Cardiac regeneration in a newborn: what does this mean for future cardiac repair research?

KEYWORDS:

• Cardiac regeneration
• paediatric cardiology
• myocardial infarction
• disease modelling
• heart disease

Human life expectancy has significantly increased due to nutritional access, improved hygiene, or medical advances such as vaccinations. Consequently, morbidities shifted from infectious diseases and malnutrition to, among other chronic diseases, ischemic complications caused by atherosclerosis and neoplasms. The current number one killer worldwide is ischemic heart disease [1] due to irreversible loss of cardiomyocytes following hypoxic injury, universally termed myocardial infarction [2]. In comparison to organ systems that carry intrinsic and effective regenerative capacity – e.g. the skin, bones, skeletal muscles, or the liver [3] – the adult human heart is incapable of clinically relevant regeneration. Whereas organisms such as Zebrafish or Axolotl can efficiently regenerate heart, we (and for that matter all other mammals studied in experimental heart attacks such as pigs, mice, and rats) have lost the capability to repair a ‘broken’ heart in our evolutionary history.

Many attempts have been undertaken to restore cardiac function following hypoxic damage. However, although conceptually very promising, several stem and progenitor cell-based strategies failed to repair myocardial scarring following injury [4,5]. Numerous other strategies are currently under investigation and are reviewed elsewhere [6]. Here, we discuss the potential of neonatal cardiac regeneration as a bona fide model system to search for novel mechanisms and pathways for heart repair in adult humans.

In 2011, Porrello et al. introduced a novel concept of cardiac regeneration in the newborn mouse, building on previous findings that neonatal cardiomyocytes are still highly proliferative at that stage [7]. They demonstrated complete cardiac regeneration of apical myocardial resection in 1-day-old neonatal mice following 21 days post injury. However, when the tip of the heart was cut off at day 7 postpartum, the regenerative capacity was lost resulting in scarring comparable to the adult mouse heart. Encouraged by this first observation of cardiac regeneration in a postnatal mammalian heart, we and at the same time the group of Eric Olson and Hesham Sadek asked the question whether neonatal mice exhibit clinically relevant heart regeneration following complex cardiac damage, namely myocardial infarction [8,9]. Indeed, visually confirmed ligation of the left anterior descending artery (LAD) in the neonatal mouse is feasible and leads to severe hypoxic injury within the anterior and apical left ventricular wall, comparable to the extent of adult LAD ligation injury. Using the LAD ligation model, we reported the regenerative potential of murine neonatal hearts following myocardial infarction. Numerous scientific groups have now extended our knowledge on mouse neonatal cardiac regeneration [10–14].

It is critical to define the limitations of the neonatal model. The initial model of apical resection has been put into question [14,15], but was also confirmed by other groups [14,16]. This launched a critical debate whether neonatal mice can indeed regenerate their heart after resection of the apex. The Lee lab provided an answer to this question by demonstrating the importance of the resection size [13]. We interpret the results of different laboratories by differences in techniques and the extent of the resection cardiac tissue. One key issue might be the size of the initial defect with complete discontinuation of the muscular layer [10]. Despite little experience using the resection model, we propose that defects that lead to transmural defects of the ventricular wall are not completely regenerated. In contrast, the neonatal cardiac LAD ligation model results in midventricular myocardial damage within the area at risk (namely anterior wall and apex), neither affecting the very inner endocardial nor outer epicardial layers. As a result, a viable myocardial scaffold encloses the area of LAD ligation-induced damage. Further supporting evidence come from clinical ‘realities’ where some neonatal hearts are at risk for scar formation following cardiac surgery [17]. This observation of persistent scars in human neonatal babies following surgery prompted us to test another mouse neonatal injury model: cryoinjury. In collaboration with the Kühn laboratory we indeed found persistent scars at the site of cryo-induced injury [11,18]. In addition to (or in combination with) transmural defects as mentioned earlier, scarring in neonates could be also explained by the type of injury and mode of cell death [10,11]. Certainly other mechanisms such as the role of macrophages and cardiac fibroblasts need to be considered [19]. In summary, many preclinical experiments prove the great recovery potential of neonatal murine hearts compared to adult animals based on histological means, functional parameters, DNA synthesis, and mitosis labels. However, current issues such as direct proof of cardiomyocte proliferation or the type and size of injury need further scientific attention to strengthen the current body of evidence.

Besides the elucidation of the underlying mechanism for neonatal cardiac repair, one key question remained: Can one translate these models to the human heart considering the fundamental differences in basic cardiac physiology? Talking to pediatric cardiologists we learned from their experience that human neonatal hearts still possess an enormous cardiac plasticity and can even recover functions after removal of the causative harmful conditions. For instance, the ALCAPA syndrome (Anomalous Left Coronary Artery From the Pulmonary Artery) designates a congenital pediatric heart disease that causes myocardial ischemia [20]. Currently, the only curative approach is cardiac surgery with correction of the coronary malformation. Whereas early correction within the first year of age leads to complete recovery of the heart, delayed diagnosis most often ends in damage and ultimately ischemic cardiomyopathy [20]. Encouraged by the clinical experience, we found a handful of documented cases of human neonatal myocardial infarctions. Perinatal cardiac infarction is a very rare clinical event, primarily due to malformation of the heart or coagulation diseases. Since such events are accompanied with high mortality, all the clinical case reports focused on the description of diagnosis and emergency, and critical care treatment in the acute setting. In the discussions, the authors hinted at a good outcome as long as the baby survived the initial ischemic event, without further descriptions (References within Reference [20])

By coincidence, we were made aware of a human perinatal myocardial infarction case due to cryptogenic thrombotic proximal LAD occlusion, followed by critical care interventions including extracorporeal membrane oxygenation (ECMO) treatment. Importantly, this case allowed us – for the first time – to explore whether newborn humans can also recover cardiac function following a severe heart attack. The child developed massive cardiac damage as defined by serum markers for cardiomyocyte cell death, electrocardiograms, echocardiography, and cardiac angiography. Remarkably, within weeks after the initial ischemic insult, we observed cardiac recovery, which translated into long-term normal heart functions. These data showed that humans have also the intrinsic capability to repair myocardial damage and cardiac regeneration [21]. Thus, fundamental insights gained from cardiac regeneration in fish and neonatal mice might be indeed translatable to future cardiac repair in humans. Since cardiac repair in neonatal mice is limited to the first week after birth, we would like to urge the pediatric cardiologists to collect further cases of human infants to map the time window for cardiac healing.

In summary, preclinical data from multiple research groups support the mammalian neonatal heart as a model for cardiac regeneration. Thus, it might indeed be possible to gain fundamental insights in cardiac repair and thereby decipher the neonatal cardiac regenerative code for the treatment of adult heart disease patients. Now we also possess the experimental armamentarium to tackle crucial scientific questions: Can we identify the transcriptional changes in cardiomyocytes leading to proliferation and myocardial regeneration? Which role plays the immune, interstitial, and the vascular compartment accompanying cardiac healing? Are the developmental changes from a regenerating neonatal to a scarring adult heart temporarily reversible? By studying developmental biology with in vivo mammalian cardiac regeneration models as a blueprint, we are convinced that the scientific community will decipher the neonatal secrets of cardiac regeneration. The overall objective must be the rejuvenation of failing hearts.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was supported by Österreichischer Herzfonds, Medizinischer Forschungsfonds Tirol and a MUI-START grant provided by the Medical University of Innsbruck [grant number 2017-01-014].