After myocardial infarction, the heart fails to regenerate and ischemic/reperfusion injury leads to cardiomyocyte loss and fibrosis leading to impaired heart function1.
Over the years, reperfusion has been shown as the most effective therapy against ischemic damage during myocardial infarction. The recanalization of the occluded coronary artery restores perfusion and prevents myocardial necrosis. However, the medical treatment for heart failure is simply symptomatic for the most part, and those medications for symptoms lead to their own issues and symptoms.
Another strategy is to address the fundamental issue of a failing heart, which is the loss of cardiomyocytes after a heart attack. Cell-based and cell-free therapies are promising alternative to existing medical and interventional treatments. Both approaches have advantages and drawbacks2, and some of them could be additive, in the future.
Cell-based therapy focuses on the direct replacement of lost tissues and the replenishment of contractility. There’s been decades of work done on multipotent cells (adult cells), such as bone-marrow derived cells. From this research, we’ve learned a lot about the clinical infrastructure, how to deliver the therapy and how to deal with patients. However, they were never shown to durably engraft or to regenerate the heart.
More recently, cardiomyocytes derived from pluripotent stem-cells have been successfully transplanted into the deficient tissues of large animal models, to promote the remuscularization of the heart, recreate new blood vessels, restore the immunological balance of the tissue and the electromechanical function of the heart.
Dr. Nakamura works at the UW Medicine Heart Regeneration Program. This translational research focuses on pluripotent stem cell-based cardiac remuscularization therapies, using various preclinical models to optimize the efficacy, safety, engraftment, and maturation of cardiomyocyte transplantation through novel genetic, metabolic, immunomodulatory, antiarrhythmic and delivery strategies.
In an interview, Dr. Nakamura explained us his current research.
Cell-free therapies, based on gene therapy, acellular cardiac patches or exosomes are also investigated, because they reduce the challenges related to the use of cell-based therapy, such as immunological risks or transitory ventricular arrhythmias. One of the most studied approaches relies on the cardioprotective effect of paracrine factors released from stem-cells, to improve heart regeneration.
As an example of cell-free therapy, Zhang et al.3 successfully developed an AAV-based gene therapy to knockdown the Hippo signaling pathway (AAV-Sav-shRNA) and induce cardiomyocyte renewal. They investigated the effects of the gene therapy on arrhythmic events in pigs following induced myocardial infarction. Myocardial infarction was induced in pigs implanted with easyTEL+ telemeters, via an angioplasty balloon blocking blood flow in the left anterior descending artery. Treatment was introduced after 14 days via injection. Continuous data was collected from the pigs and then ecgAUTO was used to characterize and quantify arrhythmias using pattern recognition.
Mixed effects analysis showed incidences of PVCs to be similar between control and test groups prior to treatment. Post treatment, the AAV-Sav-shRNA group shows a significant decrease in PVC incidence when compared to the control. Atrial tachycardia for the shRNA treated group show a statistically significant difference when comparing the cumulative events after treatment. These results indicate that gene therapy is a promising avenue to treat refractory postinfarct arrhythmias.
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