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Competing Interests: The authors have no conflicts to disclose and did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

A simple, non-invasive algorithm for maximal lactate steady state (MLSS) assessment has not been developed. We examined whether MLSS can be estimated from the sweat lactate threshold (sLT) using a novel sweat lactate sensor for healthy adults, with consideration of their exercise habits. Fifteen adults representing diverse fitness levels were recruited. Participants with/without exercise habits were defined as trained/untrained, respectively. Constant-load testing for 30 min at 110%, 115%, 120%, and 125% of sLT intensity was performed to determine MLSS. The tissue oxygenation index (TOI) of the thigh was also monitored. MLSS was not fully estimated from sLT, with 110%, 115%, 120%, and 125% of sLT in one, four, three, and seven participants, respectively. The MLSS based on sLT was higher in the trained group as compared to the untrained group. A total of 80% of trained participants had an MLSS of 120% or higher, while 75% of untrained participants had an MLSS of 115% or lower based on sLT. Furthermore, compared to untrained participants, trained participants continued constant-load exercise even if their TOI decreased below the resting baseline (P < 0.01). MLSS was successfully estimated using sLT, with 120% or more in trained participants and 115% or less in untrained participants. This suggests that trained individuals can continue exercising despite decreases in oxygen saturation in lower extremity skeletal muscles., (© 2023. The Author(s).)

Aortic stenosis (AS), a late complication of thoracic radiation therapy for chest lesions, is often coincident with porcelain aorta or hostile thorax. We herein report a 59-year-old man with a history of mediastinal Hodgkin lymphoma treated with radiation therapy but later presenting with heart failure caused by severe AS. Severe calcification in the mediastinum and around the ascending aorta made it difficult to perform surgical aortic valve replacement. The patient therefore underwent transcatheter aortic valve implantation (TAVI). It is important to recognize radiation-induced AS early, now that TAVI is a well-established treatment required by increasing numbers of successfully treated cancer patients.

Background: Catheter ablation (CA) for atrial fibrillation (AF) is widely performed. However, the indication for CA in patients with asymptomatic persistent AF is still controversial., Methods: Among 259 consecutive patients who were hospitalized for initial CA of AF, a total of 45 patients who had asymptomatic persistent AF were retrospectively analyzed. Quality of life (QOL) before and 1 year after CA was evaluated, and changes in the cardiac function over 5 years after CA were also examined. QOL was assessed using the AF QOL questionnaire (AFQLQ) developed by the Japanese Heart Rhythm Society. In addition, cardiac function was assessed by measuring the plasma B-type natriuretic peptide (BNP) level, left ventricular ejection fraction (LVEF), left atrial diameter (LAD) with transthoracic echocardiogram, and left atrial (LA) volume with computed tomography (CT)., Results: The AFQLQ significantly improved after CA in terms of "symptom frequency" and "activity limits and mental anxiety." The plasma BNP level, LVEF, and LAD significantly improved in the first 3 months after the first CA, with no significant changes thereafter (from 149.0 pg/dL [95% confidence intervals {CI}, 114.5-183.5 pg/dL] to 49.8 pg/dL [95% CI, 26.5-70.1], P  < .0001; from 60.8% [95% CI, 58.1%-63.6%] to 65.0% [95% CI, 62.6-67.4], P  = .001; and from 41.3 mm [95% CI, 39.7-42.9] to 36.8 [95% CI, 34.5-39.1 mm], P  < .0001, respectively). LA volume revealed LA reverse remodeling after CA., Conclusion: Improvement in the QOL and cardiac function after CA of asymptomatic persistent AF was revealed. Asymptomatic persistent AF should be appropriately treated by CA., Competing Interests: Authors declare no conflict of interest for this article. The study protocol was approved on May 13, 2017 by a suitably constituted Ethics Committee of Tenri Hospital (no. 429), and it conforms to the provisions of the Declaration of Helsinki., (© 2020 The Authors. Journal of Arrhythmia published by John Wiley & Sons Australia, Ltd on behalf of the Japanese Heart Rhythm Society.)

