Elucidating left atrial electrical potential with microelectrode catheter: A case of coronary sinus ostial atresia with small persistent left superior vena cava.

A 51-year-old woman presented with recurring palpitations. Electrocardiography revealed narrow QRS tachycardia with short RP configuration. Computed tomography showed coronary sinus (CS) ostial atresia along with a small persistent left superior vena cava (PLSVC). Electrophysiological study identified the retrograde earliest atrial activation site (EAAS) at the CS ostium without decremental properties, and para-Hisian pacing suggested retrograde atrioventricular nodal conduction. Using a 1.6-Fr microelectrode catheter distally placed in the CS via the PLSVC, EAAS was confirmed within the left atrium, not the CS ostium. Transseptal approach revealed a left lateral accessory pathway, which was successfully eliminated.

Improvement in quality of life and cardiac function after catheter ablation for asymptomatic persistent atrial fibrillation.

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.

Successful Transcatheter Aortic Valve Implantation in a Patient with Radiation-induced Aortic Stenosis for Mediastinal Hodgkin Lymphoma.

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.

Propranolol Attenuates Late Sodium Current in a Long QT Syndrome Type 3-Human Induced Pluripotent Stem Cell Model.

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 ß-blockers, the drug used for their treatment, is uncertain. Recently, a large multicenter LQT3 cohort study demonstrated that ß-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 ßs (GDPßs), 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 ß-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 ß-adrenergic receptor signaling pathway.

Impact of right ventricular function on development of significant tricuspid regurgitation in patients with chronic atrial fibrillation.

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/m2), 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.

Occurrence of right ventricular dysfunction immediately after pericardiocentesis.

The changes in cardiac function that occur after pericardiocentesis are unclear. An understanding of the effect of pericardiocentesis on right ventricular (RV) and left ventricular (LV) function is clinically important. This study was performed to assess RV and LV function with echocardiography before and after pericardiocentesis. In total, 19 consecutive patients who underwent pericardiocentesis for more than moderate pericardial effusion were prospectively enrolled from August 2015 to October 2017. Comprehensive transthoracic echocardiography was performed before, immediately after (within 3 h), and 1 day after pericardiocentesis to investigate the changes in RV and LV function. The mean age of all patients was 72.6 ± 12.2 years. No pericardiocentesis-related complications occurred during the procedure, but one patient died of right heart failure 8 h after pericardiocentesis. After pericardiocentesis, RV inflow and outflow diameters increased (p < 0.05 versus values before pericardiocentesis), and the parameters of RV function (tricuspid annular plane systolic excursion, tricuspid lateral annular systolic velocity, fractional area change, and RV free wall longitudinal strain) significantly decreased (p < 0.001 versus values before pericardiocentesis). These abnormal values or RV dysfunction remained 1 day after pericardiocentesis (p > 0.05 versus values immediately after pericardiocentesis). Conversely, no parameters of LV function changed after pericardiocentesis. Of 19 patients, 13 patients showed RV dysfunction immediately after pericardiocentesis and 6 patients did not. RV free wall longitudinal strain before pericardiocentesis in patients with post-procedural RV dysfunction was reduced compared to those without post-procedural RV dysfunction ( - 18.9 ± 3.6 versus - 28.4 ± 6.3%; p = 0.005). The area under the curve values for prediction of post-procedural RV dysfunction was 0.910 for RV free wall longitudinal strain. The occurrence of RV dysfunction after pericardiocentesis should be given more attention, and pre-procedural RV free wall longitudinal strain may be a predictor of post-procedural RV dysfunction.

Very long-term follow-up data of non-ischemic idiopathic dilated cardiomyopathy after beta-blocker therapy: recurrence of left ventricular dysfunction and predictive value of 123I-metaiodobenzylguanidine scintigraphy.

