Nitrergic inhibition of sympathetic arteriolar constrictions in the female rodent urethra.

During the urine storage phase, tonically contracting urethral musculature would have a higher energy consumption than bladder muscle that develops phasic contractions. However, ischaemic dysfunction is less prevalent in the urethra than in the bladder, suggesting that urethral vasculature has intrinsic properties ensuring an adequate blood supply. Diameter changes in rat or mouse urethral arterioles were measured using a video-tracking system. Intercellular Ca2+ dynamics in arteriolar smooth muscle (SMCs) and endothelial cells were visualised using NG2- and parvalbumin-GCaMP6 mice, respectively. Fluorescence immunohistochemistry was used to visualise the perivascular innervation. In rat urethral arterioles, sympathetic vasoconstrictions were predominantly suppressed by α,ß-methylene ATP (10 µM) but not prazosin (1 µM). Tadalafil (100 nM), a PDE5 inhibitor, diminished the vasoconstrictions in a manner reversed by N-ω-propyl-l-arginine hydrochloride (l-NPA, 1 µM), a neuronal NO synthesis (nNOS) inhibitor. Vesicular acetylcholine transporter immunoreactive perivascular nerve fibres co-expressing nNOS were intertwined with tyrosine hydroxylase immunoreactive sympathetic nerve fibres. In phenylephrine (1 µM) pre-constricted rat or mouse urethral arterioles, nerve-evoked vasodilatations or transient SMC Ca2+ reductions were largely diminished by l-nitroarginine (l-NA, 10 µM), a broad-spectrum NOS inhibitor, but not by l-NPA. The CGRP receptor antagonist BIBN-4096 (1 µM) shortened the vasodilatory responses, while atropine (1 µM) abolished the l-NA-resistant transient vasodilatory responses. Nerve-evoked endothelial Ca2+ transients were abolished by atropine plus guanethidine (10 µM), indicating its neurotransmitter origin and absence of non-adrenergic non-cholinergic endothelial NO release. In urethral arterioles, NO released from parasympathetic nerves counteracts sympathetic vasoconstrictions pre- and post-synaptically to restrict arteriolar contractility. KEY POINTS: Despite a higher energy consumption of the urethral musculature than the bladder detrusor muscle, ischaemic dysfunction of the urethra is less prevalent than that of the bladder. In the urethral arterioles, sympathetic vasoconstrictions are predominately mediated by ATP, not noradrenaline. NO released from parasympathetic nerves counteracts sympathetic vasoconstrictions by its pre-synaptic inhibition of sympathetic transmission as well as post-synaptic arteriolar smooth muscle relaxation. Acetylcholine released from parasympathetic nerves contributes to endothelium-dependent, transient vasodilatations, while CGRP released from sensory nerves prolongs NO-mediated vasodilatations. PDE5 inhibitors could be beneficial to maintain and/or improve urethral blood supply and in turn the volume and contractility of urethral musculature.

Changes in spinal sagittal balance after a new osteoporotic vertebral compression fracture.

We conduct a longitudinal study to examine how new VCF alter spinal sagittal balance. New VCF increased SVA by an average of 2.8 cm. Sagittal balance deteriorates as a VCF develops in the lower lumbar spine. A new fracture below L1 increased the relative risk of a deterioration of sagittal balance 2.9-fold compared to one above Th12. PURPOSE: Studies on the relationship between osteoporotic vertebral fractures and spinal sagittal balance have all been limited to cross-sectional studies. The aim of this study is to conduct a longitudinal study to examine how new vertebral compression fracture (VCF) alter spinal sagittal balance. METHODS: Subjects were patients undergoing periodic examinations after treatment of a vertebral fracture or lumbar spinal canal stenosis. Forty patients who developed a new VCF were included in this study. Full-spine standing radiographs were compared before and after the fracture to examine changes in spinopelvic parameters and factors determining the changes in sagittal balance. RESULTS: The mean age of the patients was 79.0 years. The mean interval between pre- and post-fracture radiographs was 22.7 months, and the mean time between development of a fracture and post-fracture radiographs was 4.6 months. After a fracture, sagittal vertical axis (SVA) increased an average of 2.78 cm and spino-sacral angle (SSA) decreased an average of 5.3°. Both ⊿SVA and ⊿SSA were not related to pre-fracture parameters. The wedge angle of the fractured vertebra was not related to changes in sagittal balance. ⊿SVA increased markedly in patients with a fracture of the lower lumbar vertebrae. receiver operating characteristic analysis revealed that the relative risk of a deterioration of sagittal balance was 2.9 times higher for a new fracture below L1 than for a fracture above Th12. CONCLUSION: New VCF increased SVA by an average of 2.8 cm. Sagittal balance deteriorates as a new fracture develops in the lower lumbar spine. Early intervention in osteoporosis is vital for the elderly.

