The absolute and relative changes in high-sensitivity cardiac troponin I are associated with the in-hospital mortality of patients with fulminant myocarditis.

BACKGROUND: We sought to describe the tendency and extent of high-sensitivity cardiac troponin I (hs-cTnI) changes in patients with fulminant myocarditis (FM) after admission and to explore the relationship between the in-hospital mortality of FM and the absolute and relative changes in hs-cTnI within 24 h and 48 h after admission. METHODS: In the retrospective study, the object are patients diagnosed with FM in our single centre. The value of cardiac troponin was recorded after patients admitted to hospital in succession. The absolute and relative changes in hs-cTnI within 24 h and 48 h were described as range distributions. Receiver operating characteristic (ROC) curve and Cox analyses were performed to determine the relationship between in-hospital mortality of FM and hs-cTnI changes. RESULTS: A total of 83 FM patients admitted to our centre from January 1, 2010 to December 31, 2019 were included; 69 patients survived and 14 patients died. In the survival group, 78% of patients experienced a decline in hs-cTnI within 24 h, while 36% of the mortality group exhibited a declining tendency in hs-cTnI (P = 0.003). Nearly 60% of survival group had a 0-2000 ng/l reduction in troponin from baseline within 24 h of admission. However, troponin levels of 50% of patients in the mortality group were 0-10,000 ng/ L higher than baseline 24 h after admission. Multivariable logistic analysis revealed that the declining tendency of hs-cTnI within 24 h, in addition to time from onset to admittance to hospital, intravenous immunoglobulin treatment and the abnormal level of creatinine, were associated with the in-hospital mortality of FM (for the declining tendency of hs-cTnI within 24 h, OR = 0.10, 95% CI 0.02-0.68, P = 0.018). The ROC curve revealed optimal cut-off values of - 618 ng/l for absolute change within 24 h (AUC = 0.800, P < 0.01), - 4389 ng/l for absolute change within 48 h (area under the curve = 0.711, P < 0.01), - 28.46% for relative change within 24 h (AUC = 0.810, P < 0.01), and - 52.23% for relative change within 48 h (AUC = 0.795, P < 0.01). Absolute changes and relative changes in hs-cTnI within 24 h and 48 h were strong predictors of in-hospital mortality by Cox regression analysis after adjustment for sex, time from onset to admission, and occurrence of ventricular tachycardia or ventricular fibrillation. CONCLUSION: Most FM patients who survived experienced a decline in hs-cTnI within 24 h. The absolute and relative changes in hs-cTnI within 24 h and 48 h were strong predictors of in-hospital mortality.

Longitudinal correlation of biomarkers of cardiac injury, inflammation, and coagulation to outcome in hospitalized COVID-19 patients.

BACKGROUND: Cardiac injury, as measured by troponin elevation, has been reported among hospitalized coronavirus disease 2019 (COVID-19) patients and portends a poor prognosis. However, how the dynamics of troponin elevation interplay with inflammation and coagulation biomarkers over time is unknown. We assessed longitudinal follow-up of cardiac injury, inflammation and coagulation markers in relation to disease severity and outcome. METHODS: We retrospectively assessed 2068 patients with laboratory-confirmed COVID-19 between January 29 and April 1, 2020 at Tongji Hospital in Wuhan, China. We defined cardiac injury as an increase in high sensitivity cardiac troponin-I (hs-cTnI) above the 99th of the upper reference limit. We explored the dynamics of elevation in hs-cTnI and the relationship with inflammation (interleukin [IL]-6, IL-8, IL-10, IL-2 receptor, tumor necrosis factor-α, C-reactive protein) and coagulation (d-dimer, fibrinogen, international normalized ratio) markers in non-critically ill versus critically ill patients longitudinally and further correlated these markers to survivors and non-survivors. RESULTS: Median age was 63 years (first to third quartile 51-70 years), 51.4% of whom were women. When compared to non-critically ill patients (N = 1592, 77.0%), critically ill (defined as requiring mechanical ventilation, in shock or multiorgan failure) patients (N = 476, 23.0%), had more frequent cardiac injury on admission (30.3% vs. 2.3%, p < 0.001), with increased mortality during hospitalization (38.4% vs. 0%, p < 0.001). Among critically ill patients, non-survivors (N = 183) had a continuous increase in hs-cTnI levels during hospitalization, while survivors (N = 293) showed a decrease in hs-cTnI level between day 4 and 7 after admission. Specifically, cardiac injury is an independent marker of mortality among critically ill patients at admission, day 4-7 and 8-14. Consistent positive correlations between hs-cTnI and interleukin (IL)-6 on admission (r = 0.59), day 4-7 (r = 0.66) and day 8-14 (r = 0.61; all p < 0.001) and d-dimer (at the same timepoints r = 0.54; 0.65; 0.61, all p < 0.001) were observed. A similar behavior was observed between hs-cTnI and most of other biomarkers of inflammation and coagulation. CONCLUSIONS: Cardiac injury commonly occurs in critically ill COVID-19 patients, with increased levels of hs-cTnI beyond day 3 since admission portending a poor prognosis. A consistent positive correlation of hs-cTnI with IL-6 and d-dimer at several timepoints along hospitalization could suggest nonspecific cytokine-mediated cardiotoxicity.

