What are the cardiac complications of folic acid deficiency?

Updated: Sep 14, 2018
  • Author: Katherine Coffey-Vega, MD; Chief Editor: Emmanuel C Besa, MD  more...
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Answer

Elevated serum homocysteine and atherosclerosis

Folate in the 5-methyl THFA form is a cosubstrate required by methionine synthase when it converts homocysteine to methionine. As a result, in the scenario of folate deficiency, homocysteine accumulates. Several recent clinical studies have indicated that mild-to-moderate hyperhomocystinemia is highly associated with atherosclerotic vascular disease such as coronary artery disease (CAD) and stroke. In this case, mild hyperhomocystinemia is defined as total plasma concentration of 15-25 mmol/L and moderate hyperhomocystinemia is defined as 26-50 mmol/L.

Genest et al found that a group of 170 men with premature coronary artery disease had a significantly higher average level of homocysteine (13.7 ± 6.4). [24] In another study, Coull et al found that among 99 patients with stroke or transient ischemic attacks (TIAs), about one third had elevated homocysteine. [25]

Elevated homocysteine levels might act as an atherogenic factor by converting a stable plaque into an unstable, potentially occlusive, lesion. Wang et al found that in patients with acute coronary syndromes, levels of homocysteine and monocyte chemoattractant protein-1 (MCP-1) were significantly higher. [26] MCP-1 is a chemokine characterized by the ability to induce migration and activation of monocytes and therefore may contribute to the pathogenesis of CAD. Homocysteine is believed to have atherogenic and prothrombotic properties via multiple mechanisms.

Bokhari et al found that among patients with CAD, the homocysteine level correlates independently with left ventricular systolic function. [27] The mechanism is unknown, but it may be due to a direct toxic effect of homocysteine on myocardial function separate from its effect on coronary atherosclerosis.

Although multiple observational studies have found a positive assocation between elevated plasma homocysteine levels and increased risk of atherosclerosis, randomized trials have not been able to demonstrate the utility of homocysteine-lowering therapy for outcomes other than stroke. [3, 4] In the Heart Outcomes Prevention Evaluation (HOPE) 2 trial, supplements combining folic acid and vitamins B-6 and B-12 did not reduce the risk of major cardiovascular events in patients with vascular disease. [28] Similarly, in the trial by Bonaa et al, treatment with B vitamins did not lower the risk of recurrent cardiovascular disease after acute myocardial infarction. [29]

While the risk of cardiac complications was not reduced with correction of hyperhomocysteinemia through supplementation, several studies have documented a reduction in stroke with supplementation. Two meta-analyses demonstrated a statistically significant reduction in stroke risk with folic acid supplementation at low doses (0.4-0.8 mg folic acid daily). [3, 4]


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