Scoring System for Prediction of Left Ventricular Longitudinal Myocardial Dysfunction in Preclinical Heart Failure Patients.

BACKGROUND: Detection of left ventricular (LV) abnormalities is essential for patients with preclinical heart failure (HF) to delay progression to clinical HF. Global longitudinal strain (GLS) is a sensitive marker for the early occurrence of subtle abnormalities in LV function, but not all echocardiographic instruments can measure GLS.Methods and Results: We studied 853 preclinical HF patients to devise a scoring system for predicting low GLS (<16%). The associations of medical history and echocardiographic parameters with low GLS were evaluated using Cox proportional hazards analysis. Model 1 of the system consisted of medical history; for Model 2, conventional echocardiographic parameters were added to Model 1. For Model 1, a score ≥5 points meant prediction of low GLS with 90.2% sensitivity and 62.9% specificity (male=1 point, hypertension=4 points, dyslipidemia=1 point, atrial fibrillation=2 points, history of cardiac surgery=2 points). For Model 2, a score ≥4 points denotes prediction of low GLS with 80.3% sensitivity and 76.5% specificity (male=1 point, hypertension=2 points, atrial fibrillation=2 points, LV mass index >116 g/m2[male] or >96 g/m2[female]=1 point, LV ejection fraction <59%=2 points, E/e' >14=1 point). CONCLUSIONS: Our scoring system provides an easy-to-use evaluation of LV longitudinal myocardial dysfunction, and may prove useful for risk stratification of patients with preclinical HF.

Importance of B-Type Natriuretic Peptide in the Detection of Patients With Structural Heart Disease in a Primary Care Setting.

BACKGROUND: Early detection and intervention for preclinical heart failure (HF) are crucial for restraining the potential increase in patients with HF. Thus, we designed and conducted a single-center retrospective cohort study to confirm the efficacy of B-type natriuretic peptide (BNP) for the early detection of preclinical HF in a primary care setting.Methods and Results: We investigated 477 patients with no prior diagnosis of HF who were under the care of general practitioners. These patients were categorized into 4 groups based on BNP concentrations: Category 1, 0 pg/mL≤BNP≤35 pg/mL; Category 2, 35 pg/mL200 pg/mL. There was a marked and statistically significant increase in the prevalence of preclinical HF with increasing BNP categories: 19.9%, 57.9%, 87.5%, and 96.0% in Categories 1, 2, 3, and 4, respectively. Compared with Category 1, the odds ratio of preclinical HF in Categories 2, 3, and 4 was determined to be 5.56 (95% confidence interval [CI] 3.57-8.67), 23.70 (95% CI 8.91-63.11), and 171.77 (95% CI 10.31-2,861.93), respectively. CONCLUSIONS: Measuring BNP is a valuable tool for the early detection of preclinical HF in primary care settings. Proactive testing in patients at high risk of HF could play a crucial role in addressing the impending HF pandemic.

Efficacy of Native T1 Mapping for Patients With Non-Ischemic Cardiomyopathy and Ventricular Functional Mitral Regurgitation Undergoing Transcatheter Edge-to-Edge Repair.

BACKGROUND: We investigated the efficacy of left ventricular (LV) myocardial damage by native T1mapping obtained with cardiac magnetic resonance (CMR) for patients undergoing transcatheter edge-to-edge repair (TEER).Methods and Results: We studied 40 symptomatic non-ischemic heart failure (HF) patients and ventricular functional mitral regurgitation (VFMR) undergoing TEER. LV myocardial damage was defined as the native T1Z-score, which was converted from native T1values obtained with CMR. The primary endpoint was defined as HF rehospitalization or cardiovascular death over 12 months after TEER. Multivariable Cox proportional hazards analysis showed that the native T1Z-score was the only independent parameter associated with cardiovascular events (hazard ratio 3.40; 95% confidential interval 1.51-7.67), and that patients with native T1Z-scores <2.41 experienced significantly fewer cardiovascular events than those with native T1Z-scores ≥2.41 (P=0.001). Moreover, the combination of a native T1Z-score <2.41 and more severe VFMR (effective regurgitant orifice area [EROA] ≥0.30 cm2) was associated with fewer cardiovascular events than a native T1Z-score ≥2.41 and less severe VFMR (EROA <0.30 cm2; P=0.002). CONCLUSIONS: Assessment of baseline LV myocardial damage based on native T1Z-scores obtained with CMR without gadolinium-based contrast media is a valuable additional parameter for better management of HF patients and VFMR following TEER.

