Calcification in Aortic Stenosis: The Skeleton Key

Acquired aortic valve disease and valvular calcification is highly prevalent in adult populations worldwide and is associated with significant cardiovascular morbidity and mortality. At present, there are no medical therapies that will prevent or regress aortic valve calcification or stenosis and surgical or transcatheter aortic valve replacement remain the only effective therapies for treating this disease. In the setting of valve injury as a result of exposure to biochemical mediators or hemodynamic forces, normal homeostatic processes are disrupted resulting in extracellular matrix degradation, aberrant matrix deposition and fibrosis, inflammatory cell infiltration, lipid accumulation, and neoangiogenesis of the valve tissue and, ultimately, calcification of the valve. Calcification of the aortic valve is now understood to be an active process that involves the coordinated actions of resident valve endothelial and interstitial cells, circulating inflammatory and immune cells, and bone marrow-derived cells. These cells may undergo a phenotype transition to become osteoblast-like cells and elaborate bone matrix, endothelial-to-mesenchymal transition, and form matrix vesicles that serve as a nidus for microcalcifications. Each of these mechanisms has been shown to contribute to aortic valve calcification suggesting that strategies that target these cellular events may lead to novel therapeutic interventions to halt the progression or reverse aortic valve calcification.

Cellular Mechanisms of Aortic Valve Calcification

Calcific aortic valve stenosis is the result of regulated cell processes. The histological hallmarks are inflammation and a remodelling of the extracellular matrix leading to bone formation. In the last 15 years the view has changed from it being an unmodifiable degenerative disease to an active biological process regulated by highly conserved ubiquitous cellular pathways. Many mechanisms and risk factors are the same as in atherosclerosis. Thus, statins and angiotensin II antagonists seemed promising treatment options. However, clinical trials failed to support this. This review describes the current understanding of major molecular mechanisms and discusses their role in clinical practice and possible therapy.

https://heart.bmj.com/content/heartjnl/95/8/616.full.pdf?95%2F8%2F616=

Aortic valve calcification: basic science to clinical practice.

Development of calcific aortic valve disease: Do we know enough for new clinical trials?

Fetuin was first isolated from bovine serum in 1944. It is now most commonly known as either fetuin-A or alpha-2-HS-glycoprotein (AHSG), the protein product of Ahsg gene. A prominent feature of this protein is the functional diversity exerted in human physiology and pathophysiology. Fetuin-A plays a role in bone metabolism, metabolic disorders such as insulin resistance and diabetes mellitus (DM), and central nervous system (CNS) disorders such as ischemic stroke (IS) and neurodegenerative diseases. In addition, emerging evidence suggests involvement of fetuin-A in the cardiovascular system. However, there are many discordant findings on the associations between fetuin-A and vascular diseases. In other words, it is unknown whether fetuin-A is an exacerbating or a protective factor in the cardiovascular system. One reason for the seemingly inconsistent behavior is the dual functionality of fetuin-A in vascular diseases where it can act as an atherogenic factor or as a vascular calcification inhibitor. In addition, the existence of confounding factors such as DM and renal dysfunction can veil the primary association between fetuin-A and clinical parameters. Considering these issues, we discuss the role of fetuin-A for atherosclerosis and vascular calcification in this review.

Fetuin-A and the cardiovascular system

Calcific aortic valve stenosis, the most frequent heart valve disorder in developed countries, is an actively regulated process with similarities to bone formation. Fetuin-A has recently been identified as a potent circulating inhibitor of calcification. While several studies involving patients with end-stage renal disease have shown an association between low serum fetuin-A and cardiovascular calcification, nothing is known about fetuin-A serum levels in non-renal patients with calcific aortic valve stenosis. Furthermore, while fetuin-A has been localized in calcified areas of atherosclerotic arteries, data about fetuin-A deposition in stenotic aortic valves are unavailable at present. Serum fetuin-A levels were determined in patients with (n=31) and without (n=28) calcified aortic valve stenosis by ELISA. Creatinine and CRP levels were determined and glomerular filtration rate (GFR) was calculated by the MDRD formula. Immunohistochemistry for fetuin-A was performed on human calcified stenotic (n=14) and control (n=8) aortic valves using a monoclonal antibody. Serum fetuin-A levels were lower in patients with calcific aortic stenosis as compared to the control group (1.41+/-0.33 versus 1.57+/-0,27 mg/dl; p=0.046). This difference was particularly evident in individuals with a normal GFR >or=60 ml/min (1.36+/-0.24 versus 1.63+/-0.27 mg/dl; p=0.007). Furthermore, specific staining of fetuin-A was found in stenotic valves but not in healthy control valves. The data suggest a role of fetuin-A in the pathogenesis calcific aortic valve stenosis independently of the renal function and support the concept that mechanisms of calcium homeostasis are involved in the development of calcific aortic stenosis.

/pdf/systemic-and-local-levels-of-fetuin-a-in-calcific-aortic-591vf84kyg.pdf

Systemic and local levels of fetuin-A in calcific aortic valve stenosis.

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Systemic and local levels of fetuin-A in calcific aortic valve stenosis.