Cryoablation with an 8-mm tip catheter in the treatment of atrioventricular nodal re-entrant tachycardia: results from a randomized controlled trial (CRYOABLATE).

AIMS: This was a randomized controlled study performed to compare 8 mm-tip catheter cryoablation (CRYO) with radiofrequency ablation (RFA) in treating atrioventricular nodal re-entrant tachycardia (AVNRT). METHODS AND RESULTS: A total of 158 patients (103 women, mean age 48.9 ± 14.1) with symptomatic AVNRT (140 typical; 18 atypical) were randomized to undergo CRYO with an 8 mm-tip catheter (n = 80) or RFA (n = 78). The primary endpoint was a composite of acute procedural failure, inadvertent permanent atrioventricular block (AVB) and recurrence at 12 months. No significant difference was observed between CRYO and RFA groups in primary endpoint (7.5 vs. 11.5%; P = 0.764), 12-month recurrence rate (3.8 vs. 1.3%; P = 0.358), inadvertent permanent AVB (0 vs. 1.3%; P = 0.307), and acute procedural failure (3.7 vs. 9%; P = 0.128). In patients with acute procedure failure, success was achieved in 5 of 7 patients (71.4%) in RFA group and 2 of 3 patients (66.7%) in CRYO group on cross-over. There was no significant difference in procedural duration between CRYO and RFA groups (72.4 ± 41.6 vs. 63.7 ± 29.8 min; P = 0.13), but fluoroscopic duration in CRYO group was significantly shorter (3.4 ± 6.3 vs. 6.7 ± 7.4 min; P = 0.005). Patient pain score (2.7 ± 2.7 vs. 4.6 ± 2.7; P < 0.001) and operator stress score (2.3 ± 1.3 vs. 4.9 ± 2; P < 0.001) were significantly lower in CRYO group. CONCLUSIONS: Cryoablation with an 8 mm-tip catheter is shown to be comparable to RFA in treating AVNRT in terms of efficacy and safety. Additional advantages in CRYO include shorter fluoroscopic time, lower patient pain perception, and operator stress level.

Type 8 long QT syndrome: pathogenic variants in CACNA1C-encoded Cav1.2 cluster in STAC protein binding site.

AIMS: Pathogenic gain-of-function variants in CACAN1C cause type-8 long QT syndrome (LQT8). We sought to describe the electrocardiographic features in LQT8 and utilize molecular modelling to gain mechanistic insights into its genetic culprits. METHODS AND RESULTS: Rare variants in CACNA1C were identified from genetic testing laboratories. Treating physicians provided clinical information. Variant pathogenicity was independently assessed according to recent guidelines. Pathogenic (P) and likely pathogenic (LP) variants were mapped onto a 3D modelled structure of the Cav1.2 protein. Nine P/LP variants, identified in 23 patients from 19 families with non-syndromic LQTS were identified. Six variants, found in 79% of families, clustered to a 4-residue section in the cytosolic II-III loop region which forms a region capable of binding STAC SH3 domains. Therefore, variants may affect binding of SH3-domain containing proteins. Arrhythmic events occurred in similar proportions of patients with II-III loop variants and with other P/LP variants (53% vs. 48%, P = 0.41) despite shorter QTc intervals (477 ± 31 ms vs. 515 ± 37 ms, P = 0.03). A history of sudden death was reported only in families with II-III loop variants (60% vs. 0%, P = 0.03). The predominant T-wave morphology was a late peaking T wave with a steep descending limb. Exercise testing demonstrated QTc prolongation on standing and at 4 min recovery after exercise. CONCLUSION: The majority of P/LP variants in patients with CACNA1C-mediated LQT8 cluster in an SH3-binding domain of the cytosolic II-III loop. This represents a 'mutation hotspot' in LQT8. A late-peaking T wave with a steep descending limb and QT prolongation on exercise are commonly seen.

Successful percutaneous retrieval of a leadless pacemaker due to an acute rise in pacing threshold.

Leadless cardiac pacemakers (LCP) have become available recently. Both its acute and long-term performance in a large population of patients remain to be tested. Subacute rise in pacing threshold has been reported as an uncommon complication. On the other hand, the retrieval technique for LCP with passive fixation mechanism has not been previously described in details. Herein we report a newly recognized complication of an acute rise in pacing threshold very soon after implantation of an LCP without radiographic dislodgement. Percutaneous retrieval of this LCP with passive fixation mechanism was successful using a novel technique with the cryoballoon steerable sheath and a snare.

