Pathophysiology of valvular heart disease

Abstract

Valvular heart disease (VHD) is caused by either damage or defect in one of the four heart valves, aortic, mitral, tricuspid or pulmonary. Defects in these valves can be congenital or acquired. Age, gender, tobacco use, hypercholesterolemia, hypertension, and type II diabetes contribute to the risk of disease. VHD is an escalating health issue with a prevalence of 2.5% in the United States alone. Considering the likely increase of the aging population worldwide, the incidence of acquired VHD is expected to increase. Technological advances are instrumental in identifying congenital heart defects in infants, thereby adding to the growing VHD population. Almost one-third of elderly individuals have echocardiographic or radiological evidence of calcific aortic valve (CAV) sclerosis, an early and subclinical form of CAV disease (CAVD). Of individuals ages >60, ~2% suffer from disease progression to its most severe form, calcific aortic stenosis. Surgical intervention is therefore required in these patients as no effective pharmacotherapies exist. Valvular calcium load and valve biomineralization are orchestrated by the concerted action of diverse cell-dependent mechanisms. Signaling pathways important in skeletal morphogenesis are also involved in the regulation of cardiac valve morphogenesis, CAVD and the pathobiology of cardiovascular calcification. CAVD usually occurs without any obvious symptoms in early stages over a long period of time and symptoms are identified at advanced stages of the disease, leading to a high rate of mortality. Aortic valve replacement is the only primary treatment of choice. Biomarkers such as asymmetric dimethylarginine, fetuin-A, calcium phosphate product, natriuretic peptides and osteopontin have been useful in improving outcomes among various disease states. This review, highlights the current understanding of the biology of VHD, with particular reference to molecular and cellular aspects of its regulation. Current clinical questions and the development of new strategies to treat various forms of VHD medically were addressed.

Keywords: aortic valve stenosis; biomineralization; calcific aortic valve disease; calcification; congenital heart disease; endothelial cells; valvular heart disease.

Figure 1.

Pathogenic pathways involved in calcific aortic valve disease. Mechanical stress or injury on the aortic valve along with other atherosclerotic risk factors causes valvular endothelial dysfunction. This leads to lipid deposition in the subendothelium where they are oxidized and factors such as oxidized low-density lipoprotein (oxLDL) are formed. Inflammatory cells such as monocytes, infiltrate the valve tissue and form foam cells by phagocytosis of the lipids. Inflammatory cytokines are released which promote remodeling of the extracellular matrix. Fibroblasts transdifferentiate into valvular myofibroblasts with an osteoblast-like phenotype, and cause calcification. Biomarkers are associated with different stages of CAVD and can be useful in following the pathogenesis of the disease. TNFα, tumor necrosis factor α; TGF-β, transforming growth factor-β; IL-1β, interleukin-1β; MMP, matrix metalloproteases; ECM, extracellular matrix; ADMA, asymmetric dimethylaminoarginine; tPA, tissue plasminogen activator; CRP, C-reactive protein; CaxP, calcium phosphate product.

Figure 2.

Crosstalk between the Notch and Wnt signaling pathways in calcific aortic valve disease. Notch 1 signaling, which represses BMP2 and Runx2 expression and impedes β-catenin stabilization and signaling, is useful in the prevention of valvular calcification. In calcific aortic valve disease, elevated levels of Wnt3a activate the coreceptor complex formed by Frizzled and Lrp5/6, leading to the stabilization of β-catenin and promoting the osteogenic transition of valve interstitial cells and valvular calcification. BMP, bone morphogenetic protein; NICD, Notch intracellular domain; Runx2, runt-related transcription factor 2.