Bakrania B, Du Toit E F, Ashton K J, Wagner K-H, Headrick J P, Bulmer A C
Heart Foundation Research Centre, Menzies Health Institute Queensland, Griffith University, Gold Coast, Qld, Australia.
Faculty of Health Sciences and Medicine, Bond University, Gold Coast, Qld, Australia.
Acta Physiol (Oxf). 2017 Aug;220(4):461-470. doi: 10.1111/apha.12858. Epub 2017 Mar 14.
Bilirubin is associated with reduced risk of cardiovascular disease, as evidenced in conditions of mild hyperbilirubinaemia (Gilbert's Syndrome). Little is known regarding myocardial stress resistance in hyperbilirubinaemic conditions or whether life-long exposure modifies cardiac function, which might contribute to protection from cardiovascular disease.
Hyperbilirubinaemic rats and littermate controls underwent echocardiography at 3, 6 and 12 months of age, with hearts subsequently assessed for resistance to 30 min of ischaemia. Heart tissue was then collected for assessment of bilirubin content.
No difference in baseline cardiac function was evident until 6 months onwards, where Gunn rats demonstrated aortic dilatation and reduced peak ejection velocities. Additionally, duration of ventricular ejection increased progressively, indicating a negative inotropic effect of bilirubin in vivo. Ex vivo analysis of baseline function revealed reduced left ventricular pressure development (LVDP) and contractility in hyperbilirubinaemic rats. Furthermore, stress resistance was improved in Gunn hearts: post-ischaemic recoveries of LVDP (76 ± 22% vs. 29 ± 17% Control, P < 0.01) and coronary flow (96 ± 9% vs. 86 ± 16% Control, P < 0.01) were improved in Gunn hearts, accompanied by reduced infarct area (21 ± 5% vs. 47 ± 15% Control, P < 0.01), and ventricular malondialdehyde and protein carbonyl content. Expression of myocardial nitric oxide-regulating genes including Nos1 and Noa1 were not significantly different.
These data reveal life-long hyperbilirubinaemia induces age-dependent hypocontractility in male Gunn rats, and improved stress resistance. In addition, bilirubin exerts sex-independent effects on vascular structure, myocardial function and ischaemic tolerance, the latter likely mediated via bilirubin's antioxidant properties.
胆红素与心血管疾病风险降低相关，轻度高胆红素血症（吉尔伯特综合征）的情况可证明这一点。关于高胆红素血症状态下的心肌应激抵抗，或者终身暴露是否会改变心脏功能（这可能有助于预防心血管疾病），目前知之甚少。
高胆红素血症大鼠和同窝对照大鼠在3、6和12月龄时接受超声心动图检查，随后评估心脏对30分钟缺血的抵抗能力。然后收集心脏组织以评估胆红素含量。
直到6个月龄时，基线心脏功能才出现明显差异，此时冈恩大鼠表现出主动脉扩张和射血峰值速度降低。此外，心室射血持续时间逐渐增加，表明胆红素在体内具有负性肌力作用。对基线功能的体外分析显示，高胆红素血症大鼠的左心室压力发展（LVDP）和收缩性降低。此外，冈恩心脏的应激抵抗能力得到改善：冈恩心脏缺血后LVDP的恢复（76±22%对29±17%对照，P<0.01）和冠状动脉血流的恢复（96±9%对86±16%对照，P<0.01）得到改善，同时梗死面积减小（21±5%对47±15%对照，P<0.01），心室丙二醛和蛋白质羰基含量降低。包括Nos1和Noa1在内的心肌一氧化氮调节基因的表达没有显著差异。
这些数据表明，终身高胆红素血症会导致雄性冈恩大鼠出现年龄依赖性收缩功能减退，并提高应激抵抗能力。此外，胆红素对血管结构、心肌功能和缺血耐受性具有性别无关的影响，后者可能通过胆红素的抗氧化特性介导。
