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InternalMed_Harrison. FIGuRE 291e-3 Inflammatory pathways that predispose atherosclerotic plaques to rupture and provoke thrombosis. A cross-section of an atheromatous plaque at the bottom of the figure shows the central lipid core that contains macrophage foam cells (yellow) and T cells (blue). The intima and media also contain arterial smooth-muscle cells (red ), which are the source of arterial collagen (depicted as triple helical coiled structures). Activated T cells (of the type 1 helper T cell subtype) secrete cytokine interferon γ, which inhibits the production of the new, interstitial collagen that is required to repair and maintain the plaque’s protective fibrous cap (upper left). The T cells can also activate the macrophages in the intimal lesion by expressing the inflammatory mediator CD40 ligand (CD154), which engages its cognate receptor (CD40) on the phagocyte. This inflammatory signalling causes overproduction of interstitial collagenases (matrix metalloproteinases [MMPs] 1, 8, and 13) that


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InternalMed_Harrison. which engages its cognate receptor (CD40) on the phagocyte. This inflammatory signalling causes overproduction of interstitial collagenases (matrix metalloproteinases [MMPs] 1, 8, and 13) that catalyze the initial rate-limiting step in collagen breakdown (top right). CD40 ligation also causes macrophages to overproduce tissue-factor procoagulant. Thus, inflammatory signalling puts the collagen in the plaque’s fibrous cap in double jeopardy—decreasing synthesis and increasing breakdown—rendering the cap susceptible to rupture. Inflammatory activation also boosts tissue-factor production, which triggers thrombus formation in the disrupted plaque. These mechanisms link inflammation in the plaque to the thrombotic complications of atherosclerosis, including the acute coronary syndromes. (Adapted from P Libby: N Engl J Med 368:2004, 2013.)


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InternalMed_Harrison. CHAPTER 291e The Pathogenesis, Prevention, and Treatment of Atherosclerosis


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InternalMed_Harrison. The 2013 cholesterol guideline focused on 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) rather than other classes of lipid-modulating drugs, including fibric acid derivatives, cholesterol absorption inhibitors such as ezetimibe, and niacin products. The guideline cites the lack of contemporary randomized clinical trial evidence that supports the efficacy of these nonstatin lipid-modifying agents in cardiovascular event reduction. The cholesterol guideline defined four statin benefit groups (Table 291e-2): (1) all individuals who have clinical atherosclerotic cardiovascular disease (ASCVD), therefore considered “secondary prevention”; (2) those with LDL cholesterol ≥190 mg/dL without a secondary cause such as a high intake of saturated or trans fats, various drugs, or certain diseases; (3) individuals with diabetes without established cardiovascular disease who are 40–75 years old and have LDL cholesterol of 70–189 mg/dL; and (4) those without


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InternalMed_Harrison. various drugs, or certain diseases; (3) individuals with diabetes without established cardiovascular disease who are 40–75 years old and have LDL cholesterol of 70–189 mg/dL; and (4) those without established ASCVD without diabetes who are 40–75 years old and who have LDL cholesterol of 70–189 mg/dL and a calculated ASCVD risk ≥7.5%. An online risk calculator based on pooled cohorts was provided to aid clinicians and patients in calculating their risk (http://my.americanheart.org/ professional/StatementsGuidelines/PreventionGuidelines/PreventionGuidelines_UCM_457698_SubHomePage.jsp). Other validated risk calculators that incorporate family history of CAD and a marker of inflammation (high-sensitivity CRP [hsCRP]) that apply to U.S. women and men exist (http://www.reynoldsriskscore.org). Downloadable applications for risk calculation on handheld devices are readily available.


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InternalMed_Harrison. The 2013 guideline emphasized a patient-centered approach and recommended that clinicians and patients engage in a risk-benefit conversation before starting statin therapy and not rely solely on calculated risks or arbitrary category assignment. It further emphasizes that medications do not supplant a healthy lifestyle. The guideline also provides some practical suggestions regarding management of muscle symptoms attributed to statins, an issue of considerable concern to many patients and practitioners alike. In a major departure from prior guidelines, the 2013 guideline eliminates LDL targets as goals of therapy. The panel did so because major clinical trials did not titrate therapy to a goal, but rather used fixed doses of statins. Instead, the new guideline suggests different intensities of statin therapy based on risk category (Fig. 291e-4). The 2013 guideline focus on statins reflects an extensive body of rigorous evidence that supports the effectiveness of this class of drugs


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InternalMed_Harrison. The 2013 guideline focus on statins reflects an extensive body of rigorous evidence that supports the effectiveness of this class of drugs PART 10 Disorders of the Cardiovascular System Low HDL cholesterola (<1.0 mmol/L [<40 mg/dL]) Family history of premature CHD aHDL cholesterol ≥1.6 mmol/L (≥60 mg/dL) has been viewed as a “negative” risk factor. Abbreviations: BMI, body mass index; BP, blood pressure; CHD, coronary heart disease; HDL, high-density lipoprotein; LDL, low-density lipoprotein. in cardiovascular event reduction and an acceptable risk-benefit relationship (Fig. 291e-5). Moreover, because almost all statins are now available as generic statins medications, cost has become much less of an impediment to their use.


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InternalMed_Harrison. The clinical use of effective pharmacologic strategies for lowering LDL has reduced cardiovascular events markedly, but a considerable burden of residual risk remains even in patients treated with high-intensity statins. Hence, current studies are evaluating other avenues to address the residual burden of cardiovascular disease that persists despite statin treatment. Inhibitors of genetic studies identified proprotein convertase subtilisin kexin-like 9 (PCSK9) as a regulator of LDL levels associated with cardiovascular outcomes. Interaction of the LDL receptor with PCSK9 hastens the receptor’s degradation, and hence yields higher circulating LDL concentrations. Genetic variants that lower PCSK9 activity appear to protect against cardiovascular events. Monoclonal antibodies that neutralize PCSK9 lower LDL levels even in statin-treated patients and are currently under investigation as novel therapeutics to lower cardiovascular risk.


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InternalMed_Harrison. LDL-lowering therapies do not appear to exert their beneficial effect on cardiovascular events by causing a marked “regression” of stenoses. Studies of lipid lowering monitored by angiography or by intravascular imaging modalities have shown at best a modest reduction in coronary artery stenoses over the duration of study, despite abundant evidence of event reduction. These results suggest that the beneficial mechanism of lipid lowering by statins does not require a substantial reduction in the fixed stenoses. Rather, the benefit may derive from “stabilization” of atherosclerotic lesions without substantially decreased stenosis. ≥190 mg/dL without secondary cause (e.g., saturated/trans fats, drugs, certain diseases) prevention with diabetes mellitus: age 40–75 years, LDL-C 70–189 mg/dL prevention without diabetes mellitus: age 40–75 years, LDL-C 70–189 mg/dL, estimated ASCVD risk ≥7.5% Abbreviations: ACC/AHA, American College of Cardiology and American Heart Association;


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InternalMed_Harrison. Abbreviations: ACC/AHA, American College of Cardiology and American Heart Association; ASCVD, atherosclerotic cardiovascular disease; LDL-C, low-density lipoprotein cholesterol. Source: Adapted from NJ Stone et al: 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults. J Am Coll Cardiol 2013, doi: 10.1016/j.jacc.2013.11.002. Such stabilization of atherosclerotic lesions and the attendant decrease in coronary events may result from the egress of lipids or from favorably influencing aspects of the biology of atherogenesis discussed above. In addition, as sizable lesions may protrude abluminally rather than into the lumen due to complementary enlargement, shrinkage of such plaques may not be apparent on angiograms. The consistent benefit of statins may depend not only on their salutary effects on the lipid profile, but also on direct modulation of plaque biology independent of lipid lowering.


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InternalMed_Harrison. As the prevalence of metabolic syndrome and diabetes increases, many patients present with low concentrations of HDL (HDL cholesterol <1.0 mmol/L [<40 mg/dL]). A baseline measurement of HDL cholesterol indubitably correlates with future cardiovascular risk. Yet, the utility of therapies that raise HDL cholesterol levels in blood as effective interventions to reduce cardiovascular vascular events has come into question. Blood HDL levels vary inversely with those of triglycerides, and the independent role of HDL versus triglycerides as a cardiovascular risk factor remains unsettled. The 2013 guideline does not advocate any specific therapy for raising HDL. Indeed, multiple recent trials failed to show that raising HDL cholesterol levels improves cardiovascular outcomes, and recent genetic studies cast doubt on low HDL as a causal risk factor for atherosclerotic events. Weight loss and physical activity can raise HDL, and these lifestyle measures merit universal adoption (Table 291e-3).


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InternalMed_Harrison. cast doubt on low HDL as a causal risk factor for atherosclerotic events. Weight loss and physical activity can raise HDL, and these lifestyle measures merit universal adoption (Table 291e-3). Nicotinic acid, particularly in combination with statins, can robustly raise HDL, but clinical trial data do not support the effectiveness of nicotinic acid in cardiovascular risk reduction. Agonists of nuclear receptors provide another potential avenue for raising HDL levels. Yet patients treated with peroxisome proliferator–activated receptors alpha and gamma (PPAR-α and -γ) agonists have not consistently shown improved cardiovascular outcomes, and at least some PPAR agonists have been associated with worsened cardiovascular outcomes. Other agents in clinical development raise HDL levels by inhibiting cholesteryl ester transfer protein (CETP). Two such agents have undergone large-scale clinical evaluation and have not shown efficacy in improving cardiovascular outcomes. Clinical studies


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InternalMed_Harrison. inhibiting cholesteryl ester transfer protein (CETP). Two such agents have undergone large-scale clinical evaluation and have not shown efficacy in improving cardiovascular outcomes. Clinical studies currently under way will assess the effectiveness of two other CETP inhibitors that lack some of the adverse off-target actions encountered with the first agent tested.


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InternalMed_Harrison. The mechanism by which elevated LDL levels promote atherogenesis may involve oxidative modification. Yet, rigorous and well-controlled clinical trials have failed to demonstrate that antioxidant vitamin therapy improves coronary heart disease (CHD) outcomes. In regard to nontraditional risk factors including homocysteine and infection, large-scale clinical trials using vitamins to lower homocysteine or using antibiotics have not reduced cardiovascular events. Therefore, the current evidence base does not support the use of vitamins or antibiotics to lower cardiovascular risk. Hypertension (See also Chap. 298) A wealth of epidemiologic data support a relationship between hypertension and atherosclerotic risk, and extensive clinical trial evidence has established that pharmacologic treatment of hypertension can reduce the risk of stroke, heart failure, and CHD events.