Utility of Contrast-Enhanced Harmonic Endoscopic Ultrasonography to Diagnose Pancreaticobiliary Maljunction.

BACKGROUND: Detection of a common channel outside the duodenal wall is important in diagnosing pancreaticobiliary maljunction (PBM). The present study evaluated the utility of contrast-enhanced harmonic endoscopic ultrasonography (CH-EUS) in diagnosing PBM. METHODS: This single-center retrospective study enrolled 45 patients who were diagnosed with PBM or high confluence of pancreatobiliary ducts (HCPBD) between January 2007 and December 2021. The diagnostic sensitivities of contrast-enhanced computed tomography (CE-CT), magnetic resonance imaging (MRI), and CH-EUS for diagnosing PBM were analyzed. Imaging findings were evaluated by two reviewers blinded to the clinicopathological results. RESULTS: Based on diagnostic criteria, 33 patients were diagnosed with PBM and 12 with HCPBD. Compared with the patients with HCPBD, those with PBM had significantly longer common channel (12.5 mm vs. 8.1 mm, P = 0.018) and common bile duct (13.0 mm vs. 8.6 mm, P = 0.049) lengths. The κ-coefficients for differentiating PBM and HCPBD were 0.871 between CE-CT and MRI, 0.330 between CE-CT and CH-EUS, and 0.611 between MRI and CH-EUS. The diagnostic sensitivity of CH-EUS (95.2%) was higher than that of CE-CT (83.3%) and MRI (82.8%), although the differences were not statistically significant. CONCLUSION: CH-EUS may be useful for the diagnosis of PBM.

Effect of tafamidis on left atrial function of patients with transthyretin amyloid cardiomyopathy.

Transthyretin amyloid cardiomyopathy (ATTR-CM) is characterized by the functional and structural effects of amyloid infiltration, predominantly within the ventricles, causing biventricular wall thickening. Amyloid infiltration can be observed in the left atrium in ATTR-CM patients, but the association of left atrial (LA) myocardial function with cardiovascular events and of changes in LA myocardial function with tafamidis administration have not yet been clarified. Our aim was, therefore, to use speckle-tracking strain for investigating LA myocardial function in patients with ATTR-CM treated with tafamidis. We studied 55 patients with biopsy-proven ATTR-CM who had been treated with tafamidis (age: 76 ± 2 years, male: 93%). For speckle-tracking analysis of LA myocardial function, the systolic LA strain (LA reservoir function) was defined for this study as LA myocardial function from the apical 4-chamber view. The primary endpoint was defined as a composite comprising cardiovascular death and/or heart failure hospitalization after tafamidis administration over a median follow-up period of 28 ± 4 months. Patients with baseline LA strain < 8.6% (median value) experienced significantly more cardiovascular events than those without (log-rank P = 0.002). Moreover, LA strain in 26 patients worsened after tafamidis administration, and multivariate logistic regression analysis showed age, global longitudinal strain and relative apical longitudinal strain index were identified as independent determinants of deterioration of LA strain after tafamidis administration. In conclusion, baseline LA reservoir function is closely associated with cardiovascular events after tafamidis administration, and could be an additional parameter for the management of patients with ATTR-CM.

Left ventricular reverse remodeling following initiation of sacubitril/valsartan for heart failure with reduced ejection fraction and low blood pressure.

