The two therapeutic strategies of surgical intervention and medical management in a patient with enhanced-fibrinolytic type of disseminated intravascular coagulation after aortic replacement for Stanford type A aortic dissection with chronic heart and renal failure.

BACKGROUND: Management of the enhanced-fibrinolytic type of disseminated intravascular coagulation (DIC) caused by aortic disorders is the two strategies of surgical intervention and medical treatment based on the patient's age and comorbidities. CASE PRESENTATION: An 81-year-old woman with a history of two previous aortic surgeries and chronic heart and renal failure was admitted for uncontrollable subcutaneous hemorrhage. The hemorrhage was caused by the enhanced-fibrinolytic type of disseminated intravascular coagulation (DIC) caused by periprosthetic graft hematoma after aortic replacement for Stanford type A aortic dissection. Open thoracic hemostasis temporarily controlled the subcutaneous hemorrhage, but she was readmitted for the recurrence seven months after discharge. On the second admission, the combination of anticoagulant and antifibrinolytic agents was successful. CONCLUSION: Management of the enhanced-fibrinolytic type of DIC caused by aortic disorders is important of a successful combination of surgical and medical therapy tailored the patient's condition.

Clopidogrel Use in CYP2C19 Loss-of-Function Carriers With High Bleeding Risk After Percutaneous Coronary Intervention.

BACKGROUND: It is not known whether clopidogrel use in cytochrome P450 (CYP) 2C19 loss-of-function (LOF) carriers with high bleeding risk (HBR) contributes to adverse outcomes after percutaneous coronary intervention (PCI).Methods and Results: This retrospective observational study included 618 consecutive patients with available CYP2C19 polymorphism information who underwent PCI between September 2014 and August 2021. Patients with HBR (319 [52%] met the Academic Research Consortium definition) were divided into 2 groups according to P2Y12inhibitor action, namely decreased (i.e., clopidogrel in CYP2C19 LOF carriers) and retained (i.e., clopidogrel in CYP2C19 LOF non-carriers or prasugrel regardless of CYP2C19 polymorphisms), and clinical outcomes at 1 year were compared using inverse probability-weighted Cox proportional hazard regression. The primary ischemic outcome (a composite of cardiovascular death, myocardial infarction, or ischemic stroke) was significantly higher in the decreased than retained group (10.2% vs. 3.0%; adjusted hazard ratio [aHR] 2.78; 95% confidence interval [CI] 1.40-5.52; P=0.004). The primary bleeding outcome (Bleeding Academic Research Consortium 3 or 5) did not differ significantly between the decreased and retained groups (3.4% vs. 6.9%, respectively; aHR 0.48; 95% CI 0.22-1.01; P=0.054). There were no interactions between the treatment groups and HBR status in primary ischemic and bleeding outcomes. CONCLUSIONS: Among patients with HBR, clopidogrel use in CYP2C19 LOF carriers was significantly associated with increased ischemic events after PCI.

Comparison Between Clopidogrel and Prasugrel Associated With CYP2C19 Genotypes in Patients Receiving Percutaneous Coronary Intervention in a Japanese Population.

BACKGROUND: The association between cytochrome P450 (CYP) 2C19 genotypes and adverse events in patients treated with clopidogrel or prasugrel after percutaneous coronary intervention (PCI) in the Japanese population is unclear.Methods and Results:This study consisted of 1,580 patients whoseCYP2C19genotypes were assessed at Shiga University of Medical Science Hospital, and 193 clopidogrel-treated and 217 prasugrel-treated patients who were followed more than 1 year after receiving PCI were analyzed. Among 1,580 patients, the prevalence of normal, intermediate, and poor metabolizers was 32%, 49%, and 17%, respectively. Overall incidence of the primary outcome, defined as a composite of cardiovascular death, myocardial infarction, definite stent thrombosis, ischemic stroke, or major bleeding was not significantly different between the clopidogrel and prasugrel groups (adjusted hazard ratio [HR] 1.98, 95% confidence interval [CI] 0.85-4.61, P=0.12). Among patients with theCYP2C19loss-of-function (LOF) allele, however, the incidence of the primary outcome was significantly higher in the clopidogrel group (adjusted HR 3.19, 95% CI 1.10-9.24, P=0.03), whereas no difference was observed among patients without theCYP2C19LOF allele (adjusted HR 0.67, 95% CI 0.14-3.26, P=0.62). CONCLUSIONS: Among patients with theCYP2C19LOF allele, the use of clopidogrel was significantly associated with increased adverse events. Thus, further investigation is needed to establish the practical use ofCYP2C19genotyping.

