DOI: 10.1161/circ.148.suppl_1.11310 ISSN: 0009-7322

Abstract 11310: T Helper 1 Lymphocytes Promote Diastolic Dysfunction and Fibrosis in a Non-Hypertensive Angiotensin II Mouse Model of Heart Failure

Michelle M Kim, Eleonora Mezzaroma, Nadia Martinez Naya, Adolfo G Mauro, Pilar Alcaide, Antonio Abbate, Stefano A Toldo
  • Physiology (medical)
  • Cardiology and Cardiovascular Medicine

Introduction: Angiotensin (Ang) II induces cardiac fibrosis and diastolic dysfunction, also in absence of hypertension (HTN). We found that a non-HTN AngII infusion fails to induce dysfunction and fibrosis in T cell receptor α deficient mice ( Tcrα -/- , bereft of T cells).

Hypothesis: Since T helper 1 (Th1) lymphocytes promote adverse remodeling in models of heart failure (HF), we hypothesized that Th1 cells are sufficient to induce diastolic dysfunction and fibrosis in a non-HTN AngII model.

Methods: Naïve CD4+ cells were isolated from wild type (WT) mice lymph nodes (LNs) and spleens (MACS columns) and differentiated into Th1 cells over 7 days using plates coated with anti-CD3 antibody (5 μg/ml) plus IL-12 (10 ng/ml) and anti-IL-4 (1 μg/ml) and from day 4, IL-2 (20 ng/ml). Adoptive transfer (AT) of 10 7 Th1 cells/500 μl PBS, naïve CD4+ cells, or PBS alone was performed into Tcrα -/- mice (3-11 months old, N=8-16/group) implanted with AngII (0.2 μg/kg/day) osmotic pumps for 4 wks. AT was repeated two weeks later. LV dimensions, ejection fraction (EF), and diastolic function (isovolumetric relaxation time - IRT) were measured with Doppler echocardiography. LV end-diastolic pressure (EDP) and peak systolic pressure (PSP) were measured with a Millar catheter. Heart slides were stained with picrosirius red to measure interstitial fibrosis.

Results: All groups had similar LV dimensions, EF, and PSP (not shown). AT of naïve CD4+ cells or PBS did not increase the IRT vs baseline (7.3±0.9 vs 7.6±0.6 and 9.9±0.7 vs 8.8±0.7 ms). AT of Th1 cells significantly increased the IRT (15.6±0.9 vs 9.0±0.7 ms, all p<0.0001). EDP was significantly higher in Th1 mice (11.5±0.8 mmHg) vs naïve CD4+ mice (4.6±0.8 mmHg) or PBS (5.2±0.6 mmHg) (all p<0.0001). Interstitial fibrosis in Th1 mice (1.4±0.2%) was significantly higher than in naïve CD4+ mice (0.7±0.1%) or PBS (0.8±0.1%) (all p<0.001).

Conclusions: Th1 cells are sufficient to induce diastolic dysfunction and fibrosis in a non-HTN AngII HF mouse model.

More from our Archive