Non-Hereditary Obesity Type Networks and New Drug Targets: An In Silico Approach.

Obesity, a chronic, preventable disease, has significant comorbidities that are associated with a great human and financial cost for society. The aim of the present work is to reconstruct the interactomes of non-hereditary obesity to highlight recent advances of its pathogenesis, and discover potential therapeutic targets. Obesity and biological-clock-related genes and/or gene products were extracted from the biomedical literature databases PubMed, GeneCards and OMIM. Their interactions were investigated using STRING v11.0 (a database of known and predicted physical and indirect associations among genes/proteins), and a high confidence interaction score of >0.7 was set. We also applied virtual screening to discover natural compounds targeting obesity- and circadian-clock-associated proteins. Two updated and comprehensive interactomes, the (a) stress- and (b) inflammation-induced obesidomes involving 85 and 93 gene/gene products of known and/or predicted interactions with an average node degree of 9.41 and 10.8, respectively, were produced. Moreover, 15 of these were common between the two non-hereditary entities, namely, ADIPOQ, ADRB2/3, CCK, CRH, CXCL8, FOS, GCG, GNRH1, IGF1, INS, LEP, MC4R, NPY and POMC, while phelligridin E, a natural product, may function as a potent FOX1-DBD interaction blocker. Molecular networks may contribute to the understanding of the integrated regulation of energy balance/obesity pathogenesis and may associate chronopharmacology schemes with natural products.

A High-Cholesterol Diet Increases Toll-like Receptors and Other Harmful Factors in the Rabbit Myocardium: The Beneficial Effect of Statins.

BACKGROUND: A high-cholesterol diet (HCD) induces vascular atherosclerosis through vascular inflammatory and immunological processes via TLRs. The aim of this study is to investigate the mRNA expression of TLRs and other noxious biomarkers expressing inflammation, fibrosis, apoptosis, and cardiac dysfunction in the rabbit myocardium during (a) high-cholesterol diet (HCD), (b) normal diet resumption and (c) fluvastatin or rosuvastatin treatment. METHODS: Forty-eight male rabbits were randomly divided into eight groups (n = 6/group). In the first experiment, three groups were fed with HCD for 1, 2 and 3 months. In the second experiment, three groups were fed with HCD for 3 months, followed by normal chow for 1 month and administration of fluvastatin or rosuvastatin for 1 month. Control groups were fed with normal chow for 90 and 120 days. The whole myocardium was removed; total RNA was isolated from acquired samples, and polymerase chain reaction, reverse transcription PCR and quantitative real-time PCR were performed. RESULTS: mRNA of TLRs 2, 3, 4 and 8; interleukin-6; TNF-a; metalloproteinase-2; tissue inhibitor of metalloproteinase-1; tumor protein 53; cysteinyl aspartate specific proteinase-3; and brain natriuretic peptide (BNP) increased in HCD. Statins but not resumption of a normal diet decreased levels of these biomarkers and increased levels of antifibrotic factors. CONCLUSIONS: HCD increases the levels of TLRs; inflammatory, fibrotic and apoptotic factors; and BNP in the rabbit myocardium. Atherogenic diets adversely affect the myocardium at a molecular level and are reversed by statins.

Vascular conditioning prevents adverse left ventricular remodelling after acute myocardial infarction: a randomised remote conditioning study.

AIMS: Remote ischemic conditioning (RIC) alleviates ischemia-reperfusion injury via several pathways, including micro-RNAs (miRs) expression and oxidative stress modulation. We investigated the effects of RIC on endothelial glycocalyx, arterial stiffness, LV remodelling, and the underlying mediators within the vasculature as a target for protection. METHODS AND RESULTS: We block-randomised 270 patients within 48 h of STEMI post-PCI to either one or two cycles of bilateral brachial cuff inflation, and a control group without RIC. We measured: (a) the perfusion boundary region (PBR) of the sublingual arterial microvessels to assess glycocalyx integrity; (b) the carotid-femoral pulse wave velocity (PWV); (c) miR-144,-150,-21,-208, nitrate-nitrite (NOx) and malondialdehyde (MDA) plasma levels at baseline (T0) and 40 min after RIC onset (T3); and (d) LV volumes at baseline and after one year. Compared to baseline, there was a greater PBR and PWV decrease, miR-144 and NOx levels increase (p < 0.05) at T3 following single- than double-cycle inflation (PBR:ΔT0-T3 = 0.249 ± 0.033 vs 0.126 ± 0.034 µm, p = 0.03 and PWV:0.4 ± 0.21 vs -1.02 ± 0.24 m/s, p = 0.03). Increased miR-150,-21,-208 (p < 0.05) and reduced MDA was observed after both protocols. Increased miR-144 was related to PWV reduction (r = 0.763, p < 0.001) after the first-cycle inflation in both protocols. After one year, single-cycle RIC was associated with LV end-systolic volume reduction (LVESV) > 15% (odds-ratio of 3.75, p = 0.029). MiR-144 and PWV changes post-RIC were interrelated and associated with LVESV reduction at follow-up (r = 0.40 and 0.37, p < 0.05), in the single-cycle RIC. CONCLUSION: RIC evokes "vascular conditioning" likely by upregulation of cardio-protective microRNAs, NOx production, and oxidative stress reduction, facilitating reverse LV remodelling. CLINICAL TRIAL REGISTRATION: http://www.clinicaltrials.gov . Unique identifier: NCT03984123.

