Prognostic value of transvalvular flow rate in patients with low-gradient severe aortic stenosis: A dobutamine stress echocardiography study.

BACKGROUNDS: There are limited data on the clinical relevance of transvalvular flow rate (Qmean ) at rest (Qrest) and at peak stress (Qstress ) during dobutamine stress echocardiography (DSE) in patients with low-gradient severe aortic stenosis (LG-SAS). METHODS: We retrospectively analyzed the clinical data of patients with LG-SAS who underwent DSE. LG-SAS was defined as an aortic valve (AV) area index of < .6 cm2 /m2 and a mean AV pressure gradient (AVPG) of < 40 mm Hg. The primary endpoint included all-cause death and heart failure hospitalization. RESULTS: Of 100 patients (mean age 79.5 ± 7.3 years; men, 45.0%; resting left ventricular ejection fraction [LVEF] 52.1% ± 15.9%; resting stroke volume index 35.8 ± 7.7 mL/m2 ; Qrest 171.8 ± 34.9 mL/s), the primary endpoint occurred in 51 patients during a median follow-up of 2.84 (interquartile range 1.01-5.21) years. When the study patients were divided into three subgroups based on Qrest and Qstress , the multivariate analysis showed that Qrest < 200 mL/s and Qstress ≥200 mL/s (hazard ratio 3.844; 95% confidence interval 1.143-12.930; p = .030), as well as Qrest and Qstress < 200 mL/s (hazard ratio 9.444; 95% confidence interval 2.420-36.850; p = .001), were significantly associated with unfavorable outcomes with Qrest and Qstress ≥200 mL/s as a reference after adjusting for resting LVEF, resting mean AVPG, chronic kidney disease, New York Heart Association functional class III/IV, and AV replacement. CONCLUSIONS: Flow conditions based on the combination of Qrest and Qstress are helpful for risk stratification in LG-SAS patients.

Resting echocardiographic predictors for true-severe aortic stenosis in patients with low-gradient severe aortic stenosis: A dobutamine stress echocardiography study.

OBJECTIVE: Dobutamine stress echocardiography (DSE) is not always feasible in patients with low-gradient severe aortic stenosis (LG-SAS), and there are limited data available on the resting echocardiographic predictors for true-severe aortic stenosis (TSAS). This study investigated resting echocardiographic predictors for TSAS. METHODS: Clinical data of 106 LG-SAS patients who underwent DSE were retrospectively analyzed. LG-SAS was defined as an aortic valve area index (AVAi) < .6 cm2 /m2 , and a mean AV pressure gradient < 40 mm Hg. The velocity ratio (VR) was calculated as the peak left ventricular outflow tract velocity/peak AV velocity. TSAS was defined as a projected AVAi < .6 cm2 /m2 . RESULTS: The mean age was 79.3 ± 7.3 years, and 45 (42.5%) were men. The resting AV data were as follows: AVAi, .50 ± .07 cm2 /m2 ; mean AV pressure gradient, 23.0 ± 7.4 mm Hg; and VR, .25 ± .05. The projected AVAi was .58 ± .09 cm2 /m2 , and TSAS was documented in 65 (61.3%) patients. In multivariate analysis, the independent predictors of TSAS were AVAi (p = 0.012) and VR (p = 0.004) with respective best cut-off values of .52 cm2 /m2 and .25 on receiver-operating characteristic curve analysis. According to incremental numbers of the predictors, correct classification percentages of TSAS significantly increased with the Cochran-Armitage trend test (16.2% in no predictors, 65.2% in one predictor, and 95.7 % in two predictors; p < 0.001). CONCLUSIONS: Resting AVAi and VR were independent predictors of TSAS in LG-SAS patients. The true severity might be predictable using the combination of resting parameters.

Angioscopic Evaluation of Atrial Septal Defect Closure Device Neo-Endothelialization.

