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Abstract Aims The human epididymis protein 4 (HE4), a novel fibrosis marker, is expressed only in activated fibroblasts and is thought to reflect ongoing left ventricular (LV) fibrosis. LV fibrosis is a feature of severe aortic stenosis (AS) and is related to the post‐operative outcome of patients with AS. We investigated the relationship between serum levels of HE4 and the post‐operative prognosis of patients with severe AS. Methods and results We measured the serum HE4 levels of 55 participants (80.8 ± 8.0 years old, male n = 26, 46%) with severe AS prior to surgical aortic valve replacement (n = 31, 56%) or transcatheter aortic valve implantation (n = 24, 44%) at Kumamoto University Hospital in 2018. We followed them for cardiovascular (CV) death or hospitalization for heart failure (HF) for 3 years. Serum HE4 levels were positively correlated with computed tomography–extracellular volume (CT‐ECV) values (r = 0.53, P = 0.004). Kaplan–Meier curves demonstrated a significantly higher probability of hospitalization for HF or CV‐related death in the patients with high HE4 (greater than the median HE4 value) compared with the patients with low HE4 (lower than the median HE4 value) (log‐rank P = 0.003). Multivariate analysis showed HE4 (log(HE4)) to be an independent prognostic factor [hazard ratio (HR): 7.50; 95% confidence interval (CI): 1.81–31.1; P = 0.005]. Receiver operating characteristic (ROC) curve analysis suggested that HE4 is a marker of increased risk of CV‐related death or hospitalization for HF at 3 years after surgery, with an area under the curve (AUC) of 0.76 (95% CI: 0.62–0.90; P = 0.003). Conclusions We found that HE4 is a potentially useful biomarker for predicting future CV events in patients scheduled for AS surgery. Measuring serum HE4 values could help consider AS surgery.

Abstract Aims There are minimal data on the prognostic impact of right atrial strain during the reservoir phase (RASr) in patients with immunoglobulin light‐chain (AL) cardiac amyloidosis. Methods and results Among 78 patients who were diagnosed with AL cardiac amyloidosis at Kumamoto University Hospital from 2007 to 2022, 72 patients with sufficient two‐dimensional speckle tracking imaging data without chemotherapy before the diagnosis were retrospectively analysed. During a median follow‐up of 403 days, 31 deaths occurred. Age and the rate of male sex were not significantly different between the all‐cause death group and the survival group (age, 70.4 ± 8.8 years vs. 67.0 ± 10.0 years, P = 0.14, male sex, 65% vs. 66%, P = 0.91). The estimated glomerular filtration rate (eGFR) was significantly lower, and B‐type natriuretic peptide (BNP) and high sensitivity cardiac troponin T (hs‐cTnT) were significantly higher, in the all‐cause death group versus the survival group (eGFR, 48.2 ± 21.0 mL/min/1.73 m2 vs. 59.4 ± 24.4 mL/min/1.73 m2, P 311.2 pg/mL) had a significantly high probability of all‐cause death (both, P

Background: Although the prevalence rate of valvular heart disease (VHD) is high in patients with systemic lupus erythematosus (SLE), the predictive factors of concomitant VHD have not been fully evaluated. Methods and results: Among 288 patients with SLE who underwent transthoracic echocardiography at Kumamoto University Hospital from 2016 to 2021, 241 patients with sufficient echocardiographic data were retrospectively analysed. Among them, 22 (9 %) had VHD (10 had mitral regurgitation, 3 had aortic regurgitation, 6 had tricuspid regurgitation, 1 had mitral regurgitation and tricuspid regurgitation, and 2 had a prosthetic cardiac valve). After excluding the two patients with a prosthetic cardiac valve, we divided the remaining patients into two groups: the VHD group and non-VHD group. Multivariate logistic regression analysis revealed that age and the platelet count were significantly and independently associated with having VHD (age: odds ratio, 1.06; 95 % confidence interval, 1.02–1.10; p

