Prevention of Symptomatic Coronary Heart Disease Through the Early Identification and Treatment of Coronary Atherosclerosis

C. Michael Wright, MD, FACC • Matthew A. Allison, MD, MPH
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ABSTRACT • INTRODUCTION • PATHOGENESIS OF CORONARY ATHEROSCLEROSIS •
CLINICAL EVALUATION OF PATIENTS FOR ATHEROSCLEROTIC DISEASE • TREATMENT OPTIONS • REFERENCES

ABSTRACT

Cardiovascular disease (CVD) has been the leading cause of death in Americans since 1900. From 1995 to 1998, in 50% of men and 63% of women who died suddenly of CHD, there were no previous symptoms of this disease. Studies have shown that over 50% of those who develop CHD are characterized as low or intermediate risk using NCEP risk factor analysis. Other standard techniques such as exercise stress testing and coronary angiography have also been found to be of limited use in terms of providing prognostic cardiac event risk information. A non-invasive test utilizing ultra-fast computed tomography (UFCT) can accurately quantify the amount of atherosclerotic plaque in the coronary arteries. This test, called coronary calcium scoring, measures plaque burden and assigns patients to risk categories based both on the total amount of plaque and the age-gender matched score quartile. The risk for acute coronary events is directly related to the plaque burden, or total amount of plaque present in the coronary arteries. The results of this technique provide valuable cardiac risk stratification information to the primary care clinician who is considering medical therapy or further cardiac testing.

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INTRODUCTION

Cardiovascular disease (CVD) has been the leading cause of death in Americans since 1900. In 1998, CVD caused 949,619 deaths or one of every 2.5 deaths. Of these, 34% occurred before age 75 and 48% were due to coronary heart disease (CHD), defined as clinically manifest coronary artery disease (CAD). With 12.4 million Americans having this condition, CHD is the single largest killer of American males and females. The lifetime risk of developing CHD after age 40 is 49% for men and 32% for women. In 50% of men and 63% of women who died suddenly of CHD, there were no previous symptoms of this disease. Furthermore, each year 40% of those who experience a myocardial infarction will die from it.1

The prevention of CHD is clearly dependent upon identification of high risk individuals before symptoms appear. Current recommendations based on the 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) are based on a stepwise analysis of lipids, CHD risk equivalents, and major non-lipid risk factors. Based on the analysis, patients are classified in one of three levels of 10-year risk for CHD: less than 10% risk; 10-20% risk; over 20% risk. Treatment recommendations are then tailored to risk level.2

Studies have shown that over 50% of those who develop CHD are characterized as low or intermediate risk using NCEP risk factor analysis. Most CHD victims have intermediate risk based on such an analysis. In addition, one large study reported that 63% of patients with over two risk factors and no CHD and 82% of patients with established CHD did not reach NCEP goals for LDL cholesterol lowering.3

A non-invasive test utilizing ultra-fast computed tomography (UFCT) can accurately quantify the amount of atherosclerotic plaque in the coronary arteries. This test, called coronary calcium scoring, measures plaque burden and assigns patients to risk categories based both on the total amount of plaque and the age-gender matched score quartile. We present an approach which can be used by primary care physicians to correctly identify patients with excessive coronary plaque burden thereby allowing for appropriate CHD risk stratification.

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PATHOGENESIS OF CORONARY ATHEROSCLEROSIS

Atherosclerosis is the pathological accumulation of lipids, inflammatory material, calcium, and connective tissue in the intimal layer of the arterial system. Autopsy studies, particularly the study of soldiers killed in action in Korea4 and the PDAY Study5 reveal the presence of extensive atherosclerosis beginning in the second decade of life. The PDAY study of 2876 subjects between 15 and 34 years of age who died of external causes examined the thoracic and abnormal aorta and the right coronary artery for both fatty streaks and fibrous plaques. In the right coronary artery, the prevalence of fibrous plaques in white men rose from 13.1% in the 15-19 age group, to 65.2% in the 30-34 age group. In white women, the prevalence was 6.8% and rose to 61.5%. Black men and women did not differ significantly from these results. The percent of the right coronary artery intimal surface involved with fatty streaks or raised lesions rose from 2.2% to 12.2% in white men, and from 2% to 10.2% in white women. These studies indicate that even though symptomatic coronary heart disease is a disease of middle-aged and older men and women, the pre-symptomatic phase of coronary atherosclerosis is a disease of the young.

