Coronary Heart Disease
Coronary heart disease (CHD) is a leading cause of death in Western countries and is increasingly common in developing countries. This atherosclerotic process includes injury to arterial endothelium, fatty streaks due to macrophage ingestion of oxidized LDL cholesterol at the damaged site, platelet aggregation, and fibrosis. These events contribute to plaque formation in the intimal layer of medium and large arteries. Progressive arterial narrowing causes ischemia, which occurs initially with exertion but may eventually occur at rest.
Atherosclerosis commonly begins in childhood and slowly progresses throughout life. There is some evidence that this process may even start during fetal development. Rapid progression may occur by the third decade of life. Symptoms often do not present until late stages. Angina pectoris is frequently the main presenting symptom. It results from ischemia due to the narrowing of one or more coronary arteries. Angina is typically described as substernal pressure, and it can radiate to the neck, arms, back, and upper abdomen. Stable angina tends to occur regularly or predictably with exertion, whereas unstable angina occurs unpredictably, often with minimal exertion or at rest.
When atherosclerotic plaques rupture, vasoconstriction and clot formation can lead to complete occlusion of a coronary artery, causing a myocardial infarction (MI). An MI may be silent, or it may be signaled by prolonged pain or discomfort similar to that associated with simple angina. Individuals with diabetes are at higher risk of having silent ischemia. Compared with men (who are more likely to experience crushing substernal chest pain), women are more likely to experience shortness of breath, jaw or back pain, and nausea/vomiting. Further, care is sometimes delayed for women because caregivers and patients may believe that women are not at significant risk for cardiac disease.
Atherosclerosis of the extremities—i.e., peripheral vascular disease—often presents as claudication, in which calf, thigh, or hip pain is associated with activity and relieved with rest. Other signs of peripheral vascular disease include underdeveloped calf muscles, hairless shiny skin on the lower extremities, dystrophic toenails, bruits over the femoral, iliac, or popliteal arteries, and decreased peripheral pulses.
Diabetes. Hyperinsulinemia or impaired glucose tolerance, without a diagnosis of diabetes, also raises the risk for CHD.
Family history. First-degree relatives with MI before age 55 (men), or 65 (women).
Obesity. Excess weight is associated with several risk factors for CHD (see Obesity chapter).
Chronic kidney disease and microalbuminuria.
Inflammation. Elevated inflammatory markers, such as CRP, are associated with risk of CHD.
Stress. Some evidence suggests that psychological stress is associated with CHD risk. Socioeconomic status has also been associated with risk, perhaps through its contribution to stress.
Diagnosis of atherosclerosis and CHD is based on a patient’s individual risk factors, along with a careful medical history, physical exam, and diagnostic tests. Stress tests and imaging studies are generally not advised for asymptomatic individuals, except when certain or multiple CHD risk factors exist, or when vigorous exercise is planned.
No blood test can definitively diagnose the presence or extent of atherosclerosis. However, a number of tests that can help predict long-term risk of future cardiovascular events, as we will see below. Diagnosis of an acute MI is more straightforward, as laboratory tests, combined with symptoms and electrocardiographic and angiographic findings, are increasingly sensitive and specific.
Diagnosing myocardial Injury
Creatine kinase-MB fraction (CK-MB). CK-MB is a specific marker for acute myocardial injury. The serum concentration rises within 4-6 hours of the onset of acute MI but is not elevated in all individuals until 12 hour post insult. Serial measurements every 2-4 hours (for about 12 hours) help determine the extent and time frame of myocardial injury. CK-MB is also useful for the determination of reinfarction, or extension of myocardial injury. Concentrations normally decrease after 1-3 days, so subsequent elevations or plateaus indicate another myocardial infarction. However, cardiac troponin is now preferred in diagnosing reinfarction.
Troponins. C ardiac troponin proteins combine with calcium to facilitate cardiac muscle cell contraction through actin-myosin interaction. Troponins are released into the bloodstream during myocardial injury with an identifiable rise 2-3 hours post insult. Although troponin I is more specific for myocardial injury than troponin T, these markers are equally useful for diagnosing acute MI.
Levels of both troponin and CK-MB increase during the early course of a MI. However, troponin is more sensitive and specific. Because troponin remains elevated for 5-14 days, it can be used to diagnose late MI. Recent data suggest that troponin rises quickly, even from an abnormal baseline, and is now preferred over CK-MB for diagnosis of reinfarction.
Estimating Long-Term Risk
Cholesterol. Elevated total and low-density lipoprotein (LDL) cholesterol concentrations, and low high-density lipoprotein (HDL) cholesterol concentrations (less than 50 mg/dL in women and 40 mg/dL in men), increase the risks for atherosclerosis and CHD events. Previously, the National Cholesterol Education Program defined elevated total cholesterol concentration as above 200 mg/dL and elevated LDL cholesterol concentration as above 100 mg/dL (with higher thresholds for some groups). Evidence indicates a significant benefit for maintaining lower levels. In epidemiologic studies and clinical trials, CHD event risk continually decreases until total cholesterol is below about 150 mg/dL and until LDL is below 40 mg/dL.