Background: Chronic atrial fibrillation (AF) can cause significant tricuspid regurgitation (TR), which may result from tricuspid annulus and right atrial enlargement. However, the impact of right ventricular (RV) function on TR development remains unclear., Methods: We retrospectively examined 175 consecutive patients with lone chronic AF (duration >1 year) without left ventricular dysfunction. TR severity was graded by the jet area and vena contracta, and moderate or severe TR were defined as significant TR. Patients were classified as significant TR (TR group) or without (NTR group) for comparison of clinical factors and transthoracic echocardiographic (TTE) parameters. To explore factors associated with TR development, we also compared previous TTE parameters among patients in TR group who showed no prior significant TR [TR-preTR(-)] and those in NTR group [NTR-preTR(-)]., Results: The mean age was 78 years (61% men). Significant TR was observed in 61 patients (35%). Compared with NTR group, the TR group was older, and had longer AF duration and larger right-sided cardiac parameters on index TTE. At previous TTE, the TR-preTR(-) group showed a larger basal RV dimension index (26.8 vs. 22.4mm/m 2 ), reduced RV free wall longitudinal strain (RVLS-FW) (-18.96 vs. -23.23), and lower tricuspid annular diameter change during a cardiac cycle (8.8% vs. 14.1%) than NTR-preTR(-) group., Conclusion: Significant TR was observed in 35% of patients with chronic AF. These patients showed enlarged RV, reduced RVLS-FW, and low tricuspid annular diameter changes before significant TR develops. RV dysfunction may be associated with TR development in chronic AF., (Copyright © 2020 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

Background: Long QT syndrome type 3 (LQT3) is caused by gain-of-function mutations in the SCN5A gene, which encodes the α subunit of the cardiac voltage-gated sodium channel. LQT3 patients present bradycardia and lethal arrhythmias during rest or sleep. Further, the efficacy of β-blockers, the drug used for their treatment, is uncertain. Recently, a large multicenter LQT3 cohort study demonstrated that β-blocker therapy reduced the risk of life-threatening cardiac events in female patients; however, the detailed mechanism of action remains unclear., Objectives: This study aimed to establish LQT3-human induced pluripotent stem cells (hiPSCs) and to investigate the effect of propranolol in this model., Method: An hiPSCs cell line was established from peripheral blood mononuclear cells of a boy with LQT3 carrying the SCN5A -N1774D mutation. He had suffered from repetitive torsades de pointes (TdPs) with QT prolongation since birth (QTc 680 ms), which were effectively treated with propranolol, as it suppressed lethal arrhythmias. Furthermore, hiPSCs were differentiated into cardiomyocytes (CMs), on which electrophysiological functional assays were performed using the patch-clamp method., Results: N1774D-hiPSC-CMs exhibited significantly prolonged action potential durations (APDs) in comparison to those of the control cells (N1774D: 440 ± 37 ms vs. control: 272 ± 22 ms; at 1 Hz pacing; p < 0.01). Furthermore, N1774D-hiPSC-CMs presented gain-of-function features: a hyperpolarized shift of steady-state activation and increased late sodium current compared to those of the control cells. 5 μM propranolol shortened APDs and inhibited late sodium current in N1774D-hiPSC-CMs, but did not significantly affect in the control cells. In addition, even in the presence of intrapipette guanosine diphosphate βs (GDPβs), an inhibitor of G proteins, propranolol reduced late sodium current in N1774D cells. Therefore, these results suggested a unique inhibitory effect of propranolol on late sodium current unrelated to β-adrenergic receptor block in N1774D-hiPSC-CMs., Conclusion: We successfully recapitulated the clinical phenotype of LQT3 using patient-derived hiPSC-CMs and determined that the mechanism, by which propranolol inhibited the late sodium current, was independent of β-adrenergic receptor signaling pathway., (Copyright © 2020 Hirose, Makiyama, Melgari, Yamamoto, Wuriyanghai, Yokoi, Nishiuchi, Harita, Hayano, Kohjitani, Gao, Kashiwa, Nishikawa, Wu, Yoshimoto, Chonabayashi, Ohno, Yoshida, Horie and Kimura.)

