Relative apical sparing obtained with speckle tracking echocardiography is not a sensitive parameter for diagnosing light-chain cardiac amyloidosis.

Background: Distinguishing light-chain cardiac amyloidosis (AL CA) from left ventricular wall thickening (LVWT) resulted from other etiologies has proven to be challenging. This study aimed to determine the sensitivity and specificity of relative apical sparing in diagnosing AL CA and investigate the differences in clinical and echocardiographic characteristics between AL CA patients with apical sparing and those with non-apical sparing. Methods: A total of 63 consecutive patients with AL CA, 102 consecutive patients with LVWT (including 51 hypertrophic cardiomyopathy (HCM) and 51 hypertension) and 33 healthy individuals were recruited retrospectively at Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology. Conventional and speckle tracking echocardiography were performed on all subjects. Results: Although wall thickening was observed in all patients, almost all functional parameters were worse in AL CA, except for relative apical longitudinal strain (LS) (P=0.906). Of 63 patients with AL CA, only 17.5% (n=11) showed an apical sparing pattern. Patients with apical sparing had poorer cardiac performance than those with non-apical sparing. Relative apical sparing showed the lowest diagnostic accuracy with an area under the curve (AUC) of 0.58 [95% confidence interval (CI): 0.49-0.67, sensitivity: 17.5%, specificity: 98.0%, P=0.095] to detect AL CA, but right ventricular strain (RVS) (AUC: 0.86, P<0.001) showed the highest among all echocardiographic parameters. When diagnosing AL CA patients with non-apical sparing, RVS continued to maintain excellent diagnostic accuracy (AUC: 0.84, P<0.001), followed by left atrial reservoir strain (LASr) (AUC: 0.77, P<0.001). Conclusions: The diagnostic value of relative apical sparing for AL CA was limited with low sensitivity. In clinical practice, the diagnosis of early AL CA patients should not solely rely on relative apical sparing.

Improvements of myocardial strain and work in diabetes patients with normal ejection fraction after empagliflozin treatment.

AIMS/INTRODUCTION: To assess the effect of empagliflozin treatment on left ventricular (LV), right ventricular (RV) and left atrial (LA) functions in diabetes patients with normal ejection fraction. MATERIALS AND METHODS: The study included a total of 128 diabetes patients with multiple cardiovascular risk factors who were subjected to a 6-month follow up from the initiation of empagliflozin treatment. Before and after treatment with empagliflozin, LV, RV and LA strain, and noninvasive myocardial work parameters were evaluated by speckle tracking echocardiography. RESULTS: In 128 diabetes patients (mean age 56 ± 8 years, 85 men) with multiple cardiovascular risk factors, myocardial strain and work parameters were impaired, despite the absence of significant clinical symptoms of heart failure. After 6-month treatment with empagliflozin, the absolute value of LV strain in all directions increased, represented by LV global longitudinal strain (-18.0 ± 1.7% to -19.2 ± 1.7% [mean ± SD]). The same trend in LV global work efficiency (93 [91-94] % to 94 [93-95] % [median (IQR)]), RV free-wall longitudinal strain (-24.0 ± 2.7% to -25.0 ± 2.8%), LA reservoir (31 ± 5% to 34 ± 5%) and conduit strain (-14 ± 4% to -16 ± 4%) was also observed. LV mass index (106.9 ± 16.8-103.6 ± 16.4 g/m2) and LV global wasted work (143 [111-185] mmHg% to 108 [88-141] mmHg%) decreased after treatment (P < 0.05 for all). LV volume and LA volume index remained unchanged after treatment. In the multivariable analysis, the change in LA reservoir strain (ß = 0.050, P = 0.035) and baseline global longitudinal strain (ß = -0.488, P < 0.001) were independent predictors of improvement in LV global longitudinal strain. CONCLUSIONS: This study suggests that 6-month treatment with empagliflozin improved LV, RV and LA functions in diabetes patients with normal ejection fraction.

