GDF5+ chondroprogenitors derived from human pluripotent stem cells preferentially form permanent chondrocytes.

It has been established in the mouse model that during embryogenesis joint cartilage is generated from a specialized progenitor cell type, distinct from that responsible for the formation of growth plate cartilage. We recently found that mesodermal progeny of human pluripotent stem cells gave rise to two types of chondrogenic mesenchymal cells in culture: SOX9+ and GDF5+ cells. The fast-growing SOX9+ cells formed in vitro cartilage that expressed chondrocyte hypertrophy markers and readily underwent mineralization after ectopic transplantation. In contrast, the slowly growing GDF5+ cells derived from SOX9+ cells formed cartilage that tended to express low to undetectable levels of chondrocyte hypertrophy markers, but expressed PRG4, a marker of embryonic articular chondrocytes. The GDF5+-derived cartilage remained largely unmineralized in vivo. Interestingly, chondrocytes derived from the GDF5+ cells seemed to elicit these activities via non-cell-autonomous mechanisms. Genome-wide transcriptomic analyses suggested that GDF5+ cells might contain a teno/ligamento-genic potential, whereas SOX9+ cells resembled neural crest-like progeny-derived chondroprogenitors. Thus, human pluripotent stem cell-derived GDF5+ cells specified to generate permanent-like cartilage seem to emerge coincidentally with the commitment of the SOX9+ progeny to the tendon/ligament lineage.

Diagnostic accuracy of whole heart coronary magnetic resonance angiography: a systematic review and meta-analysis.

BACKGROUND: The purpose of this meta-analysis was to comprehensively investigate the diagnostic ability of 1.5 T and 3.0 T whole heart coronary angiography (WHCA) to detect significant coronary artery disease (CAD) on X-ray coronary angiography. METHODS: A literature search of electronic databases, including PubMed, Web of Science Core Collection, Cochrane advanced search, and EMBASE, was performed to retrieve and integrate articles showing significant CAD detectability of 1.5 and 3.0 T WHCA. RESULTS: Data from 1899 patients from 34 studies were included in the meta-analysis. 1.5 T WHCA had a summary area under ROC of 0.88 in the patient-based analysis, 0.90 in the vessel-based analysis, and 0.92 in the segment-based analysis. These values for 3.0 T WHCA were 0.94, 0.95, 0.96, respectively. Contrast-enhanced 3.0 T WHCA had significantly higher specificity than non-contrast-enhanced 1.5 T WHCA on a patient-based analysis (0.87, 95% CI 0.80-0.92 vs. 0.74, 95% CI 0.64-0.82, P = 0.02). There were no differences in diagnostic performance on a patient-based analysis by use of vasodilators, beta-blockers or between Asian and Western countries. CONCLUSIONS: The diagnostic performance of WHCA was deemed satisfactory, with contrast-enhanced 3.0 T WHCA exhibiting higher specificity compared to non-contrast-enhanced 1.5 T WHCA in a patient-based analysis. There were no significant differences in diagnostic performance on a patient-based analysis in terms of vasodilator or beta-blocker use, nor between Asian and Western countries. However, further large-scale multicentre studies are crucial for the widespread global adoption of WHCA.

Machine learning to predict left ventricular reverse remodeling by guideline-directed medical therapy by utilizing texture feature of extracellular volume fraction in patients with non-ischemic dilated cardiomyopathy.

Extracellular volume fraction (ECV) by cardiac magnetic resonance (CMR) allows for the non-invasive quantification of diffuse myocardial fibrosis. Texture analysis and machine learning are now gathering attention in the medical field to exploit the ability of diagnostic imaging for various diseases. This study aimed to investigate the predictive value of texture analysis of ECV and machine learning for predicting response to guideline-directed medical therapy (GDMT) for patients with non-ischemic dilated cardiomyopathy (NIDCM). A total of one-hundred and fourteen NIDCM patients [age: 63 ± 12 years, 91 (81%) males] were retrospectively analyzed. We performed texture analysis of ECV mapping of LV myocardium using dedicated software. We calculated nine histogram-based features (mean, standard deviation, maximum, minimum, etc.) and five gray-level co-occurrence matrices. Five machine learning techniques and the fivefold cross-validation method were used to develop prediction models for LVRR by GDMT based on 14 texture parameters on ECV mapping. We defined the LVRR as follows: LVEF increased ≥ 10% points and decreased LVEDV ≥ 10% on echocardiography after GDMT > 12 months. Fifty (44%) patients were classified as non-responders. The area under the receiver operating characteristics curve for predicting non-responder was 0.82 for eXtreme Gradient Boosting, 0.85 for support vector machine, 0.76 for multi-layer perception, 0.81 for Naïve Bayes, 0.77 for logistic regression, respectively. Mean ECV value was the most critical factor among texture features for differentiating NIDCM patients with LVRR and those without (0.28 ± 0.03 vs. 0.36 ± 0.06, p < 0.001). Machine learning analysis using the support vector machine may be helpful in detecting high-risk NIDCM patients resistant to GDMT. Mean ECV is the most crucial feature among texture features.