Comparison of Apolipoprotein B/A1 ratio, Framingham risk score and TC/HDL-c for predicting clinical outcomes in patients undergoing percutaneous coronary intervention.

BACKGROUND: Apolipoproteins (Apo) are known atherogenic factors that play important roles in many mechanisms related to coronary heart disease (CHD). However, it is unclear whether the apoB/apoA1 ratio is an equal or a better predictor than the Framingham Risk Score or TC/HDL-c for predicting clinical outcomes in patients undergoing percutaneous coronary intervention. METHODS: We investigated the association between Apolipoprotein B/A1 ratio and cardiovascular risk factors as well as the severity of CHD in 2256 Han Chinese patients. The potential of Apolipoprotein B/A1 ratio, Framingham Risk Score and TC/HDL-c were assessed as a marker to predict cardiovascular adverse events in a prospective subgroup of 1639 CHD patients during a 5-year follow-up. RESULTS: In the multivariate model, adjusted odds ratios (ORs) were significant for 3-VD vs. 1-VD (OR = 2.36; 95% CI: 1.65-3.38, for the fourth vs. first quartile; Ptrend < 0.001). The subgroup analysis showed that patients with a higher ApoB/ApoA1 ratio had an increased risk of developing multi-branch lesions and potentially suffer more cardiovascular adverse events (anginas, myocardial infarctions, heart failures, strokes, and cardiac deaths) in the future (adjusted HR =1.92; 95% CI: 1.10-3.13, for the fourth vs. first quartile). In the ROC analysis, the AUC for ApoB/A1 ratio was larger than that of Framingham Risk Score (0.604 vs. 0.543, p = 0.01) and TC/HDL-c (0.604 vs. 0.525, p < 0.01). CONCLUSION: Our results suggest a significant association between ApoB/ApoA1 ratio and CHD severity and cardiovascular outcomes among patients with existing CHD and ApoB/A1 ratio demonstrated a better predictive accuracy for clinical outcomes compared with Framingham Risk Score and TC/HDL-c.

miR-1322 regulates ChREBP expression via binding a 3'-UTR variant (rs1051943).

The carbohydrate response element-binding protein (ChREBP), also referred to as MLXIPL, plays a crucial role in the regulation of glucose and lipid metabolism. Existing studies have shown an association between genetic variations of the ChREBP gene and lipid levels, such as triglycerides and high-density lipoprotein cholesterol. However, mechanistic studies of this association are limited. In this study, bioinformatic analysis revealed that the polymorphism rs1051943A occurs in the complementary binding sequence of miR-1322 in the ChREBP 3'-untranslated region (UTR). Studies of potential mechanisms showed that the A allele could facilitate miR-1322 binding, and luciferase activity significantly decreased when co-transfected with a ChREBP 3'-UTR luciferase reporter vector and miR-1322 mimics in HepG2 cells. Furthermore, miR-1322 significantly regulated the expression of ChREBP downstream genes and reduced the synthesis of lipids. The expression of miR-1322 was up-regulated by glucose and palmitic acid stimulation. Population studies showed that rs1051943-A allele was only found in the Han Chinese and Uighur ethnic groups, different from European populations (G allele frequency = 0.07). In summary, we provide evidence that the rs1051943 A allele creates a functional miR-1322 binding site in ChREBP 3'-UTR and post-transcriptionally down-regulates its expression, possibly associated with levels of plasma lipids and glucose.

