Characteristic cardiovascular manifestation in homozygous and heterozygous familial hypercholesterolemia

Kawaguchi, Akito; Miyatake, Kunio; Yutani, Chikao; Beppu, Shintarou; Tsushima, Motoo; Yamamura, Taku; Yamamoto, Akira

doi:10.1016/s0002-8703(99)70485-0

Cited by 74 publications

(50 citation statements)

References 33 publications

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“…Whereas hypercholesterolemia is a risk factor for CAVD, lipid‐lowering techniques do not significantly reduce CAVD incidence 21, 22, 23. In both heterozygous FH and HoFH, CAVD prevalence is significantly higher than in the normotypic population, but still occurs at a greatly reduced rate relative to the development of atherosclerosis in FH individuals 1, 8, 9, 39. By examining the aortic valves from an FH animal model known to recapitulate the atherosclerotic events of human HoFH with high fidelity, we sought to better understand the relationship between hypercholesterolemia and development of CAVD.…”

Section: Discussionmentioning

confidence: 99%

“…Although less studied than atherosclerosis in FH, the increased incidence of CAVD in FH patients is significant, with over half of homozygous FH (HoFH) males and 21% to 41% of HoFH females exhibiting aortic regurgitation or more‐advanced valvular dysfunction 8, 9. This correlation is not entirely unexpected, given that CAVD has been associated with hyperlipidemia,10 and stenotic valves are rich in oxidized lipids and apolipoproteins B and E 11, 12.…”

Section: Introductionmentioning

confidence: 99%

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Development of Aortic Valve Disease in Familial Hypercholesterolemic Swine: Implications for Elucidating Disease Etiology

Porras

Shanmuganayagam

Meudt

et al. 2015

JAHA

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BackgroundFamilial hypercholesterolemia (FH) is a prevalent hereditary disease associated with increased atherosclerosis and calcific aortic valve disease (CAVD). However, in both FH and non‐FH individuals, the role of hypercholesterolemia in the development of CAVD is poorly understood. This study used Rapacz FH (RFH) swine, an established model of human FH, to investigate the role of hypercholesterolemia alone in the initiation and progression of CAVD. The valves of RFH swine have not previously been examined.Methods and ResultsAortic valve leaflets were isolated from wild‐type (0.25‐ and 1‐year‐old) and RFH (0.25‐, 1‐, 2‐, and 3‐year‐old) swine. Adult RFH animals exhibited numerous hallmarks of early CAVD. Significant leaflet thickening was found in adult RFH swine, accompanied by extensive extracellular matrix remodeling, including proteoglycan enrichment, collagen disorganization, and elastin fragmentation. Increased lipid oxidation and infiltration of macrophages were also evident in adult RFH swine. Intracardiac echocardiography revealed mild aortic valve sclerosis in some of the adult RFH animals, but unimpaired valve function. Microarray analysis of valves from adult versus juvenile RFH animals revealed significant upregulation of inflammation‐related genes, as well as several commonalities with atherosclerosis and overlap with human CAVD.ConclusionsAdult RFH swine exhibited several hallmarks of early human CAVD, suggesting potential for these animals to help elucidate CAVD etiology in both FH and non‐FH individuals. The development of advanced atherosclerotic lesions, but only early‐stage CAVD, in RFH swine supports the hypothesis of an initial shared disease process, with additional stimulation necessary for further progression of CAVD.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Development of Aortic Valve Disease in Familial Hypercholesterolemic Swine: Implications for Elucidating Disease Etiology

Porras

Shanmuganayagam

Meudt

et al. 2015

JAHA

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“…[17][18][19][20] The results of prospective studies are somewhat conflicting. 21,22,29,30 The present study is the latest prospective trial to show that statins such as rosuvastatin have a profound effect on lowering (28) 27 (27) Coronary bypass surgery † 5 (5) 5 (5) Cardiac death 2 (2) 5 (5)…”

Section: Discussionmentioning

confidence: 93%

“…Indeed, valvular AS and supravalvular AS are known complications in patients with familial hypercholesterolemia, and sclerotic changes in the aortic valve are ubiquitous in homozygotes and common in heterozygotes. 27,28 It is thus a reasonable hypothesis that statins, which are effective in treating hypercholesterolemia and reducing coronary events, may also be effective in reducing the rate of progression of AS. Several retrospective studies have supported this notion.…”

