Nomogram for predicted probability of cervical cancer and its precursor lesions using miRNA in cervical mucus, HPV genotype and age.

Cervical cancer is the fourth most common cancer in women worldwide. Although cytology or HPV testing is available for screening, these techniques have their drawbacks and optimal screening methods are still being developed. Here, we sought to determine whether aberrant expression of miRNAs in cervical mucus could be an ancillary test for cervical neoplasms. The presence of miRNAs in 583 and 126 patients (validation and external cohorts) was determined by real-time RT-PCR. Performance of a combination with five miRNAs (miR-126-3p, -451a -144-3p, -20b-5p and -155-5p) was estimated by ROC curve analysis. Predicted probability (PP) was estimated by nomograms comprising -ΔCt values of the miRNAs, HPV genotype and age. A combination of five miRNAs showed a maximum AUC of 0.956 (95% CI: 0.933-0.980) for discriminating cancer. Low PP scores were associated with good prognosis over the 2-year observation period (p < 0.05). Accuracy for identifying cancer and cervical intraepithelial neoplasia (CIN) 3 + by nomogram was 0.983 and 0.966, respectively. PP was constant with different storage conditions of materials. We conclude that nomograms using miRNAs in mucus, HPV genotype and age could be useful as ancillary screening tests for cervical neoplasia.

Lower accuracy of cytological screening for high-grade squamous intraepithelial neoplasia in women over 50 years of age in Japan.

BACKGROUND: As the population ages in developed countries, the number of Pap smears for cervical cancer screening of older women is increasing. There is concern that cervical atrophy may cause misinterpretation of results for this segment of the population. The present study evaluated the accuracy of screening for high-grade intraepithelial lesions (HSILs) in women younger or older than 50 years, to determine whether aging affects cytological interpretation. METHODS: Patients with HSIL cytology (N = 1565) were dichotomized into those aged 20-49 years or aged ≥ 50 years. Association between histology results and age was examined. Pearson's chi-squared test and Cochran-Armitage trend test were used for statistical analysis. RESULTS: The positive predictive value (PPV) for cervical intraepithelial neoplasia (CIN)2 and worse was 65.2% (62/95) in older women but 87.3% (482/552) in younger women (p < 0.001). Older patients had a significantly lower PPV (p = 1.69 × 10-8). Separately analyzing chronic cervicitis, CIN1 and overt cancer grouped together, compared with another group composed of CIN2 and CIN3, we found that the PPV for CIN2 and CIN3 was lower in older than in younger women [44.2% (42/95)-vs-82.4% (455/552), p < 0.001], respectively. CONCLUSIONS: HSILs are associated with a wide range of disease categories as age increases, and the accuracy of HSIL interpretation is lower in older women.

Changes to the cervicovaginal microbiota and cervical cytokine profile following surgery for cervical intraepithelial neoplasia.

Persistent HPV infection associated with immune modulation may result in high-grade squamous intraepithelial lesions (CIN)2/3. Currently, there is little information on the cervicovaginal microbiome, local cytokine levels and HPV infection related to CIN. Follow-up of patients after local surgery provides an opportunity to monitor changes in the cervicovaginal environment. Accordingly, we undertook this longitudinal retrospective study to determine associations between HPV genotypes, cervicovaginal microbiome and local cytokine profiles in 41 Japanese patients with CIN. Cervicovaginal microbiota were identified using universal 16S rRNA gene (rDNA) bacterial primers for the V3/4 region by PCR of genomic DNA, followed by MiSeq sequencing. We found that Atopobium vaginae was significantly decreased (p < 0.047), whereas A. ureaplasma (p < 0.022) increased after surgery. Cytokine levels in cervical mucus were measured by multiplexed bead-based immunoassays, revealing that IL-1ß (p < 0.006), TNF-α (p < 0.004), MIP-1α (p < 0.045) and eotaxin (p < 0.003) were significantly decreased after surgery. Notably, the level of eotaxin decreased in parallel with HPV clearance after surgery (p < 0.028). Thus, local surgery affected the cervicovaginal microbiome, status of HPV infection and immune response. Changes to the cervicovaginal microbiota and cervical cytokine profile following surgery for cervical intraepithelial neoplasia may be important for understanding the pathogenesis of CIN in future.