Wavelet transform based defringing in interference imaging spectrometer.

The constructive and destructive fringe-like pattern (FP) introduced by the fringing effects is a universal phenomenon emerging in the imaging system using the back-illuminated CCD. Generally, the flat fielding or modeling based methods were applied to suppressing the FP and featured as time-consuming, duplicated, and hardware-based. In this paper, a method based on the wavelet transform was proposed for the interferogram processing in interference imaging spectrometer. An artificial interferogram construction method was developed and utilized to evaluate the quality of the reconstructed interferogram. The performance of defringing was significantly determined by the wavelet decomposition. Through numerical simulation, 4 wavelets were selected out of 50 typical wavelets; the decomposition levels with better performance were determined. The feasibility of the defringing and performance evaluation methods were verified by the simulation and practical experiments. It provides us with a software-based, time-saving, without prior knowledge, automatic approach for defringing.

Overcoming Insulin Insufficiency by Forced Follistatin Expression in ß-cells of db/db Mice.

Diabetes poses a substantial burden to society as it can lead to serious complications and premature death. The number of cases continues to increase worldwide. Two major causes of diabetes are insulin resistance and insulin insufficiency. Currently, there are few antidiabetic drugs available that can preserve or protect ß-cell function to overcome insulin insufficiency in diabetes. We describe a therapeutic strategy to preserve ß-cell function by overexpression of follistatin (FST) using an AAV vector (AAV8-Ins-FST) in diabetic mouse model. Overexpression of FST in the pancreas of db/db mouse increased ß-cell islet mass, decreased fasting glucose level, alleviated diabetic symptoms, and essentially doubled lifespan of the treated mice. The observed islet enlargement was attributed to ß-cell proliferation as a result of bioneutralization of myostatin and activin by FST. Overall, our study indicates overexpression of FST in the diabetic pancreas preserves ß-cell function by promoting ß-cell proliferation, opening up a new therapeutic avenue for the treatment of diabetes.

Genetic associations of childhood and adult BMI on chronic heart failure and ischemic stroke: A Mendelian randomization.

Background: Obesity has been confirmed to be associated with cardiovascular disease, but previous studies have focused on adults, and whether childhood obesity is associated with cardiovascular disease in adulthood needs further research. Objective: This Mendelian randomization (MR) study aimed to investigate the associations of childhood and adult body mass index (BMI) with the risk of chronic heart failure (CHF) and ischemic stroke (IS). Methods: Independent genetic instruments, demonstrating a strong association with exposure at the genome-wide significance level (P < 5 × 10-8), were carefully selected from comprehensive genome-wide association studies conducted within relevant European populations. Summary-level data for CHF and IS were obtained from the EBI database and large consortia of European population. To enhance robustness and generalizability, the analysis was replicated in an East Asian population cohort. Results: According to a MR analysis based on a European population, a higher adult BMI was associated with an increased risk of CHF [(odds ratio (OR) 1.594, 95% confidence interval (CI) 1.483-1.713)] and IS (OR 1.163, 95%CI 1.096-1.233). In addition, higher childhood BMI level was associated with a higher risk of CHF (OR 1.323, 95%CI 1.153-1.524).and the effect was mainly driven by adult BMI. Replication analyses of adult BMI in East Asian populations showed consistent findings that adult BMI was associated with the risk of CHF (OR 2.167, 95%CI 1.786-2.630) and IS (OR 1.259, 95%CI 1.128-1.406). Conclusions: Our study findings provide compelling evidence for the significant influence of adult BMI on the occurrence of CHF and IS. Furthermore, our observations suggest that the positive association between childhood BMI and the risk of CHF in adulthood can largely be attributed to individuals who maintain obesity into later life.

