Atherosclerosis is a multifactorial disease presenting with diverse clinical phenotypes. For example, manifestations range from an elderly patient with few or no symptoms and three-vessel disease, to an asymptomatic individual in his mid-forties dying suddenly from an isolated coronary obstructive lesion.
Not surprisingly, a number of different diagnostic and risk estimate tools and treatment modalities have been developed tailored to the various stages of the disease and risk stratification.
This chapter discusses some concepts, diagnostic tools, and therapies now emerging that could become part of tomorrow’s practice. The long-term aim in treatment of coronary artery disease (CAD) eradication of its malignant aspects of death and disability which are primarily consequences of acute coronary syndromes.
Lifestyle Adjustment for the Prevention of Acute Coronary Syndromes
Atherosclerosis is now seen as a largely preventable disease, as dynamic changes are increasingly seen in its epidemiology, clinical manifestations, and prognosis among individuals and societies. Thus, the prevalence of cardiovascular disease became epidemic in the last century, peaking in 1964 to 1965, then steadily declined by up to 50% until now despite a fivefold increase in the proportion of the population aged more than 65 years. The IMPACT statistical model applied to the epidemiologic data obtained between 1980 and 2000 could attribute 47% of this reduction to treatment modalities, including secondary preventive therapies after myocardial infarction or revascularization (11%); initial treatments for acute myocardial infarction or unstable angina (10%); treatments for heart failure (9%); revascularization for chronic angina (5%); and other therapies (12%). Another 44% could be attributed to changes in risk factors, including reductions in total cholesterol (24%), systolic blood pressure (20%), smoking prevalence (12%), and physical inactivity (5%). The gain observed during these 2 decades was partially offset, however, by an increase in the body mass index and in the prevalence of diabetes that accounted for an increased mortality rate of 8% and 10%, respectively. These new facets of risk factors are linked to the components of the so-called metabolic syndrome (see Chapter 1 ), and keep expanding as the prevalence of obesity and associated risk factors including hypertension, dyslipidemia, and diabetes, keep getting higher in adults and children from industrialized and developing countries, particularly in urban settings. The World Health Organization reported that in 2005, approximately 1.6 billion adults (older than 15 years) and 20 million children (aged 5 years or younger) were overweight, and 400 million adults definitively obese. The projections for 2015 are 2.3 billion overweight adults and 700 million obese. These figures may signal a renewed increase in the incidence of coronary artery disease.
Primary prevention is an issue for both society and individuals; it is foremost a lifestyle question. In their task of caring for patients as health specialists, physicians are particularly well positioned to promote prevention in the community. The importance of such interventions is reinforced by the high prevalence of CAD, which still ranks first as the cause of mortality, by the well-documented efficacy of interventions currently available, and by the dynamics of atherosclerosis, the prevalence of which can rapidly shift and plaques rapidly progress and regress in an individual. An optimistic rather than a defeatism approach is better stimulation for patients. As a bonus, it is good to know that lifestyle interventions favorably affect the rates of cancer, the second most frequent cause of death after cardiovascular disease. It is now well documented that cancer and atherosclerosis share very similar risk factors ( Box 19-1 ).
BOX 19-1 * Many of these risk factors are the same as those for cardiovascular disease, providing an opportunity to impact concomitantly on the two main killers in our society.
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Growing older
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Tobacco
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Sunlight
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Ionizing radiation
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Certain chemicals and other substances
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Some viruses and bacteria
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Certain hormones
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Family history of cancer
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Alcohol
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Poor diet, lack of physical activity, or being overweight
Overlap Between Primary and Secondary Prevention
The driving principles in prevention and treatment of coronary artery disease are first to screen for the disease; second, appreciate the individual degree of risk; and third, apply risk-tailored treatment. Risk is best appreciated by evaluating the presence of traditional and new risk factors helped by appropriate surrogate markers. Two important clues are readily available at first contact with a patient. One is any evidence of atherosclerosis in a vascular region at the medical history or upon clinical examination for example, the presence of a carotid murmur or altered pulse in the lower limbs; the other is the mere presence of a symptomatic disease, which per se carries a worse prognosis than the asymptomatic disease. The measured ankle-brachial pressure index (ABPI) is the ratio of the blood pressure in the lower legs to the blood pressure in the arms, which has 90% sensitivity and 98% specificity for detecting hemodynamically significant stenosis in major leg arteries.
Risk Scores
Based on a half-century of epidemiologic research, the Framingham score has served as reference in the various guideline recommendations and has been instrumental for validating the value of various interventions. This registry was initiated in 1948, when it recruited 5209 men and women aged 30 to 62 years free from cardiovascular disease (CVD) in the town of Framingham, Massachusetts. Five cohorts were subsequently added, the first being the offspring cohort in 1971. The strengths of the score have been well delineated, as well as its weaknesses, which are mainly related to the relatively homogeneous regional population that has been enrolled and the underrepresentation of important subgroups, such as nonwhites, diabetics, and renal failure patients. Many other systems have been developed following the Framingham model to predict cardiovascular disease and coronary heart disease. Major systems were the Joint British Societies’ cardiovascular disease risk prediction chart, the Cardio Risk Manager (CRM) calculator, the PROCAM risk score (using triglyceride levels and the presence of diabetes and a family history of premature myocardial infarction in addition to the Framingham criteria), the UKPDS risk engine, looking more specifically at diabetic patients, the HeartScore (Systematic Coronary Risk Evaluation) system of the European Society of Cardiology, and the QRISK study. The HeartScore includes 12 European cohort studies, 250,000 patients, 3 million person-years of observation, and 7000 fatal cardiovascular events recorded; its goal was to define from lifestyle and risk factor data, the therapeutic targets for CVD prevention focusing mainly on mortality prediction. The first QRISK (QRISK1) study was the largest risk prediction study; it was generated by retrospectively extracting data on traditional risk factors and indicators of social deprivation, family history, antihypertensive treatment, and subsequent cardiovascular events in almost 2 million people from the QRESEARCH primary care database, covering about 7% of the population of the United Kingdom.
