Coronary heart disease

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Coronary heart disease (CHD), also called coronary artery disease (CAD), is a vascular disease caused by abnormalities the arteries that supply the heart with blood (called the coronary arteries). The usual cause of coronary heart disease is atherosclerosis.

Etiology/cause

The cause and manifestation of coronary heart disease is multifactorial. About 3/4 of the risk of coronary heart disease is due to three risk factors: hypercholesterolemia (total cholesterol > 182 mg/dL [4.71 mmol/L]), hypertension (diastolic blood pressure > 90 mm Hg), and cigarette smoking.[1]

Atherosclerosis

For more information, see: Atherosclerosis.

Atherosclerosis is a degenerative disease of the arterial walls, in which the normal elastic walls of the arteries become thickened and replaced with deposits of fatty material, including cholesterol. As the walls of the affected arteries thicken, the hollow lumen at the center of each, that conduit through which oxygen enriched blood normally pulses, becomes narrower and, eventually, the flow of blood within it is decreased. With narrowing of the artery's lumen and reduced flow comes the risk of sudden occlusion of the artery, especially if the lining is abnormally roughened by deposits of irregular plaques of minerals and fats. However, the site of current stenoses does not predict the site of a subsequent myocardial infarction.[2]

About 10% of patients with chronic angina have atherosclerosis of the left main coronary artery.[3][4] In males over age 70 with definite angina, almost 50% have obstruction of the left main coronary artery.[4]

The extent of coronary obstructions can be quantified with:

Plaque rupture and inflammation

Rupture of atherosclerotic plaques may cause acute coronary syndrome. Inflammation may underlay the association between elevated C-reactive protein levels and coronary heart disease.

Surprisingly, more fatal ruptures occur on plaques that are not severely stenosed.[7][8][9]

Periodontal disease may contribute to this inflammation.[10][11] Poor oral hygiene is associated with elevated C-reactive protein and fibrinogen.[11]

Coronary vasospasm

Approximately 15% of NSTEMI and 2% of STEMI patients have no obstruction of coronary arteries and in about half of these patients, spasm of a coronary artery can be induced.[12]

Syndrome X

Cardiac syndrome X is the presence of typical angina, abnormal exercise-test results, and normal coronary arteries (including no vasospasm).[13] Syndrome X may be caused by subendocardial hypoperfusion that can be demonstrated by cardiovascular magnetic resonance imaging during the administration of adenosine.[13]

Hyperuricemia

For more information, see: Hyperuricemia.

Hyperuricemia has been proposed as contributing to coronary heart disease.

Diagnosis

History, physical examination, and risk factors

Angina pectoris, or simply angina, is the chest pain due to coronary heart disease; however, most patients do not report angina.[14] The nature of the chest pain affects the probability of underlying coronary disease.[15]

The likeilood of coronary heart disease is associated with the number of risk factors and the nature of chest pain.[16][17] A table of probabilities is available online.

The Pryor nomogram, a clinical prediction rule, can help diagnose patients with suspected chest pain in a non emergent setting.[18][19]

Cardiac stress test

For more information, see: Stress test.
Sensitivity and specificity of cardiac stress tests[20]
  Sensitivity Specificity
Exercise electrocardiography 68% 77%
Stress echocardiography 76% 88%
Myocardial perfusion imaging
thallium planar 		79% 73%
Myocardial perfusion imaging
single-photon emission computed tomography (SPECT) 		88% 77%
Positron emission tomography (PET), 68% 77%

The sensitivity and specificity of the various cardiac stress tests have been summarized.[20]

Exercise treadmill test

The exercise treadmill test (ETT) can help diagnose and prognose patients with suspected CHD. The likelihood of a positive treadmill test depends on the severity of the underlying coronary disease.[3] For example, 87% of patients with obstruction of the left main coronary artery will have a positive treatmill test, whereas only 57% of patients with obstructions of one or two of the other coronaries will have a positive treadmill test. The treadmill can help predict the location of coronary stenoses.[21]

Stress myocardial perfusion imaging

Stress echocardiography

Stress ventriculography

Diagnostic imaging

Several types of imaging, ranging from noninvasive to minimally invasive to invasive, can assess the degree of CHD. They include techniques using radiation transmitted through the body, imaging of radioisotopes in the body, or imaging using other mechanisms such as MRI and ultrasonography.