Postoperative supraventricular tachycardia and polymorphic ventricular tachycardia due to a novel SCN5A variant: a case report of a rare comorbidity that is difficult to diagnose.

BACKGROUND: Loss-of-function mutations of human cardiac sodium channel gene SCN5A induce a wide range of arrhythmic disorders. Mutation carriers with co-existing conditions such as congenital heart diseases and histories of cardiac surgeries, could develop complex arrhythmic events that are difficult to diagnose. CASE PRESENTATION: A 41-year-old Japanese male with a history of a surgical closure of an ASD presented impairment of consciousness by wide QRS tachycardia. Because the patient's baseline ECG in sinus rhythm showed similar QRS axis with right bundle brunch block morphology, we suspected supraventricular tachycardia (SVT). During hospitalization, the patient developed polymorphic ventricular tachycardia that was induced by bradycardia. In an electrophysiological study, the SVT was identified as right atrial incisional tachycardia circulating around the scar in the right atrium. The genetic analysis revealed a heterozygous SCN5A c.4037-4038 del TC, p. L1346HfsX38 variant. We diagnosed this patient as having progressive cardiac conduction disorder (PCCD) and polymorphic VT caused by the mutation. Incisional tachycardia with wide QRS morphology was a by-standing comorbidity related to the history of cardiac surgery which could miss lead the diagnosis. The patient's SVT was eliminated by radiofrequency catheter ablation. An implantable cardioverter defibrillator (ICD) was implanted for the secondary prevention of polymorphic VT. Cardiac pace-making therapy by the ICD to avoid bradycardia effectively suppressed the patient's arrhythmic events. CONCLUSIONS: We treated a patient with a sodium channel gene variant. Co-existing SVT originated by a scar in the right atrium made the diagnosis extremely difficult. A multilateral diagnostic approach using an ECG analysis, an electrophysiological study, and genetic screening enabled effective combination therapy comprised of catheter ablation and an ICD.

A Decision Tree-Based Survival Analysis of Patients with a History of Inappropriate Implantable Cardioverter-Defibrillator Therapy.

Implantable cardioverter-defibrillators (ICDs) improve survival in patients who are at risk of sudden death. However, inappropriate therapy is commonly given to ICD recipients, and this situation may be associated with an increased risk of death. This study aimed to construct a risk stratification scheme by using decision tree analysis in patients who received inappropriate ICD therapy.Mortality was calculated from a retrospective data analysis of a multicenter cohort involving 417 ICD recipients. Inappropriate therapy was defined as therapy for nonventricular arrhythmias, including sinus tachycardia, supraventricular tachycardia, atrial fibrillation/flutter, oversensing, and lead failure. Inappropriate therapy included antitachycardia pacing, cardioversion, and defibrillation. The prognostic factors were identified by a Cox proportional hazards regression analysis, and we constructed a decision tree.During an average follow-up of 5.2 years, 48 patients (12%) had all-cause death. A multivariate Cox hazard model revealed that the age (hazard ratio [HR] 1.06, P < 0.001), ln B-type natriuretic peptide (BNP) (HR 1.47, P = 0.02), nonsinus rhythm at implantation (HR 2.70, P < 0.05), and inappropriate therapy occurring during sedentary/awake conditions (HR 3.51, P = 0.001) correlated with an increased risk of mortality. An inappropriate therapy due to abnormal sensing (HR 0.16, P = 0.04) decreased the risk of mortality. Furthermore, a decision tree analysis stratified the patients well by using 4 covariates: BNP, activity at the time of inappropriate therapy, mechanism of inappropriate therapy, and baseline rhythm at ICD implantation (log-rank test, P < 0.0001).We identified the predictors of mortality in inappropriate ICD therapy recipients and constructed a risk stratification scheme by using decision tree analysis.

