eMedicine Specialties > Cardiology > Atherosclerosis and Risk Factors

Coronary Artery Atherosclerosis: Differential Diagnoses & Workup

Author: Vibhuti N Singh, MD, MPH, FACC, FSCAI, Director, Suncoast Cardiovascular Center; Chair, Cardiology Division and Cath Labs, Department of Medicine, Bayfront Medical Center; Clinical Assistant Professor, Division of Cardiology, University of South Florida College of Medicine
Coauthor(s): Prakash C Deedwania, MD, FACC, FAHA, FACP, FCCP, Professor of Medicine, University of California, San Francisco School of Medicine; Chief, Cardiology Section, Veterans Affairs Medical Center, UCSF Program at Fresno, California; Director, Cardiovascular Research, UCSF Central San Joaquin Program; Rakesh K Sharma, MD, FACC, Adjunct Associate Professor of Medicine and Cardiology; University of Arkansas for Medical Sciences, Medical Center of South Arkansas
Contributor Information and Disclosures

Updated: Oct 29, 2009

Differential Diagnoses

Angina Pectoris
Hypertensive Heart Disease
Atherosclerosis
Isolated Coronary Artery Anomalies
Buerger Disease (Thromboangiitis Obliterans)
Kawasaki Disease
Cardiomyopathy, Dilated
Myocardial Ischemia
Coronary Artery Vasospasm
Myocarditis
Diabetes Mellitus, Type 1
Nicotine Addiction
Diabetes Mellitus, Type 2
Pericarditis, Acute
Giant Cell Arteritis
Right Ventricular Infarction
Hypercholesterolemia, Familial
Treadmill and Pharmacologic Stress Testing
Hypercholesterolemia, Polygenic
Unstable Angina
Hypertension

Workup

Laboratory Studies

  • Routine blood tests
    • CBC count
    • Chemistry panel
    • Thyroid function tests - To exclude thyroid disorders
  • Fasting lipid profile
    • Total cholesterol level
    • LDL-C level
    • HDL cholesterol (HDL-C) level
    • Triglyceride level
  • Special tests
    • Specific lipid studies (if necessary)
      • Small, dense LDL-C level
      • Lipoprotein(a) level
      • Apoprotein profile
    • Miscellaneous tests
      • Homocysteine level
      • Inflammatory markers (eg, CRP)
  • Tests specific to the presentation of ACS
    • Serum markers
      • Creatine kinase with MB isozymes
      • Troponins (I or T)
      • Lactate dehydrogenase and lactate dehydrogenase isozymes
      • Serum aspartate aminotransferase
    • Inflammatory markers - CRP

Imaging Studies

  • Echocardiography
    • Transthoracic echocardiography helps assess left ventricular function, wall motion abnormalities in the setting of ACS or AMI, and mechanical complications of AMI.
    • Transesophageal echocardiography is most often used for assessing possible aortic dissection in the setting of AMI.
    • Stress echocardiography can be used to evaluate hemodynamically significant stenoses in stable patients who are thought to have CAD.
    • Treadmill echocardiography stress testing and dobutamine echocardiography stress testing provide equivalent predictive values.

      Coronary artery atherosclerosis. Stress test, par...

      Coronary artery atherosclerosis. Stress test, part 1. See Image 2 for part 2. Resting ECG showing normal baseline ST segments.

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      Coronary artery atherosclerosis. Stress test, par...

      Coronary artery atherosclerosis. Stress test, part 1. See Image 2 for part 2. Resting ECG showing normal baseline ST segments.


      Coronary artery atherosclerosis. Stress test, par...

      Coronary artery atherosclerosis. Stress test, part 2. See Image 1 for part 1. Stress ECG showing significant ST-segment depression.

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      Coronary artery atherosclerosis. Stress test, par...

      Coronary artery atherosclerosis. Stress test, part 2. See Image 1 for part 1. Stress ECG showing significant ST-segment depression.

