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66 | Chapter 4 versus the control population. The concept of 2 different phases of AoVC progression is not only essential but could explain the discordant findings. The National Heart, Lung, and Blood Institute Aortic Stenosis Working Group for CAVD (1) also emphasized this concept in early valve sclerosis versus late valve stenosis. Lipid Density Compared with he-FH patients with LDLR-defective mutations, patients with LDLR- negativemutational he-FHhadhigher levelsof total cholesterol andmaximumuntreated low-density lipoprotein cholesterol (3). In addition, he-FH patients with LDLR-negative mutations began statin treatment at a younger age and used statins for a longer period of time. Figure 1 illustrates the results of the study in patients with he-FH, including the effect of functional low-density lipoprotein (LDL) receptors and proportional increases in LDL with the degree of AoVC. Figure 1 |  The LDL-Density-Gene Effect (A) The control heart with the normal low-density lipoprotein receptor (LDLR).  (B) Heterozygous familial hypercholesterolemia–defective receptor mutation and mild calcific aortic valve disease.  (C) Heterozygous familial hypercholesterolemia–negative receptor mutation and severe calcific aortic valve disease. + = a semi-quantitative measurement of approximately 10% effect; AoVC = aortic valve calcification; density = concentration; CAC = coronary artery calcification; LDL = low-density lipoprotein. To the best of our knowledge, this study by ten Kate et al. (3) is the first to correlate in patients the role of LDL and the effect of the LDL receptor genetic contribution in terms of phenotypic expression of calcification in the valve and in the coronary arteries. The LDL-density theories (4–6) provide a hemodynamic explanation for why abnormal calcification develops secondary to high LDL density concentration up-regulating