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Transcript of The Myofilament Ca 2+ Sensitizer Levosimendan Preserves Systolic Function in Rats with Volume...
![Page 1: The Myofilament Ca 2+ Sensitizer Levosimendan Preserves Systolic Function in Rats with Volume Overload Heart Failure Kristin Lewis, DVM Pathology Resident/Graduate.](https://reader036.fdocuments.us/reader036/viewer/2022062423/5697bfae1a28abf838c9cc9c/html5/thumbnails/1.jpg)
The Myofilament Ca2+ Sensitizer Levosimendan Preserves Systolic Function in
Rats with Volume Overload Heart Failure
Kristin Lewis, DVMPathology Resident/Graduate Research Associate
The Ohio State University, Columbus, OHThe Research Institute, Nationwide Children’s Hospital, Columbus, OH
![Page 2: The Myofilament Ca 2+ Sensitizer Levosimendan Preserves Systolic Function in Rats with Volume Overload Heart Failure Kristin Lewis, DVM Pathology Resident/Graduate.](https://reader036.fdocuments.us/reader036/viewer/2022062423/5697bfae1a28abf838c9cc9c/html5/thumbnails/2.jpg)
2 types of hemodynamic overload HF
© Increased afterload© Concentric hypertrophy© Fibrosis© Examples:
• Hypertension• Aortic stenosis
© Increased preload© Eccentric hypertrophy© ECM degradation© Examples:
• Aortic/Mitral regurgitation • Myocardial infarct• Ventricular septal defect• Arterio-venous fistulae
Volume OverloadPressure Overload
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VolumeOverload
Progression of Volume Overload (VO) to Heart Failure
Death
Mitral regurgitation
SystolicDysfunction
DiastolicDysfunction
HF
LV Remodeling LV Dysfunction Overt HF
Time (months to years) Time (months)
Reversible Irreversible
Arterio-venous Fistulae
![Page 4: The Myofilament Ca 2+ Sensitizer Levosimendan Preserves Systolic Function in Rats with Volume Overload Heart Failure Kristin Lewis, DVM Pathology Resident/Graduate.](https://reader036.fdocuments.us/reader036/viewer/2022062423/5697bfae1a28abf838c9cc9c/html5/thumbnails/4.jpg)
MR treatment options
• Surgical repair/replacement– Optimal timing for patients with symptoms or decreased
function is defined– Optimal timing for asymptomatic patients is controversial
• Intervene early or “watch and wait”?
– Post-operative dysfunction
• Pharmacologic therapy– Can these agents delay surgery or improve function post-
operatively?– Optimal agents?
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VO-induced HF with aortocaval fistula (ACF) in the rat
Aorta
18g
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Sham 4 wk ACF
ACF progressive increase in LVEDd, LVEDs
LVEDd LVEDs
15 wk ACF8 wk ACF
Chest wall“Anterior”
“Posterior”
Time
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VO is accompanied by functional deterioration
Sham ACF0
10
20
30
40
50
% Fractional Shortening
*
0 200 400 6000
50
100
150
Volume (l)
Pre
ssur
e (m
m H
g)
*
*= P < 0.05 vs. ShamLVEDd LVEDs % 𝐹𝑆=100 𝑥𝐿𝑉𝐸𝐷𝑑−𝐿𝑉𝐸𝐷𝑠
𝐿𝑉𝐸𝐷𝑑
![Page 8: The Myofilament Ca 2+ Sensitizer Levosimendan Preserves Systolic Function in Rats with Volume Overload Heart Failure Kristin Lewis, DVM Pathology Resident/Graduate.](https://reader036.fdocuments.us/reader036/viewer/2022062423/5697bfae1a28abf838c9cc9c/html5/thumbnails/8.jpg)
-6.0 -5.5 -5.0 -4.5 -4.0
0
20
40
60
80
100
pCa
Fo
rce
(m
N/m
m2 )
Sham
ACF
*
ACF Altered Ca2+ responsiveness and handling
8 wk ACF
PLB
pPLB
SERCA2a
Sham ACF
8 wk ACF
*** p<0.001 vs. Sham
Arb
itra
ry U
nit
s
Serca 2a pPLB/PLB0
1
2
3 ShamACF
***
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Hypothesis
Therapeutic strategies targeting myofilament Ca2+ sensitivity will preserve/improve LV
function in valvular heart disease
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Myofilament Ca2+ sensitizer: Levosimendan
HemodymanicsMyocyte isolationTissue collection
(n=28)
(n=22)ACF
SHAM
ACF (n=23)
0 wk 8 wk
ECHO(q2w)
Levo, 1 mg/kg
Adapted from Papp Z, et al. Int J Cardiol. 2011 Jul 23.
