Diabetes disturbs functional adaptation of the remote myocardium after ischemia/reperfusion.

Diabetes mellitus type 2 is associated with adverse clinical outcome after myocardial infarction. To better understand the underlying causes we here investigated sarcomere protein function and its calcium-dependent regulation in the non-ischemic remote myocardium (RM) of diabetic mice (db/db) after transient occlusion of the left anterior descending coronary artery. Before and 24 h after surgery db/db and non-diabetic db/+ underwent magnetic resonance imaging followed by histological and biochemical analyses of heart tissue. Intracellular calcium transients and sarcomere function were measured in isolated cardiomyocytes. Active and passive force generation was assessed in skinned fibers and papillary muscle preparations. Before ischemia and reperfusion (I/R), beat-to-beat calcium cycling was depressed in diabetic cardiomyocytes. Nevertheless, contractile function was preserved owing to increased myofilament calcium sensitivity and higher responsiveness of myocardial force production to ß-adrenergic stimulation in db/db compared to db/+. In addition, protein kinase C activity was elevated in db/db hearts leading to strong phosphorylation of the titin PEVK region and increased titin-based tension of myofilaments. I/R impaired the function of whole hearts and RM sarcomeres in db/db to a larger extent than in non-diabetic db/+, and we identified several reasons. First, the amplitude and the kinetics of cardiomyocyte calcium transients were further reduced in the RM of db/db. Underlying causes involved altered expression of calcium regulatory proteins. Diabetes and I/R additively reduced phospholamban S16-phosphorylation by 80% (P < 000.1) leading to strong inhibition of the calcium ATPase SERCA2a. Second, titin stiffening was only observed in the RM of db/+, but not in the RM of db/db. Finally, db/db myofilament calcium sensitivity and force generation upon ß-adrenergic stimulation were no longer enhanced over db/+ in the RM. The findings demonstrate that impaired cardiomyocyte calcium cycling of db/db hearts is compensated by increased myofilament calcium sensitivity and increased titin-based stiffness prior to I/R. In contrast, sarcomere function of the RM 24 h after I/R is poor because both these compensatory mechanisms fail and myocyte calcium handling is further depressed.

Cardiac impairment in Long Covid 1-year post-SARS-CoV-2 infection

BackgroundLong Covid is associated with multiple symptoms and impairment in multiple organs. Cardiac impairment has been reported to varying degrees by varying methodologies in cross-sectional studies. Using cardiac magnetic resonance (CMR), we investigated the 12-month trajectory of cardiac impairment in individuals with Long Covid. Methods534 individuals with Long Covid underwent baseline CMR (T1 and T2 mapping, cardiac mass, volumes, function, and strain) and multi-organ MRI at 6 months (IQR 4.3,7.3) since first post-COVID-19 symptoms and 330 were rescanned at 12.6 (IQR 11.4, 14.2) months if abnormal findings were reported at baseline. Symptoms, standardised questionnaires, and blood samples were collected at both timepoints. Cardiac impairment was defined as one or more of: low left or right ventricular ejection fraction (LVEF and RVEF), high left or right ventricular end diastolic volume (LVEDV and RVEDV), low 3D left ventricular global longitudinal strain (GLS), or elevated native T1 in [≥]3 cardiac segments. A significant change over time was reported by comparison with 92 healthy controls. ResultsThe technical success of this multiorgan assessment in non-acute settings was 99.1% at baseline, and 98.3% at follow up, with 99.6% and 98.8% for CMR respectively. Of individuals with Long Covid, 102/534 [19%] had cardiac impairment at baseline; 71/102 had complete paired data at 12 months. Of those, 58% presented with ongoing cardiac impairment at 12 months. High sensitivity cardiac troponin I and B-type natriuretic peptide were not predictive of CMR findings, symptoms, or clinical outcomes. At baseline, low LVEF, high RVEDV and low GLS were associated with cardiac impairment. Low LVEF at baseline was associated with persistent cardiac impairment at 12 months. ConclusionCardiac impairment, other than myocarditis, is present in 1 in 5 individuals with Long Covid at 6 months, persisting in over half of those at 12 months. Cardiac-related blood biomarkers are unable to identify cardiac impairment in Long COVID. Subtypes of disease (based on symptoms, examination, and investigations) and predictive biomarkers are yet to be established. Interventional trials with pre-specified subgroup analyses are required to inform therapeutic options.

E3-ligase knock down revealed differential titin degradation by autopagy and the ubiquitin proteasome system.

