Hyperhomocysteinemia A New Cardiac Risk Factor

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HyperhomocysteinemiaA New Cardiac Risk Factor?

• Michael Pursley M.D.
• Resident Grand Rounds
• January 26, 1999

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CASE PRESENTATION

• HPI 42 wm transferred to NCBH secondary to
  newly dx nqwmi.
• CRF Negative, except for FH
• PMHX Non significant
• MEDS None
• SOC negative tobacco, occ. ETOH
• FH father, brother early CAD

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PHYSICAL EXAM

• VS HR 79, BP 136/72, RR 16 Afebrile
• GEN WDWN, Mildly Obese NAD
• NECK No JVD, No Bruits
• CVS RRR, No MRG, No S3, S4
• LUNG BBS CTA
• ABD NTND, BS
• EXT Pulses Full, Warm, No Edema

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LABS

• CK/Tpn Peak 2000/25
• CBC/BMP WNL
• Lipids 183/255/26/106
• Fasting tHcy level 32mmol/l
• Chest Xray -- NACPD

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ECG
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Role of Homocysteine?
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Role of Homocysteine

• Is there evidence that homocysteine is a risk
  factor for CAD?
• What are the relative risks and odds ratios
  linking CAD and homocysteine?
• What role do other conventional risk factors play
  in hyperhomocysteinemia?
• Is there evidence to support treatment as primary
  or secondary prevention?

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GOALS

• Homocysteine
• Definition
• History
• Metabolism
• Etiologies
• Pathophys

• Connection of CAD with homocysteine
• 5 Studies
• Lots of numbers
• Treatment and Discussion

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INTRODUCTION

• 1969 -- McCully, et al. Arterial thrombosis and
  atherosclerosis via autopsy
• 1976 -- Wilken. First to show increased tHcy
  levels in patients with CAD

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Metabolism

• Remethylation cycle
• Recycle pathway
• Key enzymes
• Methionine synthase
• Methylenetetrahydro-folate reductase
• Key vitamins
• B12 -- coenzyme for methionine synthase
• Folate -- cosubstrate

• Transsulfuration cycle
• Excretory pathway
• Key enzymes
• Cystathione B-synthase
• Key vitamins
• B6 -- coenzyme for Cystathione B-synthase

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Etiologies

• Genetic
• Cystathione B-synthase
• Homo 1200,000
• Heter 1300
• Methylenetetrahydrofolate reductase
• Homo 9 - 17 population
• Heter 30 - 41 population
• Methionine Synthase

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Etiologies

• Nutritional
• Folate
• B12
• B6
• Disease
• Renal Failure
• Hypothyroidism
• Malignancy
• Medicines
• Estrogens ?
• Phenytoin, Carbamazepine
• Methotrexate

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Other Homocysteine Facts

• Methionine Challenge
• Oral Load of 0.1 mg/kg of methionine
• Levels at 4 and 8 hrs
• ? Utility

• Measurement
• Total tHcy levels include tHcy, tHcy thiolactone,
  mixed disulfides
• Protein bound 70-80of pool
• Levels
• 5 - 15 mmole/l Normal
• 15 - 30 mmole/l Mod
• 30-100 mmole/l Int
• gt100 mmol.l Severe

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Pathophysiology

• Endothelial Damage
• Increased Platelet Aggregation
• Abnormalities of fibrinolysis
• Correlation with Fibrinogen

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Hyperhomocysteinemia and CAD

• Many Studies linking tHcy and CAD
• Most prospective - case controlled
• Most follow fasting tHcy levels
• Most include other risk factors
• Most look at PVD and CVA as well
• Some measure vitamin levels

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POP QUIZ

• Clearly suffering from acute hyperhomocystein-emia
  
• Has more hair on chest/back than head
• Shouldnt give up his day job
• Is just a freak

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Clark, et al.NEJM19913241149-54

• Case controlled study
• First to study prevalence of tHcy in CAD
• First to study tHcy as an independent risk
• Used methionine loading test

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Clark, et al.NEJM19913241149-54

• 27 heterozygotes of cystathione B-synthase
• VS
• 25 normal samples
• Level of 24 mmole/l
• 92 sensitivity
• 100 spec

• 123 patients with premature disease (lt55)
• 50 with CAD
• 30 with CVA
• 20 with PVD
• Loaded levels obtained

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Clark, et al.NEJM19913241149-54

• 30 of premature CAD patients had levels gt24
  mmole/l
• Correlated to an odds ratio of 2.5
• ? Folate levels

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Stampfer, et alJAMA 1992268877-81

• First prospective case controlled study
• Large, all male (participants of Physicians
  health study)
• Followed for 5 years
• Endpoint of Myocardial Infarction or
  cardiovascular death

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Stampfer, et alJAMA 1992268877-81

• 14,916 males, ages 40 - 84
• 271 met criteria
• 271 case controlled matches normal

