ER-resident STIM1/2 couples Ca2+ entry by NMDA receptors to pannexin-1 activation.

Pannexin-1 (Panx1) is a large-pore ion and solute permeable channel highly expressed in the nervous system, where it subserves diverse processes, including neurite outgrowth, dendritic spine formation, and N-methyl D-aspartate (NMDA) receptor (NMDAR)-dependent plasticity. Moreover, Panx1 dysregulation contributes to neurological disorders, including neuropathic pain, epilepsy, and excitotoxicity. Despite progress in understanding physiological and pathological functions of Panx1, the mechanisms that regulate its activity, including its ion and solute permeability, remain poorly understood. In this study, we identify endoplasmic reticulum (ER)-resident stromal interaction molecules (STIM1/2), which are Ca2+ sensors that communicate events within the ER to plasma membrane channels, as binding and signaling partners of Panx1. We demonstrate that Panx1 is activated to its large-pore configuration in response to stimuli that recruit STIM1/2 and map the interaction interface to a hydrophobic region within the N terminus of Panx1. We further characterize a Panx1 N terminus-recognizing antibody as a function-blocking tool able to prevent large-pore Panx1 activation by STIM1/2. Using either the function-blocking antibody or re-expression of Panx1 deletion mutants in Panx1 knockout (KO) neurons, we show that STIM recruitment couples Ca2+ entry via NMDARs to Panx1 activation, thereby identifying a model of NMDAR-STIM-Panx1 signaling in neurons. Our study highlights a previously unrecognized and important role of the Panx1 N terminus in regulating channel activation and membrane localization. Considering past work demonstrating an intimate functional relation between NMDARs and Panx1, our study opens avenues for understanding activation modality and context-specific functions of Panx1, including functions linked to diverse STIM-regulated cellular responses.

3D Fractal Dimension Analysis: Prognostic Value of Right Ventricular Trabecular Complexity in Participants with Arrhythmogenic Cardiomyopathy.

BACKGROUND: Arrhythmogenic cardiomyopathy (ACM) is characterized by progressive myocardial fibro-fatty infiltration accompanied by trabecular disarray. Traditionally, two-dimensional (2D) instead of 3D fractal dimension (FD) analysis has been used to evaluate trabecular disarray. However, the prognostic value of trabecular disorder assessed by 3D FD measurement remains unclear. PURPOSE: To investigate the prognostic value of right ventricular trabecular complexity in ACM patients using 3D FD analysis based on cardiac MR cine images. STUDY TYPE: Retrospective. POPULATION: 85 ACM patients (mean age: 45 ± 17 years, 52 male). FIELD STRENGTH/SEQUENCE: 3.0T/cine imaging, T2-short tau inversion recovery (T2-STIR), and late gadolinium enhancement (LGE). ASSESSMENT: Using cine images, RV (right ventricular) volumetric and functional parameters were obtained. RV trabecular complexity was measured with 3D fractal analysis by box-counting method to calculate 3D-FD. Cox and logistic regression models were established to evaluate the prognostic value of 3D-FD for major adverse cardiac events (MACE). STATISTICAL TESTS: Cox regression and logistic regression to explore the prognostic value of 3D-FD. C-index, time-dependent receiver operating characteristic (ROC) curves and area under the ROC curve (AUC) to evaluate the incremental value of 3D-FD. Intraclass correlation coefficient for interobserver variability. P < 0.05 indicated statistical significance. RESULTS: 26 MACE were recorded during the 60 month follow-up (interquartile range: 48-67 months). RV 3D-FD significantly differed between ACM patients with MACE (2.67, interquartile range: 2.51 ~ 2.81) and without (2.52, interquartile range: 2.40 ~ 2.67) and was a significant independent risk factor for MACE (hazard ratio, 1.02; 95% confidence interval: 1.01, 1.04). In addition, prognostic model fitness was significantly improved after adding 3D-FD to RV global longitudinal strain, LV involvement, and 5-year risk score separately. DATA CONCLUSION: The myocardial trabecular complexity assessed through 3D FD analysis was found associated with MACE and provided incremental prognostic value beyond conventional ACM risk factors. EVIDENCE LEVEL: 4 TECHNICAL EFFICACY: Stage 1.

Prognostic value of right ventricular trabecular complexity in patients with arrhythmogenic cardiomyopathy.

