1. DR RAKESH JAIN SENIOR RESIDENT,CARDIOLOGY GOVERNMENT MEDICAL COLLEGE, CALICUT 06.05.2013 NON CONVENTIONAL CORONARY RISK FACTORS

2. INTRODUCTION  Despite remarkable advances in CV health promotion over past several decades, CVD remains the leading cause of death worldwide.  Although atherosclerotic disease not become clinically apparent until adulthood, atherosclerotic process begins in early childhood.  Effective prevention relies on accurate identification of individual at risk of developing heart disease.

3.  Treatment to prevent CHD events by modifying risk factors is currently based on the Framingham risk model, which sorts persons into -  LOW RISK : 10 yrs risk of major CHD events <10%  INTERMEDIATE RISK : 10 yrs risk of major CHD events 10- 20%  HIGH RISK : 10 yrs risk of major CHD events > 20% NCEP ATP III, JAMA 2001;285:2486-97

4. Note: Risk estimates were derived from the experience of the Framingham Heart Study, a predominantly Caucasian population in Massachusetts, USA. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA. 2001;285:2486-2497. ASSESSING CHD RISK Step 1: Age YearsPoints 20-34-9 35-39-4 40-440 45-493 50-546 55-598 60-6410 65-6911 70-7412 75-7913 Step 2: Total Cholesterol TC Points atPoints atPoints atPoints atPoints at (mg/dL) Age 20-39Age 40-49Age 50-59Age 60-69Age 70-79 <16000000 160-19943210 200-23975310 240-27996421  280118531 HDL-C (mg/dL) Points  60-1 50-590 40-491 <402 Step 3: HDL-Cholesterol Systolic BPPointsPoints (mm Hg)if Untreatedif Treated <12000 120-12901 130-13912 140-15912  16023 Step 4: Systolic Blood Pressure Step 5: Smoking Status Points atPoints atPoints atPoints atPoints at Age 20-39Age 40-49Age 50-59Age 60-69Age 70-79 Nonsmoker00000 Smoker85311 Age Total cholesterol HDL-cholesterol Systolic blood pressure Smoking status Point total Step 6: Adding Up the Points Point Total10-Year RiskPoint Total10-Year Risk <0<1%118% 01%1210% 11%1312% 21%1416% 31%1520% 41%1625% 52%  17  30% 62% 73% 84% 95% 106% Step 7: CHD Risk ATP III Framingham Risk Scoring ww.lipidhealth.org

5. GAP IN CAD RISK ASSESSMENT  High risk persons benefit from aggressive risk reduction measures, low risk persons not require any intervention,  what to do with intermediate group?  Not all individuals with coronary heart disease have traditional risk factors Diabetes Mellitus Hypertension Tobacco Exposure Lipid Disorders Family History

6. RATIONALE FOR NEW MARKERS  If the risk model could be improved, treatment might be better targeted, thereby maximizing screening benefits and minimizing harms.  The most likely opportunity to improve the model is use of additional risk factors to reclassify those in the intermediate- risk group to either high or low risk.

7. Criteria’s for evaluating clinical value of new risk factor  Presence of reliable assay  Independence from other risk factors  Clear statistical association of test and clinical endpoint  Ability to improve prediction beyond traditional risk factors  Acceptable cost for assay Circulation 2003;107:499-511

8. NEWER RISK FACTORS 1. High-sensitivity C-Reactive protein (hsCRP) 2. Lipoprotein (a) 3. Homocysteine 4. fibrinogen 5. CAC score 6. Ankle-brachial index 7. Carotid IMT 8. HbA1C 9. Urinary albumin excretion 10. Leucocyte count 11. Periodontal disease

9. HIGH-SENSITIVITY C-REACTIVE PROTEIN (HSCRP)  Circulating acute phase reactant  Play a makor role in innate immunity  Many-fold increase with injury & infection  Synthesized in liver, induced primarily by interleukin-6 (IL-6)  Stable levels in circulation, not affected by meals, no circadian levels  Most widely studied new marker for CAD

10. CRP V/S HS-CRP  Standard CRP tests determine levels which are increased up to 1,000-fold in response to infection or tissue destruction, but cannot adequately assess the normal range  High-sensitivity CRP (hs-CRP) assays detect levels of CRP within the normal range, levels proven to predict future cardiovascular events.

