Albert M. Kim

Intracardiac and extracardiac markers of inflammation during atrial fibrillation

BACKGROUND A decrease in inflammation after cure of atrial arrhythmias suggests that such arrhythmias are proinflammatory, and lower inflammatory marker levels in the coronary sinus suggest that atrial arrhythmias result in intracardiac appropriation of inflammatory cytokines. OBJECTIVE The purpose of this study was to investigate the effect of atrial fibrillation on inflammatory markers drawn from intracardiac and extracardiac chambers. METHODS We performed a case-control study of 167 AF patients and 207 controls. Blood from intracardiac and extracardiac sites was obtained from a subset of patients undergoing curative AF ablation (n = 46). RESULTS No significant differences in C-reactive protein (CRP) or interleukin-6 (IL-6) levels were seen between patients with and those without a history of AF. Both levels were significantly higher when blood was drawn during AF than during sinus rhythm: median CRP 3.1 mg/dL (interquartile range [IQR] 1.0-6.0) versus 1.7 mg/dL (IQR 0.7-3.9, P = .0005); median IL-6 2.3 ng/mL (IQR 1.5-3.9) versus 1.5 ng/mL (IQR 0.7-2.5, P = .007). This finding persisted after adjusting for potential confounders. AF ablation patients in AF exhibited a positive median left atrial minus coronary sinus gradient CRP (0.3 mg/dL, IQR -0.03-1.1), whereas those in sinus rhythm had a negative median left atrial minus coronary sinus gradient CRP (-0.2, IQR -0.8-[-0.02], P = .01). Femoral artery minus femoral vein gradients in AF versus sinus rhythm did not show any differences. CONCLUSION AF at the time of the blood draw, rather than a history of AF, was independently associated with inflammation. Differences in transcardiac gradients suggest that AF results in sequestration of inflammatory cytokines in the heart.

Lipid-Reduction Variability and Antidrug-Antibody Formation with Bococizumab

BACKGROUND Bococizumab, a humanized monoclonal antibody targeting proprotein convertase subtilisin–kexin type 9 (PCSK9), reduces levels of low‐density lipoprotein (LDL) cholesterol. However, the variability and durability of this effect are uncertain. METHODS We conducted six parallel, multinational lipid‐lowering trials enrolling 4300 patients with hyperlipidemia who were randomly assigned to receive 150 mg of bococizumab or placebo subcutaneously every 2 weeks and who were followed for up to 12 months; 96% were receiving statin therapy at the time of enrollment. The patients were assessed for lipid changes over time, stratified according to the presence or absence of antidrug antibodies detected during the treatment period. RESULTS At 12 weeks, patients who received bococizumab had a reduction of 54.2% in the LDL cholesterol level from baseline, as compared with an increase of 1.0% among those who received placebo (absolute between‐group difference, ‐55.2 percentage points). Significant between‐group differences were also observed in total cholesterol, non–high‐density lipoprotein cholesterol, apolipoprotein B, and lipoprotein(a) (P<0.001 for all comparisons). However, high‐titer antidrug antibodies developed in a substantial proportion of the patients who received bococizumab, which markedly diminished the magnitude and durability of the reduction in LDL cholesterol levels. In addition, among patients with no antidrug antibodies, there was wide variability in the reduction in LDL cholesterol levels at both 12 weeks and 52 weeks. Major cardiovascular events occurred in 57 patients (2.5%) who received bococizumab and in 55 (2.7%) who received placebo (hazard ratio, 0.96; 95% confidence interval, 0.66 to 1.39; P=0.83). The most common adverse event among patients who received bococizumab was injection‐site reaction (12.7 per 100 person‐years). CONCLUSIONS In six multinational trials evaluating bococizumab, antidrug antibodies developed in a large proportion of the patients and significantly attenuated the lowering of LDL cholesterol levels. Wide variation in the relative reduction in cholesterol levels was also observed among patients in whom antidrug antibodies did not develop. (Funded by Pfizer; SPIRE ClinicalTrials.gov numbers, NCT01968954, NCT01968967, NCT01968980, NCT02100514, NCT02135029, and NCT02458287.)

Impact of Remote Magnetic Catheter Navigation on Ablation Fluoroscopy and Procedure Time

Background: Remote magnetic catheter navigation (RCN) is gaining acceptance in clinical cardiac electrophysiology, but details regarding how RCN affects procedure execution are not well characterized.

Arrhythmogenesis by single ectopic beats originating in the Purkinje system

Cells in the Purkinje system (PS) are known to be more vulnerable than ventricular myocytes to secondary excitations during the action potential (AP) plateau or repolarization phases, known as early afterdepolarizations (EADs). Since myocytes have a lower intrinsic AP duration than the PS cells to which they are coupled, EADs occurring in distal branches of the PS are more likely to result in propagating ectopic beats. In this study, we use a computer model of the rabbit ventricles and PS to investigate the consequences of EADs occurring at different times and places in the cardiac conduction system. We quantify the role of tissue conductivity and excitability, as well as interaction with sinus excitation, in determining whether an EAD-induced ectopic beat will establish reentrant activity. We demonstrate how a single ectopic beat arising from an EAD in the distal PS can give rise to reentrant arrhythmia; in contrast, EADs in the proximal PS were unable to initiate reentry. Clinical studies have established the PS as a potential substrate for reentry, but the underlying mechanisms of these types of disorder are not well understood, nor are conditions leading to their development clearly defined; this work provides new insights into the role of the PS in such circumstances. Our findings indicate that simulated EADs in the distal PS can induce premature beats, which can lead to the tachycardias involving the conduction system due to interactions with sinus activity or impaired myocardial conduction velocity.

