Effects of T3 Administration on Ex Vivo Rat Hearts Subjected to Normothermic Perfusion: Therapeutic Implications in Donor Heart Preservation and Repair.

The present study investigated the effects of triiodothyronine (T3) administration in ex vivo model of rat heart normothermic perfusion. T3 is cardioprotective and has the potential to repair the injured myocardium. Isolated hearts were subjected to normothermic perfusion (NP) with Krebs-Henseleit for 4 h with vehicle (NP) or 60 nM T3 in the perfusate (NP + T3). Left ventricular end diastolic pressure (LVEDP), left ventricular developed pressure (LVDP), perfusion pressure (PP) and percentage of change of these parameters from the baseline values were measured. Activation of stress induced kinase signaling was assessed in tissue samples. Baseline parameters were similar between groups. LVEDP was increased from the baseline by 13% (70) for NP + T3 vs. 139% (160) for NP group, p = 0.048. LVDP was reduced by 18.2% (5) for NP + T3 vs. 25.3% (19) for NP group, p = 0.01. PP was increased by 41% (19) for NP + T3 vs.91% (56) for NP group, p = 0.024. T3 increased activation of pro-survival Akt by 1.85 fold (p = 0.047) and AMPK by 2.25 fold (p = 0.01) and reduced activation of pro-apoptotic p38 MAPK by 3fold (p = 0.04) and p54 JNK by 4.0 fold (p = 0.04). Administration of T3 in normothermic perfusion had favorable effects on cardiac function and perfusion pressure and switched death to pro-survival kinase signaling.

Donor Heart Preservation: Current Knowledge and the New Era of Machine Perfusion.

Heart transplantation remains the conventional treatment in end-stage heart failure, with static cold storage (SCS) being the standard technique used for donor preservation. Nevertheless, prolonged cold ischemic storage is associated with the increased risk of early graft dysfunction attributed to residual ischemia, reperfusion, and rewarming damage. In addition, the demand for the use of marginal grafts requires the development of new methods for organ preservation and repair. In this review, we focus on current knowledge and novel methods of donor preservation in heart transplantation. Hypothermic or normothermic machine perfusion may be a promising novel method of donor preservation based on the administration of cardioprotective agents. Machine perfusion seems to be comparable to cold cardioplegia regarding donor preservation and allows potential repair treatments to be employed and the assessment of graft function before implantation. It is also a promising platform for using marginal organs and increasing donor pool. New pharmacological cardiac repair treatments, as well as cardioprotective interventions have emerged and could allow for the optimization of this modality, making it more practical and cost-effective for the real world of transplantation. Recently, the use of triiodothyronine during normothermic perfusion has shown a favorable profile on cardiac function and microvascular dysfunction, likely by suppressing pro-apoptotic signaling and increasing the expression of cardioprotective molecules.

Low concentrations of bisphenol A promote the activation of the mitochondrial apoptotic pathway on Beta-TC-6 cells via the generation of intracellular reactive oxygen species and mitochondrial superoxide.

Τhe natural history of type 2 diabetes mellitus is characterized by a progressive loss of pancreatic beta cell function and insulin resistance. Bisphenol A (BPA) is an endocrine-disrupting chemical that is used widely in industry; people are exposed to BPA and its products daily. Studies have delineated that BPA alters the function of pancreatic beta cells. Herein, we examined the effect of low doses of BPA on pancreatic beta cell viability and apoptosis and we tried to elucidate the mechanisms involved in these processes. Beta-TC-6 (ATCC® CRL-11506™) cells were cultured with a medium containing the following dilutions of BPA: 0.002, 0.02, 0.1, 0.2, 2 µΜ up to 72 h. We examined the viability and adenosine triphosphate (ATP) levels of cells. Then, we measured apoptosis, cell cycle, and insulin levels. We quantified the levels of proteins implicated in the mitochondrial pathway of apoptosis; and finally, we quantified the intracellular reactive oxygen species and mitochondrial superoxide. We found that the exposure of Beta-TC-6 cells to BPA results in a decrease in cell viability, ATP levels, and an increase in insulin levels. We found an increase in apoptosis levels and a decrease in cell cycle levels. In addition, we provide evidence of the levels of apoptotic proteins. Finally, we found an increase in the cellular reactive oxygen species and mitochondrial superoxide production. Exposure to low concentrations of BPA triggers the mitochondrial pathway of apoptosis via the generation of intracellular reactive oxygen species and mitochondrial superoxide on Beta-TC-6 cells in a dose-dependent way.

