In developed countries, coronary artery disease is the leading cause of death in both sexes, accounting for about one third of all deaths. Mortality rate among white men is about 1/10,000 at ages 25 to 34 and nearly 1/100 at ages 55 to 64. Mortality rate among white men aged 35 to 44 is 6.1 times that among age-matched white women. For unknown reasons, the sex difference is less marked in nonwhites and in patients with diabetes mellitus. Mortality rate among women increases after menopause and, by age 75, equals or even exceeds that of men.
Etiology of Coronary Artery Disease
Usually, coronary artery disease is due to
Coronary artery atherosclerosis Atherosclerosis Atherosclerosis is characterized by patchy intimal plaques (atheromas) that encroach on the lumen of medium-sized and large arteries; the plaques contain lipids, inflammatory cells, smooth muscle... read more : Subintimal deposition of atheromas in large and medium-sized coronary arteries
Less often, coronary artery disease is due to
Vascular endothelial dysfunction can promote atherosclerosis and contribute to coronary artery spasm. Of increasing importance, endothelial dysfunction is now also recognized as a cause of angina in the absence of epicardial coronary artery stenosis or spasm (see Syndrome X Syndrome X (Microvascular Angina) Syndrome X is cardiac microvascular dysfunction or constriction causing angina in patients with normal epicardial coronary arteries on angiography. (See also Overview of Coronary Artery Disease... read more ).
Rare causes include coronary artery embolism, dissection, aneurysm (eg, in Kawasaki disease Kawasaki Disease Kawasaki disease is a vasculitis, sometimes involving the coronary arteries, that tends to occur in infants and children between the ages of 1 year and 8 years. It is characterized by prolonged... read more ), and vasculitis (eg, in systemic lupus erythematosus Systemic Lupus Erythematosus (SLE) Systemic lupus erythematosus is a chronic, multisystem, inflammatory disorder of autoimmune etiology, occurring predominantly in young women. Common manifestations may include arthralgias and... read more , syphilis Syphilis Syphilis is caused by the spirochete Treponema pallidum and is characterized by 3 sequential clinical, symptomatic stages separated by periods of asymptomatic latent infection. Common manifestations... read more ).
Pathophysiology of Coronary Artery Disease
Coronary atherosclerosis is often irregularly distributed in different vessels but typically occurs at points of turbulence (eg, vessel bifurcations). As the atheromatous plaque grows, the arterial lumen progressively narrows, resulting in ischemia (often causing angina pectoris Angina Pectoris Angina pectoris is a clinical syndrome of precordial discomfort or pressure due to transient myocardial ischemia without infarction. It is typically precipitated by exertion or psychologic stress... read more ). The degree of stenosis required to cause ischemia varies with oxygen demand.
Occasionally, an atheromatous plaque ruptures or splits. Reasons are unclear but probably relate to plaque morphology, plaque calcium content, and plaque softening due to an inflammatory process. Rupture exposes collagen and other thrombogenic material, which activate platelets and the coagulation cascade, resulting in an acute thrombus, which interrupts coronary blood flow and causes some degree of myocardial ischemia. The consequences of acute ischemia, collectively referred to as acute coronary syndromes Overview of Acute Coronary Syndromes (ACS) Acute coronary syndromes result from acute obstruction of a coronary artery. Consequences depend on degree and location of obstruction and range from unstable angina to non–ST-segment elevation... read more (ACS), depend on the location and degree of obstruction and range from unstable angina, non-ST elevation myocardial infarction (NSTEMI), to ST elevation myocardial infarction (STEMI), which can result in transmural infarction, and other complications Complications of Acute Coronary Syndromes Numerous complications can occur as a result of an acute coronary syndrome and increase morbidity and mortality. Complications can be roughly categorized as Electrical dysfunction (conduction... read more including malignant ventricular arrhythmias, conduction defects, heart failure, and sudden death.
Coronary artery spasm
Coronary artery spasm is a transient, focal increase in vascular tone, markedly narrowing the lumen and reducing blood flow; symptomatic ischemia (variant angina Variant Angina Variant angina is angina pectoris secondary to epicardial coronary artery spasm. Symptoms include angina at rest and rarely with exertion. Diagnosis is by ECG and provocative testing with ergonovine... read more ) may result. Marked narrowing can trigger thrombus formation, causing infarction or life-threatening arrhythmia. Spasm can occur in arteries with or without atheroma.
