Impact of Functional Mitral Regurgitation on Left Ventricular Strain in Nonischemic Dilated Cardiomyopathy Patients with Type 2 Mellitus Diabetes: A Magnetic Resonance Feature Tracking Study.

BACKGROUND: The impact of functional mitral regurgitation and type 2 mellitus diabetes (T2DM) on left ventricular (LV) strain in nonischemic dilated cardiomyopathy (NIDCM) patients remains unclear. PURPOSE: To evaluate the impact of mitral regurgitation severity on LV strain, and explore additive effect of T2DM on LV function across varying mitral regurgitation severity levels in NIDCM patients. STUDY TYPE: Retrospective. POPULATION: 352 NIDCM (T2DM-) patients (49.1 ± 14.6 years, 67% male) (207, 85, and 60 no/mild, moderate, and severe mitral regurgitation) and 96 NIDCM (T2DM+) patients (55.2 ± 12.4 years, 77% male) (47, 30, and 19 no/mild, moderate, and severe mitral regurgitation). FIELD STRENGTH/SEQUENCE: 3.0 T/balanced steady-state free precession sequence. ASSESSMENT: LV geometric parameters and strain were measured and compared among groups. Determinants of LV strain were investigated. STATISTICAL TEST: Student's t-test, Mann-Whitney U test, one-way ANOVA, Kruskal-Wallis test, univariable and multivariable linear regression. P < 0.05 was considered statistically significant. RESULTS: LV GLPS and longitudinal PDSR decreased gradually with increasing mitral regurgitation severity in NIDCM patients with T2DM(GLPS: -5.7% ± 2.1% vs. -4.3% ± 1.6% vs. -2.6% ± 1.3%; longitudinal PDSR:0.5 ± 0.2 sec-1 vs. 0.4 ± 0.2 sec-1 vs. 0.3 ± 0.1 sec-1). NIDCM (T2DM+) demonstrated decreased GCPS and GLPS in the no/mild subgroup, reduced LV GCPS, GLPS, and longitudinal PDSR in the moderate subgroup, and reduced GRPS, GCPS, GLPS, and longitudinal PDSR in the severe subgroup compared with NIDCM (T2DM-) patients. Multivariable regression analysis identified that mitral regurgitation severity (ß = -0.13, 0.15, and 0.25 for GRPS, GCPS, and GLPS) and the presence of T2DM (ß = 0.14 and 0.13 for GCPS and GLPS) were independent determinants of LV strains in NIDCM patients. DATA CONCLUSION: Increased mitral regurgitation severity is associated with reduced LV strains in NIDCM patients with T2DM. The presence of T2DM exacerbated the decline of LV function across various mitral regurgitation levels in NIDCM patients, resulting in reduced LV strains. TECHNICAL EFFICACY: Stage 3.

Progress in Cardiac Magnetic Resonance Feature Tracking for Evaluating Myocardial Strain in Type-2 Diabetes Mellitus.

The global prevalence of type-2 diabetes mellitus (T2DM) has caused harm to human health and economies. Cardiovascular disease is one main cause of T2DM mortality. Increased prevalence of diabetes and associated heart failure (HF) is common in older populations, so accurately evaluating heart-related injury and T2DM risk factors and conducting early intervention are important. Quantitative cardiovascular system imaging assessments, including functional imaging during cardiovascular disease treatment, are also important. The left-ventricular ejection fraction (LVEF) has been traditionally used to monitor cardiac function; it is often preserved or increased in early T2DM, but subclinical heart deformation and dysfunction can occur. Myocardial strains are sensitive to global and regional heart dysfunction in subclinical T2DM. Cardiac magnetic resonance feature-tracking technology (CMR-FT) can visualize and quantify strain and identify subclinical myocardial injury for early management, especially with preserved LVEF. Meanwhile, CMR-FT can be used to evaluate the multiple cardiac chambers involvement mediated by T2DM and the coexistence of complications. This review discusses CMR-FT principles, clinical applications, and research progress in the evaluation of myocardial strain in T2DM.

Assessment of left atrioventricular coupling and left atrial function impairment in diabetes with and without hypertension using CMR feature tracking.