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InternalMed_Harrison. Diabetes Mellitus, Insulin Resistance, and the Metabolic Syndrome (See also Chap. 417) Most patients with diabetes mellitus die of atherosclerosis and its complications. Aging and rampant obesity underlie a current epidemic of type 2 diabetes mellitus. The abnormal lipoprotein profile associated with insulin resistance, known as diabetic dyslipidemia, accounts for part of the elevated cardiovascular risk in patients with type 2 diabetes. Although diabetic individuals often have LDL cholesterol levels near the average, the LDL particles tend to be smaller and denser and, therefore, more atherogenic. Other features of diabetic dyslipidemia include low HDL and elevated triglyceride levels. Hypertension also frequently accompanies obesity, insulin resistance, and dyslipidemia. This commonly encountered clinical cluster of risk factors has become known as the metabolic syndrome (Chap. 422). Despite legitimate concerns about whether clustered components confer more risk than the individual


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InternalMed_Harrison. clinical cluster of risk factors has become known as the metabolic syndrome (Chap. 422). Despite legitimate concerns about whether clustered components confer more risk than the individual components, the metabolic syndrome concept may offer clinical utility.


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InternalMed_Harrison. Heart-healthy lifestyle habits are the foundation of ASCVD prevention. In individuals not receiving cholesterol-lowering drug therapy, recalculate estimated 10-y ASCVD risk every 4–6 y in individuals aged 40-75 y without clinical ASCVD or diabetes and with LDL–C 70-189 mg/dL. Age >75 y OR if not candidate for high-intensity statin Moderate-intensity statin High-intensity statin (Moderate-intensity statin if not candidate for high-intensity statin) Moderate-intensity statin Estimated 10-y ASCVD risk ˜7.5% High-intensity statin Estimate 10-y ASCVD risk with pooled cohort equations Clinical ASCVD LDL–C ˜190 mg/dL Diabetes Type 1 or 2 age 40–75 y Yes Yes Yes Yes Age °75 y High-intensity statin (Moderate-intensity statin if not candidate for high-intensity statin) No No No Yes CHAPTER 291e The Pathogenesis, Prevention, and Treatment of Atherosclerosis Moderate-to-high intensity statin ˜7.5% estimated 10-y ASCVD risk and age 40–75 y


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InternalMed_Harrison. CHAPTER 291e The Pathogenesis, Prevention, and Treatment of Atherosclerosis Moderate-to-high intensity statin ˜7.5% estimated 10-y ASCVD risk and age 40–75 y ASCVD prevention benefit of statin therapy may be less clear in other groups In selected individuals, consider additional factors influencing ASCVD risk and potential ASCVD risk benefits and adverse effects, drug–drug interactions, and patient preferences for statin treatment FIGuRE 291e-4 Major recommendations for statin therapy for atherosclerotic cardiovascular disease (ASCVD) prevention. LDL-C, low-density lipoprotein cholesterol. (From NJ Stone et al: J Am Coll Cardiol, 2013, doi: 10.1016/j.jacc.2013.11.002.)


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InternalMed_Harrison. Therapeutic objectives for intervention in these patients include addressing the underlying causes, including obesity and low physical activity, by initiating lifestyle measures (see below). Establishing that strict glycemic control reduces the risk of macrovascular complications of diabetes has proved much more elusive than the beneficial effects on microvascular complications such as retinopathy and renal disease. Indeed, “tight” glycemic control may increase adverse events in patients with type 2 diabetes, lending even greater importance to aggressive control of other aspects of risk in this patient population. In this regard, multiple clinical trials have demonstrated unequivocal benefit of statin therapy in diabetic patients over all ranges of LDL cholesterol levels (but not those with end-stage renal disease or advanced heart failure). Among the oral hypoglycemic agents, metformin possesses the best evidence base for cardiovascular event reduction. The novel oral hypoglycemic


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InternalMed_Harrison. with end-stage renal disease or advanced heart failure). Among the oral hypoglycemic agents, metformin possesses the best evidence base for cardiovascular event reduction. The novel oral hypoglycemic agents tested in sufficiently powered trials, the dipeptidyl peptidase-4 (DPP-4) inhibitors saxagliptin and alogliptin, did not show cardiovascular benefit. Indeed, saxagliptin was associated with a slight increase in heart failure. Diabetic populations appear to derive particular benefit from antihypertensive strategies that block the action of angiotensin II. Thus, the antihypertensive regimen for patients with the metabolic syndrome should include angiotensinconverting enzyme inhibitors or angiotensin receptor blockers when possible. Many of these individuals will require more than one anti-hypertensive agent to reach the 2013 goals for individuals 18 years of age or older with diabetes to achieve a systolic blood pressure of less than 140 mmHg and a diastolic blood pressure of less


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InternalMed_Harrison. agent to reach the 2013 goals for individuals 18 years of age or older with diabetes to achieve a systolic blood pressure of less than 140 mmHg and a diastolic blood pressure of less than 90 mmHg.


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InternalMed_Harrison. Male Sex/Postmenopausal State Decades of observational studies have verified excess coronary risk in men compared with premenopausal women. After menopause, however, coronary risk accelerates in women. Although observational and experimental studies have suggested that estrogen therapy reduces coronary risk, large-scale randomized clinical trials have not demonstrated a net benefit of estrogen with or without progestins on CHD outcomes. In the Heart LDL cholesterol reduction (mmol/L) with statin treatment 1 0 5 10 15 20 1.5 2 2.5 <5% ˜5% to <10% ˜10% to <20% ˜20% to <30% ˜30% 2.7 2.2 1.2 1.7 46 38 30 20 21 16 11 14 11 8 754 25 17 8 risk of PART 10 Disorders of the Cardiovascular System FIGuRE 291e-5 The Cholesterol Treatment Trialists Collaboration meta-analyzed 27 randomized clinical trials evaluating statin therapy.


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InternalMed_Harrison. PART 10 Disorders of the Cardiovascular System FIGuRE 291e-5 The Cholesterol Treatment Trialists Collaboration meta-analyzed 27 randomized clinical trials evaluating statin therapy. They found profound decreases in both major vascular events and vascular death (not shown) proportional to the magnitude of low-density lipoprotein (LDL) cholesterol reduction achieved with statin treatment. This diagram shows the results of this meta-analysis for vascular death. (From Lancet 380:581, 2012.) and Estrogen/Progestin Replacement Study (HERS), postmenopausal female survivors of acute MI were randomized to an estrogen/progestin combination or to placebo. This study showed no overall reduction in recurrent coronary events in the active treatment arm. Indeed, early in the 5-year course of this trial, a trend occurred toward an increase


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InternalMed_Harrison. The adult population should be encouraged to practice heart healthy lifestyle behaviors, including: • Consume a dietary pattern that emphasizes intake of vegetables, fruits, and whole grains; include low-fat dairy products, poultry, fish, legumes, nontropical vegetable oils, and nuts; and limit intake of sodium, sweets, sugar-sweetened beverages, and red meats. • Adapt this dietary pattern to appropriate calorie requirements, personal and cultural food preferences, and nutrition therapy for other medical conditions (including diabetes mellitus). • Achieve this pattern by following plans such as the DASH dietary pattern, the USDA Food Pattern, or the AHA Diet.


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InternalMed_Harrison. • Achieve this pattern by following plans such as the DASH dietary pattern, the USDA Food Pattern, or the AHA Diet. • Engage in 2 h and 30 min a week of moderate-intensity or 1 h and 15 min (75 min) a week of vigorous-intensity aerobic physical activity, or an equivalent combination of moderateand vigorous-intensity aerobic physical activity. Aerobic activity should be performed in episodes of at least 10 min, preferably spread throughout the week. • Achieve and maintain a healthy weight. Refer to the 2013 Obesity Expert Panel Report for recommendations on weight loss and maintenance. Abbreviations: ACC/AHA, American College of Cardiology and American Heart Association; DASH, Dietary Approaches to Stop Hypertension; USDA, U.S. Department of Agriculture. Source: Adapted from RH Eckel et al: 2013 AHA/ACC Guideline on Lifestyle Management to Reduce Cardiovascular Risk. J Am Coll Cardiol 2013, doi: 10.1016/j.jacc.2013.11.003.


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InternalMed_Harrison. in vascular events in the treated women. Extended follow-up of this cohort did not disclose an accrual of benefit in the treatment group. The Women’s Health Initiative (WHI) study arm, using a similar estrogen plus progesterone regimen, was halted due to a small but significant hazard of cardiovascular events, stroke, and breast cancer. The estrogen without progestin arm of WHI (conducted in women without a uterus) was stopped early due to an increase in strokes, and failed to afford protection from MI or CHD death during observation over 7 years. The excess cardiovascular events in these trials may result from an increase in thromboembolism (Chap. 413). Physicians should work with women to provide information and help weigh the small but evident CHD risk of estrogen ± progestin versus the benefits for postmenopausal symptoms and osteoporosis, taking personal preferences into account. Post hoc analyses of observational studies suggest that estrogen therapy in women younger than or


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InternalMed_Harrison. the benefits for postmenopausal symptoms and osteoporosis, taking personal preferences into account. Post hoc analyses of observational studies suggest that estrogen therapy in women younger than or closer to menopause than the women enrolled in WHI might confer cardiovascular benefit. Thus, the timing in relation to menopause or the age at which estrogen therapy begins may influence its risk/benefit balance.


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InternalMed_Harrison. The lack of efficacy of estrogen therapy in cardiovascular risk reduction highlights the need for redoubled attention to known modifiable risk factors in women. Meta-analysis supports the efficacy of statins to reduce cardiovascular events in women in primary prevention, as well as in those who have already experienced a cardiovascular event. Dysregulated Coagulation or Fibrinolysis Thrombosis ultimately causes the gravest complications of atherosclerosis. The propensity to form thrombi and/or lyse clots once they form influences the manifestations of atherosclerosis. Thrombosis provoked by atheroma rupture and subsequent healing may promote plaque growth. Certain individual characteristics can influence thrombosis or fibrinolysis and have received attention as potential coronary risk factors. For example, 30.0 25.0 20.0 15.0 10.0 5.0 0.0 10–205–100.5–1.01.0–3.03.0–10.0>10.0hsCRP mg/L


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InternalMed_Harrison. FIGuRE 291e-6 C-reactive protein (CRP) level adds to the predictive value of the Framingham score. hsCRP, high-sensitivity measurement of CRP. (Adapted from PM Ridker et al: Circulation 109:2818, 2004.) fibrinogen levels correlate with coronary risk and provide information about coronary risk independent of the lipoprotein profile. The stability of an arterial thrombus depends on the balance between fibrinolytic factors, such as plasmin, and inhibitors of the fibrinolytic system, such as plasminogen activator inhibitor 1 (PAI-1). Individuals with diabetes mellitus or the metabolic syndrome have elevated levels of PAI-1 in plasma, and this probably contributes to the increased risk of thrombotic events. Lp(a) (Chap. 421) may modulate fibrinolysis, and individuals with elevated Lp(a) levels have increased CHD risk.


