A Closed-chest Model to Induce Transverse Aortic Constriction in Mice
April 5th, 2018
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Here, we present a protocol of Transverse Aortic constriction (TAC) via a lateral thoracotomy. This technique is a minimally invasive, closed chest surgical procedure aiming to simulate pressure overload and heart failure in mice utilizing standard TAC laboratory settings.
Overview
This article presents a protocol for performing transverse aortic constriction (TAC) in a murine closed chest model. This minimally invasive technique is designed to induce left ventricular hypertrophy while minimizing surgical trauma and inflammatory responses.
Key Study Components
Area of Science
- Cardiovascular research
- Immunology
- Surgical techniques in animal models
Background
- Transverse aortic constriction simulates pressure overload and heart failure.
- Minimally invasive procedures reduce respiratory complications.
- Understanding cardiac macrophage responses is crucial in left ventricular hypertrophy.
- Maintaining rib cage integrity minimizes trauma during surgery.
Purpose of Study
- To establish a reliable method for inducing left ventricular hypertrophy in mice.
- To analyze the immune response in the context of cardiac hypertrophy.
- To validate the effectiveness of TAC through physiological measurements.
Methods Used
- Anesthesia and preparation of the mouse.
- Incision and exposure of the aortic arch.
- Placement of a spacer and suturing techniques.
- Post-operative care and validation of TAC success through Doppler measurements.
Main Results
- Successful TAC resulted in increased blood velocity in the right carotid artery.
- Heart weight to body weight ratios significantly increased in TAC mice.
- No significant differences in heart rates between aortic banded and non-banded mice.
- End systolic and diastolic volumes increased significantly post-TAC.
Conclusions
- This TAC protocol can be performed efficiently and with minimal trauma.
- The method provides insights into the immune response associated with left ventricular hypertrophy.
- Proper execution of the technique allows for standardized results in cardiovascular research.
Frequently Asked Questions
What is transverse aortic constriction?
Transverse aortic constriction (TAC) is a surgical procedure used to induce pressure overload and heart failure in animal models.
Why is a minimally invasive approach preferred?
Minimally invasive techniques reduce surgical trauma and complications, allowing for more accurate physiological measurements.
What are the main advantages of this TAC protocol?
The main advantages include reduced respiratory issues, minimized inflammatory response, and the ability to use different sized mice.
How is the success of the TAC measured?
Success is measured through Doppler flow velocity assessments and physiological parameters such as heart weight ratios.
What are the implications of this study for immunology?
This study helps elucidate the role of cardiac macrophages in the development of left ventricular hypertrophy, providing insights into immune responses.
Executive Industry Relevance
This closed-chest transverse aortic constriction (TAC) model reduces surgical trauma and preserves physiological breathing patterns, enabling more reliable preclinical assessment of cardiac hypertrophy and heart failure mechanisms. By minimizing immune confounding from thoracotomy, the model improves target validation confidence in cardiovascular and immunology drug discovery programs. The approach supports rapid recovery and reproducible hemodynamic outcomes, facilitating efficient lead identification and mechanistic de-risking in early discovery.
Strategic Applications in Biopharma R&D
Early Discovery & Target Validation
- Scientific Value: Enables interrogation of therapeutic hypotheses in pressure overload models with reduced surgical confounders.
- Operational Value: Supports functional target validation by isolating cardiac-specific responses from systemic inflammation.
- Predictive Value: Enhances portfolio triage through consistent left ventricular hypertrophy readouts across cohorts.
Screening & Assay Development
- Assay Readiness: Generates disease-relevant systems with standardized hypertrophic phenotypes for compound screening.
- Quantitative Outputs: Provides Doppler flow velocity and heart weight-to-body weight ratios as measurable, translatable endpoints.
- Scalability: Adaptable to different mouse sizes, supporting cross-study consistency and platform reuse.
Translational & Preclinical Research
- Disease Relevance: Models eccentric hypertrophy with systolic dysfunction, mirroring clinical heart failure phenotypes.
- Translational Continuity: Maintains physiological parameters from discovery through preclinical validation, reducing attrition risk.
- Mechanistic De-risking: Enables analysis of cardiac macrophage involvement in hypertrophy with minimal nonspecific immune activation.
Pipeline & Workflow Integration
The method fits within the discovery continuum from target validation to preclinical efficacy testing, providing a standardized, low-trauma model for hemodynamic and immunophenotypic assessment.
- Discovery Biology: Facilitates hypothesis testing on pathways driving ventricular remodeling under pressure overload.
- Screening: Delivers reproducible hypertrophy models suitable for evaluating compound effects on cardiac structure and function.
- Analytics: Outputs include systolic blood pressure via left ventricular catheterization and Doppler-derived flow velocities for objective phenotyping.
- Translational Research: Connects to preclinical continuity via sustained pressure overload and volumetric changes over 21 days.
- Enterprise Reuse: Establishes a reusable surgical platform for longitudinal studies in cardiovascular and immunometabolic research.
Operational & Enterprise Impact
- Scientific Value: Predictive confidence in target engagement through reduced mechanistic ambiguity from surgical trauma.
- Operational Value: Standardization and reproducibility via closed-chest technique and validated physiological benchmarks.
- Strategic Value: Improved go/no-go decisions by isolating drug effects from procedure-induced inflammation.
- Portfolio Impact: Risk-adjusted prioritization based on reliable hypertrophy and functional endpoints.
Implementation Considerations
- Requires expertise in microsurgical techniques and vascular dissection under magnification.
- Dependent on instrumentation including surgical microscopes, Doppler probes, and precision suturing tools.
- Necessitates cross-team standardization of postoperative care and physiological monitoring protocols.
- Adaptation considerations include variations in mouse strain and body weight affecting surgical access and suture tension.
- Practical limitations include the technical challenge of spacer placement and knot tying under 200% magnification.
Biopharma FAQs
Why does closed-chest TAC improve target validation confidence?
By preserving rib cage integrity and minimizing surgical trauma, the closed-chest approach reduces nonspecific immune activation and respiratory confounding, enabling clearer attribution of phenotypic changes to the target pathway rather than procedure-induced artifacts.
How does Doppler flow velocity measurement support independent variable isolation in the discovery pipeline?
Doppler assessment quantifies post-stenotic flow changes in the carotid arteries, providing a direct, physiological readout of aortic banding efficacy that isolates the hemodynamic variable from surgical or anesthetic variability.
What quantitative dependent variable measurements enable predictive confidence in hypertrophy models?
Heart weight-to-body weight ratios and left ventricular end systolic/diastolic volumes serve as validated, quantitative endpoints that correlate with pressure overload and support dose-response modeling in preclinical studies.
Why do replication requirements matter for cross-functional collaboration in TAC studies?
Consistent replication ensures that hypertrophy phenotypes and hemodynamic outcomes are reproducible across operators and sites, which is essential for aligning discovery, preclinical, and translational teams on go/no-go criteria.
What statistical analysis capabilities are required before implementing this TAC model in screening workflows?
Implementation requires the ability to analyze longitudinal hemodynamic data, compare ventricular volume changes over time, and assess statistical significance of hypertrophy indices relative to sham controls using parametric or nonparametric tests as appropriate for sample size and distribution.
