Hyperhomocysteinemia (HHcy) has been linked to impaired left ventricular function and clinical class in patients with chronic heart failure. We hypothesized that HHcy stimulates myocardial brain natriuretic peptide (BNP) expression and induces adverse left ventricular remodeling. Methods: We randomized 50 rats into 5 groups. Groups Co1 and Co2 (controls) received a typical diet. Groups Meth, Hcy1, and Hcy2 were fed the same diet supplemented with 2.4% methionine, 1% homocystine, and 2%

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... ne, respectively. After 12 weeks, we measured total plasma homocysteine (tHcy) and BNP in plasma and tissue, and we performed histomorphometric analyses. Results: All animals had comparable baseline body weight [mean (SD) 234 (26) g] and total circulating Hcy [4.7 (1.7) mol/L]. After 12 weeks of treatment, total circulating Hcy increased in Meth, Hcy1, and Hcy2 [27.3 (8.8), 40.6 (7.0), and 54.0 (46.0) mol/L, respectively] and remained unchanged in Co1 and Co2. Serum BNP significantly increased in 1 of 10 animals in Meth, 3 of 10 animals in Hcy1, and 3 of 10 animals in Hcy2. Median (25th-75th percentile) BNP tissue concentrations in Hcy1 and Hcy2 were 55% higher than in the corresponding controls [Co1 vs Hcy1, 225 (186 -263) vs 338 (262-410) pg/mg protein, P ‫؍‬ 0.05; Co2 vs Hcy2, 179 (107-261) vs 308 (192-429) pg/mg protein, P ‫؍‬ 0.12]. In the Meth group, BNP expression was comparable to that of controls [200 (159 -235) vs 225 (186 -263) pg/mg protein, P ‫؍‬ 0.32]. The percentage of perivascular and interstitial collagen and mast cell infiltration were comparable in all groups, indicating no adverse cardiac remodeling. Conclusion: Three months of intermediate HHcy stimulated increased cardiac BNP expression that was not accompanied by adverse cardiac remodeling.