The relationship between processed meat, red meat, and risk of cardiovascular disease and type 2 diabetes: A Mendelian randomization study.

BACKGROUND: Numerous observational studies have indicated a potential association between the consumption of processed and red meat and an increased risk of cardiovascular disease and type 2 diabetes mellitus (T2DM). However, the presence of a causal relationship remains uncertain. Therefore, the purpose of this study is to evaluate the impact of processed meat and red meat (pork, lamb, and beef) on the risk of cardiovascular disease, including coronary artery disease (CAD), hypertension, and stroke, and T2DM, using a Two-Sample Mendelian randomization (MR) analysis. METHODS: MR analysis was conducted using the inverse-variance weighted (IVW), weighted median (WM), and MR Egger methods. To identify heterogeneity and pleiotropy, Cochrane's Q test and MR-Egger test were employed. Additionally, the stability of the MR results was assessed using the leave-one-out method. RESULTS: IVW analyses reveal no causal association between the consumption of processed and red meat and the incidence of CAD, hypertension, stroke, and T2DM (P > 0.05). When considering processed meat intake, heterogeneity is observed in hypertension and stroke outcomes (P < 0.05). For pork intake, heterogeneity is seen in hypertension, stroke, and T2DM (P < 0.05). Lamb intake shows heterogeneity in hypertension and T2DM (P < 0.05). However, other exposures and outcomes examined show no heterogeneity (P > 0.05). No significant pleiotropy is detected for all exposures through an MR-Egger test (P > 0.05). Furthermore, the Leave-one-out test demonstrates the robustness of the results. CONCLUSION: The study discerned no observable impact of red and processed meat consumption on CAD, hypertension, stroke, and T2DM. The findings of this study challenge the prevailing conventional perspective in the field.

This study aimed to investigate whether eating processed and red meat increases the risk of heart disease, high blood pressure, stroke, and type 2 diabetes. Using a genetic analysis method called Mendelian randomization, the research team analyzed genome-wide data to assess meat consumption and its potential health effects.

Chinese Society of Cardiology guidelines on the diagnosis and treatment of adult fulminant myocarditis.

Fulminant myocarditis is an acute diffuse inflammatory disease of myocardium. It is characterized by acute onset, rapid progress and high risk of death. Its pathogenesis involves excessive immune activation of the innate immune system and formation of inflammatory storm. According to China's practical experience, the adoption of the "life support-based comprehensive treatment regimen" (with mechanical circulation support and immunomodulation therapy as the core) can significantly improve the survival rate and long-term prognosis. Special emphasis is placed on very early identification,very early diagnosis,very early prediction and very early treatment.

Polymorphisms of TRIB1 genes for coronary artery disease and stroke risk: A systematic review and meta-analysis.

BACKGROUND AND AIMS: In recent years, the results of the association between Tribbles Pseudokinase 1 (TRIB1) gene polymorphism and the risk of coronary artery disease (CAD) and stroke are inconsistent. This study aimed to systematically review the literature on TRIB1 gene polymorphisms and susceptibility to coronary atherosclerotic heart disease (CAD) and stroke. METHODS: This study collected studies published until May 2022 through a systematic search of PubMed, Web of Science, and Google Scholar databases. After a systematic literature search, pooled odds ratio (OR) and their corresponding 95 % confidence interval (CI) were used to assess the strength of the association. RESULTS: We identified 6 studies on rs17321515, including 12,892 controls and 4583 patients, and 3 on rs2954029, including 1732 controls and 1305 patients. In different genetic models, the rs2954029 genetic polymorphism significantly increased the risk of CAD and stroke. In the codominant model, the AA genotype increased the risk of CAD and stroke (OR = 1.74, 95 % CI = 1.39-2.17, P < 0.001); the TA genotype also increased the prevalence of CAD and stroke risk (OR = 1.39, 95 % CI = 1.18-1.64, P < 0.001). Compared with the control group, the TT + TA genotype increased the risk of CAD and stroke in the dominant genetic model (OR = 1.46, 95 %CI = 1.25-1.71, P < 0.001), and in the recessive model, the TA + AA genotype increased the risk of CAD and stroke (OR = 1.41, 95 % CI = 1.15-1.72, P < 0.001). In addition, the TRIB1 rs17321515 polymorphism was not found to be associated with the risk of CAD and stroke, which may be related to other factors such as race. CONCLUSIONS: The rs2954029 A allele was significantly associated with an increased risk of CAD and stroke, according to the present meta-analysis. However, the association of rs17321515 polymorphism with susceptibility to CAD and stroke has not been found in this study.