Background Current guidelines recommend at least 6 months of antithrombotic therapy and antibiotic prophylaxis after septal-occluding device deployment in transcatheter closure of atrial septal defect. It has been estimated that it takes ≈6 months for complete neo-endothelialization; however, neo-endothelialization has not previously been assessed in vivo in humans. Methods and Results The neointimal coverage of septal occluder devices was evaluated 6 months after implantation in 15 patients by angioscopy from the right atrium. Each occluder surface was divided into 9 areas; the levels of endothelialization in each area were semiquantitatively assessed by 4-point grades. Device neo-endothelialization was sufficient in two thirds of patients, but insufficient in one third. In the comparison between patients with sufficiently endothelialized devices of average grade score ≥2 (good endothelialization group, n=10) and those with poorly endothelialized devices of average grade score <2 (poor endothelialization group, n=5), those in the poor endothelialization group had larger devices deployed (27.0 mm [25.0-31.5 mm] versus 17.0 mm [15.6-22.5 mm], respectively) and progressive right heart dilatation. The endothelialization was poorer around the central areas. Moreover, the prevalence of thrombus formation on the devices was higher in the poorly endothelialized areas than in the sufficiently endothelialized areas (Grade 0, 94.1%; Grade 1, 63.2%; Grade 2, 0%; Grade 3, 1.6%). Conclusions Neo-endothelialization on the closure devices varied 6 months after implantation. Notably, poor endothelialization and thrombus attachment were observed around the central areas and on the larger devices.

A New Bitterness Evaluation Index Obtained Using the Taste Sensor for 48 Active Pharmaceutical Ingredients of Pediatric Medicines.

The aim of this study was to evaluate bitterness by using "CCDP; Change in concentration-dependent potential" considering dose-dependency of active pharmaceutical ingredients (APIs) as new and useful bitterness evaluation index compared with bitter sensor output value which is conventional bitterness evaluation index for 48 pediatric medicines from the recent edition of the WHO model list of essential medicines for children (7th edn, 2019). Solutions (0.01, 0.03, 0.1 mM) of the compounds were evaluated by an artificial taste sensor using membranes sensitive to bitterness. The dose-response slope of the sensor outputs was defined as CCDP. On the basis of principal component analysis of CCDPs, chlorpromazine hydrochloride, amitriptyline hydrochloride, propranolol hydrochloride, primaquine phosphate and haloperidol were predicted to express the strongest levels of basic bitterness, surpassing that of quinine hydrochloride. Correlation analysis (Fisher's exact tests and multiple regression analysis) was performed to determine the relation between CCDPs and various physicochemical properties participated in hydrophilicity and hydrophobicity. It is revealed that contribution physicochemical factors are different by individual basic bitterness sensor (AC0, AN0 or BT0), and this result becomes the criterion of the sensor choice to evaluate basic bitterness intensity using basic bitterness sensors. Hydrophobic and hydrophilic interactions could be simulated by ligand docking modeling for haloperidol, miconazole and quinine hydrochloride. The pharmaceutical products need a bitterness evaluation in consideration of concentration-dependency to vary in a dose depending on a patient individual. Thus, it was concluded that CCDP correlated to hydrophilicity and hydrophobicity is useful as a bitterness evaluation index of APIs in pediatric medicines.

Prognostic significance of right ventricular function during exercise in asymptomatic/minimally symptomatic patients with nonobstructive hypertrophic cardiomyopathy.

