Repairing a Broken Engine: New Approaches to Treat Heart Failure
Repairing a Broken Engine: New Approaches to Treat Heart Failure
Dipayan Chaudhuri, MD, PhD, explains his research to seek new therapies to treat mitochondrial dysfunction in heart failure.
The presentation was part of Vitae 2022, an annual celebration of excellence in which University of Utah Health rising star researchers share their science and how they got to where they are today.
PLEASE SUBSCRIBE FOR NEW VIDEOS: / uofuhealthcare
RESOURCES:
Chaudhari Lab: http://chaix.u2m2.utah.edu/amandine-c…
U of U Health Research: https://uofuhealth.utah.edu/research
Vitae 2022: https://uofuhealth.utah.edu/newsroom/…
This information was accurate as of February 1, 2022. Consult local medical authority or your healthcare provider for specific advice.
ABOUT UNIVERSITY OF UTAH HEALTH:
University of Utah Health provides leading-edge and compassionate care for a referral area that encompasses Idaho, Wyoming, Montana, and much of Nevada. A hub for health sciences research and education in the region, U of U Health has a $458 million research enterprise and trains scientists and the majority of Utah’s physicians and health care providers at its Colleges of Health, Nursing, and Pharmacy and Schools of Dentistry and Medicine. With more than 20,000 employees, the system includes 12 community clinics and five hospitals. U of U Health is recognized nationally as a transformative health care system and provider of world-class care.
#uofuhealth #Vitae2022
Share this video with others: • Repairing a Broken Engine: New Approa…
SUBSCRIBE to learn more: / uofuhealthcare
UNIVERSITY OF UTAH HEALTH ACROSS THE WEB:
University of Utah Health: https://healthcare.utah.edu/
Facebook: https: https://www.facebook.com/UofUHealth/
Twitter: https://twitter.com/UofUHealth
Instagram: https://www.instagram.com/uofuhealth/
Content
4.88 -> so this is a cardiac catheterization
7.88 -> which is a series of live images that we
11.4 -> take via X-ray and you can see the
13.92 -> hearts beating you can see a catheter
15.9 -> all the way on the left injecting
17.46 -> contrast into the coronary tree and
19.8 -> right where that red dot is is you can
21.9 -> see a blockage
24.18 -> we can fix that by opening up that
26.88 -> blockage and putting in a series of
28.619 -> stents to restore blood flow to the
31.08 -> heart
32.16 -> I like showing this case because
33.78 -> although I took care of this patient my
35.88 -> wife Dr Abraham actually performed this
38.34 -> procedure
40.02 -> um although we can restore blood flow
42.54 -> the heart itself still gets injured
44.82 -> during all the time that it's blocked
47.399 -> if that injury is severe enough you get
49.26 -> a condition called heart failure
51.719 -> so this is an echocardiogram of a normal
53.94 -> human heart you can see that all four
55.86 -> chambers are beating quite vigorously
58.86 -> if you get a heart attack and have
60.96 -> severe enough injury it looks more like
63.6 -> this where the chambers are fairly weak
66.24 -> and unable to pump
67.979 -> this condition is called heart failure
70.26 -> so how do we treat heart failure
73.02 -> so I want you guys to do a little bit of
74.76 -> a thought experiment with me imagine
76.799 -> that you're driving your car and you hit
78.6 -> a pothole and all of a sudden your
81 -> engine isn't working so well and it's
82.619 -> making a funny noise and your car won't
84.36 -> go
85.259 -> so you take it to the mechanic imagine
87.54 -> what you would think if the mechanic
89.4 -> told you this
90.6 -> from now on
92.22 -> only one person in the car you can't
94.68 -> have any passengers it's going to stress
96.78 -> the car out too much
98.34 -> from now on you can't take it above 30
100.5 -> because it's going to stress the car too
102.119 -> much and from now on no going uphill or
105.659 -> into the mountains because it's going to
107.1 -> stress the heart the car too much so I
109.5 -> think in this in this circumstance any
111.42 -> of us would ask but why can't you just
113.82 -> fix the engine
115.38 -> so
117.119 -> this is how we treat heart failure we
120.18 -> reduce the stress on the heart we can do
122.46 -> this in a variety of ways by reducing
125.1 -> the amount of blood the heart has to
126.719 -> pump by reducing how fast it can go or
129.84 -> how hard it has to beat all of these
132.42 -> therapies are incredibly effective but
134.64 -> they don't get at the problem with the
136.08 -> engine and in heart failure one of the
138.36 -> most common
139.459 -> dysfunctions are within the mitochondria
142.86 -> so what are mitochondria mitochondria
