New hope for predicting and treating heart failure in babies born with a fatal heart defect

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PITTSBURGH – Almost a third of babies born with hypoplastic left heart syndrome, or HLHS, die of heart failure before their first birthday. By uncovering the cellular processes that lead to heart failure in these young patients, a new study may hold the answers to identify and treat those most at risk of premature death.

Published today in Cell Stem Cell by scientists at the University of Pittsburgh School of Medicine, the study found that two commonly used drugs, Viagra and an over-the-counter drug called tauroursodeoxycholic acid (TUDCA), restored the processes that lead to heart failure in cells. from patients, opening up potential avenues for new HLHS treatments.

“HLHS is one of the deadliest types of congenital heart disease,” said Cecilia Lo, Ph.D., chair of Pitt’s Department of Developmental Biology and lead author of the study. “What causes heart failure in HLHS patients who die before the age of one year is unknown, and the only treatment option is a heart transplant, which is often not possible. If we can find the cause, then there is hope for therapy.”

To get to the heart of the serious causes of HLHS, Lo and Xinxiu (Cindy) Xu, Ph.D., the study’s first author and a postdoctoral researcher in Lo’s lab, collected skin cells from three healthy people and of 10 HLHS patients, who either had milder disease, surviving past age five without a transplant, or severe HLHS, meaning they died or required a heart transplant within their first year of life.

First, Xu reprogrammed patient skin cells into induced pluripotent stem cells, which can become any type of cell. Next, she added a blend of growth factors and nutrients that prompt stem cells to develop into heart cells.

Looking at heart cells under a microscope, the researchers noticed clear differences between cells from different groups of patients. Just as a living heart squeezes and slackens to pump blood, so do heart cells in a dish, even without blood to circulate. Cells from patients with milder HLHS looked and behaved the same as those from healthy people, pulsing rapidly and steadily. In contrast, cells in the severe group pulsated in a more languid way, eerily reminiscent of what doctors see in the hearts of many living HLHS patients.

On closer inspection, the researchers found that heart cells in both groups of patients had defective mitochondria, the energy-generating centers, but this dysfunction was worse in the severe group. Cardiac cells from patients with severe HLHS also failed to rally natural defenses against the stress caused by the mitochondrial defect.

Having identified what was wrong at the cellular level, the researchers now had targets for therapies. They found that sildenafil, commonly known as Viagra, and TUDCA rescued the mitochondrial defect in the heart cells of patients with severe disease.

Xu explained that while the heart is a car, the mitochondria is like an engine. She considers sildenafil as engine oil, “lubricating” mitochondrial function, preventing it from overheating. TUDCA, on the other hand, is like a coolant, also protecting the engine from overheating. Either of these drugs can reduce the stress caused by faulty mitochondria, helping the heart cells of severe patients to do what patients with milder HLHS naturally do.
Cindy Xu_release

“We chose these drugs because we know they are safe and already clinically approved for other conditions,” Lo added. “This means it will take less time to get treatments for patients compared to developing entirely new drugs.”

For HLHS patients, this could mean that new therapies – which do not rely on heart transplantation – are on the horizon to treat heart failure.

Lo said the study opens up possibilities for using stem cell-derived heart cells to model heart failure in dishes and screen for drugs faster than traditional animal model approaches.

The findings could also lead to the development of tests that prioritize patients for early heart transplantation.

“Because the defect is at the cellular level, a simple blood test might be able to detect defective mitochondria, allowing for early identification of patients most vulnerable to heart failure,” Lo said. “Ultimately, these results will help achieve our goal of improving the clinical care and quality of life for patients with congenital heart disease such as HLHS.”

Other contributing authors included Abha S. Bais, Ph.D., HisatoYagi, Ph.D., Timothy N. Feinstein, Ph.D., Xiaoqin Liu, MD, Ph.D., Krithika Sudhakar Rao, Ph.,D., Haoting He, Philip Adams, DO, Sruti Shiva, Ph..D., Dennis Kostka, Ph.D., and Jiuann-Huey Ivy Lin, MD, Ph.D., all of Pitt ; KangJin, BS, and Bruce Aronow, Ph.D., of the University of Cincinnati and Cincinnati Children’s Hospital Research Foundation; Wenjuan Zhu, Ph.D., of the Chinese University of Hong Kong; Phong Nguyen, MS, and Joseph Crinscione, BS, from the University of Rochester; Gloria S. Pryhuber, MD, Gisela Beutner, Ph.D., and George A. Porter Jr, MD, Ph.D., all of the University of Rochester Medical Center; Kalyani B. Karunakaran, Indian Institute of Science; and Catherine K. Duo, Ph.D., of the University of Rochester and the University of Maryland.

This research was supported by the National Institutes of Health (HL132024, HL142788, HL144776, and PR140183), the Children’s Heart Foundation, UPMC Children’s Hospital of Pittsburgh, and the American Heart Association.


CAPTION: Cecilia Lo, Ph.D., professor and chair of the Department of Developmental Biology at the University of Pittsburgh

CAPTION: Xinxiu “Cindy” Xu, Ph.D, postdoctoral associate at the University of Pittsburgh

CREDIT: Xu, J. et al. Stem Cell Cell, 10.1016/j.stem.2022.03.003 (2022)

LEGEND: Single heart cells from healthy people (controls) and patients with milder (group I) or severe (group II) forms of hypoplastic left heart. Control and Group I cells beat rapidly and regularly, while Group II cells beat much more slowly.

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