A unique cuff-sewing method to implant heartmate3 LVAD for arrhythmogenic right ventricular cardiomyopathy, facilitated by 3D-printing heart model.

Implantation of left ventricular assist device (LVAD) for arrhythmogenic right ventricular (RV) cardiomyopathy is challenging associated with small LV cavity, laterally dislocated LV apex, thin and fragile RV free wall. A 43-year-old male with more than 10 years of medical treatment developed congestive heart failure related to biventricular failure. Durable LVAD was indicated to prevent further deterioration of the RV function, which would be exacerbated by progression of LV dysfunction. To simulate surgery, we printed-out a 3D heart model based on enhanced CT scanning study to identify the optimal coring position in the LV apex, by which the inflow directs the mitral valve. We then found that the mini-cuff of the HeartMate3 should be fixed in the paper-thin RV free wall by the usual cuff-sewing method. In the surgery, after the coring as planned, 5 pairs of interrupted sutures on the medial side were passed from the luminal side of the LV and then to the mini-cuff, and the lateral side of the mini-cuff was fixed with a continuous sutures, not to sew into the RV wall. The surgery was completed without complications with a good hemodynamics. The 3D heart model facilitated this unique method, indicating a usefulness of printed-out heart model for cases with unusual cardiac anatomy, which needs implantation of durable LVAD.

Thyrotropin-secreting pituitary adenomas induce left atrial enlargement with subclinical atrial fibrillation: an echocardiographic study.

PURPOSE: Thyrotropin-secreting pituitary adenoma (TSHoma) is rare but occasionally causes cardiovascular complications such as atrial fibrillation (AF) due to hyperthyroidism. Graves' disease (GD) is a common hyperthyroid condition often associated with subclinical AF. Some reports have shown echocardiographic changes in patients with GD. We aimed to evaluate the preoperative cardiac function in patients with TSHomas and compared the results among patients with TSHomas and GD and control subjects. METHODS: Patients with TSHomas (n = 6) and GD (n = 20) were compared with control subjects with normal cardiac function (n = 20) based on echocardiographic findings. The average age, sex, and proportions of patients with a history of diabetes mellitus and hypertension were equal in each group, and the AF prevalence was matched in patients with TSHomas and GD. The values of left ventricular end-diastolic diameter (LVEDd), left ventricular end-systolic diameter (LVEDs), left ventricular ejection fraction (LVEF), and left atrial diameter (LAD) were used to assess cardiac function. RESULTS: In echocardiography, LAD showed a significant difference between patients with TSHomas and control subjects (p = 0.026). The mean LAD values were 36.9 ± 7.1, 38.2 ± 8.9, and 28.7 ± 3.9 mm for patients with TSHomas and GD and control subjects, respectively. There were no significant differences in other echocardiographic parameters among the groups. Before treatment, serum thyroid hormone levels (free triiodothyronine and thyroxin) were not significantly different among patients with TSHomas and GD. CONCLUSION: We found that patients with TSHomas or GD had enlarged LADs. This finding suggests that AF may be more hidden in patients with TSHomas than previously reported.

Everolimus-Eluting Biodegradable Abluminal Coating Stent versus Durable Conformal Coating Stent: Termination of the Inflammatory Response Associated with Neointimal Healing in a Porcine Coronary Model.

OBJECTIVES: We evaluated the effect of the different carrier systems on early vascular response through histological analysis and scanning electron microscopy using a porcine model. BACKGROUND: Although Synergy™ and Promus PREMIER™ share an identical stent material and drug elution (everolimus), they use different drug carrier systems: biodegradable abluminal coating polymer or durable conformal coating polymer, respectively. However, data regarding the impact of the different coating systems on vessel healing are currently limited. METHODS: Twelve Synergy™ and Promus PREMIER™ were implanted in 12 swine. Histopathological analysis of the stented segments was performed on the 2nd and 14th days after implantation. Morphometric analysis of the inflammation and intimal fibrin content was also performed. RESULTS: On the 2nd day, neointimal thickness, percentage of neointimal area, and inflammatory and intimal fibrin content scores were not significantly different between the two groups. On the 14th day, the inflammatory and intimal fibrin content scores were significantly lower in Synergy™ versus those observed in Promus PREMIER™. In Synergy™, smooth muscle cells were found and the neointimal layers were smooth. In contrast, inflammatory cells were observed surrounding the struts of Promus PREMIER™. CONCLUSIONS: These results demonstrate that termination of reactive inflammation is accelerated after abluminal coating stent versus implantation of conformal coating stent.