11. C-REACTIVE PROTEIN: RISK FACTOR OR RISK MARKER?  CRP previously known to be a marker of high risk in cardiovascular disease  More recent data may implicate CRP as an actual mediator of atherogenesis  Multiple hypotheses for the mechanism of CRP- mediated atherogenesis by -  Endothelial dysfunction via ↓ NO synthesis  ↑LDL deposition in plaque by CRP-stimulated macrophages

12. Does hs-CRP predicts first events ?

13. HS-CRP AND RISK OF FUTURE MI IN APPARENTLY HEALTHY MEN [PROSPECTIVE PHYSICIANS' HEALTH STUDY, A COHORT OF ALMOST 22,000 HEALTHY, MIDDLE-AGED MEN WERE TRACKED OVER AN 8- TO 10-YEAR PERIOD FOR FIRST EVER OCCURRENCE OF MYOCARDIAL INFARCTION (MI)] Ridker PM et al. N Engl J Med 1997;336:973-979. 1 <0.055 Relative Risk of MI P = 0.03 Quartile of hs-CRP (range, mg/dL) 2 0.056–0.114 3 0.115–0.210 4 >0.211 P < 0.001 P Trend <0.001

14. HS-CRP AS A RISK FACTOR FOR FUTURE CVD : PRIMARY PREVENTION COHORTS 01.02.03.04.05.06.0 Kuller MRFIT 1996CHD Death Ridker PHS 1997MI Ridker PHS 1997Stroke Tracy CHS/RHPP 1997CHD Ridker PHS 1998,2001PAD Ridker WHS 1998,2000,2002CVD Koenig MONICA 1999CHD Roivainen HELSINKI 2000CHD Mendall CAERPHILLY 2000CHD Danesh BRHS 2000CHD Gussekloo LEIDEN 2001Fatal Stroke Lowe SPEEDWELL 2001CHD Packard WOSCOPS 2001CV Events* Ridker AFCAPS 2001CV Events* Rost FHS2001Stroke Pradhan WHI 2002MI,CVD death Albert PHS 2002Sudden Death Sakkinen HHS 2002MI Relative Risk (upper vs lower quartile) Ridker PM. Circulation 2003;107:363-9

15. DOES CRP PROVIDE PREDICTIVE INFORMATION BEYOND EXISTING GLOBAL PREDICTORS? Ridker PM. Circulation 2003;107:363-9

16. HS-CRP ADDS TO PREDICTIVE VALUE OF TC:HDL RATIO IN DETERMINING RISK OF FIRST MI Total Cholesterol:HDL Ratio Ridker et al, Circulation. 1998;97:2007–2011. hs-CRP Relative Risk

17. RISK FACTORS FOR FUTURE CARDIOVASCULAR EVENTS: WHS 01.02.04.06.0 Lipoprotein(a) Homocysteine IL-6 TC LDLC sICAM-1 SAA Apo B TC: HDLC hs-CRP hs-CRP + TC: HDLC Relative Risk of Future Cardiovascular Events Ridker et al, N Engl J Med. 2000;342:836-43

18. “Large series of prospective epidemiologic studies has demonstrated that CRP, when measured with high- sensitivity assays (hsCRP), strongly and independently predicts risk of myocardial infarction, stroke, peripheral arterial disease, and sudden cardiac death in apparently healthy individuals”

19. IS THERE CLINICAL EVIDENCE THAT INFLAMMATION CAN BE MODIFIED BY PREVENTIVE THERAPIES ?

20. ELEVATED CRP LEVELS IN OBESITY: NHANES 1988-1994 Visser M et al. JAMA 1999;282:2131-2135. Normal Percent with CRP 0.22 mg/dL OverweightObese

21. EFFECTS OF WEIGHT LOSS ON CRP CONCENTRATIONS IN OBESE HEALTHY WOMEN  83 women (mean BMI 33.8, range 28.2-43.8 kg/m 2 ) placed on very low fat, energy-restricted diet for 12 weeks  Baseline CRP positively associated with BMI (r=0.281, p=0.01)  Average weight loss 7.9 kg & CRP reduced by 26% (p<0.001) at 12 weeks  Change in CRP correlated with change in TC (r=0.240, p=0.03) but not changes in LDL-C, HDL-C, or glucose  At 12 weeks, CRP concentration highly correlated with TG (r=0.287, p=0.009), but not with other lipids or glucose Heilbronn LK et al. Arterioscler Thromb Vasc Biol 2001;21:968-970.

