The Role of Lipoprotein(a) in Calcific Aortic Valve Disease

Increasing age is a major risk factor for calcific aortic valve disease (CAVD). Interestingly, SIRT6 knockout mice have a marked progeroid phenotype, and we recently reported that sirtuin enzyme expression is dramatically reduced with aging and that SIRT6 expression is reduced further in valves from patients with end-stage CAVD. It is unknown, however, whether experimentally reducing SIRT6 promotes osteogenic signaling in the valve and ultimately accelerates progression of CAVD. Thus, we used cultured mouse aortic valve interstitial cells and ldlr-deficient, apolipoprotein B100-only mice (LA) that were SIRT6 wild-type (LA-SIRT6 +/+ ) or heterozygous (LA-SIRT6 +/- ) and fed a Western diet for 3 or 12 months to determine the role of SIRT6 in valve calcification. In vitro , reduction of SIRT6 increased histone acetylation and significantly increased mRNA and protein levels of the osteogenic genes Runx2 and Sp7 in response to bone morphogenetic protein 2 (100ng/ml BMP2 for 18 hours), and siRNA knockdown of SIRT6 increased mRNA levels of Sp7 even in the absence of exogenous bone morphogens. Using high-resolution ultrasound to evaluate aortic valve function in vivo, we found that 3 month old LA-SIRT6 +/- mice did not have significant impairments in valve function compared to LA-SIRT6 +/+ mice. In contrast, 12 month old LA-SIRT6 +/- had dramatically worsened aortic valve dysfunction and stenosis compared to LA-SIRT6 +/+ mice, which was also associated with reductions in left ventricular ejection fraction. Collectively, our data strongly suggest SIRT6 plays a critical role in the tonic repression of osteogenic signaling in the aortic valve, and that age-related reductions in SIRT6 are likely to increase susceptibility to valve calcification in response to risk factors for CAVD such as hypercholesterolemia. Collectively, increasing activity of SIRT6 or reducing acetylation of its targets may serve as viable therapeutic strategies to slow progression of age-related valvular calcification and stenosis.

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Role of Ectonucleotidases and Purinergic Receptors in Calcific Aortic Valve Disease

Molecular Biology of Valvular Heart Disease ◽

10.1007/978-1-4471-6350-3_14 ◽

2014 ◽

pp. 117-126

Author(s):

Patrick Mathieu ◽

Ablajan Mahmut ◽

Philippe Pibarot ◽

Yohan Bossé ◽

Marie-Chloé Boulanger

Keyword(s):

Aortic Valve ◽

Aortic Valve Disease ◽

Purinergic Receptors ◽

Valve Disease ◽

Calcific Aortic Valve Disease

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Experimental Evidence for the Role of Atherosclerosis in Calcific Aortic Valve Disease

Cardiac Valvular Medicine ◽

10.1007/978-1-4471-4132-7_4 ◽

2012 ◽

pp. 23-33

Author(s):

Malayannan Subramaniam ◽

Thomas C. Spelsberg ◽

Nalini Marie Rajamannan

Keyword(s):

Aortic Valve ◽

Experimental Evidence ◽

Aortic Valve Disease ◽

Valve Disease ◽

Calcific Aortic Valve Disease

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Lipoprotein (a) in calcific aortic valve disease: from genomics to novel drug target for aortic stenosis

The Journal of Lipid Research ◽

10.1194/jlr.r051870 ◽

2015 ◽

Vol 57 (6) ◽

pp. 917-924 ◽

Cited By ~ 47

Author(s):

George Thanassoulis

Keyword(s):

Aortic Valve ◽

Aortic Stenosis ◽

Drug Target ◽

Aortic Valve Disease ◽

Valve Disease ◽

Calcific Aortic Valve Disease ◽

Lipoprotein A ◽

Novel Drug

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Investigation of the Role of Serum Matrix Gla-Protein as a Biomarker of Calcific Aortic Valve Disease

Journal of Pharmacy and Nutrition Sciences ◽

10.29169/1927-5951.2019.09.03.3 ◽

2019 ◽

Vol 9 (3) ◽

pp. 152-156

Author(s):

Amal Al Nawasreh ◽

Hussam Shebli ◽

Sahar Fahoum

Keyword(s):

Aortic Valve ◽

Aortic Valve Disease ◽

Matrix Gla Protein ◽

Valve Disease ◽

Rapid Screening ◽

Enzyme Linked Immunosorbent Assay ◽

Control Group ◽

Calcific Aortic Valve Disease ◽

Cardiovascular Morbidity And Mortality

Background: Calcific aortic valve disease (CAVD) is a major contributor to cardiovascular morbidity and mortality. Circulating total uncarboxylated Matrix ?-carboxyglutamate (Gla) protein (t-ucMGP) is a promising biomarker for rapid screening of subjects prone to cardiovascular calcification who may need more invasive vascular diagnostics. Preliminary data show that low t-ucMGP levels are indicative for prevalent vascular calcification. Hence, the aim of our study was to investigate the possible role of circulating t-ucMGP as a biomarker may help in identification patients with CAVD, taking into consideration that CAVD is a form of vascular calcification.Methods & Materials: We analyzed serum t-ucMGP levels by enzyme-linked immunosorbent assay (ELISA) in 50 patients with echocardiographically proven CAVD and 21 control subjects.Results: Serum t-ucMGP levels were significantly lower in patients with CAVD (29.29±12.18 nmol/l) compared to the control group (36.84±21.79 nmol/l, p = 0.003).Conclusion: Serum t-ucMGP may help as a noninvasive biomarker for identification of these patients.