Traditional and new composite endpoints in heart failure clinical trials: facilitating comprehensive efficacy assessments and improving trial efficiency

Composite endpoints are commonly used as the primary measure of efficacy in heart failure clinical trials to assess the overall treatment effect and to increase the efficiency of trials. Clinical trials still must enrol large numbers of patients to accrue a sufficient number of outcome events and have adequate power to draw conclusions about the efficacy and safety of new treatments for heart failure. Additionally, the societal and health system perspectives on heart failure have raised interest in ascertaining the effects of therapy on outcomes such as repeat hospitalization and the patients burden of disease. Thus, novel methods for using composite endpoints in clinical trials (e.g. clinical status composite endpoints, recurrent event analyses) are being applied in current and planned trials. Endpoints that measure functional status or reflect the patient experience are important but used cautiously because heart failure treatments may improve function yet have adverse effects on mortality. This paper discusses the use of traditional and new composite endpoints, identifies qualities of robust composites, and outlines opportunities for future research.

Cardiac Safety Implications of hNav1.5 Blockade and a Framework for Pre-Clinical Evaluation

The human cardiac sodium channel (hNav1.5, encoded by the SCN5A gene) is critical for action potential generation and propagation in the heart. Drug-induced sodium channel inhibition decreases the rate of cardiomyocyte depolarization and consequently conduction velocity and can have serious implications for cardiac safety. Genetic mutations in hNav1.5 have also been linked to a number of cardiac diseases. Therefore, off-target hNav1.5 inhibition may be considered a risk marker for a drug candidate. Given the potential safety implications for patients and the costs of late stage drug development, detection, and mitigation of hNav1.5 liabilities early in drug discovery and development becomes important. In this review, we describe a pre-clinical strategy to identify hNav1.5 liabilities that incorporates in vitro, in vivo, and in silico techniques and the application of this information in the integrated risk assessment at different stages of drug discovery and development.

Diagnosis and Ablation of Multiform Fascicular Tachycardia

Ablation Multiform Fascicular Tachycardia. Introduction: Fascicular tachycardia (FT) is an uncommon cause of monomorphic sustained ventricular tachycardia (VT). We describe 6 cases of FT with multiform QRS morphologies.

Prospective observations in the clinical and electrophysiological characteristics of intra-isthmus reentry.

ECG and EGM of IIR. Introduction: Intra‐isthmus reentry (IIR) is a circuit within the cavotricuspid isthmus (CTI). The purpose of this study is to prospectively define the electrogram and surface ECG characteristics of IIR, and its clinical implications.

New medicinal products for chronic heart failure: advances in clinical trial design and efficacy assessment

Despite the availability of a number of different classes of therapeutic agents with proven efficacy in heart failure, the clinical course of heart failure patients is characterized by a reduction in life expectancy, a progressive decline in health‐related quality of life and functional status, as well as a high risk of hospitalization. New approaches are needed to address the unmet medical needs of this patient population. The European Medicines Agency (EMA) is undertaking a revision of its Guideline on Clinical Investigation of Medicinal Products for the Treatment of Chronic Heart Failure. The draft version of the Guideline was released for public consultation in January 2016. The Cardiovascular Round Table of the European Society of Cardiology (ESC), in partnership with the Heart Failure Association of the ESC, convened a dedicated two‐day workshop to discuss three main topic areas of major interest in the field and addressed in this draft EMA guideline: (i) assessment of efficacy (i.e. endpoint selection and statistical analysis); (ii) clinical trial design (i.e. issues pertaining to patient population, optimal medical therapy, run‐in period); and (iii) research approaches for testing novel therapeutic principles (i.e. cell therapy). This paper summarizes the key outputs from the workshop, reviews areas of expert consensus, and identifies gaps that require further research or discussion. Collaboration between regulators, industry, clinical trialists, cardiologists, health technology assessment bodies, payers, and patient organizations is critical to address the ongoing challenge of heart failure and to ensure the development and market access of new therapeutics in a scientifically robust, practical and safe way.

Once-weekly administration of a long-acting FGF21 analogue modulates lipids, bone turnover markers, blood pressure, and body weight differently in obese hypertriglyceridemic subjects and in non-human primates

To assess the safety, tolerability, pharmacokinetics and pharmacodynamics of PF‐05231023, a long‐acting fibroblast growth factor 21 (FGF21) analogue, in obese people with hypertriglyceridaemia on atorvastatin, with or without type 2 diabetes.