Acute myocardial infarction in a patient positive for lupus anticoagulant: a case report.

BACKGROUND: Autoimmune diseases, such as systemic lupus erythematosus (SLE), are associated with thrombosis and atherosclerosis. Presence of lupus anticoagulant is an independent risk factor for atherosclerotic diseases. CASE PRESENTATION: A 56-year-old man with past history of hypertension, and cerebral infarction was admitted to our hospital owing to acute chest pain. He was diagnosed with acute myocardial infarction based on his symptoms and electrocardiogram results, which demonstrated ST elevation in the precordial leads. Coronary angiography images revealed total occlusion at the proximal site of the left anterior descending artery. A drug-eluting stent was deployed, which successfully recovered coronary blood flow. The patient had fever of unknown cause when he was 30 years old; on admission, he presented with a low-grade fever and reddish exanthema affecting both cheeks. Based on his physical signs as well as elevated antinuclear antibodies (anti-double-stranded DNA), decreased lymphocytes, and a positive direct Coombs test, he was diagnosed with SLE. Owing to a positive lupus anticoagulant test, he was also suspected to have antiphospholipid syndrome (APS). Triple antithrombotic therapy, including dual antiplatelet therapy with aspirin and clopidogrel during coronary stenting and single anticoagulation therapy with warfarin, was initiated. CONCLUSIONS: Careful diagnosis of autoimmune diseases should be performed in patients with thrombosis and atherosclerosis. Moreover, risk factors for coronary artery disease should be strictly controlled in patients with APS.

Effects of prehospital epinephrine administration on neurologically intact survival in bystander-witnessed out-of-hospital cardiac arrest patients with non-shockable rhythm depend on prehospital cardiopulmonary resuscitation duration required to hospital arrival.

The effects of prehospital epinephrine administration on post-arrest neurological outcome in out-of-hospital cardiac arrest (OHCA) patients with non-shockable rhythm remain unclear. To examine the time-dependent effectiveness of prehospital epinephrine administration, we analyzed 118,396 bystander-witnessed OHCA patients with non-shockable rhythm from the prospectively recorded all-Japan OHCA registry between 2011 and 2014. Patients who achieved prehospital return of spontaneous circulation without prehospital epinephrine administration were excluded. Patients with prehospital epinephrine administration were stratified according to the time from the initiation of cardiopulmonary resuscitation (CPR) by emergency medical service (EMS) providers to the first epinephrine administration (≤ 10, 11-19, and ≥ 20 min). Patients without prehospital epinephrine administration were stratified according to the time from CPR initiation by EMS providers to hospital arrival (≤ 10, 11-19, and ≥ 20 min). The primary outcome was 1-month neurologically intact survival (cerebral performance category 1 or 2; CPC 1-2). Multivariate logistic regression analysis demonstrated that there was no significant difference in the chance of 1-month CPC 1-2 between patients who arrived at hospital in ≤ 10 min without prehospital epinephrine administration and patients with time to epinephrine administration ≤ 19 min. However, compared to patients who arrived at hospital in ≤ 10 min without prehospital epinephrine administration, patients with time to epinephrine administration ≥ 20 min and patients who arrived at hospital in 11-19, and ≥ 20 min without prehospital epinephrine administration were significantly associated with decreased chance of 1-month CPC 1-2 (p < 0.05, < 0.05, and < 0.001, respectively). In conclusion, when prehospital CPR duration from CPR initiation by EMS providers to hospital arrival estimated to be ≥ 11 min, prehospital epinephrine administered ≤ 19 min from CPR initiation by EMS providers could improve neurologically intact survival in bystander-witnessed OHCA patients with non-shockable rhythm.

Application of an enhanced device to transluminal retrieval of malappositioned coronary stents: An experimental study.

