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

Date:
April 7, 2022
Source:
University of Pittsburgh
Summary:
Almost one third of babies born with hypoplastic left heart
syndrome, or HLHS, die from heart failure before their first
birthday. By uncovering cellular processes that drive heart
failure in these young patients, a new study may hold the answers
to identifying and treating those at highest risk of early death.



FULL STORY ========================================================================== Almost one third of babies born with hypoplastic left heart syndrome, or
HLHS, die from heart failure before their first birthday. By uncovering cellular processes that drive heart failure in these young patients,
a new study may hold the answers to identifying and treating those at
highest risk of early death.


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

"HLHS is one of the most lethal types of congenital heart disease," said Cecilia Lo, Ph.D., chair of the Department of Developmental Biology at
Pitt, and senior author of the study. "What causes heart failure in HLHS patients who die before one year of age is unknown, and the only treatment option is a heart transplant, which often is not possible. If we can
find the cause, then there is hope for therapy." To get to the heart of
severe HLHS causes, Lo and Xinxiu (Cindy) Xu, Ph.D., first author of the
study and a postdoctoral researcher in Lo's lab, collected skin cells from three healthy people and 10 HLHS patients, who had either milder disease, surviving past age five without a transplant, or severe HLHS, meaning
they died or required a heart transplant in their first year of life.

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

By observing the heart cells under a microscope, the researchers noticed
clear differences among cells from different patient groups. Just as a
living heart squeezes and releases to pump blood, so too do heart cells
in a dish, even without blood to circulate. Cells from patients with
milder HLHS looked and behaved similarly to those from healthy people,
pulsing quickly and steadily.

In contrast, cells from the severe group throbbed in a more languid
manner, eerily reminiscent of what doctors see in the hearts of many
living HLHS patients.



========================================================================== Looking more closely, the researchers found that heart cells from both
patient groups had defective mitochondria, the energy-generating centers,
but this dysfunction was worse in the severe group. Heart cells from
severe HLHS patients also failed to rally natural defenses against stress caused by the mitochondrial defect.

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

Xu explained that if the heart is a car, the mitochondrion is like
an engine.

She thinks of sildenafil as engine oil, "lubricating" mitochondrial
function, preventing it from overheating. TUDCA, on the other hand,
is like coolant, also protecting the engine from overheating. Either of
these drugs can reduce stress caused by defective mitochondria, helping
heart cells from severe patients to achieve what patients with milder
HLHS accomplish naturally.

"We chose these drugs because we know they are safe and already approved
in the clinic for other conditions," added Lo. "This means it will
take less time to get treatments to patients compared with developing
entirely new drugs." For HLHS patients, this could mean new therapies
-- that don't rely on heart transplant -- are on the horizon to treat
heart failure.



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

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

"Because the defect is on a cellular level, a simple blood test might
be able to detect defective mitochondria, allowing early identification
of patients most vulnerable to heart failure," said Lo. "Ultimately,
these findings will help achieve our goal of improving the clinical care
and quality of life for patients with the congenital heart disease such
as HLHS." Other authors who contributed to the study were Abha S. Bais,
Ph.D., Hisato Yagi, Ph.D., Timothy N. Feinstein, Ph.D., Xiaoqin Liu,
M.D., Ph.D., Krithika Sudhakar Rao, Ph.D., Haoting He, Phillip Adams,
D.O., Sruti Shiva, Ph.D., Madhavi K. Ganapathiraju, Ph.D., Dennis Kostka, Ph.D., and Jiuann-Huey Ivy Lin, M.D., Ph.D., all of Pitt; Kang Jin,
B.S., 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, M.S., and Joseph Criscione, B.S., of the University of Rochester; Gloria S. Pryhuber,
M.D., Gisela Beutner, Ph.D., and George A. Porter Jr, M.D., Ph.D.,
all of the University of Rochester Medical Center; Kalyani B.

Karunakaran, of the Indian Institute of Science; and Catherine K. Kuo,
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.


========================================================================== Story Source: Materials provided by University_of_Pittsburgh. Note:
Content may be edited for style and length.


========================================================================== Journal Reference:
1. Xinxiu Xu, Kang Jin, Abha S. Bais, Wenjuan Zhu, Hisato Yagi,
Timothy N.

Feinstein, Phong K. Nguyen, Joseph D. Criscione, Xiaoqin Liu,
Gisela Beutner, Kalyani B. Karunakaran, Krithika S. Rao, Haoting He,
Phillip Adams, Catherine K. Kuo, Dennis Kostka, Gloria S. Pryhuber,
Sruti Shiva, Madhavi K. Ganapathiraju, George A. Porter, Jiuann-Huey
Ivy Lin, Bruce Aronow, Cecilia W. Lo. Uncompensated mitochondrial
oxidative stress underlies heart failure in an iPSC-derived
model of congenital heart disease. Cell Stem Cell, 2022; DOI:
10.1016/j.stem.2022.03.003 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/04/220407141859.htm

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