Placental Genetic Variants in the Upstream Region of the FLT1 Gene in Pre-eclampsia.

BACKGROUND: Soluble fms-like tyrosine kinase 1 (sFlt-1) is believed to be a prominent component in the pathogenesis of pre-eclampsia, although the precise etiology has remained elusive. In this study, the etiological role of FLT1 variant was further validated in pre-eclampsia by examining this association in a Japanese sample population. METHODS: The genotypes of three variants (rs4769613, rs12050029 and rs149427560) were examined in the upstream region of the FLT1 gene in placentas from pre-eclamptic (n=47) or normotensive control (n=49) pregnancy samples. Additionally, FLT1 mRNA levels in placenta were determined by qRT-PCR. ELISA was further used to detect circulating sFlt-1 levels in maternal sera. The intergroup comparisons were made using the Mann-Whitney U test or one way analysis of variance and P values of less than 0.05 were considered statistically significant. RESULTS: First, the rs4769613 (C>T) and rs12050029 (G>A) genotypes were examined in placentas but no significant differences were found in the genotype or allele-type frequencies. Next, nearby short tandem repeat, rs149427560, was examined which manifested four size variants. In the genotypewise analysis, the frequency of the 474/476 heterozygote was significantly lower in pre-eclampsia (p<0.05). As expected, the FLT1 mRNA levels were significantly elevated in the pre-eclamptic placentas and sFlt-1 was higher in pre-eclamptic maternal sera. However, the genotype of these variants did not affect the FLT1 mRNA or serum sFlt-1 levels. CONCLUSION: Our findings did not support the hypothesis that genetic variations around the FLT1 gene affect the subtle expression changes underlying the etiologic pathway of pre-eclampsia. The hypothesis deserves further investigation through a larger sample size.

MicroRNA­126­3p suppresses HeLa cell proliferation, migration and invasion, and increases apoptosis via the PI3K/PDK1/AKT pathway.

We previously reported that relative to normal cervical mucus, microRNA 126­3p (miR­126­3p) is present in significantly greater amounts in the cervical mucus of patients with overt cervical cancer or precursor lesions. Here, we investigated the effects of enforced miR­126­3p expression in the cervical cancer cell line, HeLa, on proliferation, migration, invasion, apoptosis and protein expression. We transfected HeLa cells with miR­126­3p miRNA and found that proliferation, migration and invasion by cell counting, wound healing, cell migration and invasion assay were significantly reduced in these cells relative to those transfected with a negative control mimic. The levels of phosphoinositide 3 kinase (PI3K), phosphorylated 3­phosphoinositide­dependent protein kinase­1 (p­PDK1) and p­AKT proteins were lower in the miR­126­3p­transfected cells. Phosphorylated 70S6K (p­p70S6K), phosphorylated glycogen synthase kinase 3ß (p­GSK3ß), phosphorylated S6K (p­S6K), cyclin D1, phosphorylated p21­activated kinase 1 (p­PAK1), Rho associated coiled­coil containing protein kinase 1 (ROCK1), myotonic dystrophy­related CDC42­binding kinases α (MRCKα) and phospholipase C γ1 (p­PLCγ1) were also downregulated. This suggests that downstream effectors of the PI3K/PDK1/AKT pathway are targets for inhibition by miR­126­3p. In contrast, apoptotic­related proteins including the BCL­2­associated agonist of cell death (Bad), B­cell lymphoma­extra­large (Bcl­xL) and BCL­2­associated X (Bax), were all upregulated by miR­126­3p, resulting in increased caspase 3/7 activity and apoptosis. Thus, enforced expression of miR­126­3p inhibited cell migration and invasion and also induced apoptosis by regulating the PI3K/PDK1/AKT pathway in HeLa cells. Hence, high levels of miR­126­3p may inhibit cervical carcinogenesis, and targeting the PI3K/PDK1/AKT pathway via miR­126­3p could represent a new approach for treating patients with cervical cancer.

