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Nitrogen vacancy (NV) centers, atomic spin defects in diamond, represent an active contender for advancing transformative quantum information science (QIS) and innovations. One of the major challenges for designing NV-based hybrid systems for QIS applications results from the difficulty of realizing local control of individual NV spin qubits in a scalable and energy-efficient way. To address this bottleneck, we introduce magnetic tunnel junction (MTJ) devices to establish coherent driving of an NV center by a resonant MTJ with voltage controlled magnetic anisotropy. We show that the oscillating magnetic stray field produced by a resonant micromagnet can be utilized to effectively modify and drive NV spin rotations when the NV frequency matches the corresponding resonance conditions of the MTJ. Our results present a new pathway to achieve all-electric control of an NV spin qubit with reduced power consumption and improved solid-state scalability for implementing cutting-edge QIS technological applications.

Background: The prognostic impact of extracardiac sarcoidosis remains unknown in cardiac sarcoidosis (CS). We aimed to evaluate the influence of extracardiac sarcoidosis on clinical outcomes and the effect of continued outpatient visits for screening of cardiac involvement., Methods: Ninety-nine patients with CS were divided into two groups: patients with systemic CS who had prior extracardiac sarcoidosis, patients with isolated CS who had no prior extracardiac sarcoidosis. Patients with systemic CS were divided according to the continuation of outpatient visits. The endpoint was cardiac death, fatal ventricular arrhythmia, or hospitalization for heart failure., Results: At the time of diagnosing CS, patients with isolated CS had a higher prevalence of high-grade atrioventricular block or fatal ventricular arrhythmia, and left ventricular contractile dysfunction than those with systemic CS. Over a median follow-up of 42 months, cardiac events occurred in 19 (37%) of 52 patients with systemic CS and in 27 (57%) of 47 patients with isolated CS. The event-free survival rate was worse in patients with isolated CS than in those with systemic CS. Cox proportional hazard analysis showed that the absence of prior extracardiac sarcoidosis was an independent predictor of adverse outcomes. Patients with systemic CS who ceased outpatient visits had a lower left ventricular ejection fraction with severe heart failure symptoms and a worse event-free survival rate than those who continued outpatient visits., Conclusions: The presence of extracardiac sarcoidosis is associated with clinical outcomes. The cessation of screening for cardiac involvement after diagnosing extracardiac sarcoidosis is associated with adverse outcomes., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Several signs of malignant early repolarizations have been proposed in patients with early repolarization syndrome (ERS). However, reports have challenged the efficacy of these signs in predicting future ventricular fibrillation (VF) in patients with ERS., Objective: This study aimed to assess the predictive value of various electrocardiogram (ECG) markers for future VF events in patients with ERS., Methods: We retrospectively evaluated the clinical characteristics of 44 patients with ERS to identify risk factors for VF during follow-up., Results: After the initial event, 16 patients experienced VF (VF group), whereas 28 did not (non-VF group). The VF group had a longer QRS interval, more fragmented QRS (fQRS), and a higher T/R voltage ratio than the non-VF group. Wide J waves were more prevalent in the VF group; however, other J-wave markers did not differ between the groups. Positive late potentials recorded on signal-averaged ECGs were more frequent in the VF group. Whereas none of the patients showed spontaneous Brugada syndrome on ECG, the VF group frequently exhibited pilsicainide-induced ST-segment elevation. These ECG markers were significantly associated with the occurrence of VF during follow-up. Patients with multiple ECG factors, including QRS abnormalities (wide QRS or fQRS), wide J waves, and a high T/R ratio, had a worse prognosis than patients without multiple factors, effectively stratifying patient risk., Conclusion: The occurrence of VF in patients with ERS may be associated with conduction abnormalities such as QRS widening, fQRS, high T/R ratio, positive late potentials, and pilsicainide test results. Therefore, ECG factors could be useful in identifying high-risk patients., Competing Interests: Disclosures H.M. and N.N. are affiliated with the endowed department by Japan Medtronic Inc., (Copyright © 2024 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Background: Some patients with chronic thromboembolic pulmonary hypertension (CTEPH) exhibit exercise intolerance due to reduced cardiac output (CO) even after successful balloon pulmonary angioplasty (BPA). Medical therapy is a potential option for such cases; however, it is unclear which patients necessitate it even after BPA., Methods: This study included 286 patients with CTEPH who underwent BPA and right heart catheterization 1 year after the final BPA and classified them into no-medication and withdrawal groups. The no-medication group comprised patients without pulmonary hypertension (PH) medications before and after BPA, while the withdrawal group included patients who received PH medications before BPA and discontinued them after BPA. We assessed differences in the changes in CO after BPA from baseline (ΔCO) between the 2 groups. Additionally, we evaluated the ΔCO among different age categories within each group: younger (<60 years), middle-aged (60-70 years), and older adults (≥70 years)., Results: After adjusting baseline covariates, overall CO did not differ significantly. However, ΔCO was significantly positive in the no-medication group but negative in the withdrawal group (0.32 and -0.33, difference in ΔCO: -0.65, 95% confidence intervals: -0.90 to -0.40). A significantly positive effect on ΔCO was observed in younger and middle-aged individuals, with a significant interaction between age and ΔCO in no-medication groups., Conclusions: Increasing CO with BPA alone may be challenging with age in patients with CTEPH. Given that discontinuation of PH medication after BPA decreased CO more than the effect of BPA, medical therapy might be necessary even after successful BPA., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The morphology of a patent foramen ovale (PFO) with a high-risk for cryptogenic ischemic stroke (CS) is an important factor in the selection of patients for transcatheter closure, but the morphological features of PFO in older patients with a history of CS are less known because the most data are obtained from younger patients., Methods and Results: The study included 169 patients who had a history of CS and PFO. The prevalence of high-risk morphologies of PFO assessed by transesophageal echocardiography was compared between patients aged ≥60 years and patients aged <60 years. We also assessed the presence of septal malalignment of PFO on the aortic wall. The probability of CS due to PFO was evaluated using the PFO-Associated Stroke Causal Likelihood classification system. Patients aged ≥60 years had a significantly higher prevalence of atrial septal aneurysm than patients aged <60 years. The prevalence of large right-to-left shunt, long-tunnel of PFO, or Eustachian valve or Chiari's network was similar between patients aged ≥60 years and <60 years. Septal malalignment was observed more frequently in patients aged ≥60 years than in those <60 years old. Nearly 90% of patients aged ≥60 years were classified as 'possible' in the PFO-Associated Stroke Causal Likelihood classification system., Conclusions: High-risk morphologies of PFO are common in older patients with a history of CS, as well as in younger patients.

