Chapter Outline
- • CHD Screening and Prevention
- • Clustering and Multiplicative Effects of Risk Factors
- • CHD Risk Estimation
- – Framingham Risk Score (FRS)
- – European Risk Scores
- – Newer Risk Scores
- • Measures to Evaluate Risk Prediction Models
- • Traditional CHD Risk Factors
- – Non-modifiable Risk Factors for CHD
- – Modifiable Risk Factors for CHD
- • Emerging Risk Factors
- – High-sensitivity C-reactive Protein (hs-CRP)
- – Lipoprotein (a) [LP(a)]
- – Hyperhomocysteinemia
- – Lipoprotein-associated Phospholipase A2 (LP-PLA2)
- – Apolipoprotein B
- – Fibrinogen and Other Hemostatic Factors
- • Sub-clinical Atherosclerosis
- • Translating Risk Factor Screening into Event Reduction
INTRODUCTION
Cardiovascular disease (CVD) remains the leading cause of death in the United States and many other parts of the world and results in substantial disability and loss of productivity. Coronary heart disease (CHD) and stroke are the leading contributors to this heavy CVD burden. The exact mechanisms underlying development of CVD still remain to be fully described. However, through population-based studies starting in the 1940s and 1950s and intervention trials later, multiple risk factors for the development of CVD have been identified. The term ‘risk factor’ was in fact first used in the context of CHD.1 A risk factor is any personal, environmental, psychosocial or genetic characteristic that gives an individual a higher likelihood of developing a particular disease. Even though the risk factor is a mere statistical association to an outcome, the current use of the term ‘risk factor’ often implies causality. On the other hand, a ‘risk marker’ has association with a disease but a cause and effect relationship either does not exist or remains to be proven. These terms have evolved over the years and are non-uniformly used in the literature.
Cardiovascular disease risk factors are generally categorized into traditional/conventional and novel/emerging risk factors (Table 1). Risk factors can be inherited or acquired, some are modifiable and others are not. Risk factors may be defined dichotomously by their presence or absence or measured as a continuous variable.2
The treatment of CVD risk factors has contributed to the fall in CVD mortality in the past 30 years, at least in developed countries.2 At the same time, the prevalence of CVD and heart failure has increased due to higher survival rates and an aging population. More recent data suggest that we have reached a plateau in CVD mortality, which correlated with the obesity and physical inactivity epidemics. This highlights the challenge of CVD management: both identification and effective treatment of risk factors are required. Despite identification of patients at risk for CHD, significant gaps remain in implementing treatment. For instance, up to 15–20% of high risk patients discharged from the hospital, such as those with acute coronary syndrome, are not initiated on recommended combination therapy of aspirin, beta-blocker, statin and angiotensin converting enzyme inhibitors. Fewer are referred to comprehensive risk reduction programs like cardiac rehabilitation suggesting that lifestyle risk factors are even less likely to be addressed.3 As our quest for finding new risk factors and development of new therapeutic strategies is ongoing, we also have to devise ways to uniformly implement effective risk factor treatment.
CHD SCREENING AND PREVENTION
The high lifetime risk of CHD warrants population wide screening for prevention and treatment. The long lag-time between the onset of atherosclerosis and its related morbidity 3and mortality allows for detection and early intervention. Screening involves routine evaluation of asymptomatic people. The widely accepted World Health Organization (WHO) criteria for screening of disease are summarized in Table 2. Screening should be cost-effective with the goal of detecting, not excluding, disease. Using established risk factors, a significant percentage of ‘at risk’ individuals can be screened as a target for preventive strategies.4
Three to five levels of prevention are described in the context of CVD (Table 3), often with dissimilar definition. The Centers for Disease Control and Prevention describe a simple classification with three levels of prevention.5 Primordial prevention or health promotion targets the population without risk factors and aims to prevent the development of risk factors. The goal of primary prevention is to prevent the development of CVD in individuals with one or more risk factors. Secondary prevention involves patients with established clinical disease with the goal to prevent recurrent CVD events and their complications. A fourth level referred to as tertiary prevention targets late stages of the disease with the goal of restoration and rehabilitation.
CLUSTERING AND MULTIPLICATIVE EFFECTS OF RISK FACTORS
Initially, risk factors for CHD, such as diabetes, hypertension and hyperlipidemia, were targeted and treated individually. However, risk factors often occur in clusters and show a multiplicative effect rather than a simple additive effect.
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This has important implications for treatment. Most persons in a population have moderate elevation in multiple risk factors rather than an extremely high level of any single risk factor. Similarly, most cardiovascular events occur in individuals with mild-to-moderate abnormality in multiple risk factors. Targeting only high levels of individual risk factors will target only a small fraction of the population. Various expert groups stress the concept of ‘comprehensive risk factor management’.
CHD RISK ESTIMATION
Despite our knowledge and understanding of many CHD risk factors, a clinical challenge is to effectively predict risk of CHD in individuals to allow appropriate and cost-effective treatment. Risk estimates are also used to raise awareness about CHD, determine population attributable risk to target specific public health measures, and to communicate risk to patients.
Coronary heart disease risk estimation measures the likelihood of a person developing a serious cardiovascular event over a specific follow-up time. Several multivariable models exist to predict the risk for future CHD and CVD (Table 4), many derived from the Framingham cohorts. Risk estimation results are critically dependent on the time frame of prediction. Earlier risk scores predicted short-term and medium-term risk of ≤ 10 years. More recently, long-term and lifetime risk estimation algorithms have been developed.6,7 Risk estimation also depends on the endpoint chosen, for instance, CHD versus overall cardiovascular risk8 and within CHD, ‘hard events’ such as myocardial infarction and CHD death or ‘hard and soft endpoints’ which also include angina pectoris and revascularization.
