Dexamethasone inhibits regeneration and causes ventricular aneurysm in the neonatal porcine heart after myocardial infarction

Highlights

• Dexamethasone inhibits heart regeneration in the hearts of 2-day old pigs after acute myocardial infarction (AMI).

• Dexamethasone causes ventricular aneurysm in the hearts of 2-day old pigs after AMI.

• Dexamethasone inhibits cardiac macrophage expansion in the hearts of 2-day old pigs after AMI.

• Dexamethasone inhibits myocyte cytokinesis in the hearts of 2-day old pigs after AMI.

Abstract

Aims

Recently, we demonstrated that the hearts of neonatal pigs (2-day old) have regenerative capacity, likely driven by cardiac myocyte division, but this potential is lost immediately after postnatal day 3. However, it is unknown if corticosteroid, a broad anti-inflammatory agent, will abrogate the regenerative capacity in the hearts of neonatal pigs. The aim of the current study is to evaluate the effect Dexamethasone (Dex), a broad anti-inflammatory agent, on heart regeneration, structure, and function of the neonatal pigs' post-myocardial infarction (MI).

Methods and results

Dex (0.2 mg/kg/day) was injected intramuscularly into the neonatal pig (age: 2 days postnatal) during the first week post-MI. Myocardial scar and left ventricular function were determined by cardiac magnetic resonance (CMR) imaging. Bromodeoxyuridine (BrdU) pulse-chase labeling, histology, immunohistochemistry, and flow cytometry were performed to determine inflammatory cell infiltration, CM cytokinesis, and myocardial fibrosis. Dex injection during the first-week suppressed acute inflammation post-MI in the pig hearts. It inhibited BrdU incorporation to pig CMs and CM cytokinesis via inhibiting aurora-B protein expression which was associated with mature scar formation and thinned walls at the infarct site. CMR imaging showed Dex caused left ventricular aneurysm and poor ejection fraction.

Conclusions

Dex inhibited CM cytokinesis and functional recovery and caused ventricular aneurysm in the hearts of 2-day old pigs post-MI.

Introduction

Heart failure after myocardial infarction (MI) is one of the leading causes of morbidity and mortality in the world. Unlike zebrafish and newts, which exhibit cardiac regeneration throughout life [1,2], the adult mammalian heart does not have the ability to replace functional myocardium that is lost following MI. The growth of mammalian heart after birth is achieved primarily by hypertrophy of existing cardiomyocytes (CMs), complemented by limited hyperplasia [3]. The adult mammalian heart has some capacity for self-renewal, which is very limited and not sufficient to generate functional cardiac muscle after MI [[4], [5], [6]].

Studies of cardiac regeneration post-injury in mice showed that preexisting CMs are the major source of new CMs after injury [4,[7], [8], [9]] and that hypoxia can induce CM mitosis [10]. Porrello et al. found that the hearts of 1-day-old neonatal mice can regenerate after partial surgical resection, but this capacity is lost by 7 days of age [7]. This regenerative response is characterized by CM proliferation from pre-existing CMs, which can undergo sarcomere disassembly and cytokinesis, in the absence of fibrosis. We and Zhu et al. showed that the hearts of 2-day-old neonatal pigs can regenerate post-MI which was characterized by CM proliferation [11,12]. Several factors have been shown to contribute to regeneration in neonatal mouse hearts, such as collateral artery network rebuilding [13], macrophages [14], and acute inflammation [9]. Dexamethasone (Dex), a type of corticosteroid drug, has been extensively used to prevent or treat bronchopulmonary dysplasia, a major morbidity of premature infants. In addition to its anti-inflammatory effect, it has been shown that postnatal Dex treatment in early life causes systolic dysfunction in neonatal and elderly rat hearts with reduced ventricular weight in the latter [15,16]. However, it's unclear whether Dex causes deleterious effect on heart regeneration of neonatal large mammalian animals' post-injury. Thus, in the current study, we aim to investigate the effect of Dex on heart structure and function of neonatal large mammals post-MI.