New guidelines from the American College of Cardiology and the American Heart Association no longer put emphasis on specific LDL treatment levels. However, they designate 4 treatment groups which gain the most benefit from pharmacologic cholesterol lowering: those between ages 40-75 with known atherosclerotic disease, those with LDL > 190mg/dL, those with diabetes, and patients 40-75 years old with a 10-year risk of an atherosclerotic disease related event of ≥ 7.5% (based on pooled cohort equations).
Low HDL levels are common in populations that follow low-fat, plant-based diets and have low coronary risk, and they appear to be the result of decreased transport rather than an increase in HDL catabolism common to individuals eating a high-fat Western diet. The ratio of total cholesterol:HDL and LDL:HDL is favorable in individuals following diets low in fat and high in fiber. The ability of HDL to exert an anti-inflammatory effect (i.e., to reduce LDL oxidation) actually increases in this situation.
Triglycerides. Elevated concentrations (above 150 mg/dL) are independently associated with CHD risk.
Homocysteine. This amino acid is atherogenic, is known to cause vascular intimal thickening and platelet aggregation, and promotes platelet rich thrombi. Men normally have a slightly higher homocysteine concentration than women. Levels tend to increase with age. Although homocysteine levels have been correlated with CHD risk, neither a cause-effect relationship nor a treatment-outcome benefit has been established in clinical trials. Therefore, it is not commonly used in clinical practice. Optimal homocysteine metabolism requires adequate amounts of vitamin B12, vitamin B6, and folic acid. A diet rich in fruits and vegetables and low in total and saturated fat can lower serum homocysteine levels.
C-reactive protein (CRP). CRP is an acute phase marker of inflammation. High sensitivity-CRP (hs-CRP) is associated with increased risk of cardiac events, with levels greater than 3 mg/dL associated with greatest risk. However, hs-CRP has not reliably been shown to have a cause-effect relationship or a treatment outcome benefit in cardiovascular disease. The usefulness of CRP and many other inflammatory and acute phase reactants as screening measures or therapeutic targets in cardiovascular disease remains unproven, , , , pending the results of additional clinical trials. The Atherosclerosis Risk in Communities Study (ARIC) concluded that routine measurement of CRP, homocysteine, and 17 other novel risk markers is not warranted and reinforced the utility of standard risk factor assessment and management. The Centers for Disease Control and Prevention and the American Heart Association have issued a statement that patients considered to be at intermediate risk for CHD, based on Framingham scores, could be further risk-stratified based on CRP levels, if treating physicians deem it appropriate.
Interleukin-6 (IL-6). IL-6 is a pro- and anti-inflammatory cytokine that has the ability to activate B cells, T cells, and macrophages. It is also the major inducer of acute phase reactants, including CRP and various other inflammatory cytokines. In contrast to CRP, IL-6 appears to have a direct causal role in CHD development. While not currently used in clinical practice, IL-6 may be a therapeutic target in the future.
Leukocyte myeloperoxidase. This enzyme, released by white blood cells during inflammation, promotes the oxidation of lipoproteins and is associated with presence of CHD and risk for future events, independently of other cardiac risk factors. , Currently, this test has little clinical utility.
Other biomarkers of inflammation have been associated with CHD risk, including IL-18, ESR, WBC count, and TNF- α, but again these tests are not typically used in clinical practice.
EKG. Findings may include ST elevation (acute myocardial injury or infarction) or depression (myocardial ischemia), T wave inversion (myocardial ischemia or MI), new left bundle branch block (acute MI) and ventricular premature complexes.
Stress tests. Methods include treadmill or bicycle exercise stress tests (EST), and EST or pharmacologic stress tests combined with nuclear imaging or echocardiography. These tests may be used for CHD diagnosis, risk stratification, and prognosis, and they often help determine the advisability for cardiac catheterization and revascularization.
EKG changes and symptoms (e.g., exertional chest pain) are monitored during stress tests, providing both determinants of CHD presence and severity and indications for test termination. Pharmacologic stress modalities are typically used when an exercise stress test is inappropriate or inconclusive. Pharmacologic stress agents include coronary vasodilators, such as dipyridamole and adenosine, and cardiac inotropes, such as dobutamine and (less commonly) arbutamine.