Refining and improving risk prediction is a major area of research in cardiovascular medicine. Key issues related to CVD risk estimation include the optimal time frame for risk assessment (short term, long term or lifetime), development of age-specific absolute risk models, defining cut offs for different risk categories, determining eligibility for pharmacological treatment, integration of imaging modalities to detect atherosclerosis and determining whether using a particular risk score will eventually result in better patient outcomes.
Framingham Risk Score (FRS)
FRS and National Cholesterol Education Program's Third Adult Treatment Panel update (NCEP ATP III) are the most widely used risk scores (Table 4). FRS predicts the 10-year risk of CHD using a multivariable mathematical model of risk.95
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The calculator is available at: (http://www.framinghamheartstudy.org/risk/hrdcoronary.html). The NCEP ATP III risk assessment tool predicts the 10-year risk of hard CHD (myocardial infarction and coronary death).10 The calculator is available at: (http://hp2010.nhlbihin.net/atpIII/calculator.asp?usertype=prof). Intensity of risk factor treatment is guided by the magnitude of absolute risk. Absolute risk is divided into three risk categories: high, intermediate and low risk (Table 5). High risk individuals include those with established CHD, diabetes, stroke, peripheral vascular disease or with multiple risk factors without established CHD, but a 10-year risk of CHD events greater than or equal to 20%. Certain individuals are considered ‘very high-risk’ and, according to the NCEP ATP III update,11 they should be the target of more intensive lipid lowering therapy. This group includes individuals with established CVD in the presence of multiple major risk factors, especially if uncontrolled, or patients with acute coronary syndromes.
The FRS predicts major CHD events well in different populations.12 Limitations of FRS are that it was developed exclusively in Caucasians. FRS does not include family history, obesity and psychosocial factors, which are important risk factors for CVD. FRS calculates only CHD risk and not the complete risk of other CVD processes including stroke, heart failure and peripheral vascular disease. The data used in the original Framingham Heart Study precede the obesity and physical inactivity epidemic. FRS is heavily influenced by age13 and gender. For instance, most non-smoking men less than 45 years and almost all women less than 65 years of age have a 10-year risk of less than 10%. Despite some limitations, FRS is the most widely used and validated risk assessment tool and is able to provide remarkably good discrimination for the majority of individuals.14
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European Risk Scores
Since FRS is based on a North American sample, in Europe different risk scores were established including the Systematic Coronary Risk Evaluation (SCORE) project and the QRESEARCH cardiovascular RISK algorithm (QRISK). The SCORE15 has been adopted by the Joint European Societies’ guidelines on CVD prevention. The SCORE risk prediction system uses only fatal CVD as the outcome measure. The risk chart provides more detail for middle-aged persons in whom the risk changes with age. Separate charts are available for higher and lower risk areas in Europe. Individuals with a 10-year risk of CVD death of 5% or more are considered at an ‘increased risk’ and qualify for intensive risk factor management.16 A newer, computer-based tool for total risk estimation, which operates using the SCORE data, is called the HEARTSCORE (http://www.heartscore.org/eu/high/Pages/Welcome.aspx). The QRISK17 algorithm was developed using the QRESEARCH database. The QRISK score includes family history of premature CHD, body mass index (BMI) and social deprivation that are not part of the FRS. A 2008 update (QRISK 2 score) contains additional variables including renal disease, atrial fibrillation and rheumatoid arthritis.18
Newer Risk Scores
Newer risk scores were developed in an attempt to overcome limitations of FRS and to incorporate emerging risk factors for CVD. A risk score's ability to reclassify patients at intermediate risk for CHD into higher risk for more aggressive management or lower risk categories for reassurance may clinically be useful. Some risk factor algorithms have eliminated laboratory based testing to reduce cost and increase availability, in particular to the primary care physicians, who are generally the first contact for the majority of the low-to-intermediate risk population.
The Reynolds risk score19 for women was developed in 24,558 women from the Women's Health Study. In addition to traditional subject-reported risk factors, it incorporates family history of myocardial infarction, high-sensitivity C-reactive protein (hs-CRP) and hemoglobin A1C. In the original study, Reynolds risk score was able to reclassify 40–50% of intermediate risk women into higher or lower risk categories. Later, a Reynolds risk score for men was developed in a cohort of 10,724 men from the Physicians Health Study II. This risk score reclassified 18% of men into a higher or lower risk category.20 The risk calculator is available at http://www.reynoldsriskscore.org.9
A general CVD risk prediction model was developed by D’Agostino et al.8 using the original and offspring cohorts of the Framingham study. The risk estimation is for all CVD events compared to only CHD events in FRS. The investigators formulated two separate risk scoring models: one based on standard risk factors including laboratory variables and another using only non-laboratory based clinical variables. This risk assessment tool also presents the concept of ‘vascular age’ of an individual. Vascular age is the chronological age with optimal risk factors that gives the same predicted risk as that of the individual whose risk is being estimated. Currently, there are no established cut-offs for what is considered high risk when using global risk score. Published studies have used a 10-year risk of a CVD event of greater than 20% as the cut-off. To overcome the limitation of short-term risk prediction, recently, long-term and lifetime risk estimation algorithms have been developed.7 Lifetime risk estimation may be useful for younger patients who have low short-term risk but high lifetime risk. In fact, data from the National Health and Nutrition Examination Survey 2003 to 2006 suggest that over 50% of US adults with a low 10-year risk have a high lifetime risk of CVD.21 Initiating earlier treatment may result in substantial benefit over the life of these individuals but also potentially exposes them to long-term pharmacological therapy, of which the safety and cost-effectiveness is not fully established.