Section: Discussionmentioning

confidence: 99%

Effect of Lipid Lowering With Rosuvastatin on Progression of Aortic Stenosis

et al. 2010

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Background-Aortic stenosis (AS) is an active process with similarities to atherosclerosis. The objective of this study was to assess the effect of cholesterol lowering with rosuvastatin on the progression of AS. Methods and Results-This was a randomized, double-blind, placebo-controlled trial in asymptomatic patients with mild to moderate AS and no clinical indications for cholesterol lowering. The patients were randomized to receive either placebo or rosuvastatin 40 mg daily. A total of 269 patients were randomized: 134 patients to rosuvastatin 40 mg daily and 135 patients to placebo. Annual echocardiograms were performed to assess AS progression, which was the primary outcome; the median follow-up was 3.5 years. The peak AS gradient increased in patients receiving rosuvastatin from a baseline of 40.8Ϯ11.1 to 57.8Ϯ22.7 mm Hg at the end of follow-up and in patients with placebo from 41.6Ϯ10.9 mm Hg at baseline to 54.8Ϯ19.8 mm Hg at the end of follow-up. The annualized increase in the peak AS gradient was 6.3Ϯ6.9 mm Hg in the rosuvastatin group and 6.1Ϯ8.2 mm Hg in the placebo group (Pϭ0.83). Treatment with rosuvastatin was not associated with a reduction in AS progression in any of the predefined subgroups. Conclusion-Cholesterol lowering with rosuvastatin 40 mg did not reduce the progression of AS in patients with mild to moderate AS; thus, statins should not be used for the sole purpose of reducing the progression of AS. Clinical Trial Registration Information-URL: http://www.controlled-trials.com/.

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“…In addition, in the elderly population, it might be difficult to select completely healthy subjects without any pathological conditions that might affect atherosclerosis and thus valvular regurgitation. 22 Left atrial diameter and LV size were not corrected by body surface area. Therefore differences in left atrial diameter or LV volume observed between those with and without valvular regurgitation might be affected by the differences in body size as a result of differences in age and gender.…”

Section: Study Limitationsmentioning

confidence: 99%

Prevalence and Correlates of Physiological Valvular Regurgitation in Healthy Subjects - A Color Doppler Echocardiographic Study in the Current Era -

Okura

Takada

Yamabe

et al. 2011

Circ J

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Background: Although echo Doppler machines have consistently advanced within a quarter of a century, age related prevalence of valvular regurgitation detected by currently available echo machines remains uncertain. The aim of this study was to investigate the prevalence and correlates of valvular regurgitation in healthy individuals. Methods and Results:A total of 1,333 apparently healthy individuals were enrolled in this study. Echocardiographic examinations were performed using a currently available echo machine. Aortic regurgitation (AR) was detected less frequently (<10%) in younger subjects. Prevalence of aortic regurgitation increased with advancing age and reached 46% in their 9 th decade. Mitral regurgitation (MR) was detected in two-thirds of the subjects >30 years old. Tricuspid regurgitation (TR) was frequently (>80%) detected in all age groups. In general, prevalence of valvular regurgitation was higher than those reported previously, except for a relatively lower prevalence of AR in the elderly population. Age was an independent correlate of AR and MR, but not of TR. The presence of AR and MR were independent correlates of TR. Conclusions:In healthy subjects, AR, MR or TR are commonly detected by using a current echo machine. These "physiological" valvular regurgitations should not be considered as a "pathological" valvular heart disease. (Circ J 2011; 75: 2699 - 2704

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Characteristic cardiovascular manifestation in homozygous and heterozygous familial hypercholesterolemia

Abstract: Kawaguchi et al.; Hypercholesterolemic valvulopathy in FH-2 -ABSTRACT Background The aortic valve dysfunction of patients with homozygous familial

Cited by 74 publications

References 33 publications

Development of Aortic Valve Disease in Familial Hypercholesterolemic Swine: Implications for Elucidating Disease Etiology

Development of Aortic Valve Disease in Familial Hypercholesterolemic Swine: Implications for Elucidating Disease Etiology

Effect of Lipid Lowering With Rosuvastatin on Progression of Aortic Stenosis

Prevalence and Correlates of Physiological Valvular Regurgitation in Healthy Subjects - A Color Doppler Echocardiographic Study in the Current Era -

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