Left ventricular volumes and systolic function after long-term right ventricular pacing may be predicted by paced QRS duration, but not pacing site.

BACKGROUND: Long-term right ventricular apical (RVA) pacing causes adverse left ventricular (LV) remodelling and clinical outcomes. METHODS: Forty-one patients (19 men, mean age 70.9±14.2, 23 right ventricular septal and 18 RVA pacing) underwent pacemaker implantation for atrioventricular block. LV volumes and left ventricular ejection fraction (LVEF) were assessed by echocardiography 39.3±17.2 months after implantation. Predictors of left ventricular systolic volume (LVESV), left ventricular diastolic volume (LVEDV) and LVEF were analysed. RESULTS: No difference was found between RVA pacing and right ventricular septal pacing groups in LVESV (40.6±22.6 vs 33±14.4ml; p=0.199), LVEDV (88.2±31.2 vs 73.7±23.9ml; p=0.102) and LVEF (56.1±8.6 vs 56±6.6%; p=0.996). With multivariate stepwise regression, only pQRSd and renal impairment independently predicted LVESV (ß=0.522, 95% CI: 0.242-0.802; p=0.001 and ß=40.3, 95% CI: 17.6-62.9; p=0.001 respectively), LVEDV (ß=0.786, 95% CI: 0.338-1.235; p=0.001 and ß=42.8, 95% CI: 6.6-79; p=0.022 respectively) and LVEF (ß=-0.161, 95% CI: -0.283 to -0.04; p=0.011 and ß=-14.8, 95% CI: -24.6 to -5.0; p=0.004 respectively). CONCLUSIONS: pQRSd and renal impairment, but not pacing site or baseline LVEF, may be predictors for LV volumes and systolic function after long-term RV pacing. pQRSd may be target for pacing site optimisation.

Attendance-related Healthcare Resource Utilisation and Costs in Patients With Brugada Syndrome in Hong Kong: A Retrospective Cohort Study.

Understanding health care resource utilisation and its associated costs are important for identifying areas of improvement regarding resource allocations. However, there is limited research exploring this issue in the setting of Brugada syndrome (BrS).This was a retrospective territory-wide study of BrS patients from Hong Kong. Healthcare resource utilisation for accident and emergency (A&E), inpatient and specialist outpatient attendances were analyzed over a 19-year period, with their associated costs presented in US dollars. A total of 507 BrS patients with a mean presentation age of 49.9 ± 16.3 years old were included. Of these, 384 patients displayed spontaneous type 1 electrocardiographic (ECG) Brugada pattern and 77 patients had presented with ventricular tachycardia/ventricular fibrillation (VT/VF). At the individual patient level, the median annualized costs were $110 (52-224) at the (A&E) setting, $6812 (1982-32414) at the inpatient setting and $557 (326-1001) for specialist outpatient attendances. Patients with initial VT/VF presentation had overall greater costs in inpatient ($20161 [9147-189215] vs $5290 [1613-24937],P < 0.0001) and specialist outpatient setting ($776 [438-1076] vs $542 [293-972],P = 0.015) compared to those who did not present VT. In addition, patients without Type 1 ECG pattern had greater median costs in the specialist outpatient setting ($7036 [3136-14378] vs $4895 [2409-10554],p=0.019). There is a greater health care demand in the inpatient and specialist outpatient settings for BrS patients. The most expensive attendance type was inpatient setting stay at $6812 per year. The total median annualized cost of BrS patients without VT/VF presentation was 78% lower compared to patients with VT/VF presentation.

Comparing the Performance of Published Risk Scores in Brugada Syndrome: A Multi-center Cohort Study.

