Potential prevention of stillbirth caused by placental abruption: a regional population-based study in Japan.

OBJECTIVE: Placental abruption is associated with adverse perinatal outcomes including intrauterine fetal demise, which subsequently results in stillbirth. However, few studies have demonstrated the preventability of stillbirth due to placental abruption. Therefore, we evaluated the possibility of preventing stillbirth caused by placental abruption by reviewing all stillbirths in our region. METHODS: This study reviewed all stillbirths after 22 weeks of gestation in Shiga Prefecture, Japan from 2010 to 2019, excluding lethal disorders. We evaluated 350 stillbirth cases, with and without placental abruption. RESULTS: There were 32 stillbirths with PA and 318 without placental abruption. The probability of preventing stillbirth was significantly higher in patients with placental abruption than in those without (30% vs. 8%, p < 0.001). We also determined the recommendations for preventing stillbirths with placental abruption. CONCLUSION: Some stillbirths caused by placental abruption can be prevented. We recommend improvements to perinatal maternal-fetal care and perinatal emergency transport systems.

Significant improvement in survival outcomes of trisomy 18 with neonatal intensive care compared to non-intensive care: a single-center study.

Background: Trisomy 18 syndrome, also known as Edwards syndrome, is a chromosomal trisomy. The syndrome has historically been considered lethal owing to its poor prognosis, and palliative care was primarily indicated for trisomy 18 neonates. Although there have been several reports on the improvement of survival outcomes in infants with trisomy 18 syndrome through neonatal intensive care, few studies have compared the impact of neonatal intensive care on survival outcomes with that of non-intensive care. Therefore, we compared the survival-related outcomes of neonates with trisomy 18 between intensive and non-intensive care. Methods: Seventeen infants of trisomy 18 admitted to our center between 2007 and 2019 were retrospectively studied. We divided the patients into a non-intensive group (n = 5) and an intensive group (n = 12) and evaluated their perinatal background and survival-related outcomes of the two groups. Results: The 1- and 3-year survival rates were both 33% in the intensive group, which was significantly higher than that in the non-intensive group (p < 0.001). Half of the infants in the intensive care group were discharged alive, whereas in the non-intensive care group, all died during hospitalization (p = 0.049). Conclusions: Neonatal intensive care for neonates with 18 trisomy significantly improved not only survival rates but also survival-discharge rates. Our findings would be helpful in providing 18 trisomy neonates with standard neonatal intensive care when discussing medical care with their parents.

Nationwide Database Analysis of Risk Factors Associated with Decreased Activities of Daily Living in Patients with Alzheimer's Disease.

BACKGROUND: Preserving activities of daily living (ADL) is the key issue for Alzheimer's disease (AD) patients and their caregivers. OBJECTIVE: To clarify the ADL level of AD patients at diagnosis and the risk factors associated with decreased ADL during long-term care (≤3 years). METHODS: Medical records of AD patients in a Japanese health insurance claims database were analyzed retrospectively to determine ADL using the Barthel Index (BI) and identify the risk factors associated with decreased ADL. RESULTS: A total of 16,799 AD patients (mean age at diagnosis: 83.6 years, 61.5% female) were analyzed. Female patients were older (84.6 versus 81.9 years; p < 0.001) and had lower BI (46.8 versus 57.6; p < 0.001) and body mass index (BMI) (21.0 versus 21.7 kg/m2; p < 0.001) than male patients at diagnosis. Disability (BI≤60) increased at age≥80 years and was significantly higher in females. Complete disability was most frequent for bathing and grooming. Risk factors for decreased ADL were determined separately by sex through comparing the ADL-preserved and ADL-decreased groups using propensity score matching by age and BI and multivariable logistic regression analysis. In males, decreased ADL was significantly associated with BMI < 21.5 kg/m2, stroke, and hip fracture, and inversely associated with hyperlipidemia. In females, decreased ADL was significantly associated with BMI < 21.5 kg/m2 and vertebral and hip fractures, and inversely associated with lower back pain. CONCLUSION: AD patients with low BMI, stroke, and fractures had increased risks of decreased ADL; such patients should be identified early and managed appropriately, including rehabilitation to preserve ADL.

