Pathophysiology and Mechanism of Calcification

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Pathophysiology and Mechanism of Calcification

Over the past several decades, the aetiology of calcific aortic valve disease (CAVD) has changed considerably. The lower prevalence of rheumatic heart disease and increased longevity in industrialised countries has resulted in a pattern shift from rheumatic to degenerative calcification as the most common cause of CAVD and subsequent calcific aortic stenosis.^16–18 CAVD is the third most common heart disease in the western world,¹⁹ following coronary heart disease and hypertension. Its prevalence in the elderly (≥65 years of age) ranges from 2–4 % when considering only severe aortic stenosis, increasing to 25 % when aortic sclerosis is included.⁹ However, a relative minority of elderly individuals develop aortic valve calcification, suggesting pathological influences other than age play a role.

Calcific aortic stenosis is the second most prevalent cause for heart surgery and is responsible for approximately 15,000 deaths annually in North America.¹⁸ Calcific aortic stenosis is a well-known disease entity and we are able to assess numerous haemodynamic parameters using cardiac catheterisation or ultrasonography as well as cardiac computed tomography and cardiac magnetic resonance imaging.²⁰ In CAVD, calcified nodules are initially observed at the base of the cusps and their presence gradually extends towards the orifice. All three cusps are usually usually affected, but one or more may be dominant. When blood flow through the stenotic aortic orifice becomes significantly restricted, haemodynamic impairment associated with serious symptoms of congestive heart failure and sudden cardiac death may occur. Severe symptomatic aortic stenosis is a Class I indication for surgical valve replacement according to the American Heart Association and American College of Cardiology guidelines for valvular heart disease.²¹

CAVD is currently considered as an actively regulated and progressive disease, characterised by a cascade of cellular changes that initially cause fibrotic thickening, followed by extensive calcification of the aortic valve leaflets. This in turn leads to significant aortic valve stenosis and eventual left ventricular outflow obstruction (see Figure 2 ),^10,22 for which surgical replacement remains the only viable treatment option. Currently there is no approved pharmacological treatment to stop the progression of CAVD. ²³ Descriptive studies using human specimens have demonstrated the hallmark features of this disease, including early atherosclerosis, cell proliferation and osteoblast expression. ^24–26

CAVD and Traditional Risk Factors for Atherosclerosis

Aortic valve stenosis was first described by Lazare Riviere in 1663. ²⁷ In the early 1900s, eminent pathologists such as Monckeberg, described CAVD as a passive degenerative process associated with rheumatic fever or aging, during which serum calcium attaches to the valve surface and binds to the leaflet to form nodules. ²⁸

In more recent decades, several studies have implicated the traditional risk factors for cardiovascular atherosclerosis in the development of CAVD. Atherosclerosis is a complex and multifactorial process that produces a lesion composed of lipids, ^29,30 macrophages, ³¹ proliferating smooth muscle cells ³² and apoptosis. ³³ It is regulated by endothelial nitric oxide synthase, ^34–38 and over time causes occlusion of the vessel diameter. Total cholesterol, increased low-density lipoprotein (LDL) cholesterol, increased lipoprotein(a), increased triglycerides, decreased high-density lipoprotein cholesterol, male sex, cigarette smoking, hypertension, and diabetes mellitus have been reported to increase the incidence of aortic stenosis, and are likely contribute to endothelial dysfunction and leaflet damage. ^2,3,39–43 The presence of LDL and atherosclerosis in calcified valves in surgical pathological studies supports the hypothesis of a common cellular mechanism. ^44,45 Furthermore, patients with familial hypercholesterolaemia develop aggressive peripheral vascular disease, coronary artery disease and aortic valve lesions, which calcify with age. ^39,46–4

Oxidised LDL (oxLDL) is implicated in vascular calcification associated with atherosclerosis. ^49,50 Elevated blood levels of oxLDL correlate with aortic valve calcification and fibrosis, ⁵¹ and oxLDL accumulation in calcific, stenotic aortic valves is well described. ^52–56 Metabolic bone diseases – including Paget’s disease, secondary hyperparathyroidism and renal disease – as well as increased serum creatinine and calcium are also linked to progression of valve calcification, but include only a relative minority of patients who have aortic stenosis. ^57–59 Understanding of these clinical risk factors provides the foundation for cellular studies and the potential for targeted medical therapies for this disease, similar to vascular atherosclerosis. However, the overall evidence indicated by the presence of atherosclerotic risk factors may partly explain why some patients who have congenitally abnormal valves develop aortic stenosis and require valve replacement sooner than those without risk factors. If atherosclerotic risk factors are important in the development of valvular heart disease, then experimental models of atherosclerosis are important in the understanding of this process. Studies in mice and rabbits have confirmed that experimental hypercholesterolaemia causes both atherosclerosis and calcification in the aortic valves. ^60–64 Two months of cholesterol diet treatment in an experimental rabbit model induced marked thickening and complex calcification in the aortic valve leaflets. The model was extended to test the pharmacological effect of atorvastatin and angiotensin receptor antagonists on the inhibition of atherosclerosis pathways and calcification. ^65–69 Other pathways, such as Wnt signalling and increased calcium concentration via kallikrein-kinin signalling, are involved in CAVD. Wnt proteins interact with trans-membrane receptors, in particular LDL receptors, and inhibit the effect of the degradation of the intracellular protein β catenin. In turn, β catenins mediate osteoblastic transformation of VICs and bone production. In vitro, atorvastatin – an inhibitor of LDL-cholesterol in blood – can neutralise this signal pathway in mice models. ^66,70–72

The molecular and cellular processes that contribute to aortic valve stenosis are not fully characterised, but could provide insights into the development of new therapeutic approaches.

Heart valves comprise a heterogeneous population of valvular endothelial cells and VICs, which maintain valve homeostasis and structural leaflet integrity. VICs, the most abundant cell type in the heart valve, play a key role in CAVD progression. ⁷³ Various VIC phenotypes have been identified in diseased human heart valves, ⁷⁴ including quiescent fibroblast-like VICs, which upon pathological cues can differentiate into activated myofibroblast-like VICs; and osteoblast- like VICs, which are responsible for the active deposition of calcium in CAVD. ^53,62,74 Additionally, several studies have demonstrated the ability of VICs to undergo osteogenic differentiation. ^26,67,75