G. Kees Hovingh

Publications (73) View all

• Article: Genetics of HDL-C: A Causal Link to Atherosclerosis?

  Julian C van Capelleveen, Andrea E Bochem, M Mahdi Motazacker, G Kees Hovingh, John J P Kastelein
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  ABSTRACT: Prospective epidemiological studies have consistently reported an inverse association between HDL cholesterol (HDL-C) levels and the risk of cardiovascular disease (CVD). However, large intervention trials on HDL-C-increasing drugs and recent Mendelian randomization studies have questioned a causal relationship between HDL-C and atherosclerosis. HDL-C levels have been shown to be highly heritable, and the combination of HDL-C-associated SNPs in recent large-scale genome-wide association studies (GWAS) only explains a small proportion of this heritability. As a large part of our current understanding of HDL metabolism comes from genetic studies, further insights in this research field may aid us in elucidating HDL functionality in relation to CVD risk. In this review we focus on the question of whether genetically defined HDL-C levels are associated with risk of atherosclerosis. We also discuss the latest insights for HDL-C-associated genes and recent GWAS data.
  Current Atherosclerosis Reports 06/2013; 15(6):326. · 2.66 Impact Factor
• Article: In vivo tissue cholesterol efflux is reduced in carriers of a mutation in APOA1.

  Adriaan G Holleboom, Lily Jakulj, Remco Franssen, Julie Decaris, Menno Vergeer, Joris Koetsveld, Jayraz Luchoomun, Alexander Glass, Mark K Hellerstein, John J P Kastelein, G Kees Hovingh, Jan Albert Kuivenhoven, Albert K Groen, Scott M Turner, Erik S G Stroes
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  ABSTRACT: Background. Atheroprotection by high density lipoprotein (HDL) is considered to be mediated through reverse cholesterol transport (RCT) from peripheral tissues. We investigated in vivo cholesterol fluxes through the RCT pathway in patients with low plasma HDL-c due to mutations in APOA1. Methods and results. Seven carriers of the L202P mutation in APOA1 (mean HDL-c: 20 mg/dl (SD 19)) and seven unaffected controls (mean HDL-c: 54 mg/dl (SD 11), p<0.0001) received a 20-hour infusion of 13C2-cholesterol (13C-C). Enrichment of plasma and erythrocyte free cholesterol and plasma cholesterol esters was measured. With a 3-compartment SAAM-II model, tissue cholesterol efflux (TCE) was calculated. TCE was reduced by 19% in carriers (4.6 mg/kg/hr (SD 0.8) versus 5.7 mg/kg/hr (SD 0.7) in controls, p = 0.02) and associated with plasma HDL-c (beta for linear regression: 0.53, p = 0.05). Fecal 13C recovery and sterol excretion 7 days post-infusion did not differ significantly between carriers and controls: 21.3% (SD 20%) versus 13.3% (SD 6.3%) (p=0.33), and 2015 mg/day (SD 1431) versus 1456 mg/day (SD 404) (p=0.43), respectively. Conclusion. TCE is reduced in carriers of mutations in APOA1, suggesting that HDL contributes to efflux 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 significantly.
  The Journal of Lipid Research 05/2013; · 5.56 Impact Factor
• Article: High-density lipoprotein as a source of cholesterol for adrenal steroidogenesis; a study in individuals with low plasmsa HDL-C.

  Andrea E Bochem, Adriaan G Holleboom, Johannes A Romijn, Menno Hoekstra, Geesje M Dallinga-Thie, Mahdi M Motazacker, G Kees Hovingh, Jan A Kuivenhoven, Erik S G Stroes
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  ABSTRACT: Few studies have addressed the delivery of lipoprotein derived cholesterol to the adrenals for steroid production in humans. While there is evidence against a role for low-density lipoprotein (LDL) it is unresolved whether high-density lipoprotein (HDL) contributes to adrenal steroidogenesis. To study this, steroid hormone profiles in urine were assessed in male subjects suffering from functional mutations in ATP-binding cassette transporter A1 (ABCA1; n=24), lecithin cholesterol:acyltransferase (LCAT; n=40) as well as in 11 subjects with low HDL-C without ABCA1/LCAT mutations. HDL-C levels were 39% lower in the ABCA1, LCAT and low HDL-C group, compared to controls (all p<0.001). In all groups with low HDL-C levels, urinary excretion of 17-ketogenic steroids was reduced by 33%, 27% and 32% compared to controls (all p<0.04). In 7 carriers of either type of mutation, ACTH stimulation did not reveal differences from normolipidemic controls. In conclusion, this study shows that basal but not stimulated corticosteroid metabolism is attenuated in subjects with low HDL-C, irrespective of its molecular origin. These findings lend support to a role for HDL as cholesterol donor for basal adrenal steroidogenesis in humans.
  The Journal of Lipid Research 03/2013; · 5.56 Impact Factor
• Article: LDL Cholesterol Goals in High-Risk Patients: How Low Do We Go and How Do We Get There?

  Joost Besseling, Julian van Capelleveen, John J P Kastelein, G Kees Hovingh
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  ABSTRACT: It is widely recognised that low-density lipoprotein cholesterol (LDL-C) is one of the most important and modifiable risk factors for cardiovascular disease (CVD). Statins (HMG-CoA reductase inhibitors) have consistently been shown to decrease both LDL-C and CVD risk in almost all patient categories, with the exception of heart and kidney failure as well as advanced aortic stenosis. As a consequence, statins have become the cornerstone in current prevention guidelines. In patients who do not reach the LDL-C target, combination therapy with additional LDL-C lowering drugs (e.g. ezetimibe, bile acid sequestrants or fibrates) should be considered. Guidelines provide different LDL-C levels to strive for, depending on the CVD risk. In this review, we describe the rationale for these LDL-C targets and how these goals might be reached by current and future therapies.
  Drugs 03/2013; · 4.23 Impact Factor
• Article: Diagnosis and treatment of familial hypercholesterolaemia.

  G Kees Hovingh, Michael H Davidson, John J P Kastelein, Anne M O'Connor
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  ABSTRACT: Familial hypercholesterolaemia (FH) is an autosomal dominant genetic disorder, associated with elevated levels of low-density lipoprotein-cholesterol (LDL-C), which can lead to premature cardiovascular disease. Early diagnosis of FH is important to prevent morbidity and mortality. Familial hypercholesterolaemia is usually diagnosed using clinical characteristics, such as family history, and cholesterol levels; however, genetic testing may provide a definite diagnosis of FH by detecting a pathological mutation. Current guidelines highlight the importance of reducing LDL-C levels in patients with FH. Statins are the current standard treatment for the majority of these patients, and have been shown to be effective in reducing the incidence of cardiovascular heart disease in patients with FH. Nevertheless, many FH patients do not achieve their target LDL-C levels; as such, new treatment options are required to decrease LDL-C levels beyond those currently achieved. There are currently several new classes of pharmacotherapy under investigation to control LDL-C levels. These include agents which modify LDL-C production, such as inhibitors of apolipoprotein B, or those which affect LDL-C catabolism, such as inhibition of pro-protein convertase subtilisin/kexin 9, a protein which is responsible for the degradation of the LDL receptor. Therapies which raise high-density lipoprotein cholesterol are also being evaluated. In this article, we consider the diagnosis of FH and the goals of therapy and review the current and potential future treatment options for patients with FH.
  European Heart Journal 02/2013; · 10.48 Impact Factor