Myocardial Hypertrophy and Circulating RNAs

– Hi, welcome. I’m Susmita Sahoo from
Icahn School of Medicine, Mount Sinai, New York. And with me is doctor Ravi Shah from Mass Gen Hospital, Massachusetts. And he presented his excellent science in today’s Early Career
Pre-Conference Session which is titled Next Best Thing
in Cardiovascular Research. Ravi, would you like to
highlight your research and educate us about it? – Thank you, Dr. Sahoo. So, myocardial hypertrophy
is one of the antecedents of heart failure across the world, and it’s caused by a
variety of different inputs, diabetes, obesity, hypertension. It’s been investigated for
the last 10 to 20 years, different genetic and
epigenetic mechanisms of how hypertrophy develops and how it leads to heart failure. And more recently, in the
last five or 10 years or so, we’ve gained interest in
understanding the role of circulating extracellular RNAs. These are non-coding RNA
molecules that are stable within circulation that we
can assay as potential insight into the mechanisms of development of hypertrophy and heart failure. And our hypothesis in this study was that circulating RNAs in the plasma that we can measure in a
large community-based cohort would give us some insights
into those mechanisms that might actually be
operative in causing thickened left ventricle and
heart failure pathologically. So, we actually had a very fortunate AHA-supported endeavor, here, by the Strategically Focused Research
Network in Heart Failure, where we were able to cross
three difference disciplines. We were allowed to quantify a whole range of circulating extracellular RNAs within the Framingham Heart Study, both by RNA sequencing as well
as by high-throughput PCR, and used the richness,
phenotypic richness, of the Framingham Heart Study to identify a subset of RNAs that
were related not only to cardiac remodeling and hypertrophy, but also to instigating heart
failure over eight years. So, these are inpatients in a community and participants in a
community looking specifically at their risk of heart failure
as a function of these RNAs. The interesting part of this and that was the opportunity afforded by the AHA, was to move forward into the basic realm and take these RNAs and
understand in silico what pathways they target, what different dysregulation occurs within animal and cellular
models of heart failure. So, we were able to go on and show that several of these
RNAs are dysregulated during pressure overloaded mice, as well as in cellular models. And modulation of some of these RNAs might actually prevent
some of the pathologic responses to stress in animals. We showed similar findings
in human failing myocardium. Patients with heart
failure who were referred for ventricular assist
device had similar patterns in expression of these RNAs. So, it’s a fully translational
approach that essentially, spans population, clinical,
and basic investigation and I’m happy that the
BCVS Early Career Committee gave me the opportunity
to present this work here. – Excellent, so, I’m kind of curious, do you have any thoughts
about where these RNAs in the blood plasma are coming from? Because plasma contains
all molecules secreted by several cell types in our body. – Right, so that’s
certainly a big question in the extracellular RNA field, and the specific RNAs that we investigated do derive from endothelium
vascular smooth muscle cells, and our research suggests that they are also expressed within cardiomyocytes. But ongoing studies within the laboratory are trying to identify
whether these specific RNAs can be contained in circulating
extracellular vesicles that would allow organs
distant to the heart to communicate to the heart
during periods of stress, such as in obesity,
diabetes, and hypertension, to promote this pro-hypertrophic pro-heart failure signaling program. – So, going forward, what
do you think is the clinical and scientific basic science
significance of your research? How do we, how can we
implement it in our research, as well as in therapeutic approaches? – So, I think there are probably
two major avenues, here. The first avenue is that these specific extracellular RNAs, this
is one of the first studies showing that they’re related
to long-term heart failure. Whereas, independent of
traditional clinical risk factors. So, whether this is going to be born out in other large populations to allow us to stratify risk of heart failure in community-dwelling participants, or it’s something that
we can use in advanced heart failure patients,
remains to be determined. Certainly, the
identification of these RNAs allows us to understand a little bit more about the mechanisms of hypertrophy that might allow us downstream to target some of these mechanisms in
ameliorating heart failure. But a second point that I
think is very important here is that most of the
discovery that we’ve had has been from mouse studies
where we produce a phenotype, and then look at the
genomics or the proteomics or the transcriptional
profiling changes that occur. One unique aspect of this
study supported by the AHA was looking specifically
at human populations and deriving things that
matter within patients who are in the community and stable, or patients with heart failure, and then taking those insights and looking within our model systems and showing that some of those
RNAs can span the spectrum. So, I think that paradigm of research is something that we
can probably reproduce in a variety of different
fields for therapeutic benefit. – Yeah, excellent, and good luck with your excellent research
and it was a pleasure to have you in the morning session today. Thank you. – Thank you.

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