NEWS & EVENTS

Research in the Treatment of Mitral Valve Prolapse

November 30 to December 2, 2021
Webinar

Description

The National Heart, Lung, and Blood Institute (NHLBI) convened a virtual Workshop on Research Priorities in the Treatment of Mitral Valve Prolapse on November 30 – December 2, 2021. The goals of the workshop were to review the state of the science and to identify resource needs and research opportunities.

Mitral valve prolapse (MVP) is a common heritable valve disease that affects 2-3% of the population, which translates to over 7 million individuals in the United States and over 170 million worldwide. MVP is a heterogeneous disease. For most individuals, isolated MVP is thought to be benign. However, up to 25% of individuals with MVP will develop significant degenerative mitral regurgitation, which can lead to heart failure. As many as 0.4 to 1.9% of individuals in some MVP cohorts have exhibited sudden cardiac arrest (SCA) or sudden cardiac death (SCD).

High rates of heart failure and excess mortality demonstrate that MVP and its complications remain a public health problem. At present, there are no reliable indicators of who will develop significant complications or how quickly. U.S. and European guidelines on the management of valvular heart disease provide few markers of outcome and little insight on monitoring for the risk of SCA/SCD in individuals with asymptomatic MVP.

Each day of the workshop had a different theme:

  • Degenerative mitral regurgitation and left ventricular systolic dysfunction

    Degenerative mitral regurgitation (DMR) due to MVP is a disease of the valve. However, if often causes disease of the myocardium, such as heart failure, linked to the severity of DMR, and ventricular or atrial dysfunction or arrhythmia. MVP can lead to excessive mechanical stress on the ventricles and the atria, and possibly to myocardial inflammation, fibrosis, and remodeling. There is no integrative approach to evaluate the risk of progression from MVP to DMR and myocardial dysfunction.

    In most instances, DMR can be repaired safely and effectively by surgery, although transcatheter techniques, such as edge-to-edge repair, are becoming more common. Operator experience is key, though, as an inadequate repair can lead to recurrent mitral regurgitation, heart failure, and death. Nevertheless, undertreatment and excess mortality remain pervasive. Only a third of individuals with severe DMR receive any mitral valve intervention during their lifetime. Because DMR is strongly linked to aging, the risk of intervention is often elevated, and optimal timing and triggers for “early” intervention in DMR are not well defined.

    Research opportunities exist to improve screening and risk stratification, and to refine the diagnostic criteria for intervention and optimal timing. These may include quantitative, mechanism-based techniques, including novel echocardiographic measures, integration of cardiac magnetic resonance imaging, precision medicine including genomics, proteomics, and metabolomics, and machine learning for rapid, deep phenotyping. They may also include basic investigations of ventricular dysfunction, inflammation, and fibrosis, and correlation of small- and large-animal models with clinical data. The resources needed include mechanistic studies to understand DMR at the cellular and myocardial level and a clinical trial to compare early intervention in asymptomatic, severe DMR with preserved function to guideline-directed medical monitoring.

  • Sudden cardiac death in MVP

    A subset of individuals with MVP will exhibit SCA or SCD, even in the absence of significant MR, and more will exhibit other frequent ventricular arrhythmias. Experimental and clinical evidence suggests that mechanical stress leads to myocardial inflammation, fibrosis, and remodeling that creates the electrophysiological substrate responsible for SCA/SCD and other serious ventricular arrhythmias. Systemic studies are needed, though, to confirm this hypothesis.

    Characteristics of the mitral valve, such as redundancy and mitral annular disjunction, increase the risk of SCA/SCD, but the precursors of SCA/SCD are poorly defined and their treatment uncertain. Research efforts to date have focused on identifying electrocardiographic and imaging parameters of risk, but the data are mostly retrospective or based on small sample sizes. Importantly, current management guidelines do not recommend routine monitoring for ventricular arrhythmia, define criteria for clinical and imaging follow-up, or provide indications for an implantable cardioverter defibrillator (ICD) for primary prevention in MVP.

    Research opportunities exist to better understand the baseline burden and mechanisms of ventricular arrhythmia in MVP, to improve risk stratification, including ambulatory electrocardiography, and to establish the best preventive measures, which could include early mitral valve repair, ablation, or an implantable cardioverter defibrillator for primary prevention. These opportunities include large-scale prospective clinical studies that take advantage of recent advances in imaging to identify abnormal ventricular mechanics associated with arrhythmia and SCA/SCD. They may also include clinical trials of potential therapies to prevent SCA/SCD, such as novel combined surgical and electrophysiologic approaches. The resources needed include standardized nomenclature, uniform imaging protocols, improved mouse genetic models and large-animal surgical models, and clinical trials to establish ideal monitoring intervals, the utility of ICD for primary prevention versus ablation, and the utility of early mitral valve repair.

  • Basic and genetic studies of MVP: toward development of medical therapies to limit progression

    MVP is a polygenic and heterogeneous disease that can include DMR, SCA/SCD, myocardial dysfunction, or any combination. Genetic studies have identified individual genes associated with MVP, but larger genetic studies could identify a broader array of genes that lead to MVP as a common endpoint and account for some of the observed clinical heterogeneity. MVP is a progressive disease. Genetic defects in the development of the mitral valve or the myocardium might lead to disease in later life.

    Mouse models are a tool to study the effects of genetic mutations and the mechanisms of MVP progression. These studies, in turn, may identify therapeutic targets to limit progression of the disease, including both its valvular and arrhythmogenic components. Large-animal models and computational models are tools to study surgical techniques and devices that may yield better repairs and prevent recurrent disease.

