Novel insights into presenilin 1 mutation associated with a distinctive dementia phenotype and cotton wool plaques.

BACKGROUND: The mutations in the presenilin 1 gene (PSEN1) are the main cause of familial Alzheimer's disease. PSEN1 mutations affect amyloid-beta peptide production, which accumulates in the brain as senile plaque and cotton wool plaques (CWPs) and relates to other neurodegenerative disorders. Here we report the second case of the PSEN1 G266S mutation, which showed distinctive neuropathological features, including abundant CWPs. Lewy body pathology, and altered amyloid-beta production. METHOD: Using the proband's samples, we performed genetic analysis of the PSEN1, APP, MAPT, and APOE genes, histopathological and immunohistochemical analysis of the brain tissue, and biochemical analysis of Aß production in COS cells transfected with wild-type or mutant PSEN1. RESULTS: The patient presented with memory loss, abnormal behavior, and visual hallucinations. Brain scans showed reduced blood flow, mild atrophy, and white matter lesions. Genetic analysis revealed a heterozygous mutation at codon 266 (G266S) of PSEN1 and polymorphism of MAPT (Q230R). The brain had many CWPs, severe cerebral amyloid angiopathy (CAA), senile plaque, Lewy bodies, and neurites. Electron microscopy displayed myelinated fiber degeneration, mitochondrial damage, and amyloid fibrils in the white matter. The production level of Aß42 in PSEN1 G266S-transfected cells significantly increased. CONCLUSION: Our findings suggest that the PSEN1 G266S mutation may cause a heterogeneous clinical and pathological phenotype, influenced by other genetic or environmental factors.

Novel anti-GARP antibody DS-1055a augments anti-tumor immunity by depleting highly suppressive GARP+ regulatory T cells.

Regulatory T (Treg) cells, which are essential for maintaining self-tolerance, inhibit anti-tumor immunity, consequently hindering protective cancer immunosurveillance, and hampering effective anti-tumor immune responses in tumor-bearing hosts. Here, we show that depletion of Treg cells via targeting glycoprotein A repetitions predominant (GARP) induces effective anti-tumor immune responses. GARP was specifically expressed by highly suppressive Treg cells in the tumor microenvironment (TME) of multiple cancer types in humans. In the periphery, GARP was selectively induced in Treg cells, but not in effector T cells, by polyclonal stimulation. DS-1055a, a novel afucosylated anti-human GARP monoclonal antibody, efficiently depleted GARP+ Treg cells, leading to the activation of effector T cells. Moreover, DS-1055a decreased FoxP3+CD4+ T cells in the TME and exhibited remarkable anti-tumor activity in humanized mice bearing HT-29 tumors. We propose that DS-1055a is a new Treg-cell-targeted cancer immunotherapy agent with augmentation of anti-tumor immunity.

A prospective observational study of video laryngoscopy-guided coaching in the pediatric intensive care unit.

BACKGROUND: There are limited data on the use of video laryngoscopy for pediatric patients outside of the operating room. AIM: Our primary aim was to evaluate whether implementation of video laryngoscopy-guided coaching for tracheal intubation is feasible with a high level of compliance and associated with a reduction in adverse tracheal intubation-associated events. METHODS: This is a pre-post observational study of video laryngoscopy implementation with standardized coaching language for tracheal intubation in a single-center, pediatric intensive care unit. The use of video laryngoscopy as a coaching device with standardized coaching language was implemented as a part of practice improvement. All patients in the pediatric intensive care unit were included between January 2016 and December 2017 who underwent primary tracheal intubation with either video laryngoscopy or direct laryngoscopy. The uptake of the implementation, sustained compliance, tracheal intubation outcomes including all adverse tracheal intubation-associated events, oxygen desaturations (<80% SpO2), and first attempt success were measured. RESULTS: Among 580 tracheal intubations, 284 (49%) were performed during the preimplementation phase, and 296 (51%) postimplementation. Compliance for the use of video laryngoscopy with standardized coaching language was high (74% postimplementation) and sustained. There were no statistically significant differences in adverse tracheal intubation-associated events between the two phases (pre- 9% vs. post- 5%, absolute difference -3%, CI95 : -8% to 1%, p = .11), oxygen desaturations <80% (pre- 13% vs. post- 13%, absolute difference 1%, CI95 : -6% to 5%, p = .75), or first attempt success (pre- 73% vs. post- 76%, absolute difference 4%, CI95 : -3% to 11%, p = .29). Supervisors were more likely to use the standardized coaching language when video laryngoscopy was used for tracheal intubation than with standard direct laryngoscopy (80% vs. 43%, absolute difference 37%, CI95 : 23% to 51%, p < .001). CONCLUSIONS: Implementation of video laryngoscopy as a supervising device with standardized coaching language was feasible with high level of adherence, yet not associated with an increased occurrence of any adverse tracheal intubation-associated events and oxygen desaturation.

