Elevated arginine vasopressin levels surrogate acute lung injury in acute decompensated heart failure.

Activated arginine vasopressin (AVP) pathway worsens congestion in heart failure (HF), but its potential to relieve pulmonary congestion is also reported. The pathophysiological role and prognostic utility of AVP elevation in acute decompensated HF (ADHF) are poorly understood. We prospectively enrolled 52 hospitalized patients for ADHF to investigate the association between acute lung injury (ALI) in ADHF and AVP levels on admission. ALI was defined as respiratory failure leading to death, or requiring a respirator or a more than 12-h non-invasive intermittent positive pressure ventilation (NIPPV) support. In addition, we investigated the prognostic value of AVP levels on admission for cardiovascular death or recurrence of ADHF after discharge. ALI was documented in 7 patients (13.5%) during a median hospital stay of 14 days. And the patients with ALI demonstrated significantly higher AVP levels than those without (32.5 ± 21.6 vs. 6.4 ± 8.7 pg/ml, p = 0.018). Besides, the patients with ALI demonstrated significantly higher heart rates (HR) and lower E/e' on admission (HR: 127 ± 24 vs. 97 ± 28 bpm; E/e': 10.6 ± 3.7 vs. 17.4 ± 6.2, all p < 0.05, respectively). Of note, significant hemodilution assessed by hemoglobin and hematocrit values were observed in the patients with ALI 48 h after admission. A receiver operating characteristic curve analysis showed that higher than 7.2 pg/ml surrogate ALI in ADHF (AUC: 0.897, p = 0.001, Sensitivity: 85.7%, and Specificity: 77.8%). In contrast, increased AVP levels on admission could not predict cardiovascular events after discharge. Elevated AVP levels on admission are associated with ALI in ADHF but not cardiovascular events after discharge.

Association Between Aortic Stiffness and Exercise Tolerance in Patients at the Risk Stage of Heart Failure.

BACKGROUND: The number of patients with heart failure (HF) has increased, and it is crucial to prevent the development of HF in patients at risk of HF. The present study aimed to risk stratify patients in Stage A and B HF based on associations between exercise-induced changes in aortic stiffness and exercise tolerance.Methods and Results: Patients in Stage A and B HF who performed a cardiopulmonary exercise test were enrolled in the study (n=106; median age 65.0 years [interquartile range 52.8-73.0 years]). Exercise tolerance was examined by the percentage of predicted peak oxygen consumption (%V̇O2peak). The ascending aortic pressure waveform was estimated non-invasively. Aortic stiffness was assessed using the augmentation index (AIx) and reflection magnitude (RM). Multivariable regression analysis showed that AIx measured both before and after exercise was significantly associated with %V̇O2peak (ß=-0.221 [P=0.049] and ß=-0.342 [P=0.003], respectively). When participants were divided into %V̇O2peak subgroups using a cut-off value of 60%, RM decreased immediately after exercise and remained lower 5 min after exercise in the group with preserved exercise tolerance, but recovered to baseline levels 5 min after exercise in the group with reduced exercise tolerance. CONCLUSIONS: Exercise-induced increases in aortic stiffness were associated with exercise tolerance in patients at risk of HF, suggesting that exercise-induced changes in aortic stiffness may be useful to stratify high-risk patients.

Malondialdehyde-Modified Low-Density Lipoprotein as a Predictor of Major Adverse Limb Events after Endovascular Therapy in Patients with Lower Extremity Arterial Disease.