Sacubitril/valsartan has become an important first-line drug for symptomatic heart failure (HF) patients, especially with left ventricular (LV) ejection fraction (LVEF) < 50%. However, the impact of sacubitril/valsartan on cardiovascular outcomes, especially LV reverse remodeling for such patients with low blood pressure, remains uncertain. We retrospectively studied 164 HF patients with LVEF < 50% who were treated with sacubitril/valsartan from two institutions. Echocardiography was performed before and 9.5 ± 5.1 months after initiation of maximum tolerated dose of sacubitril/valsartan. The maximum tolerated dose of sacubitril/valsartan was lower for the low blood pressure group (≤ 100 mmHg in systole) than for the non-low blood pressure group (> 100 mmHg in systole) (165 ± 106 mg vs. 238 ± 124 mg, P = 0.017). As expected, significant LV reverse remodeling was observed in the non-low blood pressure group after initiation of sacubitril/valsartan. It was noteworthy that significant LV reverse remodeling was also observed in the low blood pressure group after initiation of sacubitril/valsartan (LV end-diastolic volume: 177.3 ± 66.0 mL vs. 137.7 ± 56.1 mL, P < 0.001, LV end-systolic volume: 131.6 ± 60.3 mL vs. 94.6 ± 55.7 mL, P < 0.001, LVEF: 26.8 ± 10.3% vs. 33.8 ± 13.6%, P = 0.015). Relative changes in LV volumes and LVEF after initiation of sacubitril/valsartan were similar for the two groups. In conclusion, significant LV reverse remodeling occurred after initiation of sacubitril/valsartan, even in HF patients with LVEF < 50% and systolic blood pressure ≤ 100 mmHg.

Left atrial volume index as a predictor for left atrial appendage thrombus in patients with non-valvular atrial fibrillation receiving appropriate oral anticoagulation therapy: A prospective multi-center study.

OBJECTIVES: We previously reported a higher left atrial volume index (LAVI) was independently associated with left atrial (LA) appendage (LAA) thrombus formation in 737 patients with non-valvular atrial fibrillation (NVAF) receiving appropriate oral anticoagulation therapy. Since our previous study was a retrospective single-center study, we designed and conducted a prospective multi-center study to verify our findings for LAVI as a predictor of LAA thrombus in patients with NVAF receiving appropriate oral anticoagulation therapy. METHODS: This prospective multi-center study comprised 746 consecutive patients with NVAF recruited between December 2021 and March 2023 from eight institutions in Japan, who were receiving appropriate oral anticoagulation therapy, had undergone transthoracic echocardiography and transesophageal echocardiography (TEE). RESULTS: LAA thrombi were observed in 21 patients (2.8%). The prevalence of LAA thrombus formation in patients with paroxysmal AF (PAF) was significantly lower than that in patients with non-PAF (0.7% vs. 4.1%, p = .006). LAA thrombus formation was detected in none (0/171) of the patients with normal size LA (LAVI ≤ 34 mL/m2 ). The prevalence of LAA thrombus formation in patients with mildly dilated LA (LAVI: 34-49.9 mL/m2 ) was 2.1% (6/283), but that in PAF patients was low at 1.0% (1/104). Furthermore, this prevalence in patients with severely dilated LA (LAVI ≥ 50 mL/m2 ) was high at 5.1% (15/292). CONCLUSIONS: The findings of this prospective multi-center study are consistent with those of our previous study. Thus, the need for TEE prior to catheter ablation or electrical cardioversion can be determined by the level of LAVI.

The safety of perioperative antiplatelet continuation without selection biases in microsurgical decompression surgery for single level lumbar spinal stenosis and lumbar disc herniotomy.

PURPOSE: Each institution or physician has to decide on an individual basis whether to continue or discontinue antiplatelet (AP) therapy before spinal surgery. The purpose of this study was to determine if perioperative AP continuation is safe during single-level microsurgical decompression (MSD) for treating lumbar spinal stenosis (LSS) and lumbar disc hernia (LDH) without selection bias. METHODS: Patients who underwent single-level MSD for LSS and LDH between April 2018 to December 2022 at our institute were included in this retrospective study. We collected data regarding baseline characteristics, medical history/comorbidities, epidural hematoma (EDH) volume, reoperation for EDH, differences between preoperative and one-day postoperative blood cell counts (ΔRBC), hemoglobin (ΔHGB), and hematocrits (ΔHCT), and perioperative thromboembolic complications. Patients were divided into two groups: the AP continuation group received AP treatment before surgery and the control group did not receive antiplatelet medication before surgery. Propensity scores for receiving AP agents were calculated, with one-to-one matching of estimated propensity scores to adjust for patient baseline characteristics and past histories. Reoperation for EDH, EDH volume, ΔRBC, ΔHGB, ΔHCT, and perioperative thromboembolic complications were compared between the groups. RESULTS: The 303 enrolled patients included 41 patients in the AP continuation group. After propensity score matching, the rate of reoperation for EDH, the EDH volume, ΔRBC, ΔHGB, ΔHCT, and perioperative thromboembolic complication rates were not significantly different between the groups. CONCLUSION: Perioperative AP continuation is safe for single-level lumbar MSD, even without biases.