22. hs-CRP (mg/L) EFFECT OF STATIN THERAPY ON HS-CRP LEVELS AT 6 WEEKS Jialal I et al. Circulation 2001;103:1933-1935. 2001 Lippincott Williams & Wilkins. 65432106543210 Baseline *** Prava (40 mg/d) Simva (20 mg/d) Atorva (10 mg/d) *p<0.025 vs. Baseline

23. Ridker et al, New Engl J Med 2001;344:1959-65 Low LDL, Low hsCRP Low LDL, High hsCRP Statin EffectiveStatin Not Effective 1.0 2.0 0.5 [A] [B] Low LDL, Low hsCRP Low LDL, High hsCRP Statin EffectiveStatin Not Effective 1.0 2.0 0.5 AFCAPS/TexCAPS Low LDL Subgroups RR AFCAPS/TEXCAPS showed statins to be effective in lowering risk in the setting of normal LDL-C, but only when inflammation was present

24. A Randomized Trial of Rosuvastatin in the Prevention of Cardiovascular Events Among 17,802 Apparently Healthy Men and Women With Elevated Levels of C-Reactive Protein (hsCRP): The JUPITER Trial Paul Ridker*, Eleanor Danielson, Francisco Fonseca*, Jacques Genest*, Antonio Gotto*, John Kastelein*, Wolfgang Koenig*, Peter Libby*, Alberto Lorenzatti*, Jean MacFadyen, Borge Nordestgaard*, James Shepherd*, James Willerson, and Robert Glynn* on behalf of the JUPITER Trial Study Group An Investigator Initiated Trial Funded by AstraZeneca, USA (Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin)

25. Rosuvastatin 20 mg (N=8901) MI Stroke Unstable Angina CVD Death CABG/PTCA Multi-National Randomized Double Blind Placebo Controlled Trial of Rosuvastatin in the Prevention of Cardiovascular Events Among Individuals With Low LDL and Elevated hsCRP 4-week run-in Ridker et al, Circulation 2003;108:2292-2297. No Prior CVD or DM Men >50, Women >60 LDL <130 mg/dL hsCRP >2 mg/L JUPITER Trial Design Placebo (N=8901) Argentina, Belgium, Brazil, Bulgaria, Canada, Chile, Colombia, Costa Rica, Denmark, El Salvador, Estonia, Germany, Israel, Mexico, Netherlands, Norway, Panama, Poland, Romania, Russia, South Africa, Switzerland, United Kingdom, Uruguay, United States, Venezuela median follow-up of 1.9years

26. JUPITER Baseline Blood Levels (median, interquartile range) RosuvastatinPlacebo (N = 8901)(n = 8901) hsCRP, mg/L4.2(2.8 - 7.1)4.3 (2.8 - 7.2) LDL, mg/dL 108 (94 - 119)108(94 - 119) HDL, mg/dL49(40 – 60)49(40 – 60) Triglycerides, mg/L118(85 - 169)118 (86 - 169) Total Cholesterol, mg/dL186 (168 - 200)185(169 - 199) Glucose, mg/dL94(87 – 102)94(88 – 102) HbA1c, %5.7(5.4 – 5.9)5.7 (5.5 – 5.9) All values are median (interquartile range). [ Mean LDL = 104 mg/dL ] Ridker et al NEJM 2008

27. JUPITER Primary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death Placebo 251 / 8901 Rosuvastatin 142 / 8901 HR 0.56, 95% CI 0.46-0.69 P < 0.00001 Number Needed to Treat (NNT) = 25 - 44 % 01234 0.00 0.02 0.04 0.06 0.08 Cumulative Incidence Number at Risk Follow-up (years) Rosuvastatin Placebo 8,9018,6318,4126,5403,8931,9581,353983544157 8,9018,6218,3536,5083,8721,9631,333955534174 Ridker et al NEJM 2008