The management of idiopathic dilated cardiomyopathy (DCM) is well established. However, a subset of patients do not have recovery from or have recurrences of left ventricular (LV) dysfunction despite receiving optimal medical therapy. There are limited long-term follow-up data about LV function and the predictive value of iodine-123-metaiodobenzylguanidine (123I-MIBG) scintigraphy, especially among the Japanese population. We retrospectively investigated 81 consecutive patients with DCM (mean LV ejection fraction (EF) 28 ± 7.5%) who had undergone 123I-MIBG scintigraphy before starting ß-blockers. According to chronological changes in LVEF, study patients were classified into three subgroups: sustained recovery group, recurrence group, and non-recovery group. The outcome measure was cardiac death. Mean age was 59 ± 11 years and median follow-up was 11.5 (5.8-15.0) years. Thirty-six patients had recovery, 11 had recurrences, and 34 did not have recovery. The sustained recovery group had the best cardiac death-free survival, followed by the recurrence and non-recovery groups. Prolonged time to initial recovery was associated with recurrence of LV dysfunction. Large LV end-diastolic diameter and reduced heart to mediastinum ratio were associated with poor prognosis. In conclusion, with ß-blocker therapy, 14% of patients showed recurrences of LV dysfunction. Thus, careful follow-up is needed, keeping in mind the possibility of recurrence, even if LVEF once improved, especially in patients whose time to initial recovery was long. 123I-MIBG scintigraphy provides clinicians with additional prognostic information.

Subacute aortic regurgitation due to traumatic tear in the aortic wall.

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. .

Complex aberrant splicing in the induced pluripotent stem cell-derived cardiomyocytes from a patient with long QT syndrome carrying KCNQ1-A344Aspl mutation.

BACKGROUND: Long QT syndrome type 1 (LQT1) is caused by mutations in KCNQ1, which encodes the α subunit of the slow delayed rectifier potassium current channel. We previously reported that a synonymous mutation, c.1032G>A, p.A344Aspl, in KCNQ1 is most commonly identified in genotyped patients with LQT1 in Japan and the aberrant splicing was analyzed in the lymphocytes isolated from patients' blood samples. However, the mechanisms underlying the observed processes in human cardiomyocytes remain unclear. OBJECTIVE: The purpose of this study was to establish and analyze patient-specific human-induced pluripotent stem cell-derived cardiomyocyte (hiPSC-CM) model carrying KCNQ1-A344Aspl. METHODS: We generated hiPSCs from the peripheral blood mononuclear cells obtained from a patient with LQT1 carrying KCNQ1-A344Aspl. Using the differentiated cardiomyocytes, we analyzed splicing variants and performed electrophysiology studies. RESULTS: We identified 7 aberrant RNA variants in A344Aspl hiPSC-CMs, which were more complex compared with those in peripheral lymphocytes. Multielectrode array analysis revealed that 1 µM isoproterenol significantly prolonged the duration of the corrected field potential in A344Aspl hiPSC-CMs as compared with that in control hiPSC-CMs. In addition, 100 nM E-4031, which inhibits the rapid component of the delayed rectifier potassium current, was shown to induce early afterdepolarization-like waveforms in A344Aspl hiPSC-CMs. Action potential durations (APDs) did not significantly differ between the hiPSC-CM groups. After administering 500 nM isoproterenol, APDs of A344Aspl hiPSC-CMs were significantly longer than those of the controls. (R)-N-(4-(4-Methoxyphenyl)thiazol-2-yl)-1-tosylpiperidine-2-carboxamide and phenylboronic acid, slow delayed rectifier potassium current activators, ameliorated the APDs of hiPSC-CMs. CONCLUSION: We identified complex aberrant messenger RNA variants in the A344Aspl hiPSC-CM model and successfully recapitulated the clinical phenotypes of the patient with concealed LQT1. This model allows the investigation of the underlying mechanisms and development of novel therapies.

Gene-Based Risk Stratification for Cardiac Disorders in LMNA Mutation Carriers.

