Heart Failure Pathophysiology
Heart failure represents the final common pathway for multiple cardiac diseases, characterized by impaired contractile function and inadequate cardiac output. Mouse models enable study of the genetic, molecular, and cellular mechanisms underlying cardiac dysfunction.
Dilated Cardiomyopathy
Dilated cardiomyopathy is characterized by ventricular dilation and systolic dysfunction. Genetic forms result from mutations in sarcomeric proteins, cytoskeletal components, or ion channels. Mouse models carrying human disease associated mutations enable study of disease mechanisms and therapeutic testing.
Hypertrophic Cardiomyopathy
Hypertrophic cardiomyopathy features abnormal cardiac hypertrophy, often caused by sarcomeric gene mutations. Mouse models enable study of hypertrophic signaling pathways and diastolic dysfunction.
Cardiac Remodeling
Pathological cardiac remodeling in response to hemodynamic stress involves cardiomyocyte hypertrophy, fibrosis, and changes in gene expression. Understanding the signaling pathways driving maladaptive remodeling is essential for developing therapies that prevent heart failure progression.
Custom Model Approaches
Sarcomeric Protein Mutations
Point mutation knockin models enable study of disease causing mutations in sarcomeric genes including MYH7, MYBPC3, TNNT2, and TNNI3. These models reproduce human cardiomyopathy phenotypes and enable mechanistic studies.
Learn about Point Mutation MiceSignaling Pathway Modulation
Knockout and conditional knockout models enable study of signaling pathways involved in cardiac hypertrophy, fibrosis, and failure. Common targets include kinases, transcription factors, and metabolic regulators.
Cardiac Specific Knockouts
Cardiac specific gene deletion using alpha myosin heavy chain Cre (αMHC Cre) or myosin light chain Cre (MLC Cre) enables study of gene function specifically in cardiomyocytes without affecting other tissues. This approach is essential when systemic knockout causes embryonic lethality or when cardiac specific phenotypes need to be distinguished from systemic effects.
Inducible Cardiac Knockouts
Tamoxifen inducible cardiac Cre lines such as αMHC MerCreMer enable adult onset gene deletion. This approach avoids developmental effects and enables study of gene function in the adult heart.
Learn about Inducible KnockoutsIon Channel and Calcium Handling Models
Arrhythmia Models
Mutations in cardiac ion channels cause inherited arrhythmia syndromes including long QT syndrome, Brugada syndrome, and catecholaminergic polymorphic ventricular tachycardia. Mouse models enable study of arrhythmia mechanisms and testing of antiarrhythmic therapies.
Calcium Handling Defects
Alterations in calcium cycling proteins including SERCA2a, phospholamban, and ryanodine receptor contribute to heart failure progression. Models modifying these genes enable study of calcium handling in cardiac dysfunction.
Cardiac Fibrosis Models
Fibroblast Specific Modifications
Cardiac fibrosis involves activation of fibroblasts and excessive extracellular matrix deposition. Fibroblast specific Cre lines enable study of gene function specifically in the fibroblast population.
TGF Beta Pathway Models
The TGF beta pathway plays central roles in cardiac fibrosis. Models modifying TGF beta ligands, receptors, or downstream signaling components enable study of profibrotic mechanisms.
Common Cardiac Cre Drivers
| Cre Driver | Target Cell Type | Application |
|---|---|---|
| Myh6-Cre | Cardiomyocytes | Standard cardiac-specific deletion |
| Tcf21-MerCreMer | Cardiac fibroblasts | Inducible fibroblast targeting |
| Postn-Cre | Activated fibroblasts | Fibrosis mechanism studies |
| αMHC-CreERT2 | Cardiomyocytes | Inducible adult-onset deletion |
Applications in Heart Failure Research
Disease Mechanism Studies
Custom models enable investigation of specific genes and pathways in heart failure pathogenesis, from initial insult through remodeling to overt failure.
Therapeutic Target Validation
Knockout and knockin models validate potential therapeutic targets by demonstrating that target modulation affects disease phenotypes.
Drug Efficacy Testing
Models that develop measurable cardiac phenotypes enable preclinical testing of therapeutic interventions. Endpoints can include echocardiographic function, survival, histological changes, and molecular markers.
Gene Therapy Development
Mouse models provide platforms for testing cardiac gene therapy approaches, including AAV mediated gene delivery and gene editing strategies.
What Researchers Say
“iTL generated our angiotensin II type 1a receptor conditional mouse. We found this company very responsive. The project started with discussions on possible construct designs. Following approval, a project manager sent monthly reports alerting us to project milestones. Our experience with iTL was so positive that we have generated more conditional mice with them.”
— Debra Rateri, BS
University of Kentucky
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