OBJECTIVES: This study investigated the application of a novel enhanced device to retrieval of deployed stents in a porcine coronary model. BACKGROUND: Recurrence of in-stent restenosis and stent thrombosis still remains to be resolved. Under these conditions, it is sometimes necessary to retrieve malfunctional stents responsible for thrombosis. However, few data exist regarding the feasibility and safety of retrieval device use in previously deployed coronary stents. METHODS: We have developed an enhanced device consisting of an asymmetric forceps, conducting shaft (1.6 mm diameter, 150 cm length), and control handle. Bare-metal stents (3 mm diameter) were implanted in four pigs to create a malapposition model. Coronary artery injury was evaluated by intravascular ultrasound (IVUS) and histological imaging on the first and 14th days. RESULTS: The device was delivered to the coronary artery using the existing catheter (7 Fr). After opening the forceps, the blade was forced into the space between the vessel wall and the stent, and the stent struts were then grasped with the forceps. This was then pulled back into the catheter, still grasping the stent struts with the forceps. All stents were successfully retrieved by this method (n = 4). On the first day, no apparent vessel wall injury was detectable by IVUS, although histological findings revealed damage to endothelial monolayer on retrieval of deployed stent. On the 14th day, mild intimal thickening was observed by IVUS and histology. CONCLUSIONS: These results demonstrate that the present device can be applied to transluminal retrieval of acquired malappositioned coronary stents.

Age-Specific Differences in the Duration of Prehospital Cardiopulmonary Resuscitation Administered by Emergency Medical Service Providers Necessary to Achieve Favorable Neurological Outcome After Out-of-Hospital Cardiac Arrest.

BACKGROUND: The appropriate duration of prehospital cardiopulmonary resuscitation (CPR)administered by emergency medical service (EMS) providers for patients with out-of-hospital cardiac arrest (OHCA) necessary to achieve 1-month survival with favorable neurological outcome (Cerebral Performance Category 1 or 2, CPC 1-2) is unclear and could differ by age.Methods and Results:We analyzed the records of 35,709 adult OHCA patients with return of spontaneous circulation (ROSC) before hospital arrival in a prospectively recorded Japanese registry between 2011 and 2014. The CPR duration was defined as the time from CPR initiation by EMS providers to prehospital ROSC. The rate of 1-month CPC 1-2 was 21.4% (7,650/35,709). The CPR duration was independently and inversely associated with 1-month CPC 1-2 (adjusted odds ratio, 0.93 per 1-min increment; 95% confidence interval, 0.93-0.94). The CPR duration increased with age (P<0.001). However, the CPR duration beyond which the proportion of OHCA patients with 1-month CPC 1-2 decreased to <1% declined with age: 28 min for patients aged 18-64 years, 25 min for 65-74 years, 23 min for 75-84 years, 20 min for 85-94 years, and 18 min for ≥95 years. CONCLUSIONS: In patients who achieved prehospital ROSC after OHCA, the duration of CPR administered by EMS providers necessary to achieve 1-month CPC 1-2 varied by age.

Early endothelialization associated with a biolimus A9 bioresorbable polymer stent in a porcine coronary model.

Although Nobori®, with a bioresorbable polymer and biolimus A9 abluminal coating, has unique characteristics, few data exist regarding endothelialization early after implantation. Fifteen Nobori® and 14 control bare-metal stents (S-stent™) were implanted in 12 pigs. Histopathology of stented segments, inflammation, and intimal fibrin content was evaluated on the 2nd and 14th day after implantation. On the 2nd day, endothelial cells were morphologically and immunohistologically confirmed on the surface of both stents, although some inflammatory cells might be involved. Stent surface endothelialization evaluated with a scanning electron microscope showed partial cellular coverage in both stents. On the 14th day, neointimal thickness and percentage of the neointimal area were significantly lower in Nobori® than in S-stent™ (51.4 ± 4.5 vs. 76.4 ± 23.6 µm, p < 0.05 and 10.8 ± 2.6 vs. 14.1 ± 4.2%, p < 0.01). No significant differences were found in these parameters on the 2nd day (17.3 ± 14.9 vs. 26.7 ± 13.6 µm and 3.7 ± 3.0 vs. 6.7 ± 3.7%), in inflammatory and intimal fibrin content scores. These results demonstrate that endothelialization could occur early after Nobori® implantation with similar inflammatory reaction to bare-metal stents, probably contributing to low frequency of in-stent thrombosis and restenosis.