Markers as Diagnostic Aids
It has become popular to validate potentially useful new markers in primary prevention by determining how they can sharpen risk stratification based on the Framingham score. The coronary artery calcium score was found useful to predict risk in individuals with a Framingham score associated with a 10-year event rate greater than 10% ( P < .001) but not in those with a risk of less than 10%. Note that the calcium score should not influence the management of patients presenting to the emergency department with chest pain. In a subset of 175 patients who participated in the Multi-Ethnic Study of Atherosclerosis (MESA) trial who underwent coronary angiography, primarily because of chest pain, 7 patients (4%) had significant coronary obstruction despite having a coronary artery calcium (CAC) score of 0 at baseline. The CAC score can miss soft plaques, which play an important role in acute coronary syndrome (ACS); its low negative predictive value does not provide sufficient reassurance and mandates the use of other diagnostic methods for ischemia detection in symptomatic patients. The usefulness of the score was also documented in various ethnic groups. It was found with the Reynolds score that adding serum levels of high-sensitivity C-reactive protein and the presence or absence of a family history of CVD before age 60 years could improve the prognostic value of the Framingham score in healthy men and women in a low- to moderate-risk category. In one study, the measure of brachial artery flow–mediated dilation and the presence of a carotid plaque, but not the maximal carotid intima-to-media ratio, significantly increased the accuracy of the score to predict coronary events, again in subjects with a low to intermediate Framingham score.
Coronary multislice computed tomography (see Chapter 16 ) provides new windows on heart anatomy and function including coronary arteries. In a study of 295 patients (61% men; mean age, 54 ± 13 years) with no known CAD, stenoses greater than or equal to 50% in one or more epicardial coronary arteries were found in 16%, 34%, and 88% of individuals classified at low, intermediate, and high Framingham score, respectively; proximal calcified or noncalcified plaques in the left main or proximal left anterior descending artery were found in 44%, 75%, and 63% of patients, respectively, showing that a significant proportion of individuals with a low to intermediate Framingham risk score can still have obstructive CAD. Such improvements in the discriminatory value of the Framingham score by various approaches may not be surprising, especially in the intermediate-risk category. Tests that have been shown to sharpen the diagnostic ability of the Framingham score include exercise testing (see Chapter 13 ), blood markers of hemostasis (e.g., fibrinogen, D-dimer, plasminogen activator inhibitor-1 [PAI-1] activity, factor VIIc) and of inflammation (e.g., interleukin 6, C-reactive protein [CRP]) and endothelial dysfunction (e.g., P-selectin, von Willebrand factor), and metabolic and renal function markers, including albuminuria.
The 2009 Canadian Cardiovascular Society guidelines for the diagnosis and treatment of dyslipidemia and prevention of cardiovascular disease in the adult suggest the use of high-sensitivity CRP in men older than 50 and women older than 60 years who are at intermediate risk (10% to 19%) by the Framingham score and who do not qualify for statin treatment with low-density lipoprotein (LDL) levels less than 3.5 mmol/L.
Identifying High-Risk Lesions
A major challenge in modern cardiology is the recognition of lesions at high risk—the so-called vulnerable plaques—before they provoke the acute coronary syndrome. These culprit lesions have been well characterized in pathologic studies and compared with stable plaques (see Chapter 6 ); their recognition in vivo would permit innovative research to identify interventions to prevent progression to an ACS and irreversible myocardial damage. Numerous innovative approaches are now being investigated for this purpose (see Chapter 17 ).
Virtual Histology–Intravascular Ultrasound
Gray-scale intravascular ultrasound (IVUS) imaging permits imaging of the vessel from inside the lumen and provides information on the site, area, volume, and remodeling of the plaque (see Chapter 14 ). Some of the limitations of IVUS can be overcome by using spectral analysis of the radiofrequency ultrasound backscatter. This technology, called virtual histology-IVUS (VH–IVUS) permits the identification of the fibrous, fibrofatty, dense calcium, and necrotic core components of the plaque (see Chapter 17 ). Plaques in ACS show a large necrotic and lipid core and thin-cap fibroatheroma, and less fibrotic component than in stable angina. Such rupture-prone plaques in one study were associated with high levels of N-terminal pro-B-type natriuretic peptide (NT–proBNP), providing an explanation for the strong predictive value for mortality of the natriuretic factor (see Chapter 1 ).
Multislice Computed Tomography
One study compared VH-IVUS and multislice computed tomography (MSCT) in the same patients ( Fig. 19-1 ). With MSCT, 32% of plaques in ACS were noncalcified and 59% were mixed, a third of them having thin-cap fibroatheroma, compared with 61% of plaques calcified in stable angina, with less than 5% having thin-cap. On VH-IVUS, the percentage of necrotic core was higher and thin cap fibroatheroma more prevalent in ACS than in stable angina.
Another study prospectively looked at the prognostic value of plaque characteristics at CT angiography in 1059 stable patients followed for 27 ± 10 months. The 45 patients who developed an acute ischemic event showed both positive vessel remodeling and low-attenuation plaques ( Fig. 19-2 ). ACS developed in 22.2% of patients with the two features and in 3.7% of patients with one feature. Only 4 of 820 patients (0.5%) with neither positive remodeling nor low-attenuating plaques developed an ACS. None of the 167 patients with normal angiograms had acute coronary events ( P < .001). The hazard ratio (HR) for an ACS with one or two plaque features was 22.8 (95% confidence interval [CI], 6.9 to 75.2; P < .001).
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