  • Nuclear imaging studies (myocardial perfusion imaging): These studies are also useful in assessing patients for hemodynamically significant coronary artery stenoses.
    • Stress and rest nuclear scintigraphic studies using thallium, sestamibi, or teboroxime are sometimes helpful.
    • Radionuclide stress myocardial perfusion imaging can be used to quantify coronary flow reserve (CFR).
      • Thallium Tl 201 or sestamibi are widely used to quantify CFR. Flow reserve is typically assessed by these techniques during exercise or with pharmacological coronary vasodilators. In contrast to invasive techniques that measure an index of absolute flow reserve (an index related to the quotient of maximal and basal flow), cardiac imaging techniques assess relative CFR (rCFR) by comparing the perfusion of ischemic regions of the left ventricle with presumably normally perfused reference regions.
      • Imaging techniques yield a less quantitative index of flow reserve than catheter-based techniques. In addition, results can be misleading in the setting of diffuse coronary disease when a normal reference region is not available. However, unlike most measures of absolute flow reserve, relative flow reserve is independent of the loading conditions because these affect all regions of the left ventricle equally.
      • Taken together, absolute flow reserve and rCFR provide a more complete description of the severity of physiological stenosis than either method alone.
    • Types of nuclear imaging include a treadmill nuclear stress test, a dipyridamole (Persantine) or adenosine nuclear stress test, and a dobutamine nuclear stress test.

      Coronary artery atherosclerosis. Stress nuclear i...

      Coronary artery atherosclerosis. Stress nuclear imaging showing anterior, apical, and septal wall perfusion defect during stress, which is reversible as observed on the rest images. This defect strongly suggests the presence of significant stenosis in the left anterior descending coronary artery.

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      Coronary artery atherosclerosis. Stress nuclear i...

      Coronary artery atherosclerosis. Stress nuclear imaging showing anterior, apical, and septal wall perfusion defect during stress, which is reversible as observed on the rest images. This defect strongly suggests the presence of significant stenosis in the left anterior descending coronary artery.

    • MI avid scintigraphy may be indicated.
  • Magnetic resonance angiography
  • Electron beam CT scanning
    • Electron beam computed tomography (EBCT) scanning is a noninvasive method of evaluating calcium content in the coronary arteries. Healthy coronary arteries lack calcium. As atherosclerotic plaques grow, calcium accumulates because of a perpetuating inflammatory process or the healing and scarring induced by this process. EBCT is currently used as a screening test in asymptomatic patients and as a diagnostic test for obstructive CAD in symptomatic patients, although experts in the field have reached no consensus regarding indications for its use.
    • The American College of Cardiology/American Heart Association Expert Consensus Document indicates the following11 :
      • EBCT scanning has been demonstrated to have high sensitivity.
      • Overall predictive accuracy is 70%.
      • EBCT has low specificity, ie, a substantial false-positive rate, which raises the index of suspicion for CAD and leads to expensive and unwarranted additional testing to exclude CAD. Consequently, O'Rourke and colleagues do not recommend EBCT scanning to help diagnose obstructive CAD.
    • Whether EBCT scanning is a worthwhile tool for screening of CAD is still unclear. Well-established clinical indicators, such as the Framingham risk score and the National Cholesterol Education Program (NCEP) risk calculator, already accurately predict the likelihood of CAD. Whether EBCT scanning adds to these indicators has yet to be shown. The Multi-Ethnic Study of Atherosclerosis (MESA), sponsored by the US National Institutes of Health, is now assessing prospective evaluation of EBCT scanning in asymptomatic subjects to answer this question.12
    • EBCT scanning may have niche uses, including (1) determining whether individuals who appear to be at intermediate risk are really at a higher risk (eg, asymptomatic elderly patients who have high calcium scores) and (2) determining a low likelihood of significant CAD if EBCT scanning demonstrates a low or absent calcium score.

Other Tests

  • Twelve-lead ECG
  • Treadmill ECG stress test
  • Holter monitoring for silent ischemia
  • Angioscopy

Procedures

Coronary angiography

Coronary arterial luminography remains the criterion standard for defining significant flow-limiting stenoses that must be revascularized through percutaneous or surgical intervention to improve prognosis. Quantitative coronary angiography (QCA) is used to perform computerized quantitative analysis of the entire coronary tree. It introduces a correction factor for the presence of diffuse disease. QCA has been widely used in many trials of atherosclerotic progression and regression.