A 37-year-old man presented with heart failure caused by severe aortic regurgitation (AR). He had a history of being involved in a traffic accident 3 months earlier. Imaging tests at admission detected no abnormalities in the aortic valve or aortic wall; however, the left coronary cusp prolapsed slightly on transthoracic echocardiography. He underwent aortic valve replacement because of uncontrolled heart failure and severe AR. Intraoperatively, the intima of the aortic wall just above the commissure of the left and right coronary cusps was torn to the short axial direction. Local aortic tear was the final diagnosis for the subacute AR. < Learning objective: Acute or subacute aortic regurgitation (AR) is comparatively rare, and it is sometimes difficult to clinically recognize. The tear in the aortic wall just above the commissure caused by a traffic accident led to the gradual progression of AR, and the diagnosis of the cause of AR was difficult despite using transesophageal echocardiography and contrast-enhanced computed tomography. We should recognize that the detection of subacute AR caused by a local aortic tear can be challenging.>.

Background: TheSCN5Agene encodes the α subunit of the cardiac voltage-gated sodium channel, Na V 1.5. The missense mutation, D1275N, has been associated with a range of unusual phenotypes associated with reduced Na V 1.5 function, including cardiac conduction disease and dilated cardiomyopathy. Curiously, the reported biophysical properties ofSCN5A-D1275N channels vary with experimental system., Methods and results: First, using a human embryonic kidney (HEK) 293 cell-based heterologous expression system, theSCN5A-D1275N channels showed similar maximum sodium conductance but a significantly depolarizing shift of activation gate (+10 mV) compared to wild type. Second, we generated human-induced pluripotent stem cells (hiPSCs) from a 24-year-old female who carried heterozygousSCN5A-D1275N and analyzed the differentiated cardiomyocytes (CMs). AlthoughSCN5Atranscript levels were equivalent between D1275N and control hiPSC-CMs, both the total amount of Na V 1.5 and the membrane fractions were reduced approximately half in the D1275N cells, which were rescued by the proteasome inhibitor MG132 treatment. Electrophysiological assays revealed that maximum sodium conductance was reduced to approximately half of that in control hiPSC-CMs in the D1275N cells, and maximum upstroke velocity of action potential was lower in D1275N, which was consistent with the reduced protein level of Na V 1.5., Conclusions: This study successfully demonstrated diminished sodium currents resulting from lower Na V 1.5 protein levels, which is dependent on proteasomal degradation, using a hiPSC-based model forSCN5A-D1275N-related sodium channelopathy.