Population pharmacokinetics and pharmacogenomics of apixaban in Japanese adult patients with atrial fibrillation.

AIMS: This study aimed to analyse the effects of genetic polymorphisms in drug transporters and metabolizing enzymes, and clinical laboratory data on the pharmacokinetic parameters of apixaban. METHODS: Data were collected from 81 Japanese patients with atrial fibrillation. Pharmacogenomic data were stratified by ABCB1, ABCG2 and CYP3A5 polymorphisms. The pharmacokinetic profile of apixaban was described by a one-compartment model with first-order absorption. Population pharmacokinetic analysis was conducted using a nonlinear mixed effect modelling (NONMEM™) program. RESULTS: The nonlinear relationship between oral clearance (CL/F) of apixaban and creatinine clearance (Ccr) was observed. The population mean of CL/F for a typical patient (Ccr value of 70 ml min-1 ) with the CYP3A5*1/*1 and ABCG2 421C/C or C/A genotypes was estimated to be 3.06 l h-1 . When Ccr values were set to the typical value, the population mean of CL/F was 1.52 times higher in patients with the CYP3A5*1/*1 genotype compared with patients with the CYP3A5*1/*3 or *3/*3 genotype, while the population mean of CL/F was 1.49 times higher in patients with the ABCG2 421C/C or C/A genotype compared with patients with the ABCG2 421A/A genotype. However, no covariates affected the population mean of the apparent volume of distribution (Vd/F) of apixaban. The population mean of Vd/F was estimated to be 24.7 l. CONCLUSION: The present study suggests that the ABCG2 421A/A and CYP3A5*3 genotypes and renal function are intrinsic factors affecting apixaban pharmacokinetics. These findings may provide useful information for precision medicine using apixaban, to avoid the risk of adverse reactions.

Impact of ABCB1, ABCG2, and CYP3A5 polymorphisms on plasma trough concentrations of apixaban in Japanese patients with atrial fibrillation.

OBJECTIVES: During anticoagulant therapy, major bleeding is one of the most severe adverse effects. This study aimed to evaluate the relationships between ABCB1, ABCG2, and CYP3A5 polymorphisms and plasma trough concentrations of apixaban, a direct inhibitor of coagulation factor X. PATIENTS AND METHODS: A total of 70 plasma concentrations of apixaban from 44 Japanese patients with atrial fibrillation were analyzed. In these analyses, the plasma trough concentration/dose (C/D) ratio of apixaban was used as a pharmacokinetic index and all data were stratified according to the presence of ABCB1 (ABCB1 1236C>T, 2677G>T/A, and 3435C>T), ABCG2 (ABCG2 421C>A), and CYP3A5 (CYP3A5*3) polymorphisms. Influences of various clinical laboratory parameters (age, serum creatinine, estimated glomerular filtration rate, aspartate amino transferase, and alanine amino transferase) on the plasma trough C/D ratio of apixaban were included in analyses. RESULTS: Although no ABCB1 polymorphisms affected the plasma trough C/D ratio of apixaban, the plasma trough C/D ratio of apixaban was significantly higher in patients with the ABCG2 421A/A genotype than in patients with the ABCG2 421C/C genotype (P<0.01). The plasma trough C/D ratio of apixaban in patients with CYP3A5*1/*3 or *3/*3 genotypes was also significantly higher than that in patients with the CYP3A5*1/*1 genotype (P<0.05). Furthermore, the plasma trough C/D ratio of apixaban decreased with increased estimated glomerular filtration rate. CONCLUSION: These results indicate that ABCG2 421A/A and CYP3A5*3 genotypes and renal function are considered potential factors affecting trough concentrations of apixaban.