In contrast to the traditional approach of identifying risk factors for CVD, others have proposed direct assessment of the presence and severity of atherosclerosis/vascular disease. Cohn et al. developed the Rasmussen score22 based on ten parameters including imaging modalities such as echocardiogram and carotid ultrasound. Similarly, the Screening for Heart Attack Prevention and Education (SHAPE) Task Force issued a consensus statement recommending that all asymptomatic men (45–75 years) and women (55–75 years) with a 10-year risk of CHD greater than 5% should undergo noninvasive imaging to detect subclinical CHD.23 The SHAPE task force II is currently working to update to these guidelines.
MEASURES TO EVALUATE RISK PREDICTION MODELS
Several metrics exist to help clinicians evaluate the performance and utility of risk prediction scores including discrimination, calibration and reclassification.24 Discrimination is the ability of a model to separate those with or without disease. The C statistic or area under the receiver operating characteristic (ROC) curve is widely used to report the discrimination ability of a risk score. It indicates the probability of a randomly selected 10case having a higher score than a noncase. For instance, a C statistic of 0.80 predicts that a patient with disease will have a higher score compared to a healthy patient 80% of the time. 1.0 is perfect discrimination and 0.5 is random chance. A C statistic greater than 0.70 is considered an acceptable level of discrimination. The C statistic does not quantitate the difference of risk between the case and the noncase. Large odds ratios or relative risks are required to achieve an acceptable C statistic score.
Calibration of a test determines its ability to accurately predict the absolute level of risk by comparing the predicted to the observed event rate. A good model will have an observed event rate close to the predicted rate. A test may have good discrimination but poor calibration. Generally, a model cannot have a perfect discrimination and be perfectly calibrated at the same time.
Other measures include likelihood ratio tests and Bayes information criterion which are sensitive assessments, used as initial measures to ascertain the global fit of the model.25 These assess the ability of a score to predict disease incidence better than by chance alone. A penalty is paid for the number of variables included. A risk score's ability to reclassify individuals from one risk category to another is also used to evaluate the utility of the model. Both the net reclassification improvement (NRI) (difference between appropriate reclassification and inappropriate reclassification) and how much the individual moved in order to be reclassified (termed the integrative discrimination index or IDI) are important when using reclassification.
TRADITIONAL CHD RISK FACTORS
Non-modifiable Risk Factors for CHD
Certain risk factors for CHD are non-modifiable including age, male gender and family history of CHD. Although, these risk factors are non-modifiable, they are an essential part of the risk prediction algorithms and identification of patients at higher risk for CHD events. Based on the Framingham Heart Study and NCEP ATP III recommendations, a positive family history of premature CHD is defined as a coronary event in parents before age 55 years in men and 65 years in women. Parental CHD, on an average, doubles the risk of CHD in an adult offspring. CVD in siblings also increases the risk of incident CVD even after adjustment for traditional risk factors and parental history of CVD. Compared to parental CVD, sibling CVD is reported to be a stronger predictor of CVD.26 The reported variability in risk with family history of 11CVD is possibly due to recall bias, difference in family size and referral bias.26
Modifiable Risk Factors for CHD
Lifestyle Risk Factors
Lifestyle risk factors including physical inactivity, diet and psychosocial factors are established risk factors for CHD and carry considerable public health importance as targets for intervention. In the INTERHEART study,27 healthy lifestyle behavior including eating fruits and vegetables, exercising regularly and avoiding smoking led to 80% lower relative risk for myocardial infarction.
Smoking: Cigarette smoking is an important risk factor not only for CVD but also due to its impact on non-cardiovascular morbidity and mortality. It is the single most important preventable cause of disease and early death.28 Smoking is a major public health threat in low-to-middle income countries where CVD is already on the rise.
Cigarette smoking has several detrimental effects on the cardiovascular system including increase in heart rate and blood pressure, increased thrombogenesis, endothelial dysfunction, increased plaque instability and less favorable effects on lipids. These processes lead to a proinflammatory state and atherosclerosis. Cigarette smoking also decreases high density lipoprotein cholesterol (HDL-C) levels. These effects are directly proportional to the amount of tobacco smoked. There is no evidence that using filters or other barriers reduces the risk. Smoking cigars and pipe raises the risk of CHD, as does passive smoking. It is unclear if decreasing, but not quitting, tobacco use provides any benefit or not.29 Quitting smoking both for asymptomatic persons and those with established CVD is an extremely effective preventive measure for decreasing CVD mortality. Past smokers continue to reduce their risk over 10 years and eventually reach that of a non-smoker. For secondary prevention, patients who quit smoking decrease their risk of recurrent myocardial infarction by 50%.30 Patients who quit smoking after coronary artery bypass have better survival and lower rates of angina and hospital admissions compared to patients who continue to smoke.31
In the clinical setting, it is important that every patient undergoes a full assessment of smoking status. This includes amount, type and duration of cigarette smoking, any other tobacco products used, social and family environment and reason for smoking. Physicians should assess the patient's knowledge about specific harmful effects of smoking on the cardiovascular system. Practitioners can use the clinical 12practice guidelines issued by the US Department of Health and Human Services to effectively intervene on tobacco users. The five steps recommended for intervention, referred to as the 5As, are summarized in Table 6. It is important to continue to address smoking cessation at every visit. Physicians can also use the opportunity at the time of an acute myocardial infarction to provide smoking cessation counseling, as patients are more likely to be motivated to quit. Multiple options exist to help with smoking cessation including providing self-help materials to patients,32 behavioral counseling33 and group therapy. Support from spouse and family may also be important. Data regarding acupuncture and hypnotherapy for smoking cessation is inconsistent and these are not currently recommended. Physicians should be aware of different pharmacological therapy options available including several nicotine preparations, the anti-depressant drug bupropion and the more recently introduced medication vareniciline. In most patients, smoking cessation is associated with only mild weight gain. Any deleterious effects of even modest-to-major weight gain are likely minor compared to the harmful effects of continued smoking.34 At a public health and policy level, restricting smoking in public places and at work, limiting tobacco advertising and promotion, and preventing tobacco sales to minors are some of the ways by which tobacco use can be decreased.
