The National Heart, Lung, and Blood Institute (NHLBI) convened a Working Group of investigators on September 21, 2009, in Chicago, Illinois, to advise the NHLBI on the state of the science and on new research directions to improve the understanding and, ultimately, the treatment of calcific aortic valve stenosis.
Calcific aortic valve disease (CAVD) covers a spectrum of disease from initial changes in the cell biology of the valve leaflets, through early calcification, tissue remodeling and aortic sclerosis, to outflow obstruction and aortic stenosis. The later stages are characterized by fibrotic thickening of the valve leaflets and the formation of new blood vessels and calcium nodules – often including the formation of actual bone – throughout the valve leaflets but concentrated near the aortic surface. Although CAVD is more common with age, it is not an inevitable consequence of aging. CAVD appears to be an actively regulated disease process that cannot be characterized simply as “senile” or “degenerative.”
Epidemiological studies show that some of the risk factors for CAVD are similar to those for vascular atherosclerosis. Age, gender, and certain clinical factors are all associated with an increased risk of CAVD. Clinical risk factors associated with the presence of CAVD include elevated low-density lipoprotein (LDL) cholesterol, but the association is relatively weak in those over 65 years old, the group at greatest risk of progressing to aortic stenosis. Other factors include smoking, hypertension, shorter height, lipoprotein (a) level, metabolic syndrome, type II diabetes, end-stage renal disease (but not mild to moderate renal disease), and imbalances in calcium or phosphate metabolism. However, the factors associated with disease initiation may differ from those that promote disease progression.
Although aortic stenosis may occur in individuals with otherwise anatomically normal aortic valves, congenital valve abnormalities markedly increase the risk. Nearly half of the individuals with aortic stenosis have a bicuspid aortic valve (BAV), an aortic valve that developed with two functional leaflets instead of the normal three. BAV occurs in about 0.6% of the population and is the most common congenital cardiac malformation. Although the causes of BAV are unclear, genetic factors have been identified in some cases. CAVD tends to develop at an earlier age in individuals with BAV and to progress more rapidly for reasons that are poorly understood. Genetic mutations associated with BAV that cause cellular dysfunction may also predispose an individual to other congenital heart defects or to dilation and dissection of the ascending aorta.
CAVD may progress to a point-of-no-return, a stage of severe calcification where damage to the valve leaflets is too severe to be reversed by drug therapy. Whether a point-of-no-return really exists, and if so, whether it’s a fundamental aspect of CAVD biology or only the limit of therapeutic ingenuity is not known.
The biology of the aortic valve is regulated by valve endothelial cells and valve interstitial cells (VICs). These cells maintain the health of the valve and mediate valve disease. VICs may behave differently in different locations within the valve and in different stages of valve development or disease. The normal signals between valve cells and the signals that trigger activation and differentiation have not been fully established. Possible triggers for VIC differentiation or dysfunction include hemodynamic shear stress, solid tissue stresses, reactive oxygen species, inflammatory cytokines and growth factors, and the cellular environment caused by other disease states, such as metabolic syndrome, diabetes mellitus, hypercholesterolemia, chronic renal disease, and disorders of calcium or phosphate metabolism. Once activated, VICs can differentiate into a variety of other cell types, including myofibroblasts and osteoblasts, although valve osteoblasts may respond to cellular signals differently than skeletal osteoblasts.
The normal signals between valve cells and the signals that trigger activation and differentiation have not been fully established. Possible triggers for VIC differentiation or dysfunction include hemodynamic shear stress, solid tissue stresses, reactive oxygen species, inflammatory cytokines and growth factors, and the cellular environment caused by other disease states, such as metabolic syndrome, diabetes mellitus, hypercholesterolemia, chronic renal disease, and disorders of calcium or phosphate metabolism. The study of bioprosthetic valves may serve as a “purer” model of calcification or VIC injury and may improve our understanding of the mechanisms of CAVD and the early events of calcification.
Mouse models of hypercholesterolemia demonstrate various features of human CAVD at the molecular and organ levels, and at least one develops stenosis. But hypercholesterolemia is only one of several conditions – including other risk factors for atherosclerosis and specific genetic mutations – that contributes to aortic stenosis, and may not be the most common. Therapies developed in high-cholesterol animal models may fail in human clinical trials, unless the therapies target final common pathways leading to CAVD, which remain to be elucidated. The implications are important for the design of future clinical trials. Large animal models, possibly including non-human primates, would be helpful but are limited by technical difficulties, expense, and the likelihood that development of disease will be slow.
