The National Heart, Lung, and Blood Institute (NHLBI) convened a Working Group of experts in heart failure, myocardial remodeling, hypertrophic cardiomyopathy (HCM), clinical trials, genetics, clinical cardiology, and cardiovascular imaging on September 4-5, 2008 in Bethesda, Maryland, to advise the Institute on new research strategies to prevent the phenotypic expression of genetically-mediated HCM and its resulting clinical syndrome. This Working Group is responsive to NHLBI Strategic Plan Goals 1 & 2 and the Division of Cardiovascular Diseases Strategic Plan Goal 2.4c.
Investing in research on HCM is important for many reasons. The incidence is relatively high in the population and much of the underlying genetics are characterized. Large gaps exist in our knowledge of how specific gene mutations lead to the varied phenotypic expressions of HCM. Molecular pathways regulating the key components of HCM – hypertrophy, fibrosis, arrhythmias, and sudden death – are not understood, and understanding these mechanisms in HCM might provide insights into more common etiologies of hypertrophy and heart failure. There is a paucity of evidence-based treatment strategies. In view of the above, the working group achieved consensus on the following recommendations.
1. Opportunities for Clinical Interventions
Support opportunities for clinical interventions in the near future since studies in experimental models suggest the possibility that some therapies may retard the progression of left ventricular hypertrophy (LVH) and other phenotypic sequelae of HCM. Also, the natural history of the progression of the phenotypic expression of HCM including LVH, myocardial ischemia, fibrosis, and arrhythmias is unknown and needs to be defined.
- Support a randomized prospective multicenter clinical trial to address the hypothesis that currently available therapeutics can prevent the progression of LVH.
Preadolescents and adolescents with genotype positive HCM and no or minimal LVH are the appropriate candidates. The majority would be positive for a mutation in the gene encoding ?-myosin heavy chain since they have more predictable progression to LVH. The study group can be enriched with subjects having diastolic dysfunction and/or an abnormal ECG. Follow patients with serial determination of LV mass by echocardiography and/or cardiac MRI, and serum samples for the identification of biomarkers. Candidate therapeutics include aldosterone antagonists, angiotensin receptor antagonists, calcium channel blockers, and HMG CoA reductase inhibitors, but the use of ?-blockers, ranolazine, TGF? pathway therapeutics, and PDE5 inhibitors were also discussed.
- Support a prospective study of the natural history of HCM. Such a study would serve as a foundation for future clinical trials designed to prevent the sequelae of the disease, and would identify biomarkers or other findings that are associated with disease progression. Subjects with genotype positive HCM and LVH established by echocardiography at all stages of phenotypic expression may be symptomatic or asymptomatic. Include annual echocardiography and cardiac MRI (the latter in a subset of patients) measurements. Periodic ambulatory rhythm monitoring, exercise testing and serum samples for identification of biomarkers that may predict disease progression may be obtained.
2. Translational Opportunities
Support translational opportunities since very little is known about the molecular factors that trigger the various phenotypic expressions of HCM in animal models and even less is known about these in patients.
- Identify novel mediators of disease in patients by supporting new studies in animal models and comparing findings in these models with human heart samples to determine the molecular signaling pathways that initiate hypertrophy and that contribute to arrhythmia generation, diastolic dysfunction, myocyte apoptosis/necrosis, abnormal calcium regulation and fibrosis in HCM.
- Identify key nodal molecules involved in HCM phenotypes (signaling pathway/proteomic analysis).
- Validate mouse models to determine their utility in advancing understanding of the pathophysiology of HCM in patients.
- Determine whether the emerging findings from transcript profiling in mouse models of HCM are mirrored in patients. This would allow the identification of transcript profiles that may regulate expression of the various HCM phenotypes.
- Identify novel mutations responsible for “genotype-negative” HCM. Many patients with overt HCM are negative for known mutations. Therefore it is important to attempt to genotype all HCM patients.