Physical inactivity: Physical activity is any bodily movement that expends energy. It is generally measured by self-reporting or occasionally by activity monitors. Cardiorespiratory fitness is a physiological characteristic of a person measured by exercise testing. Regular physical activity improves cardiorespiratory fitness. Any planned physical activity with the intent of improving one's health or fitness is considered exercise. It is important to note that not all physical activity is exercise.
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Physical inactivity is an important and increasingly common lifestyle factor contributing to the global burden of CVD. Data from several lines of investigation link physical inactivity to CHD morbidity and mortality. Physical inactivity and excess caloric intake have greatly contributed to the global obesity epidemic. Physical activity exerts multiple cardiovascular benefits including decreased risk of developing hypertension, insulin resistance, and dyslipidemia and beneficial effects on endothelial function and thrombogenesis. The minimum recommended level of physical activity includes moderate intensity exercise for 30 minutes on at least 5 days of the week. The daily 30 minutes can be accumulated in as little as 10-minute sessions and may include walking, cycling, gardening, elliptical, swimming, recreational sports, etc. There are no recommendations for the maximum amount of physical activity and the ‘optimal’ level likely varies among different individuals and the endpoint desired (metabolic change vs peak fitness). Nearly half of the population fails to meet even the recommended minimum physical activity.35 The small amount of excess risk reported with vigorous physical activity is negligible compared to the beneficial effects of regular physical activity. In patients with established CHD, physical activity and cardiac rehabilitation decrease risk of future coronary events and mortality.36
Guidelines to help physicians evaluate physical activity level and counsel appropriately have been published.37 Physicians should assess the level of physical activity (both leisure time and at work) for all patients. Physical activity can be measured by recall questionnaire, diary or using a pedometer. Exercise prescriptions can provide more specific instructions to help with compliance. Referral to exercise programs or rehabilitation centers should be made as appropriate.
Nutrition: Diet is an important risk factor for CVD and also directly influences multiple CVD risk factors. Several dietary factors including the intake of fruits, vegetables, fatty acids, fiber, alcohol, excess salt and the ratio of carbohydrates, fat and lipids have been studied in relation to CHD risk (Table 7). Both epidemiological studies and intervention trials have demonstrated the importance of a balanced diet for CHD prevention.
Dietary lipids have an important role in the formation of atheromatous plaque. Diets, high in saturated and trans-fatty acids, are linked to higher rates of CHD.38 Saturated fatty acids increase low density lipoprotein cholesterol (LDL-C) concentration. The principal source of saturated fatty acids is animal products and some commercially prepared meals. Consumption of polyunsaturated fatty acids decreases LDL-C.14
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Primary food sources of polyunsaturated fatty acids include vegetable oil, soya bean and rapeseed. Eicosapentaenoic acids (EPA) and docosahexaenoic acids (DHA) are members of the n-3 fatty acid group derived from fish oil. Intake of EPA and DHA reduces plasma triglycerides, increases HDL-C and has beneficial effects on the cardiovascular system. Multiple proposed mechanisms for the benefit of fish consumption and omega-3 fatty acids include anti-inflammatory, antiarrhythmic and antithrombotic effects.39 Guidelines recommend less than 30% of total calories from dietary fat and less than 7% from saturated fats.40,41 Dietary primary prevention trials show benefit of reduced saturated fatty acid intake and increase in polyunsaturated fat intake on clinical cardiovascular endpoints.42 Such dietary data should not be extrapolated to include intake of corresponding supplements.
High sodium intake is linked to hypertension, CHD and death. Current recommendations for the general population are to consume less than 5–6 gram of salt daily (equivalent of roughly 2,000–2,400 mg of sodium).41,43 A diet rich in fiber and natural products, fruits and vegetables decreases risk of CHD.38 The idea of combining foods or different diets, a portfolio, to achieve cholesterol control was suggested in the 1990s. The dietary portfolio contains four main elements including soy, nuts, viscous fibers and plant sterols and has been shown to reduce cholesterol.44
Nutrition is often neglected when counseling about CVD prevention and treatment. Healthcare providers quote lack of time and knowledge as barriers to successful nutrition counseling. Misleading information from the media is compounded by the lack of clinical trials. Despite patient counseling, the results are often disappointing in bringing substantial change in nutrition habits. In general, a cardioprotective or healthy diet is well balanced and includes different food sources. It should include the recommended amounts of fatty acids and sodium. The diet should be rich in fruits, vegetables, whole grains and high fiber foods. Fish should be consumed at least twice weekly.40 A balanced diet also helps to maintain a healthy body weight. Consultation with a dietitian should be sought whenever available.
