The study was undertaken by scientists at the Stanford University
School of Medicine
and the findings of the study appear online in the journal
.
Studying Activity of Lab-grown Heart Muscle Cells of Dilated Cardiomyopathy Patients
- The team looked at heart muscle
cells of patients having familial dilated cardiomyopathy,
which is linked to a specific mutation termed the lamin
mutation
- To obtain heart
muscle from these patients, the research team
generated
pluripotent stem cells in the lab from the patient's own skin cells.
- These pluripotent cells can then be
made to differentiate into any specialized tissue of the human body
including heart muscle cells
- Similarly, pluripotent stem cells can also be made from a small quantity (about 10
ml) of patient's blood
- Heart muscle cells from normal
patients grown in the lab show rhythmic beating similar to normal heartbeat,
but heart
cells from patients with familial dilated cardiomyopathy linked to the
lamin mutation beat irregularly and show
abnormal electrical activity
- The defect could be rectified by
introducing a copy of the normal gene using
gene-editing technology, and making the heart muscle cells beat normally
- In the same way,
introducing the lamin mutation into healthy heart cells caused them to
beat irregularly
- Cells with the lamin mutation
demonstrated calcium levels, a key ion that modulates heart muscle
contraction
Thus, the research team confirmed that heart muscle cells in patients
with lamin mutation and dilated cardiomyopathy had irregular rhythm and did not
contract normally.
Testing
Effects of Specific Drugs on
Irregular Heart Rhythm
- The study team found that the lamin
mutation abnormally activated several genes associated with the
platelet-derived growth factor (PDGF) pathway
- The PDGF pathway is critical in
forming blood vessels and is normally only activated when the
heart muscle is under stress
- To clarify whether the abnormal PDGF
pathway caused the irregular rhythm or was the result of the abnormal
rhythm, the team treated heart cells in patients with lamin mutation with two drugs
namely crenolanib and sunitinib that
block the PDGF receptor
- After the addition of these drugs,
the heart cells began to beat rhythmically, and their gene activation
resembled that of heart cells from healthy persons
Thus, scientists confirmed that the abnormal PDGF pathway caused the irregular rhythm of the heart in dilated cardiomyopathy that could be suppressed by drugs such as
sunitinib and crenolanib.
The
two drugs are FDA-approved to treat several
cancers. However, earlier studies by the team have shown that the drugs can
injure the heart at high doses, and thus, need to be further
evaluated to identify the correct dose or find suitable alternatives.
Using Cells
Derived From Patient's Stem Cells To Test New Drugs
The
current research is part of the greater efforts of the study team
in obtaining specialized cells such as heart or brain
cells from patient stem cells
to study disease
effects and response to newer drugs.
"With
10 ml of blood, we can make clinically usable amounts of your beating heart
cells in a dish," said the study's senior author, Joseph Wu, MD, PhD,
director of the Stanford Cardiovascular Institute and a pioneer of the
technique.
"And
if you tell me you're taking some kind of medication for your heart -- like
beta-blockers or statins -- we can add that to see how it affects your heart.
That's the beauty of this approach."
Dr. Wu further states that
he has asked research scholars in his lab to use his blood to generate his
heart cells, liver and brain cells to test the efficacy of drugs he may need to
take in the future.
About Dilated
Cardiomyopathy
- In dilated cardiomyopathy, the left
ventricle, which is the
main pumping chamber of the heart expands to such an extent that the heart
is unable to contract properly
- Patients with dilated cardiomyopathy suffer from
breathlessness, chest pain and sometimes may result in
sudden and deadly cardiac arrest
- Approximately 1 in every 250
Americans is diagnosed with a type of dilated cardiomyopathy
of unknown etiology and up to 35% of these
cases run in families
- Current treatments aim to alleviate
symptoms and improve quality of life
In
summary,
scientists
identified
a
key biological pathway that could be a potential drug target to treat familial
dilated cardiomyopathy (DCM). Reference :
- Researchers Identify Possible Drug Target for Deadly Heart Condition - (http://med.stanford.edu/news/all-news/2019/07/researchers-identify-possible-drug-target-for-heart-condition.html)