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InternalMed_Harrison. Aspirin reduces CHD events in several contexts. Chapter 293 discusses aspirin therapy in stable ischemic heart disease, Chap. 294 reviews recommendations for aspirin treatment in acute coronary syndromes, and Chap. 446 describes aspirin’s role in preventing recurrent ischemic stroke. In primary prevention, pooled trial data show that low-dose aspirin treatment (81 mg/d to 325 mg on alternate days) can reduce the risk of a first MI in men. Although the Women’s Health Study (WHS) showed that aspirin (100 mg on alternate days) reduced strokes by 17%, it did not prevent MI in women. Current AHA guidelines recommend the use of low-dose aspirin (75–160 mg/d) for women with high cardiovascular risk (≥20% 10-year risk), for men with a ≥10% 10-year risk of CHD, and for all aspirin-tolerant patients with established cardiovascular disease who lack contraindications.


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InternalMed_Harrison. Inflammation An accumulation of clinical evidence shows that markers of inflammation correlate with coronary risk. For example, plasma levels of CRP, as measured by a high-sensitivity assay (hsCRP), prospectively predict the risk of MI. CRP levels also correlate with the outcome in patients with acute coronary syndromes. In contrast to several other novel risk factors, CRP adds predictive information to that derived from established risk factors, such as those included in the Framingham score (Fig. 291e-6). Mendelian randomization studies do not support a causal role for CRP in cardiovascular disease. Thus, CRP serves as a validated biomarker of risk, but probably not as a direct contributor to pathogenesis. Elevations in acute-phase reactants such as fibrinogen and CRP reflect the overall inflammatory burden, not just vascular foci of inflammation. Visceral adipose tissue releases proinflammatory cytokines that drive CRP production and may represent a major extravascular


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InternalMed_Harrison. Placebo 7832 1.11 LDL ˜ 70 mg/dL, hsCRP ˜ 2 mg/L 1384 1.11 LDL < 70 mg/dL, hsCRP ˜ 2 mg/L 2921 0.62 LDL ˜ 70 mg/dL, hsCRP < 2 mg/L 726 0.54 LDL < 70 mg/dL, hsCRP < 2 mg/L 2685 0.38 stimulus to the elevation of inflammatory markers in obese and 291e-9 overweight individuals. Indeed, CRP levels rise with body mass index (BMI) or visceral adipose depot as assessed by imaging, and weight reduction lowers CRP levels. Infectious agents might also furnish inflammatory stimuli related to cardiovascular risk.


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InternalMed_Harrison. Statin therapy likely reduces cardiovascular events in part by muting the inflammatory aspects of the pathogenesis of atherosclerosis. For example, in statin trials conducted in both primary (JUPITER) and secondary (PROVE-IT/TIMI-22) prevention populations, prespecified analyses showed that those who achieved lower levels of both LDL and CRP had better clinical outcomes than did those who only reached the lower level of either the inflammatory marker or the atherogenic lipoprotein (Fig. 291e-7). The anti-inflammatory effect of statins appears independent of LDL lowering, because these two variables correlated very poorly in individual subjects in multiple clinical trials.


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InternalMed_Harrison. Lifestyle Modification The prevention of atherosclerosis presents a long-term challenge to all health care professionals and for public health policy. Both individual practitioners and organizations providing health care should strive to help patients optimize their risk factor profiles long before atherosclerotic disease becomes manifest. The current accumulation of cardiovascular risk in youth and in certain minority populations presents a particularly vexing concern from a public health perspective.


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InternalMed_Harrison. The ACC/AHA 2013 Guideline on Lifestyle Management to Reduce Cardiovascular Risk relied on rigorous evidentiary reviews. Few lifestyle interventions have undergone rigorous evaluation in randomized clinical trials. Therefore, these guidelines reflected judicious analysis of carefully selected observational studies and of intervention studies that relied primarily on biomarkers or surrogate endpoints rather than “hard” cardiovascular outcomes. Table 291e-3 summarizes the ACC/ AHA lifestyle recommendations.


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InternalMed_Harrison. The care plan for all patients seen by internists should include measures to assess and minimize cardiovascular risk. Physicians must counsel patients about the health risks of tobacco use and provide guidance and resources regarding smoking cessation. Similarly, physicians should advise all patients about prudent dietary and physical activity habits for maintaining ideal body weight. Both National Institutes of Health (NIH) and AHA statements recommend at least 30 min of moderate-intensity physical activity per day. Obesity, particularly the male pattern of centripetal or visceral fat accumulation, can contribute to the elements of the “metabolic syndrome” cluster. Physicians should encourage their patients to take personal responsibility for behavior related to modifiable risk factors for the development of premature atherosclerotic disease. Conscientious counseling and patient education may forestall the need for pharmacologic measures intended to reduce coronary risk.


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InternalMed_Harrison. Issues in Risk Assessment A growing panel of markers of coronary risk presents a perplexing array to the practitioner. Markers measured in peripheral blood include size fractions of LDL particles and concentrations of homocysteine, Lp(a), fibrinogen, CRP, PAI-1, myeloperoxidase, lipoprotein-associated phospholipase A2, and imaging assessment of subclinical atherosclerosis, among many others. In general, such specialized tests add little to the information available from a careful history and physical examination combined with measurement of a plasma lipoprotein profile and fasting blood glucose. The hsCRP measurement may well prove an exception in view of its robustness in risk CHAPTER 291e The Pathogenesis, Prevention, and Treatment of Atherosclerosis P < 0.001


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InternalMed_Harrison. FIGuRE 291e-7 Evidence from the JUPITER study that both low-density lipoprotein (LDL)-lowering and anti-inflammatory actions contribute to the benefit of statin therapy in primary prevention. See text for explanation. hsCRP, high-sensitivity measurement of C-reactive protein (CRP). (Adapted from PM Ridker et al: Lancet 373:1175, 2009.) 291e-10 prediction, ease of reproducible and standardized measurement, relative stability in individuals over time, ability to add to the risk information disclosed by standard measurements such as the components of the Framingham risk score, and most importantly, the demonstration in a large-scale trial (JUPITER) that allocating therapy can reduce cardiovascular events in those deemed ineligible by traditional risk assessment criteria. The addition of information regarding a family history of premature atherosclerosis (a simply obtained indicator of genetic susceptibility), together with the inflammation marker hsCRP, permits correct reclassification


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InternalMed_Harrison. regarding a family history of premature atherosclerosis (a simply obtained indicator of genetic susceptibility), together with the inflammation marker hsCRP, permits correct reclassification of risk in individuals, especially those whose Framingham scores place them at intermediate risk. Available data do not support the routine use of imaging studies to screen for subclinical disease (e.g., measurement of carotid intimamedia thickness, coronary artery calcification, and use of computed tomographic coronary angiograms [CTA]). Inappropriate use of such imaging modalities may promote excessive alarm in asymptomatic individuals and prompt invasive diagnostic and therapeutic procedures of unproven value for both asymptomatic atherosclerosis and incidental findings. Widespread application of such modalities for screening should await proof that targeting therapies based on their application provides clinical benefit. The 2013 ACC/AHA Guideline on the Assessment of Cardiovascular Risk


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InternalMed_Harrison. of such modalities for screening should await proof that targeting therapies based on their application provides clinical benefit. The 2013 ACC/AHA Guideline on the Assessment of Cardiovascular Risk recommends the use of newer risk markers if uncertainty persists after assessing quantitative risk using the pooled cohort calculator. The guideline states that family history, hsCRP, coronary artery calcium (CAC) score, or ankle-brachial index (ABI) may then be considered to inform treatment decision making. It discourages carotid intimamedia thickness (CIMT) for routine measurement in clinical practice for risk assessment for a first ASCVD event. The guideline panel deemed the contribution to risk assessment for a first ASCVD event using apolipoprotein B (ApoB), chronic kidney disease, albuminuria, or cardiorespiratory fitness as uncertain at present.


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InternalMed_Harrison. PART 10 Disorders of the Cardiovascular System Progress in human genetics holds considerable promise for risk prediction and for individualization of cardiovascular therapy. Many early reports identified single-nucleotide polymorphisms (SNPs) in candidate genes as predictors of cardiovascular risk. The validation of such genetic markers of risk and drug responsiveness in multiple populations often proved disappointing. The era of GWAS has led to discovery of sites of genetic variation that reproducibly indicate heightened cardiovascular risk (e.g., chromosome 9p21). The advent of technology that permits relatively rapid and inexpensive exome or whole-genome sequencing promises to identify new therapeutic targets, sharpen risk prediction, and deploy preventive or therapeutic measures in a more personalized manner. Despite this considerable promise, genetic scores for risk prediction have not yet demonstrated consistent improvement over algorithms that use traditional tools.


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InternalMed_Harrison. THE CHALLENGE OF IMPLEMENTATION: CHANGING PHYSICIAN AND PATIENT BEHAVIOR


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InternalMed_Harrison. Despite declining age-adjusted rates of coronary death, cardiovascular mortality worldwide is rising due to aging of the population and due to subsiding of communicable diseases and increased prevalence of risk factors in developing countries. Enormous challenges remain regarding translation of the current evidence base into practice. Physicians must learn how to help individuals adopt a healthy lifestyle in a culturally appropriate manner and to deploy their increasingly powerful pharmacologic tools most economically and effectively. The obstacles to implementation of current evidence-based prevention and treatment of atherosclerosis involve economics, education, physician awareness, and patient adherence to recommended regimens. Future goals in the treatment of atherosclerosis should include more widespread implementation of the current evidence-based guidelines regarding risk factor management and, when appropriate, drug therapy.


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InternalMed_Harrison. activation as they apply to the precipitation of thrombotic complica-292e-1 tions of atherosclerosis. Atlas of Atherosclerosis Knowledge about the biology of human atherosclerosis and the risk factors for the disease has expanded considerably. The application of vascular biology to human atherosclerosis has revealed many new insights into the mechanisms that promote clinical events. The series of animated video presentations presented here illustrates some of the evolving information about risk factors for atherosclerosis and the pathophysiology of clinical events.


