Effects of homoarginine supplementation on heart and skeletal muscle of rats with heart failure with preserved ejection fraction

AIM: Heart failure with preserved ejection fraction (HFpEF) is associated with left ventricular stiffness, impaired diastolic relaxation, and severe exercise intolerance. Decreased homoarginine (hArg) levels are an independent predictor of mortality in cardiovascular disease and correlate with impaired exercise performance. We recently reported alterations in arginine, hArg, and related amino acids in obese ZSF1 rats (O‐ZSF1), with a HFpEF phenotype. Although low hArg is associated with diastolic dysfunction in humans, potential effects of hArg supplementation were not tested yet. METHODS AND RESULTS: At an age of 6 weeks, 12 O‐ZSF1 were randomized into two groups: (1) O‐ZSF1 rats supplemented with hArg in their drinking water (sO‐ZSF1) or (2) O‐ZSF1 rats receiving no hArg supplementation (O‐ZSF1). At an age of 32 weeks, effects of primary prevention by hArg supplementation on echocardiographic, histological, and functional parameters of heart and skeletal muscle were determined. Lean ZSF1 rats (L‐ZSF1) served as controls. hArg supplementation did not prevent impairment of diastolic relaxation (E/e′: O‐ZSF1 21 ± 3 vs. sO‐ZSF1 22 ± 3, P = 0.954, L‐ZSF1 18 ± 5) but resulted in more cardiac fibrosis (histological collagen staining: +57% in sO‐ZSF1 vs. O‐ZSF1, P = 0.027) and increased collagen gene expression (Col1a1: +48% in sO‐ZSF1 vs. O‐ZSF1, P = 0.026). In contrary, right ventricular function was preserved by hArg supplementation (TAPSE (mm): O‐ZSF1 1.2 ± 0.3 vs. sO‐ZSF1 1.7 ± 0.3, P = 0.020, L‐ZSF1 1.8 ± 0.4). Musculus soleus maximal specific muscle force (N/cm(2)) in O‐ZSF1 (30.4 ± 0.8) and sO‐ZSF1 (31.9 ± 0.9) was comparable but significantly reduced compared with L‐ZSF1 (36.4 ± 0.7; both P < 0.05). Maximal absolute muscle force (g) (O‐ZSF1: 177.6 ± 7.8, sO‐ZSF1: 187.8 ± 5.0, L‐ZSF1: 181.5 ± 7.9, all P > 0.05) and cross‐sectional fibre area (arbitrary units) (O‐ZSF1: 1697 ± 57, sO‐ZSF1: 1965 ± 121, L‐ZSF1: 1691 ± 104, all P > 0.05) were not altered. CONCLUSIONS: Preservation of physiological hArg level in HFpEF may not be suited to prevent alterations in left ventricular and skeletal muscle function and structure. However, hArg supplementation may be beneficial for right ventricular function especially in pulmonary hypertension in HFpEF. We may speculate that clinically observed decreased hArg level are not the cause but the consequence of a yet unrecognized pathomechanism that underpins HFpEF.