CORONARY ARTERY DISEASE RISK FACTORS

n.b. For purposes of guiding management of dyslipidemias, NCEP specifies a small list of risk factors as counting--See under "Dyslipidemias" for details.  The NCEP recommends counting CAD risk factors among those in the "major" category below, though sedentary lifestyle and dyslipidemias in general aren't counted; HDL < 35 counts as a risk factor, though; Also, HDL > 59 counts as a "negative" risk factor, i.e. if it's there, you subtract 1 from the count of risk factors

 

MAJOR (per JAMA 269:3015, 1993):

  1. Age (e.g., >45yo for men, >55yo for women unless premature menopause w/o HRT)
  2. Family history (e.g., MI or sudden death at <55yo in father or other 1st-degree male relative, or <65yo in mother or other 1st-degree female relative)
  3. Smoking
  4. Hypertension
  5. Dyslipidemias (high LDL, low HDL, high TC/HDL or LDL/HDL ratio--Click on link for details)
  6. Diabetes Mellitus
  1. Unknown whether glycemic control affects risk
  2. Raises risk more for women than for men (NEJM 332:1758, 1995-rvw)
  1. Sedentary lifestyle

OTHERS:

  1. High HDL (> 60mg/dl) is a "negative" risk factor per NCEP (see under "dyslipidemias")
  1. Obesity
    1. Traditionally considered a weak but significant independent factor; may contribute secondarily through effects on glucose metabolism, BP, etc.
    2. 115,000 women enrolled in Nurses' Health study 30-55yo and free of CV disease or Ca at enrollment followed for 16y. In multivariate analysis (adjusted for age, tobacco consumption, menopausal status, use of OCP's and postmenopausal HRT, and parental h/o MI before age 60), the following results were obtained (NEJM 333:677, 1995--abst):
      1. For all women, RR of death during study interval attained statistical significance only in women with BMI > 32 (RR 1.5)
      2. For women who never smoked, RR of death during study interval attained statistical significance in women from BMI 27 upward (1.4 for BMI 27-28.9; 1.7 for BMI 29-31.9; 1.9 for BMI > 31.9)
      3. For women who never smoked and had stable weight in 4y after intake, RR of death during study interval attained statistical significance in women from BMI 27 upward (1.6 for BMI 27-28.9; 2.1 for BMI 29-31.9; 2.2 for BMI > 31.9)--in this analysis, also adjusted for EtOH and saturated fat intake and physical activity.
    3. 44,702 women enrolled in Nurses' Health Study 40-65yo and free of CAD, CVA, and Ca at baseline followed for 8y. (JAMA 280:1843--abst)
      1. WHR and waist circumference were independently associated with risk of CAD; adjustments included adjustment for BMI
    4. Data from men in the Framingham study who were examined biennially over 30y. Baseline weight was significantly correlated with mortality; including after multivariate analysis (abstract didn't say what factors were controlled for; Ann. Int. Med. 103:1006, 1985--abst)
    5. 3983 men with mean age at entry of 30.8 years followed for 26y. After adjustment for age and BP, BMI was a significant predictor of onset of ischemic heart disease. (Am. J. Cardiol 39:452, 1977--abst)
    6. 3y prospective study of 29,000 US men age 40-75y at intake. BMI, waist-hip ratio, and weight gain since age 21 were ass'd with increased incidence of CAD. RR after adjustment for "other coronary risk factors" was 1.72 (sig.) for men < 65yo with BMI 25-28.9, 2.61 (sig.) for BMI 29-32.9, and 3.4 (sig.) for BMI > 32.9, c/w men w/BMI < 23. Abstract states that for men > 65yo, association was "much weaker." (Am. J. Epidemiol. 141:1117, 1995--abst)
  1. Hyperhomocysteinemia
  1. Severely increased levels in homocystinuria associated with accelerated atherosclerosis
  2. Moderately increased concentrations of homocysteine in men and women without homocystinuria ass'd with increased incidence of atherosclerosis, CAD, CVA, and overall mortality (though one case-control study of 140 pts with peripheral arterial disease and 14,776 controls followed over 9y failed to show an independent effect after adjusting for other serum markers--JAMA 285:2481, 2001)
