Cardiovascular disease is the leading cause of death worldwide. Following a heart attack (myocardial infarction), heart cells (cardiomyocytes) die and the dead cells are replaced by fibrotic cells (fibroblasts) because new cardiomyocytes are unable to grow. Fibroblasts proliferate at the damaged area and a fibrotic scar forms on the heart. Myocardial scar tissue leads to heart dysfunction via two major pathways:
(A) The scarred tissue is stretched during heart contraction and the scarred area thins and the heart chamber dilates, contributing to the development of congestive heart failure.
(B) The scarred tissue does not conduct electrical impulses as well as normal tissue, resulting in asynchronous contraction, increasing the chance of dangerous arrhythmias.
Advances in medical therapy, including pharmacological, interventional therapy/device and surgical corrections/transplantation have saved many patients after heart attack. However, these treatments do not repair the damaged heart and cardiovascular diseases remain the number one killer worldwide. A considerable need exists for new treatment strategies to repair, regenerate, and rejuvenate the damaged heart, especially considering that aging is a major cardiovascular risk factor. The proportion of the population categorized as aged is steadily growing, putting a substantial strain on the healthcare system.
Our cardiovascular research laboratory was established in 1993 at the Toronto General Research Institute and focused on cardiac repair and regeneration using cell/stem cell therapy and cardiac tissue engineering technology.
Cell/Stem Cell Therapy
In 1993, we developed a muscle cell implantation technique to repair the injured heart. Since heart failure occurs after heart attack due to fibrotic tissue formation and arrested growth of muscle cells, we implanted cardiomyocytes into scar tissue to use healthy muscle cells to replace and repair dead scar tissue and restore heart function. In 2006, we demonstrated that implanted muscle cells (cardiomyocytes) can survive in the damaged area and improve heart function. This study and our following studies demonstrated a new treatment to repair the heart and improve its function.
Stem cells are those which can differentiate into a variety of different cell types as determined by inducing factors. In 1995, we tested whether stem cells implanted into heart tissue are able to become heart cells. In 1999, we published a paper demonstrating the ability of stem cells to regenerate the damaged heart (this paper has been cited ~1800 times).
When we translated these technologies to clinical applications, we realized that patients with heart failure are aged, and thus have fewer muscle and stem cells for heart repair and regeneration. Aging reduces both the quantity and quality of stem cells, impairing tissue repair and regeneration after an injury. Currently, we are investigating the mechanisms by which transplanted young stem cells rejuvenate the aged organism, both in the heart and other organs, such as the eye and brain. Young stem cells delivered to aged individuals home to the injured organ and facilitate repair processes. Clarifying the mechanisms by which young stem cells rejuvenate the aged organism will facilitate the development of next generation cell therapy techniques for aged patients with cardiovascular and neurodegenerative disorders.
In cell and stem cell therapy, our research path has progressed from repair (1990-2000) and regeneration (2000-2010) to rejuvenation (2010-present).
Cardiac Tissue Engineering
Congenital or acquired cardiac defects are unable to be repaired using stem cell therapy and require surgical repair using synthetic material such as a graft. Since these materials have no growth or functional potential, our research team has focused on the possibility of using biomaterial and stem cells to create heart tissue that is able to beat. In 1996, we demonstrated that we could create heart tissue in a culture condition (cell culture dish). Using this cell-engineered cardiac tissue, we repaired a cardiac defect and prevented heart failure.
In these studies we found that heart cells in 3D cardiac tissue cannot communicate well and contraction was unable to be synchronized. To create most suitable heart tissue, our research group has synthesized novel conductive biomaterials that can be injected into damaged heart tissue to improve the electrical conduction of the heart.
Currently, we are investigating the ability of conductive hydrogels to reduce the incidence of arrhythmias that occur following a heart attack by bridging the gap between viable cardiomyocytes in scarred heart tissue. Developing biocompatible conductive materials that can easily integrate into damaged heart tissue to facilitate the heart’s conduction open the door for new treatment options.
After a heart attack, the death of muscle cells causes a scar to form on the heart. This scar stops the normal path of electrical signals that allows the heart to beat in a coordinated fashion to efficiently eject blood from the heart. In addition, the disrupted signals can induce extra inefficient heart beats (arrhythmia). Patients with abnormal conduction or arrhythmias often need a pacemaker, but electrical stimulation of the heart from the pacemaker disrupts the normal beating sequence and induces dysfunction of the heart. Both the heart attack and the electrical stimulation result in abnormal signal conduction in the heart.
We are designing new materials (conductive biomaterials) which will repair the heart and properly conduct electrical signals across the scar following a heart attack. These new materials will enhance the transmission of electrical signals that control the pumping of the heart. The goal is to restore the normal pattern of coordinated heart contraction. Our new materials are unique because they facilitate electrical conduction and keep the heart beating synchronously. Our aim is to provide a new treatment for cardiac patients that will be more effective than current therapies. This new approach could allow patients to return to their normal lifestyle and remain active without the need of a pacemaker.