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Levo may attenuate the increase in LVEDD
LVEDd LVEDs
Sham ACF-Veh ACF-Levo
**** p<0.0001 vs Sham-Veh; ^ p<0.05, ^^ p<0.01 vs ACF-Veh
LVEDD
0 2 4 6 86
8
10
12
Study Week
(m
m) ****,̂ ^
********
****
********
****,^
Sham-VehACF-VehACF-Levo
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Levo improved LV systolic function
* p<0.05, ** p<0.01, *** p<0.001, **** p<0.0001 vs Sham-Veh^ p<0.05, ^^^^ p<0.0001 vs ACF-Veh
Fractional Shortening
0 2 4 6 825
30
35
40
45
50
Study week
%
**** ****
^̂ ^̂ ^̂ ^̂***
ACF-LevoACF-VehSham-Veh
Ees, Adj
mm
Hg
/uL
Sham-Veh ACF-Veh ACF-Levo0.0
0.2
0.4
0.6
0.8
1.0
***
*,̂
PRSW, Adj
mm
Hg
Sham-Veh ACF-Veh ACF-Levo0
50
100
150
*
^
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Levo ↑myofilament Ca2+ sensitivity & ↑ maximal force without ↑ Ca2+ transient
-6.0 -5.5 -5.0 -4.5 -4.0
0
20
40
60
80
100
120
pCa
Fo
rce
(m
N/m
m2 )
ShamACF-Veh
ACF-Levo
**
^̂ ^
* p<0.05, ** p<0.01 vs Sham-Veh^ p<0.05, ^^^ p<0.001, ^^^^ p<0.0001 vs ACF-Veh
Peak[Ca2+]i
360
/380
Sham-Veh ACF-Veh ACF-Levo0
10
20
30*
^̂ ^̂
AS/PK
m*m
sec/
m
Sham-Veh ACF-Veh ACF-Levo0
20
40
60
*,̂
Peah h
t0
ACF-Veh
Sham-Veh
ACF-Levo
AreaC
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Levo does not result in vasodilation
Mean arterial pressureP
ress
ure
(m
mH
g)
Sham-Veh ACF-Veh ACF-Levo0
50
100
150
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Levo improved LV diastolic function
**** p<0.0001 vs Sham-Veh^ p<0.05, ^^^ p<0.001 vs ACF-Veh
Relaxation constantTau (W)
Sham-Veh ACF-Veh ACF-Levo0
5
10
15
mS
ec
^
dp/dtmin
Sham-Veh ACF-Veh ACF-Levo-10000
-8000
-6000
-4000
-2000
0
mm
Hg
/sec
****
^̂ ^
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cMyBP-C and cTnI• Cardiac Myosin Binding
Protein-C (cMyBP-C)– Thick filament associated
protein– Phosphorylation ↑
contraction and relaxation & ↓Ca2+ sensitivity
• Cardiac Troponin I (cTnI)– Thin filament associated protein– Phosphorylation ↓Ca2+
sensitivity earlier onset of relaxation
Adapted from Landstrom AP, et al. Circulation. 2010 Dec 7;122(23):2441-9Colson BA et al. J Mol Cell Cardiol. 2012 Nov; 53(5):609-16Michalek AJ et al. Biophys J. 2013 Jan 22;104(2):442-52.
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Phosphorylation at cMyBP-C Ser273, Ser302 and cTnI Ser23/24 may drive functional improvement
pSer273
Total cMyBP-C
Sham ACF ACF+L Sham ACF ACF+L
pSer302
Total cMyBP-C
Sham ACF ACF+L
pSer23/24
Total cTnI
cMyBP-C Ser273 Phosphoryation
Sham ACF-Veh ACF-Levo0.0
0.5
1.0
1.5
2.0
2.5
pS
er27
3/to
tal
*,̂ ^
cMyBP-C Ser302 Phosphorylation
Sham ACF-Veh ACF-Levo0
1
2
3
4
5
pS
er30
2/to
tal
*,̂
cTnI Ser23/24 Phosphorylation
Sham ACF-Veh ACF-Levo0.0
0.5
1.0
1.5
2.0
pT
nI/T
nI
*,̂ ^
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Summary Myofilament Ca2+ sensitizer therapy improved systolic and
diastolic function
Improved systolic function is due to increased myofilament Ca2+ sensitivity
Improved diastolic function may be due to cMyBP-C and/or cTnI phosphorylation
Myofilament Ca2+ sensitizer therapy mildly attenuated increase in LVEDD
Therapeutic strategies targeting myofilament Ca2+ sensitivity may improve function prior to load reduction surgery
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Acknowledgements
Nationwide Children’s Hospital• Lucchesi lab
– Pam Lucchesi– Aaron Trask– Aaron West– Jean Zhang– Anu Guggilam– Kirk Hutchinson– Mary Cismowski
• Vivarium– Natalie Snyder– Brenna Barbour– Erin Grove
The Ohio State University• Veterinary Biosciences
Funding Sources• ACVP/STP Coalition
Fellowship & Genentech• NIH R01-HL056046• Nationwide Children’s