Aims: Although right ventricular (RV) dysfunction is associated with adverse outcomes in tricuspid regurgitation (TR), the potential role of right atrial (RA) function is unknown. We aimed to investigate the relationship between RA function and clinical outcomes in patients with significant TR., Methods: This retrospective study included 169 outpatients with moderate or severe TR due to left-sided heart diseases who underwent transthoracic echocardiography between June 2020 and April 2023 (average age, 75 ± 10 years; male, 40%). Patients with atrial fibrillation were excluded from this study due to the inaccuracy of the evaluation using 2D speckle-tracking echocardiography. RA function was compared between patients with and without events, which were defined as all-cause mortality or hospitalization due to heart failure. RA function was calculated as RA global longitudinal strain (RAGLS) with the 2D speckle-tracking echocardiography., Results: During a median follow-up of 13 months, 19 patients had events (all-cause mortality: 14 cases, hospitalization due to heart failure: 5 cases). RAGLS was lower in patients with events than in those without events (13% ± 10% vs. 18% ± 9%, P = 0.02). When the patients were categorized into two groups [low RAGLS ≤ 16.2% vs. high RAGLS > 16.2%, high RA volume index (RAVI) ≥ 50 mL/m 2 vs. low RAVI < 50 mL/m 2 ], Kaplan-Meier curves showed that patients with low RAGLS had higher event rates than those with high RAGLS (log-rank test, P = 0.003). Patients with high RAVI had higher event rates than those with low RAVI (log-rank test, P < 0.001). In the multivariate Cox regression analysis, low RAGLS (≤16.2%) was significantly associated with events in a model that included RV dysfunction (RV fractional area change ≤ 35%) or high RAVI (≥50 mL/m 2 ) (hazard ratio: 4.55, 95% confidence interval: 1.51-13.71, P < 0.01; hazard ratio: 4.57, 95% confidence interval: 1.52-13.79, P < 0.01, respectively)., Conclusions: RAGLS is associated with all-cause mortality and hospitalization due to heart failure in patients with significant TR. Our results suggest that RA function is a sensitive marker for identifying the risk stratification of significant TR., (© 2024 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background: In patients with Brugada syndrome, myocardial fibrosis can be identified through epicardial biopsy or cardiac magnetic resonance (CMR) imaging with late gadolinium enhancement (LGE). However, the myocardial alterations in patients with early repolarization syndrome (ERS) remain poorly elucidated., Objective: The objective of this study was to investigate the presence of myocardial fibrosis in patients with ERS by LGE in CMR., Methods: We retrospectively evaluated 20 patients with ERS, all of whom exhibited J waves in the contiguous 2 leads. The location of J waves was classified as in the septum (V 1 -V 2 ), anterior (V 3 -V 4 ), lateral (I, aVL, V 5 -V 6 ), inferior (II, III, aVF), or posterior (V 7 -V 9 ) regions. To compare the distribution of LGE on CMR imaging with J waves, sections on short-axis view of the left ventricle (LV) were categorized as located in the septum, anterior, lateral, inferior, and posterior regions., Results: Overall, 85% of ERS patients displayed LGE, which was more prevalent in the septum and posterior regions, followed by the inferior and lateral regions. The presence or absence of J waves and LGE coincided in 61% of LV areas, whereas discordance between the distributions of J waves and LGE was observed in 38%. LGE was most frequent in the septum (75%), where its reflection in J waves may be less robust. The appearance of LGE was not associated with symptoms, electrical storm, or ventricular fibrillation occurrence during follow-up., Conclusion: LGE is common in patients with ERS, and the distribution of J waves and LGE coincides in approximately 60% of LV areas., Competing Interests: Disclosure H.M. and N.N. are affiliated with a department endowed by Japan Medtronic Inc., (Copyright © 2024 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Despite guideline-based recommendation of the interchangeable use of instantaneous wave-free ratio (iFR) and fractional flow reserve (FFR) to guide revascularization decision-making, iFR/FFR could demonstrate different physiological or clinical outcomes in some specific patient or lesion subsets. Therefore, we sought to investigate the impact of difference between iFR and FFR-guided revascularization decision-making on clinical outcomes in patients with left main disease (LMD). In this international multicenter registry of LMD with physiological interrogation, we identified 275 patients in whom physiological assessment was performed with both iFR/FFR. Major adverse cardiovascular event (MACE) was defined as a composite of death, non-fatal myocardial infarction, and ischemia-driven target lesion revascularization. The receiver-operating characteristic analysis was performed for both iFR/FFR to predict MACE in respective patients in whom revascularization was deferred and performed. In 153 patients of revascularization deferral, MACE occurred in 17.0% patients. The optimal cut-off values of iFR and FFR to predict MACE were 0.88 (specificity:0.74; sensitivity:0.65) and 0.76 (specificity:0.81; sensitivity:0.46), respectively. The area under the curve (AUC) was significantly higher for iFR than FFR (0.74; 95%CI 0.62-0.85 vs. 0.62; 95%CI 0.48-0.75; p = 0.012). In 122 patients of coronary revascularization, MACE occurred in 13.1% patients. The optimal cut-off values of iFR and FFR were 0.92 (specificity:0.93; sensitivity:0.25) and 0.81 (specificity:0.047; sensitivity:1.00), respectively. The AUCs were not significantly different between iFR and FFR (0.57; 95%CI 0.40-0.73 vs. 0.46; 95%CI 0.31-0.61; p = 0.43). While neither baseline iFR nor FFR was predictive of MACE in patients in whom revascularization was performed, iFR-guided deferral seemed to be safer than FFR-guided deferral., (© 2024. The Author(s).)

Diabetes mellitus (DM) is a major risk and prognostic factor for heart failure (HF). Insulin resistance (IR) is an important component of DM, but the relationship between IR and HF prognosis has not yet been established across a wide variety of HF populations. We retrospectively evaluated the relationship between IR and clinical outcomes of HF patients at our hospital between 2017 and 2021. IR was defined as a homeostatic model assessment of IR (HOMA-IR) index ≥ 2.5, calculated from fasting blood glucose and insulin concentrations. The primary outcome was a composite of all-cause death and hospitalisation for HF (HHF). Among 682 patients included in the analyses, 337 (49.4%) had IR. The median age was 70 [interquartile range (IQR): 59-77] years old, and 66% of the patients were men. Among the patients, 41% had a left ventricular ejection fraction below 40%, and 32% had DM. The median follow-up period was 16.5 [IQR: 4.4-37.3] months. IR was independently associated with the primary outcome (HR: 1.91, 95% CI: 1.39-2.62, p < 0.0001), death (hazard ratio [HR]: 1.86, 95% confidence interval [CI]: 1.28-2.83, p < 0.01), and HHF (HR: 1.91, 95% CI: 1.28-2.83, p < 0.01). HOMA-IR is an independent prognostic factor of HF in a wide variety of HF populations.

Images obtained from single-photon emission computed tomography for myocardial perfusion imaging (MPI SPECT) contain noises and artifacts, making cardiovascular disease diagnosis difficult. We developed a deep learning-based diagnosis support system using MPI SPECT images. Single-center datasets of MPI SPECT images (n = 5443) were obtained and labeled as healthy or coronary artery disease based on diagnosis reports. Three axes of four-dimensional datasets, resting, and stress conditions of three-dimensional reconstruction data, were reconstructed, and an AI model was trained to classify them. The trained convolutional neural network showed high performance [area under the curve (AUC) of the ROC curve: approximately 0.91; area under the recall precision curve: 0.87]. Additionally, using unsupervised learning and the Grad-CAM method, diseased lesions were successfully visualized. The AI-based automated diagnosis system had the highest performance (88%), followed by cardiologists with AI-guided diagnosis (80%) and cardiologists alone (65%). Furthermore, diagnosis time was shorter for AI-guided diagnosis (12 min) than for cardiologists alone (31 min). Our high-quality deep learning-based diagnosis support system may benefit cardiologists by improving diagnostic accuracy and reducing working hours., (© 2024. The Author(s).)

Background: Stem cell research, particularly in the domain of induced pluripotent stem cell (iPSC) technology, has shown significant progress. The integration of artificial intelligence (AI), especially machine learning (ML) and deep learning (DL), has played a pivotal role in refining iPSC classification, monitoring cell functionality, and conducting genetic analysis. These enhancements are broadening the applications of iPSC technology in disease modelling, drug screening, and regenerative medicine. This review aims to explore the role of AI in the advancement of iPSC research., Methods: In December 2023, data were collected from three electronic databases (PubMed, Web of Science, and Science Direct) to investigate the application of AI technology in iPSC processing., Results: This systematic scoping review encompassed 79 studies that met the inclusion criteria. The number of research studies in this area has increased over time, with the United States emerging as a leading contributor in this field. AI technologies have been diversely applied in iPSC technology, encompassing the classification of cell types, assessment of disease-specific phenotypes in iPSC-derived cells, and the facilitation of drug screening using iPSC. The precision of AI methodologies has improved significantly in recent years, creating a foundation for future advancements in iPSC-based technologies., Conclusions: Our review offers insights into the role of AI in regenerative and personalized medicine, highlighting both challenges and opportunities. Although still in its early stages, AI technologies show significant promise in advancing our understanding of disease progression and development, paving the way for future clinical applications., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Vo et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Heterogeneity among both primed and naive pluripotent stem cell lines remains a major unresolved problem. Here we show that expressing the maternal-specific linker histone H1FOO fused to a destabilizing domain (H1FOO-DD), together with OCT4, SOX2, KLF4, and LMYC, in human somatic cells improves the quality of reprogramming to both primed and naive pluripotency. H1FOO-DD expression was associated with altered chromatin accessibility around pluripotency genes and with suppression of the innate immune response. Notably, H1FOO-DD generates naive induced pluripotent stem cells with lower variation in transcriptome and methylome among clones and a more uniform and superior differentiation potency. Furthermore, we elucidated that upregulation of FKBP1A, driven by these five factors, plays a key role in H1FOO-DD-mediated reprogramming., Competing Interests: Declaration of interests A.K. and K.F. are co-inventors on a patent describing the method for producing human iPSCs from somatic cells using H1FOO-DD. K.F. is a co-founder and CEO of Heartseed Inc., and S.T., S. Yuasa, and K.F. own equity in Heartseed Inc. S.T. is an advisor of Heartseed Inc. J.K. and H.H. are employees and K.K. is a board member of ID Pharma Co., Ltd., without compensation relating to this study. S. Yamanaka is a scientific advisor to iPS Academia Japan without salary., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Metabolic dysfunction-associated steatotic liver disease (MASLD) is the proposed name change for non-alcoholic fatty liver disease (NAFLD). This study aimed to investigate the association of cardiovascular disease risk with MASLD and NAFLD in patients who underwent clinically indicated coronary computed tomography angiography (CCTA)., Methods: This retrospective study included 2289 patients (60% men; mean age: 68 years) with no history of coronary artery disease who underwent CCTA. The steatotic liver was defined as a hepatic-to-spleen attenuation ratio of < 1.0 on CT just before CCTA. MASLD is defined as the presence of hepatic steatosis along with at least one of the five cardiometabolic risk factors. Adverse CCTA findings were defined as obstructive and/or high-risk plaques. Major adverse cardiac events (MACE) encompassed composite coronary events, including cardiovascular death, acute coronary syndrome, and late coronary revascularization., Results: MASLD and NAFLD were identified in 415 (18%) and 368 (16%) patients, respectively. Adverse CCTA findings were observed in 40% and 38% of the patients with MASLD and with NAFLD, respectively. Adverse CCTA findings were significantly associated with MASLD (p = 0.007) but not NAFLD (p = 0.253). During a median follow-up of 4.4 years, 102 (4.4%) MACE were observed. MASLD was significantly associated with MACE (hazard ratio 1.82, 95% CI 1.18-2.83, p = 0.007), while its association with NAFLD was not significant (p = 0.070). By incorporating MASLD into a prediction model of MACE, including the risk score and adverse CCTA findings, global chi-squared values significantly increased from 87.0 to 94.1 (p = 0.008)., Conclusions: Patients with MASLD are likely to have a higher risk of cardiovascular disease than those with NAFLD. Concurrent assessment of MASLD during CCTA improves the identification of patients at a higher risk of cardiovascular disease among those with clinically indicated CCTA., (© 2024. The Author(s).)

