Lower levels of ADAMTS 13 are associated with

Lower levels of ADAMTS 13 are associated with cardiovascular disease Bongers T. N, Bruijne E, Dippel D, Jong A, Deckers J, Poldermans D. Lower levels of ADAMTS 13 are associated with cardiovascular disease. Atherosclerosis. (In Press), doi: 10. 1016/j. atherosclerosis. 2009. 04. 013. by Supakanya Lasom Master Degree Student of Medical Sciences,

Cardiovascular disease (CVD) v CVD is the leading cause of death worldwide v 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 v Coronary heart disease (CHD) v Angina - intense chest pain v Heart attack - myocardial infarction v Congestive heart failure v Cerebrovascular disease v Transient ischaemic attacks (TIA) or “mini strokes” v Strokes v Peripheral vascular disease (PVD) v Aneurysms Adapted from Libby P. Circulation. 2001; 104: 365 -372.

Multiple Risk Factors for Atherothrombosis Lifestyle • Smoking • Diet • Lack of exercise Generalize disorders • Age • Obesity Genetic trait • gender Atherothrombotic Manifestations )AMI and stroke) Local factor • Blood flow pattern • Shear stress • Vessel diameter • Arterial wall structure • % atherostenosis Inflammation • Elevated CRP http: //www. nutrizone. co. za/slides/100/pages/ss 1 s 3_JPG. htm 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 (v. WF) www. vwf. group. shef. ac. uk/pictures. html • large glycoprotein encoded by a gene on chromosome 12 p 13. 3 • synthesized by vascular endothelial cells and megakaryocytes • Size: 270 -20, 000 k. Da

von Willebrand factor (v. WF) v v. WF is stored in Weibel-Pallade bodies of endothelial cells and the α-granules of both megakaryocytes and platelets v VWF multimers (UL-v. WF), can bind better to the extracellular matrix than regular multimers and form higher strength bonds with platelet GPIb-IX-V than plasma v. WF v UL-v. WF are rapidly degraded into smaller forms , do not bind platelets spontaneously by ADAMTS 13

ADAMTS 13) a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13( v von Willebrand factor-cleaving protease )v. WF-CP) v Gene location: 9 q 34, 29 exons, 1427 aa v Multi-domain protein v Synthesized by hepatic cell

ADAMTS 13 • Degrades ultralarge v. Wf multimers, generating smaller form and decreasing their activity • Directly cleaves the peptide bond between Tyr 1605 and Met 1606 of the VWF A 2 domain http: //hematology. wustl. edu/faculty/sadler/vwf. gif

ADAMTS 13 regulate v. WF adhesive properties ccforum. com/content/figures/cc 5064 -1 -l. jpg v. Deficiency or severely reduced activity of ADAMTS 13 leads to accumulation of ULVWF multimers in plasma and results in a thrombotic diseases.

Hypothesis • Low level of ADAMTS 13 will result in an increased risk of cardiovascular disease

Objectives v. To investigate the relationship between ADAMTS 13, v. WF activity, the genetic variation in ADAMTS 13 and the risk of cardiovascular disease in young individuals.

Method v 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 – v. WF antigen measured by in-house ELISA – v. WF activity measured by in-house ELISA – ADAMTS 13 antigen and activity measured by Technozym ADAMTS 13 kit v Genotyping of ADAMTS 13 v rs 2301612 v rs 2073932 v rs 652600 v rs 603551 v The genotype assays determined by allele-specific Taqman analysis

Table 1: Baseline characteristics of case and control group

Table 2: Plasma ADAMTS 13 antigen, ADAMTS 13 activity, v. WF antigen and v. WF; CB activity levels in all cases and controls.

Table 3: Relationship between levels of v. WF, ADAMTS 13 and risk on cardiovascular disease p<0. 001 p<0. 004 p<0. 012

Figure 1: The relationship between low levels of ADAMTS 13, high levels of v. WF and risk of cardiovascular disease. OR 7. 7, 95% CI 3. 3 -17. 7, p<0. 001 Individuals who were both in the highest tertile of ADAMTS 13 and in the lowest tertile of v. WF were use as reference. *P<0. 05; **p<0. 001.

Subgroup analysis Table 4: Plasma ADAMTS 13 antigen and ADAMTS 13 activity levels in CHD subgroup and controls. Individuals in the lowest tertile for ADAMTS 13 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)

Genetic variation of ADAMTS 13 Table 5: ADAMTS 13 gene polymorphisms in cases and controls

Genetic variation of ADAMTS 13 Table 5: ADAMTS 13 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 v Levels of ADAMTS 13 are lower and levels of v. WF are higher in young patients with CVD. v Low levels of ADAMTS 13 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). v Individuals who have the lowest levels of ADAMTS 13 combined with the highest levels of v. WF have the highest risk of CVD.

Discussion v The lowest levels of ADAMTS 13 were seen in haplotype GAAT that associated with the risk of PAD. ØTo confirm this association, the larger studies are required. v Genetic variation in ADAMTS 13 does not play a major role in the reduction of ADAMTS 13 levels found in patients with CVD.

Conclusion v. Reduced levels of ADAMTS 13 are associated with an increased risk of cardiovascular disease, but the genetic variation does not play a major role.

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