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Hyperhomocysteinemia A New Cardiac Risk Factor?

Hyperhomocysteinemia A New Cardiac Risk Factor?. Michael Pursley M.D. Resident Grand Rounds January 26, 1999. 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

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Hyperhomocysteinemia A New Cardiac Risk Factor?

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  1. HyperhomocysteinemiaA New Cardiac Risk Factor? Michael Pursley M.D. Resident Grand Rounds January 26, 1999

  2. 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

  3. 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

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

  5. ECG

  6. Role of Homocysteine?

  7. 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?

  8. Homocysteine Definition History Metabolism Etiologies Pathophys Connection of CAD with homocysteine 5 Studies Lots of numbers Treatment and Discussion GOALS

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

  10. 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 Metabolism

  11. Etiologies • Genetic • Cystathione B-synthase • Homo 1:200,000 • Heter 1:300 • Methylenetetrahydrofolate reductase • Homo 9 - 17% population • Heter 30 - 41% population • Methionine Synthase

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

  13. 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 70-80%of pool Levels 5 - 15 mmole/l Normal 15 - 30 mmole/l Mod 30-100 mmole/l Int >100 mmol.l Severe Other Homocysteine Facts

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

  15. 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

  16. POP QUIZ • Clearly suffering from acute hyperhomocystein-emia • Has more hair on chest/back than head • Shouldn’t give up his day job • Is just a freak

  17. Clark, et al.NEJM1991;324:1149-54 • Case controlled study • First to study prevalence of tHcy in CAD • First to study tHcy as an independent risk • Used methionine loading test

  18. 27 heterozygotes of cystathione B-synthase VS 25 “normal” samples Level of 24 mmole/l 92% sensitivity 100% spec 123 patients with premature disease (<55) 50% with CAD 30% with CVA 20% with PVD Loaded levels obtained Clark, et al.NEJM1991;324:1149-54

  19. Clark, et al.NEJM1991;324:1149-54 • 30% of premature CAD patients had levels >24 mmole/l • Correlated to an odds ratio of 2.5 • ? Folate levels

  20. Stampfer, et alJAMA 1992;268:877-81 • First prospective case controlled study • Large, all male (participants of Physicians health study) • Followed for 5 years • Endpoint of Myocardial Infarction or cardiovascular death

  21. 14,916 males, ages 40 - 84 271 met criteria 271 case controlled matches “normal” Fasting tHcy levels drawn Other risk factors monitored (HTN, Cholesterol) Stampfer, et alJAMA 1992;268:877-81

  22. Stampfer, et alJAMA 1992;268:877-81 • Case tHcy level • 11.1 mmol/l • Control tHcy level • 10.5 mmol/l • 5.7% difference

  23. Stampfer, et alJAMA 1992;268:877-81 • 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

  24. Tromso StudyInt J Epidem 1995;24:704-8 • Large, prospective nested case controlled study • Both genders enrolled • Followed for three years • Endpoints were coronary disease or death (any cause)

  25. Tromso StudyInt J Epidem 1995;24:704-8 • 21,826 people (ages 12 - 61) • 123 patients met criteria • 4 controls per case matched • Fasting tHcy levels measured

  26. Tromso StudyInt J Epidem 1995;24:704-8 • 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

  27. ECAPJAMA 1997;227:1775-81 • 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

  28. 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 ECAPJAMA 1997;227:1775-81

  29. ECAPJAMA 1997;227:1775-81 • Showed tHcy had additive affect with cholesterol and multiplicative affect with tobacco and HTN. • Patients with increased tHcy had lower folate, B12

  30. Malinow, et alCirc 1993;87:1007-13 • 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

  31. Malinow, et alCirc 1993;87:1007-13 • 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

  32. Malinow, et alCirc 1993;87:1007-13 • Evaluated asymptomatic carotids • Significance • Showed increase OR at tHcy levels previously thought normal • One of a few studies that measured fibrinogen (positive correlation)

  33. Summary of Odds Ratio’s and Relative Risk’s

  34. 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

  35. 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

  36. 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

  37. GuidelinesArch Int Med 1998;158:1301-06

  38. 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

  39. 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

  40. 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

  41. 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

  42. 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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