Hyperhomocysteinemia Linked to Worse Outcomes

HOLLYWOOD, FLA. -- Hyperhomocysteinemia was found to be linked to a significantly increased risk of artery and graft occlusion following infrainguinal revascularization according to a review of 229 patients treated at a single center.

Based on this finding, physicians at the Western Vascular Institute in Galway, Ireland, began last year to routinely treat patients with hyperhomocysteinemia with a folic acid and vitamin B12 supplement for several weeks before performing peripheral artery angioplasty or bypass, Dr. Helen Heneghan said during an interview at ISET 2008, an international symposium on endovascular therapy.

They diagnose hyperhomocysteinemia in patients who have a fasting serum plasma level that exceeds 13 micromol/L.

The supplemental regimen is 500 mcg folic acid and 1 mg vitamin B12 daily, a treatment that usually reduces plasma homocysteine levels by about 3-4 micromol/L after about 6 weeks, a drop that should cut the relative risk for peripheral artery occlusion following revascularization by about 25%, said Dr. Heneghan, a vascular surgeon at the institute.

This practice began last May, but as of early 2008 not enough data had accumulated to gauge its actual effectiveness.

The relationship between hyperhomocysteinemia and the outcome of peripheral revascularization was examined with data collected from 953 patients who underwent an infrainguinal procedure for critical limb ischemia at the institute during 2002-2006. About 70% of the patients underwent angioplasty, with or without stenting, and the remaining patients had arterial bypass using either an autologous vein or a polytetrafluoroethylene graft.

Among the entire group, 229 patients had an accurate measure of their fasting serum homocysteine level prior to surgery. A level above 13 micromol/L was identified in 69 patients (30%), including 33 women and 36 men. Sixty-one of the 69 patients had mild hyperhomocysteinemia, with a level of no more than 20 micromol/L.

During the first 24 months of follow-up, primary patency was much better in patients who had normal homocysteine levels at the time of treatment. After 2 years, the primary patency rate was 74% in patients with normal levels at baseline, compared with 35% in patients with hyperhomocysteinemia, a statistically significant difference, Dr. Heneghan reported at the meeting.

The two groups of patients did not show significant differences in the primary assisted patency or secondary patency, but patients with normal homocysteine levels at baseline showed trends toward a longer duration for both of these patencies, compared with hyperhomocysteinemia patients.

Patients with normal homocysteine levels at baseline also avoided amputation longer. The average time until amputation of the affected leg was 31 months in the hyperhomocysteinemia group, compared with 34 months in the normal group, a statistically significant difference.

Occlusion of the treated vessel eventually developed in 26% of the normal patients and 65% of the patients with elevated homocysteine at baseline, another significant difference. There was no significant difference in the rates of all-cause death during 4 years of follow-up in the two groups.

In a multivariate analysis that controlled for several other baseline comorbidities, hyperhomocysteinemia remained significantly linked with an increased risk for amputation and graft occlusion, Dr. Heneghan reported.

Other baseline factors that were not significantly linked with outcome in this statistical model included diabetes, hypertension, smoking, hyperlipidemia, and renal impairment.

Although evidence collected by several research groups in recent years has been mixed on a link between hyperhomocysteinemia and various forms of cardiovascular disease, the new findings suggest that an elevated serum level of homocysteine is not just a marker for elevated vascular risk but rather plays a direct, causal role in worsening outcomes following peripheral revascularization, Dr. Heneghan said in an interview.

She suggested several ways by which homocysteine might have a harmful effect, including antagonizing nitric oxide, boosting lipid oxidation and arterial plaque formation, and stimulating smooth-muscle cell proliferation.