In arteries without atheroma, basal coronary artery tone is probably increased, and response to vasoconstricting stimuli is probably exaggerated. The exact mechanism is unclear but may involve endothelial cell abnormalities of nitric oxide production or an imbalance between endothelium-derived contracting and relaxing factors.
In arteries with atheroma, the atheroma causes endothelial dysfunction, possibly resulting in local hypercontractility. Proposed mechanisms include loss of sensitivity to intrinsic vasodilators (eg, acetylcholine) and increased production of vasoconstrictors (eg, angiotensin II, endothelin, leukotrienes, serotonin, thromboxane) in the area of the atheroma. Recurrent spasm may damage the intima, leading to atheroma formation.
Use of vasoconstricting drugs (eg, cocaine, nicotine) and emotional stress also can trigger coronary spasm.
Coronary artery dissection
Coronary artery dissection is a rare, non-traumatic tear in the coronary intima with creation of a false lumen. Blood flowing through the false lumen expands it, which restricts blood flow through the true lumen sometimes causing coronary ischemia or infarction. Dissection may occur in atherosclerotic or non-atherosclerotic coronary arteries. Non-atherosclerotic dissection is more likely in pregnant or postpartum women and/or patients with fibromuscular dysplasia or other connective tissue disorders.
Risk Factors for Coronary Artery Disease
Risk factors for coronary artery disease are the same as risk factors for atherosclerosis Risk Factors for Atherosclerosis Atherosclerosis is characterized by patchy intimal plaques (atheromas) that encroach on the lumen of medium-sized and large arteries; the plaques contain lipids, inflammatory cells, smooth muscle... read more :
High blood levels of low-density lipoprotein (LDL) cholesterol (see Dyslipidemia Dyslipidemia Dyslipidemia is elevation of plasma cholesterol, triglycerides (TGs), or both, or a low high-density lipoprotein cholesterol level that contributes to the development of atherosclerosis. Causes... read more )
High blood levels of lipoprotein a
Low blood levels of high-density lipoprotein (HDL) cholesterol
High level of apoprotein B (apo B)
High blood levels of C-reactive protein (CRP)
Smoking may be a stronger predictor of myocardial infarction in women (especially those < 45). Genetic factors play a role, and several systemic disorders (eg, hypertension, hypothyroidism) and metabolic disorders (eg, hyperhomocysteinemia) contribute to risk. A high level of apo B may identify increased risk when total cholesterol or LDL level is normal.
High blood levels of C-reactive protein indicate plaque instability and inflammation and may be a stronger predictor of risk of ischemic events than high levels of LDL. High blood levels of triglycerides and insulin (reflecting insulin resistance) may be risk factors, but data are less clear. CAD risk is increased by smoking tobacco; by a diet high in fat and calories and low in phytochemicals (found in fruits and vegetables), fiber, and vitamins C, D, and E; a diet relatively low in omega-3 (n-3) polyunsaturated fatty acids (PUFAs—at least in some people); and by poor stress management.
Coronary Artery Anatomy
The right and left coronary arteries arise from the right and left coronary sinuses in the root of the aorta just above the aortic valve orifice (see figure Arteries of the heart Arteries of the heart Coronary artery disease (CAD) involves impairment of blood flow through the coronary arteries, most commonly by atheromas. Clinical presentations include silent ischemia, angina pectoris, acute... read more ). The coronary arteries divide into large and medium-sized arteries that run along the heart’s surface (epicardial coronary arteries) and subsequently send smaller arterioles into the myocardium.
The left coronary artery begins as the left main artery and quickly divides into the left anterior descending (LAD), circumflex, and sometimes an intermediate artery (ramus intermedius). The LAD artery usually follows the anterior interventricular groove and, in some people, continues over the apex. This artery supplies the anterior septum (including the proximal conduction system) and the anterior free wall of the left ventricle (LV). The circumflex artery, which is usually smaller than the LAD artery, supplies the lateral LV free wall.
