Department of Cardiology, Heart Center Leipzig at University Leipzig, Leipzig, Germany.
Laboratory of Molecular and Experimental Cardiology, TU Dresden, Heart Center Dresden, Dresden, Germany.
ESC Heart Fail. 2022 Dec;9(6):4348-4351. doi: 10.1002/ehf2.14110. Epub 2022 Aug 31.
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.
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 ) 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.
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.
射血分数保留型心力衰竭（HFpEF）与左心室僵硬度增加、舒张功能障碍和严重运动不耐受有关。同型瓜氨酸（hArg）水平降低是心血管疾病死亡的独立预测因子，与运动能力受损相关。我们最近报道了肥胖 ZSF1 大鼠（O-ZSF1）中精氨酸、hArg 和相关氨基酸的变化，表现出 HFpEF 表型。尽管 hArg 水平降低与人类舒张功能障碍有关，但尚未测试 hArg 补充的潜在影响。
在 6 周龄时，将 12 只 O-ZSF1 随机分为两组：（1）在饮用水中补充 hArg 的 O-ZSF1 大鼠（sO-ZSF1）或（2）不接受 hArg 补充的 O-ZSF1 大鼠（O-ZSF1）。在 32 周龄时，确定 hArg 补充对心脏和骨骼肌的超声心动图、组织学和功能参数的一级预防作用。 lean ZSF1 大鼠（L-ZSF1）作为对照组。hArg 补充并未预防舒张功能障碍（E/e'：O-ZSF1 为 21±3，sO-ZSF1 为 22±3，P=0.954，L-ZSF1 为 18±5），但导致更多的心脏纤维化（组织学胶原染色：sO-ZSF1 比 O-ZSF1 增加 57%，P=0.027）和胶原基因表达增加（Col1a1：sO-ZSF1 比 O-ZSF1 增加 48%，P=0.026）。相反，hArg 补充可维持右心室功能（TAPSE（mm）：O-ZSF1 为 1.2±0.3，sO-ZSF1 为 1.7±0.3，P=0.020，L-ZSF1 为 1.8±0.4）。O-ZSF1（30.4±0.8）和 sO-ZSF1（31.9±0.9）的比目鱼肌最大比肌力（N/cm）可比较，但与 L-ZSF1（36.4±0.7；均 P<0.05）相比明显降低。最大绝对肌力（g）（O-ZSF1：177.6±7.8，sO-ZSF1：187.8±5.0，L-ZSF1：181.5±7.9，均 P>0.05）和横截面积（任意单位）（O-ZSF1：1697±57，sO-ZSF1：1965±121，L-ZSF1：1691±104，均 P>0.05）均未改变。
HFpEF 中生理性 hArg 水平的维持可能不适合预防左心室和骨骼肌功能和结构的改变。然而，hArg 补充可能对右心室功能有益，特别是在 HFpEF 中的肺动脉高压。我们可以推测，临床观察到的 hArg 水平降低不是 HFpEF 潜在机制的原因，而是尚未被认识到的病理机制的后果。