  • The role of QCA in regression studies is as follows:
    • The Familial Atherosclerosis Treatment Study (FATS) analyzed 9 angiographic trials of lipid-reducing therapy. Approximately 50% of subjects in the control group exhibited progression, but only 25% of the subjects in the treatment group did so. Regression was observed in 8% of the control group and in 28% of the treatment group. Subjects with mild-to-moderate lesions showed the most benefit.13,14
    • The reduction in the number of clinical coronary events was much more pronounced (disproportionately greater), although the effect on lesion progression was only modest. For example, in the FATS, only 12% of subjects showed regression. The mean regression in the stenosis was less than 1%; however, this resulted in a 70% reduction in coronary events. ACS is known to develop in nonocclusive (<50%) plaques in most patients. The luminographic images obtained by coronary arteriograms miss mild-to-moderate vulnerable plaques, which cause most of the acute events.
  • Limitations of coronary arteriography are as follows:
    • Severity of stenosis is generally estimated visually, but estimation is limited by the fact that interobserver variability may range from 30-60%.
    • The presence of diffuse disease also may lead to underestimation of stenoses because the stenosed areas are expressed as a percent of luminal diameter compared with adjacent normal coronary segments, and, in diffuse disease, no such segments exist. This usually occurs in diabetic patients, in whom coronary arteries are traditionally described as small-caliber vessels, when that appearance is actually due to the presence of diffuse symmetrical involvement of the entire vessel, as elucidated by recent IVUS studies.
Coronary artery atherosclerosis. Cardiac catheter...

Coronary artery atherosclerosis. Cardiac catheterization and coronary angiography in the left panel shows severe left anterior descending coronary artery stenosis. This lesion was treated with stent placement in the left anterior descending coronary artery, as observed in the right panel.

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Coronary artery atherosclerosis. Cardiac catheter...

Coronary artery atherosclerosis. Cardiac catheterization and coronary angiography in the left panel shows severe left anterior descending coronary artery stenosis. This lesion was treated with stent placement in the left anterior descending coronary artery, as observed in the right panel.


Coronary blood flow determinations


Because of the inherent limitations of coronary angiography, attention has been directed to using physiological approaches for determining the severity of coronary stenoses. The 5 methods of measuring human coronary blood flow in the cardiac catheterization laboratory are (1) thermodilution, (2) digital subtraction angiography, (3) electromagnetic flow meters, (4) Doppler velocity probes (for measuring CFR), and (5) pressure wires (for measuring fractional flow reserve [FFR]). Although most current methods measure relative changes in coronary blood flow, useful information about the physiological significance of stenosis, cardiac hypertrophy, and pharmacological interventions can be obtained from these measurements.

Doppler
Doppler velocity probes use a Doppler flow meter, which is based on the principle of the Doppler effect. This is the most widely applied technique for measuring coronary flow in humans. High-frequency sound waves are reflected from moving red blood cells and undergo a shift in sound frequency proportional to the velocity of the blood flow.

In pulsed-wave Doppler methods, a single piezoelectric crystal can both transmit and receive high-frequency sound waves. These methods have been successfully applied in humans by using miniaturized crystals fixed to the tip of catheters. Technological developments have further miniaturized steerable 12-MHz Doppler guidewires to a diameter of 0.014 inches.

Flow to a stenosis can therefore be assessed distally and proximally. The Doppler guidewire measures phasic flow velocity patterns and tracks linearly with flow rates in small, straight coronary arteries.

Indications for Doppler velocity probe use include determining the severity of intermediate stenosis (40-60%) and evaluating whether normal blood flow has been restored after PTCA.

The use of smaller Doppler catheters allows measurement of selective coronary artery flow velocity. By noting the increase in flow velocity following administration of a strong coronary vasodilator, such as papaverine or adenosine, the CFR can be defined. CFR provides an index of the functional significance of coronary lesions that obviates some of the ambiguity of anatomical description.

