Overexpression of tissue-nonspecific alkaline phosphatase (TNAP) in endothelial cells accelerates coronary artery disease in a mouse model of familial hypercholesterolemia

Objective: Vascular calcification in asymptomatic individuals is an independent predictor of coronary heart disease (CHD). It is therefore plausible that vascular calcification plays a direct pathophysiological role in atherosclerosis, an underlying cause of CHD. The purpose of this study was to examine the contribution that vascular calcification has on the development of coronary atherosclerosis in a mouse model of familial hypercholesterolemia. Approach and Results: Calcification was induced by overexpression of tissue-nonspecific alkaline phosphatase (TNAP) in endothelial cells of mice harboring a point mutation in the low density lipoprotein receptor ( ldlr, wicked high cholesterol, WHC). Mice were fed an atherogenic diet; echocardiographic and biochemical data were collected longitudinally. Atherosclerosis and vascular calcification were analyzed histologically in the aorta, aortic sinus and coronary arteries. TNAP mice were also treated with a combination of an atherogenic diet and a specific inhibitor of TNAP (SBI-425). Combined with the ldlr mutation and an atherogenic diet, TNAP-driven arterial calcification led to severe atherosclerosis with 100% morbidity characterized by occlusive coronary artery disease, pathological cardiac hypertrophy with dilated LV and reduced ejection fraction (EF). We detected an interaction between vascular calcification and atherosclerosis in mice with endothelial TNAP overexpression. This interaction was particularly prominent in coronary circulation. Targeting TNAP activity therapeutically helped improve survival and heart function of endothelial TNAP overexpressor mice, however the incomplete inhibition of TNAP by SBI-425 was a limitation of this study. Conclusions: Vascular calcification via TNAP overexpression in endothelial cells promotes coronary atherosclerosis and is pathogenic under conditions of hypercholesterolemia.

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GENETICALLY CONFIRMED FAMILIAL HYPERCHOLESTEROLEMIA IN PATIENTS WITH PREMATURE CORONARY ARTERY DISEASE

Canadian Journal of Cardiology ◽

10.1016/j.cjca.2020.07.055 ◽

2020 ◽

Vol 36 (10) ◽

pp. S19

Author(s):

D. Vikulova ◽

M. Trinder ◽

C. Brown ◽

L. Jackson ◽

S. Pimstone ◽

...

Keyword(s):

Coronary Artery Disease ◽

Coronary Artery ◽

Familial Hypercholesterolemia ◽

Premature Coronary Artery Disease ◽

Artery Disease

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Ezetimibe Completely Replaced LDL-Apheresis for the Treatment of Familial Hypercholesterolemia and Coronary Artery Disease after CABG—A Case Report

Journal of Biomedical Science and Engineering ◽

10.4236/jbise.2013.62a028 ◽

2013 ◽

Vol 06 (02) ◽

pp. 232-235

Author(s):

Ikuo Yokoyama

Keyword(s):

Coronary Artery Disease ◽

Case Report ◽

Coronary Artery ◽

Familial Hypercholesterolemia ◽

Ldl Apheresis ◽

Artery Disease

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A case of familial hypercholesterolemia with premature coronary artery disease

Heart India ◽

10.4103/heartindia.heartindia_27_18 ◽

2018 ◽

Vol 6 (4) ◽

pp. 156

Author(s):

DigvijayDeeliprao Nalawade ◽

JaywantM Nawale ◽

AjayS Chaurasia ◽

Dhirendra Tiwari

Keyword(s):

Coronary Artery Disease ◽

Coronary Artery ◽

Familial Hypercholesterolemia ◽

Premature Coronary Artery Disease ◽

Artery Disease

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Circulating endothelial cells in coronary artery disease and acute coronary syndrome

Trends in Cardiovascular Medicine ◽

10.1016/j.tcm.2015.01.013 ◽

2015 ◽

Vol 25 (7) ◽

pp. 578-587 ◽

Cited By ~ 22

Author(s):

David E. Schmidt ◽

Marco Manca ◽

Imo E. Hoefer

Keyword(s):

Coronary Artery Disease ◽

Endothelial Cells ◽

Acute Coronary Syndrome ◽

Coronary Artery ◽

Circulating Endothelial Cells ◽

Coronary Syndrome ◽

Artery Disease

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Abstract 18995: Statins in Familial Hypercholesterolemia - Effects on Coronary Artery Disease and All-cause Mortality

Circulation ◽

10.1161/circ.132.suppl_3.18995 ◽

2015 ◽

Vol 132 (suppl_3) ◽

Author(s):