28. JUPITER Secondary Endpoint – All Cause Mortality Placebo 247 / 8901 Rosuvastatin 198 / 8901 HR 0.80, 95%CI 0.67-0.97 P= 0.02 - 20 % 01234 0.00 0.01 0.02 0.03 0.04 0.05 0.06 Cumulative Incidence Number at Risk Follow-up (years) Rosuvastatin Placebo 8,9018,8478,7876,9994,3122,2681,6021,192683227 8,9018,8528,7756,9874,3192,2951,6141,196684246 Ridker et al NEJM 2008

29. JUPITER Implications for Primary Prevention Among men and women age 50 or over : If diabetic, treat If LDLC > 160 mg/dL, treat If hsCRP > 2 mg/L, treat A simple evidence based approach to statin therapy for primary prevention. Ridker et al NEJM 2008

30. CRP IMPROVES NET RECLASSIFICATION INDEX  From the Physicians Health Study: hs CRP and parental history improved risk prediction 5.3% overall and 14.2% for patients at intermediate risk by traditional risk scores (both P<0.001) (Ridker et al., Circulation 2008)  Framingham Heart Study: hs-CRP improved prediction of cardiovascular disease by 5.6% (P=0.014) and of coronary heart disease by 11.8% (P=0.009) (Wilson et al. Circulation: Cardiovascular Quality and Outcomes 2008)

31. Recommendations for Measurement of C-Reactive Protein CLASS IIa 1. In men 50 years of age or older or women 60 years of age or older with LDL cholesterol less than 130 mg/dL; not on lipid-lowering, hormone replacement, or immunosuppressant therapy; without clinical CHD, diabetes, chronic kidney disease, severe inflammatory conditions, or contraindications to statins, measurement of CRP can be useful in the selection of patients for statin therapy. (Level of Evidence: B) CLASS IIb 1. In asymptomatic intermediate-risk men 50 years of age or younger or women 60 years of age or younger, measurement of CRP may be reasonable for cardiovascular risk assessment. (Level of Evidence: B) CLASS III: NO BENEFIT 1. In asymptomatic high-risk adults, measurement of CRP is not recommended for cardiovascular risk assessment. (Level of Evidence: B) 2. In low-risk men younger than 50 years of age or women 60 years of age or younger, measurement of CRP is not recommended for cardiovascular risk assessment. (Level of Evidence: B) (2010 ACCF/AHA guideline for assessment of cardiovascular risk in asymptomatic adults: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2010;56:e50–103.)

32. 1 mg/L 3 mg/L10 mg/L Low Risk Moderate Risk High Risk Acute Phase Response Ignore Value, Repeat Test in 3 weeks >100 mg/L Ridker PM. Circulation 2003;107:363-9 CLINICAL APPLICATION OF HS-CRP FOR CARDIOVASCULAR RISK PREDICTION Current guidelines from the Canadian Cardiovascular Society strongly endorse evaluation of hsCRP in these intermediate-risk individuals and suggest that statin therapy be considered for those with levels higher than 2 mg/liter. Genest J, et al: 2009 Canadian Cardiovascular Society/Canadian guidelines for the diagnosis and treatment of dyslipidemia and prevention of cardiovascular disease in the adult—2009 recommendations. Can J Cardiol 2009; 25:567.

33. HOMOCYSTEINE  Intermediary amino acid formed by the conversion of methionine to cysteine  Moderate hyperhomocysteinemia occurs in 5-7% of the population  Recognized as an independent risk factor for the development of atherosclerotic vascular disease and venous thrombosis  Can result from genetic defects(MTHFR mutation), drugs(methotrexate, carbamezepine, niacin), vitamin deficiencies, or smoking, hypothyroidism, renal insufficiency.

