Adam Berman

Electrical stimulation to optimize cardioprotective exosomes from cardiac stem cells

Injured or ischemic cardiac tissue has limited intrinsic capacity for regeneration. While stem cell transplantation is a promising approach to stimulating cardiac repair, its success in humans has thus far been limited. Harnessing the therapeutic benefits of stem cells requires a better understanding of their mechanisms of action and methods to optimize their function. Cardiac stem cells (CSC) represent a particularly effective cellular source for cardiac repair, and pre-conditioning CSC with electrical stimulation (EleS) was demonstrated to further enhance their function, although the mechanisms are unknown. Recent studies suggest that transplanted stem cells primarily exert their effects through communicating with endogenous tissues via the release of exosomes containing cardioprotective molecules such as miRNAs, which upon uptake by recipient cells may stimulate survival, proliferation, and angiogenesis. Exosomes are also effective therapeutic agents in isolation and may provide a feasible alternative to stem cell transplantation. We hypothesize that EleS enhances CSC-mediated cardiac repair through its beneficial effects on production of cardioprotective exosomes. Moreover, we hypothesize that the beneficial effects of biventricular pacing in patients with heart failure may in part result from EleS-induced preconditioning of endogenous CSC to promote cardiac repair. With future research, our hypothesis may provide applications to optimize stem cell therapy and augment current pacing protocols, which may significantly advance the treatment of patients with heart disease.

COMPASS: A Novel Risk-Adjustment Model for Catheter Ablation in Pediatric and Congenital Heart Disease Patients

BACKGROUND Robust risk-adjustment algorithms are often necessary if data from clinical registries is to be used to compare rates of important clinical outcomes between participating centers. Although such algorithms have been successfully developed for surgical and catheter-based cardiac interventions in children, outcomes of pediatric and congenital catheter ablation have not been modeled with respect to case mix. METHODS A working group was appointed by the Pediatric and Congenital Electrophysiology Society to develop a risk-adjustment algorithm for use in conjunction with a modernized, multicenter registry database. Expert consensus was used to develop relevant outcome measures, an inclusive list of possible predictors, and estimates of associated incremental risk. Historical data from the Pediatric Radiofrequency Ablation Registry was reanalyzed using multivariate regression to create statistical models of ablation outcomes. RESULTS Acute ablation failure and serious adverse event rates were modeled as outcomes. Statistical modeling was performed on 4486 cases performed in 19 centers. For ablation failure rate, a simple model including general category of arrhythmia mechanism and presence of structural congenital heart disease accounted for ∼71% of outcome variance. The model was useful for identification of between-center variability in the historical data set. Although expert consensus predicted the need for a more complex model, predicted univariate effects were similar to those generated by statistical modeling. Serious adverse events were too infrequent to permit statistical association with any predictive variable, but could be compared with the mean rate observed among all centers. CONCLUSION A substantial component of the intercenter variability of acute ablation outcomes in a historical database of pediatric and congenital ablation patients may be accounted for by a simple statistical model, exposing variations in outcome specific to centers. This will be a useful initial model for use a modern registry for pediatric catheter ablation outcomes.

Localization of fossa ovalis and Brockenbrough needle prior to left atrial ablation using three-dimensional mapping with EnSite Fusion™

BackgroundTransseptal catheterization of the interatrial septum has traditionally been performed under the guidance of fluoroscopy, echocardiography, and hemodynamic pressure monitoring. We hypothesized that the fossa ovalis could be identified on pre-ablation chest computerized tomography (CT) scan utilizing EnSite Verismo™ and Fusion™ software thereby permitting its real-time visualization during transseptal puncture.ObjectiveThe purpose of this study is to generate multi-center data demonstrating the feasibility of the identification of the fossa ovalis and visualization of the transseptal needle tip using EnSite Verismo™ segmentation and EnSite Fusion™ prior to transseptal puncture.MethodsPatients scheduled to undergo transseptal puncture for ablation were enrolled. Pre-ablation CT scans were performed in all patients. The Verismo™ software tool was used to import and segmentally manipulate a three-dimensional CT image on the EnSite™ system workstation. EnSite Fusion™ registration was used to register the right atrial image and label and confirm the fossa ovalis’ location prior to transseptal puncture.ResultsAnalysis of the pre-ablation CT scan using EnSite Fusion™ successfully allowed assessment of the anatomy and location of the fossa ovalis. Additionally, the transseptal needle tip location was located within the CT scan designated fossa ovalis location in 96% of cases.ConclusionIt is possible to visualize the fossa ovalis on pre-ablation CT and localize the transseptal needle accurately within the margins of the fossa ovalis utilizing EnSite Fusion™ and Verismo™ software.

