Coronary heart disease: Difference between revisions

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| European Coronary Surgery Study<br>1988<br>767 patients<ref name="pmid3260659">{{cite journal |author=Varnauskas E |title=Twelve-year follow-up of survival in the randomized European Coronary Surgery Study |journal=N. Engl. J. Med. |volume=319 |issue=6 |pages=332–7 |year=1988 |month=August |pmid=3260659 |doi= |url= |issn=}}</ref> || Greater survival with surgery - especially during first 5 years.
| European Coronary Surgery Study<br>1988<br>767 patients<ref name="pmid3260659">{{cite journal |author=Varnauskas E |title=Twelve-year follow-up of survival in the randomized European Coronary Surgery Study |journal=N. Engl. J. Med. |volume=319 |issue=6 |pages=332–7 |year=1988 |month=August |pmid=3260659 |doi= |url= |issn=}}</ref> || Greater survival with surgery - especially during first 5 years.
|-
|-
! Pooled results<ref name="pmid7914958">{{cite journal |author=Yusuf S, Zucker D, Peduzzi P, ''et al'' |title=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 |journal=Lancet |volume=344 |issue=8922 |pages=563–70 |year=1994 |month=August |pmid=7914958 |doi= |url= |issn=}}</ref> || Surgery fared better except for patients with one or two vessel disease with neither vessel being te LAD or left main.
! Pooled results<ref name="pmid7914958">{{cite journal |author=Yusuf S, Zucker D, Peduzzi P, ''et al'' |title=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 |journal=Lancet |volume=344 |issue=8922 |pages=563–70 |year=1994 |month=August |pmid=7914958 |doi= |url= |issn=}}</ref> || Surgery fared better except for patients with one or two vessel disease with neither vessel being the LAD or left main.
|}
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Coronary heart disease (CHD), or 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. One factor, 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.[1] The incidence of coronary events was higher during the match, especially for people who had pre-existing coronary disease.

Regarding which coronary arteries become blocked, about 10% of patients with chronic angina have left main disease.[2][3] IN males over age 70 with definite angina, almost 50% have obstruction of the left main coronary artery.[3]

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.[4] The nature of the chest pain affects the probability of underlying coronary disease.[5]

The Pryor nomogram, a clinical prediction rule, can help diagnose patients with suspected chest pain in a non emergent setting.[6][7]

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[8] and the newer Cleveland Clinic model[9]. 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.[9]

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.

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 tomography angiography

Cardiac computed tomography angiography (CCTA) uses multidetector spiral computed tomography.[10][11] The physiologic significance of obstructions estimated to be 60% to 80% is difficult to predict.[12]

Treatment

Medications

Invasive treatments

Major randomized controlled trials of surgery for chronic stable angina
Trial results
Veterans Administration cooperative study
1977
686 patients[13]		 No difference overall
Coronary Artery Surgery Study
(CASS)
1984
780 patients[14]		 No difference overall
European Coronary Surgery Study
1988
767 patients[15]		 Greater survival with surgery - especially during first 5 years.
Pooled results[16] 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 above 50%, no angina or their angina is controlled with medicines, do not benefit from either percutaneous transluminal coronary angioplasty (PCI)[17] or from coronary artery bypass surgery[14].

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.[14].

Regarding patients who must undergo invasive treatment, a systematic review comparing percutaneous coronary interventions and coronary artery bypass surgery (CABG) found that CABG was more effective but was more likely to be complicated by stroke.[18]

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.[19]

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.[20] However, the American Heart Association, based on a non-systematic review, recommends that doctors counsel patients on exercise [21]

Preventive diets

Dietary changes can potentially lead to large changes in the cholesterol.[22]

Aspirin

Aspirin, in doses of less than 75 to 81 mg/d[23], can reduce the incidence of cardiovascular events.[24] 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'.[25] 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.[26]

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.[27] Subgroup analysis showed that all benefit was confined to women over 65 years old.[27] 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'.[28]

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%[29][30]. More recently, a meta-analysis reported an almost identical relative risk reduction of 29.2% in low risk patients treated for 4.3 years [31]. A relative risk reduction of 19% in coronary mortality was found in a meta-analysis of patients at all levels of risk.[32]

Various clinical practice guidelines have addressed the treatment of hypercholesterolemia. The American College of Physicians has addressed hypercholesterolemia in patients with diabetes [33]. 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")[34].
  • 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[35]; however, their 2004 revisions have been criticized for use of nonrandomized, observational data.[36]

Omega-3 fatty acids (fish oil)

Biochemistry

(PD) Image: National Library of Medicine (NLM)
Polyunsaturated fatty acids (PUFAs) metabolic pathways in humans.[37]

Dietary fatty acids can be divided into saturated fatty acids and unsaturated fatty acids.[37] Unsaturated fatty acids can be further divided into monounsaturated and polyunsaturated fatty acids (PUFAs).

PUFAs are divided into two groups: omega-3 fatty acids and omega-6 fatty acids. Whereas omega-3 fatty acid have health benefits due to several mechanisms; omega-6 fatty acids are precursors to arachidonic acid (AA) which leads to thrombaxanes which promote platelet aggregation and vasoconstriction.

Two PUFAs, alpha-linolenic acid (ALA) and linoleic acid (LA) are called essential fatty acids because human function requires them, yet humans cannot synthesize then in vivo.[37] ALA is a omega-3 fatty acid while AL is a omega-6 fatty acid. In North America, LA comprises 89% of the total PUFAs consumed, while ALA comprises 9%.[37] LA is in many commonly used oils, including safflower, sunflower, soy, and corn oil. ALA is in leafy green vegetables and in canola and soybean oil.

