A neonatal leporine model of age-dependent natural heart regeneration after myocardial infarction

Hanjay Wang; Camille E Hironaka; Danielle M Mullis; Haley J Lucian; Hye Sook Shin; Nicholas A Tran; Akshara D Thakore; Shreya Anilkumar; Matthew A Wu; Michael J Paulsen; Yuanjia Zhu; Sam W Baker; Y Joseph Woo

doi:10.1016/j.jtcvs.2021.08.013

A neonatal leporine model of age-dependent natural heart regeneration after myocardial infarction

J Thorac Cardiovasc Surg. 2022 Dec;164(6):e389-e405. doi: 10.1016/j.jtcvs.2021.08.013. Epub 2021 Aug 17.

Affiliations

¹ Department of Cardiothoracic Surgery, Stanford University, Stanford, Calif; Stanford Cardiovascular Institute, Stanford University, Stanford, Calif.
² Department of Cardiothoracic Surgery, Stanford University, Stanford, Calif.
³ Department of Cardiothoracic Surgery, Stanford University, Stanford, Calif; Department of Bioengineering, Stanford University, Stanford, Calif.
⁴ Department of Comparative Medicine, Stanford University, Stanford, Calif.
⁵ Department of Cardiothoracic Surgery, Stanford University, Stanford, Calif; Stanford Cardiovascular Institute, Stanford University, Stanford, Calif; Department of Bioengineering, Stanford University, Stanford, Calif. Electronic address: joswoo@stanford.edu.

PMID: 34649718
DOI: 10.1016/j.jtcvs.2021.08.013

Abstract

Objectives: 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.

Methods: 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.

Results: 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 &lt; .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.

Conclusions: A neonatal leporine myocardial infarction model reveals that newborn rabbits are capable of age-dependent natural heart regeneration.

Keywords: heart regeneration; myocardial infarction; neonate; rabbit.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cicatrix
Heart / diagnostic imaging
Myocardial Infarction* / diagnostic imaging
Myocytes, Cardiac
Rabbits
Regeneration
Stroke Volume
Swine
Ventricular Function, Left*

Grants and funding

R01 HL089315/HL/NHLBI NIH HHS/United States