Background: Early repolarization syndrome (ERS) is an idiopathic ventricular fibrillation (VF) associated with inferolateral J waves. While electrical storm (ES) in ERS is not rare, their characteristics and risk factors are not fully understood., Objective: This study aimed to clarify the significance of ES in ERS., Methods: We evaluated 44 patients with ERS who experienced VF/sudden cardiac death or arrhythmic syncope. We assessed clinical characteristics to identify the risk factors for ES., Results: In total, 13 patients (30%) experienced ES (ES group). Of these, 11 patients (85%) experienced ES during the acute phase of initial VF episodes and 2 patients (2%) experienced ES during follow-up. VF associated with ES occurred during therapeutic hypothermia in 6 of 13 patients (46%). The J-wave voltage during therapeutic hypothermia was higher in the ES group than that in the patients without ES. Isoproterenol was used in 5 patients (38%), which decreased J-wave voltage and relieved ES. Among the clinical markers, shorter QT and QTp intervals (the interval from QRS onset to the peak of T wave), pilsicainide-induced ST elevation, and high scores on the Shanghai Score System were associated with ES. Although pilsicainide induced ST elevation in 6 of 34 patients (18%), spontaneous Brugada electrocardiographic patterns did not appear to be associated with VF. Therapeutic hypothermia was also a risk factor for acute phase ES., Conclusion: Patients with ERS in the ES group frequently had short QT and QTp intervals, pilsicainide-induced ST elevations, and high Shanghai Score System scores. Therapeutic hypothermia was also associated with acute phase ES., Competing Interests: Disclosures Drs Morita and Nishii are affiliated with the endowed department of Japan Medtronic Inc., (Copyright © 2024 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Background: Remote monitoring (RM) of cardiac implantable electrical devices (CIEDs) can detect various events early. However, the diagnostic ability of CIEDs has not been sufficient, especially for lead failure. The first notification of lead failure was almost noise events, which were detected as arrhythmia by the CIED. A human must analyze the intracardiac electrogram to accurately detect lead failure. However, the number of arrhythmic events is too large for human analysis. Artificial intelligence (AI) seems to be helpful in the early and accurate detection of lead failure before human analysis., Objective: To test whether a neural network can be trained to precisely identify noise events in the intracardiac electrogram of RM data., Methods: We analyzed 21 918 RM data consisting of 12 925 and 1884 Medtronic and Boston Scientific data, respectively. Among these, 153 and 52 Medtronic and Boston Scientific data, respectively, were diagnosed as noise events by human analysis. In Medtronic, 306 events, including 153 noise events and randomly selected 153 out of 12 692 nonnoise events, were analyzed in a five-fold cross-validation with a convolutional neural network. The Boston Scientific data were analyzed similarly., Results: The precision rate, recall rate, F1 score, accuracy rate, and the area under the curve were 85.8 ± 4.0%, 91.6 ± 6.7%, 88.4 ± 2.0%, 88.0 ± 2.0%, and 0.958 ± 0.021 in Medtronic and 88.4 ± 12.8%, 81.0 ± 9.3%, 84.1 ± 8.3%, 84.2 ± 8.3% and 0.928 ± 0.041 in Boston Scientific. Five-fold cross-validation with a weighted loss function could increase the recall rate., Conclusions: AI can accurately detect noise events. AI analysis may be helpful for detecting lead failure events early and accurately., Competing Interests: Nobuhiro Nishii and Hiroshi Morita belong to the Endowed Department of Medtronic Japan Co. Ltd. Nobuhiro Nishi received lecture fees from Medtronic Japan Co. Ltd. and Boston Scientific Japan. None of the other authors have any additional relationships with industry., (© 2024 The Authors. Journal of Arrhythmia published by John Wiley & Sons Australia, Ltd on behalf of Japanese Heart Rhythm Society.)

Aims: Right ventricular to pulmonary artery (RV-PA) coupling has been established as a prognostic marker in patients with severe tricuspid regurgitation (TR) undergoing transcatheter tricuspid valve interventions (TTVI). RV-PA coupling assesses right ventricular systolic function related to pulmonary artery pressure levels, which are ideally measured by right heart catheterization. This study aimed to improve the RV-PA coupling concept by relating tricuspid annular plane systolic excursion (TAPSE) to mean pulmonary artery pressure (mPAP) levels. Moreover, instead of right heart catheterization, this study sought to employ an extreme gradient boosting (XGB) algorithm to predict mPAP levels based on standard echocardiographic parameters., Methods and Results: This multicentre study included 737 patients undergoing TTVI for severe TR; among them, 55 patients from one institution served for external validation. Complete echocardiography and right heart catheterization data were available from all patients. The XGB algorithm trained on 10 echocardiographic parameters could reliably predict mPAP levels as evaluated on right heart catheterization data from external validation (Pearson correlation coefficient R: 0.68; P value: 1.3 × 10-8). Moreover, predicted mPAP (mPAPpredicted) levels were superior to echocardiographic systolic pulmonary artery pressure (sPAPechocardiography) levels in predicting 2-year mortality after TTVI [area under the curve (AUC): 0.607 vs. 0.520; P value: 1.9 × 10-6]. Furthermore, TAPSE/mPAPpredicted was superior to TAPSE/sPAPechocardiography in predicting 2-year mortality after TTVI (AUC: 0.633 vs. 0.586; P value: 0.008). Finally, patients with preserved RV-PA coupling (defined as TAPSE/mPAPpredicted > 0.617 mm/mmHg) showed significantly higher 2-year survival rates after TTVI than patients with reduced RV-PA coupling (81.5% vs. 58.8%, P < 0.001). Moreover, independent association between TAPSE/mPAPpredicted levels and 2-year mortality after TTVI was confirmed by multivariate regression analysis (P value: 6.3 × 10-4)., Conclusion: Artificial intelligence-enabled RV-PA coupling assessment can refine risk stratification prior to TTVI without necessitating invasive right heart catheterization. A comparison with conservatively treated patients is mandatory to quantify the benefit of TTVI in accordance with RV-PA coupling., Competing Interests: Conflict of interest: None declared., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: The interplay between the right ventricle and the pulmonary artery, known as right ventricular to pulmonary artery (RV-PA) coupling, is crucial for assessing right ventricular systolic function against the afterload from the pulmonary circulation. Pulmonary artery pressure levels are ideally measured by right heart catheterization. Yet, echocardiography represents the most utilized method for evaluating pulmonary artery pressure levels, albeit with limitations in accuracy. This study therefore aims to evaluate the prognostic significance of right ventricular to pulmonary artery (RV-PA) coupling expressed as tricuspid annular plane systolic excursion (TAPSE) related to systolic pulmonary artery pressure (sPAP) levels measured by right heart catheterization (TAPSE/sPAP invasive ) or estimated by transthoracic echocardiography (TAPSE/sPAP echocardiography ) in patients with severe aortic stenosis undergoing transcatheter aortic valve replacement (TAVR)., Methods: Using data from a bicentric registry, this study compares TAPSE/sPAP invasive vs. TAPSE/sPAP echocardiography in predicting 1-year all-cause mortality after TAVR., Results: Among 333 patients with complete echocardiography and right heart catheterization data obtained before TAVR, their mean age was 79.8 ± 6.74 years, 39.6% were female, and general 1-year survival was 89.8%. sPAP invasive and sPAP echocardiography showed only moderate correlation (Pearson correlation coefficient R : 0.53, p  value: <0.0001). TAPSE/sPAP invasive was superior to TAPSE/sPAP echocardiography in predicting 1-year all-cause mortality after TAVR (area under the curve: 0.662 vs. 0.569, p value: 0.025). Patients with reduced TAPSE/sPAP invasive levels (< 0.365 mm/mmHg) evidenced significantly lower 1-year survival rates than patients with preserved TAPSE/sPAP invasive levels (81.8 vs. 93.6%, p value: 0.001; hazard ratio for 1-year mortality: 3.09 [95% confidence interval: 1.55-6.17]). Echocardiographic follow-up data revealed that patients with reduced RV-PA coupling suffer from persistent right ventricular dysfunction (TAPSE: 16.6 ± 4.05 mm vs. 21.6 ± 4.81 mm in patients with preserved RV-PA coupling) and severe tricuspid regurgitation (diagnosed in 19.7 vs. 6.58% in patients with preserved RV-PA coupling)., Conclusions: RV-PA coupling expressed as TAPSE/sPAP invasive can refine stratification of severe aortic stenosis patients into low-risk and high-risk cohorts for mortality after TAVR. Moreover, it can help to anticipate persistent extra-aortic valve cardiac damage, which will demand further treatment., Competing Interests: The authors report no conflict of interest., (© 2024 The Author(s).)