Short- and long-term benefits of drug-eluting stents compared to bare metal stents even in treatment for large coronary arteries.

Although drug-eluting stents (DES) for percutaneous coronary intervention (PCI) have dramatically reduced the incidence of in-stent restenosis, their deployment for large-size coronary lesions is still controversial because of problems such as late in-stent thrombosis and late catch-up in DES. We aimed to evaluate the long-term outcome beyond 2 years of bare metal stents (BMS) as compared with DES in large vessels. Consecutive 228 patients who underwent PCI with large-size stents (>3.5 mm in diameter) in our hospital were enrolled in this study. The end points of this study are target lesion revascularization (TLR) and occurrence of major adverse cardiac events (MACE) for subject patients. We analyzed 183 patients (152 men, mean age 65.8 ± 10.5 years) whose outcome could be followed up for at least 2 years. At the first 8-month follow-up, clinically driven TLR rate was significantly higher in patients who received BMS than those who received DES (17.2 vs. 2.2 %, p < 0.05), although the rate of TLR was not different between the 2 groups beyond 8 months. Thus, overall rate of TLR was higher in BMS than in DES (22.7 vs. 5.4 %, p < 0.05). Under these conditions, the higher rate of TLR for BMS was observed in simple as well as complex lesions with or without diabetes, although there were no significant differences in MACE between BMS and DES. Multivariate analysis showed that BMS was an only independent factor of TLR at the 8 month follow-up period [p = 0.004, odds ratio 9.58, 95 % confidence interval (2.10-43.8)]. These results demonstrate that the rate of in-stent restenosis in large-size coronary lesions was transiently higher in the first 8 months for patients implanted with BMS compared with DES in which no in-stent thrombosis and TLR beyond 2 years were observed. We suggest using the DES even in large-size coronary lesions in terms of short- and long-term outcomes.

Analysis of cardiomyocyte movement in the developing murine heart.

The precise assemblage of several types of cardiac precursors controls heart organogenesis. The cardiac precursors show dynamic movement during early development and then form the complicated heart structure. However, cardiomyocyte movements inside the newly organized mammalian heart remain unclear. We previously established the method of ex vivo time-lapse imaging of the murine heart to study cardiomyocyte behavior by using the Fucci (fluorescent ubiquitination-based cell cycle indicator) system, which can effectively label individual G1, S/G2/M, and G1/S-transition phase nuclei in living cardiomyocytes as red, green, and yellow, respectively. Global analysis of gene expression in Fucci green positive ventricular cardiomyocytes confirmed that cell cycle regulatory genes expressed in G1/S, S, G2/M, and M phase transitions were upregulated. Interestingly, pathway analysis revealed that many genes related to the cell cycle were significantly upregulated in the Fucci green positive ventricular cardiomyocytes, while only a small number of genes related to cell motility were upregulated. Time-lapse imaging showed that murine proliferating cardiomyocytes did not exhibit dynamic movement inside the heart, but stayed on site after entering the cell cycle.

Impact of Enhanced Production of Endogenous Heme Oxygenase-1 by Pitavastatin on Survival and Functional Activities of Bone Marrow-derived Mesenchymal Stem Cells.

Although mesenchymal stem cells (MSCs) have a therapeutic potential for the repair of tissue injuries, their poor viability in damaged tissue limits their effectiveness. Statins can induce an increased production of heme oxygenase-1 (HO-1), which may prevent this detrimental effect in MSCs. We investigated the protective effect of statin-induced overexpression of HO-1 by examining changes in gene expression and function in MSCs after pitavastatin treatment. The relative expression of the HO-1 and endothelial nitric oxide synthase genes in MSCs was significantly increased after treatment with pitavastatin (MSCs). Immunocytological analysis showed that MSCs also stained with phospho-Akt. After exposure to oxidative stress, MSCs showed increased resistance to induced cell death compared with control MSCs. Under serum starvation conditions, MSCs treated with 1 µM pitavastatin showed enhanced cell proliferation and a marked increase in vascular endothelial growth factor production compared with control MSCs. Interestingly, MSCs showed enhanced tube formation under both normoxia and hypoxia. These results demonstrate that pitavastatin can enhance endogenous HO-1 expression in MSCs, which may protect the cells into the environment of oxidative stress with partial activation of endothelial nitric oxide synthase and Akt phosphorylation.