BACKGROUND: The risk stratification of hypertrophic cardiomyopathy (HCM) without left ventricular outflow tract (LVOT) obstruction and the utility of exercise stress echocardiography (ESE) remains unclear. We investigated the value of right ventricular (RV) function and RV-pulmonary artery (PA) coupling during exercise in asymptomatic/minimally symptomatic patients with nonobstructive HCM (nHCM). METHOD AND RESULTS: This retrospective study evaluated 74 HCM patients (age 63 ± 13 years, 65% men) without LVOT obstruction (≥30 mmHg) who underwent​ ESE. Eight patients (11%) suffered from HCM-related cardiac events during a median 2.5 years follow-up. During exercise, tricuspid annular plane systolic excursion (Ex-TAPSE) and Ex-TAPSE/systolic pulmonary artery pressure [SPAP] ratio were more impaired in patients with than in those without events (22 ± 4 vs 26 ± 4 mm, P = .005; and 0.45 [0.41, 0.47] vs 0.56 [0.47, 0.82] mm/mmHg, P = .002). In Cox regression analysis, Ex-TAPSE (HR: 1.397, P = .002) and the Ex-TAPSE/SPAP ratio (HR: 2.737, P = .006) were associated with cardiac events. In Kaplan-Meier analysis, patients with a low Ex-TAPSE (<24 mm) and Ex-TAPSE/SPAP ratio (<0.50 mm/mmHg) had a higher incidence of adverse outcomes than those with high Ex-TAPSE (Log rank, P < .001 and =.001, respectively). CONCLUSIONS: A low Ex-TAPSE and Ex-TAPSE/SPAP ratio were associated with adverse outcomes in nHCM. Evaluation of RV functional performance during exercise may play a crucial role in the risk stratification of nHCM.

Effect of Diastolic Flow Reversal Patterns on Clinical Outcomes Following Transcatheter Aortic Valve Implantation　- An Intraprocedural Echocardiography Study.

BACKGROUND: Although diastolic flow reversal (DFR) in the descending aorta, assessed via transesophageal echocardiography (TEE), is a simple and easy indicator for evaluating aortic regurgitation, the association between DFR pattern and clinical outcomes following transcatheter aortic valve implantation (TAVI) is unclear. The purpose of this study was to evaluate the effect of DFR patterns on clinical outcomes following TAVI.Methods and Results:Two-hundred and eleven patients (mean age, 83.6±5.7 years; 69% female) who underwent TAVI were retrospectively assessed via intraprocedural TEE. DFR was evaluated using pulsed-wave Doppler in the descending aorta before and after TAVI. The primary endpoint was major adverse cardio-cerebrovascular events (MACCEs). Although only 7 patients (3.3%) had moderate or severe paravalvular leak, as assessed by color Doppler echocardiography, holo-DFR (HDFR) was observed in 33 patients (16.0%) after TAVI. MACCEs occurred in 40 patients during the median follow up of 282 days (interquartile range: 160-478 days). The estimated cumulative MACCE-free survival at 1 year was significantly lower in patients with HDFR than in those without HDFR. A Cox proportional hazards analysis revealed that HDFR after TAVI was independently associated with MACCEs. CONCLUSIONS: HDFR was associated with an increased risk of MACCEs after TAVI. DFR evaluated by intraprocedural echocardiography could serve as a simple and easy method for predicting clinical outcomes.

Prognostic impact of transcatheter mitral valve repair in patients with exercise-induced secondary mitral regurgitation.

AIMS: Although exercise-induced secondary mitral regurgitation (MR) is known to have a poor prognosis, the therapeutic strategy towards this condition remains to be investigated. In the present study, we aimed to investigate the prognostic impact of transcatheter mitral valve repair (TMVr) using the MitraClip in patients with exercise-induced secondary MR. METHODS AND RESULTS: Of the 200 consecutive patients with secondary MR who underwent exercise stress echocardiography, 46 (23%) that presented with exercise-induced secondary MR [i.e. increase in effective regurgitant orifice area (EROA) of ≥ 0.13 cm2] were enrolled in the present investigation. The composite endpoints of all-cause mortality and hospitalization for heart failure were evaluated. Of the 46 patients included in the current cohort, 19 (41%) underwent TMVr and 27 (59%) were medically managed (control group). Although the TMVr group tended to present with a greater EROA at rest (0.26 ± 0.10 vs. 0.20 ± 0.08 cm2, P = 0.047), there were no differences in the EROA changes during exercise between the two groups (0.18 ± 0.10 vs. 0.18 ± 0.04 cm2, P = 0.940). While the TMVr group reported a higher event-free survival rate after the 13-month follow-up period (log-rank P = 0.017), the Cox proportional-hazard analysis suggested the TMVr to be associated with clinical outcomes (hazard ratio: 0.419, P = 0.044). CONCLUSION: As opposed to the medical management, TMVr treatment was associated with a lower risk of composite endpoints in patients with exercise-induced secondary MR. Exercise stress echocardiography is considered to have played an important role in decision-making for secondary MR.

