12:00 p.m. - 5:00 p.m. ET
Description
Sponsor: DCVS, NHLBI, Virtual Workshop
The National Heart, Lung, and Blood Institute (NHLBI), of the National Institutes of Health (NIH), convened a virtual workshop on “Prioritizing Discovery and Advancements in Arrhythmia Therapies.” Participants of this workshop included early career investigators, leading experts in basic, translational, and clinical research in cardiovascular and neuroscience, and representatives of academic institutions, federal agencies, and non-federal agencies. The charge of the workshop was to identify the highest priority research gaps and opportunities for future research strategies to guide the field of arrhythmia research and therapy. The specific objectives were to:
- Identify basic science findings that are ready for translation into clinical research.
- Evaluate research gaps and barriers to improve targeting of anti-arrhythmia drug and procedural device-based therapies.
- Explore novel approaches to improve management of arrhythmia, reduce irreversible cardiac remodeling, and prevent arrhythmia-related deaths, heart failure (HF), and strokes in patients.
- Identify optimal approaches to integrate artificial intelligence (AI)/eHealth-based diagnosis and management, inclusive of variables such as social determinants of health and age- and sex-based differences, to improve earlier detection and risk of arrhythmia, as well as aid in invasive arrhythmia treatment with the ultimate goal of reducing suffering and death from arrhythmias and cardiovascular diseases across the lifespan.
The workshop is responsive to NHLBI Strategic Vision Objectives 1, 5, 6, and 7.
Background
Cardiac arrhythmias affect about 5% of the U.S. population and are a major cause of morbidity and mortality, resulting in more than 250,000 deaths annually in the United States. As arrhythmias may present without symptoms and can reoccur or intensify suddenly, they may be undiagnosed in patients. Therefore, the true prevalence of arrhythmias may not be accurately assessed. Atrial fibrillation (AF) is often detected after a stroke or development of left ventricular dysfunction; is associated with substantial mortality and morbidity; and poses a significant burden to patients and health care services. Also, AF may precede or exist in tandem with heart failure (HF). Ventricular arrhythmia incidence increases with age and is higher in women. Despite a tremendous amount of research funding and resources dedicated to arrhythmia research and anti-arrhythmia therapies, there remains a significant unmet need for novel approaches to arrhythmia management. There is urgency in developing rational strategies employing modern tools and approaches for the application of detection and treatment strategies in the face of competing risks from comorbidities. Additionally, there is very limited understanding of social determinants of arrhythmias and age- and gender-based differences in arrhythmia prognosis. A better classification on subsets of arrhythmia (tachycardia, bradycardia, ventricular tachycardia, and ventricular flutter/fibrillation) in patients is needed.
Discussions
The workshop discussions centered on six areas: 1) fundamental concepts and conduction systems; 2) atrial arrhythmias; 3) ventricular arrhythmias; 4) interface with heart failure; 5) arrhythmias at a population level; and 6) novel approaches to arrhythmia detection, treatment, and management.
The following gaps and opportunities were identified to inform future research.
Basic and Translational Sciences
Gaps:
- Inflammation is known to be a component of arrhythmogenic cardiomyopathy; however, the role of inflammation, potential genes affecting inflammatory responses, and their role as risk factors and triggers of arrhythmic events, remains largely unknown.
- A full understanding of cardiac conduction mechanisms and their contribution to disease progression and morbidity and mortality is currently lacking.
- Genetic contributors and the mechanisms underlying genetic variation and gene networks associated with AF are not fully known.
- The mechanisms that cause ventricular arrhythmias, including the potential roles of remodeling cardiac structure and functional neuroanatomy as drivers of arrhythmia risk and near-term arrhythmia triggers, are not fully understood.
Opportunities:
1. Investigate genetic mechanisms and the role of inflammation in arrhythmogenesis, as well as the contributive roles of comorbidities, lifestyle, and environmental influences.
2.A. Understand the basic mechanisms of impulse formation and propagation, including investigations of sodium-channel clusters. Explore the potential of peptides (and peptide mimetics) as novel anti-arrhythmic therapies.
2.B. Identify new therapeutic targets in order to develop the next generation pharmaceutical therapies, augmented by the use of enhanced computational screening and modeling to accelerate historically long drug-development timelines. The potential to repurpose libraries of approved FDA compounds could drive progress in drug development.
2.C. Develop tools, including organoid models, to advance spatial and cell-type specific knowledge of the chamber-specific conduction system or biology to better inform arrhythmia science.
3.A. Identify root causes and develop new treatment strategies for those pediatric and young onset arrhythmias for which devices designed for the adult population may be less effective.
3.B. Formulate strategies through improved modeling and genetic modifications to overcome limitations of animal models (both small and large), appropriateness of the models, inter-relationships between models, when studying human health to translating to human arrhythmias.
3.C. Explore how sex-specific differences contribute to basic phenomena such as QT duration, arrhythmic risk, and cardiovascular outcomes.
Clinical and Population Sciences
Gaps:
- Significant gaps and challenges exist especially for pediatric arrhythmias including detection, prevention, and treatment, which provide opportunities to improve precision anti-arrhythmia therapies that may have translation to pediatric patients.
- The potential clinical utility of polygenic risk scores (PRS), particularly when combined with other lifestyle and environmental risk factors, for heart disease and arrhythmias is unclear.