Abstract Background Transthyretin amyloid cardiomyopathy (ATTR-CM), characterized by the extracellular deposition of an insoluble amyloid protein in the heart, is one of the main causes of heart failure in elderly patients. In this study, our primary objective was to explore the diverse applications and temporal significance of 1-h and 3-h imaging using 99mTc-PYP in the context of ATTR-CM. Additionally, we compared tracer kinetics in the heart and bone to comprehensively assess the diagnostic advantages and time-related considerations associated with these two incubation periods. Methods Twenty-seven patients at Nagasaki University Hospital who underwent 99mTc-PYP planar, and SPECT cardiac imaging were classified into two groups (ATTR-CM-positive and -negative groups) based on the American Heart Association statement. Cardiac retention was assessed with both a semiquantitative visual score and a quantitative analysis. To assess bone accumulation, a ROI with an equal volume was drawn on the sternum and calculated as the bone-to-contralateral ratio (B/CL). We also evaluated correlation between heart-to-contralateral lung (H/CL) ratio and left ventricular wall thickness. Results Among patients who underwent 99mTc-PYP imaging, the H/CL ratio was significantly higher at 1 h than at 3 h regardless of the group (from 2.20 ± 0.36 to 1.99 ± 0.35, p

Abstract Background and Aims Measurement of coronary microvascular resistance (MR) is essential for diagnosing nonocclusive coronary artery ischemia, but whether coronary branches of different diameters can be similarly assessed using hyperemic microvascular resistance index (hMVRI) calculated from average peak velocity (APV) remains unclear. We investigated the relationship between coronary arteries of different diameters and hMVRI. Methods Thirty patients with suspected angina pectoris and nonobstructive coronary stenosis with fractional flow reserve >0.8 underwent evaluation of all coronary arteries using a Doppler velocity and pressure‐equipped guidewire. Quantitative coronary angiography (QCA) was used to analyze vessel diameter (DQCA). Coronary blood flow (CBFQCA) was calculated as πDQCA2/4 (0.5 × APV) and hMVRIQCA as distal coronary pressure divided by CBFQCA during maximal hyperemia. Results The hMVRI was significantly higher for the right coronary artery than for the left anterior descending artery, but no significant differences between arteries were seen for CBFQCA and hMVRIQCA. Although the correlation between CBFQCA and APV was weak, CBFQCA divided into three groups according to DQCA showed very strong correlations with APV. Slopes of the straight line between APV and CBFQCA for small‐, middle‐, and large‐diameter groups were 0.48, 0.30, and 0.21, respectively, with slope decreasing as diameter increased. Conclusions Comparative evaluation of MR in coronary branches with varying vessel diameters requires vessel diameter to be accounted for.

Background: Left ventricular (LV) apical sparing by transthoracic echocardiography (TTE) has not been widely accepted to diagnose transthyretin amyloid cardiomyopathy (ATTR-CM), because it is time consuming and requires a level of expertise. We hypothesized that automatic assessment may be the solution for these problems. Methods-and-Results: We enrolled 63 patients aged ≥70 years who underwent 99mTc-labeled pyrophosphate (99mTc-PYP) scintigraphy on suspicion of ATTR-CM and performed TTE by EPIQ7G, and had enough information for two-dimensional speckle tracking echocardiography at Kumamoto University Hospital from January 2016 to December 2019. LV apical sparing was described as a high relative apical longitudinal strain (LS) index (RapLSI). Measurement of LS was repeated using the same apical images with three different measurement packages as follows: (1) full-automatic assessment, (2) semi-automatic assessment, and (3) manual assessment. The calculation time for full-automatic assessment (14.7 ± 1.4 sec/patient) and semi-automatic assessment (66.7 ± 14.4 sec/patient) were significantly shorter than that for manual assessment (171.2 ± 59.7 sec/patient) (p