OBJECTIVES: The present study aimed to investigate the incremental prognostic value of the right ventricular fractal dimension (FD), a novel marker of myocardial trabecular complexity by cardiac magnetic resonance (CMR) in patients with arrhythmogenic cardiomyopathy (ACM). METHODS: Consecutive patients with ACM undergoing CMR were followed up for major cardiac events, including sudden cardiac death, aborted cardiac arrest, and appropriate implantable cardioverter defibrillator intervention. Prognosis prediction was compared by Cox regression analysis. We established a multivariable model supplemented with RV FD and evaluated its discrimination by Harrell's C-statistic. We compared the category-free, continuous net reclassification improvement (cNRI) and integrated discrimination index (IDI) before and after the addition of FD. RESULTS: A total of 105 patients were prospectively included from three centers and followed up for a median of 60 (48, 66) months; experienced 36 major cardiac events were recorded. Trabecular FD displayed a strong unadjusted association with major cardiac events (p < 0.05). In the multivariable Cox regression analysis, RV maximal apical FD maintained an independent association with major cardiac events (hazard ratio, 1.31 (1.11-1.55), p < 0.002). The Hosmer-Lemeshow goodness of fit test displayed good fit (X2 = 0.68, p = 0.99). Diagnostic performance was significantly improved after the addition of RV maximal apical FD to the multivariable baseline model, and the continuous net reclassification improvement increased 21% (p = 0.001), and the integrated discrimination index improved 16% (p = 0.045). CONCLUSIONS: In patients with ACM, CMR-assessed myocardial trabecular complexity was independently correlated with adverse cardiovascular events and provided incremental prognostic value. CLINICAL RELEVANCE STATEMENT: The application of FD values for assessing RV myocardial trabeculae may become an accessible and promising parameter in monitoring and early diagnosis of risk factors for adverse cardiovascular events in patients with ACM. KEY POINTS: • Ventricular trabecular morphology, a novel quantitative marker by CMR, has been explored for the first time to determine the severity of ACM. • Patients with higher maximal apical fractal dimension of RV displayed significantly higher cumulative incidence of major cardiac events. • RV maximal apical FD was independently associated with major cardiac events and provided incremental prognostic value in patients with ACM.

Prognostic value of left ventricular trabeculae fractal analysis in patients with dilated cardiomyopathy.

BACKGROUND: The prognostic value of left ventricular (LV) myocardial trabecular complexity on cardiovascular magnetic resonance (CMR) in dilated cardiomyopathy (DCM) remains unknown. This study aimed to evaluate the prognostic value of LV myocardial trabecular complexity using fractal analysis in patients with DCM. METHODS: Consecutive patients with DCM who underwent CMR between March 2017 and November 2021 at two hospitals were prospectively enrolled. The primary endpoints were defined as the combination of all-cause death and heart failure hospitalization. The events of cardiac death alone were defined as the secondary endpoints.LV trabeculae complexity was quantified by measuring the fractal dimension (FD) of the endocardial border based on fractal geometry on CMR. Cox proportional hazards regression and Kaplan-Meier survival analysis were used to examine the association between variables and outcomes. The incremental prognostic value of FD was assessed in nested models. RESULTS: A total of 403 patients with DCM (49.31 ± 14.68 years, 69% male) were recruited. After a median follow-up of 43 months (interquartile range, 28-55 months), 87 and 24 patients reached the primary and secondary endpoints, respectively. Age, heart rate, New York Heart Association functional class >II, N-terminal pro-B-type natriuretic peptide, LV ejection fraction, LV end-diastolic volume index, LV end-systolic volume index, LV mass index, presence of late gadolinium enhancement, global FD, LV mean apical FD, and LV maximal apical FD were univariably associated with the outcomes (all P < 0.05). After multivariate adjustment, LV maximal apical FD remained a significant independent predictor of outcome [hazard ratio = 1.179 (1.116, 1.246), P < 0.001]. The addition of LV maximal apical FD in the nested models added incremental prognostic value to other common clinical and imaging risk factors (all <0.001; C-statistic: 0.84-0.88, P < 0.001). CONCLUSION: LV maximal apical FD was an independent predictor of the adverse clinical outcomes in patients with DCM and provided incremental prognostic value over conventional clinical and imaging risk factors.

Creatine chemical exchange saturation transfer (CEST) CMR imaging reveals myocardial early involvement in idiopathic inflammatory myopathy at 3T: feasibility and initial experience.

OBJECTIVES: To measure creatine distribution in idiopathic inflammatory myopathy (IIM) patients' myocardial segments and investigate whether cardiovascular magnetic resonance (CMR) chemical exchange saturation transfer (CEST) creatine mapping can detect subclinical myocardial changes, CEST's ability was further compared with other conventional CMR mapping sequences. METHODS: Forty IIM patients (53.5 ± 10.5 years, 26 males) and eight healthy controls (35.4 ± 6 years, 5 males) underwent CMR scans on a 3.0-T MR scanner. Patients with IIM were further classified into two subgroups according to cardiac troponin T (cTn-T) values: the elevated cTn-T subgroup (n = 14) and the normal cTn-T subgroup (n = 26). Cine imaging, T2 SPAIR, LGE imaging, T1 mapping, T2 mapping, and Cr (creatine) CEST were performed. RESULTS: Cr mapping showed significantly reduced creatine in IIM patients among global myocardium (IIM: 0.109 ± 0.063, controls: 0.121 ± 0.021, p < 0.05), and decreased creatine signals were detected in all 16 cardiac segments (p < 0.05). Patients also had significantly prolonged native T1 and decreased enhanced T1 values in each cardiac segment (p < 0.05). There was no significant difference of LVEF and T2 values between IIM patients and controls. Between the two subgroups, elevated cTn-T was linked with creatine and extracellular volume fraction (ECV) values, providing a global average creatine signal of 0.107 vs 0.112 (p < 0.05) and 24.7 vs 32.4 (p < 0.05). CONCLUSION: Creatine CEST mapping can detect early-stage heart involvement with negative LGE findings in IIM. Compared with T1 mapping, CEST provides increased sensitivity to ECV measurement, making it significantly better than T1, and a promising CMR sequence for screening subclinical myocardial damage. KEY POINTS: • IIM patients with potential or ongoing heart involvement, elevated ECV, and reduced Cr CEST values could provide valuable information. • ECV and Cr CEST values were closely related to elevated cTn-T.