Objective: To investigate the diagnostic performance of a calcium-removal image reconstruction algorithm with photon-counting detector-computed tomography (PCD-CT), a technology that hides only the calcified plaque from the spectral data in coronary calcified lesions., Methods: This retrospective study included 17 patients who underwent PCD-coronary CT angiography (CCTA) with at least one significant coronary stenosis (≥50 %) with calcified plaque by CCTA and invasive coronary angiography (ICA) performed within 60 days of CCTA. A total of 162 segments with calcified plaque were evaluated for subjective image quality using a 4-point scale. Their calcium-removal images were reconstructed from conventional images, and both images were compared with ICA images as the reference standard. The contrast-to noise ratios for both images were calculated., Results: Conventional and calcium-removal images had a subjective image quality of 2.7 ± 0.5 and 3.2 ± 0.9, respectively (p < 0.001). The percentage of segments with a non-diagnostic image quality was 32.7 % for conventional images and 28.3 % for calcium-removal images (p < 0.001). The segment-based diagnostic accuracy revealed an area under the receiver operating characteristic curve of 0.87 for calcium-removal images and 0.79 for conventional images (p = 0.006). Regarding accuracy, the specificity and positive predictive value of calcium-removal images were significantly improved compared with those of conventional images (80.5 % vs. 69.5 %, p = 0.002 and 64.1 % vs. 52.0 %, p < 0.001, respectively). The objective image quality of the mean contrast-to-noise ratio did not differ between the images (13.9 ± 3.6 vs 13.3 ± 3.4, p = 0.356) CONCLUSIONS: Calcium-removal images with PCD-CT can potentially be used to evaluate diagnostic performance for calcified coronary artery lesions., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Ischemic heart disease (IHD) poses a significant challenge in cardiovascular health, with current treatments showing limited success. Induced pluripotent derived-cardiomyocyte (iPSC-CM) therapy within regenerative medicine offers potential for IHD patients, although its clinical impacts remain uncertain. This study utilizes meta-analysis to assess iPSC-CM outcomes in terms of efficacy and safety in IHD animal model studies. A meta-analysis encompassing PUBMED, ScienceDirect, Web of Science, and the Cochrane Library databases, from inception until October 2023, investigated iPSC therapy effects on cardiac function and safety outcomes. Among 51 eligible studies involving 1012 animals, despite substantial heterogeneity, the iPSC-CM transplantation improved left ventricular ejection fraction (LVEF) by 8.23% (95% CI, 7.15 to 9.32%; p < 0.001) compared to control groups. Additionally, cell-based treatment reduced the left ventricle fibrosis area and showed a tendency to reduce left ventricular end-systolic volume (LVESV) and end-diastolic volume (LVEDV). No significant differences emerged in mortality and arrhythmia risk between iPSC-CM treatment and control groups. In conclusion, this meta-analysis indicates iPSC-CM therapy's promise as a safe and beneficial intervention for enhancing heart function in IHD. However, due to observed heterogeneity, the efficacy of this treatment must be further explored through large randomized controlled trials based on rigorous research design.

Shared decision-making (SDM) is a pivotal process in seeking optimal individual treatment and incorporating clinical evidence and patients' autonomous preferences. However, patients' actual attitudes toward participation in decision-making for state-of-the-art heart failure (HF) treatment remain unclear. We conducted a questionnaire-based survey distributed by nurses and physicians specializing in HF care to assess patients' preferred and perceived participation roles in treatment decision-making during the index hospitalization, rated on five scales (from extremely passive to purely autonomous attitudes). Simultaneously, we investigated the important factors underlying treatment decision-making from the perspective of hospitalized HF patients. Of the 202 patients who were approached by our multidisciplinary HF team between 2017 and 2020, 166 (82.2%) completed the survey. Logistic regression analyses were conducted to identify the clinical determinants of patients who reported that they left all decisions to physicians (i.e., extremely passive attitude). Of the 166 participants (male 67.5%, median age 73 years), 32.5% preferred an extremely passive attitude, while 61.4% reported that they actually chose an extremely passive attitude. A sole determinant of choosing an extremely passive decision-making role was lower educational status (odds ratio: 2.11, 95% confidence interval 1.11-4.00). The most important factor underlying the decision-making was "Physician recommendation" (89.2%). Notably, less than 50% considered "In alignment with my values and preferences" as an important factor underlying treatment decision-making. The majority of HF patients reported that they chose an extremely passive approach, and patients prioritized physician recommendation over their own values and preferences., (© 2023. Springer Nature Japan KK, part of Springer Nature.)

Machine learning is a subfield of artificial intelligence. The quality and versatility of machine learning have been rapidly improving and playing a critical role in many aspects of social life. This trend is also observed in the medical field. Generally, there are three main types of machine learning: supervised, unsupervised, and reinforcement learning. Each type of learning is adequately selected for the purpose and type of data. In the field of medicine, various types of information are collected and used, and research using machine learning is becoming increasingly relevant. Many clinical studies are conducted using electronic health and medical records, including in the cardiovascular area. Machine learning has also been applied in basic research. Machine learning has been widely used for several types of data analysis, such as clustering of microarray analysis and RNA sequence analysis. Machine learning is essential for genome and multi-omics analyses. This review summarizes the recent advancements in the use of machine learning in clinical applications and basic cardiovascular research., Competing Interests: Declaration of competing interest The authors declare that they have no conflicts of interest., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

There have been no studies comparing clinical outcomes of physiology-guided revascularization in patients with unprotected left main coronary disease (ULMD) between percutaneous coronary intervention (PCI) vs. coronary artery bypass grafting (CABG). The aim of this study was to assess the long-term clinical outcomes between PCI and CABG of patients with physiologically significant ULMD. From an international multicenter registry of ULMD patients interrogated with instantaneous wave-free ratio (iFR), we analyzed data from 151 patients (85 PCI vs. 66 CABG) who underwent revascularization according to the cutoff value of iFR ≤ 0.89. Propensity score matching was employed to adjust for baseline clinical characteristics. The primary endpoint was a composite of all-cause death, non-fatal myocardial infarction, and ischemia-driven target lesion revascularization. The secondary endpoints were the individual components of the primary endpoint. Mean age was 66.6 (± 9.2) years, 79.2% male. Mean SYNTAX score was 22.6 (± 8.4) and median iFR was 0.83 (IQR 0.74-0.87). After performing propensity score matching analysis, 48 patients treated with CABG were matched to those who underwent PCI. At a median follow-up period of 2.8 years, the primary endpoint occurred in 8.3% in PCI group and 20.8% in CABG group, respectively (HR 3.80; 95% CI 1.04-13.9; p = 0.043). There was no difference in each component of the primary event (p > 0.05 for all). Within the present study, iFR-guided PCI was associated with lower cardiovascular events rate in patients with ULMD and intermediate SYNTAX score, as compared to CABG. State-of-the-art PCI vs. CABG for ULMD. Study design and primary endpoint in patients with physiologically significant ULMD. MACE was defined as the composite of all-cause death, non-fatal myocardial infarction, and target lesion revascularization. The blue line denotes the PCI arm, and the red line denotes the CABG arm. PCI was associated with significantly lower risk of MACE than CABG. CABG: coronary artery bypass grafting; iFR: instantaneous wave-free ratio; MACE: major adverse cardiovascular events; PCI: percutaneous coronary intervention; ULMD: unprotected left main coronary artery disease., (© 2023. The Author(s).)

The voltage-controlled magnetic anisotropy (VCMA) effect is a key to realising high-speed, ultralow-power consumption spintronic devices. The fcc-Co-(111)-based stack is a promising candidate for the achievement of large VCMA coefficients. However, only a few studies on the fcc-Co-(111)-based stack have been reported and the VCMA effect has not been well understood. Previously, we observed a significant increase in the voltage-controlled coercivity (VCC) in the Pt/Ru/Co/CoO/TiO x structure upon post-annealing. However, the mechanism underlying this enhancement remains unclear. This study performs multiprobe analyses on this structure before and after post-annealing and discusses the origin of the VCMA effect at the Co/oxide interface. X-ray magnetic circular dichroism measurement revealed an increase in the orbital magnetic moment owing to post-annealing, accompanied by a significant increase in VCC. We speculate that the diffusion of Pt atoms into the vicinity of Co/oxide interface enhances the interfacial orbital magnetic moment and the VCMA at the interface. These results provide a guideline for designing structures to obtain a large VCMA effect in fcc-Co-(111)-based stacks., (© 2023. The Author(s).)