Comparison Between Healthcare-Associated and Community-Acquired Infective Endocarditis at Tertiary Care Hospitals in Japan.

BACKGROUND: Healthcare-associated infective endocarditis (HAIE) has become increasingly recognized worldwide because the underlying patient conditions are completely different from those of community-acquired infective endocarditis (CIE). However, data on HAIE in the Japanese population is lacking. We sought to clarify the patient characteristics and prognosis of HAIE in a Japanese population.Methods and Results:A retrospective study was conducted in 158 patients who were diagnosed with infective endocarditis, 53 of whom (33.5%) were classified as HAIE. Compared with patients with CIE, those with HAIE were older (median age 72 vs. 61 years; P=0.0002) and received surgical treatment less frequently (41.5% vs. 62.9%; P=0.01). Regarding causative microorganisms, staphylococci,including methicillin-resistant pathogens, were more common in patients with HAIE (32.1% vs. 14.3%; P=0.01). Patients with HAIE had higher in-hospital mortality (32.1% vs. 4.8%; P<0.0001) and Kaplan-Meier analysis showed worse prognosis for patients with HAIE than CIE (P<0.0001, log-rank test). On multivariate Cox analysis, HAIE (hazard ratio 3.26; 95% confidence interval 1.49-7.14), age ≥60 years, surgical treatment, stroke, and heart failure were independently associated with mortality. CONCLUSIONS: HAIE has different clinical characteristics and causative microorganisms, as well as worse prognosis, than CIE. Preventive strategies, and the prompt and appropriate identification of HAIE may improve the outcome of infective endocarditis.

Cytokine expression profiles in cervical mucus from patients with cervical cancer and its precursor lesions.

Human papillomavirus (HPV) infection can persist in the cervical epithelium without provoking a strong host immune response, leading to the development of cervical cancer. Cytokines, which mediate innate and adaptive immune activities, are secreted in the cervical mucus; however, there is currently no appropriate method for assessing cytokine levels in mucus specimens. Here, we employed multiplexed bead-based immunoassays to examine cytokine levels in cervical mucus using both weighted-volume and total protein concentration methods to adjust for different specimen volumes in individual patients. Out of 18 cytokines initially examined in the primary cohort patient group (n = 28), 14 were detected in more than 10% of the samples. Of these 14 cytokines, expression levels of interferon (IFN)-γ, granulocyte-macrophage colony-stimulating factor (GM-CSF), RANTES, and eotaxin were significantly increased with the disease severity in the secondary cohort patient group (n = 235). We also examined associations between cytokine levels and clinical parameters, such as cytology and HPV genotype. Of the 14 cytokines, granulocyte colony-stimulating factor (G-CSF) was downregulated in HPV-positive specimens. Examination of co-expression patterns of cytokines in relation to HPV infection status revealed that several pairs of cytokines were simultaneously upregulated in HPV-positive cases, including INF-γ and interleukin (IL)-17A, GM-CSF and monocyte chemoattractant protein-1 (MCP-1), GM-CSF and RANTES, IL-17A and RANTES, and MCP-1 and eotaxin. Interestingly, upregulation of GM-CSF and RANTES might reflect a shift in immuno-regulatory cytokines in HPV-positive specimens, potentially associated with more severe cervical neoplasia.

Preliminary therapeutic outcomes of using direct oral anticoagulants to treat venous thromboembolism in gynecological cancer patients.