Other Imaging Tests
Cardiac catheterization with coronary angiography. A catheter is inserted into a peripheral artery (either radial artery or femoral artery) and advanced under fluoroscopic guidance to the coronary artery ostia. A radiopaque dye is then injected to identify the locations and severities of coronary blockages. This invasive procedure is performed when coronary artery stenosis is known or suspected, and the need for coronary artery angioplasty, stent placement, or bypass surgery is anticipated.
Intravascular ultrasound (IVUS). IVUS is highly sensitive to the presence and composition of coronary artery plaques. Its 3 major uses currently are to clarify the severity of stenoses identified on angiography, to characterize the composition of and degree of calcification within plaques, and to assess the deployment of coronary artery stents.
Computed tomography (CT). Coronary artery calcification (CAC) is correlated with CHD events. Multidetector CT accurately identifies and quantifies coronary artery calcification. This test has several applications in CHD, including diagnosis, disease distribution, risk stratification, prognosis, and treatment decisions. CAC scoring is a helpful screening method in specific patient populations but has limited value for low-risk, asymptomatic patients. In 2010, the American College of Cardiology/American Heart Association (ACC/AHA) suggested that screening for coronary artery disease by measurement of CAC is reasonable for CVD risk assessment in asymptomatic adults at Framingham intermediate risk (10%-20% 10-year risk). This screening is not recommended for patients at low or high risk.
Coronary CT angiography (CCTA) uses intravenous contrast to obtain noninvasive coronary angiograms. Technical advances such as 64-slice scanners can produce angiograms that rival invasive coronary angiography. CCTA is not recommended as a general screening tool but may be useful in specific patient populations, such as those with equivocal stress test results or those who are unable to perform any type of stress test. This modality continues to have limitations, but the entire approach to CHD diagnosis and risk stratification may change as this technology advances.
Magnetic resonance imaging (MRI). Cardiac MRI has historically been best suited for evaluation of cardiac chambers, pericardium, thoracic vessels, and congenital heart disease. However, technical advances to minimize the effects of cardiac motion have expanded MRI applications to include CHD evaluation. Such applications overlap substantially with CTA, and the role for MRI in CHD remains uncertain.
Diet and lifestyle changes to modify risk factors (e.g., smoking, obesity, hypertension, lack of physical activity, and dyslipidemia) are the cornerstone of treatment, with m edications playing an adjunctive role. Unfortunately, counseling of patients regarding the importance of diet and exercise in the prevention of heart disease remains suboptimal.
Important preventive steps include the following:
Drugs are used to reduce the symptoms of angina, as well to control specific risk factors.
Nitrates (sublingual nitroglycerin versus oral forms) are vasodilators and provide greatest benefit through decreased preload (venodilation).
Beta-blockers (e.g., propranolol, atenolol, metoprolol) decrease myocardial oxygen demand by decreasing contractility and heart rate.
Calcium-channel blockers (diltiazem, verapamil, nifedipine, amlodipine) relax arterial smooth muscle, resulting in decreased afterload.
Antiplatelet therapy. For those who can tolerate aspirin, 81-325 mg daily is prescribed to decrease CHD event risk. Clopidogrel (75 mg daily) is an alternative for persons unable to tolerate aspirin, or for those who have had CHD events despite aspirin. Clopidogrel (and newer, similar medications, such as ticagrelor and prasugrel) may also be combined with low-dose aspirin (81 mg daily) for high-risk patients and aspirin failures, and after stent placement.
Lipid-lowering agents, such as the following, may also be prescribed. (See Dyslipidemias chapter.)
Surgery and Other Mechanical Interventions
For high-risk CHD patients, including those with prominent symptoms, severe multivessel coronary artery disease (CAD), acute coronary syndromes, or MI, coronary revascularization may be achieved with percutaneous transluminal coronary angioplasty, intracoronary stent placement, or co ronary artery bypass graft (CABG) surgery. For most categories of patients, stenting and CABG have similar success rates for relief of symptoms and control of CHD event risk. The need for subsequent revascularization is usually lower after CABG than after angioplasty or stent placement.
The Role of Exercise
Regular exercise is effective in primary and secondary cardiovascular risk reduction, including in patients who are post-MI. Current guidelines recommend exercise intensity be aimed at achieving a heart rate of 50%-90% of maximal heart rate, based on age. However, growing evidence suggests that high intensity aerobic training, with heart rate maintained at 85%-95% of max is safe and may confer additional long term benefits for CHD patients participating in organized cardiac rehab programs, beginning cautiously with appropriate supervision. , In addition to aerobic training, studies indicate that resistance exercise may reduce CHD risk by lowering blood pressure, lowering LDL cholesterol, reducing body fat, and improving insulin resistance.
Current recommendations from the 2013 ACC/AHA Statement on Lifestyle therapy suggest physical activity be performed 3-4 sessions a week, lasting on average 40 minutes per session and involving moderate-to-vigorous intensity.