A Radiomic MRI based Nomogram for Prediction of Heart Failure with Preserved Ejection Fraction in Systemic Lupus Erythematosus Patients: Insights From a Three-Center Prospective Study.

BACKGROUND: Myocardial T1 and extracellular volume (ECV) fraction values have important roles in the prognostication of heart failure with preserved ejection fraction (HFpEF). However, the traditional mean quantification of intensity levels is not sufficient. PURPOSE: To evaluate a T1 map-based radiomic nomogram as a long-term prognosticator for HFpEF in systemic lupus erythematosus (SLE) patients. STUDY TYPE: Prospective. POPULATION: A total of 115 SLE patients and 50 age- and gender-matched controls. FIELD STRENGTH/SEQUENCE: A 3.0 T scanner; cine imaging, precontrast and post-contrast T1 mapping and T2 mapping sequences. ASSESSMENT: A radiomic nomogram was developed based on precontrast T1 mapping. Three independent readers assessed and compared the ECV value and the value of the radiomic nomogram for predicting HFpEF in SLE patients. STATISTICAL TEST: Cox proportional hazard models, Youden index for determining cut-off values for high HFpEF risk vs. low HFpEF risk classification, Kaplan-Meier analysis, intraclass correlation (ICC), and Uno C statistic test. RESULTS: During a median follow-up of 27 (interquartile range, 19-37) months, 31 SLE patients developed HFpEF. Patients with elevated ECV (≥31%) and a higher output (≥42.7) from the radiomic feature "S_33_sum average" of the precontrast T1 map had a significantly higher risk of developing HFpEF than those who had lower ECV (<31%) and an output <42.7. Patients with a higher "S_33_sum average" value on precontrast T1 map had a significantly increased risk for HFpEF (hazard ratio, 1.363, 95% CI, 1.130-1.645), after adjusting for covariates including ECV and LVEF. Finally, "S_33_sum average" from precontrast T1 mapping had modest but significantly incremental prognostic value over the mean ECV value (Uno C statistic comparing models, 0.860 vs. 0.835). DATA CONCLUSION: The precontrast T1 map-based radiomic nomogram, as a measure of diffuse myocardial fibrosis was associated with HFpEF and provided modest prognostic value for predicting HFpEF in SLE patients. EVIDENCE LEVEL: 1 TECHNICAL EFFICACY: Stage 2.

Myocardial extracellular volume fraction radiomics analysis for differentiation of reversible versus irreversible myocardial damage and prediction of left ventricular adverse remodeling after ST-elevation myocardial infarction.

OBJECTIVES: Our study sought to explore the prognostic value of radiomic TA (texture analysis) on quantitative ECV (extracellular volume) fraction mapping to differentiate between reversible and irreversible myocardial damage and to predict left ventricular adverse remodeling in patients with reperfused STEMI (ST-elevation myocardial infarction). METHODS: This observational prospective cohort study identified 70 patients (62 ± 9 years, 62 men [85.70%]) with STEMI for TA who consecutively performed native and contrast T1 mapping. Texture features were extracted from each stack of ECV mapping based on ROI (region of interest) analysis. RESULTS: After texture feature selection and dimension reduction, five selected texture features were found to be statistically significant for differentiating the extent of myocardial injury. ROC (receiver operating characteristic) curve analysis for the differentiation of unsalvageable infarction and salvageable myocardium demonstrated a significantly higher AUC (area under the curve) (0.91 [95% CI, 0.86-0.96], p < 0.0001) for horizontal fraction than other texture features (p < 0.05). LVAR (left ventricular adverse remodeling) was predicted by those selected features. The differences in qualitative and quantitative baseline parameters and horizontal fractions were significant between the patients with and without LVAR. LGE (late gadolinium enhancement) and horizontal fraction features of infarcted myocardium in acute STEMI were the only two parameters selected in forming the optimal overall multivariable model for LVAR at 6 months. CONCLUSIONS: Radiomic analysis of ECV could discriminate reversible from irreversible myocardial injury after STEMI. LGE as well as radiomics TA (texture analysis) of ECV may provide an alternative to predict LVAR and functional recovery. KEY POINTS: • ECV quantification was able to differentiate between infarcted myocardium and non-infarcted myocardium. • Radiomics analysis of ECV could discriminate reversible from irreversible myocardial injury. • Radiomics TA analysis shows a promising similarity with LGE findings which could aid the prognosis of myocardial infarction patients.