The management of Brugada Syndrome (BrS) patients at intermediate risk of arrhythmic events remains controversial. The present study evaluated the predictive performance of different risk scores in an Asian BrS population and its intermediate risk subgroup. This retrospective cohort study included consecutive patients diagnosed with BrS from January 1, 1997 to June 20, 2020 from Hong Kong. The primary outcome is sustained ventricular tachyarrhythmias. Two novel risk risk scores and 7 machine learning-based models (random survival forest, Ada boost classifier, Gaussian naïve Bayes, light gradient boosting machine, random forest classifier, gradient boosting classifier and decision tree classifier) were developed. The area under the receiver operator characteristic curve (AUC) [95% confidence intervals] was compared between the different models. This study included 548 consecutive BrS patients (7% female, age at diagnosis: 50 ± 16 years, follow-up: 84 ± 55 months). For the whole cohort, the score developed by Sieira et al showed the best performance (AUC: 0.806 [0.747-0.865]). A novel risk score was developed using the Sieira score and additional variables significant on univariable Cox regression (AUC: 0.855 [0.808-0.901]). A simpler score based on non-invasive results only showed a statistically comparable AUC (0.784 [0.724-0.845]), improved using random survival forests (AUC: 0.942 [0.913-0.964]). For the intermediate risk subgroup (N = 274), a gradient boosting classifier model showed the best performance (AUC: 0.814 [0.791-0.832]). A simple risk score based on clinical and electrocardiographic variables showed a good performance for predicting VT/VF, improved using machine learning.

Persistent iatrogenic atrial septal defect after pulmonary vein isolation by cryoballoon: an under-recognized complication.

AIMS: Iatrogenic atrial septal defect (IASD) has been reported as a complication of transseptal puncture. This study aims to investigate the incidence, echocardiographic characteristics, and clinical outcome of persistent IASD after pulmonary vein isolation (PVI) by cryoballoon catheter delivered by a large transseptal sheath. METHODS AND RESULTS: Thirteen patients (9 males, mean age 54.9 ± 13.0) with paroxysmal (10) or persistent (3) atrial fibrillation underwent PVI with cryoballoon catheter. Single transseptal puncture was performed with a BRK-1 shaped Brockenbrough needle and an 8 F sheath which was exchanged for a steerable transseptal sheath (15 F outer diameter and 12 F inner diameter) with the support of a stiff guidewire. Pulmonary vein isolation was performed with a 28 mm cryoballoon catheter. The incidence of persistent IASD was evaluated by transoesophageal echocardiography performed at 6 and 9 months after the procedure. At 6 months, five (38%) patients had persistent IASD with left-to-right shunt. The mean size of the IASD was 5.5 ± 2.4 mm. At 9 months, one patient had closure of the IASD and four (31%) patients had persistent IASD with mean size of 4.6 ± 1.4 mm. No patient died or suffered clinically from paradoxical embolism. CONCLUSIONS: Persistent IASD is a common complication after PVI by cryoballoon catheter. Only left-to-right, but not right-to-left, interatrial shunting occurred as a result of the IASD. There was no clinical occurrence of paradoxical embolism. Patients should be screened for this complication after cryoballoon procedures and regular reassessment with echocardiographic or other techniques should be performed for monitoring.

Ventricular Tachyarrhythmia Risk in Paediatric/Young vs. Adult Brugada Syndrome Patients: A Territory-Wide Study.

Introduction: Brugada syndrome (BrS) is a cardiac ion channelopathy with a higher prevalence in Asia compared to the Western populations. The present study compared the differences in clinical and electrocardiographic (ECG) presentation between paediatric/young (≤25 years old) and adult (>25 years) BrS patients. Method: This was a territory-wide retrospective cohort study of consecutive BrS patients presenting to public hospitals in Hong Kong. The primary outcome was spontaneous ventricular tachycardia/ventricular fibrillation (VT/VF). Results: The cohort consists of 550 consecutive patients (median age of initial presentation = 51 ± 23 years; female = 7.3%; follow-up period = 83 ± 80 months), divided into adult (n = 505, mean age of initial presentation = 52 ± 19 years; female = 6.7%; mean follow-up period = 83 ± 80 months) and paediatric/young subgroups (n = 45, mean age of initial presentation = 21 ± 5 years, female = 13.3%, mean follow-up period = 73 ± 83 months). The mean annual VT/VF incidence rate were 17 and 25 cases per 1,000 patient-year, respectively. Multivariate analysis showed that initial presentation of type 1 pattern (HR = 1.80, 95% CI = [1.02, 3.15], p = 0.041), initial asymptomatic presentation (HR = 0.26, 95% CI = [0.07, 0.94], p = 0.040) and increased P-wave axis (HR = 0.98, 95% CI = [0.96, 1.00], p = 0.036) were significant predictors of VT/VF for the adult subgroup. Only initial presentation of VT/VF was predictive (HR = 29.30, 95% CI = [1.75, 492.00], p = 0.019) in the paediatric/young subgroup. Conclusion: Clinical and ECG presentation of BrS vary between the paediatric/young and adult population in BrS. Risk stratification and management strategies for younger patients should take into consideration and adopt an individualised approach.

