A Novel Metabolic Pathway to Treat Heart Failure

by Adrienne Mueller, PhD
September 12, 2022

Heart failure is a broad term that encompasses numerous conditions, all serious and potentially fatal. A leading cause of heart failure is genetic dilated cardiomyopathy or DCM. DCM is a disease in which the heart muscle stretches and becomes thin. As a result, the heart cannot pump enough blood to the rest of the body. It is a progressive heart disorder with no cure. Even though genetic DCM is a disease caused by DNA errors inherited from the parents, we currently do not know the specific molecular mechanisms that cause DCM. And because we don't know the cause, we have difficulty developing effective treatments.

In a recent study published in the European Heart Journal, Ioannis Karakikes, PhD, and colleagues created heart cells from patients’ skin to model the disease in the lab. Using these patient 'avatars,' the investigators had direct access to the heart tissue without requiring invasive experiments in patients. They then grew those cells in the lab and established a new screening platform to identify drugs that can treat the disease.

Small molecule kinase inhibitors (PPIs) activate serine biosynthesis, which leads to improved mitochondrial metabolism, ultimately causing an increase in ATP (energy) and contraction in heart muscle cells.

In this study, the patient's heart cells were exposed to numerous drugs to determine which could make the heart cells beat stronger. The investigators found that a combination of drugs could fix the contractile and metabolic defects in DCM-afflicted cells. Moreover, they were able to identify that a previously unknown process called 

the serine biosynthesis pathway, which produces serine from sugar inside the cells, drove the action of these drugs. Notably, the investigators tested these drugs in several patients' heart cells in the lab – a clinical trial in the dish. Their data suggest that the activation of the serine biosynthesis pathway can make the patients' cells beat stronger regardless of the underlying genetic error, indicating a common target for genetic DCM. The findings of this study will pave the way for future efforts to develop novel treatments for this complicated and life-threatening disease.

Additional Stanford Cardiovascular Institute-affiliated investigators who contributed to this study include Arne A.N. Bruyneel, Vittavat Termglinchan, Emma Monte, Nirmal Vadgama, Takaaki Furihata, Alexandra A. Gavidia, Jennifer Arthur Ataam, Nike Bharucha, Noel Martinez-Amador, Mohamed Ameen, Pooja Nair, Ricardo Serrano, Balpreet Kaur, Dries A.M. Feyen, Michael P. Snyder, and Mark Mercola.

Ioannis Karakikes, PhD