Treatment Preferences in Patients with Hypothyroidism: an Analysis of Eleven Randomized Controlled Trials.

INTRODUCTION: Levothyroxine (L-T4) monotherapy is the standard of care for the treatment of hypothyroidism. A minority of the L-T4-treated patients remain symptomatic and report better outcomes with combination therapy that contains liothyronine (L-T3) or with desiccated thyroid extract (DTE). GOAL: To assess patient preferences in the treatment of hypothyroidism. METHODS: A systematic review, meta-analysis, meta-regression, and network meta-analysis (NMA) of randomized controlled trials (RCTs) comparing treatments for adults with hypothyroidism (L-T4 vs. L-T4+L-T3 or DTE). Searches were conducted in PubMed, Embase, and Cochrane databases up to April 10, 2024. Data extraction and quality assessment were independently performed by four researchers. RESULTS: Eleven RCTs (eight cross-over studies) with a total of 1,135 patients were considered. Overall, 24% of patients preferred L-T4 versus 52 % who preferred L-T4+L-T3 or DTE; 24% had no preference. The meta-analysis confirmed the preference for combination therapy over L-T4 monotherapy (RR: 2.20, 95% CI: 1.38 to 3.52; p = 0.0009). Excluding four studies reduced the high heterogeneity (I2 = 81%) without affecting the results (RR: 1.97, 95% CI: 1.52 to 2.54; p < 0.00001; I2 = 24%). This preference profile remained when only crossover studies were considered (RR: 2.84, 95% CI: 1.50 to 5.39; p < 0.00001). Network meta-analysis confirmed the preference for DTE and L-T3+L-T4 versus L-T4 alone. CONCLUSION: Patients with hypothyroidism prefer combination therapy (L-T3+L-T4 or DTE) over L-T4 monotherapy. The strength of these findings justifies considering patient preferences in the setting of shared decision-making in the treatment of hypothyroidism.

Arterite de takayasu complicada com dissecção de aorta como apresentação primária de atividade da doença / Takayasu arteritis complicated with aortic dissection as the primary presentation of disease activity

INTRODUÇÃO: A arterite de Takayasu é uma vasculite de grandes vasos, crônica, granulomatosa, mais comum no adulto. É caracterizada por estenose, oclusão e aneurisma da aorta e seus principais ramos. A apresentação clínica pode variar, sendo mais comum a forma mais insidiosa, com sintomas como febre, fadiga, claudicação, diminuição de pulso. Contudo, pode apresentar-se de maneira atípica e mais catastrófica, como em acidente vascular encefálico (AVC), perda visual aguda ou dissecção de aorta. RELATO DO CASO: Paciente feminina, 44 anos, previamente hipertensa sem tratamento. Admitida em serviço terciário de cardiologia com quadro de dispneia e dor torácica de início no mesmo dia. Diagnosticada dissecção de aorta Stanford A. Prontamente abordada para correção de arco aórtico com implante de tubo supracoronariano, sendo a abordagem do segmento descendente postergada após compensação clínica. Paciente evolui com sonolência, confusão mental, plaquetopenia importante e hemiplegia direita. Em angiotomografia de aorta de controle, apresentou isquemia esplênica e renal à esquerda e espessamento de parede de artérias renais e aorta, além de espessamento de carótidas bilateralmente. Aventada a hipótese de arterite de Takayasu diante dos sinais e sintomas, realizada pulsoterapia com metilprednisolona por 3 dias e manutenção com prednisona e ciclofosfamida, apresentou melhora expressiva do quadro neurológico. DISCUSSÃO: O diagnóstico da arterite de Takayasu é um desafio e envolve elementos clínicos e radiológicos. Classicamente dividida em duas fases: a "pré-oclusiva" - caracterizada por sintomas gerais sistêmicos - e a "oclusiva" ou "vascular" - que envolve estenoses arteriais ou aneurismas. A dissecção de aorta é uma apresentação rara da arterite de Takayasu, correspondendo a 5% das complicações dos aneurismas de aorta secundários à esta doença. Neste cenário, a dissecção de aorta tipo Stanford B é mais frequente que a tipo A. A hipertensão arterial é um dos fatores de risco mais importantes, juntamente com a inflamação do vaso, para dissecção da aorta. Em nosso caso, paciente apresentava hipertensão de longa data mal controlada associada a arterite de Takayasu em atividade e sem diagnóstico prévio. CONCLUSÃO: A arterite de Takayasu é a vasculite de grandes vasos mais comum em adultos, contudo por seus sintomas insidiosos apresenta baixo diagnóstico. A dissecção de aorta consiste em uma das complicações raras e pode ser a manifestação inicial.