Contrast defect of left atrial appendage on computed tomography is associated with higher risk of recurrence after catheter ablation in patients with paroxysmal atrial fibrillation.

The previous study has shown that the contrast defect of the left atrial appendage (LAA) on contrast-enhanced cardiac computed tomography (CT) is associated with a higher rate of stroke in patients with atrial fibrillation (AF). This study aimed to investigate the association between LAA CT contrast defect and the risk of arrhythmia recurrence after catheter ablation (CA) in patients with paroxysmal AF. A total of 283 paroxysmal AF patients [age: 67 ± 10 years, 185 (65%) males] who underwent cardiac CT before CA were retrospectively analyzed. The presence or absence of LAA CT contrast defect was visually assessed using early phase CT images. Recurrence was an episode of atrial arrhythmia beyond the first 90 days post-ablation. LAA flow velocity was measured using transesophageal echocardiography in 246 paroxysmal AF patients. Sixty-eight (24%) patients had an LAA CT contrast defect. LAA flow velocity was significantly reduced in patients with LAA CT defect compared to those without (56.8 ± 28.7 cm/s vs. 41.1 ± 19.1 cm/s, p < 0.001). During a median follow-up period of 858 days, arrhythmia recurrence was identified in 85 (30%) patients. On a Kaplan Meier curve, patients with LAA CT contrast defect had significantly higher recurrence rates than those without (p = 0.043). On a multivariable Cox regression analysis, LAA CT contrast defect was a significant and independent predictor after adjustment of age, sex and left atrial volume index (hazard ratio: 1.79, 95% confidence interval: 1.03-3.07, p = 0.036). LAA CT contrast defect was associated with decreased LAA flow velocity and a higher rate of arrhythmia recurrence after CA, suggesting its usefulness as a non-invasive predictor for high-risk AF patients resistant to CA therapy.

Native T1 heterogeneity for predicting reverse remodeling in patients with non-ischemic dilated cardiomyopathy.

A recent study has shown that the heterogeneity of native T1 mapping may be a new prognostic factor for patients with non-ischemic dilated cardiomyopathy (NIDCM). This study aimed to investigate the predictive value of native T1 heterogeneity of the left ventricular (LV) myocardium, as assessed by pixel-wise histogram analysis, for predicting left ventricular reverse remodeling (LVRR) by medical therapy in patients with NIDCM. A total of one hundred and thirteen NIDCM patients (mean age: 63 ± 12 years; 91 males and 22 females; mean LV ejection fraction (EF): 37 ± 10%) were retrospectively analyzed. T1 mapping images were acquired using a modified look-locker inversion recovery (MOLLI) sequence. We performed histogram analysis of native T1 mapping of LV myocardium, mean (T1-mean) and standard deviation (T1-STD) of native T1 time from each pixel were calculated. Extracellular volume fraction (ECV) was also evaluated. LVRR was defined as LVEF increased ≥ 10% points and decrease in LV end-diastolic volume ≥ 10% at 12 months from initiation of medical therapy. Cutoff value of T1-mean and T1-STD was set as median value of each parameter. Sixty (53%) NIDCM patients reached LVRR. Area under the receiver-operating characteristics curve for predicting LVRR was 0.763 (95% confidence interval (CI) 0.679-0.847) for %LGE, 0.757 (95% CI 0.663-0.850) for T1-mean, 0.724 (95% CI 0.625-0.823) for T1-STD, 0.800 (95% CI 0.717-0.882) for ECV, respectively. Proportion of LVRR was significantly lower in NIDCM patients with high T1-mean and high T1-STD (12%) compared to NIDCM with high T1-mean and low T1-STD (65%) (p < 0.001). Adding T1-STD to T1-mean improved AUC from 0.757 to 0.806, comparable to AUC of ECV. Combination of T1-mean and T1-STD, a parameter of heterogeneity of native T1 of the LV myocardium, may be a useful for prediction of LVRR by medical therapy without use of gadolinium contrast for patients with NIDCM.