Histogram Analysis of Native T1 Mapping and Its Relationship to Left Ventricular Late Gadolinium Enhancement, Hypertrophy, and Segmental Myocardial Mechanics in Patients With Hypertrophic Cardiomyopathy.

BACKGROUND: The use of native T1 mapping for evaluation of hypertrophic cardiomyopathy (HCM) is being explored, and its combination with histogram analysis may benefit the accuracy of such assessments. PURPOSE: To investigate the relationship of segmental left ventricular wall thickness (LVWT), myocardial fibrosis, and strain parameters with segmental histogram parameters of native T1 mapping in HCM patients. STUDY TYPE: Retrospective. SUBJECTS: Ninety-three HCM patients without previous cardiovascular diseases were included. FIELD STRENGTH/SEQUENCE: 3.0T cardiac MR. Steady-state free precession cine imaging, modified Look-Locker inversion recovery, phase-sensitive inversion recovery. ASSESSMENT: Images were assessed by three experienced radiologists. STATISTICAL TESTS: Mann-Whitney U-tests, area under the curve (AUC), Spearman's rank correlation, intraclass correlation coefficient, and Bland-Altman test were used for statistical analysis. RESULTS: A higher LVWT value correlated with higher means, minimums, 10th /25th /50th /75th /90th percentiles, maximums, kurtosis, entropy, and lower SD and energy of T1 mapping (P < 0.05 for all), with the correlation being stronger for entropy and energy (Spearman's rho = 0.439 and -0.413, respectively) than other parameters. Late gadolinium enhancement positive (LGE+) segments exhibited higher mean, minimum, 10th /25th /50th /75th /90th percentiles, maximum, entropy, and lower energy of T1 times than late gadolinium enhancement negative (LGE-) segments (P < 0.001 for all). Impaired strain function parameters (peak thickening and thickening rate in radial, circumferential, and longitudinal directions) demonstrated a weak correlation with higher entropy (P < 0.001 for all) and lower energy (P < 0.001 for all). DATA CONCLUSION: Histogram parameters of native T1 mapping provide more information than mean T1 times alone. Among these parameters, entropy and energy may correlate better with LVWT, myocardial late gadolinium enhancement, and strain parameters than mean T1 times in HCM patients. LEVEL OF EVIDENCE: 2 Technical Efficacy Stage: 2 J. Magn. Reson. Imaging 2019;49:668-677.

BOLD cardiac MRI for differentiating reversible and irreversible myocardial damage in ST segment elevation myocardial infarction.

OBJECTIVES: BOLD imaging is a quantitative MRI technique allowing the evaluation of the balance between supply/demand in myocardial oxygenation and myocardial haemorrhage. We sought to investigate the ability of BOLD imaging to differentiate reversible from irreversible myocardial injury as well as the chronological progression of myocardial oxygenation after reperfusion in patients with ST segment elevation myocardial infarction (STEMI). METHODS: Twenty-two patients (age, 60 ± 11 years; 77.3% male) with STEMI underwent cardiac MRIs on four occasions: on days 1, 3, 7 and 30 after reperfusion. BOLD MRI was obtained with a multi-echo turbo field echo (TFE) sequence on a 3-T scanner to assess myocardial oxygenation in MI. RESULTS: T2* value in MI with intramyocardial haemorrhage (IMH) was the lowest (9.77 ± 3.29 ms), while that of the salvaged zone was the highest (33.97 ± 3.42 ms). T2* values in salvaged myocardium demonstrated a unimodal temporal pattern from days 1 (37.91 ± 2.23 ms) to 30 (30.68 ± 1.59 ms). T2* values in the MI regions were significantly lower than those in remote myocardium, although the trends in both were constant overall. There was a slightly positive correlation between T2* in MI regions and EF (Rho = 0.27, p < 0.05) or SV (Rho = 0.22, p = 0.04) and a slightly negative correlation between T2* in salvaged myocardium and LVEDV (Rho = - 0.23, p < 0.05). CONCLUSIONS: BOLD MRI performed in post-STEMI patients allows accurate evaluation of myocardial damage severity and could differentiate reversible from irreversible myocardial injury. The increased T2* values may imply the pathophysiological mechanism of salvaged myocardium. BOLD MRI could represent a more accurate alternative to the other currently available options. KEY POINTS: • Myocardial oxygenation and haemorrhage after myocardial infarction affect BOLD MRI values • BOLD MRI could be used to differentiate irreversible from reversible myocardial damage • Changed oxygenation implies the pathophysiological mechanism of salvaged myocardium.

