Implantation of an Isoproterenol Mini-Pump to Induce Heart Failure in Mice
October 3rd, 2019
The chronic administration of isoproterenol via an implanted osmotic pump has been used widely to mimic advanced heart failure in mice. Here, we describe detailed methods in surgical mini-pump implantation for the continuous isoproterenol administration over 3 weeks, as well as, echocardiographic assessment for the successful model creation.
The chronic administration of isoproterenol via an osmotic pump has been widely used to recapitulate changes in advanced heart failure in mice. This method is simple and requires less surgical expertise than other models, such as LAD and TAC. Demonstrating the procedure will be Dr.Vincent Ren, a research scientist from Dr.Yibin Wang's laboratory.
After weighing and recording the body weight of each mouse, calculate the appropriate amount and concentration of isoproterenol for each animal, and dissolve the isoproterenol in 120 microliters of sterile 0.9%sodium chloride. Mix thoroughly for one minute to completely solubilize the isoproterenol, and weigh and record the weight of one empty osmotic pump, together with and without its flow moderator, per mouse. Attach a 27-gauge, blunt-tipped filling tube provided with the osmotic pumps, and load one, one-milliliter syringe with 120 microliters of the isoproterenol solution per mouse.
Holding a pump in the upright position, insert the filling tube through the pump opening at the top until the tip of the filling tube sits near the bottom of the pump reservoir, and slowly depress the syringe plunger until the isoproterenol solution fills to the pump opening. When the pump has been loaded, carefully remove the filling tube, and wipe off the excess solution. Insert back the flow moderator to close the pump, and wipe off any excess solution.
Then reweigh the pump to confirm that over 90%of the reservoir volume has been filled. Place the mouse in the supine position on a heated pad, and remove the air from the lower abdomen. For surgical osmotic pump implantation, confirm a lack of response to toe pinch in an anesthetized mouse, and apply ointment to the animal's eyes.
Clean the exposed skin with a suitable disinfectant, and make a one-centimeter midline skin incision. Use a pair of blunt-ended scissors to carefully dissect the skin from the underlying peritoneal walls, and use forceps to pull the peritoneal walls away from the underlying bowel. Use fine scissors to cut a 0.8-centimeter hole in the peritoneal wall, and insert the osmotic pump flow moderator end first into the peritoneal cavity.
When the pump is in place, use 5-0 absorbable sutures in an interrupted fashion to close the hole in the peritoneal wall, and use 6-0 nonabsorbable sutures to close the skin. Then place the mouse in a dedicated incubator with monitoring until full recumbency before returning the animal to its home cage. Here, a summary of the weekly changes based on the selected echocardiographic parameters and the expected time to model development are presented.
Although variations are observed between mouse strains, on average, interventricular septal wall thickness at end diastole and fractional shortening increase in the first week but decrease by later time points. The left ventricular internal diameter at end diastole and the left ventricular mass increase over a period of three weeks. Further, mouse hearts demonstrate visibly larger left ventricular chamber dimensions under isoproterenol, as well as greater amounts of fibrosis relative to saline-treated controls.
It is critical to maintain a sterile surgical environment during the survival surgery to minimize post-operative infection and morbidity. Successful model creation can be assessed in vivo by serial echocardiography for hypertrophy, dilation, and dysfunction, as well as ex vivo via histological and molecular assessment of harvested cardiac tissue. We have applied this method to over 100 strains of inbred mice to assess cardiac remodeling traits due to chronic beta-adrenergic stimulation.
The results are published and readily available.
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Overview
This article describes a method for chronic administration of isoproterenol via an osmotic pump to model advanced heart failure in mice. The procedure is straightforward and requires less surgical expertise compared to other models.
Key Study Components
Area of Science
- Cardiovascular research
- Animal models of disease
- Pharmacological interventions
Background
- Isoproterenol is commonly used to induce heart failure in research settings.
- Chronic administration mimics the progression of heart failure.
- Osmotic pumps provide a continuous delivery method.
- This model is less invasive than traditional surgical techniques.
Purpose of Study
- To establish a reliable model of advanced heart failure in mice.
