CD4+ T Cells Promote the Transition from Hypertrophy to Heart Failure During Chronic Pressure Overload
Background—The mechanisms by which the heart adapts to chronic pressure overload, producing a compensated hypertrophy and eventually heart failure (HF) are still not well defined. We aimed to investigate the involvement of T cells in the progression to HF using transverse aortic constriction model (TAC).
Methods and Results—Chronic heart failure was associated with accumulation of T lymphocytes and activated/effector CD4+ T cells within cardiac tissue. After TAC, enlarged heart-mediastinal draining lymph nodes showed a high density of both CD4+ and CD8+ T cell subsets. To investigate the role of T cells in HF, TAC was performed on RAG2KO mice lacking B and T lymphocytes. As compared to WT TAC, RAG2KO mice did not develop cardiac dilation, showed improved contractile function and blunted adverse remodeling. Reconstitution of the T cell compartment into RAG2KO mice prior to TAC enhanced contractile dysfunction, fibrosis, collagen accumulation and cross-linking. To determine the involvement of a specific T cell subset, we performed TAC on mice lacking CD4+ (MHCIIKO) and CD8+ T cell subsets (CD8KO). In contrast to CD8KO, MHCIIKO did not develop ventricular dilation and dysfunction. MHCIIKO also displayed very low fibrosis, collagen accumulation and cross-linking within cardiac tissue. Interestingly, mice with transgenic CD4+ TCR specific for ovalbumin (OT-II) failed to develop HF and adverse remodeling.
Conclusions—These results demonstrate for the first time a crucial role of CD4+ T cells and specific antigen recognition in the progression from compensated cardiac hypertrophy to HF.
- Received October 25, 2013.
- Revision received March 12, 2014.
- Accepted March 14, 2014.