OBJECTIVES: Venous thromboembolism (VTE) is often a problematic complication in patients with gynecological cancer. Despite increasing opportunities to use direct oral anticoagulants (DOACs) to treat VTE, there are no reports on the therapeutic outcomes of DOACs in patients with gynecological cancer; however, there are some studies on cancer patients in general. We retrospectively examined the efficacy and safety of using DOACs to treat VTE in such patients. METHODS: The study cohort comprised 43 patients with gynecological cancer and VTE who received treatment between May 2005 and April 2016. They were divided into two groups: DOACs used (DOAC group, n=21) and only unfractionated heparin (UFH) and warfarin used (standard group, n=22). The rates of improvement and recurrence of VTE and incidence of adverse events were compared between these groups. RESULTS: At 6 months, the VTE of 85% of patients in the DOAC group and of 75% in the standard group had improved (p=0.59). No recurrences of VTE occurred in the DOAC group; where VTE recurred in 12.5% of patients in the standard group. Adverse events occurred in three patients in the DOAC group (15.3%) and one in the standard group (7.7%). Chemotherapy significantly impacted improvement in VTE (p=0.01). CONCLUSIONS: Rates of VTE improvement and of recurrence of VTE and adverse events did not differ significantly between the study groups.

Identification of miRNAs in cervical mucus as a novel diagnostic marker for cervical neoplasia.

microRNAs (miRNAs) play important roles in regulation of gene expression during cervical carcinogenesis. We investigated expression profiles of miRNAs in cervical cancer and its precursor lesions by utilizing cervical mucus. Cervical mucus was collected from 230 patients with a normal cervix, cervical intraepithelial neoplasia (CIN), squamous cell carcinoma (SCC), or adenocarcinoma (AD). The levels of miRNA in the mucus were quantified by miRNA array and real-time reverse-transcriptase polymerase chain reaction (RT-PCR). The performance for detecting diseases was statistically analysed. The expression of miRNAs was further validated in the surgical tissues of enrolled patients. Four miRNAs (miR-126-3p, -20b-5p, -451a, and -144-3p) were significantly up-regulated in SCC and AD compared with normal, and their expression levels correlated with disease severity and high-risk human papillomavirus infection. Receiver operating characteristic curve analyses revealed that the area under the curve values for miR-126-3p, -20b-5p, -451a, and -144-3p were 0.89, 0.90, 0.94, and 0.93, respectively, for SCC plus AD compared with normal, showing high accuracy of cancer detection. Real-time RT-PCR analyses confirmed the expression of these four miRNAs in frozen tissues from cervical cancer. miR-126-3p, -20b-5p, -451a, and -144-3p in cervical mucus are promising biomarkers for cervical cancer and high-grade CINs.

Estrogen variation during the menstrual cycle does not influence left ventricular diastolic function and untwisting rate in premenopausal women.

BACKGROUND: Although a cardioprotective effect of estrogen has been suggested by experimental studies, clinical data on the influence of estrogen on left ventricular (LV) diastolic function are sparse. The LV untwisting rate obtained by 2D speckle tracking echocardiography (2D-STE) is correlated with the time constant of LV pressure decay (tau), and this correlation is independent of left atrial pressure. Therefore, we used conventional Doppler echocardiography and 2D-STE to investigate changes in LV diastolic function during a single menstrual cycle in premenopausal women. METHODS: Twenty healthy premenopausal woman (mean age, 28.1±2.7 years) were enrolled. Clinical and echocardiographic data were obtained during the follicular phase (F-phase) and luteal phase (L-phase) of a single menstrual cycle. We compared the clinical and echocardiographic data, and estrogen levels between the two phases. RESULTS: There were no significant differences in LV diastolic parameters derived from Doppler echocardiography (E/A, p=0.295; E/e', p=0.449, DcT, p=0.178) or 2D-STE (peak untwisting rate, p=0.892; time-to-peak untwisting, p=0.951) between the two phases of the menstrual cycle. However, there was a significant decrease in estrogen levels between the F- and L-phases (177±119pg/ml vs. 35±12pg/ml, p<0.0001). CONCLUSIONS: LV diastolic function in healthy premenopausal women did not significantly change during the menstrual cycle. Estrogen does not appear to have a significant acute effect on LV diastolic function in premenopausal woman.

