Nonclinical, heart failure

1. Rat Dual Pressure Telemetry 1
Nonclinical Rodent Models
of Heart Failure

2. Left Anterior Descending Coronary Artery Ligation
Occlusion
site
Temporary Ligation - Temporary ligature can be removed
for timed reperfusion. The suture is placed under the LAD
coronary artery and tied to a PE tubing. Reperfusion occurs
by removing the tubing.
Permanent Ligation - The ligature placed under the LAD
coronary artery and tied.
LAD- Left anterior descending

3. Temporary Ligation
Permanent Ligation
LAD coronary
Artery Ligation
Ischemia
30-60 min
Reperfusion
2-24 hr End Points
Infarct Size: 2-24hrs - India Ink/TTC staining
Hemodynamic assessments: PV Loop
Echocardiography
Biomarkers: Blood and tissue
LAD coronary
Artery Ligation
Ischemia
2-16 weeks
End Points
Hemodynamic assessments- Echocardiography
Telemetry
PV Loop
Biomarkers- Blood and tissue
Infarct Size- Picrosirius red staining
Rats (SD, ZDF, CD® IGS) Mice (C57Bl/6)
Anesthesia – Isoflurane, ketamine/xylazine
Body temperature – 36.5-37.5 °C
Intubated - Ventilation with room air
Proper ligation of the LAD is confirmed by observing
blanching of myocardial tissue.
LAD- Left anterior descending
TCC- Triphenyl tetrazolium chloride staining

4. Temporary Ligation
30 min Ischemia
2 hr Reperfusion
Area at Risk (AAR)
Healthy Tissue
Infarct
Zone (IZ)
Left Ventricle

5. Permanent Ligation - Echocardiography
Anesthesia – Isoflurane, body temperature – 36.5-37.5 °C
Imaged - B-mode in the parasternal long axis (MS250S -Vevo 2100). Trace of the endocardial area will be obtained at
diastole and systole.
Day 15 Post MI - ≥40% reduction in the EF from Day-1 → 60% success rate
Diastole Diastole
Systole Systole
Day -1
Day -1
Day 15
Day 15

6. Echocardiographic Parameters in the Rat Model of Myocardium Infarction

7. Day 15 Post-MI – PV Loop
Anesthesia – Isoflurane
Body temperature – 36.5-37.5°C
Intubated -Ventilation with room air
Systemic Pressure
Femoral Artery Millar Catheter
LV Pressure -Volume
Closed Chest Approach – Right Carotid Artery
LV Volume (µL)
300250200150100500
LVPressure(mmHg)
-0
50
100
150
LV Volume (µL)
300250200150100500
LVPressure(mmHg)
-0
50
100
150
As expected, we observed a Dobutamine dose-related increase in heart rate in the naïve and MI SD rats

8. Day 15 Post-MI – PV Loop – Dobutamine Challenge
Dobutamine effect is diminished in sub-
chronic myocardial infarction in rats.

9. Isoproterenol Inducing Cardiac Hypertrophy in Mice
Carvedilol significantly inhibits the development of
isoproterenol-induced cardiac hypertrophy
Study Design - Cardiac Hypertrophy Model
Male 129S1/SvlmJ Mice (20-30 grams)
1 2 3 4 5 6 7 8 9 10 11-20 21
----------
Isoproterenol (10mg/kg - SC) from Day 1 to Day 7
Carvedilol (30 mg/kg, IP) - from Day 1 to Day 21
Echo Day 10 and 21 - PSAX M-mode
Day 21- Tissue collection
Isoproterenol Dosing

10. TAC induced Cardiac Remodeling
A titanium micro clip is placed around
the transverse aorta
Acute Stage → Compensatory Hypertrophy
Chronic Stage → Heart Failure
Study Design - TAC Model
Male C57Bl/6 Mice (≈30 grams)
Day 1- TAC Surgery Day 2 - Day 27 Day 28 - Echo + Tissue and Blood Collection
TAC - Transverse aorta clamped with a titanium microclip, the diameter similar to a 27G needle
Sham Group - Transverse aorta will be cleaned of surrounding tissue but not clamped
Dosed: Vehicle 6.67mL/kg/dose (2X daily), Losartan 30mg/kg (1X daily) - Day 1-28 - oral administration
Echo - PSAX M-mode
4 Weeks Post-TAC

11. TAC Model – Acute Stage – Compensatory Hypertrophy
Four weeks of TAC induces cardiac hypertrophy without chamber dilatation
PSAX
PSAX
M-mode
M-mode
Sham-Vehicle
TAC-Vehicle