Territory-wide cohort study of Brugada syndrome in Hong Kong: predictors of long-term outcomes using random survival forests and non-negative matrix factorisation.

OBJECTIVES: Brugada syndrome (BrS) is an ion channelopathy that predisposes affected patients to spontaneous ventricular tachycardia/fibrillation (VT/VF) and sudden cardiac death. The aim of this study is to examine the predictive factors of spontaneous VT/VF. METHODS: This was a territory-wide retrospective cohort study of patients diagnosed with BrS between 1997 and 2019. The primary outcome was spontaneous VT/VF. Cox regression was used to identify significant risk predictors. Non-linear interactions between variables (latent patterns) were extracted using non-negative matrix factorisation (NMF) and used as inputs into the random survival forest (RSF) model. RESULTS: This study included 516 consecutive BrS patients (mean age of initial presentation=50±16 years, male=92%) with a median follow-up of 86 (IQR: 45-118) months. The cohort was divided into subgroups based on initial disease manifestation: asymptomatic (n=314), syncope (n=159) or VT/VF (n=41). Annualised event rates per person-year were 1.70%, 0.05% and 0.01% for the VT/VF, syncope and asymptomatic subgroups, respectively. Multivariate Cox regression analysis revealed initial presentation of VT/VF (HR=24.0, 95% CI=1.21 to 479, p=0.037) and SD of P-wave duration (HR=1.07, 95% CI=1.00 to 1.13, p=0.044) were significant predictors. The NMF-RSF showed the best predictive performance compared with RSF and Cox regression models (precision: 0.87 vs 0.83 vs. 0.76, recall: 0.89 vs. 0.85 vs 0.73, F1-score: 0.88 vs 0.84 vs 0.74). CONCLUSIONS: Clinical history, electrocardiographic markers and investigation results provide important information for risk stratification. Machine learning techniques using NMF and RSF significantly improves overall risk stratification performance.

Territory-Wide Chinese Cohort of Long QT Syndrome: Random Survival Forest and Cox Analyses.

Introduction: Congenital long QT syndrome (LQTS) is a cardiac ion channelopathy that predisposes affected individuals to spontaneous ventricular tachycardia/fibrillation (VT/VF) and sudden cardiac death (SCD). The main aims of the study were to: (1) provide a description of the local epidemiology of LQTS, (2) identify significant risk factors of ventricular arrhythmias in this cohort, and (3) compare the performance of traditional Cox regression with that of random survival forests. Methods: This was a territory-wide retrospective cohort study of patients diagnosed with congenital LQTS between 1997 and 2019. The primary outcome was spontaneous VT/VF. Results: This study included 121 patients [median age of initial presentation: 20 (interquartile range: 8-44) years, 62% female] with a median follow-up of 88 (51-143) months. Genetic analysis identified novel mutations in KCNQ1, KCNH2, SCN5A, ANK2, CACNA1C, CAV3, and AKAP9. During follow-up, 23 patients developed VT/VF. Univariate Cox regression analysis revealed that age [hazard ratio (HR): 1.02 (1.01-1.04), P = 0.007; optimum cut-off: 19 years], presentation with syncope [HR: 3.86 (1.43-10.42), P = 0.008] or VT/VF [HR: 3.68 (1.62-8.37), P = 0.002] and the presence of PVCs [HR: 2.89 (1.22-6.83), P = 0.015] were significant predictors of spontaneous VT/VF. Only initial presentation with syncope remained significant after multivariate adjustment [HR: 3.58 (1.32-9.71), P = 0.011]. Random survival forest (RSF) model provided significant improvement in prediction performance over Cox regression (precision: 0.80 vs. 0.69; recall: 0.79 vs. 0.68; AUC: 0.77 vs. 0.68; c-statistic: 0.79 vs. 0.67). Decision rules were generated by RSF model to predict VT/VF post-diagnosis. Conclusions: Effective risk stratification in congenital LQTS can be achieved by clinical history, electrocardiographic indices, and different investigation results, irrespective of underlying genetic defects. A machine learning approach using RSF can improve risk prediction over traditional Cox regression models.

