Thyroid hormone treatment counteracts cellular phenotypical remodeling in diabetic organs.

Diabetes mellitus and alterations in thyroid hormone (TH) signaling are closely linked. Though the role of TH signaling in cell differentiation and growth is well known, it remains unclear whether its alterations contribute to the pathobiology of diabetic cells. Here, we aim to investigate whether the administration of exogenous T3 can counteract the cellular remodeling that occurs in diabetic cardiomyocytes, podocytes, and pancreatic beta cells. Treating diabetic rats with T3 prevents dedifferentiation, pathological growth, and ultrastructural alterations in podocytes and cardiomyocytes. In vitro, T3 reverses glucose-induced growth in human podocytes and cardiomyocytes, restores cardiomyocyte cytoarchitecture, and reverses pathological alterations in kidney and cardiac organoids. Finally, T3 treatment counteracts glucose-induced transdifferentiation, cell growth, and loss in pancreatic beta cells through TH receptor alpha1 activation. Our studies indicate that TH signaling activation substantially counteracts diabetes-induced pathological remodeling, and provide a potential therapeutic approach for the treatment of diabetes and its complications.

Thyroid Hormone and Heart Failure: Charting Known Pathways for Cardiac Repair/Regeneration.

Heart failure affects more than 64 million people worldwide, having a serious impact on their survival and quality of life. Exploring its pathophysiology and molecular bases is an urgent need in order to develop new therapeutic approaches. Thyroid hormone signaling, evolutionarily conserved, controls fundamental biological processes and has a crucial role in development and metabolism. Its active form is L-triiodothyronine, which not only regulates important gene expression by binding to its nuclear receptors, but also has nongenomic actions, controlling crucial intracellular signalings. Stressful stimuli, such as acute myocardial infarction, lead to changes in thyroid hormone signaling, and especially in the relation of the thyroid hormone and its nuclear receptor, which are associated with the reactivation of fetal development programmes, with structural remodeling and phenotypical changes in the cardiomyocytes. The recapitulation of fetal-like features of the signaling may be partially an incomplete effort of the myocardium to recapitulate its developmental program and enable cardiomyocytes to proliferate and finally to regenerate. In this review, we will discuss the experimental and clinical evidence about the role of the thyroid hormone in the recovery of the myocardium in the setting of heart failure with reduced and preserved ejection fraction and its future therapeutic implications.

Changes in Thyroid Hormone Signaling Mediate Cardiac Dysfunction in the Tg197 Mouse Model of Arthritis: Potential Therapeutic Implications.

Background Rheumatoid Arthritis (RA) patients show a higher risk of heart failure. The present study investigated possible causes of cardiac dysfunction related to thyroid hormone (TH) signaling in a RA mouse model. Methods A TNF-driven mouse model of RA[TghuTNF (Tg197)] was used. Cardiac function was evaluated by echocardiography. SERCA2a and phospholamban protein levels in left ventricle (LV) tissue, thyroid hormone levels in serum, TH receptors in LV and TH-related kinase signaling pathways were measured. T3 hormone was administered in female Tg197 mice. Results We show LV and atrial dilatation with systolic dysfunction in Tg197 animals, accompanied by downregulated SERCA2a. We suggest an interaction of pro-inflammatory and thyroid hormone signaling indicated by increased p38 MAPK and downregulation of TRß1 receptor in Tg197 hearts. Interestingly, female Tg197 mice showed a worse cardiac phenotype related to reduced T3 levels and Akt activation. T3 supplementation increased Akt activation, restored SERCA2a expression and improved cardiac function in female Tg197 mice. Conclusions TNF overexpression of Tg197 mice results in cardiac dysfunction via p38 MAPK activation and downregulation of TRß1. Gender-specific reduction in T3 levels could cause the worse cardiac phenotype observed in female mice, while T3 administration improves cardiac function and calcium handling via modified Akt activation.

Thyroid Hormone Signalling in Human Evolution and Disease: A Novel Hypothesis.

Thyroid hormone (TH) signalling is a universally conserved pathway with pleiotropic actions that is able to control the development, metabolism, and homeostasis of organisms. Using evidence from paleoecology/palaeoanthropology and data from the physiology of modern humans, we try to assess the natural history of TH signalling and its role in human evolution. Our net thesis is that TH signalling has likely played a critical role in human evolution by facilitating the adaptive responses of early hominids to unprecedently challenging and continuously changing environments. These ancient roles have been conserved in modern humans, in whom TH signalling still responds to and regulates adaptations to present-day environmental and pathophysiological stresses, thus making it a promising therapeutic target.

Thyroid Hormone Signalling Alteration in Diabetic Nephropathy and Cardiomyopathy: a "Switch" to the Foetal Gene Programme.

PURPOSE OF THE REVIEW: In this study, we will analyse how diabetes induces the reactivation of organs' developmental programmes and growth, discuss how thyroid hormone (TH) signalling orchestrates these processes, and suggest novel strategies for exploiting TH-mediated reparative and regenerative properties. RECENT FINDINGS: Diabetes is a global pandemic that poses an enormous threat to human health. The kidney and the heart are among the organs that are the most severely damaged by diabetes over time. They undergo profound metabolic, structural, and functional changes that may be due (at least partially) to a recapitulation of their early developmental programmes. There is growing evidence to suggest that this foetal reprogramming is controlled by the TH/TH receptor alpha 1 (TRα1) axis. We introduce the hypothesis that in diabetes-and probably in other diseases-TH signalling acts in an antagonistic manner: it recapitulates a foetal profile that is necessary to coordinate metabolic and structural adaptations to sustain energy preservation and growth, but in the long term the persistent changes in these pathways are detrimental.