Addressing Disparities in Stroke Prevention for Atrial Fibrillation Educational Opportunities

Disparities in atrial fibrillation (AF)-related stroke and mortality persist, especially racial disparities, within the US “Stroke Belt.” This study identified barriers to optimal stroke prevention to develop a framework for clinician education. A comprehensive educational needs assessment was developed focusing on clinicians within the Stroke Belt. The mixed qualitative-quantitative approach included regional surveys and one-on-one clinician interviews. Identified contributors to disparities included implicit racial biases, lack of awareness of racial disparities in AF stroke risk, and lack of effective multicultural awareness and training. Additional barriers affecting disparities included patient medical mistrust and clinician-patient communication challenges. General barriers included lack of consistency in assessing stroke and anticoagulant-related bleeding risk, underuse of standardized risk assessment tools, discomfort with novel anticoagulants, and patient education deficiencies. Effective cultural competency training is one strategy to reduce disparities in AF-related stroke and mortality by improving implicit clinician bias, addressing medical mistrust, and improving clinician-patient communication.

How to prevent and manage radiation-induced coronary artery disease

Radiation-induced coronary heart disease (RICHD) is the second most common cause of morbidity and mortality in patients treated with radiotherapy for breast cancer, Hodgkin’s lymphoma and other prevalent mediastinal malignancies. The risk of RICHD increases with radiation dose. Exposed patients may present decades after treatment with manifestations ranging from asymptomatic myocardial perfusion defects to ostial, triple-vessel disease and sudden cardiac death. RICHD is insidious, with a long latency and a tendency to remain silent late into the disease course. Vessel involvement is often diffuse and is preferentially proximal. The pathophysiology is similar to that of accelerated atherosclerosis, characterised by the formation of inflammatory plaque with high collagen and fibrin content. The presence of conventional risk factors potentiates RICHD, and aggressive risk factor management should ideally be initiated prior to radiation therapy. Stress echocardiography is more sensitive and specific than myocardial perfusion imaging in the detection of RICHD, and CT coronary angiography shows promise in risk stratification. Coronary artery bypass grafting is associated with higher risks of graft failure, perioperative complications and all-cause mortality in patients with RICHD. In most cases, the use of drug-eluting stents is preferable to surgical intervention, bare metal stenting or balloon-angioplasty alone.

Genomic-based diagnosis of arrhythmia disease in a personalized medicine era

ABSTRACT Introduction: Although thousands of potentially disease-causing mutations have been identified in a handful of genes, the genetic heterogeneity has led to diagnostic confusions, stemming directly from the limitations in our arsenal of genetic tools. Areas covered: We discuss the genetic basis of cardiac ion channelopathies, the gaps in our knowledge and how Next-generation sequencing technology (NGS) and can be used to bridge them, and how induced pluripotent stem cell (iPSC) derived-cardiomyocytes can be used for drug discovery. Expert commentary: Univariate, arrhythmogenic arrhythmias can explain some congenital arrhythmias, however, it is far from a comprehensive understanding of the complexity of many arrhythmias. Mutational screening is a critical step in personalized medicine and is critical to the management of patients with arrhythmias. The success of personalized medicine requires a more efficient way to identify a high number of genetic variants potentially implicated in cardiac arrhythmogenic diseases than traditional sequencing methods (eg, Sanger sequencing). Next-generation sequencing technology provides us with unprecedented opportunities to achieve high-throughput, rapid, and cost-effective detection of congenital arrhythmias in patients. Moreover, in personalized medicine era, IPSC derived-cardiomyocytes can be used as ‘cardiac arrhythmia in a dish’ model for drug discovery, and help us improve management of arrhythmias in patients by developing patient-specific drug therapies with target specificity.

A novel high throughput approach to screen for cardiac arrhythmic events following stem cell treatment

Although stem cell therapy is promising for repairing damaged cardiac tissue and improving heart function, there are safety concerns, especially regarding the risk of arrhythmias, which can be life threatening. To address this issue, we propose to develop a novel screening system to evaluate arrhythmic risk associated with stem cell therapy using a high-throughput multielectrode array system that can measure conduction velocity and action potential duration in cardiomyocytes co-cultured with different types of stem cells, such as mesenchymal stem cells, skeletal myoblasts, and resident cardiac stem cells. We will assess the arrhythmic potential of each of these types of stem cells under normoxic and hypoxic conditions, with/without application of oxidative stress or catecholamines. We hypothesize that these methods will prove to be an effective way to screen for arrhythmic risk of cardiac stem cell therapy. Ultimately, our approach can potentially be personalized to develop a robust screening protocol in order to identify which stem cell type carries the least amount of risk for arrhythmia. This system will have great clinical benefit to improve the risk/benefit ratio of human stem cell therapy for heart disease.