Thyroid Hormone Signalling: From the Dawn of Life to the Bedside.

Thyroid hormone (TH) signalling is a key modulator of fundamental biological processes that has been evolutionarily conserved in both vertebrate and invertebrate species. TH may have initially emerged as a nutrient signal to convey environmental information to organisms to induce morpho-anatomical changes that could maximise the exploitation of environmental resources, and eventually integrated into the machinery of gene regulation and energy production to become a key regulator of development and metabolism. As such, TH signalling is particularly sensitive to environmental stimuli, and its alterations result in fundamental changes in homeostasis and physiology. Stressful stimuli of various origins lead to changes in the TH-TH receptor (TR) axis in different adult mammalian organs that are associated with phenotypical changes in terminally differentiated cells, the reactivation of foetal development programmes, structural remodelling and pathological growth. Here, we discuss the evolution of TH signalling, review evolutionarily conserved functions of THs in essential biological processes, such as metamorphosis and perinatal development, and analyse the role of TH signalling in the phenotypical and morphological changes that occur after injury, repair and regeneration in adult mammalian organs. Finally, we examine the potential of TH treatment as a therapeutic strategy for improving organ structure and functions following injury.

Comorbid TNF-mediated heart valve disease and chronic polyarthritis share common mesenchymal cell-mediated aetiopathogenesis.

OBJECTIVES: Patients with rheumatoid arthritis and spondyloarthritisshow higher mortality rates, mainly caused by cardiac comorbidities. The TghuTNF (Tg197) arthritis model develops tumour necrosis factor (TNF)-driven and mesenchymalsynovial fibroblast (SF)-dependent polyarthritis. Here, we investigate whether this model develops, similarly to human patients, comorbid heart pathology and explore cellular and molecular mechanisms linking arthritis to cardiac comorbidities. METHODS: Histopathological analysis and echocardiographic evaluation of cardiac function were performed in the Tg197 model. Valve interstitial cells (VICs) were targeted by mice carrying the ColVI-Cretransgene. Tg197 ColVI-Cre Tnfr1fl/fl and Tg197 ColVI-Cre Tnfr1cneo/cneo mutant mice were used to explore the role of mesenchymal TNF signalling in the development of heart valve disease. Pathogenic VICs and SFs were further analysed by comparative RNA-sequencing analysis. RESULTS: Tg197 mice develop left-sided heart valve disease, characterised by valvular fibrosis with minimal signs of inflammation. Thickened valve areas consist almost entirely of hyperproliferative ColVI-expressing mesenchymal VICs. Development of pathology results in valve stenosis and left ventricular dysfunction, accompanied by arrhythmic episodes and, occasionally, valvular regurgitation. TNF dependency of the pathology was indicated by disease modulation following pharmacological inhibition or mesenchymal-specific genetic ablation or activation of TNF/TNFR1 signalling. Tg197-derived VICs exhibited an activated phenotype ex vivo, reminiscent of the activated pathogenic phenotype of Tg197-derived SFs. Significant functional similarities between SFs and VICs were revealed by RNA-seq analysis, demonstrating common cellular mechanisms underlying TNF-mediated arthritides and cardiac comorbidities. CONCLUSIONS: Comorbidheart valve disease and chronic polyarthritis are efficiently modelled in the Tg197 arthritis model and share common TNF/TNFR1-mediated, mesenchymal cell-specific aetiopathogenic mechanisms.

Plasma Irisin Levels in Subjects with Type 1 Diabetes: Comparison with Healthy Controls.