Polycystic οvary syndrome revisited: An interactions network approach.

BACKGROUND: The polycystic ovary syndrome (PCOS) has genetic, epigenetic, metabolic and reproductive aspects, while its complex pathophysiology has not been conclusively deciphered. AIM: The goal of this research was to screen the gene/gene products associated with PCOS and to predict any possible interactions with the highest possible fidelity. MATERIALS AND METHODS: STRING v10.5 database and a confidence level of 0.7 were used. RESULTS: A highly interconnected network of 48 nodes was created, where insulin (INS) appears to be the major hub. INS upstream and downstream defects were analysed and revealed that only the kisspeptin- and glucagon-coding genes were upstream of INS. CONCLUSION: A metabolic dominance was inferred and discussed herein with its implications in puberty, obesity, infertility and cardiovascular function. This study, thus, may contribute to the resolution of a scientific conflict between the USA and EU definitions of the syndrome and/or provide a new P4 medicine approach.

Chronic Systemic Inflammation Measured by Bioimpedance Technology Before and After Sleeve Gastrectomy: A Feasibility Study.

Stress induces obesity, while extreme obesity causes stress, anxiety, and even depression. Yet, knowledge on the underlying mechanism(s) has many gaps. To this end, we designed a feasibility study, focused on 18 bariatric patients recruited by the First Propaideutic Department of Surgery at the Hippokration University Hospital in Athens, Greece. The patients (aged 23-58 y, weight 101-185.4 kg before surgery) were weighted and evaluated by advanced bioimpedance technology 2-3 days before surgery at the Biomedical Research Foundation of the Academy of Athens. We employed Bioimpedance Electrolytic Extracellular Tomography (Tomeex), which characterizes (a) neurodegenerative responsiveness to stress, (b) sensory and autonomic tones by basal extracellular conductance (BEC), and (c) activity of limbic and cortical brain areas. The patients' mean body weight loss after 6 months was 48.8 ± 3.1Kg, while stress levels evaluated by appropriate questionnaires decreased (Spearman coefficient significance level p < 0.05). Anxiety and depressive symptoms decreased by 70%, accompanied by changes in measured sensory and autonomic tones (p = 0.003). Baseline blood markers, such as hsCRP and glucose, predicted lower abdominal inflammation (p = 0.034 and p = 0.058, respectively) 6 months postoperatively. In conclusion, chronic inflammation measures by bioimpedance are a useful non-invasive monitoring tool in bariatric surgery.

Fractal Dynamics in the RR Interval of Craniopharyngioma and Adrenal Tumor in Adolescence.

Heart rate variability (HRV) is the physiological phenomenon of variation in the time interval between heartbeats. It is measured by the variation in the beat-to-beat interval and/or RR variability (where R is a point corresponding to the peak of the QRS complex of the ECG wave and RR is the interval between successive Rs) and other components extracted from these. HRV is a field of research interest in pathophysiology (in general) and cancer prognosis (more specifically). Adolescents with adrenal tumor or craniopharyngioma were investigated, herein. Αutonomic nervous system recordings were performed with Task Force® Monitor (gold standard of the Task Force of the European Society of Cardiology and the North American Society of Electrophysiology). The RR interval (RRI) time series calculations were performed with the MatLab® computational environment and included the estimation of fractal dimension and Lyapunov exponent. Fractal dimensions were calculated by estimating N and R, where N represents the number of "squares" needed for a fractal shape to be completed and their respective "square size" R. By definition, if the first derivative of d ln N/d ln R remains constant for a space of R, this is the fractal dimension of the shape, in the present case of the time series trajectory. We found that RRI manifested different fractal dynamics, thus, a complex pattern of progression in these two morbid entities, suggesting the need for further investigation in ANS contribution to tumor pathophysiology.

