The American College of Cardiology (ACC)/American Heart Association (AHA) Task Force on Practice Guidelines was formed to make recommendations regarding the diagnosis and treatment of patients with known or suspected cardiovascular disease. Coronary artery disease (CAD) is the leading cause of death in the United States. Unstable angina (UA) and the closely related condition non–ST-segment elevation myocardial infarction (NSTEMI) are very common manifestations of this disease. These life-threatening disorders are a major cause of emergency medical care and hospitalizations in the United States. In 1996, the National Center for Health Statistics reported 1 433 000 hospitalizations for UA or NSTEMI. In recognition of the importance of the management of this common entity and of the rapid advances in the management of this condition, the need to revise guidelines published by the Agency for Health Care Policy and Research (AHCPR) and the National Heart, Lung and Blood Institute in 1994 was evident. This Task Force therefore formed the current committee to develop guidelines for the management of UA and NSTEMI. The present guidelines supersede the 1994 guidelines.

The customary ACC/AHA classifications I, II, and III summarize both the evidence and expert opinion and provide final recommendations for both patient evaluation and therapy:

Class I: Conditions for which there is evidence and/or general agreement that a given procedure or treatment is useful and effective .

Class II: Conditions for which there is conflicting evidence and/or a divergence of opinion about the usefulness/efficacy of a procedure or treatment. 

Class IIa: Weight of evidence/opinion is in favor of usefulness/efficacy. 

Class IIb: Usefulness/efficacy is less well established by evidence/opinion. 

Class III: Conditions for which there is evidence and/or general agreement that the procedure/treatment is not useful/effective and in some cases may be harmful. 

The weight of the evidence was ranked highest (A) if the data …

/pdf/acc-aha-guidelines-for-the-management-of-patients-with-4ru5c6nutz.pdf

ACC/AHA guidelines for the management of patients with unstable angina and non-ST-segment elevation myocardial infarction: Executive summary and recommendations: A report of the American College of Cardiology/American Heart Association task force on practice guidelines (committee on the management of patients with unstable angina)

Objective. —To determine the risk of elevated total homocysteine (tHcy) levels for arteriosclerotic vascular disease, estimate the reduction of tHcy by folic acid, and calculate the potential reduction of coronary artery disease (CAD) mortality by increasing folic acid intake. Data Sources. —MEDLINE search for meta-analysis of 27 studies relating homocysteine to arteriosclerotic vascular disease and 11 studies of folic acid effects on tHcy levels. Study Selection and Data Extraction. —Studies dealing with CAD, cerebrovascular disease, and peripheral arterial vascular disease were selected. Three prospective and six population-based case-control studies were considered of high quality. Five cross-sectional and 13 other case-control studies were also included. Causality of tHcy's role in the pathogenesis of vascular disease was inferred because of consistency across studies by different investigators using different methods in different populations. Data Synthesis. —Elevations in tHcy were considered an independent graded risk factor for arteriosclerotic vascular diseases. The odds ratio (OR) for CAD of a 5-μmol/L tHcy increment is 1.6(95% confidence interval [Cl], 1.4 to 1.7) for men and 1.8 (95% Cl, 1.3 to 1.9) for women. A total of 10% of the population's CAD risk appears attributable to tHcy. The OR for cerebrovascular disease (5-μmol/L tHcy increment) is 1.5 (95% Cl, 1.3 to 1.9). Peripheral arterial disease also showed a strong association. Increased folic acid intake (approximately 200 μg/d) reduces tHcy levels by approximately 4 μmol/L. Assuming that lower tHcy levels decrease CAD mortality, we calculated the effect of (1) increased dietary folate, (2) supplementation by tablets, and (3) grain fortification. Under different assumptions, 13 500 to 50 000 CAD deaths annually could be avoided; fortification of food had the largest impact. Conclusions. —A 5-μmol/L tHcy increment elevates CAD risk by as much as cholesterol increases of 0.5 mmol/L (20 mg/dL). Higher folic acid intake by reducing tHcy levels promises to prevent arteriosclerotic vascular disease. Clinical trials are urgently needed. Concerns about masking cobalamin deficiency by folic acid could be lessened by adding 1 mg of cobalamin to folic acid supplements. ( JAMA . 1995;274:1049-1057)

https://jamanetwork.com/journals/jama/articlepdf/389728/jama_274_13_028.pdf

A quantitative assessment of plasma homocysteine as a risk factor for vascular disease. Probable benefits of increasing folic acid intakes

This review focuses on the role of oxidative processes in atherosclerosis and its resultant cardiovascular events. There is now a consensus that atherosclerosis represents a state of heightened oxidative stress characterized by lipid and protein oxidation in the vascular wall. The oxidative modification hypothesis of atherosclerosis predicts that low-density lipoprotein (LDL) oxidation is an early event in atherosclerosis and that oxidized LDL contributes to atherogenesis. In support of this hypothesis, oxidized LDL can support foam cell formation in vitro, the lipid in human lesions is substantially oxidized, there is evidence for the presence of oxidized LDL in vivo, oxidized LDL has a number of potentially proatherogenic activities, and several structurally unrelated antioxidants inhibit atherosclerosis in animals. An emerging consensus also underscores the importance in vascular disease of oxidative events in addition to LDL oxidation. These include the production of reactive oxygen and nitrogen species by vascular cells, as well as oxidative modifications contributing to important clinical manifestations of coronary artery disease such as endothelial dysfunction and plaque disruption. Despite these abundant data however, fundamental problems remain with implicating oxidative modification as a (requisite) pathophysiologically important cause for atherosclerosis. These include the poor performance of antioxidant strategies in limiting either atherosclerosis or cardiovascular events from atherosclerosis, and observations in animals that suggest dissociation between atherosclerosis and lipoprotein oxidation. Indeed, it remains to be established that oxidative events are a cause rather than an injurious response to atherogenesis. In this context, inflammation needs to be considered as a primary process of atherosclerosis, and oxidative stress as a secondary event. To address this issue, we have proposed an "oxidative response to inflammation" model as a means of reconciling the response-to-injury and oxidative modification hypotheses of atherosclerosis.

