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Articles by John J.P. Kastelein
Total Records ( 3 ) for John J.P. Kastelein
  Sung Kee Ryu , Barbara A. Hutten , Maud N. Vissers , Albert Wiegman , John J.P. Kastelein and Sotirios Tsimikas
 

Background

Lipoprotein-associated phospholipase A2 (Lp-PLA2) is an independent risk factor of cardiovascular disease and a target of treatment. Lp-PLA2 levels in children have not been previously reported. The effect of statin therapy on Lp-PLA2 mass and activity in children with familial hypercholesterolemia (FH) is also not known.

Methods

Lp-PLA2 mass and activity levels were measured at baseline and after 2 years in 178 children with FH randomized to pravastatin or placebo and in 78 unaffected and untreated siblings. At the end of the randomized period, all FH children were then placed on pravastatin for an additional 2 years, and Lp-PLA2 mass and activity levels were correlated with changes in carotid intima-media thickness during 4 years of follow-up.

Results

Baseline levels of Lp-PLA2 mass and activity were significantly greater in children with FH compared with unaffected siblings (mass: 240.3 ± 41.6 vs 222.1 ± 36.5 ng/mL, P = .002; activity: 205.7 ± 41.6 vs 124.3±23.0 nmol/min/mL, P < .0001). In the randomized FH cohort, after 2 years treatment, Lp-PLA2 mass (217.8 ± 35.0 vs 231.5 ± 34.8 ng/mL, P = .001) and activity (178.8 ± 37.3 vs 206.2 ± 33.5 nmol/min/mL, P < .0001) were significantly reduced by pravastatin compared with placebo. Change in Lp-PLA2 activity was related to change in low-density lipoprotein cholesterol (pravastatin: r = 0.53, P < .0001, placebo: r = 0.23, P < .001) but change in Lp-PLA2 mass was not related to change in low-density lipoprotein cholesterol. Baseline levels of Lp-PLA2 mass and activity were not significantly associated with carotid intima-media thickness at baseline or at 4 years.

Conclusion

Lp-PLA2 mass and activity are significantly elevated in children with heterozygous FH compared with unaffected siblings and are significantly reduced by pravastatin therapy.

  John J.P. Kastelein , Kevin C. Maki , Andrey Susekov , Marat Ezhov , Borge G. Nordestgaard , Ben N. Machielse , Douglas Kling and Michael H. Davidson
 

Background

Omega-3 fatty acids in free fatty acid form have enhanced bioavailability, and plasma levels are less influenced by food than for ethyl ester forms.

Objective

The aim was to evaluate the safety and lipid-altering efficacy in subjects with severe hypertriglyceridemia of an investigational pharmaceutical omega-3 free fatty acid (OM3-FFA) containing eicosapentaenoic acid and docosahexaenoic acid.

Methods

This was a multinational, double-blind, randomized, out-patient study. Men and women with triglycerides (TGs) ≥500 mg/dL, but <2000 mg/dL, took control (olive oil [OO] 4 g/d; n = 99), OM3-FFA 2 g/d (plus OO 2 g/d; n = 100), OM3-FFA 3 g/d (plus OO 1 g/d; n = 101), or OM3-FFA 4 g/d (n = 99) capsules for 12 weeks in combination with the National Cholesterol Education Program Therapeutic Lifestyle Changes diet.

Results

Fasting serum TGs changed from baseline by −25.9% (P < .01 vs OO), −25.5% (P < .01 vs OO), and −30.9% (P < .001 vs OO) with 2, 3, and 4 g/d OM3-FFA, respectively, compared with −4.3% with OO. Non-high-density lipoprotein cholesterol (non-HDL-C), total cholesterol-to-HDL-C ratio, very low-density lipoprotein cholesterol, remnant-like particle cholesterol, apolipoprotein CIII, lipoprotein-associated phospholipase A2, and arachidonic acid were significantly lowered (P < .05 at each OM3-FFA dosage vs OO); and plasma eicosapentaenoic acid and docosahexaenoic acid were significantly elevated (P < .001 at each OM3-FFA dosage vs OO). With OM3-FFA 2 and 4 g/d (but not 3 g/d), low-density lipoprotein cholesterol was significantly increased compared with OO (P < .05 vs OO). High-sensitivity C-reactive protein responses with OM3-FFA did not differ significantly from the OO response at any dosage. Fewer subjects reported any adverse event with OO vs OM3-FFA, but frequencies across dosage groups were similar. Discontinuation due to adverse event, primarily gastrointestinal, ranged from 5% to 7% across OM3-FFA dosage groups vs 0% for OO.

Conclusions

OM3-FFA achieved the primary end point for TG lowering and secondary end point of non-HDL-C lowering at 2, 3, and 4 g/d in persons with severe hypertriglyceridemia. This trial was registered at www.clinicaltrials.gov as NCT01242527.

  Gerald F. Watts , Samuel Gidding , Anthony S. Wierzbicki , Peter P. Toth , Rodrigo Alonso , W. Virgil Brown , Eric Bruckert , Joep Defesche , Khoo Kah Lin , Michael Livingston , Pedro Mata , Klaus G. Parhofer , Frederick J. Raal , Raul D. Santos , Eric J.G. Sijbrands , William G. Simpson , David R. Sullivan , Andrey V. Susekov , Brian Tomlinson , Albert Wiegman , Shizuya Yamashita and John J.P. Kastelein
  Familial hypercholesterolemia (FH) is a dominantly inherited disorder present from birth that markedly elevates plasma low-density lipoprotein cholesterol and causes premature coronary heart disease. There are at least 20 million people with FH worldwide, but the majority remains undetected, and current treatment is often suboptimal. To address this major gap in coronary prevention we present, from an international perspective, consensus-based guidance on the care of FH. The guidance was generated from seminars and workshops held at an international symposium. The recommendations focus on the detection, diagnosis, assessment, and management of FH in adults and children and set guidelines for clinical purposes. They also refer to best practice for cascade screening and risk notifying and testing families for FH, including use of genetic testing. Guidance on treatment is based on risk stratification, management of noncholesterol risk factors, and the safe and effective use of low-density lipoprotein-lowering therapies. Recommendations are given on lipoprotein apheresis. The use of emerging therapies for FH is also foreshadowed. This international guidance acknowledges evidence gaps but aims to make the best use of contemporary practice and technology to achieve the best outcomes for the care of FH. It should accordingly be used to inform clinical judgment and be adjusted for country-specific and local healthcare needs and resources.
 
 
 
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