Prevalence and risk factors of osteonecrosis of the femoral head in patients with ANCA-associated vasculitis: a multicentre cohort study.

OBJECTIVE: We aimed to determine the prevalence and risk factors for osteonecrosis of the femoral head (ONFH) in a multicentre cohort of patients with antineutrophil cytoplasmic antibody-associated vasculitis (AAV). METHODS: One hundred and eighty-six AAV patients who underwent radiographs and MRI screening of bilateral hip joints at more than 6 months after initial remission induction therapy (RIT) were retrospectively assessed for the presence of ONFH. RESULTS: Among 186 AAV patients, 33 (18%) were diagnosed with ONFH. Among the patients with ONFH, 55% were asymptomatic and 64% had bilateral ONFH. Seventy-six per cent of ONFH joints were in precollapse stages (stage ≤2), whereas 24% of ONFH joints were in collapse stages (stage ≥3). Moreover, 56% of the precollapse stage joints were already at risk of future collapse (type ≥C-1). Even in asymptomatic ONFH patients, 39% of the precollapse stage joints were type ≥C-1. Prednisolone dose of ≥20 mg/day on day 90 of RIT was an independent risk factor for ONFH in AAV patients (OR 1.072, 95% CI 1.017 to 1.130, p=0.009). Rituximab use was a significant beneficial factor against ONFH (p=0.019), but the multivariate analysis rejected its significance (p=0.257). CONCLUSION: Eighteen per cent of AAV patients developed ONFH, and two-thirds of the ONFH joints were already in collapse stages or at risk of future collapse. Prednisolone dose of ≥20 mg/day on day 90 of RIT was an independent risk factor for ONFH. A rapid reduction of glucocorticoids in RIT and early detection of precollapse ONFH by MRI may decrease and intervene ONFH development in AAV patients.

Insufficient antenatal identification of fetal growth restriction leading to intrauterine fetal death: a regional population-based study in Japan.

OBJECTIVE: Fetal growth restriction (FGR) is associated with perinatal adverse outcomes including intrauterine fetal death. Antenatally unidentified FGR has a higher risk of intrauterine fetal death than that identified antenatally. We, therefore, investigated the antenatal identification of FGR among intrauterine fetal deaths, and assessed the perinatal factors associated with the identification of FGR. METHODS: This retrospective and population-based study reviewed all stillbirths in Shiga Prefecture, Japan, from 2007 to 2016 with exclusion criteria of multiple births, births at unidentified gestational weeks or < 22 gestational weeks, and lethal disorders. We analyzed cases of FGR, using the Japanese clinical definition: Z-score of estimated fetal weight for gestational age <-1.5 standard deviations (SD). RESULTS: We identified 94 stillbirths with FGR among 429 stillbirths. Thirty-seven cases were antenatally identified during pregnancy management (39%). Dividing cases by a Z-score of -2.5 SD, 51 cases were classified as ≤-2.5 SD. Twenty-eight of the 51 cases (55%) with a Z-score <-2.5 SD were antenatally identified as having FGR, whereas 9 of the 43 cases (21%) with a Z-score ≥-2.5 SD were antenatally identified as having FGR (p = .002). Among cases with a Z-Score <-2.5 SD, 16 of 21 (76%) beyond 28 weeks' gestation and 12 of 30 (40%) before 28weeks' gestation were antenatally identified as having FGR (p = .023). CONCLUSION: Fetal growth restriction leading to intrauterine fetal death in Japan was antenatally identified in less than half of cases. Antenatal identification of FGR was associated with the severity of growth restriction.

Severity of Placental Abruption in Restrained Pregnant Vehicle Drivers: Correct Seat Belt Use Confirmed by Finite Element Model Analysis.