Effectiveness of Additional Immunosuppressive Drugs for Corticosteroid-refractory Immune Checkpoint Inhibitor-induced Myocarditis: Two Case Reports.

Immune checkpoint inhibitors (ICIs) improve the outcomes of several types of cancer. However, they are also associated with various immune-related adverse events including myocarditis. ICI-induced myocarditis is a rare, potentially life-threatening adverse event. We herein report two cases of corticosteroid-refractory ICI-induced myocarditis. In both cases, additional immunosuppressive therapies, such as intravenous immunoglobulin and tacrolimus, successfully resolved myocarditis. Given the corticosteroid-refractory nature of these cases, we suggest that prompt addition of other immunosuppressive drugs to corticosteroid therapy should be considered in the treatment of ICI-induced myocarditis.

Successful echocardiography-guided medical management of severe early post-implant right ventricular failure in a patient with left ventricular assist device support: a case report.

BACKGROUND: Post-implant right heart failure (RHF) has been recognized as a crucial prognostic factor in patients receiving left ventricular assist devices (LVADs), and its management has long attracted attention from cardiologists and surgeons. CASE PRESENTATION: This report described an 18-year-old female with acutely deteriorating heart failure due to dilated cardiomyopathy who underwent paracorporeal pulsatile-flow LVAD and developed early post-implant RHF. At postoperative day (POD) six, she was almost asymptomatic at rest on 2.5 mg/kg/min of dobutamine; however, the echocardiogram, performed as part of the daily postoperative care, revealed a severely enlarged right ventricle with a decompressed left ventricle, implying the development of post-implant RHF. Bolus infusion of saline and reduction of pump flow (6.0 L/min to 3.0 L/min) led to normalization of both ventricular shapes in 30 s, suggesting that RHF could be managed without surgical interventions. Milrinone was started on POD six, followed by sildenafil administration on POD seven. Fluid balance was strictly adjusted under the close observation of daily echocardiograms. Milrinone and dobutamine were discontinued on PODs 18 and 21, respectively. The patient was listed for a heart transplant on POD 40. Despite reduced right ventricular function (right ventricular stroke work index of 182.34 mmHg*ml/m- 2, body surface area 1.5 m2), she was successfully converted to implantable LVAD on POD 44 with no recurrence of post-implant RHF thereafter for four years. CONCLUSIONS: In post-implant RHF management, early detection, together with proper and prompt medical management, is crucial to avoiding any surgical intervention. Close observation of daily echocardiograms might be helpful in detecting subclinical RHF and is useful for post-implant medical management.

Efficacy of catheter cleaning methods using intravenous indwelling catheter, 10% silver nitrate solution and a monofilament nylon thread for deeply progressed superficial driveline infections: case series.

Driveline infection (DLI) is treated by local irrigation via driveline exit site (DLES) and surgical debridement is considered in patients with deep DLI. We describe three cases of deeply progressed superficial DLI that were considered to require surgical debridement but could be treated with a unique catheter cleaning method using intravenous indwelling catheter, a cotton swab with 10% silver nitrate solution and a monofilament nylon thread. Case 1 was a 60-y-old man with ischemic cardiomyopathy with left ventricular assist device implantation 2 y before. Daily bedside debridement with 10% silver nitrate solution was performed via the DLES. Case 2 was a 43-y-old man with ischemic cardiomyopathy who had recurrent DLI with methicillin-resistant Staphylococcus aureus, and case 3 was a 49-y-old woman with hypertrophic cardiomyopathy, who also showed improvement in their DLI with Pseudomonas aeruginosa. These cleaning methods may be useful for the deeply progressed superficial DLI.

The complement C3-complement factor D-C3a receptor signalling axis regulates cardiac remodelling in right ventricular failure.

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.

Congestive heart failure associated with POEMS syndrome that was adequately distinguished from cardiac amyloidosis: a case report and literature review.