Cardiac involvement in coronavirus disease 2019 assessed by cardiac magnetic resonance imaging: a meta-analysis.

In this systematic review and meta-analysis, we sought to evaluate the prevalence of cardiac involvement in patients with COVID-19 using cardiac magnetic resonance imaging. A literature review was performed to investigate the left ventricular (LV) and right ventricular (RV) ejection fraction (EF), the prevalence of LV late gadolinium enhancement (LGE), pericardial enhancement, abnormality on T1 mapping, and T2 mapping/T2-weighted imaging (T2WI), and myocarditis (defined by modified Lake Louis criteria). Pooled mean differences (MD) between COVID-19 patients and controls for LVEF and RVEF were estimated using random-effects models. We included data from 10.462 patients with COVID-19, comprising 1.010 non-athletes and 9.452 athletes from 29 eligible studies. The meta-analysis showed a significant difference between COVID-19 patients and controls in terms of LVEF [MD = - 2.84, 95% confidence interval (CI) - 5.11 to - 0.56, p < 0.001] and RVEF (MD = - 2.69%, 95% CI - 4.41 to - 1.27, p < 0.001). However, in athletes, no significant difference was identified in LVEF (MD = - 0.74%, 95% CI - 2.41 to - 0.93, p = 0.39) or RVEF (MD = - 1.88%, 95% CI - 5.21 to 1.46, p = 0.27). In non-athletes, the prevalence of LV LGE abnormalities, pericardial enhancement, T1 mapping, T2 mapping/T2WI, myocarditis were 27.5% (95%CI 17.4-37.6%), 11.9% (95%CI 4.1-19.6%), 39.5% (95%CI 16.2-62.8%), 38.1% (95%CI 19.0-57.1%) and 17.6% (95%CI 6.3-28.9%), respectively. In athletes, these values were 10.8% (95%CI 2.3-19.4%), 35.4% (95%CI - 3.2 to 73.9%), 5.7% (95%CI - 2.9 to 14.2%), 1.9% (95%CI 1.1-2.7%), 0.9% (0.3-1.6%), respectively. Both LVEF and RVEF were significantly impaired in COVID-19 patients compared to controls, but not in athletes. In addition, the prevalence of myocardial involvement is not negligible in patients with COVID-19.

Aneuploidy and sex concordance rate between cell-free DNA analysis from spent culture media of preimplantation embryo and DNA from whole embryo with respect to different morphological grading.

Purpose: The aneuploidy and sex concordance between cell-free DNA in spent culture media (SCM) and DNA from whole embryo with respect to different morphological grading were examined to evaluate the feasibility of non-invasive preimplantation genetic testing for aneuploidy (niPGT-A). Methods: A total of 46 pairs of embryos and corresponding SCM were divided into two groups based on the morphological grade. DNA was extracted from 22 and 24 pairs of low- and high-grade embryos, respectively, and respective SCM followed by chromosomal analysis using next-generation sequencing. Aneuploidy study and sex determination were conducted for both groups, and concordance rates were calculated. Results: For low-grade embryos, 63.6% (14/22) were determined as aneuploidy by whole embryo analysis, and concordance rates were 54.5% (12/22) using niPGT-A. On the contrary, for high-grade embryos 41.7% (10/24) were determined as aneuploidy by whole embryo analysis, and concordance rates were 62.5% (15/24) using niPGT-A. The concordance rates were not statistically different between the low-grade and high-grade embryo groups (p = 0.804). For sex determination, concordance rates between whole embryo and SCM were 81.8% (18/22) and 87.5% (21/24) in low- and high-grade groups, respectively. Conclusion: Aneuploidy and sex evaluation by niPGT-A may be feasible for both morphologically low- and high-grade embryos.

Cardiovascular magnetic resonance assessment of coronary flow reserve improves risk stratification in heart failure with preserved ejection fraction.