Paediatric/young versus adult patients with long QT syndrome.

INTRODUCTION: Long QT syndrome (LQTS) is a less prevalent cardiac ion channelopathy than Brugada syndrome in Asia. The present study compared the outcomes between paediatric/young and adult LQTS patients. METHODS: This was a population-based retrospective cohort study of consecutive patients diagnosed with LQTS attending public hospitals in Hong Kong. The primary outcome was spontaneous ventricular tachycardia/ventricular fibrillation (VT/VF). RESULTS: A total of 142 LQTS (mean onset age=27±23 years old) were included. Arrhythmias other than VT/VF (HR 4.67, 95% CI (1.53 to 14.3), p=0.007), initial VT/VF (HR=3.25 (95% CI 1.29 to 8.16), p=0.012) and Schwartz score (HR=1.90 (95% CI 1.11 to 3.26), p=0.020) were predictive of the primary outcome for the overall cohort, while arrhythmias other than VT/VF (HR=5.41 (95% CI 1.36 to 21.4), p=0.016) and Schwartz score (HR=4.67 (95% CI 1.48 to 14.7), p=0.009) were predictive for the adult subgroup (>25 years old; n=58). A random survival forest model identified initial VT/VF, Schwartz score, initial QTc interval, family history of LQTS, initially asymptomatic and arrhythmias other than VT/VF as the most important variables for risk prediction. CONCLUSION: Clinical and ECG presentation varies between the paediatric/young and adult LQTS population. Machine learning models achieved more accurate VT/VF prediction.

Incidence and predictors of atrial fibrillation in a Chinese cohort of Brugada syndrome.

BACKGROUND: Atrial electrophysiological abnormalities have previously been reported in Brugada syndrome. We investigated the incidence and electrocardiographic predictors of atrial fibrillation (AF) in a Chinese cohort of Brugada syndrome patients. METHODS: A retrospective study of Brugada syndrome patients admitted to tertiary centers in Hong Kong. RESULTS: A total of 275 patients were included (median age at presentation: 53 [40-64], 247 (90%) males) with a median follow-up duration of 67 (31-113) months. A total of 14 patients (5%) developed AF. Inter-atrial block and AV block were found in 36% (n = 100) and 13% (n = 37) of all patients. Compared to those in sinus rhythm, patients with AF showed significantly longer P-wave duration (PWD) (125 [116-137] vs. 114 [106-124] ms, P = 0.009) and PR interval (190 [163-214] vs. 169 [153-184] ms; P = 0.023). They were more likely to develop syncope (79 vs. 43%; P = 0.012) or VT/VF (43 vs. 14%; P = 0.012), undergo electrophysiological studies (36 vs. 19%; P = 0.005) and receive ICDs (71 vs. 25%; P = 0.001). Univariate logistic regression showed that mean PWD (odds ratio [OR]: 1.03 [1.00-1.06], P = 0.021), PR interval (OR: 1.02 [1.01-1.04]; P = 0.010) and QT interval (OR: 1.02 [1.00-1.04], P = 0.012), syncope (OR: 4.80 [1.31-17.61], P = 0.018) and R-wave amplitude in lead V5 (OR: 0.30 [0.09-1.00]; P = 0.05) significantly predicted incident AF. Receiver operating characteristic analysis revealed an optimum cut-off point of 123 ms and area under the curve of 0.71 for PWD. CONCLUSION: The incidence of AF was 5% in this cohort. PWD, PR and QT intervals significantly predicted AF and are simple electrocardiographic markers for identifying potential at-risk patients.

Identification of Novel SCN5A Single Nucleotide Variants in Brugada Syndrome: A Territory-Wide Study From Hong Kong.