Background: The majority of randomized controlled trials of revascularization decision-making excludes left main coronary artery disease (LMD). Therefore, contemporary clinical outcomes of patients with stable coronary artery disease and LMD with proven ischemia remain poorly understood. The aim of this study was to assess the long-term clinical outcomes of physiologically significant LMD according to the treatment strategies of revascularization versus revascularization deferral., Methods: In this international multicenter registry of stable LMD interrogated with the instantaneous wave-free ratio, patients with physiologically significant ischemia (instantaneous wave-free ratio ≤0.89) were analyzed according to the coronary revascularization (n=151) versus revascularization deferral (n=74). Propensity score matching was performed to adjust for baseline clinical characteristics. The primary end point was a composite of death, nonfatal myocardial infarction, and ischemia-driven target lesion revascularization of left main stem. The secondary end points were as follows: cardiac death or spontaneous LMD-related myocardial infarction; and ischemia-driven target lesion revascularization of left main stem., Results: At a median follow-up period of 2.8 years, the primary end point occurred in 11 patients (14.9%) in the revascularized group and 21 patients (28.4%) in the deferred group (hazard ratio, 0.42 [95% CI, 0.20-0.89]; P =0.023). For the secondary end points, cardiac death or LMD-related myocardial infarction occurred significantly less frequently in the revascularized group (0.0% versus 8.1%; P =0.004). The rate of ischemia-driven target lesion revascularization of left main stem was also significantly lower in the revascularized group (5.4% versus 17.6%; hazard ratio, 0.20 [95% CI, 0.056-0.70]; P =0.012)., Conclusions: In patients who underwent revascularization for stable coronary artery disease and physiologically significant LMD determined by instantaneous wave-free ratio, the long-term clinical outcomes were significantly improved as compared with those in whom revascularization was deferred., Competing Interests: Disclosures Dr Warisawa has received consulting fees from Abbott Medical Japan and Philips Japan. Dr Cook has received speaker’s honoraria from Philips Volcano and Boston Scientific. Dr Seligman has received a research grant from Amgen. Dr Howard is supported by the Wellcome Trust (212183/Z/18/Z). Dr Kikuta reports speaker fees from Abbott Vascular and Philips. Dr Sen is supported by the Academy of Medical Sciences and Imperial Biomedical Research Center. Dr Sen (G1000357) is supported by the Medical Research Council, and has served on the Speakers Bureau, and participated in educational events for Pfizer, Phillips, Daichi-Sankyo, and AstraZeneca. Dr Sen has received speaker fees from Volcano, Pfizer, and Medtronic. Dr Al-Lamee has received a speaker honorarium from Philips Volcano. Dr Matsuo receive consultant fees from Zeon Medical, and speaker fees from Abbott Vascular Japan, Philips Japan, and Boston Scientific Japan. Dr Davies holds patents pertaining to the iFR technology. Dr Davies is a consultant for Philips Volcano, and has received research grants from Philips Volcano. The other authors report no conflicts.

Objectives: We aimed to evaluate the diagnostic accuracy of quantitative flow ratio (QFR) in left main (LM) coronary stenoses, using Fractional Flow Reserve (FFR) as reference., Background: QFR has demonstrated a high accuracy in determining the functional relevance of coronary stenoses in non-LM. However, there is an important paucity of data regarding its diagnostic value in the specific anatomical subset of LM disease., Methods: This is a retrospective, observational, multicenter, international, and blinded study including patients with LM stenoses. Cases with significant ostial LM disease were excluded. QFR was calculated from conventional angiograms at blinded fashion with respect to FFR., Results: Sixty-seven patients with LM stenoses were analyzed. Overall, LM had intermediate severity, both from angiographic (diameter stenosis [%DS] 43.8 ± 11.1%) and functional perspective (FFR 0.756 ± 0.105). Mean QFR was 0.733 ± 0.159. Correlation between QFR and FFR was moderate (r = 0.590). Positive and negative predictive value, sensitivity and specificity were 85.4%, 64%, 85.4%, and 69.6% respectively. Classification agreement of QFR and FFR in terms of functional stenosis severity was 78.1%. Area under the receiver operating characteristics of QFR using FFR as reference was 0.82 [95% confidence interval [CI], 0.71-0.93], and significantly better than angiographic evaluation including %DS (area under the receiver-operating characteristic curve [AUC] 0.45 [95% CI, 0.32-0.58], p < 0.001) and minimum lumen diameter (AUC 0.60 [95% CI, 0.47-0.74], p < 0.001)., Conclusions: Compared with FFR, QFR has acceptable diagnostic performance in determining the functional relevance of LM stenosis, being better than conventional angiographic assessment. Nonetheless, caution should be taken when applying functional angiography techniques for the assessment of LM stenosis given its particular anatomical characteristics., (© 2023 The Authors. Catheterization and Cardiovascular Interventions published by Wiley Periodicals LLC.)

Definitive diagnosis of familial hypercholesterolemia (FH) is paramount for the risk management of patients and their relatives. The present study aimed to investigate the frequency of gene variants contributing to low-density lipoprotein cholesterol (LDL-C) metabolism and their clinical relevance in patients with early-onset coronary artery disease (EOCAD). Among 63 consecutive patients with EOCAD (men <55 years or women <65 years) who underwent percutaneous coronary intervention (PCI) from 2013 to 2019 at Keio University Hospital, 52 consented to participate in this retrospective study. Targeted sequencing of LDLR , PCSK9 , APOB , and LDLRAP1 was performed. Of the 52 patients enrolled (42 men; mean age: 50 ± 6 years), one ( LDLR , c.1221&#95;1222delCGinsT) harbored a pathogenic mutation, and one ( APOB , c.10591A>G) harbored variants of uncertain significance. Both the patients harboring the variants were male, showing no history of diabetes mellitus or chronic kidney disease, no family history of EOCAD, and no physical findings of FH (i.e., tendon xanthomas or Achilles tendon thickening). Patients harboring the LDLR variant had three-vessel disease, were on a statin prescription at baseline, and had stable LDL-C levels; however, the case showed a poor response to the intensification of medication after PCI. Approximately 3.8% of patients with EOCAD harbored variants of gene related to LDL-C metabolism; there were no notable indicators in the patients' background or clinical course to diagnose FH. Given the difficulty in diagnosing FH based on clinical manifestations and family history, genetic testing could enable the identification of hidden risk factors and provide early warnings to their relatives., Competing Interests: F.K. has a financial relationship with a research grant from Recordati S.p.A., (Copyright © 2023 Hiroshi Miyama et al.)

Objective: Congenital heart disease (CHD) is caused by cardiovascular developmental defects and has a global prevalence of ∼1%. The etiology of CHD is multifactorial and remains generally unknown, despite advances in analytical techniques based on next-generation sequencing (NGS). The aim of our study was to elucidate the multi-genetic origin and pathogenesis of an intriguing familial case with complex CHD., Methods: We performed an original trio-based gene panel analysis using NGS of the family, including two siblings with CHD of single ventricular phenotype, and their unaffected parents. The pathogenicity of the detected rare variants was investigated in silico , and the functional effects of the variants were confirmed in vitro using luciferase assays. The combinatorial effect of gene alterations of the putative responsible genes was tested in vivo using genetically engineered mutant mice., Results: NGS-based gene panel analyses revealed two heterozygous rare variants in NODAL and in TBX20 common to the siblings and to just one of parents. Both variants were suspected pathogenic in silico, and decreased transcriptional activities of downstream signaling pathways were observed in vitro . The analyses of Nodal and Tbx20 double mutant mice demonstrated that Nodal +/- Tbx20 -/- embryos showed more severe defects than Nodal +/+ Tbx20 -/- embryos during early heart development. The expression of Pitx2 , a known downstream target of Nodal , was downregulated in Tbx20 -/- mutants., Conclusions: Two rare variants on NODAL and TBX20 genes detected in this family were considered to be loss-of-function mutations. Our results suggest that NODAL and TBX20 may be complementary for the cardiac development, and a combinatorial loss-of-function of NODAL and TBX20 could be implicated in digenic inherence as the etiology of complex CHD associated with single ventricle defects in this family., Competing Interests: HY receives research grants from Actelion Pharmaceuticals Japan Ltd. and Abbvie Japan Inc. The other authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Yoshida, Uchida, Kodo, Ishizaki-Asami, Maeda, Katsumata, Yuasa, Fukuda, Kosaki, Watanabe, Nakagawa and Yamagishi.)

