John J.P. Kastelein is Professor of Medicine and Chairman of the Department of Vascular Medicine at the Academic Medical Center (AMC) of the University of Amsterdam, where he holds the Strategic Chair of Genetics of Cardiovascular Disease.

He received his medical degree in Amsterdam in 1980 where he subsequently received specialty training in internal medicine. Then, between 1986 and 1988, he was trained in medical genetics, lipidology and molecular biology at the University of British Columbia under the guidance of Prof. Dr. M.R. Hayden.

Upon his return to the Netherlands, he was awarded a doctorate (cum laude) and in 1989 he founded the Lipid Research Clinic at the Academic Medical Centre in Amsterdam, which is currently serving as a tertiary referral centre for over 5000 patients each year and has become part of the department of Vascular Medicine.

The most important concept in Dr. Kastelein’s research career, developed by him initially at the University of British Columbia and subsequently transformed into practice, is the “extreme genetics” approach. This approach teaches that the study of rare human disorders that are associated with premature coronary disease have broader relevance for the understanding of the etiology of heart disease in general and will yield therapeutic targets that are valid for all patients.

This approach has been very successful in Dr. Kastelein’s hands, insofar that Familial Hypercholesterolemia is now internationally recognized as the paradigm for the relationship between LDL-C and heart disease, a relationship substantiated by at least 50 peer reviewed manuscripts and 10 postdoctoral theses in his curriculum vitae.

The same “extreme genetics” concept was applied to disorders of HDL-C and elevated triglycerides and lead to the discovery of the cholesterol efflux protein ABCA1 and later to gene therapy for lipoprotein lipase deficiency.

Dr. Kastelein is currently a board member of the Heinrich Wieland Preize, one of the most prestigious scientific prizes in Germany for achievements in biochemistry. He is president of the Dutch Atherosclerosis Society (DAS) and chairs the National Scientific Committee on Familial Hypercholesterolemia (EHC). He also is a member of the Royal Dutch Society for Medicine & Physics, the Council for Basic Science of the American Heart Association and the European Atherosclerosis Society. He also is a board member of the International Task Force for CHD Prevention and was recently appointed to the Executive Board of the International Atherosclerosis Society (IAS).

Professor Kastelein was also one of the founders of Amsterdam Molecular Therapeutics Inc. (AMT), a gene therapy company based on the concept of gene replacement in hereditary lipoprotein disorders. In the summer of 2007, AMT enjoyed a successful Initial Public Offering (IPO) at EuroNext in Amsterdam. The results of the first successful human gene therapy trial were widely publicized in the media and are currently under review by Nature Medicine.

Professor Kastelein’s current research interests can be found in the etiology, diagnosis, prevention and treatment of hypertriglyceridaemia, hypercholesterolaemia and low HDL cholesterol, all conditions associated with atherosclerosis and cardiovascular disease.

He has published over 415 research papers in peer reviewed journals, including Nature Genetics, Lancet, New England Journal of Medicine, JAMA and Circulation and has an index of 55.

Dr. Kastelein is a principal investigator of the Bloodomics and CardioGenics consortia, two large European Union supported endeavors under the Framework Programme 7, that aim to elucidate the molecular basis of atherosclerosis and premature coronary disease.

Besides the scientific programmes aimed at the etiology of atherogenesis, Dr. Kastelein also serves on a number of executive and steering committees of large intervention studies, including the IDEAL, TNT, CAPTIVATE, ENHANCE, ILLUMINATE, RADIANCE and numerous others of which TNT (2005) and RADIANCE 1 (2007) are published in the New England Journal of Medicine, IDEAL (2006) in JAMA and RADIANCE 2 (2007) in Lancet.

Recently Dr. Kastelein has developed the use of non-invasive B-mode ultrasound studies of the carotid arteries for the diagnosis and assessment of novel treatments for atherosclerosis. This has lead to the recognition of the AMC as the world-wide leading center for this technique, which has recently been exported to a substantial number of academic sites throughout Europe. This has culminated in the set up of the Network of Imaging Centers in Europe (NICE), which Dr. Kastelein directs. Dr. Kastelein’s achievements in this field are internationally recognized by numerous invited reviews on this subject, of which the latest will appear shortly in Nature Clinical Practice.