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InternalMed_Harrison. The importance of blood pressure as a risk factor for atherosclerosis and cardiovascular events has long been recognized. More recent clinical information has highlighted the importance of pulse pressure—the difference between the systolic pressure and minimum diastolic arterial pressure—as a prognostic indicator of cardiovascular risk. The video clip on pulse pressure explains the pathophysiology of this readily measured clinical variable.


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InternalMed_Harrison. Physicians possess a great deal of knowledge about the role of cholesterol in the prediction of atherosclerosis and its complications, but knowledge about the mechanism that links hypercholesterolemia to cardiovascular events has lagged the epidemiologic and observational findings. Low-density lipoprotein (LDL) provides an example of a well-understood cardiovascular risk factor. Several of the animations included in this series highlight the role of modified LDL as a trigger for inflammation and other aspects of the pathobiology of arterial plaques that lead to their aggravation and clinical events. Physicians have useful tools for modulating LDL, but other aspects of dyslipidemia are on the rise and provide a growing challenge to the practitioner. In particular, low levels of high-density lipoprotein (HDL) and elevated levels of triglycerides characterize the constellation of findings denoted by some as the “metabolic syndrome.” In the wake of increasing obesity worldwide, these


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InternalMed_Harrison. lipoprotein (HDL) and elevated levels of triglycerides characterize the constellation of findings denoted by some as the “metabolic syndrome.” In the wake of increasing obesity worldwide, these features of the lipoprotein profile require renewed focus. Several of the animations in this collection discuss the concept of the metabolic syndrome and the role of lipid profile components other than LDL in atherogenesis.


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InternalMed_Harrison. The traditional approach to atherosclerosis focused on arterial stenoses as a cause of ischemia and cardiovascular events. Physicians now have effective revascularization modalities for addressing flow-limiting stenoses, but atherosclerotic plaques that do not cause stenoses nonetheless may precipitate clinical events, such as unstable angina and acute myocardial infarction. Thus, it is necessary to add to the traditional focus on stenosis an enlarged appreciation of the pathobiology of atherosclerosis that underlies many acute coronary syndromes. The animation on the development and complication of atherosclerotic plaque explains some of these emerging concepts in plaque From Peter Libby, MD: Changes and Challenges in Cardiovascular Protection: A Special CME Activity for Physicians. Created under an unrestricted educational grant from Merck & Co., Inc. Copyright © 2002, Cardinal Health; used with permission.


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InternalMed_Harrison. Video 292e-1 Pulse pressure. Considerable evidence suggests that pulse pressure serves as an important risk factor for future cardiovascular events. This video clip explains the derivation of pulse pressure and some of the pathophysiology that determines this parameter. (With permission from the Academy for Health Care Education.) Video 292e-2 Plaque instability. Most coronary thromboses result from a physical disruption of the atherosclerotic plaque. This animation explains some of the current concepts of the pathophysiology of atherosclerotic plaque disruption and how it triggers arterial thrombosis. Video 292e-3 Lipoprotein menagerie. The lipid profile confers important information regarding cardiovascular risk and the effects of therapies; understanding lipoprotein metabolism provides insight into the pathophysiology of arterial disease. This animation presents the rudiments of lipoprotein metabolism that are important in clinical medicine.


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InternalMed_Harrison. Video 292e-4 Formation and complication of atherosclerotic plaques. Physicians now understand the generation of atherosclerotic plaques as a dynamic process involving an interchange between cells of the artery wall, inflammatory cells recruited from blood, and risk factors such as lipoproteins. This animation reviews current thinking about how risk factors alter the biology of the artery wall and can incite initiation and progression of atherosclerosis. It also discusses the importance of inflammation in these processes and portrays the role of inflammation in plaque disruption and thrombosis. Finally, this animation depicts the concept of stabilization of atherosclerotic plaques by interventions such as lipid lowering. Video 292e-5 Atherogenesis. This video clip highlights some of the current thinking about mechanisms of atherogenesis. Video 292e-6 Metabolic syndrome. A number of important cardiovascular risk factors tend to cluster in a pattern that has been described by some as the


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InternalMed_Harrison. thinking about mechanisms of atherogenesis. Video 292e-6 Metabolic syndrome. A number of important cardiovascular risk factors tend to cluster in a pattern that has been described by some as the metabolic syndrome. Although controversy persists regarding whether cardiovascular risk due to these factors is additive or synergistic, their clinical importance is growing. This animation discusses some of the metabolic derangements that underlie the metabolic syndrome.


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InternalMed_Harrison. CHAPTER 292e Atlas of Atherosclerosis Elliott M. Antman, Joseph Loscalzo Ischemic heart disease (IHD) is a condition in which there is an inadequate supply of blood and oxygen to a portion of the myocardium; it typically occurs when there is an imbalance between myocardial oxygen supply and demand. The most common cause of myocardial ischemia is atherosclerotic disease of an epicardial coronary artery (or arteries) sufficient to cause a regional reduction in myocardial blood flow and inadequate perfusion of the myocardium supplied by the involved coronary artery. Chapter 291e deals with the development and treatment of atherosclerosis. This chapter focuses on the chronic manifestations and treatment of IHD. The subsequent chapters address the acute phases of IHD. economic costs than any other illness in the developed world.


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InternalMed_Harrison. economic costs than any other illness in the developed world. IHD is the most common, serious, chronic, life-threatening illness in the United States, where 13 million persons have IHD, >6 million have angina pectoris, and >7 million have sustained a myocardial infarction. Genetic factors, a high-fat and energy-rich diet, smoking, and a sedentary lifestyle are associated with the emergence of IHD (Chap. 291e). In the United States and Western Europe, IHD is growing among low-income groups, but primary prevention has delayed the disease to later in life in all socioeconomic groups. Despite these sobering statistics, it is worth noting that epidemiologic data show a decline in the rate of deaths due to IHD, about half of which is attributable to treatments and half to prevention by risk factor modification.


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InternalMed_Harrison. Obesity, insulin resistance, and type 2 diabetes mellitus are increasing and are powerful risk factors for IHD. These trends are occurring in the general context of population growth and as a result of the increase in the average age of the world’s population. With urbanization in countries with emerging economies and a growing middle class, elements of the energy-rich Western diet are being adopted. As a result, the prevalence of risk factors for IHD and the prevalence of IHD itself are both increasing rapidly, so that in analyses of the global burden of disease, there is a shift from communicable to noncommunicable diseases. Population subgroups that appear to be particularly affected are men in South Asian countries, especially India and the Middle East. In light of the projection of large increases in IHD throughout the world, IHD is likely to become the most common cause of death worldwide by 2020.


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InternalMed_Harrison. Central to an understanding of the pathophysiology of myocardial ischemia is the concept of myocardial supply and demand. In normal conditions, for any given level of a demand for oxygen, the myocardium will control the supply of oxygen-rich blood to prevent under-perfusion of myocytes and the subsequent development of ischemia and infarction. The major determinants of myocardial oxygen demand (MVO2) are heart rate, myocardial contractility, and myocardial wall tension (stress). An adequate supply of oxygen to the myocardium requires a satisfactory level of oxygen-carrying capacity of the blood (determined by the inspired level of oxygen, pulmonary function, and hemoglobin concentration and function) and an adequate level of coronary blood flow. Blood flows through the coronary arteries in a phasic fashion, with the majority occurring during diastole. About 75% of the total coronary resistance to flow occurs across three sets of arteries: (1) large epicardial arteries (Resistance 1 =


InternalMed_Harrison

InternalMed_Harrison. a phasic fashion, with the majority occurring during diastole. About 75% of the total coronary resistance to flow occurs across three sets of arteries: (1) large epicardial arteries (Resistance 1 = R1), (2) prearteriolar vessels (R2), and (3) arteriolar and intramyocardial capillary vessels (R3). In the absence of significant flow-limiting atherosclerotic obstructions, R1 is trivial; the major determinant of coronary resistance is found in R2 and R3.


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InternalMed_Harrison. The normal coronary circulation is dominated and controlled by the heart’s requirements for oxygen. This need is met by the ability of the coronary vascular bed to vary its resistance (and, therefore, blood flow) considerably while the myocardium extracts a high and relatively fixed percentage of oxygen. Normally, intramyocardial resistance vessels demonstrate a great capacity for dilation (R2 and R3 decrease). For example, the changing oxygen needs of the heart with exercise and emotional stress affect coronary vascular resistance and in this manner regulate the supply of oxygen and substrate to the myocardium (metabolic regulation). The coronary resistance vessels also adapt to physiologic alterations in blood pressure to maintain coronary blood flow at levels appropriate to myocardial needs (autoregulation).


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InternalMed_Harrison. By reducing the lumen of the coronary arteries, atherosclerosis limits appropriate increases in perfusion when the demand for flow is augmented, as occurs during exertion or excitement. When the luminal reduction is severe, myocardial perfusion in the basal state is reduced. Coronary blood flow also can be limited by spasm (see Prinzmetal’s angina in Chap. 294), arterial thrombi, and, rarely, coronary emboli as well as by ostial narrowing due to aortitis. Congenital abnormalities such as the origin of the left anterior descending coronary artery from the pulmonary artery may cause myocardial ischemia and infarction in infancy, but this cause is very rare in adults.


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InternalMed_Harrison. Myocardial ischemia also can occur if myocardial oxygen demands are markedly increased and particularly when coronary blood flow may be limited, as occurs in severe left ventricular hypertrophy due to aortic stenosis. The latter can present with angina that is indistinguishable from that caused by coronary atherosclerosis largely owing to subendocardial ischemia (Chap. 283). A reduction in the oxygen-carrying capacity of the blood, as in extremely severe anemia or in the presence of carboxyhemoglobin, rarely causes myocardial ischemia by itself but may lower the threshold for ischemia in patients with moderate coronary obstruction.


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InternalMed_Harrison. Not infrequently, two or more causes of ischemia coexist in a patient, such as an increase in oxygen demand due to left ventricular hypertrophy secondary to hypertension and a reduction in oxygen supply secondary to coronary atherosclerosis and anemia. Abnormal constriction or failure of normal dilation of the coronary resistance vessels also can cause ischemia. When it causes angina, this condition is referred to as microvascular angina.