Clinical Impact of New-Onset Left Bundle-Branch Block After Transcatheter Aortic Valve Implantation in the Japanese Population　- A Single High-Volume Center Experience.

BACKGROUND: Although left bundle-branch block (LBBB) is a known conduction disorder that occurs after transcatheter aortic valve implantation (TAVI), its clinical impact in the Japanese population remains unclear.Methods and Results:Of the 298 consecutive patients who underwent TAVI from January 2016 to December 2018 in a high-volume center in Japan, 68 with prior or periprocedural permanent pacemaker implantation (PPI), pre-existing LBBB, death during hospitalization, aborted procedure, or incomplete data were excluded. Among the final cohort of 230 patients, new-onset LBBB occurred in 90 (39%) after TAVI and persisted at 1-month follow up in 29 patients (13%; persistent new-onset LBBB, PN-LBBB). On multivariable analysis, self-expandable valve (SEV) use was found to be the only predictor of PN-LBBB (odds ratio: 4.39, 95% confidence interval: 1.69-11.41, P=0.002). There were no differences between patients with and without PN-LBBB in terms of overall mortality (18.8% vs. 26.0%, log-rank P=0.90) or need for late PPI (4.0% vs. 3.5%, log-rank P=0.74), yet there was an increased re-admission rate for heart failure (HF) in the PN-LBBB group (15.6% vs. 8.0%, log-rank P=0.046) at a median follow up of 431 (interquartile range, 271-733) days. CONCLUSIONS: PN-LBBB following TAVI was not associated with mortality or late PPI, but with a higher incidence of HF-related re-hospitalization at the mid-term follow up.

Bitterness-Suppressing Effect of Umami Dipeptides and Their Constituent Amino Acids on Diphenhydramine: Evaluation by Gustatory Sensation and Taste Sensor Testing.

Diphenhydramine, a sedating antihistamine, is an agonist of human bitter taste receptor 14 (hTAS2R14). Diphenhydramine hydrochloride (DPH) was used as a model bitter medicine to evaluate whether the umami dipeptides (Glu-Glu and Asp-Asp) and their constituent amino acids (Glu, Asp) could suppress its bitterness intensity, as measured by human gustatory sensation testing and using the artificial taste sensor. Various concentrated (0.001-5.0 mM) Glu-Glu, Asp-Asp, Glu and Asp significantly suppressed the taste sensor output of 0.5 mM DPH solution in a dose-dependent manner. The effect of umami dipeptides and their constituent amino acids was tending to be ranked as follows, Asp-Asp > Glu-Glu >> Gly-Gly, and Asp > Glu >> Gly (control) respectively. Whereas human bitterness intensity of 0.5 mM DPH solution with various concentrated (0.5, 1.0, 1.5 mM) Glu-Glu, Asp-Asp, Glu and Asp all significantly reduced bitterness intensity of 0.5 mM DPH solution even though no statistical difference was observed among four substances. The taste sensor outputs and the human gustatory sensation test results showed a significant correlation. A surface plasmon resonance study using hTAS2R14 protein and these substances suggested that the affinity of Glu-Glu, Asp-Asp, Glu and Asp for hTAS2R14 protein was greater than that of Gly-Gly or Gly. The results of docking-simulation studies involving DPH, Glu-Glu and Asp-Asp with hTAS2R14, suggested that DPH is able to bind to a space near the binding position of Glu-Glu and Asp-Asp. In conclusion, the umami dipeptides Glu-Glu and Asp-Asp, and their constituent amino acids, can all efficiently suppress the bitterness of DPH.

