Application of the LDL-Density-Radius Theory: The Aortic Valve

Abstract

With the decline incidence of rheumatic carditis, calcific aortic valve disease (CAVD) [1] has become the most common indication for surgical valve replacement in the United States and in Europe [2]. Numerous epidemiologic studies identified risk factors for CAVD, which are similar to those of vascular atherosclerosis, including smoking, male gender, body mass index, hypertension, elevated lipid and inflammatory markers, metabolic syndrome and renal failure [3–19]. For years, this disease process was thought to be due to a degenerative phenomenon by which calcium attached to the surface of the aortic valve leaflet. Understanding calcification, as the critical end-stage process which causes progression to severe stenosis and leads to poor outcomes [20], is becoming important in the results of the randomized trials for treating aortic stenosis with medical therapy. To date, these trials, including SALTIRE, Simvastatin Ezetimibe in Aortic Stenosis (SEAS), Aortic Stenosis Progression Observation: Measuring the Effects of Rosuvastatin (ASTRONOMER), have all been negative [21–23]. Over the past decade, data from several studies have confirmed that all of these traditional risk factors, including metabolic syndrome [13] and renal failure [14], which are important in the development of vascular atherosclerosis, and are also implicated in the development of CAVD [3–19]. These findings provide the foundation to study targeted strategies for medical therapy, including for example, medications for hyperlipidemia, hypertension and diabetes. There are a growing number of experimental in vivo models of calcific AS, which demonstrate primarily that lipids [24–30], diabetes [30] and renal failure [31] are important in the development of this disease. There is also increasing evidence that these cells undergo specific differentiation steps towards the development of this bone phenotype as shown in in vitro studies [32–34]. In addition, there are a growing number of retrospective [35–38] and the large-scale prospective clinical trials [21–23] testing the hypothesis that atherosclerotic CAVD may be targeted with medical therapy. The only clinical trial to date Rosuvastatin Affecting Aortic Valve Endothelium to Slow the Progression of Aortic Stenosis trial (RAAVE) was a positive study testing the hypothesis that treating elevated LDL as compared to normal LDL patients slows progression of CAVD [21]. The retrospective studies published to date are shown in Fig. 17.2 [35–38].