[A Case of Diffuse Large B Cell Lymphoma of the Extrahepatic Bile Duct Cholangiocarcinoma].

The patient was an 81-year-old man who was hospitalized with poor appetite and obstructive jaundice. An abdominal CT scan showed remarkable thickening of the wall from the cystic duct to extrahepatic bile duct. Endoscopic retrograde cholangiopancreatography( ERCP)revealed stricture at the extrahepatic bile duct. Cholangiocarcinoma was diagnosed and pancreaticoduodenectomy was performed. The histopathological diagnosis was diffuse large B cell lymphoma (DLBCL). The patient was stable after the operation. We present a case report describing the resection of DLBCL of the extrahepatic bile duct along with a review of the literature.

[A Case of Gastric Endocrine Carcinoma].

The patient was an 80-year-old man, hospitalized with poor appetite, light-headedness, and black stool. Esophagogastroduodenoscopy showed an ulcerative lesion in cardia, and the tumor was diagnosed as gastric cancer using the biopsy specimens. The patient underwent a gastrectomy with D1-node dissection. Pathologically, the small tumor cells infiltrated the muscularis propria of the gastric wall, and these tumor cells immunohistochemically showed a positive reaction for synaptophysin. Therefore, the tumor was diagnosed as small cell-neuroendocrine carcinoma of the stomach. Metastasis was not observed in regional lymph nodes, and the TNM classification was defined as pStage ⅠB. After surgery, adjuvant chemotherapy was not performed. The patient is well without recurrence for more than 7 months after the surgery. We experienced and report a case of gastric endocrine cell carcinoma that underwent resection and provide a review of the literature.

[A Case of Disseminated Myelocarcinoma with Bone Metastasis 15 Years after Mastectomy and Relatively Long-Term Survival through Multidisciplinary Treatment].

The patient was a 62-year-old woman who had undergone mastectomy in August 2003 for cancer of the right breast. In addition to radiation therapy in the remaining breast, chemotherapy and endocrine therapy were subsequently performed. The patient had a 10-year recurrence-free postoperative course followed by annual surveillance. Beginning in 2016, an elevation in the serum level of tumor markers was detected; however, no accumulations were found in PET-CT over 2 consecutive years(2016 and 2017). Thereafter, serum levels of tumor markers continued to rise, and a PET-CT in 2018 revealed costal accumulations leading to a diagnosis of late-stage bone metastasis in postoperative year 15. Although hormone therapy was resumed, a continuing rise in the serum level of tumor markers led to a diagnosis of diffuse bone metastasis by MRI in 2019. Treatment with abemaciclib was initiated, and with effective radiotherapy, the PS was maintained at 0-1, serum levels of tumor markers decreased, and the lesions themselves continued at SD. However, in June 2020, multiple liver metastases appeared in an abdominothoracic CT scan. The patient refused chemotherapy; this, a BSC policy was adopted. Acute hemolytic anemia occurred immediately thereafter, and the PS gradually deteriorated. The patient died in September 2020, 17 years and 1 month after surgery.

Narrower QRS may be enough to respond to cardiac resynchronization therapy in lightweight patients.

