Atherosclerosis of coronary artery without angina pectoris

5 What are the outcomes ascertained by the 2013 American College of Cardiology/American Heart Association atherosclerotic cardiovascular disease risk estimator, and how does it differ from the Framingham coronary artery heart risk estimator used in the Adult Treatment Panel III guideline?

ASCVD risk as defined by the 2013 ACC/AHA guideline includes nonfatal myocardial infarction (MI), Coronary Heart disease (CHD) death, and nonfatal and fatal stroke. In contrast, the traditional Framingham risk score (as recommended by the National Cholesterol Education Program [NCEP] Adult Treatment Panel [ATP] III cholesterol guidelines) includes nonfatal MI and coronary heart disease death (note that there is also a Framingham cardiovascular disease [CVD] risk estimator). Unlike the Framingham CHD risk estimator, the new Pooled Cohort Equations were developed in cohorts that included African Americans and hence thought to improve accuracy in ASCVD prediction in African American individuals.

Heart Disease

Atherosclerotic heart disease (ASHD) is present in differing degrees in all patients older than 65 years. Heart disease is the number-one cause of death in the elderly population. Possible signs and symptoms of ASHD include elevated blood pressure, irregularities in cardiac rhythm, undue fatigue, and “discomfort” in the chest on exertion (e.g., angina pectoris). The administration of sedative medications may be indicated in these patients to decrease endogenous catecholamine output as a method of minimizing the development of potentially serious complications.

Angina pectoris is a common clinical manifestation of ASHD. Angina may be seen in both the premyocardial and postmyocardial infarction patient. This patient may be at greater risk for a medical emergency during treatment. Inhalation sedation with nitrous oxide-oxygen (N2O-O2) is an excellent sedative technique for this patient. Drug therapy for angina includes the administration of nitrates, which are vasodilators. Postural hypotension may develop when these agents are administered in the management of an acute episode. Proper positioning minimizes the development of postural hypotension.

8.13.2.1 Overview of Pathophysiology

Coronary atherosclerosis is a condition that results when the coronary arteries, which deliver blood to the heart, become narrowed by fatty deposits called plaques. Ischemic heart disease or coronary heart disease (CHD) refers to a set of conditions thought to result from coronary atherosclerosis (Knuuti et al., 2019). Myocardial ischemia—the inadequate flow of blood to cardiac tissue—results when arterial narrowing can cause insufficient blood supply to the heart. Ischemia, in turn, can sometimes be accompanied by chest pain, a condition called angina pectoris. Severe or repeated myocardial ischemia also predisposes the heart to life-threatening disturbances of cardiac rhythm, which can result in sudden cardiac death. A myocardial infarction (MI), or heart attack, results when cardiac tissue dies because arterial plaque becomes unstable and a complete blockage occurs, or when ischemia becomes prolonged or severe (Ibanez et al., 2017; Collet et al., 2021).

Dictionary of Terms

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ASCVD: Atherosclerotic cardiovascular disease

CHO: Carbohydrates

CVD: Cardiovascular disease

DBP: Diastolic blood pressure

HDL-C: High-density lipoprotein cholesterol

LDL-C: Low-density lipoprotein cholesterol

MetS: Metabolic Syndrome

MNT: Medical Nutrition Therapy

MUFA: Monounsaturated fatty acids

PUFA: Polyunsaturated fatty acids

RCT: Randomized controlled trial

RDN: Registered Dietitian Nutritionist

ROS: Reactive oxygen species

SBP: Systolic blood pressure

SFA: Saturated fatty acids

TC: Total cholesterol

TG: Triglycerides

Coronary Artery Calcium

ASCVD risk prediction models are heavily weighted toward chronologic age, yet “arterial” or “biologic age” is frequently discordant with chronologic age. Assessment of CAC is a useful surrogate measure of total coronary atherosclerotic burden and therefore arterial age.106

CAC is performed using noncontrast cardiac-gated CT scanning. CAC scans can be performed on any modern CT equipment and thus can be performed similarly around the world. The entire procedure takes about 10 minutes, with most of the time spent placing electrodes and positioning the patient on the table. With modern scanners, scans are acquired in under a second using approximately 0.5 to 2 mSv of radiation (approximately equivalent to 2 bilateral mammograms or 10 chest x-rays). In most metropolitan centers in the United States, CAC scans cost between $75 and $150.