Factors influencing slippage after microsurgical single level lumbar spinal decompression surgery - Are the psoas and multifidus muscles involved?

PURPOSE: Patients with lumbar spinal stenosis (LSS) require microsurgical decompression (MSD) surgery; however, MSD is often associated with postoperative instability at the operated level. Paraspinal muscles support the spinal column; lately, paraspinal volume has been used as a good indicator of sarcopenia. This study aimed to determine preoperative radiological factors, including paraspinal muscle volume, associated with postoperative slippage progression after MSD in LSS patients. METHODS: Patients undergoing single-level (L3/4 or L4/5) MSD for symptomatic LSS and followed-up for ≥ 5 years in our institute were reviewed retrospectively to measure preoperative imaging parameters focused on the operated level. Paraspinal muscle volumes (psoas muscle index [PMI] and multifidus muscle index [MFMI]) defined using the total cross-sectional area of each muscle/L3 vertebral body area in the preoperative lumbar axial CT) were calculated. Postoperative slippage in the form of static translation (ST) ≥ 2 mm was assessed on the last follow-up X-ray. RESULTS: We included 95 patients with average age and follow-up periods of 69 ± 8.2 years and 7.51 ± 2.58 years, respectively. PMI and MFMI were significantly correlated with age and significantly larger in male patients. Female sex, preoperative ST, dynamic translation, sagittal rotation angle, facet angle, pelvic incidence, lumbar lordosis, and PMI were correlated with long-term postoperative worsening of ST. However, as per multivariate analysis, no independent factor was associated with postoperative slippage progression. CONCLUSION: Lower preoperative psoas muscle volume in LSS patients is an important predictive factor of postoperative slippage progression at the operated level after MSD. The predictors for postoperative slippage progression are multifactorial; however, a well-structured postoperative exercise regimen involving psoas muscle strengthening may be beneficial in LSS patients after MSD.

Intra- and inter-fractional variations of tumors with fiducial markers measured using respiratory-correlated computed tomography images for respiratory gated lung stereotactic body radiation therapy.

PURPOSE: This study evaluated the intra- and inter-fractional variation of tumors with fiducial markers (FMs), relative to the tumor-FM distance, to establish how close an FM should be inserted for respiratory-gated stereotactic body radiation therapy (RG-SBRT). METHODS: Forty-five lung tumors treated with RG-SBRT were enrolled. End-expiratory computed tomography (CT) (CTplan) and four-dimensional-CT (4D-CT) scans were obtained for planning. End-expiratory CT (CTfr) scanning was performed before each fraction. The FMs were divided into two groups based on the median tumor-FM distance in the CTplan (Dp). For the intra-fractional variation, the correlations between the corresponding tumor and FM intra-fractional motions, defined as the centroid coordinates of those in each 0-90% phase, with the 50% phase of 4D-CT as the origin, were calculated in the left-right, anterior-posterior, and superior-inferior directions. Furthermore, the maximum difference in the tumor-FM distance in each phase of 4D-CT scan, based on those in the 50% phase of 4D-CT scan (Dmax), was obtained. Inter-fractional variation was defined as the maximum distance between the tumors in CTplan and CTfr, when the CT scans were fused based on each FM or vertebra. RESULTS: The median Dp was 26.1 mm. While FM intra-fractional motions were significantly and strongly correlated with the tumor intra-fractional motions in only anterior-posterior and superior-inferior directions for the Dp > 26 mm group, they were significantly and strongly correlated in all directions for the Dp ≤ 26 mm group. In all directions, Dmax values of the Dp ≤ 26 mm group were lower than those of the Dp > 26 mm group. The inter-fractional variations based on the Dp ≤ 26 mm were smaller than those on the Dp > 26 mm and on the vertebra in all directions. CONCLUSIONS: Regarding intra- and inter-fractional variation, FMs for Dp ≤ 26 mm can increase the accuracy for RG-SBRT.

Illustrative review of cardiac amyloidosis by multimodality imaging.