Efficacy of Antiarrhythmic Drugs Short-Term Use After Catheter Ablation for Atrial Fibrillation (EAST-AF) trial.

AIMS: Substantial portion of early arrhythmia recurrence after catheter ablation for atrial fibrillation (AF) is considered to be due to irritability in left atrium (LA) from the ablation procedure. We sought to evaluate whether 90-day use of antiarrhythmic drug (AAD) following AF ablation could reduce the incidence of early arrhythmia recurrence and thereby promote reverse remodelling of LA, leading to improved long-term clinical outcomes. METHODS AND RESULTS: A total of 2038 patients who had undergone radiofrequency catheter ablation for paroxysmal, persistent, or long-lasting AF were randomly assigned to either 90-day use of Vaughan Williams class I or III AAD (1016 patients) or control (1022 patients) group. The primary endpoint was recurrent atrial tachyarrhythmias lasting for >30 s or those requiring repeat ablation, hospital admission, or usage of class I or III AAD at 1 year, following the treatment period of 90 days post ablation. Patients assigned to AAD were associated with significantly higher event-free rate from recurrent atrial tachyarrhythmias when compared with the control group during the treatment period of 90 days [59.0 and 52.1%, respectively; adjusted hazard ratio (HR) 0.84; 95% confidence interval (CI) 0.73-0.96; P = 0.01]. However, there was no significant difference in the 1-year event-free rates from the primary endpoint between the groups (69.5 and 67.8%, respectively; adjusted HR 0.93; 95% CI 0.79-1.09; P = 0.38). CONCLUSION: Short-term use of AAD for 90 days following AF ablation reduced the incidence of recurrent atrial tachyarrhythmias during the treatment period, but it did not lead to improved clinical outcomes at the later phase.

Adenosine triphosphate-guided pulmonary vein isolation for atrial fibrillation: the UNmasking Dormant Electrical Reconduction by Adenosine TriPhosphate (UNDER-ATP) trial.

AIMS: Most of recurrent atrial tachyarrhythmias after pulmonary vein isolation (PVI) for atrial fibrillation (AF) are due to reconnection of PVs. The aim of the present study was to evaluate whether elimination of adenosine triphosphate (ATP)-induced dormant PV conduction by additional energy applications during the first ablation procedure could reduce the incidence of recurrent atrial tachyarrhythmias. METHODS AND RESULTS: We randomly assigned 2113 patients with paroxysmal, persistent, or long-lasting AF to either ATP-guided PVI (1112 patients) or conventional PVI (1001 patients). The primary endpoint was recurrent atrial tachyarrhythmias lasting for >30 s or those requiring repeat ablation, hospital admission, or usage of Vaughan Williams class I or III antiarrhythmic drugs at 1 year with the blanking period of 90 days post ablation. Among patients assigned to ATP-guided PVI, 0.4 mg/kg body weight of ATP provoked dormant PV conduction in 307 patients (27.6%). Additional radiofrequency energy applications successfully eliminated dormant conduction in 302 patients (98.4%). At 1 year, 68.7% of patients in the ATP-guided PVI group and 67.1% of patients in the conventional PVI group were free from the primary endpoint, with no significant difference (adjusted hazard ratio [HR] 0.89; 95% confidence interval [CI] 0.74-1.09; P = 0.25). The results were consistent across all the prespecified subgroups. Also, there was no significant difference in the 1-year event-free rates from repeat ablation for any atrial tachyarrhythmia between the groups (adjusted HR 0.83; 95% CI 0.65-1.08; P = 0.16). CONCLUSION: In the catheter ablation for AF, we found no significant reduction in the 1-year incidence of recurrent atrial tachyarrhythmias by ATP-guided PVI compared with conventional PVI.

The Speckle Tracking Imaging for the Assessment of Cardiac Resynchronization Therapy (START) study.