AIM: Adverse limb events after endovascular therapy (EVT) are a major concern. This study aimed to investigate the relationship between serum malondialdehyde-modified low-density lipoprotein (MDA-LDL) level, a potentially potent indicator of atherosclerosis, and clinical outcomes after EVT in patients with lower extremity arterial disease (LEAD). METHODS: A total of 208 LEAD patients who underwent EVT and MDA-LDL measurements were retrospectively analyzed. Those with chronic limb-threatening ischemia (CLTI) were included in the CLTI subgroup (n=106). Patients were further categorized into the High or Low MDA-LDL groups according to the cut-off value calculated by receiver operating characteristic analysis. Major adverse limb events (MALE), a composite of cardiovascular death, limb-related death, major amputation, and target-limb revascularization, were evaluated. RESULTS: MALE occurred in 73 (35%) patients. The median follow-up interval was 17.4 months. The MDA-LDL cut-off values were 100.5 U/L (area under the curve [AUC] 0.651) in the overall population and 98.0 U/L (AUC 0.724) in the CLTI subgroup. Overall, the High MDA-LDL group showed significantly higher total cholesterol (189.7±37.5 mg/dL vs. 159.3±32.0 mg/dL, p＜0.01), low-density lipoprotein cholesterol (114.3±29.7 mg/dL vs. 87.3±25.3 mg/dL, p＜0.01), and triglyceride (166.9±91.1 mg/dL vs. 115.8±52.3 mg/dL, p＜0.01) than the Low MDA-LDL group. Multivariate Cox regression analyses revealed that MDA-LDL and C-reactive protein were independent predictors of MALE. In the CLTI subgroup, MDA-LDL was an independent predictor of MALE. The High MDA-LDL group showed worse MALE-free survival rates than the Low MDA-LDL group in overall (p＜0.01) and in the CLTI subgroup (p=0.01). CONCLUSIONS: Serum MDA-LDL level was associated with MALE after EVT.

A case of an elderly female who developed subacute pleuropericarditis following BNT162b2 mRNA COVID-19 vaccination.

Despite the established safety of BNT162b2 coronavirus disease 2019 (COVID-19) vaccine, some rare but serious complications have been previously reported. Here, we report a rare case of an elderly female who developed subacute pleuropericarditis after the vaccination. An 88-year-old female experienced weight gain and dyspnea three days after the second dose of BNT162b2 vaccination, and one month later, presented to our hospital due to the exacerbation of the symptoms. Computed tomography showed remarkable pericardial and bilateral pleural effusions, and transthoracic echocardiogram visualized collapse signs of right and left atrium which indicates pre-tamponade. Percutaneous drainages of pericardial and pleural effusions stabilized her vital condition and revealed that all of them were exudative, indicating the presence of pleuropericarditis. Finally, we diagnosed this case as COVID-19 vaccine-associated pleuropericarditis because there were no signs of bacterial/viral infection or any other relevant causes except for the vaccination. When the pericardial and pleural effusions are concurrently found after COVID-19 vaccination, vaccine-associated pleuropericarditis should be considered as a differential diagnosis. The aggressive drainage of pericardial and pleural effusions could be helpful not only for diagnosis but also for treatment in the clinical management of COVID-19 vaccine-associated pleuropericarditis. Learning objective: Although the safety and efficacy of BNT162b2 have been widely accepted, it is clinically important to know the potential risk of side effects. When the pericardial and pleural effusions are concurrently found after the vaccination, coronavirus disease 2019 vaccine-associated pleuropericarditis should be considered as a differential diagnosis.

Home blood pressure on winter mornings could be exaggerated: A comparison with summer mornings.

PURPOSE: Self-measured blood pressure at home (HBP) is quite important for the management of hypertension. We hypothesized that winter HBP measured according to the recommendation of the guidelines, but not HBP measured inside bed before getting up, is elevated in response to cold ambient temperatures in winter. This study aimed to investigate differences in HBP measured before and after getting up in winter and summer.Methods: Hypertensive subjects whose blood pressure was stably controlled were enrolled (n = 46, 73 years). They were instructed to measure HBP while in bed just after waking (HBP-bed), in addition to the ordinary HBP measurement in the morning (HBP-morning) according to the guidelines. The mean value of HBP for 7 consecutive days before the day of a regular hospital visit was considered as the HBP of each subject, and characteristics of the winter and summer BPs were investigated.Results: HBP-morning was significantly higher (P < .001) in winter than in summer, but HBP-bed was lower in winter than in summer (P < .05). HBP-morning was significantly higher than HBP-bed in winter, while HBP-morning was not different from HBP-bed in summer, resulting in greater changes in HBP after getting up in winter than in summer (P < .0001). Changes in HBP after getting up were significantly correlated with serum creatinine levels and the urinary albumin-to-creatinine ratio.Conclusions: These findings imply that elevated HBP-morning in winter reflects the response of BP to cold after getting up. Seasonal profiles of HBPs before and after getting up should be noted in the management of hypertension.

