Structural and functional remodeling following pharmacologic intervention in
volume overload heart failureKristin Lewis, DVM
Pathology Resident/Graduate Research AssociateThe 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
© Increased afterload© Concentric hypertrophy© Fibrosis© Examples:
• Hypertension• Aortic stenosis
© Increased preload© Eccentric hypertrophy© ECM degradation© Examples:
• Aortic/Mitral regurgitation • Area opposite infarct• Ventricular septal defect
Volume OverloadPressure Overload
VolumeOverload
Progression of Volume Overload (VO) to Heart Failure
Death
Valvular DysfunctionAortic regurgitationMitral regurgitation
Myocardial Infarct
Septal Defects
SystolicDysfunction
DiastolicDysfunction
HF
LV Remodeling LV Dysfunction Overt HF
Time (months to years) Time (months)
Reversible Irreversible
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
Aorta
18g
Sham 4 wk ACF
ACF progressive increase in LVDd
LVDd LVDs
15 wk ACF8 wk ACF
VO is accompanied by functional deterioration
Sham ACF0
10
20
30
40
50 % FS
*
0 200 400 6000
50
100
150
Volume (l)
Pres
sure
(mm
Hg)
*
*= P < 0.05 vs. Sham
Will reversal of ACF improve LV structure and function?
Stent graft Suture
LV chamber geometry is normalized 4wks post-reversal
*= P < 0.05 vs. Sham†= P < 0.05 vs. ACF
LVDd
0 4 117
8
9
10
11
12
13*
*
*
††
Weeks post-reversal
LVD
d (m
m)
Hutchinson KR, et al. J Appl Physiol. 2011 Sep 1
4 w
k AC
F ±
4 w
k Re
v4
wk
ACF
± 11
wk
Rev
ACF + ReversalACF OnlySham
0
50
100
150
0 200 400 6000 200 400 6000
50
100
150
0 200 400 600
Pres
sure
(mm
Hg)
Volume (µL)
†
* *
*
ACF reversal decreased LV contractility @ 4 weeks & normalization of LV contractility @ 11 weeks
*= P < 0.05 vs. Sham†= P < 0.05 vs. ACF
Hutchinson KR, et al. J Appl Physiol. 2011 Sep 1
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 β1-AR
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
0 wk
Treatmentstart
HemodynamicsNecropsy
4 wk
(n=10)
(n=8)ACF
SHAM
15 wk
VEH
MET
LEVO
ECHO(q2w)
ACF
ACF
(n=9)
(n=9)
VEH
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)
0 2 4 6 8-1
0
1
2
3 Sham, VehACF, VehACF, MetACF, Levo
Time from treatment start (weeks)
Cha
nge
in L
VDd
(mm
)
Levo early reversal of eccentric dilation index
(2*PWTd)/LVDd following treatment (Mean +/- SEM)
0 2 4 6 80.2
0.3
0.4
0.5Sham, VehACF, VehACF, MetACF, Levo
Time from treatment start (weeks)
(2*P
WTd
)/LVD
d
%FS is consistent with treatment
% Fractional shortening following treatment (Mean +/- SEM)
0 2 4 6 820
25
30
35
40
45Sham, VehACF, VehACF, MetACF, Levo
Time from treatment start (weeks)
% F
ract
iona
l sho
rten
ing
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, MMP-9, TIMP-2
• Future studies:– Repeat current study +
myocyte isolation– ACF + earlier treatment– ACF + reversal +
treatment
Acknowledgements
Nationwide Childrens• Lucchesi lab
– 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