Most are performed before and after cardiac stress, which may be induced either by controlled exercise or pharmacologically, with drugs that stimulate the heart.

Techniques

Electron beam computed tomography

Electron beam computed tomography (EBCT) is also called ultrafast CT.

Cardiac computed tomographic angiography
For more information, see: Computed tomographic cardiac angiography.

Computed tomographic cardiac angiography has accuracy of:[22]

Single-Photon Emission-Computed Tomography
Stress echocardiography

Ultrasound-based echocardiography has long been a preferred method for assessing valvular function. cardiac output and wall movement, but, especially with the use of ultrasound-appropriate contrast media, allows better vascular visualization.

Cardiac catheterization and angiography

Indications for renal arteriography at the time of coronary arteriography have been summarized.[23]

Magnetic resonance imaging

Magnetic resonance imaging has accuracy of:[22]

Evaluation: Coronary calcium score

Both types of computed tomography, electron beam computed tomography (EBCT) and multidetector spiral computed tomography, can measure the amount of calcium in the walls of the coronary arteries in order to diagnose coronary heart disease.

Clinical practice guidelines conflict regarding the role of the coronary calcium score. The U.S. Preventive Services Task Force[24] does not endorse using the score while the American Heart Association[25] does endorse the score. The Task Force that the best study was still compromised by using volunteers rather than being community based.[26]

Treatment

Medications

Ranolazine may increased exercise capacity and reduce symptoms[27] but not reduce cardiac events.[28]

Adrenergic beta-antagonists

Adrenergic beta-antagonists were first shown to be effective in 1981.[29]

Invasive treatments

For more information, see: myocardial revascularization.

Patient who have a left ventricular ejection fraction above 50%, no angina or their angina is controlled with medicines, do not benefit from either percutaneous transluminal coronary angioplasty (PCI)[30] or from coronary artery bypass surgery[31].

Coronary artery bypass versus percutaneous transluminal coronary angioplasty[32]
  Outcomes at 5 years Procedural related stroke
Relief of angina Repeat revascularization
CABG 84% 10% 1.2%
PTCA 79% With stents 40%
Without stents 46%		 0.6%
Abbreviations:
CABG. Coronary artery bypass grafting
PTCA. Percutaneous transluminal coronary angioplasty

Regarding patients who must undergo invasive treatment, a systematic review comparing percutaneous transluminal coronary angioplasty and coronary artery bypass grafting (CABG) surgery found that CABG was more effective but was more likely to be complicated by stroke.[32]

Percutaneous cardiac intervention

For more information, see: Percutaneous transluminal coronary angioplasty.

Patient who have a stable angina and left ventricular ejection fraction above 35% do not reduce mortality from percutaneous transluminal coronary angioplasty (PCI)[33] although there is some reduction in angina for the first one to three years after procedure and few patients received stents[34][35][33]. The relief from angina, as compared to relief from medical therapy, may be reduced when evidence-based medications are used.[30]

Patients are more likely to benefit from PCI when clinical practice guidelines are followed.[36]

Stents

Meta-anlayses have found that the rate of late thrombosis was <2% between years 1 and 4.[37][38][39]

Coronary artery bypass

For more information, see: Coronary artery bypass.


Patient who have a left ventricular ejection fraction between 35 and 49 percent benefit from coronary artery bypass if they have disease of three coronary arteries.[31].

Complications

Acute coronary syndrome

For more information, see: Acute coronary syndrome.