The current Doppler probe method has limitations. Limitations include (1) only changes in flow velocity, rather than absolute velocity or volumetric flow, are measurable; (2) the change in flow velocity is directly proportional to changes in volumetric flow only when vessel dimensions are constant at the site of the sample volume; (3) other factors, including left ventricular hypertrophy and myocardial scarring, can also affect CFR; and (4) changes in luminal diameter and arterial cross-sectional area during interventions are not reflected in measurements of flow velocity, thus potentially causing underestimation of the true volume flow.

In summary, Doppler wires have a miniaturized Doppler crystal placed at the tip of an angioplasty guidewire, permitting measurement of phasic and mean coronary blood flow velocities. Because this technique does not measure absolute coronary blood flow, several indices of flow velocity have been used for assessing the physiological significance of coronary stenoses. Coronary flow velocity reserve is the ratio of maximum flow velocity to baseline flow velocity.

Patients with a coronary flow velocity ratio of less than 2 typically have other corroborating evidence of myocardial ischemia and improve symptomatically with revascularization. Conversely, patients with a ratio of more than 2 usually lack other objective evidence of myocardial ischemia and have a favorable outcome with conservative management; therefore, flow velocity measurements can be helpful in the treatment of patients with coronary lesions of intermediate severity. The diastolic-to-systolic velocity ratio has also been used to evaluate stenosis severity. In normal arteries, diastolic flow velocity far exceeds systolic velocity; however, the two are more equal distal to significant stenoses. A ratio of less than 1.7 has been used to define significant coronary lesions.

During coronary interventions, the Doppler guidewire can be used to judge the adequacy with which stenosis severity has been reduced. Patients with higher CFRs at completion of the procedure have a lower prevalence of abrupt reocclusion and restenosis.

rCFR
rCFR is calculated as follows: ([rCFR] = CFR target/CFR reference). rCFR involves Doppler coronary flow measurements of target and reference vessel CFR with a Doppler-tipped guidewire. Compared with patients who have negative stress imaging study findings, patients who have positive stress study findings showed more angiographically severe stenoses (74% +/- 13% vs 44% +/- 24%; P = .0005) with lower target CFRs (1.68 +/- 0.55 vs 2.46 +/- 0.74; P = .002) and lower rCFRs (0.72 +/- 0.22 vs 1 +/- 0.26; P <.003).15

Based on cut points (CFR >1.9; rCFR >0.75), compared with CFR, rCFR had similar agreement (kappa 0.54 vs 0.5), sensitivity (63% vs 71%), specificity (88% vs 83%), and positive predictive value (83% vs 81%) with myocardial perfusion tomography.

Although rCFR, as with CFR, correlates with stress myocardial perfusion imaging results, rCFR did not have significant incremental prognostic value over CFR alone for myocardial perfusion imaging. However, rCFR does provide additional information regarding the status of the microcirculation in patients with CAD and complements the CFR for lesion assessment.

FFR
With regard to FFR, the measurement of pressure gradients across coronary stenoses was originally advocated to assess the results of coronary angioplasty. Owing to the large profile of catheters used, this technique was never widely applied. However, new technology using 0.018-inch guidewires to assess pressure gradients across stenoses has been introduced.

Myocardial FFR has been used as an index of functional severity of coronary artery stenosis.

Pressure gradients are determined by measuring the ratio of the mean pressure distal to a coronary stenosis compared with that proximal to the stenosis. The proximal stenosis is measured through the tip of the guiding catheter, and the distal pressure is measured through the tip of the guidewire. Maximal vasodilation is induced by intracoronary administration of either adenosine or papaverine.

FFR is calculated from the ratio of the mean pressure distal to a coronary stenosis to the mean aortic pressure during maximal hyperemia. If the FFR is less than 0.75, sensitivity is at least 80% and specificity is at least 85% for an abnormal exercise test result.

Pressure wire measurement has been less well validated than Doppler flow reserve measurement; however, early studies indicate improved clinical utility owing to the ease of use and the reproducibility of results.

In summary, myocardial FFR is a recently developed index of the functional severity of coronary stenoses that is calculated only from simultaneous pressure measurements proximally and distally to a stenosis obtained with a pressure monitoring guidewire.