Post-MI patients and patients with established CHD should be referred, if possible, to an outpatient cardiac rehab team who can adequately evaluate risk and develop individual exercise plans that are safe and effective. Patients at risk for CHD should always have a thorough clinical examination with appropriate ancillary testing before starting an exercise program. High-risk patients should not attempt vigorous exercise without the supervision of a trained medical professional.
Many post-MI patients develop symptoms of depression and nearly 1 in 5 meets the criteria for major depressive disorder, which is associated with poor therapy compliance and poor outcomes. Post-MI care should include screening for and treating depression with stress reduction therapy, physical activity and medication, if needed. ,
The role of diet in coronary heart disease is evident from its pathological process, which involves the formation of arterial plaques, alterations in endothelial function, heightened risk for thrombosis, and inflammatory processes. Diet plays a role through the regulation of blood lipids and by influencing endothelial function and the underlying inflammation that causes disease progression. Diets promoting cardiovascular health should begin as early as possible because the atherosclerosis that contributes to coronary artery disease begins in childhood.
Pioneering studies by Dean Ornish, M.D., Caldwell Esselstyn Jr., M.D., and others have shown that a low-fat plant-based diet, combined with regular exercise and a healthy overall lifestyle, can prevent, delay, and reverse the progression of atherosclerosis, with subsequent reduction in cardiovascular events.
The primary goals of dietary intervention are described below.
Controlling blood lipid concentrations. Saturated fats, trans fats, and cholesterol in the diet increase concentrations of blood lipids, particularly LDL cholesterol, while soluble fiber tends to reduce them. Controlling blood lipoprotein concentrations with a combination of diet, exercise, and medication, if necessary, is a cornerstone of treatment for most CHD patients, as described in more detail in the Dyslipidemias chapter.
Reducing blood pressure. Hypertension is a major risk factor for CHD. The same d ietary and lifestyle changes that reduce total and LDL cholesterol can also significantly reduce blood pressure and lower the risk of a cardiac event.
Controlling blood sugar levels. Diabetes is a major contributor to coronary disease and, in turn, CHD is a leading cause of death for people with diabetes. Dietary interventions can increase insulin sensitivity for individuals with type 2 diabetes and improve blood glucose control for individuals with type 1 or type 2 diabetes.
Improving antioxidant status and endothelial function. Dietary antioxidants, folate, magnesium, and other substances in foods may reduce the burden of oxidized LDL and improve endothelial function through increased availability of nitric oxide.
Reducing inflammation. The role of inflammatory processes in atherosclerosis is increasingly apparent. Loss of excess body fat reduces C-reactive protein, an indicator of inflammation.
The following dietary steps help patients in achieving these goals:
Avoiding animal-derived food products. Dairy products, meat, and eggs are the primary sources of saturated fat and cholesterol. Following diets low in saturated fat and cholesterol can help reduce progression of atherosclerosis.
The National Cholesterol Education Program has recommended moderate reductions in total fat ( ≤ 30% of energy), saturated fat ( ≤ 7% of energy), and cholesterol ( < 200 mg/d) intake. In clinical trials, such changes reduce plasma LDL cholesterol concentration about 5%. Low-fat plant-based (vegetarian and vegan) regimens are significantly more effective, reducing LDL cholesterol approximately 15%-30%., , Such regimens have also been shown to reduce body weight and blood pressure and to be useful in programs for reversing atherosclerosis.
Low-fat plant-based diets are also highly acceptable to patients, provided they are prescribed along with basic diet instruction and support. Combining daily aerobic exercise with a healthful diet adds to its benefit, particularly with regard to weight and blood glucose control.
Avoidinghydrogenated and partially hydrogenated oils. These products contain trans fats that increase LDL cholesterol and can reduce HDL choles terol. , , Trans fatty acids also have pro-inflammatory effects similar to those of saturated fat and adversely affect vascular reactivity, reducing arterial flow-mediated dilation (a direct measure of vascular endothelial function).
Increasing fiber-containing whole plant foods. Soluble fiber, as is found in oats, barley, and beans, is particularly cardioprotective. Fruits and vegetables are also sources of soluble dietary fiber and pectin, and are associated with reduced atherosclerotic progression. Most Americans do not consume adequate fiber, but large studies have shown that individuals following plant-based diets typically have fiber intakes that meet or exceed recommendations.
Consuming soy and other legumes. Both epidemiologic and clinical studies have shown that soy products (e.g., soy milk and meat substitutes) may reduce CHD risk. In addition to reducing blood lipids, soy has cardioprotective effects, such as lowering oxidized LDL and blood pressure. Other legumes have also lowered total and LDL cholesterol in randomized controlled trials.