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Correlations between lipoprotein(a) gene polymorphisms and calcific aortic valve disease and coronary heart disease in Han Chinese

Journal of International Medical Research ◽

10.1177/0300060520965353 ◽

2020 ◽

Vol 48 (10) ◽

pp. 030006052096535

Author(s):

Hongzhi Dong ◽

Hongliang Cong ◽

Jing Wang ◽

Yiyao Jiang ◽

Chao Liu ◽

...

Keyword(s):

Coronary Heart Disease ◽

Heart Disease ◽

Aortic Valve ◽

Aortic Valve Disease ◽

Density Lipoprotein ◽

Han Chinese ◽

Valve Disease ◽

Calcific Aortic Valve Disease ◽

Lipoprotein A ◽

Minor Alleles

Objective To investigate the relationship between lipoprotein(a) gene ( LPA) polymorphisms and calcific aortic valve disease (CAVD) and coronary heart disease (CHD) in Han Chinese. Methods A total of 148 patients were recruited (n = 71 with CAVD and n = 77 with CHD) based on a diagnosis achieved using color Doppler echocardiography, coronary angiography, or computed tomography angiography. Seventy-one control individuals without CAVD or CHD were also recruited. Biomarkers including levels of lipoprotein(a) [Lp(a)], low-density lipoprotein and high-density lipoprotein cholesterol, apolipoprotein A1, and apolipoprotein B were tested. LPA polymorphisms rs10455872, rs6415084, rs3798221, and rs7770628 were analyzed using SNaPshot SNP. Results Lp(a) levels were significantly higher in CAVD and CHD groups compared with controls. There was no significant difference in the allelic frequency distribution of rs3798221, rs7770628, or rs6415084 between CHD, CAVD, and control groups. Linear regression showed that rs3798221, rs7770628, and rs6415084 were associated with increased Lp(a) concentrations. Two CAVD patients among the 219 participants carried AG minor alleles at rs10455872, while the remainder carried AA minor alleles. Conclusion rs3798221, rs6415084, and rs7770628 polymorphisms within LPA are associated with higher Lp(a) plasma levels, which correlate with increased CAVD and CHD risks.

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Evaluation of Lipoprotein(a) Electrophoretic and Immunoassay Methods in Discriminating Risk of Calcific Aortic Valve Disease and Incident Coronary Heart Disease: The Multi-Ethnic Study of Atherosclerosis

Clinical Chemistry ◽

10.1373/clinchem.2016.270751 ◽

2017 ◽

Vol 63 (11) ◽

pp. 1705-1713 ◽

Cited By ~ 8

Author(s):

Jing Cao ◽

Brian T Steffen ◽

Weihua Guan ◽

Matthew Budoff ◽

Erin D Michos ◽

...

Keyword(s):

Coronary Heart Disease ◽

Heart Disease ◽

Aortic Valve ◽

Aortic Valve Disease ◽

Valve Disease ◽

Calcific Aortic Valve Disease ◽

Incident Coronary Heart Disease ◽

Lipoprotein A ◽

Ethnic Study ◽

Lower Limits

Abstract BACKGROUND A number of lipoprotein(a) [Lp(a)] analytical techniques are available that quantify distinct particle components, yet their clinical efficacy has not been comprehensively evaluated. This study determined whether Lp(a) mass [Lp(a)-M], Lp(a) cholesterol content [Lp(a)-C], and particle concentration [Lp(a)-P] differentially discriminated risk of calcific aortic valve disease (CAVD) or incident coronary heart disease (CHD) among 4679 participants of the Multi-Ethnic Study of Atherosclerosis (MESA). METHODS Lp(a)-M, Lp(a)-C, and Lp(a)-P were measured in individuals without clinical evidence of CHD at baseline. Relative risk regression and Cox proportional analysis determined associations between Lp(a) and the presence of CAVD or 12-year risk of CHD, respectively. To control for the relatively high lower limits of quantification for Lp(a)-C and Lp(a)-P assays, the upper 25th and 15th percentiles were selected as analytical cutoff points. RESULTS Regardless of method or analytical cutoff, high Lp(a) concentrations were significantly associated with CAVD and CHD in MESA participants following adjustment for typical cardiovascular risk factors. Stratifying by race/ethnicity rendered most associations nonsignificant after correction for multiple comparisons, but Lp(a) remained associated with CAVD in whites irrespective of method (all P < 0.0001). CONCLUSIONS Associations of Lp(a)-C, Lp(a)-P, and Lp(a)-M with CAVD or incident CHD were similar in this entire MESA sample using a dichotomized statistical approach. However, the high lower limits of quantification and imprecision of the Lp(a)-C and Lp(a)-P assays limited their usefulness in our analyses and would likely do so in research and clinical settings.

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