The Relationship between Bitter Taste Sensor Response and Physicochemical Properties of 47 Pediatric Medicines and Their Biopharmaceutics Classification.

The purpose of this study was to investigate the relationship between response to the bitterness taste sensor and physicochemical parameters of 47 pediatric medicines and to classify these medicines according to the biopharmaceutics classification system (BCS). Forty-seven bitter compounds, most of which were on the WHO model list of essential medicines for children (March 2017), were used in the study. Solutions (0.1 mM) were evaluated by an artificial taste sensor using membranes sensitive to bitterness. On the basis of principal component analysis of taste sensor measurements, chlorpromazine, haloperidol, propranolol, amitriptyline, diphenhydramine were predicted to express the strongest levels of basic bitterness, surpassing that of quinine. Correlation tests between bitter taste sensor outputs and physicochemical properties were then carried out and the compounds classified in terms of their biopharmaceutical properties. High log P values (≥2.82), physiological charge (≥1), low log S values (<-3) and small polar surface area (PSA; <45.59 Å2) were found to correlate significantly with the responses of bitter taste sensors. Forty-one of the 47 compounds could be placed into one of four groups in the BCS, on the basis of dose number (D0), an indicator of solubility which takes into account clinical dosage, and fractional absorption (Fa). For medicines classified in group 4, the factors D0 > 1 and Fa < 0.85 significantly correlated with the responses of the taste sensor for basic bitterness. It was concluded that lipophilicity, physiological charge, solubility, PSA and D0 are the main factors affecting the bitterness of pediatric medicines.

Preparation and Evaluation of Poly-γ-glutamic Acid Hydrogel Mixtures with Amlodipine Besylate: Effect on Ease of Swallowing and Taste Masking.

The purpose of the study was to prepare a poly-γ-glutamic acid hydrogel (PGA gel), to evaluate physicochemical properties, its ease of swallowing using texture profile analysis (TPA) and its taste-masking effects on amlodipine besylate (AML) using the artificial taste sensor and human gustatory sensation testing. Using TPA, 0.5 and 1.0% (w/v) PGA gels in the absence of drug were within the range of acceptability for use in people with difficulty swallowing according to permission criteria published by the Japanese Consumers Affairs Agency. The elution of AML from prepared PGA gels was complete within an hour and the gel did not appear to influence the bioavailability of AML. The sensor output of the basic bitterness sensor AN0 in response to AML mixed with 0.5 and 1.0% PGA gels was suppressed to a significantly greater degree than AML mixed with 0.5 and 1.0% agar. In human gustatory sensation testing, 0.5 and 1.0% PGA gels containing AML showed a potent bitterness-suppressing effect. Finally, 1H-NMR spectroscopic analysis was carried out to examine the mechanism of bitterness suppression when AML was mixed with PGA gel. The signals of the proton nearest to the nitrogen atom of AML shifted clearly upfield, suggesting an interaction between the amino group of AML and the carboxyl group of PGA gel. In conclusion, PGA gel is expected to be a useful excipient in formulations of AML, not only increasing ease of swallowing but also masking the bitterness of the basic drug.

A rare case of gradual enlargement of a multifocal myelolipoma of the posterior mediastinum for 12 years after surgical resection of an adrenal myelolipoma.