    Research opportunities include large-scale genetic and expression studies that can compensate for the observed clinical heterogeneity. Additional opportunities include basic studies to understand the development of the mitral valve, the natural history of MVP, and the biomechanical stresses that lead to myocardial fibrosis and remodeling.

The workshop participants overwhelmingly identified the need for a multi-center open-access database of de-identified patient data that could capture the heterogeneity of MVP in diverse populations. Whether the individual workshop participants called it a registry, a consortium, or a web-based platform, the database could contain both routine clinical data and research data, both retrospective data and prospective follow-up, including patient-reported outcomes. It could also include imaging studies and a biorepository for omics and other potential biomarkers of disease and progression.

The workshop participants plan to publish a detailed report, which will include an overview of the field and an expanded list and rationale for the identified research opportunities.

Agenda

11:00 a.m - 1:50 p.m
-
Day 1: Degenerative mitral regurgitation (MR) and left ventricular (LV) systolic dysfunction

Moderators: 
Francesca Nesta Delling, MD MPH 
Robert A. Levine, MD

Introduction
Francesca Nesta Delling, MD MPH (11:00 am)
Congressman Andy Barr (11:05 am)
U.S. House of Representatives, Sixth District of Kentucky
Sponsor of the Cardiovascular Advances in 
Research and Opportunities Legacy (CAROL) Act

Heart failure and indications for intervention
Speaker: Maurice Sarano, MD (11:10 am)
Discussant: Thierry Le Tourneau, MD 
Group Discussion (11:30 am)

Timing of valvular interventions: cardiac MRI versus echo-cardiography
Speaker: Dipan Shah, MD (11:40 am)
Discussant: Jonathan Weinsaft, MD 
Group Discussion (12:00 pm)

Persistent LV systolic dysfunction after mitral valve intervention
Speaker: Michael Borger, MD (12:10 pm)
Discussant: Judy Hung, MD
Group Discussion (12:30 pm)

Break (15 minutes)  
 
Preventing recurrent MR following surgical or percutaneous mitral valve intervention
Speaker: David Adams, MD (12:55 pm)
Discussant: Sammy Elmariah, MD MPH
Group Discussion (1:15 pm)

Human impact and patient perspective
Speaker: John Lewis (1:25 pm)

Summary
Francesca Nesta Delling, MD MPH (1:35 pm)

Adjourn (1:50 pm)

11:00 a.m - 2:10 p.m
-
Day 2: Sudden cardiac death in MVP

Moderators: 
Francesca Nesta Delling, MD MPH 
Peter Noseworthy, MD

Introduction
Francesca Nesta Delling, MD MPH (11:00 am)

Identifying MVP at risk for ventricular arrhythmia and sudden cardiac death

Echocardiography
Speaker: Robert A. Levine, MD (11:05 am)
Discussant: Maurice Sarano, MD
Group Discussion (11:25 am)

Cardiac MRI and PET
Speaker 1 (cardiac MRI): Martina Perazzolo-Marra, MD (11:35 am)
Speaker 2 (PET): Marc Miller, MD 
Discussant: Dipan Shah, MD
Group Discussion (12:05 pm)

Complex ventricular ectopy with and without myocardial fibrosis
Speaker: Cristina Basso, MD (12:15 pm)
Discussant: Peter Noseworthy, MD
Group Discussion (12:35 pm)

Break (10 minutes) (12:45 pm)

Preventive measures for ventricular arrhythmia and sudden cardiac death

EP study: deciding between radio-frequency catheter ablation and ICD
Presenter: Peter Noseworthy, MD (12:55 pm)
Discussant: Edward Gerstenfeld, MD
Group Discussion (1:15 pm)

Mitral valve surgery for prevention of sudden death
Speaker: David Adams, MD (1:25 pm)
Discussant: Marc Miller, MD
Group Discussion (1:45 pm)

Human impact and patient perspective
Speaker: John Lewis (1:55 pm)

Summary
Francesca Nesta Delling, MD MPH (2:05 pm)

Adjourn  (2:10 pm) 

11:00 a.m - 1:45 p.m
-
Day 3: Basic and genetic studies of MVP: toward development of medical therapies to limit progression

Moderators: 
Francesca Nesta Delling, MD MPH
Robert A. Levine, MD

Introduction
Francesca Nesta Delling, MD MPH (11:00 am)

Genetics of MVP: human studies
Speaker: Nabila Bouatia-Naji, PhD (11:05 am)
Discussant: Francesca Nesta Delling, MD MPH
Group Discussion (11:25 am)

Developmental basis of MVP: from mouse models to medical therapies
Speaker: Chip Norris, PhD (11:35 am)
Discussant: Robert A. Levine, MD
Group Discussion (11:55 am)

Mechanisms of myocardial fibrosis and ventricular arrhythmia in MVP mouse models
Speaker: Chip Norris, PhD (12:05 pm)
Discussant: Cristina Basso, MD
Group Discussion (12:25 pm)

Break (10 minutes)  

Development of biomechanically optimized surgical and transcatheter approaches to mitral valve repair
Presenter: Murali Padala, PhD (12:45 pm)
Discussant: Michael Borger, MD
Group Discussion (1:05 pm)

Human impact and patient perspective
Speaker: John Lewis (1:15 pm)

Summary
Francesca Nesta Delling, MD MPH (1:30 pm)

Adjourn (1:45 pm)