PURPOSE: The study was designed to assess the effect of co-occurrence of diabetes mellitus (DM) and hypertension on the deterioration of left atrioventricular coupling index (LACI) and left atrial (LA) function in comparison to individuals suffering from DM only. METHODS: From December 2015 to June 2022, we consecutively recruited patients with clinically diagnosed DM who underwent cardiac magnetic resonance (CMR) at our hospital. The study comprised a total of 176 patients with DM, who were divided into two groups based on their blood pressure status: 103 with hypertension (DM + HP) and 73 without hypertension (DM-HP). LA reservoir function (reservoir strain (εs), total LA ejection fraction (LAEF)), conduit function (conduit strain (εe), passive LAEF), booster-pump function (booster strain (εa) and active LAEF), LA volume index (LAVI), LV global longitudinal strain (LVGLS), and LACI were evaluated and compared between the two groups. RESULTS: After adjusting for age, sex, body surface area (BSA), and history of current smoking, total LAEF (61.16 ± 14.04 vs. 56.05 ± 12.72, p = 0.013) and active LAEF (43.98 ± 14.33 vs. 38.72 ± 13.51, p = 0.017) were lower, while passive LAEF (33.22 ± 14.11 vs. 31.28 ± 15.01, p = 0.807) remained unchanged in the DM + HP group compared to the DM-HP group. The DM + HP group had decreased εs (41.27 ± 18.89 vs. 33.41 ± 13.94, p = 0.006), εe (23.69 ± 12.96 vs. 18.90 ± 9.90, p = 0.037), εa (17.83 ± 8.09 vs. 14.93 ± 6.63, p = 0.019), and increased LACI (17.40±10.28 vs. 22.72±15.01, p = 0.049) when compared to the DM-HP group. In patients with DM, multivariate analysis revealed significant independent associations between LV GLS and εs (ß=-1.286, p < 0.001), εe (ß=-0.919, p < 0.001), and εa (ß=-0.324, p = 0.036). However, there was no significant association observed between LV GLS and LACI (ß=-0.003, p = 0.075). Additionally, hypertension was found to independently contribute to decreased εa (ß=-2.508, p = 0.027) and increased LACI in individuals with DM (ß = 0.05, p = 0.011). CONCLUSIONS: In DM patients, LV GLS showed a significant association with LA phasic strain. Hypertension was found to exacerbate the decline in LA booster strain and increase LACI in DM patients, indicating potential atrioventricular coupling index alterations.

Biventricular Dysfunction and Ventricular Interdependence in Patients With Pulmonary Hypertension: A 3.0-T Cardiac MRI Feature Tracking Study.

BACKGROUND: Pulmonary hypertension (PH) results in right ventricular (RV) dysfunction, subsequently leading to left ventricular (LV) impairment. The mechanism underlying ventricular interdependence is largely uninvestigated. PURPOSE: To explore the biventricular dysfunction and the ventricular interdependence in PH patients. STUDY TYPE: Retrospective. POPULATION: One hundred and seven PH patients (mean pulmonary artery pressure >20 mmHg) and 72 age- and sex-matched controls with cardiac magnetic resonance imaging (MRI) studies. FIELD STRENGTH/SEQUENCE: 3.0 T/balanced steady-state free precession sequence. ASSESSMENT: LV and RV ejection fractions (EF) and RV and LV radial, circumferential, and longitudinal strains were assessed using commercial software. Strains were compared between controls, PH patients with preserved RVEF (RVEF ≥40%, N = 48), and PH patients with reduced RVEF (RVEF <40%, N = 59). STATISTICAL TESTS: Chi-squared tests or Fisher's exact test, t tests or Mann-Whitney U test, one-way ANOVA with Bonferroni's post hoc correction or Kruskal-Wallis test, Pearson or Spearman correlation, and multivariable linear regression analysis. A two-tailed P < 0.05 was deemed statistically significant. RESULTS: RV strain decreased sequentially from controls, through PH with preserved RVEF, to PH with reduced RVEF. PH patients with reduced RVEF had significantly lower LV strain, especially septal strain, and LV peak diastolic strain rate compared with both controls and PH patients with preserved RVEF. Multivariable analyses showed that RVEF was independently correlated with LV strain; furthermore, independent of RVEF, RV strain was significantly correlated with LV strain (LVGRS: ß = 0.416; LVGCS: ß = -0.371; LVGLS: ß = 0.283). DATA CONCLUSION: Subclinical impairment of RV function was found in PH with preserved RVEF. LV strain was impaired when RV was dysfunctional, which was associated with worsening RV strain. Therefore, while focusing on improving RV function, LV dysfunction in PH patients should also be monitored and treated early in order to slow the progression of the disease. LEVEL OF EVIDENCE: 3 TECHNICAL EFFICACY: Stage 3.

