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Lower levels of ADAMTS13 are associated with cardiovascular disease

Lower levels of ADAMTS13 are associated with cardiovascular disease. by Supakanya Lasom Master Degree Student of Medical Sciences,.

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Lower levels of ADAMTS13 are associated with cardiovascular disease

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  1. 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:10.1016/j. atherosclerosis.2009.04.013.

  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.gif

  3. 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 Atherothrombosis: A Generalized and Progressive Process Adapted from Libby P. Circulation. 2001;104:365-372.

  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.1;2002:273–288

  6. von Willebrand factor (vWF) www.vwf.group.shef.ac.uk/pictures.html • large glycoproteinencoded by a gene on chromosome 12p13.3 • synthesized by vascular endothelial cells and megakaryocytes • Size: 270-20,000 kDa

  7. 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 byADAMTS13

  8. 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

  9. ADAMTS13 • Degrades ultralarge vWf multimers, generating smaller form and decreasing their activity • Directly cleaves the peptide bond betweenTyr1605 and Met1606 of the VWF A2 domain http://hematology.wustl.edu/faculty/sadler/vwf.gif

  10. 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.

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

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

  13. 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 Method

  14. Table 1: Baseline characteristics of case and control group

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

  16. Table 3: Relationship between levels of vWF, ADAMTS13 and risk on cardiovascular disease p<0.001 p<0.004 p<0.012

  17. 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, p<0.001 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.

  18. 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)

  19. Genetic variation of ADAMTS13 Table 5: ADAMTS13 gene polymorphisms in cases and controls

  20. 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 0.3-1.0, p=0.06)

  21. 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 riskof 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.

  22. 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.

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

  24. Thank you for your attention

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