Prognosis

See also: Vascular disease#Prognosis

Coronary calcium score

Coronary calcium score for predicting myocardial infarction or death from coronary heart disease amond 6814 persons without known cardiovascular disease[40]
Score Number of patients Hazard ratio
0 8/3409 1.0
1-100 25/1728 3.9
101-300 24/752 7.1
> 300 32/833 6.8

Both types of computed tomography, electron beam computed tomography (EBCT) and multidetector spiral computed tomography, can measure the amount of calcium in the walls of the coronary arteries in order to estimate prognosis. The calcium score improves upon using clinical risk factors for prognosticating. [40] Using clinical risk factors alone, the area under the receiver operating-characteristic curve (AUC) was 0.79 while the AUC rose to 0.83 when the calcium score was added. The clinical importance of this rise is not clear.[41]

A more recent cohort study found that the calcium score added to traditional risk factors in predicting cardiac outcomes.[42] The Net reclassification improvement was 25%.

Cardiac stress test

Various cardiac stress tests are available.

Exercise treadmill test

The exercise treadmill test (ETT) can help diagnose and prognose patients with suspected CHD. Clinical prediction rules are available to help interpret the results of the ETT. These rules are the Duke Treadmill score[43] and the newer Cleveland Clinic model[44]. The Duke score has been more extensively studied; however, in a direct comparison by the authors of the Cleveland Clinic model, the latter performed better (c-index: 0.83 vs. 0.73).[44]

The ETT adds to clinical risk factors in prediction complications. The area under the receiver-operator-characteristics-curve (AUC) for clinical data alone is 0.798 and rises to 0.857 when the ETT is added.[43]

The ETT also adds to the cardiac catheterization in prognosticating[45][46][47] although some researchers have questioned the extent of information provided by the treadmill test[17]. However, in one study among information available from cardiac catheterization, only the left ventricular ejection fraction contributed to the ETT in predicting complications[47] whereas in another study, both the left ventricular ejection fraction and the number of stenoses aided prediction[45].

Cardiac catheterization

Rates of occlusion after 4-5 years[48]
Severity of original stenosis Rate of subsequent occlusion
No stenosis 0.7%
5% to 49% 2.3%
50% to 80% 10.1%
81% to 95% 23.6%

Much research has addressed the association between severity of coronary obstructions and subsequent complications such as myocardial infarctions. Coronary obstructions are more likely to progress or occlude within 4-5 years if the obstructions are severe according to the CASS investigation.[48] 23% of subsequent occlusions were associated with a myocardial infarction. The cholesterol level or the exercise test did not improve the ability to prediction occlusion in the CASS investigation.

Surprisingly, while patients with more severe stenoses are more likely to develop occlusions predicting the exact site of furture occlusions is very difficult. Most subsequent occlusions occur in arteries that originally did not have severe stenoses and were originally not the most severely stenotic arteries in a patient.[2][49][50][51]

In addition, when occlusions develop in severely stenotic vessels, these occlusions may be less likely to cause a myocardial infarction.[51]

In summary, the concept of which coronary stenoses are vulnerable to subsequent plaque rupture and occlusion many be more important that the degree of stenosis of a vessel.[52]

Screening

Asymptomatic adults should not be screened for coronary artery disease with an electrocardiogram.[53]

Prevention

For more information, see: Vascular disease#Prevention.


