Effect of folic acid supplementation on levels of circulating Monocyte Chemoattractant Protein-1 and the presence of intravascular ultrasound derived virtual histology thin-cap fibroatheromas in patients with stable angina pectoris

Kjetil H Løland, Øyvind Bleie, Elin Strand, Per M Ueland, Jan E Nordrehaug, Hector M Garcia-Garcia, Patrick W Serruys, Ottar Nygård, Kjetil H Løland, Øyvind Bleie, Elin Strand, Per M Ueland, Jan E Nordrehaug, Hector M Garcia-Garcia, Patrick W Serruys, Ottar Nygård

Abstract

Background: Virtual Histology Intravascular Ultrasound (VH-IVUS) may be used to detect early signs of unstable coronary artery disease. Monocyte Chemoattractant Protein-1 (MCP-1) is linked with coronary atherosclerosis and plaque instability and could potentially be modified by folic acid treatment.

Methods: In a randomized, prospective study, 102 patients with stable angina pectoris (SAP) received percutaneous coronary intervention and established medical treatment as well as either homocysteine-lowering folic acid/vitamin B12 (± B6) or placebo (± B6) for 1 year before VH-IVUS was performed. The presence of VH-Thin-Cap Fibroatheroma (VH-TCFA) in non-intervened coronary vessels was registered and serum levels of MCP-1 were measured. The patients were subsequently followed for incident myocardial infarction (MI).

Results: Patients treated with folic acid/vitamin B12 had a geometric mean (SD) MCP-1 level of 79.95 (1.49) versus 86.00 (1.43) pg/mL for patients receiving placebo (p-value 0.34). VH-TCFA lesions were present in 7.8% of patients and did not differ between intervention arms (p-value 0.47). Serum levels of MCP-1 were 1.46 (95% CI 1.12 to 1.92) times higher in patients with VH-TCFA lesions than in those without (p-value 0.005). Afterwards, patients were followed for median 2.1 years and 3.8% experienced a myocardial infarction (MI), which in post-hoc Cox regression analyses was independently predicted by both MCP-1 (P-value 0.006) and VH-TCFA (p-value 0.01).

Conclusions: In patients with SAP receiving established medical treatment, folic acid supplementation is not associated with either presence of VH-TCFA or levels of MCP-1. MCP-1 is however associated with VH-TCFA, a finding corroborated by increased risk for future MI. ClinicalTrials.gov Identifier: NCT00354081.

Conflict of interest statement

Competing Interests: Alpharma Inc provided the study capsules, generated the randomization sequence, and concealed the randomization code free of charge and rendered a limited grant to finance the initial phase of the trial. However, Alpharma Inc had no role in the design or implementation of the trial, had no access to study data, and did not participate in data analysis or interpretation or in the preparation, review, or approval of the manuscript. This does not alter our adherence to all the PLOS ONE policies on sharing data and materials.

Figures

Figure 1. Flow-chart of patient inclusion.
Figure 1. Flow-chart of patient inclusion.
The chart shows the flow of patients from the WENBIT-trial (n=3090) to inclusion in the current IVUS-VH study (n=105). All patients were randomized to B-vitamin treatment at WENBIT-baseline. Of the 1359 patients who had PCI at WENBIT-baseline, 371 had new, scheduled angiography at the WENBIT-one year follow-up. Of these 371 patients, 231 had received IVUS in a non-intervened vessel. IVUS-VH analysis and MCP-1 measurements were performed on 102 of these 231 patients and constituted our current study population. MCP-1 measurements were performed both at WENBIT-baseline (B-vitamin randomization) and at IVUS-VH study inclusion. Abbreviations are FA, folic acid (0.8 mg); B12, vitamin B12 (0.4 mg); B6, vitamin B6 (40 mg); WENBIT, Western Norway B-vitamin Intervention Trial; IVUS, intravascular ultrasound; IVUS-VH, intravascular ultrasound – virtual histology; PCI, Percutaneous coronary intervention and MCP-1, monocyte chemoattractant protein-1.
Figure 2. Grayscale IVUS and Virtual Histology…
Figure 2. Grayscale IVUS and Virtual Histology of TCFA.
A thin cap fibroatheroma (asterisk) in the proximal left anterior descending coronary artery of one of the study patients. The left panel shows an intravascular ultrasound radiofrequency image which is subsequently used to make the virtual histology image in the right panel. Green is fibrous tissue, yellow is fibro-fatty, red is necrotic core and white is calcified tissue.
Figure 3. MCP-1 Levels According to Folic…
Figure 3. MCP-1 Levels According to Folic Acid Supplementation at VH–IVUS Study Inclusion.
Cumulative distribution frequency plots showing plasma Monocyte Chemotactic Protein-1 (MCP-1) on the x-axis in patients receiving folic acid/vitamin B12 (solid line) and placebo or B6 (dashed line).
Figure 4. MCP-1 and Presence of Occult…
Figure 4. MCP-1 and Presence of Occult Thin-Cap Fibroatheroma at VH–IVUS Study Inclusion.
Cumulative distribution frequency plots of Monocyte Chemotactic Protein-1 (MCP-1) in patients with (solid line) and without (dashed line) Virtual Histology Thin-Cap Fibroatheroma (VH-TCFA).

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