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InternalMed_Harrison. Epicardial coronary arteries are the major site of atherosclerotic disease. The major risk factors for atherosclerosis (high levels of plasma low-density lipoprotein [LDL], low plasma high-density lipoprotein [HDL], cigarette smoking, hypertension, and diabetes mellitus [Chap. 291e]) disturb the normal functions of the vascular endothelium. These functions include local control of vascular tone, maintenance of an antithrombotic surface, and control of inflammatory cell adhesion and diapedesis. The loss of these defenses leads to inappropriate constriction, luminal thrombus formation, and abnormal interactions between blood cells, especially monocytes and platelets, and the activated vascular endothelium. Functional changes in the vascular milieu ultimately result in the subintimal collections of fat, smooth muscle cells, fibroblasts, and intercellular matrix that define the atherosclerotic plaque. Rather than viewing atherosclerosis strictly as a vascular problem, it is useful to


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InternalMed_Harrison. of fat, smooth muscle cells, fibroblasts, and intercellular matrix that define the atherosclerotic plaque. Rather than viewing atherosclerosis strictly as a vascular problem, it is useful to consider it in the context of alterations in the nature of the circulating blood (hyperglycemia; increased concentrations of LDL cholesterol, tissue factor, fibrinogen, von Willebrand factor, coagulation factor VII, and platelet microparticles). The combination of a “vulnerable vessel” in a patient with “vulnerable blood” promotes a state of hypercoagulability and hypofibrinolysis. This is especially true in patients with diabetes mellitus.


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InternalMed_Harrison. Atherosclerosis develops at irregular rates in different segments of the epicardial coronary tree and leads eventually to segmental reductions in cross-sectional area, i.e., plaque formation. There is also a predilection for atherosclerotic plaques to develop at sites of increased 1579 turbulence in coronary flow, such as at branch points in the epicardial arteries. When a stenosis reduces the diameter of an epicardial artery by 50%, there is a limitation of the ability to increase flow to meet increased myocardial demand. When the diameter is reduced by ~80%, blood flow at rest may be reduced, and further minor decreases in the stenotic orifice area can reduce coronary flow dramatically to cause myocardial ischemia at rest or with minimal stress.


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InternalMed_Harrison. Segmental atherosclerotic narrowing of epicardial coronary arteries is caused most commonly by the formation of a plaque, which is subject to rupture or erosion of the cap separating the plaque from the bloodstream. Upon exposure of the plaque contents to blood, two important and interrelated processes are set in motion: (1) platelets are activated and aggregate, and (2) the coagulation cascade is activated, leading to deposition of fibrin strands. A thrombus composed of platelet aggregates and fibrin strands traps red blood cells and can reduce coronary blood flow, leading to the clinical manifestations of myocardial ischemia.


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InternalMed_Harrison. The location of the obstruction influences the quantity of myo cardium rendered ischemic and determines the severity of the clinical manifestations. Thus, critical obstructions in vessels, such as the left main coronary artery and the proximal left anterior descending coronary artery, are particularly hazardous. Chronic severe coronary narrowing and myocardial ischemia frequently are accompanied by the development of collateral vessels, especially when the narrowing develops gradually. When well developed, such vessels can by themselves provide sufficient blood flow to sustain the viability of the myocardium at rest but not during conditions of increased demand.


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InternalMed_Harrison. With progressive worsening of a stenosis in a proximal epicardial artery, the distal resistance vessels (when they function normally) dilate to reduce vascular resistance and maintain coronary blood flow. A pressure gradient develops across the proximal stenosis, and poststenotic pressure falls. When the resistance vessels are maximally dilated, myocardial blood flow becomes dependent on the pressure in the coronary artery distal to the obstruction. In these circumstances, ischemia, manifest clinically by angina or electrocardiographically by ST-segment deviation, can be precipitated by increases in myocardial oxygen demand caused by physical activity, emotional stress, and/or tachycardia. Changes in the caliber of the stenosed coronary artery due to physiologic vasomotion, loss of endothelial control of dilation (as occurs in atherosclerosis), pathologic spasm (Prinzmetal’s angina), or small platelet-rich plugs also can upset the critical balance between oxygen supply and demand and


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InternalMed_Harrison. control of dilation (as occurs in atherosclerosis), pathologic spasm (Prinzmetal’s angina), or small platelet-rich plugs also can upset the critical balance between oxygen supply and demand and thereby precipitate myocardial ischemia.


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InternalMed_Harrison. During episodes of inadequate perfusion caused by coronary atherosclerosis, myocardial tissue oxygen tension falls and may cause transient disturbances of the mechanical, biochemical, and electrical functions of the myocardium (Fig. 293-1). Coronary atherosclerosis is a focal process that usually causes nonuniform ischemia. During ischemia, regional disturbances of ventricular contractility cause segmental hypokinesia, akinesia, or, in severe cases, bulging (dyskinesia), which can reduce myocardial pump function.


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InternalMed_Harrison. The abrupt development of severe ischemia, as occurs with total or subtotal coronary occlusion, is associated with almost instantaneous failure of normal muscle relaxation and then contraction. The relatively poor perfusion of the subendocardium causes more intense ischemia of this portion of the wall (compared with the subepicardial region). Ischemia of large portions of the ventricle causes transient left ventricular failure, and if the papillary muscle apparatus is involved, mitral regurgitation can occur. When ischemia is transient, it may be associated with angina pectoris; when it is prolonged, it can lead to myocardial necrosis and scarring with or without the clinical picture of acute myocardial infarction (Chap. 295). A wide range of abnormalities in cell metabolism, function, and structure underlie these mechanical disturbances during ischemia. The normal myocardium metabolizes fatty acids and glucose to carbon


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InternalMed_Harrison. FIGURE 293-1 Cascade of mechanisms and manifestations of ischemia. (Modified from LJ Shaw et al: J Am Coll Cardiol 54:1561, 2009. Original figure illustration by Rob Flewell.) dioxide and water. With severe oxygen deprivation, fatty acids cannot be oxidized, and glucose is converted to lactate; intracellular pH is reduced, as are the myocardial stores of high-energy phosphates, i.e., ATP and creatine phosphate. Impaired cell membrane function leads to the leakage of potassium and the uptake of sodium by myocytes as well as an increase in cytosolic calcium. The severity and duration of the imbalance between myocardial oxygen supply and demand determine whether the damage is reversible (≤20 min for total occlusion in the absence of collaterals) or permanent, with subsequent myocardial necrosis (>20 min).


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InternalMed_Harrison. Ischemia also causes characteristic changes in the electrocardiogram (ECG) such as repolarization abnormalities, as evidenced by inversion of T waves and, when more severe, displacement of ST segments (Chap. 268). Transient T-wave inversion probably reflects nontransmural, intramyocardial ischemia; transient ST-segment depression often reflects patchy subendocardial ischemia; and ST-segment elevation is thought to be caused by more severe transmural ischemia. Another important consequence of myocardial ischemia is electrical instability, which may lead to isolated ventricular premature beats or even ventricular tachycardia or ventricular fibrillation (Chap. 277). Most patients who die suddenly from IHD do so as a result of ischemia-induced ventricular tachyarrhythmias (Chap. 327).


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InternalMed_Harrison. Although the prevalence is decreasing, postmortem studies of accident victims and military casualties in Western countries still show that coronary atherosclerosis can begin before age 20 and is present even among adults who were asymptomatic during life. Exercise stress tests in asymptomatic persons may show evidence of silent myocardial ischemia, i.e., exercise-induced ECG changes not accompanied by angina pectoris; coronary angiographic studies of such persons may reveal coronary artery plaques and previously unrecognized obstructions (Chap. 272). Postmortem examination of patients with such obstructions without a history of clinical manifestations of myocardial ischemia often shows macroscopic scars secondary to myocardial infarction in regions supplied by diseased coronary arteries, with or without collateral circulation. According to population studies, ~25% of patients who survive acute myocardial infarction may not come to medical attention, and these patients have the same


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InternalMed_Harrison. with or without collateral circulation. According to population studies, ~25% of patients who survive acute myocardial infarction may not come to medical attention, and these patients have the same adverse prognosis as do those who present with the classic clinical picture of acute myocardial infarction (Chap. 295). Sudden death may be unheralded and is a common presenting manifestation of IHD (Chap. 327).


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InternalMed_Harrison. Patients with IHD also can present with cardiomegaly and heart failure secondary to ischemic damage of the left ventricular myocardium that may have caused no symptoms before the development of heart failure; this condition is referred to as ischemic cardiomyopathy. In contrast to the asymptomatic phase of IHD, the symptomatic phase is characterized by chest discomfort due to either angina pectoris or acute myocardial infarction (Chap. 295). Having entered the symptomatic phase, the patient may exhibit a stable or progressive course, revert to the asymptomatic stage, or die suddenly.


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InternalMed_Harrison. This episodic clinical syndrome is due to transient myocardial ischemia. Various diseases that cause myocardial ischemia and the numerous forms of discomfort with which it may be confused are discussed in Chap. 19. Males constitute ~70% of all patients with angina pectoris and an even greater proportion of those less than 50 years of age. It is, however, important to note that angina pectoris in women is often atypical in presentation (see below).


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InternalMed_Harrison. The typical patient with angina is a man >50 years or a woman >60 years of age who complains of episodes of chest discomfort, usually described as heaviness, pressure, squeezing, smothering, or choking and only rarely as frank pain. When the patient is asked to localize the sensation, he or she typically places a hand over the sternum, sometimes with a clenched fist, to indicate a squeezing, central, substernal discomfort (Levine’s sign). Angina is usually crescendo-decrescendo in nature, typically lasts 2 to 5 min, and can radiate to either shoulder and to both arms (especially the ulnar surfaces of the forearm and hand). It also can arise in or radiate to the back, interscapular region, root of the neck, jaw, teeth, and epigastrium. Angina is rarely localized below the umbilicus or above the mandible. A useful finding in assessing a patient with chest discomfort is the fact that myocardial ischemic discomfort does not radiate to the trapezius muscles; that radiation pattern is more


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InternalMed_Harrison. the mandible. A useful finding in assessing a patient with chest discomfort is the fact that myocardial ischemic discomfort does not radiate to the trapezius muscles; that radiation pattern is more typical of pericarditis.


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InternalMed_Harrison. Although episodes of angina typically are caused by exertion (e.g., exercise, hurrying, or sexual activity) or emotion (e.g., stress, anger, fright, or frustration) and are relieved by rest, they also may occur at rest (Chap. 294) and while the patient is recumbent (angina decubitus). The patient may be awakened at night by typical chest discomfort and dyspnea. Nocturnal angina may be due to episodic tachycardia, diminished oxygenation as the respiratory pattern changes during sleep, or expansion of the intrathoracic blood volume that occurs with recumbency; the latter causes an increase in cardiac size (end-diastolic volume), wall tension, and myocardial oxygen demand that can lead to ischemia and transient left ventricular failure.