Irisin is a myokine that increases energy expenditure. In this cross-sectional study, we examined for differences in plasma irisin concentrations between subjects with type 1 diabetes mellitus and healthy individuals and searched for associations between plasma irisin levels and clinical and biochemical characteristics as well as self-reported physical activity. A total of 79 subjects with type 1 diabetes [age 38.2±12.5 years, men/women (n): 27/52], were consecutively recruited. Moreover, 53 healthy controls, matched for age and body mass index with those with diabetes were recruited. Plasma irisin was measured with ELISA. Participants were asked about their physical activity during the last week. We also measured trunk and visceral fat. Circulating irisin levels were lower in subjects with diabetes than in controls [median value (interquartile range): 53.0 (35.2, 106.3) vs. 178.1 (42.6, 641.6) ng/ml, respectively, p<0.001]. In the group of diabetes, univariate analysis showed that irisin levels were associated with waist circumference (beta=-0.283, p=0.023), serum triglycerides (beta=-0.282, p=0.031), and trunk fat (beta=-0.324, p=0.012). In multivariate analysis after adjustment for potential confounders, irisin levels were associated independently only with waist circumference (beta=-0.403, p=0.005). Among controls, multivariate analysis demonstrated that irisin levels were associated with pack-years of smoking (beta=-0.563, p=0.012) and fasting triglycerides (beta=-0.338, p=0.041). Circulating irisin levels were lower in subjects with diabetes in comparison with healthy-matched controls. In conclusion, plasma irisin concentrations in subjects with diabetes were associated with waist circumference, while in controls with serum triglycerides and pack-years of smoking.

Principal Aspects Regarding the Maintenance of Mammalian Mitochondrial Genome Integrity.

Mitochondria have emerged as key players regarding cellular homeostasis not only due to their contribution regarding energy production through oxidative phosphorylation, but also due to their involvement in signaling, ion regulation, and programmed cell death. Indeed, current knowledge supports the notion that mitochondrial dysfunction is a hallmark in the pathogenesis of various diseases. Mitochondrial biogenesis and function require the coordinated action of two genomes: nuclear and mitochondrial. Unfortunately, both intrinsic and environmental genotoxic insults constantly threaten the integrity of nuclear as well as mitochondrial DNA. Despite the extensive research that has been made regarding nuclear genome instability, the importance of mitochondrial genome integrity has only recently begun to be elucidated. The specific architecture and repair mechanisms of mitochondrial DNA, as well as the dynamic behavior that mitochondria exert regarding fusion, fission, and autophagy participate in mitochondrial genome stability, and therefore, cell homeostasis.

Translating thyroid hormone effects into clinical practice: the relevance of thyroid hormone receptor α1 in cardiac repair.

Thyroid hormone (TH) appears to have a critical role in cardiac repair after injury beyond its role in development and metabolism homeostasis. This unique action is due to the fact that TH effect on the heart is shown to be differentiated depending on its administration on injured or healthy myocardium. Thus, TH can limit ischemia-reperfusion injury via a fine balance between pro-apoptotic and pro-survival signaling pathways. This response is thyroid hormone receptor (TRα1) dependent. Furthermore, an interaction between stress-induced growth kinase signaling and TRα1 is shown to occur and determine postischemic remodeling and cardiac recovery depending on the availability of TH. This new evidence is consistent with clinical observations showing the cardioprotective effect of TH treatment in cardiac surgery, transplantation and heart failure. TH and/or thyroid analogs may be novel agents in treating heart diseases.

Carnitine modulates crucial myocardial adenosine triphosphatases and acetylcholinesterase enzyme activities in choline-deprived rats.

Choline is an essential nutrient, and choline deficiency has been associated with cardiovascular morbidity. Choline is also the precursor of acetylcholine (cholinergic component of the heart's autonomic nervous system), whose levels are regulated by acetylcholinesterase (AChE). Cardiac contraction-relaxation cycles depend on ion gradients established by pumps like the adenosine triphosphatases (ATPases) Na(+)/K(+)-ATPase and Mg(2+)-ATPase. This study aimed to investigate the impact of dietary choline deprivation on the activity of rat myocardial AChE (cholinergic marker), Na(+)/K(+)-ATPase, and Mg(2+)-ATPase, and the possible effects of carnitine supplementation (carnitine, structurally relevant to choline, is used as an adjunct in treating cardiac diseases). Adult male albino Wistar rats were distributed among 4 groups, and were fed a standard or choline-deficient diet for one month with or without carnitine in their drinking water (0.15% w/v). The enzyme activities were determined spectrophotometrically in the myocardium homogenate. Choline deficiency seems to affect the activity of the aforementioned parameters, but only the combination of choline deprivation and carnitine supplementation increased myocardial Na(+)/K(+)-ATPase activity along with a concomitant decrease in the activities of Mg(2+)-ATPase and AChE. The results suggest that carnitine, in the setting of choline deficiency, modulates cholinergic myocardial neurotransmission and the ATPase activity in favour of cardiac work efficiency.