Dietary fish oils are converted to eicosapentaenoic acid (EPA) which is further converted to docosahexaenoic acid (DHA). Both EPA and HHA are omega-3 fatty acids.

Studies of benefit

The benefit of fish oil is controversial with conflicting conclusions reached by a negative meta-analysis[38][39] of randomized controlled trials by the international Cochrane Collaboration and a partially positive systematic review[37] by the Agency for Healthcare Research and Quality. Since these two reviews, a randomized controlled trial reported a reduction on coronary events in Japanese hypercholesterolemic patients.[40]

Subsequent randomized controlled trials have also had conflicting results finding both benefit[40] and harm[41].

Homocysteine lowering

A meta-analysis concluded that lowering homocysteine with folic acid and other supplements may reduce stroke.[42] However, the two largest randomized controlled trials included in the meta-analysis had conflicting results. Lonn reported positive results[43]; whereas the trial by Toole was negative.[44]

Since the meta-analysis, two additional trials have shown no reduction in cardiovascular endpoint despite successfully lowering the plasma homocysteine level.[45][46]

References

  1. ↑ 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.
  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. ↑ 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.
  5. ↑ 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.
  6. ↑ 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
  7. ↑ 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]
  8. ↑ 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]
  9. ↑ 9.0 9.1 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]
  10. ↑ 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.
  11. ↑ 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.
  12. ↑ 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.
  13. ↑ 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]
  14. ↑ 14.0 14.1 14.2 (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. [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
  15. ↑ 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]
  16. ↑ 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]
  17. ↑ 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.”
  18. ↑ 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]
  19. ↑ http://www.who.int/nutrition/topics/5_population_nutrient/en/index12.html
  20. ↑ (2002) "Behavioral counseling in primary care to promote physical activity: recommendation and rationale". Ann. Intern. Med. 137 (3): 205-7. PMID 12160370. [e]
  21. ↑ Thompson PD, Buchner D, Pina IL, et al (2003). "Exercise and physical activity in the prevention and treatment of atherosclerotic cardiovascular disease: a statement from the Council on Clinical Cardiology (Subcommittee on Exercise, Rehabilitation, and Prevention) and the Council on Nutrition, Physical Activity, and Metabolism (Subcommittee on Physical Activity)". Circulation 107 (24): 3109-16. DOI:10.1161/01.CIR.0000075572.40158.77. PMID 12821592. Research Blogging. http://www.ngc.gov/summary/summary.aspx?ss=15&doc_id=5360&string=#s23
  22. ↑ 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]
  23. ↑ 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.
  24. ↑ 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.
  25. ↑ (2002) "Aspirin for the primary prevention of cardiovascular events: recommendation and rationale". Ann Intern Med 136 (2): 157-60. PMID 11790071.
  26. ↑ http://www.med-decisions.com/
  27. ↑ 27.0 27.1 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.
  28. ↑ http://circ.ahajournals.org/cgi/content/abstract/CIRCULATIONAHA.107.181546v1
  29. ↑ 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]
  30. ↑ Screening for Lipid Disorders: Recommendations and Rationale. Retrieved on 2007-10-17.
  31. ↑ 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.
  32. ↑ 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.
  33. ↑ 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.
  34. ↑ 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]
  35. ↑ 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.
  36. ↑ 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]
  37. ↑ 37.0 37.1 37.2 37.3 37.4 Wang C, Harris WS, Chung M, Lichtenstein AH, Balk EM, Kupelnick B, Jordan HS, Lau J (2006). "n-3 Fatty acids from fish or fish-oil supplements, but not alpha-linolenic acid, benefit cardiovascular disease outcomes in primary- and secondary-prevention studies: a systematic review". Am. J. Clin. Nutr. 84 (1): 5-17. PMID 16825676. [e] http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=hstat1a.chapter.38290
  38. ↑ Hooper L, Thompson RL, Harrison RA, Summerbell CD, Ness AR, Moore HJ, Worthington HV, Durrington PN, Higgins JP, Capps NE, Riemersma RA, Ebrahim SB, Davey Smith G (2006). "Risks and benefits of omega 3 fats for mortality, cardiovascular disease, and cancer: systematic review". BMJ 332 (7544): 752-60. DOI:10.1136/bmj.38755.366331.2F. PMID 16565093. Research Blogging.
  39. ↑ Hooper L, Thompson RL, Harrison RA, et al (2004). "Omega 3 fatty acids for prevention and treatment of cardiovascular disease". Cochrane Database Syst Rev (4): CD003177. DOI:10.1002/14651858.CD003177.pub2. PMID 15495044. Research Blogging.
  40. ↑ 40.0 40.1 Yokoyama M, Origasa H, Matsuzaki M, et al (2007). "Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis". Lancet 369 (9567): 1090-8. DOI:10.1016/S0140-6736(07)60527-3. PMID 17398308. Research Blogging. Cite error: Invalid <ref> tag; name "pmid17398308" defined multiple times with different content
  41. ↑ Raitt MH, Connor WE, Morris C, et al (2005). "Fish oil supplementation and risk of ventricular tachycardia and ventricular fibrillation in patients with implantable defibrillators: a randomized controlled trial". JAMA 293 (23): 2884–91. DOI:10.1001/jama.293.23.2884. PMID 15956633. Research Blogging.
  42. ↑ 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
  43. ↑ 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
  44. ↑ 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
  45. ↑ "". [e]
  46. ↑ 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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