Abstract Aims To clarify the usefulness of left atrial (LA) function and left ventricular (LV) function obtained by two‐dimensional (2D) speckle tracking echocardiography to diagnose concomitant transthyretin amyloid cardiomyopathy (ATTR‐CM) in patients with aortic stenosis (AS). Methods and results We analysed 72 consecutive patients with moderate to severe AS who underwent 99mTc‐pyrophosphate (PYP) scintigraphy at Kumamoto University Hospital from January 2012 to September 2020. We divided these 72 patients into 2 groups based on their 99mTc‐PYP scintigraphy positivity or negativity. Among 72 patients, 16 patients (22%) were positive, and 56 patients (78%) were negative for 99mTc‐PYP scintigraphy. In clinical baseline characteristics, natural logarithm troponin T was significantly higher in the 99mTc‐PYP scintigraphy‐positive than scintigraphy‐negative group (−2.9 ± 0.5 vs. −3.5 ± 0.8 ng/mL, P 0.47 s−1 was 96.6% (28/29). Conclusions Left atrial and LV strain analysis were significantly associated with 99mTc‐PYP scintigraphy positivity in ATTR‐CM patients with moderate to severe AS. The combination of the peak LSR in LA and RapLSI might be a useful predictor of the presence of ATTR‐CM in patients with moderate to severe AS.

Abstract Background and Aims An autonomic nervous disorder is an important characteristic of cardiac amyloidosis; however, the prevalence of autonomic dysfunction in wild‐type transthyretin amyloidosis (ATTRwt) has not been established. Analysis of the R‐R interval coefficient of variation (CVR‐R) is a noninvasive method to measure parasympathetic activity. We aimed to assess autonomic dysfunction of ATTRwt and determine the utility of CVR‐R for the detection of ATTRwt in other cardiac diseases. Methods This is a single‐center, retrospective, case‐control study. Fifty patients with heart failure (HF) were studied. The etiologies of HF were as follows: ATTRwt, n = 10; previous myocardial infarction (MI), n = 20; and left ventricular hypertrophy (LVH) due to other disease processes (e.g., aortic stenosis), n = 20. We measured the CVR‐R at rest (CVR‐Rrest), CVR‐R with deep breaths (CVR‐Rbreath), and the change rate (CVR‐Rdiff rate). The relative change formula is as follows: CVR‐Rdiff rate = (CVR‐Rbreath − CVR‐Rrest)/CVR‐Rrest× 100 (%). Results There was no difference in the CVR‐Rrest levels among the three groups. The CVR‐Rdiff rate levels in the ATTRwt group were significantly lower (ATTRwt: −8.77 [−43.8 to 10.9]; LVH: 67.4 [38.7 to 89.4]; MI: 83.7 [60.4 to 142.9]). Based on the receiver operative characteristic curve analysis to identify ATTRwt in HF, the best cut‐off value for the CVR‐Rdiff rate was 19.7 (area under the curve: 0.848). Conclusion Our data suggested autonomic dysfunction in patients with ATTRwt. Measurement of the CVR‐R in HF patients may be a convenient support tool for the detection of ATTRwt.

Abstract Aims This study was performed to investigate whether left atrial (LA) strain by echocardiography provides prognostic information in patients with wild‐type transthyretin amyloid cardiomyopathy (ATTRwt‐CM). Methods and results Among 129 patients who were diagnosed with ATTRwt‐CM at Kumamoto University Hospital from December 2002 to December 2019, 113 patients who had enough information for two‐dimensional speckle tracking echocardiography were enrolled in this study. During a median follow‐up of 668 days, 28 cardiovascular deaths occurred. Compared with patients in the non‐event group, those in the cardiovascular death group were significantly older (81.5 ± 7.4 vs. 78.1 ± 6.1 years, P

