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Coronary Artery Disease: HELP
Articles by Joep C. Defesche
Based on 6 articles published since 2010
(Why 6 articles?)

Between 2010 and 2020, Joep Defesche wrote the following 6 articles about Coronary Artery Disease.
+ Citations + Abstracts
1 Review Familial hypercholesterolaemia. 2017

Defesche, Joep C / Gidding, Samuel S / Harada-Shiba, Mariko / Hegele, Robert A / Santos, Raul D / Wierzbicki, Anthony S. ·Department of Clinical Genetics, Academic Medical Centre, PO Box 22 660, University of Amsterdam, 1100 DD Amsterdam, The Netherlands. · Nemours Cardiac Center, Alfred I. DuPont Hospital for Children, Wilmington, Delaware, USA. · Department of Molecular Innovation in Lipidology, National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka, Japan. · Department of Medicine, Schulich School of Medicine and Dentistry, London, Ontario, Canada. · Robarts Research Institute, 4288A 1151 Richmond Street North, University of Western Ontario, N6A 5B7 London, Ontario, Canada. · Lipid Clinic Heart Institute (Incor), University of São Paulo, Medical School Hospital, São Paulo, Brazil. · Preventive Medicine Centre and Cardiology Program Hospital Israelita Albert Einstein, São Paulo, Brazil. · Metabolic Medicine and Chemical Pathology, Guy's and St. Thomas' Hospitals, London, UK. ·Nat Rev Dis Primers · Pubmed #29219151.

ABSTRACT: Familial hypercholesterolaemia is a common inherited disorder characterized by abnormally elevated serum levels of low-density lipoprotein (LDL) cholesterol from birth, which in time can lead to cardiovascular disease (CVD). Most cases are caused by autosomal dominant mutations in LDLR, which encodes the LDL receptor, although mutations in other genes coding for proteins involved in cholesterol metabolism or LDLR function and processing, such as APOB and PCSK9, can also be causative, although less frequently. Several sets of diagnostic criteria for familial hypercholesterolaemia are available; common diagnostic features are an elevated LDL cholesterol level and a family history of hypercholesterolaemia or (premature) CVD. DNA-based methods to identify the underlying genetic defect are desirable but not essential for diagnosis. Cascade screening can contribute to early diagnosis of the disease in family members of an affected individual, which is crucial because familial hypercholesterolaemia can be asymptomatic for decades. Clinical severity depends on the nature of the gene that harbours the causative mutation, among other factors, and is further modulated by the type of mutation. Lifelong LDL cholesterol-lowering treatment substantially improves CVD-free survival and longevity. Statins are the first-line therapy, but additional drugs, such as ezetimibe, bile acid sequestrants, PCSK9 inhibitors and other emerging therapies, are often required.

2 Article Ten years of lipoprotein apheresis for familial hypercholesterolemia in Malaysia: A creative approach by a cardiologist in a developing country. 2016

Khoo, Kah Lin / Page, Michael M / Liew, Yin Mei / Defesche, Joep C / Watts, Gerald F. ·Klinik Dr Khoo Kah Lin, Kuala Lumpur, Malaysia; Cardiology Department, Sentosa Medical Centre, Kuala Lumpur, Malaysia. · Lipid Disorders Clinic, Department of Cardiology, Royal Perth Hospital, Perth, Western Australia, Australia; Department of Clinical Biochemistry, PathWest Laboratory Medicine, Fiona Stanley Hospital, Murdoch, Australia. · Klinik Dr Khoo Kah Lin, Kuala Lumpur, Malaysia. · Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. · Lipid Disorders Clinic, Department of Cardiology, Royal Perth Hospital, Perth, Western Australia, Australia; School of Medicine and Pharmacology, University of Western Australia, Perth, Western Australia, Australia. Electronic address: gerald.watts@uwa.edu.au. ·J Clin Lipidol · Pubmed #27678436.

ABSTRACT: BACKGROUND: Familial hypercholesterolemia (FH) leads to premature coronary artery disease and aortic stenosis, with undertreated severe forms causing death at a young age. Lipoprotein apheresis (LA) is often required for lowering low-density lipoprotein cholesterol levels in severe FH. OBJECTIVES: The objective of this study was to present the first experiences with LA in Malaysia, between 2004 and 2014. METHODS: We retrospectively collected data from patient records to assess the effectiveness, adverse effects, patient quality of life, and costs associated with an LA service for genetically confirmed homozygous and heterozygous FH. RESULTS: We treated 13 women and 2 men aged 6 to 59 years, 10 with homozygous and 5 with heterozygous FH, all on maximally tolerated cholesterol-lowering drug therapy, for a total of 65 patient-years. Acute lowering of low-density lipoprotein cholesterol post apheresis was 56.3 ± 7.2%, with time-averaged mean lowering of 34.9 ± 13.9%. No patients experienced any cardiovascular events during the period of receiving LA. Patients receiving LA experienced few side effects and enjoyed reasonable quality of life, but inability to continue treatment was frequent because of cost. CONCLUSION: LA for severe FH can be delivered effectively in the short term in developing nations, but costs are a major barrier to sustaining this mode of treatment for this high-risk group of patients. New drug therapies for FH, such as the proprotein convertase subtilisin/kexin type 9 inhibitors, microsomal triglyceride transfer protein inhibitors, and apolipoprotein-B100 antisense oligonucleotides may allow improved care for these patients, but costs and long-term safety remain as issues to be addressed.

