CORONARY RISK FACTORS

CORONARY RISK FACTORS Giuseppe Biondi Zoccai DivisionofCardiology, UniversityofTurin, Turin, Italy Meta-analysis and Evidence-based medicine Training in Cardiology(METCARDIO), Ospedaletti, Italy

LEARNING GOALS • Scope of the problem • Established risk factors • Risk factors still under investigation • So what?

SCOPE OF THE PROBLEM • Cardiovascular disease is the leading cause of mortality in developed countries • Atherosclerosis is the main cause of cardiovascular disease • Coronary atherosclerosis and atherothrombosis represent the single most important prognostic contributor to cardiovascular disease

DEVELOPMENT OF ATHEROTHROMBOSIS The 7 stages of development of an atherosclerotic plaque. First LDL moves into the subendothelium and is oxidized by macrophage and SMCs (1 and 2). Release of growth factors and cytokines attracts additional monocytes (3 and 4). Foam cell accumulation and SMC proliferation result in growth of the plaque (6, 7, and 8). Fuster, Circ 2004

FROM ATHEROSCLEROSIS TO ATHEROTHROMBOSIS

CORONARY ARTERY DISEASE 3 out of every 10 individuals who develop a heart attack or sudden death from coronary artery disease have no prior warning or symptoms

PREVENTION STRATEGIES • Primary prevention: strategies to reduce the incidence of disease in apparently healthy subjects (e.g. vaccine) • Secondary prevention: strategies to reduce the mortality and morbidity burden of disease once it has occurred (e.g. aspirin after AMI) • Tertiary prevention: strategies to reduce the functional/symptomatic burden of disease after it has completed its natural history (e.g. wheel-chair training after stroke)

IMPACT AND ROLE OF PREVENTION OFATHEROTHROMBOSIS Symptomatic coronary athero-thrombosis SECONDARY PREVENTION Symptomatic non-coronary atherothrombosis PRIMARY PREVENTION Subclinical atherosclerosis PATIENTS AT RISK Two or more risk factors One risk factor No risk factors (i.e. low risk) Fuster, Circ 1999

RISK FACTORS AND GLOBAL DEATHS

CAUSES OF DEATH IN EUROPE MEN WOMEN

RISK FACTORS IN ITALY

ARE THERE ANY OUT OF THE BLUE MYOCARDIAL INFARCTIONS? • 1 or more risk factor is present in 80-90% of patients with atherothrombosis • Thus addressing established risk factors will potentially reduce by 80-90% the mortality and morbidity burden of atherothrombosis

DISTRIBUTION OF RISK FACTORS AMONG PATIENTS WITH CAD Khot et al, JAMA 2003

CARDIOVASCULAR DISEASE Ischemic heart disease ≈ Coronary heart disease ≈ Coronary artery disease • Heart disease • Myocardial disease • Structural disease • Vascular disease • Arterial disease • Venous disease • Pulmonary arterial disease • Pulmonary venous disease

ISCHEMIC HEART DISEASE • Silentcoronaryatherothrombosis • Silentmyocardial ischemia • Stable angina pectoris • Ischemic cardiomyopathy • Unstable angina pectoris • Non-ST-elevationmyocardialinfarction • ST-elevationmyocardialinfarction • Suddenischemiccardiacdeath

CORONARY RISK FACTORS: DEFINITION • A coronary risk factor is a clinical or biologic feature associated in a clinically relevant fashion with increased (in some cases decreased) risk of coronary events • Similarly, risk factors can be identified for any other condition/occurrence, e.g. cardiac events, coronary atherosclerosis, multivascular atherosclerosis, stroke, claudication, …

METHODS OF INQUIRY • EPIDEMIOLOGIC STUDIES – case-control or cohort studies • PATHOLOGIC STUDIES – biopsy or autopsy • EXPERIMENTAL HUMAN STUDIES – randomized clinical trials • EXPERIMENTAL ANIMAL STUDIES – mice, rats, rabbits, pigs, dogs, monkeys Each piece of evidence shares with the research study from which it stems strengths and weaknesses

AN INCOMPLETE LIST Age Family history of premature atherosclerosis Geneticpredisposition Male sex Population Diabetesmellitus Dyslipidemias (high total, high LDL, low HDL, high total-to-HDLcholesterol , high triglycerides) Hypertension Obesity Smoking Autoimmune disease Birthweight Dislipidemias (high small-dense LDL, high lipoprotein(a) level) High CRP level Hyperhomocysteinemia Hyperinsulinemia Infection 5-Lipoxygenase polymorphisms Low intake of fruits and vegetables Metabolicsyndrome More than moderate alcoholintake Prothromboticstates Psychosocialfactors Renalinsufficiency Sedentarylifestyle Unmodifiable Modifiable, established as independent Modifiable, still under study

AGE • Usually defined as: • 45 years or more for men • 55 years or more for women without premature menopause • Risk however is not discontinuous but rather increases in a continuous, albeit non-linear, fashion

FAMILY HISTORY • Myocardial infarction, coronary revascularization, sudden ischemic or unexplained death before 55 years of age in father or other male 1st-degree relative (i.e., brother or son) • Myocardial infarction, coronary revascularization, sudden ischemic or unexplained death before 65 years of age in mother or other female first-degree relative (i.e., sister or daughter) • Family history of non-coronary atherothrombosis, diabetes, or hypertension, may also confer some, more limited, risk

