Lower levels of ADAMTS13 are associated with cardiovascular disease

1
Lower levels of ADAMTS13 are associated with
cardiovascular disease
Bongers T.N, Bruijne E, Dippel D, Jong A, Deckers
J, Poldermans D. Lower levels of ADAMTS13 are
associated with cardiovascular disease.
Atherosclerosis. (In Press), doi10.1016/j.
atherosclerosis.2009.04.013.

• by Supakanya Lasom
• Master Degree Student of Medical Sciences,

2
Cardiovascular disease (CVD)

• CVD is the leading cause of death worldwide
• CVD includes Coronary Heart Disease or diseases
  of the arteries (Arteriosclerosis, including
  hardening of the arteries, or Atherosclerosis)

http//www.clivir.com/pictures/heart_disease/MI.gi
f
3
Atherothrombosis A Generalized and Progressive
Process

• Coronary heart disease (CHD)
• Angina - intense chest pain
• Heart attack - myocardial infarction
• Congestive heart failure
• Cerebrovascular disease
• Transient ischaemic attacks (TIA) or mini
  strokes
• Strokes
• Peripheral vascular disease (PVD)
• Aneurysms

Adapted from Libby P. Circulation.
2001104365-372.
4
Multiple Risk Factors for Atherothrombosis

• Lifestyle
• Smoking
• Diet
• Lack of exercise

• Generalize disorders
• Age
• Obesity

Atherothrombotic Manifestations (AMI and stroke)

• Systemic conditions
• Hypertension
• Hyperlipidemia
• Diabetes

• Genetic trait
• gender

• Local factor
• Blood flow pattern
• Shear stress
• Vessel diameter
• Arterial wall structure
• atherostenosis

• Hypercoagulable
• states

• Inflammation
• Elevated CRP

http//www.nutrizone.co.za/slides/100/pages/ss1s3_
JPG.htm
5
Platelets and CVD
Willoughby et al, European Journal of
Cardiovascular Nursing.12002273288
6
(No Transcript)
7
von Willebrand factor (vWF)
www.vwf.group.shef.ac.uk/pictures.html

• large glycoprotein encoded by a gene on
  chromosome 12p13.3
• synthesized by vascular endothelial cells and
  megakaryocytes
• Size 270-20,000 kDa

8
von Willebrand factor (vWF)

• vWF is stored in Weibel-Pallade bodies of
  endothelial cells and the a-granules of both
  megakaryocytes and platelets
• VWF multimers (UL-vWF), can bind better to the
  extracellular matrix than regular multimers and
  form higher strength bonds with platelet
  GPIb-IX-V than plasma vWF
• UL-vWF are rapidly degraded into smaller forms ,
  do not bind platelets spontaneously by ADAMTS13

9
ADAMTS13 (a disintegrin and metalloproteinase
with a thrombospondin type 1 motif, member 13)

• von Willebrand factor-cleaving protease (vWF-CP)
• Gene location 9q34, 29 exons, 1427 aa
• Multi-domain protein
• Synthesized by hepatic cell

10
ADAMTS13

• Degrades ultralarge vWf multimers, generating
  smaller form and decreasing their activity
• Directly cleaves the peptide bond between Tyr1605
  and Met1606 of the VWF A2 domain

http//hematology.wustl.edu/faculty/sadler/vwf.gif
11
ADAMTS13 regulate vWF adhesive properties
ccforum.com/content/figures/cc5064-1-l.jpg

• Deficiency or severely reduced activity of
  ADAMTS13 leads to accumulation of ULVWF multimers
  in plasma and results in a thrombotic diseases.

12
Hypothesis

• Low level of ADAMTS13 will result in an increased
  risk of cardiovascular disease

13
Objectives

• To investigate the relationship between
• ADAMTS13, vWF activity, the genetic variation in
  ADAMTS13 and the risk of cardiovascular disease
  in young individuals.

14
Method

• Patients cases374, controls332
• Cases Coronary heart disease (CHD) 218
• Ischemic stroke (IS) 109
• Peripheral artery disease (PAD) 47
• Age lt45 years old in male, lt55 years old in
  female
• Blood collection 1-3 months after the first
  ischemic event
• Biochemical analysis
• vWF antigen measured by in-house ELISA
• vWF activity measured by in-house ELISA
• ADAMTS13 antigen and activity measured by
  Technozym ADAMTS13 kit

• Genotyping of ADAMTS13
• rs2301612
• rs2073932
• rs652600
• rs603551
• The genotype assays determined by allele-specific
  Taqman analysis

15
Table 1 Baseline characteristics of case and
control group
16
Table 2 Plasma ADAMTS13 antigen, ADAMTS13
activity, vWF antigen and vWFCB activity
levels in all cases and controls.
17
Table 3 Relationship between levels of vWF,
ADAMTS13 and risk on cardiovascular disease
plt0.001
plt0.004
plt0.012
18
Figure 1 The relationship between low levels of
ADAMTS13, high levels of vWF and risk of
cardiovascular disease.
OR 7.7, 95 CI 3.3-17.7, plt0.001
Individuals who were both in the highest tertile
of ADAMTS13 and in the lowest tertile of vWF were
use as reference. Plt0.05 plt0.001.
19
Subgroup analysis
Table 4 Plasma ADAMTS13 antigen and ADAMTS13
activity levels in CHD subgroup and controls.
Individuals in the lowest tertile for ADAMTS13
antigen have an eight times increased risk for
CHD compared with individuals in the highest
tertile (OR 8.2, 95 CI 4.5-14.7)
20
Genetic variation of ADAMTS13
Table 5 ADAMTS13 gene polymorphisms in cases and
controls
21
Genetic variation of ADAMTS13
Table 5 ADAMTS13 gene polymorphisms in cases and
controls
14 lower activity in the controls and 8 lower
in the cases compare with the CGAT , p0.05
Haplotype GAAT was associated with a decreased
risk of PAD (OR 0.5,95 CI 0.3-1.0, p0.06)
22
Discussion

• Levels of ADAMTS13 are lower and levels of vWF
  are higher in young patients with CVD.
• Low levels of ADAMTS13 are associated with a
  higher risk of cardiovascular disease. The
  relationship was strongest in the subgroup of
  patients with CHD(OR 8.2, 95 CI 4.5-14.7,
  plt0.001).
• Individuals who have the lowest levels of
  ADAMTS13 combined with the highest levels of vWF
  have the highest risk of CVD.

23
Discussion

• The lowest levels of ADAMTS13 were seen in
  haplotype GAAT that associated with the risk of
  PAD.
• To confirm this association, the larger studies
  are required.
• Genetic variation in ADAMTS13 does not play a
  major role in the reduction of ADAMTS13 levels
  found in patients with CVD.

24
Conclusion

• Reduced levels of ADAMTS13 are associated with an
  increased risk of cardiovascular disease, but the
  genetic variation does not play a major role.

25
Thank you for your attention