35. EPIDEMIOLOGY Prevalence of hyperhomocysteinemia is not insignificant: 1. General population: 5 - 10% 2. Elderly population: 30 - 40% 3. Pts with vascular disease: 20 - 40%.  Annu Rev Med 1998;49:31-62. HCY and cardiovascular disease. Refsum H, Ueland PM, et.al.  JAMA 1993;270:2693-8. Vitamin status and intake as primary determinants of HCYemia in an elderly population. Selhub J, Jacques PF, et.al.  Jacques PF, Bostom AG, Wilson PW, et.al. Determinants of plasma total HCY concentration in the Framingham Offspring cohort. Am J Clin Nutr. 2001;73:613-621.

36. “It is estimated that in about two-thirds of cases of hyperhomocysteinemia, vitamin deficiency is the primary cause.” “Folic acid deficiency is the most common cause of elevated HCY levels.”  Reference: Selhub J, Jacques PF, et.al. Vitamin Status and intake as primary determinants of HCYemia in an elderly population. JAMA 1993; 270: 2693-2698.  Reference: Jacques PF, Selhub J, et.al The effect of folic acid fortification on plasma folate and total HCY concentration. N Engl J Med 1999;13:1449-1454

37. MECHANISM OF INJURY Working hypothesis is that elevated homocysteine levels:  promote oxidant injury to the vascular endothelium  impairs endothelium-dependent relaxation  alters the coagulant properties of blood  Ozdemir R, Barutcu I, et.al. Vascular Endothelial Function and Plasma Homocysteine Levels in Behcet’s Disease, Am J Cardiol 2004;94:522-525.  Austin RC, Lentz SR, Werstuck GH. Role of HyperHCYemia in endothelial dysfunction and atherothrombotic disease. Cell Death Differ. 2004 Jul;11 Supple 1:S56-64.

38. CLINICAL TRIALS Vitamin Intervention for Stroke Prevention (VISP) study:  3680 patients with prior stroke  High dose v/s low dose vitamin regimens containing folate & pyridoxine was given.  No evidence of differential benefit in the high-dose group, despite greater homocysteine level reduction Another trial  636 postangioplasty patients  Treated with folate, vitamin B 6, and vitamin B 12,  Rates of in-stent stenosis were actually higher in most intervention groups compared with those allocated to placebo.  This negative trial is clinically important, because it conflicts with prior work that had suggested benefit in this setting. JAMA 2004;291:565-575 N Engl J Med 2004; 350:2673

39.  3749 participants with recent myocardial infarction were treated folate, vitamin B 6, and vitamin B 12  Mean total homocysteine was lowered by 27% in the intervention group  No significant effect on the primary endpoint (hazard ratio [HR], 1.08; 95% CI, 0.93 to 1.25)  In fact, there was trend toward increased risk in intervention group (HR, 1.22; 95% CI, 1.00 to 1.50) Similarly Heart Outcomes Prevention Evaluation (HOPE-2) trial involving 5522 pts with vascular disease or diabetes & Veterans Administration trial involving 2056 pts with advanced renal disease results in no benefits as compared to placebo. Norwegian Vitamin Trial (NORVIT)

40. SCREENING AND TREATMENT RECOMMENDATIONS FOR HOMOCYSTEINE In 2000, the Canadian Task Force on Preventive Health Care concluded that there was a link between total HCY levels and CAD based on cohort and case- control studies, but found the evidence insufficient to recommend for or against HCY screening in both the general and high-risk populations. Despite reduced enthusiasm and lack of evidence that homocysteine reduction lowers risk, there remain specific patient populations for whom homocysteine evaluation may prove appropriate, including those lacking traditional risk factors, those with renal failure, or those with markedly premature atherosclerosis or a family history of myocardial infarction and stroke at a young age Reference: CMAJ.2000 Jul 11;163(1):21-9. Preventive health care, 2000 update: screening and management of hyperHCCYemia for the prevention of CAD evens. The Canadian Task Force on Preventive Health Care. Booth GL, Wang EE.

41. CAC SCORE: COMPUTED TOMOGRAPHY FOR CORONARY CALCIUM  Assessed by multidetector CT or electron beam tomography  Detect and quantify coronary calcium, a marker of atherosclerosis  CT scanning should generally not be done in men 40 years old and women 50 years old due to the very low prevalence of detectable calcium in these age groups & radiation exposure

42. DATA ON INDEPENDENT RELATIONSHIP TO CARDIOVASCULAR EVENTS  Total amount of coronary calcium (usually expressed as the Agatston score) provides information about future CAD events over and above the information provided by standard risk factors.  Intermediate-risk patients with an elevated CAC score (intermediate FRS and CAC 300) had a 2.8% annual rate of cardiac death or MI (roughly equivalent to a 10-year rate of 28%) that would be considered high risk.