3 Article Characterization of Autosomal Dominant Hypercholesterolemia Caused by PCSK9 Gain of Function Mutations and Its Specific Treatment With Alirocumab, a PCSK9 Monoclonal Antibody. 2015

Hopkins, Paul N / Defesche, Joep / Fouchier, Sigrid W / Bruckert, Eric / Luc, Gérald / Cariou, Bertrand / Sjouke, Barbara / Leren, Trond P / Harada-Shiba, Mariko / Mabuchi, Hiroshi / Rabès, Jean-Pierre / Carrié, Alain / van Heyningen, Charles / Carreau, Valérie / Farnier, Michel / Teoh, Yee P / Bourbon, Mafalda / Kawashiri, Masa-Aki / Nohara, Atsushi / Soran, Handrean / Marais, A David / Tada, Hayato / Abifadel, Marianne / Boileau, Catherine / Chanu, Bernard / Katsuda, Shoji / Kishimoto, Ichiro / Lambert, Gilles / Makino, Hisashi / Miyamoto, Yoshihiro / Pichelin, Matthieu / Yagi, Kunimasa / Yamagishi, Masakazu / Zair, Yassine / Mellis, Scott / Yancopoulos, George D / Stahl, Neil / Mendoza, Johanna / Du, Yunling / Hamon, Sara / Krempf, Michel / Swergold, Gary D. · ·Circ Cardiovasc Genet · Pubmed #26374825.

ABSTRACT: BACKGROUND: Patients with PCSK9 gene gain of function (GOF) mutations have a rare form of autosomal dominant hypercholesterolemia. However, data examining their clinical characteristics and geographic distribution are lacking. Furthermore, no randomized treatment study in this population has been reported. METHODS AND RESULTS: We compiled clinical characteristics of PCSK9 GOF mutation carriers in a multinational retrospective, cross-sectional, observational study. We then performed a randomized placebo-phase, double-blind study of alirocumab 150 mg administered subcutaneously every 2 weeks to 13 patients representing 4 different PCSK9 GOF mutations with low-density lipoprotein cholesterol (LDL-C) ≥70 mg/dL on their current lipid-lowering therapies at baseline. Observational study: among 164 patients, 16 different PCSK9 GOF mutations distributed throughout the gene were associated with varying severity of untreated LDL-C levels. Coronary artery disease was common (33%; average age of onset, 49.4 years), and untreated LDL-C concentrations were higher compared with matched carriers of mutations in the LDLR (n=2126) or apolipoprotein B (n=470) genes. Intervention study: in PCSK9 GOF mutation patients randomly assigned to receive alirocumab, mean percent reduction in LDL-C at 2 weeks was 62.5% (P<0.0001) from baseline, 53.7% compared with placebo-treated PCSK9 GOF mutation patients (P=0.0009; primary end point). After all subjects received 8 weeks of alirocumab treatment, LDL-C was reduced by 73% from baseline (P<0.0001). CONCLUSIONS: PCSK9 GOF mutation carriers have elevated LDL-C levels and are at high risk of premature cardiovascular disease. Alirocumab, a PCSK9 antibody, markedly lowers LDL-C levels and seems to be well tolerated in these patients. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique Identifier: NCT01604824.

4 Article Cardiovascular risk in relation to functionality of sequence variants in the gene coding for the low-density lipoprotein receptor: a study among 29,365 individuals tested for 64 specific low-density lipoprotein-receptor sequence variants. 2012

Huijgen, Roeland / Kindt, Iris / Defesche, Joep C / Kastelein, John J P. ·Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands. r.huijgen@amc.uva.nl ·Eur Heart J · Pubmed #22390909.

ABSTRACT: AIMS: A plethora of mutations in the LDL-receptor gene (LDLR) underlie the clinical phenotype of familial hypercholesterolaemia (FH). For the diagnosis of FH, it is important, however, to discriminate between pathogenic and non-pathogenic mutations. The aim of the current study was to assess whether true pathogenic mutations were indeed associated with the occurrence of coronary artery disease (CAD) when compared with non-functional variants. The latter variants should not exhibit such an association with CAD. METHODS AND RESULTS: We assessed 29 365 individuals tested the 64 most prevalent LDLR variants. First, we determined pathogenicity for each of these sequence variants. Subsequently, a Cox-proportional hazard model was used to compare event-free survival, defined as the period from birth until the first CAD event, between carriers and non-carriers of LDLR mutations. Fifty-four sequence variants in the LDLR gene were labelled as pathogenic and 10 as non-pathogenic. The 9 912 carriers of a pathogenic LDLR mutation had a shorter event-free survival than the 18 393 relatives who did not carry that mutation; hazard ratio 3.64 [95% confidence interval (CI): 3.24-4.08; P< 0.001]. In contrast, the 355 carriers of a non-pathogenic LDLR variant had similar event-free survival as the 705 non-carrying relatives; hazard ratio 1.00 (95% CI: 0.52-1.94; P= 0.999). CONCLUSION: These findings with respect to clinical outcomes substantiate our criteria for functionality of LDLR sequence variants. They also confirm the CAD risk associated with FH and underline that these criteria can be used to decide whether a specific sequence variant should be used in cascade screening.

