Ischemic heart disease is a leading cause of heart failure and is commonly treated with revascularization. Cardiomyocyte death, and left ventricular (LV) remodeling are pathophysiological responses to myocardial ischemia. Coronary reperfusion has been shown to both salvage myocardium and contribute to cardiomyocyte death. As a result of necrosis, the infarcted myocardium can extend from the subendocardium through the subepicardium and expand in a time‐dependent process. To characterize the time‐dependent effects of cardiac ischemia, we employed a rat ischemia‐reperfusion (IR) model and evaluated the cardiac remodeling and functional consequences of 30, 45, or 60 minutes (min) ischemia. All studies were conducted in accordance with GSK policy and reviewed by the Institutional Animal Care and Use Committee. Adult male Lewis rats were grouped into sham (n=11), 30 min (n=8), 45 min (n=6) or 60 min (n=5) occlusion of the left anterior descending coronary artery followed by reperfusion for 28 days (I/R). Heart function was measured by echocardiography on day 1 and day 28 after I/R. Left ventricular fibrosis was measured by Masson's trichrome stain on day 29. The results showed that the survival at day 29 was similar in 30 min (100%), 45 min (100%), or 60 min (83%) I/R. On day 1, compared to sham, 30, 45 or 60 min of ischemia significantly increased LV mass to body weight ratio by 34%, 15% and 13%, respectively, with sustained hypertrophy on day 28 (34%, 20%, 24%). Ejection fraction was significantly decreased by 17%, 19% and 20% on day 1 with sustained dysfunction on day 28 (13%, 13%, and 17%). At the level of the infarct, fractional area change was significantly decreased by 24%, 29% and 33% on day 1 with sustained dysfunction on day 28 (31%, 29%, and 36%). Compared to sham, end systolic volume in 30, 45, or 60 min I/R was significantly elevated at day 1 by 38%, 33%, 33% and increased significantly more by day 28 (86%, 57%, 72%), respectively. Interestingly, there was no significant change in end diastolic volume on day 1 post I/R, but it was significantly increased on day 28 by 50%, 29%, and 32% compared to sham. At 4 weeks following 30, 45, or 60 min I/R, LV collagen was significantly increased similarly across I/R groups (13, 14, or 16‐fold). There was a strong, negative correlation between LV fibrosis and systolic function. There were no significant differences in the variances of cardiac structure and function measurements among the I/R groups at any time point. Unlike the permanent cardiac ischemia model where infarcts progress to the subepicardial region, all groups of transient I/R rats had nontransmural infarcts. These data indicate that the maximum systolic dysfunction developed early in transient ischemia‐reperfusion injury, but LV remodeling progressed over time. Furthermore, there was no significant difference in the rat cardiac pathophysiological response to transient ischemia for up to one hour. The reperfused myocardium following 30–60 min ischemia retained the ability to limit cardiomyocyte death and attenuate the progression of necrosis and systolic dysfunction. Support or Funding Information GlaxoSmithKline, King of Prussia, PA

Background The amino acid response (AAR) is an evolutionarily conserved protective mechanism activated by amino acid deficiency through a key kinase, general control nonderepressible 2. In addition to mobilizing amino acids, the AAR broadly affects gene and protein expression in a variety of pathways and elicits antifibrotic, autophagic, and anti‐inflammatory activities. However, little is known regarding its role in cardiac stress. Our aim was to investigate the effects of halofuginone, a prolyl‐tRNA synthetase inhibitor, on the AAR pathway in cardiac fibroblasts, cardiomyocytes, and in mouse models of cardiac stress and failure. Methods and Results Consistent with its ability to inhibit prolyl‐tRNA synthetase, halofuginone elicited a general control nonderepressible 2–dependent activation of the AAR pathway in cardiac fibroblasts as evidenced by activation of known AAR target genes, broad regulation of the transcriptome and proteome, and reversal by l‐proline supplementation. Halofuginone was examined in 3 mouse models of cardiac stress: angiotensin II/phenylephrine, transverse aortic constriction, and acute ischemia reperfusion injury. It activated the AAR pathway in the heart, improved survival, pulmonary congestion, left ventricle remodeling/fibrosis, and left ventricular function, and rescued ischemic myocardium. In human cardiac fibroblasts, halofuginone profoundly reduced collagen deposition in a general control nonderepressible 2–dependent manner and suppressed the extracellular matrix proteome. In human induced pluripotent stem cell–derived cardiomyocytes, halofuginone blocked gene expression associated with endothelin‐1‐mediated activation of pathologic hypertrophy and restored autophagy in a general control nonderepressible 2/eIF2α‐dependent manner. Conclusions Halofuginone activated the AAR pathway in the heart and attenuated the structural and functional effects of cardiac stress.

