Discovery could lead to new treatments
In people with chronic heart failure, the heart doesn't pump blood as effectively as it should. This leaves the patient weak, tired, and short of breath. The disease is life-threatening, and around half of patients diagnosed with chronic heart failure die within 5 years.
Some patients benefit from an implanted pump called a left ventricular assist device (LVAD). This device boosts the amount of blood pushed out of the heart with each heartbeat, taking over some of the work for the weakened organ. The LVAD can be a "bridge to transplant" for patients awaiting a new heart, or it can be implanted permanently as a lifetime therapy.
Surprisingly, in some LVAD recipients, the device enabled their own heart to recover and grow stronger, but no one knew how this happened. Now, researchers at U of U Health have uncovered the molecular interactions that help these hearts recover. Published in Cell Metabolism, the finding could help develop new medications to treat heart failure earlier, before patients require an LVAD or a transplant.
Healthy heart muscle cells need energy to keep contracting and pumping blood, and this energy is generated through metabolism, a set of chemical reactions that takes place within these cells. Patients who recovered function after receiving an LVAD, the researchers found, produced more of a metabolic protein called mitochondrial pyruvate carrier, or MPC. This protein transports the molecule pyruvate into the mitochondria where it is oxidized and fuels energy production. Without it, pyruvate cannot enter the mitochondria and instead stays in the cytoplasm. There, it is converted to lactate as a way to store energy for future use.
"This was very interesting to us," said Stavros G. Drakos, M.D., Ph.D., cardiologist and director of Cardiovascular Research for the U of U Health Division of Cardiology, and senior author of the study. "Mitochondrial pyruvate carrier has not been examined in the context of heart failure."
MPC was first identified in 2012 by Jared Rutter, Ph.D., U of U professor of biochemistry and Dee Glen and Ida Smith Endowed Chair for Cancer Research. Drakos and Rutter teamed up on this project to investigate how MPC contributes to heart failure.
We think it's reversing the metabolic program that occurs in heart failure
In heart failure, when metabolism goes awry, the cells begin to bulk up and grow larger, a condition called cardiac hypertrophy. "It's similar to the kind of biomass creation that happens in cancer cells," explained Ahmad Cluntun, Ph.D., postdoctoral fellow in the Rutter lab and co-first author of this study. "Unlike cancer cells, they can't proliferate, so they build biomass and get bigger."
By overexpressing MPC in heart muscle cells in the lab, the researchers successfully reversed cardiac hypertrophy. Eliminating MPC, on the other hand, caused hypertrophy to develop. Mice genetically engineered to lack MPC also developed cardiac hypertrophy and heart failure.
"This opens the possibility of prescreening chronic heart failure patients based on MPC expression," Drakos said. Patients with adequate MPC, he explained, could safely wait and see if their heart muscle recovers on an LVAD, rather than rushing into a transplant. But the finding could also have a wider impact for treating heart failure patients before the disease progresses to the point where they need an LVAD.
Metabolism is a game of push and pull within the cell that relies on perfectly balanced chemical reactions. A protein called MCT4 acts in opposition to MPC in carrying out cellular metabolism. The biotech company Vettore Biosciences, which was founded by Rutter, has developed a drug that blocks MCT4, and is investigating it as a possible cancer therapy. When the U of U researchers tested it on heart cells in the lab, and also in mice, the drug successfully reduced cardiac hypertrophy.
"We think it's reversing the metabolic program that occurs in heart failure," explained Rachit Badolia, Ph.D., postdoctoral fellow in the Drakos lab and co-first author of this study.
If the drug works in people, it could be prescribed to patients before they reach end stage heart failure, repairing the heart before it becomes irreparably damaged. "We would be changing the natural course of the disease by applying an effective therapy earlier," Drakos said.
Some 8 million people in the US are currently living with heart failure, and approximately 550,000 new cases are diagnosed each year. As the population ages, rates of chronic heart failure are increasing accordingly. "The disease is costly, it's lethal, and it's frequent," Drakos said. "Developing therapies for this is a big public health target."
-Written by Caroline Seydel
The research was supported with funding from National Institutes of Health, the Thoracic Surgery Foundation, the American Association for Thoracic Surgery Graham Foundation, and the American College of Surgeons, the Nora Eccles Treadwell Foundation and the AHA Heart Failure Strategically Focused Research Network
Jared Rutter founded Vettore Biosciences and co-authors on this study are Vettore Biosciences employees.