- The molecular mechanisms of sudden cardiac death (SCD), sudden unexpected death (SUD), etiologies of arrhythmias, and their overlap with heart failure causes, as well as the interplay among cardiac, neural, and other systems, are not well understood.
Opportunities:
1.A. Elucidate the role of sex-based differences, the contribution of social determinants of health, in the biology, development, progression, and prognosis of arrhythmic disorders across the lifespan.
1.B. Create efficient and accurate screening protocols to better identify those at risk for AF, other arrhythmias, and their adverse consequences. Include participants with diverse demographics and multi-ancestry human research cohorts that may provide a deeper understanding of populations and hereditary risks and help translate better to impact clinical care and reduce disparities.
1.C. Leverage AI/eHealth-based tools and electronic health record (EHR) information (inclusive of social determinants of health and age- and gender-based differences) to more precisely improve risk stratification, prognosis, and develop novel interventions and therapeutics for arrhythmic disorders.
2.A. Develop PRS as a useful tool to help further refine an individual’s overall genetic predisposition to disease, in combination with environmental and behavioral factors and across ancestry groups, to gain mechanistic insight from the best performing PRS.
2.B. Form registries and databases across institutions using common data elements to facilitate greater data-sharing and allowing for prospective data collection, creation of searchable and interactive EHRs, and facilitating the mitigation of biases.
2.C. Identify important, well-defined endpoints, particularly those emphasizing the patient perspective, towards guiding clinical trials and evaluating outcomes.
2.D. Investigate early onset AF to prevent and preempt recurrence, as well as slow progression of accompanying disease states.
3.A. Establish large, multi-ancestry studies with well-phenotyped cohorts to elucidate genes and biological processes underlying cardiac arrhythmias, SCD, and SUD.
3.B. Explore and develop AI and signal-processing tools across all areas of arrhythmia science to improve collection of complex, multi-layered data, detection, analysis, the accuracy of arrhythmia interpretation through harmonization, as well as potentially improve invasive therapeutic management.
3.C. Use connected smart devices, such as smart watches and phones, to develop near-term prevention and preemption strategies.
Publication Plans
A white paper outlining gaps and opportunities identified in the workshop is in preparation.
Workshop Participants
Co-Chairs
- Elizabeth McNally, MD, PhD, Northwestern University
- Kalyanam Shivkumar, MD, PhD, University of California, Los Angeles
Faculty Speakers
- Olujimi Ajijola, MD, PhD, University of California, Los Angeles
- Christine Albert, MD, MPH, Cedars-Sinai, Smidt Heart Institute
- Emelia J. Benjamin, MD, ScM, Boston University Chobanian & Avedisian School of Medicine
- Colleen E. Clancy, PhD, University of California, Davis
- Sana Mustapha Al-Khatib, MD, MHS, Duke University Medical Center
- Kenneth Bilchick, MD, University of Virginia
- Mario Delmar, MD, PhD, New York University
- J. Kevin Donahue, MD, University of Massachusetts Medical School
- Glenn Fishman, MD, New York University Langone Health
- Ilan Goldenberg, MD, University of Rochester Medical Center
- Robert G. Gourdie, PhD, Virginia Tech
- David T. Huang, MD, University of Rochester
- Björn C. Knollmann, MD, PhD, Vanderbilt University Medical Center
- Steven A. Lubitz, MD, MPH, Harvard Medical School
- Francis Marchlinski, MD, University of Pennsylvania
- Nicholas A. Marston, MD, MPH, Brigham and Women’s Hospital
- Ivan Moskowitz, MD, PhD, University of Chicago
- Peter Noseworthy, MD, MBA, Mayo Clinic College of Medicine and Science
- Hetal Odobasic, MS, Food and Drug Administration
- Randall S. Prather, PhD, University of Missouri
- Przemysław Radwański, PharmD, PhD, Ohio State University
- Sridharan Rajamani, PhD, Johnson & Johnson
- Stacey Rentschler, MD, PhD, Washington University
- Dan Roden, MD, Vanderbilt University Medical Center
- Andrea Russo, MD, Cooper University Health Care
- Jeffrey E. Saffitz, MD, PhD, Harvard Medical School
- Nona Sotoodehnia, MD, MPH, University of Washington School of Public Health
- Robert Gregory Webster, MD, MPH, Northwestern University
- Sean Wu, MD, PhD, Stanford University
Early Career Investigators
- Patrick M. Boyle, PhD, University of Washington
- Jessica L. Caldwell, PhD, University of California, Davis
- Mona M. El Refaey, PhD, Ohio State University
- William Rowland Goodyer, MD, PhD, Stanford University
- Peter Hanna, MD, PhD, University of California, Los Angeles
- Shaan Khurshid, MD, PhD, Harvard Medical School
- Darae Ko, MD, Harvard Medical School
- Olurotimi (Rotimi) Mesubi, MBBS, MPH, Johns Hopkins University
- Joseph Palatinus, MD, PhD, University of Utah
- Anna Pfenniger, MD, PhD, Northwestern University
NIH/ NHLBI Staff
- Ravi Balijepalli, PhD
- Bishow Adhikari, PhD
- Sujata Shanbhag, MD
- Olga Tjurmina, PhD
- David Schopfer, MD
- Patricia Bandettini, MD
- Patrice Desvigne-Nickens, MD
- George Sopko, MD
The findings, knowledge gaps, and opportunities described here represent a summary of individual opinions and ideas expressed during the workshop. The summary does not represent a consensus opinion or directive made to or by NHLBI or NIH.