Thr92Ala-DIO2 heterozygosity is associated with skeletal muscle mass and myosteatosis in patients with COVID-19.

Introduction: The type 2 deiodinase and its Thr92Ala-DIO2 polymorphism have been linked to clinical outcomes in acute lung injury and coronavirus disease 2019 (COVID-19). Objective: The objective was to identify a potential association between Thr92Ala-DIO2 polymorphism and body composition (appendicular muscle mass, myosteatosis, and fat distribution) and to determine whether they reflect the severity or mortality associated with the disease. Methods: In this prospective cohort study (June-August 2020), 181 patients hospitalized with moderate-to-severe COVID-19 underwent a non-contrast-enhanced computed tomography (CT) of the thorax to assess body composition, laboratory tests, and genotyping for the Thr92Ala-DIO2 polymorphism. Results: In total, 181 consecutive patients were stratified into three subgroups according to the genotype: Thr/Thr (n = 64), Thr/Ala (n = 96), and Ala/Ala (n = 21). The prevalence of low muscle area (MA) (< 92 cm²) was 52.5%. Low MA was less frequent in Ala/Thr patients (44.8%) than in Thr/Thr (60.9%) or Ala/Ala patients (61.9%) (P = 0.027). Multivariate logistic regression analysis confirmed that the Thr/Ala allele was associated with a reduced risk of low MA (41% to 69%) and myosteatosis (62% to 72%) compared with Thr/Thr + Ala/Ala (overdominant model). Kaplan-Meier curves showed that patients with low muscle mass and homozygosity had lower survival rates than the other groups. Notably, the heterozygotes with MA ≥92 cm² exhibited the best survival rate. Conclusion: Thr92Ala-DIO2 heterozygosity is associated with increased skeletal MA and less myosteatosis in patients with COVID-19. The protective effect of Thr92Ala-DIO2 heterozygosity on COVID-19 mortality is restricted to patients with reduced MA.

TSH Trajectories During Levothyroxine Treatment in the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil) Cohort.

CONTEXT: Thyroid-stimulating hormone (TSH) trajectory classification represents a novel approach to defining the adequacy of levothyroxine (LT4) treatment for hypothyroidism over time. OBJECTIVE: This is a proof of principle study that uses longitudinal clinical data, including thyroid hormone levels from a large prospective study to define classes of TSH trajectories and examine changes in cardiovascular (CV) health markers over the study period. METHODS: Growth mixture modeling (GMM), including latent class growth analysis (LCGA), was used to classify LT4-treated individuals participating in the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil) based on serial TSH levels. Repeated measure analyses were then utilized to assess within-class changes in blood pressure, lipid levels, hemoglobin A1c, and CV-related medication utilization. RESULTS: From the 621 LT4-treated study participants, the best-fit GMM approach identified 4 TSH trajectory classes, as defined by their relationship to the normal TSH range: (1) high-high normal TSH, (2) normal TSH, (3) normal to low TSH, and (4) low to normal TSH. Notably, the average baseline LT4 dose was lowest in the high-high normal TSH group (77.7 µg, P < .001). There were no significant differences in CV health markers between the classes at baseline. At least 1 significant difference in CV markers occurred in all classes, highlighted by the low to normal class, in which total and high-density lipoprotein cholesterol, triglycerides, and A1c all increased significantly (P = .049, P < .001, P < .001, and P = .001, respectively). Utilization of antihypertensive, antihyperlipidemic, and antidiabetes medications increased in all classes. CONCLUSION: GMM/LCGA represents a viable approach to define and examine LT4 treatment by TSH trajectory. More comprehensive datasets should allow for more complex trajectory modeling and analysis of clinical outcome differences between trajectory classes.

Thyroid Hormone Homeostasis in Levothyroxine-treated Patients: Findings From ELSA-Brasil.