BACKGROUND: The aim of this study is to report on the genetic composition of Brugada syndrome (BrS) patients undergoing genetic testing in Hong Kong. METHODS: Patients with suspected BrS who presented to the Hospital Authority of Hong Kong between 1997 and 2019, and underwent genetic testing, were analyzed retrospectively. RESULTS: A total of 65 subjects were included (n = 65, 88% male, median presenting age 42 [30-54] years old, 58% type 1 pattern). Twenty-two subjects (34%) showed abnormal genetic test results, identifying the following six novel, pathogenic or likely pathogenic mutations in SCN5A: c.674G > A, c.2024-11T > A, c.2042A > C, c.4279G > T, c.5689C > T, c.429del. Twenty subjects (31%) in the cohort suffered from spontaneous ventricular tachycardia/ventricular fibrillation (VT/VF) and 18 (28%) had incident VT/VF over a median follow-up of 83 [Q1-Q3: 52-112] months. Univariate Cox regression demonstrated that syncope (hazard ratio [HR]: 4.27 [0.95-19.30]; P = 0.059), prior VT/VF (HR: 21.34 [5.74-79.31; P < 0.0001) and T-wave axis (HR: 0.970 [0.944-0.998]; P = 0.036) achieved P < 0.10 for predicting incident VT/VF. After multivariate adjustment, only prior VT/VF remained a significant predictor (HR: 12.39 [2.97-51.67], P = 0.001). CONCLUSION: This study identified novel mutations in SCN5A in a Chinese cohort of BrS patients.

Outcomes in Brugada Syndrome Patients With Implantable Cardioverter-Defibrillators: Insights From the SGLT2 Registry.

BACKGROUND AND OBJECTIVES: Brugada syndrome (BrS) is a cardiac ion channelopathy with characteristic electrocardiographic patterns, predisposing affected individuals to sudden cardiac death (SCD). Implantable cardioverter-defibrillator (ICD) is used for primary or secondary prevention in BrS, but its use remains controversial amongst low-risk asymptomatic patients. The present study aims to examine indicators for ICD implantation amongst BrS patients with different disease manifestations. METHODS: This study included BrS patients who received ICDs between 1997 and 2018. The cohort was divided into three categories based on presentations before ICD implantation: asymptomatic, syncope, ventricular tachycardia/ventricular fibrillation (VT/VF). Univariate and multivariate Cox-regression analysis were performed to identify independent predictors of appropriate and inappropriate shock delivery. RESULTS: A total of 136 consecutive patients were included with a median follow-up of 95 (IQR: 80) months. Appropriate shocks were delivered in 34 patients (25.0%) whereas inappropriate shocks were delivered in 24 patients (17.6%). Complications occurred in 30 patients (22.1%). Type 1 Brugada pattern were found to be an independent predictor of appropriate shock delivery, whilst the presence of other arrhythmia was predictive for both appropriate and inappropriate ICD shock delivery under multivariate Cox regression analysis. CONCLUSION: ICD therapy is effective for primary and secondary prevention of SCD in BrS. Whilst appropriate shocks occur more frequently in BrS patients presenting with VT/VF, they also occur in asymptomatic patients. Further research in risk stratification can improve patient prognosis while avoid unnecessary ICD implantation.

Treatment of atrioventricular nodal re-entrant tachycardia by cryoablation with a 6 mm-tip catheter vs. radiofrequency ablation.

AIMS: To compare recurrence rate and other procedural characteristics in patients undergoing atrioventricular nodal re-entrant tachycardia (AVNRT) treatment with catheter cryoablation (CRYO) delivered by 6 mm-tip catheter or radiofrequency (RF) ablation. METHODS AND RESULTS: This is a retrospective case-control study including 80 patients with AVNRT treated with CRYO from March 2002 to June 2008. They were compared with another 80 consecutive patients who underwent RF ablation for AVNRT within the same period. Procedural success of 97.5 and 95% were achieved in CRYO and RF group, respectively. There was no permanent atrioventricular block (AVB) in the CRYO group, whereas two (2.5%) patients developed permanent first-degree or second-degree AVB in RF group (P = 0.155). Higher recurrence was found in the CRYO group (9 vs. 1.3%; P = 0.032) with no difference in the composite endpoint of procedural failure and recurrence between the groups (P = 0.263). There was significantly shorter fluoroscopy time (18.6 +/- 10.8 vs. 25.9 +/- 17.0 min; P = 0.002) and more energy applications required (3.1 +/- 1.7 vs. 1.9 +/- 1.1; P < 0.001) in the CRYO than the RF group. CONCLUSION: Compared with RF ablation, CRYO with 6 mm-tip catheter for treating AVNRT results in higher recurrence and potentially lower incidence of permanent AVB. Fluoroscopy time has been shown to be reduced by CRYO.