Cardiac involvement in amyloidosis is characterized by the extracellular deposition of misfolded proteins in the heart with the pathognomonic histological property of green birefringence when viewed under cross-polarized light after staining with Congo red. Although considered a rare disease, recent data suggest that cardiac amyloidosis is underappreciated as a cause of common cardiac diseases or syndromes. The prognosis for transthyretin (TTR) amyloidosis (ATTR) amyloidosis is better than that for amyloid light-chain amyloidosis; however, it is not as good as for other etiologies heart failure. Although there is no proven therapy for patients with ATTR cardiomyopathy (ATTR-CM), tafamidis meglumine, a TTR stabilizer, a study in 2018 found it was associated with reductions in all-cause mortality and cardiovascular-related hospitalizations, as well as with a reduction in the decline in functional capacity and quality of life compared with a placebo for patients with ATTR-CM. As a result of these findings, tafamidis meglumine is currently the only drug approved for patients with both wild-type and variant ATTR-CM, and should be considered for patients whose survival can be reasonably expected. In addition, recent advances in cardiac imaging, diagnostic strategies, and therapies have improved so that interest has been growing in the diagnosis of ATTR-CM by means of non-invasive imaging modalities as a potential means for better management of patients with ATTR-CM. This article reviews the efficacy of non-invasive imaging, especially echocardiography, cardiac magnetic imaging, and 99mTc-pyrophosphate scintigraphy for diagnosis of cardiac amyloidosis.

Impact of Tafamidis on Echocardiographic Cardiac Function of Patients With Transthyretin Cardiac Amyloidosis.

BACKGROUND: The efficacy of a therapy for patients with transthyretin amyloid cardiomyopathy (ATTR-CM) has not been proven, but tafamidis has been associated with favorable outcomes. However, echocardiographic details of the association of tafamidis with cardiac morphology remain undetermined. Moreover, whether the efficacy of tafamidis varies with the degree of cardiac involvement remains unknown. Using echocardiography, this study investigated the impact of tafamidis on the cardiac morphology of patients with ATTR-CM.Methods and Results: Of 52 consecutive patients with biopsy-proven ATTR-CM at Kobe University Hospital, we included 41 for whom details of follow-up echocardiographic examinations after the administration of tafamidis were available. All patients underwent standard and speckle-tracking echocardiography before and a mean (±SD) of 16±8 months after the administration of tafamidis. No significant changes were observed in any representative echocardiographic parameters after the administration of tafamidis. Furthermore, there were no significant changes observed in subgroup analyses (e.g., left ventricular [LV] ejection fraction ≥50% vs. <50%; LV mass index <150 vs. ≥150 g/m2; New York Heart Association Class I-II vs. Class III; age ≥80 vs. <80 years). CONCLUSIONS: Tafamidis may prevent worsening of various representative echocardiographic parameters of patients with ATTR-CM. This effect is also seen in patients with relatively advanced disease and in those who are elderly.

Association Between Serum 3-Hydroxyisobutyric Acid and Prognosis in Patients With Chronic Heart Failure　- An Analysis of the KUNIUMI Registry Chronic Cohort.

BACKGROUND: Diabetes increases the risk of heart failure (HF). 3-Hydroxyisobutyric acid (3-HIB) is a muscle-derived metabolite reflecting systemic insulin resistance. In this study, we investigated the prognostic impact of 3-HIB in patients with chronic HF.Methods and Results: The KUNIUMI Registry chronic cohort is a community-based cohort study of chronic HF in Awaji Island, Japan. We analyzed the association between serum 3-HIB concentrations and adverse cardiovascular (CV) events in 784 patients from this cohort. Serum 3-HIB concentrations were significantly higher in patients with than without diabetes (P=0.0229) and were positively correlated with several metabolic parameters. According to Kaplan-Meier analysis, rates of CV death and HF hospitalization at 2 years were significantly higher among HF patients without diabetes in the high 3-HIB group (3-HIB concentrations above the median; i.e., >11.30 µmol/L) than in the low 3-HIB group (log-rank P=0.0151 and P=0.0344, respectively). Multivariable Cox proportional hazard models adjusted for established risk factors for HF revealed high 3-HIB as an independent predictor of CV death (hazard ratio [HR] 1.82; 95% confidence interval [CI] 1.16-2.85; P=0.009) and HF hospitalization (HR 1.72; 95% CI 1.17-2.53, P=0.006) in HF patients without diabetes, whereas no such trend was seen in subjects with diabetes. CONCLUSIONS: In a community cohort, circulating 3-HIB concentrations were associated with prognosis in chronic HF patients without diabetes.