FFR represents the fraction of the normal maximal coronary flow that can be achieved in an artery in which flow is restricted by a coronary stenosis. The concept of FFR is founded in the previously noted observation that myocardial perfusion is entirely pressure dependent during maximal hyperemia.

Maximal blood flow in the presence of a stenosis is therefore determined by the driving pressure distal (Pd) to the stenosis, whereas the theoretical normal maximal blood flow is determined by the pressure proximal (Pp) to the stenosis. FFR is calculated during maximal hyperemia (obtained with adenosine or papaverine) as FFR = Pd/Pp. FFR less than 0.75 is typically associated with other objective evidence of myocardial ischemia.

Measurement of FFR in patients with coronary stenoses of moderate severity has been shown to be a useful index of the functional severity of the stenoses and the need for coronary revascularization. Measurement of FFR can also guide the adequacy of reducing coronary stenosis severity with balloon angioplasty or stenting.

Intravascular ultrasound

  • IVUS demonstrates the luminal dimensions and, more importantly, the tissue composition of the vascular wall in tomographic subsegments that can be summated to create a 3-dimensional picture showing arterial remodeling and the diffuseness of atherosclerosis with clarity unobtainable by angiography (luminography).
  • IVUS delineates vascular remodeling—both positive (Glagov phenomenon) and negative. Positive remodeling shows adaptive outward expansion of the external elastic membrane to accommodate growing plaques. Negative remodeling exhibits discrete areas of vascular luminal encroachment by the ingrowing plaques.
  • In a 2000 IVUS study of 85 subjects, Schoenhagen and colleagues demonstrated that positive remodeling is more commonly associated with unstable angina, whereas negative remodeling is associated with stable angina.16
  • The apparently paradoxical findings of angiographic studies suggesting that AMI most often occurs in less than 50% of stenosed arterial segments, and those of autopsy studies showing AMI to be associated with large plaques, are reconciled by IVUS findings. IVUS shows the responsible lesions to be large plaques that have positively remodeled, thus causing minimal luminal encroachment and exhibiting echolucency suggesting a lipid-rich pool in the plaque center.
  • The ability of IVUS to identify positively remodeled plaques and the presence of diffuse disease in some ways makes it better than angiography, the less-than-perfect criterion standard. IVUS can much more clearly demonstrate the presence or absence of fibrosis, calcium, and ulceration, as well as eccentricity of the plaques.
  • Ostial lesions can also be better defined by IVUS.

Stenosis severity and clinical events

  • The severity of stenoses and their propensity to cause MI, unstable angina, or sudden coronary death are poorly correlated.
  • Pathologic and angiographic studies have revealed that MIs and unstable angina are most often caused by rupture of atherosclerotic plaques with formation of a superimposed occlusive thrombus.
  • Most atherosclerotic lesions responsible for these serious events are mild stenoses of inconsequential hemodynamic significance and are characterized by an abundance of lipid, numerous inflammatory cells, and a thin, fragile fibrous cap.
  • These observations suggest that although measurements of CFR may be useful in the assessment of the severity of stenoses and in the identification of lesions responsible for effort angina, they are not likely to identify the more dangerous plaques responsible for unstable angina, AMI, and sudden ischemic death.

More on Coronary Artery Atherosclerosis

Overview: Coronary Artery Atherosclerosis
Differential Diagnoses & Workup: Coronary Artery Atherosclerosis
Treatment & Medication: Coronary Artery Atherosclerosis
Follow-up: Coronary Artery Atherosclerosis
Multimedia: Coronary Artery Atherosclerosis
References
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Further Reading

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Keywords

coronary heart disease, heart disease, atherosclerosis, hardening of the arteries, heart attack, atherosclerotic coronary artery disease, myocardial ischemia, myocardial infarction, acute coronary syndrome, ACS, congestive heart failure

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Contributor Information and Disclosures

Author

Vibhuti N Singh, MD, MPH, FACC, FSCAI, Director, Suncoast Cardiovascular Center; Chair, Cardiology Division and Cath Labs, Department of Medicine, Bayfront Medical Center; Clinical Assistant Professor, Division of Cardiology, University of South Florida College of Medicine
Vibhuti N Singh, MD, MPH, FACC, FSCAI is a member of the following medical societies: American College of Cardiology, American College of Physicians, American Heart Association, American Medical Association, and Florida Medical Association
Disclosure: Nothing to disclose.