References

  1. ↑ Magnus P, Beaglehole R (2001). "The real contribution of the major risk factors to the coronary epidemics: time to end the "only-50%" myth". Arch. Intern. Med. 161 (22): 2657–60. PMID 11732929. [e]
  2. ↑ 2.0 2.1 Little WC, Constantinescu M, Applegate RJ, Kutcher MA, Burrows MT, Kahl FR et al. (1988). "Can coronary angiography predict the site of a subsequent myocardial infarction in patients with mild-to-moderate coronary artery disease?". Circulation 78 (5 Pt 1): 1157-66. PMID 3180375. [e]
  3. ↑ 3.0 3.1 Lee TH, Fukui T, Weinstein MC, Tosteson AN, Goldman L (1988). "Cost-effectiveness of screening strategies for left main coronary artery disease in patients with stable angina". Med Decis Making 8 (4): 268–78. PMID 3141736. [e]
  4. ↑ 4.0 4.1 Chaitman BR, Bourassa MG, Davis K, et al (August 1981). "Angiographic prevalence of high-risk coronary artery disease in patient subsets (CASS)". Circulation 64 (2): 360–7. PMID 7249303. [e]
  5. ↑ Valgimigli M, Serruys PW, Tsuchida K, et al (April 2007). "Cyphering the complexity of coronary artery disease using the syntax score to predict clinical outcome in patients with three-vessel lumen obstruction undergoing percutaneous coronary intervention". Am. J. Cardiol. 99 (8): 1072–81. DOI:10.1016/j.amjcard.2006.11.062. PMID 17437730. Research Blogging.
  6. ↑ Mark DB, Nelson CL, Califf RM, et al (May 1994). "Continuing evolution of therapy for coronary artery disease. Initial results from the era of coronary angioplasty". Circulation 89 (5): 2015–25. PMID 8181125. [e]
  7. ↑ Mann JM, Davies MJ (1996). "Vulnerable plaque. Relation of characteristics to degree of stenosis in human coronary arteries.". Circulation 94 (5): 928-31. PMID 8790027. [e]
  8. ↑ Kolodgie FD, Virmani R, Burke AP, Farb A, Weber DK, Kutys R et al. (2004). "Pathologic assessment of the vulnerable human coronary plaque.". Heart 90 (12): 1385-91. DOI:10.1136/hrt.2004.041798. PMID 15547008. PMC PMC1768577. Research Blogging.
  9. ↑ Virmani R, Kolodgie FD, Burke AP, Farb A, Schwartz SM (2000). "Lessons from sudden coronary death: a comprehensive morphological classification scheme for atherosclerotic lesions.". Arterioscler Thromb Vasc Biol 20 (5): 1262-75. PMID 10807742. [e]
  10. ↑ Humphrey LL, Fu R, Buckley DI, Freeman M, Helfand M (December 2008). "Periodontal disease and coronary heart disease incidence: a systematic review and meta-analysis". J Gen Intern Med 23 (12): 2079–86. DOI:10.1007/s11606-008-0787-6. PMID 18807098. Research Blogging.
  11. ↑ 11.0 11.1 de Oliveira C, Watt R, Hamer M (2010). "Toothbrushing, inflammation, and risk of cardiovascular disease: results from Scottish Health Survey.". BMJ 340: c2451. DOI:10.1136/bmj.c2451. PMID 20508025. Research Blogging.
  12. ↑ Ong P, Athanasiadis A, Hill S, Vogelsberg H, Voehringer M, Sechtem U (August 2008). "Coronary artery spasm as a frequent cause of acute coronary syndrome: The CASPAR (Coronary Artery Spasm in Patients With Acute Coronary Syndrome) Study". J. Am. Coll. Cardiol. 52 (7): 523–7. DOI:10.1016/j.jacc.2008.04.050. PMID 18687244. Research Blogging.
  13. ↑ 13.0 13.1 Panting JR, Gatehouse PD, Yang GZ, et al (June 2002). "Abnormal subendocardial perfusion in cardiac syndrome X detected by cardiovascular magnetic resonance imaging". N. Engl. J. Med. 346 (25): 1948–53. DOI:10.1056/NEJMoa012369. PMID 12075055. Research Blogging.
  14. ↑ Gehi AK, Ali S, Na B, Schiller NB, Whooley MA (July 2008). "Inducible ischemia and the risk of recurrent cardiovascular events in outpatients with stable coronary heart disease: the heart and soul study". Arch. Intern. Med. 168 (13): 1423–8. DOI:10.1001/archinte.168.13.1423. PMID 18625923. Research Blogging.