Atherosclerotic lesions progress gradually through six phases. The American Heart Association6 classifies these phases as lesion types I-IV (Table 1). The evolving atherosclerotic plaque begins to advance from the benign fatty streak phase to the more ominous intermediate lesion beginning in the third decade. Volume increases in the plaque are now known to produce arterial remodeling. Studies using intravascular ultrasound (IVUS) have demonstrated that arteries may show either positive remodeling (expansion of the coronary lumen) or negative remodeling (shrinkage of the coronary lumen).7 Current hypotheses suggest that positive remodeling occurs during the early, proliferative, growth phase of plaque development, while negative remodeling occurs during the late phase, and may be associated with a more stable and mature plaque.

The occurrence of positive remodeling may significantly delay the appearance of symptoms related to coronary atherosclerosis. Diffuse progression of disease can occur in the wall of the artery in the absence of clinically significant stenoses. The risk for acute coronary events is directly related to the plaque burden, or total amount of plaque present in the coronary arteries. As plaque burden increases, the risk for plaque rupture or erosion also increases, due to the greater amount of arterial surface area with plaque. The acute event becomes more probable when stable plaque becomes unstable. In the absence of prior ischemia, patients are often asymptomatic until the acute coronary event. This is supported by studies that reveal 70% of men and 64% of women present with myocardial infarction or death as their first symptom of underlying ischemic heart disease. Furthermore, 60-70% of acute coronary syndromes occur in areas of the coronary arteries with less than 60% stenosis prior to the event.8

Clearly, there is a long preclinical phase to coronary heart disease. The goal of preventive cardiology is to identify patients with coronary atherosclerosis before symptoms appear.

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SCREENING FOR ATHEROSCLEROTIC CORONARY ARTERY DISEASE

Lipid Analysis

Currently, evaluation of cholesterol indices is the preferred initial step when assessing a patient for the likelihood of cardiovascular atherosclerosis and subsequent cardiac events. Abnormalities in these indices usually lead to lifestyle and dietary modification, further testing for the presence of atherosclerotic lesions, treatment with cholesterol lowering medications or some combination of these. However, 80% of people who develop CHD have the same total cholesterol levels as those who do not develop CHD9. Arteriographic studies of CHD patients have revealed no correlation between LDL cholesterol and disease severity10. Some reports have shown that the use of fasting cholesterol levels as a screening technique is neither highly sensitive or specific11. Typical odds ratios for the prediction of coronary events ranges from two to five for these indices12.

Stress Testing

In the family practice setting, the traditional tool for evaluating symptomatic patients for the presence of significant obstructive coronary lesions is the exercise stress test. Unfortunately, even in high risk patients this modality has very low sensitivity and positive predictive value13. Stress testing is unable to detect nonobstructive CHD 14 which accounts for about 50% of myocardial infarctions and sudden coronary deaths15. The 1997 ACC/AHA guidelines for exercise testing classify stress testing as a Class III recommendation and thereby question the use of this test as a screening tool for CHD16.

Coronary Angiography

Evaluation of future cardiac event risk by assessing degree of coronary stenosis by angiography is also problematic. Current research has found that percent stenosis is not a good prognostic indicator as evidenced by the fact that acute myocardial infarctions occur in 65% of patients with less than 50% worst stenosis and in 86% of patients with stenosis no greater than 70% as measured by angiography17. The emphasis has therefore switched from determining the degree of stenotic lesions to identifying those patients with “vulnerable plaque” and the total plaque burden18.

Ultra-Fast Computed Tomography

UFCT can be performed using either electron beam tomography or helical computed tomography. It is a noninvasive technique that can determine total plaque burden19 and has been found to be a powerful predictor of future coronary events20. In fact, some studies have shown UFCT as superior to coronary angiographic measures in predicting subsequent cardiac endpoints such as cardiac death or nonfatal MI21. UFCT is a reproducible22 and relatively inexpensive screening procedure used to detect coronary calcification, which is a marker for atherosclerosis23 and has been shown to be directly related to the severity and extent of underlying coronary disease24. Mintz et al found a strong relation between coronary calcification and atherosclerotic plaque burden using UFCT and intravascular ultrasound (IVUS)25. Although the relationship between calcified and vulnerable plaque remains undefined, 60 – 80% of “culprit” lesions for sudden cardiac death contained moderate calcification26 (defined as a coronary calcium score of more than 100 and less than 400). The sensitivity and specificity of the coronary artery calcium score obtained from UFCT are estimated at 97% and 72%, respectively, in detecting greater than 50% stenosis27. Typical odds ratios in predicting coronary disease events by UFCT cluster in the teens28.

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CLINICAL EVALUATION OF PATIENTS FOR ATHEROSCLEROTIC DISEASE

Baseline testing

Lipids

According the NCEP ATP III guidelines2, all adults aged 20 years or older should have a fasting lipoprotein profile obtained at least every 5 years. If the test is nonfasting, only use of the HDL and total cholesterol (TC) levels are recommended and repeat fasting levels should be obtained if the TC is >= 200 mg/dL or the HDL is < 40 mg/dL.