• Fasting tHcy levels drawn
• Other risk factors monitored (HTN, Cholesterol)

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Stampfer, et alJAMA 1992268877-81

• Case tHcy level
• 11.1 mmol/l
• Control tHcy level
• 10.5 mmol/l
• 5.7 difference

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Stampfer, et alJAMA 1992268877-81

• Distribution of case vs. controls similar until
  95th percentile (15.8 mmol/l tHcy)
• Preponderance of cases vs controls in this area
  (11 vs 6)
• RR of 3.1

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Tromso StudyInt J Epidem 199524704-8

• Large, prospective nested case controlled study
• Both genders enrolled
• Followed for three years
• Endpoints were coronary disease or death (any
  cause)

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Tromso StudyInt J Epidem 199524704-8

• 21,826 people (ages 12 - 61)
• 123 patients met criteria
• 4 controls per case matched
• Fasting tHcy levels measured

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Tromso StudyInt J Epidem 199524704-8

• Case tHcy level
• 12.7 mmol/l
• Control tHcy level
• 11.3 mmol/l
• 12.4 reduction
• RR 1.32 for 4 mmol increase in tHcy at no
  threshold level

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ECAPJAMA 19972271775-81

• Large, case controlled study
• Evaluated the independence and relationship of
  tHcy and other conventional risk factors
• First to evaluate the effects in women
• First to fully evaluate vitamin use

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ECAPJAMA 19972271775-81

• 750 patients with recent Dx of atherosclerosis
• 51 CHD
• 800 matched controls

• Fasting tHcy levels
• Cases 11.1 mmol/l
• Controls 9.7 mmol/l
• 12.9 reduction
• RR 1.4 for every 5 mmol/l increase

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ECAPJAMA 19972271775-81

• Showed tHcy had additive affect with cholesterol
  and multiplicative affect with tobacco and HTN.
• Patients with increased tHcy had lower folate, B12

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Malinow, et alCirc 1993871007-13

• Case controlled, asymptomatic patients from ARIC
  study, ages 45 - 64
• Measured carotid wall thickness
• Cases were defined as patients with thickened
  intimal walls
• Matched with controls (normal carotids)
• Measured fasting tHcy levels

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Malinow, et alCirc 1993871007-13

• 11.1 reduction of tHcy in controls vs cases
• tHcy noted to have a positive correlation with
  age, HTN, fibrinogen and an inverse relation with
  HDL

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Malinow, et alCirc 1993871007-13

• Evaluated asymptomatic carotids
• Significance
• Showed increase OR at tHcy levels previously
  thought normal
• One of a few studies that measured fibrinogen
  (positive correlation)

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Summary of Odds Ratios and Relative Risks
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Putting it all together

• Based on the current evidence and assuming that
  decreased levels meant decreased mortality
• Boushey, et al recently performed a meta-analysis
  and stated that the OR for CAD to be 1.6 for
  every 5 mmol/l increment

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Boushey, et al

• Stretching the numbers, the authors predicted
  that 10 of the United States CAD risk was
  independently attributable to tHcy
• Stretching farther, they estimated that 13,500 to
  50,000 CAD deaths could be prevented each year

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Treatment

• Currently there is no data showing a decreased
  mortality or prevention of MI with treatment of
  hyperhomocysteinemia
• The treatment is centered around folate, B12 and
  B6
• Multiple studies showing the effect of single vs
  combination therapy

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GuidelinesArch Int Med 19981581301-06
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Folate

• Folate replacement is essential, as it is a
  cosubstrate
• Dosing ranges from 400 mgs to 5 gms
• The most effective lowest studied is 650 mgs
  Boushey, et al, in which there was a tHcy
  decrease of about 42
• Preliminary studies from the Cleveland Clinic
  show doses of 400 mgs to only have 15 reduction
  of levels and to have 35 non-responders

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B12 (Cobalamin)

• Co-enzyme for methionine synthase
• B12 replacement seems effective in lowering tHcy
  levels only in cases of overt deficiency
• Otherwise, there is no supportive evidence that
  independently it is effective
• In deficient states the daily recommended dose is
  1 mg

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B6 (Pyridoxine)

• Co-enzyme for cystathione B-synthase
• Even less data showing effectiveness as a single
  agent
• May be more effective in lowering post-load
  levels in patients with normal fasting levels
• Daily recommended dose is 5 mg

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Summary

• tHcy has received lots of attention over the past
  3 decades as a possible progenitor of
  atherosclerosis
• In vitro and In vivo studies have shown tHcy to
  be adverse to the endothelium, platelets and
  clotting factors
• Clinical studies have linked tHcy to CAD
• There is adequate treatment for
  hyperhomocysteinemia

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Discussion and Unanswered Questions

• Does treatment decrease morbidity and mortality?
• What role do vitamin deficiencies play? Is
  folate deficiency the actual causative agent?
• Does tHcy represent another inflammatory reactant
  (i.e. fibrinogen, c-reactive protein)?

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