Clinical trials have combined these dietary lipid-lowering strategies. A vegetarian diet emphasizing specific cholesterol-lowering foods appears to be particularly effective, lowering LDL cholesterol concentration approximately 30% in 4 weeks, an effect similar to that of statin drugs. In addition to excluding animal products, the regimen includes each of the following (quantities are based on a 2,000-calorie diet):
- Soluble fiber (oats, barley, eggplant, okra, psyllium): 20 grams
- Soy protein (soy milk and soy meat analogues): 40 grams
- Whole almonds: 28 grams
- Plant sterols (from enriched foods): 2 grams
Increasing fruits and vegetables. Fruits and vegetables can help reduce atherosclerosis and lower risk for CHD, particularly if the diet is low in saturated fat. However, the benefits of these foods go beyond their having no cholesterol, very little saturated fat, and abundant fiber. Among their active components are vitamin C, antioxidant flavonoids, and folic acid.
Several studies have shown that higher dietary intakes of carotenoid-containing fruits and vegetables are associated with a decreased risk of coronary artery disease. Others have found an inverse relationship between lower blood levels of carotenoids and higher risk for cardiovascular events.
In addition to the above considerations, evidence suggests that other dietary factors may be helpful, as described below.
In epidemiological studies, w hole grain consumption is associated with a lower risk of heart disease, as is frequent consumption of nuts. In addition to providing the lipid-lowering benefit of dietary fiber, these foods provide magnesium and vitamin E, both of which are inversely related to coronary heart disease occurrence or mortality. , Nuts are high in fat and calories, however, and may influence body weight.
Other dietary factors under consideration:
Fish, fish oil, and omega-3 supplements are unproven. Although some studies have suggested that omega-3 polyunsaturated fatty acids in fish reduce the incidence of heart disease, , the overall evidence does not support the addition of fish or omega-3 supplements to an otherwise plant-focused diet to reduce cardiovascular disease risk., , ,
The role of alcohol remains controversial. No controlled clinical trials have examined the effect of alcohol intake on cardiovascular endpoints. Nevertheless, moderate alcohol consumption (1-2 drinks/day) may reduce cardiovascular disease risk through several mechanisms: increasing blood concentrations of HDL cholesterol, plasminogen, and tissue plasminogen activator; improving endothelial function; and decreasing platelet aggregation, fibrinogen, and lipoprotein. However, even modest levels of alcohol consumption contribute to several medical conditions, including gastrointestinal and breast cancers, diseases of the liver, pancreas, central nervous system, and cardiovascular system, and m ore than moderate drinking is associated with increased cardiac mortality.
Survival and Prognosis after Coronary Events
A low-fat vegetarian diet reduces the risk for repeated coronary events. In a 12-year study, i ndividuals who adhered to a low-fat (< 10% of energy) vegetarian diet as part of treatment for pre-existing heart disease had an absence of coronary events. Diet interventions that have also included exercise, stress reduction, and smoking cessation appear to cause regression of atherosclerotic lesions.
Mediterranean-style diets also decrease the risk for repeated cardiovascular events. The combination of known protective nutrients found in the plant-based Mediterranean diet significantly reduced cardiac death, nonfatal MI, and a omposite of end-points including unstable angina, stroke, heart failer, and pulmonary or peripheral embolism when compared with a Western diet. However, Mediterranean diets are higher in fat (25%-25%) than low-fat vegetarian diets and are therefore not likely to be as effective for weight loss or regression of atherosclerotic lesions.
Nutrition consultation to advise patient regarding the above diet and arrange follow-up.
Referral to a cardiac rehabilitation program.
Physical therapy and psychiatry or social support referrals as appropriate.
What to Tell the Family
Atherosclerosis and coronary heart disease are preventable, treatable, and in some cases reversible. Vegetarian diets, along with other healthful lifestyle changes, are particularly effective and appear to be as acceptable to patients as other regimens. Because such diets usually require learning new cooking techniques and acquiring new tastes, families play an important role in joining the patient in the process of dietary change. Family members can support the heart disease patient by following a similar diet and exercise regimen, which will likely benefit their health as well.
- Skilton MR. Intrauterine risk factors for precocious atherosclerosis. Pediatrics. 2008;121(3):570-4. [PMID:18310207]
- McNeill AM, Rosamond WD, Girman CJ, et al. The metabolic syndrome and 11-year risk of incident cardiovascular disease in the atherosclerosis risk in communities study. Diabetes Care. 2005;28(2):385-90. [PMID:15677797]
- Thygesen K, Alpert JS, Jaffe AS, et al. Third universal definition of myocardial infarction. Circulation. 2012;126(16):2020-35. [PMID:22923432]
- National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation. 2002;106(25):3143-421. [PMID:12485966]
- Grundy SM, Cleeman JI, Merz CN, et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III Guidelines. J Am Coll Cardiol. 2004;44(3):720-32. [PMID:15358046]
- Stone NJ, Robinson JG, Lichtenstein AH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014;129(25 Suppl 2):S1-45. [PMID:24222016]
- Ornish D, Scherwitz LW, Billings JH, et al. Intensive lifestyle changes for reversal of coronary heart disease. JAMA. 1998;280(23):2001-7. [PMID:9863851]
- Roberts CK, Ng C, Hama S, Eliseo AJ, Barnard RJ. Effect of a short-term diet and exercise intervention on inflammatory/anti-inflammatory properties of HDL in overweight/obese men with cardiovascular risk factors. J Appl Physiol (1985) . 2006;101:1727-1732.