The role of endothelial cell in cardiac hypertrophy: Focusing on angiogenesis and intercellular crosstalk.

Cardiac hypertrophy is characterized by cardiac structural remodeling, fibrosis, microvascular rarefaction, and chronic inflammation. The heart is structurally organized by different cell types, including cardiomyocytes, fibroblasts, endothelial cells, and immune cells. These cells highly interact with each other by a number of paracrine or autocrine factors. Cell-cell communication is indispensable for cardiac development, but also plays a vital role in regulating cardiac response to damage. Although cardiomyocytes and fibroblasts are deemed as key regulators of hypertrophic stimulation, other cells, including endothelial cells, also exert important effects on cardiac hypertrophy. More particularly, endothelial cells are the most abundant cells in the heart, which make up the basic structure of blood vessels and are widespread around other cells in the heart, implicating the great and inbuilt advantage of intercellular crosstalk. Cardiac microvascular plexuses are essential for transport of liquids, nutrients, molecules and cells within the heart. Meanwhile, endothelial cell-mediated paracrine signals have multiple positive or negative influences on cardiac hypertrophy. However, a comprehensive discussion of these influences and consequences is required. This review aims to summarize the basic function of endothelial cells in angiogenesis, with an emphasis on angiogenic molecules under hypertrophic conditions. The secondary objective of the research is to fully discuss the key molecules involved in the intercellular crosstalk and the endothelial cell-mediated protective or detrimental effects on other cardiac cells. This review provides a more comprehensive understanding of the overall role of endothelial cells in cardiac hypertrophy and guides the therapeutic approaches and drug development of cardiac hypertrophy.

Left ventricular function changes and echocardiographic predictors in adult survivors of fulminant myocarditis treated with the Chinese protocol.

Disagreement exists regarding the long-term prognosis and recovery of left ventricular (LV) function in patients with fulminant myocarditis (FM). This study reported the outcome and LV ejection fraction (EF) changes in FM treated with Chinese protocol, and assessed whether global longitudinal strain (GLS) by two-dimensional speckle tracking echocardiography (2-D STE) could provide additional information. This retrospective study included 46 FM adult patients who applied timely circulatory support and immunomodulatory therapy with adequate doses of both glucocorticoids and immunoglobulins as core approaches and survived after acute phase. They all presented with acute onset of cardiac symptoms < 2 weeks. LV end-diastolic dimensions, LVEF and GLS at discharge and 2-year were obtained and compared. We then performed linear regression and ROC analysis to determine independent factors to predict normalization of GLS at 2-year. At 2 years, the survival was 100% in our cohort. And the GLS improved modestly (15.40 ± 3.89% vs 17.24 ± 2.89%, P = 0.002). At two years, a proportion of patients whose LV function remained abnormal, being 22% evaluated by EF (< 55%) and higher to 37% by GLS (< 17%). Moreover, GLS at discharge but not at presentation correlated with GLS at 2-year (r = 0.402, P = 0.007). The FM adult treated with Chinese protocol have good survival and modest improvement of LV function during 2-year.

Characteristics of Electrocardiogram Findings in Fulminant Myocarditis.