CONTEXT: The effectiveness of levothyroxine (LT4) in restoring thyroid hormone (TH) homeostasis, particularly serum thyroxine (T4) and triiodothyronine (T3) levels, remains debatable. OBJECTIVE: This work aimed to assess TH homeostasis in LT4-treated individuals using data from the Longitudinal Study of Adult Health in Brazil (ELSA-Brasil) study. METHODS: The ELSA-Brasil study follows 15 105 adult Brazilians (aged 35-74 years) over 8.2 years (2008-2019) with 3 observation points assessing health parameters including serum thyrotropin (TSH), free T4 (FT4), and free T3 (FT3) levels. We analyzed 186 participants that initiated treatment with LT4 during the study, and 243 individuals continuously treated with LT4 therapy. RESULTS: Initiation of therapy with LT4 resulted in an 11% to 19% decrease in TSH, an approximately 19% increase in FT4, and a 7% reduction in FT3 serum levels (FT3 dropped >10% in ∼40% of the LT4-treated patients). This was associated with an increase in triglyceride levels and utilization of hypolipidemic and antidiabetic medications. Participants continuously treated with LT4 exhibited a stable elevation in serum FT4 and a reduction in serum FT3 and TSH levels. While 115 participants (47.3%) had at least 1 serum FT4 levels above the control reference range (>1.52 ng/dL), 38 participants (15.6%) had at least 1 serum FT3 below the reference range (<0.23 ng/dL). CONCLUSION: The present results challenge the dogma that treatment with LT4 for hypothyroidism restores TH homeostasis in all patients. A substantial number of LT4-treated patients exhibit repeated FT4 and FT3 levels outside the normal reference range, despite normal TSH levels. Further studies are needed to define the clinical implications of these findings.

Intervenção multiprofissional na administração medicamentosa via enteral em unidade de terapia intensiva cardiológica de hospital público / Multidisciplinary intervention in enteral drug administration in a cardiology intensive care unit of a public hospital

INTRODUÇÃO: Medicamentos sólidos administrados por cateter enteral (CE) requerem trituração, solubilização, cuidados com interação alimentar no preparo e administração evitando déficit na farmacoterapia. MÉTODOS: Trata-se de estudo de intervenção e elaboração de protocolo interprofissional de padronização da sistemática de medicamentos por CE em Unidade de Terapia Intensiva (UTI) de hospital público cardiológico de São Paulo, no segundo semestre de 2021, construído a partir do diagnóstico situacional, centrado na assistência em interface com Enfermagem e Medicina para intervenções interprofissionais. RESULTADOS: No diagnóstico situacional, caracterizou-se 82 medicamentos prescritos para administração por via CE na UTI Cardiológica. Em relação aos medicamentos com várias apresentações em dosagens diferentes, levou-se em conta o princípio ativo do medicamento. Foi realizado o agrupamento, com informações sobre o nome do medicamento, apresentação, trituração, dissolução sem trituração, volume mínimo de água destilada para solubilização e outras observações, gerando conteúdo consultivo, aprovado pela Comissão de Farmácia e Terapêutica, tanto para uso da equipe médica na prescrição quanto para a equipe de enfermagem na administração, inclusive para equipe de compras para aquisição por meio licitatório. Para os farmacêuticos, foi elaborado um fluxograma de intervenção farmacêutica, para sistematizar as medidas que podem ser tomadas partindo da identificação do medicamento prescrito por essa via, com as respectivas condutas baseadas nas particularidades do setor público (Figura 1). As competências profissionais desenvolvidas por meio deste estudo foram o trabalho colaborativo interprofissional para elaborar projeto de intervenção centrada no paciente a partir de situações problemas, a comunicação efetiva, a liderança colaborativa compreendendo as atribuições e o trabalho em equipe. CONCLUSÃO: Estruturou-se o protocolo de padronização de medicamentos por CE ao cardiopata em UTI e seu fluxo de intervenção interprofissional. Experienciar este processo colaborativo interprofissional possibilitou mudanças no serviço. A problematização do cenário, as intervenções assistenciais, educativas e gerenciais fundamentadas pela pesquisa, mobilizaram recursos humanos locais para inovações no processo de trabalho. Para a continuidade deste estudo, busca-se sua implementação e avaliação de processo com medida de indicadores que qualificam a assistência evitando-se ocorrências como obstrução de CE, falhas na prescrição, no preparo e na administração de medicamentos por essa via.

Multisensory Stimulation Improves Cognition and Behavior in Adult Male Rats Born to LT4-treated Thyroidectomized Dams.