Subclinical cardiac impairments in fetuses conceived through assisted reproductive technology by speckle tracking echocardiography.

OBJECTIVES: To evaluate the changes of cardiac morphology and function in fetuses conceived through assisted reproductive technologies (ART) by speckle tracking echocardiography. METHODS: A retrospective study was conducted in 101 spontaneously conceived (SC) fetuses and 99 ART-conceived ones. Fetal echocardiography was performed, fetal cardiac morphology and function were analyzed using two-dimensional speckle tracking software, including global sphericity index (GSI), global longitudinal strain (GLS), fractional area change (FAC) of the left and right ventricles, as well as segmental sphericity index (SI), end-diastolic diameter (ED), and fractional shortening (FS) in 24 segments. RESULTS: Compared to the SC fetuses, the ART-conceived fetuses exhibited decreased GSI (median [interquartile range], 1.22 [1.16-1.27] vs. 1.18 [1.11-1.24], p=0.007), decreased right ventricular GLS (24.9 [21.5-27.6] vs. 23.2 [20.4-26.8], p=0.026), and decreased right ventricular FAC (mean ± standard deviation, 39.7 ± 6.4 vs. 37.2 ± 7.1, p=0.003). Analysis of the 24 segments showed that ART-conceived fetuses had reduced SI in the apical segments of right ventricle and increased ED in several segments of the right ventricle. CONCLUSIONS: Fetuses conceived through ART had a more spherical shape of the global heart and predominantly right-sided cardiac remodeling and systolic function impairment.

Evaluation of Fetal Cardiac Function in Maternal Gestational Diabetes Mellitus by Speckle-Tracking Echocardiography.

OBJECTIVES: Gestational diabetes mellitus (GDM) is the most common metabolic disease that occurs during pregnancy and may result in fetal cardiac dysfunction. Our study aimed to assess the cardiac function in fetuses of mothers with GDM by a quantitative analysis software based on speckle-tracking echocardiography. METHODS: Forty-nine fetuses exposed to GDM and 50 normal fetuses were enrolled, and fetal echocardiography were performed and analyzed in this prospective cross-sectional study. We compared cardiac systolic function between the two groups using fetal cardiac quantitative analysis software. RESULTS: In the GDM group, left ventricular (24 ± 4 versus 28 ± 4, P < .001) and right ventricular global longitudinal strain (23 ± 4 versus 26 ± 4, P = .002) and right ventricular free wall strain (26 ± 6 versus 29 ± 5, P = .006) were significantly lower compared with the control group, whereas there was no significant difference in global spherical index (1.2 ± 0.1 versus 1.2 ± 0.1, P = .425). Additionally, 24-segment transverse fraction shortening of the right ventricle was more impaired than the left, and the segments with reduced fraction shortening were mainly located in the mid and apical sections of the right ventricle, and midsection of the left ventricle. CONCLUSION: Fetuses exposed to GDM may have cardiac dysfunction before the onset of cardiac morphologic abnormalities, and the right ventricle is more vulnerable than the left during fetal development.

Improving hard metal implant and soft tissue integration by modulating the "inflammatory-fibrous complex" response.

Soft tissue integration is one major difficulty in the wide applications of metal materials in soft tissue-related areas. The inevitable inflammatory response and subsequent fibrous reaction toward the metal implant is one key response for metal implant-soft tissue integration. It is of great importance to modulate this inflammatory-fibrous response, which is mainly mediated by the multidirectional interaction between fibroblasts and macrophages. In this study, macrophages are induced to generate M1 and M2 macrophage immune microenvironments. Their cytokine profiles have been proven to have potentially multi-regulatory effects on fibroblasts. The multi-reparative effects of soft tissue cells (human gingival fibroblasts) cultured on metal material (titanium alloy disks) in M1 and M2 immune microenvironments are then dissected. Fibroblasts in the M1 immune microenvironment tend to aggravate the inflammatory response in a pro-inflammatory positive feedback loop, while M2 immune microenvironment enhances multiple functions of fibroblasts in soft tissue integration, including soft tissue regeneration, cell adhesion on materials, and contraction to immobilize soft tissue. Enlighted by the close interaction between macrophages and fibroblasts, we propose the concept of an "inflammatory-fibrous complex" to disclose possible methods of precisely and effectively modulating inflammatory and fibrous responses, thus advancing the development of metal soft tissue materials.

