Structural and functional remodeling following pharmacologic intervention in

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

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)

Pre

ssur

e (m

m H

g)

*

*= 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)

Ch

ang

e in

L

VD

d

(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

WT

d)/

LV

Dd

%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

ion

al s

ho

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