  15. ↑ Swap CJ, Nagurney JT (2005). "Value and limitations of chest pain history in the evaluation of patients with suspected acute coronary syndromes". JAMA 294 (20): 2623–9. DOI:10.1001/jama.294.20.2623. PMID 16304077. Research Blogging.
  16. ↑ Diamond GA, Forrester JS (1979). "Analysis of probability as an aid in the clinical diagnosis of coronary-artery disease.". N Engl J Med 300 (24): 1350-8. DOI:10.1056/NEJM197906143002402. PMID 440357. Research Blogging.
  17. ↑ 17.0 17.1 Weiner DA, Ryan TJ, McCabe CH, Kennedy JW, Schloss M, Tristani F et al. (1979). "Exercise stress testing. Correlations among history of angina, ST-segment response and prevalence of coronary-artery disease in the Coronary Artery Surgery Study (CASS).". N Engl J Med 301 (5): 230-5. DOI:10.1056/NEJM197908023010502. PMID 449990. Research Blogging.
  18. ↑ Pryor DB, Shaw L, McCants CB, et al (1993). "Value of the history and physical in identifying patients at increased risk for coronary artery disease". Ann. Intern. Med. 118 (2): 81–90. PMID 8416322. [e] Online calculator
  19. ↑ Pryor DB, Harrell FE, Lee KL, Califf RM, Rosati RA (1983). "Estimating the likelihood of significant coronary artery disease". Am. J. Med. 75 (5): 771–80. PMID 6638047. [e]
  20. ↑ 20.0 20.1 Garber AM, Solomon NA (May 1999). "Cost-effectiveness of alternative test strategies for the diagnosis of coronary artery disease". Ann. Intern. Med. 130 (9): 719–28. PMID 10357690. [e]
  21. ↑ Mark DB, Hlatky MA, Lee KL, Harrell FE, Califf RM, Pryor DB (January 1987). "Localizing coronary artery obstructions with the exercise treadmill test". Ann. Intern. Med. 106 (1): 53–5. PMID 3789578. [e]
  22. ↑ 22.0 22.1 Schuetz GM, Zacharopoulou NM, Schlattmann P, Dewey M (2010). "Meta-analysis: noninvasive coronary angiography using computed tomography versus magnetic resonance imaging.". Ann Intern Med 152 (3): 167-77. DOI:10.1059/0003-4819-152-3-201002020-00008. PMID 20124233. Research Blogging.
  23. ↑ White CJ, Jaff MR, Haskal ZJ, Jones DJ, Olin JW, Rocha-Singh KJ et al. (2006). "Indications for renal arteriography at the time of coronary arteriography: a science advisory from the American Heart Association Committee on Diagnostic and Interventional Cardiac Catheterization, Council on Clinical Cardiology, and the Councils on Cardiovascular Radiology and Intervention and on Kidney in Cardiovascular Disease.". Circulation 114 (17): 1892-5. DOI:10.1161/CIRCULATIONAHA.106.178777. PMID 17030686. Research Blogging.
  24. ↑ Helfand M, Buckley DI, Freeman M, Fu R, Rogers K, Fleming C et al. (2009). "Emerging risk factors for coronary heart disease: a summary of systematic reviews conducted for the U.S. Preventive Services Task Force.". Ann Intern Med 151 (7): 496-507. PMID 19805772.
  25. ↑ Greenland P, Bonow RO, Brundage BH, Budoff MJ, Eisenberg MJ, Grundy SM et al. (2007). "ACCF/AHA 2007 clinical expert consensus document on coronary artery calcium scoring by computed tomography in global cardiovascular risk assessment and in evaluation of patients with chest pain: a report of the American College of Cardiology Foundation Clinical Expert Consensus Task Force (ACCF/AHA Writing Committee to Update the 2000 Expert Consensus Document on Electron Beam Computed Tomography).". Circulation 115 (3): 402-26. DOI:10.1161/CIRCULATIONAHA..107.181425. PMID 17220398. Research Blogging.
  26. ↑ Greenland P, LaBree L, Azen SP, Doherty TM, Detrano RC (2004). "Coronary artery calcium score combined with Framingham score for risk prediction in asymptomatic individuals.". JAMA 291 (2): 210-5. DOI:10.1001/jama.291.2.210. PMID 14722147. Research Blogging.
