Prognostic value of right atrial strain in systemic sclerosis based on tissue tracking analysis using cine cardiac magnetic resonance imaging: a retrospective observational study.

Interstitial lung disease and cardiac involvement are common manifestations and prognostic factors of systemic sclerosis. However, it is unclear whether impaired right atrial function associated with interstitial lung disease in systemic sclerosis can be used as a prognostic factor in this patient population. Therefore, this study aimed to investigate the relationship between right atrial function, interstitial lung disease, and prognosis in patients with systemic sclerosis using tissue tracking analysis with cine cardiac magnetic resonance imaging. In this retrospective observational study, a total of 40 patients with systemic sclerosis were enrolled. Tissue tracking analysis was used to obtain time curves of right atrial strain. Reservoir (total strain), conduit (passive strain), and booster (active strain) pump function were calculated, and right atrial strain, interstitial lung disease, and clinical outcomes were examined. An adverse clinical event was defined as all-cause death. Overall, 23 patients had interstitial lung disease (58%). Six patients died during the follow-up (median, 44 months). The total skin score and right ventricular systolic pressure on echocardiography were higher in patients with an event than in those without an event (28 ± 16% vs. 13 ± 13%, P = 0.02; 46.3 ± 10.7 mmHg vs. 36.0 ± 8.5 mmHg, P = 0.01, respectively). Further, right atrial total strain and active strain were significantly lower in patients with an event than in those without an event (14.3 ± 11.3% vs. 25.8 ± 11.4%, P = 0.03; 3.48 ± 2.37 vs. 11.7 ± 6.78, P = 0.007, respectively). Multivariate analysis revealed that active strain was an independent predictor of all-cause death (hazard ratio 0.76, P = 0.029). Kaplan-Meier analysis revealed that the survival rate was significantly higher in patients with right atrial active strain levels above the cutoff 7.4 (P < 0.05). In systemic sclerosis, right atrial booster function was predictive of mortality. Hence, right atrial functional assessment may have incremental prognostic value for patients with systemic sclerosis, leading to better risk stratification.

Deep learning approach using SPECT-to-PET translation for attenuation correction in CT-less myocardial perfusion SPECT imaging.

OBJECTIVE: Deep learning approaches have attracted attention for improving the scoring accuracy in computed tomography-less single photon emission computed tomography (SPECT). In this study, we proposed a novel deep learning approach referring to positron emission tomography (PET). The aims of this study were to analyze the agreement of representative voxel values and perfusion scores of SPECT-to-PET translation model-generated SPECT (SPECTSPT) against PET in 17 segments according to the American Heart Association (AHA). METHODS: This retrospective study evaluated the patient-to-patient stress, resting SPECT, and PET datasets of 71 patients. The SPECTSPT generation model was trained (stress: 979 image pairs, rest: 987 image pairs) and validated (stress: 421 image pairs, rest: 425 image pairs) using 31 cases of SPECT and PET image pairs using an image-to-image translation network. Forty of 71 cases of left ventricular base-to-apex short-axis images were translated to SPECTSPT in the stress and resting state (stress: 1830 images, rest: 1856 images). Representative voxel values of SPECT and SPECTSPT in the 17 AHA segments against PET were compared. The stress, resting, and difference scores of 40 cases of SPECT and SPECTSPT were also compared in each of the 17 segments. RESULTS: For AHA 17-segment-wise analysis, stressed SPECT but not SPECTSPT voxel values showed significant error from PET at basal anterior regions (segments #1, #6), and at mid inferoseptal regions (segments #8, #9, and #10). SPECT, but not SPECTSPT, voxel values at resting state showed significant error at basal anterior regions (segments #1, #2, and #6), and at mid inferior regions (segments #8, #9, and #11). Significant SPECT overscoring was observed against PET in basal-to-apical inferior regions (segments #4, #10, and #15) during stress. No significant overscoring was observed in SPECTSPT at stress, and only moderate over and underscoring in the basal inferior region (segment #4) was found in the resting and difference states. CONCLUSIONS: Our PET-supervised deep learning model is a new approach to correct well-known inferior wall attenuation in SPECT myocardial perfusion imaging. As standalone SPECT systems are used worldwide, the SPECTSPT generation model may be applied as a low-cost and practical clinical tool that provides powerful auxiliary information for the diagnosis of myocardial blood flow.