Obesity: Obesity is an independent risk factor for CVD and increases mortality. Obesity is also associated with multiple other CVD risk factors (Table 8), which in turn adversely affects the heart.45 Obesity has reached epidemic proportions in many industrialized countries and its prevalence continues to increase, posing a major global health problem. Prevalence of childhood and adolescent obesity is also on the rise. Sedentary lifestyle, ease of access to food, increase in portion size and caloric intake are important reasons for the current obesity epidemic.19
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Genetic factors and certain other environmental factors also predispose some individuals to excess weight.
Mechanisms by which obesity is associated with CVD are not completely understood. Adipocytes act as an endocrine organ and may play a central role in the pathogenesis through the release of adipocytokines. The role of different fat depots is also under active research. Several measures exist to define obesity, the commonest being body mass index (BMI). The BMI is calculated as weight (kg)/height (m2). Obesity is defined as BMI of greater than or equal to 30 (Table 9). Other indexes of obesity include waist circumference and waist-hip ratio, increases in which are also linked to adverse cardiovascular outcomes. Different cut-offs for abnormal waist circumferences according to ethnicity are summarized in Table 10. Both BMI and waist circumference should be recorded for overall risk assessment and tracked over time as a vital sign.
Weight loss can prevent and improve obesity related risk factors and CVD. Interventions for weight management include dietary changes, increased physical activity, pharmacological therapy and surgical treatment.
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A weight reducing diet combined with exercise can result in significant weight loss.46 Reduction in calorie intake, regardless of the proportion of macronutrients (fats, proteins or carbohydrates), results in clinically meaningful weight loss.47
Despite great interest in pharmacotherapy for obesity, its clinical use is limited by modest weight loss, high relapse rate and side effects of the medications. Fenfluramine and dexfenfluramine were withdrawn due to their adverse effects on heart valves. Orlistat, a gastrointestinal lipase inhibitor, induces weight loss by decreasing fat absorption.48 It is FDA approved and is available also for over the counter use for weight loss. Common side effects include oily stools, diarrhea and gas. Rimonabant, a selective cannabinoid-1 receptor blocker, improved weight and cardiovascular risk factors,49 but was not approved in the United States over concerns about psychiatric side effects and did not reduce cardiovascular events in one large clinical trial.50
Surgical treatment for obesity includes various malabsorptive or restrictive procedures. In patients who have failed an adequate diet and exercise program, with severe obesity (BMI ≥ 40) or medically complicated obesity with a BMI greater than or equal to 35, bariatric surgery may be considered.51,52 Long-term follow-up of patients after bariatric surgery continues to show weight loss, improvement in CVD risk factors and lower mortality.53
Psychosocial factors: Several psychosocial factors are associated with increased risk of CVD including depression, stress, anxiety, social isolation, lack of social support and stress at work.54 In a meta-analysis, depression was shown to 21increase the risk of CHD by 64%.55 In the MRFIT study greater depressive symptoms were associated with increased 18-year mortality.56 Depression especially after coronary events is not only common but also increases the incidence of recurrent coronary event by threefold.57 Lower socioeconomic class and adverse events in life are also associated with CVD. Poor socio-economic status is linked to increased risk of CHD through multiple mechanisms including unhealthy diet, lack of access to health care, excessive stress and tobacco use.
Type A behavior with associated hostility and anger raises the risk of CHD.58 Social isolation and lack of social support may increase the risk of CHD by 2–3 fold in men and 3–5 fold in women.59 Marital discord worsens prognosis in acute coronary syndrome. Psychosocial risk factors tend to cluster in the same individuals and groups; for instance, job stress is linked to depression, hostility, anger and social isolation. This compounds the risk of CVD.
Psychosocial factors raise the risk of CVD through several mechanisms including greater likelihood of unhealthy behaviors such as smoking, alcohol and drug use and increased calorie intake and direct physiologic effects such as increased platelet activation and increase in inflammatory cytokines60 and neuroendocrine reactivity61 to stress.
Management of psychosocial risk factors is challenging in part due to the difficulty in defining an individual's level of risk and in part due to complex treatment. Moreover, the influence of these factors in any individual may change over time. Few trials show benefits of behavioral intervention on CVD risk or outcomes. Meditation decreases blood pressure and carotid artery intimal thickness in men. Extended cardiac rehabilitation (stress management combined with physical training and cooking sessions) improved depression, anxiety and quality of life at one year in patients with CHD.62 In the Recurrent Coronary Prevention Project, behavioral counseling resulted in reduced type A behavior and decrease in cardiac risk.63 Behavioral treatment in The Enhancing Recovery in Coronary Heart Disease (ENRICHD) trial reduced depression and social isolation in post-MI patients, but did not improve survival.64 To reduce psychosocial risk factors, emphasis needs to be placed on modifying stress, improving quality of life and recognizing and treating depression and other mood disorders.