BACKGROUND: Coronary microvascular dysfunction (CMD) has been proposed as a novel mechanism for the pathophysiology of heart failure (HF) with preserved ejection fraction (HFpEF). Recent studies have suggested the potential utility of coronary flow reserve (CFR) as a marker of CMD in patients with HFpEF. Phase contrast (PC) cine cardiovascular magnetic resonance (CMR) of the coronary sinus has emerged as a non-invasive method to quantify CFR. We aimed to investigate the prognostic value of CMR-derived CFR in patients with HFpEF. METHODS: Data from 163 HFpEF patients (73 ± 9 years; 86 [53%] female) were retrospectively analyzed. Coronary sinus blood flow was measured in all patients, and myocardial blood flow was calculated as coronary sinus blood flow divided by left ventricular mass. CFR was calculated as the myocardial blood flow during adenosine triphosphate infusion divided by that at rest. Adverse events were defined as all-cause death and hospitalization due to HF exacerbation. Event-free survival stratified according to CFR < 2.0 was estimated with Kaplan-Meier survival methods and Log-rank test. RESULTS: During a median follow-up of 4.1 years, 26 patients (16%) experienced adverse events. CMR-derived CFR was significantly lower in HFpEF with adverse events compared with those without (1.93 ± 0.38 vs. 2.67 ± 0.52, p < 0.001). On a Kaplan Meier curve, the rates of adverse events were significantly higher in HFpEF patients with CFR < 2.0 compared with HFpEF with CFR ≥ 2.0 (p < 0.001). The area under the curve of CFR for predicting adverse events was significantly higher than that of LGE (0.881 vs. 0.768, p = 0.037) and GLS (0.881 vs. 0.747, p = 0.036). CONCLUSIONS: CFR assessed using coronary sinus PC cine CMR may be useful as a non-invasive prognostic marker for HFpEF patients.

Prognostic value of resting coronary sinus flow determined by phase-contrast cine cardiovascular magnetic resonance in patients with known or suspected coronary artery disease.

BACKGROUND: Phase-contrast cine cardiovascular magnetic resonance (CMR) of the coronary sinus has emerged as a non-invasive method to measure coronary sinus blood flow (CSBF) and coronary flow reserve (CFR). We aimed to compare the prognostic value of resting CSBF and CFR for predicting major adverse cardiac events (MACE) in patients with known or suspected coronary artery disease (CAD) who underwent vasodilator stress CMR. METHODS: We studied 693 patients with known CAD and 519 patients with suspected CAD admitted to our hospital between 2009 and 2019. The CFR was calculated as the CSBF during adenosine triphosphate infusion divided by CSBF at rest. MACE was defined as composite of cardiovascular death, acute coronary syndrome, heart failure hospitalization, and sustained ventricular tachyarrhythmia. RESULTS: During a median follow-up of 4.6 years, 92 patients (8%) experienced MACE. The resting CSBF was significantly higher in patients with MACE than in patients without MACE (114.7 ± 44.9 mL/min vs. 84.7 ± 30.9 mL/min, p < 0.001 for known CAD; 122.2 ± 33.3 mL/min vs. 86.6 ± 36.7 mL/min, p < 0.001 for suspected CAD). The resting CSBF remained a significant predictor for MACE after adjusting clinical and CMR variables (hazard ratio [HR] of resting CSBF higher than the median: 3.18, p = 0.0083 for known CAD; HR: 23.3, p < 0.001 for suspected CAD). The area under the curve for predicting MACE was 0.73 for resting CSBF, 0.72 for CFR (p = 0.78) in patients with known CAD, and 0.82 for resting CSBF, 0.83 (p = 0.58) for CFR in patients with suspected CAD. CONCLUSIONS: The resting CSBF may be a useful non-invasive method for the risk stratification of patients with known or suspected CAD without any radiation exposure, contrast media, or pharmacological vasodilator agents.

Human pluripotent stem cell-derived chondroprogenitors for cartilage tissue engineering.

The cartilage of joints, such as meniscus and articular cartilage, is normally long lasting (i.e., permanent). However, once damaged, especially in large animals and humans, joint cartilage is not spontaneously repaired. Compensating the lack of repair activity by supplying cartilage-(re)forming cells, such as chondrocytes or mesenchymal stromal cells, or by transplanting a piece of normal cartilage, has been the basis of therapy for biological restoration of damaged joint cartilage. Unfortunately, current biological therapies face problems on a number of fronts. The joint cartilage is generated de novo from a specialized cell type, termed a 'joint progenitor' or 'interzone cell' during embryogenesis. Therefore, embryonic chondroprogenitors that mimic the property of joint progenitors might be the best type of cell for regenerating joint cartilage in the adult. Pluripotent stem cells (PSCs) are expected to differentiate in culture into any somatic cell type through processes that mimic embryogenesis, making human (h)PSCs a promising source of embryonic chondroprogenitors. The major research goals toward the clinical application of PSCs in joint cartilage regeneration are to (1) efficiently generate lineage-specific chondroprogenitors from hPSCs, (2) expand the chondroprogenitors to the number needed for therapy without loss of their chondrogenic activity, and (3) direct the in vivo or in vitro differentiation of the chondroprogenitors to articular or meniscal (i.e., permanent) chondrocytes rather than growth plate (i.e., transient) chondrocytes. This review is aimed at providing the current state of research toward meeting these goals. We also include our recent achievement of successful generation of "permanent-like" cartilage from long-term expandable, hPSC-derived ectomesenchymal chondroprogenitors.