Comparison of methods using paraffin-embedded tissues and exfoliated cervical cells to evaluate human papillomavirus genotype attribution.

Monitoring the attribution of human papillomavirus (HPV) genotypes to cervical precancerous lesions is essential in assessing the efficacy of HPV vaccines. To resolve the lack of studies comparing the HPV genotyping procedures used to estimate HPV genotype attribution, we undertook a retrospective cross-sectional study to determine the appropriate genotyping procedures for evaluating the potential efficacy of HPV vaccines. Three procedures, including two different genotyping methods, Clinichip HPV test (C-Chip) and modified GP5+/6+ PCR coupled to fluorescent bead sorter detection (MGP), using exfoliated cervical cells (C-Chip and C-MGP, respectively) or formalin-fixed paraffin-embedded tissues (F-MGP), were compared. The overall agreement in detecting high-risk HPV was 88.5-92.1% among the three procedures, and genotype-specific agreement was 83.9-100% for all pairwise comparisons. In cervical intraepithelial neoplasia grade 2/3 specimens, HPV16/18 attribution estimated with the hierarchical attribution method was consistent among the procedures: 52.3% (45/86) for C-Chip, 54.7% (47/86) for C-MGP, and 52.3% (45/86) for F-MGP (P = 0.81). HPV16/18/31/33/45/52/58 hierarchical attribution was 88.4% (76/86) with C-Chip, 86.0% (74/86) with C-MGP, and 83.7% (72/86) with F-MGP (P = 0.49). In cervical intraepithelial neoplasia grade 3 specimens, the corresponding hierarchical attribution was 96.4% (53/55) with C-Chip, 89.1% (49/55) with C-MGP, and 94.5% (52/55) with F-MGP (P = 0.27). Although F-MGP is theoretically a reliable method for determining HPV genotype attribution, it is acceptable to use C-Chip or C-MGP, coupled to the hierarchical attribution formula to correct the bias of multiple infections. These approaches using exfoliated cervical cells are practical for monitoring the efficacy of HPV vaccines.

When and how aortic stenosis is first diagnosed: A single-center observational study.

BACKGROUND: The development of clinical symptoms is associated with cardiovascular events in patients with aortic stenosis (AS). Thus, early diagnosis of AS is clinically important. However, there are few data on symptom status or the severity of AS when patients are first diagnosed, or on how AS is detected in routine practice. We aimed to investigate when and how AS patients are first diagnosed in our hospital. METHODS: We retrospectively enrolled 198 AS patients diagnosed from 1989 to 2009, and identified their symptoms and AS severity at the time of the first diagnosis. We also assessed the reasons why they came to the hospital based on their medical records. RESULTS: Of the 198 patients, 82 (41.6%) had voluntarily visited or been referred to our hospital after developing clinical symptoms (Symptomatic group). The remaining 116 patients (58.4%) had been asymptomatic, and cardiovascular disease was suspected during an annual or occasional health checkup (Asymptomatic group). The initial findings in the Asymptomatic group that led to the diagnosis of AS were: a systolic murmur on auscultation (62%), abnormal electrocardiography (27%), or abnormal echocardiography (11%). The Symptomatic group had significantly greater AS severity and an increased left ventricular mass index, and experienced more cardiac events (valve replacement or cardiac death) during the follow-up period. CONCLUSIONS: About 40% of the AS patients in this study were not diagnosed until they developed clinical symptoms, suggesting that many other patients in the community might have a latent risk of cardiovascular events. Auscultation plays an important role in the early diagnosis of AS.

Significance of Coronary Artery Disease and Left Ventricular Afterload in Unoperated Asymptomatic Aortic Stenosis.