Hypertension
Hypertension defined as a blood pressure of greater than or equal to 140/90 mm Hg is a major risk factor for CVD. In fact, there is a strong, graded relationship between blood pressure and fatal coronary events: risk doubles for every 2220 mm Hg increase in systolic blood pressure or 10 mm Hg increase in diastolic blood pressure. Various mechanisms by which hypertension leads to coronary events include hemodynamic stress on blood vessels and heart, increased myocardial oxygen demand, diminished coronary blood flow and impaired endothelial function. Several trials have shown reduction in cardiovascular morbidity and mortality by reduction in blood pressure.65
The seventh report of the Joint National Committee (JNC) on prevention, detection, evaluation, and treatment of high blood pressure recommends a treatment goal of less than 140/90 mm Hg for all individuals, however, in patients with CHD, renal insufficiency, congestive heart failure, peripheral vascular disease and diabetes a stricter goal of less than 130/80 mm Hg is recommended.66 Treatment of pre-hypertension (blood pressure 120–139/80–89 mm Hg) with Candesartan reduced the risk of incident hypertension in the TROPHY trial.67 Whether lowering of blood pressure to ‘normal’ (< 120/80 mm Hg) is beneficial is not clear. The next JNC guidelines are expected to be released in 2012.
Nonpharmacological interventions such as dietary modification,68 moderation of alcohol consumption, smoking cessation, increasing physical activity and weight loss improve blood pressure and are recommended for any level of hypertension. Multiple drug classes exist to treat hypertension including beta blockers, calcium channel blockers, diuretics, angiotensin converting enzyme inhibitors, angiotensin receptor blockers, renin inhibitors, vasodilators and centrally acting agents. First-line therapy is usually tailored to drug availability, cost, comorbid medical conditions and side effect profile of medications. Blood pressure lowering is more important than the choice of drug class. In a meta-analysis of 29 randomized controlled trials,69 Turnbull et al. found that there were no significant differences in the primary endpoint of major cardiovascular events between regimens based on angiotensin converting enzyme inhibitors, calcium antagonists, diuretics or beta-blockers.
Hyperlipidemia
There is a strong positive association between total cholesterol and LDL-C and CVD risk. Elevated triglycerides and low HDL-C are also independent risk factors for CVD. Individuals with severely elevated levels of LDL-C due to genetic abnormalities show premature atherosclerosis. Conversely, individuals with certain loss of function variants of the PCSK9 gene, who have moderate life-long reduction in LDL-C, have up to 88% reduction in risk of CHD.70 Different 23mechanisms by which LDL-C increases CHD include delivery of cholesterol to blood vessels, proinflammatory properties, role in plaque formation and plaque instability. High levels of HDL-C convey reduced risk of CHD. HDL-C exerts its protective effects on the cardiovascular system through numerous mechanisms including reverse cholesterol transport, antioxidant properties, inhibition of apoptosis and dysfunction of endothelial cells and inhibition of LDL oxidation.71 Low HDL-C and elevated triglycerides frequently occur with the presence of small dense LDL particles. This pattern of dyslipidemia is referred to as diabetic or atherogenic dyslipidemia.
Elevated LDL-C is the primary target for therapy and reduction in LDL-C substantially reduces CHD risk. In patients with elevated triglycerides (> 200 mg/dL), non-HDL-C (total cholesterol minus HDL-C) is a secondary target for therapy due to a strong association with CHD risk.72 Non-HDL-C highly correlates with levels of apolipoprotein B which is the major apolipoprotein of all major atherogenic lipoproteins. The non-HDL-C treatment goal is 30 mg/dL higher than LDL-C.
Lifestyle changes are important for management of hyperlipidemia including reduction in intake of saturated fats and cholesterol, increasing fiber intake, increasing physical activity and weight reduction. Pharmacological therapy is required to treat hyperlipidemia in many patients. The availability of HMG-CoA reductase inhibitors (statins) has revolutionized treatment for both primary and secondary prevention of CVD. Multiple large randomized controlled clinical trials have shown benefits of using statins for treatment of hyperlipidemia with an estimated 20–40% reduction in major cardiovascular events and mortality.73 The reduction in risk for an individual depends both on their initial overall risk for CVD as well as the degree of elevation in cholesterol, in particular LDL-C. Statins are usually first-line agents but combination therapy is sometimes required when LDL-C elevation is pronounced or multiple lipid abnormalities are present. Available agents include bile acid sequestrants, nicotinic acid, fibrates, ezetimibe or high doses of EPA/DHA. For low HDL-C, after controlling LDL-C and instituting lifestyle changes, niacin or fibrates can be used. Caution should be used when combining fibrate therapy with statins as it increases the risk of myopathy. Markedly elevated triglyceride levels (> 500 mg/dL) should be treated to prevent pancreatitis.
Diabetes Mellitus
Diabetes is a strong and independent risk factor for CVD. Whether diabetes confers a risk of events similar to that of established CHD is controversial,74,75 but current guidelines 24consider diabetes a CHD equivalent. Mechanisms by which diabetes causes CHD include increase in platelet aggregability, increase in inflammatory mediators, impaired endothelial function, dyslipidemia, increase in highly small, dense highly atherogenic LDL-C, among others.
Intensive glycemic control (hemoglobin A1C ∼7%) prevents microvascular complications but the impact on macrovascular complications including cardiovascular events is less well established. Recent large trials including the ACCORD76 and ADVANCE77 failed to show benefit of tighter control of diabetes (Hemoglobin A1C <6–6.5%) compared to usual glycemic control (Hemoglobin A1C 7–7.9%) on major cardiovascular events. The American Diabetes Association and other major societies recommend a target Hemoglobin A1C goal of less than 7%.78
Lifestyle interventions for prevention and treatment of diabetes are well established and are the recommended initial strategy.79,80 Several different classes of drugs exist for treatment of diabetes, the details of which are beyond the scope of this chapter.