Most people have right dominance: The right coronary artery passes along the atrioventricular (AV) groove over the right side of the heart; it supplies the sinus node (in 55%), right ventricle, and usually the AV node and inferior myocardial wall. About 10 to 15% of people have left dominance: The circumflex artery is larger and continues along the posterior AV groove to supply the posterior wall and AV node.
Arteries of the heart
Treatment of Coronary Artery Disease
Medical therapy including antiplatelet drugs, lipid-lowering drugs (eg, statins), and beta-blockers
Percutaneous coronary intervention
For acute thrombosis, sometimes fibrinolytic drugs
Coronary artery bypass grafting
Treatment generally aims to reduce cardiac workload by decreasing oxygen demand and improving coronary artery blood flow, and, over the long term, to halt and reverse the atherosclerotic process. Coronary artery blood flow can be improved by percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG). An acute coronary thrombosis may sometimes be dissolved by fibrinolytic drugs Fibrinolytics Treatment of acute coronary syndromes (ACS) is designed to relieve distress, interrupt thrombosis, reverse ischemia, limit infarct size, reduce cardiac workload, and prevent and treat complications... read more .
(See also Drugs for Acute Coronary Syndromes Drugs for Acute Coronary Syndromes Treatment of acute coronary syndromes (ACS) is designed to relieve distress, interrupt thrombosis, reverse ischemia, limit infarct size, reduce cardiac workload, and prevent and treat complications... read more .)
Medical management of patients with CAD depends on symptoms, cardiac function, and presence of other disorders. Recommended therapy includes antiplatelet drugs to prevent clot formation and statins to lower LDL cholesterol levels (improving short-term and long-term outcomes probably by improving atheromatous plaque stability and endothelial function). Beta-blockers are effective in reducing symptoms of angina (by reducing heart rate and contractility, decreasing myocardial oxygen demand) and reducing mortality post-infarction, especially in the presence of post-myocardial infarction (MI) LV dysfunction. Calcium channel blockers are also helpful, often combined with beta-blockers in managing angina and hypertension but have not been proven to reduce mortality. Nitrates modestly dilate coronary arteries and decrease venous return, decreasing cardiac work and relieving angina quickly. Longer acting nitrate formulations help decrease angina events but do not decrease mortality. Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) are most effective in CAD patients with LV dysfunction.
Little evidence exists to guide therapy for patients with endothelial dysfunction. Treatment is generally similar to that for typical large-vessel atherosclerosis, but there is concern that use of beta-blockers may enhance endothelial dysfunction.
Percutaneous coronary intervention (PCI)
PCI is indicated for certain patients with acute coronary syndrome Overview of Acute Coronary Syndromes (ACS) Acute coronary syndromes result from acute obstruction of a coronary artery. Consequences depend on degree and location of obstruction and range from unstable angina to non–ST-segment elevation... read more (ACS) or with stable ischemic heart disease who have angina despite optimal medical therapy.
At first, PCI was done with balloon angioplasty alone. However, roughly 5 to 8% of patients developed abrupt vessel closure after balloon angioplasty, resulting in acute myocardial infarction and often requiring emergency bypass surgery (1 Treatment references Coronary artery disease (CAD) involves impairment of blood flow through the coronary arteries, most commonly by atheromas. Clinical presentations include silent ischemia, angina pectoris, acute... read more ). In addition, 30 to 40% of patients developed restenosis within 6 months, and 1 in 3 ultimately required repeat angioplasty or CABG. Insertion of a bare-metal stent after angioplasty reduced the rate of restenosis, but many patients still required repeat treatment.
Drug-eluting stents, which release an antiproliferative drug (eg, everolimus, zotarolimus) over a period of several weeks, have reduced the rate of restenosis to < 10%. When controversy over drug-eluting stents and abrupt stent thrombosis arose in 2006, use of drug-eluting stents decreased in most centers. Subsequent studies have shown that the risk of acute thrombosis is much less than originally believed. With development of new platforms for drug-eluting stents, the incidence of in-stent thrombosis has markedly decreased. Now, most PCI is done with stents, and about three fourths of all stents used in the US are drug-eluting.