Diagnostic performance of intravoxel incoherent motion diffusion-weighted imaging in the assessment of the dynamic status of myocardial perfusion.

BACKGROUND: Acute myocardial infarction (AMI) is a major cause of morbidity and mortality worldwide and places a significant financial burden on our society. PURPOSE: To determine the feasibility of cardiac intravoxel incoherent motion (IVIM) in the consecutive evaluation of myocardial perfusion in myocardial infarction patients postpercutaneous coronary intervention (PCI) and to investigate the dynamic biological phenomena in myocardial perfusion after AMI. STUDY TYPE: Prospective observational study. POPULATION: Twenty ST-segment elevation myocardial infarction (STEMI) patients after reperfusion therapy and 12 healthy volunteers served as controls. FIELD STRENGTH/SEQUENCE: Cardiac MRI at 3T, including steady-state free precession (SSFP) cine imaging, T2 -short time inversion recovery (T2 -STIR), late gadolinium enhancement (LGE), T2 mapping, and IVIM diffusion-weighted imaging (DWI) were performed. ASSESSMENT: Myocardial T2 value and IVIM-DWI-associated parameters (ADCfast , ADCslow , and f value) of the infarcted myocardium at different timepoints, remote myocardium, and normal myocardium were analyzed by two experienced radiologists. STATISTICAL TESTS: Independent sample's t-test, Pearson's, and Spearman's correlation and interobserver variability were applied. P ≤ 0.05 was considered significant. RESULTS: The T2 value in ischemic myocardium measured on day 3 (73.58 ± 4.37 msec) was greater than at any other timepoint (24 hours, day 7, day 30; 66.66 ± 4.71 msec, 68.36 ± 4.18 msec, 64.98 ± 5.39 msec, respectively, P < 0.001). ADCfast and f values were significantly lower in ischemic myocardium than in the remote myocardium as well. The f value in ischemic myocardium at day 3 (0.0989 ± 0.02) was lower than at any other timepoint (24 hours, 7 day, 30 day; 0.1203 ± 0.02, 0.1109 ± 0.02, 0.1213 ± 0.02, respectively, P < 0.001. DATA CONCLUSION: This preliminary study demonstrated that a dynamic process exists in the status of myocardial edema and myocardial perfusion in MI patients after PCI. The findings suggest myocardial perfusion would be best evaluated between day 3 and day 7. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018;48:1602-1609.

Myocardial fibrosis evaluated by diffusion-weighted imaging and its relationship to 3D contractile function in patients with hypertrophic cardiomyopathy.

BACKGROUND: Previous studies have shown that diffusion-weighted imaging (DWI) is sensitive to myocardial fibrosis in ischemic and nonischemic cardiomyopathy. PURPOSE: To explore the prognostic value of apparent diffusion coefficient (ADC) for detecting myocardial fibrosis and its relationship to the contractile function in hypertrophic cardiomyopathy (HCM). STUDY TYPE: Prospective. POPULATION: A total of 45 HCM patients and 20 controls. FIELD STRENGTH/SEQUENCE: 3.0T cardiac MRI. The cardiac MR sequences included cine, T1 mapping, and DWI. ASSESSMENT: According to the presence of late gadolinium enhancement (LGE) and the extracellular volume (ECV) values (+2 SD of control subjects), respectively, reader W and reader J assessed the value of ADC of each segment for detecting myocardial fibrosis and its relationship to impaired contractile function in HCM patients. STATISTICAL TESTS: Independent sample t-test, Pearson analysis, and intraclass correlation (ICC). RESULTS: The value of ECV was 23.6 ± 3.0% for control. ECV ≥ 29.6% and ECV < 29.6% groups were classified. ADC values in the ECV ≥ 29.6% group were significantly increased compared to the ECV < 29.6% group, (2.41 ± 0.23 µm2 /ms vs. 2.03 ± 0.16 µm2 /ms, P < 0.005). Compared to the LGE - group, ECV (32.1 ± 2.3% vs. 29.0 ± 2.8%, P < 0.005) and ADC (2.60 ± 0.18 µm2 /ms vs. 2.10 ± 0.07 µm2 /ms, P < 0.005) values were significantly increased in the LGE + group. ADC values were linearly associated with ECV values (R2 = 0.65) in HCM patients. ADC values were linearly associated with circumferential and longitudinal strain (R2 = 0.60, R2 = 0.46), as well as circumferential, longitudinal, and radial strain rate (R2 = 0.13, R2 = 0.25, R2 = 0.17, respectively). DATA CONCLUSION: Contractile dysfunction in HCM is predominantly associated with ADC, which is a feasible alternative to ECV and LGE for detecting myocardial fibrosis. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018;48:1139-1146.

Oxygenation-sensitive cardiovascular magnetic resonance in hypertensive heart disease with left ventricular myocardial hypertrophy and non-left ventricular myocardial hypertrophy: Insight from altered mechanics and cardiac BOLD imaging.