Gestational hypothyroidism can impair development, cognition, and mood. Here, we tested whether multisensory stimulation (MS) improves the phenotype of rats born to surgically thyroidectomized (Tx) dams suboptimally treated with LT4. 8-week-old female Tx Wistar rats were kept on daily LT4 (0.7 µg/100 g body weight) dosed by gavage (serum TSH and T4 levels indicated moderate hypothyroidism) and 3 weeks later placed for breeding. MS of the litter started at age 60 days and lasted for 8 weeks. It consisted of twice per week of physical, cognitive, sensorial, and food stimuli. The offspring were assessed before and after MS for standardized tests of locomotor activity, cognition, and mood. Gestational hypothyroidism resulted in reduced litter size and increased offspring mortality. The pups exhibited delayed physical development, impairment of short- and long-term memory, and anxiety- and depressive-like behaviors. Nonetheless, ambulatory activity, social memory, and social preference were not affected by gestational hypothyroidism. MS restored short-term memory and anxiety while improving depressive like-behaviors. MS did not improve long-term memory. MS also did not modify the performance of control litter born to intact dams. We conclude that cognition and mood impairments caused by moderate gestational hypothyroidism were reversed or minimized in rats through MS. Further studies should define the molecular mechanisms involved.

Age Worsens the Cognitive Phenotype in Mice Carrying the Thr92Ala-DIO2 Polymorphism.

The Thr92Ala-Dio2 polymorphism has been associated with reduced cognition in 2-month-old male mice and increased risk for cognitive impairment and Alzheimer's disease in African Americans. This has been attributed to reduced thyroid hormone (TH) signaling and endoplasmic reticulum (ER) stress in the brain. Here we studied the Thr92Ala-Dio2 mouse model and saw that older male mice (7-8-month-old) exhibited a more severe cognition impairment, which extended to different aspects of declarative and working memories. A similar phenotype was observed in 4-5-month-old female mice. There were no structural alterations in the prefrontal cortex (PFC) and hippocampus of the Thr92Ala-Dio2 mouse. Nonetheless, in both male and female PFC, there was an enrichment in genes associated with TH-dependent processes, ER stress, and Golgi apparatus, while in the hippocampus there was additional enrichment in genes associated with inflammation and apoptosis. Reduced TH signaling remains a key mechanism of disease given that short-term treatment with L-T3 rescued the cognitive phenotype observed in males and females. We conclude that in mice, age is an additional risk factor for cognitive impairment associated with the Thr92Ala-Dio2 polymorphism. In addition to reduced TH signaling, ER-stress, and involvement of the Golgi apparatus, hippocampal inflammation and apoptosis were identified as potentially important mechanisms of a disease.

Heterozygote Advantage of the Type II Deiodinase Thr92Ala Polymorphism on Intrahospital Mortality of COVID-19.

CONTEXT: The type 2 deiodinase and its Thr92Ala-DIO2 polymorphism have been linked to clinical outcomes in acute lung injury and pulmonary fibrosis. OBJECTIVE: Our objectives were to evaluate were cumulative mortality during admission according to Thr92Ala-DIO2 polymorphism. METHODS: Here we conducted an observational, longitudinal, and prospective cohort study to investigate a possible association between the Thr92Ala-DIO2 polymorphism and intrahospital mortality from COVID-19 in adult patients admitted between June and August 2020. Blood biochemistry, thyroid function tests, length of stay, comorbidities, complications, and severity scores were also studied according to Thr92Ala-DIO2 polymorphism. RESULTS: In total, 220 consecutive patients (median age 62; 48-74 years) were stratified into 3 subgroups: Thr/Thr (n = 79), Thr/Ala (n = 119), and Ala/Ala (n = 23). While the overall mortality was 17.3%, the lethality was lower in Ala/Thr patients (12.6%) than in Thr/Thr patients (21.7%) or Ala/Ala patients (23%). The heterozygous genotype (Thr/Ala) was associated with a 47% reduced risk of intrahospital mortality whereas univariate and multivariate logistic regression adjusted for multiple covariates revealed a reduction that ranged from 51% to 66%. The association of the Thr/Ala genotype with better clinical outcomes was confirmed in a metanalysis of 5 studies, including the present one. CONCLUSION: Here we provide evidence for a protective role played by Thr92Ala-DIO2 heterozygosity in patients with COVID-19. This protective effect follows an inheritance model known as overdominance, in which the phenotype of the heterozygote lies outside the phenotypical range of both homozygous.

Thyroid Hormone Levels During Hospital Admission Inform Disease Severity and Mortality in COVID-19 Patients.