Despite wearing a seat belt, pregnant drivers often suffer from negative fetal outcomes in the event of motor accidents. In order to maintain the safety of pregnant drivers and their fetuses, we assessed the severity of placental abruption caused by motor vehicle collisions using computer simulations. We employed a validated pregnant finite element model to determine the area of placental abruption. We investigated frontal vehicle collisions with a speed of 40 km/h or less involving restrained pregnant drivers with a gestational age of 30 weeks. For a crash speed of 40 km/h, the placental abruption area was 7.0% with a correctly positioned lap belt across the lower abdomen; it was 36.3% with the belt positioned at the umbilicus. The area of placental abruption depended on collision speed, but we found that with a correctly positioned belt it likely would not lead to negative fetal outcomes. We examined the effects on placental abruptions of reconfiguring seat belt width and force limiter setting. A wider lap belt and lower force limiter setting reduced the area of placental abruption to 3.5% and 1.1%, respectively; however, they allowed more forward movement upon collision. A 2.5 kN force limiter setting may be appropriate with respect to both forward movement and reduced placental abruption area. This study confirmed the importance of correctly using seat belts for pregnant drivers. It provides valuable evidence about improving safety equipment settings.

Effect of vasopressin V2-receptor antagonist tolvaptan on syndrome of inappropriate antidiuresis (SIAD) after transsphenoidal pituitary surgery: recovery of measured osmolality.

Background: Delayed hyponatremia after pituitary surgery can be treated with the V2-receptor antagonist, oral tolvaptan. We investigated the pharmacological effect of oral tolvaptan against SIAD in patients with hyponatremia after pituitary surgery. Methods: Thirty-nine patients with pituitary adenoma treated by endoscopic transsphenoidal surgery developed SIAD according to the major guidelines, and 7 patients (17.9%) were treated with tolvaptan. Tolvaptan was administrated orally half a tablet (3.75 mg) once in the first two cases, and half a tablet twice in the other five cases. Serum osmolality, urinary osmolality, urinary sodium concentration, urinary volume, and serum sodium and potassium concentration were evaluated before administration, and after the last oral administration of tolvaptan. Serum osmolality and urine osmolality were physically measured. Results: Serum sodium concentration was significantly increased from 132.1 ± 4.0 to 143.0 ± 2.9 mmol/L (mean ± standard deviation, n = 7, P < 0.001). Serum osmolality was significantly increased from 266.3 ± 7.7 to 289.6 ± 6.7 mOsm/kg (n = 7, P < 0.001). Urine osmolality was significantly reduced from 607.1 ± 240.4 to 262.7 ± 115.6 mOsm/kg (n = 7, P = 0.01). Urinary sodium concentration was significantly decreased from 121.3 ± 48.4 to 36.9 ± 35.0 mOsm/kg (n = 7, P = 0.001). Urine output (24-hour including the first administration) was significantly increased from 1384.2 ± 550.7 to 3291.3 ± 1710.9 mL/day (n = 6, P = 0.026). Conclusions: Oral tolvaptan administration corrects SIAD after pituitary surgery. Hyponatremia after pituitary surgery was confirmed to be due to SIAD.

An iPS-derived in vitro model of human atrial conduction.

Atrial fibrillation (AF) is the most common arrhythmia in the United States, affecting approximately 1 in 10 adults, and its prevalence is expected to rise as the population ages. Treatment options for AF are limited; moreover, the development of new treatments is hindered by limited (1) knowledge regarding human atrial electrophysiological endpoints (e.g., conduction velocity [CV]) and (2) accurate experimental models. Here, we measured the CV and refractory period, and subsequently calculated the conduction wavelength, in vivo (four subjects with AF and four controls), and ex vivo (atrial slices from human hearts). Then, we created an in vitro model of human atrial conduction using induced pluripotent stem (iPS) cells. This model consisted of iPS-derived human atrial cardiomyocytes plated onto a micropatterned linear 1D spiral design of Matrigel. The CV (34-41 cm/s) of the in vitro model was nearly five times faster than 2D controls (7-9 cm/s) and similar to in vivo (40-64 cm/s) and ex vivo (28-51 cm/s) measurements. Our iPS-derived in vitro model recapitulates key features of in vivo atrial conduction and may be a useful methodology to enhance our understanding of AF and model patient-specific disease.