BACKGROUND: BOLD (blood oxygen level dependent) MRI can detect regional condition of myocardial oxygen supply and demand by means of paramagnetic properties. PURPOSE: Noninvasive assessment of myocardial oxygenation by BOLD MRI in hypertensive patients with hypertension (HTN) left ventricular myocardial hypertrophy (LVMH) and HTN non-LVMH and its correlation with myocardial mechanics were performed. STUDY TYPE: Prospective. POPULATION: Twenty patients with HTN LVMH, 21 patients with HTN non-LVMH, and 23 normotensive controls were enrolled. FIELD STRENGTH/SEQUENCE: Cine imaging, T2* and T1 mapping sequences were achieved at 3.0T. ASSESSMENT: Dedicated T1 mapping, T2*, and cine imaging analysis were performed by two radiologists using cvi42. STATISTICAL TESTS: One-way analysis of variance, Kruskal-Wallis test, Bland-Altman analysis, Pearson's correlation coefficient, Spearman's rank correlation. RESULTS: T2* values of HTN LVMH group were significantly lower versus the controls (23.78 ± 3.09 versus 30.77 ± 2.71; P < 0.001) and HTN non-LVMH group (23.78 ± 3.09 versus 28.64 ± 4.23; P < 0.001). Left ventricular peak circumferential strain were reduced in HTN LVMH patients compared with other two groups (-11.32 [-15.64, -10.3], -16.78 [-19.35, -15.34], and -19.73 [-20.57, -18.73]; P < 0.05); and longitudinal strain of HTN LVMH patients were lower than other two groups (-11.31 ± 2.91, -15.1 ± 3.06, and -18.85 ± 1.85; P < 0.05); radial strain of HTN LVMH patients were also lower than other two groups (25.03 ± 16, 40.95 ± 17.5 and 47.9 ± 10.23; P < 0.05). Extracellular volume correlated with peak circumferential, longitudinal, and radial strain (spearman rho = 0.6, 0.64, and -0.69; P < 0.05), respectively; T2* negatively correlated with peak circumferential and longitudinal strain (spearman rho = -0.43 and -0.49; P < 0.05), respectively. Patients with lower T2* values had significant decreases in myocardial mechanics (P < 0.05). DATA CONCLUSION: HTN LVMH patients have both impaired myocardial mechanics and decreased T2* values compared with HTN non-LVMH and normotensive groups. BOLD MRI could provide a feasible assessment modality for detecting altered T2* due to the change of de-oxygenated hemoglobin and hence to the change of signal intensity in oxygenation-sensitive images. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 3 J. Magn. Reson. Imaging 2018;47:1297-1306.

A Germline Variant in the PANX1 Gene Has Reduced Channel Function and Is Associated with Multisystem Dysfunction.

Pannexin1 (PANX1) is probably best understood as an ATP release channel involved in paracrine signaling. Given its ubiquitous expression, PANX1 pathogenic variants would be expected to lead to disorders involving multiple organ systems. Using whole exome sequencing, we discovered the first patient with a homozygous PANX1 variant (c.650G→A) resulting in an arginine to histidine substitution at position 217 (p.Arg217His). The 17-year-old female has intellectual disability, sensorineural hearing loss requiring bilateral cochlear implants, skeletal defects, including kyphoscoliosis, and primary ovarian failure. Her consanguineous parents are each heterozygous for this variant but are not affected by the multiorgan syndromes noted in the proband. Expression of the p.Arg217His mutant in HeLa, N2A, HEK293T, and Ad293 cells revealed normal PANX1 glycosylation and cell surface trafficking. Dye uptake, ATP release, and electrophysiological measurements revealed p.Arg217His to be a loss-of-function variant. Co-expression of the mutant with wild-type PANX1 suggested the mutant was not dominant-negative to PANX1 channel function. Collectively, we demonstrate a PANX1 missense change associated with human disease in the first report of a "PANX1-related disorder."

Preliminary study of diffusion kurtosis imaging in thyroid nodules and its histopathologic correlation.

OBJECTIVES: To evaluate the utility of diffusion kurtosis imaging (DKI) of patients with thyroid nodules and to assess the probable correlation with histopathological factors. METHODS: The study included 58 consecutive patients with thyroid nodules who underwent magnetic resonance imaging (MRI) examination, including DKI and diffusion-weighted imaging (DWI). Histopathological analysis of paraffin sections included cell density and immunohistochemical analysis of Ki-67 and vascular endothelial growth factor (VEGF). Statistical analyses were performed using Student's t-test, receiver operating characteristic (ROC) curves and Spearman's correlation. RESULTS: The diffusion parameters, cell density and immunohistochemistry analysis between malignant and benign lesions showed significant differences. The largest area under the ROC curve was acquired for the D value (AUC = 0.797). The highest sensitivity was shown with the use of K (threshold = 0.832, sensitivity = 0.917). The Ki-67 expression generally stayed low. A moderate correlation was found between ADC, D and cell density (r = -0.536, P = 0.000; r = -0.570, P = 0.000) and ADC, D and VEGF expression (r = -0.451, P = 0.000; r = -0.522, P = 0.000). CONCLUSION: The DKI-derived parameters D and K demonstrated an advantage compared to conventional DWI for thyroid lesion diagnosis. While the histopathological study indicated that the D value correlated better with extracellular change than the ADC value, the K value probably changed relative to the intracellular structure. KEY POINTS: • DWI and DKI parameters can identify PTC from benign thyroid nodules. • Correlations were found between diffusion parameters and histopathological analysis. • DKI obtains better diagnostic accuracy than conventional DWI.

