Biventricular Assessment of Cardiac Function and Pressure-Volume Loops by Closed-Chest Catheterization in Mice
June 15th, 2020
6.6K views
Presented here is a protocol to assess biventricular heart function in mice by generating pressure-volume (PV) loops from the right and left ventricle in the same animal using closed chest catheterization. The focus is on the technical aspect of surgery and data acquisition.
Overview
This protocol details a method for assessing biventricular heart function in mice through the generation of pressure-volume (PV) loops using closed chest catheterization. It emphasizes the surgical techniques and data acquisition necessary for accurate measurements.
Key Study Components
Area of Science
- Cardiovascular physiology
- Mouse models
- Cardiac function assessment
Background
- Understanding cardiac function is crucial for studying cardiovascular diseases.
- Pressure-volume loops provide insights into both systolic and diastolic function.
- This technique allows for simultaneous assessment of both ventricles in the same animal.
- Closed chest catheterization is a minimally invasive approach for such assessments.
Purpose of Study
- To develop a protocol for comprehensive characterization of cardiac function in mice.
- To quantify systolic and diastolic functions of both ventricles.
- To facilitate research on cardiovascular diseases using mouse models.
Methods Used
- Isolation of the right carotid artery and jugular vein for catheterization.
- Insertion of catheters into the right and left ventricles to measure pressure and volume.
- Monitoring pressure waveforms to confirm catheter placement.
- Recording pressure-volume loops for analysis of cardiac function.
Main Results
- Successful generation of pressure-volume loops for both ventricles.
- Quantification of systolic and diastolic pressures obtained.
- Identification of optimal catheter placement through waveform analysis.
- Insights into cardiac contractility and efficiency derived from the data.
Conclusions
- This technique provides a robust method for assessing cardiac function in mice.
- It can be applied to study the effects of various cardiovascular conditions.
- Proper surgical technique and catheter placement are critical for success.
Frequently Asked Questions
What is the main focus of this protocol?
The protocol focuses on assessing biventricular heart function in mice through pressure-volume loops.
Why is it important to assess both ventricles?
Assessing both ventricles provides a comprehensive understanding of cardiac function and potential diseases.
What are pressure-volume loops?
Pressure-volume loops are graphical representations of the relationship between pressure and volume in the heart during the cardiac cycle.
What techniques are used for catheterization?
The protocol involves isolating the carotid artery and jugular vein for catheter insertion into the ventricles.
How does this technique contribute to cardiovascular research?
It allows for detailed analysis of cardiac function, which is essential for understanding cardiovascular diseases.
Executive Industry Relevance
Assessing biventricular cardiac function in preclinical models is critical for de-risking cardiovascular drug candidates by providing mechanistic insights into systolic and diastolic performance. Closed-chest pressure-volume loop acquisition in mice enables physiologically relevant hemodynamic profiling that mirrors clinical catheterization, supporting translational confidence in target validation and lead optimization. This approach reduces biological ambiguity in early discovery by delivering quantitative, replicable data on ventricular interdependence and contractility.
Strategic Applications in Biopharma R&D
Early Discovery & Target Validation
- Scientific Value: Enables interrogation of therapeutic hypotheses by quantifying systolic and diastolic function in both ventricles within the same animal.
- Operational Value: Provides reproducible hemodynamic parameters that support biological de-risking of targets involved in cardiac contractility and ventricular remodeling.
- Predictive Value: Facilitates portfolio triage by delivering contractility and lusitropy metrics that predict in vivo efficacy and safety signals.
Screening & Assay Development
- Assay Readiness: Generates standardized pressure-volume loops that serve as quantitative functional readouts for compound screening in cardiovascular disease models.
- Reproducibility: Requires consistent surgical technique and catheter positioning to ensure reliable loop morphology and hemodynamic parameter extraction.
- Scalability: Supports longitudinal assessment in disease progression models, enabling dose-response and time-course analyses in therapeutic studies.
Translational & Preclinical Research
- Disease Relevance: Allows evaluation of right ventricular function in pulmonary hypertension models by measuring afterload and systolic pressure responses.
- Translational Continuity: Mirrors clinical catheterization procedures, enhancing relevance to human cardiovascular pathophysiology.
- Mechanistic De-risking: Delivers advanced measures of ventricular efficiency and diastolic function that inform go/no-go decisions in preclinical advancement.
Pipeline & Workflow Integration
The method integrates into the discovery continuum from target validation through lead identification to preclinical efficacy testing, providing functional cardiac phenotyping at each stage.
- Discovery Biology: Supports hypothesis testing by enabling simultaneous left and right ventricular pressure-volume analysis to clarify pathway-specific effects on cardiac function.
- Screening: Delivers assay-ready, quantitative outputs such as end-systolic pressure, end-diastolic volume, and stroke work for evaluating compound impact on hemodynamics.
- Analytics: Provides derived parameters including contractility (ESPVR), lusitropy (tau), and ventricular efficiency for comparative analysis across experimental groups.
- Translational Research: Connects early discovery to preclinical validation by offering clinically analogous hemodynamic profiling in disease models.
- Enterprise Reuse: Establishes a reusable surgical and analytical platform for cardiovascular phenotyping across multiple therapeutic areas and project stages.
Operational & Enterprise Impact
- Scientific Value: Increases predictive confidence in target validation by reducing mechanistic ambiguity in cardiac function assessment.
- Operational Value: Enhances reproducibility and standardization through defined surgical criteria and pressure-volume loop quality thresholds.
- Strategic Value: Improves capital efficiency by enabling early identification of cardiotoxic or ineffective candidates, reducing late-stage failure risk.
- Portfolio Impact: Supports risk-adjusted advancement decisions through objective, quantitative biomarkers of ventricular systolic and diastolic performance.
Implementation Considerations
- Requires expertise in microsurgical techniques for carotid artery and jugular vein isolation in mice.
- Dependent on high-fidelity pressure-volume catheter systems and admittance technology for accurate volume conductance measurements.
- Necessitates standardized training to ensure consistent catheter positioning and loop acquisition across operators.
- Must account for physiological variables such as heart rate, loading conditions, and temperature during data collection.
- Limited by the technical challenge of achieving stable, coaxial catheter placement in both ventricles, which directly impacts loop fidelity and parameter accuracy.
Biopharma FAQs
Why does ventricular interdependence matter in target validation?
Assessing both ventricles in the same animal reveals how left and right heart function influence each other, which is critical for understanding cardiovascular drug effects on ventricular interaction and avoiding misleading functional interpretations.
How does closed-chest catheterization improve physiological relevance in hemodynamic profiling?
The closed-chest approach avoids the preload and afterload alterations caused by thoracotomy, preserving native cardiovascular conditions and providing pressure-volume data that more accurately reflect clinical catheterization findings.
What quantitative parameters are derived from pressure-volume loop analysis?
Pressure-volume loops enable measurement of systolic and diastolic pressures, end-systolic and end-diastolic volumes, stroke work, contractility (end-systolic elastance), lusitropy (tau), and ventricular efficiency, supporting comprehensive functional assessment.
Why are replication requirements essential for cross-functional collaboration in cardiovascular research?
Consistent loop morphology and hemodynamic parameters across experiments ensure data comparability between discovery, screening, and preclinical teams, enabling reliable target prioritization and go/no-go decisions based on reproducible functional outcomes.
What analytical capabilities are required before implementing pressure-volume loop acquisition in a discovery pipeline?
Implementation requires expertise in microsurgical vascular access, pressure-volume catheter manipulation, real-time waveform interpretation for catheter positioning, and post-acquisition analysis of loop morphology to derive systolic and diastolic functional parameters.
