Coronary heart disease

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Coronary heart disease (CHD), also called coronary artery disease (CAD), is caused by abnormalities the arteries that supply the heart with blood. Those arteries are called the coronary arteries and the usual cause of coronary artery disease is athersosclerosis. 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.

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]

Inflammation may underlay the association between elevated C-reactive protein levels and coronary heart disease.

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.[2] The incidence of coronary events was higher during the match, especially for people who had pre-existing coronary disease.

Atherosclerotic obstruction

About 10% of patients with chronic angina have left main disease.[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 the Duke Coronary Artery Disease Index.[5]

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.[6]

Syndrome X

Cardiac syndrome X is the presence of typical angina, abnormal exercise-test results, and normal coronary arteries (including no vasospasm).[7] Syndrome X may be caused by subendocardial hypoperfusion that can be demonstrated by cardiovascular magnetic resonance imaging during the administration of adenosine.[7]

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.[8] The nature of the chest pain affects the probability of underlying coronary disease.[9]

The Pryor nomogram, a clinical prediction rule, can help diagnose patients with suspected chest pain in a non emergent setting.[10][11]

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[12] and the newer Cleveland Clinic model[13]. 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.[13]

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.

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.[14][15][16] The physiologic significance of obstructions estimated to be 60% to 80% is difficult to predict.[17]

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

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)[18] or from coronary artery bypass grafting surgery[19].

Regarding patients who must undergo invasive treatment, a systematic review comparing percutaneous coronary interventions and coronary artery bypass grafting (CABG) surgery found that CABG was more effective but was more likely to be complicated by stroke.[20]

Percutaneous cardiac intervention

Patient who have a stable angina and left ventricular ejection fraction above 35% do not reduce mortality from percutaneous transluminal coronary angioplasty (PCI)[18] although there is some reduction in angina for the first three years after procedure[21].

Coronary artery bypass graftiing

Major randomized controlled trials of surgery for chronic stable angina
Trial results
Veterans Administration cooperative study
1977
686 patients[22]		 3 year survival was 87% of the medical group and 88% of the surgical group. No significant difference.
Coronary Artery Surgery Study
(CASS)
1984
780 patients[19]		 The 5 year survival 92% with medical therapy and 95% with surgery (not significant). "The likelihood of nonfatal Q-wave myocardial infarction was 11 and 14 per cent, respectively (not significant). The five-year probability of remaining alive and free of infarction was 82 per cent in the patients assigned to medical therapy and 83 per cent in the patients assigned to surgery (not significant)."
European Coronary Surgery Study
1988
767 patients[23]		 5 year survival was 92% with surgery and 83% with medical therapy.
Pooled results[24] Surgery fared better except for patients with one or two vessel disease with neither vessel being the LAD or left main.

Patient who have a left ventricular ejection fraction between 35 and 49 percent benefit from coronary artery bypass surgery if they have disease of three coronary arteries.[19].

Complications

Acute coronary syndrome

For more information, see: Acute coronary syndrome.

Prognosis

Framingham risk

The Framingham risk uses clinical risk factors that are combined in an equation developed from the Framingham Heart Study to calculate prognosis. An online calculator is available at http://hp2010.nhlbihin.net/atpiii/calculator.asp.

Coronary calcium score

Coronary calcium score for predicting myocardial infarction or death from coronary heart disease amond 6814 persons without known cardiovascular disease[25]
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. [25] 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.[26]

C-reactive protein

For more information, see: C-reactive protein.

Abnormal high sensitivity C-reactive protein (CRP) values may assist in assessing cholesterol measurements in apparently healthy people due to the theory that chronic inflammation precedes atherosclerosis.[27] However, the ability of the CRP to add to other methods of predicting heart disease such as the Framingham risk tool is limited.[27]

In one study, the CRP did not add to the coronary calcium score.[25]

Cardiac catheterization

-
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%

Coronary obstructions are more likely to progress or occlude within 4-5 years if the obstructions are severe according to the CASS investigation.[28] 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.

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.[29]

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.

Exercise

Separate to the question of the benefits of exercise; it is unclear whether doctors should spend time counseling patients to exercise. The U.S. Preventive Services Task Force (USPSTF), based on a systematic review of randomized controlled trials, found 'insufficient evidence' to recommend that doctors counsel patients on exercise.[30] However, the American Heart Association, based on a non-systematic review, recommends that doctors counsel patients on exercise [31]

Preventive diets

Dietary changes can potentially lead to large changes in the cholesterol.[32]

Aspirin

Aspirin, in doses of less than 75 to 81 mg/d[33], can reduce the incidence of cardiovascular events.[34] The U.S. Preventive Services Task Force 'strongly recommends that clinicians discuss aspirin chemoprevention with adults who are at increased risk for coronary heart disease'.[35] The Task Force defines increased risk as 'Men older than 40 years of age, postmenopausal women, and younger persons with risk factors for coronary heart disease (for example, hypertension, diabetes, or smoking) are at increased risk for heart disease and may wish to consider aspirin therapy'. More specifically, high-risk persons are 'those with a 5-year risk ≥ 3%'. A risk calculator is available.[36]