Kisspeptin and the Genetic Obesity Interactome.

BACKGROUND: Kisspeptin (encoded by the KISS1 gene in humans) is an excitatory neuromodulatory peptide implicated in multiple homeostatic systems, including anti-oxidation, glucose homeostasis, nutrition, locomotion, etc. Therefore, in the current obesity epidemic, kisspeptin is gaining increasing interest as a research objective. AIM: To construct an updated interactome of genetic obesity, including the kisspeptin signal transduction pathway. METHODS: Kisspeptin and obesity-related genes or gene products were extracted from the biomedical literature, and a network of functional associations was created. RESULTS: The generated network contains 101 nodes corresponding to gene/gene products with known and/or predicted interactions. In this interactome, KISS1 and KISS1R are connected directly to the luteinizing hormone receptor (LHCGR), gonadotropin-releasing hormone receptor (GNRH1), and indirectly, through the latter, to proopiomelanocortin (POMC), glucagon, leptin (LEP), and/or pro-protein convertase subtilisin/kexin-type 1 (PCSK1), all of which are critically implicated in obesity disorders. CONCLUSIONS: Our updated obesidome includes kisspeptin and its connections to the genetic obesity signalosome with 12 major hubs: glucagon (GCG), insulin (INS), arginine vasopressin (AVP), G protein subunit beta 1 (GNB1) and proopiomelanocortin (POMC), melanocortin 4 receptor (MC4R), leptin (LEP), gonadotropin-releasing hormone 1 (GNRH1), adrenoceptor beta 2 and 3 (ADRB2-3), glucagon-like peptide 1 receptor (GLP1R), and melanocortin 3 receptor (MC3R) genes were identified as major "hubs" for genetic obesity, providing novel insight into the body's energy homeostasis.

Entropy in Cardiac Autonomic Nervous System of Adolescents with General Learning Disabilities or Dyslexia.

Heart rate variability (HRV) represents one of the two key markers of the autonomic nervous system. It is measured by the time variation in the beat-to-beat interval, while the period between successive beats is defined as the RR interval (RRI). Its components are classified as linear and non-linear. In the field of psychophysiology, HRV is investigated as a key player of possible predictive or diagnostic value. Female adolescents with general learning disabilities or dyslexia were recruited at the Center for Adolescent Medicine and UNESCO Chair on Adolescent Health Care of the National and Kapodistrian University of Athens. Adolescents were further assessed for HRV. Data were collected with the Task Force® Monitor at the Cardiovascular Laboratory of the Biomedical Research Foundation of the Academy of Athens. The RRI time-series were estimated for approximate entropy (AE), conditional entropy (CE), corrected conditional entropy (CCE), fuzzy entropy (FE), permutation entropy (PE), sample entropy (SE), and Shannon's entropy (ShE). RRI manifested complex dynamics, indicating a complex pattern of progression. This finding suggests that RRI conceals non-linear dynamics, which if investigated in depth could provide more knowledge on the relation between RRI and learning disorders.

Adults' Stress Response to Unexpected Oral and Arithmetic Tasks in Supine Position.

To study the autonomic nervous system (ANS) and hypothalamus pituitary adrenal axis (HPA) response before and after mental stress test in healthy adolescents and adults, is the aim of this study. Twenty healthy adults (aged 23-46 years) entered the Trier Social Stress Test (TSST), after informed consent signing. The procedure was modified: (a) the participants' position was supine as ANS system changes were to be assessed, (b) the interviewers were entering and departing from the session room. Salivary cortisol (marker of HPA axis response) samples were collected at the end of the baseline and 20 min after TSST. ANS of the heart was measured with CNS Task Force Monitor in supine position and was recorded during relaxation (15 min) and after TSST. The sympathovagal balance (LF/HF ratio) for each phase was computed. Evaluations were conducted with R. The HPA axis disturbance between baseline and 20 min after TSST was significant (g = 0.545 [0.092, 0.999]) and in adolescents (whereas, the mean intervals of the sinus rhythm RR parameter were found largely changed (g = 0.834 [0.340, 1.327]). The sympathovagal balance component of heart rate variability LF/HF ratio was founded unchanged (g = 0.215 [-0.211, 0.641]). RR changes were not correlated to salivary cortisol concentrations at any phase. Mean RRIs and salivary cortisol levels were significantly increased, although HPA axis showed medium size effect. However, the systems effectively counterbalance the perturbation, since the LF/HF ratio does not change. Our findings suggest further research in stress effect on HPA and ANS cross-talk and dynamics.