- Loscalzo J. Homocysteine trials--clear outcomes for complex reasons. N Engl J Med. 2006;354(15):1629-32. [PMID:16531615]
- Appel LJ, Miller ER, Jee SH, et al. Effect of dietary patterns on serum homocysteine: results of a randomized, controlled feeding study. Circulation. 2000;102(8):852-7. [PMID:10952952]
- Pearson TA, Mensah GA, Alexander RW, et al. Markers of inflammation and cardiovascular disease: application to clinical and public health practice: A statement for healthcare professionals from the Centers for Disease Control and Prevention and the American Heart Association. Circulation. 2003;107:499–511.
- Hansson GK. Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med. 2005;352(16):1685-95. [PMID:15843671]
- Scirica BM, Morrow DA. Is C-reactive protein an innocent bystander or proatherogenic culprit? The verdict is still out. Circulation. 2006;113(17):2128-34; discussion 2151. [PMID:16651484]
- Blankenberg S, McQueen MJ, Smieja M, et al. Comparative impact of multiple biomarkers and N-Terminal pro-brain natriuretic peptide in the context of conventional risk factors for the prediction of recurrent cardiovascular events in the Heart Outcomes Prevention Evaluation (HOPE) Study. Circulation. 2006;114(3):201-8. [PMID:16831981]
- Miller M, Zhan M, Havas S. High attributable risk of elevated C-reactive protein level to conventional coronary heart disease risk factors: the Third National Health and Nutrition Examination Survey. Arch Intern Med. 2005;165(18):2063-8. [PMID:16216995]
- Folsom AR, Chambless LE, Ballantyne CM, et al. An assessment of incremental coronary risk prediction using C-reactive protein and other novel risk markers: the atherosclerosis risk in communities study. Arch Intern Med. 2006;166(13):1368-73. [PMID:16832001]
- IL6R Genetics Consortium Emerging Risk Factors Collaboration, Sarwar N, Butterworth AS, et al. Interleukin-6 receptor pathways in coronary heart disease: a collaborative meta-analysis of 82 studies. Lancet. 2012;379(9822):1205-13. [PMID:22421339]
- Brennan ML, Penn MS, Van Lente F, et al. Prognostic value of myeloperoxidase in patients with chest pain. N Engl J Med. 2003;349(17):1595-604. [PMID:14573731]
- Karakas M, Koenig W, Zierer A, et al. Myeloperoxidase is associated with incident coronary heart disease independently of traditional risk factors: results from the MONICA/KORA Augsburg study. J Intern Med. 2012;271(1):43-50. [PMID:21535251]
- Nair A, Kuban BD, Tuzcu EM, et al. Coronary plaque classification with intravascular ultrasound radiofrequency data analysis. Circulation. 2002;106(17):2200-6. [PMID:12390948]
- Greenland P, Alpert JS, Beller GA, et al. 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(25):e50-103. [PMID:21144964]
- Ma J, Urizar GG, Alehegn T, et al. Diet and physical activity counseling during ambulatory care visits in the United States. Prev Med. 2004;39(4):815-22. [PMID:15351551]
- Lawler PR, Filion KB, Eisenberg MJ. Efficacy of exercise-based cardiac rehabilitation post-myocardial infarction: a systematic review and meta-analysis of randomized controlled trials. Am Heart J. 2011;162(4):571-584.e2. [PMID:21982647]
- Rognmo Ø, Moholdt T, Bakken H, et al. Cardiovascular risk of high- versus moderate-intensity aerobic exercise in coronary heart disease patients. Circulation. 2012;126(12):1436-40. [PMID:22879367]
- Warburton DE, McKenzie DC, Haykowsky MJ, et al. Effectiveness of high-intensity interval training for the rehabilitation of patients with coronary artery disease. Am J Cardiol. 2005;95(9):1080-4. [PMID:15842976]
- Braith RW, Stewart KJ. Resistance exercise training: its role in the prevention of cardiovascular disease. Circulation. 2006;113(22):2642-50. [PMID:16754812]
- Eckel RH, Jakicic JM, Ard JD, et al. 2013 AHA/ACC guideline on lifestyle management to reduce cardiovascular risk: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014;129(25 Suppl 2):S76-99. [PMID:24222015]
- van Melle JP, de Jonge P, Spijkerman TA, et al. Prognostic association of depression following myocardial infarction with mortality and cardiovascular events: a meta-analysis. Psychosom Med. 2004;66(6):814-22. [PMID:15564344]
- Colquhoun DM, Bunker SJ, Clarke DM, et al. Screening, referral and treatment for depression in patients with coronary heart disease. Med J Aust. 2013;198(9):483-4. [PMID:23682890]
- Zieske AW, Malcom GT, Strong JP. Natural history and risk factors of atherosclerosis in children and youth: the PDAY study. Pediatr Pathol Mol Med. 2002;21(2):213-37. [PMID:11942537]
- Clifton PM, Keogh JB, Foster PR, Noakes M. Effect of weight loss on inflammatory and endothelial markers and FMD using two low-fat diets. Int J Obes (Lond) . 2005;29:1445-1451.