Persistent Endothelial Dysfunction in Coronavirus Disease-2019 Survivors Late After Recovery.

BACKGROUND: Coronavirus disease 2019 (COVID-19) can result in an endothelial dysfunction in acute phase. However, information on the late vascular consequences of COVID-19 is limited. METHODS: Brachial artery flow-mediated dilation (FMD) examination were performed, and inflammatory biomarkers were assessed in 86 survivors of COVID-19 for 327 days (IQR 318-337 days) after recovery. Comparisons were made with 28 age-matched and sex-matched healthy controls and 30 risk factor-matched patients. RESULTS: Brachial artery FMD was significantly lower in the survivors of COVID-19 than in the healthy controls and risk factor-matched controls [median (IQR) 7.7 (5.1-10.7)% for healthy controls, 6.9 (5.5-9.4)% for risk factor-matched controls, and 3.5(2.2-4.6)% for COVID-19, respectively, p < 0.001]. The FMD was lower in 25 patients with elevated tumor necrosis factor (TNF)-α [2.7(1.2-3.9)] than in 61 patients without elevated TNF-α [3.8(2.6-5.3), p = 0.012]. Furthermore, FMD was inversely correlated with serum concentration of TNF-α (r = -0.237, p = 0.007). CONCLUSION: Survivors of COVID-19 have a reduced brachial artery FMD, which is inversely correlated with increased serum concentration of TNF-α. Prospective studies on the association of endothelial dysfunction with long-term cardiovascular outcomes, especially the early onset of atherosclerosis, are warranted in survivors of COVID-19.

Mesopore Controls the Responses of Blood Clot-Immune Complex via Modulating Fibrin Network.

Formation of blood clots, particularly the fibrin network and fibrin network-mediated early inflammatory responses, plays a critical role in determining the eventual tissue repair or regeneration following an injury. Owing to the potential role of fibrin network in mediating clot-immune responses, it is of great importance to determine whether clot-immune responses can be regulated via modulating the parameters of fibrin network. Since the diameter of D-terminal of a fibrinogen molecule is 9 nm, four different pore sizes (2, 8, 14, and 20 nm) are rationally selected to design mesoporous silica to control the fibrinogen adsorption and modulate the subsequent fibrin formation process. The fiber becomes thinner and the contact area with macrophages decreases when the pore diameters of mesoporous silica are greater than 9 nm. Importantly, these thinner fibers grown in pores with diameters larger than 9 nm inhibit the M1-polorazation of macrophages and reduce the productions of pro-inflammatory cytokines and chemokines by macrophages. These thinner fibers reduce inflammation of macrophages through a potential signaling pathway of cell adhesion-cytoskeleton assembly-inflammatory responses. Thus, the successful regulation of the clot-immune responses via tuning of the mesoporous pore sizes indicates the feasibility of developing advanced clot-immune regulatory materials.

Normalized Cardiac Structure and Function in COVID-19 Survivors Late After Recovery.