The sarcomere protein titin is a major determinant of cardiomyocyte stiffness and ventricular distensibility. The constant mechanical stress on titin requires well-controlled protein quality control, the exact mechanisms of which have not yet been fully elucidated. Here, we analyzed E3-ligases potentially responsible for cardiac titin ubiquitination and specifically studied the involvement of the autophagosomal system in titin degradation. Pharmacological inhibition of autophagy and the proteasome in cultured primary rat cardiomyocytes significantly elevated titin ubiquitination and increased titin degradation. Using in-vitro pull down assays we identified binding of E3-ligases MuRF1-3, CHIP and Fbx32 to several titin domains. Immunofluorescence analysis showed sarcomeric localization of the E3-ligases. siRNA-mediated knock-down of the E3-ligases MuRF-1, -3 and a combination of CHIP/Fbx32 significantly reduced autophagy-related titin ubiquitination, whereas knock-down of MuRF-2 and -3 reduced proteasome-related titin ubiquitination. We demonstrated that the proteasomal and the autophagosomal-lysosomal system participate in degradation of the titin filament. We found that ubiquitination and degradation of titin are partially regulated by E3-ligases of the MuRF family. We further identified CHIP and Fbx32 as E3-ligases involved in titin ubiquitination.

Physiological Disturbance in Fatty Liver Energy Metabolism Converges on IGFBP2 Abundance and Regulation in Mice and Men.

Fatty liver occurs from simple steatosis with accumulated hepatic lipids and hepatic insulin resistance to severe steatohepatitis, with aggravated lipid accumulation and systemic insulin resistance, but this progression is still poorly understood. Analyses of hepatic gene expression patterns from alb-SREBP-1c mice with moderate, or aP2-SREBP-1c mice with aggravated, hepatic lipid accumulation revealed IGFBP2 as key nodal molecule differing between moderate and aggravated fatty liver. Reduced IGFBP2 expression in aggravated fatty liver was paralleled with promoter hypermethylation, reduced hepatic IGFBP2 secretion and IGFBP2 circulating in plasma. Physiologically, the decrease of IGFBP2 was accompanied with reduced fatty acid oxidation and increased de novo lipogenesis potentially mediated by IGF1 in primary hepatocytes. Furthermore, methyltransferase and sirtuin activities were enhanced. In humans, IGFBP2 serum concentration was lower in obese men with non-alcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH) compared to non-obese controls, and liver fat reduction by weight-loss intervention correlated with an increase of IGFBP2 serum levels. In conclusion, hepatic IGFBP2 abundance correlates to its circulating level and is related to hepatic energy metabolism and de novo lipogenesis. This designates IGFBP2 as non-invasive biomarker for fatty liver disease progression and might further provide an additional variable for risk prediction for pathogenesis of fatty liver in diabetes subtype clusters.

Rhein, a novel Histone Deacetylase (HDAC) inhibitor with antifibrotic potency in human myocardial fibrosis.

Although fibrosis depicts a reparative mechanism, maladaptation of the heart due to excessive production of extracellular matrix accelerates cardiac dysfunction. The anthraquinone Rhein was examined for its anti-fibrotic potency to mitigate cardiac fibroblast-to-myofibroblast transition (FMT). Primary human ventricular cardiac fibroblasts were subjected to hypoxia and characterized with proteomics, transcriptomics and cell functional techniques. Knowledge based analyses of the omics data revealed a modulation of fibrosis-associated pathways and cell cycle due to Rhein administration during hypoxia, whereas p53 and p21 were identified as upstream regulators involved in the manifestation of cardiac fibroblast phenotypes. Mechanistically, Rhein acts inhibitory on HDAC classes I/II as enzymatic inhibitor. Rhein-mediated cellular effects were linked to the histone deacetylase (HDAC)-dependent protein stabilization of p53 under normoxic but not hypoxic conditions. Functionally, Rhein inhibited collagen contraction, indicating anti-fibrotic property in cardiac remodeling. This was accompanied by increased abundance of SMAD7, but not SMAD2/3, and consistently SMAD-specific E3 ubiquitin ligase SMURF2. In conclusion, this study identifies Rhein as a novel potent direct HDAC inhibitor that may contribute to the treatment of cardiac fibrosis as anti-fibrotic agent. As readily available drug with approved safety, Rhein constitutes a promising potential therapeutic approach in the supplemental and protective intervention of cardiac fibrosis.