- Bemelmans WJ, Lefrandt JD, Feskens EJ, et al. Change in saturated fat intake is associated with progression of carotid and femoral intima-media thickness, and with levels of soluble intercellular adhesion molecule-1. Atherosclerosis. 2002;163(1):113-20. [PMID:12048128]
- Hunninghake DB, Stein EA, Dujovne CA, et al. The efficacy of intensive dietary therapy alone or combined with lovastatin in outpatients with hypercholesterolemia. N Engl J Med. 1993;328(17):1213-9. [PMID:8464431]
- Esselstyn CB. Updating a 12-year experience with arrest and reversal therapy for coronary heart disease (an overdue requiem for palliative cardiology). Am J Cardiol. 1999;84(3):339-41, A8. [PMID:10496449]
- Barnard ND, Scialli AR, Bertron P, et al. Effectiveness of a low-fat vegetarian diet in altering serum lipids in healthy premenopausal women. Am J Cardiol. 2000;85(8):969-72. [PMID:10760336]
- Barnard ND, Scialli AR, Turner-McGrievy G, et al. Acceptability of a low-fat vegan diet compares favorably to a step II diet in a randomized, controlled trial. J Cardiopulm Rehabil. 2004;24(4):229-35. [PMID:15286527]
- Roberts CK, Won D, Pruthi S, et al. Effect of a short-term diet and exercise intervention on oxidative stress, inflammation, MMP-9, and monocyte chemotactic activity in men with metabolic syndrome factors. J Appl Physiol (1985) . 2006;100:1657-1665.
- Dyerberg J, Christensen JH, Eskesen D, et al. Trans, and n-3 polyunsaturated fatty acids and vascular function-a yin yang situation? Atheroscler Suppl. 2006;7(2):33-5. [PMID:16713391]
- Ascherio A, Willett WC. Health effects of trans fatty acids. Am J Clin Nutr. 1997;66(4 Suppl):1006S-1010S. [PMID:9322581]
- Brouwer IA, Wanders AJ, Katan MB. Effect of animal and industrial trans fatty acids on HDL and LDL cholesterol levels in humans--a quantitative review. PLoS ONE. 2010;5(3):e9434. [PMID:20209147]
- Mozaffarian D. Trans fatty acids - effects on systemic inflammation and endothelial function. Atheroscler Suppl. 2006;7(2):29-32. [PMID:16713393]
- Wu H, Dwyer KM, Fan Z, et al. Dietary fiber and progression of atherosclerosis: the Los Angeles Atherosclerosis Study. Am J Clin Nutr. 2003;78(6):1085-91. [PMID:14668268]
- Clemens R, Kranz S, Mobley AR, et al. Filling America's fiber intake gap: summary of a roundtable to probe realistic solutions with a focus on grain-based foods. J Nutr. 2012;142(7):1390S-401S. [PMID:22649260]
- Rizzo NS, Jaceldo-Siegl K, Sabate J, et al. Nutrient profiles of vegetarian and nonvegetarian dietary patterns. J Acad Nutr Diet. 2013;113(12):1610-9. [PMID:23988511]
- Zhang X, Shu XO, Gao YT, et al. Soy food consumption is associated with lower risk of coronary heart disease in Chinese women. J Nutr. 2003;133(9):2874-8. [PMID:12949380]
- Jenkins DJ, Kendall CW, Marchie A, et al. Effects of a dietary portfolio of cholesterol-lowering foods vs lovastatin on serum lipids and C-reactive protein. JAMA. 2003;290(4):502-10. [PMID:12876093]
- Bazzano LA, Thompson AM, Tees MT, et al. Non-soy legume consumption lowers cholesterol levels: a meta-analysis of randomized controlled trials. Nutr Metab Cardiovasc Dis. 2011;21(2):94-103. [PMID:19939654]
- Jenkins DJ, Popovich DG, Kendall CW, et al. Effect of a diet high in vegetables, fruit, and nuts on serum lipids. Metab Clin Exp. 1997;46(5):530-7. [PMID:9160820]
- Tucker KL, Hallfrisch J, Qiao N, et al. The combination of high fruit and vegetable and low saturated fat intakes is more protective against mortality in aging men than is either alone: the Baltimore Longitudinal Study of Aging. J Nutr. 2005;135(3):556-61. [PMID:15735093]