Background: Coronavirus disease 2019 can result in myocardial injury in the acute phase. However, information on the late cardiac consequences of coronavirus disease 2019 (COVID-19) is limited. Methods: We conducted a prospective observational cohort study to investigate the late cardiac consequences of COVID-19. Standard echocardiography and myocardial strain assessment were performed, and cardiac blood biomarkers were tested in 86 COVID-19 survivors 327 days (IQR 318-337 days) after recovery. Comparisons were made with 28 age-matched and sex-matched healthy controls and 30 risk factor-matched patients. Results: There were no significant differences in all echocardiographic structural and functional parameters, including left ventricular (LV) global longitudinal strain, right ventricular (RV) longitudinal strain, LV end-diastolic volume, RV dimension, and the ratio of peak early velocity in mitral inflow to peak early diastolic velocity in the septal mitral annulus (E/e') among COVID-19 survivors, healthy controls and risk factor-matched controls. Even 26 patients with myocardial injury at admission did not have any echocardiographic structural and functional abnormalities. There were no significant differences among the three groups with respect to serum concentrations of N-terminal pro-B-type natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin I (cTnI). Conclusion: This study showed that COVID-19 survivors, including those with myocardial injury at admission and those with severe and critical types of illness, do not have any echocardiographic evidence of cardiac structural and functional abnormalities 327 days after diagnosis.

Interleukin-20 differentially regulates bone mesenchymal stem cell activities in RANKL-induced osteoclastogenesis through the OPG/RANKL/RANK axis and the NF-κB, MAPK and AKT signalling pathways.

The immune and skeletal systems share common mechanisms, and the crosstalk between the two has been termed osteoimmunology. Osteoimmunology mainly focuses on diseases between the immune and bone systems including bone loss diseases, and imbalances in osteoimmune regulation affect skeletal homeostasis between osteoclasts and osteoblasts. The immune mediator interleukin-20 (IL-20), a member of the IL-10 family, enhances inflammation, chemotaxis and angiogenesis in diseases related to bone loss. However, it is unclear how IL-20 regulates the balance between osteoclastogenesis and osteoblastogenesis; therefore, we explored the mechanisms by which IL-20 affects bone mesenchymal stem cells (BMSCs) in osteoclastogenesis in primary cells during differentiation, proliferation, apoptosis and signalling. We initially found that IL-20 differentially regulated preosteoclast proliferation and apoptosis; BMSC-conditioned medium (CM) significantly enhanced osteoclast formation and bone resorption, which was dose-dependently regulated by IL-20; IL-20 inhibited OPG expression and promoted M-CSF, RANKL and RANKL/OPG expression; and IL-20 differentially regulated the expression of osteoclast-specific gene and transcription factors through the OPG/RANKL/RANK axis and the NF-kB, MAPK and AKT pathways. Therefore, IL-20 differentially regulates BMSCs in osteoclastogenesis and exerts its function by activating the OPG/RANKL/RANK axis and the NF-κB, MAPK and AKT pathways, which make targeting IL-20 a promising direction for targeted regulation in diseases related to bone loss.

The effect of risedronate on orthodontic tooth movement in ovariectomized rats.

OBJECTIVE: This study aimed to investigate the effect of risedronate on orthodontic tooth movement in ovariectomized rats. METHODS: Forty-five female Sprague-Dawley rats were divided into three groups. Bilateral ovariectomies were performed on the rats in the ovariectomy and ovariectomy + risedronate groups. Two weeks after ovariectomy, risedronate was administered intraperitoneally every three days in the ovariectomy + risedronate group, while rats in the ovariectomy and sham groups were administered saline until they were sacrificed. One month after ovariectomy, nickel-titanium alloy closed-coil springs were placed between the maxillary left first molar and the maxillary left incisor. On days 3, 7 and 14, five rats from each group were sacrificed. The distance of orthodontic tooth movement was measured by a digital caliper, and slides were obtained for histological analysis. RESULTS: The distance of orthodontic tooth movement and the number of tartar-resistant acid phosphatase (TRAP)-positive cells were the highest in the ovariectomy group, followed by those in the ovariectomy + risedronate group, on days 3, 7 and 14. The positive expression levels of receptor activator of nuclear factor-kappa ß (RANK) ligand and cathepsin K were the strongest while the positive expression of osteoprotegerin in the ovariectomy group was the weakest, followed by the corresponding expression levels in the ovariectomy + risedronate group, on days 3, 7 and 14. CONCLUSIONS: Risedronate can inhibit orthodontic tooth movement in ovariectomized rats and may function by regulating the RANK/RANK ligand/osteoprotegerin pathway.