Crossed cerebellar diaschisis as an indicator of severe cerebral hyperperfusion after direct bypass for moyamoya disease.

Cerebral hyperperfusion (HP) complicates the postoperative course of patients with moyamoya disease (MMD) after direct revascularization surgery. Crossed cerebellar diaschisis (CCD) has been considered to be rarely associated with HP after revascularization surgery. This study aimed to describe the clinical features and factors associated with CCD secondary to cerebral HP after revascularization surgery for MMD. We analyzed 150 consecutive hemispheres including 101 in adults and 49 in pediatric patients who underwent combined direct and indirect bypass for MMD. Using single-photon emission computed tomography (SPECT), serial cerebral blood flow (CBF) was measured immediately after the surgery and on postoperative days 2 and 7. Pre- and postoperative voxel-based analysis of SPECT findings was performed to compare the changes in regional CBF. Multivariate logistic regression analysis was performed to test the effect of multiple variables on CCD. Asymptomatic and symptomatic HP was observed in 41.3% (62/150) and 16.7% (25/150) of the operated hemispheres, respectively. CCD was observed in 18.4% (16/87) of these hemispheres with radiological HP. Multivariate analysis revealed that the occurrence of CCD was significantly associated with symptomatic HP (p = 0.0015). Voxel-based analysis showed that the CBF increase in the operated frontal cortex, and the CBF reduction in the contralateral cerebellar hemisphere on day 7 were significantly larger in symptomatic HP than in asymptomatic HP (median 11.3% vs 7.5%; - 6.0% vs - 1.7%, respectively). CCD secondary to postoperative HP is more common than anticipated in MMD. CCD could potentially be used as an indicator of severe postoperative HP in patients with MMD.

Complication rate, cure rate, and long-term outcomes of microsurgery for intracranial dural arteriovenous fistulae: a multicenter series and systematic review.

Although microsurgery is an established treatment modality for intracranial dural arteriovenous fistula (dAVF), data regarding the perioperative complication rate, cure rate, and long-term outcomes remain scarce. The aims of this study were to describe our original experience with microsurgery, including the surgical complications and pitfalls, and conduct a systematic review of the relevant literature. A multicenter cohort of patients with dAVF treated by microsurgery was retrospectively assessed. In addition, the PubMed database was searched for published studies involving microsurgery for dAVF, and the complication rate, cure rate, and long-term outcomes were estimated. The total number of patients in our multicenter series and published articles was 553 (593 surgeries). The overall rates of transient complications, permanent complications, death, and incomplete treatment were 11.4, 4.0, 1.2, and 6.5%, respectively. A favorable outcome was achieved for 90.1% patients, even though almost half of the patients presented with intracranial hemorrhage. Of note, the incidence of recurrence was only one per 8241 patient-months of postoperative follow-up. Surgeries for anterior cranial fossa dAVF were associated with a lower complication rate, whereas those for tentorial dAVF were associated with higher complication and incomplete treatment rates. The complication and incomplete treatment rates were lower with simple disconnection of cortical venous drainage than with radical occlusion/resection of dural shunts. Our findings suggest that the cure rate, complication rates, and outcomes of microsurgery for dAVF are acceptable; thus, it could be a feasible second-line treatment option for dAVF. However, surgeons should be aware of the specific adverse events of microsurgery.

Efficacy of Carotid Artery Stenting Performed under General Anesthesia with Somatosensory Evoked Potential Monitoring.

OBJECTIVES: During carotid artery stenting (CAS), hemodynamics may be affected by the carotid sinus reflex in some cases. Although general anesthesia has been reported to stabilize intraoperative hemodynamics, the patient's neurological condition must be assessed indirectly. Therefore, we investigated the changes in intraoperative hemodynamics and perioperative complications of CAS under general anesthesia and evaluated the efficacy of somatosensory evoked potential (SEP) monitoring in detecting a reduction in perfusion during CAS. MATERIALS AND METHODS: From April 2011 to August 2016,57 consecutive patients who underwent CAS under general anesthesia were evaluated. The follow-up period ranged from 3 to 8 years. During CAS, anesthesiologists monitored and managed the hemodynamics. SEP monitoring was performed during the CAS procedure in all patients. RESULTS: Intraoperative hypotension (systolic blood pressure ≤ 100 mmHg) was evident in 16 patients (28.1%), and 13 patients (22.8%) experienced intraoperative bradycardia; however, all of these cases were promptly managed under general anesthesia. None of the patients showed systolic blood pressure < 50 mmHg from baseline. Regarding perioperative complications, none of the patients exhibited myocardial infarction or postoperative hyperperfusion symptoms, and there was no mortality. Among 21 patients (36.8%) with a decrease in the intraoperative SEP, 3 (5.3%) exhibited transient ischemic symptoms and 1 (1.8%) had postoperative infarction. CONCLUSIONS: CAS under general anesthesia is a safe and effective management option in terms of intraoperative hemodynamic stability. In addition, our findings indicate that SEP monitoring could be helpful in evaluating transient postoperative cerebral ischemia or cerebral infarction after CAS.