A prolonged QRS duration (QRSd) is promising for a response to cardiac resynchronization therapy (CRT). The variation in human body sizes may affect the QRSd. We hypothesized that conduction disturbances may exist in Japanese even with a narrow (< 130 ms)-QRS complex; such patients could be CRT candidates. We investigated the relationships between QRSd and sex and body size in Japanese. We retrospectively analyzed the values of 338 patients without heart failure (HF) (controls) and 199 CRT patients: 12-lead electrocardiographically determined QRSd, left ventricular diastolic and systolic diameters (LVDd and LVDs), body surface area (BSA), body mass index (BMI), and LVEF. We investigated the relationships between the QRSd and BSA, BMI, and LVD. The men's and women's BSA values were 1.74 m2 and 1.48 m2 in the controls (p < 0.0001), and 1.70 m2 and 1.41 m2 in the CRT patients (p < 0.0001). The men's and women's QRSd values were 96.1 ms and 87.4 ms in the controls (p < 0.0001), and 147.8 ms and 143.9 ms in the CRT group (p = 0.4633). In the controls, all body size and LVD variables were positively associated with QRSd. The CRT response rate did not differ significantly among narrow-, mid-, and wide-QRS groups (83.6%, 91.3%, 92.4%). An analysis of the ROC curve provided a QRS cutoff value of 114 ms for CRT responder. The QRSd appears to depend somewhat on body size in patients without HF. The CRT response rate was better than reported values even in patients with a narrow QRSd (< 130 ms). When patients are considered for CRT, a QRSd > 130 ms may not be necessary, and the current JCS guidelines appear to be appropriate.

Benefit of Rate Response with Closed-Loop Stimulation in Patients with Difficult Hemodialysis.

Rate-responsive pacing is known to improve quality of life (QOL) in patients with sick sinus syndrome and chronotropic incompetence. However, the sensors for rate response include accelerometers, closed-loop stimulation (CLS), and minute ventilation sensors (MV sensors), each of which has a different mode of action. For this reason, it is important to select appropriate sensors that match the daily habits and behavioral patterns of the patient. For example, young and active patients are expected to have a rate increase when an accelerometer is used, while elderly patients and patients with a physical disability who are only able to move slowly often have a poor response to the accelerometer. MV sensors are therefore better suited to these patients. Furthermore, CLS is considered effective for patients who require an increase in heart rate when at rest, for example, patients undergoing maintenance dialysis.We describe a representative case, demonstrating the effectiveness of closed-loop stimulation in a patient with hypotension during dialysis.

Adverse Clinical Events during Long-Term Follow-Up After Catheter Ablation of Atrial Fibrillation.

Pulmonary vein isolation (PVI) of atrial fibrillation (AF) can reduce the AF burden and, potentially, reduce the long-term risk of strokes and death. However, it remains unclear whether anticoagulants can be stopped after PVI because of post-ablation AF recurrence in some patients. This study aimed to investigate the discontinuation rate of anticoagulants and long-term incidence of strokes after PVI.We enrolled 512 consecutive Japanese patients with AF (mean age, 63.4 ± 10.4 years; 123 women; 234 with non-paroxysmal AF; CHADS2 score/CHA2DS2-VASC score, 1.32 ± 1.12/2.21 ± 1.54) who underwent PVI between 2012 and 2015. During a 28.0 ± 17.1 -month follow-up, anticoagulants were terminated in 230 (44.9%) of the 512 patients, AF recurred in 200 (39.1%), and 10 (1.95%) suffered from a stroke. Death occurred in 5 (0.98%) patients. Although the incidence of strokes, by a Kaplan-Meier analysis, was similar, the incidence of death was lower (Hazard ratio 0.37, 95% confidence interval 0.12-0.93, P = 0.041) in the AF ablation group than the control group without ablation after 1:1 propensity score matching (the control data was derived from 2,986 patients in the SAKURA AF Registry, a large-cohort AF registry).Anticoagulants were discontinued in nearly half the patients who underwent AF ablation; of these, 39.1% experienced AF recurrences, 1.95% suffered from strokes, and 0.98% died, but the risk of death after AF ablation appeared to be lower than that in a propensity score-matched control group without ablation during long-term follow-up.

Clinical Manifestations and Long-Term Mortality in Lamin A/C Mutation Carriers From a Japanese Multicenter Registry.