Background: Illness severity in patients infected with COVID-19 is variable. Methods: Here, we conducted an observational, longitudinal, and prospective cohort study to investigate serum thyroid hormone (TH) levels in adult COVID-19 patients, admitted between June and August 2020, and to determine whether they reflect the severity or mortality associated with the disease. Results: Two hundred forty-five patients [median age: 62 (49-75) years] were stratified into non-critical (181) and critically ill (64) groups. Fifty-eight patients (23.6%) were admitted to the intensive care unit, and 41 (16.7%) died. Sixteen (6.5%) exhibited isolated low levels of free triiodothyronine (fT3). fT3 levels were lower in critically ill compared with non-critical patients [fT3: 2.82 (2.46-3.29) pg/mL vs. 3.09 (2.67-3.63) pg/mL, p = 0.007]. Serum reverse triiodothyronine (rT3) was mostly elevated but less so in critically ill compared with non-critical patients [rT3: 0.36 (0.28-0.56) ng/mL vs. 0.51 (0.31-0.67) ng/mL, p = 0.001]. The univariate logistic regression revealed correlation between in-hospital mortality and serum fT3 levels (odds ratio [OR]: 0.47; 95% confidence interval [CI 0.29-0.74]; p = 0.0019), rT3 levels (OR: 0.09; [CI 0.01-0.49]; p = 0.006) and the product fT3 × rT3 (OR: 0.47; [CI 0.28-0.74]; p = 0.0026). Serum thyrotropin, free thyroxine, and fT3/rT3 values were not significantly associated with mortality and severity of the disease. A serum cutoff level of fT3 (≤2.6 pg/mL) and rT3 (≤0.38 ng/mL) was associated with 3.46 and 5.94 OR of mortality, respectively. We found three COVID-19 mortality predictors using the area under the receiver operating characteristic (ROC) curve (AUC score): serum fT3 (AUC = 0.66), rT3 (AUC = 0.64), and the product of serum fT3 × rT3 (AUC = 0.70). Non-thyroidal illness syndrome (fT3 < 2.0 pg/mL) was associated with a 7.05 OR of mortality ([CI 1.78-28.3], p = 0.005) and the product rT3 × fT3 ≤ 1.29 with an 8.08 OR of mortality ([CI 3.14-24.2], p < 0.0001). Conclusions: This prospective study reports data on the largest number of hospitalized moderate-to-severe COVID-19 patients and correlates serum TH levels with illness severity, mortality, and other biomarkers to critical illness. The data revealed the importance of early assessment of thyroid function in hospitalized patients with COVID-19, given the good prognostic value of serum fT3, rT3, and fT3 × rT3 product. Further studies are necessary to confirm these observations.

Temporal Pole Responds to Subtle Changes in Local Thyroid Hormone Signaling.

To study thyroid hormone (TH) signaling in the human brain, we analyzed published microarray data sets of the temporal pole (Brodmann area 38) of 19 deceased donors. An index of TH signaling built on the expression of 19 well known TH-responsive genes in mouse brains (T3S+) varied from 0.92 to 1.1. After Factor analysis, T3S+ correlated independently with the expression of TH transporters (MCT8, LAT2), TH receptor (TR) beta and TR coregulators (CARM1, MED1, KAT2B, SRC2, SRC3, NCOR2a). Unexpectedly, no correlation was found between T3S+ vs DIO2, DIO3, SRC1, or TRα. An unbiased systematic analysis of the entire transcriptome identified a set of 1649 genes (set #1) with strong positive correlation with T3S+ (r > 0.75). Factor analysis of set #1 identified 2 sets of genes that correlated independently with T3S+, sets #2 (329 genes) and #3 (191 genes). When processed through the Molecular Signatures Data Base (MSigDB), both sets #2 and #3 were enriched with Gene Ontology (GO)-sets related to synaptic transmission and metabolic processes. Ranking individual human brain donors according to their T3S+ led us to identify 1262 genes (set #4) with >1.3-fold higher expression in the top half. The analysis of the overlapped genes between sets #1 and #4 resulted in 769 genes (set #5), which have a very similar MSigDB signature as sets #2 and #3. In conclusion, gene expression in the human temporal pole can be assessed through T3S+ and fluctuates with subtle variations in local TH signaling.

Survival curve identifies critical period for postoperative mortality in cardiac patients undergoing emergency general surgery.

