A diastolic dysfunction model in non-human primates with transverse aortic constriction.

Transverse aortic constriction (TAC) has been widely used to study cardiac hypertrophy, fibrosis, diastolic dysfunction, and heart failure in rodents. Few studies have been reported in preclinical animal models. The similar physiology and anatomy between non-human primates (NHPs) and humans make NHPs valuable models for disease modeling and testing of drugs and devices. In the current study, we aimed to establish a TAC model in NHPs and characterize the structural and functional profiles of the heart after TAC. A non-absorbable suture was placed around the aorta between the brachiocephalic artery and left common carotid artery to create TAC. NHPs were divided into 2 groups according to pressure gradient (PG): the Mild Group (PG=31.01 ± 12.40 mmHg, n=3) and the Moderate Group (PG=53.00 ± 9.37 mmHg, n=4). At 4 weeks after TAC, animals in both TAC groups developed cardiac hypertrophy: enlarged myocytes and increased wall thickness of the left ventricular (LV) anterior wall. Although both TAC groups had normal systolic function that was similar to a Sham Group, the Moderate Group showed diastolic dysfunction that was associated with more severe cardiac fibrosis, as evidenced by a reduced A wave velocity, large E wave velocity/A wave velocity ratio, and short isovolumic relaxation time corrected by heart rate. Furthermore, no LV arrhythmia was observed in either animal group after TAC. A diastolic dysfunction model with cardiac hypertrophy and fibrosis was successfully developed in NHPs.

IL-11 is a crucial determinant of cardiovascular fibrosis.

Fibrosis is a common pathology in cardiovascular disease. In the heart, fibrosis causes mechanical and electrical dysfunction and in the kidney, it predicts the onset of renal failure. Transforming growth factor ß1 (TGFß1) is the principal pro-fibrotic factor, but its inhibition is associated with side effects due to its pleiotropic roles. We hypothesized that downstream effectors of TGFß1 in fibroblasts could be attractive therapeutic targets and lack upstream toxicity. Here we show, using integrated imaging-genomics analyses of primary human fibroblasts, that upregulation of interleukin-11 (IL-11) is the dominant transcriptional response to TGFß1 exposure and required for its pro-fibrotic effect. IL-11 and its receptor (IL11RA) are expressed specifically in fibroblasts, in which they drive non-canonical, ERK-dependent autocrine signalling that is required for fibrogenic protein synthesis. In mice, fibroblast-specific Il11 transgene expression or Il-11 injection causes heart and kidney fibrosis and organ failure, whereas genetic deletion of Il11ra1 protects against disease. Therefore, inhibition of IL-11 prevents fibroblast activation across organs and species in response to a range of important pro-fibrotic stimuli. These results reveal a central role of IL-11 in fibrosis and we propose that inhibition of IL-11 is a potential therapeutic strategy to treat fibrotic diseases.