Congestive heart failure (CHF) is a common complication in patients with AL amyloidosis but is rare in another plasma cell dyscrasia, POEMS syndrome. A 52-year-old man developed POEMS syndrome with a solitary plasmacytoma complicated by CHF mimicking cardiac amyloidosis (CA). His neurological symptoms and CHF did not improve after radiotherapy (50 Gy) targeting the plasmacytoma. Based on typical findings of noninvasive examinations such as elevated serum NT-proBNP (12,631 pg/mL), a pseudo-infarct pattern on electrocardiography, interventricular septal thickening with a granular sparkling appearance and an apical sparing pattern of longitudinal strain on echocardiography, and late gadolinium enhancement of the left ventricular wall on cardiac magnetic resonance imaging (MRI), severe CA ineligible for autologous peripheral blood stem cell transplantation (auto-PBSCT) was strongly suspected. However, myocardial biopsy failed to reveal amyloid deposits, and CHF markedly improved after only one cycle of chemotherapy with melphalan and dexamethasone. Accordingly, CA was denied as the etiology of his heart failure, and the patient was finally diagnosed with POEMS syndrome. As a result, high-dose melphalan followed by auto-PBSCT improved his neurological symptoms. Careful evaluation is therefore needed to appropriately treat patients with POEMS syndrome complicated by CHF, even when the results of non-invasive examinations are typical for AL amyloidosis.

Circulating nerve growth factor receptor positive cells are associated with severity and prognosis of pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) remains a disease with a poor prognosis, so early detection and treatment are very important. Sensitive and non-invasive markers for PAH are urgently required. This study was performed to identify sensitive markers of the clinical severity and prognosis of PAH. Patients diagnosed with PAH (n = 30) and control participants (n = 15) were enrolled in this observational study. Major EPC and MSC markers (including CD34, CD133, VEGFR2, CD90, PDGFRα, and NGFR) in peripheral blood mononuclear cells (PBMNCs) were assessed by flow cytometry. Associations of these markers with hemodynamic parameters (e.g. mean pulmonary arterial pressure, pulmonary vascular resistance, and cardiac index) were assessed. Patients with PAH were followed up for 12 months to assess the incidence of major adverse events, defined as death or lung transplantation. Levels of circulating EPC and MSC markers in PBMNCs were higher in patients with PAH than in control participants. Among the studied markers, nerve growth factor receptor (NGFR) was significantly positively correlated with hemodynamic parameters. During the 12-month follow-up period, major-event-free survival was significantly higher in patients with PAH who had relatively low frequencies of NGFR positive cells than patients who had higher frequencies. These results suggested that the presence of circulating NGFR positive cells among PBMNCs may be a novel biomarker for the severity and prognosis of PAH.

Early Detection of Symptom Exacerbation in Patients With SARS-CoV-2 Infection Using the Fitbit Charge 3 (DEXTERITY): Pilot Evaluation.

BACKGROUND: Some patients with COVID-19 experienced sudden death due to rapid symptom deterioration. Thus, it is important to predict COVID-19 symptom exacerbation at an early stage prior to increasing severity in patients. Patients with COVID-19 could experience a unique "silent hypoxia" at an early stage of the infection when they are apparently asymptomatic, but with rather low SpO2 (oxygen saturation) levels. In order to continuously monitor SpO2 in daily life, a high-performance wearable device, such as the Apple Watch or Fitbit, has become commercially available to monitor several biometric data including steps, resting heart rate (RHR), physical activity, sleep quality, and estimated oxygen variation (EOV). OBJECTIVE: This study aimed to test whether EOV measured by the wearable device Fitbit can predict COVID-19 symptom exacerbation. METHODS: We recruited patients with COVID-19 from August to November 2020. Patients were asked to wear the Fitbit for 30 days, and biometric data including EOV and RHR were extracted. EOV is a relative physiological measure that reflects users' SpO2 levels during sleep. We defined a high EOV signal as a patient's oxygen level exhibiting a significant dip and recovery within the index period, and a high RHR signal as daily RHR exceeding 5 beats per day compared with the minimum RHR of each patient in the study period. We defined successful prediction as the appearance of those signals within 2 days before the onset of the primary outcome. The primary outcome was the composite of deaths of all causes, use of extracorporeal membrane oxygenation, use of mechanical ventilation, oxygenation, and exacerbation of COVID-19 symptoms, irrespective of readmission. We also assessed each outcome individually as secondary outcomes. We made weekly phone calls to discharged patients to check on their symptoms. RESULTS: We enrolled 23 patients with COVID-19 diagnosed by a positive SARS-CoV-2 polymerase chain reaction test. The patients had a mean age of 50.9 (SD 20) years, and 70% (n=16) were female. Each patient wore the Fitbit for 30 days. COVID-19 symptom exacerbation occurred in 6 (26%) patients. We were successful in predicting exacerbation using EOV signals in 4 out of 5 cases (sensitivity=80%, specificity=90%), whereas the sensitivity and specificity of high RHR signals were 50% and 80%, respectively, both lower than those of high EOV signals. Coincidental obstructive sleep apnea syndrome confirmed by polysomnography was detected in 1 patient via consistently high EOV signals. CONCLUSIONS: This pilot study successfully detected early COVID-19 symptom exacerbation by measuring EOV, which may help to identify the early signs of COVID-19 exacerbation. TRIAL REGISTRATION: University Hospital Medical Information Network Clinical Trials Registry UMIN000041421; https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000047290.