Calmodulin is a ubiquitous Ca2+ sensor molecule encoded by three distinct calmodulin genes, CALM1-3. Recently, mutations in CALM1-3 have been reported to be associated with severe early-onset long-QT syndrome (LQTS). However, the underlying mechanism through which heterozygous calmodulin mutations lead to severe LQTS remains unknown, particularly in human cardiomyocytes. We aimed to establish an LQTS disease model associated with a CALM2 mutation (LQT15) using human induced pluripotent stem cells (hiPSCs) and to assess mutant allele-specific ablation by genome editing for the treatment of LQT15. We generated LQT15-hiPSCs from a 12-year-old boy with LQTS carrying a CALM2-N98S mutation and differentiated these hiPSCs into cardiomyocytes (LQT15-hiPSC-CMs). Action potentials (APs) and L-type Ca2+ channel (LTCC) currents in hiPSC-CMs were analyzed by the patch-clamp technique and compared with those of healthy controls. Furthermore, we performed mutant allele-specific knockout using a CRISPR-Cas9 system and analyzed electrophysiological properties. Electrophysiological analyses revealed that LQT15-hiPSC-CMs exhibited significantly lower beating rates, prolonged AP durations, and impaired inactivation of LTCC currents compared with control cells, consistent with clinical phenotypes. Notably, ablation of the mutant allele rescued the electrophysiological abnormalities of LQT15-hiPSC-CMs, indicating that the mutant allele caused dominant-negative suppression of LTCC inactivation, resulting in prolonged AP duration. We successfully recapitulated the disease phenotypes of LQT15 and revealed that inactivation of LTCC currents was impaired in CALM2-N98S hiPSC model. Additionally, allele-specific ablation using the latest genome-editing technology provided important insights into a promising therapeutic approach for inherited cardiac diseases., (© The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Introduction: Human induced pluripotent stem cells (hiPSCs) offer a unique opportunity for disease modeling. However, it is not invariably successful to recapitulate the disease phenotype because of the immaturity of hiPSC-derived cardiomyocytes (hiPSC-CMs). The purpose of this study was to establish and analyze iPSC-based model of catecholaminergic polymorphic ventricular tachycardia (CPVT), which is characterized by adrenergically mediated lethal arrhythmias, more precisely using electrical pacing that could promote the development of new pharmacotherapies., Method and Results: We generated hiPSCs from a 37-year-old CPVT patient and differentiated them into cardiomyocytes. Under spontaneous beating conditions, no significant difference was found in the timing irregularity of spontaneous Ca2+ transients between control- and CPVT-hiPSC-CMs. Using Ca2+ imaging at 1 Hz electrical field stimulation, isoproterenol induced an abnormal diastolic Ca2+ increase more frequently in CPVT- than in control-hiPSC-CMs (control 12% vs. CPVT 43%, p<0.05). Action potential recordings of spontaneous beating hiPSC-CMs revealed no significant difference in the frequency of delayed afterdepolarizations (DADs) between control and CPVT cells. After isoproterenol application with pacing at 1 Hz, 87.5% of CPVT-hiPSC-CMs developed DADs, compared to 30% of control-hiPSC-CMs (p<0.05). Pre-incubation with 10 μM S107, which stabilizes the closed state of the ryanodine receptor 2, significantly decreased the percentage of CPVT-hiPSC-CMs presenting DADs to 25% (p<0.05)., Conclusions: We recapitulated the electrophysiological features of CPVT-derived hiPSC-CMs using electrical pacing. The development of DADs in the presence of isoproterenol was significantly suppressed by S107. Our model provides a promising platform to study disease mechanisms and screen drugs., Competing Interests: The authors have declared that no competing interests exist.

Background: The purpose of this study was to evaluate the long-term safety of the Igaki-Tamai stent, the first-in-human fully biodegradable coronary stent made of poly-l-lactic acid., Methods and Results: Between September 1998 and April 2000, 50 patients with 63 lesions were treated electively with 84 Igaki-Tamai stents. Overall clinical follow-up (>10 years) of major adverse cardiac events and rates of scaffold thrombosis was analyzed together with the results of angiography and intravascular ultrasound. Major adverse cardiac events included all-cause death, nonfatal myocardial infarction, and target lesion revascularization/target vessel revascularization. During the overall clinical follow-up period (121 ± 17 months), 2 patients were lost to follow-up. There were 1 cardiac death, 6 noncardiac deaths, and 4 myocardial infarctions. Survival rates free of all-cause death, cardiac death, and major adverse cardiac events at 10 years were 87%, 98%, and 50%, respectively. The cumulative rates of target lesion revascularization (target vessel revascularization) were 16% (16%) at 1 year, 18% (22%) at 5 years, and 28% (38%) at 10 years. Two definite scaffold thromboses (1 subacute, 1 very late) were recorded. The latter case was related to a sirolimus-eluting stent, which was implanted for a lesion proximal to an Igaki-Tamai stent. From the analysis of intravascular ultrasound data, the stent struts mostly disappeared within 3 years. The external elastic membrane area and stent area did not change., Conclusion: Acceptable major adverse cardiac events and scaffold thrombosis rates without stent recoil and vessel remodeling suggested the long-term safety of the Igaki-Tamai stent.