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Ischemic Heart Disease

Chapter 284 | Harrison's 22e · Part 6 – Cardiovascular Disorders · Chapter 284

Key Clinical Points

  1. IHD is defined by an imbalance between myocardial oxygen supply and demand.
  2. The most common cause of myocardial ischemia is atherosclerotic disease of the epicardial coronary arteries.
  3. Coronary resistance: 75% occurs in prearteriolar vessels (R2) and arteriolar/capillary vessels (R3); R1 (epicardial) is typically trivial unless obstructed.
  4. Myocardial oxygen demand is determined by heart rate, contractility, and wall tension (stress).
  5. High-risk features for immediate intervention include low exercise capacity, ischemia at low workload, EF <40%, or ACS presentation.
  6. Nitroglycerin and other nitrates are used for symptom relief; Beta Blockers and Calcium Channel Blockers are core medical therapies.
  7. Dihydropyridines are a common class of CCBs with varying durations of action (e.g., Amlodipine, Felodipine).
  8. Coronary artery calcification (measured by Agatston score) helps identify atherosclerotic plaques via CT.
  9. Multimodal imaging (Echocardiography, Nuclear Imaging, Cardiac MRI) is essential to differentiate viable myocardium from infarcted tissue.
  10. CABG may be superior for multivessel disease as it addresses both current and future culprit lesions proximal to the graft.

DEFINITION & PATHOPHYSIOLOGY

• Definition: Ischemic heart disease (IHD) is a condition where there is an inadequate supply of blood and oxygen to a portion of the myocardium, typically due to an imbalance between myocardial oxygen supply and demand. • Primary Cause: Most commonly atherosclerotic disease of an epicardial coronary artery sufficient to cause regional reduction in blood flow. • Myocardial Oxygen Demand: Determined by heart rate, myocardial contractility, and myocardial wall tension (stress). • Myocardial Oxygen Supply: Determined by oxygen-carrying capacity of the blood (Hb concentration, pulmonary function) and coronary blood flow. • Coronary Circulation Dynamics: ◦ 75% of total coronary resistance occurs across three sets: (1) large epicardial arteries (R1), (2) prearteriolar vessels (R2), and (3) arteriolar/intramyocardial capillary vessels (R3). ◦ In the absence of atherosclerosis, R1 is trivial; primary resistance is in R2 and R3. ◦ Arteriolar vessels (R2 and R3) have a high capacity for dilation to meet demand via autoregulation and metabolic regulation. • Atherosclerosis Impact: ◦ Reduces lumen → limits flow during increased demand. ◦ Severe narrowing may lead to the development of collateral vessels, especially if the narrowing develops gradually. • High-Risk Locations: ◦ Left main coronary artery. ◦ Proximal left anterior descending (LAD) coronary artery. ◦ Ostial narrowing (e.g., from pulmonary artery; rare in adults). • Other Causes of Ischemia: Vasospastic angina, thrombi, and rarely, coronary emboli.

• Global Impact: IHD is a major contributor to disability-adjusted life-years (DALYs) globally. • Prevalence: Over 200 million people live with IHD globally; approximately 20.5 million in the United States. • Risk Factors: ◦ Genetic factors ◦ High-fat and energy-rich diet ◦ Smoking ◦ Sedentary lifestyle ◦ Obesity, insulin resistance, and type 2 diabetes mellitus.

DIAGNOSTIC APPROACH

  1. Initial Risk Stratification:
  2. High Risk: Includes patients with low exercise capacity or ischemia at low workload; EF <40%; or ACS presentation.
  3. Low/Equivocal Risk: Patients with lower clinical likelihood of CAD or where noninvasive results are unclear.
  4. Noninvasive Testing (for Low/Equivocal Risk):
  5. Options: Functional stress testing with imaging for myocardial ischemia OR computed tomography angiography (CTA) to establish diagnosis prior to treatment.
  6. Invasive Coronary Angiography (for High Risk or Clear Ischemia):
  7. Indicated for patients with high clinical likelihood of CAD, symptoms despite antianginal therapy, or high-risk features based on initial evaluation.
  8. Key Indicator: A positive test for ischemia is often identified by ≥ 3 mm horizontal ST-segment depression during exercise (e.g., after 4.5 min).

