Colo. – Researchers at the University of Colorado School of
Medicine have identified a potential treatment target for patients with a
common type of heart failure.
published in the February 7 issue of the journal Science Translational
Medicine, the researchers tested the effect of an investigational drug
called givinostat in treating diastolic dysfunction, which is a heart
relaxation abnormality that contributes to heart failure with preserved
ejection fraction (HFpEF).
refers to cases where the heart can pump blood normally, but is not able to
fill as efficiently as a healthy heart. Millions of people worldwide suffer
from HFpEF, which can be caused by hypertension, diabetes, aging or other
conditions. Individuals with HFpEF die at an alarming rate and, unfortunately,
there are no effective drugs to treat this form of heart failure.
studying of the hearts of patients with diastolic dysfunction and HFpEF, the
research team found that fibrosis, the commonly suspected culprit in these cases,
is not the sole cause of diastolic dysfunction. Instead, their findings
indicated that there was a defect in the ability of the muscle cells of the
heart to relax.
address whether this defect in the muscle cells could be treated, the
researchers, led by CU faculty members Mark Y. Jeong, MD, assistant professor
of medicine, and Timothy A. McKinsey, PhD, associate professor of medicine,
tested whether givinostat might improve the heart’s ability to relax in the
face of hypertension or aging. They found that the investigational drug, tested
in rat and mouse models, helped the heart relax properly. Thus, the findings
hold promise for treating patients with diastolic dysfunction and HFpEF.
are exciting findings because we may be able to help patients with a form of
heart failure that has been recalcitrant to standard-of-care therapies,” said
McKinsey. “Givinostat is currently in clinical development for the treatment of
muscular dystrophy. Our data suggest the possibility that givinostat could be
‘repurposed’ for the treatment of HFpEF. Obviously it is early days, but we are
excited to test givinostat in a large animal model of HFpEF as the next step
toward translating our findings to humans. Our data also reveal relaxation
impairment of muscle cells as a previously unrecognized process that
contributes to diastolic dysfunction of the heart. Thus, other therapeutic
strategies that improve this defect could also be useful for the treatment of
addition to Jeong and McKinsey, others affiliated with CU who are authors on
the paper are Ying H. Lin, PhD; Sara A. Wennersten; Kimberly M. Demos-Davies;
Maria A. Cavasin, PhD; Jennifer H. Mahaffey, MS; T. Brett Reece, MD; Amrut
Ambardekar, MD; and Charles A. Dinarello, MD. Investigators from the University
of Arizona (Chandrasekhar Saripalli, MS, and Henk L. Granzier, PhD) and
Italfarmaco (Valmen Monzani and Paolo Mascagni, PhD) also contributed to the
for researchers working on this study was provided by the National Institutes of
Health, the Colorado Clinical and Translational Sciences Institute, the
Hartford/Jahnigen Center of Excellence in Geriatrics, a Sarnoff Endowment
Fellow-to-Faculty Transition Award, the American Heart Association, and the
Boettcher Foundation’s Webb-Waring Biomedical Research Program.
is also director of the Consortium for Fibrosis Research & Translation
(CFReT), which is one of the programs supported through the CU School of
Medicine’s Transformational Research Funding initiative (www.cfret.org).