GPATCH4 contributes to nucleolus morphology and its dysfunction impairs cell viability.

The nucleolus serves a multifaceted role encompassing not only rRNA transcription and ribosome synthesis, but also the intricate orchestration of cell cycle regulation and the modulation of cellular senescence. G-patch domain containing 4 (GPATCH4) stands as one among the nucleolar proteins; however, its functional significances remain still unclear. In order to elucidate the functions of GPATCH4, we examined the effects of its dysfunction on cellular proliferation, alterations in nucleolar architecture, apoptotic events, and cellular senescence. Through experimentation conducted on cultured neuroblastoma SH-SY5Y cells, the reduction of GPATCH4 caused inhibition of cellular proliferation, concurrently fostering escalated apoptotic susceptibilities upon exposure to high-dose etoposide. In the realm of nucleolar morphology comparisons, a discernible decline was noted in the count of nucleoli per nucleus, concomitant with a significant expansion in the area occupied by individual nucleoli. Upon induction of senescence prompted by low-dose etoposide, GPATCH4 knockdown resulted in decreased cell viability and increased expression of senescence-associated markers, namely senescence-associated ß-galactosidase (SA-ß-GAL) and p16. Furthermore, GPATCH4 dysfunction elicited alterations in the gene expression profile of the ribosomal system. In sum, our findings showed that GPATCH4 is a pivotal nucleolar protein that regulates nucleolar morphology and is correlated with cell viability.

13N-ammonia positron emission tomography for diagnosis and monitoring of ischemia without obstructive coronary artery disease.

BACKGROUND: Ischemia with no obstructive coronary arteries (INOCA), a chronic disorder with a poor prognosis, remains challenging to diagnose. 13N-ammonia positron emission tomography (13NH3 PET), which can quantify microcirculation, is its most reliable detection method. We aimed to investigate the differences in 13NH3 PET findings between INOCA and coronary artery disease (CAD). METHODS: Overall, consecutive 433 patients with known or suspected CAD underwent adenosine-stress 13NH3 PET. Based on the European Society of Cardiology guidelines, INOCA was defined as typical angina without coronary stenosis (INOCA n = 45, CAD n = 293, no CAD n = 95). Papillary muscle ischemia (PMI) and global myocardial flow reserve (MFR) were examined as microvascular injuries using 13NH3 PET. RESULTS: PMI was observed significantly more frequently in patients with INOCA than in those with CAD (40.0% vs. 11.6%, respectively; p = 0.02). Global MFR (1.84 ± 0.54 vs. 2.08 ± 0.66, respectively; p < 0.0001) and reactive hyperemia index were significantly lower in patients with INOCA than in those with CAD. Forty-five major adverse cardiac events (MACE) were recorded in a median follow-up time of 827 days. Kaplan-Meier analysis revealed that the survival rate worsened in patients with INOCA and PMI (log-rank test, p = 0.001). In the Cox proportional hazards model, PMI was an independent predictive factor for MACE (odds ratio, 4.16; 95% confidence interval, 2.13-8.15; p < 0.0001). CONCLUSIONS: PMI presence and decreased MFR were 13NH3 PET findings characteristic of INOCA. 13NH3 PET can be used to monitor the treatment course.

Myocardial Strain Derived from 13N-ammonia Positron Emission Tomography: Detection of Ischemia-Related Wall Motion Abnormality.