MANAGEMENT & TREATMENT

  1. Nitroglycerin Therapy:
  2. Ointment: 0.5–2 in.; Two or three times daily.
  3. Transdermal patch: 0.2–0.8 mg/h; Every 24 h (remove at bedtime for 12–14 h).
  4. Sublingual tablet: 0.3–0.6 mg; As needed, up to three doses 5 min apart.
  5. Spray: One or two sprays; As needed, up to three doses 5 min apart.
  6. Isosorbide 5-mononitrate:
  7. Oral: 20 mg; Twice daily (given 7–8 h apart).
  8. Oral sustained release: 30–240 mg; Once daily.
  9. Beta Blockers:
  10. Acebutolol: 200–600 mg twice daily.
  11. Betaxolol: 10–20 mg/d.
  12. Esmolol (intravenous): 50–300 μg/kg/min.
  13. Metoprolol: 50–200 mg twice daily.
  14. Nebivolol: 5–40 mg/d.
  15. Propranolol: 80–120 mg twice daily.
  16. Calcium Channel Blockers (CCBs):
  17. Dihydropyridines:
  18. Amlodipine: 5–10 mg qd
  19. Felodipine: 5–10 mg qd
  20. Isradipine: 2.5–10 mg bid
  21. Nicardipine: 20–40 mg tid
  22. Nifedipine (IR): 30–90 mg daily; (SR): 30–180 mg
  23. Nisoldipine: 20–40 mg qd
  24. Nondihydropyridines:
  25. Immediate release: 30–80 mg 4 times daily
  26. Slow release: 120–320 mg qd
  27. Revascularization Decision Pathway (Flowchart 3):
  28. Step 1: Identify High-Risk Features? (Low exercise capacity, ischemia at low workload, EF <40%, or ACS presentation).
  29. Step 2: If YES → Refer for coronary artery angiography.
  30. Step 3: Assess Suitability for Revascularization.
  31. If Suitable:
  32. Single-vessel disease → PCI.
  33. LM +/or multi-vessel disease → Assess: PCI vs CABG.
  34. If NOT Suitable → Consider unconventional treatments.
  35. Step 4: If NO (to High-Risk Features) → Are exertional symptoms controlled?
  36. Yes → Continue medical therapy; periodic stress assessment.
  37. No → Refer for coronary artery angiography → Assess Suitability → PCI or CABG.

CLINICAL PEARLS & SUMMARY

• Revascularization Strategy: - PCI: Targeted at the "culprit" lesion. - CABG: Directed at the epicardial vessel, including both current culprit lesions and future culprits proximal to the graft insertion. This often provides superior results in multivessel disease. • Pharmacology Precautions: - Nitrates: Contraindicated in hypertrophic obstructive cardiomyopathy; avoid with PDE5 inhibitors (e.g., sildenafil). - Beta Blockers: Avoid in patients with asthma, severe bradycardia, or heart block. - CCB Dihydropyridines: Caution in patients with heart failure or low blood pressure; avoid in those taking other heart rate-lowering agents (e.g., flecainide). • Imaging Utility: - Echocardiography: Identifies structural changes and wall motion abnormalities. - Nuclear Imaging: Detects inducible ischemia (difference between rest and stress perfusion). - Cardiac MRI: Differentiates viable myocardium from permanent scar tissue. - CT Angiography: Quantifies calcification (Agatston score) and maps coronary anatomy (RCA, LAD, LCx).