Alcohol
Numerous prospective studies have suggested an inverse relation between moderate alcohol consumption (1–2 drinks per day) and CHD.81 Mechanisms by which alcohol may exert beneficial effects on CHD include antioxidant effects, increase in HDL-C and antithrombotic action.82 It is unclear if any particular type of alcoholic beverage is more protective. At the same time, alcohol use is associated with several health problems including cardiomyopathy, sudden cardiac death, cardiac arrhythmias, hypertension and stroke. Alcohol is an addictive substance and abuse of it remains a major public health problem.
Due to limitations of observational data, lack of clinical trials and the health hazards associated with its use, alcohol intake is not recommended as a cardioprotective strategy.83 For patients with current or past abuse, systemic diseases including hepatic or cardiac problems, it is best to advise against alcohol use. On a case-by-case basis, for individuals who drink, 1–2 drinks per day for men and 1 drink for women is acceptable to advise.
EMERGING RISK FACTORS
More than a hundred non-traditional or emerging risk factors have been reported.84 Whether they independently predict risk of CHD or add incremental information to existing risk factors continues to generate controversy and poses an obstacle to their incorporation into risk assessment and routine clinical practice. 25For a risk factor to be accurate and effective in predicting risk, it must meet certain criteria: It must have a strong, consistent association with the disease in a dose-response manner that is biologically plausible. It should be measured easily with acceptable reference values. It should be an independent predictor of major CHD events. It should reclassify a substantial number of individuals who were previously stratified by traditional risk factors and the results should be generalizable to different population groups.14 Before a novel risk factor or marker is incorporated into guidelines, its predictive value must be tested in multiple ways in different populations.
A recent US Preventive Services Task Force Recommendation Statement concludes that the current evidence is insufficient to assess the balance of benefits and harms of using non-traditional risk factors for screening asymptomatic men and women.14,85 Similarly, NCEP ATP III guidelines do not recommend routine use of emerging risk factors for risk assessment.
The emerging risk factors include both laboratory-based tests for biomarkers of atherosclerosis and noninvasive imaging modalities for detecting atherosclerosis. Some of the more commonly used emergent risk factors will briefly be reviewed.
High-Sensitivity C-Reactive Protein (hs-CRP)
hs-CRP has been extensively studied to help in risk stratification for CHD events. CRP is an acute phase reactant that is made by the liver. Inflammatory conditions result in a rise in CRP levels. Several CVD risk factors are also associated with higher levels of CRP. For cardiovascular risk prediction, an hs-CRP assay exists with levels less than 1.0 mg/L considered low risk, between 1.0–3.0 as intermediate risk and greater than 3.0 as high risk. hs-CRP independently predicts coronary events,86 however, the risk is modest with about 1.5 times elevated risk of coronary events in patients with CRP greater than 2.0, after adjustment for traditional CHD risk factors.87 The American Heart Association and Centers for Disease Control and Prevention endorse using hs-CRP as an optional test to help with further classification in particular of those patients who are at intermediate risk by FRS (Class IIa).88
Weight loss, physical activity, smoking cessation, cholesterol therapy with statins and niacin all decrease hs-CRP levels. In a subgroup of the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/Tex-CAPS) study Ridker et al.89 showed that participants with LDL-C below and hs-CRP above the median benefited from lovastatin therapy [relative risk, 0.58 (0.34, 0.98)] in contrast to those 26participants with both LDL-C and hs-CRP below the median whose coronary events were not reduced [relative risk, 1.08 (0.56–2.08)]. Results from the randomized controlled JUPITER trial90 suggest that hs-CRP could be used to select patients (women ≥ 60 years, men ≥ 50 years) for primary prevention with statins. For secondary prevention, a sub-analysis from the PROVE IT study showed that lowering hs-CRP in patients with acute coronary syndrome with statins resulted in lower risk of future coronary events.91
Lipoprotein (a) [Lp(a)]
Lp(a) consists of an LDL particle linked to an apo-A polypeptide chain. Levels of Lp(a) are genetically determined. There are no observed gender differences but racial differences exist. Whether Lp(a) is causally linked to CHD remains controversial.92 A recent study using genetic data suggested causal relation of elevated Lp(a) to myocardial infarction.93
The European Atherosclerosis Society recommends screening for Lp(a) in patients at intermediate or high risk for CHD.94 Levels of Lp(a) less than 50 mg/dL were recommended as the treatment goal using niacin, while acknowledging that randomized controlled trials are lacking. A North American panel endorsed testing for Lp(a) in patients who are moderate to high risk according to FRS, and decreasing the LDL-C treatment goal by 30 mg/dL in patients with high levels of Lp(a) (> 200 ng/mL).95
Hyperhomocysteinemia
Homocysteine is an intermediary product of methionine metabolism. Homocysteine can cause endothelial dysfunction and result in a procoagulant state. Many cross-sectional and prospective observational studies report a positive association between homocysteine levels and CVD. Untreated patients who are homozygous for homocystinuria have serum homocysteine concentrations five times above normal and increased risk of vascular events.