  27. ↑ Chaitman BR et al. Effects of ranolazine with atenolol, amlodipine, or diltiazem on exercise tolerance and angina frequency in patients with severe chronic angina: a randomized controlled trial. Combination Assessment of Ranolazine In Stable Angina (CARISA) Investigators. JAMA. 2004 Jan 21;291(3):309-16. PMID: 14734593
  28. ↑ Morrow et al; MERLIN-TIMI 36 Trial Investigators. Effects of ranolazine on recurrent cardiovascular events in patients with non-ST-elevation acute coronary syndromes: the MERLIN-TIMI 36 randomized trial. JAMA. 2007 Apr 25;297(16):1775-83. PMID: 17456819
  29. ↑ (April 1981) "Timolol-induced reduction in mortality and reinfarction in patients surviving acute myocardial infarction". N. Engl. J. Med. 304 (14): 801–7. PMID 7010157. [e]
  30. ↑ 30.0 30.1 Wijeysundera HC, Nallamothu BK, Krumholz HM, Tu JV, Ko DT (2010). "Meta-analysis: effects of percutaneous coronary intervention versus medical therapy on angina relief.". Ann Intern Med 152 (6): 370-9. DOI:10.1059/0003-4819-152-6-201003160-00007. PMID 20231568. Research Blogging.
  31. ↑ 31.0 31.1 (March 1984) "Myocardial infarction and mortality in the coronary artery surgery study (CASS) randomized trial". N. Engl. J. Med. 310 (12): 750–8. PMID 6608052. “This is the CASS randomized controlled trial.” [e]
  32. ↑ 32.0 32.1 Bravata DM, Gienger AL, McDonald KM, et al (2007). "Systematic Review: The Comparative Effectiveness of Percutaneous Coronary Interventions and Coronary Artery Bypass Surgery". Ann Intern Med. PMID 17938385. [e]
  33. ↑ 33.0 33.1 Boden WE, O'Rourke RA, Teo KK, et al (April 2007). "Optimal medical therapy with or without PCI for stable coronary disease". N. Engl. J. Med. 356 (15): 1503–16. DOI:10.1056/NEJMoa070829. PMID 17387127. Research Blogging. “This is the COURAGE randomized controlled trial.”
  34. ↑ Hochman JS, Lamas GA, Buller CE, Dzavik V, Reynolds HR, Abramsky SJ et al. (2006). "Coronary intervention for persistent occlusion after myocardial infarction.". N Engl J Med 355 (23): 2395-407. DOI:10.1056/NEJMoa066139. PMID 17105759. PMC PMC1995554. Research Blogging.
  35. ↑ Weintraub WS, Spertus JA, Kolm P, et al (August 2008). "Effect of PCI on quality of life in patients with stable coronary disease". N. Engl. J. Med. 359 (7): 677–87. DOI:10.1056/NEJMoa072771. PMID 18703470. Research Blogging. (see Table 3 in the article)
  36. ↑ Anderson HV, Shaw RE, Brindis RG, et al (November 2005). "Relationship between procedure indications and outcomes of percutaneous coronary interventions by American College of Cardiology/American Heart Association Task Force Guidelines". Circulation 112 (18): 2786–91. DOI:10.1161/CIRCULATIONAHA.105.553727. PMID 16267252. Research Blogging.
  37. ↑ Mauri L, Hsieh WH, Massaro JM, Ho KK, D'Agostino R, Cutlip DE (March 2007). "Stent thrombosis in randomized clinical trials of drug-eluting stents". N. Engl. J. Med. 356 (10): 1020–9. DOI:10.1056/NEJMoa067731. PMID 17296821. Research Blogging.
  38. ↑ Stone GW, Moses JW, Ellis SG, et al (March 2007). "Safety and efficacy of sirolimus- and paclitaxel-eluting coronary stents". N. Engl. J. Med. 356 (10): 998–1008. DOI:10.1056/NEJMoa067193. PMID 17296824. Research Blogging.
  39. ↑ Kastrati A, Mehilli J, Pache J, et al (March 2007). "Analysis of 14 trials comparing sirolimus-eluting stents with bare-metal stents". N. Engl. J. Med. 356 (10): 1030–9. DOI:10.1056/NEJMoa067484. PMID 17296823. Research Blogging.