Aims: Patients with mitral regurgitation (MR) present with considerable heterogeneity in cardiac damage depending on underlying aetiology, disease progression, and comorbidities. This study aims to capture their cardiopulmonary complexity by employing a machine-learning (ML)-based phenotyping approach., Methods and Results: Data were obtained from 1426 patients undergoing mitral valve transcatheter edge-to-edge repair (MV TEER) for MR. The ML model was developed using 609 patients (derivation cohort) and validated on 817 patients from two external institutions. Phenotyping was based on echocardiographic data, and ML-derived phenotypes were correlated with 5-year outcomes. Unsupervised agglomerative clustering revealed four phenotypes among the derivation cohort: Cluster 1 showed preserved left ventricular ejection fraction (LVEF; 56.5 ± 7.79%) and regular left ventricular end-systolic diameter (LVESD; 35.2 ± 7.52 mm); 5-year survival in Cluster 1, hereinafter serving as a reference, was 60.9%. Cluster 2 presented with preserved LVEF (55.7 ± 7.82%) but showed the largest mitral valve effective regurgitant orifice area (0.623 ± 0.360 cm2) and highest systolic pulmonary artery pressures (68.4 ± 16.2 mmHg); 5-year survival ranged at 43.7% (P-value: 0.032). Cluster 3 was characterized by impaired LVEF (31.0 ± 10.4%) and enlarged LVESD (53.2 ± 10.9 mm); 5-year survival was reduced to 38.3% (P-value: <0.001). The poorest 5-year survival (23.8%; P-value: <0.001) was observed in Cluster 4 with biatrial dilatation (left atrial volume: 312 ± 113 mL; right atrial area: 46.0 ± 8.83 cm2) although LVEF was only slightly reduced (51.5 ± 11.0%). Importantly, the prognostic significance of ML-derived phenotypes was externally confirmed., Conclusion: ML-enabled phenotyping captures the complexity of extra-mitral valve cardiac damage, which does not necessarily occur in a sequential fashion. This novel phenotyping approach can refine risk stratification in patients undergoing MV TEER in the future., Competing Interests: Conflict of interest: None declared ., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background Tricuspid regurgitation (TR) frequently develops in patients with long-standing pulmonary hypertension, and both pathologies are associated with increased morbidity and mortality. This study aimed to improve prognostic assessment in patients with severe TR undergoing transcatheter tricuspid valve intervention (TTVI) by relating the extent of TR to pulmonary artery pressures. Methods and Results In this multicenter study, we included 533 patients undergoing TTVI for moderate-to-severe or severe TR. The proportionality framework was based on the ratio of tricuspid valve effective regurgitant orifice area to mean pulmonary artery pressure. An optimal threshold for tricuspid valve effective regurgitant orifice area/mean pulmonary artery pressure ratio was derived on 353 patients with regard to 2-year all-cause mortality and externally validated on 180 patients. Patients with a tricuspid valve effective regurgitant orifice area/mean pulmonary artery pressure ratio ≤1.25 mm 2 /mm Hg (defining proportionate TR) featured significantly lower 2-year survival rates after TTVI than patients with disproportionate TR (56.6% versus 69.6%; P =0.005). In contrast with patients with disproportionate TR (n=398), patients with proportionate TR (n=135) showed more pronounced mPAP levels (37.9±9.06 mm Hg versus 27.9±8.17 mm Hg; P <2.2×10 -16 ) and more severely impaired right ventricular function (tricuspid annular plane systolic excursion: 16.0±4.11 versus 17.0±4.64 mm; P =0.012). Moreover, tricuspid valve effective regurgitant orifice area was smaller in patients with proportionate TR when compared with disproportionate TR (0.350±0.105 cm 2 versus 0.770±0.432 cm 2 ; P <2.2×10 -16 ). Importantly, proportionate TR remained a significant predictor for 2-year mortality after adjusting for demographic and clinical variables (hazard ratio, 1.7; P =0.006). Conclusions The proposed proportionality framework promises to improve future risk stratification and clinical decision-making by identifying patients who benefit the most from TTVI (disproportionate TR). As a next step, randomized controlled studies with a conservative treatment arm are needed to quantify the net benefit of TTVI in patients with proportionate TR.

Background: Sublineage BA.5 of the SARS-CoV-2 Omicron variant rapidly spread and replaced BA.2 in July 2022 in Tokyo. A high viral load can be a possible cause of high transmissibility., Methods and Results: The copy numbers of SARS-CoV-2 in nasopharyngeal swab samples obtained from all patients visiting the hospital where this research was conducted were measured using reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Viral genotypes were determined using PCR-based melting curve analysis. Next, whole-genome sequencing was performed using approximately one fifth of the samples to verify the viral genotypes determined using PCR. Then, the copy numbers of the BA.1, BA.2, and BA.5 cases were compared. Contrary to expectations, the copy numbers of the BA.5 cases (median 4.7 × 10 4 copies/μL, n = 291) were significantly (p = .001) lower than those of BA.2 cases (median 1.1 × 10 5 copies/μL, n = 184). There was no significant difference (p = .44) between the BA.5 and BA.1 cases (median, 3.3 × 10 4 copies/μL; n = 215)., Conclusion: The results presented here suggest that the increased infectivity of BA.5 is not caused by higher viral loads, but presumably by other factors such as increased affinity to human cell receptors or immune escape due to its L452R mutation., (© 2023 The Authors. Immunity, Inflammation and Disease published by John Wiley & Sons Ltd.)

Background: Understanding patient perspectives of self-care is critical for improving multidisciplinary education programs and adherence to such programs. However, perspectives of self-care for patients with heart failure (HF) as well as the association between patient perspectives and patient-physician communication remain unclear., Methods: Confidence levels regarding self-care behaviors (eight lifestyle behaviors and four consulting behaviors) and self-monitoring were assessed using a self-administered questionnaire survey, which was directly distributed by dedicated physicians and nurses to consecutive patients hospitalized with HF in a tertiary-level hospital. Patient-physician communication was evaluated according to the quality of physician-provided information regarding "treatment and treatment choices" and "prognosis" using the Prognosis and Treatment Perception Questionnaire. Out of 202 patients, 187 (92.6 %) agreed to participate, and 176 completed the survey [valid response rate, 87.1 %; male, 67.0 %; median age, 73 (63-81) years]. Multivariate logistic regression analyses were conducted to predict low confidence in self-care (score in the lowest quartile)., Results: High confidence (confident or completely confident >75 % of patients) was observed for all self-care behavior categories except low-salt diet (63.1 %), regular exercise (63.1 %), and flu vaccination (65.9 %). Lower confidence in self-care behavior was associated with low quality of patient-physician communication. With regard to self-monitoring, 62.5 % of patients were not confident in distinguishing worsening symptoms of HF from other diseases; non-confidence was also associated with low quality of patient-physician communication., Conclusions: Hospitalized patients with HF had low confidence regarding regular exercise, salt restriction, and flu vaccination. The results also suggest patient-physician communication affects patient confidence., Competing Interests: Declaration of competing interest Dr. Kohsaka reports investigator-initiated grant funding from Bayer and Daiichi Sankyo. Dr. Shiraishi is affiliated with an endowed department by Nippon Shinyaku Co., Ltd. and received a research grant from the SECOM Science and Technology Foundation and an honorarium from Otsuka Pharmaceutical Co., Ltd., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

The number of patients with heart failure and related deaths is rapidly increasing worldwide, making it a major problem. Cardiac hypertrophy is a crucial preliminary step in heart failure, but its treatment has not yet been fully successful. In this study, we established a system to evaluate cardiomyocyte hypertrophy using a deep learning-based high-throughput screening system and identified drugs that inhibit it. First, primary cultured cardiomyocytes from neonatal rats were stimulated by both angiotensin II and endothelin-1, and cellular images were captured using a phase-contrast microscope. Subsequently, we used a deep learning model for instance segmentation and established a system to automatically and unbiasedly evaluate the cardiomyocyte size and perimeter. Using this system, we screened 100 FDA-approved drugs library and identified 12 drugs that inhibited cardiomyocyte hypertrophy. We focused on ezetimibe, a cholesterol absorption inhibitor, that inhibited cardiomyocyte hypertrophy in a dose-dependent manner in vitro. Additionally, ezetimibe improved the cardiac dysfunction induced by pressure overload in mice. These results suggest that the deep learning-based system is useful for the evaluation of cardiomyocyte hypertrophy and drug screening, leading to the development of new treatments for heart failure., (Copyright © 2022. Published by Elsevier Inc.)

