UTSW. US: Prolonged use of a left ventricular assist device (LVAD)
by patients with heart failure may induce regeneration of heart muscle
by preventing oxidative damage to a cell-regulator mechanism,
UT Southwestern Medical Center investigators have found.
LVADs are mechanical pumps that are sometimes implanted in patients
who are awaiting heart transplants. LVADs substitute for the damaged
heart by pumping blood throughout the body.
Dr. Hesham Sadek,
Assistant Professor of Internal Medicine at UT Southwestern, is senior
author of the study, which looked at pre- and post-LVAD samples of heart
muscle in 10 patients with heart failure. The study authors examined
the paired tissue samples for markers of DNA damage and cell
proliferation.
Their study builds on earlier work with mice that demonstrated that
newborn mammalian hearts are capable of a strong, regenerative response
to injury by activating cell division. The earlier studies further
showed that the ability to respond to injury is lost due to changes in
circulation that occur after birth, which lead to a more oxygenated
environment in the heart, ultimately causing oxidative damage to the
cellular machinery that controls heart-muscle regeneration.
In the current study, the investigators reasoned that, by assisting
the damaged heart, LVADs would alleviate oxidative damage that occurs
within the heart-muscle cells.
“We looked at markers of what is called the DNA damage response in
cardiomyocytes (heart-muscle cells) of these patients,” said Dr. Sadek.
“The response is composed of a cascade of proteins that is activated in
response to DNA damage and in turn shuts off the ability of
cardiomyocytes to divide. We found that patients who were on LVAD for
more than six months had significantly decreased levels of DNA damage
response.”
Next, the investigators examined the paired tissue samples for
markers of cell division. They found that patients who were on LVADs for
six months or longer had a significant increase in cardiomyocyte
proliferation. The increase in cell proliferation was nearly triple, in
fact.
“This result shows that patients with mechanical assist devices have
the ability to make their muscle cells divide,” said Dr. Sadek. “And the
obvious question now is, ‘Are these hearts regenerating? Could LVADs be
used as a cure for heart failure?’ ”
Heart failure is a debilitating and deadly disease in which the
heart, as a result of injury, cannot pump blood efficiently and hence
cannot provide sufficient oxygen to organs throughout the body. About 6
million people in the United States are living with heart failure,
according to the American Heart Association, and the incidence is
expected to soar over the next 20 years as the population ages and as
heart-attack treatments improve and more people survive heart attacks.
Dr. Pradeep Mammen,
Associate Professor of Internal Medicine at UT Southwestern, is
co-senior author of the study. “Putting in a mechanical pump rests the
heart and apparently sends a signal to make new heart cells. This is
the first time that this phenomenon has been shown to occur in human
heart failure.”
Dr. Sadek said the next step is to document that the cell division
they observed produces viable heart tissue and a stronger pump.
The Chief of Cardiology at UT Southwestern called the new research
“exciting.” “Dr. Sadek's findings raise the prospect of reawakening
otherwise quiescent cardiac muscle cells, coaxing them into regenerating
new and healthy cells. This has been an over-arching objective of the
field for many years. The next step will be to leverage these exciting
results to rebuild the failing heart,” said Dr. Joseph Hill, Professor of Internal Medicine and Molecular Biology.
“This is an exciting advance. We have a long way to go, but hopefully
this study will be an important first step toward uncovering methods of
promoting myocardial recovery,” said Dr. Mark Drazner, Professor of Internal Medicine and Medical Director of the Heart Failure, LVAD, and Cardiology Transplant Program.
Dr. Sadek and Dr. Mammen are members of the newly established Hamon Center for Regenerative Science and Medicine,
made possible by a $10 million endowment gift from the Hamon Charitable
Foundation. The Center’s goal is to understand the basic mechanisms for
tissue and organ formation, and then to use the knowledge to
regenerate, repair, and replace tissues damaged by aging and injury.
Dr. Eric Olson,
Professor of Molecular Biology and Chairman of the Department of
Molecular Biology, is the head of the Hamon Center. “This is a
fascinating study and a wonderful example of the translation of a
discovery in basic science to an important new insight into human
disease,” said Dr. Olson. “Dr. Sadek’s work provides fresh new ideas for
stimulating heart regeneration, which is one of the biggest challenges
in cardiovascular medicine today.”
This paper appears online in the Journal of the American College of Cardiology.
Other UT Southwestern investigators involved in this study are Dr. Diana Canseco, Assistant Instructor in Internal Medicine; Dr. Wataru Kimura,
Assistant Instructor in Internal Medicine; Dr. Sonia Garg, cardiology
fellow; Dr. Shibani Mukherjee, Instructor in Psychiatry; Dr. Souparno
Bhattacharya, research assistant; Salim Abdisalaam, graduate student; Dr. Sandeep Das, Associate Professor of Internal Medicine; and Dr. Asaithamby Aroumougame; Assistant Professor of Radiation Oncology.
Dr. Drazner holds the James M. Wooten Chair in Cardiology. Dr. Hill
holds the Frank M. Ryburn, Jr. Chair in Heart Research and the James T.
Willerson, M.D. Distinguished Chair in Cardiovascular Diseases. Dr.
Olson holds the Annie and Willie Nelson Professorship in Stem Cell
Research, the Pogue Distinguished Chair in Research on Cardiac Birth
Defects, and the Robert A. Welch Distinguished Chair in Science.
This research is supported by grants from NIH and the Foundation for Heart Failure Research.