BACKGROUND: Mutation in the lamin A/C gene (LMNA) is associated with several cardiac phenotypes, such as cardiac conduction disorders (CCD), atrial arrhythmia (AA), malignant ventricular arrhythmia (MVA) and left ventricular dysfunction (LVD), leading to sudden cardiac death (SCD) and/or end-stage heart failure. We investigated how these phenotypes are associated with each other and which of them are most important for total mortality. Methods and Results: A multicenter registry included 110 LMNA mutation carriers (age, 43±15 years, male: 62%) from 60 families. After genetic diagnosis of LMNA mutation (missense: 27%, non-missense: 73%), patients or subjects were followed to evaluate the manifestations of their phenotypes and the risk of total mortality; 90 patients could be followed (median: 5 [0-35] years). Prevalence of the 4 clinical phenotypes was significantly increased during follow-up. Among these phenotypes, AA was significantly associated with MVA. CCD was significantly associated with LVD. LVD, meanwhile, was significantly associated with CCD and MVA. Male sex was significantly associated with MVA. Furthermore, during follow-up, 17 patients died: 12 end-stage heart failure, 4 SCD and 1 stroke. LVD was the only independent predictor for all-cause death (OR: 41.7, 95% CI: 4.1-422.3; P=0.0016). CONCLUSIONS: Several cardiac phenotypes were age-dependently increased in LMNA mutation carriers, suggesting that ICD or CRT-D could suppress SCD after middle age; however, LVD leading to end-stage heart failure was the only independent predictor for total mortality.

Longer Duration of Urinary Catheterization Increases Catheter-Associated Urinary Tract Infection in PICU.

OBJECTIVES: Catheter-associated urinary tract infections account for 30% of healthcare-associated infections. To date, few studies have addressed pediatric catheter-associated urinary tract infection in PICUs. The aim of our study was to assess the risk of catheter-associated urinary tract infection in relation to the duration of catheterization in the PICU. DESIGN: Retrospective cohort study. SETTING: PICU at a tertiary children's hospital. PATIENTS: Our study was conducted between April 2012 and June 2015 at Tokyo Metropolitan Children's Medical Center in Japan. Children in the PICU with an urethral catheter were included. Catheter-associated urinary tract infection cases were defined according to the National Healthcare Safety Network criteria. The patients' demographic data and isolated organisms were reviewed. Duration of catheterization and the catheter-associated urinary tract infection occurrence rate were analyzed. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Among 1,890 catheterizations, 23 catheter-associated urinary tract infection cases were identified. The overall occurrence rate was 2.35/1,000 catheter-days. Among the patients with catheter-associated urinary tract infection, 13 were boys. The median age was 11 months (interquartile range, 7-35 mo), and the median duration of catheterization was 7 days (interquartile range, 5-12 d). The isolated bacteria were Escherichia coli (26.5%), Enterococcus faecalis (17.6%), and Klebsiella pneumoniae (11.8%). Two species were isolated in each of 11 cases (47.8%). Each additional day of catheterization increased the risk of catheter-associated urinary tract infection (odds ratio, 1.06; 95% CI, 1.02-1.10, and odds ratio adjusted for contact precaution status and surgical procedures was 1.05; 95% CI, 1.01-1.09). CONCLUSIONS: Longer duration of catheterization increased the risk of catheter-associated urinary tract infection by 5% each day at the PICU. Prompt removal of the urethral catheter is strongly recommended whenever feasible.

Effects of Verapamil and Pinacidil on Extracellular K+, pH, and the Incidence of Ventricular Fibrillation during 60 Minutes of Ischemia.

Ca++-channel antagonist verapamil and ATP-sensitive K+-channel opener pinacidil are known to decrease the rise in extracellular K+ ([K+]e) level and pH (pHe) that occurs during reversible acute myocardial ischemia and to lessen the accompanying activation delay. Verapamil is also known to decrease the incidence of ventricular tachycardia (VT)/fibrillation (VF) during acute myocardial ischemia; however, the effects of ATP-sensitive K+-channel opener on the incidence of VT/VF are controversial. We studied, in an in vivo pig model, the effects of verapamil and pinacidil on the changes in [K+]e level and pHe, local activation, and the incidence of VT/VF during 60 minutes of ischemia. Thirty-one pigs were divided into 2 groups: a verapamil group (9 control pigs and 8 verapamil-treated pigs) and pinacidil group (5 control pigs and 9 pinacidil-treated pigs). In the verapamil group, VF developed in 1 of the 9 control pigs, whereas no VF developed in 8 verapamil-treated pigs. In the pinacidil group, VF developed in 3 of the 5 control pigs and all 9 pinacidil-treated pigs. Under verapamil treatment (versus the control condition), onset of the second rise in [K+]e level was delayed, and the maximum rise in [K+]e level was decreased. Under pinacidil treatment (versus the control condition), time to the onset of VT/VF was shorter than that under the control condition, and VT/VF developed at lower [K+]e level and higher pHe. In conclusion, VF may develop at a lesser [K+]e rise and pHe fall in the presence of pinacidil during acute myocardial ischemia.