Tissue-specific relaxin-2 is differentially associated with the presence/size of an arterial aneurysm and the severity of atherosclerotic disease in humans.

Circulating or tissue-related biomarkers are of clinical value for risk stratification in patients with abdominal aortic aneurysms. Relaxin-2 (RL2) has been linked to the presence and size of arterial aneurysms, and to the extent of atherosclerosis in human subjects. Here, we assessed the expression levels of RL2 in aneurysmal (AA, n = 16) and atherosclerotic (ATH, n = 22) arteries, and established the correlation between RL2 levels and the presence/size of AA and the clinical severity of atherosclerosis. The expression levels of metalloproteinases (MMPs) and endothelial nitric oxide synthetase (eNOS) were also detected for correlations with different phenotypes of atherosclerosis and AA. Temporal artery biopsy specimens (n = 6) and abdominal aortic tissues harvested from accident victims during autopsy (n = 10) were used as controls. Quantitative tissue biomarker analysis revealed that tissue-specific RL2 was increased in patients with larger or symptomatic AA compared to subjects with atherosclerotic disease and healthy controls. In situ RL2 levels were proportional to the size and the severity of aneurysmatic disease, and were substantially elevated in patients with symptomatic aneurysm of any diameter or asymptomatic aneurysm of a diameter >350% of that of the normal artery. In contrast, tissue RL2 was inversely associated with the clinical severity of atherosclerotic lesions. Correlation between RL2 and MMP2 was different between ATH1 and ATH2, depending on atherosclerosis grade. Overall, tissue RL2 is differentially associated with discrete phenotypes of arterial disease and might exert multipotent biological effects on vascular wall integrity and remodeling in human subjects.

Cellular Phone User's Age or the Duration of Calls Moderate Autonomic Nervous System? A Meta-Analysis.

BACKGROUND: The European Health Risk Assessment Network on Electromagnetic Fields Exposure (EFHRAN) reported in 2012: "Children and adolescents represent the first generation of Europeans to be exposed to diffuse EMF since their conception and birth, thus, they are expected to be more sensitive to these fields." On the other hand, the body's physiologic processes are regulated by the autonomic nervous system (ANS) in a way that warrants further elucidation. OBJECTIVE: Age and duration of exposure are investigated for modifying the variance of the reported effects of mobile/cellular phone call (CPC) on ANS indexed, herein, by the heart rate variability (HRV). METHOD: Five studies targeted to 124 healthy subjects (aged 15.3-28.4 years (24.3 ± 5.2), who have been recorded in supine position before and/or sham versus real exposure (to a CPC lasting 5-32 minutes), are included in this meta-analysis. Age and duration of a CPC are evaluated as predictors in two separate meta-regressions. RESULTS: The meta-analysis identified a heterogeneity I2 = 63.2% for all outcomes and I2 = 65.2% for sympathovagal balance. Thus, we performed meta-regressions: for the sympathovagal balance rather than the combined parameters effect, the goodness of fit model presents significance only for age - the residual sum of squares compared to chi-square distribution (QR) is 4.24 for age (p = 0.12) - while, for minutes of exposure, QR = 8.2805 (p = 0.016). CONCLUSIONS: The sympathovagal balance - indispensible for health/homeostasis maintenance - is strongly predicted by age. Minutes of exposure did not affect overall HRV or sympathovagal balance. The results endorse/validate the EFHRAN 2012 suggestion for future research targeting to youngsters.

Differential expression patterns of Toll Like Receptors and Interleukin-37 between calcific aortic and mitral valve cusps in humans.