  3. Hyperhomocysteinemia has also been associated with increased risk for Osteoporotic Fractures in several prospective cohort studies (NEJM 350:2033, 2004--JW; NEJM 350:2042, 2004--JW) and with Dementia (for the latter, follow link for info on trials of homocysteine-lowering therapy for Dementia)
  4. Folic acid, B6, and cardiovascular disease
    1. Folate necessary to convert homocysteine to methionine
    2. Population studies of folate and B6 intake
      1. Oral supplements of folate (in doses of 0.4-5mg/d), pyridoxine, and cobalamin have lowered moderately elevated plasma homocysteine levels to nl in some men (Med letter 39:12, 1997; BMJ 316:894, 1998--JW; Am. J. Cardiol. 83:821, 1999--AFP)
      2. In a prospective trial of 5,056 adults 35-79yo without known heart disease at baseline, serum and dietary folate were poorly correlated, but over 15y of f/u, subjects in lowest serum folate quartile had RR 1.69 for coronary death comparted with those in highest quartile. For women RR was 2.83. (JAMA 275:1893, ???)
      3. Folate & B6 intake (through diet or supplements) were inversely ass'd with risk of CAD dx in a 14y study of 80,000 women participating in the Nurses' Health Study (JAMA 279:359, 1998--JW)
    3. Prospective trials of folate etc. supplementation
      1. Several randomized trials have confirmed that folate supplementation (or folate + B12 supplementation) lowers serum homocysteine concentrations (Med. Lett. 45:85, 2003)
      2. A combination "homocysteine-lowering" regimen (folic acid 1mg, vit. B12 400ug, vit. B6 10mg QD) was ass'd with sig. lower risk of (death, nonfatal MI, or repeat revascularization) vs. placebo (15.4% vs. 22.8%; risk of death nonsig. lower--1.5% vs. 2.8%) over mean f/u of 11mos in 553 post-angioplasty patients (JAMA 288:973, 2002--abst)
      3. Folic acid 0.5mg PO QD was not ass'd with any difference in a composite endpoint (mortality or any of certain vascular events) c/w placebo in a 24mo randomized trial in 593 pts with stable CAD. (J. Am. Coll. Cardiol. 41:2105, 2003--abst)
      4. 3680 pts with h/o ischemic CVA and elevated homocysteine levels randomized to (folic acid 2.5mg/d + pyridoxine 25mg/d + cobalamin 0.4mg/d) vs. infinitesimal doses of all 3; over mean 2y f/u, no sig. diff. between the group in incidence of recurrence CVA, coronary events, or death.  (JAMA 291:565, 2004--JW)
      5. A combination of (folate, B6, and B12 PO) vs. placebo was, after 6mos, ass'd with no diff. in restenosis risk in a randomized trial in 636 pts s/p successful PTCA (NEJM 350:2673, 2004--JW) 
      6. In a study in 5,522 pts randomized to (folic acid 2.5mg, vit. B6 50mg, and vit. B12 1mg) vs. placebo; at 5y, there were no sig. diffs. in (cardiovascular death, MI, or CVA) ("Heart Outcomes Prevention Evaluation" study ("HOPE"); (NEJM 354:1567, 2006--JW)
      7. In a meta-analysis of 12 randomized trials of folate (0.5mg-15mg/d) vs. placebo, folate was associated with sig. reduction in homocysteine levels but had no sig. effect on incidence of CAD or CVA events or all-cause mortality (JAMA 296:2720, 2006--JW)
      8. In a study in 819 pts 50-70yo with serum homocysteine levels of 13umol/L or greater randomized to 0.8mg folic acid vs. placebo QD, after 3y, the folic acid group had sig. slower declines in information-processing speed ("FACIT" Trial; Lancet 369:208, 2007--JW)
      9. In a study in 5,442 women > 40yo with CAD or CAD risk factors randomized to a combination of (folate 2.5mg, vit. b6 50mg, and vit. b12 1mg) QD vs. placebo, after mean 7y f/u, there was no sig. diff. in incidence of (MI, CVA, coronary revascularization, or cardiac death) ("Women's Antioxidant and Folic Acid Cardiovascular Study" ("WAFACS") trial; JAMA 299:2027, 2008-JW)
  1. A case control study of 85 pairs of men with & w/o CAD showed statistically significant increased risk of CAD with all 3 of the following c/w those who had normal parameters for at least 2; the association held up after multivariate adjustment for LDL, HDL, and TG levels (JAMA 279:1955, 1998)
    1. High fasting plasma insulin
    2. High apolipoprotein B levels (the major structual protein of LDL, IDL, and VLDL
    3. Small, dense LDL particles
  1. Depression