Background: The clinical value of residual quantitative flow ratio (rQFR), a novel function of QFR technique, is unknown., Aim: We investigated the clinical value of rQFR, aimed to predict residual ischemia after virtual percutaneous coronary intervention (vPCI)., Methods: This is a substudy of the COE-PERSPECTIVE registry, which investigated the prognostic value of post-PCI fractional flow reserve (FFR). From pre-PCI angiograms, QFR and rQFR were analyzed and their diagnostic performance was assessed at blinded fashion using pre-PCI FFR and post-PCI FFR as reference, respectively. The prognostic value of rQFR after vPCI was assessed according to vessel-oriented composite outcome (VOCO) at 2 years., Results: We analyzed 274 patients (274 vessels) with FFR-based ischemic causing lesions (49%) from 555 screened patients. Pre-PCI QFR and FFR were 0.63 ± 0.10 and 0.66 ± 0.11 (R = 0.756, p < 0.001). rQFR after vPCI and FFR after real PCI were 0.93 ± 0.06 and 0.86 ± 0.07 (R = 0.528, p < 0.001). The mean difference between rQFR and post-PCI FFR was 0.068 (95% limit of agreement: -0.05 to 0.19). Diagnostic performance of rQFR to predict residual ischemia after PCI was good (area under the curve [AUC]: 0.856 [0.804-0.909], p < 0.001). rQFR predicted well the incidence of 2-year VOCO after index PCI (AUC: 0.712 [0.555-0.869], p = 0.041), being similar to that of actual post-PCI FFR (AUC: 0.691 [0.512-0.870], p = 0.061). rQFR ≤0.89 was associated with increased risk of 2-year VOCO (hazard ratio [HR]: 12.9 [2.32-71.3], p = 0.0035). This difference was mainly driven by a higher rate of target vessel revascularization (HR: 16.98 [2.33-123.29], p = 0.0051)., Conclusions: rQFR estimated from pre-PCI angiography and virtual coronary stenting mildly overestimated functional benefit of PCI. However, it well predicted suboptimal functional result and long-term vessel-related clinical events., Clinical Trial Registration: Influence of fractional flow reserve on the Clinical OutcomEs of PERcutaneouS Coronary Intervention (COE-PESPECTIVE) Registry, NCT01873560., (© 2022 Wiley Periodicals LLC.)

Background: Understanding sex differences is critical for improving outcomes in patients with cardiovascular conditions. Sleep and psychological disturbances contribute to the development and progression of cardiovascular diseases, and important sex differences persist in their incidence and association with clinical outcomes., Methods: Sex-based variation in sleep and psychological disturbances were assessed in consecutive patients with cardiovascular diseases in a single university hospital. The prevalence of insomnia, sleep disordered breathing (SDB), anxiety, and depression was assessed using the Pittsburgh Sleep Quality Index (PSQI), nocturnal pulse oximeter, and the Hospital Anxiety and Depression Scale (HADS). The effect of sex on the prevalence of sleep and psychological disturbances as well as their associations was quantified using multivariate logistic regression models., Results: Among 1,233 patients (mean age 63.6 years, 25% women), women were significantly less likely than men to experience SDB (17.5% vs 31.5%, p < 0.001), but more likely to report an increased burden of insomnia (54.7% vs 43.3%, p = 0.001) and depression (23.9% vs 16.7%, p = 0.004). Insomnia was associated with depression, which was more remarkable among women (p value for interaction: 0.039). SDB was associated with anxiety among women but not men (p value for interaction: 0.003). There was no significant difference in the prevalence of anxiety between women and men., Conclusions: Among patients with cardiovascular disease, women reported an increased burden of insomnia and depression compared to men. The association between sleep and psychological disturbances may be more pronounced in women, suggesting that cardiologists should increase efforts for identification of such comorbidities and administer corresponding treatment, especially in women., (© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Substantial emotional or physical stress may lead to an imbalance in the brain, resulting in stress cardiomyopathy (SC) and transient left ventricular (LV) apical ballooning. Even though these conditions are severe, their precise underlying mechanisms remain unclear. Appropriate animal models are needed to elucidate the precise mechanisms. In this study, we established a new animal model of epilepsy-induced SC. The SC model showed an increased expression of the acute phase reaction protein, c-Fos, in the paraventricular hypothalamic nucleus (PVN), which is the sympathetic nerve center of the brain. Furthermore, we observed a significant upregulation of neuropeptide Y (NPY) expression in the left stellate ganglion (SG) and cardiac sympathetic nerves. NPY showed neither positive nor negative inotropic and chronotropic effects. On the contrary, NPY could interrupt β-adrenergic signaling in cardiomyocytes when exposure to NPY precedes exposure to noradrenaline. Moreover, its elimination in the left SG via siRNA treatment tended to reduce the incidence of SC. Thus, our results indicated that upstream sympathetic activation induced significant upregulation of NPY in the left SG and cardiac sympathetic nerves, resulting in cardiac dysfunctions like SC., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Arai, Kanazawa, Kimura, Munakata, Yamakawa, Shinmura, Yuasa, Sano and Fukuda.)

Patients infected with the Omicron variant of severe acute respiratory syndrome coronavirus 2 has increased worldwide since the beginning of 2022 and the variant has spread more rapidly than the Delta variant, which spread in the summer of 2021. It is important to clarify the cause of the strong transmissibility of the Omicron variant to control its spread. In 694 patients with coronavirus disease 2019, the copy numbers of virus in nasopharyngeal swab-soaked samples and the viral genotypes were examined using quantitative polymerase chain reaction (PCR) and PCR-based melting curve analysis, respectively. Whole-genome sequencing was also performed to verify the viral genotyping data. There was no significant difference (p = 0.052) in the copy numbers between the Delta variant cases (median 1.5 × 10 5 copies/μl, n = 174) and Omicron variant cases (median 1.2 × 10 5 copies/μl, n = 328). During this study, Omicron BA.1 cases (median 1.1 ×10 5 copies/μl, n = 275) began to be replaced by BA.2 cases (median 2.3 × 10 5 copies/μl, n = 53), and there was no significant difference between the two groups (p = 0.33). Our results suggest that increased infectivity of the Omicron variant and its derivative BA.2 is not caused by higher viral loads but by other factors, such as increased affinity to cell receptors or immune escape., (© 2022 The Authors. Journal of Medical Virology published by Wiley Periodicals LLC.)

Background The implementation of advance care planning (ACP) in heart failure management is insufficient. Social isolation (SI) could be a barrier to ACP initiation, albeit the relationship between SI and patients' preference for ACP or end-of-life care remains unknown. Methods and Results We conducted a questionnaire survey, including assessments of SI using the 6-item Lubben Social Network Scale as well as patients' perspectives on ACP and end-of-life care. Of the 160 patients approached by our multidisciplinary heart failure team during admission, 120 patients (75.0%) completed the survey (median age, 73.0 years; men, 74.2%). A Cox proportional hazard model was constructed to elucidate the short-term (180-day) prognostic impact of SI. Overall, 28.3% of participants were at high risk for SI (6-item Lubben Social Network Scale score <12). High-risk patients had more negative attitudes toward ACP than those without (61.8% versus 80.2%; P =0.035). The actual performance of ACP conversation in patients with and without high risk were 20.6% and 30.2%, respectively. Regarding preference in end-of-life care, "Saying what one wants to tell loved ones" (73.5% versus 90.6%; P =0.016) and "Spending enough time with family" (58.8% versus 77.9%; P =0.035) were less important in high-risk patients. High risk for SI was associated with higher 180-day risk-adjusted all-cause mortality (hazard ratio, 7.89 [95% CI, 1.53-40.75]). Conclusions In hospitalized patients with heart failure, high risk for SI was frequently observed. High-risk patients were associated with a negative attitude toward ACP, despite higher mortality. Further research is required to establish an ideal approach to provide ACP in socially vulnerable patients.