BACKGROUND: We sought to identify the feasibility of speckle tracking echocardiography (STE) to predict cardiac resynchronization therapy (CRT) responders in a prospective multicenter study. METHODS AND RESULTS: Patients who were newly implanted with a CRT device were enrolled. Time (T) from QRS to maximum peak radial and circumferential strain (CS) in 6 segments on the left ventricular (LV) short-axis plane, and to the maximum peak of longitudinal strain in 18 segments on 3 apical LV planes was measured (Tmax). In segments with multiple peaks on the time-strain curves, time to the first peak (Tfirst) was also assessed. Difference in T between the earliest and latest segment and standard deviation (SD) of T in each strain component were assessed. CRT responders were defined as having LV end-systolic volume reduction >15% at 6 months after CRT. Clinical outcomes were assessed with a composite endpoint of death from cardiac causes or unplanned hospitalization for heart failure. Among 180 patients, 109 patients were identified as responders. Tfirst-SD of CS >116 ms was selected as the best independent predictor of CRT responders (P<0.001, hazard ratio=9.83, 95% confidence interval 3.78-25.6). In addition, Tfirst-SD of CS was associated with the clinical endpoints. CONCLUSIONS: This prospective multicenter study revealed the high feasibility of dyssynchrony assessment by STE, which may improve the ability to predict CRT responders.

The role of fibroblasts in complex fractionated electrograms during persistent/permanent atrial fibrillation: implications for electrogram-based catheter ablation.

RATIONALE: Electrogram-based catheter ablation, targeting complex fractionated atrial electrograms (CFAEs), is empirically known to be effective in halting persistent/permanent atrial fibrillation (AF). However, the mechanisms underlying CFAEs and electrogram-based ablation remain unclear. OBJECTIVE: Because atrial fibrosis is associated with persistent/permanent AF, we hypothesized that electrotonic interactions between atrial myocytes and fibroblasts play an important role in CFAE genesis and electrogram-based catheter ablation. METHODS AND RESULTS: We used a human atrial tissue model in heart failure and simulated propagation and spiral wave reentry with and without regionally proliferated fibroblasts. Coupling of fibroblasts to atrial myocytes resulted in shorter action potential duration, slower conduction velocity, and lower excitability. Consequently, heterogeneous fibroblast proliferation in the myocardial sheet resulted in frequent spiral wave breakups, and the bipolar electrograms recorded at the fibroblast proliferation area exhibited CFAEs. The simulations demonstrated that ablation targeting such fibroblast-derived CFAEs terminated AF, resulting from the ablation site transiently pinning the spiral wave and then pushing it out of the fibroblast proliferation area. CFAEs could not be attributed to collagen accumulation alone. CONCLUSIONS: Fibroblast proliferation in atria might be responsible for the genesis of CFAEs during persistent/permanent AF. Our findings could contribute to better understanding of the mechanisms underlying CFAE-targeted AF ablation.

Association with the nonparoxysmal atrial fibrillation duration and outcome of ExTRa Mapping-guided rotor ablation.

Background: Additional ablation strategies after pulmonary vein isolation (PVI) for patients with nonparoxysmal atrial fibrillation (non-PAF) lasting ≥2 years have not been fully effective. This is presumably because of insufficient identification of non-PAF maintenance mechanisms. In this study, we employed a novel online and real-time phase mapping system, ExTRa Mapping, to identify and modulate rotors as one of the non-PAF maintenance mechanisms in patients with non-PAF sustained after PVI. We investigated the relationship between outcomes of ExTRa Mapping-guided rotor ablation (ExTRa-ABL) and non-PAF duration prior to this procedure. Methods: This study consisted of 73 non-PAF patients (63 ± 8 years, non-PAF duration 31 ± 37 months) who underwent the first ExTRa-ABL in patients with non-PAF sustained after completion of PVI. Results: Freedom from non-PAF/atrial tachycardia (AT) recurrence at 12 months after ExTRa-ABL was achieved in 50 (69%) of patients. The non-PAF duration prior to ExTRa-ABL was significantly longer in patients with non-PAF/AT recurrence after ExTRa-ABL compared with those without (56 ± 50 vs. 19 ± 22 months, p = .001). In patients with non-PAF duration of ≤60 months prior to ExTRa-ABL, compared with >60 months, non-PAF/AT-free rate was significantly higher (68.9% vs. 23.1%, p < .001), during the follow-up of 36 ± 18 months. Conclusions: A non-PAF duration of ≤60 months prior to ExTRa-ABL was associated with a better outcome. The effect of ExTRa-ABL was considered to be limited in patients with >60 months of non-PAF duration.