Prospective clinical studies of CAVD are hampered by the typically slow and variable progression of the disease. Patients who present with aortic stenosis are already in the later stages of the disease. Echocardiography is the standard for evaluating the severity of aortic stenosis and is a useful surrogate endpoint for clinical studies in the later stages. CT is a relatively high-resolution and high-sensitivity technique for evaluating aortic valve calcium and is a useful endpoint for clinical studies in the earlier stages. However, molecular imaging, with sub-millimeter resolution, may be able to identify and study the mechanisms of even earlier subclinical aortic valve calcification.
Current information does not yet support a specific pharmacological target or design of a large CAVD treatment clinical trial. Recent studies showing lipid reduction to be ineffective may have been limited by the late stage of the disease or by an insensitive measure of effect. Whether patients at an earlier stage, e.g., with aortic sclerosis, or with specific known risk factors such as BAV, should be treated with lipid lowering therapy, angiotensin converting enzyme inhibitors, or novel pharmacological interventions – even if they don’t meet the current criteria for therapy – remains an open question.
The Recommendations are presented as being of equal weight, not in priority order.
- Identify genetic, anatomic, and clinical risk factors for the distinct phases of initiation and progression of CAVD, to identify individuals at higher risk, to determine interactions between risk factors, to establish the correlations between phenotype and genotype for BAV, and to determine whether the severity of aortic stenosis is a risk factor for surgical aortic valve replacement. These factors should encompass the unique contributions of atherosclerosis, metabolic syndrome, hypercholesterolemia, type II diabetes, and chronic kidney disease. New, larger epidemiological studies and existing epidemiological datasets in which CT scans, echocardiograms, or possibly magnetic resonance imaging scans have been obtained, could be used in this effort.
- Develop high-resolution and high-sensitivity imaging modalities that can identify early and subclinical CAVD, including molecular imaging and other innovative imaging approaches. Continue research to define the state-of-the-art for detecting early calcification not identified by traditional echocardiographic imaging.
- Understand the pathogenesis and pathophysiology of bicuspid aortic valve.
- Understand the basic science (e.g., early events, mechanisms and regulatory effects) of CAVD, including signaling pathways and the roles of valve interstitial and endothelial cells and the autocrine and paracrine signaling between them, the extracellular matrix and matrix stiffness, the interacting mechanisms of cardiovascular calcification and physiologic bone mineralization, and micro-scale mechanotransduction and macro-scale hemodynamics.
- Develop and validate suitable multi-scale in vitro, ex vivo, and animal models. Improved models are needed that realistically duplicate the conditions in which human CAVD develops. Metabolic studies are needed, from the cellular level through the patient level, to define those conditions.
- Identify the relationship between calcification of the aortic valve and bone and the reciprocal regulation of these processes.
- Encourage, promote, or establish tissue banks that make valve tissue from surgery, pathology, and autopsy unsuitable or unneeded for transplantation – with and without CAVD – available for research. Human valve cell lines should be derived including immortalized VICs.
- Conduct clinical studies specific to CAVD to determine the feasibility of earlier pharmacological intervention and to determine the risk factors and optimal timing of surgical valve replacement.
A broader report, including an overview of the field, a review of the literature, and an expanded rationale for these recommendations, was published as Rajamannan et al, Calcific aortic valve disease: not simply a degenerative process, Circulation 2011;124(16):1783-91.
Division of Cardiovascular Sciences
Frank Evans, PhD
Division of Cardiovascular Sciences
Working Group Members
- Nalini M. Rajamannan, MD, Northwestern University Feinberg School of Medicine
- Elena Aikawa, MD, PhD, Brigham and Women’s Hospital and Harvard Medical School
- K. Jane Grande-Allen, PhD, Rice University
- Donald Heistad, MD, University of Iowa Carver College of Medicine
- Kristyn S. Masters, PhD, University of Wisconsin
- Patrick Mathieu, MD, Quebec Heart and Lung Institute
- Kevin O’Brien, MD, University of Washington
- Catherine M. Otto, MD, University of Washington
- Frederick Schoen, MD, PhD, Brigham and Women’s Hospital and Harvard Medical School
- Craig Simmons, PhD, University of Toronto
- Dwight Towler, MD, PhD, Washington University in St. Louis
- Ajit Yoganathan, PhD, Georgia Institute of Technology
Last Updated: March 2010