145.62 -> are the part of every cell that make the
147.9 -> fuel they have two membranes and
150.54 -> embedded in this inner membrane is a
152.34 -> series of proteins that turns everything
154.56 -> you eat into fuel the heart can use a
157.5 -> molecule known as ATP
160.44 -> in heart failure mitochondria don't make
163.14 -> enough fuel
165.42 -> we've chosen to study this form of
167.64 -> dysfunction in a series of rare diseases
169.8 -> known as the mitochondrial
171 -> cardiomyopathies and cardiomyopathy is
173.34 -> just a fancy way of saying heart failure
175.44 -> these are diseases that occur primarily
178.019 -> in children and in infants who are born
180.599 -> with mutations in their mitochondrial
183.239 -> proteins and although the mutations can
185.7 -> occur in a wide range of proteins these
188.519 -> children will often get a cardiomyopathy
191.04 -> or heart failure
192.9 -> so in order to understand our approach
195.54 -> to study these disorders I thought I'd
197.58 -> take a little detour and tell you about
199.8 -> my background
201.12 -> so
202.8 -> although I was born in India I grew up
206.159 -> in a small town in Venezuela along the
209.099 -> northern coast and I had never done
211.92 -> research or been in a lab or done any
214.14 -> kind of science until the sophomore year
215.819 -> of my of college where a friend told me
218.94 -> to check out some labs and I happened to
220.739 -> meet Andy bass Andy turned out to be a
223.68 -> wonderful mentor and what Andy does is
226.319 -> he's a neurobiologist who studies these
228.72 -> fish which are known as the plain fin
230.58 -> midshipmen found along the Northwestern
232.62 -> coast of the United States
234.239 -> one of the interesting things about
235.739 -> these fish is that the male who's in the
237.959 -> middle there sings to attract the female
240.78 -> to its nest
242.879 -> and so Andy was showing me uh the lab
245.22 -> when I first met him and we happened to
247.14 -> go into a room where a student was
249.78 -> performing an experiment and I heard
251.7 -> this
260.16 -> so that humming that you hear is the
263.16 -> song of the male and all the clicks are
266.46 -> electrical activity in the brain of a
268.62 -> female who's listening to that song
271.259 -> and you know for me that was it I was
274.32 -> hooked I thought this was the coolest
275.759 -> thing I'd ever seen and since then I've
279.24 -> kind of dedicated my career uh towards
282.06 -> understanding how electrical activity
284.04 -> affects cellular function so following
287.16 -> that experience I went on to grad school
288.84 -> and I happened to have the privilege of
291.18 -> working with David Yu who unfortunately
293.04 -> passed away about 10 years ago and I
296.52 -> learned a lot of things in David's lab I
298.979 -> want to tell you about two of them so if
300.6 -> you look at this picture I'm not sure
302.759 -> exactly when this picture was taken it
304.74 -> might have been 2002 it might have been
306.36 -> 2003 but one thing I can tell you is
308.52 -> that this picture was taken around nine
309.9 -> o'clock at night and that's because
311.759 -> David and I had finally after several
314.58 -> hours of battling the electrical
316.38 -> equipment you see behind us reduce the
318.72 -> noise noise in it enough to get some
321.36 -> really nice recordings those green
323.46 -> squiggles that you can see on the screen
325.86 -> and if you look at me I'm pretty tired I
329.34 -> want to go home but David has just
332.52 -> boundless enthusiasm and I think that
334.8 -> was one of the things he taught me that
336.36 -> you know a lot of what we do ends in
338.46 -> Failure so you got to celebrate even the
340.74 -> smallest of victories
342.479 -> the other thing I learned in this lab
344.16 -> was calcium channels so these are
346.74 -> proteins that are embedded in the
348.3 -> membrane and whether it's on the surface
350.4 -> of the cell or within the cell and what
352.44 -> they do is they take calcium from one
354.3 -> side of the membrane to the other
356.1 -> I went on to study these within the
357.96 -> mitochondria during my postdoc with
359.699 -> David Clapham
361.44 -> and so since that time we've chosen to
364.86 -> study the mitochondrial calcium channels
367.259 -> the one we study in particular is this
369.36 -> one known as the mitochondrial calcium
371.039 -> uniporter so what does calcium do within
374.46 -> the mitochondria so I'm going to use
376.32 -> exercises as an example so whenever you
379.32 -> exercise calcium levels go up within
382.139 -> your within the cells in your heart and
384.3 -> they get transmitted to within the