T2* mapping at 3.0T MRI for differentiation of papillary thyroid carcinoma from benign thyroid nodules.

PURPOSE: To study the quantitative T2* mapping for thyroid nodules and to explore the use of T2* values to differentiate papillary thyroid carcinoma (PTC) from benign thyroid nodules, with histopathological examination as a reference standard. MATERIALS AND METHODS: Twenty-eight consecutive patients with thyroid nodules were subjected to a 3.0T magnetic resonance imaging (MRI) examination. T2 * mapping was acquired using six echo times with a multiecho fast field echo (mFFE) sequence and constructed by exponentially fitting the multiecho T2* images pixel-by-pixel. The quality of the native T2* image was evaluated. An independent sample t-test was used to evaluate the statistical difference of the mean T2* value and the mean ratio of lesion to contralateral normal tissue between PTC and benign thyroid nodules. A receiver operating characteristic (ROC) curve was used to calculate the sensitivity and specificity. RESULTS: The T2* value (mean: 21.73 ± 2.09 msec) and the ratio (mean: 1.61 ± 0.11) of PTC group were both significantly lower (P < 0.001) than those of the benign group (mean T2* value: 28.78 ± 5.02 msec, mean ratio: 2.18 ± 0.43). Applying a threshold value of 25.00 msec for T2* values and 1.795 for the ratio of lesion regions to normal tissue regions to identify PTC yielded a sensitivity of 84.2% and 89.5%, respectively, and a specificity of 100% for both. CONCLUSION: T2* mapping can potentially provide quantitative information to separate PTC from benign thyroid nodules.

Quetiapine attenuates glial activation and proinflammatory cytokines in APP/PS1 transgenic mice via inhibition of nuclear factor-κB pathway.

BACKGROUND: In Alzheimer's disease, growing evidence has shown that uncontrolled glial activation and neuroinflammation may contribute independently to neurodegeneration. Antiinflammatory strategies might provide benefits for this devastating disease. The aims of the present study are to address the issue of whether glial activation and proinflammatory cytokine increases could be modulated by quetiapine in vivo and in vitro and to explore the underlying mechanism. METHODS: Four-month-old amyloid precursor protein (APP) and presenilin 1 (PS1) transgenic and nontransgenic mice were treated with quetiapine (5mg/kg/d) in drinking water for 8 months. Animal behaviors, total Aß levels, and glial activation were evaluated by behavioral tests, enzyme-linked immunosorbent assay, immunohistochemistry, and Western blot accordingly. Inflammatory cytokines and the nuclear factor kappa B pathway were analyzed in vivo and in vitro. RESULTS: Quetiapine improves behavioral performance, marginally affects total Aß40 and Aß42 levels, attenuates glial activation, and reduces proinflammatory cytokines in APP/PS1 mice. Quetiapine suppresses Aß1-42-induced activation of primary microglia by decresing proinflammatory cytokines. Quetiapine inhibits the activation of nuclear factor kappa B p65 pathway in both transgenic mice and primary microglia stimulated by Aß1-42. CONCLUSIONS: The antiinflammatory effects of quetiapine in Alzheimer's disease may be involved in the nuclear factor kappa B pathway. Quetiapine may be an efficacious and promising treatment for Alzheimer's disease targeting on neuroinflammation.

Chronic phencyclidine induces inflammatory responses and activates GSK3ß in mice.

Use of phencyclidine (PCP) in rodents can mimic some aspects of schizophrenia. However, the underlying mechanism is still unclear. Growing evidence indicates that neuroinflammation plays a significant role in the pathophysiology of schizophrenia. In this study, we focused on inflammatory responses as target of PCP for inducing schizophrenia-like symptoms. 3-month-old C57BL/6J mice received daily injections of PCP (20 mg/kg, i.p.) or saline for one week. PCP-injected mice produced schizophrenia-like behaviours including impaired spatial short-term memory assessed by the Y-maze task and sensorimotor gating deficits in a prepulse inhibition task. Simultaneously, chronic PCP administration induced astrocyte and microglial activation in both the cortex and hippocampus. Additionally, the proinflammatory cytokine interleukin-1ß was significantly up-regulated in PCP administrated mice. Furthermore, PCP treatment decreased ratio of the phospho-Ser9 epitope of glycogen synthase kinase-3ß (GSK3ß) over total GSK3ß, which is indicative of increased GSK3ß activity. These data demonstrate that chronic PCP in mouse produces inflammatory responses and GSK3ß activation.