The number of non-cardiac major surgeries carried out has significantly increased in recent years to around 200 million procedures carried out annually. Approximately 30% of patients submitted to non-cardiac surgery present some form of cardiovascular comorbidity. In emergency situations, with less surgery planning time and greater clinical severity, the risks become even more significant. The aim of this study is to determine the incidence and clinical outcomes in patients with cardiovascular disease submitted to non-cardiac surgical procedures in a single cardiovascular referral center. This is a prospective cohort study of patients with cardiovascular disease submitted to non-cardiovascular surgery. All procedures were carried out by the same surgeon, between January 2006 and January 2018. 240 patients included were elderly, 154 were male (64%), 8 patients presented two diagnoses. Of the resulting 248 procedures carried out, 230 were emergency (92.8%). From the data obtained it was possible to estimate the day from which the occurrence of mortality is less probable in the postoperative phase. Our research evaluated the epidemiological profile of the surgeries and we were able to estimate the survival and delimit the period of greatest risk of mortality in these patients. The high rate of acute mesenteric ischemia was notable, a serious and frequently fatal condition.

Survival curve identifes critical period for postoperative mortality in cardiac patients undergoing emergency general surgery

The number of non-cardiac major surgeries carried out has signifcantly increased in recent years to around 200 million procedures carried out annually. Approximately 30% of patients submitted to non-cardiac surgery present some form of cardiovascular comorbidity. In emergency situations, with less surgery planning time and greater clinical severity, the risks become even more signifcant. The aim of this study is to determine the incidence and clinical outcomes in patients with cardiovascular disease submitted to non-cardiac surgical procedures in a single cardiovascular referral center. This is a prospective cohort study of patients with cardiovascular disease submitted to non-cardiovascular surgery. All procedures were carried out by the same surgeon, between January 2006 and January 2018. 240 patients included were elderly, 154 were male (64%), 8 patients presented two diagnoses. Of the resulting 248 procedures carried out, 230 were emergency (92.8%). From the data obtained it was possible to estimate the day from which the occurrence of mortality is less probable in the postoperative phase. Our research evaluated the epidemiological profle of the surgeries and we were able to estimate the survival and delimit the period of greatest risk of mortality in these patients. The high rate of acute mesenteric ischemia was notable, a serious and frequently fatal condition.

Induction of Type 2 Iodothyronine Deiodinase After Status Epilepticus Modifies Hippocampal Gene Expression in Male Mice.

Status epilepticus (SE) is an abnormally prolonged seizure that results from either a failure of mechanisms that terminate seizures or from initiating mechanisms that inherently lead to prolonged seizures. Here we report that mice experiencing a 3 hours of SE caused by pilocarpine exhibit a rapid increase in expression of type 2 iodothyronine deiodinase gene (Dio2) and a decrease in the expression of type 3 iodothyronine deiodinase gene in hippocampus, amygdala and prefrontal cortex. Type 3 iodothyronine deiodinase in hippocampal sections was seen concentrated in the neuronal nuclei, typical of ischemic injury of the brain. An unbiased analysis of the hippocampal transcriptome of mice undergoing 3 hours of SE revealed a number of genes, including those involved with response to oxidative stress, cellular homeostasis, cell signaling, and mitochondrial structure. In contrast, in mice with targeted disruption of Dio2 in astrocytes (Astro D2KO mouse), the highly induced genes in the hippocampus were related to inflammation, apoptosis, and cell death. We propose that Dio2 induction caused by SE accelerates production of T3 in different areas of the central nervous system and modifies the hippocampal gene expression profile, affecting the balance between adaptive and maladaptive mechanisms.

The Foxo1-Inducible Transcriptional Repressor Zfp125 Causes Hepatic Steatosis and Hypercholesterolemia.

Liver-specific disruption of the type 2 deiodinase gene (Alb-D2KO) results in resistance to both diet-induced obesity and liver steatosis in mice. Here, we report that this is explained by an ∼60% reduction in liver zinc-finger protein-125 (Zfp125) expression. Zfp125 is a Foxo1-inducible transcriptional repressor that causes lipid accumulation in the AML12 mouse hepatic cell line and liver steatosis in mice by reducing liver secretion of triglycerides and hepatocyte efflux of cholesterol. Zfp125 acts by repressing 18 genes involved in lipoprotein structure, lipid binding, and transport. The ApoE promoter contains a functional Zfp125-binding element that is also present in 17 other lipid-related genes repressed by Zfp125. While liver-specific knockdown of Zfp125 causes an "Alb-D2KO-like" metabolic phenotype, liver-specific normalization of Zfp125 expression in Alb-D2KO mice rescues the phenotype, restoring normal susceptibility to diet-induced obesity, liver steatosis, and hypercholesterolemia.