Persistent Left Superior Vena cava with the Absence of the Right Superior Vena Cava and Atrial Appendage: Complex Pacemaker Implantation in a Patient Presenting with a Rare Vascular Anomaly.

A persistent left superior vena cava (PLSVC) is a commonly observed anatomical anomaly that is frequently detected incidentally via computed tomography (CT) imaging. However, the occurrence of a PLSVC with a right superior vena cava (RSVC) defect, also known as "isolated PLSVC," is a much rarer anomaly. This peculiar malformation can lead to sinoatrial dysfunction, thus necessitating pacemaker implantation, which requires delicate manipulation due to various anatomical complexities. We herein present a case of a sick sinus syndrome with this rare anomaly, which required special consideration when performing pacemaker lead placement.

FFR-CT is extremely useful in detecting hemodynamically significant left-main coronary artery stenosis with right coronary artery hypoplasia: A case report.

Left main coronary artery (LMCA) stenosis in patients with coronary artery disease (CAD) is associated with a significant increase in cardiac events, and determining its contribution to ischemia is essential. Currently, several noninvasive modalities are available for the ischemic assessment of CAD. In multi-vessel disease, including LMCA disease, the accuracy of myocardial perfusion scintigraphy (MPS) for detecting myocardial ischemia can be poor. Fractional flow reserve from computed tomography (FFR-CT) has emerged as a promising noninvasive modality that can provide functional myocardial ischemia information. Herein, we describe the case of a 50-year-old woman with type 2 diabetes who presented to the hospital due to intermittent chest pain on exertion. Coronary computed tomography angiography showed right coronary artery hypoplasia, 25 % stenosis in the LMCA, and 75 % stenosis in the left anterior descending. FFR-CT identified myocardial ischemia due to LMCA stenosis, but MPS did not. Invasive coronary angiography with conventional fractional flow reserve was mostly consistent with the results of FFR-CT. Learning objective: Fractional flow reserve from computed tomography (FFR-CT), which is a novel noninvasive method, can provide absolute, not relative, functional myocardial ischemia information by applying computational fluid dynamics to coronary computed tomography angiography on a lesion-by-lesion basis. FFR-CT can be extremely useful in detecting patients with left main coronary artery stenosis with right coronary artery hypoplasia.

Successful Management of a Young Athlete with Type 2 Long QT Syndrome by Genotype-specific Risk Stratification and Bridging Therapy with a Wearable Cardioverter Defibrillator.

We herein report a 14-year-old boy with repetitive nocturnal syncope related to medication-refractory long QT syndrome (LQTS). Although the use of an implantable cardioverter-defibrillator (ICD) was inevitable to prevent sudden cardiac death, he refused immediate implantation in order to play in a baseball competition six weeks away. Given his genetic diagnosis of type 2 LQTS, which is associated with cardiac events unrelated to exercise, we prescribed a wearable cardioverter defibrillator (WCD) to be donned at night, without limiting his exercise participation. An ICD was implanted after the competition. We successfully performed the preplanned treatment while maximizing the patient's quality-of-life with a WCD and genotype-specific risk stratification.

Lipocalin-type prostaglandin D synthase is associated with coronary vasospasm and vasomotor reactivity in response to acetylcholine.