Objective: A novel artificial intelligence-based phenotyping approach to stratify patients with severe aortic stenosis (AS) prior to transcatheter aortic valve replacement (TAVR) has been proposed, based on echocardiographic and haemodynamic data. This study aimed to analyse the recovery of extra-aortic valve cardiac damage in accordance with this novel stratification system following TAVR., Methods: The proposed phenotyping approach was previously established employing data from 366 patients with severe AS from a bicentric registry. For this consecutive study, echocardiographic follow-up data, obtained on day 147±75.1 after TAVR, were available from 247 patients (67.5%)., Results: Correction of severe AS by TAVR significantly reduced the proportion of patients suffering from concurrent severe mitral regurgitation (from 9.29% to 3.64%, p value: 0.0015). Moreover, pulmonary artery pressures were ameliorated (estimated systolic pulmonary artery pressure: from 47.2±15.8 to 43.3±15.1 mm Hg, p value: 0.0079). However, right heart dysfunction as well as the proportion of patients with severe tricuspid regurgitation remained unchanged. Clusters with persistent right heart dysfunction ultimately displayed 2-year survival rates of 69.2% (95% CI 56.6% to 84.7%) and 74.6% (95% CI 65.9% to 84.4%), which were significantly lower compared with clusters with little or no persistent cardiopulmonary impairment (88.3% (95% CI 83.3% to 93.5%) and 85.5% (95% CI 77.1% to 94.8%))., Conclusions: This phenotyping approach preprocedurally identifies patients with severe AS, who will not recover from extra-aortic valve cardiac damage following TAVR and whose survival is therefore significantly reduced. Importantly, not the degree of pulmonary hypertension at initial presentation, but the irreversibility of right heart dysfunction determines prognosis., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: The relationship between the white-coat effect (WCE), defined as white-coat hypertension under treatment, and the frequency of orthostatic hypotension (OH) is not known. We conducted an orthostatic test in patients with WCE to determine the frequency of OH., Methods: This was a cross-sectional study of 5631 patients with hypertension visiting general practitioners nationwide, in which 4305 patients with hypertension recorded their home blood pressure (BP) and consented to the orthostatic test. Patients with hypertension were divided into four groups: controlled hypertension (CHT), masked hypertension (MHT), sustained hypertension (SHT), and WCE. The orthostatic test was performed, and BP and pulse rate were measured immediately and 1 min after orthostasis., Results: The OH frequencies immediately after standing in CHT, WCE, SHT, and MHT patients were 7, 11.7, 12.1, and 6.6%, respectively, and those at 1 min after standing were 7.1, 13.1, 11.6 and 6.9%, respectively (Chi-square test, P < 0.01, respectively). Logistic regression analysis was performed to examine the relationship between WCE and the frequency of OH. The frequency of OH immediately after standing was significantly increased [adjusted odds ratio (AOR), 1.702; 95% confidence interval (CI), 1.246-2.326; P < 0.01]. The frequency of OH at 1 min after standing was also significantly higher (AOR, 1.897; 95% CI, 1.396-2.578; P < 0.01)., Conclusion: When the standing test was performed for patients with WCE, the frequency of OH increased. Thus, it is important to recognize the possibility of OH in patients with WCE to avoid adverse events associated with excessive hypotension., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Failure of the right ventricle plays a critical role in any type of heart failure. However, the mechanism remains unclear, and there is no specific therapy. Here, we show that the right ventricle predominantly expresses alternative complement pathway-related genes, including Cfd and C3aR1. Complement 3 (C3)-knockout attenuates right ventricular dysfunction and fibrosis in a mouse model of right ventricular failure. C3a is produced from C3 by the C3 convertase complex, which includes the essential component complement factor D (Cfd). Cfd-knockout mice also show attenuation of right ventricular failure. Moreover, the plasma concentration of CFD correlates with the severity of right ventricular failure in patients with chronic right ventricular failure. A C3a receptor (C3aR) antagonist dramatically improves right ventricular dysfunction in mice. In summary, we demonstrate the crucial role of the C3-Cfd-C3aR axis in right ventricular failure and highlight potential therapeutic targets for right ventricular failure., (© 2022. The Author(s).)

Sleep disorders and sleep duration have attracted considerable attention as potential modifiable risk factors for the development and progression of heart failure (HF). However, whether these sleep behaviors could aggravate the underlying cardiac condition remains ambiguous. We evaluated the associations between the levels of plasma B-type natriuretic peptide (BNP) and sleep-disordered breathing (SDB), sleep quality and quantity, or daytime sleepiness in cardiovascular diseases (CVD) patients. A total of 1717 consecutive patients with CVD [median age, 66 years (55-74 years); female, 27.5%] were enrolled. SDB was screened by nocturnal pulse oximetry; sleep quality and quantity were determined by Pittsburg Sleep Quality Index, and daytime sleepiness was examined by Epworth Sleepiness Scale. The median plasma BNP level was 54.9 pg/ml (23.5-146.4 pg/ml). Multiple regression analyses showed that the BNP level in the highest quintile (BNP > 181.8 pg/ml) was associated with SDB (severe: OR, 5.88; 95% CI 3.17-10.88; moderate: OR, 3.62; 95% CI 2.17-6.02; mild: OR, 2.22: 95% CI 1.42-3.47). There were no significant associations between other sleep parameters and higher BNP levels. The relationship between SDB and BNP levels was unchanged regardless of the previous history of symptomatic HF. SDB was independently associated with the elevated plasma BNP level in patients with a variety of CVD., (© 2021. Springer Japan KK, part of Springer Nature.)

Cardiovascular disease (CVD) is a major global health concern. Several therapeutic strategies for CVDs are available, such as medicine, cardiac assist devices, and heart transplantation. However, they are insufficient for the treatment of severe CVD. To develop novel, innovative treatment approaches for CVDs, it is imperative to understand the underlying pathophysiology and to undertake basic research on this facet. The generation of induced pluripotent stem (iPS) cells has opened avenues for developing new strategies for disease analysis and drug development. This technology has made it possible to obtain pluripotent stem cells from patients with genetic disorders, model the disease in a dish, and use such cells for future regeneration therapy. Meanwhile, artificial intelligence (AI), which is widely used for big data analysis in basic research, has potential in various applications in medicine. New tools such as iPS cells and AI can provide much needed novel insights into CVDs. This review focuses on the recent progress in cardiovascular research using these new technologies.

Induced pluripotent stem cells (iPSCs) are terminally differentiated somatic cells that differentiate into various cell types. iPSCs are expected to be used for disease modeling and for developing novel treatments because differentiated cells from iPSCs can recapitulate the cellular pathology of patients with genetic mutations. However, a barrier to using iPSCs for comprehensive drug screening is the difficulty of evaluating their pathophysiology. Recently, the accuracy of image analysis has dramatically improved with the development of artificial intelligence (AI) technology. In the field of cell biology, it has become possible to estimate cell types and states by examining cellular morphology obtained from simple microscopic images. AI can evaluate disease-specific phenotypes of iPS-derived cells from label-free microscopic images; thus, AI can be utilized for disease-specific drug screening using iPSCs. In addition to image analysis, various AI-based methods can be applied to drug development, including phenotype prediction by analyzing genomic data and virtual screening by analyzing structural formulas and protein-protein interactions of compounds. In the future, combining AI methods may rapidly accelerate drug discovery using iPSCs. In this review, we explain the details of AI technology and the application of AI for iPSC-based drug screening.

Aims: Hypothesizing that aortic outflow velocity profiles contain more valuable information about aortic valve obstruction and left ventricular contractility than can be captured by the human eye, features of the complex geometry of Doppler tracings from patients with severe aortic stenosis (AS) were extracted by a convolutional neural network (CNN)., Methods and Results: After pre-training a CNN (VGG-16) on a large data set (ImageNet data set; 14 million images belonging to 1000 classes), the convolutional part was employed to transform Doppler tracings to 1D arrays. Among 366 eligible patients [age: 79.8 ± 6.77 years; 146 (39.9%) women] with pre-procedural echocardiography and right heart catheterization prior to transcatheter aortic valve replacement (TAVR), good quality Doppler tracings from 101 patients were analysed. The convolutional part of the pre-trained VGG-16 model in conjunction with principal component analysis and k-means clustering distinguished two shapes of aortic outflow velocity profiles. Kaplan-Meier analysis revealed that mortality in patients from Cluster 2 ( n = 40, 39.6%) was significantly increased [hazard ratio (HR) for 2-year mortality: 3; 95% confidence interval (CI): 1-8.9]. Apart from reduced cardiac output and mean aortic valve gradient, patients from Cluster 2 were also characterized by signs of pulmonary hypertension, impaired right ventricular function, and right atrial enlargement. After training an extreme gradient boosting algorithm on these 101 patients, validation on the remaining 265 patients confirmed that patients assigned to Cluster 2 show increased mortality (HR for 2-year mortality: 2.6; 95% CI: 1.4-5.1, P -value: 0.004)., Conclusion: Transfer learning enables sophisticated pattern recognition even in clinical data sets of limited size. Importantly, it is the left ventricular compensation capacity in the face of increased afterload, and not so much the actual obstruction of the aortic valve, that determines fate after TAVR., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology.)

The rapid spread of the Delta variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) became a serious concern worldwide in summer 2021. We examined the copy number and variant types of all SARS-CoV-2-positive patients who visited our hospital from February to August 2021 using polymerase chain reaction (PCR) tests. Whole genome sequencing was performed for some samples. The R.1 variant (B.1.1.316) was responsible for most infections in March, replacing the previous variant (B.1.1.214); the Alpha (B.1.1.7) variant caused most infections in April and May; and the Delta variant (B.1.617.2) was the most prevalent in July and August. There was no significant difference in the copy numbers among the previous variant cases (n = 29, median 3.0 × 10 4 copies/µl), R.1 variant cases (n = 28, 2.1 × 10 5 copies/µl), Alpha variant cases (n = 125, 4.1 × 10 5 copies/µl), and Delta variant cases (n = 106, 2.4 × 10 5 copies/µl). Patients with Delta variant infection were significantly younger than those infected with R.1 and the previous variants, possibly because many elderly individuals in Tokyo were vaccinated between May and August. There was no significant difference in mortality among the four groups. Our results suggest that the increased infectivity of Delta variant may be caused by factors other than the higher viral loads. Clarifying these factors is important to control the spread of Delta variant infection., (© 2021 Wiley Periodicals LLC.)