Lower levels of ADAMTS13 are associated with cardiovascular disease

by Supakanya LasomMaster Degree Student of Medical Sciences,

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), doi:10.1016/j. atherosclerosis.2009.04.013.

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.gif

Atherothrombosis: A Generalized and Progressive Process

Coronary heart disease (CHD) Angina - intense chest pain Heart attack - myocardial infarcti

on Congestive heart failure

Cerebrovascular disease Transient ischaemic attacks (TIA)

or “mini strokes” Strokes

Peripheral vascular disease (PVD) Aneurysms

Adapted from Libby P. Circulation. 2001;104:365-372.

Multiple Risk Factors for Atherothrombosis

Atherothrombotic Manifestations(AMI and stroke)

Generalize disorders•Age•Obesity

Lifestyle•Smoking •Diet•Lack of exercise

Genetic trait•gender

Inflammation•Elevated CRP

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

Systemic conditions•Hypertension•Hyperlipidemia•Diabetes

http://www.nutrizone.co.za/slides/100/pages/ss1s3_JPG.htm

•Hypercoagulable states

Platelets and CVD

Willoughby et al, European Journal of Cardiovascular Nursing.1;2002:273–288

von Willebrand factor (vWF)

• large glycoprotein encoded by a gene on chromosome 12p13.3

• synthesized by vascular endothelial cells and megakaryocytes

• Size: 270-20,000 kDa

www.vwf.group.shef.ac.uk/pictures.html

von Willebrand factor (vWF)

vWF is stored in Weibel-Pallade bodies of endothelial cells and the α-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

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 aaMulti-domain proteinSynthesized by hepatic cell

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

ADAMTS13 regulate vWF adhesive properties

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

Hypothesis

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

Objectives

To investigate the relationship between

ADAMTS13, vWF activity, the genetic variation in ADAMTS13 and the risk of cardiovascular disease in young individuals.

Method

Patients: cases=374, controls=332• Cases: Coronary heart disease (CHD)= 218

: Ischemic stroke (IS)= 109

: Peripheral artery disease (PAD)= 47

• Age: <45 years old in male, <55 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

Table 1: Baseline characteristics of case and control group

Table 2: Plasma ADAMTS13 antigen, ADAMTS13 activity, vWF antigen and vWF;CB activity levels in all cases and controls.

Table 3: Relationship between levels of vWF, ADAMTS13 and risk on cardiovascular disease

p<0.001

p<0.012

p<0.004

Figure 1: The relationship between low levels of ADAMTS13, high levels of vWF and risk of cardiovascular disease.

Individuals who were both in the highest tertile of ADAMTS13 and in the lowest tertile of vWF were use as reference. *P<0.05; **p<0.001.

OR 7.7, 95% CI 3.3-17.7, p<0.001

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)

Table 5: ADAMTS13 gene polymorphisms in cases and controlsGenetic variation of ADAMTS13

Genetic variation of ADAMTS13Table 5: ADAMTS13 gene polymorphisms in cases and controls

14% lower activity in the controls and 8% lower in the

cases compare with the CGAT , p=0.05

Haplotype GAAT was associated with a decreased risk of PAD (OR 0.5,95% CI 0.3-1.0, p=0.06)

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, p<0.001).

Individuals who have the lowest levels of ADAMTS13 combined with the highest levels of vWF have the highest risk of CVD.

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.

Conclusion

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

Thank you for your attention