Background: Due to the limitation of spatial resolution, cardiac nuclear medicine images have not been applied to feature-tracking method to automatic extraction of myocardial contours. We have successfully applied the feature-tracking method to high-resolution cine 13N-ammonia positron emission tomography (PET) images to calculate the regional myocardial strains. Here, we investigate the potential of 13N-ammonia PET-derived strain to detect ischemia-related wall motion abnormality. Methods: Data of adenosine-stress/rest 13N-ammonia PET for 95 coronary artery disease patients was retrospectively analyzed. Using an original algorithm dedicated to 13N-ammonia PET, the longitudinal strain (LS) corresponding to the three main coronary artery territories [right coronary artery (RCA), left anterior descending artery (LAD), and left circumflex coronary artery (LCX)] was calculated from semi-automatic endocardial contours extraction on cine 13N-ammonia PET images of the left ventricular long-axis. The presence of ischemia in three main territories was determined from rest and stress-perfusion images. Results: In all three coronary territories, LS at stress was significantly smaller at rest in the ischemic region RCA: -19.2±8.0% vs. -22.7±6.1%, LAD: -19.0±6.9% vs. -24.4±6.4%, LCX: -20.5%±7.6% vs. -22.6±6.9%). In contrast, in the non-ischemic region, there was no significant difference between the LS at stress and at rest. Receiver-operating-characteristic analysis revealed that using the optimal cutoff of the LS ratio of stress to rest, ischemia could be diagnosed with area under the curve of 0.82 in the RCA, 0.86 in the LAD, and 0.69 in the LCX. Conclusions: Myocardial strain derived from endocardial feature-tracking of 13N-ammonia PET cine imaging is reduced in the ischemia induced by adenosine-stress. The LS ratio of stress to rest may detect wall motion abnormality related to ischemia.

Cardiac magnetic resonance imaging T1 mapping and late gadolinium enhancement entropy: Prognostic value in patients with systemic sclerosis.

BACKGROUND: Systemic sclerosis (SSc) affects the myocardium, thereby resulting in a poor prognosis. Late gadolinium enhancement (LGE) entropy, derived from routine cardiac magnetic resonance (CMR) LGE images, is an index that reflects the complexity of the left ventricular myocardium. The aim of this study was to investigate whether LGE entropy can serve as a prognostic factor in patients with SSc. METHODS: Twenty-four patients with SSc, who underwent CMR-T1 mapping and LGE to identify myocardial damage, were enrolled, and LGE entropy was measured. Extracellular volume (ECV) values were calculated using the same CMR-LGE images. The endpoint was major adverse cardiac events (MACEs), comprising all-cause death, hospitalization due to heart failure, and the onset of sustained ventricular tachycardia and ventricular fibrillation. The ability to predict MACE was assessed using receiver operating characteristic (ROC) analysis, and the predictability of LGE entropy was analyzed using Kaplan-Meier analysis. RESULTS: The ROC curve analysis demonstrated a cut-off value of 7.39 for MACE with LGE entropy and had a sensitivity and specificity of 80 % and 79 %, respectively. Patients with LGE entropy ≥7.39 had a significantly higher MACE rate than those with LGE entropy <7.39 (p = 0.010). Moreover, LGE entropy ≥7.39 was a poor prognostic factor in patients without elevated ECV values. CONCLUSIONS: LGE entropy can be used to predict MACE and allows for further risk stratification in addition to ECV determination.

Linking cardiac and extracardiac sarcoidosis and their clinical outcome: 18F-FDG PET/CT analysis in patients with systemic cardiac sarcoidosis.

OBJECTIVE: To clarify the link between cardiac sarcoidosis (CS) and extra-CS (ECS) in systemic CS (SCS) patients in terms of extent and clinical outcome by serial FDG-PET/CT. METHODS: Thirty-five SCS patients treated for > 2 years were enrolled in this study. In the overall analysis, patient-based comparisons of the complete resolution (CR) and recurrence rate between CS and ECS lesions were performed. Then, subgroup analyses were performed according to the extent (mono- vs. multi-organ ECS group) and clinical outcome (stable vs. unstable ECS group) of ECS. Pre-treatment cardiac FDG uptake was compared between the mono- and multi-organ ECS groups. The rates of CR, recurrence, and major adverse cardiac events (MACE) were compared between the two groups. RESULTS: The CR rate was significantly higher in CS than ECS lesions [77.1% (27/35) vs. 48.5% (17/35), p = 0.01], whereas recurrence rates were similar between CS and ECS [40.7% (11/27) vs. 58.8% (10/17)]. Both the mono- and multi-organ ECS groups showed similar SUVmax, cardiac metabolic volume, and cardiac metabolic activity in the pre-treatment condition. The CR rates were similar between the mono- and multi-organ ECS groups [71.4% (15/21) vs. 85.7% (12/14)], but the recurrence rate was significantly lower in the multi-organ ECS group [60.0% (9/15) vs. 16.7% (2/12), p = 0.02]. The CR [71.4% (5/7) vs. 78.6% (22/28)] and recurrence rates [60.0% (3/5) vs. 36.3% (8/22)] were not significantly different between the stable and unstable ECS groups. The occurrence of MACE was also not significantly different between the mono- and multi-organ ECS groups [19.0% (4/21) vs. 28.6% (4/14)] or between the stable and unstable ECS groups [42.9% (3/7) vs. 17.8% (5/28)]. CONCLUSIONS: CS lesions respond to treatment better than ECS lesions, and the extent and clinical outcome of ECS lesion are not linked with those of CS lesions.