43.  Pooled data from 6 studies of 27,622 asymptomatic patients  The 11,815 subjects who had CAC scores of 0 had a low rate of events over the subsequent 3 to 5 years (0.4%, based on 49 events) CAC SCORERR for CHD eventsMI/death Rate 00.4 % 100-4004.3 % (95% CI 3.5 to 5.2; p˂0.0001) 400-10007.2 % (95% CI 5.2 to 9.9; p˂0.0001)4.6 % ≥100010.8 % (95% CI 4.2 to 27.7; p˂0.0001)7.1 %

44.  Relationships between CAC outcomes are similar in men and women and different ethnic groups  Higher baseline CAC was strongly associated with initiation of aspirin therapy, dietary changes, and increased exercise.

45. RECOMMENDATIONS FOR CALCIUM SCORING METHODS CLASS IIa 1. Measurement of CAC is reasonable for cardiovascular risk assessment in asymptomatic adults at intermediate risk (10% to 20% 10-year risk). (Level of Evidence: B) CLASS IIb 1. Measurement of CAC may be reasonable for cardiovascular risk assessment in persons at low to intermediate risk (6% to 10% 10-year risk). (Level of Evidence: B) CLASS III: NO BENEFIT 1. Persons at low risk (6% 10-year risk) should not undergo CAC measurement for cardiovascular risk assessment. (Level of Evidence: B) (2010 ACCF/AHA guideline for assessment of cardiovascular risk in asymptomatic adults. J Am Coll Cardiol 2010;56:e50 103.)

46. ANKLE-BRACHIAL INDEX  An office-based test to check for the presence of PAD  Value of 0.9 indicating the presence of PAD, which is defined as 50% stenosis (high sensitivity and specificity)  Abnormally low ABI or high ABI (˃1.3) shown to be a predictor of cardiovascular events

47. ASSOCIATION WITH INCREASED RISK  Recent collaborative study combined data from 16 studies included a total of 24,955 men and 23,399 women without a history of CHD  Mean age ranged from 47 to 78 years  FRS-predicted rate of CHD ranged from 11% to 32% in men and from 7% to 15% in women  For an ABI of 0.9 compared with an ABI of 1.11 to 1.4, the HR for cardiovascular mortality and major events was 3.33 for men and 2.71 for women  When adjusted for the FRS, the HRs were only moderately lower (2.34 in men and 2.35 in women), demonstrating the additive predictive value of the ABI beyond the FRS.

48.  An ABI of 1.4 was also associated with higher risk within most of the FRS categories  Greatest incremental benefit of ABI for predicting risk in men was in those with a high FRS (˃20%), in whom a normal ABI reduced risk to intermediate.  In women the greatest benefit was in those with a low FRS (˂10%), in whom an abnormally low or high ABI would reclassify them as high risk.

49. RECOMMENDATION FOR MEASUREMENT OF ANKLE-BRACHIAL INDEX CLASS IIa 1. Measurement of ABI is reasonable for cardiovascular risk assessment in asymptomatic adults at intermediate risk. (Level of Evidence: B) (2010 ACCF/AHA guideline for assessment of cardiovascular risk in asymptomatic adults. J Am Coll Cardiol 2010;56:e50 103.)