Joost Besseling ◽

Gerard K Hovingh ◽

John J Kastelein ◽

Barbara A Hutten

Keyword(s):

Coronary Artery Disease ◽

Coronary Artery ◽

Familial Hypercholesterolemia ◽

Lipid Lowering ◽

Premature Coronary Artery Disease ◽

Lipid Lowering Therapy ◽

Time Varying ◽

All Cause Mortality ◽

Artery Disease

Introduction: Heterozygous familial hypercholesterolemia (heFH) is characterized by high levels of low-density lipoprotein cholesterol (LDL-C) and increased risk for premature coronary artery disease (CAD) and death. Reduction of CAD and mortality by statins has not been properly quantified in heFH. The aim of the current study is to determine the effect of statins on CAD and mortality in heFH. Methods: All adult heFH patients identified by the Dutch FH screening program between 1994 and 2014 and registered in the PHARMO Database Network were eligible. Of these patients we obtained hospital, pharmacy (in- and outpatient), and mortality records in the period between 1995 and 2015. The effect of statins (time-varying) on CAD and all-cause mortality was determined using a Cox proportional hazard model, while correcting for the use of other lipid-lowering therapy, thrombocyte aggregation inhibitors, antihypertensive and antidiabetic medication (all time-varying). Furthermore, we used inverse probability for treatment weighting (IPTW) to account for differences between statin-treated and untreated patients regarding history of CAD before follow-up, age at start of follow-up and age of screening, as well as body mass index, LDL-C and triglycerides. Results: Of the 25,479 identified heFH patients, 11,021 gave informed consent to obtain their medical records, of whom 2,447 could be retrieved. We excluded 766 patients younger than 18. The remaining 1,681 heFH patients comprised our study population and these had very similar characteristics as compared to the 23,798 excluded FH patients, e.g. mean (SD) LDL-C levels were 214 (74) vs. 203 (77) mg/dL. Among 1,151 statin users, there were 133 CAD events and 15 deaths during 10,115 statin treated person-years, compared to 17 CAD events and 9 deaths during 4,965 person-years in 530 never statin users (combined rate: 14.6 vs. 5.2, respectively, p<0.001). After applying IPTW to account for indication bias and correcting for use of other medications, the hazard ratio of statin use for CAD and all-cause mortality was 0.61 (0.40 - 0.93). Conclusions: In heFH patients, statins lower the risk for CAD and mortality by 39%.

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Abstract P431: ASSOCIATION OF LIPOPROTEIN(A) WITH CARDIOVASCULAR EVENTS IN YOUNG NON-FAMILIAL HYPERCHOLESTEROLEMIA

Circulation ◽

10.1161/circ.141.suppl_1.p431 ◽

2020 ◽

Vol 141 (Suppl_1) ◽

Author(s):

Pao-Hsien Chu

Keyword(s):

Cardiovascular Disease ◽

Coronary Artery Disease ◽

Coronary Artery ◽

Fatty Liver ◽

Familial Hypercholesterolemia ◽

Cardiovascular Events ◽

Healthy Population ◽

Lipoprotein A ◽

A Value ◽

Artery Disease

Background and aims: Elevated lipoprotein(a) is an independent risk factor for atherosclerotic cardiovascular disease especially in familial hypercholesterolemia. The association of elevated lipoprotein(a) within non-familial hypercholesterolemia or healthy population however, is not known. Therefore, we investigated the associations between elevated lipoprotein(a) and the risk of cardiovascular disease in a non-familial hypercholesterolemia clinically healthy young age cohort. Methods: In this retrospective cohort study, we reviewed medical records of 3,427 participants with lipoprotein(a) levels from a tertiary healthcare center in Taiwan. We further classified lipoprotein(a) level into four groups and analyzed cardiovascular events. Results: Our study population had a mean age 46 years old that were 78% male. Mean total cholesterol and low-density lipoprotein level were 195 mg/dL and 118 mg/dL respectively. Overall, 12.9% of the participants had an elevated lipoprotein(a) level (>30 mg/dL), and 2.7% had a very high level (>70 mg/dL). Thirty-three events including 6 participants with stroke and 27 with coronary artery disease were identified. A lipoprotein(a) level >70 mg/dL was associated with a higher risk of coronary artery disease events in Kaplan-Meier analysis. Aging was associated with a higher lipoprotein(a) value in the male participants but not in the female participants. However, the severity of fatty liver was not positively associated with lipoprotein(a) value. Conclusions: Elevated lipoprotein(a) was associated with coronary events but not the severity of fatty liver disease in non-familial hypercholesterolemia clinically healthy population. Aging may be associated with a higher lipoprotein(a) level in males but not females.

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