The Pleiotropic Effects of Lipid-Modifying Interventions: Exploring Traditional and Emerging Hypolipidemic Therapies.

Atherosclerotic cardiovascular disease poses a significant global health issue, with dyslipidemia standing out as a major risk factor. In recent decades, lipid-lowering therapies have evolved significantly, with statins emerging as the cornerstone treatment. These interventions play a crucial role in both primary and secondary prevention by effectively reducing cardiovascular risk through lipid profile enhancements. Beyond their primary lipid-lowering effects, extensive research indicates that these therapies exhibit pleiotropic actions, offering additional health benefits. These include anti-inflammatory properties, improvements in vascular health and glucose metabolism, and potential implications in cancer management. While statins and ezetimibe have been extensively studied, newer lipid-lowering agents also demonstrate similar pleiotropic effects, even in the absence of direct cardiovascular benefits. This narrative review explores the diverse pleiotropic properties of lipid-modifying therapies, emphasizing their non-lipid effects that contribute to reducing cardiovascular burden and exploring emerging benefits for non-cardiovascular conditions. Mechanistic insights into these actions are discussed alongside their potential therapeutic implications.

The Han:SPRD Rat: A Preclinical Model of Polycystic Kidney Disease.

Autosomal Dominant Polycystic Kidney Disease (ADPKD) stands as the most prevalent hereditary renal disorder in humans, ultimately culminating in end-stage kidney disease. Animal models carrying mutations associated with polycystic kidney disease have played an important role in the advancement of ADPKD research. The Han:SPRD rat model, carrying an R823W mutation in the Anks6 gene, is characterized by cyst formation and kidney enlargement. The mutated protein, named Samcystin, is localized in cilia of tubular epithelial cells and seems to be involved in cystogenesis. The homozygous Anks6 mutation leads to end-stage renal disease and death, making it a critical factor in kidney development and function. This review explores the utility of the Han:SPRD rat model, highlighting its phenotypic similarity to human ADPKD. Specifically, we discuss its role in preclinical trials and its importance for investigating the pathogenesis of the disease and developing new therapeutic approaches.

Inhibition of thyroid hormone receptor α1 impairs post-ischemic cardiac performance after myocardial infarction in mice.

Thyroid hormone receptor α1 (TRα1) is shown to be critical for the maturation of cardiomyocytes and for the cellular response to stress. TRα1 is altered during post ischemic cardiac remodeling but the physiological significance of this response is not fully understood. Thus, the present study explored the potential consequences of selective pharmacological inhibition of TRα1 on the mechanical performance of the post-infarcted heart. Acute myocardial infarction was induced in mice (AMI), while sham operated animals served as controls (SHAM). A group of mice was treated with debutyl-dronedarone (DBD), a selective TRα1 inhibitor (AMI-DBD). AMI resulted in low T3 levels in plasma and in down-regulation of TRα1 and TRß1 expression. Left ventricular ejection fraction (LVEF%) was significantly reduced in AMI [33 (SEM 2.1) vs 79(2.5) in SHAM, p < 0.05] and was further declined in AMI-DBD [22(1.1) vs 33(2.1), respectively, p < 0.05]. Cardiac mass was increased in AMI but not in AMI-DBD hearts, resulting in significant increase in wall tension index. This increase in wall stress was accompanied by marked activation of p38 MAPK, a kinase that is sensitive to mechanical stretch and exerts negative inotropic effect. Furthermore, AMI resulted in ß-myosin heavy chain overexpression and reduction in the ratio of SR(Ca)ATPase to phospholamban (PLB). The latter further declined in AMI-DBD mainly due to increased expression of PLB. AMI induces downregulation of thyroid hormone signaling and pharmacological inhibition of TRα1 further depresses post-ischemic cardiac function. p38 MAPK and PLB may, at least in part, be involved in this response.

Prognostic scoring system for peripheral nerve repair in the upper extremity.

