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Stroes

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Stroes

  1. 1. Low HDL is Characterized by Endothelial Dysfunction, Which is Reversible upon HDL increase CE TG A-I A-I Radjesh J. Bisoendial1 , MD; G. Kees Hovingh1 , MD; Han Levels1 PhD; Peter Lerch2 MD, PhD; Irmgard Andresen2 , MD, PhD; John J.P. Kastelein1 , MD, PhD; Erik S.G. Stroes1 , MD, PhD 1 Academic Medical Center University Hospital of Amsterdam The Netherlands 2 ZLB Bioplasma AG, Bern, Switzerland A-II
  2. 2. INTRODUCTIONAmerican Heart Association 2002  LDL lowering: reduction 20-40 % in CV events  HDL » a promising target  ABC-A1 mutation carriership » isolated-low-HDL model in vivo  NO deficiency » early event in atherogenesis The Scandinavian Simvastatin Survival Study, Lancet 1994; Downs JR et al, JAMA 1998; Shepherd J et al, N Engl J Med 1995; Sacks FM et al, N Engl J Med 1996; LIPID study group, N Engl J Med 1998.
  3. 3. STUDY QUESTIONSAmerican Heart Association 2002 We therefore assessed: 1. the implications of isolated-low-HDL for endothelial vasomotor function in ABCA1 heterozygotes 2. the beneficial vascular effects in response to acute HDL increase
  4. 4. METHODSAmerican Heart Association 2002  Subjects: 9 ABCA1 heterozygotes vs 9 controls  Venous occlusion strain-gauge plethysmography: » Serotonin » Sodium nitroprusside » L-NMMA  Systemic infusion of reconstituted HDL: 80 mg/kg body weight over 4 hours
  5. 5. Table 1. Base-line Clinical Characteristics ABCA1 heterozygotes (n=9) Controls (n=9) Age, years 42.9 ± 13.9 46.1 ± 13,5 Sex, male/female 3/6 3/6 BMI, kg/m2 26.1 ± 2.7 25.8 ± 3.5 Smoking 2/9 2/9 Systolic blood pressure, mmHg 131.6 ± 23.4 130.1 ± 13.4 Diastolic blood pressure, mmHg 79.0 ± 8.9 78.1 ± 5.9 Heart rate, bpm 62.2 ± 9.0 60.1 ± 10.5 Basal FBF, ml.100 mL FAV-1 .min-1 ) 3.2 ± 1.0 2.6 ± 0.6 values represent mean ± SD. RESULTSAmerican Heart Association 2002
  6. 6. Table 2. Laboratory Data Before and After rHDL infusion ABCA1 heterozygotes Controls before rHDL after rHDL before rHDL after rHDL (n=9) (n=9) (n=9) (n=9) TC (mmol/L) 4.3 ± 1.3 5.7 ± 1.4 5.7 ± 2.4 6.6 ± 2.3 HDL (mmol/L) 0.5 ± 0.2† 1.5 ± 0.3‡ 1.2 ± 0.3 2.1 ± 0.6‡ LDL (mmol/L) 3.4 ± 0.9 3.3 ± 0.7 3.9 ± 2.1 3.5 ± 1,9 TG (mmol/L) 1.5 ± 1.0 2.9 ± 2.4 1.3 ± 1.5 2.6 ± 3.0 values represent mean ± SD. †P<0.05 vs controls, ‡ <0.05 vs baseline value American Heart Association 2002 RESULTS
  7. 7. L-NMMA induced vasoconstriction before and after rHDL American Heart Association 2002 RESULTS 0 50 100 200 400 -60 -50 -40 -30 -20 -10 0 10 ABCA1 heterozygotes before rHDL normocholesterolemics before rHDL ABCA1 heterozygotes after rHDL normocholesterolemics after rHDL † p=0.001 † baseline: ABCA1 heterozygotes vs normocholesterolemic controls ‡ ABCA1 heterozygotes: baseline vs after rHDL infusion Dose L-NMMA (µg.100 mL FAV-1 . min-1 ) %changeinforearmbloodflow ‡ p=0.001
  8. 8. Serotonin induced vasodilation before and after rHDL American Heart Association 2002 RESULTS 0 0,6 1,8 6,0 0 20 40 60 80 100 120 140 160 ABCA1 heterozygotes before rHDL normocholesterolemics before rHDL ABCA1 heterozygotes after rHDL † p<0.0001 † baseline: ABCA1 heterozygotes vs normocholesterolemic controls ‡ ABCA1 heterozygotes: baseline vs after rHDL infusion normocholesterolemics after rHDL Dose 5-HT (ng .100 mL FAV-1 . min-1 ) %changeinforearmbloodflow ‡ p<0.001
  9. 9. SNP induced vasodilation before and after rHDL American Heart Association 2002 RESULTS 0 6 60 180 600 0 100 200 300 400 500 600 ABCA1 heterozygotes before rHDL normocholesterolemics before rHDL ABCA1 heterozygotes after rHDL normocholesterolemics after rHDL † p=0.30 † baseline: ABCA1 heterozygotes vs normocholesterolemic controls (ng.100 mL FAV-1 . min-1 ) %changeinforearmbloodflow
  10. 10. SUMMARYAmerican Heart Association 2002 1. Isolated-low-HDL is associated with impaired basal and stimulated eNOS activity in ABCA1 heterozygotes 2. Both basal and stimulated eNOS activity are completely restored after a single, rapid infusion of rHDL
  11. 11. American Heart Association 2002 DISCUSSION Direct interactions between HDL and eNOS*** ApoA-I induced repairment of intracellular lipid-trafficking and caveolar processing** Dysfunctional ABC-A1 causes impaired lipid trafficking and caveolar disruption with profound effects on eNOS activity* *Orso E et al, Nat Gen 2000 **Sviridov D et al, Biochem J 2001 ***Yuhanna IS et al, Nat Med 2001; Li XA et al, J Biol Chem 2002
  12. 12. American Heart Association 2002 CONCLUSIONS  ABCA1 gene mutations ⇒ isolated-low-HDL states  HDL » a potent regulator of NO pathway in vivo  Clinical benefits of HDL increasing strategies
  13. 13. Dept. Vascular Medicine R.J. Bisoendial, MD G.K. Hovingh, MD B. Karstenskov H. Levels, PhD J. Meijers, PhD Prof. J.J.P. Kastelein, MD, PhD Prof. H.R. Büller, MD, PhD E.S.G. Stroes, MD, PhD Dept. Internal Medicine Prof. M.M. Levi, MD, PhD Dept. Gastroenterology Prof. S.J. van Deventer, MD, PhD ACKNOWLEDGMENTSAmerican Heart Association 2002

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