5 Article Apolipoprotein isoform E4 does not increase coronary heart disease risk in carriers of low-density lipoprotein receptor mutations. 2011

Versmissen, Jorie / Oosterveer, Daniëlla M / Hoekstra, Menno / Out, Ruud / Berbée, Jimmy F P / Blommesteijn-Touw, Adriana C / van Vark-van der Zee, Leonie / Vongpromek, Ranitha / Vanmierlo, Tim / Defesche, Joep C / Mulder, Monique / Kastelein, John J P / Sijbrands, Eric J G. ·Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands. ·Circ Cardiovasc Genet · Pubmed #22010136.

ABSTRACT: BACKGROUND: In humans, the E4 allele of the apolipoprotein E gene is associated with increased coronary heart disease risk. Surprisingly, in rodents, apolipoprotein E4 only accelerates the atherosclerotic process when transgenic for the human low-density lipoprotein receptor (LDLR) protein. We therefore investigated whether the LDLR locus interacted with the apolipoprotein E gene genotype on coronary heart disease risk in patients clinically diagnosed with familial hypercholesterolemia with and without LDLR mutation. We investigated whether the presence of an LDLR mutation diminishing LDLR function was protective in E4/E4 carriers. METHODS AND RESULTS: In a cohort of 2400 patients clinically diagnosed with familial hypercholesterolemia, we found an LDLR gene mutation in 1383 patients, whereas in 1013 patients, such mutation was not present. In 92 patients homozygous for the apolipoprotein E4, the presence of an LDLR mutation conferred lower coronary heart disease risk (hazard ratio, 0.16; 95% CI, 0.05-0.58; P=0.005). Mirroring these results, the apolipoprotein E4/E4 genotype was also associated with lower coronary heart disease risk in patients with familial hypercholesterolemia with an LDLR mutation (hazard ratio, 0.26; hazard ratio, 0.08-0.80; P=0.02). CONCLUSIONS: LDLR function is key to the detrimental effects of apolipoprotein E4 in humans. Kinetic studies in humans are now required to study the consequences of our observation for prevention of both coronary heart disease and Alzheimer disease.

6 Article Mannose binding lectin 2 haplotypes do not affect the progression of coronary atherosclerosis in men with proven coronary artery disease treated with pravastatin. 2011

Alipour, Arash / Cabezas, Manuel Castro / Elte, Jan Willem F / Vallvé, Joan-Carles / Ribalta, Josep / Zwinderman, Aeilko H / Defesche, Joep C / Jukema, J Wouter. ·Department of Internal Medicine, St. Franciscus Gasthuis Rotterdam, The Netherlands. ·Atherosclerosis · Pubmed #21211797.

ABSTRACT: OBJECTIVE: Mannose binding lectin (MBL) is one of the three initiators of complement activation. Polymorphisms of the MBL2 gene and its promoter, and especially haplotypes, determine MBL plasma levels. MBL deficiency has been associated with the development of atherosclerosis. We evaluated whether the rate of angiographic progression of coronary atherosclerosis during pravastatin treatment was associated with MBL2 haplotypes in REGRESS, a placebo-controlled 2 years intervention study. METHODS: Three polymorphic sites in exon 1 (rs1800450, rs1800451 and rs5030737) of the MBL2 gene and 2 sites (rs7096206 and rs11003125) in the promoter region were genotyped in 398 subjects. Genotyping was performed using Applied Biosystems® TaqMan® Genotyping Assays. We divided the group in high, intermediate and low MBL2 secretor haplotypes. Quantitative coronary angiography was performed. Endpoints were mean segment diameter (MSD) and minimum obstruction diameter (MOD) established by quantitative coronary angiography. RESULTS: At inclusion, 50.1, 31.7 and 17.6% of the patients in the REGRESS cohort carried the high, intermediate and low MBL2 secretor haplotypes, respectively. In 0.6% of the patients, the haplotype was not informative. There were no baseline differences between the MBL2 haplotypes for age, BMI, lipid levels, leukocyte counts, CRP, MSD and MOD. The intermediate MBL2 placebo group showed the greatest increase in MSD compared to the low MBL2 group (P=0.03). No difference was found for the change in MOD. No significant interaction between MBL2 haplotype groups and pravastatin therapy was observed. CONCLUSION: In men with proven coronary artery disease, MBL2 secretor haplotypes are not associated to the rate of progression of coronary sclerosis nor does pravastatin treatment influence progression based on MBL2 haplotypes.