BACKGROUND: Because the covariates of cardiovascular events in unoperated patients with asymptomatic aortic stenosis (AS) have not been adequately evaluated, we aimed to identify them. METHODS AND RESULTS: A total of 230 patients with asymptomatic severe AS were retrospectively enrolled. The patients were divided into 2 groups based on aortic valve replacement (AVR) after enrollment: a non-AVR group (n=112), and an AVR group (n=118). The primary clinical endpoint was cardiovascular events, which were defined as cardiovascular death or hospitalization. Coronary artery disease [hazard ratio (HR): 3.62, 95% confidence interval (CI): 1.585-8.245, P<0.01] and high valvulo-arterial impedance (HR: 3.08, 95% CI: 1.261-7.532, P<0.05) were identified as independent covariates of cardiovascular events in the non-AVR group. The relative risk of cardiovascular events rose with an increase in the number of risk factors (P<0.0001). CONCLUSIONS: In unoperated patients with asymptomatic AS, the presence of coronary artery disease and increased global left ventricular afterload may be associated with a poor prognosis.

Coronary microvascular function is independently associated with left ventricular filling pressure in patients with type 2 diabetes mellitus.

BACKGROUND: Left ventricular (LV) diastolic dysfunction is known as an early marker of myocardial alterations in patients with diabetes. Because microvascular disease has been regarded as an important cause of heart failure or diastolic dysfunction in diabetic patients, we tested the hypothesis that coronary flow reserve (CFR), which reflects coronary microvascular function, is associated with LV diastolic dysfunction in patients with type 2 diabetes. METHODS: We studied asymptomatic patients with type 2 diabetes but without overt heart failure. Transthoracic Doppler echocardiography was performed that included pulsed tissue Doppler of the mitral annulus and CFR of the left anterior descending artery (induced by adenosine 0.14 mg/kg/min). The ratio of mitral velocity to early diastolic velocity of the mitral annulus (E/e') was used as a surrogate marker of diastolic function. We also evaluated renal function, lipid profile, parameters of glycemic control and other clinical characteristics to determine their association with E/e'. Patients with LV ejection fraction <50%, atrial fibrillation, valvular disease, regional wall motion abnormality, renal failure (serum creatinine >2.0 mg/dl) or type 1 diabetes were excluded. Patients with a CFR <2.0 were also excluded based on the suspicion of significant coronary artery stenosis. RESULTS: We included 67 asymptomatic patients with type 2 diabetes and 14 non-diabetic controls in the final study population. In univariate analysis, age, presence of hypertension, LV mass index, estimated glomerular filtration rate and CFR were significantly associated with E/e'. Multivariate analysis indicated that both LV mass index and CFR were independently associated with E/e'. In contrast, there were no significant associations between parameters of glycemic control and E/e'. CONCLUSIONS: CFR was associated with LV filling pressure in patients with type 2 diabetes. This result suggests a possible link between coronary microvascular disease and LV diastolic function in these subjects.

Bradyarrhythmias may induce central sleep apnea in a patient with obstructive sleep apnea.

The relationship between central sleep apnea (CSA) and bradyarrhythmia remains unclear. We report the case of a 70-year-old man with severe obstructive sleep apnea and bradyarrhythmia due to sick sinus syndrome in whom concomitant CSA was alleviated after pacemaker implantation.

Retrospective comparative study of irinotecan and pegylated liposomal doxorubicin for platinum-resistant or -refractory epithelial ovarian and primary peritoneal carcinoma.