Indices of left ventricular voltage on electrocardiogram are closely associated with serum cardiac troponin I levels in normotensive Japanese individuals.

The high-sensitivity cardiac troponin I (hs-cTnI) in serum can increase due to an increase in left ventricular (LV) overload in individuals with hypertension. Since LV voltage on an electrocardiogram (ECG) reflects LV load, it is possible that LV voltage is closely associated with hs-cTnI in individuals without hypertension. This study investigated the association between LV voltage indices and serum hs-cTnI levels in normotensive Japanese individuals.Subjects who visited the Enshu Hospital for a health check-up were screened for their eligibility. Subjects with renal dysfunction, cancer, active inflammatory disease, or a history of cardiovascular events were excluded, as were subjects with obvious ST segment or T wave abnormality, Wolff-Parkinson-White syndrome, pacemaker implantation, or frequent arrhythmia in the ECG. Exclusion of individuals with hypertension left 803 subjects (54.8 ±â€Š11.3 years) for final inclusion. The R wave voltage in lead V5 (RV5 voltage), the Sokolow-Lyon voltage (a sum of the QRS wave (a complex wave consists of Q, R, and S wave) of the S wave voltage in lead V1 and the R wave voltage in lead V5), and the Cornell product (a product of QRS duration and QRS voltage) were evaluated by ECG as LV voltage indices. Laboratory measurements included serum hs-cTnI levels. Possible associations between indices of LV voltage on ECG and serum hs-cTnI levels were cross-sectionally investigated in the normotensive subjects.The median values [interquartile range] of hs-cTnI and BNP were and 2.1 [1.4-3.0] and 13.8 [7.7-24.9] pg/mL, respectively. Multivariate regression analysis identified that the levels of hs-cTnI, but not BNP, were significantly associated with RV5 voltage (ß 0.090, P = .0087), Sokolow-Lyon voltage (ß 0.112, P = .0009), and Cornell product (ß 0.101, P = .039) after adjustment for possible confounding factors. Moreover, the RV5 voltage, Sokolow-Lyon voltage, and Cornell product were significantly associated with the hs-cTnI levels after adjustment for possible confounding factors including ECG findings (ß 0.109, P = .0075; ß 0.125, P = .0010; and ß 0.096, P = .0116, respectively).Indices of LV voltage in ECG had close associations with serum hs-cTnI levels in normotensive subjects. These findings support that the ECG findings of LV voltage have significant associations with slight myocardial micro-damage even in normotensive subjects.

Close association between circulating high-sensitivity cardiac troponin I and metabolic syndrome in the general population.