Binding to an Unusual Inactive Kinase Conformation by Highly Selective Inhibitors of Inositol-Requiring Enzyme 1α Kinase-Endoribonuclease.

A series of imidazo[1,2- b]pyridazin-8-amine kinase inhibitors were discovered to allosterically inhibit the endoribonuclease function of the dual kinase-endoribonuclease inositol-requiring enzyme 1α (IRE1α), a key component of the unfolded protein response in mammalian cells and a potential drug target in multiple human diseases. Inhibitor optimization gave compounds with high kinome selectivity that prevented endoplasmic reticulum stress-induced IRE1α oligomerization and phosphorylation, and inhibited endoribonuclease activity in human cells. X-ray crystallography showed the inhibitors to bind to a previously unreported and unusually disordered conformation of the IRE1α kinase domain that would be incompatible with back-to-back dimerization of the IRE1α protein and activation of the endoribonuclease function. These findings increase the repertoire of known IRE1α protein conformations and can guide the discovery of highly selective ligands for the IRE1α kinase site that allosterically inhibit the endoribonuclease.

Concomitant-acquired Long QT and Brugada syndromes associated with indapamide-induced hypokalemia and hyponatremia.

Electrolyte disturbances are known to cause acquired Long QT syndrome (LQTS) and Brugada syndrome. While a reduction in INa due to SCN5A mutation is implicated as the underlying mechanism in Brugada syndrome, hyponatremia, which can give rise to a reduced INa, has never been reported in literature as a cause or precipitating factor in this syndrome. We detailed a case in which concomitant-acquired LQTS and Brugada syndrome were associated with severe hypokalemia and hyponatremia following indapamide use for treatment of hypertension and highlighted the potential role of hyponatremia in the pathogenesis of the acquired form of Brugada syndrome.

A Molecular Hybridization Approach for the Design of Potent, Highly Selective, and Brain-Penetrant N-Myristoyltransferase Inhibitors.

Crystallography has guided the hybridization of two series of Trypanosoma brucei N-myristoyltransferase (NMT) inhibitors, leading to a novel highly selective series. The effect of combining the selectivity enhancing elements from two pharmacophores is shown to be additive and has led to compounds that have greater than 1000-fold selectivity for TbNMT vs HsNMT. Further optimization of the hybrid series has identified compounds with significant trypanocidal activity capable of crossing the blood-brain barrier. By using CF-1 mdr1a deficient mice, we were able to demonstrate full cures in vivo in a mouse model of stage 2 African sleeping sickness. This and previous work provides very strong validation for NMT as a drug target for human African trypanosomiasis in both the peripheral and central nervous system stages of disease.

Exercise-induced desaturation and electrocardiogram changes in people with severe lung disease: an exploratory investigation of 25 serial cases.

BACKGROUND: Arterial desaturation is a commonly accepted clinical basis for discontinuing physical activity in people with chronic obstructive pulmonary disease. OBJECTIVE: The purpose of this exploratory study was to examine the electrocardiograms of people with severe chronic obstructive pulmonary disease recovering from exercise-induced arterial desaturation. SUBJECTS: Subjects (n = 25) walked for 6 minutes while oxygen saturation was monitored. METHODS: When the Spo2 decreased below 90%, subjects were asked to sit and rest while the electrocardiograms were recorded. For all patients, Spo2 decreased 11.6% on average below baseline during walking. Four patients developed dysrhythmias during desaturation, with a mean lowest Spo2 of 85%. The Spo2 in six other patients continued to decrease below 80% despite rest, yet these patients did not develop new dysrhythmias. CONCLUSIONS: Our findings suggest that a decrease in Spo2 during exercise does not necessarily correlate with cardiac rhythm.