Regarding healthy women, the more recent Women's Health Study randomized controlled trial found insignficant benefit from aspirin in the reduction of cardiac events; however there was a signficant reduction in stroke.[37] Subgroup analysis showed that all benefit was confined to women over 65 years old.[37] In spite of the insignficant benefit for women < 65 years old, recent practice guidelines by the American Heart Association recommend to 'consider' aspirin in 'healthy women' <65 years of age 'when benefit for ischemic stroke prevention is likely to outweigh adverse effects of therapy'.[38]

Antilipemic drugs

The U.S. Preventive Services Task Force (USPSTF) estimated that after 5 to 7 years of treatment with statins, the relative risk reduction of coronary heart disease events is decreased by approximately 30%[39][40]. More recently, a meta-analysis reported an almost identical relative risk reduction of 29.2% in low risk patients treated for 4.3 years [41]. A relative risk reduction of 19% in coronary mortality was found in a meta-analysis of patients at all levels of risk.[42]

Various clinical practice guidelines have addressed the treatment of hypercholesterolemia. The American College of Physicians has addressed hypercholesterolemia in patients with diabetes [43]. Their recommendations are:

  • Recommendation 1: Lipid-lowering therapy should be used for secondary prevention of cardiovascular mortality and morbidity for all patients (both men and women) with known coronary artery disease and type 2 diabetes.
  • Recommendation 2: Statins should be used for primary prevention against macrovascular complications in patients (both men and women) with type 2 diabetes and other cardiovascular risk factors.
  • Recommendation 3: Once lipid-lowering therapy is initiated, patients with type 2 diabetes mellitus should be taking at least moderate doses of a statin (the accompanying evidence report states "simvastatin, 40 mg/d; pravastatin, 40 mg/d; lovastatin, 40 mg/d; atorvastatin, 20 mg/d; or an equivalent dose of another statin")[44].
  • Recommendation 4: For those patients with type 2 diabetes who are taking statins, routine monitoring of liver function tests or muscle enzymes is not recommended except in specific circumstances.

The National Cholesterol Education Program revised their guidelines[45]; however, their 2004 revisions have been criticized for use of nonrandomized, observational data.[46]

Omega-3 fatty acids (fish oil)

For more information, see: Fish oil.


Homocysteine lowering

A meta-analysis concluded that lowering homocysteine with folic acid and other supplements may reduce stroke.[47] However, the two largest randomized controlled trials included in the meta-analysis had conflicting results. Lonn reported positive results[48]; whereas the trial by Toole was negative.[49]

Since the meta-analysis, two additional trials have shown no reduction in cardiovascular endpoint despite successfully lowering the plasma homocysteine level.[50][51]