In-Hospital Mortality in Acute Myocardial Infarction According to Population Density and Primary Angioplasty Procedures Volume.

BACKGROUND: Low population density may be associated with high mortality in acute myocardial infarction (AMI) patients. The purpose of this study was to investigate the effect of population density and hospital primary percutaneous coronary intervention (PCI) volume on AMI in-hospital mortality in Japan.Methods and Results:This is a retrospective study of 64,414 AMI patients transported to hospital by ambulances. The main outcome measure was in-hospital mortality. The median population density was 1,147 (interquartile range, 342-5,210) persons/km2. There was a significant negative relationship between population density and in-hospital mortality (OR for a quartile down in population density 1.086, 95% CI 1.042-1.132, P<0.001). Patients in less densely populated areas were more often transported to hospitals with a lower primary PCI volume, and they had a longer distance to travel. By using multivariable analysis, primary PCI volume was found to be significantly associated with in-hospital mortality, but distance to hospital was not. When divided into the low- and high-volume hospitals, using the cut-off value of 115 annual primary PCI procedures, the increase in in-hospital mortality associated with low population density was observed only in patients hospitalized in the low-volume hospitals. CONCLUSIONS: Increased in-hospital mortality related to low population density was observed only in AMI patients who were transported to the low primary PCI volume hospitals, but not in those who were transported to high-volume hospitals.

Platelet-Derived Thrombogenicity Measured by Total Thrombus-Formation Analysis System in Patients With ST-Segment Elevation Myocardial Infarction Undergoing Primary Percutaneous Coronary Intervention.

BACKGROUND: Prompt and potent antiplatelet effects are important aspects of management of ST-elevation myocardial infarction (STEMI) patients undergoing primary percutaneous coronary intervention (PPCI). We evaluated the association between platelet-derived thrombogenicity during PPCI and enzymatic infarct size in STEMI patients.Methods and Results:Platelet-derived thrombogenicity was assessed in 127 STEMI patients undergoing PPCI by: (1) the area under the flow-pressure curve for the PL-chip (PL18-AUC10) using the total thrombus-formation analysis system (T-TAS); and (2) P2Y12reaction units (PRU) using the VerifyNow system. Patients were divided into 2 groups (High and Low) based on median PL18-AUC10during PPCI. PRU levels during PPCI were suboptimal in both the High and Low PL18-AUC10groups (median [interquartile range] 266 [231-311] vs. 272 [217-317], respectively; P=0.95). The percentage of final Thrombolysis in Myocardial Infarction (TIMI) 3 flow was lower in the High PL18-AUC10group (75% vs. 90%; P=0.021), whereas corrected TIMI frame count (31.3±2.5 vs. 21.0±2.6; P=0.005) and the incidence of slow-flow/no-reflow phenomenon (31% vs. 11%, P=0.0055) were higher. The area under the curve for creatine kinase (AUCCK) was greater in the High PL18-AUC10group (95,231±7,275 IU/L h vs. 62,239±7,333 IU/L h; P=0.0018). Multivariate regression analysis identified high PL18-AUC10during PPCI (ß=0.29, P=0.0006) and poor initial TIMI flow (ß=0.37, P<0.0001) as independent determinants of AUCCK. CONCLUSIONS: T-TAS-based high platelet-derived thrombogenicity during PPCI was associated with enzymatic infarct size in patients with STEMI.

Prognostic role of bronchial asthma in patients with heart failure.

