Insights into the use of biomarkers in calcific aortic valve disease

Abstract

Calcific aortic valve disease (CAVD) is the most common acquired valvular disorder in developed countries. CAVD ranges from mild thickening of the valve, known as aortic valve sclerosis (AVSc), to severe impairment of the valve motion, which is termed aortic valve stenosis (AVS). The prevalence of CAVD is nearing epidemic status: its preceding stage, in which there is aortic sclerosis without obstruction of the left ventricular outflow, is present in almost 30% of adults aged over 65 years. As there is no existing medical therapy to treat or slow the progression of CAVD, surgery for advanced disease represents the only available treatment. Aortic valve replacement is the second most frequently performed cardiac surgical procedure after coronary artery bypass grafting, and consequently CAVD represents a major societal and economic burden. The pathophysiological development of CAVD is incompletely defined. At the present time, the major methods for its diagnosis are clinical examination, echocardiography, and cardiac catheterization. Yet, due to the multiple biological pathways leading to CAVD, there are many potential biomarkers that might be suitable for deriving clinically useful information regarding the presence, severity, progression, and prognosis of CAVD. Although at the present time the available data do not permit recommendations for clinicians, they do support a paradigm of screening patients based on multiple biomarkers to provide the information necessary to optimize future therapeutic interventions. This review summarizes the results of several studies investigating the value of potential biomarkers that have been used to predict the severity, progression, and prognosis of CAVD.

Figure 1. Macroscopic Appearance of a Healthy and a Diseased Aortic Valve

The left panel shows normal aortic valve leaflets with no calcification or sclerosis, the right panel displays a stenosed valve with leaflet and annular fibrosis and heavy leaflet calcification.

Figure 2. Trends of Aortic Valve Replacements and US Population Growth

Number of annually performed AVRs and population growth in the USA between 1985 and 1999. Data obtained from the National Center for Health Statistics (ICD-9-CM) and the US Census Bureau. AVR = Aortic valve replacement

Figure 3. Pathogenesis of Calcific Aortic Valve Disease

Mechanical stress on the aortic valve in addition to atherosclerotic risk factors, leads to valvular endothelial dysfunction/leakage, followed by deposition of lipids and other compounds in the subendothelium where they are oxidized. Blood monocytes infiltrate the valve tissue and phagocytize the modified lipids, thus becoming foam cells. T-lymphocytes secrete cytokines, which promote inflammation and remodeling of the extracellular matrix. Fibroblasts transdifferentiate into valvular myofibroblast with an osteoblast-like phenotype, thus leading to active calcification and bone formation. TNF-α=Tumor necrosis factor α, TGF-β1=Transforming growth factor β1, IL-1β=Interleukin-1β