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EXPERIMENTAL STUDIES

Effects of folate supplementation in hyperhomocysteinemic pigs

Pierre Ambrosi, MD^*, Pierre H. Rolland, PhD, Heidi Bodard, PhD, André Barlatier, PhD, Philippe Charpiot, PhD, Gwladys Guisgand, BSc, Alain Friggi, PhD, Odette Ghiringhelli, BSc, Gilbert Habib, MD^*, Gilles Bouvenot, MD, Danielle Garçon, PhD and Roger Luccioni, MD, FACC^*

^* Department of Cardiology, Hôpital de la Timone, Marseille, France
INSERM CJF 94-01, Marseille, France
Laboratory of Biochemistry, Faculté de Pharmacie, Marseille, France
Laboratory of Therapeutics, Faculté de Médecine, Marseille, France

Manuscript received March 4, 1998; revised manuscript received January 29, 1999, accepted March 15, 1999.

Reprint requests and correspondence: Dr. Pierre Ambrosi, Department of Cardiology, Hôpital de la Timone, 13385 Marseille, France

OBJECTIVES

The aim of this study was to evaluate the therapeutic effects of folic acid in the pig model of hyperhomocysteinemia.

BACKGROUND

We have previously shown that pigs fed a methionine-rich diet develop hyperhomocysteinemia, arterial lesions and thrombotic events. Elevated homocysteine level is an independent risk factor for atherosclerosis that can be markedly lowered with daily folic acid administration. However, it is not known whether this treatment can prevent arterial lesions.

METHODS

Three groups of pigs were studied: 8 control subjects received a standard diet; 8 received a methionine-rich diet for four months; 8 received a methionine-rich diet for 1 month and then the methionine-rich diet + 5 mg/day folic acid for 3 months. At month 4 after hemodynamic investigation, all the pigs were sacrificed.

RESULTS

Control animals developed few usual vascular streaks. All the pigs fed a methionine-rich diet without folic acid treatment developed hyperhomocysteinemia (10.3 ± 1.3 µmol/liter at basal state, 18.2 ± 2.5 µmol/liter at one month and 14.6 ± 3.8 µmol/liter at four months), hemodynamic abnormalities and diffuse arterial lesions with smooth muscle cell hyperplasia, endothelial alterations and elastic lamina dislocation. In this group, one pig died of venous thromboembolism and one of myocardial infarction. The pigs fed a methionine-rich diet + folic acid displayed similar arterial lesions and two had thrombotic events (one myocardial infarction and one pulmonary embolism), despite normalization of homocysteine levels (10.9 ± 1.3 µmol/liter at basal state, 19.5 ± 2.5 µmol/liter at one month and 11.4 ± 3.8 µmol/liter at four months).

CONCLUSIONS

In the pig model of hyperhomocysteinemia, 5 mg/day folic acid did not prevent arterial lesions or thrombotic events.

Abbreviations and Acronyms   M0 = basal state   M1 = month 1   M4 = month 4   C group = control group   M group = pigs receiving a methionine-rich diet   M+F group = pigs receiving a methionine-rich diet+folates   D = external arterial diameter   P = blood pressure   Q = blood flow

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