INTRODUCTION: A myelolipoma is a rare benign tumor that is composed of adipose tissue and hematopoietic elements. Myelolipomas most commonly occur in the unilateral adrenal gland. Posterior mediastinal myelolipomas are extremely rare. We herein present a rare case of a multifocal myelolipoma of the mediastinum that gradually enlarged over a 12-year period after surgical resection of an adrenal myelolipoma. This is the first report of multifocal myelolipomas of the posterior mediastinum and adrenal gland. PRESENTATION OF CASE: A posterior mediastinal tumor was incidentally found by chest X-ray and computed tomography (CT) examination of a 74-year-old woman. The patient had a medical history of resection of a myelolipoma of the left adrenal gland 12 years earlier. We performed tumor extirpation under video-assisted thoracic surgery (VATS). The size of the tumor was 4.5 cm, and the postoperative diagnosis was a myelolipoma. DISCUSSION: Posterior mediastinal myelolipomas are extremely rare, and only 39 cases of mediastinal myelolipoma have been reported to date. No reports have described a multifocal myelipoma of mediastinal myelolipoma. To our knowledge, this is the first report of multifocal myelipomas of the adrenal gland and posterior mediastinum. CONCLUSION: A differential diagnosis of myelolipoma of the posterior mediastinum is important in patients with a history of myelolipoma of the adrenal gland.

A 3-Step Chemiluminescence Method for Chemical Oxygen Demand Measurement.

Direct chemiluminescence emission from the reaction of acidic permanganate and organic compounds was employed for determining the chemical oxygen demand (COD) in water (1-step CL COD). Due to the diversity of organic pollutants in water, there are no standards for COD measurements, and many compounds do not show any chemiluminescence signal in the 1-step CL COD method. As a result, this method shows a low correlation with the conventional CODMn method. In this study, a new 3-step CL COD method was developed to overcome these drawbacks. The basic principle of the 3-step CL COD method is based on the principle of "back titration" in the CODMn method: (i) the sample is treated with permanganate under heating, (ii) the excess permanganate is treated with pyrogallol, and (iii) the excess pyrogallol is measured by the chemiluminescence reaction with permanganate. The reagent concentration, sample volume, and heating temperature were optimized, and the 3-step CL COD method successfully obtained the signal from some samples that cannot be detected by 1-step CL COD method. The calibration graph is linear in the range of 0 - 12.86 mg/L with a detection limit of 0.082 mg/L. This method is continuous, sensitive and low cost compared with the conventional method, and is applicable for on-site monitoring. The effect of the chloride ion was investigated, and showed an insignificant effect after two-times dilution of high-salinity samples. The correlation with the CODMn method for various organic compounds showed a good coefficient of determination, R2 = 0.9773 (n = 16).

A rare case of an intercostal lung herniation with fractures of the fifth and sixth ribs after thoracic surgery.

INTRODUCTION: Lung herniation is a rare condition defined as a protrusion of the pleural-covered lung parenchyma through an abnormal defect or weakness in the thoracic wall. Postoperative lung herniation is reported to result from a preceding operation with inadequate closure of the chest wall. PRESENTATION OF CASE: A 77-year-old woman was admitted to our hospital for treatment of hemoptysis and nausea. One year previously, she had undergone wedge resection of the right lower lobe (S6) for treatment of primary lung adenocarcinoma. Upon admission, chest radiograph and chest computed tomography showed a right lung herniation through the fifth enlarged intercostal space with right fifth and sixth rib fractures. She underwent surgical closure of the intercostal hernia using synthetic materials with fixation of the fifth and sixth ribs. The patient had developed no recurrence 9 months after surgical repair. DISCUSSION: In the present case, adequate closure of the right pleural cavity was ensured by fixation of both fifth and sixth ribs during the preceding video-assisted thoracic surgery for the primary lung carcinoma. Our patient may have had some exacerbation factors for lung herniation, increased intrathoracic pressure, attenuation of chest wall by prolonged coughing and rib fracture, and high abdominal pressure due to her hunched-over posture. CONCLUDION: It is important to know some exacerbation factors for postoperative intercostal lung herniation. Addition of monofirament-suture fixation of the ribs to patch repair is very effective for lung herniation repair in patients with concurrent lung herniation and rib fractures.