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. ↑ 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.
  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. ↑ 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]
  6. ↑ 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.
  7. ↑ 7.0 7.1 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.
  8. ↑ 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.
  9. ↑ 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.
  10. ↑ 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
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  12. ↑ 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]
  13. ↑ 13.0 13.1 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]
  14. ↑ 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.
  15. ↑ 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.
  16. ↑ 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.
  17. ↑ 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.
  18. ↑ 18.0 18.1 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.”
  19. ↑ 19.0 19.1 19.2 (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] Cite error: Invalid <ref> tag; name "pmid6608052" defined multiple times with different content Cite error: Invalid <ref> tag; name "pmid6608052" defined multiple times with different content
  20. ↑ 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]
  21. ↑ 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)
  22. ↑ Murphy ML, Hultgren HN, Detre K, Thomsen J, Takaro T (September 1977). "Treatment of chronic stable angina. A preliminary report of survival data of the randomized Veterans Administration cooperative study". N. Engl. J. Med. 297 (12): 621–7. PMID 331107. [e]
  23. ↑ Varnauskas E (August 1988). "Twelve-year follow-up of survival in the randomized European Coronary Surgery Study". N. Engl. J. Med. 319 (6): 332–7. PMID 3260659. [e]
  24. ↑ Yusuf S, Zucker D, Peduzzi P, et al (August 1994). "Effect of coronary artery bypass graft surgery on survival: overview of 10-year results from randomised trials by the Coronary Artery Bypass Graft Surgery Trialists Collaboration". Lancet 344 (8922): 563–70. PMID 7914958. [e]
  25. ↑ 25.0 25.1 25.2 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.
  26. ↑ 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.
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  28. ↑ 28.0 28.1 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]
  29. ↑ http://www.who.int/nutrition/topics/5_population_nutrient/en/index12.html
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  32. ↑ McMurry MP, Cerqueira MT, Connor SL, Connor WE (1991). "Changes in lipid and lipoprotein levels and body weight in Tarahumara Indians after consumption of an affluent diet". N. Engl. J. Med. 325 (24): 1704-8. PMID 1944471. [e]
  33. ↑ Campbell CL, Smyth S, Montalescot G, Steinhubl SR (2007). "Aspirin dose for the prevention of cardiovascular disease: a systematic review". JAMA 297 (18): 2018-24. DOI:10.1001/jama.297.18.2018. PMID 17488967. Research Blogging.
  34. ↑ Berger J, Roncaglioni M, Avanzini F, Pangrazzi I, Tognoni G, Brown D (2006). "Aspirin for the primary prevention of cardiovascular events in women and men: a sex-specific meta-analysis of randomized controlled trials". JAMA 295 (3): 306-13. PMID 16418466.
  35. ↑ (2002) "Aspirin for the primary prevention of cardiovascular events: recommendation and rationale". Ann Intern Med 136 (2): 157-60. PMID 11790071.
  36. ↑ http://www.med-decisions.com/
  37. ↑ 37.0 37.1 Ridker P, Cook N, Lee I, Gordon D, Gaziano J, Manson J, Hennekens C, Buring J (2005). "A randomized trial of low-dose aspirin in the primary prevention of cardiovascular disease in women". N Engl J Med 352 (13): 1293-304. DOI:10.1056/NEJMoa050613. PMID 15753114. Research Blogging.
  38. ↑ http://circ.ahajournals.org/cgi/content/abstract/CIRCULATIONAHA.107.181546v1
  39. ↑ Pignone MP, Phillips CJ, Atkins D, Teutsch SM, Mulrow CD, Lohr KN (2001). "Screening and treating adults for lipid disorders". American journal of preventive medicine 20 (3 Suppl): 77–89. PMID 11306236. [e]
  40. ↑ Screening for Lipid Disorders: Recommendations and Rationale. Retrieved on 2007-10-17.
  41. ↑ Thavendiranathan P, Bagai A, Brookhart M, Choudhry N (2006). "Primary prevention of cardiovascular diseases with statin therapy: a meta-analysis of randomized controlled trials". Arch Intern Med 166 (21): 2307-13. PMID 17130382.
  42. ↑ Baigent C, Keech A, Kearney PM, et al (2005). "Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins". Lancet 366 (9493): 1267-78. DOI:10.1016/S0140-6736(05)67394-1. PMID 16214597. Research Blogging.
  43. ↑ Snow V, Aronson M, Hornbake E, Mottur-Pilson C, Weiss K (2004). "Lipid control in the management of type 2 diabetes mellitus: a clinical practice guideline from the American College of Physicians". Ann Intern Med 140 (8): 644-9. PMID 15096336.
  44. ↑ Vijan S, Hayward RA (2004). "Pharmacologic lipid-lowering therapy in type 2 diabetes mellitus: background paper for the American College of Physicians". Ann. Intern. Med. 140 (8): 650-8. PMID 15096337. [e]
  45. ↑ Grundy SM, Cleeman JI, Merz CN, Brewer HB, Clark LT, Hunninghake DB, Pasternak RC, Smith SC, Stone NJ (2004). "Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III Guidelines". J. Am. Coll. Cardiol. 44 (3): 720-32. DOI:10.1016/j.jacc.2004.07.001. PMID 15358046. Research Blogging.
  46. ↑ Hayward RA, Hofer TP, Vijan S (2006). "Narrative review: lack of evidence for recommended low-density lipoprotein treatment targets: a solvable problem". Ann. Intern. Med. 145 (7): 520-30. PMID 17015870. [e]
  47. ↑ Wang X, Qin X, Demirtas H, et al (2007). "Efficacy of folic acid supplementation in stroke prevention: a meta-analysis". Lancet 369 (9576): 1876-82. DOI:10.1016/S0140-6736(07)60854-X. PMID 17544768. Research Blogging. PMID 17544768
  48. ↑ Lonn E, Yusuf S, Arnold MJ, et al (2006). "Homocysteine lowering with folic acid and B vitamins in vascular disease". N. Engl. J. Med. 354 (15): 1567-77. DOI:10.1056/NEJMoa060900. PMID 16531613. Research Blogging. PMID 16531613
  49. ↑ Toole JF, Malinow MR, Chambless LE, et al (2004). "Lowering homocysteine in patients with ischemic stroke to prevent recurrent stroke, myocardial infarction, and death: the Vitamin Intervention for Stroke Prevention (VISP) randomized controlled trial". JAMA 291 (5): 565-75. DOI:10.1001/jama.291.5.565. PMID 14762035. Research Blogging. PMID 14762035
  50. ↑ "". [e]
  51. ↑ Ebbing M, Bleie O, Ueland PM, Nordrehaug JE, Nilsen DW, Vollset SE, et al. Mortality and Cardiovascular Events in Patients Treated With Homocysteine-Lowering B Vitamins After Coronary Angiography: A Randomized Controlled Trial. JAMA. 2008 Aug 20;300(7):795-804.

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