PURPOSE: This study was conducted to retrospectively compare the efficacy and safety of irinotecan (CPT-11) and pegylated liposomal doxorubicin (PLD) in patients with platinum-resistant or -refractory recurrent epithelial ovarian and primary peritoneal carcinoma. METHODS: Nineteen patients who received CPT-11 and eleven patients who received PLD were enrolled. CPT-11 was intravenously administered at a starting dose of 60-100 mg/m(2) on day 1, 8, and 15 every 28 days, and PLD was administered at a starting dose of 40-50 mg/m(2) on day 1 every 28 days. Primary outcomes were overall response rate (complete response [CR] + partial response [PR]), disease control rate (CR + PR + stable disease), and progression-free survival (PFS) in each group. Clinical response was evaluated every two or three cycles using the Response Evaluation Criteria in Solid Tumors criteria; CA125 analysis was not performed. RESULTS: The overall response rate was 21.1 % (PR, four cases) and 0 % (p = 0.10) in the CPT-11 and PLD groups, respectively, and the disease control rate was 73.7 and 45.5 % (p = 0.12), respectively. Median PFS was 25.3 (range 5.4-69.9) weeks and 12.7 (range 4.0-43.1) weeks in the CPT-11 and PLD groups, respectively; however, this difference was not statistically significant (p = 0.064). Major adverse events in the CPT-11 group were neutropenia, nausea, and diarrhea, whereas those in the PLD group included thrombocytopenia, anemia, stomatitis, and hand-foot syndrome. CONCLUSIONS: This retrospective study demonstrated comparable efficacy outcomes for CPT-11 and PLD. The overall response rate, disease control rate, and median PFS were more favorable in the CPT-11 group compared to the PLD group, although the difference was not significant. The adverse event profiles were different between groups. These results suggest that CPT-11 might be a feasible choice as single-agent salvage chemotherapy for platinum-resistant or -refractory recurrent epithelial ovarian and primary peritoneal carcinoma beside established regimen like PLD.

Factors responsible for elevated plasma B-type natriuretic peptide levels in severe aortic stenosis: comparison between elderly and younger patients.

BACKGROUND: Elevated plasma B-type natriuretic peptide (BNP) is a predictor of outcome and helpful for risk stratification in aortic stenosis (AS). However, left ventricular (LV) diastolic dysfunction progresses with aging and may also influence plasma BNP levels in elderly patients. We hypothesized that plasma BNP levels may be influenced by age in severe AS, and that factors that affect the elevation of plasma BNP levels may be different between elderly and younger patients with AS. METHODS: We performed echocardiography in 341 patients with severe AS [aortic valve area (AVA)<1.0cm(2)] and classified them into two groups by age (elderly ≥75 years old, n=201; younger patients <75 years old, n=140). We used multivariate linear regression analysis to assess the factors that determine plasma BNP levels in both groups. RESULTS: Age was found to be one of the independent determinants of plasma BNP levels in all patients (ß=0.135, p=0.005). Although AVA was similar in the two groups, plasma BNP levels and E/e' were significantly higher in elderly than younger patients [133.0 (IQR, 73.3-329.7)pg/dl vs 92.8 (IQR, 40.6-171.8)pg/dl, p<0.01; 20±8 vs 16±6, p<0.01, respectively). In multivariate stepwise linear regression analysis, AVA index, LV ejection fraction, mass index, E/e', estimated systolic pulmonary artery pressure (eSPAS), and the presence of atrial fibrillation were independent determinants of plasma BNP levels in younger patients. In contrast, the independent determinants of plasma BNP levels in elderly patients were LV ejection fraction, mass index, E/e', eSPAS, the presence of atrial fibrillation, age, and hemoglobin levels, but not AVA index. CONCLUSIONS: There may be differences in the factors that influence plasma BNP levels between elderly and younger patients with severe AS. In elderly patients, plasma BNP levels may be influenced more by these factors than AS severity compared with younger patients.

Early hemodynamic performance of the trifecta bioprosthetic valve in patients with aortic valve disease.