Role of Oxidative Modifications in Atherosclerosis

An elevated level of total homocysteine (tHcy) in blood, denoted hyperhomocysteinemia, is emerging as a prevalent and strong risk factor for atherosclerotic vascular disease in the coronary, cerebral, and peripheral vessels, and for arterial and venous thromboembolism. The basis for these conclusions is data from about 80 clinical and epidemiological studies including more than 10,000 patients. Elevated tHcy confers a graded risk with no threshold, is independent of but may enhance the effect of the conventional risk factors, and seems to be a particularly strong predictor of cardiovascular mortality. Hyperhomocysteinemia is attributed to commonly occurring genetic and acquired factors including deficiencies of folate and vitamin B12. Supplementation with B-vitamins, in particular with folic acid, is an efficient, safe, and inexpensive means to reduce an elevated tHcy level. Studies are now in progress to establish whether such therapy will reduce cardiovascular risk.

/pdf/homocysteine-and-cardiovascular-disease-1zad76k6jt.pdf

Homocysteine and Cardiovascular Disease

In 1969, McCully made the clinical observation linking elevated plasma homocyst(e)ine concentrations with vascular disease.1 He reported autopsy evidence of extensive arterial thrombosis and atherosclerosis in two children with elevated plasma homocyst(e)ine concentrations and homocystinuria. On the basis of this observation, he proposed that elevated plasma homocyst(e)ine (hyperhomocyst(e)inemia) can cause atherosclerotic vascular disease. The term “homocyst(e)ine” is used to define the combined pool of homocysteine, homocystine, mixed disulfides involving homocysteine, and homocysteine thiolactone found in the plasma of patients with hyperhomocyst(e)inemia. Subsequent investigations have confirmed McCully's hypothesis, and it has recently become clear that hyperhomocyst(e)inemia is an independent risk factor . . .

Homocysteine and atherothrombosis

Rapid high-performance liquid chromatographic assay for total homocysteine levels in human serum.

Vitamin B-12, vitamin B-6, and folate nutritional status in men with hyperhomocysteinemia

We have previously shown that a modest vitamin supplement containing folic acid, vitamin B-12 and vitamin B-6 is effective in reducing elevated plasma homocysteine concentrations. The effect of supplementation of the individual vitamins on moderate hyperhomocysteinemia has now been investigated in a placebo-controlled study. One hundred men with hyperhomocysteinemia were randomly assigned to five groups and treated with a daily dose of placebo, folic acid (0.65 mg), vitamin B-12 (0.4 mg), vitamin B-6 (10 mg) or a combination of the three vitamins for 6 wk. Folic acid supplementation reduced plasma homocysteine concentrations by 41.7% (P < 0.001), whereas the daily vitamin B-12 supplement lowered homocysteine concentrations by 14.8% (P < 0.01). The daily pyridoxine dose did not reduce significantly plasma homocysteine concentrations. The combination of the three vitamins reduced circulating homocysteine concentrations by 49.8%, which was not significantly different (P = 0.48) from the reduction achieved by folate supplementation alone. Our results indicate that folate deficiency may be an important cause of hyperhomocysteinemia in the general population.

Vitamin Requirements for the Treatment of Hyperhomocysteinemia in Humans

Homocysteine, an atherogenic amino acid, is either remethylated to methionine or metabolized to cysteine by the transsulfuration pathway. The biochemical conversion of homocysteine to cysteine is dependent upon two consecutive, vitamin B-6-dependent reactions. To study the effect of a selective vitamin B-6 deficiency on transsulfuration, we performed oral methionine load tests on 22 vitamin B-6-deficient asthma patients treated with theophylline (a vitamin B-6 antagonist) and 24 age- and sex-matched controls with a normal vitamin B-6 status. Both groups had normal circulating vitamin B-12 and folate concentrations. Methionine loading resulted in significantly higher increases in circulating total homocyst(e)ine (P < 0.01) and cystathionine (P < 0.05) concentrations in vitamin B-6-deficient patients compared with controls. 6 wk of vitamin B-6 supplementation (20 mg/d) significantly (P < 0.05) reduced post-methionine load increases in circulating total homocyst(e)ine concentrations in deficient subjects, but had no significant effect on the increase in total homocyst(e)ine concentrations in controls. The increases in post-methionine load circulating cystathionine concentrations were significantly (P < 0.01) reduced in both groups after vitamin supplementation. It is concluded that a vitamin B-6 deficiency may contribute to impaired transsulfuration and an abnormal methionine load test, which is associated with premature vascular disease.

https://dm5migu4zj3pb.cloudfront.net/manuscripts/118000/118763/JCI96118763.pdf

Johan B. Ubbink

Papers

Rapid high-performance liquid chromatographic assay for total homocysteine levels in human serum.

Vitamin B-12, vitamin B-6, and folate nutritional status in men with hyperhomocysteinemia

Vitamin Requirements for the Treatment of Hyperhomocysteinemia in Humans

The effect of a subnormal vitamin B-6 status on homocysteine metabolism.

Stability of pyridoxal-5-phosphate semicarbazone: applications in plasma vitamin B6 analysis and population surveys of vitamin B6 nutritional status.