TABLES & DATA

• Table 1: NYHA/CCS Classification - Class I: No limitations of physical activity. - Class II: Slight limitation; comfortable at rest. - Class III: Marked limitation; less than ordinary physical activity causes symptoms. - Class IV: Inability to carry on any physical activity without discomfort. • Table 2: METs and Stages - Stage 10: 35.0 METs - Stage 1: 3.5 METs • Table 3: Energy Requirements (METs) - < 3 METs: Self-care, Desk work, Driving. - 3–5 METs: Cleaning windows, Bed making, Carrying objects (15–30 lb). - 5–7 METs: Easy digging, Raking, Carrying objects (30–60 lb). - 7–9 METs: Heavy shoveling, Power lawn mowing, Carpentry. - > 9 METs: Carrying loads (>90 lb), Climbing stairs quickly, Dancing, Basketball. • Table 4: Nitroglycerin Doses - Ointment: 0.5–2 in.; Transdermal patch: 0.2–0.8 mg/h; Sublingual: 0.3–0.6 mg; Spray: 1–2 sprays. • Table 5: Beta Blockers - Acebutolol (200–600 mg), Betaxolol (10–20 mg), Esmolol (50–300 μg/kg/min), Metoprolol (50–200 mg), Nebivolol (5–40 mg), Propranolol (80–120 mg). • Table 6: Calcium Channel Blockers - Dihydropyridines: Amlodipine (5–10 mg), Felodipine (5–10 mg), Isradipine (2.5–10 mg), Nicardipine (20–40 mg), Nifedipine (IR 30–90, SR 30–180), Nisoldipine (20–40 mg). - Nondihydropyridines: IR (30–80 mg 4x daily), SR (120–320 mg qd). • Table 7: Antianginal Agents Summary - Nitrates: Contraindicated in hypertrophic obstructive cardiomyopathy; avoid with PDE5 inhibitors. - Beta Blockers: Contraindicated in asthma, bradycardia, or heart block. - CCB Dihydropyridines: Contraindicated in heart failure and low blood pressure.

Reference Tables

TABLE 284-1 Cardiovascular Disease Classification Chart CLASS I

Harrison's 22e, p.2093

CLASS NEW YORK HEART ASSOCIATION
FUNCTIONAL CLASSIFICATION		 CANADIAN CARDIOVASCULAR
SOCIETY FUNCTIONAL
CLASSIFICATION
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.		 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.
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.
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.		 Marked limitation of ordinary
physical activity. Walking one
to two blocks on the level and
climbing one flight of stairs at
normal pace.
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.

TABLE 284-2 Relation of Metabolic Equivalent Tasks (METs) to Stages in Various Testing Protocols FUNCTIONAL

Harrison's 22e, p.2097

FUNCTIONAL
CLASS		 CLINICAL STATUS O COST
2
mL/Kg/min		 METs TREADMILL PROTOCOLS
NORMAL
AND
I		 BRUCE Modified 3 min Stages BRUCE 3 min Stages
MPH %GR MPH %GR
6.0 22 6.0 22
YTIVITCA
,EGA
NO
TNEDNEPED
,YHTLAEH		 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
YHTLAEH
YRATNEDES		 35.0 10
31.5 9
28.0 8
DETIMIL 24.5 7 2.5 12 2.5 12
II CITAMOTPMYS 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

TABLE 284-3 Energy Requirements for Some Common Activities

Harrison's 22e, p.2099

LESS THAN 3 METs 3–5 METs 5–7 METs 7–9 METs MORE THAN 9 METs
Self-Care
Washing/shaving Cleaning windows Easy digging in garden Heavy shoveling Carrying loads upstairs (objects >90 lb)
Dressing Raking Level hand lawn mowing Carrying objects (60–90 lb) Climbing stairs (quickly)
Light housekeeping Power lawn mowing Carrying objects (30–60 lb) Shoveling heavy snow
Desk work Bed making/stripping
Driving auto Carrying objects (15–30 lb)
Occupational
Stocking shelves (light objects)
Light welding/carpentry		 Carpentry (exterior)
Shoveling dirt
Sawing wood		 Digging ditches (pick and
shovel)
Recreational
Golf (cart) Dancing (social) Tennis (singles) Canoeing Squash
Knitting Golf (walking) Snow skiing (downhill) Mountain climbing Ski touring
Sailing Light backpacking Vigorous basketball
Tennis (doubles) Basketball
Stream fishing
Physical Conditioning
Level walking (3–4 mph)
Level biking (6–8 mph)
Light calisthenics		 Level walking (4.5–5.0 mph)
Bicycling (9–10 mph)
Swimming, breast stroke		 Level jogging (5 mph)
Swimming (crawl stroke)
Rowing machine
Heavy calisthenics
Bicycling (12 mph)