Clinical and transcriptomic features of persistent exacerbation-prone severe asthma in U-BIOPRED cohort.

BACKGROUND: Exacerbation-prone asthma is a feature of severe disease. However, the basis for its persistency remains unclear. OBJECTIVES: To determine the clinical and transcriptomic features of frequent exacerbators (FEs) and persistent FEs (PFEs) in the U-BIOPRED cohort. METHODS: We compared features of FE (≥2 exacerbations in past year) to infrequent exacerbators (IE, <2 exacerbations) and of PFE with repeat ≥2 exacerbations during the following year to persistent IE (PIE). Transcriptomic data in blood, bronchial and nasal epithelial brushings, bronchial biopsies and sputum cells were analysed by gene set variation analysis for 103 gene signatures. RESULTS: Of 317 patients, 62.4% had FE, of whom 63.6% had PFE, while 37.6% had IE, of whom 61.3% had PIE. Using multivariate analysis, FE was associated with short-acting beta-agonist use, sinusitis and daily oral corticosteroid use, while PFE was associated with eczema, short-acting beta-agonist use and asthma control index. CEA cell adhesion molecule 5 (CEACAM5) was the only differentially expressed transcript in bronchial biopsies between PE and IE. There were no differentially expressed genes in the other four compartments. There were higher expression scores for type 2, T-helper type-17 and type 1 pathway signatures together with those associated with viral infections in bronchial biopsies from FE compared to IE, while there were higher expression scores of type 2, type 1 and steroid insensitivity pathway signatures in bronchial biopsies of PFE compared to PIE. CONCLUSION: The FE group and its PFE subgroup are associated with poor asthma control while expressing higher type 1 and type 2 activation pathways compared to IE and PIE, respectively.

Increased Difficulties in Maternal Perception of Decreased Fetal Movement in Cases of Severe Fetal Growth Restriction: A Population-Based Study in Japan.

Fetal growth restriction (FGR) is defined as fetuses who have failed to achieve a normal weight for gestational age. FGR is associated with adverse perinatal outcomes, including stillbirth. Pregnant women often perceive decreased fetal movements before intrauterine fetal death. Previous reports on the association between fetal movements and FGR have mainly targeted livebirths, with few focusing on stillbirths. Studying stillbirths, not livebirths, may help improve perinatal adverse outcomes. This study evaluated the association between FGR leading to stillbirth and maternal perception of decreased fetal movement. This was a population-based study reviewing all stillbirths in Shiga Prefecture, Japan for 10 years. We analyzed 219 stillbirth cases, those with versus without FGR. We then compared maternal visits to healthcare providers due to perception of decreased fetal movement between these two groups. There were 82 stillbirths with FGR, and the remaining 137 stillbirth were without FGR. Women with FGR, compared with those without, were significantly less often to visit the outpatient department due to decreased fetal movement (30%; 25/82 vs. 46%; 63/137: P = 0.034). Pregnant women have more difficulty perceiving decreased fetal movements in cases with severe FGR than in those without FGR. Healthcare providers, including midwives, may need to closely monitor FGR pregnancy in addition to instructing pregnant women to be aware of decreased fetal movement.

Hematopoietic Stem Cells in Wound Healing Response.