  1. In a prospective study of 3,700 men & women > 70yo with no known CAD at outset with median f/u x 4y, after adjustment for other risk factors, there was a sig. increase in risk of CV death in depressed pts only for men and only for new depression (as opposed to depression of remote onset) (Am. J. Cardiol. 81:988, 1998--JW)
  1. Personality/behavior
    1. "Type A" behavior significantly and independently ass'd with risk for CAD in a prospective study of 1,305 men assessed with the "Type A Behavior" section of the MMPI-2 (Circ. 98:405, 1998--JW)
  1. Infections/Systemic inflammation (possible)
    1. C. pneumoniae has been identified in atherosclerotic placques
    2. Some studies have shown a decrease in risk of MI after abx tx (see under "Treatment of Stable CAD")
    3. Positive IgG Ab against Chlamydia pneumoniae, Helicobacter pylori, HSV, and CMV were not ass'd with increased risk of cardiovascular events in a case-control study of 366 women, using data from the Women's Health Study (Ann. Int. Med. 131:573, 1999--JW)
    4. C-Reactive Protein
      1. In a prospective trial of 5661 men 40-59 followed for 18y, CRP and Amyloid A levels were sig. ass'd with risk for coronary events; WBC, albumin levels, plasma homocysteine levels, and titers for H. pylori and Chlamydia pneumoniae were not (BMJ 321:199, 2000--JW)
      2. C-Reactive Protein elevation sig. and independently ass'd with risk of arterial disease in a case-control study of 140 pts with peripheral arterial disease and 14,776 controls followed over 9y (JAMA 285:2481, 2001)
      3. Serum CRP levels were a more accurate predictor of risk of cardiovascular events than LDL in an 8y cohort study of 28,000 middle-aged women (NEJM 347:155, 2002--JW)
      4. In a prospective study of 18,000 people followed for mean 18y, pts in top 3rd of baseline CRP levels had sig. higher risk for coronary events (OR 1.45) (NEJM 350:1387, 2004--JW)
      5. Specific treatment of C-Reactive Protein levels to reduce cardiovascular risk
        1. In a study of 17,802 men >50yo and women > 60yo with no known DM or cardiovascular disease, LDL < 130, and CRP 2mg/L or greater randomized to rosuvastatin 20mg/d vs. placebo, after median 1.9y f/u, rosuvastatin recipients had sig. lower incidence of (unstable angina, MI, CVA, regascularization, or cardiovascular death) (HR 0.56)  and all-cause mortality (HR 0.8); rosuvastatin group had sig. higher incidence of new-onset DM ("JUPITER" trial; NEJM 359:2195, 2008-JW)
        2. In a follow-up study of 15,548 pts from the JUPITER cohort who had LDL and CRP levels checked after 1y, there were sig. and independent reductions in LDL and CRP among rosuvastatin recipients; rosuvastatin recipients whose CRP levels fell < 2 mg/dL had sig. greater reductions in adverse cardiovascular events than those whose CRP levels remained 2 mg/dL or higher (Lancet 373:1175, 2009-JW)
        3. In a follow-up analysis of the 5,695 JUPITER subjects > 70yo, the primary outcome was reduced with Rosuvastatin by 39% (sig.); so was all-cause mortality (20% risk reduction) (data presented at European Society of Cardiology conference, reported in FP News 9/15/09 p. 1).
    5. Systemic Lupus Erythematosus is associated with increase risk
  1. Glutathione peroxidase 1
    1. Found in high concentrations in atherosclerotic placques.
    2. In a prospective study of 636 pts with suspected CAD followed for median 4.7y, higher baseline blood GP1 levels were ass'd with lower rates of cardiovascular events, even adjusting for other risk factors (NEJM 349:1605, 2003--JW)
  2. Epsilon-4 allele of apolipoprotein E (APOE4)
  3. Lipoprotein associated phospholipase A2
    1. An enzyme involved in repair of lipoproteins
    2. Independent predictor of coronary events in population studies (Med. Lett. 45:83, 2003)
  4. Anemia
    1. In a population-based cohort study of 14,420 people followed for avg. 6.1y, anemia (Hb < 13g/dL in men, < 12g/dL in women) was an independent predictor of development of CV disease (HR 1.4 after adjustment for confounders) (JACC 40:27, 2002--JW)
  5. Recent cessation of NSAID use (possible--click on link for details)
  6. Psoriasis (click on link for details)