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1. Isolated-low HDL levels in ABCA1 heterozygotes is associated with impaired basal and stimulated endothelial nitric oxide synthase activity. 2. A single rapid infusion of reconstituted HDL completely restored both basal and stimulated endothelial nitric oxide synthase activity in ABCA1 heterozygotes. 3. Impaired lipid trafficking and caveolar disruption caused by dysfunctional ABCA1 profoundly affects endothelial nitric oxide synthase activity.
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- 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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
Notas do Editor
- First of all, I would like to express my appreciation towards the American Heart Association committee (on Scientific Sessions Program), who accepted the abstract of our current study for presentation in this oral session.
- Cardiovascular disease resulting from atherosclerosis represents the leading cause of death and morbidity in the Western societies. It was Gofman and colleagues who almost three decades ago noticed the relationship between lipoprotein levels and CVD in the Framingham Heart Study. Major breakthroughs to modern day cardiovascular research, including the ‘discovery’ of statins, have been ascribed to their findings.Although these statins targeting LDL cholesterol, in both primary and secondary prevention trials were shown to markedly reduce major cardiovascular events, 60 to 70% cannot be prevented by current therapeutic strategies.
- Therefore, to evaluate whether low HDL per se adversely affects vascular reactivity, we first assessed the presence of endothelial dysfunction as a hallmark of preclinical atherosclerosis in these subjects carrying ABCA1 mutations and second, we determined its reversibility upon HDL-increase.
- Nine ABCA1 heterozygotes and nine sex- and age-matched controls were included in the present study. All subjects had normal levels of LDL and TG, whereas none of them had diabetes mellitus, hypertension or congestive heart failure. Assessment of vascular function was performed using venous occlusion, strain-gauge plethysmography. Forearm blood flow responses to intraarterial administration of the endothelium-dependent vasodilator serotonin (5HT) and endothelium independent vasodilator sodium nitroprusside (SNP), and the competitive inhibitor of nitric oxide synthase L-NMMA (N-monomethyl-L-arginine) were measured. After systemic infusion of reconstituted HDL, which contains human purified apo A-I and phophatidylcholine primarily (kindly provided by ZLB), dose-response curves were repeated.
- The baseline clinical characteristics of the ABCA1 heterozygotes and control subjects are summarized in this table. As you can see, both groups were similar, particularly systolic and diastolic blood pressures, body-mass index and forearm blood flow were not significantly different.
- At baseline ABCA1 heterozygotes had decreased HDL levels compared to controls, that is .5 versus 1.2. Other lipid parameters were not significantly different and remained unaltered by rHDL infusion. As you can see, intravenous cholesterol-free rHDL infusion increased the plasma HDL level two to three times to 1.5 and 2.1 in ABCA1 mutants and controls, respectively.
- The next slides are somewhat complicated, so I will help you through. The lines connecting open and closed circles represent (FBF responses of) the ABAC1 heterozygotes (to L-NMMA) before and after rHDL infusion, whereas the lines connecting the open and closed triangles represent control FBF responses. On the x-axis: the cumulative doses of LNMMA are displayed. On the y-axis: the percentage vasoconstriction in the measurement arm is displayed. At baseline, the vasoconstrictor response to L-NMMA, reflecting basal NO activity, was blunted in ABCA1 heterozygotes compared to controls (p=0.001). After a single rapid infusion of rHDL, the L-NMMA constrictor response was increased significantly (p=0.001), reaching values comparable to control subjects. In contrast, rHDL infusion had no effect on L-NMMA response in control subjects .
- Again the lines connecting open and closed circles represent FBF responses of the ABCA1 heterozygotes (in response to serotonin) before and after rHDL infusion, respectively. The lines connecting open and closed triangles represent control FBF responses. On the x-axis: the cumulative doses of serotonin are displayed. On the y-axis: the percentage vasodilation in the measurement arm is displayed. The intraarterial infusion of serotonin increased FBF in a dose-dependent manner in both groups. At baseline, the FBF response to serotonin, reflecting stimulated NO activity, was impaired significantly in ABCA1 heterozygotes compared to controls (p&lt;0.0001) After rHDL infusion, inducing normalization of HDL levels, FBF response to serotonin increased significantly to values comparable with control responses (p&lt;0.001).
- In contrast, the endothelium-independent vasodilation in response to SNP was not different between ABCA1 heterozygotes and controls, and was not affected by rHDL infusion (in either group)
- In summary, endothelial function, as indicated by basal and stimulated NO activity, is impaired in ABCA1 heterozygotes showing isolated-low-HDL, compared to normocholesterolemic controls. Second, an increase in HDL by a single, rapid infusion of reconstituted HDL results in complete recovery of endothelial function.
- Altough, defective ABCA1-mediated cholesterol efflux in ABCA1 heterozygotes is associated with advanced arterial`wall thickening and increased risk for early onset CVD the acute improvements in vascular function are less likely to be related to the RCT pathway: On this slide, we summarized possible mechanisms which could explain the consequences of altering HDL levels for NO bioavailibility in these individuals. First, demonstrated by the research group of Gerd Smitz, dysfunctional ABCA1 leads to disturbed caveolar processing, which profoundly affects eNOS activity. In fact, basal NO activity was impaired in these ABCA1 heterozygotes. Furthermore, apoAI was found to stimulate intracellular lipid trafficking, restoring this caveolar processing within 10 minutes. This could explain the rapid vascular reponsiveness to rHDL infusion. Additionally, HDL was recently found to directly activate eNOS via an SR-B1 dependent pathway
- Although low HDL resulting from dysfunctional ABCA1 is rare, our study provides excellent rationale for the atherogenicity of isolated-low-HDL states in general. Indeed, these data show that isolated low HDL even in these subjects with impaired RCT is not only associated with accelerated atherosclerosis but is also entirely reversible upon HDL increase. This indicates that HDL is a potent regulator of the NO pathway in vivo. Finally, this study illustrates the potential of HDL increasing strategies in CV prevention, targeting the acute beneficial effects on biovascular integrity next to long-term enhancement of the anti-atherogenic RCT pathway.
- Finally, I thank all participants for their contribution.