Fulminant myocarditis (FM) is an acute and severe form of myocarditis with rapid progression and poor clinical outcomes in the absence of acute or chronic coronary artery disease. Electrocardiogram (ECG) abnormalities can provide preliminary clues for diagnosis; however, there is a lack of systemic descriptions on ECG changes in FM populations. Thus, a retrospective analysis of 150 consecutive FM patients and 300 healthy controls was performed to determine the characteristic ECG findings in FM. All patients included had markedly abnormal ECG findings. Specifically, 83 (55.33%) patients had significantly lower voltage with remarkably decreased QRS amplitudes in all leads compared with healthy controls (p < 0.01), and 77 (51.33%) patients had a variety of arrhythmias with lethality ventricular tachycardia/ventricular fibrillation in 21 (14.00%) patients and third-degree atrioventricular block in 21 (14.00%) patients, whereas sinus tachycardia was only found in 43 (28.67%) patients with the median heart rate (HR; 88.00 bpm, IQR: 76.00-113.50) higher than that of controls (73.00 bpm, IQR: 68.00-80.00) (p = 0.000). Conduction and repolarization abnormalities were common in patients. A longer QTc interval (452.00 ms, IQR: 419.00-489.50) and QRS duration (94.00 ms, IQR: 84.00-119.00) were observed in patients compared to controls (QTc interval = 399.00 ms, IQR: 386.00-414.00; QRS duration = 90.00 ms, IQR: 86.00-98.00) (p < 0.05). Additionally, HR > 86.50 bpm, QTc > 431.50 ms, and RV5 + SV1 < 1.715 mV can be used to predict FM. Thus, marked and severe ECG abnormalities provide preliminary clues for the diagnosis of FM.

Post-Natal knockdown of fukutin-related protein expression in muscle by long-termRNA interference induces dystrophic pathology [corrected].

Limb-girdle muscular dystrophy 2I (LGMD2I) is caused by mutations in the fukutin-related protein (FKRP) gene. Unlike its severe allelic forms, LGMD2I usually involves slower onset and milder course without defects in the central nervous system. The lack of viable animal models that closely recapitulate LGMD2I clinical phenotypes led us to use RNA interference technology to knock down FKRP expression via postnatal gene delivery so as to circumvent embryonic lethality. Specifically, an adeno-associated viral vector was used to deliver short hairpin (shRNA) genes to healthy ICR mice. Adeno-associated viral vectors expressing a single shRNA or two different shRNAs were injected one time into the hind limb muscles. We showed that FKRP expression at 10 months postinjection was reduced by about 50% with a single shRNA and by 75% with the dual shRNA cassette. Dual-cassette injection also reduced a-dystroglycan glycosylation and its affinity to laminin by up to 70% and induced α-dystrophic pathology, including fibrosis and central nucleation, in more than 50% of the myofibers at 10 months after injection. These results suggest that the reduction of approximately or more than 75% of the normal level of FKRP expression induces chronic dystrophic phenotypes in skeletal muscles. Furthermore, the restoration of about 25% of the normal FKRP level could be sufficient for LGMD2I therapy to correct the genetic deficiency effectively and prevent dystrophic pathology.

A myocardium tropic adeno-associated virus (AAV) evolved by DNA shuffling and in vivo selection.

To engineer gene vectors that target striated muscles after systemic delivery, we constructed a random library of adeno-associated virus (AAV) by shuffling the capsid genes of AAV serotypes 1 to 9, and screened for muscle-targeting capsids by direct in vivo panning after tail vein injection in mice. After 2 rounds of in vivo selection, a capsid gene named M41 was retrieved mainly based on its high frequency in the muscle and low frequency in the liver. Structural analyses revealed that the AAVM41 capsid is a recombinant of AAV1, 6, 7, and 8 with a mosaic capsid surface and a conserved capsid interior. AAVM41 was then subjected to a side-by-side comparison to AAV9, the most robust AAV for systemic heart and muscle gene delivery; to AAV6, a parental AAV with strong muscle tropism. After i.v. delivery of reporter genes, AAVM41 was found more efficient than AAV6 in the heart and muscle, and was similar to AAV9 in the heart but weaker in the muscle. In fact, the myocardium showed the highest gene expression among all tissues tested in mice and hamsters after systemic AAVM41 delivery. However, gene transfer in non-muscle tissues, mainly the liver, was dramatically reduced. AAVM41 was further tested in a genetic cardiomyopathy hamster model and achieved efficient long-term delta-sarcoglycan gene expression and rescue of cardiac functions. Thus, direct in vivo panning of capsid libraries is a simple tool for the de-targeting and retargeting of viral vector tissue tropisms facilitated by acquisition of desirable sequences and properties.