Patients without significant infarct or complications may quickly return to work and usual activities after stenting, but strenuous activities should be avoided for 6 weeks.
In-stent thrombosis occurs because of the inherent thrombogenicity of metallic stents. Most cases occur within the first 24 to 48 hours. However, late stent thrombosis, occurring after 30 days and as late as ≥ 1 year (rarely), can occur with both bare-metal and drug-eluting stents, especially after cessation of antiplatelet therapy. Progressive endothelialization of the bare-metal stent occurs within the first few months and reduces the risk of thrombosis. However, the antiproliferative drugs released by drug-eluting stents inhibit this process and prolong the risk of thrombosis. Thus, patients who undergo stent placement are treated with various antiplatelet drugs Antiplatelet Drugs Treatment of acute coronary syndromes (ACS) is designed to relieve distress, interrupt thrombosis, reverse ischemia, limit infarct size, reduce cardiac workload, and prevent and treat complications... read more . The current standard regimen for patients with a bare-metal or drug-eluting stent consists of all of the following:
Intraprocedural anticoagulation with heparin or a similar agent (eg, bivalirudin, particularly for those at high risk of bleeding)
Aspirin given indefinitely
Clopidogrel, prasugrel, or ticagrelor for at least 6 to 12 months
The best results are obtained when the newer antiplatelet drugs are begun before the procedure.
Glycoprotein IIb/IIIa inhibitors are no longer routinely used in stable patients (ie, no comorbidities, no acute coronary syndrome) having elective stent placement. Although controversial, they may be beneficial in some patients with an acute coronary syndrome but should not be considered routine. It is unclear whether it is beneficial to give glycoprotein IIb/IIIa inhibitors before arrival in the cardiac catheterization laboratory, but most national organizations do not recommend their use in this situation (2 Treatment references Coronary artery disease (CAD) involves impairment of blood flow through the coronary arteries, most commonly by atheromas. Clinical presentations include silent ischemia, angina pectoris, acute... read more ).
A statin is started after stent insertion, if one is not already being used because PCI by itself does not cure or prevent the progression of CAD. Statin therapy has been shown to improve long-term event-free survival (3 Treatment references Coronary artery disease (CAD) involves impairment of blood flow through the coronary arteries, most commonly by atheromas. Clinical presentations include silent ischemia, angina pectoris, acute... read more ). Patients who receive a statin before the procedure have a lower risk of periprocedural MI.
Overall risk of PCI is comparable with that for CABG. Mortality rate is < 1%; Q wave MI rate is < 2%. In < 1%, intimal dissection causes obstruction requiring emergency CABG. Risk of stroke with PCI is clearly less than with CABG (0.34% vs 1.2%).
Coronary artery bypass grafting (CABG)
CABG uses arteries (eg, internal mammary, radial) whenever possible, and if necessary, sections of autologous veins (eg, saphenous) to bypass diseased segments of the coronary arteries. At 1 year, about 85% of venous bypass grafts are patent, and after 5 years, one third or more are completely blocked. However, after 10 years, as many as 97% of internal mammary artery grafts are patent. Arteries also hypertrophy to accommodate increased flow. CABG is superior to PCI in patients with diabetes and in patients with multivessel disease amenable to grafting.
Coronary artery bypass grafting is typically done during cardiopulmonary bypass with the heart stopped; a bypass machine pumps and oxygenates blood. Risks of the procedure include stroke and MI. For patients with a normal-sized heart, no history of MI, good ventricular function, and no additional risk factors, risk is < 5% for perioperative MI, 1 to 2% for stroke, and ≤ 1% for mortality; risk increases with age, poor LV function, and presence of underlying disease. Operative mortality rate is 3 to 5 times higher for a second bypass than for the first.
After cardiopulmonary bypass, about 25 to 30% of patients develop cognitive dysfunction or behavioral changes, possibly caused by microemboli originating in the bypass machine. Cognitive or behavioral changes are more prevalent in older patients, prompting suspicion that these changes are most likely due to diminished "neuronal reserve," making older patients more susceptible to minor injuries incurred during cardiopulmonary bypass. Dysfunction ranges from mild to severe and may persist for weeks to years. To minimize this risk, some centers use a beating heart technique (off-pump CABG, which uses no cardiopulmonary bypass), in which a device mechanically stabilizes the part of the heart upon which the surgeon is working. However, long-term studies have failed to demonstrate lasting benefits of this approach in comparison to conventional on-pump CABG.