Individuals with metabolic syndrome reportedly have an increased risk of cardiovascular disease, although the association between asymptomatic myocardial damage and metabolic syndrome has not been sufficiently investigated. The present study investigated possible associations between circulating cardiac troponin and metabolic syndrome or related factors. Subjects undergoing their annual health checkups were enrolled in the study (n = 1242). Laboratory measurements included serum high-sensitivity cardiac troponin I (hs-cTnI) and plasma B-type natriuretic peptide (BNP). Individual salt intake was estimated by calculating 24-h urinary sodium excretion from spot urine. Subjects whose electrocardiograms revealed ST-T segment abnormalities or who had renal insufficiency or a history of cardiovascular events were excluded. Subjects with metabolic syndrome had higher hs-cTnI levels than those without, but their BNP levels were equivalent. hs-cTnI levels were significantly associated with the presence and components of metabolic syndrome. Logistic regression analysis with the endpoint of hs-cTnI levels higher than the median value identified metabolic syndrome as an independent determinant of increased hs-cTnI levels. Additionally, urinary salt excretion levels were increased in subjects with metabolic syndrome or any of its components. Logistic regression analysis with the endpoint of metabolic syndrome revealed that hs-cTnI levels were independently associated with the presence of metabolic syndrome. A close association between hs-cTnI levels and the presence of metabolic syndrome, at least partially mediated by increased salt intake, was confirmed to exist in the general population. The findings support the idea that patients with metabolic syndrome develop asymptomatic myocardial damage without obvious ischaemic findings, which leads to increased cardiovascular risk.

Corrigendum: Urinary Exosome-Derived microRNAs Reflecting the Changes in Renal Function in Cats.

[This corrects the article DOI: 10.3389/fvets.2018.00289.].

Urinary Exosome-Derived microRNAs Reflecting the Changes in Renal Function in Cats.

Increased incidence of kidney disease (KD) is a common concern in human and companion animals. Cats, in particular, are highly susceptible to KD. Novel KD biomarkers would help to address these problems. Therefore, we are focusing on microRNA, a highly conserved nucleic acid, as a KD biomarker for various animals. We previously reported that altered levels of urinary exosome (UExo)-derived microRNAs indicate renal pathologies in dogs. This study comprehensively examined UExo-derived microRNAs, which reflected the KD status in cats. The examined cats were divided into two groups: normal renal function (NR) and KD. Based on our previous data in dogs and cats, as well as the present data on UExo-derived microRNAs in cats by next-generation sequencing, let-7b, let-7f, miR-10a, miR-10b, miR-21a, miR-22, miR-26a, miR-27b, miR-146a, miR-181a, miR-191, and miR-486a were identified as biomarker candidates. In summary, the levels of UExo-derived let-7b, miR-22, and miR-26a significantly decreased in cats with KD from the early stages of the disease. UExo-derived miRNA levels normalized to urinary creatinine or total RNA of miR-21a was significantly higher in the KD group. Importantly, the ratio of UExo-derived miR-21a to let-7b showed a significant and strongest correlation with serum creatinine (ρ = 0.751), blood urea nitrogen (ρ = 0.754), and urinary creatinine (ρ = -0.421) among all examined indices. Further, the ratio of miR-181a to let-7b or miR-10b significantly correlated with the progression of renal dysfunction in the KD group. Thus, we identified that UExo-derived microRNAs in cats, and their raw and normalized levels could indicate altered renal function.

Morphofunctional analysis of antigen uptake mechanisms following sublingual immunotherapy with beads in mice.

BACKGROUND: Recently, sublingual immunotherapy (SLIT) has been used as a safe and efficient method for the treatment of and immunization against asthma and various allergies. However, the routes of antigen/allergen (particulate antigen) uptake through the mucosa of the oral cavity remain incompletely understood, as do the roles of sex and age in the process. For this purpose, to elucidate the mechanism and efficacy of SLIT among different sexes and ages, microbeads were dripped into the sublingual region to mimic particulate antigen uptake by the sublingual mucosa. METHODS: Twenty microliters of either phosphate buffered saline (PBS) or fluorescently labelled microbeads (latex and silica beads) were placed under the tongue of both male and female C57BL/6 mice at young (3 months) and old (6 months) ages. The lower jaw was examined 30 min after administration, and beads were detected with a fluorescence stereomicroscope. Morphological observations of the mucosa of the fluorescent areas were made with a scanning electron microscope (SEM) and an all-in-one light fluorescence microscope (LM). Fluorescence intensity was compared between both sexes and ages. RESULTS: Stereomicroscopic observation revealed fluorescent illuminations in three compartments of the sublingual mucosa: the sublingual caruncles (SC), the oral rostral mucosa (OR) and the buccal mucosa (BM). Interestingly, the fluorescence intensity tended to be higher among females than among males in the SC region in particular. However, there were no significant age-related differences. SEM and LM revealed beads in the lumina of both mandibular ducts and sublingual ducts (Sd). Additionally, the apical cytoplasm of some Sd cells contained silica beads. However, there was no specification in the OR mucosa or BM. CONCLUSIONS: This study reveals the major role Sd plays in local immunity via the antigen uptake mechanisms. Furthermore, our data suggest that the efficacy of SLIT in humans could be affected by sex.