There are few reports investigating the relationship between bronchial asthma (BA) and heart failure (HF). We hypothesized BA may have impact on prognosis in patients with HF. Among 323 consecutive outpatients with HF, 191 patients without chronic obstructive pulmonary disease were analyzed. Twenty patients had BA, most of whom (80.0%) had preserved left ventricular ejection fraction (LVEF ≥ 50%). The use of ß-blockers was less frequent (55.0% vs 83.0%. p = 0.01), systolic blood pressure (133 ± 22 vs 120 ± 17 mmHg, p = 0.003), and heart rate (83 ± 14 vs 74 ± 15 bpm, p = 0.02) were higher in patients with BA than those without BA. During median follow up of 24 months, 45 (23.6%) experienced primary outcome defined as a composite of all-cause death, nonfatal myocardial infarction, nonfatal ischemic stroke, and unexpected hospitalization due to HF. Multivariate Cox regression analysis revealed that the presence of BA was independently associated with the occurrence of primary outcome (hazard ratio 3.08, 95% CI 1.42-6.71, p = 0.004). In the subgroup analysis of patients with preserved LVEF, patients with BA exhibited worse outcomes (p = 0.03 by log-rank). Patients with HF complicated by BA, most of whom had preserved LVEF, exhibited worse outcomes than those without BA.

Randomized controlled trial of landiolol, a short-acting beta-1 adrenergic receptor blocker, illustrating changes in high-molecular weight adiponectin levels after elective percutaneous coronary intervention.

Adiponectin (APN) has cardioprotective properties and bisoprolol has been reported to increase myocardial APN expression and reduce myocardial damage. Administration of landiolol, which has a higher cardio-selectivity and shorter half-life than bisoprolol, during the percutaneous coronary intervention (PCI) may increase serum APN and high-molecular weight (HMW)-APN, an active form of APN, in patients with stable angina pectoris (SAP). We recruited 70 patients with SAP and randomized them to intravenous landiolol during PCI (N = 35) or control group (N = 35). The primary endpoint was serum APN and HMW-APN level 3 days after PCI. There was no difference in the primary endpoint between the landiolol and control groups (8.93 ± 5.24 vs. 10.18 ± 5.81 µg/mL, p = 0.35 and 3.36 ± 2.75 vs. 4.28 ± 3.13 µg/mL, p = 0.20) for APN and HMW-APN levels, respectively. APN and HMW-APN level were significantly decreased 1 day after PCI [-0.55 ± 0.92 µg/mL (9.87-9.32 µg/mL), p < 0.001 and -0.20 ± 0.45 µg/mL (3.89-3.69 µg/mL), p < 0.001, respectively]. Additionally, the absolute change in HMW-APN was significantly smaller in the landiolol group compared to the control group (-0.08 ± 0.27 vs. -0.31 ± 0.55 µg/mL, p = 0.031). Multiple linear regression analysis showed that use of landiolol was an independent predictor of change in HMW-APN (ß = 0.276, p = 0.014). Serum APN and HMW-APN level 3 days after PCI were similar between patients treated with and without landiolol. APN and HMW-APN decreased 1 day after PCI in the SAP and landiolol mitigated decrease in HMW-APN.

Vascular Smooth Muscle Cell Derived from IPS Cell of Moyamoya Disease - Comparative Characterization with Endothelial Cell Transcriptome.

BACKGROUND: Moyamoya disease (MMD) is an occlusive cerebrovascular disease, causing stroke in children and young adults with unknown etiology. The fundamental pathology is fibrocellular intimal thickening of cerebral arteries, in which vascular smooth muscle cells (VSMCs) are observed as one of the major cell types. Although the characteristics of circulating smooth muscle progenitor cells have been previously reported, the VSMCs are poorly characterized in MMD. We aimed to characterize VSMCs in MMD using induced pluripotent stem cell (iPSC)-technology. METHODS: We differentiated VSMCs from neural crest stem cells (NCSCs) using peripheral blood mononuclear cell-derived iPSCs and compared biological and transcriptome features under naïve culture conditions between three independent healthy control (HC) subjects and three MMD patients. VSMC transcriptome profiles were also compared to those of endothelial cells (ECs) differentiated from the same iPSCs. RESULTS: Homogeneous spindle-shaped cells differentiated from iPSCs exhibited smooth muscle cell marker expressions, including α-smooth muscle actin (αSMA, 82.3 ± 6.7% and 81.0 ± 6.7%); calponin (91.3 ± 2.1% and 90.9 ± 1.3%); myosin heavy chain-11 (MYH11, 96.9 ± 0.7% and 97.1 ± 0.3%) without significance of differences between the two groups. Real-time PCR showed few PECAM1 and CD34 gene expressions in both groups, indicating features of differentiated VSMCs. There were no significant differences in cellular proliferation (p = 0.45), migration (p = 0.60), and contractile abilities (p = 0.96) between the two groups. Transcriptome analysis demonstrated similar gene expression profiles of VSMCs in HC subjects and MMD patients with six differentially expressed genes (DEGs); while ECs showed a distinct transcriptome profile in MMD patients with 120 DEGs. The Wnt-signaling pathway was a significant pathway in VSMCs. CONCLUSIONS: This is the first study that established VSMCs from NCSCs using MMD patient-derived iPSCs and demonstrated similar biological function and transcriptome profile of iPSC-derived VMSCs in MMD patients and HC subjects under naïve single culture condition. Comparative transcriptome features between iPSC-derived VSMCs and ECs, displaying distinct transcriptome in the ECs, suggested that pathological traits can be driven by naïve ECs predominantly and VSMCs may require specific environmental factors in MMD, which provides novel insight into the pathophysiology of MMD. Our iPSC derived VSMC model can contribute to further investigations of diagnostic and therapeutic target of MMD in addition to the current iPSC derived EC model.

