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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

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.


Cardiovascular disease cvd
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 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.


Multiple risk factors for atherothrombosis
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


Platelets and cvd
Platelets and CVD

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


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


Von willebrand factor vwf
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


Adam ts13 a disintegrin and metalloproteinase with a thrombospondin type 1 motif member 13
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


Adam ts13
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


Adamts13 regulate vwf adhesive properties
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.


Hypothesis
Hypothesis

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


Objectives
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

Method



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<0.004

p<0.012


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.


Subgroup analysis
Subgroup analysis high levels of vWF and risk of cardiovascular disease.

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)


Genetic variation of ADAMTS13 high levels of vWF and risk of cardiovascular disease.

Table 5: ADAMTS13 gene polymorphisms in cases and controls


Genetic variation of adamts13
Genetic variation of ADAMTS13 high levels of vWF and risk of cardiovascular disease.

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)


Discussion
Discussion high levels of vWF and risk of cardiovascular disease.

  • 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.


Discussion1
Discussion high levels of vWF and risk of cardiovascular disease.

  • 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
    Conclusion high levels of vWF and risk of cardiovascular disease.

    • 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 high levels of vWF and risk of cardiovascular disease.

    your attention


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