Synthesis and characterization of radioiodinated 3-phenethyl-2-indolinone derivatives for SPECT imaging of survivin in tumors.

Survivin, overexpressed in most cancers, is associated with poor prognosis and resistance to radiation therapy and chemotherapy. Herein, we report the synthesis of three 3-phenethyl-2-indolinone derivatives and their application as in vivo imaging agents for survivin. Of these, 3-(2-(benzo[d][1,3]dioxol-5-yl)-2-oxoethyl)-3-hydroxy-5- iodoindolin-2-one (IPI-1) showed the highest binding affinity (Kd = 68.3 nM) to recombinant human survivin, as determined by quartz crystal microbalance (QCM). In vitro studies demonstrated that the [125I]IPI-1 binding in survivin-positive MDA-MB-231 cells was significantly higher than that in survivin-negative MCF-10A cells. In addition, uptake of [125I]IPI-1 by MDA-MB-231 cells decreased in a dose-dependent manner in the presence of the high-affinity survivin ligand S12; this is indicative of specific binding of [125I]IPI-1 to cellular survivin protein in vitro. Biodistribution studies in MDA-MB-231 tumor-bearing mice demonstrated the moderate uptake of [125I]IPI-1 in the tumor tissue (1.37% ID/g) at 30 min that decreased to 0.32% ID/g at 180 min. Co-injection of S12 (2.5 mg/kg) slightly reduced tumor uptake and the tumor/muscle ratio of [125I]IPI-1. Although further structural modifications are necessary to improve pharmacokinetic properties, our results indicate that PI derivatives may be useful as tumor-imaging probes targeting survivin.

Cotton rats (Sigmodon hispidus) possess pharyngeal pouch remnants originating from different primordia.

Pharyngeal pouches in mammals develop into specific derivatives. If the differentiation of the pharyngeal pouches is anomalous, their remnants can result in cysts, sinuses, and fistulae in the differentiated organs or around the neck. In the present study, we found several pharyngeal pouch remnants, such as cystic structures in thymus and parathyroid gland and fossulae extended from the piriform fossa, in the inbred cotton rats maintained at Hokkaido Institute of Public Health (HIS/Hiph) and University of Miyazaki (HIS/Mz). In HIS/Hiph, the fossulae extended from the apex of the piriform fossa into the thyroid glands and were lined with stratified squamous and cuboidal epithelium. Calcitonin-positive C-cells were present within their epithelium in HIS/Hiph. In contrast, the fossulae of HIS/Mz ran outside the thyroid glands toward the parathyroid glands; they were lined with columnar ciliated epithelium and a few goblet cells, but had no C-cells, which was consistent with the cystic structures in the thymus and the parathyroid gland. These results indicated that the fossulae were a remnant of the ultimobranchial body in HIS/Hiph and of the thymopharyngeal duct in HIS/Mz. Thus, the fossulae of the piriform fossa resembled the piriform sinus fistula in human. In conclusion, cotton rats frequently possessed pharyngeal pouch remnants, including the piriform sinus fistula, and therefore, might serve as a novel model to elucidate the mechanisms of pharyngeal pouch development.

Urinary exosome-derived microRNAs reflecting the changes of renal function and histopathology in dogs.