Aberrant RNA m6A modification in gastrointestinal malignancies: versatile regulators of cancer hallmarks and novel therapeutic opportunities.

Gastrointestinal (GI) cancer is one of the most common malignancies, and a leading cause of cancer-related death worldwide. However, molecular targeted therapies are still lacking, leading to poor treatment efficacies. As an important layer of epigenetic regulation, RNA N6-Methyladenosine (m6A) modification is recently linked to various biological hallmarks of cancer by orchestrating RNA metabolism, including RNA splicing, export, translation, and decay, which is partially involved in a novel biological process termed phase separation. Through these regulatory mechanisms, m6A dictates gene expression in a dynamic and reversible manner and may play oncogenic, tumor suppressive or context-dependent roles in GI tumorigenesis. Therefore, regulators and effectors of m6A, as well as their modified substrates, represent a novel class of molecular targets for cancer treatments. In this review, we comprehensively summarize recent advances in this field and highlight research findings that documented key roles of RNA m6A modification in governing hallmarks of GI cancers. From a historical perspective, milestone findings in m6A machinery are integrated with a timeline of developing m6A targeting compounds. These available chemical compounds, as well as other approaches that target core components of the RNA m6A pathway hold promises for clinical translational to treat human GI cancers. Further investigation on several outstanding issues, e.g. how oncogenic insults may disrupt m6A homeostasis, and how m6A modification impacts on the tumor microenvironment, may dissect novel mechanisms underlying human tumorigenesis and identifies next-generation anti-cancer therapeutics. In this review, we discuss advances in our understanding of m6A RNA modification since its discovery in the 1970s to the latest progress in defining its potential clinic relevance. We summarize the molecular basis and roles of m6A regulators in the hallmarks of GI cancer and discuss their context-dependent functions. Furthermore, the identification and characterization of inhibitors or activators of m6A regulators and their potential anti-cancer effects are discussed. With the rapid growth in this field there is significant potential for developing m6A targeted therapy in GI cancers.

Early evaluation of severe immune checkpoint inhibitor-associated myocarditis: a real-world clinical practice.

PURPOSE: Immune checkpoint inhibitor (ICI)-associated myocarditis is a rare but severe complication for patients treated with immunotherapy. This study aims to explore the predictive significance of patients' clinical features and examination results for the severity of ICI-associated myocarditis. METHODS: Data from a real-world cohort of 81 cancer patients who developed ICI-associated myocarditis after immunotherapy were retrospectively analyzed. The development of myocarditis of Common Terminology Criteria for Adverse Events (CTCAE) grades 3-5 and/or the major adverse cardiovascular event (MACE) was set as endpoints. Logistic regression was used to evaluate the predictive value of each factor. RESULTS: CTCAE grades 3-5 and MACE developed in 43/81 (53.1%) and 28/81 (34.6%) cases, respectively. The likelihood of CTCAE grades 3-5 and MACE increased with the accumulation of organs affected by the ICI-associated adverse events and initial clinical symptoms. Concurrent systematic therapies during ICI treatment did not raise the risk of myocarditis severity, while prior chemotherapy did. Besides classical serum cardiac markers, a higher neutrophil ratio was also related to poorer cardiac outcomes, whereas higher lymphocyte and monocyte ratios were predictors of favorable cardiac outcomes. The CD4+ T cell ratio and CD4/CD8 ratio were negatively related to CTCAE grades 3-5. Several cardiovascular magnetic resonance parameters were associated with myocarditis severity, whereas the predictive value of echocardiography and electrocardiogram was weak. CONCLUSION: This study comprehensively evaluated the prognostic value of patients' clinical characteristics and examination results and identified several predictors of severe ICI-associated myocarditis, which will facilitate early detection of severe ICI-associated myocarditis in patients receiving immunotherapy.