- Joshipura KJ, Hu FB, Manson JE, et al. The effect of fruit and vegetable intake on risk for coronary heart disease. Ann Intern Med. 2001;134(12):1106-14. [PMID:11412050]
- Hirvonen T, Pietinen P, Virtanen M, et al. Intake of flavonols and flavones and risk of coronary heart disease in male smokers. Epidemiology. 2001;12(1):62-7. [PMID:11138821]
- Voutilainen S, Rissanen TH, Virtanen J, et al. Low dietary folate intake is associated with an excess incidence of acute coronary events: The Kuopio Ischemic Heart Disease Risk Factor Study. Circulation. 2001;103(22):2674-80. [PMID:11390336]
- Osganian SK, Stampfer MJ, Rimm E, et al. Dietary carotenoids and risk of coronary artery disease in women. Am J Clin Nutr. 2003;77(6):1390-9. [PMID:12791615]
- Rissanen TH, Voutilainen S, Nyyssönen K, et al. Low serum lycopene concentration is associated with an excess incidence of acute coronary events and stroke: the Kuopio Ischaemic Heart Disease Risk Factor Study. Br J Nutr. 2001;85(6):749-54. [PMID:11430780]
- Mozaffarian D, Kumanyika SK, Lemaitre RN, et al. Cereal, fruit, and vegetable fiber intake and the risk of cardiovascular disease in elderly individuals. JAMA. 2003;289(13):1659-66. [PMID:12672734]
- Ellsworth JL, Kushi LH, Folsom AR. Frequent nut intake and risk of death from coronary heart disease and all causes in postmenopausal women: the Iowa Women's Health Study. Nutr Metab Cardiovasc Dis. 2001;11(6):372-7. [PMID:12055701]
- Al-Delaimy WK, Rimm EB, Willett WC, et al. Magnesium intake and risk of coronary heart disease among men. J Am Coll Nutr. 2004;23(1):63-70. [PMID:14963055]
- Kushi LH, Folsom AR, Prineas RJ, et al. Dietary antioxidant vitamins and death from coronary heart disease in postmenopausal women. N Engl J Med. 1996;334(18):1156-62. [PMID:8602181]
- Nestel P, Clifton P, Colquhoun D, et al. Indications for omega-3 long chain polyunsaturated fatty acid in the prevention and treatment of cardiovascular disease. Heart, Lung and Circ . 2015;24:769-779.
- Endo J, Arita M. Cardioprotective mechanism of omega-3 polyunsaturated fatty acids. J Cardiol. 2016;67(1):22-7. [PMID:26359712]
- Mangat I. Do vegetarians have to eat fish for optimal cardiovascular protection? Am J Clin Nutr. 2009;89(5):1597S-1601S. [PMID:19321560]
- Sanders TA. Plant compared with marine n-3 fatty acid effects on cardiovascular risk factors and outcomes: what is the verdict? Am J Clin Nutr. 2014;100 Suppl 1:453S-8S. [PMID:24898234]
- Smith DA. ACP Journal Club. Review: omega-3 polyunsaturated fatty acid supplements do not reduce major cardiovascular events in adults. Ann Intern Med. 2012;157(12):JC6-5. [PMID:23247954]
- Rizos EC, Ntzani EE, Bika E, et al. Association between omega-3 fatty acid supplementation and risk of major cardiovascular disease events: a systematic review and meta-analysis. JAMA. 2012;308(10):1024-33. [PMID:22968891]
- Vogel RA. Alcohol, heart disease, and mortality: a review. Rev Cardiovasc Med. 2002;3(1):7-13. [PMID:12439349]
- Room R, Babor T, Rehm J. Alcohol and public health. Lancet. 2005;365(9458):519-30. [PMID:15705462]
- O'Keefe JH, Bybee KA, Lavie CJ. Alcohol and cardiovascular health: the razor-sharp double-edged sword. J Am Coll Cardiol. 2007;50(11):1009-14. [PMID:17825708]
- de Lorgeril M, Salen P, Martin JL, et al. Mediterranean diet, traditional risk factors, and the rate of cardiovascular complications after myocardial infarction: final report of the Lyon Diet Heart Study. Circulation. 1999;99(6):779-85. [PMID:9989963]