportion of deaths due to SAD varied widely, from 14% (18 of 131 deaths) in patients with NYHA II to 49% (37 of 76 deaths) in those younger than 60 years. Conclusions and Relevance In a contemporary population of patients with coronary heart disease without severe systolic dysfunction, SAD accounts for a significant proportion of overall mortality. Moderately reduced LVEF, age, and NYHA class distinguished SAD and non-SAD, whereas other markers were equally associated with both modes of death. Absolute and proportional risk of SAD varied significantly across clinical subgroups, and both will need to be maximized in future risk stratification efforts.

Ablation strategies for the management of symptomatic Brugada syndrome: A systematic review

BACKGROUND Ablation approaches have been described for the management of symptomatic ventricular arrhythmias in patients with Brugada syndrome, but this treatment is still considered experimental. OBJECTIVE We aimed to perform a systematic review of the current evidence on the use of catheter ablation in Brugada syndrome. METHODS MEDLINE, Embase, and Scopus were searched for articles describing the use of catheter ablation for ventricular arrhythmia management in Brugada syndrome. RESULTS We included 11 case series and 11 case reports including a total of 233 patients. Ablation strategies included epicardial mapping with substrate modification (n = 180; 77.3%), endocardial-only mapping with substrate modification (n = 17; 7.3%), ventricular fibrillation (VF)-triggering premature ventricular complex ablation (n = 5; 2.1%), and mixed approaches (n = 31; 13.3%). During a 2.5- to 78-month follow-up period, the success rates in preventing ventricular tachycardia or VF (VT/VF) were 96.7%, 70.6%, and 80% with epicardial, endocardial, and triggering premature ventricular complex ablation approaches, respectively. Among patients who underwent both epicardial and endocardial mapping, there was no identifiable endocardial substrate in 92.9% of cases. Elimination of type 1 Brugada-pattern electrocardiogram was attained in 98.3% and 34.8% of the epicardial and endocardial ablation groups, respectively. VT/VF occurred in 7 of 9 patients (77.8%) who had persistent or recurrent J-ST elevation and in none of the 24 patients with complete resolution during follow-up. Pharmacologic provocation augmented the abnormal area. CONCLUSION Epicardial substrate modification appears to be more effective than endocardial-only approach in preventing VT/VF. Persistent or recurrent J-ST elevation appears to represent a marker of failure of ablation. Ablation seems to be an acceptable strategy for patients with Brugada syndrome and VT/VF.