T Cells Play a Causal Role in Diastolic Dysfunction during Uremic Cardiomyopathy

Background Uremic cardiomyopathy, characterized by left ventricular hypertrophy, diastolic dysfunction, and impaired myocardial strain, contributes to increased cardiovascular mortality in patients with CKD. Emerging evidence suggests a pathogenic role for T cells during chronic heart failure. Methods To determine whether T cells contribute to uremic cardiomyopathy pathogenesis, wemodeled this condition by inducing CKD via 5/6th nephrectomy in mice.We used flow cytometry to assess expres- sion of markers of T cell memory or activation by lymphocytes from CKD mice and controls, as well as lymphocyte capacity for cytokine production. Flow cytometry was also used to quantify immune cells isolated from heart tissue. To test effects of T cell depletion on cardiac function, we gave CKD mice anti-CD3 antibody injections to deplete T cells and compared heart function (assessed by echocardiog- raphy) with that of controls. Finally, we correlated T cell phenotypes with structural and functional mea- sures on clinically acquired echocardiograms in children with CKD. ResultsMice with CKD accumulated T cells bearing markers of memory differentiation (CD44hi) and acti- vation (PD-1, KLRG1, OX40), as reported previously in human CKD. In addition,mice with CKD showed T cells infiltrating the heart. T cell depletion significantly improved both diastolic function and myocardial strain in CKD mice without altering hypertension or degree of renal dysfunction. In children with CKD, increasing frequency of T cells bearing activation markers PD-1 and/or CD57 was associated with wors- ening diastolic function on echocardiogram. Conclusions CKD results in an accumulation of proinflammatory T cells that appears to contribute to myocardial dysfunction.