He has directed 30 postdoctoral theses and currently he heads a team of 6 internists, 6 postdoctoral fellows, 21 MD PhD students, and a large number of laboratory technicians and clinical trial / study coordinators.

Dr. Kastelein’s position in the AMC and the department of Vascular Medicine allows him to devote the majority of his time to science and in particular to scientific guidance of his large number of PhD students. Most of these young scientists are destined to become medical specialists in an academic environment and carry the torch of scientific research with a focus on human clinical relevance. But some have chosen other paths: Dr. Ir. Joep Defesche is director of the DNA diagnostics laboratory at the AMC in Amsterdam; Dr. Simon Pimstone is CEO of Xenon Pharmaceuticals Inc., Dr. Bert Wiegman is medical director of the AMC, Dr. Emily van Aalst is finishing her training as an internist at John Hopkins Medical School in Baltimore (USA), Dr. Kees Hovingh currently holds the position of visiting scientist at Dr. Seidmans laboratory at Harvard Medical School in Boston (USA), and Dr. Singaraja is a senior scientist at the Centre of Molecular Medicine at the University of British Columbia, Canada.

Dr. Kastelein’s current and most important asset is the collection of families with hereditary disorders of lipoprotein metabolism. This family database currently holds over 5000 individuals. Since these individuals exhibit a distinct phenotype—most often an abnormal lipoprotein profile in conjunction with coronary artery disease—the culprit gene is of physiological relevance in a human disease pathway and, in fact, begs cloning. Again, the “extreme genetics” approach will be applied to these kindreds and will undoubtedly lead to the elucidation of novel genes and novel pathways into atherogenesis. However, this is a daunting task, requiring personnel active in the field to identify and track family members for linkage studies and a large infrastructure for SNP analysis, large scale sequencing, in-vitro and rodent studies and human validation studies. Much of these resources are available to Dr. Kastelein either at AMC itself or through one of the many collaborators in Europe or the US.

Why Have HDL Raising Drugs Failed to Demonstrate Improved Patient Outcomes?

Monday, March 17, 2008
9:00 PM

Download Dr. Kastelein’s complete slide set [3.91 MB PPT].

Torcetrapib, an inhibitor of cholesteryl ester transfer protein (CETP), has been shown to increase cardiovascular event rate in spite of conferring a significant high-density lipoprotein cholesterol (HDL-C) increase. Using data from both RADIANCE trials, assessing the impact of torcetrapib on carotid intima-media thickness (cIMT), we aimed to explore potential mechanisms underlying this adverse outcome.

Methods and Results
We pooled data from the RADIANCE 1 & 2 studies, which examined cIMT in 904 subjects with familial hypercholesterolemia and in 752 subjects with mixed dyslipidemia. Subjects were randomized to either atorvastatin monotherapy (A) or torcetrapib combined with atorvastatin (T/A). Mean common cIMT progression was more pronounced in subjects receiving T/A than in those receiving A (0.0076 ± 0.0011 vs. 0.0025 ± 0.0011 mm/year; p=0.0014). Subjects treated with T/A had higher post-randomization systolic blood pressure (SBP; 122.7 vs. 119.3 mmHg; p<0.0001), plasma sodium (140.4 vs. 139.9 mEq/dL; p<0.0001) and bicarbonate levels (25.1 vs. 24.9 mEq/dL; p=0.016), in conjunction with lower potassium levels (4.17 vs. 4.26 mEq/dL, p<0.0001) compared to subjects receiving A only. These electrolyte changes were associated with both blood pressure increases and cardiovascular events. Markedly, the use of renin-angiotensin-aldosterone-system (RAAS) inhibitors tended to aggravate blood pressure increase. As expected, low-density lipoprotein cholesterol (LDL-C) reduction remained associated with decreased cIMT progression, whereas SBP increase predicted increased cIMT progression in the T/A arm. In contrast, HDL-C increase was not associated with cIMT change.

Conclusions
These analyses provide evidence in support of off-target toxicity, relating to mineralocorticoid excess, which might have contributed to the adverse outcome of torcetrapib use. The absence of an inverse relationship between HDL-C change and cIMT progression suggests that torcetrapib-induced HDL-C increase did not mediate atheroprotection. Future studies with CETP inhibitors that are structurally different from torcetrapib should settle this issue.