A novel apoA-I mutation (L178P) leads to endothelial dysfunction, increased arterial wall thickness, and premature coronary artery disease

Hovingh, G. Kees; Brownlie, Alison; Bisoendial, Radjesh J.; Dubé, Marie‐Pierre; Levels, Johannes H.M.; Petersen, Wilma; Dullaart, Robin; Stroes, Erik S.G.; Zwinderman, Aeilko H.; Groot, Eric de; Hayden, Michael R.; Kuivenhoven, Jan Albert; Kastelein, John J.P.

doi:10.1016/j.jacc.2004.06.070

Cited by 125 publications

(95 citation statements)

References 41 publications

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“…Subjects were considered a case if they were between 18 and 70 years of age and if they were heterozygous for the functional p.L202P mutation in APOA1 (c.C643T) ( 19 ) in our lipid clinic. Control subjects were unaffected and unrelated normolipidemic individuals recruited via advertisements.…”

Section: Subjectsmentioning

confidence: 99%

In vivo tissue cholesterol efflux is reduced in carriers of a mutation in APOA1

Holleboom

Jakulj

Franssen

et al. 2013

Journal of Lipid Research

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This article is available online at http://www.jlr.org Supplementary key words reverse cholesterol transport • high density lipoprotein • genetics • fecal sterol excretionEpidemiological studies have demonstrated a strong inverse relationship between plasma high density lipoprotein cholesterol (HDL-c) concentrations and the risk of cardiovascular disease ( 1-4 ). However, the anti-atherogenic properties of HDL could not be substantiated in a recent meta-regression analysis: pharmacological increases in HDL-c did not translate into a decreased cardiovascular disease risk ( 5 ). These fi ndings have emphasized the need for other measures than plasma HDL-c concentrations to assess the atheroprotective properties of HDL. Ideally, such measures should relate directly to the mechanistic pathways that form the basis of the proposed anti-atherogenic effects of HDL in humans ( 3, 6 ).The most frequently studied function of HDL is its role in the reverse transport of cholesterol from peripheral tissues (RCT). RCT has been proposed as the uptake of cholesterol from peripheral cells by nascent HDL particles mainly consisting of lipid-poor apolipoprotein A-I (apoA-I), mediated by lipid transporter molecules such as ATP-binding cassette transporter A1 and G1 (ABCA1 and ABCG1) and scavenger receptor type B-I (SR-BI) and the subsequent Abstract Atheroprotection by high density lipoprotein (HDL) is considered to be mediated through reverse cholesterol transport (RCT) from peripheral tissues. We investigated in vivo cholesterol fl uxes through the RCT pathway in patients with low plasma high density lipoprotein cholesterol (HDL-c) due to mutations in APOA1 . Seven carriers of the L202P mutation in APOA1 (mean HDL-c: 20 ± 19 mg/dl) and seven unaffected controls (mean HDL-c: 54 ± 11 mg/dl, P < 0.0001) received a 20 h infusion of 13 C 2 -cholesterol ( 13 C-C). Enrichment of plasma and erythrocyte free cholesterol and plasma cholesterol esters was measured. With a threecompartment SAAM-II model, tissue cholesterol effl ux (TCE) was calculated. TCE was reduced by 19% in carriers (4.6 ± 0.8 mg/kg/h versus 5.7 ± 0.7 mg/kg/h in controls, P = 0.02). Fecal 13 C recovery and sterol excretion 7 days postinfusion did not differ signifi cantly between carriers and controls: 21.3 ± 20% versus 13.3 ± 6.3% ( P = 0.33), and 2,015 ± 1,431 mg/day versus 1456 ± 404 mg/day ( P = 0.43), respectively. TCE is reduced in carriers of mutations in APOA1 , suggesting that HDL contributes to effl ux of tissue cholesterol in humans. The residual TCE and unaffected fecal sterol excretion in our severely affected carriers suggest, however, that non-HDL pathways contribute to RCT signifi cantly. -Holleboom, A.