Involvement of Intracellular TAGE and the TAGE-RAGE-ROS Axis in the Onset and Progression of NAFLD/NASH.

The repeated excessive intake of sugar, a factor that contributes to the onset of nonalcoholic fatty liver disease (NAFLD) and its progression to the chronic form of nonalcoholic steatohepatitis (NASH), markedly increases the hepatocyte content of glyceraldehyde (GA), a glucose/fructose metabolic intermediate. Toxic advanced glycation end-products (toxic AGEs, TAGE) are synthesized by cross-linking reactions between the aldehyde group of GA and the amino group of proteins, and their accumulation has been implicated in the development of NAFLD/NASH and hepatocellular carcinoma (HCC). Our previous findings not only showed that hepatocyte disorders were induced by the intracellular accumulation of TAGE, but they also indicated that extracellular leakage resulted in elevated TAGE concentrations in circulating fluids. Interactions between extracellular TAGE and receptor for AGEs (RAGE) affect intracellular signaling and reactive oxygen species (ROS) production, which may, in turn, contribute to the pathological changes observed in NAFLD/NASH. RAGE plays a role in the effects of the extracellular leakage of TAGE on the surrounding cells, which ultimately promote the onset and progression of NAFLD/NASH. This review describes the relationships between intracellular TAGE levels and hepatocyte and hepatic stellate cell (HSC) damage as well as the TAGE-RAGE-ROS axis in hepatocytes, HSC, and HCC cells. The "TAGE theory" will provide novel insights for future research on NAFLD/NASH.

Comparison of Phenotypes in Subcutaneous Fat and Perivascular Adipose Tissue Surrounding the Saphenous Vein in Coronary Artery Bypass Grafting.

BACKGROUND: The saphenous vein (SV) is used as an essential conduit in coronary artery bypass grafting (CABG), but the long-term patency of SV grafts is a crucial issue. The use of the novel "no-touch" technique of harvesting the SV together with its surrounding tissue has been reported to result in good long-term graft patency of SV grafts. We recently showed that perivascular adipose tissue (PVAT) surrounding the SV (SV-PVAT) had lower levels of metaflammation and consecutive adipose tissue remodeling than did PVAT surrounding the coronary artery. However, the difference between SV-PVAT and subcutaneous adipose tissue (SCAT) remains unclear.Methods and Results: Fat pads were sampled from 55 patients (38 men, 17 women; mean [±SD] age 71±8 years) with coronary artery disease who underwent elective CABG. Adipocyte size was significantly larger in SV-PVAT than SCAT. The extent of fibrosis was smaller in SV-PVAT than SCAT. There were no significant differences between SCAT and SV-PVAT in macrophage infiltration area, quantified by antibodies for CD68, CD11c, and CD206, or in gene expression levels of metaflammation-related markers. Expression patterns of adipocyte developmental and pattern-forming genes differed between SCAT and SV-PVAT. CONCLUSIONS: The properties of SV-PVAT are close to, but not the same as, those of SCAT, possibly resulting from inherent differences in adipocytes. SV-PVAT has healthy expansion with less fibrosis in fat than SCAT.

Glomerular expression and urinary excretion of fatty acid-binding protein 4 in IgA nephropathy.