CAC scanning leverages the fact that calcified deposits in the coronary arteries strongly attenuate x-rays and are thus visible on unenhanced images. Contiguous voxels approximately 130 Hounsfield units are considered to be calcium. CAC scans are generally scored using the Agatston score, which is a summed score of all calcified lesions in the coronary arteries through the complete z-axis of the heart, weighted for the density (x-ray attenuation) of the calcium. Agatston scoring uses a 120-kV electron, variable mA based on patient body weight, acquiring up to 40 slices at a fixed 2.5-mm to 3-mm slice increment. The ideal way to score a CAC scan remains controversial, with potential benefit in differently accounting for the density of calcium and regional distribution of calcium, as well as extracoronary calcification.107 Future advancements will likely increase the sensitivity to minute calcium deposits and will likely further reduce the associated radiation.107

CAC scoring does not identify isolated noncalcified plaque, although its prevalence is less common when calcium is not present anywhere in the coronary tree. Current evidence does not support a strong incremental predictive value for the detection of isolated noncalcified plaque in the asymptomatic primary prevention patient.108,109

When added to traditional risk factor models, CAC improves risk discrimination more than any other available test. In the community-based Multi-Ethnic Study of Atherosclerosis (MESA), the area under the receiver operating characteristic (ROC) curve for the prediction of CHD events was significantly improved when a CAC-based model was compared to a model with only traditional risk factors.110 Individuals without risk factors but elevated CAC have substantially higher event rates than those who have multiple risk factors but no CAC.111,112 In MESA, individuals with no risk factors and CAC greater than 300 had an event rate 3.5 times higher than individuals with 3 or more risk factors and CAC of 0.112 Even minimal CAC (scores 1 to 10) is associated with 3-fold increased CHD risk compared to those with a CAC of 0.113 Additionally, there appears to be no upper threshold of risk with increasing CAC scores.114

In addition to its role in “upgrading” or elevating predicted risk in younger patients when significant CAC is present,29 perhaps the most important potential role of CAC testing in the modern era using currently available risk scores may be for downgrading or “derisking” an older adult with a CAC score of 0 who might otherwise be recommended for pharmacologic therapy based on models that are dominated by chronologic age.115 We have previously found that the number needed to treat to prevent one ASCVD event would generally be unfavorable using a high- or moderate-intensity statin,116,117 a polypill,118 or aspirin119 for primary prevention when CAC = 0 (Table 29.4).

A recent analysis from MESA showed that there is substantial heterogeneity among groups of asymptomatic adults recommended for statin therapy under the 2013 ACC/AHA guidelines.120 Of the MESA participants who would be recommended or considered for statins under the guidelines, nearly half (44%) had CAC = 0 at baseline and their observed 10-year ASCVD event rate was overall low (4.2 events/1000 person-years). Of note, approximately half of these events are strokes, and a good number of them are not atherosclerotic in nature but are secondary to hypertension and/or atrial fibrillation, and it is unclear if statin therapy would be helpful in these conditions. In contrast, the respective ASCVD event rates for those with any CAC greater than 0 was 11.2/1000 person-years.

With specific relevance to individuals reluctant to take preventive medicines, recent cost-effectiveness analyses suggest that CAC is broadly cost-effective for steering treatment toward those with measurable CAC when the mild disutility of taking daily prevention medication is factored into decision-making.12,121 Importantly, a score of CAC = 0 is associated with an excellent long-term prognosis with annual mortality of less than 1% up to 15 years in asymptomatic adults.122,123 When compared to other “negative” risk markers (carotid intimal medial thickness < 25th percentile, absence of carotid plaque, ABI > 0.9 and < 1.3, hs-CRP < 2 mg/L, homocysteine < 10 μmol/L, N-terminal pro-brain natriuretic peptide <100 pg/mL, no microalbuminuria, no family history of CHD, absence of metabolic syndrome, and healthy lifestyle), the absence of CAC conferred the greatest downward shift in ASCVD risk.124

Clinicians now have a tool for incorporating CAC scores into estimates of 10-year risk. The MESA CHD risk score,125 available online at http://www.mesa-nhlbi.org/MESACHDRisk/MesaRiskScore/RiskScore.aspx, allows entry of age, sex, race/ethnicity, traditional Framingham risk factors, family history of CHD, and CAC score with resultant 10-year risks of CHD (distinct from the ASCVD endpoint used in the 2013 guidelines) before and after incorporation of CAC data. We believe that a MESA CHD risk score greater than 5% is a reasonable threshold for consideration of initiating more aggressive preventive therapy, i.e., a statin and possibly aspirin.