So far, predictive models with individualized estimates of prognosis for patients with peripheral nerve injuries are lacking. Our group has previously shown the prognostic value of a standardized scoring system by examining the functional outcome after acute, sharp complete laceration and repair of median and/or ulnar nerves at various levels in the forearm. In the present study, we further explore the potential mathematical model in order to devise an effective prognostic scoring system. We retrospectively collected medical record data of 73 cases with a peripheral nerve injury in the upper extremity in order to estimate which patients would return to work, and what time was necessary to return to the pre-injury work. Postoperative assessment followed the protocol described by Rosén and Lundborg. We found that return to pre-injury work can be predicted with high sensitivity (100%) and specificity (95%) using the total numerical score of the Rosén and Lundborg protocol at the third follow-up interval (TS3) as well as the difference between the TS3 and the total score at second follow-up interval (TS2). In addition, the factors age and type of injured nerve (median, ulnar, or combined) can determine the time of return to work based on a mathematical model. This prognostic protocol can be a useful tool to provide information about the functional and social prospects of the patients with these types of injuries.

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.

SGLT-2 Inhibitors and the Inflammasome: What's Next in the 21st Century?

The nucleotide-binding domain-like receptor protein 3 (NLRP3) inflammasome in the kidney and the heart is increasingly being suggested to play a key role in mediating inflammation. In the kidney, NLRP3 activation was associated with the progression of diabetic kidney disease. In the heart, activation of the NLRP3 inflammasome was related to the enhanced release of interleukin-1ß (IL-1ß) and the subsequent induction of atherosclerosis and heart failure. Apart from their glucose-lowering effects, SGLT-2 inhibitors were documented to attenuate activation of the NLRP3, thus resulting in the constellation of an anti-inflammatory milieu. In this review, we focus on the interplay between SGLT-2 inhibitors and the inflammasome in the kidney, the heart and the neurons in the context of diabetes mellitus and its complications.

Endothelin Modulates Rhythm Disturbances and Autonomic Responses to Acute Emotional Stress in Rats.

The ubiquitous peptide endothelin is currently under investigation as a modulatory factor of autonomic responses to acute emotional stress. Baseline plasma levels of endothelin alter blood pressure responses, but it remains unclear whether autonomic activity and arrhythmogenesis (i.e., brady- or tachyarrhythmias) are affected. We recorded sympathetic and vagal indices (derived from heart rate variability analysis), rhythm disturbances, voluntary motion, and systolic blood pressure after acute emotional stress in conscious rats with implanted telemetry devices. Two strains were compared, namely wild-type and ETB-deficient rats, the latter displaying elevated plasma endothelin. No differences in heart rate or blood pressure were evident, but sympathetic responses were blunted in ETB-deficient rats, contrasting prompt activation in wild-type rats. Vagal withdrawal was observed in both strains at the onset of stress, but vagal activity was subsequently restored in ETB-deficient rats, accompanied by low voluntary motion during recovery. Reflecting such distinct autonomic patterns, frequent premature ventricular contractions were recorded in wild-type rats, as opposed to sinus pauses in ETB-deficient rats. Thus, chronically elevated plasma endothelin levels blunt autonomic responses to acute emotional stress, resulting in vagal dominance and bradyarrhythmias. Our study provides further insights into the pathophysiology of stress-induced tachyarrhythmias and syncope.

Cardiotrophin-1 in Asymptomatic Hypertensive Patients With Mild Diastolic Dysfunction: Potential Prognostic Value in Early Stages of Hypertensive Heart Disease.

BACKGROUND: Regardless of the advancements in modern technology and treatment options, heart failure (HF) exhibits impervious mortality and morbidity rates. Arterial hypertension poses one of the greatest risks for developing HF, yet the exact pathophysiological path and changes that lead from isolated hypertension to HF are still unclear. Cardiotrophin-1 (CT-1) serves as a promising prognostic biomarker for the onset of HF in hypertensive patients. The aim of this study was to investigate whether CT-1 levels are elevated in a selected group of asymptomatic hypertensive patients. METHODS: In a selected cohort of 40 asymptomatic patients with early diastolic dysfunction (grade I), without any signs of increased filling pressures in the left ventricle, as well as 20 healthy individuals, the levels of CT-1 brain natriuretic peptide (BNP) along with various echocardiographic parameters were evaluated. RESULTS: The mean age of the hypertensive patients was 56 ± 5 years and 52± 3.5 years for the normotensive controls. The hypertensive group exhibited higher levels of CT-1, which was not affected by left ventricular hypertrophy. Notably, in patients with normal E/E' < 8 (n = 30), CT-1 levels were 1165 ± 471 pg/ml compared to 2069 ± 576 pg/ml in patients with marginal E/E' > 8 and <14 (n = 10), p = 0.001. CONCLUSIONS: Our study demonstrated elevated CT-1 levels in a cohort of asymptomatic hypertensive patients, exhibiting mild diastolic dysfunction. These findings are suggestive of the potentially prognostic value of this particular biomarker in the early stages of hypertensive heart disease.