UFCT

The initial coronary calcium score may be obtained based on the patient’s age and risk factors (Table 2). As shown in Table 3, for men and women with zero risk factors the initial scan is obtained at age 45 and 55, respectively. For patients with one or more risk factors, the timing of the initial scan should be moved up five years (i.e. 40 for men, 50 for women). For patients with a family history of symptomatic CHD in a first degree relative, the scan should be obtained prior to the relative’s age of onset of symptoms. Diabetic patients should be considered for UFCT starting at age 35 since this disease is considered a coronary heart disease equivalent29. Furthermore, if the physician is considering starting the patient on a cholesterol-lowering medication, UFCT may be performed prior to institution of therapy in order to assess the urgency of such action. For example, a patient with an elevated LDL cholesterol or a low HDL cholesterol may be afforded more time for lifestyle modifications if the calcium score is low (i.e. less than the 25th percentile for age).

Follow up testing

To Rule Out Obstructive CHD

In addition to identifying patients with coronary atherosclerosis who would benefit from aggressive risk factor management to slow, arrest, or reverse the disease, CCS can be used to identify patients at high risk for obstructive coronary artery disease. It has been demonstrated by Bielak et al. that a coronary calcium score greater than or equal to one has 99.1% sensitivity but 38.6% specificity for predicting coronary stenoses27. These authors also found that in patients older than 50, a score over 200 was predictive of greater than 50% coronary stenoses, while in patients under 50 years of age a score over 100 was predictive of similar stenoses. Therefore, as the calcium score increases, the likelihood of a significant stenosis increases. The standard score categories and likelihood of stenosis are shown in Table 4. Recommendations for proceeding with stress testing or coronary angiography are presented in Table 5.

To Assess Cardiac Event Risk (Plaque) Progression

Follow-up UFCT testing may be recommended to patients to assess plaque progression. In general, the lower the score, the less frequently follow-up scanning should be recommended. Calcium scores in untreated patients may increase by 30-70% per year30. Table 6 shows suggested strategies for follow-up scanning. Once two sequential scans have been obtained, further assessments should be determined by rates of progression. At rates of progression less than 15-20% per year, follow-up assessments may be spaced several years apart. At faster rates of progression, implying poorly controlled coronary atherosclerosis, more frequent re-assessments may be indicated until the atherosclerotic process is under adequate control.

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TREATMENT OPTIONS

Preventive treatment of patients for coronary atherosclerosis is multi-modal and based on the coronary calcium age/gender percentile and the individual's cardiac risk factors. See Figure 1 for suggested treatment algorithm.

Low Risk (Less than 25th age-gender percentile on CCS)

Patients in this quartile should be strongly encouraged to incorporate lifestyle modifications such as weight reduction to healthy body weight (BMI < 25) and smoking cessation. Other lifestyle modifications include an exercise program that incorporates aerobic exercise at 60 – 80% of their maximum allowable heart rate at least four times a week that is of 15 - 30 minutes in duration per session. A resistance exercise training program should be included in the exercise regimen so as to maintain the patient's muscle mass thereby enhancing the patient's ability to maintain ideal weight via skeletal muscle metabolism. Dietary modifications include a high soluble fiber, low fat diet that incorporates foods that contain omega-3 fatty acids. Antioxidants such as vitamin C and E have been associated with decreased oxidation of LDL in atherosclerotic plaque and improved endothelial function. Folic acid, pyridoxine and cyanocobalamin supplementation should be considered for those patients with high homocysteine levels31. Finally, these patients can be treated with lipid lowering medications on the basis of NCEP guidelines with the understanding that more time can be afforded for lifestyle and dietary modifications to be effective.

Low to Moderate Risk (25 – 50th age-gender percentile on CCS)

Patients in this quartile should be placed on one baby aspirin (81 mg) per day in addition to the lifestyle recommendations detailed above. These patients should attempt to have their blood pressure (BP) below 140/90 mmHg. Their triglycerides should be below 180 mg/dL and their TC to HDL ratio should be less than four. Cholesterol lowering medications may again be considered based on NCEP.