MicroRNAs act as post-transcriptional regulators, and urinary exosome (UExo)-derived microRNAs may be used as biomarkers. Herein, we screened for UExo-derived microRNAs reflecting kidney disease (KD) status in dogs. Examined dogs were divided into healthy kidney control (HC) and KD groups according to renal dysfunction. We confirmed the appearance of UExo having irregular globe-shapes in a dog by immunoblot detection of the exosome markers, TSG101 and CD9. Based on our previous data using KD model mice and the data obtained herein by next generation sequencing of UExo-derived microRNAs in dogs, miR-26a, miR-146a, miR-486, miR-21a, and miR-10a/b were selected as candidate microRNAs. In particular, UExo-derived miR-26a and miR-10a/b were significantly decreased in KD dogs, and miR-26a levels negatively correlated with deteriorated renal function compared to the other miRNAs. UExo-derived miR-21a levels corrected or not to that of internal control microRNAs in UExo, miR-26a and miR-191, significantly increased with renal dysfunction. In kidney tissues, the decrease of miR-26a and miR-10a/b in the glomerulus and miR-10b in the tubulointerstitium negatively correlated with deteriorated renal function and histopathology. Increased miR-21a in the tubulointerstitium rather than in the glomerulus correlated with deteriorated renal histopathology. In conclusion, microRNAs reflecting the changes in renal function and histopathology in dogs were identified in this study.

Review of High-intensity Interval Training in Cardiac Rehabilitation.

For the secondary prevention of cardiovascular disease, comprehensive cardiac rehabilitation is required. This involves optimal medical therapy, education on nutrition and exercise therapy, and smoking cessation. Of these, efficient exercise therapy is a key factor. A highly effective training protocol is therefore warranted, which requires a high rate of compliance. Although moderate-intensity continuous training has been the main training regimen recommended in cardiac rehabilitation guidelines, high-intensity interval training has been reported to be more effective in the clinical and experimental setting from the standpoint of peak oxygen uptake and central and peripheral adaptations. In this review, we illustrate the scientific evidence for high-intensity interval training. We then verify this evidence and discuss its significance and the remaining issues.

Synthesis and evaluation of a radioiodinated 4,6-diaryl-3-cyano-2-pyridinone derivative as a survivin targeting SPECT probe for tumor imaging.

Survivin is overexpressed in most of the cancerous tissues but not in terminally differentiated normal tissues, making it an attractive target for diagnosis and therapy of various types of cancers. In this study, we aimed to develop 4,6-diaryl-3-cyano-2-pyridinone (DCP) derivatives, as novel cancer imaging probes that target survivin. Chloro and iodo analogs of DCP (CDCP and IDCP, respectively) were successfully synthesized by using a previously unreported carbon monoxide-free procedure. IDCP exhibited a slightly higher binding affinity for recombinant human survivin (Kd=34 nM) than that of CDCP (Kd=44 nM). Fluorescence staining indicated that both CDCP and IDCP showed high signals in MDA-MB-231 cells with high levels of survivin expression. Significantly low fluorescent signals were observed in MCF-10A cells, which showed low levels of survivin expression. [(125)I]IDCP was synthesized for the application of IDCP to single photon emission computed tomography (SPECT) imaging. Quantitative in vitro binding of [(125)I]IDCP in cell cultures showed results consistent to those observed after fluorescent staining. In vivo biodistribution studies in tumor-bearing mice demonstrated that the tumor uptake of [(125)I]IDCP increased gradually with time and was 0.65% injected dose per gram (% ID/g) at 180 min. The maximum tumor/blood and tumor/muscle ratio at 60 min were 0.87 and 2.27, respectively, indicating inadequate [(125)I]IDCP accumulation in tumors necessary for in vivo imaging. Although further structural modifications are necessary to improve pharmacokinetic properties of IDCP, this study demonstrates the feasibility of using the DCP backbone as a scaffold for the development of survivin-targeting tumor imaging probes.