Coauthor(s)

Prakash C Deedwania, MD, FACC, FAHA, FACP, FCCP, Professor of Medicine, University of California, San Francisco School of Medicine; Chief, Cardiology Section, Veterans Affairs Medical Center, UCSF Program at Fresno, California; Director, Cardiovascular Research, UCSF Central San Joaquin Program
Prakash C Deedwania, MD, FACC, FAHA, FACP, FCCP is a member of the following medical societies: American Association for the Advancement of Science, American Association of Physicians of Indian Origin, American College of Cardiology, American College of Chest Physicians, American College of Physicians, American Federation for Clinical Research, American Heart Association, American Society for Clinical Pharmacology and Therapeutics, American Society of Hypertension, American Thoracic Society, Heart Failure Society of America, and New York Academy of Sciences
Disclosure: Nothing to disclose.

Rakesh K Sharma, MD, FACC, Adjunct Associate Professor of Medicine and Cardiology; University of Arkansas for Medical Sciences, Medical Center of South Arkansas
Rakesh K Sharma, MD, FACC is a member of the following medical societies: American College of Cardiology, American College of International Physicians, American College of Physicians, American Heart Association, and American Medical Association
Disclosure: Nothing to disclose.

Medical Editor

George A Stouffer III, MD, Henry A Foscue Distinguished Professor of Medicine and Cardiology, Director of Interventional Cardiology, Cardiac Catheterization Laboratory, Chief of Clinical Cardiology, Division of Cardiology, University of North Carolina Medical Center
George A Stouffer III, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Cardiology, American College of Physicians, American Heart Association, Phi Beta Kappa, and Society for Cardiac Angiography and Interventions
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

Marschall S Runge, MD, PhD, Charles and Anne Sanders Distinguished Professor of Medicine, Chairman, Department of Medicine, Vice Dean for Clinical Affairs, University of North Carolina at Chapel Hill School of Medicine
Marschall S Runge, MD, PhD is a member of the following medical societies: American Association for the Advancement of Science, American College of Cardiology, American College of Physicians-American Society of Internal Medicine, American Federation for Clinical Research, American Federation for Medical Research, American Heart Association, American Physiological Society, American Society for Clinical Investigation, American Society for Investigative Pathology, Association of American Physicians, Association of Professors of Cardiology, Association of Professors of Medicine, Southern Society for Clinical Investigation, and Texas Medical Association
Disclosure: Pfizer Honoraria Speaking and teaching; Merck Honoraria Speaking and teaching; Orthoclinica Diagnostica Consulting fee Consulting

CME Editor

Amer Suleman, MD, Consultant in Electrophysiology and Cardiovascular Medicine, Department of Internal Medicine, Division of Cardiology, Medical City Dallas Hospital
Amer Suleman, MD is a member of the following medical societies: American College of Physicians, American Heart Association, American Institute of Stress, American Society of Hypertension, Federation of American Societies for Experimental Biology, Royal Society of Medicine, and Society of Cardiac Angiography and Interventions
Disclosure: Nothing to disclose.

Chief Editor

Yasmine Subhi Ali, MD, MSCI, Assistant Professor of Medicine, Director of Preventive Cardiology, Director of Echocardiography, Meharry Medical College; Assistant Clinical Professor of Medicine, Vanderbilt University School of Medicine
Yasmine Subhi Ali, MD, MSCI is a member of the following medical societies: American College of Cardiology, American College of Physicians, American Heart Association, American Medical Association, American Society of Echocardiography, American Society of Nuclear Cardiology, and National Lipid Association
Disclosure: Pfizer I own a small number of shares of Pfizer stock. These were NOT given to me by Pfizer, but rather purchased by myself as a personal investor for my diversified investment portfolio. None

 
 
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