Department of Medicine (Division of Cardiology), Emory University School of Medicine, Atlanta, GA, USA.
Circulation. 2010 Feb 2;121(4):519-28. doi: 10.1161/CIRCULATIONAHA.109.883777. Epub 2010 Jan 18.
Heart failure with preserved ejection fraction is 1 consequence of hypertension and is caused by impaired cardiac diastolic relaxation. Nitric oxide (NO) is a known modulator of cardiac relaxation. Hypertension can lead to a reduction in vascular NO, in part because NO synthase (NOS) becomes uncoupled when oxidative depletion of its cofactor tetrahydrobiopterin (BH(4)) occurs. Similar events may occur in the heart that lead to uncoupled NOS and diastolic dysfunction.
In a hypertensive mouse model, diastolic dysfunction was accompanied by cardiac oxidation, a reduction in cardiac BH(4), and uncoupled NOS. Compared with sham-operated animals, male mice with unilateral nephrectomy, with subcutaneous implantation of a controlled-release deoxycorticosterone acetate pellet, and given 1% saline to drink were mildly hypertensive and had diastolic dysfunction in the absence of systolic dysfunction or cardiac hypertrophy. The hypertensive mouse hearts showed increased oxidized biopterins, NOS-dependent superoxide production, reduced NO production, and dephosphorylated phospholamban. Feeding hypertensive mice BH(4) (5 mg/d), but not treating with hydralazine or tetrahydroneopterin, improved cardiac BH(4) stores, phosphorylated phospholamban levels, and diastolic dysfunction. Isolated cardiomyocyte experiments revealed impaired relaxation that was normalized with short-term BH(4) treatment. Targeted cardiac overexpression of angiotensin-converting enzyme also resulted in cardiac oxidation, NOS uncoupling, and diastolic dysfunction in the absence of hypertension.
Cardiac oxidation, independently of vascular changes, can lead to uncoupled cardiac NOS and diastolic dysfunction. BH(4) may represent a possible treatment for diastolic dysfunction.
射血分数保留的心力衰竭是高血压的一种后果，是由心脏舒张松弛受损引起的。一氧化氮（NO）是心脏舒张的已知调节剂。高血压可导致血管中 NO 减少，部分原因是当其辅助因子四氢生物蝶呤（BH 4）氧化耗竭时，NO 合酶（NOS）失去偶联。类似的事件可能发生在心脏中，导致NOS 失偶联和舒张功能障碍。
在高血压小鼠模型中，舒张功能障碍伴随着心脏氧化、心脏 BH 4 减少和 NOS 失偶联。与假手术动物相比，单侧肾切除术、皮下植入控释去氧皮质酮醋酸盐丸并给予 1%盐水饮用的雄性小鼠轻度高血压，舒张功能障碍而无收缩功能障碍或心脏肥大。高血压小鼠心脏显示氧化生物喋呤增加、NOS 依赖性超氧化物产生增加、NO 产生减少和磷酸化肌钙蛋白 I 脱磷酸化。给高血压小鼠喂食 BH 4（5mg/d），而不是用肼屈嗪或四氢生物蝶呤治疗，可改善心脏 BH 4 储存、磷酸化肌钙蛋白 I 水平和舒张功能障碍。心肌细胞分离实验显示舒张功能障碍，短期 BH 4 治疗可使舒张功能恢复正常。血管紧张素转换酶的心脏特异性过表达也导致心脏氧化、NOS 失偶联和舒张功能障碍，而没有高血压。
心脏氧化可导致心脏 NOS 失偶联和舒张功能障碍，独立于血管变化。BH 4 可能是舒张功能障碍的一种潜在治疗方法。