50. CAROTID INTIMA-MEDIA THICKNESS  Noninvasive, nonionizing radiation test using ultrasound imaging (common carotid artery)  Risk of incident CHD events increases in a continuous fashion as carotid IMT increases (RR increases approximately 15% per 0.10-mm increase in carotid IMT) after adjustment for traditional CVD risk factors

51. STUDIES Kuopio Ischemic Heart Disease Risk Factor study:  Risk of future MI in Finnish men increased by 11% for every 0.1-mm increment in carotid IMT  For carotid IMT values 1 mm, there was a 2-fold greater risk of acute MI over 3 years ARIC study:  Every 0.19-mm increment in carotid IMT, risk of death or MI increased by 36% in middle-aged patients (45 to 65 years of age) Rotterdam study: same results as ARIC Among intermediate-risk patients (10% to 20%, 10-year estimated risk group), the addition of carotid IMT led to clinical net reclassification In approximately 9.9%

52. RECOMMENDATION FOR MEASUREMENT OF CAROTID INTIMA-MEDIA THICKNESS CLASS IIa 1. Measurement of carotid artery IMT is reasonable for cardiovascular risk assessment in asymptomatic adults at intermediate risk. (Level of Evidence: B) (2010 ACCF/AHA guideline for assessment of cardiovascular risk in asymptomatic adults. J Am Coll Cardiol 2010;56:e50 103.)

53. LIPOPROTEIN (A)  LDL-like particle consisting of apolipoprotein (a) moiety attached to apoB-100, structural homology to plasminogen  Plasma levels are under genetic control and don’t vary with diet or exercise  Acute phase reactant, doubling in concentration after IL-6 stimulation  Mechanism in atherothrombosis  Its close homology to plasminogen may result in inhibiting endogenous fibrinolysis by competing with plasminogen binding on the endothelium  Lp(a) binds and inactivates tissue factor pathway inhibitor and may increase the expression of plasminogen activator inhibitor  Lp(a) also colocalizes within atherosclerotic lesions and may have local actions through oxidized phospholipids pathways

54.  Updated meta-analysis of 36 prospective studies that included more than 12,000 cardiovascular endpoints, the adjusted risk ratios for each standard deviation increase in plasma Lp(a) level were 1.13 for CHD and 1.10 for ischemic stroke.  Adjustment for classic cardiovascular risk factors only modestly attenuated these effects, in part because there is little correlation between Lp(a) and other markers of risk.  Whether the assessment of Lp(a) truly adds prognostic information to overall risk in primary prevention remains uncertain, however, because in most studies, Lp(a) has typically predictive value for those already known to be at high risk as a result of the presence of other risk factors, in particular elevated LDL-C levels.

55. RECOMMENDATION FOR LIPOPROTEIN(A)  Lipoprotein(a) level is unlikely to be useful for stratifying intermediate-risk persons, commercial assays are poorly standardized and prevalence of high serum level (˃1.07ụmol/L) in intermediate-risk persons is uncertain, hence not recommended. (clinical guidelines for emerging cad risk factors for CAD. Ann Intern Med; 2009.151:496-507)

56. FIBRINOGEN  Circulating glycoprotein involved in final steps of coagulation  Other actions:  Regulation of cell adhesion, chemotaxis and proliferation  Vasoconstriction at sites of vascular injury  Stimulation of platelet aggregation  Influence on blood viscosity

57.  Acute phase reactant, increasing up to 4-fold after infectious or inflammatory stimuli  Levels also increased by:  Cigarette smoking  Diabetes  Hypertension  Obesity  Sedentary lifestyle  Levels lowered with fibrates and niacin; no effect from statins or aspirin

58. FIBRINOGEN AND CHD RISK FACTORS  Fibrinogen levels increase with age and body mass index, and higher cholesterol levels  Smoking can reversibly elevated fibrinogen levels, and cessation of smoking can lower fibrinogen.  Those who exercise, eat vegetarian diets, and consume alcohol have lower levels. Exercise may also lower fibrinogen and plasma viscosity.  Studies also show statin-fibrate combinations (simvastatin-clofibrate) and estrogen therapy to lower fibrinogen.