Myocardial Inactivation of Thyroid Hormones in Patients with Aortic Stenosis.

OBJECTIVE: The human heart expresses the type 2 deiodinase (D2) that activates thyroxine (T4) to triiodothyronine (T3). At the same time, the inactivating type 3 deiodinase (D3) has been found in a rat model of right ventricular hypertrophy. It is not known whether the human myocardium metabolizes thyroid hormone. This study examined myocardial thyroid hormone metabolism in patients with aortic valve stenosis (AS) undergoing aortic valve replacement and in patients with coronary artery disease (CAD) undergoing coronary artery bypass grafting surgery. METHODS: Myocardial thyroid hormone metabolism was assessed by analyzing the difference in serum thyroid hormone levels between the aortic root (incoming blood) and the coronary sinus (outgoing blood) of patients undergoing cardiac surgery. A total of 23 patients with AS and 35 patients with CAD were included. Patients received a pre-surgical echocardiogram, and pre-, during and post-surgical thyroid hormone serum levels were collected in the myocardial and peripheral circulations. RESULTS: Patients with AS exhibited the expected left ventricle (LV) hypertrophy (i.e., 20-30% increase in LV posterior wall and interventricular septum thickness and ∼10% increase in AS in LV diastolic diameter). Immediately before cardiopulmonary bypass, blood flowing through the AS myocardium exhibited a 4.6% reduction in T3 and 6.9% increase in rT3 levels, decreasing the serum T3/rT3 ratio by 9.6%. T4 and thyrotropin serum levels remained similar between the aortic root and coronary sinus. In contrast, no myocardial thyroid hormone metabolism was observed in CAD patients. Notably, the AS myocardium lost the ability to inactivate thyroid hormone after cardiopulmonary bypass, possibly due to myocardial stunning. CONCLUSIONS: There is accelerated thyroid hormone inactivation in the AS myocardium, which is likely the result of D3 expression. No evidence to suggest thyroid hormone activation in the myocardium was obtained in the present study.

Disruption of beta3 adrenergic receptor increases susceptibility to DIO in mouse.

The brown adipose tissue (BAT) mediates adaptive changes in metabolic rate by responding to the sympathetic nervous system through ß-adrenergic receptors (AR). Here, we wished to define the role played by the ARß3 isoform in this process. This study focused on the ARß3 knockout mice (ARß3KO), including responsiveness to cold exposure, diet-induced obesity, intolerance to glucose, dyslipidaemia and lipolysis in white adipose tissue (WAT). ARß3KO mice defend core temperature during cold exposure (4°C for 5 h), with faster BAT thermal response to norepinephrine (NE) infusion when compared with wild-type (WT) mice. Despite normal BAT thermogenesis, ARß3KO mice kept on a high-fat diet (HFD; 40% fat) for 8 weeks exhibited greater susceptibility to diet-induced obesity, markedly increased epididymal adipocyte area with clear signs of inflammation. The HFD-induced glucose intolerance was similar in both groups but serum hypertriglyceridemia and hypercholesterolemia were less intense in ARß3KO animals when compared with WT controls. Isoproterenol-induced lipolysis in isolated white adipocytes as assessed by glycerol release was significantly impaired in ARß3KO animals despite normal expression of key proteins involved in lipid metabolism. In conclusion, ARß3 inactivation does not affect BAT thermogenesis but increases susceptibility to diet-induced obesity by dampening WAT lipolytic response to adrenergic stimulation.

Infarto agudo do miocárdio no perioperatório de cirurgia de revascularização miocárdica / Acute myocardial infarction in the perioperative of coronary artery bypass surgery

A cirurgia de revascularização miocárdica constitui um dos tratamentos de escolha da doença coronária e apresenta mortalidade entre 2-5% em procedimentos eletivos, segundo estudos americanos. O avanço tecnológico melhorou as taxas de complicação, embora a taxa de infarto agudo do miocárdio perioperatório ou infarto agudo do miocárdio tipo 5 é difícil, pois alterações tanto eletrocardiográficas como de biomarcadores podem estar relacionadas à injúria cirúrgica...