Moderate to High Risk (50 – 75th age-gender percentile on CCS)

Patients in this quartile should attempt to have their BP less than 130/85 mmHg while concomitantly lowering their triglycerides below 150 mg/dL and their TC/HDL ratio to less than three. Most of these patients will be candidates for lipid lowering medications in addition to the lifestyle and dietary modifications listed above. The medication of choice for these patients is the HMG-CoA reductase inhibitors (statins). In addition to idealizing the lipid profile, these medications stabilize plaque and improve endothelial function by reducing the lipid content in the plaque core and possibly by anti-inflammatory properties32. These medications have also been associated with a decreased cardiac event rate33. Other medications that could be considered based on the lipid profile include niacin, fibrates and cholesterol binding resins.

High Risk (More than 75th age-gender percentile on CCS)

Patient’s whose CCS places them in the highest age/gender quartile are at the highest risk for subsequent coronary events34. They should lower their triglycerides to less than 140 mg/dL and the TC/HDL ratio to less than 2.5. These patients should be treated aggressively and may require either double or triple lipid lowering therapy or a statin in combination with a diet consisting of not more than 10% of calories from fat. Such treatment has been shown to decrease coronary events by 93% at eight years35.

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REFERENCES

1. 2001 Heart and Stroke Statistical Update, American Heart Association, Available at http://www.amhrt.org.

2. Executive summary of the 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). JAMA 2001; 285: 2486-97.

3. Pearson T. 70th Scientific Sessions, American Hear Association, 11/12/97, Orlando, Florida.

4. Enos WF, Holmes RH, Beyer, J Coronary Disease Among United States Soldiers Killed in Action in Korea. JAMA 1953; 152: 1090-1093.

5. Strong JP, Malcom GT, McMahan CA, Tracy RE, Newman WP 3rd, Herderick EE, et al. Prevalence and Extent of Atherosclerosis in Adolescents and Young Adults JAMA 1999;281: 727-735.

6. Stary HC, Chandler AB, Dinsmore RE, Fuster V, Glagov S, Insull W Jr, et al. A Definition of Advanced Types of Atherosclerotic Lesions and a Histological Classification of Atherosclerosis. Circulation 1995; 92:1355-1362.

7. Schoenhagen P, Ziada KM, Vince DG, Nissen SE, Tuzcu EM Arterial remodeling and coronary artery disease: the concept of "dilated" versus "obstructive" coronary atherosclerosis. JACC 2001; 38: 297-306.

8. 2001 Heart and Stroke Statistical Update, American Heart Association

9. Kannel, WB, Castelli, WP, Gordon,T. Cholesterol in the Prediction of Atherosclerotic Disease. Ann Intern Med 1979;90:85-91.

10. Philips, NR, Waters, D, Havel, RJ. Plasma Lipoproteins and Progression of Coronary Artery Disease Evaluated by Angiography and Clinical Events.

11. Grover SA, Coupal L, Hu XP. Identifying adults at increased risk of coronary disease. How well do the current cholesterol guidelines work? JAMA 1995; 274: 801-6.

12. Bostom AG, Cupples LA, Jenner JL, Ordovas JM, Seman LJ, Wilson PW, et al. Elevated plasma lipoprotein (a) and coronary heart disease in men aged 55 and younger. JAMA 1996; 276: 544-548.

13. Ekelund LG, Suchindran CM, McMahon RP, Heiss G, Leon AS, Romhilt DW et al. Coronary heart disease morbidity and mortality in hypercholesterolemic men predicted from an exercise stress test: The Lipid Research Clinics Coronary Primary Prevention Trial. J Am Coll Cardiol 1989; 14: 556 – 63.

14. Arnese M, Salustri A, Fioretti PM, Cornel JH, Boersma E, Reijs AE, de Feyter PJ, Roelandt JR. Quantitative angiographic measurements of isolated left anterior descending coronary artery stenosis correlation with exercise echocardiography and technetium-99m 2-methoxy isobutyl isonitril single-photon emission computed tomography. J Am Coll Cardiol 1995; 25: 1486 – 91.

15. Fishbein MC & Siegel RJ. How big are coronary atherosclerotic plaques that rupture? Circulation 1996; 94: 2662 – 6.

16. ACC/AHA Guidelines for Exercise Testing. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Exercise Testing). J Am Coll Cardiol 1997; 30: 290 – 3.

17. Falk E, Shah PK and Fuster V. Coronary plaque disruption. Circulation 1995; 92: 657-71.

18. Hasdai D, Bell MR, Grill DE, Berger PB, Garratt KN, Rihal CS, Hammes LN, Holmes DR Jr. Outcome > or = 10 years after successful percutaneous transluminal coronary angioplasty. AM J Cardiol. 1997; 79: 1005-11.

19. Mautner GC, Mautner SL, Froehlich J, Feuerstein IM, Proschan MA, Roberts WC, Doppman JL. Coronary artery calcification: assessment with electron beam CT and histomorphometric correlation. Radiology 1994; 192: 619-23.