CT Radiomics Predict EGFR-T790M Resistance Mutation in Advanced Non-Small Cell Lung Cancer Patients After Progression on First-line EGFR-TKI.

RATIONALE AND OBJECTIVES: We aim to explore the value of chest CT radiomics in predicting the epidermal growth factor receptor (EGFR)-T790M resistance mutation of advanced non-small cell lung cancer (NSCLC) patients after the failure of first-line EGFR-tyrosine kinase inhibitor (EGFR-TKI). MATERIALS AND METHODS: A total of 211 and 135 advanced NSCLC patients with tumor tissue-based (Cohort-1) or circulating tumor DNA (ctDNA)-based (Cohort-2) EGFR-T790M testing were included, respectively. Cohort-1 was used for modeling and Cohort-2 was for models' validation. Radiomic features were extracted from tumor lesions on chest nonenhanced CT (NECT) and/or contrast-enhanced CT (CECT). We used eight feature selectors and eight classifier algorithms to establish radiomic models. Models were evaluated by area under the receiver operating characteristic curve (AUC), calibration curve, and decision curve analysis (DCA). RESULTS: CT morphological manifestations of peripheral location and pleural indentation sign were associated with EGFR-T790M. For NECT, CECT, and NECT+CECT radiomic features, the feature selector and classifier algorithms of LASSO and Stepwise logistic regression, Boruta and SVM, and LASSO and SVM were chosen to develop the optimal model, respectively (AUC: 0.844, 0.811, and 0.897). All models performed well in calibration curves and DCA. Independent validation of models in Cohort-2 revealed that both NECT and CECT models individually had limited power for predicting EGFR-T790M mutation detected by ctDNA (AUC: 0.649, 0.675), while the NECT+CECT radiomic model had a satisfactory AUC (0.760). CONCLUSION: This study proved the feasibility of using CT radiomic features to predict the EGFR-T790M resistance mutation, which could be helpful in guiding personalized therapeutic strategies.

Early longitudinal changes in left ventricular function and morphology in diabetic pigs: evaluation by 3.0T magnetic resonance imaging.

BACKGROUND: Previous researches on large animal models of diabetic cardiomyopathy were insufficient. The aim of this study was to evaluate early changes in left ventricular (LV) function and morphology in diabetic pigs using a cardiac magnetic resonance (CMR) time-volume curve and feature tracking technique. METHODS: Streptozotocin (STZ) was used to induce diabetic in sixteen pigs. 3.0T MRI scanned the pig's heart before and 2, 6, 10 and 16 months after modelling. CMR biomarkers, including time-volume curve and myocardial strain, were compared to analyse the longitudinal changes in LV function and morphology. Pearson correlation was used to evaluate the relationship between LV strain and remodelling. Cardiac specimens were obtained at 6, 10, and 16 months after modelling to observe the myocardial ultrastructural and microstructure at different courses of diabetes. RESULTS: Twelve pigs developed diabetes. The 80% diastolic volume recovery rate (DVR) at 6 months after modelling was significantly higher than that before modelling (0.78 ± 0.08vs. 0.67 ± 0.15). The LV global longitudinal peak strain (GLPS) (- 10.21 ± 3.15 vs. - 9.74 ± 2.78 vs. - 9.38 ± 3.71 vs. - 8.71 ± 2.68 vs. - 6.59 ± 2.90%) altered gradually from the baseline data to 2, 6, 10 and 16 months after modelling. After 16 months of modelling, the LV remodelling index (LVRI) of pigs increased compared with that before modelling (2.19 ± 0.97 vs. 1.36 ± 0.45 g/ml). The LVRI and myocardial peak strain were correlated in diabetic pigs (r= - 0.40 to - 0.54), with GLPS being the most significant. Electron microscopy and Masson staining showed that myocardial damage and fibrosis gradually increased with the progression of the disease. CONCLUSION: Intravenous injection of STZ can induce a porcine diabetic cardiomyopathy model, mainly characterized by decreased LV diastolic function and strain changes accompanied by myocardial remodelling. The changes in CMR biomarkers could reflect the early myocardial injury of diabetic cardiomyopathy.