  40. ↑ 40.0 40.1 Detrano R, Guerci AD, Carr JJ, et al (March 2008). "Coronary calcium as a predictor of coronary events in four racial or ethnic groups". N. Engl. J. Med. 358 (13): 1336–45. DOI:10.1056/NEJMoa072100. PMID 18367736. Research Blogging.
  41. ↑ Weintraub WS, Diamond GA (March 2008). "Predicting cardiovascular events with coronary calcium scoring". N. Engl. J. Med. 358 (13): 1394–6. DOI:10.1056/NEJMe0800676. PMID 18367744. Research Blogging.
  42. ↑ Polonsky TS, McClelland RL, Jorgensen NW, Bild DE, Burke GL, Guerci AD et al. (2010). "Coronary artery calcium score and risk classification for coronary heart disease prediction.". JAMA 303 (16): 1610-6. DOI:10.1001/jama.2010.461. PMID 20424251. Research Blogging.
  43. ↑ 43.0 43.1 Mark DB, Shaw L, Harrell FE, et al (1991). "Prognostic value of a treadmill exercise score in outpatients with suspected coronary artery disease". N. Engl. J. Med. 325 (12): 849–53. PMID 1875969. [e]
  44. ↑ 44.0 44.1 Lauer MS, Pothier CE, Magid DJ, Smith SS, Kattan MW (2007). "An externally validated model for predicting long-term survival after exercise treadmill testing in patients with suspected coronary artery disease and a normal electrocardiogram". Ann. Intern. Med. 147 (12): 821–8. PMID 18087052. [e]
  45. ↑ 45.0 45.1 Weiner DA, Ryan TJ, McCabe CH, et al (March 1984). "Prognostic importance of a clinical profile and exercise test in medically treated patients with coronary artery disease". J. Am. Coll. Cardiol. 3 (3): 772–9. PMID 6229569. [e]
  46. ↑ Mark DB, Hlatky MA, Harrell FE, Lee KL, Califf RM, Pryor DB (June 1987). "Exercise treadmill score for predicting prognosis in coronary artery disease". Ann. Intern. Med. 106 (6): 793–800. PMID 3579066. [e]
  47. ↑ 47.0 47.1 Morris CK, Morrow K, Froelicher VF, et al (June 1993). "Prediction of cardiovascular death by means of clinical and exercise test variables in patients selected for cardiac catheterization". Am. Heart J. 125 (6): 1717–26. PMID 8498316. [e]
  48. ↑ 48.0 48.1 Alderman EL, Corley SD, Fisher LD, et al (October 1993). "Five-year angiographic follow-up of factors associated with progression of coronary artery disease in the Coronary Artery Surgery Study (CASS). CASS Participating Investigators and Staff". J. Am. Coll. Cardiol. 22 (4): 1141–54. PMID 8409054. [e]
  49. ↑ Giroud D, Li JM, Urban P, Meier B, Rutishauer W (March 1992). "Relation of the site of acute myocardial infarction to the most severe coronary arterial stenosis at prior angiography". Am. J. Cardiol. 69 (8): 729–32. PMID 1546645. [e]
  50. ↑ Glaser R, Selzer F, Faxon DP, et al (January 2005). "Clinical progression of incidental, asymptomatic lesions discovered during culprit vessel coronary intervention". Circulation 111 (2): 143–9. DOI:10.1161/01.CIR.0000150335.01285.12. PMID 15623544. Research Blogging.
  51. ↑ 51.0 51.1 Ambrose JA, Tannenbaum MA, Alexopoulos D, et al (July 1988). "Angiographic progression of coronary artery disease and the development of myocardial infarction". J. Am. Coll. Cardiol. 12 (1): 56–62. PMID 3379219. [e]
  52. ↑ Naghavi M, Libby P, Falk E, et al (October 2003). "From vulnerable plaque to vulnerable patient: a call for new definitions and risk assessment strategies: Part I". Circulation 108 (14): 1664–72. DOI:10.1161/01.CIR.0000087480.94275.97. PMID 14530185. Research Blogging.
  53. ↑ Moyer VA, on behalf of the U.S. Preventive Services Task Force* (2012). "Screening for Coronary Heart Disease With Electrocardiography: U.S. Preventive Services Task Force Recommendation Statement.". Ann Intern Med. DOI:10.7326/0003-4819-157-7-201210020-00514. PMID 22847227. Research Blogging.

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