BACKGROUND: Mutations in LMNA (lamin A/C), which encodes lamin A and C, typically cause age-dependent cardiac phenotypes, including dilated cardiomyopathy, cardiac conduction disturbance, atrial fibrillation, and malignant ventricular arrhythmias. Although the type of LMNA mutations have been reported to be associated with susceptibility to malignant ventricular arrhythmias, the gene-based risk stratification for cardiac complications remains unexplored. METHODS AND RESULTS: The multicenter cohort included 77 LMNA mutation carriers from 45 families; cardiac disorders were retrospectively analyzed. The mean age of patients when they underwent genetic testing was 45±17, and they were followed for a median 49 months. Of the 77 carriers, 71 (92%) were phenotypically affected and showed cardiac conduction disturbance (81%), low left ventricular ejection fraction (<50%; 45%), atrial arrhythmias (58%), and malignant ventricular arrhythmias (26%). During the follow-up period, 9 (12%) died, either from end-stage heart failure (n=7) or suddenly (n=2). Genetic analysis showed truncation mutations in 58 patients from 31 families and missense mutations in 19 patients from 14 families. The onset of cardiac disorders indicated that subjects with truncation mutations had an earlier occurrence of cardiac conduction disturbance and low left ventricular ejection fraction, than those with missense mutations. In addition, the truncation mutation was found to be a risk factor for the early onset of cardiac conduction disturbance and the occurrence of atrial arrhythmias and low left ventricular ejection fraction, as estimated using multivariable analyses. CONCLUSIONS: The truncation mutations were associated with manifestation of cardiac phenotypes in LMNA-related cardiomyopathy, suggesting that genetic analysis might be useful for diagnosis and risk stratification.

Development of a Patient-Derived Induced Pluripotent Stem Cell Model for the Investigation of SCN5A-D1275N-Related Cardiac Sodium Channelopathy.

BACKGROUND: TheSCN5Agene encodes the α subunit of the cardiac voltage-gated sodium channel, NaV1.5. The missense mutation, D1275N, has been associated with a range of unusual phenotypes associated with reduced NaV1.5 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 NaV1.5 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 NaV1.5. CONCLUSIONS: This study successfully demonstrated diminished sodium currents resulting from lower NaV1.5 protein levels, which is dependent on proteasomal degradation, using a hiPSC-based model forSCN5A-D1275N-related sodium channelopathy.

Allele-specific ablation rescues electrophysiological abnormalities in a human iPS cell model of long-QT syndrome with a CALM2 mutation.

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.

Patient-Specific Human Induced Pluripotent Stem Cell Model Assessed with Electrical Pacing Validates S107 as a Potential Therapeutic Agent for Catecholaminergic Polymorphic Ventricular Tachycardia.

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.

Cardiac sodium channel mutation associated with epinephrine-induced QT prolongation and sinus node dysfunction.

BACKGROUND: Long-QT syndrome (LQTS) is an inherited arrhythmia characterized by prolonged ventricular repolarization and malignant tachyarrhythmias. LQT1, LQT2, and LQT3 are caused by mutations in KCNQ1 (LQT1), KCNH2 (LQT2), and SCN5A (LQT3), which account for approximately 90% of genotyped LQTS patients. Most cardiac events in LQT1 patients occur during exercise, whereas patients with LQT3 tend to have arrhythmic events during rest or asleep. OBJECTIVE: The study aimed to identify a genetic mutation in a Japanese man who presented with sinus node dysfunction and prolonged QT interval on exercise and epinephrine stress tests, as well as to clarify the electrophysiological properties of mutant channels. METHODS: LQTS-related genes were screened in this patient. Electrophysiological functional assays were conducted with a heterologous expression system. RESULTS: We identified a heterozygous missense SCN5A mutation, V2016M, which changes the last amino acid of the cardiac sodium channel. Electrophysiological analyses revealed that the mutant channels exhibited a loss-of-function feature, decreased peak sodium current densities (wild type 175.2 ± 17.6 pA/pF; V2016M 97.2 ± 16.0 pA/pF; P < .01). In addition, the mutant channels showed gain-of-function features: increased late sodium currents by protein kinase A activation (wild type 0.07 ± 0.01%; V2016M 0.17 ± 0.03%; P < .05) and impaired inactivation of sodium channels by protein kinase A or C activation. CONCLUSION: We identified an SCN5A mutation in a patient with sinus node dysfunction and epinephrine-induced QT prolongation, which was an atypical phenotype for LQT3. The electrophysiological properties of the mutant channels might be associated with the overlapping clinical features of the patient.

Long-Term (>10 Years) clinical outcomes of first-in-human biodegradable poly-l-lactic acid coronary stents: Igaki-Tamai stents.

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.