The Early Identification of Subclinical Atherosclerosis by Noninvasive Imaging Research (EISNER) study126 found that randomization to CAC scanning versus no scanning did not increase overall downstream medical testing; rather randomization to CAC scanning was associated with modestly improved risk factor control. Findings from a population-based cohort showed that identification of severe CAC (> 400) was associated with higher rates of initiation and continuation of important preventive medications including lipid-lowering agents, blood pressure-lowering agents, and aspirin.127

Limitations of CAC scoring include the modest amount of radiation exposure (as discussed earlier) and the detection of incidental findings (most commonly, noncalcified lung nodules) in approximately 4% to 8% of persons,128 who may need follow-up CT scans to document stability. Also, it is imperative that clinicians are advised how to use CAC scores in their management practices (i.e., initiating aspirin and high-intensity statin when scores are high); misunderstanding of how to use CAC could lead to unnecessary referrals for coronary angiography in asymptomatic individuals (and the potential complications and expense stemming from that procedure).

Additionally, of concern to some, is the lack of definitive clinical trial evidence demonstrating that CAC-based treatment decision-making is superior to traditional global risk assessment in reducing ASCVD outcomes in a cost-effective manner. It is important to note that we do not have any RCTs for ASCVD risk estimators either. Due to the low risk and low cost of a CAC scan and the cost involved for a large RCT, it seems unlikely in the near future that a CAC-based clinical trial (or any clinical trials comparing CHD risk assessment modalities among asymptomatic individuals) will be funded in the United States. However, the ROBINSCA clinical trial of CAC screening versus risk factor screening is ongoing in the Netherlands and may offer future insights.129 In the meantime, approaches to ASCVD risk assessment must rely on the best evidence from observational studies.130

Most guidelines suggest that men starting at age 40 and women at age 45 with at least one additional risk factor such as a family history of premature atherosclerotic vascular disease or an ASCVD 10-year risk estimate of at least 5% could be considered for a CAC scan. The 2013 ACC/AHA prevention guidelines state that an Agatston score of 300 units or more, or a score on or above the 75th percentile for age, sex, and ethnicity, is a factor that indicates that the person is likely at a higher risk level and would warrant strong consideration of statin therapy and intensified lifestyle changes. Other data from MESA indicates that an Agatston score of at least 100 units portends a “CHD-equivalent level” of risk.116 Prior data suggest that the absolute CAC score is a better indicator of near-term risk than age/sex/race percentiles, although percentiles may have more value for communicating lifetime risk.131

Whereas CAC progression is strongly predictive of outcomes,132 there is no need to rescan a person who has a higher CAC score (e.g., > 100) because clinical decision-making will likely not change. It is reasonable to rescan a patient with a CACs of 0 approximately 4 to 5 years later.133 However, in a smoker134 or a person with diabetes,135 a CAC score of 0 provides less reassurance for a very low ASCVD event rate; in these patients, this low-risk finding should be supported by other clinical information and rescanning should be considered after a shorter interval.

Finally, appropriate use criteria and some guidelines have stated that it is reasonable to do an ETT or stress myocardial perfusion imaging (MPI) in asymptomatic persons with high CAC scores (> 400) if they are planning to engage in vigorous physical activity; this can help to rule out high-grade obstructive disease. Prior AHA guidelines have also stated that asymptomatic diabetics with a CAC score greater than 400 may be considered for stress MPI for more advanced cardiovascular risk assessment (IIb recommendation).9 However, all patients with advanced subclinical coronary atherosclerosis should undergo aggressive lifestyle and pharmacologic management of their risk factors.

EPIDEMIOLOGY

Coronary atherosclerosis is associated with many risk factors, such as cigarette smoking, hyperlipidemia, family history, hypertension, and diabetes mellitus (see Chapter 9).1 The prevalence and extent of coronary atheroma and angina pectoris increase with age and have a male preponderance.2 Distribution among ethnic groups is unequal, with higher rates in Indo-Asians and lower rates in East Asians and Afro-Caribbeans compared with whites.3

The epidemiology of coronary artery disease and angina pectoris is changing. In some regions of the world, such as North America, Western Europe, Japan, and Australia, the incidence, mortality rates, and in-hospital case fatalities are declining,4 although the overall prevalence of coronary artery disease is still rising—in keeping with an aging population. However, Eastern Europe, in particular, is experiencing escalating rates of coronary artery disease and associated mortality rates.