BACKGROUND: Fatty acid-binding protein 4 (FABP4) is secreted from adipocytes and macrophages in adipose tissue and acts as an adipokine. It has recently been reported that FABP4, but not liver-type FABP (L-FABP/FABP1), is also expressed in injured glomerular endothelial cells and infiltrating macrophages in the glomerulus and that urinary FABP4 (U-FABP4) is associated with proteinuria and kidney function impairment in nephrotic patients. However, the link between glomerular FABP4 and U-FABP4 has not been fully addressed in IgA nephropathy (IgAN). METHODS: We investigated the involvement of FABP4 in human and mouse IgAN. RESULTS: In patients with IgAN (n = 23), the ratio of FABP4-positive area to total area within glomeruli (G-FABP4-Area) and U-FABP4 were positively correlated with proteinuria and were negatively correlated with eGFR. In 4-28-week-old male grouped ddY mice, a spontaneous IgAN-prone mouse model, FABP4 was detected in glomerular endothelial cells and macrophages, and G-FABP4-Area was positively correlated with urinary albumin-to-creatinine ratio (r = 0.957, P < 0.001). Endoplasmic reticulum stress markers were detected in glomeruli of human and mouse IgAN. In human renal glomerular endothelial cells, FABP4 was induced by treatment with vascular endothelial growth factor and was secreted from the cells. Treatment of human renal glomerular endothelial cells or mouse podocytes with palmitate-bound recombinant FABP4 significantly increased gene expression of inflammatory cytokines and endoplasmic reticulum stress markers, and the effects of FABP4 in podocytes were attenuated in the presence of an anti-FABP4 antibody. CONCLUSION: FABP4 in the glomerulus contributes to proteinuria in IgAN, and U-FABP4 level is a useful surrogate biomarker for glomerular damage in IgAN.

Prediction of cardiovascular events using myocardial strain ratio derived from 13N-ammonia positron emission tomography.

OBJECTIVES: Myocardial flow reserve (MFR), derived from ammonia N-13 positron emission tomography (NH3-PET), can predict the prognosis of patients with various heart diseases. We aimed to investigate whether myocardial strain ratio (MSR) was useful in predicting MACE and allowed for further risk stratification of cardiovascular events in patients with ischemic heart disease (IHD) in addition to MFR. METHODS: Ninety-five patients underwent NH3-PET because of IHD. MFR was determined as the ratio of hyperemic to resting myocardial blood flow (MBF). MSR was defined as the ratio of strains at stress and rest. The endpoint was major adverse cardiac events (MACE), including all-cause death, acute coronary syndrome, heart failure hospitalization, and revascularization. The ability to predict MACE was assessed using receiver operating characteristic (ROC) analysis, and the predictability of ME was analyzed using Kaplan-Meier analysis. The Cox proportional hazards regression model was used to calculate the hazard ratio (HR) with 95% confidence interval (CI). RESULTS: The ROC curve analysis demonstrated a cutoff of 0.93 for MACE with MSR (sensitivity and specificity of 77% and 71%, respectively). Patients with MSR < 0.93 displayed a significantly higher MACE rate than those with MSR ≥ 0.93 (p = 0.0036). The Cox proportional hazards regression analysis indicated that MSR was an independent marker that could predict MACE in imaging and clinical parameters (HR, 7.32; 95% CI: 1.59-33.7, p = 0.011). CONCLUSIONS: MSR was an independent predictor of MACE and was useful for further risk stratification in IHD. MSR has the potential for a new indicator of revascularization in patients with IHD. KEY POINTS: • We hypothesized that combining myocardial flow reserve (MFR) with the myocardial strain ratio (MSR) obtained by applying the feature-tracking technique to ammonia N-13 PET would make it predictive of major adverse cardiac events (MACE) compared to MFR alone. • MSR was an independent predictor of MACE, allowing for further risk stratification in addition to MFR in patients with ischemic heart disease. • MSR is a potential new indicator of revascularization.

FDG uptake patterns in isolated and systemic cardiac sarcoidosis.

