Transcript Kristin Lewis, DVM - ACVP/STP Coalition

Structural and functional remodeling
following pharmacologic intervention in
volume overload heart failure
Kristin Lewis, DVM
Pathology Resident/Graduate Research Associate
The Ohio State University, Columbus, OH
The Research Institute, Nationwide Children’s Hospital, Columbus, OH
Why are we interested in heart failure?
• ~5 million Americans currently have CHF
– ~550,000 new cases diagnosed annually
• Contributes to ~300,000 deaths each year
– Sudden death is 6-9x more likely in CHF patients than
in the general population
• HF is responsible for >11 million physician visits
annually and more hospitalizations than all forms
of cancer combined
http://www.emoryhealthcare.org/heart-failure/learn-about-heart-failure/statistics.html
2 types of hemodynamic overload  HF
Pressure Overload
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


Increased afterload
Concentric hypertrophy
Fibrosis
Examples:
• Hypertension
• Aortic stenosis
Volume Overload
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
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
Increased preload
Eccentric hypertrophy
ECM degradation
Examples:
• Aortic/Mitral regurgitation
• Area opposite infarct
• Ventricular septal defect
Progression of Volume Overload (VO) to Heart Failure
Reversible
Irreversible
Valvular Dysfunction
Aortic regurgitation
Mitral regurgitation
Systolic
Dysfunction
Septal Defects
Volume
Overload
HF
Death
Diastolic
Dysfunction
Myocardial Infarct
LV Remodeling
LV Dysfunction
Time (months to years)
Overt HF
Time (months)
Overall hypothesis:
Early intervention will result in return of LV
structure and function to baseline levels
Volume overload-induced HF with
aortocaval fistula (ACF) in the rat
18g
Aorta
ACF progressive increase in LVDd
Sham
8 wk ACF
LVDd
LVDs
4 wk ACF
15 wk ACF
VO is accompanied by functional deterioration
% FS
50
40
*
30
20
10
0
Pressure (mm Hg)
150
*
100
50
0
Sham
ACF
0
200
400
Volume (l)
*= P < 0.05 vs. Sham
600
Will reversal of ACF improve LV
structure and function?
Stent graft
Suture
LV chamber geometry is normalized 4wks post-reversal
LVDd
13
*
LVDd (mm)
12
11
*
*
10
†
9
†
8
7
0
4
11
Weeks post-reversal
*= P < 0.05 vs. Sham
†= P < 0.05 vs. ACF
Hutchinson KR, et al. J Appl Physiol. 2011 Sep 1
Sham
ACF Only
150
ACF + Reversal
*
*
100
50
Pressure (mmHg)
4 wk ACF ± 11 wk Rev
4 wk ACF ± 4 wk Rev
ACF reversal  decreased LV contractility @ 4 weeks &
normalization of LV contractility @ 11 weeks
0
150
†
*
100
50
0
0
200
400
*= P < 0.05 vs. Sham
†= P < 0.05 vs. ACF
Hutchinson KR, et al. J Appl Physiol. 2011 Sep 1
600
0
200
400
600
Volume (µL)
0
200
400
600
AIM 1
In a rat model of ACF-induced volume overload:
Determine the optimal time to initiate medical
therapy by comparing the temporal efficacy of
β-blocker (metoprolol) or myofilament Ca2+
sensitizer (levosimendan) therapy
Beta-blocker: Metoprolol
• Preferentially binds to β1AR in the heart & blocks
NE binding
• Clinical mechanism of
action poorly understood:
– Theoretically:
•  HR, contractility,
conduction velocity,
relaxation rate
– Clinically:
•  contractility
• Benefit may be 2o to
blockade of excess Epi/NE
stimulation
http://www.cvpharmacology.com/cardioinhibitory/beta-blockers.htm
Levosimendan (and OR-1896) act through
multiple cardiovascular targets
Papp Z, et al. Int J Cardiol. 2011 Jul 23.
Study Design
• Sprague dawley rats, 210-260 g
• Treatment:
– Vehicle: water
– Metoprolol: 30 mg/kg x 4 wk, 50 mg/kg x 4 wk, 80 mg/kg x 3 wk
– Levosimendan: 1 mg/kg
ECHO
(q2w)
Treatment
start
Hemodynamics
Necropsy
SHAM
VEH
(n=10)
ACF
VEH
(n=8)
ACF
MET
(n=9)
ACF
LEVO
(n=9)
0 wk
4 wk
15 wk
Body weight gain unaffected by
surgery or treatment
Met enhanced progression to HF
Levo & Met  delayed and enhanced
increases in LVDd, respectively
Change in LVDd following treatment (Mean +/- SEM)
Change in LVDd (mm)
3
Sham, Veh
ACF, Veh
ACF, Met
ACF, Levo
2
1
0
-1
0
2
4
6
8
Time from treatment start (weeks)
Levo  early reversal of eccentric
dilation index
(2*PWTd)/LVDd following treatment (Mean +/- SEM)
(2*PWTd)/LVDd
0.5
Sham, Veh
ACF, Veh
ACF, Met
ACF, Levo
0.4
0.3
0.2
0
2
4
6
8
Time from treatment start (weeks)
%FS is consistent with treatment
% Fractional shortening
% Fractional shortening following treatment (Mean +/- SEM)
45
Sham, Veh
ACF, Veh
ACF, Met
ACF, Levo
40
35
30
25
20
0
2
4
6
8
Time from treatment start (weeks)
Summary
• In our model of volume overload:
– Metoprolol accelerates the progression to HF
– Levosimendan delays the progression to HF
• Treatment started at lower LVDd
– 1) return to pre-surgical LVDd
– 2) maintenance of LVDd
Next steps
• Current study:
– Structure:
• ECHO
• Routine histology, organ
weights
• Collagen content, TGF-β
• MMPs/TIMPs
• α-MHC, β-MHC
– Function:
• ECHO
• PV Loops
• ANP, BNP, Connexin 43
• Future studies:
– Repeat current study +
myocyte isolation
– ACF + earlier treatment
– ACF + reversal + treatment
Next steps
• Current study:
– In vivo:
• ECHO
• PV loops
– Ex vivo:
• Organ weights/ratios
• Routine histology: heart,
liver, lungs, kidney
• Picrosirius red
• qPCR: Col1a1, Col3a1,
elastin, α-MHC, β-MHC,
ANP, BNP, TGF-β
• Immunoblot: MMP-13,
MT1-MMP, MMP-7, MMP9, TIMP-2
• Future studies:
– Repeat current study +
myocyte isolation
– ACF + earlier treatment
– ACF + reversal + treatment
Acknowledgements
Nationwide Childrens
• Lucchesi lab
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Pam Lucchesi
Anu Guggilam
Maarten Galanctowicz
Aaron Trask
Kathryn Halleck
Kirk Hutchinson
Aaron West
Mary Cismowski
Jean Zhang
• Vivarium
– Natalie Snyder
The Ohio State University
• Veterinary Biosciences
Funding Sources
• ACVP/STP Coalition
Fellowship
• NIH HL056046
• Nationwide Children’s
Hospital