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InternalMed_Harrison. The threshold for the development of angina pectoris may vary by time of day and emotional state. Many patients report a fixed threshold for angina, which occurs predictably at a certain level of activity, such as climbing two flights of stairs at a normal pace. In these patients, coronary stenosis and myocardial oxygen supply are fixed, and ischemia is precipitated by an increase in myocardial oxygen demand; they are said to have stable exertional angina. In other patients, the threshold for angina may vary considerably within any particular day and from day to day. In such patients, variations in myocardial oxygen supply, most likely due to changes in coronary vasomotor tone, may play an important role in defining the pattern of angina. A patient may report symptoms upon minor exertion in the morning (a short walk or shaving) yet by midday be capable of much greater effort without symptoms. Angina may also be precipitated by unfamiliar tasks, a heavy meal, exposure to cold, or a


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InternalMed_Harrison. in the morning (a short walk or shaving) yet by midday be capable of much greater effort without symptoms. Angina may also be precipitated by unfamiliar tasks, a heavy meal, exposure to cold, or a combination of these factors.


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InternalMed_Harrison. Exertional angina typically is relieved in 1–5 min by slowing or ceasing activities and even more rapidly by rest and sublingual nitroglycerin (see below). Indeed, the diagnosis of angina should be suspect if it does not respond to the combination of these measures. The severity of angina can be conveniently summarized by the Canadian Cardiac Society functional classification (Table 293-1). Its impact on the patient’s functional capacity can be described by using the New York Heart Association functional classification (Table 293-1). I Patients have cardiac disease but without the resulting limitations of physical activity. Ordinary physical activity does not cause undue fatigue, palpitation, dyspnea, or anginal pain. II Patients have cardiac disease resulting in slight limitation of physical activity. They are comfortable at rest. Ordinary physical activity results in fatigue, palpitation, dyspnea, or anginal pain.


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InternalMed_Harrison. III Patients have cardiac disease resulting in marked limitation of physical activity. They are comfortable at rest. Less than ordinary physical activity causes fatigue, palpitation, dyspnea, or anginal pain. IV Patients have cardiac disease resulting in inability to carry on any physical activity without discomfort. Symptoms of cardiac insufficiency or of the anginal syndrome may be present even at rest. If any physical activity is undertaken, discomfort is increased. Ordinary physical activity, such as walking and climbing stairs, does not cause angina. Angina present with strenuous or rapid or prolonged exertion at work or recreation. Slight limitation of ordinary activity. Walking or climbing stairs rapidly, walking uphill, walking or stair climbing after meals, in cold, or when under emotional stress or only during the few hours after awakening. Walking more than two blocks on the level and climbing more than one flight of stairs at a normal pace and in normal conditions.


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InternalMed_Harrison. Marked limitation of ordinary physical activity. Walking one to two blocks on the level and climbing more than one flight of stairs in normal conditions. Inability to carry on any physical activity without discomfort— anginal syndrome may be present at rest. Source: Modified from L Goldman et al: Circulation 64:1227, 1981. Sharp, fleeting chest pain or a prolonged, dull ache localized to the 1581 left submammary area is rarely due to myocardial ischemia. However, especially in women and diabetic patients, angina pectoris may be atypical in location and not strictly related to provoking factors. In addition, this symptom may exacerbate and remit over days, weeks, or months. Its occurrence can be seasonal, occurring more frequently in the winter in temperate climates. Anginal “equivalents” are symptoms of myocardial ischemia other than angina. They include dyspnea, nausea, fatigue, and faintness and are more common in the elderly and in diabetic patients.


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InternalMed_Harrison. Systematic questioning of a patient with suspected IHD is important to uncover the features of an unstable syndrome associated with increased risk, such as angina occurring with less exertion than in the past, occurring at rest, or awakening the patient from sleep. Since coronary atherosclerosis often is accompanied by similar lesions in other arteries, a patient with angina should be questioned and examined for peripheral arterial disease (intermittent claudication [Chap. 302]), stroke, or transient ischemic attacks (Chap. 446). It is also important to uncover a family history of premature IHD (<55 years in first-degree male relatives and <65 in female relatives) and the presence of diabetes mellitus, hyperlipidemia, hypertension, cigarette smoking, and other risk factors for coronary atherosclerosis (Chap. 291e).


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InternalMed_Harrison. The history of typical angina pectoris establishes the diagnosis of IHD until proven otherwise. The coexistence of advanced age, male sex, the postmenopausal state, and risk factors for atherosclerosis increase the likelihood of hemodynamically significant coronary disease. A particularly challenging problem is the evaluation and management of patients with persistent ischemic-type chest discomfort but no flow-limiting obstructions in their epicardial coronary arteries. This situation arises more often in women than in men. Potential etiologies include microvascular coronary disease (detectable on coronary reactivity testing in response to vasoactive agents such as intracoronary adenosine, acetylcholine, and nitroglycerin) and abnormal cardiac nociception. Treatment of microvascular coronary disease should focus on efforts to improve endothelial function, including nitrates, beta blockers, calcium antagonists, statins, and angiotensin-converting enzyme (ACE) inhibitors. Abnormal


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InternalMed_Harrison. coronary disease should focus on efforts to improve endothelial function, including nitrates, beta blockers, calcium antagonists, statins, and angiotensin-converting enzyme (ACE) inhibitors. Abnormal cardiac nociception is more difficult to manage and may be ameliorated in some cases by imipramine.


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InternalMed_Harrison. The physical examination is often normal in patients with stable angina when they are asymptomatic. However, because of the increased likelihood of IHD in patients with diabetes and/or peripheral arterial disease, clinicians should search for evidence of atherosclerotic disease at other sites, such as an abdominal aortic aneurysm, carotid arterial bruits, and diminished arterial pulses in the lower extremities. The physical examination also should include a search for evidence of risk factors for atherosclerosis such as xanthelasmas and xanthomas (Chap. 291e). Evidence for peripheral arterial disease should be sought by evaluating the pulse contour at multiple locations and comparing the blood pressure between the arms and between the arms and the legs (ankle-brachial index). Examination of the fundi may reveal an increased light reflex and arteriovenous nicking as evidence of hypertension. There also may be signs of anemia, thyroid disease, and nicotine stains on the fingertips from


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InternalMed_Harrison. of the fundi may reveal an increased light reflex and arteriovenous nicking as evidence of hypertension. There also may be signs of anemia, thyroid disease, and nicotine stains on the fingertips from cigarette smoking.


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InternalMed_Harrison. Palpation may reveal cardiac enlargement and abnormal contraction of the cardiac impulse (left ventricular dyskinesia). Auscultation can uncover arterial bruits, a third and/or fourth heart sound, and, if acute ischemia or previous infarction has impaired papillary muscle function, an apical systolic murmur due to mitral regurgitation. These auscultatory signs are best appreciated with the patient in the left lateral decubitus position. Aortic stenosis, aortic regurgitation (Chap. 283), pulmonary hypertension (Chap. 304), and hypertrophic cardiomyopathy (Chap. 287) must be excluded, since these disorders may cause angina in the absence of coronary atherosclerosis. Examination during an anginal attack is useful, since ischemia can cause transient left ventricular failure with the appearance of a third 1582 and/or fourth heart sound, a dyskinetic cardiac apex, mitral regurgitation, and even pulmonary edema. Tenderness of the chest wall, localization of the discomfort with a single


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InternalMed_Harrison. of a third 1582 and/or fourth heart sound, a dyskinetic cardiac apex, mitral regurgitation, and even pulmonary edema. Tenderness of the chest wall, localization of the discomfort with a single fingertip on the chest, or reproduction of the pain with palpation of the chest makes it unlikely that the pain is caused by myocardial ischemia. A protuberant abdomen may indicate that the patient has the metabolic syndrome and is at increased risk for atherosclerosis.


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InternalMed_Harrison. Although the diagnosis of IHD can be made with a high degree of confidence from the history and physical examination, a number of simple laboratory tests can be helpful. The urine should be examined for evidence of diabetes mellitus and renal disease (including microalbuminuria) since these conditions accelerate atherosclerosis. Similarly, examination of the blood should include measurements of lipids (cholesterol—total, LDL, HDL—and triglycerides), glucose (hemoglobin ), creatinine, hematocrit, and, if indicated based on the physical examination, thyroid function. A chest x-ray is important as it may show the consequences of IHD, i.e., cardiac enlargement, ventricular aneurysm, or signs of heart failure. These signs can support the diagnosis of IHD and are important in assessing the degree of cardiac damage. Evidence exists that an elevated level of high-sensitivity C-reactive protein (CRP) (specifically, between 0 and 3 mg/dL) is an independent risk factor for IHD and may be useful


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InternalMed_Harrison. of cardiac damage. Evidence exists that an elevated level of high-sensitivity C-reactive protein (CRP) (specifically, between 0 and 3 mg/dL) is an independent risk factor for IHD and may be useful in therapeutic decision making about the initiation of hypolipidemic treatment. The major benefit of high-sensitivity CRP is in reclassifying the risk of IHD in patients in the “intermediate” risk category on the basis of traditional risk factors.


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InternalMed_Harrison. A 12-lead ECG recorded at rest may be normal in patients with typical angina pectoris, but there may also be signs of an old myocardial infarction (Chap. 268). Although repolarization abnormalities, i.e., ST-segment and T-wave changes, as well as left ventricular hypertrophy and disturbances of cardiac rhythm or intraventricular conduction are suggestive of IHD, they are nonspecific, since they also can occur in pericardial, myocardial, and valvular heart disease or, in the case of the former, transiently with anxiety, changes in posture, drugs, or esophageal disease. The presence of left ventricular hypertrophy (LVH) is a significant indication of increased risk of adverse outcomes from IHD. Of note, even though LVH and cardiac rhythm disturbances are nonspecific indicators of the development of IHD, they may be contributing factors to episodes of angina in patients in whom IHD has developed as a consequence of conventional risk factors. Dynamic ST-segment and T-wave changes that


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InternalMed_Harrison. of IHD, they may be contributing factors to episodes of angina in patients in whom IHD has developed as a consequence of conventional risk factors. Dynamic ST-segment and T-wave changes that accompany episodes of angina pectoris and disappear thereafter are more specific.