Sphingosine-1-phosphate Attenuates Endoplasmic Reticulum Stress-induced Cardiomyocyte Apoptosis Through Sphingosine-1-phosphate Receptor 1.

BACKGROUND: Endoplasmic reticulum stress (ER stress) is involved in the development and progression of various forms of heart disease and may lead to myocardial apoptosis. Sphingosine-1-phosphate (S1P) possesses cardioprotective properties, including anti-apoptosis. However, little is known about the link between S1P and ER stress-induced myocardial apoptosis. This study investigated the regulatory role of S1P in ER stress-induced apoptosis in cardiomyocytes. METHODS: ER stress and myocardial apoptosis were induced by transverse aortic constriction (TAC) or tunicamycin in mice, which were then treated with 2-acetyl-5-tetrahydroxybutyl imidazole (THI) or S1P. AC16 cells were treated with tunicamycin or thapsigargin, or pretreated with S1P, sphingosine-1-phosphate receptor (S1PR) subtype antagonists, S1PR1 agonist, and PI3K and MEK inhibitors. Cardiac function, the level of S1P in plasma and heart, ER stress markers, cell viability, and apoptosis were detected. RESULTS: S1P reduced the expression of ER stress-related molecules and ER stress-induced myocardial apoptosis in mice subjected to TAC or an injection of tunicamycin. Furthermore, in AC16 cells exposed to thapsigargin or tunicamycin, S1P decreased the expression of ER stress-related molecules, promoting cell viability and survival. Nevertheless, the S1PR1 antagonist abrogated the protection of S1P. Subsequently, in TAC S1PR1 heterozygous (S1PR1+/-) mice, S1P had no effect on ER stress and apoptosis in cardiomyocytes. Notably, in vitro, the impact of anti-ER stress-induced myocardial apoptosis by the S1PR1 agonist was reversed by PI3K and MEK inhibitors. CONCLUSION: This study is the first to demonstrate that S1P relieves ER stress-induced myocardial apoptosis via S1PR1/AKT and S1PR1/ERK1/2, which are potential therapeutic targets for heart disease.

Using multi-parametric quantitative MRI to screen for cardiac involvement in patients with idiopathic inflammatory myopathy.

Idiopathic inflammatory myopathies (IIM) is a group of heterogeneous autoimmune systemic diseases, which not only involve skeletal muscle but also myocardium. Cardiac involvement in IIM, which eventually develops into heart failure, is difficult to identify by conventional examinations at early stage. The aim of this study was to investigate if multi-parametric cardiac magnetic resonance (CMR) imaging can screen for early cardiac involvement in IIM, compared with clinical score (Myositis Disease Activity Assessment Tool, MDAAT). Forty-nine patients of IIM, and 25 healthy control subjects with comparable age-range and sex-ratio were enrolled in this study. All subjects underwent CMR examination, and multi-slice short-axis and 4-chamber cine MRI were acquired to evaluate biventricular global circumferential strain (GCS) and global longitudinal strain (GLS). Native T1 and T2 mapping were performed, and post-contrast T1 mapping and LGE were acquired after administration of contrast. A CMR score was developed from native T1 mean and T2 mean for the identification of cardiac involvement in the IIM cohort. Using contingency tables MDAAT and CMR were compared and statistically analyzed using McNemar test. McNemar's test revealed no significant difference between CMR score and MDAAT (p = 0.454). CMR score had potential to screen for early cardiac involvement in IIM patients, compared to MDAAT.

Sphingosine-1-Phosphate Protects Against the Development of Cardiac Remodeling via Sphingosine Kinase 2 and the S1PR2/ERK Pathway.