A standardized rat burr hole defect model to study maxillofacial bone regeneration.

With high incidence rate and unique regeneration features, maxillofacial burr hole bone defects require a specially designed bone defect animal model for the evaluation of related bone regenerative approaches. Although some burr hole defect models have been developed in long bones or calvarial bones, the mandible has unique tissue development origins and regenerative environments. This suggests that the defect model should be prepared in the maxillofacial bone area. After dissecting the anatomic structures of rat mandibles, we found that creating defects in the anterior tooth area avoided damaging important organs and improved animal welfare. Furthermore, the available bone volume at the anterior tooth area was superior to that of the posterior tooth and ascending ramus areas. We then managed to standardize the model by controlling the age, weight and gender of the animal, creating standardized measurement instruments and reducing the variations derived from various operators. We also succeeded in deterring the self-rehabilitation of the proposed model by increasing the defect size. The 6 × 2 mm and 8 × 2 mm defects were found to meet the requirements of bone regenerative studies. This study provided a step-by-step standardized burr hole bone defect model with minimal tissue damage in small animals. The evaluations resulting from this model testify to the in vitro outcomes of the proposed regenerative approaches and provide preliminary screening data for further large animal and clinical trials. Therefore, the inclusion of this model may optimize the evaluation systems for maxillofacial burr hole bone defect regenerative approaches. STATEMENT OF SIGNIFICANCE: Unremitting effort has been devoted to the development of bone regenerative materials to restore maxillofacial burr hole bone defects because of their high clinical incidence rate. In the development of these biomaterials, in vivo testing in small animals is necessary to evaluate the effects of candidate biomaterials. However, little has been done to develop such defect models in small animals. In this study, we developed a standardized rat mandible burr hole bone defect model with minimal injury to the animals. A detailed description and supplementary video were provided to guide the preparation. The development of this model optimizes the maxillofacial bone regenerative approach evaluation system.

Antinociceptive effects of the adenylyl cyclase inhibitor ST034307 on tooth-movement-induced nociception in rats.

OBJECTIVE: This study aimed to investigate the antinociceptive effects of the selective adenylyl cyclase type 1 (AC1) inhibitor ST034307 on tooth movement nociception through orofacial nociceptive behavior tests and molecular examination. METHODS: We placed fixed nickel-titanium alloy closed-coil springs around the incisors of male Sprague-Dawley rats to induce tooth movement. We subsequently administered ST034307 (3 mg/kg), for 2 days, intraperitoneally, and then subjected the rats to a battery of behavioral tests (n = 10/group) to assess orofacial nociception. The changes in the expression of key molecules in the anterior cingulate cortex were measured by ELISA (n = 8/group) and Western blotting (n = 8/group). RESULTS: Tooth movement increased face-grooming activities and rat grimace scale scores. Tooth movement was also associated with enhanced cyclic adenosine monophosphate (cAMP) generation as well as protein kinase A (PKA) activation. Moreover, the phosphorylation of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors and expression of N-methyl-d-aspartate (NMDA) receptors in the anterior cingulate cortex increased during tooth movement. ST034307 significantly decreased mouth wiping and rat grimace scale scores, accompanied by reductions in cAMP generation, PKA activation, AMPA receptor phosphorylation, and NMDA receptor expression in the anterior cingulate cortex. CONCLUSIONS: These results suggest that adenylyl cyclase type 1 plays an important role in the development of orthodontic tooth movement nociception. Furthermore, ST034307 can be used as an effective pharmacotherapy for orthodontic nociception.