Abstract

Atherosclerotic cardiovascular disease is the number one killer of both men and women in industrialized countries. Occlusion of the arteries to the heart, the coronary arteries, leads to myocardial ischemia, an imbalance between oxygen supply and demand in the heart muscle. If the ischemia is of sufficient severity and duration, death of myocardium, myocardial infarction (MI), occurs. This can lead to failure of the heart as a pump, or to electrical system failure leading to arrhythmias and sudden death. Other complications in individuals who survive, include aneurysms, ruptures, and/or valvular dysfunction of the heart. The only effective early treatment to date is to reperfuse the ischemic muscle. Myocardial conditioning can have a temporizing and partially protective effect on evolving MI. As more is learned about the molecular biology of the ischemic myocardium, there is optimism regarding the potential for novel methods of myocardial preservation and regeneration for those who suffer from this disease. This chapter focuses on the morphologic features of the coronary arteries and the heart in patients with ischemic heart disease.

Conclusions

Assessment of ASCVD risk during the cancer diagnostic and prognostic work up is important because the risk of morbidity and mortality from cardiovascular events in this clinical population may be additive or multiplicative to the risk of cardiotoxicity due to chemotherapy and radiation therapy. Statins are relatively well-tolerated agents and appropriate intensity of statin therapy is used to reduce ASCVD risk in those most likely to benefit. Statin therapy, regardless of its actual antitumor activity, should be considered for adjunctive therapy to treat existing ASCVD and reduction of ASCVD risk in cancer patients in close communication and integrated care with oncology. Further studies should be directed to identifying the group of patients who are most likely to benefit from earlier statin use and investigate the effect of statin on cancer, development, survival, and cardiovascular health of cancer patients through well-established larger randomized clinical trials.

Epidemiology

Coronary atherosclerosis is associated with many risk factors, such as cigarette smoking, hyperlipidemia, family history, hypertension, and diabetes mellitus (see Chapters 24 through 29Chapter 24Chapter 25Chapter 26Chapter 27Chapter 28Chapter 29).1 The prevalence and extent of both coronary atheroma and angina pectoris increase with age and have a male preponderance.2 Distribution among ethnic groups is unequal, with higher rates in Indo-Asians and lower rates in East Asians and Afro-Caribbeans compared with whites.3

The epidemiology of coronary heart disease (CHD) and angina pectoris is changing. In some regions of the world—such as North America, Western Europe, Japan, and Australia—the incidence, mortality rates, and in-hospital case fatalities are declining,4 although the overall prevalence of CHD is still rising, in keeping with an aging population. However, Eastern Europe in particular is experiencing escalating rates of CHD and associated mortality, with age-adjusted death rates also rising in many of the developing economies. The World Health Organization (WHO) estimates that the global number of deaths from CHD will have risen from approximately 7 million in 2002 to 11 million by 2020.

Conclusion

Coronary atherosclerosis is the most common cause of ischemic heart disease. Atherosclerosis without thrombosis is generally a benign disease, however. Disrupted atheromatous plaques are commonly associated with the formation of mural or occlusive thrombi, usually adherent to the area of damage. Certain types of plaques—those rich in lipids and surrounded by a thin fibrous cap—are the most prone to rupture. Numerous factors, intrinsic and extrinsic to the plaque itself, interact to cause the formation of a vulnerable lesion and, ultimately, plaque disruption. Fissuring or rupturing of plaques plays a fundamental role in the onset of acute coronary syndromes. In addition, repetitive damage to the plaque with thrombosis and fibrotic organization is important in the insidious progression of coronary artery disease.

Over the past several years, much has been learned concerning the specific mechanisms involved in the pathophysiology of acute coronary syndromes. As discussed in subsequent chapters, this improved understanding has led to the development of treatments directed at specific steps in the pathogenesis of unstable angina, MI, and sudden cardiac death. Through these and future advances, physicians and scientists may hope to make a significant impact on the number one cause of death in industrialized society.