AIMS: We aimed to investigate the pre-treatment characteristics and treatment responses of isolated and systemic cardiac sarcoidosis (ICS and SCS) from FDG-PET/CT studies and to compare the prognoses of the two groups. METHODS: FDG-PET/CT images taken before and after treatment of 31 ICS and 91 SCS patients were analyzed retrospectively. Treatment response and recurrence were determined from the course of FDG-PET/CT. Treatment response and the incidence of both recurrence and major adverse cardiac events (MACE) were assessed in 16 ICS and 35 SCS patients who had been treated for more than 2 years. RESULTS: A focal uptake pattern was more often observed than a focal-on-diffuse uptake pattern in both the ICS (74.2%) and SCS (63.7%) groups. Right ventricular involvement was significantly more frequent in SCS than ICS (44.0% vs. 9.6%, p < .001). SUVmax, cardiac metabolic volume (CMV), and cardiac metabolic activity (CMA) were significantly higher in SCS than ICS (SUVmax, 9.1 ± 4.1 vs. 4.8 ± 2.1; CMV, 118.0 ± 111.3 ml vs. 68.3 ± 94.7 ml; CMA, 541.6 ± 578.7 MBq vs. 265.1 ± 396.0 MBq, p < .001). Treatment responses in the two groups were similar, and complete resolution of cardiac uptake after immunosuppressive treatment was obtained in 62.5% of ICS patients and 77.1% of SCS patients (not significantly different). Likewise, no significant difference was found in the incidence of recurrence (40.0% for ICS, 44.4% for SCS) or MACE (25.0% for ICS, 22.8% for SCS). CONCLUSION: SCS patients had more active and extensive CS lesions than ICS patients before treatment, but the two groups showed similar treatment responses and prognoses.

Assessing anti-SARS-CoV-2 cellular immunity in 571 vaccines by using an IFN-γ release assay.

Memory T cell responses have been analyzed only in small cohorts of COVID-19 vaccines. Herein, we aimed to assess anti-SARS-CoV-2 cellular immunity in a large cohort using QuantiFERON assays, which are IFN-γ release assays (IGRAs) based on short-term whole blood culture. The study included 571 individuals receiving the viral spike (S) protein-expressing BNT162b2 mRNA vaccine. QuantiFERON assays revealed antigen-specific IFN-γ production in most individuals 8 weeks after the second dose. Simultaneous flow cytometric assays to detect T cells expressing activation-induced markers (AIMs) performed for 28 randomly selected individuals provided data correlating with the QuantiFERON data. Simultaneous IFN-γ enzyme-linked immunospot and AIM assays for another subset of 31 individuals, based on short-term peripheral blood mononuclear cell culture, also indicated a correlation between IFN-γ production and AIM positivity. These observations indicated the acquisition of T cell memory responses and supported the usability of IGRAs to assess cellular immunity. The QuantiFERON results were weakly correlated with serum IgG titers against the receptor-binding domain of the S protein and were associated with pre-vaccination infection and adverse reactions after the second dose. The present study revealed cellular immunity after COVID-19 vaccination, providing insights into the effects and adverse reactions of vaccination.

Glutamatergic pathways in the brains of turtles: A comparative perspective among reptiles, birds, and mammals.

Glutamate acts as the main excitatory neurotransmitter in the brain and plays a vital role in physiological and pathological neuronal functions. In mammals, glutamate can cause detrimental excitotoxic effects under anoxic conditions. In contrast, Trachemys scripta, a freshwater turtle, is one of the most anoxia-tolerant animals, being able to survive up to months without oxygen. Therefore, turtles have been investigated to assess the molecular mechanisms of neuroprotective strategies used by them in anoxic conditions, such as maintaining low levels of glutamate, increasing adenosine and GABA, upregulating heat shock proteins, and downregulating K ATP channels. These mechanisms of anoxia tolerance of the turtle brain may be applied to finding therapeutics for human glutamatergic neurological disorders such as brain injury or cerebral stroke due to ischemia. Despite the importance of glutamate as a neurotransmitter and of the turtle as an ideal research model, the glutamatergic circuits in the turtle brain remain less described whereas they have been well studied in mammalian and avian brains. In reptiles, particularly in the turtle brain, glutamatergic neurons have been identified by examining the expression of vesicular glutamate transporters (VGLUTs). In certain areas of the brain, some ionotropic glutamate receptors (GluRs) have been immunohistochemically studied, implying that there are glutamatergic target areas. Based on the expression patterns of these glutamate-related molecules and fiber connection data of the turtle brain that is available in the literature, many candidate glutamatergic circuits could be clarified, such as the olfactory circuit, hippocampal-septal pathway, corticostriatal pathway, visual pathway, auditory pathway, and granule cell-Purkinje cell pathway. This review summarizes the probable glutamatergic pathways and the distribution of glutamatergic neurons in the pallium of the turtle brain and compares them with those of avian and mammalian brains. The integrated knowledge of glutamatergic pathways serves as the fundamental basis for further functional studies in the turtle brain, which would provide insights on physiological and pathological mechanisms of glutamate regulation as well as neural circuits in different species.

