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.

About 10% of patients with chronic angina have atherosclerosis of the left main coronary artery.[2][3] In males over age 70 with definite angina, almost 50% have obstruction of the left main coronary artery.[3]

The extent of coronary obstructions can be quantified with the Duke Coronary Artery Disease Index.[4]

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. Periodontal disease may contribute to this inflammation.[5]

Emotional stress

The role of emotional stress was supported in a study of the incidence of coronary events in the Munich area during the 2006 World Cup Football (soccer) championship.[6] The incidence of coronary events was higher during the match, especially for people who had pre-existing coronary disease. Stress, via increases in unhealthy behaviors, was also identified as more important than hypertension or C-reactive protein level in predicting coronary events.[7]

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.[8]

Syndrome X

Cardiac syndrome X is the presence of typical angina, abnormal exercise-test results, and normal coronary arteries (including no vasospasm).[9] Syndrome X may be caused by subendocardial hypoperfusion that can be demonstrated by cardiovascular magnetic resonance imaging during the administration of adenosine.[9]

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.[10] The nature of the chest pain affects the probability of underlying coronary disease.[11]

The Pryor nomogram, a clinical prediction rule, can help diagnose patients with suspected chest pain in a non emergent setting.[12][13]

Cardiac stress test

For more information, see: Stress test.
Sensitivity and specificity of cardiac stress tests[14]
  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.[14]

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.[2] 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.[15]

Stress myocardial perfusion imaging

Stress echocardiography

Stress ventriculography

X-ray computed tomography

There are two types of computed tomography used for noninvasive coronary arteriography.

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 (CT cardiac angiography) uses multidetector spiral computed tomography.[16][17][18] The physiologic significance of obstructions estimated to be 60% to 80% is difficult to predict.[19]

Accuracy using 64-row CT for detecting stenoses of 50%[20][21][22]
  Patients Per patient Per segment
Sensitivity Specificity Sensitivity Specificity
CORE 64 study.[20]
2008		 291 patients with suspected coronary heart disease and calcium scores ≤ 600 85% 90% 75% 93%
Meijboom et al.[21]
2008		 360 symptomatic patients 99% 64% 88% 90%
ACCURACY study.[22]
2008		 230 symptomatic patients 95% 83% 84% 90%

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 diease.

Treatment

Medications

Ranolazine may increased exercise capacity and reduce symptoms[23] but not reduce cardiac events.[24]

Adrenergic beta-antagonists

Adrenergic beta-antagonists were first shown to be effective in 1981.[25]

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)[26] or from coronary artery bypass surgery[27].


Coronary artery bypass versus percutaneous transluminal coronary angioplasty
  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.[28]

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)[26] although there is some reduction in angina for the first three years after procedure[29].

Patients are more likely to benefit from PCI when clinical practice guidelines are followed.[30]

Stents

Meta-anlayses have found that the rate of late thrombosis was <2% between years 1 and 4.[31][32][33]

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.[27].

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[34]
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. [34] 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.[35]

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[36] and the newer Cleveland Clinic model[37]. 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).[37]

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.[36]

The ETT also adds to the cardiac catheterization in prognosticating[38][39][40] although some researchers have questioned the extent of information provided by the treadmill test[41]. However, in one study among information available from cardiac catheterization, only the left ventricular ejection fraction contributed to the ETT in predicting complications[40] whereas in another study, both the left ventricular ejection fraction and the number of stenoses aided prediction[38].

Cardiac catheterization

Rates of occlusion after 4-5 years[42]
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.[42] 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.[43][44][45][46]

In addition, when occlusions develop in severely stenotic vessels, these occlusions may be less likely to cause a myocardial infarction.[46]

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.[47]

Prevention

For more information, see: Vascular disease#Prevention.

Coronary heart disease is the most common form of heart disease in the Western world. Prevention centers on the modifiable risk factors, which include decreasing cholesterol levels, addressing obesity and hypertension, avoiding a sedentary lifestyle, making healthy dietary choices, and stopping smoking. There is some evidence that lowering uric acid and homocysteine levels may contribute. In diabetes mellitus, there is little evidence that blood sugar control actually improves cardiac risk. Some recommend a diet rich in omega-3 fatty acids and vitamin C. The World Health Organization (WHO) recommends "low to moderate alcohol intake" to reduce risk of coronary heart disease.[48]

An increasingly growing number of other physiological markers and homeostatic mechanisms are currently under scientific investigation. Among these markers are low density lipoprotein and asymmetric dimethylarginine. Patients with CHD and those trying to prevent CHD are advised to avoid fats that are readily oxidized (e.g., saturated fats and trans-fats), limit carbohydrates and processed sugars to reduce production of Low density lipoproteins while increasing High density lipoproteins, keeping blood pressure normal, exercise and stop smoking. These measures limit the progression of the disease. Recent studies have shown that dramatic reduction in LDL levels can cause mild regression of coronary heart disease.