Effect of Metabolic Dysfunction-Associated Fatty Liver Disease on Left Ventricular Deformation and Atrioventricular Coupling in Patients With Metabolic Syndrome Assessed by MRI.

BACKGROUND: Metabolic dysfunction-associated fatty liver disease (MAFLD) was recently recognized as an important risk factor for cardiovascular diseases. PURPOSE: To examine the effect of MAFLD on cardiac function in metabolic syndrome by MRI. STUDY TYPE: Retrospective. POPULATION: One hundred seventy-nine patients with metabolic syndrome (MetS), 101 with MAFLD (MAFLD [+]) and 78 without (MAFLD [-]). Eighty-one adults without any of the components of MetS or cardiac abnormalities were included as control group. FIELD STRENGTH/SEQUENCE: 3.0 T; balanced steady-state free precession sequence. ASSESSMENT: Left atrial (LA) strain was assessed during three phases: reservoir strain (LA-RS), conduit strain (LA-CS), and booster strain (LA-BS). Left ventricular (LV) global longitudinal (LV-GLS) strain was also derived. The left atrioventricular coupling index (LACI) was calculated as the ratio of LA end-diastolic volume (LA-EDV) and LV-EDV. STATISTICAL TESTS: Student's t test or Mann-Whitney U test; One-way analysis of variance. A P value <0.05 was considered statistically significant. RESULTS: Among MetS patients, individuals with MAFLD had significantly lower magnitude LV-GLS (-11.6% ± 3.3% vs. -13.8% ± 2.7%) than those without MAFLD. For LA strains, LA-RS (36.9% ± 13.7% vs. 42.9% ± 13.5%) and LA-CS (20.0% ± 10.6% vs. 24.1% ± 9.2%) were also significantly reduced in MAFLD (+) compared to MAFLD (-). The LACIs (17.2% [12.9-21.2] % vs. 15.8% [12.2-19.7] %) were significantly higher in patients with MAFLD compared to those without MAFLD. After adjustment for other clinical factors, MAFLD was found to be independently correlated with LV-GLS (ß = -0.270) and LACI (ß = 0.260). DATA CONCLUSION: MAFLD had an unfavorable effect on LV myocardial strain in MetS. Moreover, LA strain and atrioventricular coupling were further impaired in patients with concomitant MAFLD compared to those without MAFLD. Last, MAFLD was independently associated with subclinical LV dysfunction and atrioventricular coupling after adjustment for other clinical factors. EVIDENCE LEVEL: 3 TECHNICAL EFFICACY: 3.

Additive effect of aortic regurgitation degree on left ventricular strain in patients with type 2 diabetes mellitus evaluated via cardiac magnetic resonance tissue tracking.

BACKGROUND: Type 2 diabetes mellitus causes left ventricular (LV) remodeling and increases the risk of aortic regurgitation (AR), which causes further heart damage. This study aimed to investigate whether AR aggravates LV deformation dysfunction and to identify independent factors affecting the global peak strain (PS) of LV remodeling in patients with type 2 diabetes mellitus (T2DM) who presented with AR and those without T2DM. METHODS: In total, 215 patients with T2DM and 83 age- and sex-matched healthy controls who underwent cardiac magnetic resonance examination were included. Based on the echocardiogram findings, T2DM patients with AR were divided into three groups (mild AR [n = 28], moderate AR [n = 21], and severe AR [n = 17]). LV function and global strain parameters were compared, and multivariate analysis was performed to identify the independent indicators of LV PS. RESULTS: The T2DM patients with AR had a lower LV global PS, peak systolic strain rate (PSSR), and peak diastolic strain rate (PDSR) in three directions than those without AR and non-T2DM controls. Patients without AR had a lower PS (radial and longitudinal) and PDSR in three directions and higher PSSR (radial and longitudinal) than healthy controls. Further, regurgitation degree was an independent factor of LV global radial, circumferential, and longitudinal PS. CONCLUSION: AR may aggravate LV stiffness in patients with T2DM, resulting in lower LV strain and function. Regurgitation degree and sex were independently correlated with LV global PS in patients with T2DM and AR.

