Abstract Body: Introduction:
Chronic ischemic heart failure (HF) is a heterogeneous disease driven by complex interactions among immune, stromal, and cardiac cell populations. Variability in inflammatory responses contributes to inconsistent disease progression and therapeutic outcomes, underscoring an unmet need for immune-based patient stratification metrics to enable precision approaches to HF. Our team has developed a biologic composed of non-integrative human induced pluripotent stem cell–derived cardiomyocytes and fibroblasts that reverses HF in preclinical models. However, clinical translation depends on identifying patients with immunologic profiles permissive for durable cardiac repair.
Methods:
We are developing an artificial intelligence (AI)–enabled blood-based diagnostic platform to define immune signatures associated with cardiac repair in HF. Blood from mini-swine treated with the biologic is analyzed using integrated multiomic immune profiling and paired with longitudinal functional cardiac outcomes to identify predictive signatures. To enhance clinical relevance, HF patient samples are evaluated ex vivo using whole-blood assays and CD14+ macrophage cultures to characterize repair-associated phenotypes are analyzed to develop machine learning pipelines for identifying immune states associated with myocardial injury and recovery.
Results:
Our data demonstrate that coordinated engagement of the immune system is essential for durable cardiac repair, facilitating maturation and integration of cardiac muscle. Circulating immune markers associated with disease severity and therapeutic responsiveness have been identified. Preliminary machine learning analyses of human peripheral blood datasets identify immune transcriptional signatures capable of discriminating inflammatory states associated with myocardial injury and recovery.
Conclusions:
This platform establishes a clinically deployable foundation for precision cardiac immunology supporting next-generation diagnostics, prognostics, and therapeutics in HF and other inflammatory or fibrotic diseases.