Hokuriku-plus familial hypercholesterolaemia registry study: rationale and study design.

INTRODUCTION: Familial hypercholesterolaemia (FH) is an autosomal-dominant inherited genetic disease. It carries an extremely high cardiovascular risk associated with significantly elevated low-density lipoprotein (LDL) cholesterol. The diagnostic rate of this disease in some European nations is quite high, due to the presence of multiple prospective registries. On the other hand, few data-and in particular multicentre data-exist regarding this issue among Japanese subjects. Therefore, this study intends to assemble a multicentre registry that aims to comprehensively assess cardiovascular risk among Japanese FH patients while taking into account their genetic backgrounds. METHODS AND ANALYSIS: The Hokuriku-plus FH registry is a prospective, observational, multicentre cohort study, enrolling consecutive FH patients who fulfil the clinical criteria of FH in Japan from 37 participating hospitals mostly in Hokuriku region of Japan from April 2020 to March 2024. A total of 1000 patients will be enrolled into the study, and we plan to follow-up participants over 5 years. We will collect clinical parameters, including lipids, physical findings, genetic backgrounds and clinical events covering atherosclerotic and other important events, such as malignancies. The primary endpoint of this study is new atherosclerotic cardiovascular disease (ASCVD) events. The secondary endpoints are as follows: LDL cholesterol, secondary ASCVD events and the occurrence of other diseases including hypertension, diabetes and malignancies. ETHICS AND DISSEMINATION: This study is being conducted in compliance with the Declaration of Helsinki, the Ethical Guidelines for Medical and Health Research Involving Human Subjects, and all other applicable laws and guidelines in Japan. This study protocol has been approved by the Institutional Review Board at Kanazawa University. We will disseminate the final results at international conferences and in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: UMIN000038210.

Function and Immunogenicity of Gene-corrected iPSC-derived Hepatocyte-Like Cells in Restoring Low Density Lipoprotein Uptake in Homozygous Familial Hypercholesterolemia.

Gene correction of induced pluripotent stem cells (iPSCs) has therapeutic potential for treating homozygous familial hypercholesterolemia (HoFH) associated with low-density lipoprotein (LDL) receptor (LDLR) dysfunction. However, few data exist regarding the functional recovery and immunogenicity of LDLR gene-corrected iPSC-derived hepatocyte-like cells (HLCs) obtained from an HoFH patient. Therefore, we generated iPSC-derived HLCs from an HoFH patient harbouring a point mutation (NM_000527.4:c.901 G > T) in exon 6 of LDLR, and examined their function and immunogenicity. From the patient's iPSCs, one homozygous gene-corrected HoFH-iPSC clone and two heterozygous clones were generated using the CRISPR/Cas9 method. Both types of iPSC-derived HLCs showed recovery of the function of LDL uptake in immunofluorescence staining analysis. Furthermore, these gene-corrected iPSC-derived HLCs showed little immunogenicity against the patient's peripheral blood mononuclear cells in a cell-mediated cytotoxicity assay. These results demonstrate that LDL uptake of iPSC-derived HLCs from HoFH can be restored by gene correction without the appearance of further immunogenicity, suggesting that gene-corrected iPSC-derived HLCs are applicable to the treatment of HoFH.