59. FIBRINOGEN STUDIES  Several recent studies have established the association of plasma fibrinogen levels with cardiovascular disease  In one pooled analysis, odds ratio for coronary disease for the highest v/s the lowest tertile of fibrinogen level was 2.3  In patients with established coronary disease, fibrinogen levels are associated with angiographic severity of disease, recurrent ischemic events, and risk of restenosis following coronary angioplasty.  BIP Study suggest that reduction of plasma fibrinogen levels in patients with high baseline fibrinogen levels and preexisting coronary artery disease leads to a decrease in the incidence of cardiac death and ischemic stroke

60. RECOMMENDATION FOR FIBRINOGEN  The lack of a single standardized assay, the presence of intraindividual variability in levels, and lack of conclusive evidence that reduction in fibrinogen levels would improve cardiovascular risk have limited the wide application of fibrinogen level reduction in clinical practice. (clinical guidelines for emerging cad risk factors for CAD. Ann Intern Med; 2009.151:496-507)

61. HEMOGLOBIN A1C (HBA1C)  Providing an estimate of average glycemic control over several months  ADA has endorsed the use of HbA1C to diagnose diabetes (HbA1C 6.5%) and to identify persons at increased risk for diabetes (HbA1C, 5.7% to 6.4%)  In a 2010 ARIC (Atherosclerosis Risk in Communities) study, demonstrated that in persons without diabetes, prediction models including HbA1C levels were associated with improved risk prediction, discrimination, and reclassification compared with prediction models that included standard risk factors and fasting glucose  This study is the strongest evidence available concerning the potential value of HbA1C for CVD risk assessment in asymptomatic persons without diabetes

62. RECOMMENDATION FOR MEASUREMENT OF HEMOGLOBIN A1C CLASS IIb 1. Measurement of hemoglobin A1C (HbA1C) may be reasonable for cardiovascular risk assessment in asymptomatic adults without a diagnosis of diabetes. (Level of Evidence: B) (2010 ACCF/AHA guideline for assessment of cardiovascular risk in asymptomatic adults. J Am Coll Cardiol 2010;56:e50 103.)

63. URINARY ALBUMIN EXCRETION  Widely available, inexpensive, and associated with cardiovascular events  Microalbuminuria is associated with increased risk of CVD both with and without diabetes  On the basis of the urinary albumin–to-creatinine ratio on a morning spot urine sample, microalbuminuria is defined as 30 to 300 mg/g and macroalbuminuria is defined as 300 mg/g.  Microalbuminuria is considered as a CVD risk biomarker for several reasons as it is associated with  Incident hypertension & progression to a higher blood pressure category  Diabetes  Impaired endothelial function and  Inflammatory markers such as CRP

64. ASSOCIATION WITH CARDIOVASCULAR RISK  A meta-analysis of 26 cohort studies with 169,949 participants reported that after accounting for standard CVD risk factors, there was a dose-response relationship between albuminuria and risk of CHD.  Compared with individuals without albuminuria, macroalbuminuria was associated with a doubling of risk (RR 2.17; 95% CI 1.87 to 2.52), and microalbuminuria was associated with a nearly 50% greater risk (RR 1.47; 95% CI 1.30 to 1.66) of CHD

65. RECOMMENDATION FOR MEASUREMENT OF URINARY ALBUMIN EXCRETION CLASS IIb 1. Measurement of Urinary Albumin Excretion may be reasonable for cardiovascular risk assessment in asymptomatic adults without a diagnosis of diabetes. (Level of Evidence: B) (2010 ACCF/AHA guideline for assessment of cardiovascular risk in asymptomatic adults. J Am Coll Cardiol 2010;56:e50 103.)

66. LEUCOCYTE COUNT & PERIODONTAL DISEASE  Studies are conflicting. The USPSTF concluded that there is at least fair evidence of no association between leukocyte count and the risk for coronary events  Fair-quality evidence indicates that periodontal disease (pocket formation, recession of gingiva and tooth loss) can predict CHD risk independent of Framingham risk factors, but these studies did not consistently define periodontal disease or CHD outcomes, and effect of treatment on major CVD not clear, hence not recommended.

67. TAKE HOME MESSAGE  Among non conventional risk factors, three has got class IIa recommendation, 1. High-sensitivity C-Reactive protein (hsCRP) 2. Ankle-brachial index 3. Carotid IMT These should be used in persons classified as intermediate-risk category by FRS.  hsCRP may be useful in men ≥50 years or women ≥60 years with LDL cholesterol ˂130 mg/dL; not on lipid-lowering, hormone replacement, or immunosuppressant therapy; without clinical CHD, diabetes, chronic kidney disease, severe inflammatory conditions, or contraindications to statins, measurement of CRP can be useful in the selection of patients for statin therapy.