BACKGROUND: Lipocalin-type prostaglandin D synthase (L-PGDS) catalyzes the biosynthesis of PGD(2), which acts as an anticoagulant, vasodilator, and inflammatory mediator. We examined the serum L-PGDS level, coronary macro- and microvasomotor functions, and their relationship in patients with chest pain and angiographically normal coronary arteries. METHODS AND RESULTS: The study included 96 patients who underwent diagnostic coronary angiography and had angiographically normal coronary arteries. Blood flow of the left anterior descending coronary artery (LAD) was analyzed by Doppler guidewire examination. Serum L-PGDS level was determined by ELISA. Infusion of acetylcholine (ACh) induced vasospasm of the LAD in all patients with vasospastic angina (VSA) (n=45), but in none of the patients without VSA (n=51). There were no significant differences in the baseline clinical characteristics of the nonVSA and VSA groups, except for the frequency of smoking. Serum L-PGDS level in the VSA group was significantly higher than that in the nonVSA group (77.1±4.4 vs. 63.9±2.5 µg/dl, P<0.01). Significant negative correlations were observed between the degree of LAD vasomotion in response to ACh and serum L-PGDS level (3 µg/min: r=-0.33; 10 µg/min: r=-0.35; 30 µg/min: r=-0.33, P<0.01). CONCLUSIONS: The L-PGDS level was elevated in patients with VSA and was associated with epicardial coronary vasomotion in response to ACh.

Diverse phenotypic expression associated with the same genetic variant in female heterozygote patients of Anderson-Fabry disease: a case series.

BACKGROUND: Anderson-Fabry disease (AFD) is an X-linked lysosomal storage disorder resulting from a mutation of alpha-galactosidase A gene (GLA), causing deficiency in alpha-galactosidase activity. The enzyme deficit can lead to storage of globotriaosylceramide in various organs including heart. Studies suggest that vasospastic angina (VSA) is associated with AFD. CASE SUMMARY: This clinical case series aimed to present two female patients with AFD, including progressive cardiac involvement: a 50-year-old woman (patient number 1) and a 39-year-old woman (patient number 2) who are siblings with a male AFD patient harbouring p. Arg342Glu missense variant in alpha-galactosidase A gene (GLA), who suffered VSA and subsequent ventricular fibrillation. Enzymatic tests and genetic analysis confirmed AFD in both female patients and histological tests revealed globotriaosylceramide deposits in their hearts. In patient number 1, a 12-lead electrocardiography and transthoracic echocardiography revealed cardiac hypertrophy. Coronary angiography revealed no organic coronary artery stenosis and vasospasms was induced by spasm provocation test. In patient number 2, no signs of cardiac hypertrophy were found, and coronary arteries had no organic stenosis with negative spasm provocation test. Both patients received enalapril therapy and enzyme replacement therapy (ERT). DISCUSSION: Different phenotype of AFD was occurred even with the same genetic variant in female heterozygote patients. The duration of exposing accumulation of Gb3 might affect cardiac hypertrophy and vasospasms. Coronary angiography with acetylcholine provocation test should be considered in female AFD patient, especially in case with cardiac hypertrophy.

Transcatheter cryo-ablation of septal accessory pathways, multicenter observational study in Japan.

BACKGROUND: Ablation using radiofrequency energy has to be carefully performed when the arrhythmia substrate is located in close proximity to the atrioventricular (AV) node due to the risk of inadvertent permanent AV block. The aim of this study was to evaluate the efficacy and safety of catheter-based cryo-therapy for septal accessory pathways (APs). METHODS: A total of eleven patients (median = 56.3 years, range 13-74 years) with septal APs underwent cryoablation. Ice-mapping was performed during sinus rhythm and an AV reciprocating tachycardia utilizing the APs as a requisite limb with cooling of the catheter tip temperature to a maximum of -30℃ for less than 45 s. Cryo-ablation was performed for 4 min at a temperature of -80℃ only if ice-mapping abolished the pre-excitation or retrograde conduction over the AP without injury to the AV nodal conduction. RESULTS: Cryo-ablation was acutely successful in all eleven patients. No permanent cryo-related complications or adverse outcomes were reported. During the follow-up (range 14-26 months), no patients experienced any arrhythmia recurrences. CONCLUSION: Ice-mapping was a feasible and reliable method to determine the exact location of the APs owing to the possibility of validating the ablation site. Cryo-ablation of APs located near the AV junction is a safe and efficacious technique with a high success rate over the long term. IRB INFORMATION: Ethical Committee of Japan Red Cross Yokohama City Bay Hospital #2018-19.

