Lower levels of ADAMTS13 are associated with cardiovascular disease by Supakanya Lasom Master 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: /j. atherosclerosis

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)

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. 2001;104:

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 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: ,000 kDa

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 aa  Multi-domain protein  Synthesized 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

ADAMTS13 regulate vWF adhesive properties ccforum.com/content/figures/cc l.jpg  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  rs  rs  rs  rs  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< OR 7.7, 95% CI , 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 )

Table 5: ADAMTS13 gene polymorphisms in cases and controls 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, p=0.05 Haplotype GAAT was associated with a decreased risk of PAD (OR 0.5,95% CI , 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 , 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.

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