- To demonstrate the surgical implantation of osmotic pumps.
- To assess the efficacy of the model through echocardiographic evaluation.
Methods Used
- Implantation of osmotic pumps for continuous isoproterenol delivery.
- Preparation of isoproterenol solution for administration.
- Monitoring of body weight and pump setup for each mouse.
- Echocardiographic assessment to evaluate heart function.
Main Results
- The method successfully mimics advanced heart failure in mice.
- Continuous delivery of isoproterenol was achieved over three weeks.
- Echocardiographic results confirmed the model's effectiveness.
- The procedure is accessible for researchers with varying surgical skills.
Conclusions
- This model provides a useful tool for studying heart failure mechanisms.
- The simplicity of the method encourages broader use in research.
- Future studies can build on this model to explore therapeutic interventions.
Frequently Asked Questions
Executive Industry Relevance
The isoproterenol-induced heart failure model via osmotic pump implantation provides a reproducible, scalable system for studying advanced cardiac remodeling in preclinical research. This approach enables target validation and mechanistic de-risking in cardiovascular drug discovery by mimicking human heart failure progression. Its applicability across >100 inbred mouse strains supports portfolio-wide target assessment and early-stage predictive confidence building.
Strategic Applications in Biopharma R&D
Early Discovery & Target Validation
- Scientific Value: Enables interrogation of therapeutic hypotheses related to beta-adrenergic signaling and cardiac stress pathways.
- Operational Value: Supports biological de-risking through consistent induction of hypertrophy, fibrosis, and ventricular dysfunction across diverse genetic backgrounds.
Screening & Assay Development
- Scientific Value: Generates quantifiable echocardiographic endpoints (e.g., ventricular dimensions, fractional shortening) for compound screening and dose-response assessment.
- Operational Value: Standardized pump implantation and ISO dosing facilitate assay reproducibility and cross-strain comparability.
Translational & Preclinical Research
- Scientific Value: Models chronic beta-adrenergic overstimulation, aligning with pathophysiological mechanisms in human heart failure with preserved or reduced ejection fraction.
- Operational Value: Enables longitudinal monitoring via serial echocardiography, supporting go/no-go decisions based on functional and structural deterioration.
Pipeline & Workflow Integration
The model fits within the cardiovascular discovery continuum from target validation through lead optimization to preclinical efficacy testing, particularly for compounds modulating adrenergic signaling or cardiac remodeling pathways.
- Discovery Biology: Facilitates pathway interrogation and target confirmation in models of sympathetic overdrive and myocardial stress.
- Screening: Provides a stable phenotypic platform for evaluating compound effects on cardiac structure and function over 3–4 weeks.
- Analytics: Delivers quantitative, serial echocardiographic readouts enabling longitudinal assessment of therapeutic intervention.
- Translational Research: Mirrors clinical progression of adverse remodeling, supporting biomarker-aligned target prioritization.
- Enterprise Reuse: Establishes a reusable surgical and pharmacological platform applicable across multiple cardiovascular indications and target classes.
Operational & Enterprise Impact
- Scientific Value: Enhances predictive confidence by modeling human-relevant cardiac dilation, hypertrophy, and dysfunction.
- Operational Value: Requires minimal surgical expertise, enabling broad adoption across research sites and reducing inter-laboratory variability.
- Strategic Value: Improves capital efficiency by enabling early identification of ineffective compounds through functional decline metrics.
- Portfolio Impact: Supports risk-adjusted prioritization by distinguishing compounds that attenuate versus exacerbate ISO-induced remodeling.
Implementation Considerations
- Requires training in aseptic surgical techniques and osmotic pump handling.
- Depends on access to calibrated micro-syringes, blunt-tipped filling tubes, and ISO-resistant pump materials.
- Necessitates standardization of ISO concentration and volume across strains to ensure consistent pharmacokinetic exposure.
- Involves postoperative monitoring for infection and distress, particularly in genetically sensitive strains.
- Relies on echocardiography expertise for accurate longitudinal assessment of chamber dimensions and systolic function.
