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253 endothelial dysfunction
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
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
Editor's Notes
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.