- Identify determinants of diastolic dysfunction (fibrosis, thickened walls, myofilament abnormalities, dysregulated Ca2+, and impaired energetics), exercise-induced sudden death, and arrhythmias.
- Employ existing or novel animal models to identify the determinants of sudden death during exercise in HCM.
- Use implantable arrhythmia monitoring in patients to explore the relationships between specific arrhythmias and genotype, phenotype, and biomarkers.
- Define the fundamental causes of atrial fibrillation in established HCM and identify strategies to prevent this arrhythmia.
3. Fundamental Research
Support fundamental research in strategic directions. The most proximal intracellular mechanisms that initiate the disease sequelae of HCM in response to mutant sarcomeric proteins are not known. Furthermore, the roles of the extracellular matrix (ECM), the vasculature, and altered metabolism in promoting disease sequelae are not clear. To address these deficiencies, new models of the disease are needed.
- Delineate initiating stimuli.
- Determine whether alterations in Ca2+ handling serve as the initiating stimulus.
- Determine whether an alteration in perceived tension/strain at the level of the sarcomere/myofilaments serves to initiate disease in response to mutant HCM proteins.
- Investigate linkages between altered sarcomeric response to Ca2+ and metabolism. Characterize the alterations in metabolism and determine whether a correction in the metabolic defects in HCM can prevent or rescue the phenotype.
- Explore strategies for preventing mutant gene expression, thereby removing the initiating stimulus.
- Define the role of the extracellular matrix in the fibrotic response in HCM.
- Generate a more complete understanding of the basic elements in signaling to the extracellular matrix in normal hearts, and in HCM.
- Determine the variants of fibroblasts including the fundamental determination of parameters such as the percentage of fibroblasts in the normal and diseased heart.
- Define the role of the vasculature.
- Determine the role of alterations in small vessels and the micro-circulation in the evolution of the HCM phenotype.
- Determine whether angiogenesis matches myocyte hypertrophy and whether ischemia and oxidative stress are important factors in the evolution of the HCM phenotype.
- Develop new/emerging approaches to defining disease mechanisms.
- Develop new animal models to uncover molecular mechanisms of HCM prior to and after the initiation of LV remodeling.
- Combine HCM models with models modifying Ca2+ handling, sarcomere response to Ca2+, and metabolism.
- Consider exploring the use of naturally occurring and transgenic HCM models in large animals such as rabbit and pig.
The Working Group report is planned for publication in a peer-reviewed journal.
Division of Cardiovascular Diseases
Working Group Members:
- Thomas Force, MD, Thomas Jefferson University
- Mark Anderson, MD, PhD, University of Iowa
- Robert Bonow, MD, Northwestern University of Medical School
- Barry Byrne, MD, PhD, University of Florida
- Thomas Cappola, MD, ScM, University of Pennsylvania
- Ray Hershberger, MD, University of Miami
- Steven Houser, PhD, Temple University
- Raghu Kalluri, PhD, Beth Israel Deaconess Medical Center
- Martin LeWinter, MD, University of Vermont
- Barry J. Maron, MD, Minneapolis Heart Institute Foundation, Inc
- Martin Maron, MD, New England Medical Center Hospitals, Inc
- Jeffery Molkentin, PhD, Cincinnati Children’s Hospital Medical Center
- Steve Ommen, MD, Mayo Cardiomyopathy Clinic
- Michael Regnier, PhD, University of Washington
- Christine Seidman, MD, Brigham and Women’s Hospital
- R. John Solaro, PhD, University of Illinois at Chicago
- W. H. Wilson Tang, MD, Cleveland Clinic
- Rong Tian, MD, PhD, Brigham and Women’s Hospital
NHLBI Staff Members:
- Patrice Desvigne-Nickens, MD
- Frank Evans, PhD
- Marvin Konstam, MD (Special Advisor)
- Isabella Liang, PhD
- Alice Mascette, MD
Last updated: January 13, 2009