Addressing the Energy Needs of the Failing Heart
By Amanda Chase, PhD
March 15, 2021
The heart is an amazing muscle – able to pump about 2,000 gallons of blood through the body in one day. 2,000 gallons of blood that are necessary for the body to function. To achieve that fantastic feat, the heart must use energy, just as any of us must expend energy to lift and move heavy objects. In cardiomyocytes (cardiac muscle cells), most of the cell’s energy is in the form of ATP produced by mitochondria.
When the heart is not able to pump as efficiently as needed, it results in heart failure. The number of patients with heart failure is steadily increasing and represents a top diagnosis of hospital admissions. Although considerable progress has been made in the treatment of chronic heart failure, none are curative treatments and there continues to be about a 10% annual morbidity rate. Importantly, heart failure has an imbalance between energy supply and demand. There is decreased ATP (energy) production while also increased energy demands from the failing heart, resulting in contractile abnormality and myocardial (heart muscle) dysfunction. As an energy imbalance is at the apparent root of heart failure, it is essential to develop a therapy that targets the intracellular energy supply directly, creating the potential for a curative therapy.
Patient specific iPSCs can be generated and made into cardiomyocytes (iCMs). The resulting extracellular vesicles that contain fully functional mitochondria can be collected and used as a therapy to address the energy imbalance characteristic of heart failure.
That critical need was recently addressed by a team of researchers led by Cardiovascular Institute affiliated first author Gentaro Ikeda, MD, PhD, and senior author Phillip Yang, MD, and published in the Journal of the American College of Cardiology. The team established a preclinical proof-of-concept that they could enhance cardiac function by transferring mitochondria and restoring myocardial energy production.
Their work relied on two important considerations: (1) Extracellular vesicles can transfer cargo to the recipient cells and mitochondria can exist inside the EVs, and (2) induced pluripotent stem cells (iPSCs) have tremendous therapeutic potential for cardiovascular disease treatment. Patient-specific iPSCs can be made into cardiomyocytes (iCMs) that produce EVs with functional mitochondria. The team was able to show that transfer of mitochondria, and nonmitochondrial cargo, by the EV restored the energy needed by cardiomyocytes to also restore the normal contractility of injured iCMs. Furthermore, they use a mouse model to show that injection of those EVs containing functional mitochondria improved cardiac function in mice after damage resulting from a heart attack. This critical study demonstrated the feasibility of using EVs to transfer mitochondria as a potentially curative treatment for heart failure.
Other authors affiliated with the Cardiovascular Institute include Michelle Santoso, Yuko Tada, Evgeniya Vaskova, Ji-Hye Jung, and Conner O’Brien.
Gentaro Ikeda, MD, PhD
Phillip Yang, MD