Significance: Emerging evidence has shown a link between the status of hematopoietic stem cells (HSCs) and wound healing responses. Thus, better understanding HSCs will contribute to further advances in wound healing research. Recent Advances: Myeloid cells such as neutrophils and monocyte-derived macrophages are critical players in the process of wound healing. HSCs actively respond to wound injury and other tissue insults, including infection and produce the effector myeloid cells, and a failing of the HSC response can result in impaired wound healing. Technological advances such as transcriptome at single-cell resolution, epigenetics, three-dimensional imaging, transgenic animals, and animal models, have provided novel concepts of myeloid generation (myelopoiesis) from HSCs, and have revealed cell-intrinsic and -extrinsic mechanisms that can impact HSC functions in the context of health conditions. Critical Issues: The newer concepts include-the programmed cellular fate at a differentiation stage that is used to be considered as the multilineage, the signaling pathways that can activate HSCs directly and indirectly, the mechanisms that can deteriorate HSCs, the roles and remodeling of the surrounding environment for HSCs and their progenitors (the niche). Future Directions: The researches on HSCs, which produce blood cells, should contribute to the development of blood biomarkers predicting a risk of chronic wounds, which may transform clinical practice of wound care with precision medicine for patients at high risk of poor healing.

Fetal movement counting is associated with the reduction of delayed maternal reaction after perceiving decreased fetal movements: a prospective study.

Maternal perception of decreased fetal movement is associated with adverse perinatal outcomes. Although there have been several studies on interventions related to the fetal movements count, most focused on adverse perinatal outcomes, and little is known about the impact of the fetal movement count on maternal behavior after the perception of decreased fetal movement. We investigated the impact of the daily fetal movement count on maternal behavior after the perception of decreased fetal movement and on the stillbirth rate in this prospective population-based study. Pregnant women in Shiga prefecture of Japan were asked to count the time of 10 fetal movements from 34 weeks of gestation. We analyzed 101 stillbirths after the intervention compared to 121 stillbirths before the intervention. In multivariable analysis, maternal delayed visit to a health care provider after the perception of decreased fetal movement significantly reduced after the intervention (aOR 0.31, 95% CI 0.11-0.83). Our regional stillbirth rates in the pre-intervention and post-intervention periods were 3.06 and 2.70 per 1000 births, respectively. Informing pregnant women about the fetal movement count was associated with a reduction in delayed maternal reaction after the perception of decreased fetal movement, which might reduce stillbirths.

Clinical efficacy and safety of second line and salvage aflibercept for advanced colorectal cancer in Akita prefecture.

BACKGROUND: Angiogenesis inhibitors (AIs) combination with cytotoxic chemotherapy is a promising treatment for patients with colorectal cancer (CRC). Aflibercept (AFL) is an option for second-line treatment of CRC, according to the 'VELOUR' trial. Currently, we can choose from three AIs, including bevacizumab, ramucirumab, and AFL. Different AIs can be used in subsequent treatment because of their distinctive mechanisms of action. We addressed the uncertainty regarding AFL efficacy and safety in heavily-treated patients by comparing outcomes of survival treatment with second-line treatment. AIM: To determine and compare the efficacy and safety profiles of AFL in the second-line and salvage therapy settings. METHODS: Clinical data of 41 patients with advanced CRC who received intravenous AFL combined with the folinic acid-fluorouracil-irinotecan (FOLFIRI) regimen were collected retrospectively from six institutions in Japan, for the period from May 2017 to March 2019. Patient characteristics collected included age, sex, tumor location, RAS and RAF status, metastatic sites, number of previous treatment cycles, therapeutic response, adverse events, duration of previous AI treatment, and survival time. The end points were time to AFL treatment failure (aTTF) and median survival time post-AFL (aMST). Statistical analyses were performed to compare the efficacy and safety in the second-line setting with those of the salvage therapy setting, which was defined as the days since the end of second-line therapy. RESULTS: All 41 patients who received AFL + FOLFIRI for advanced CRC had metastatic or unresectable cancer. Twenty-two patients received AFL in the second-line setting and nineteen in the salvage therapy setting. The patient characteristics were similar in the two groups, except for two factors. The median duration of the previous AI administration was shorter in the second-line patients compared with that in the salvage therapy patients (144 d vs 323 d, P = 0.006). In the second-line and salvage therapy groups, the objective response rates were 11% and 0%, respectively (P = 0.50), and the disease control rates were 53% and 50%, respectively (P = 1.00). In the second-line and salvage therapy groups, the aTTF (123 d vs 71 d, respectively), aMST (673 d vs 396 d, respectively), and incidence of adverse events of grade 3 [8 (36%) vs 9 (47%)] were not significantly different between the two groups. CONCLUSION: AFL can be used to treat advanced CRC patients, with a similar safety and efficacy in the salvage therapy setting as in the second-line setting.