Prognostic value of right atrial strains in arrhythmogenic right ventricular cardiomyopathy.

OBJECTIVES: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiomyopathy characterized by progressive fibrofatty infiltration of atrial and ventricular myocardium resulting in adverse cardiac events. Atrial function has been increasingly recognized as prognostically important for cardiovascular disease. As the right atrial (RA) strain is a sensitive parameter to describe RA function, we aimed to analyze the prognostic value of the RA strain in ARVC. METHODS: RA strain parameters were derived from cardiac magnetic resonance (CMR) images of 105 participants with definite ARVC. The endpoint was defined as a combination of sudden cardiac death, survival cardiac arrest, and appropriate implantable cardioverter-defibrillator intervention. Cox regression and Kaplan-Meier survival analyses were performed to evaluate the association between RA strain parameters and endpoint. Concordance index (C index), net reclassification index (NRI), and integrated discrimination improvement (IDI) were calculated to assess the incremental value of RA strain in predicting the endpoint. RESULTS: After a median follow-up of 5 years, 36 (34.3%) reaching the endpoint displayed significantly reduced RA strain parameters. At Kaplan-Meier analysis, impaired RA reservoir (RARS) and booster strains (RABS) were associated with an increased risk of the endpoint. After adjusting for conventional risk factors, RARS (hazard ratio [HR], 0.956; p = 0.005) and RABS (HR, 0.906; p = 0.002) resulted as independent predictors for endpoint at Cox regression analyses. In addition, RARS and RABS improved prognostic value to clinical risk factors and CMR morphological and functional predictors (all p < 0.05). CONCLUSION: RARS and RABS were independent predictors for adverse cardiac events, which could provide incremental prognostic value for conventional predictors in ARVC. CRITICAL RELEVANCE STATEMENT: We evaluated the prognostic value of right atrial strain in ARVC patients and suggested cardiologists consider RA strain as a predictive parameter when evaluating the long-term outcome of ARVC patients in order to formulate better clinical therapy. KEY POINTS: • Patients with ARVC had significantly reduced RA strain and strain rates compared with healthy participants. • Participants with lower RA reservoir and booster stains were associated with a significantly higher risk of adverse cardiac events. • RA booster and reservoir strain provide incremental value to conventional parameters.

Fractal analysis of left ventricular trabeculae in post-STEMI: from acute to chronic phase.

PURPOSE: The temporal evolution of ventricular trabecular complexity and its correlation with major adverse cardiovascular events (MACE) remain indeterminate in patients presenting with acute ST elevation myocardial infarction (STEMI). METHODS: This retrospective analysis enrolled patients undergoing primary percutaneous coronary intervention (pPCI) for acute STEMI, possessing cardiac magnetic resonance (CMR) data in the acute (within 7 days), subacute (1 month after pPCI), and chronic phases (6 months after pPCI) from January 2015 to January 2020 at the three participating sites. Fractal dimensions (FD) were measured for the global, infarct, and remote regions of left ventricular trabeculae during each phase. The potential association of FD with MACE was analyzed using multivariate Cox regression. RESULTS: Among the 200 analyzed patients (182 men; median age, 61 years; age range, 50-66 years), 37 (18.5%) encountered MACE during a median follow-up of 31.2 months. FD exhibited a gradual decrement (global FD at acute, subacute, and chronic phases: 1.253 ± 0.049, 1.239 ± 0.046, 1.230 ± 0.045, p < 0.0001), with a more pronounced decrease observed in patients subsequently experiencing MACE (p < 0.001). The global FD at the subacute phase correlated with MACE (hazard ratio 0.89 (0.82, 0.97), p = 0.01), and a global FD value below 1.26 was associated with a heightened risk. CONCLUSION: In patients post-STEMI, the global FD, serving as an indicator of left ventricular trabeculae complexity, independently demonstrated an association with subsequent major adverse cardiovascular events, beyond factors encompassing left ventricular ejection fraction, indexed left ventricular end-diastolic volume, infarct size, heart rate, NYHA class, and post-pPCI TIMI flow. CRITICAL RELEVANCE STATEMENT: In patients who have had an ST-segment elevation myocardial infarction, global fractal dimension, as a measure of left ventricular trabeculae complexity, provided independent association with subsequent major adverse cardiovascular event. KEY POINTS: • Global and regional FD decreased after STEMI, and more so in patients with subsequent MACE. • Lower global FD at the subacute phase and Δglobal FD from acute to subacute phase were associated with subsequent MACE besides clinical and CMR factors. • Global FD at the subacute phase independently correlated with MACE and global FD value below 1.26 was associated with higher risk.