Aim: This study was conducted to investigate the meaning of left ventricular (LV) apical sparing in patients with wild-type transthyretin amyloid cardiomyopathy (ATTRwt-CM). Methods and results: 165 patients who were diagnosed with ATTRwt-CM at Kumamoto University Hospital from January 2002 to December 2020 and had sufficient data for two-dimensional speckle tracking echocardiography were enrolled. Of these, 86 patients (52 %) had LV apical sparing (relative apical longitudinal strain index (RapLSI) > 1.0). Multivariable logistic regression analysis revealed the following variables were significantly associated with LV apical sparing: interventricular septal thickness in diastole (odds ratio (OR), 1.19; 95 % confidence interval (CI), 1.01–1.41; p

Background: We aimed to clarify the predictive factors for left ventricular (LV) function after aortic valve replacement (AVR) in patients with aortic regurgitation (AR). Methods and results: Among 555 patients who underwent AVR at our institution from January 2015 to December 2020, we enrolled 44 patients for whom only AVR (or AVR + aortic replacement) was performed. We defined LV dysfunction under any of the following criteria: LV ejection fraction (LVEF) 65 mm, LV systolic dimension (LVDs) >50 mm, or LVDs/body surface area > 25 mm/m2. Multivariable logistic regression analysis revealed high natural logarithm (ln) C-reactive protein (CRP) and low LVEF in the pre-AVR period significantly associated with LV dysfunction after AVR (ln CRP: odds ratio [OR] 4.15, 95 % confidence interval [CI] 1.44–11.98, p

Abstract Aims The prediction of future heart failure (HF) in stable outpatients is often difficult for general practitioners and cardiologists. Recently, the H2FPEF score (0–9 points) has been proposed for the discrimination of HF with preserved ejection fraction from non‐cardiac causes of dyspnoea. The six clinical and echocardiographic variables that constitute the H2FPEF score include the following: (i) obesity (H); (ii) the use of ≥2 antihypertensive drugs (H); (iii) atrial fibrillation (F); (iv) pulmonary hypertension (P); (v) an age > 60 years (E); and (vi) E/e' > 9 (F). We performed an external validation study that investigated whether the H2FPEF score could predict future HF‐related events in stable outpatients with cardiovascular risk factor(s) in Japan. Methods and results In this prospective cohort study, after exclusion of 195 from 551 consecutive, stable Japanese outpatients with at least one cardiovascular risk factor who were enrolled between September 2010 and July 2013, the remaining 356 outpatients (171 men, 185 women, mean age 73.2 years) were eligible for the analysis. We calculated the H2FPEF score (0–9 points), and followed up the patients for an average of 517 days. In all of the 356 patients, the mean H2FPEF score was 3.1 ± 1.8, and 15 developed HF‐related events during the follow‐up period, including cardiovascular death (n = 2) and hospitalization for HF decompensation (n = 13). Multivariate Cox proportional hazards analysis showed that the H2FPEF score was an independent predictor of future HF‐related events (P < 0.001 for all three models). Kaplan–Meier survival curves showed a significantly higher probability of HF‐related events in the outpatients with a high H2FPEF score (P < 0.001). In receiver operating characteristic (ROC) curve analysis, the H2FPEF score was significantly associated with the occurrence of future HF‐related events (P < 0.001). In ROC curve analysis, the sensitivity, specificity, and positive likelihood ratio of a H2FPEF score of 7 points to predict HF‐related events were 47%, 96%, and 11.4%, respectively. Conclusions The H2FPEF score could provide useful information for future HF‐related events in stable outpatients with cardiovascular risk factor(s) in Japan.

Restrictive cardiomyopathy (RCM) is a rare type of primary myocardial disease, and its pathological features remain unclear. We report the case of a 78-year-old Japanese woman with RCM and MHY7 mutation who died of heart failure 13 years after the diagnosis. Upon autopsy, focal myocyte amorphous degeneration positive for ubiquitin was revealed, as well as myocardial disarrangement and interstitial fibrosis. Electron microscope demonstrated electron-dense structure in the cardiac myocytes. These may be one of the pathological features of RCM.