SHARPIN stabilizes ß-catenin through a linear ubiquitination-independent manner to support gastric tumorigenesis.

BACKGROUND: Aberrant activation of Wnt/ß-catenin signaling by dysregulated post-translational protein modifications, especially ubiquitination is causally linked to cancer development and progression. Although Lys48-linked ubiquitination is known to regulate Wnt/ß-catenin signaling, it remains largely obscure how other types of ubiquitination, such as linear ubiquitination governs its signaling activity. METHODS: The expression and regulatory mechanism of linear ubiquitin chain assembly complex (LUBAC) on Wnt/ß-catenin signaling was examined by immunoprecipitation, western blot and immunohistochemical staining. The ubiquitination status of ß-catenin was detected by ubiquitination assay. The impacts of SHARPIN, a core component of LUBAC on malignant behaviors of gastric cancer cells were determined by various functional assays in vitro and in vivo. RESULTS: Unlike a canonical role in promoting linear ubiquitination, SHARPIN specifically interacts with ß-catenin to maintain its protein stability. Mechanistically, SHARPIN competes with the E3 ubiquitin ligase ß-Trcp1 for ß-catenin binding, thereby decreasing ß-catenin ubiquitination levels to abolish its proteasomal degradation. Importantly, SHARPIN is required for invasiveness and malignant growth of gastric cancer cells in vitro and in vivo, a function that is largely dependent on its binding partner ß-catenin. In line with these findings, elevated expression of SHARPIN in gastric cancer tissues is associated with disease malignancy and correlates with ß-catenin expression levels. CONCLUSIONS: Our findings reveal a novel molecular link connecting linear ubiquitination machinery and Wnt/ß-catenin signaling via SHARPIN-mediated stabilization of ß-catenin. Targeting the linear ubiquitination-independent function of SHARPIN could be exploited to inhibit the hyperactive ß-catenin signaling in a subset of human gastric cancers.

BRD4 Promotes Gastric Cancer Progression and Metastasis through Acetylation-Dependent Stabilization of Snail.

Cancer metastasis, a leading cause of death in patients, is associated with aberrant expression of epigenetic modifiers, yet it remains poorly defined how epigenetic readers drive metastatic growth and whether epigenetic readers are targetable to control metastasis. Here, we report that bromodomain-containing protein 4 (BRD4), a histone acetylation reader and emerging anticancer therapeutic target, promotes progression and metastasis of gastric cancer. The abundance of BRD4 in human gastric cancer tissues correlated with shortened metastasis-free gastric cancer patient survival. Consistently, BRD4 maintained invasiveness of cancer cells in vitro and their dissemination at distal organs in vivo. Surprisingly, BRD4 function in this context was independent of its putative transcriptional targets such as MYC or BCL2, but rather through stabilization of Snail at posttranslational levels. In an acetylation-dependent manner, BRD4 recognized acetylated lysine 146 (K146) and K187 on Snail to prevent Snail recognition by its E3 ubiquitin ligases FBXL14 and ß-Trcp1, thereby inhibiting Snail polyubiquitination and proteasomal degradation. Accordingly, genome-wide transcriptome analyses identified that BRD4 and Snail regulate a partially shared metastatic gene signature in gastric cancer cells. These findings reveal a noncanonical posttranscriptional regulatory function of BRD4 in maintaining cancer growth and dissemination, with immediate translational implications for treating gastric metastatic malignancies with clinically available bromodomain inhibitors. SIGNIFICANCE: These findings reveal a novel posttranscriptional regulatory function of the epigenetic reader BRD4 in cancer metastasis via stabilizing Snail, with immediate translational implication for treating metastatic malignancies with clinically available bromodomain inhibitors. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/79/19/4869/F1.large.jpg.