Research

Cardiac fibrosis (CF) is a hallmark of heart failure (HF) causing decreased mechanical function of the heart, yet therapies attempting to directly target CF have not been clinically effective, demonstrating the need for greater understanding of fibrotic mechanisms during HF. Cardiac Fibroblasts (CFBs), the main drivers of CF, are activated in HF by numerous stimuli including signals from immune cells.

While the extent of cardiac fibrosis is associated to worse prognosis in heart failure patients, the lack of clinically available antifibrotic therapies highlights a need for greater understanding of the fibrotic mechanisms of heart failure. Cardiac inflammation is T cell dependent and is directly associated with CF in HF, as we have shown that T-cell deficient mice do not develop cardiac fibrosis. T cell interactions with CFB result in a two-way crosstalk in which T cells induce CFB transformation, and CFB in turn function as non-professional antigen presenting cells that induce T cell activation. Our laboratory investigates the newly appreciated role of CFBs as non-professional antigen presenting cells in the context of heart failure by studying both the induction of CFB MHC-II and its role in the activation of CFBs.

Heart Failure with Preserved Ejection Fraction (HFpEF): Despite the well- known association of heart failure with systemic chronic inflammation, traditional anti-inflammatory therapies have so far been unsuccessful to date. This is in part due to the complexity of this syndrome, which embraces different etiologies in which cardiac damage results from different triggers and risk factors. Understanding the immune mechanisms involved in the inflammatory response associated with the development and progression of different etiologies of HF is key to identify biomarkers of disease and discover new therapies for this complex syndrome. The Alcaide lab investigates T cell-mediated cardiac pathology in HFpEF, a condition which comprises half of HF diagnoses, has rising incidence and current HF medications are not effective. A key characteristic of HFpEF is systemic chronic low-grade inflammation associated with combined obesity and hypertension. While these two risk factors each induce specific T cell immune responses, they do not independently induce HFpEF. Using pre-clinical models of HFpEF that combine obesity and hypertension, we investigate how cell-intrinsic stress reprograms T cell activity towards a cardiac inflammatory potential that impacts cardiac relaxation.

Chemotherapy cardiotoxicity and heart failure: Cancer and cardiovascular disease are the two most common causes of death worldwide. They share common risk factors and hallmarks of chronic inflammation, including aberrant activation of the T cell immune response. The dual role of T cells as contributors to cardiac damage in heart failure and as potent effectors of anti-tumor immunity and the emergence of cardiovascular complications in cancer patients treated with chemotherapy further highlight investigating T cell immune responses in this context. The Alcaide lab investigates the effects of broadly used chemotherapy (anthracyclines and Immune Check point Inhibitors) in pathological cardiac T cell immune responses that result in fibrosis and heart failure. The ultimate goals are to discover new targets that allow dampening cardiac inflammation without altering the anti-tumor immune response. We use cancer pre-clinical models and chemotherapy cardiotoxicity models to elucidate the molecular mechanisms that initiate and perpetuate cytotoxic immune responses in chemotherapy induced heart failure, determine the T cell communication pathways with the tumor and cardiac stroma, and investigate the translational potential of these molecular signatures as predictive markers in patients at risk of developing heart failure due to long term use chemotherapy.