A Pilot Study on Measuring Tissue Motion During Carotid Surgery Using Video-Based Analyses for the Objective Assessment of Surgical Performance.

BACKGROUND: The 'gentle' handling of tissue (i.e., 'respect for tissue') is a fundamental aspect of surgical performance and learning. To date, there have been no methodological assessments that quantitatively measure 'gentleness.' Therefore, the aims of this study were (1) to propose a novel metric for gentle surgical maneuvers, (2) to validate the feasibility of this methodology, and (3) to explore safer surgical techniques through this methodology. METHODS: Using surgical video-based motion software, the motion of the carotid artery around plaque was analyzed and quantified during a carotid endarterectomy. Kinematic parameters (minimum and maximum acceleration, and maximum and mean velocity) were compared among the surgical tasks and techniques, as well as between novice and expert surgeons. RESULTS: The surgical tasks of dissecting the common carotid artery, passing the proximal vessel loops, and ligating vessels showed the highest absolute values of kinematic parameters. Dissections perpendicular to the line of the internal carotid artery tended to show higher kinematic parameters than those in the parallel direction, with blunt dissections typically higher than sharp dissections. The kinematic parameters of novice surgeons were significantly higher than those of experts, and receiver operating curve analysis showed a strong discriminative power. CONCLUSION: This study shows that tissue motion parameters could be a novel and feasible surrogate marker for the objective assessment on the 'gentleness' of surgical performance. Future studies should be performed to further elucidate the relationship on the direct correlation between tissue kinematic data and clinical outcomes or surgical adverse events.

Novel Hemoglobin-Based Oxygen Carrier Bound With Albumin Shows Neuroprotection With Possible Antioxidant Effects.

Background and Purpose- A hemoglobin-albumin cluster, 1 core of hemoglobin covalently bound with 3 shell albumins, designated as HemoAct was developed as a hemoglobin-based oxygen carrier. We aim to investigate neuroprotection by HemoAct in transient cerebral ischemia and elucidate its underlying mechanisms. Methods- Male rats were subjected to 2-hour transient middle cerebral artery occlusion and were then administered HemoAct transarterially at the onset of reperfusion. Neurological and pathological findings were examined after 24 hours of reperfusion to identify neuroprotection by HemoAct. Intermittent measurements of cortical blood flow and oxygen content were performed, and a histopathologic analysis was conducted on rats during the early phase of reperfusion to assess the therapeutic mechanism of HemoAct. In addition, the antioxidant effects of HemoAct were examined in hypoxia/reoxygenation-treated rat brain microvascular endothelial cells. Results- Neurological deterioration, infarct and edema development, and the activation of MMP-9 (matrix metalloprotease-9) and lipid peroxidation after 24 hours of reperfusion were significantly ameliorated by the HemoAct treatment. Reductions in blood flow and tissue partial oxygen pressure in the cortical penumbra after 6 hours of reperfusion were significantly ameliorated by the HemoAct treatment. The histopathologic analysis of the cortical penumbra revealed that HemoAct in HemoAct-treated rats showed superior microvascular perfusion with the mitigation of microvascular narrowing changes than autologous erythrocytes in nontreated rats. Although HemoAct extravasated into the ischemic core with serum protein, it did not induce an increase in serum extravasation or reactive oxygen species production in the ischemic core. In vitro experiments with rat brain microvascular endothelial cells revealed that HemoAct significantly suppressed cellular reactive oxygen species production in hypoxia/reoxygenation-treated cells, similar to albumin. Conclusions- HemoAct exerted robust neuroprotection in transient cerebral ischemia. Superior microvascular perfusion with an oxygen delivery capability and possible antioxidant effects appear to be the underlying neuroprotective mechanisms.