Coronary artery disease in renal transplant recipients: an angiographic study.

BACKGROUND: Cardiovascular disease is the leading cause of mortality in renal transplant recipients (RT). Coronary artery disease (CAD) in such patients is poorly studied. METHODS: During 2012-2017, 50 patients with a renal graft (functioning for a minimum of 6 months) were subjected to coronary angiography in our institution. They were matched (for age, gender, diabetes, and indication for angiography) with 50 patients with end-stage renal disease (ESRD) undergoing chronic dialysis and 50 patients with normal renal function who were subjected to coronary angiography during the same period. The extent and severity of CAD were assessed by using the SYNTAX score. RESULTS: RT had a significantly longer duration of ESRD than patients on dialysis (17.5±7.1 vs. 8.5±8.7 years, p<0.01). Mean SYNTAX score was 13.3±12.0 in RT, 20.6±17.5 in patients on dialysis, and 9.4±9.2 in control patients (p<0.01). At least one significantly calcified lesion was present in 75.7% of RT recipients, 92.1% of patients on dialysis, and 15.8% of control patients (p<0.01). Percutaneous coronary intervention (PCI) was successful in 93.8% of the attempted cases in RT, 75% of patients on chronic dialysis, and 100% of control patients (p=0.04). In the RT group, SYNTAX score significantly correlated with smoking (p=0.02) and the total vintage of ESRD (p=0.04). CONCLUSIONS: In this angiographic study, CAD was less severe in RT than in patients on long-term dialysis despite a longer duration of ESRD. Coronary artery calcification was highly prevalent after renal transplantation. PCI in RT had a high rate of angiographic success.

Association Between High-Dose Spironolactone and Decongestion in Patients with Acute Heart Failure: An Observational Retrospective Study.

BACKGROUND: Acute congestive heart failure (ACHF) is a state of severe, secondary hyperaldosteronism. Relief of congestion has prognostic implications. Our aim was to assess associations between high-dose spironolactone and (1) decongestion and (2) safety in patients with ACHF. METHODS: The charts of 20 patients who were hospitalized with ACHF and received high doses of spironolactone (75-300 mg daily, group A) on top of standard of care (SOC) treatment were retrospectively studied and compared with the ones of 20 matched patients who received SOC treatment alone (group B). RESULTS: The two groups were similar as per their baseline characteristics. Mean daily spironolactone dose was 143 ± 56 in group A vs. 25 ± 25 mg in group B (P < 0.001). Patients of group A demonstrated significantly greater daily urine output (median [25th, 75th percentile] 2.9 [2.3, 3.9] vs. 2.2 [1.9, 2.5] L/day, P = 0.009), daily weight loss (1.1 [0.9, 1.7] vs. 0.4 [0.2, 1.2] kg/day, P = 0.005) and total body weight loss (10.5 [7.3, 13.8] vs. 3.8 [3.0, 6.0] kg, P < 0.001) compared with patients of group B. There were no differences in incidence of renal dysfunction, hypokalemia and hyperkalemia. CONCLUSION: In patients with ACHF, administration of high doses of spironolactone on top of SOC treatment appears safe and is associated with greater decongestion than SOC alone.

Short-term ventricular restraint attenuates post-infarction remodeling in rats.

BACKGROUND/OBJECTIVES: Left ventricular restraint attenuates post-infarction remodeling, but may be associated with unfavorable long-term histological response. We hypothesized that beneficial effects can be obtained with short-term restraint during the early post-infarction period; for this purpose, we evaluated a biodegradable scaffold in the in vivo rat model and compared it with epicardial hydrogel application. METHODS: A total of 230 Wistar rats (358 ± 7 g) were studied. Implantation was performed with and without prior myocardial infarction, induced by permanent coronary artery ligation. Diastolic filling was evaluated by left ventricular pressure recordings after scaffold implantation. Degradation rates and inflammatory/foreign body response were studied at 3, 7 and 15 days post-ligation. Remodeling indices were evaluated by echocardiography 15 days post-ligation. RESULTS: No differences were found in diastolic pressure. Biodegradability was ~50% by 7 days and 100% by 15 days for both materials. Likewise, inflammatory/foreign body response peaked at 3 days post-implant, with subsequent remission, but fibroblastic reaction was more pronounced after scaffold than after hydrogel implantation. Post-ligation, ejection fraction was higher in the scaffold (40.0 ± 1.5%) or hydrogel groups (37.0 ± 1.3%), compared to controls (30.6 ± 1.9%). Wall tension index was lower with either biomaterial, but left ventricular end-diastolic diameter was shorter (p=0.044) and sphericity was attenuated (p=0.029) after scaffold, compared to hydrogel implantation. CONCLUSIONS: Both biomaterials showed a favorable histological response and attenuated remodeling, but epicardial restraint produced better results compared to hydrogel alone. The latter approach merits further investigation due to the ease of implantation.