ARTERIAL HYPERTENSION • Systolic blood pressure of ≥140 mmHg or diastolic ≥90 mmHg, confirmed by measurements on at least 2 separate occasions, or on antihypertensive medication • Also risk factor for stroke, peripheral artery disease, and diastolic heart failure

DYSLIPIDEMIA • Total serum cholesterol of >200mg/dL (5.2 mmol/L) or high-density lipoprotein cholesterol of <35 mg/dL (0.9 mmol/L), or on lipid-lowering medication • If low-density lipoprotein cholesterol is available, use >130 mg/dL (3.4 mmol/L) rather than total cholesterol of >200 mg/Dl • Also risk factor for peripheral artery disease

SMOKING • Current cigarette smoker or those who quit within the previous 6 months • Atherothrombotic risk usually approaches baseline risk after 3-5 years after quitting, but COPD does not • Some risk is also conferred by cigars, pipes, and passive smoking

SMOKING Yusuf et al, Lancet 2004

DIABETES MELLITUS • Diabetes mellitus is diagnosed if (any one): • Fasting plasma glucose level at or above 126 mg/dL • Hemoglobin A1C at or above 6.5% • Plasma glucose at or above 200 mg/dL two hours after a 75 g oral glucose load • Symptoms of hyperglycemia and casual plasma glucose at or above 200 mg/dL • Given that the risk of CAD events in diabetics is similar to the risk of recurrent CAD events in those with established CAD, diabetes is considered a coronary risk equivalent

DIABETES MELLITUS: FROM INFLAMMATION TO ATHEROTHROMBOSIS Biondi-Zoccai et al, JACC 2003

ADDITIVE DETRIMENTAL EFFECTS OF RISK FACTORS MRFIT

ADDITIVE DETRIMENTAL EFFECTS OF RISK FACTORS PANDORA

ADDITIVE DETRIMENTAL EFFECTS OF RISK FACTORS Yusuf et al, Lancet 2004

AN INCOMPLETE LIST Age Population Family history of premature atherosclerosis Geneticpredisposition Male sex Dyslipidemias (high total, high LDL, low HDL, high total-to-HDLcholesterol , high triglycerides) Smoking Diabetes mellitus Hypertension Obesity Autoimmune disease Birthweight Dislipidemias (high small-dense LDL, high lipoprotein(a) level) High CRP level Hyperhomocysteinemia Hyperinsulinemia Infection 5-Lipoxygenase polymorphisms Low intake of fruits and vegetables Metabolicsyndrome More than moderate alcoholintake Prothromboticstates Psychosocialfactors Renalinsufficiency Sedentarylifestyle Unmodifiable Modifiable, establishedasindependent Modifiable, still under study

C-REACTIVE PROTEIN Ridker et al, NEJM 2000

C-REACTIVE PROTEIN Ridker et al, NEJM 2002

SOME OTHER NEW RISK FACTORS Yusuf et al, Lancet 2004

POPULATION ATTRIBUTABLE RISKS Yusuf et al, Lancet 2004

MASSIFIED VS PERSONALIZED CARE

FROM DIAGNOSIS TO RISK-STRATIFICATION • In as much as when interpreting the stress ECG or when admitting to the ER patients with suspected acute coronary syndromes, there has been a significant shift from diagnostic work-up to risk stratification • Risk factors and scores prove seminal to achieve a successful prognostic work-up in most, albeit not all, individual patients

RISK ASSESSMENT Count major risk factors: • For patients with multiple (2+) risk factors • Perform 10-year risk assessment • For patients with 0–1 risk factor • 10 year risk assessment not required • Most patients have 10-year risk <10% ATP III

USING A CHECKLIST Acharjee et al, AJC 2010

THE FRAMINGHAM HEART STUDY

BUILDING A RISK SCORE • Population at risk • Adjudication of events • Test for association between individual patient features (e.g. gender) and incidence of events (e.g. % of death in males vs. females) • Test to confirm association between several features and events, in order to adjust for covariates • Calculation of adjusted odds ratios (or relative risks, or absolute risk) with 95% confidence intervals and area under the curve

BUILDING A RISK SCORE • Population at risk • Adjudication of events • Test for association between individual patient features (e.g. gender) and incidence of events (e.g. % of death in males vs. females) • Test to confirm association between several features and events, in order to adjust for covariates • Calculation of adjusted odds ratios (or relative risks, or absolute risk) with 95% confidence intervals and area under the curve Final proof of causality is only obtained when a given intervention effective at reducing a given risk factor leads to reduction in events

GLOBAL ABSOLUTE CARDIOVASCULAR RISK http://www.cuore.iss.it/valutazione/valutazione.asp

NCEP/ATP III – 9 STEPS* • Step 1: Obtain, complete & fasting lipids • Interpret: LDL < 100mg/dl optimal • LDL 100-129 near optimal • LDL 130-159 borderline high • LDL 160-189 high • LDL >190 very high • (mg/dl x 0.0259mmol/l = SI units) *http://www.nhlbi.nih.gov/about/ncep/index.htm

CORONARY RISK FACTORS