by Niki Akbarian

Graphic design by Lauren Jones

Congenital Heart Disease (CHD) encompasses a wide variety of abnormalities in the structure of the heart that occur before birth in the fetus while it is developing during pregnancy.¹ CHD is the most common birth defect, with an annual prevalence of 12.3 per 1,000 births in Canada.² Some CHDs, such as atrial septal defect or ventricular septal defect, may have minimal impact on heart function and can sometimes resolve on their own without requiring treatment. On the other hand, other forms of CHDs, such as single ventricle defects or hypoplastic left heart syndrome, are severe diseases that significantly impair the structure and function of the heart, necessitating urgent medical care and intervention to ensure the survival of affected newborns.³

Professor Osami Honjo, a cardiovascular surgeon at The Hospital for Sick Children (SickKids) and a Senior Associate Scientist in the Translational Medicine program at the SickKids Research Institute, aims to optimize heart transplantation and mechanical circulatory support for neonates and infants with severe, life-threatening CHDs. Dr. Honjo completed his medical education at the Shimane Medical University and completed cardiovascular surgery residency and a PhD in Cardiovascular Physiology at the Okayama University in Japan. In 2004, he joined the University of Toronto as a Congenital Heart Surgery Research Fellow, where he has since led groundbreaking research at both the University of Toronto and the SickKids Research Institute.

With extensive experience in treating various forms of CHD, Dr. Honjo notes that single ventricle physiology presents the most severe outcomes, often resulting in irreparable heart damage and end-stage heart failure. “Patients with single ventricle physiology require three operations to sustain long-term heart function,” Dr. Honjo explains. “Despite these interventions, they may still experience circulatory failure, and the only options for ensuring their survival are mechanical circulatory support or heart transplantation.” Yet, these life-saving measures are confronted with several challenges, including a shortage of heart donors, post-transplant rejection, and the lack of feasible mechanical circulatory support devices for the neonatal and infant populations. Hence, Dr. Honjo’s research is dedicated to overcoming these limitations, aiming to optimize heart transplantation and mechanical circulatory devices for pediatrics with single ventricle physiology.

Over the past five years, Dr. Honjo and his team have concentrated on advancing ex-vivo heart perfusion for pediatric patients—a technique designed to resuscitate and rehabilitate donor hearts for transplantation. Donor hearts can be obtained through two primary methods: donation after brain death (DBD), which is more commonly used in clinical settings; or donation after circulatory death (DCD), where the heart must be arrested before retrieval. Hearts retrieved through DCD are often more damaged due to prolonged ischemia (lack of blood supply), making rehabilitation essential before transplantation. This is where ex-vivo heart perfusion plays a critical role in providing mechanical support to reanimate the heart in a controlled environment using a small circulatory device, thus protecting the heart by minimizing ischemic time.

Given the smaller size of infant hearts, ex-vivo perfusion of DCD hearts presents unique challenges in pediatric care, particularly in determining the optimal perfusion rate—the amount of blood that needs to be circulated to the heart for effective rehabilitation. Dr. Honjo and his team have explored these challenges using large animal models, including piglets, to identify the best methods for setting the perfusion rate. Specifically, the rate can be adjusted by either controlling the flow or the pressure of blood circulation to the heart. In their studies, Dr. Honjo and his team observed that a flow-targeted perfusion rate leads to less swelling and edema of the heart muscle, which, in turn, preserves the heart’s function and enhances both systolic and diastolic ventricular performance.⁴

The working theory behind this observation is that, when a donor’s heart is retrieved through DCD, it suffers from ischemic injury. Once connected to the ex-vivo perfusion device, the heart experiences a secondary injury known as ischemia-reperfusion injury, which occurs when blood flow is restored to previously ischemic tissues, leading to further cellular dysfunction and death. During this reperfusion phase, the micro-vessels in the heart exhibit unpredictable constrictions and relaxations, causing fluctuations in coronary vascular resistance. If the ex-vivo perfusion is solely based on maintaining a specific coronary artery pressure, these fluctuations can result in the heart muscle receiving too much or too little blood flow. However, flow-targeted perfusion ensures consistent coronary blood flow regardless of changes in coronary vascular resistance. Indeed, Dr. Honjo and his team were pioneers in highlighting the advantages of flow-targeted over pressure-targeted perfusion rates for the pediatric population.

Another key area of research in Dr. Honjo’s lab, in collaboration with Dr. Mansoor Husain’s lab at Toronto General Hospital, focuses on identifying pharmacological therapies that aid in the recovery of DCD hearts. In their recent publication, the team highlighted the protective effects of Exenatide, a glucagon-like peptide-1 receptor agonist, for enhancing cardiac function and reducing reperfusion injury in DCD hearts.⁵

Despite significant advancements, Dr. Honjo emphasizes that future studies must address certain limitations that challenge the clinical applicability of their findings. Firstly, important structural and anatomical differences remain that limit the direct translation of results from piglet models to human patients. Additionally, due to the substantial time and resources required for in-vivo transplantation after ex-vivo perfusion, most animal studies in the field of ex-vivo heart perfusion assess heart function using an ex-vivo device rather than by transplanting the heart back into the animal, challenging the clinical relevance of the findings. Addressing these limitations could lead to a more effective evaluation of strategies and therapeutic agents aimed at minimizing reperfusion injury during the ex-vivo phase, ultimately improving outcomes for pediatric patients following the transplantation of DCD hearts.

Indeed, DCD hearts have revolutionized adult cardiac care by expanding the pool of heart donors, including those from greater distances and with borderline cardiac function, thereby reducing the high waiting list mortality among adults with heart disease. Dr. Honjo hopes that their research will bring about a similar transformation in pediatric heart transplantation. “We are hoping that our work will make some difference in the pediatric heart transplantation world,” Dr. Honjo says.

References

1. Kadowaki S, Siraj MA, Chen W, et al. Cardioprotective actions of a glucagon‐like peptide‐1 receptor agonist on Hearts donated after circulatory death. Journal of the American Heart Association. 2023 Feb 7;12(3). doi:10.1161/jaha.122.027163
2. Sun R, Liu M, Lu L, et al. Congenital heart disease: Causes, diagnosis, symptoms, and treatments. Cell Biochemistry and Biophysics. 2015 Feb 1;72(3):857–60. doi:10.1007/s12013-015-0551-6
3. Miao Q, Dunn S, Wen SW, et al. Association between maternal marginalization and infants born with congenital heart disease in Ontario Canada. BMC Public Health. 2023 Apr 28;23(1). doi:10.1186/s12889-023-15660-5
4. Congenital heart defects in children [Internet]. Mayo Foundation for Medical Education and Research; 2024 [cited 2024 Aug 19]. Available from: https://www.mayoclinic.org/diseases-conditions/congenital-heart-defects-children/symptoms-causes/syc-20350074
5. Kobayashi J, Luo S, Akazawa Y, et al. Flow-targeted pediatric ex vivo heart perfusion in donation after circulatory death: A porcine model. The Journal of Heart and Lung Transplantation. 2020 Mar;39(3):267–77. doi:10.1016/j.healun.2019.11.023