CAD may progress despite bypass surgery. Postoperatively, the rate of proximal obstruction of bypassed vessels increases. Vein grafts become obstructed early if thrombi form and later (several years) if atherosclerosis causes slow degeneration of the intima and media. Aspirin prolongs vein graft patency. Continued smoking has a profound adverse effect on patency. After CABG, a statin should be started or continued at maximally tolerated doses.
1. Byrne RA, Joner M, and Kastrati A: Stent thrombosis and restenosis: what have we learned and where are we going? The Andreas Gruntzig Lecture ESC 2014. Eur Heart J 36(47):3320–3331, 2015. doi: 10.1093/eurheartj/ehv511
2. O'Gara PT, Kushner FG, Ascheim DD, et al: 2013 ACCF/AHA Guideline for the management of ST-elevation myocardial infarction. JACC 61: e78–140, 2013. doi.org/10.1161/CIR.0b013e3182742cf6
3. Stone NJ, Robinson J, Lichtenstein AH, et al: 2013 ACC/AHA Guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults. JACC 63: 2889–2934, 2014. doi.org/10.1161/01.cir.0000437738.63853.7a
Prevention of Coronary Artery Disease
Prevention of coronary artery disease involves modifying atherosclerosis risk factors Treatment Atherosclerosis is characterized by patchy intimal plaques (atheromas) that encroach on the lumen of medium-sized and large arteries; the plaques contain lipids, inflammatory cells, smooth muscle... read more :
Modification of serum lipid levels
Reduction of salt intake
Control of hypertension and diabetes
Antihypertensive recommendations vary. In the US, for patients who are at low risk (< 10%) of atherosclerotic cardiovascular disease (ASCVD), antihypertensives are recommended if blood pressure is > 140/90. In patients with coronary artery disease or whose risk of ASCVD is > 10%, antihypertensive treatment is recommended for blood pressure > 130/80 mm Hg (1 Prevention references Coronary artery disease (CAD) involves impairment of blood flow through the coronary arteries, most commonly by atheromas. Clinical presentations include silent ischemia, angina pectoris, acute... read more ).
Modification of serum lipid levels (particularly with statins) may slow or even partially reverse the progression of CAD. Treatment goals have been modified. Instead of trying to achieve specific target low density lipoprotein cholesterol (LDL) levels, patients are selected for treatment based on their risk of ASCVD. Lower risk patients with elevated LDL may not require statin treatment. Four higher risk patient groups have been identified in whom the benefit of statin therapy outweighs the risk of adverse events:
Patients with clinical ASCVD
Patients with LDL cholesterol ≥ 190 mg/dL (≥ 4.9 mmol/L)
Patients age 40 to 75 years with diabetes and LDL cholesterol levels of 70 to 189 mg/dL (1.8 to 4.9 mmol/L)
Patients age 40 to 75 years with diabetes and LDL cholesterol levels of 70 to 189 mg/dL (1.8 to 4.9 mmol/L) with ASCVD risk > 7.5%
Nicotinic acid or a fibrate may be added for patients with an high-density lipoprotein (HDL) cholesterol level < 40 mg/dL (< 1.03 mmol/L), although several recent trials have failed to demonstrate a lower risk of ischemia or slowed progression of atherosclerosis when drugs are used to raise HDL (2 Prevention references Coronary artery disease (CAD) involves impairment of blood flow through the coronary arteries, most commonly by atheromas. Clinical presentations include silent ischemia, angina pectoris, acute... read more ).
1. Whelton PB, Carey RM, Aronow WS, et al: ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: A report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol 71:e127–e248, 2018.
2. AIM-HIGH Investigators, Boden WE, Probstfield JL, Anderson T, et al: Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N Engl J Med 365(24): 2255–2267, 2011. doi: 10.1056/NEJMoa1107579