Impact of Sinus Node Recovery Time after Long-Standing Atrial Fibrillation Termination on the Long-Term Outcome of Catheter Ablation.

Atrial electrical and structural remodeling is related to the perpetuation of atrial fibrillation (AF) subsequent to sinus node dysfunction. We investigated the relationship between AF recurrence after catheter ablation and sinus node dysfunction in long-standing persistent AF patients using the sinus node recovery time (SNRT) after defibrillation.Fifty-one consecutive patients who underwent a first ablation for long-standing persistent AF were enrolled. Intracardiac cardioversion was applied before ablation in the absence of any antiarrhythmic drugs, and the power required to defibrillate, number, and SNRT after defibrillation were measured. All patients underwent the same designed radiofrequency catheter ablation procedure.No patient required permanent pacemaker implantation due to sinus dysfunction after the ablation. During the follow-up period of 28.4 months (3.6-43.7), 35 out of 51 patients (69%) experienced an AF recurrence. The AF recurrence was significantly associated with an older age (60 ± 11 versus 52 ± 12 years in the non-recurrence group, P = 0.0196), longer SNRT after defibrillation (1722 [1410-2656] versus 1295 [676-1651] msec, P = 0.0125), and larger left atrial (LA) volume (59 ± 25 versus 41 ± 15 mL, P = 0.0119). There were no significant differences in the AF duration, AF cycle length, and right and total atrial conduction times between the 2 groups. A longer SNRT after defibrillation (adjusted HR 2.13, 95%CI 1.16-3.71, P = 0.0152) and larger LA volume (adjusted HR 1.03, 95%CI 1.01-1.04, P = 0.0054) were independent predictors of AF recurrence after ablation.Assessment of the SNRT after defibrillation may help to predict a successful ablation in patients with long-standing persistent AF.

[A Case of Fatal Interstitial Pneumonia during FOLFIRI plus Cetuximab Therapy for Liver Metastasis of Colon Cancer].

The patient was a 76-year-old woman who underwent sigmoidectomy in April 2011 for sigmoid colon cancer with multiple concurrent liver metastases. She was treated postoperatively with mFOLFOX6 plus cetuximab but was diagnosed with the progressive disease at the end of course 14. The patient started receiving FOLFIRI plus cetuximab therapy in May 2012. Later in August 2012, she was examined for respiratory distress on the scheduled date of receiving course 7 and was diagnosed with drug-induced interstitial pneumonia resulting from systemic chemotherapy. The patient was administered oxygen, and her symptoms improved temporarily with steroid half-pulse and endotoxin adsorption therapy, but on inpatient day 10, her respiratory condition deteriorated. She was treated with steroid pulse therapy, but died of respiratory failure on inpatient day 17. The main adverse events associated with FOLFIRI plus cetuximab therapy are gastrointestinal symptoms, hematotoxicity, peripheral nerve damage, and dermatological symptoms. However, reports of respiratory conditions such as interstitial pneumonia are rare. Although the incidence is low, interstitial pneumonia can be severe and fatal and therefore requires close attention.

Programmed Ventricular Stimulation for Risk Stratification in the Brugada Syndrome: A Pooled Analysis.