Adverse Cardiac Events in Cardiac Sarcoidosis Prediction by 123I-betamethyl-p-iodophenyl-pentadecanoic Acid Single-Photon Emission Computed Tomography and Cardiac Magnetic Resonance Late Gadolinium Enhancement.

Late gadolinium enhancement (LGE) on cardiac magnetic resonance (CMR) imaging can help detect myocardial damage. 123I-betamethyl-p-iodophenyl-pentadecanoic acid single-photon emission computed tomography (BMIPP-SPECT) was developed to evaluate fatty acid metabolism and has been reported to help detect myocardial damage in cardiac sarcoidosis (CS). We analyzed data from CMR-LGE and performed BMIPP-SPECT in patients with CS taking prednisolone and investigated the association of BMIPP-SPECT with LGE as a prognostic factor in CS. Patients with CS who underwent BMIPP-SPECT and CMR-LGE at the time of diagnosis within 2 months were classified into those with and without a major adverse cardiac event (MACE). Total BMIPP-SPECT defect score (BDS) and LGE extent score (LES) were used to estimate myocardial damage. The relation between BDS and LES was explored using Pearson's correlation coefficient. Their ability to predict MACEs was analyzed using Kaplan-Meier analysis. Medical data of 45 patients were analyzed retrospectively (mean follow-up, 4.5 years). BDS and LES were significantly correlated (p <0.0001). BDS was significantly greater for the group with MACE than that without MACE (p = 0.0008). LES of patients with MACE was significantly greater than those without MACE (p = 0.0045). Patients with BDS ≥16 had a significantly higher MACE rate than those with BDS <16 (p = 0.0029). The group with LES ≥9 was significantly associated with MACE (p = 0.0098). In conclusion, BDS reflected myocardial damage similar to that detected by CMR-LGE and was a predictive marker of MACE in patients with CS. BMIPP-SPECT may help predict the prognosis of patients with CS who cannot undergo CMR-LGE.

Dynamic coronary CT Angiography-Estimated coronary flow in Non-Obstructive, Plaque-free coronary Arteries: Association with dyslipidemia and diabetes.

Rationale and Objectives: In this study, we implemented dynamic coronary CT angiography (CCTA) in order to estimate the coronary flow rate in morphologically normal coronary arteries as well as to identify factors affecting the coronary flow rate. Materials and Methods: We retrospectively enrolled 95 consecutively presenting patients without stenosis or plaque in their major coronary arteries on CCTA conducted with a 320-detector scanner (mean age, 57 years; 43 % men). Time-attenuation curves of the distal sites of the major coronary arteries and the aortic root were extracted from dynamic CCTA data. Coronary flow rate, an indicator of coronary blood flow, was calculated via a convolution-integration method integrating the two curves. Patients with dyslipidemia were divided according to the presence or absence of familial hypercholesterolemia (FH) as well as according to the receipt of statin therapy. Results: We found that the coronary flow rate was statistically significantly lower in statin-naïve patients with dyslipidemia (n = 27, 0.56 ± 0.10) than in patients without dyslipidemia (n = 32, 0.64 ± 0.10, p = 0.0013). In FH (n = 26), the coronary flow rate was statistically significantly lower in statin-naïve patients (n = 7, 0.65 ± 0.08) than in those taking statins (n = 19, 0.72 ± 0.10, p = 0.0221). Coronary flow rate likewise exhibited a statistically significant negative correlation with hemoglobin A1c (Pearson r, -0.437; p = 0.0003), but no correlation with other coronary risk factors. The coronary flow rate was statistically significantly lower in patients with diabetes (n = 14, 0.55 ± 0.10) than in those without diabetes (n = 81, 0.61 ± 0.11, p = 0.0461). Conclusion: We found a reduction in coronary flow rate in patients with statin-naive dyslipidemia and diabetes, even within morphologically normal coronary arteries.

Effects of Toxic AGEs (TAGE) on Human Health.