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InternalMed_Harrison. Electrocardiographic The most widely used test for both the diagnosis of IHD and the estimation of risk and prognosis involves recording the 12-lead ECG before, during, and after exercise, usually on a treadmill (Fig. 293-2). The test consists of a standardized incremental increase in external workload (Table 293-2) while symptoms, the ECG, and arm blood pressure are monitored. Exercise duration is usually symptom-limited, and the test is discontinued upon evidence of chest discomfort, severe shortness of breath, dizziness, severe fatigue, ST-segment depression >0.2 mV (2 mm), a fall in systolic blood pressure >10 mmHg, or the development of a ventricular tachyarrhythmia. This test is used to discover any limitation in exercise performance, detect typical ECG signs of myocardial ischemia, and establish their relationship to chest discomfort. The ischemic ST-segment response generally is defined as flat or downsloping depression of the ST segment >0.1 mV below baseline (i.e., the PR


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InternalMed_Harrison. and establish their relationship to chest discomfort. The ischemic ST-segment response generally is defined as flat or downsloping depression of the ST segment >0.1 mV below baseline (i.e., the PR segment) and lasting longer than 0.08 s (Fig. 293-1). Upsloping or junctional ST-segment changes are not considered characteristic of ischemia and do not constitute a positive test. Although T-wave abnormalities, conduction disturbances, and ventricular arrhythmias that develop during exercise should be noted, they are also not diagnostic. Negative exercise tests in which the target heart rate (85% of maximal predicted heart rate for age and sex) is not achieved are considered nondiagnostic.


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InternalMed_Harrison. In interpreting ECG stress tests, the probability that coronary artery disease (CAD) exists in the patient or population under study (i.e., pretest probability) should be considered. Overall, false-positive or false-negative results occur in one-third of cases. However, a positive result on exercise indicates that the likelihood of CAD is 98% in males who are >50 years with a history of typical angina pectoris and who develop chest discomfort during the test. The likelihood decreases if the patient has atypical or no chest pain by history and/or during the test.


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InternalMed_Harrison. The incidence of false-positive tests is significantly increased in patients with low probabilities of IHD, such as asymptomatic men age <40 or premenopausal women with no risk factors for premature atherosclerosis. It is also increased in patients taking cardioactive drugs, such as digitalis and antiarrhythmic agents, and in those with intraventricular conduction disturbances, resting ST-segment and T-wave abnormalities, ventricular hypertrophy, or abnormal serum potassium levels. Obstructive disease limited to the circumflex coronary artery may result in a false-negative stress test since the lateral portion of the heart that this vessel supplies is not well represented on the surface 12-lead ECG. Since the overall sensitivity of exercise stress electrocardiography is only ~75%, a negative result does not exclude CAD, although it makes the likelihood of three-vessel or left main CAD extremely unlikely.


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InternalMed_Harrison. A medical professional should be present throughout the exercise test. It is important to measure total duration of exercise, the times to the onset of ischemic ST-segment change and chest discomfort, the external work performed (generally expressed as the stage of exercise), and the internal cardiac work performed, i.e., by the heart rate–blood pressure product. The depth of the ST-segment depression and the time needed for recovery of these ECG changes are also important. Because the risks of exercise testing are small but real—estimated at one fatality and two nonfatal complications per 10,000 tests—equipment for resuscitation should be available. Modified (heart rate–limited rather than symptom-limited) exercise tests can be performed safely in patients as early as 6 days after uncomplicated myocardial infarction (Table 293-2). Contraindications to exercise stress testing include rest angina within 48 h, unstable rhythm, severe aortic stenosis, acute myocarditis, uncontrolled


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InternalMed_Harrison. myocardial infarction (Table 293-2). Contraindications to exercise stress testing include rest angina within 48 h, unstable rhythm, severe aortic stenosis, acute myocarditis, uncontrolled heart failure, severe pulmonary hypertension, and active infective endocarditis.


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InternalMed_Harrison. The normal response to graded exercise includes progressive increases in heart rate and blood pressure. Failure of the blood pressure to increase or an actual decrease with signs of ischemia during the test is an important adverse prognostic sign, since it may reflect ischemia-induced global left ventricular dysfunction. The development of angina and/or severe (>0.2 mV) ST-segment depression at a low workload, i.e., before completion of stage II of the Bruce protocol, and/or ST-segment depression that persists >5 min after the termination of exercise increases the specificity of the test and suggests severe IHD and a high risk of future adverse events.


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InternalMed_Harrison. Cardiac Imaging (See also Chap. 270e) When the resting ECG is abnormal (e.g., preexcitation syndrome, >1 mm of resting ST-segment depression, left bundle branch block, paced ventricular rhythm), information gained from an exercise test can be enhanced by stress myocardial radionuclide perfusion imaging after the intravenous administration of thallium-201 or 99m-technetium sestamibi during exercise (or with pharmacologic) stress. Contemporary data also suggest positron emission tomography (PET) imaging (with exercise or pharmacologic stress) using N-13 ammonia or rubidium-82 nuclide as another technique for assessing perfusion. Images obtained immediately after cessation of exercise to detect regional ischemia are compared with those obtained at rest to confirm reversible ischemia and regions of persistently absent uptake that signify infarction.


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InternalMed_Harrison. A sizable fraction of patients who need noninvasive stress testing to identify myocardial ischemia and increased risk of coronary events cannot exercise because of peripheral vascular or musculoskeletal disease, exertional dyspnea, or deconditioning. In these circumstances, an intravenous pharmacologic challenge is used in place of exercise. For example, dipyridamole or adenosine can be given to create a coronary “steal” by temporarily increasing flow in nondiseased


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InternalMed_Harrison. CHAPTER 293 Ischemic Heart DiseaseAEvaluation of the patient with known or suspected IHD Can patient exercise adequately? Are confounding features present on resting ECG? Perform treadmill exercise test An imaging study should be performed Yes No Possible indications for stress testing of patient: 1. Dx of IHD uncertain 2. Assess functional capacity of patient 3. Assess adequacy of treatment program for IHD 4. Markedly abnormal calcium score on EBCT 2-D Echo Nuclear perfusion scan Cardiac MR scan Cardiac PET scan ECHOECG MIBI CMR PET No Yes


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InternalMed_Harrison. FIGURE 293-2 Evaluation of the patient with known or suspected ischemic heart disease. On the left of the figure is an algorithm for identifying patients who should be referred for stress testing and the decision pathway for determining whether a standard treadmill exercise with electrocardiogram (ECG) monitoring alone is adequate. A specialized imaging study is necessary if the patient cannot exercise adequately (pharmacologic challenge is given) or if there are confounding features on the resting ECG (symptom-limited treadmill exercise may be used to stress the coronary circulation). Panels B–E, continued on the next page, are examples of the data obtained with ECG monitoring and specialized imaging procedures. CMR, cardiac magnetic resonance; EBCT, electron beam computed tomography; ECHO, echocardiography; IHD, ischemic heart disease; MIBI, methoxyisobutyl isonitrite; MR, magnetic resonance; PET, positron emission tomography. A. Lead V4 at rest (top panel) and after 4.5 min of


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InternalMed_Harrison. ECHO, echocardiography; IHD, ischemic heart disease; MIBI, methoxyisobutyl isonitrite; MR, magnetic resonance; PET, positron emission tomography. A. Lead V4 at rest (top panel) and after 4.5 min of exercise (bottom panel). There is 3 mm (0.3 mV) of horizontal ST-segment depression, indicating a positive test for ischemia. (Modified from BR Chaitman, in E Braunwald et al [eds]: Heart Disease, 8th ed, Philadelphia, Saunders, 2008.) B. A 45-year-old avid jogger who began experiencing classic substernal chest pressure underwent an exercise echo study. With exercise the patient’s heart rate increased from 52 to 153 beats/min. The left ventricular chamber dilated with exercise, and the septal and apical portions became akinetic to dyskinetic (red arrow). These findings are strongly suggestive of a significant flow-limiting stenosis in the proximal left anterior descending artery, which was confirmed at coronary angiography. (Modified from SD Solomon, in E. Braunwald et al [eds]: Primary


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InternalMed_Harrison. of a significant flow-limiting stenosis in the proximal left anterior descending artery, which was confirmed at coronary angiography. (Modified from SD Solomon, in E. Braunwald et al [eds]: Primary Cardiology, 2nd ed, Philadelphia, Saunders, 2003.) C. Stress and rest myocardial perfusion single-photon emission computed tomography images obtained with 99m-technetium sestamibi in a patient with chest pain and dyspnea on exertion. The images demonstrate a medium-size and severe stress perfusion defect involving the inferolateral and basal inferior walls, showing nearly complete reversibility, consistent with moderate ischemia in the right coronary artery territory (red arrows). (Images provided by Dr. Marcello Di Carli, Nuclear Medicine Division, Brigham and Women’s Hospital, Boston, MA.) D. A patient with a prior myocardial infarction presented with recurrent chest discomfort. On cardiac magnetic resonance (CMR) cine imaging, a large area of anterior akinesia was noted (marked by the


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InternalMed_Harrison. D. A patient with a prior myocardial infarction presented with recurrent chest discomfort. On cardiac magnetic resonance (CMR) cine imaging, a large area of anterior akinesia was noted (marked by the arrows in the top left and right images, systolic frame only). This area of akinesia was matched by a larger extent of late gadolinium-DTPA enhancements consistent with a large transmural myocardial infarction (marked by arrows in the middle left and right images). Resting (bottom left) and adenosine vasodilating stress (bottom right) first-pass perfusion images revealed reversible perfusion abnormality that extended to the inferior septum. This patient was found to have an occluded proximal left anterior descending coronary artery with extensive collateral formation. This case illustrates the utility of different modalities in a CMR examination in characterizing ischemic and infarcted myocardium. DTPA, diethylenetriamine penta-acetic acid. (Images provided by Dr. Raymond Kwong,


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InternalMed_Harrison. the utility of different modalities in a CMR examination in characterizing ischemic and infarcted myocardium. DTPA, diethylenetriamine penta-acetic acid. (Images provided by Dr. Raymond Kwong, Cardiovascular Division, Brigham and Women’s Hospital, Boston, MA.) E. Stress and rest myocardial perfusion PET images obtained with rubidium-82 in a patient with chest pain on exertion. The images demonstrate a large and severe stress perfusion defect involving the mid and apical anterior, anterolateral, and anteroseptal walls and the left ventricular apex, showing complete reversibility, consistent with extensive and severe ischemia in the mid-left anterior descending coronary artery territory (red arrows). (Images provided by Dr. Marcello Di Carli, Nuclear Medicine Division, Brigham and Women’s Hospital, Boston, MA.)