BACKGROUND: The Trifecta valve (St Jude Medical) is a novel supra-annular aortic bioprosthesis designed to improve hemodynamic performance. We hypothesized that the Trifecta may offer better hemodynamic performance in Japanese patients, in whom the annulus is smaller, compared with Western populations. We compared the early results of hemodynamic performance between the Trifecta and the Magna (Edwards Lifescience) valves at our institution. METHODS AND RESULTS: The Trifecta was implanted in 33 patients and the Magna was implanted in 41 patients who had aortic valve disease. Postoperative echocardiography was performed just before discharge, and the mean pressure gradient (MPG), effective orifice area (EOA) index and energy loss coefficient (ELCo) index were compared between the 2 groups. The average prosthesis size was similar between the 2 groups (21.1 vs. 21.3mm). The Trifecta group had a significantly lower MPG (P=0.001) and larger EOA index and ELCo index than the Magna group (P<0.001 for both). On multivariate linear regression analysis, use of the Trifecta was the strongest independent determinant of postoperative MPG, EOA and ELCo index. CONCLUSIONS: The Trifecta valve provides excellent early postoperative hemodynamic performance in Japanese patients. Patients with a small annulus size relative to body size may benefit more from the Trifecta in terms of postoperative hemodynamic performance.

Assessment of elevation of and rapid change in left ventricular filling pressure using a novel global strain imaging diastolic index.

BACKGROUND: The aim of this study was to determine whether global strain imaging diastolic index (SIDI) obtained using 2-D speckle tracking imaging (2DSI) could predict elevation in and rapid change of LV filling pressure. METHODS AND RESULTS: Patients (n=126) underwent echocardiography and 2DSI during simultaneous cardiac catheterization. There were 60 patients in whom the same measurements were repeated 5min after i.v. glyceryl trinitrate. LV pre-atrial contraction pressure (pre-A) was measured as a surrogate of LV filling pressure. SIDI was defined as the change of LV longitudinal strain measured using 2DSI during the first one-third of diastole. Then, longitudinal global SIDI (L-global SIDI) was calculated as the mean SIDI of 18 LV segments. Mitral inflow and tissue Doppler imaging were also assessed. Among 126 patients, 93 patients had LV pre-A ≥15mmHg. L-global SIDI had a better correlation with LV pre-A (P<0.001, r=-0.56) than E/e' (P<0.01, r=0.35). On receiver operating characteristic curve analysis, L-global SIDI <0.48 was the optimum cut-off to predict LV pre-A ≥15mmHg (sensitivity, 82%; specificity, 68%). In addition, the ratio of L-global SIDI (after nitrate/before nitrate) was correlated with the ratio of LV pre-A (after nitrate/before nitrate; P=0.02, r=-0.34). CONCLUSIONS: A novel L-global SIDI derived from 2DSI may reflect elevated LV filling pressure and its rapid change better than conventional diastolic parameters.

Prediction of coronary artery stenosis at rest in patients with normal left ventricular wall motion. Segmental analyses using strain imaging diastolic index.

Noninvasive detection of coronary artery stenosis usually requires a stress test in patients without left ventricular (LV) regional wall motion abnormalities (RWMA). In contrast, abnormal regional LV relaxation caused by ischemia may persist beyond recovery from transient ischemia. The aim of the present study was to determine whether segmental analysis of abnormal regional LV relaxation using the strain imaging diastolic index (SI-DI) at rest could predict coronary artery stenosis in the three major vessels in patients without LV dysfunction or RWMA. We performed 2D speckle tracking echocardiography and coronary angiography in 85 patients without RWMA with suspected coronary artery disease. Patients with LV dysfunction or acute coronary syndrome were excluded. Echocardiographic images of the LV were obtained in the apical 2-, 3-, and 4-chamber views and divided into 6 segments. In each segment, SI-DI derived from transverse strain imaging was determined. Forty-eight patients had significant coronary artery stenosis (≥ 70%). The optimal cutoff values of SI-DI were 60.5% in the mid anteroseptal segment for detecting left anterior descending artery stenosis (sensitivity, 83.3%; specificity, 81.1%), 60.5% in the basal anterolateral segment for detecting left circumflex artery stenosis (sensitivity, 80.9%; specificity, 90.3%), and 61.5% in the basal inferior segment for detecting right coronary artery stenosis (sensitivity, 74.1%; specificity, 77.8%). A segmental analysis of SI-DI at rest predicted coronary artery stenosis in the three major vessels in patients without RWMA. This noninvasive method may be useful for detecting coronary artery stenosis without a stress test.