385.86 -> mitochondria via this channel that we
387.72 -> study within the mitochondria calcium
390.12 -> acts as a sort of accelerator it boosts
392.819 -> the activity of these proteins to
394.56 -> generate more ATP this is what allows
396.96 -> you to exercise and run hard
400.319 -> so in these diseases that we study there
403.68 -> are mutations that affect the ability of
406.02 -> the heart to make ATP that's that
408.24 -> cellular fuel that the heart uses
409.979 -> they're not making enough ATP well we've
413.039 -> spent the last few years defining is
414.96 -> that there is a feedback pathway that
417.06 -> the mitochondria uses it senses this
419.4 -> this reduction in ATP and actually makes
422.759 -> more channels these channels then let in
426.419 -> a lot more calcium and that calcium can
429.24 -> then boost the activity of the proteins
432.18 -> that are there to restore or even rescue
434.699 -> this energetic failure
437.639 -> that's very so mitochondria engage this
440.28 -> Pathway to preserve energy production in
443.039 -> heart failure
444.24 -> so that work took several years and it
446.699 -> was Pi it was uh led by Enrique balderas
449.699 -> who's a postdoc in the lab along with
451.8 -> two other post-docs Sal and David as
454.62 -> well as Sandra who's a graduate student
456.24 -> in the lab and that defining that
459.12 -> pathway was really important but it kind
461.34 -> of gets to the deeper question which is
463.08 -> can we actually use this channel as a
465.84 -> potential therapy for mitochondrial
467.699 -> disease
468.66 -> so to get at that question I'm just
470.22 -> going to show one proof of concept type
472.56 -> experiment that we did in collaboration
474.36 -> with Eileen Rodan who's a drosophila
476.96 -> geneticist and a nephrologist in our
479.699 -> department of Internal Medicine John is
482.46 -> a technician in her lab and he does this
484.139 -> experiment that I'm going to show you
485.28 -> here he's got this platform that's
487.62 -> sitting in a bowl of water and he's just
489.3 -> gonna dump a bunch of flies on there and
491.759 -> these flies are normal flies and they're
493.38 -> just going to take off within a few
494.819 -> seconds
495.9 -> these flies have mitochondrial diseases
498.919 -> and so they are much weaker oh
504.36 -> let's see oh there we go Okay so
507.78 -> let's give them a second there yeah so
509.819 -> these flies are much weaker and they
511.8 -> can't they can't take off they have
513.659 -> mitochondrial disease
515.52 -> so what we did was let's see if we can
518.399 -> vary the amount of calcium and actually
521.52 -> affect the viability of these flies so
524.399 -> normal flies it took them in about five
526.32 -> seconds half the Flies were gone if they
529.32 -> have mitochondrial disease it takes them
531.6 -> closer to 10 seconds if you actually get
534.779 -> rid of that calcium channel they're
537.06 -> pretty severely impaired half of them
539.519 -> can't even fly anymore
541.32 -> but now here's the key experiment we
543.72 -> actually boosted the levels of that
546 -> channel and what we found is that we
548.04 -> could rescue their weakness and turn
550.62 -> flies that had mitochondrial disease
552.42 -> back into have the strength of flies
555.18 -> that were otherwise healthy
557.76 -> and so since then we've been trying to
560.16 -> see if we can perform this same kind of
563.339 -> boosting using drugs instead of genetic
566.519 -> tools and for that it's a collaborative
569.1 -> process in which we've Enlisted the help
571.56 -> of multiple different
573.98 -> collaborators including harivankalyapati
576.899 -> at the Huntsman Cancer Institute eruk
579.48 -> Chao and the department of biochemistry
581.7 -> and Randy Peterson from the College of
584.76 -> Pharmacy and this work's been funded by
587.339 -> both the pivot Center here at the U as
590.16 -> well as the NIH and some private
593.1 -> companies that have given us access to
595.08 -> some of their compounds
596.82 -> so our goal ultimately is to use this
602.279 -> channel to turn a heart that's beating
604.68 -> weekly and ideally get it to accelerate
607.8 -> and turn into a heart that's beating
609.66 -> normally
610.68 -> so with that I'd like to thank you for
612.36 -> your attention and these are the people
613.86 -> who actually did all the work and I'd
615.959 -> like to give a special thanks to the
617.7 -> Nora Eccles Treadwell Foundation which
620.04 -> you know really went out of their way to
621.6 -> support a lot of this work thank you
623.399 -> very much
624.07 -> [Applause]
Source: https://www.youtube.com/watch?v=bFJlGt-w1pY