Cardiovascular 2019 Reputation Fold-Over Cardiovascular National Reputation foldover (1)

UAB MEDICINE CARDIOVASCULAR SERVICES UPDATE 2019
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‘RESETTING’ DYSFUNCTIONAL T-CELLS COULD REVERSE CHRONIC HEART FAILURE
A heart attack triggers an acute inflammatory response,
followed by resolution of inflammation and wound healing.
A severe heart attack, however, can cause chronic and
sustained inflammation that leads to heart failure and death. role in chronic ischemic heart failure.” Restoring the proper
function of T-regs in humans, Dr. Prabhu adds, is “an
appealing therapeutic target for the resolution of chronic
inflammation in ischemic cardiomyopathy.”
In mouse experiments, University of Alabama at Birmingham
scientists have found a way to hit an immunological
“reset button” that stops this inappropriately sustained
inflammation. It reverses the pathologic enlargement and
pumping failure of the heart, and it suggests a therapeutic
approach to treating human heart failure. Published in the
journal Circulation, the research is being led by UAB Medicine
cardiovascular disease physician Sumanth Prabhu, MD. Furthermore, the UAB researchers showed that the
dysfunctional T-reg cells were essential for adverse left-
ventricular remodeling. Essentiality was demonstrated by
selectively ablating the dysfunctional T-reg cells at four weeks
after inducing heart failure. Ablation was done by giving
diphtheria toxin to genetically engineered mice that have the
diphtheria toxin receptor inserted into T cells at the Foxp3
gene site, or by giving the mice anti-CD25 antibodies.
The research found that a group of immune cells called
regulatory T-lymphocyte cells, or T-regs, appear to go
rogue in heart failure. Instead of their normal job to resolve
inflammation, the dysfunctional T-reg cells become pro-
inflammatory and prevent the growth of new capillaries.
Experimental removal of those dysfunctional T-reg cells from
heart-failure mice acted as a reset button to reverse heart
failure, and the replacement T-regs that the mice produced
resolved inflammation. This shows, Dr. Prabhu says, that
dysfunctional T-reg cells play “an essential pathogenetic T-reg ablation reversed left-ventricular remodeling over the
next four weeks. Also, ablation with antibody halted further
increase in left-ventricular remodeling, while remodeling
in the heart failure mice given a non-specific antibody
continued to worsen. Ablation alleviated fibrosis and systemic
inflammation in the heart, and it enhanced growth of new
capillaries. Importantly, the new T-reg cells produced
by the mice after an ablation pulse were no longer pro-
inflammatory; instead, they showed restoration of normal
T-reg immunosuppressive capacity.
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NEONATAL PIG HEARTS CAN HEAL FROM HEART ATTACK
Researchers at the University of Alabama at Birmingham
and at several institutions in Singapore have discovered
that the hearts of newborn piglets can almost completely
heal themselves after experimental heart attacks. This
regenerative capacity is short-lived, disappearing by day
three after birth. Still, this study marks the first time the ability
to regrow heart muscle has been shown in large mammals.
Published in the journal Circulation, this research has
significant clinical implications, says lead UAB researchers
Jianyi “Jay” Zhang, MD, PhD, and Wuqiang Zhu, MD,
PhD. Although no study has ever assessed neonatal heart
regeneration in humans (except a case study of one patient),
there is evidence that surgical correction of anomalous
coronary arteries in the first three months of life is associated
with significant improvement of systolic function. Therefore,
identifying a regenerative window in larger mammals is
a crucial step toward understanding the human heart
regenerative window, and it may serve as a platform for future
clinical studies in human infants afflicted by devastating heart
conditions.
This could establish new guidelines for timing of pediatric
heart surgeries that benefit from the regenerative potential
of the newborn human heart, help to design novel surgical
techniques for pediatric heart surgery, and assist in
developing new therapeutic modalities to enhance or prolong
this regenerative window. Most importantly, understanding
the mechanisms that underlie the drastic changes in neonatal
cardiac cardiomyocyte proliferation during the first week of
life may lead to the ability to manipulate these mechanisms to
promote myocardial regeneration in injured hearts, not only in
children but also in adult patients.
The research found that one-day-old piglets were able to
functionally and structurally recover from experimental heart
attacks, as measured by heart pumping ability, thickness
of the heart muscle in the left ventricle, and a near absence
of fibrotic scar tissue. In contrast, three-day-old piglets had
significant functional and structural impairments, and two-
day-old piglets showed only partial recovery.