Moderate hyperhomocysteinemia and cardiovascular risk

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Moderate hyperhomocysteinemia and cardiovascular
risk

• From homocystinuria to prospective population
  studies
• Determinants
• Homocysteine as risk factor Interactions
• Total homocysteine and mortality in cardiac
  patients
• Total homocysteine and mortality in the Hordaland
  cohort
• Homocysteine lowering therapy with vitamins
• Interventions studies

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Homocystinuria
Dilated veins in a homocystinuric patient with
thrombosis of the inferior vena cava
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Homocystinuria Prognosis according to tHcy level
Mudd et al, 1985
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Annual publication rates within the fields of
homocysteine and folate(Source
http//www.ncbi.nlm.nih.gov/PubMed/)
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Distribution of various forms of homocysteine in
plasma
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Homocysteine metabolism and its relation to
B-vitamins
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The C677T MTHFR polymorphismand folate
distribution
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The C677T MTHFR polymorphismand folate
distribution
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Hyperhomocysteinemia Genetic causes
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Hyperhomocysteinemia Acquired causes
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tHcy distribution under various physiological
conditions
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Plasma tHcy vs serum vitamin levels in healthy
subjects and in CAD patients
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The folate-tHcy relation and the C677T MTHFR
polymorphism
The COMAC Study Meleady et al 2000
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Dose-response relationship for tHcy vs.
riboflavin according to MTHFR C677T genotype and
folate status
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Total homocysteine, and its relation to folate
and cobalamin, from birth to senescence
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Hordaland county
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The Hordaland Homocysteine Study Study Population
Invited Attended Study Population Total
series 24815 18043 16176 Sex Men 12488 8573
7591 Women 12327 9470 8585 Age 40-42 17303
12594 12266 43-64 999 683
592 65-67 6513 4766 3318 Subjects who
reported a history of diabetes mellitus, angina,
former acute myocardial infarction, stroke, or
treatment for hypertenison were excluded.
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The Hordaland Homocysteine Study Lifestyle
factors and tHcy
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Coffee consumptionThe Hordaland Homocysteine
Study
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Effects of lifestyle factors on the upper and
lower tails of the tHcy distribution
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Distribution of plasma tHcy in women aged 40-42 y
according to contrasting life-style
The Hordaland Homocysteine study
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Hyperhomocysteinemic (gt40 µmol/L) subjects in the
general population
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Characteristics of hyperhomocysteinemic subjects
in the general population
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Homocysteine and creatinine
tHcy and creatinine among 496 men undergoing
coronary angiography for suspected
CAD Nygård et al. NEJM 1997)
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Relation between tHcy and GFR indiabetic
patients with normal serum creatinine
Wollesen et al
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Plasma total homocysteine levels during
short-term iatrogenic hypothyroidism
Lien et al, 2000
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Thyroid status affects riboflavin metabolism
(mainly flavokinase) and thereby metabolism of
folate, cobalamin and vitamin B6
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Diseases and modifiable factors affecting tHcy
level
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Meta-analyses of tHcy and the C677T MTHFR
polymorphism
The ORs for per 5 µmol/L tHcy increase The ORs
for elevated tHcy The ORs for TT vs. CC
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Interaction between tHcy and risk factors for
vascular disease
Modified from Graham et al, 1995 (The COMAC
study)
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tHcy and mortality in cardiac patients

• Subjects with suspected coronary artery disease
  who underwent coronary angiography in 1991/1992
• 587 had CAD, 52 were free of CAD
• Results
• Retrospective data on previous MI
• Cross sectional data on the degree of CA October
  18, 1999
• Prospective data on mortality until April 1996

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Coronary Artery Stenosis and tHcy Cross
Sectional Data
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tHcy and Overall Mortality Kaplan-Meier and
Cox-Adjusted Plots of Survival
Nygård et al, 1997
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Dose-Response Relation BetweentHcy and Mortality
Nygård et al, 1997
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All causes and CVD mortality

• 4766 men and women
• 65-67 years at baseline
• Mortality during follow-up from 1992-93 until
  early 1997
• Median follow-up 4.1 years
• 259 deaths
• 121 cardiovascular
• 136 non-cardiovascular

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Cardiovascular and non-cardiovascular mortality
in 65-67 years old men and women in the
Hordaland Homocysteine study
Vollset el al (2001), AJCN, 74 130-6
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Total mortality in 65-67 years old men and women
in the Hordaland Homocysteine study
Vollset el al (2001), AJCN, 74 130-6
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Cause-specific mortality ratios per 5 µmol/L
tHcy increment The Hordaland Homocysteine Study
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The relation between total homocysteine and total
mortality according to CVD risk and status
Data from the Hordaland Homocysteine studies
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Mortality follow-up (1992-1998) in two age
groupThe Hordaland Homocysteine Study
Vollset et al, unpublished 2002
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Reduction in major adverse cardiac events by
folate treatment in 196 patients undergoing
coronary angioplasty(Modified from Schnyder et
al (2001) NEJM 3451593)
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High resolutionultrasound
Determination of flow-mediated vasodilatation, a
measure of endothelial function
Wall tracking System (Valdirec)
Pneumatic cuff
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Acute elevation of tHcy inhibits flow-mediated
vasodilatation
Chambers, 1999
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The relation between FMD and reduced homocysteine
in 14 healthy subjects undergoing homocysteine or
methionine loading (Chambers et al, 2001)
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The relation between flow-mediated vasodilatation
and reduced homocysteine in 14 healthy subjects
undergoing loading
Chambers et al, 2001
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Reduction in tHcy level with varying doses of
folic acid
Pretreatment tHcy of 12 µmol/L and folate of 12
nmol/L Data given as ratio of treated
control with 95 CI (log scale)
Modified from Homocysteine LoweringTrialist
" Collaboration", 1998
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Predicted proportional reduction in tHcy with
folic acid (0.5-5 mg/d) according to pretreatment
tHcy and folate levels
Modified from Homocysteine LoweringTrialist
"Collaboration", 1998
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Time course of tHcy reduction at different doses
of folate
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Reduction of tHcy by 5-formyltetrahydrofolate
Geisler et al, 1998
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HypotheticalReductionin Mortalityby
Decreasing tHcy
Nygård et al, 1997
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Planned and ongoing intervention trials with
homocysteine lowering therapy
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tHcy as risk factor for cardiovascular disease

• Strong and independent
• Dose-dependent, no treshold
• Prevalent
• Acquired and genetic determinants
• Interaction with other risk factors
• Predicts the acute event
• Mechanism unknown
• Intervention studies with tHcy lowering therapy
  needed

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The LOCUS web site at http//www.uib.no/people
/mfapu/Pages/LOCUS.html
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Estimated changes in tHcy according to vitamin
status or creatinine level by multiple regression
P0.008
Plt0.001
P0.01
P0.001