BACKGROUND: The role of programmed ventricular stimulation in identifying patients with Brugada syndrome at the highest risk for sudden death is uncertain. METHODS AND RESULTS: We performed a systematic review and pooled analysis of prospective, observational studies of patients with Brugada syndrome without a history of sudden cardiac arrest who underwent programmed ventricular stimulation. We estimated incidence rates and relative hazards of cardiac arrest or implantable cardioverter-defibrillator shock. We analyzed individual-level data from 8 studies comprising 1312 patients who experienced 65 cardiac events (median follow-up, 38.3 months). A total of 527 patients were induced into arrhythmias with up to triple extrastimuli. Induction was associated with cardiac events during follow-up (hazard ratio, 2.66; 95% confidence interval [CI], 1.44-4.92, P<0.001), with the greatest risk observed among those induced with single or double extrastimuli. Annual event rates varied substantially by syncope history, presence of spontaneous type 1 ECG pattern, and arrhythmia induction. The lowest risk occurred in individuals without syncope and with drug-induced type 1 patterns (0.23%, 95% CI, 0.05-0.68 for no induced arrhythmia with up to double extrastimuli; 0.45%, 95% CI, 0.01-2.49 for induced arrhythmia), and the highest risk occurred in individuals with syncope and spontaneous type 1 patterns (2.55%, 95% CI, 1.58-3.89 for no induced arrhythmia; 5.60%, 95% CI, 2.98-9.58 for induced arrhythmia). CONCLUSIONS: In patients with Brugada syndrome, arrhythmias induced with programmed ventricular stimulation are associated with future ventricular arrhythmia risk. Induction with fewer extrastimuli is associated with higher risk. However, clinical risk factors are important determinants of arrhythmia risk, and lack of induction does not necessarily portend low ventricular arrhythmia risk, particularly in patients with high-risk clinical features.

Effects of Propranolol and Verapamil on Changes in TQ and ST Segment Potentials During Graded Coronary Flow Reduction in a Porcine Myocardial Ischemia Model.

Acute myocardial ischemia causes TQ depression and ST elevation. However, the effects of cardioprotective drugs such as ß-blockers and Ca++-antagonists on the extent of TQ depression, ST elevation, and myocardial ischemic injury are not fully understood.We created a carotid-coronary shunt in 30 pigs, and extracellular K+ ([K+]e), TQ, and ST segments were recorded simultaneously with K+-selective plunge electrodes placed in the left anterior descending artery (LAD) distribution during graded LAD flow reduction before and after administration of propranolol or verapamil. Unipolar DC-coupled electrograms were recorded from the reference pole of the K+-selective plunge electrodes. The microvolt readings from the K+-selective electrodes were converted to [K+]e and then to the changes in potassium equilibrium potential (ΔEK). The shunted LAD flow was reduced in a stepwise fashion at 5-minute intervals.segment depression at the similar ΔEK was not affected by propranolol or verapamil. However, ST segment elevation was reduced by propranolol but exacerbated by verapamil at the similar ΔEK.TQ-ST changes recorded by AC coupled ECG are not a reliable index of ischemia and therefore cannot be used to evaluate the effects of drugs that might affect the electrophysiologic properties of ischemic myocardium.

Ventriculoatrial Intervals ≤70 ms in Orthodromic Atrioventricular Reciprocating Tachycardia.

BACKGROUND: Although a ventriculoatrial interval (VAI) of ≤70 ms is used to distinguish atrioventricular nodal reentrant tachycardia from orthodromic atrioventricular reciprocating tachycardia (AVRT), a VAI of ≤70 ms is sometimes observed in cases of AVRT. The study aimed to evaluate the short VAI that is seen in AVRT and to understand its underlying mechanism. METHODS: Electrophysiologic studies of 46 consecutive patients with AVRT involving an accessory pathway (AP) were examined retrospectively. RESULTS: AP was right sided in seven patients and left sided in 39. A VAI (interval from QRS onset to the earliest intracardiac atrial electrogram recorded by any mapping catheter during AVRT) ≤70 ms during AVRT (short VAI) was observed in eight patients: six with a left lateral AP and two with a left posteroseptal AP. During AVRT involving a left-sided AP, the QRS-V interval (from the earliest QRS onset to the local ventricular electrogram at a site which showed earliest atrial electrogram recorded from the coronary sinus catheter) was significantly shorter (37 ± 7 ms vs 54 ± 13 ms, P = 0.001) and supernormal conduction (QRS duration or the QRS-V interval shortening by ≥10 ms during AVRT) was more frequently seen (63% vs 6%, P = 0.02) in the short VAI group than in the normal VAI group. Furthermore, these parameters were shown to be determinants for short VAI. CONCLUSIONS: A short VAI is sometimes observed during AVRT involving a left-sided AP. The short VAI may be caused by rapid propagation or supernormal conduction between the proximal Purkinje-muscle junction and basal left ventricular myocardium.