The purpose of this study was to determine which measurements of diastolic dysfunction are most correlated with cardiac fibrosis. Mice were subjected to Sham (n=7) or transverse aortic constriction (TAC, n=6) for 10 weeks, examined by speckle‐tracking echocardiography and left ventricle (LV) pressure catheter, and portions of the LV were processed for biomarkers and histological analysis. In TAC mice as compared to Sham, Masson's Trichrome staining revealed an increase in fibrosis by 800% (P<0.01); with the majority of the collagen located in the mid‐wall of the myocardium. LV insoluble collagen hydroxyproline (HDXP) increased by 99% (P<0.01); and the collagen cross‐linker pyridinoline (PYD) increased by 100% (P<0.001). Tau was increased by 46% (P<0.01) and diastolic radial and circumferential strain rates were decreased by 41% and 44%, respectively (both P<0.01). The correlations between PYD and diastolic dysfunction were: r = 0.79, 0.76, and 0.85 for Tau, radial and circumferential strain rates, respectively. Similar correlations were observed for HDXP and diastolic dysfunction. In summary, cardiac fibrosis and diastolic dysfunction are highly correlated in the mouse TAC model with diastolic circumferential strain rate better correlated with cardiac fibrosis, possibly due to the majority of the fibrosis being located in the mid‐wall, where myofibers are aligned circumferentially.

Speckle tracking echo strain imaging has not been used longitudinally to assess both systolic and diastolic function following myocardial ischemia (I)/reperfusion (R) injury. We tested the hypothesis that strain imaging can precisely detect systolic and diastolic dysfunction earlier than conventional echocardiography in rats following a 30 min I and 4 weeks R. Conventional and speckle tracking echocardiography were performed prior to I (baseline), at 48 hr and at 2 and 4 weeks after R. I/R injury reduced ejection fraction by 20%, 18% and 22%, at 48 hr, 2 and 4 weeks, respectively (all p<0.05 vs. sham, n=6–10). Global systolic circumferential strain decreased by 29%, 26% and 29%, respectively (all P<0.05); segmental systolic circumferential strain was reduced by 80%, 46% and 41% (all P<0.001). Conventional Doppler echocardiography showed no difference in IVRT and E/E OE (p=NS vs. sham) at any time points following R. In contrast, global and segmental diastolic circumferential strain rate were significantly reduced at all time points following R. At 4 weeks, I/R injury also significantly reduced cardiac reserve, markedly increased cardiac fibrosis and apoptosis, up‐regulated NCX1 and down‐regulated SERCA‐2a protein expression. Our results demonstrate that speckle tracking echocardiography provides a more sensitive technique for early detection of both systolic and diastolic dysfunction in the failing heart.

We utilized various mouse models of IBD to demonstrate that TL1A expression on the surface of DCs is increased in inflamed intestines. Moreover, Tl1a−/− naive CD4+ T cells exhibited impaired ability for Th1 or Th17 differentiation ex vivo, and ...The binding of tumor necrosis factor–like cytokine 1A (TL1A) to death receptor 3 (DR3) plays an important role in the interaction between dendritic cells (DCs) and T cells and contributes to intestinal inflammation development. However, the mechanism by ...