20. Georgiou D, Budoff MJ, Kaufer E, Kennedy JM, Lu B, Brundage BH. Screening patients with chest pain in the emergency department using electron beam tomography: a follow-up study. J Am Coll Cardiol; 38: 105-10.

21. Detrano R, Hsiai T, Wang S, et al. Prognostic value of coronary calcification and angiographic stenoses in patients undergoing coronary angiography. J Am Coll Cardiol 1996; 27: 1972-78.

22. Achenbach S, Ropers D, Mohlenkamp S, Schmermund A, Muschiol G, Groth J, Kusus M, Regenfus M, Daniel WG, Erbel R, Moshage W. Variability of repeated coronary artery calcium measurements by electron beam computed tomography. Am J Cardiol 2001; 87: 210-3.

23. Sangiorgi G, Rumberger JA, Edwards WD, Gregoire J, Fitzpatrick LA, Schwartz RS. Arterial calcification and not lumen stenosis is highly correlated with atherosclerotic plaque burden in humans: a histologic study of 723 coronary artery segments using nondecalcifying methodology. J Am Coll Cardiol 1998; 31: 126-33.

24. Rifkin RD, Parisi AF, Folland E. Coronary calcification in the diagnosis of coronary artery disease. Am J Cardiol 1979, 44: 141-7.

25. Mintz GS, Pichard AD, Popma JJ, Kent KM, Satler LF, Bucher TA, Leon MB. Determinants and correlates of target lesion calcium in coronary artery disease: a clinical, angiographic and intravascular ultrasound study. J Am Coll Cardiol 1997; 29: 268-274.

26. Burke AP, Farb A, Malcolm GT, Liang Y, Smialek J, Virmani R. Coronary risk factors and plaque morphology in men with coronary disease who died suddenly. N Engl J Med 1997; 336: 1276 – 82.

27. Bielak LF, Rumberger JA, Sheedy PF 2nd, Schwartz RS, Peyser PA. Probabilistic model for prediction of angiographically defined obstructive coronary artery disease using electron beam computed tomography score strata. Circulation 2000; 102: 380-5.

28. Guerci AD, Arad Y. Potential use of calcium scanning to determine the need for and intensity of lipid-lowering therapy in asymptomatic adults. Curr Cardiol Reports 2001; 3: 408-15.

29. Hecht HS. Practice guidelines for electron beam tomography: a report of the Society of Atherosclerosis Imaging. Am J Cardiol 2000; 86: 705 – 6.

30. Callister TQ, Raggi P, Cooil B, Lippolis NJ, Russo D Effect of HMG-CoA reductase inhibitors on coronary artery disease as assessed by electron-beam computed tomography. N Engl J Med 1998;339:1972-78.

31. Selwyn AP, Kinlay S, Creager M, Libby P, Ganz P. Atherogenic lipids, vascular dysfunction, and clinical signs of ischemic heart disease. Circulation 1997; 95: 5 - 7.

32. Vaughan CJ, Delanty N. Neuroprotective properties of statins in cerebral ischemia and stroke. Stroke. 2000;31:989.

33. Sacks FM, Pfeffer MA, Moye LA, Rouleau JL, Rutherford JD, Cole TG et al. The effect of pravastatin on coronary events after myocardial infarction patients with average cholesterol levels. Cholesterol and Recurrent Events Trial. N Engl J Med 1996; 335: 1001- 9.

34. Guerci AD, Arad Y. Potential use of calcium scanning to determine the need for and intensity of lipid-lowering therapy in asymptomatic adults. Curr Cardiol Reports 2001; 3: 408-415.

35. Brown BG, Hillger L, Zhao XQ, Poulin D, Albers JJ. Types of change in coronary stenosis severity and their relative importance in overall progression and regression of coronary disease. Observations from the FATS Trial. Familial Atherosclerosis Treatment Study. Ann N Y Acad Sci 1995; 748:407-17.

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TABLES

Table 1 – American Heart Association Atherosclerosis Classification

Table 2 – Cardiac Risk Factors

¹Men ³ 45 years; women ³ 55 years

²CHD in male first-degree relative < 55 years; CHD in female first-degree relative < 65 years

³Blood pressure ³ 140/90 mmHg or on antihypertensive medication

Table 3 – Timing of UFCT

Table 4 – Interpretation of Coronary Calcium Scores

Table 5- Work-up for Myocardial Ischemia Based on Calcium Score

Table 6- Suggested Schedules for Follow-Up Coronary Calcium Scanning

* For men <45 and women <55, consider deferring follow-up for longer based on clinical condition

Figure 1 – Suggested Treatment Options