OBJECTIVE: Cardiac remodeling is a common pathological change in various cardiovascular diseases and can ultimately result in heart failure. Thus, there is an urgent need for more effective strategies to aid in cardiac protection. Our previous work found that sphingosine-1-phosphate (S1P) could ameliorate cardiac hypertrophy. In this study, we aimed to investigate whether S1P could prevent cardiac fibrosis and the associated mechanisms in cardiac remodeling. METHODS: Eight-week-old male C57BL/6 mice were randomly divided into a sham, transverse aortic constriction (TAC) or a TAC+S1P treatment group. RESULTS: We found that S1P treatment improved cardiac function in TAC mice and that the cardiac fibrosis ratio in the TAC+S1P group was significantly lower and was accompanied by a decrease in α-smooth muscle actin (α-SMA) and collagen type I (COL I) expression compared with the TAC group. We also found that one of the key S1P enzymes, sphingosine kinase 2 (SphK2), which was mainly distributed in cytoblasts, was downregulated in the cardiac remodeling case and recovered after S1P treatment in vivo and in vitro. In addition, our in vitro results showed that S1P treatment activated extracellular regulated protein kinases (ERK) phosphorylation mainly through the S1P receptor 2 (S1PR2) and spurred p-ERK transposition from the cytoplasm to cytoblast in H9c2 cells exposed to phenylephrine. CONCLUSION: These findings suggest that SphK2 and the S1PR2/ERK pathway may participate in the anti-remodeling effect of S1P on the heart. This work therefore uncovers a novel potential therapy for the prevention of cardiac remodeling.

Soluble ST2 Is a Sensitive and Specific Biomarker for Fulminant Myocarditis.

Background The aim of the study was to identify biomarkers that can facilitate early diagnosis and treatment of fulminant myocarditis (FM) in order to reduce mortality. Methods and Results First, the expression profiles of circulating cytokines were determined in the plasma samples from 4 patients with FM and 4 controls using human cytokine arrays. The results showed that 39 cytokines from patients with FM were changed at admission. Among them, 8 cytokines returned to normal levels at discharge, including soluble ST2 (sST2), which showed the most marked dynamic changes from disease onset to resolution. Then, in a cohort of 76 patients with FM, 57 patients with acute hemodynamic dysfunction attributable to other causes, and 56 patients with non-FM, receiver operating characteristic curve analyses suggested that plasma sST2 level was able to differentiate FM from non-FM or other FM-unrelated acute heart failure more robustly N-terminal pro-B-type natriuretic peptide or cardiac troponin I. Moreover, longitudinal analysis of plasma sST2 was performed in 10 patients with FM during hospitalization and 16 patients with FM during follow-up. Finally, the diagnostic value was validated in an additional 26 patients with acute onset of unstable hemodynamics. The cutoff value of plasma sST2 for optimal diagnosis of FM was established at 58.39 ng/mL, where a sensitivity of 85.7% and specificity of 94.7% were achieved. Conclusions Elevated sST2 level was associated with mechanical stress or inflammation. Especially, sST2 might be used as a potential biomarker for the rapid diagnosis of FM, which was characterized by strong mechanical stretch stimulation and severe inflammatory response. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT03268642.

Effective rescue of dystrophin improves cardiac function in dystrophin-deficient mice by a modified morpholino oligomer.

Antisense oligonucleotide-mediated exon skipping is able to correct out-of-frame mutations in Duchenne muscular dystrophy and restore truncated yet functional dystrophins. However, its application is limited by low potency and inefficiency in systemic delivery, especially failure to restore dystrophin in heart. Here, we conjugate a phosphorodiamidate morpholino oligomer with a designed cell-penetrating peptide (PPMO) targeting a mutated dystrophin exon. Systemic delivery of the novel PPMO restores dystrophin to almost normal levels in the cardiac and skeletal muscles in dystrophic mdx mouse. This leads to increase in muscle strength and prevents cardiac pump failure induced by dobutamine stress in vivo. Muscle pathology and function continue to improve during the 12-week course of biweekly treatment, with significant reduction in levels of serum creatine kinase. The high degree of potency of the oligomer in targeting all muscles and the lack of detectable toxicity and immune response support the feasibility of testing the novel oligomer in treating Duchenne muscular dystrophy patients.