Sparsely methylated mitochondrial cell free DNA released from cardiomyocytes contributes to systemic inflammatory response accompanied by atrial fibrillation.

Systemic inflammation is assumed to be the consequence and the cause of atrial fibrillation (AF); however, the underlying mechanism remains unclear. We aimed to evaluate the level of cell-free DNA (cfDNA) in patients with AF and AF mimicking models, and to illuminate its impact on inflammation. Peripheral blood was obtained from 54 patients with AF and 104 non-AF controls, and cfDNA was extracted. We extracted total cfDNA from conditioned medium after rapid pacing to HL-1 cells. Nuclear and mitochondrial DNA were separately extracted and fragmented to simulate nuclear-cfDNA (n-cfDNA) and mitochondrial-cfDNA (mt-cfDNA). The AF group showed higher cfDNA concentration than the non-AF group (12.6 [9.0-17.1] vs. 8.1 [5.3-10.8] [ng/mL], p < 0.001). The copy numbers of n-cfDNA and mt-cfDNA were higher in AF groups than in non-AF groups; the difference of mt-cfDNA was particularly apparent (p = 0.011 and p < 0.001, respectively). Administration of total cfDNA and mt-cfDNA to macrophages significantly promoted IL-1ß and IL-6 expression through TLR9, whereas n-cfDNA did not. Induction of cytokine expression by methylated mt-cfDNA was lower than that by unmethylated mt-cfDNA. Collectively, AF was associated with an increased cfDNA level, especially mt-cfDNA. Sparsely methylated mt-cfDNA released from cardiomyocytes may be involved in sterile systemic inflammation accompanied by AF.

A "ligand-targeting" peptide-drug conjugate: Targeted intracellular drug delivery by VEGF-binding helix-loop-helix peptides via receptor-mediated endocytosis.

As a new alternative to antibody-drug conjugates, we generated "ligand-targeting" peptide-drug conjugates (PDCs), which utilize receptor-mediated endocytosis for targeted intracellular drug delivery. The PDC makes a complex with an extracellular ligand and then binds to the receptor on the cell surface to stimulate intracellular uptake via the endocytic pathway. A helix-loop-helix (HLH) peptide was designed as the drug carrier and randomized to give a conformationally constrained peptide library. The phage-displayed library was screened against vascular endothelial growth factor (VEGF) to yield the binding peptide M49, which exhibited strong binding affinity (KD = 0.87 nM). The confocal fluorescence microscopy revealed that peptide M49 formed a ternary complex with VEGF and its receptor, which was then internalized into human umbilical vein endothelial cells (HUVECs) via VEGF receptor-mediated endocytosis. The backbone-cyclized peptide M49K was conjugated with a drug, monomethyl auristatin E, to afford a PDC, which inhibited VEGF-induced HUVEC proliferation. HLH peptides and their PDCs have great potential as a new modality for targeted molecular therapy.

Factors Affecting the Severity of Placental Abruption in Pregnant Vehicle Drivers: Analysis with a Novel Finite Element Model.