Risk factors for cardiovascular disease in professors from a public university / Factores de riesgo para enfermedad cardiovascular en profesores de una universidad pública / Fatores de risco para doença cardiovascular em professores de uma universidade pública

Objective. To determine the prevalence of risk factors for cardiovascular disease among professors of a public university. Methodology. This cross-sectional study included 145 professors from the Federal University of Viçosa (UFV), MG, Brazil, in 2010. Analyzed variables included age, weight, height, waist, hip and abdominal circumferences, in addition to total cholesterol, triglycerides, glucose, and resting systolic and diastolic blood pressures. Results. A total of 71% were men, the average age of the men was higher than that of the women (46.9 versus 43.2 years old); half of the participants were overweight (46.9% were overweight and 9.0% were obese). Other factors were: 17.2% presented a waist-hip ratio at risk; 46.9% had greater than normal abdominal circumference; 4.0% presented high total cholesterol, 20.2% high triglycerides, 4.8% of the individuals presented abnormal glucose metabolism; and 16.6% were hypertensive. In comparison with men, women presented lower systolic blood pressure, diastolic blood pressure, body mass index, and abdominal, hip and waist circumferences. There was a trend of increased waist/hip and abdominal circumferences, total cholesterol, triglycerides, and systolic blood pressure as individuals aged. Conclusion. The college professors addressed in this study present important risk factors for cardiovascular disease. Hence, prevention and control measures need to be implemented in order to reduce the problem, a process in which nursing professionals play a key role in the achievement of success.

Objetivo. Determinar la prevalencia de factores de riesgo para enfermedad cardiovascular en profesores de una universidad pública. Metodología. Estudio de corte transversal. Se evaluaron 145 profesores de la Universidad Federal de Viçosa-MG (UFV), en 2010. Las variables analizas fueron edad, peso, talla, circunferencia de cintura, cadera y abdominal, además del colesterol total, triglicéridos, glucosa y tensión arterial sistólica y diastólica en reposo. Resultados. 71%, hombres; la edad promedio de estos fue mayor que la de las mujeres (46.9 versus 43.2 años), uno de cada dos participantes estaba pasado de peso (46.9% sobrepeso y 9.0% obesidad). Otros factores observados fueron: un 17.2% tenía un índice cintura/cadera de riesgo; el 46.9%, alta circunferencia abdominal; el 4.0%, colesterol total alto; el 20.2%, triglicéridos altos; un 4.8%, con metabolismo anormal de glucosa y 16.6% hipertensos. En comparación con los hombres, las mujeres tenían valores más bajos para la presión arterial sistólica, presión arterial diastólica, índice de masa corporal, circunferencia abdominal y la relación cintura/cadera. Hubo una tendencia al aumento de los valores de las variables de la relación cintura/cadera, circunferencia abdominal, el colesterol total, los triglicéridos y la presión arterial sistólica, con el aumento de edad. Conclusión. Los profesores universitarios participantes en este estudio tienen importantes frecuencias de exposición a factores de riesgo para enfermedad cardiovascular. Es necesario implementar medidas de prevención y control para la reducción de esta problemática, en las cuales Enfermería es clave para su éxito.

Objetivo. Determinar a prevalência de fatores de risco para doença cardiovascular em professores de uma universidade pública. Metodologia. Estudo de corte transversal. Avaliaram-se 145 professores da Universidade Federal de Viçosa-MG (UFV), em 2010. As variáveis analisas foram idade, peso, medida, circunferência de cintura, quadril e abdominal, além do colesterol total, triglicérides, glucose e tensão arterial sistólica e diastólica em repouso. Resultados. 71% eram homens, a idade média das homens foi maior que a das mulheres (46.9 contra 43.2 anos), um de cada dois participante tinha estava passado de importância (46.9% sobrepeso e 9.0% obesidade). Outros fatores observados foram: 17.2% tinha um índice cintura/quadril de risco, 46.9% com alta circunferência abdominal, 4.0% com colesterol total alto, 20.2% de triglicérides altos, um 4.8% com metabolismo anormal de glucose e 16.6% foram hipertensos. Em comparação com os homens, as mulheres tinham valores mais baixos para a pressão arterial sistólica, pressão arterial diastólica, índice de massa corporal, circunferência abdominal e a relação cintura/quadril. Teve uma tendência ao aumento dos valores das variáveis da relação cintura/quadril, circunferência abdominal, o colesterol total, os triglicérides e a pressão arterial sistólica, com o aumento de idade. Conclusão. Os professores universitários deste estudo têm importantes frequências de exposição a fatores de risco para doença cardiovascular. É necessário implementar medidas de prevenção e controle para a redução desta problemática, nas quais Enfermagem é importante para seu sucesso.