A nonsynonymous polymorphism in semaphorin 3A as a risk factor for human unexplained cardiac arrest with documented ventricular fibrillation.

Unexplained cardiac arrest (UCA) with documented ventricular fibrillation (VF) is a major cause of sudden cardiac death. Abnormal sympathetic innervations have been shown to be a trigger of ventricular fibrillation. Further, adequate expression of SEMA3A was reported to be critical for normal patterning of cardiac sympathetic innervation. We investigated the relevance of the semaphorin 3A (SEMA3A) gene located at chromosome 5 in the etiology of UCA. Eighty-three Japanese patients diagnosed with UCA and 2,958 healthy controls from two different geographic regions in Japan were enrolled. A nonsynonymous polymorphism (I334V, rs138694505A>G) in exon 10 of the SEMA3A gene identified through resequencing was significantly associated with UCA (combined P = 0.0004, OR 3.08, 95%CI 1.67-5.7). Overall, 15.7% of UCA patients carried the risk genotype G, whereas only 5.6% did in controls. In patients with SEMA3A(I334V), VF predominantly occurred at rest during the night. They showed sinus bradycardia, and their RR intervals on the 12-lead electrocardiography tended to be longer than those in patients without SEMA3A(I334V) (1031±111 ms versus 932±182 ms, P = 0.039). Immunofluorescence staining of cardiac biopsy specimens revealed that sympathetic nerves, which are absent in the subendocardial layer in normal hearts, extended to the subendocardial layer only in patients with SEMA3A(I334V). Functional analyses revealed that the axon-repelling and axon-collapsing activities of mutant SEMA3A(I334V) genes were significantly weaker than those of wild-type SEMA3A genes. A high incidence of SEMA3A(I334V) in UCA patients and inappropriate innervation patterning in their hearts implicate involvement of the SEMA3A gene in the pathogenesis of UCA.

Initial and Secondary ST-T Alternans During Acute Myocardial Ischemia in the In-Situ Pig Heart.

The factors responsible for the ST-T wave alternans (STTA) and associated arrhythmias during acute ischemia have not been clarified.In acutely ischemic porcine myocardium, we recorded transmural unipolar and bipolar electrocardiograms and mid-myocardial extracellular K(+) ([K(+)]e) from the center of the ischemic zone during 8-minute episodes of ischemia. Two different STTAs occurred. The initial STTA, which occurred at 4 minutes 15 seconds ± 12 seconds of ischemia during sinus rhythm, was most prominent in the subendocardium, independent of [K(+)]e and activation block, and heart rate dependent. It occurred in 13/19 (68%) occlusions at heart rates ≤ 100 bpm and in 22/23 (96%) at > 100 bpm. The second STTA was more obvious and greatest in the subepicardium. It began in the later phase of ischemia and was also heart rate dependent (5/19 [26%] occlusions at heart rates ≤ 100 bpm and 10/23 [44%] at > 100 bpm). This STTA was consistently associated with 2:1 change in the bipolar electrogram morphology, possibly due to 2:1 conduction block. Ventricular fibrillation (VF) occurred only at > 100 bpm.The initial STTA may be independent of conduction abnormalities and represent primary repolarization alternans. The second STTA may be secondary to and indicative of 2:1 activation block or marked alternans of the action potential amplitude/duration. The associated VF most likely reflects the underlying conduction abnormality.

MRI Mode Programming for Safe Magnetic Resonance Imaging in Patients With a Magnetic Resonance Conditional Cardiac Device.

Although diagnostically indispensable, magnetic resonance imaging (MRI) has been, until recently, contraindicated in patients with an implantable cardiac device. MR conditional cardiac devices are now widely used, but the mode programming needed for safe MRI has yet to be established. We reviewed the details of 41 MRI examinations of patients with a MR conditional device. There were no associated adverse events. However, in 3 cases, paced beats competed with the patient's own beats during the MRI examination. We describe 2 of the 3 specific cases because they illustrate these potentially risky situations: a case in which the intrinsic heart rate increased and another in which atrial fibrillation occurred. Safe MRI in patients with an MR conditional device necessitates detailed MRI mode programming. The MRI pacing mode should be carefully and individually selected.