BACKGROUND: Significant differences are mentioned in the progress of calcification between aortic and mitral valve. Evidence of inflammation in calcific aortic and mitral valve disease suggests that pathways of Toll Like Receptors (TLR) and Interleukin (IL)-37 expression may contribute to this process. We sought to investigate the role of TLR-mediated inflammatory response and IL-37 pathway expression on aortic and mitral valve calcification. MATERIAL AND METHODS: One-hundred twenty stenotic valve cusps/leaflets (60 aortic, 60 mitral) were excised during surgery and were collected for histological, immunohistochemistry and morphometric analysis at our department. After total RNA isolation from a second part of valve cusps/leaflets, cDNA synthesis and quantitative reverse transcription polymerase chain reaction (qRT-PCR) protocols were performed and relative mRNA levels of target genes were assessed. RESULTS: By histological analysis, the anti-inflammatory IL-37 levels were increased in mitral valve leaflets (MVL) compared to aortic valve cusps (AVCu) while all other biomarkers, including TLR, presented a reverse pattern with decreased levels as compared to AVCu. In terms of calcification biomarkers, only osteopontin differed between AVCu and MVL. mRNA analysis confirmed increased expression of IL-37 and decreased levels of TLR in MVL compared to AVCu. CONCLUSIONS: Stenotic cusps of aortic valves express lower IL-37 and increased TLRs levels than stenotic mitral valve leaflets, suggesting a differential pro-calcification and pro-inflammatory profile between the two valves. This may explain the higher incidence of calcification of AVCu than MVL and offer therapeutic considerations.

Stronger correlation with myocardial ischemia of high-sensitivity troponin T than other biomarkers.

BACKGROUND: Acute myocardial infarction (AMI) is considered a major cause of death and disability. Myocardial perfusion scintigraphy (MPS) as a non-invasive diagnostic imaging procedure and certain biomarkers associated with myocardial ischemia (ISCH), such as ischemia-modified albumin (IMA), neuropeptide Y (NPY), N-terminal pro b-type natriuretic peptide (NT-proBNP), and high-sensitivity troponin T (hsTnT) could probably aid in the detection of myocardial infarction. METHODS: Between December 2011 and June 2012, we prospectively analyzed patients who underwent a MPS study with the clinical question of myocardial ISCH. An exercise test was performed along with a MPS. Blood was drawn from the patients before exercise and the within 3 minutes from achieving maximum load and was analyzed for the aforementioned biomarkers. RESULTS: A total of 71 patients (56 men and 15 women) were enrolled with a mean age of 61 ± 12 years. Twenty-six patients (36.6%) showed reduced uptake on stress MPS images that normalized at rest, a finding consistent with ISCH. Between ISCH and non-ISCH groups, only hsTnT levels showed a significant difference with the highest levels pertaining to the former group both before (0.0075 ng/ml vs 0.0050 ng/ml, P = 0.023) and after stress exercise (0.0085 vs 0.0050, P = 0.015). The most prominent differences were seen in higher stages of the Bruce protocol (stress duration > 9.05 minutes - P < 0.017). None of the IMA, NPY, and NP-pro BNP showed significant differences in time between the two groups. CONCLUSIONS: Although IMA, NPY, and NT-pro BNP may not detect minor ischemic myocardial insults, serum hsTnT holds a greater ability of detecting not only myocardial infarction but also less severe ischemia. Further studies with larger cohorts of patients are warranted in order to better define the role of hsTnT as a screening tool for myocardial ischemia.

Overexpression of Toll-Like Receptors 2, 3, 4, and 8 Is Correlated to the Vascular Atherosclerotic Process in the Hyperlipidemic Rabbit Model: The Effect of Statin Treatment.

BACKGROUND: Atherosclerosis is the major cause of cardiovascular disease; hypercholesterolemia is a major risk factor. We hypothesized that specific TLR members (TLR2, TLR3, TLR4, TLR8) may play a role in atherosclerosis progression and its accompanying inflammatory response. We determined the association of atherosclerotic lesions and TLR mRNA expression in different aortic sites. We also assessed the effects of fluvastatin (Flu) treatment on TLR expression and plaque characteristics. METHODS: Male rabbits, fed with an atherogenic diet for a duration of 3 months, were screened for advanced atherosclerotic lesions in the aorta. Additional animals received normal diet or normal diet plus Flu for 1 additional month. TLR mRNA expression in various thoracic and abdominal aortic segments was assessed, together with atherosclerotic changes. RESULTS: After high lipid diet, the atherosclerotic burden increased more in the abdominal than in the thoracic aorta; TLR2, 3, 4, and 8 also increased significantly. Flu decreased atherosclerotic plaque, calcium deposition, lipid cores, intraplaque hemorrhage, erythrocyte membranes, endothelial cells, and macrophage infiltration, while increasing smooth muscle cells in plaques of both aortic segments; it also lowered TLR2, 3, 4, and 8 expression in all aortic segments to a stronger degree than resumption of normal diet. There was a strong association between blood and tissue parameters during experimental period and finally a strong correlation found between these parameters with mRNA of TLR2, 3, 4, and 8 in various stages. CONCLUSION: For the first time TLR2, 3, 4, and 8 mRNA expression is prospectively explored after hypercholesterolemic diet in the rabbit model. TLR2, 3, 4, and 8 mRNA expression is strongly upregulated and correlates with the progression of atherosclerosis in the aorta. Flu significantly inhibited this progress and reduced inflammation via TLR downregulation which was strongly associated with regression of plaque morphology and atherosclerosis promoting factors.

