Cardiovasculaire Geneeskunde.nl

Homocysteïne: uitgemeten?!

Slides (presentatie) - Feb. 27, 2011

Homocysteïne: uitgemeten?

Drie stellingen en twee vragen

1.Hoe hoger de plasmaspiegel Hcy, des te hoger het risico op hartvaatziekten

Marfan-like stature Scoliosis and osteoporosis Mental retardation Lens dislocation High incidence of venous thromboembolism and atherothrombosis

‘Mild’ Hyperhomocysteinaemia Is Common

High Plasma Hcy Is Associated with a Greater Risk of Cardiovascular Disease

Two meta-analyses (Clarke, JAMA 2002; Wald, BMJ 2002) 3 mol/L (~25%) Hcy increase   ischaemic heart disease (%) 11 (4-17) 15 (10-20)  stroke (%) 19 (5-31) 22 (14-30)

2.Het verband tussen Hcy en hartvaatziekten is waarschijnlijk causaal

Causaal of niet? Rothman, 1976; Rothman and Greenland, 1998

Two meta-analyses (Clarke, JAMA 2002; Wald, BMJ 2002) 3 mol/L (~25%) Hcy increase   ischaemic heart disease (%) 11 (4-17) 15 (10-20)  stroke (%) 19 (5-31) 22 (14-30)

diet

Vascular Outcomes in Cystathionine Beta Synthase Deficiency ATVB 2001;21:2080

Associated Treatment Potential with CVD? effective? bias? Severe yes yes natural history HHcy (>100 µM) Mild yes residual confounding, HHcy eg by lifestyle (12-30 µM) factors

Mendelian Randomisation The random assortment of genes transferred from parent to offspring at the time of gamete formation Akin to an RCT of genetic variants Depends on genetic variant resulting in the intermediate phenotype of interest Potential biases include population stratification and linkage disequilibrium (the association of genetic polymorphisms because the polymorphisms are close together on the genome)

Diet

MTHFR, TT vs CC

MTHFR, TT vs CC

Associated Treatment Potential with CVD? effective? bias? Severe yes yes natural history HHcy (>100 µM) Mild yes residual confounding, HHcy eg by lifestyle (12-30 µM) factors MTHFR yes - linkage disequilibrium, Polymorphism other

The assumption that the association between hyperhomocysteinaemia and cardiovascular disease is indeed causal is the simplest explanation of the totality of the observations

Associated Treatment Potential with CVD? effective? bias? Severe yes yes natural history HHcy (>100 µM) Mild yes residual confounding, HHcy eg by lifestyle (12-30 µM) factors MTHFR yes - linkage disequilibrium, Polymorphism other

3.Verlaging van ‘milde’ Hcy met B-vitaminen verlaagt het risico op HVZ niet

‘Mild’ HHcy Can Be Lowered with Folic Acid

Wald, BMJ 2006

Verlaging van ‘milde’ HHcy: RCT’s Cochrane, 2009

Cochrane 2009 n=24210 Coronaire hartziekten 1,03 (0,94-1,13) Herseninfarct 0,89 (0,73-1,08) Sterfte 1,00 (0,92-1,09) Kanker 1,06 (0,90-1,25) (n=12361)

Study of the Effectiveness of Additional Reductions of Cholesterol and Homocysteine Jama 2010;303:2486

Study of the Effectiveness of Additional Reductions of Cholesterol and Homocysteine Jama 2010;303:2486

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Associated Treatment Potential with CVD? effective? bias? Severe yes yes natural history HHcy (>100 µM) Mild yes no residual confounding, HHcy eg by lifestyle (12-30 µM) factors MTHFR yes - linkage disequilibrium, Polymorphism other

4.Er klopt iets niet, maar wat?

Foliumzuur (>200 µg/d) is niet hetzelfde als 5-methyltetrahydrofolaat

Hoge dosis foliumzuur (>1 mg/d) is niet hetzelfde als natuurlijke folaatinname (~400 µg/d)

5.Wat nu?

MTHFR - FAD binding is weakened in the TT genotype and is strengthened by 5-CH3-THF

Low folate status impairs DNA methylation in individuals with the TT genotype

Hcy may cause cardiovascular disease through multiple mechanisms

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2. Many types of folate species exist, with different functions

… the redox state …

… many types of intracellular folates …

High folate during disease process: Stimulation inflammatory cells (eg macrophages) Stimulatie proliferating cells (eg vsmc)

Geen verband gen en confounders Geen verband gen en ziekte los van risicofactor Risicofactor is werkelijk dé causale factor

Cochrane 2009 Cochrane + Search n=24210 n=37845 CHZ 1,03 (0,94-1,13) Stroke 0,89 (0,73-1,08) MACE . . . 1,01 (0,97-1,05) Sterfte 1,00 (0,92-1,09) Kanker 1,06 (0,90-1,25) (n=12361)

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