We clarified factors affecting the severity of placental abruption in motor vehicle collisions by quantitively analyzing the area of placental abruption in a numerical simulation of an unrestrained pregnant vehicle driver at collision velocities of 3 and 6 m/s. For the simulation, we constructed a novel finite element model of a small 30-week pregnant woman, which was validated anthropometrically using computed tomography data and biomechanically using previous examinations of post-mortem human subjects. In the simulation, stress in the elements of the utero-placental interface was computed, and those elements exceeding a failure criterion were considered to be abrupted. It was found that a doubling of the collision velocity increased the area of placental abruption 10-fold, and the abruption area was approximately 20% for a collision velocity of 6 m/s, which is lower than the speed limit for general roads. This result implies that even low-speed vehicle collisions have negative maternal and fetal outcomes owing to placental abruption without a seatbelt restraint. Additionally, contact to the abdomen, 30 mm below the umbilicus, led to a larger placental abruption area than contact at the umbilicus level when the placenta was located at the uterus fundus. The results support that a reduction in the collision speed and seatbelt restraint at a suitable position are important to decrease the placental abruption area and therefore protect a pregnant woman and her fetus in a motor vehicle collision.

Sequential estimation of the generated curing heat of composite materials by data assimilation: A numerical study.

The models and parameters related to the generated curing heat in the molding simulation of composite materials are dependent on the type of resin used and the experimental conditions. Therefore, in this study, we estimated the generated curing heat that changes with time by a data assimilation method, which combines the observation values with simulation values, so that the heat curing simulation of carbon fiber reinforced polymers (CFRPs) becomes closer to the experimental conditions. In the data assimilation method, the temperature distribution on the surface of the composite material was used as an observation value, and the generated curing heat was estimated using an ensemble Kalman filter. By optimizing the data assimilation parameters in advance using the response surface method and estimating the generated curing heat by numerical experiments, the generated curing heat could be estimated with an accuracy represented by the time mean error of less than 6%.

In vitro generation of functional murine heart organoids via FGF4 and extracellular matrix.

Our understanding of the spatiotemporal regulation of cardiogenesis is hindered by the difficulties in modeling this complex organ currently by in vitro models. Here we develop a method to generate heart organoids from mouse embryonic stem cell-derived embryoid bodies. Consecutive morphological changes proceed in a self-organizing manner in the presence of the laminin-entactin (LN/ET) complex and fibroblast growth factor 4 (FGF4), and the resulting in vitro heart organoid possesses atrium- and ventricle-like parts containing cardiac muscle, conducting tissues, smooth muscle and endothelial cells that exhibited myocardial contraction and action potentials. The heart organoids exhibit ultrastructural, histochemical and gene expression characteristics of considerable similarity to those of developmental hearts in vivo. Our results demonstrate that this method not only provides a biomimetic model of the developing heart-like structure with simplified differentiation protocol, but also represents a promising research tool with a broad range of applications, including drug testing.

Chamber-specific transcriptional responses in atrial fibrillation.

Atrial fibrillation (AF) is the most common cardiac arrhythmia, yet the molecular signature of the vulnerable atrial substrate is not well understood. Here, we delineated a distinct transcriptional signature in right versus left atrial cardiomyocytes (CMs) at baseline and identified chamber-specific gene expression changes in patients with a history of AF in the setting of end-stage heart failure (AF+HF) that are not present in heart failure alone (HF). We observed that human left atrial (LA) CMs exhibited Notch pathway activation and increased ploidy in AF+HF but not in HF alone. Transient activation of Notch signaling within adult CMs in a murine genetic model is sufficient to increase ploidy in both atrial chambers. Notch activation within LA CMs generated a transcriptomic fingerprint resembling AF, with dysregulation of transcription factor and ion channel genes, including Pitx2, Tbx5, Kcnh2, Kcnq1, and Kcnip2. Notch activation also produced distinct cellular electrophysiologic responses in LA versus right atrial CMs, prolonging the action potential duration (APD) without altering the upstroke velocity in the left atrium and reducing the maximal upstroke velocity without altering the APD in the right atrium. Our results support a shared human/murine model of increased Notch pathway activity predisposing to AF.