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InternalMed_Harrison. NORMAL AND I BRUCE Modified 3 min Stages BRUCE 3 min Stages MPH %GR MPH %GR 6.0 22 6.0 22 HEALTHY, DEPENDENT ON AGE, ACTIVITY 5.5 20 5.2 20 5.0 18 5.0 18 56.0 16 52.5 15 49.0 14 45.5 13 4.2 16 4.2 16 42.0 12 38.5 11 3.4 14 3.4 14 SEDENTARY HEALTHY35.0 10 31.5 9 28.0 8 LIMITED 24.5 7 2.5 12 2.5 12 II SYMPTOMATIC 21.0 6 17.5 5 1.7 10 1.7 10 III 14.0 4 10.5 3 1.7 5 7.0 2 1.7 0 IV 3.5 1 Abbreviations: GR, grade; MPH, miles per hour. Source: Modified from GF Fletcher et al: Circulation 104:1694, 2001. segments of the coronary vasculature at the expense of diseased segments. Alternatively, a graded incremental infusion of dobutamine may be administered to increase MVO2. A variety of imaging options are available to accompany these pharmacologic stressors (Fig. 293-2). The development of a transient perfusion defect with a tracer such as thallium-201 or 99m-technetium sestamibi is used to detect myocardial ischemia.


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InternalMed_Harrison. Echocardiography is used to assess left ventricular function in patients with chronic stable angina and patients with a history of a prior myocardial infarction, pathologic Q waves, or clinical evidence of heart failure. Two-dimensional echocardiography can assess both global and regional wall motion abnormalities of the left ventricle that are transient when due to ischemia. Stress (exercise or dobutamine) echocardiography may cause the emergence of regions of akinesis or dyskinesis that are not present at rest. Stress echocardiography, like stress myocardial perfusion imaging, is more sensitive than exercise electrocardiography in the diagnosis of IHD. Cardiac magnetic resonance (CMR) stress testing is also evolving as an alternative to radionuclide, PET, or echocardiographic stress imaging. CMR stress testing performed with dobutamine infusion can be used to assess wall motion abnormalities accompanying ischemia, as well as myocardial perfusion. CMR can be used to provide more


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InternalMed_Harrison. imaging. CMR stress testing performed with dobutamine infusion can be used to assess wall motion abnormalities accompanying ischemia, as well as myocardial perfusion. CMR can be used to provide more complete ventricular evaluation using multislice magnetic resonance imaging (MRI) studies.


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InternalMed_Harrison. Atherosclerotic plaques become progressively calcified over time, and coronary calcification in general increases with age. For this reason, methods for detecting coronary calcium have been developed as a measure of the presence of coronary atherosclerosis. These methods involve computed tomography (CT) applications that achieve rapid acquisition of images (electron beam [EBCT] and multidetector [MDCT] detection). Coronary calcium detected by these imaging techniques most commonly is quantified by using the Agatston score, which is based on the area and density of calcification. Although the diagnostic accuracy of this imaging method is high (sensitivity, 90–94%; specificity, 95–97%; negative predictive value, 93–99%), its prognostic utility has not been defined. Thus, its role in CT, EBCT, and MDCT scans for the detection and management of patients with IHD has not been clarified.


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InternalMed_Harrison. (See also Chap. 272) This diagnostic method outlines the lumina of the coronary arteries and can be used to detect or exclude serious coronary obstruction. However, coronary arteriography provides no information about the arterial wall, and severe atherosclerosis that does not encroach on the lumen may go undetected. Of note, atherosclerotic plaques characteristically are scattered throughout the coronary tree, tend to occur more frequently at branch points, and grow progressively in the intima and media of an epicardial coronary artery at first without encroaching on the lumen, causing an outward bulging of the artery—a process referred to as remodeling (Chap. 291e). Later in the course of the disease, further growth causes luminal narrowing.


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InternalMed_Harrison. Indications Coronary arteriography is indicated in (1) patients with chronic stable angina pectoris who are severely symptomatic despite medical therapy and are being considered for revascularization, i.e., a percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG); (2) patients with troublesome symptoms that present diagnostic difficulties in whom there is a need to confirm or rule out the diagnosis of IHD; (3) patients with known or possible angina pectoris who have survived cardiac arrest; (4) patients with angina or evidence of ischemia on noninvasive testing with clinical or laboratory evidence of ventricular dysfunction; and (5) patients judged to be at high risk of sustaining coronary events based on signs of severe ischemia on noninvasive testing, regardless of the presence or severity of symptoms (see below). Examples of other indications for coronary arteriography include the following: 1.


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InternalMed_Harrison. Examples of other indications for coronary arteriography include the following: 1. Patients with chest discomfort suggestive of angina pectoris but a negative or nondiagnostic stress test who require a definitive diagnosis for guiding medical management, alleviating psychological stress, career or family planning, or insurance purposes. 2. Patients who have been admitted repeatedly to the hospital for a suspected acute coronary syndrome (Chaps. 294 and 295), but in whom this diagnosis has not been established and in whom the presence or absence of CAD should be determined. 1586 3. Patients with careers that involve the safety of others (e.g., pilots, firefighters, police) who have questionable symptoms or suspicious or positive noninvasive tests and in whom there are reasonable doubts about the state of the coronary arteries. 4. Patients with aortic stenosis or hypertrophic cardiomyopathy and angina in whom the chest pain could be due to IHD. 5.


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InternalMed_Harrison. 4. Patients with aortic stenosis or hypertrophic cardiomyopathy and angina in whom the chest pain could be due to IHD. 5. Male patients >45 years and females >55 years who are to undergo a cardiac operation such as valve replacement or repair and who may or may not have clinical evidence of myocardial ischemia. 6. Patients after myocardial infarction, especially those who are at high risk after myocardial infarction because of the recurrence of angina or the presence of heart failure, frequent ventricular premature contractions, or signs of ischemia on the stress test. 7. Patients with angina pectoris, regardless of severity, in whom noninvasive testing indicates a high risk of coronary events (poor exercise performance or severe ischemia). 8. Patients in whom coronary spasm or another nonatherosclerotic cause of myocardial ischemia (e.g., coronary artery anomaly, Kawasaki disease) is suspected.


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InternalMed_Harrison. 8. Patients in whom coronary spasm or another nonatherosclerotic cause of myocardial ischemia (e.g., coronary artery anomaly, Kawasaki disease) is suspected. Noninvasive alternatives to diagnostic coronary arteriography include CT angiography and CMR angiography (Chap. 270e). Although these new imaging techniques can provide information about obstructive lesions in the epicardial coronary arteries, their exact role in clinical practice has not been rigorously defined. Important aspects of their use that should be noted include the substantially higher radiation exposure with CT angiography compared to conventional diagnostic arteriography and the limitations on CMR imposed by cardiac movement during the cardiac cycle, especially at high heart rates.


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InternalMed_Harrison. The principal prognostic indicators in patients known to have IHD are age, the functional state of the left ventricle, the location(s) and severity of coronary artery narrowing, and the severity or activity of myocardial ischemia. Angina pectoris of recent onset, unstable angina (Chap. 294), early postmyocardial infarction angina, angina that is unresponsive or poorly responsive to medical therapy, and angina accompanied by symptoms of congestive heart failure all indicate an increased risk for adverse coronary events. The same is true for the physical signs of heart failure, episodes of pulmonary edema, transient third heart sounds, and mitral regurgitation and for echocardiographic or radioisotopic (or roentgenographic) evidence of cardiac enlargement and reduced (<0.40) ejection fraction.


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InternalMed_Harrison. Most important, any of the following signs during noninvasive testing indicates a high risk for coronary events: inability to exercise for 6 min, i.e., stage II (Bruce protocol) of the exercise test; a strongly positive exercise test showing onset of myocardial ischemia at low workloads (≥0.1 mV ST-segment depression before completion of stage II, ≥0.2 mV ST-segment depression at any stage, ST-segment depression for >5 min after the cessation of exercise, a decline in systolic pressure >10 mmHg during exercise, or the development of ventricular tachyarrhythmias during exercise); the development of large or multiple perfusion defects or increased lung uptake during stress radioisotope perfusion imaging; and a decrease in left ventricular ejection fraction during exercise on radionuclide ventriculography or during stress echocardiography. Conversely, patients who can complete stage III of the Bruce exercise protocol and have a normal stress perfusion scan or negative stress


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InternalMed_Harrison. ventriculography or during stress echocardiography. Conversely, patients who can complete stage III of the Bruce exercise protocol and have a normal stress perfusion scan or negative stress echocardiographic evaluation are at very low risk for future coronary events. The finding of frequent episodes of ST-segment deviation on ambulatory ECG monitoring (even in the absence of symptoms) is also an adverse prognostic finding.


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InternalMed_Harrison. On cardiac catheterization, elevations of left ventricular end-diastolic pressure and ventricular volume and reduced ejection fraction are the most important signs of left ventricular dysfunction and are associated with a poor prognosis. Patients with chest discomfort but normal left ventricular function and normal coronary arteries have an excellent prognosis. Obstructive lesions of the left main (>50% luminal diameter) or left anterior descending coronary artery proximal to the origin of the first septal artery are associated with a greater risk than are lesions of the right or left circumflex coronary artery because of the greater quantity of myocardium at risk. Atherosclerotic plaques in epicardial arteries with fissuring or filling defects indicate increased risk. These lesions go through phases of inflammatory cellular activity, degeneration, endothelial dysfunction, abnormal vasomotion, platelet aggregation, and fissuring or hemorrhage. These factors can temporarily worsen the


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InternalMed_Harrison. phases of inflammatory cellular activity, degeneration, endothelial dysfunction, abnormal vasomotion, platelet aggregation, and fissuring or hemorrhage. These factors can temporarily worsen the stenosis and cause thrombosis and/or abnormal reactivity of the vessel wall, thus exacerbating the manifestations of ischemia. The recent onset of symptoms, the development of severe ischemia during stress testing (see above), and unstable angina pectoris (Chap. 294) all reflect episodes of rapid progression in coronary lesions.


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InternalMed_Harrison. With any degree of obstructive CAD, mortality is greatly increased when left ventricular function is impaired; conversely, at any level of left ventricular function, the prognosis is influenced importantly by the quantity of myocardium perfused by critically obstructed vessels. Therefore, it is essential to collect all the evidence substantiating past myocardial damage (evidence of myocardial infarction on ECG, echocardiography, radioisotope imaging, or left ventriculography), residual left ventricular function (ejection fraction and wall motion), and risk of future damage from coronary events (extent of coronary disease and severity of ischemia defined by noninvasive stress testing). The larger the quantity of established myocardial necrosis is, the less the heart is able to withstand additional damage and the poorer the prognosis is. Risk estimation must include age, presenting symptoms, all risk factors, signs of arterial disease, existing cardiac damage, and signs of impending