The habitual and excessive consumption of sugar (i.e., sucrose and high-fructose corn syrup, HFCS) is associated with the onset and progression of lifestyle-related diseases (LSRD). Advanced glycation end-products (AGEs) have recently been the focus of research on the factors contributing to LSRD. Approaches that inhibit the effects of AGEs may be used to prevent and/or treat LSRD; however, since the structures of AGEs vary depending on the type of reducing sugars or carbonyl compounds to which they respond, difficulties are associated with verifying that AGEs are an etiological factor. Cytotoxic AGEs derived from glyceraldehyde, a triose intermediate in the metabolism of glucose and fructose, have been implicated in LSRD and are called toxic AGEs (TAGE). A dietary imbalance (the habitual and excessive intake of sucrose, HFCS, or dietary AGEs) promotes the generation/accumulation of TAGE in vivo. Elevated circulating levels of TAGE have been detected in non-diabetics and diabetics, indicating a strong relationship between the generation/accumulation of TAGE in vivo and the onset and progression of LSRD. We herein outline current findings on "TAGE as a new target" for human health.

Intracellular Toxic Advanced Glycation End-Products May Induce Cell Death and Suppress Cardiac Fibroblasts.

Cardiovascular disease (CVD) is a lifestyle-related disease (LSRD) induced by the dysfunction and cell death of cardiomyocytes. Cardiac fibroblasts are activated and differentiate in response to specific signals, such as transforming growth factor-ß released from injured cardiomyocytes, and are crucial for the protection of cardiomyocytes, cardiac tissue repair, and remodeling. In contrast, cardiac fibroblasts have been shown to induce injury or death of cardiomyocytes and are implicated in the pathogenesis of diseases such as cardiac hypertrophy. We designated glyceraldehyde-derived advanced glycation end-products (AGEs) as toxic AGEs (TAGE) due to their cytotoxicity and association with LSRD. Intracellular TAGE in cardiomyocytes decreased their beating rate and induced cell death in the absence of myocardial ischemia. The TAGE levels in blood were elevated in patients with CVD and were associated with myocardial ischemia along with increased risk of atherosclerosis in vascular endothelial cells in vitro. The relationships between the dysfunction or cell death of cardiac fibroblasts and intracellular and extracellular TAGE, which are secreted from certain organs, remain unclear. We examined the cytotoxicity of intracellular TAGE by a slot blot analysis, and TAGE-modified bovine serum albumin (TAGE-BSA), a model of extracellular TAGE, in normal human cardiac fibroblasts (HCF). Intracellular TAGE induced cell death in normal HCF, whereas TAGE-BSA did not, even at aberrantly high non-physiological levels. Therefore, only intracellular TAGE induced cell death in HCF under physiological conditions, possibly inhibiting the role of HCF.

Dynamics of antibody titers and cellular immunity among Japanese healthcare workers during the 6 months after receiving two doses of BNT162b2 mRNA vaccine.

BACKGROUND: The antibody titer is known to wane within months after receiving two doses of the Pfizer-BioNTech BNT162b2 mRNA SARS-CoV-2 vaccine. However, knowledge of the cellular immune response dynamics following vaccination is limited. This study to aimed to determine antibody and cellular immune responses following vaccination, and the incidence and determinants of breakthrough infection. METHODS: This prospective cohort study a 6-month follow-up period was conducted among Japanese healthcare workers. All participants received two doses of BNT162b2 vaccine. Anti-SARS-CoV-2 antibody titers and T-cell immune responses were measured in serum samples collected at several timepoints before and after vaccination. RESULTS: A total of 608 participants were included in the analysis. Antibody titers were elevated 3 weeks after vaccination and waned over the remainder of the study period. T-cell immune responses showed similar dynamics. Six participants without predisposing medical conditions seroconverted from negative to positive on the IgG assay for nucleocapsid proteins, indicating breakthrough SARS-CoV-2 infection. Five of the six breakthrough infections were asymptomatic. CONCLUSIONS: Both humoral and cellular immunity waned within 6 months after BNT162b2 vaccination. The incidence of asymptomatic breakthrough infection within 6 months after vaccination was approximately one percent. UMIN CLINICAL TRIALS REGISTRY ID: UMIN000043340.