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 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]
  3. ↑ 3.0 3.1 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]
  4. ↑ 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]
  5. ↑ 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.
  6. ↑ Wilbert-Lampen U, Leistner D, Greven S, et al (2008). "Cardiovascular events during World Cup soccer". N. Engl. J. Med. 358 (5): 475–83. DOI:10.1056/NEJMoa0707427. PMID 18234752. Research Blogging.
  7. ↑ Hamer M, Molloy GJ, Stamatakis E (December 2008). "Psychological distress as a risk factor for cardiovascular events pathophysiological and behavioral mechanisms". J. Am. Coll. Cardiol. 52 (25): 2156–62. DOI:10.1016/j.jacc.2008.08.057. PMID 19095133. Research Blogging.
  8. ↑ 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.
  9. ↑ 9.0 9.1 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.
  10. ↑ 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.
  11. ↑ 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.
  12. ↑ 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
  13. ↑ 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]
  14. ↑ 14.0 14.1 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]
  15. ↑ 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]
  16. ↑ Stein PD, Yaekoub AY, Matta F, Sostman HD (August 2008). "64-slice CT for diagnosis of coronary artery disease: a systematic review". The American journal of medicine 121 (8): 715–25. DOI:10.1016/j.amjmed.2008.02.039. PMID 18691486. Research Blogging.
  17. ↑ Mowatt G, Cook JA, Hillis GS, et al (July 2008). "64-slice computed tomography angiography in the diagnosis and assessment of coronary artery disease: systematic review and meta-analysis". Heart. DOI:10.1136/hrt.2008.145292. PMID 18669550. Research Blogging.
  18. ↑ Rubinshtein R, Halon DA, Gaspar T, et al (November 2007). "Impact of 64-slice cardiac computed tomographic angiography on clinical decision-making in emergency department patients with chest pain of possible myocardial ischemic origin". Am. J. Cardiol. 100 (10): 1522–6. DOI:10.1016/j.amjcard.2007.06.052. PMID 17996512. Research Blogging.
  19. ↑ Sato A, Hiroe M, Tamura M, et al (April 2008). "Quantitative measures of coronary stenosis severity by 64-Slice CT angiography and relation to physiologic significance of perfusion in nonobese patients: comparison with stress myocardial perfusion imaging". J. Nucl. Med. 49 (4): 564–72. DOI:10.2967/jnumed.107.042481. PMID 18344444. Research Blogging.
  20. ↑ 20.0 20.1 Miller, Julie M.; Carlos E. Rochitte, Marc Dewey, Armin Arbab-Zadeh, Hiroyuki Niinuma, Ilan Gottlieb, Narinder Paul, Melvin E. Clouse, Edward P. Shapiro, John Hoe, Albert C. Lardo, David E. Bush, Albert de Roos, Christopher Cox, Jeffery Brinker, Joao A.C. Lima (2008-11-27). "Diagnostic Performance of Coronary Angiography by 64-Row CT". N Engl J Med 359 (22): 2324-2336. DOI:10.1056/NEJMoa0806576. PMID 19038879. Retrieved on 2008-11-27. Research Blogging.
  21. ↑ 21.0 21.1 Meijboom WB, Meijs MF, Schuijf JD, et al. (December 2008). "Diagnostic accuracy of 64-slice computed tomography coronary angiography: a prospective, multicenter, multivendor study". J. Am. Coll. Cardiol. 52 (25): 2135–44. DOI:10.1016/j.jacc.2008.08.058. PMID 19095130. Research Blogging.
  22. ↑ 22.0 22.1 Budoff MJ, Dowe D, Jollis JG, et al. (November 2008). "Diagnostic performance of 64-multidetector row coronary computed tomographic angiography for evaluation of coronary artery stenosis in individuals without known coronary artery disease: results from the prospective multicenter ACCURACY (Assessment by Coronary Computed Tomographic Angiography of Individuals Undergoing Invasive Coronary Angiography) trial". J. Am. Coll. Cardiol. 52 (21): 1724–32. DOI:10.1016/j.jacc.2008.07.031. PMID 19007693. Research Blogging.
  23. ↑ 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
  24. ↑ 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
  25. ↑ (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]
  26. ↑ 26.0 26.1 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.”
  27. ↑ 27.0 27.1 (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]
  28. ↑ 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]
  29. ↑ 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)
  30. ↑ 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.
  31. ↑ 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.
  32. ↑ 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.
  33. ↑ 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.
  34. ↑ 34.0 34.1 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.
  35. ↑ 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.
  36. ↑ 36.0 36.1 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] Cite error: Invalid <ref> tag; name "pmid1875969" defined multiple times with different content
  37. ↑ 37.0 37.1 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]
  38. ↑ 38.0 38.1 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]
  39. ↑ 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]
  40. ↑ 40.0 40.1 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]
  41. ↑ Weiner DA, Ryan TJ, McCabe CH, et al (August 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. PMID 449990. [e]
  42. ↑ 42.0 42.1 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]
  43. ↑ Little WC, Constantinescu M, Applegate RJ, et al (November 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]
  44. ↑ 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]
  45. ↑ 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.
  46. ↑ 46.0 46.1 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]
  47. ↑ 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.
  48. ↑ http://www.who.int/nutrition/topics/5_population_nutrient/en/index12.html

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