Objective This study was performed to investigate the physical performance parameters, including lower extremity function parameters, that may be risk factors for falls in patients with chronic heart failure. Methods Seventy patients with stable chronic heart failure were included in this retrospective cross-sectional study. The five-repetition sit-to-stand test (5STS) time, Controlling Nutritional Status (CONUT) score, and number of drugs were assessed. Results Simple linear regression analysis revealed that the 5STS time was positively correlated with age, the CONUT score, and the number of drugs but was negatively associated with the handgrip force, quadriceps force, and quadriceps muscle thickness. Multiple linear regression analysis showed a significant association between the 5STS time and the CONUT score, quadriceps force, and number of drugs. Conclusion The muscle strength, nutritional status, and number of drugs should be evaluated to prevent lower extremity weakness in patients with stable chronic heart failure.

Vibrio vulnificus is a Gram-negative pathogenic bacterium that causes serious infections in humans and requires iron for growth. A clinical isolate, V. vulnificus M2799, secretes a catecholate siderophore, vulnibactin, that captures ferric ions from the environment. In the ferric-utilization system in V. vulnificus M2799, an isochorismate synthase (ICS) and an outer membrane receptor, VuuA, are required under low-iron conditions, but alternative proteins FatB and VuuB can function as a periplasmic-binding protein and a ferric-chelate reductase, respectively. The vulnibactin-export system is assembled from TolCV1 and several RND proteins, including VV1_1681. In heme acquisition, HupA and HvtA serve as specific outer membrane receptors and HupB is a sole periplasmic-binding protein, unlike FatB in the ferric-vulnibactin utilization system. We propose that ferric-siderophore periplasmic-binding proteins and ferric-chelate reductases are potential targets for drug discovery in infectious diseases.

Cholesterol-rich arterial plaques characterize atherosclerosis, a significant cause of heart disease. Nutraceuticals have received attention over the years, demonstrating potential benefits towards treating and preventing cardiovascular diseases (CVD), including atherosclerosis. Curcumin, a potent polyphenol present in Curcuma longa, has shown remarkable anti-atherosclerotic activity via anti-inflammatory and anti-oxidative properties. The bioavailability and low water solubility of curcumin limit its clinical translational purposes. These issues can be circumvented effectively by nano-drug delivery systems that can target atherosclerotic plaque sites. In this work, we chose to use curcumin and a natural bioenhancer called Bioperine (derived from Piper nigrum) inside a polymeric nano-drug delivery system for targeting atherosclerotic plaque sites. We selected two different ratios of curcumin:Bioperine to study its comparative effect on the inhibition of oxidized low-density lipoprotein (Ox-LDL)-induced foam cell formation. Our studies demonstrated that Cur-Bio PLGA NPs (both ratios) maintained the cell viability in THP-1 monocyte-derived macrophages above 80% at all periods. The 1:0.2:10 ratio of Cur-Bio PLGA NPs at a concentration of 250 μg/mL illustrated an enhanced reduction in the relative cholesterol content in the THP-1-derived foam cells compared to the 1:1:10 ratio. Confocal microscopy analysis also revealed a reduction in macrophage-mediated foam cell formation when administered with both the ratios of Cur-Bio PLGA NPs. Relative fold change in the mRNA expression of the genes involved in the inflammatory pathways in the atherosclerotic process downregulated NF-κB, CCL2/MCP-1, CD-36, and STAT-3 activity while upregulating the SCAR-B1 expression when treated with the Cur-Bio PLGA NPs. This study thus highlights the importance of natural-based compounds towards the therapeutic intervention against atherosclerotic activity when administered as preventive medicine.