Plasma cystine/methionine ratio is associated with left ventricular diastolic function in patients with heart disease.

Elevated circulating homocysteine (Hcy) is a well-known risk factor for cardiovascular diseases (CVDs), including coronary artery disease (CAD) and heart failure (HF). It remains unclear how Hcy and its derivatives relate to left ventricular (LV) diastolic function. The aim of the present study was to investigate the relationship between plasma Hcy-related metabolites and diastolic dysfunction (DD) in patients with heart disease (HD). A total of 62 HD patients with preserved LV ejection fraction (LVEF ≥ 50%) were enrolled. Plasma Hcy and its derivatives were measured by liquid chromatography‒mass spectrometry (LC-MS/MS). Spearman's correlation test and multiple linear regression models were used to analyze the associations between metabolite levels and LV diastolic function. The cystine/methionine (CySS/Met) ratio was positively correlated with LV diastolic function, which was defined from the ratio of mitral inflow E and mitral e' annular velocities (E/e') (Spearman's r = 0.43, p < 0.001). When the subjects were categorized into two groups by E/e', the high-E/e' group had a significantly higher CySS/Met ratio than the low-E/e' group (p = 0.002). Multiple linear regression models revealed that the CySS/Met ratio was independently associated with E/e' after adjustment for age, sex, body mass index (BMI), diabetes mellitus, hypertension, chronic kidney disease (CKD),　hemoglobin, and lipid peroxide (LPO) {standardized ß (95% CI); 0.14 (0.04-0.23); p = 0.005}. Hcy, CySS, and Met did not show a significant association with E/e' in the same models. A high plasma CySS/Met ratio reflected DD in patients with HD.

Impact of Smad4 and p53 mutations on the prognosis of patients with pancreatic ductal adenocarcinoma undergoing chemotherapy.

BACKGROUND: This prospective cohort study evaluated the feasibility of using endoscopic ultrasound-guided fine-needle biopsy (EUS-FNB) samples for comprehensive mutational analysis of cancer-related genes using microtissues. METHODS: Fifty patients with suspected pancreatic cancer presenting consecutively at the Kindai University Hospital between January 2018 and January 2019 were enrolled. Cancerous tissues from EUS-FNB were obtained from each tumor and subjected to histological examination and mutational analysis. The primary endpoint was the collection rate of EUS-FNB specimens suitable for comprehensive cancer panels using deep sequencing. Clinical history and genetic variations between the disease control and progressive disease groups of patients on chemotherapy were evaluated as secondary endpoints. RESULTS: The collection rate of EUS-FNB specimens suitable for comprehensive cancer panels using deep sequencing was 93.6%. The cancer panel was sequenced for 25 patients with pancreatic cancer treated initially with systemic chemotherapy. Mutation in p53 and Smad4 were positively and negatively associated, respectively, with disease control at the initial evaluation. The median time to progression in 15 patients with p53 and without Smad4 mutations was 182.0 days; whereas, it was 92.5 days in other 10 patients; this difference was significant (p = 0.020). CONCLUSIONS: Tissue samples from EUS-FNB were suitable for mutational analysis. Pancreatic cancers with p53 and without Smad4 mutations responded better to chemotherapy and had a better prognosis than those others.

Identification of factors associated with progression of left atrial enlargement in patients with atrial fibrillation.

Left atrial (LA) enlargement frequently occurs in atrial fibrillation (AF) patients, and this enlargement is associated with the development of heart failure, thromboembolism, or atrial functional mitral regurgitation (AFMR). AF patients can develop LA enlargement over time, but its progression depends on the individual. So far, the factors that cause progressive LA enlargement in AF patients have thus not been elucidated, so that the aim of this study was to identify the factors associated with the progression of LA enlargement in AF patients. We studied 100 patients with persistent or permanent AF (aged: 67 ± 2 years, 40 females). Echocardiography was performed at baseline and 12 (5-30) months after follow-up. LA size was evaluated as the LA volume index which was calculated with the biplane modified Simpson's method from apical four-and two-chamber views, and then normalized to the body surface area (LAVI). The deterioration of AFMR after follow-up was defined as a deterioration in severity of mitral regurgitation (MR) by a grade of 1 or more. Multivariate regression analysis demonstrated that hypertension (p = .03) was an independently associated parameter of progressive LA enlargement, as was baseline LAVI. In addition, the Kaplan-Meier curve indicated that patients with hypertension tended to show greater deterioration of AFMR after follow-up than those without hypertension (log-rank p = .08). Hypertension proved to be strongly associated with progression of LA enlargement over time in patients with AF. Our findings provide new insights for better management of patients with AF to prevent the development of AFMR.

