Wang Hanjay, Hironaka Camille E, Mullis Danielle M, Lucian Haley J, Shin Hye Sook, Tran Nicholas A, Thakore Akshara D, Anilkumar Shreya, Wu Matthew A, Paulsen Michael J, Zhu Yuanjia, Baker Sam W, Woo Y Joseph
Department of Cardiothoracic Surgery, Stanford University, Stanford, Calif; Stanford Cardiovascular Institute, Stanford University, Stanford, Calif.
Department of Cardiothoracic Surgery, Stanford University, Stanford, Calif.
J Thorac Cardiovasc Surg. 2022 Dec;164(6):e389-e405. doi: 10.1016/j.jtcvs.2021.08.013. Epub 2021 Aug 17.
Neonatal rodents and piglets naturally regenerate the injured heart after myocardial infarction. We hypothesized that neonatal rabbits also exhibit natural heart regeneration after myocardial infarction.
New Zealand white rabbit kits underwent sham surgery or left coronary ligation on postnatal day 1 (n = 94), postnatal day 4 (n = 11), or postnatal day 7 (n = 52). Hearts were explanted 1 day postsurgery to confirm ischemic injury, at 1 week postsurgery to assess cardiomyocyte proliferation, and at 3 weeks postsurgery to assess left ventricular ejection fraction and scar size. Data are presented as mean ± standard deviation.
Size of ischemic injury as a percentage of left ventricular area was similar after myocardial infarction on postnatal day 1 versus on postnatal day 7 (42.3% ± 5.4% vs 42.3% ± 4.7%, P = .9984). Echocardiography confirmed severely reduced ejection fraction at 1 day after postnatal day 1 myocardial infarction (33.7% ± 5.3% vs 65.2% ± 5.5% for postnatal day 1 sham, P = .0001), but no difference at 3 weeks after postnatal day 1 myocardial infarction (56.0% ± 4.0% vs 58.0% ± 3.3% for postnatal day 1 sham, P = .2198). Ejection fraction failed to recover after postnatal day 4 myocardial infarction (49.2% ± 1.8% vs 58.5% ± 5.8% for postnatal day 4 sham, P = .0109) and postnatal day 7 myocardial infarction (39.0% ± 7.8% vs 60.2% ± 5.0% for postnatal day 7 sham, P < .0001). At 3 weeks after infarction, fibrotic scar represented 5.3% ± 1.9%, 14.3% ± 4.9%, and 25.4% ± 13.3% of the left ventricle area in the postnatal day 1, postnatal day 4, and postnatal day 7 groups, respectively. An increased proportion of peri-infarct cardiomyocytes expressed Ki67 (15.9% ± 1.8% vs 10.2% ± 0.8%, P = .0039) and aurora B kinase (4.0% ± 0.9% vs 1.5% ± 0.6%, P = .0088) after postnatal day 1 myocardial infarction compared with sham, but no increase was observed after postnatal day 7 myocardial infarction.
A neonatal leporine myocardial infarction model reveals that newborn rabbits are capable of age-dependent natural heart regeneration.
新生啮齿动物和仔猪在心肌梗死后可自然再生受损心脏。我们推测新生兔在心肌梗死后也表现出自然心脏再生能力。
对出生第1天（n = 94）、出生第4天（n = 11）或出生第7天（n = 52）的新西兰白兔幼崽进行假手术或左冠状动脉结扎。术后1天取出心脏以确认缺血性损伤，术后1周评估心肌细胞增殖，术后3周评估左心室射血分数和瘢痕大小。数据以平均值±标准差表示。
出生第1天与出生第7天心肌梗死后，缺血性损伤面积占左心室面积的百分比相似（42.3%±5.4%对42.3%±4.7%，P = 0.9984）。超声心动图证实出生第1天心肌梗死后1天射血分数严重降低（出生第1天假手术组为65.2%±5.5%，出生第1天心肌梗死组为33.7%±5.3%，P = 0.0001），但出生第1天心肌梗死后3周无差异（出生第1天假手术组为58.0%±3.3%，出生第1天心肌梗死组为56.0%±4.0%）。出生第4天和出生第7天心肌梗死后射血分数未能恢复（出生第4天假手术组为58.5%±5.8%，出生第4天心肌梗死组为49.2%±1.8%，P = 0.0109；出生第7天假手术组为60.2%±5.0%，出生第7天心肌梗死组为39.0%±7.8%，P < 0.0001）。梗死3周后，出生第1天、出生第4天和出生第7天组的纤维化瘢痕分别占左心室面积的5.3%±1.9%、14.3%±4.9%和25.4%±13.3%。与假手术组相比，出生第1天心肌梗死后梗死周边心肌细胞中表达Ki67（15.9%±1.8%对10.2%±0.8%，P = 0.0039）和极光B激酶（4.0%±0.9%对1.5%±0.6%，P = 0.0088）的比例增加，但出生第7天心肌梗死后未观察到增加。
新生兔心肌梗死模型显示新生兔具有年龄依赖性的自然心脏再生能力。