TABLE 284-4 Nitrate Therapy in Patients with Ischemic Heart Disease

Harrison's 22e, p.2100

PREPARATION OF AGENT DOSE SCHEDULE
Nitroglycerina
Ointment 0.5–2 in. Two or three times daily
Transdermal patch 0.2–0.8 mg/h Every 24 h; remove at bedtime for
12–14 h
Sublingual tablet 0.3–0.6 mg As needed, up to three doses
5 min apart
Spray One or two
sprays		 As needed, up to three doses
5 min apart
10–40 mg
80–120 mg
Isosorbide 5-mononitrate
Oral 20 mg Twice daily (given 7–8 h apart)
Oral sustained release 30–240 mg Once daily

TABLE 284-5 Properties of Beta Blockers in Clinical Use for Ischemic Heart Disease

Harrison's 22e, p.2100

DRUGS SELECTIVITY PARTIAL
AGONIST
ACTIVITY		 USUAL DOSE FOR ANGINA
Acebutolol β
1		 Yes 200–600 mg twice daily
β
1		 No
Betaxolol β
1		 No 10–20 mg/d
β
1		 No
Esmolol
(intravenous)a		 β
1		 No 50–300 μg/kg/min
None Yes
Metoprolol β
1		 No 50–200 mg twice daily
None No
Nebivolol β (at low doses)
1		 No 5–40 mg/d
None Yes
Propranolol None No 80–120 mg twice daily
None No

TABLE 284-6 Calcium Channel Blockers in Clinical Use for Ischemic Heart Disease DRUGS Dihydropyridines Amlodipine…

Harrison's 22e, p.2101

DRUGS USUAL DOSE DURATION
OF ACTION		 SIDE EFFECTS
Dihydropyridines
Amlodipine 5–10 mg qd Long Headache, edema
Felodipine 5–10 mg qd Long Headache, edema
Isradipine 2.5–10 mg bid Medium Headache, fatigue
Nicardipine 20–40 mg tid Short Headache, dizziness,
flushing, edema
Nifedipine Immediate release:a
30–90 mg daily orally
Slow release:
30–180 mg orally		 Short Hypotension,
dizziness,
flushing, nausea,
constipation, edema
Nisoldipine 20–40 mg qd Short Similar to nifedipine
Nondihydropyridines
Immediate release:
30–80 mg 4 times daily
Slow release:
120–320 mg qd		 Short
Long
Immediate release:
80–160 mg tid
Slow release: 120–480
mg qd		 Short
Long

TABLE 284-7 Antianginal Agents AGENT Agents That Have a Physiologic Effect Short-acting and long-acting nitrates

Harrison's 22e, p.2102

AGENT COMMON SIDE EFFECTS CONTRAINDICATIONS POTENTIAL DRUG INTERACTIONS
Agents That Have a Physiologic Effect
Short-acting and long-acting
nitrates		 Headache, flushing, hypotension,
syncope and postural
hypotension, reflex tachycardia,
methemoglobinemia		 Hypertrophic obstructive cardiomyopathy Phosphodiesterase type 5 inhibitors
(sildenafil and similar agents), beta-
adrenergic blockers, calcium channel
blockers
Beta blockers Fatigue, depression, bradycardia,
heart block, bronchospasm,
peripheral vasoconstriction,
postural hypotension, impotence,
masked signs of hypoglycemia		 Low heart rate or heart conduction disorder, cardiogenic
shock, asthma, severe peripheral vascular disease,
decompensated heart failure, vasospastic angina; use
with caution in patients with COPD (cardioselective
beta blockers may be used if patient receives adequate
treatment with long-acting beta agonists)		 Heart rate–lowering calcium channel
blockers, sinus node or AV conduction
depressors
Calcium-channel blockers
Heart rate–lowering agents Bradycardia, heart conduction
defect, low ejection fraction,
constipation, gingival hyperplasia		 Cardiogenic shock, severe aortic stenosis, obstructive
cardiomyopathy		 CYP3A4 substrates (digoxin, simvastatin,
cyclosporine)
Dihydropyridine Headache, ankle swelling fatigue,
flushing, reflex tachycardia		 Low heart rate or heart rhythm disorder, sick-sinus
syndrome, congestive heart failure, low blood pressure		 Agents with cardiodepressant effects
(beta blockers, flecainide), CYP3A4
substrates
Agents That Affect Myocardial Metabolism
Dizziness, constipation, nausea,
QT interval prolongation		 Liver cirrhosis