Risk stratification of patients with cardiac sarcoidosis: the ILLUMINATE-CS registry.

AIMS: This study evaluated the prognosis and prognostic factors of patients with cardiac sarcoidosis (CS), an underdiagnosed disease. METHODS AND RESULTS: Patients from a retrospective multicentre registry, diagnosed with CS between 2001 and 2017 based on the 2016 Japanese Circulation Society or 2014 Heart Rhythm Society criteria, were included. The primary endpoint was a composite of all-cause death, hospitalization for heart failure, and documented fatal ventricular arrhythmia events (FVAE), each constituting exploratory endpoints. Among 512 registered patients, 148 combined events (56 heart failure hospitalizations, 99 documented FVAE, and 49 all-cause deaths) were observed during a median follow-up of 1042 (interquartile range: 518-1917) days. The 10-year estimated event rates for the primary endpoint, all-cause death, heart failure hospitalizations, and FVAE were 48.1, 18.0, 21.1, and 31.9%, respectively. On multivariable Cox regression, a history of ventricular tachycardia (VT) or fibrillation [hazard ratio (HR) 2.53, 95% confidence interval (CI) 1.59-4.00, P < 0.001], log-transformed brain natriuretic peptide (BNP) levels (HR 1.28, 95% CI 1.07-1.53, P = 0.008), left ventricular ejection fraction (LVEF) (HR 0.94 per 5% increase, 95% CI 0.88-1.00, P = 0.046), and post-diagnosis radiofrequency ablation for VT (HR 2.65, 95% CI 1.02-6.86, P = 0.045) independently predicted the primary endpoint. CONCLUSION: Although mortality is relatively low in CS, adverse events are common, mainly due to FVAE. Patients with low LVEF, with high BNP levels, with VT/fibrillation history, and requiring ablation to treat VT are at high risk.

Investigation of the combination of intratumoral and peritumoral radiomic signatures for predicting epidermal growth factor receptor mutation in lung adenocarcinoma.

PURPOSE: We investigated optimal peritumoral size and constructed predictive models for epidermal growth factor receptor (EGFR) mutation. METHODS: A total of 164 patients with lung adenocarcinoma were retrospectively analyzed. Radiomic signatures for the intratumoral region and combinations of intratumoral and peritumoral regions (3, 5, and 7 mm) from computed tomography images were extracted using analysis of variance and least absolute shrinkage. The optimal peritumoral region was determined by radiomics score (rad-score). Intratumoral radiomic signatures with clinical features (IRS) were used to construct predictive models for EGFR mutation. Combinations of intratumoral and 3, 5, or 7 mm-peritumoral signatures with clinical features (IPRS3, IPRS5, and IPRS7, respectively) were also used to construct predictive models. Support vector machine (SVM), logistic regression (LR), and LightGBM models with five-fold cross-validation were constructed, and the receiver operating characteristics were evaluated. Area under the curve (AUC) of the training and test cohorts values were calculated. Brier scores (BS) and decision curve analysis (DCA) were used to evaluate the predictive models. RESULTS: The AUC values of the SVM, LR, and LightGBM models derived from IRS were 0.783 (95% confidence interval: 0.602-0.956), 0.789 (0.654-0.927), and 0.735 (0.613-0.958) for training, and 0.791 (0.641-0.920), 0.781 (0.538-0.930), and 0.734 (0.538-0.930) for test cohort, respectively. Rad-score confirmed that the 3 mm-peritumoral size was optimal (IPRS3), and AUCs values of SVM, LR, and lightGBM models derived from IPRS3 were 0.831 (0.666-0.984), 0.804 (0.622-0.908), and 0.769 (0.628-0.921) for training and 0.765 (0.644-0.921), 0.783 (0.583-0.921), and 0.796 (0.583-0.949) for test cohort, respectively. The BS and DCA of the LR and LightGBM models derived from IPRS3 were better than those from IRS. CONCLUSION: Accordingly, the combination of intratumoral and 3 mm-peritumoral radiomic signatures may be helpful for predicting EGFR mutations.