The association between late-phase early recurrence within the blanking period after atrial fibrillation catheter ablation and long-term recurrence: Insights from a large-scale multicenter study.

BACKGROUND: The relationship between the timing of the first early recurrence and late recurrence after a single catheter ablation procedure for atrial fibrillation is controversial. METHODS: The Efficacy of Short-Term Use of Antiarrhythmic Drugs After Catheter Ablation for Atrial Fibrillation trial followed 2038 patients who underwent radiofrequency catheter ablation for atrial fibrillation. RESULTS: Of the patients, 907 (45%) had early recurrences within 90 days after the initial ablation. We divided these patients into two groups according to the timing of the first early recurrence episode, namely the ER1 group (early recurrence during the early phase; 0-30 days, n = 814) and ER2 group (early recurrence during the late phase; 31-90 days, n = 93). Three years after ablation, patients with early recurrences had a significantly lower event-free rate from late recurrences after a 90-day blanking period than patients without early recurrences (36.2% and 74.2%, respectively; log-rank, P < 0.0001). Three years after ablation, the event-free rate was significantly higher in the ER1 than the ER2 group (38.3% and 17.1%, respectively; log-rank, P < 0.0001). Moreover, the event-free rate at 3 years in the ER2 group was extremely low (5.6%) in patient with non-paroxysmal atrial fibrillation. CONCLUSION: Early recurrences were strongly associated with late recurrences, especially in patients with the first recurrence episode at >1 month within the blanking period after a single ablation procedure. Therefore, these patients should undergo close observation during follow-up, when they had especially with non-paroxysmal atrial fibrillation.

LMNA Missense Mutation Causes Nonsense-Mediated mRNA Decay and Severe Dilated Cardiomyopathy.

BACKGROUND: LMNA is a known causative gene of dilated cardiomyopathy and familial conduction disturbance. Nonsense-mediated mRNA decay, normally caused by nonsense mutations, is a safeguard process to protect cells from deleterious effects of inappropriate proteins from mutated genes. Nonsense-mediated mRNA decay induced by nonstop codon mutations is rare. We investigated the effect of an LMNA missense mutation identified in 2 families affected by cardiac laminopathy. METHODS: Genomic DNA and total RNA were isolated from patients' peripheral blood lymphocytes or cardiac tissue. LMNA-coding exons were screened by direct sequencing. Complementary DNAs were generated by a reverse transcription-polymerase chain reaction from total RNA. Quantitative polymerase chain reaction was performed to quantify the LMNA complementary DNA amount by using specific primers for lamins A and C. A minigene splicing reporter experiment was performed to assess the effect of detected variants on RNA splicing. The protein expressions of both isoforms were analyzed by Western blotting. RESULTS: We detected a missense variant c.936 G>C (p. Q312H) at the end of exon 5 of LMNA by genomic DNA sequencing in 2 unrelated families affected by dilated cardiomyopathy and cardiac conduction disturbance. This variant was previously reported in a French family suffering from muscular dystrophy and cardiac conduction disturbance. Sequencing of complementary DNA demonstrated that the mutated allele was absent. By quantitative polymerase chain reaction assay, we confirmed a 90% reduction in LMNA complementary DNA. The minigene splicing reporter assay demonstrated a splicing error by the variant. Western blot analysis revealed that lamin A and C expressions were reduced far >50%. CONCLUSIONS: We report an LMNA missense mutation found in 2 families, which disrupted a normal splicing site, led to nonsense-mediated mRNA decay, and resulted in severe cardiac laminopathy.