Effects of Hypericin on Cultured Primary Normal Human Dermal Fibroblasts Under Increased Oxidative Stress.

INTRODUCTION: Wound healing is a dynamic process that begins with inflammation, proliferation, and cell migration of a variety of fibroblast cells. As a result, identifying possible compounds that may improve fibroblast cell wound healing capacity is crucial. Hypericin is a natural quinine that has been reported to possess a wide range of pharmacological profiles, including antioxidant and anti-inflammatory, activities. Herein we examined for the first time the effect of hypericin on normal human dermal fibroblasts (NHDFs) under oxidative stress. METHODS: NHDF were exposed to different concentrations of hypericin (0-20 µg/mL) for 24 h. For the oxidative stress evaluation, H2O2 was used as a stressor factor. Cell viability and proliferation levels were evaluated. Immunohistochemistry and flow cytometry were performed to assess cell apoptosis levels and with confocal microscopy we identified the mitochondrial superoxide production under oxidative stress and after the treatment with hypericin. Scratch assay was performed under oxidative stress to evaluate the efficacy of hypericin in wound closure. To gain an insight into the molecular mechanisms of hypericin bioactivity, we analyzed the relative expression levels of genes involved in oxidative response and in wound healing process. RESULTS: We found that the exposure of NHDF to hypericin under oxidative stress resulted in an increase in cell viability and ATP levels. We found a decrease in apoptosis and mitochondrial superoxide levels after treatment with hypericin. Moreover, treatment with hypericin reduced wound area and promoted wound closure. The levels of selected genes showed that hypericin upregulated the levels of antioxidants genes. Moreover, treatment with hypericin in wound under oxidative stress downregulated the levels of proinflammatory cytokines, and metalloproteinases; and upregulated transcription factors and extracellular matrix genes. CONCLUSION: These findings indicated that hypericin possesses significant in vitro antioxidant activity on NHDF and provide new insights into its potential beneficial role in the management of diabetic ulcers.

Dose-dependent effects of thyroid hormone on post-ischemic cardiac performance: potential involvement of Akt and ERK signalings.

The present study explored the effects of thyroid hormone (TH) treatment on post-ischemic cardiac function and potential implicated mechanisms. Acute myocardial infarction (AMI) was induced in mice by coronary artery ligation while sham-operated animals served as controls. This procedure resulted in a marked depression of cardiac function and significant reduction in TH levels in plasma. TH was given at a dose aiming to normalize T3 levels in plasma [AMI-TH (A)] and also at higher doses. The group of animals treated with the highest dose of TH, which displayed significantly increased mortality rate was included in the study [AMI-TH (B)]. In AMI-TH (A) mice, TH significantly improved left ventricular (LV) ejection fraction (EF%), [27.9% (1.4) in AMI versus 38.0 (3.1) in AMI-TH (A), P < 0.05], and favorably remodeled LV chamber while α-MHC was the dominant isoform expressed. In AMI-TH (B) mice, TH treatment resulted in increased mortality as compared to untreated mice (73% vs 47%, P < 0.05), while the favorable effect of TH was not evident in the survived animals. At the molecular level, TH, at the replacement dose, modestly increased p-Akt levels in the myocardium without any change in p-ERK levels. On the contrary, TH at the higher dose resulted in further increase in p-Akt along with an increase in p-ERK levels. In conclusion, TH appears to have a dose-dependent bimodal effect on post-ischemic cardiac performance and this effect may, at least in part, be mediated by a distinct pattern of activation of Akt and ERK signaling.