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Section: Subjectsmentioning

confidence: 99%

In vivo tissue cholesterol efflux is reduced in carriers of a mutation in APOA1

Holleboom

Jakulj

Franssen

et al. 2013

Journal of Lipid Research

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“…atheroprotection or not. A life-long exposure to 30-60% reductions of HDL-C levels as a consequence of mutations in ABCA1 , APOAI , or LCAT has been reported to be associated with increased cIMT and CVD risk in several family studies (49,(158)(159)(160)(161)(162) but other investigators have not found this (163,164). The APOA1 Milano defect, leading to very low levels of HDL-C, has been associated with a normal cIMT in carriers (165).…”

Section: Cetpmentioning

confidence: 99%

The HDL hypothesis: does high-density lipoprotein protect from atherosclerosis?

Vergeer

Holleboom

Kastelein

et al. 2010

Journal of Lipid Research

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200

122

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This article is available online at http://www.jlr.org the imagination. Because of a general consensus that HDL protects against atherosclerosis, what we shall term the HDL hypothesis, strategies have been developed to raise plasma HDL levels or to improve HDL function. However, it is increasingly questioned whether such interventions will indeed reduce the risk of atherosclerosis. This review summarizes the reported evidence that supports the HDL hypothesis. EPIDEMIOLOGYA low plasma HDL-C concentration is among the strongest, statistically independent risk factors for cardiovascular disease (CVD) (2). In a widely cited meta-analysis of four large studies (total number of individuals studied: 15,252), a 1 mg/dl increase of HDL-C levels was reported to be associated with a 2-3% decreased CVD risk (3). This result provides an epidemiological argument in favor of therapeutically raising HDL-C levels. One may draw parallels with the detrimental consequences of elevated lowdensity lipoprotein cholesterol (LDL-C) levels and blood pressure, which have been successfully controlled through therapy, resulting in signifi cant reductions of cardiovascular mortality and morbidity (4, 5) . It should be noted, however, that the associations between elevated LDL-C and blood pressure and increased CVD risk refl ect causal relationships, whereas such a relation between low HDL-C levels and increased CVD is not undisputed (6, 7). This is related to the fact that HDL-C levels are infl uenced by many different variables that also affect CVD risk: 1 ) Men have on average lower HDL-C levels than women (8). (1) reported that plasma levels of high-density lipoprotein cholesterol (HDL-C) were reduced in patients with coronary artery disease. In 1977, Gordon et al. (2) subsequently showed that low HDL-C is a risk factor for coronary heart disease in the Framingham study. These important fi ndings have given rise to a large number of diverse HDL studies over the last few decades. The numerous different and apparently unrelated beneficial effects that have since been ascribed to HDL appeal to

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“…Various studies have shown a strong correlation between IMT and cardiovascular risk factors [41][42][43] . Over the past decade, several large observational studies have demonstrated that baseline CIMT is an independent predictor of future clinical cardiovascular events [44][45][46][47][48][49][50] .…”

Section: B-mode Ultrasound Carotid Intima-media Thicknessmentioning

confidence: 99%

Métodos por imagem da aterosclerose em estudos de progressão/regressão: marcador substituto ou janela direta para o processo patológico da aterosclerose?

Schoenhagen¹,

Tuzcu²

2008

Arq. Bras. Cardiol.

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SummaryCAD remains a major global cause of morbidity and mortality. Comprehensive drug development programs of novel pharmacological treatment strategies frequently utilize traditional mortality/morbidity endpoints studies and additional surrogate endpoints trials. This parallel approach allows an assessment of efficacy several years in advance of the availability of data from clinical endpoint trials. Several atherosclerosis imaging markers have been introduced into these drug-development strategies, including angiography, carotid ultrasound, IVUS, MRI, and CT. This review will discuss the current status of atherosclerosis imaging as an endpoint in progression/regression trials, with an emphasis on evidence-based data. In addition to a discussion of the results of individual imaging modalities, the emerging data comparing different modalities and approaches are presented.

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A novel apoA-I mutation (L178P) leads to endothelial dysfunction, increased arterial wall thickness, and premature coronary artery disease

Cited by 125 publications

References 41 publications

In vivo tissue cholesterol efflux is reduced in carriers of a mutation in APOA1

In vivo tissue cholesterol efflux is reduced in carriers of a mutation in APOA1

The HDL hypothesis: does high-density lipoprotein protect from atherosclerosis?

Métodos por imagem da aterosclerose em estudos de progressão/regressão: marcador substituto ou janela direta para o processo patológico da aterosclerose?

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