Endothelial cell dysfunction in women with cardiac syndrome X and MTHFR C677T mutation

The etiology of chest pain with normal epicardial coronary arteries (cardiac syndrome X) seems to be related to endothelial cell dysfunction. Multiple factors are implicated in the pathophysiology, including elevated levels of homocysteine in the blood. Mutations in the MTHFR gene are associated with elevated levels of homocysteine.

To test whether abnormal homocysteine metabolism is associated with syndrome X.

Forty-two women with chest pain, positive stress test and normal coronary arteries (syndrome X) and 100 asymptomatic women (controls) were studied for the C677T mutation. Vitamin B12, folic acid, and plasma levels of homocysteine were also measured. Endothelial cell function was studied in 10 patients with syndrome X and homozygosity for C677T mutation, and in 10 matched healthy controls. Folic acid (5 mg daily) was prescribed to syndrome X patients after initial measurements of ECF. Following 13 weeks of treatment, ECF and blood tests were repeated and compared to baseline measurements.

Homozygosity for C677T mutation was doubled in syndrome X vs. control (33%, 14/42 vs. 16%, 16/100, P < 0.02), and homocysteine levels were increased (9.16 +/- 2.4 vs. 8.06 +/- 2.6 pmol/L, P = 0.02). In the 10 homozygous patients, homocysteine levels decreased significantly after treatment with 5 mg/day folic acid (10 +/- 3.3 vs. 5.4 +/- 1.1 micromol/L, P = 0.004). Abnormal baseline ECF improved after treatment with folic acid: flow-mediated dilatation was greater (11.3 +/- 7.9% vs. 0.7 +/- 4.5%, P < 0.002), as was nitroglycerin-mediated dilatation (15.2 +/- 9.0% vs. 5.6 +/- 6.4%, P < 0.003). Frequency of chest pain episodes was significantly reduced after 13 weeks of folic acid treatment.

Our findings establish the association between the C677Tmutation, endothelial cell dysfunction and cardiac syndrome X, and provide a novel and simple therapy for a subset of patients with syndrome X and homozygosity for the C677T mutation.