BACKGROUND: We investigated the effects of a novel method of anesthesia combining propofol and volatile anesthesia on the incidence of postoperative nausea and vomiting in patients undergoing laparoscopic gynecological surgery. METHODS: Patients were randomly divided into three groups: those maintained with sevoflurane (Group S, n = 42), propofol (Group P, n = 42), or combined propofol and sevoflurane (Group PS, n = 42). We assessed complete response (no postoperative nausea and vomiting and no rescue antiemetic use), incidence of nausea and vomiting, nausea severity score, vomiting frequency, rescue antiemetic use, and postoperative pain at 2 and 24 h after surgery. RESULTS: The number of patients who exhibited a complete response was greater in Groups P and PS than in Group S at 0-2 h (74%, 76% and 43%, respectively, p = 0.001) and 0-24 h (71%, 76% and 38%, respectively, p < 0.0005). The incidence of nausea at 0-2 h (Group S = 57%, Group P = 26% and Group PS = 21%, p = 0.001) and 0-24 h (Group S = 62%, Group P = 29% and Group PS = 21%, p < 0.0005) was also significantly different among groups. However, there were no significant differences among groups in the incidence or frequency of vomiting or rescue antiemetic use at 0-24 h. CONCLUSION: Combined propofol and volatile anesthesia during laparoscopic gynecological surgery effectively decreases the incidence of postoperative nausea. We term this novel method of anesthesia "combined intravenous-volatile anesthesia (CIVA)".

Macrophages in the atheroma region produce matrix metalloproteinases (MMPs) and decrease plaque stability. Tissue oxygen tension decreases in the arterial wall of the atherosclerotic region. Hypoxia inducible factor (HIF)-1α plays a critical role in the transcriptional activation of hypoxia inducible genes. However, the precise roles of HIF-1α independent pathways in hypoxic responses are largely unknown. Xanthine oxidase (XO) is an enzyme that utilizes molecular oxygen and produces reactive oxygen species (ROS). Here, we show that ROS derived from XO increases MMP-3, -10, and -13 expression in murine macrophages. We found that the transcript levels of macrophage MMP-3, -10, and -13 were increased in hypoxic conditions. Hypoxia induced MMP expression in HIF-1α deficient macrophages. N-acetylcysteine (NAC) or febuxostat, an XO inhibitor, suppressed MMP expression in murine macrophages. Febuxostat decreased the incidence of plaque rupture in apolipoprotein-E-deficient mice. Our results indicate that febuxostat stabilized atherosclerotic plaque via suppressing the activities of macrophage MMP-9 and -13. Febuxostat administration is a potential therapeutic option in the management of atherosclerotic patients.

Protein introduction into cells is more difficult in plants than in mammalian cells, although it was reported that protein introduction was successful in shoot apical meristem and leaves only together with a cell-penetrating peptide. In this study, we tried to introduce superfolder green fluorescent protein (sGFP)-fused to adenylate cyclase as a reporter protein without a cell-penetrating peptide into the cells of tobacco leaves by treatment with atmospheric non-thermal plasmas. For this purpose, CO2 or N2 plasma was generated using a multi-gas plasma jet. Confocal microscopy indicated that sGFP signals were observed inside of leaf cells after treatment with CO2 or N2 plasma without substantial damage. In addition, the amount of cyclic adenosine monophosphate (cAMP) formed by the catalytic enzyme adenylate cyclase, which requires cellular calmodulin for its activity, was significantly increased in leaves treated with CO2 or N2 plasma, also indicating the introduction of sGFP-fused adenylate cyclase into the cells. These results suggested that treatment with CO2 or N2 plasma could be a useful technique for protein introduction into plant tissues.

In this study, a small-sized plasma jet source with a 3.7 mm head diameter was created via a 3D printer. The jet’s emission properties and OH radical concentrations (generated by argon, helium, and nitrogen plasmas) were investigated using optical emission spectrometry (OES) and electron spin resonance (ESR). As such, for OES, each individual gas plasma propagates emission lines that derive from gases and ambient air inserted into the measurement system. For the case of ESR, a spin adduct of the OH radical is typically observed for all gas plasma treatment scenarios with a 10 s treatment by helium plasma generating the largest amount of OH radicals at 110 μM. Therefore, it was confirmed that a plasma jet source made by a 3D printer can generate stable plasmas using each of the aforementioned three gases.