Dietary intake of folate, vitamin B6 and B12 affect homocysteine levels. Despite observational data linking homocysteine to CVD, multiple randomized controlled trials using supplementation with vitamin B12 and folic acid showed no reduction in the risk of major cardiovascular events in patients with or without pre-existing vascular disease.96,97 The 2007 American Heart Association guidelines for prevention of CVD in women recommend against using folic acid supplementation, with or without B6 and B12 for CVD prevention.9827
Lipoprotein-Associated Phospholipase A2 (Lp-PLA2)
Lp-PLA2 is an enzyme expressed by inflammatory cells in atherosclerotic plaques. In observational and epidemiological studies, Lp-PLA2 was modestly associated with an increased risk of CHD.99 There is an approximately 10% increase in coronary events per one standard deviation higher Lp-PLA2 activity and mass. In one study100 Lp-PLA2 increased the ROC curve minimally suggesting some clinical improvement in risk discrimination. Eventhough the FDA has approved a test for Lp-PLA2 for CHD, there is no trial evidence to date that Lp-PLA2 modification changes risk.
Apolipoprotein B
Apoliporotein B (Apo B) is a structural component of several lipoprotein particles which are atherogenic. Standardized assays for measurement of Apo B are available. Apo B is associated with increased risk of CHD.101 Whether Apo B measurement predicts CHD risk beyond commonly assessed risk factors in the FRS is uncertain.102
Plasma Apo B levels may be useful as a treatment target. A target value of less than 85 mg/dL for patients at high risk for CHD is proposed by the Canadian Cardiovascular Society.103 American Association of Clinical Chemistry recommends a treatment goal of less than 80 mg/dL in patients whose target LDL-C by NCEP ATPIII guidelines is less than 100 mg/dL.104
Fibrinogen and Other Hemostatic Factors
Several hemostatic factors involved in coagulation and fibrinolysis are associated with increased risk of CHD105 (Table 11). Fibrinogen levels in the upper third of the control distribution are associated with a 2.0–2.5 times excess risk of future CVD.106
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The current assays are not standardized and whether fibrinogen and other hemostatic factors add to traditional risk factors is unclear. Physical activity can decrease levels of fibrinogen but there is no evidence from randomized trials that fibrinogen modification by lifestyle or pharmacological therapy decreases CHD events.
SUB-CLINICAL ATHEROSCLEROSIS
Detecting sub-clinical atherosclerosis with noninvasive imaging modalities has generated great interest. This is distinct from the general ‘risk factor’ concept. Whether early detection of atherosclerosis should lead to modification in therapy and whether such modification in therapy offers clinical benefit is not clear.
The presence of calcium in coronary arteries correlates with atherosclerosis and is measured using cardiac tomographic imaging. Coronary artery calcium (CAC) score, which quantifies the extent of coronary calcium, is reported as percentiles of calcification according to age and sex. A ‘negative’ test has a CAC score of 0 and is associated with a low risk of subsequent coronary events. Numerous studies show that CAC testing is an independent predictor of coronary events in both men and women, from multiple racial and ethnic groups.107,108 CAC score has high sensitivity and negative predictive value for angiographically obstructive CAD but its positive predictive value is low.24 To date, it is unclear whether CAC testing should lead to change in therapy if that results in a favorable impact on clinical outcomes. Cost and radiation exposure also limit widespread CAC screening. CAC score may be used in select intermediate risk patients for further risk stratification.
Vascular intimal thickening is one of the earliest changes of atherosclerosis. Carotid arteries can easily be visualized because of their location and using ultrasound techniques the intima-media thickness can be determined noninvasively, without exposure to radiation. Increased carotid intima-media thickness is an independent predictor of cardiovascular risk.109 Carotid intima-media thickness also correlates with multiple CVD risk factors.110 Statin treatment decreases carotid intima-media thickness. There is lack of consensus on examination techniques and reference standards for quantifying intima-media thickness.85 Recently, the American Society of Echocardiography published a consensus statement proposing standardization of imaging and measurement protocols.111 Correct patient selection, assessment of clinical benefit of treatment and lack of outcome data limits widespread use at present.29
Ankle brachial index is a noninvasive test to diagnose and assess the severity of peripheral vascular disease. It is the ratio of systolic blood pressure in the ankle, measured at the level of the posterior tibial or dorsalis pedis artery, to that of the brachial artery. A lower value of ankle brachial index is not only an indicator for the severity of peripheral vascular disease but also correlates independently with major coronary events and stroke.112,113 When used in conjunction with FRS, a low ankle brachial index (≤ 0.90) approximately doubled the risk of cardiovascular events and death.114
At a population level, the best approach currently is probably to use the traditional risk factors for CHD screening. It is generally agreed that the established risk factors for CHD have very good ability to discriminate those at risk for CHD and account for over 90% of population attributable risk.27 We need to ensure that the traditional risk factors and risk prediction tools are applied routinely in clinical practice. At the same time, clinicians should be aware of the emerging risk factors and may use their clinical judgment to use additional screening modalities to better gauge an individual patient's risk.
TRANSLATING RISK FACTOR SCREENING INTO EVENT REDUCTION
It is our responsibility to fully implement strategies to ensure that any risk factors identified are fully treated. Barriers to such implementation exist at the physician, patient, system and societal level.115 Physicians can, through better communication and education, ensure better adherence to risk factor reduction strategies. Specific verbal and written instructions and prompt follow-up can help increase adherence. Monitoring progress goals and providing feedback can help patients to stay on track, particularly with lifestyle modifications. There should be open communication between the specialists and primary care physicians. Enabling easy access to electronic medical records from index hospitalization as well as specialist visits should help primary care physicians to deliver risk factor reduction treatment on a long-term basis.
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