Bioimpedance Measurements in Adolescents with Polycystic Ovary Syndrome: A Pilot Study.

Limited data are available on the body composition of adolescent women with polycystic ovary syndrome (PCOS). The aim of this study was to examine differences in body composition indices of metabolism, homeostasis and inflammation, between Greek adolescent females suffering from PCOS and age- and body mass index (BMI)-matched non-PCOS controls. Thirteen PCOS patients and nine non-PCOS controls, aged 13-24 years participated in this cross-sectional study. Study participants underwent assessment by a novel dual frequency bioimpedance device (BIA-ACC). The following body composition indices were measured in each adolescent: extra cellular water (ECW) as inflammation marker, total body water (TBW) as homeostasis marker, extracellular mass to body cell mass ratio (ECM/BCM), fat mass (FM), fat-free mass (FFM) and intracellular water (ICW) as markers of body mass composition and metabolism. Non-linear analysis showed no statistically significant differences in the body composition characteristics between PCOS patients and controls. Further studies with larger sample sizes are needed to confirm whether adolescents with PCOS actually have similar body composition profile with their non-PCOS peers.

Evaluating the Homeostasis Assessment Model Insulin Resistance and the Cardiac Autonomic System in Bariatric Surgery Patients: A Meta-Analysis.

Morbid obesity is a severe chronic disease and subject to surgical methods for losing weight. This intervention is expected to drive to better quality of life and health status. Other important aspects which may be influenced are: HOMA-IR (as insulin resistance marker) and heart rate variability (as cardiac function and autonomic nervous system marker), which are independent and valid predictors of future cardiac, neurological, metabolic health. We pooled 4 studies (646 subjects) resulting to HOMA-IR and nine HRV components-grouped in those undergone to gastric bypass (RYGP) and those operated with vertical sleeve gastrectomy (SG) method. We performed a meta-analysis in patients for HOMA-IR and HRV, using Hedge's g correction of Cohen d for small samples. We concluded that RYGP favors insulin resistance decrease, whereas SG increases the vagal tone, improving cardiac function. The severity of cardiovascular diseases history suggests the selection of the surgery method: SG for the most severe cardiovascular cases and RYGP for those with higher HOMA-IR.

Interactome of Obesity: Obesidome : Genetic Obesity, Stress Induced Obesity, Pathogenic Obesity Interaction.

Obesity is a chronic disease of increasing prevalence reaching epidemic proportions. Genetic defects as well as epigenetic effects contribute to the obesity phenotype. Investigating gene (e.g. MC4R defects)-environment (behavior, infectious agents, stress) interactions is a relative new field of great research interest. In this study, we have made an effort to create an interactome (henceforth referred to as "obesidome"), where extrinsic stressors response, intrinsic predisposition, immunity response to inflammation and autonomous nervous system implications are integrated. These pathways are presented in one interactome network for the first time. In our study, obesity-related genes/gene products were found to form a complex interactions network.

Thyroid hormones and cardiac remodeling.

Thyroid hormones have many cardioprotective actions expressed mainly through the action of T3 on thyroid receptors α1 and ß1. They are procontractile anti-apoptotic, anti-inflammatory, and anti-fibrotic, promote angiogenesis and regeneration, and have beneficial effects on microRNA profiles. They have proven to be anti-remodeling in numerous animal studies, mostly in rodents; a specific action on the border zone has been described. Studies in humans with DIPTA have been in conclusion. Remodeling can be defined as an increase of ≥20 % of the end-diastolic or end-systolic volume, together with a return to the fetal phenotype. An overview of animal and clinical studies is given.