Nepalese indoor cookstove smoke extracts alter human airway epithelial gene expression, DNA methylation and hydroxymethylation.

Household air pollution caused by inefficient cooking practices causes 4 million deaths a year worldwide. In Nepal, 86% of the rural population use solid fuels for cooking. Over 25% of premature deaths associated with air pollution are respiratory in nature. Here we aimed to identify molecular signatures of different cookstove and fuel type exposures in human airway epithelial cells, to understand the mechanisms mediating cook stove smoke induced lung disease. Primary human airway epithelial cells in submerged culture were exposed to traditional cook stove (TCS), improved cook stove (ICS) and liquefied petroleum gas (LPG) stove smoke extracts. Changes to gene expression, DNA methylation and hydroxymethylation were measured by bulk RNA sequencing and HumanMethylationEPIC BeadChip following oxidative bisulphite conversion, respectively. TCS smoke extract alone reproducibly caused changes in the expression of 52 genes enriched for oxidative stress pathways. TCS, ICS and LPG smoke extract exposures were associated with distinct changes to DNA methylation and hydroxymethylation. A subset of TCS induced genes were associated with differentially methylated and/or hydroxymethylated CpGs sites, and enriched for the ferroptosis pathway and the upstream regulator NFE2L2. DNA methylation and hydroxymethylation changes not associated with a concurrent change in gene expression, were linked to biological processes and molecular pathways important to airway health, including neutrophil function, transforming growth factor beta signalling, GTPase activity, and cell junction organisation. Our data identified differential impacts of TCS, ICS and LPG cook stove smoke on the human airway epithelium transcriptome, DNA methylome and hydroxymethylome and provide further insight into the association between indoor air pollution exposure and chronic lung disease mechanisms.

Preventative Effects of Cordyceps cicadae Mycelial Extracts on the Early-Stage Development of Cataracts in UVB-Induced Mice Cataract Model.

Cataracts, a prevalent age-related eye condition, pose a significant global health concern, with rising rates due to an aging population and increased digital device usage. In Taiwan, cataract prevalence is particularly high, reaching up to 90% among individuals aged 70 and above. The lens of the eye absorbs short-wave light, which can lead to oxidative stress in lens epithelial cells and contribute to cataract formation. Exposure to ultraviolet (UV) light further exacerbates the risk of cataracts by generating reactive oxygen species. Heat-shock proteins (HSPs), involved in protein maintenance and repair, have been linked to cataract development. Cordyceps cicadae (C. cicadae), a traditional Chinese medicine, has a long history of use and is known for its pharmacological effects. N6-(2-hydroxyethyl) adenosine (HEA), a bioactive compound found in C. cicadae, exhibits anti-inflammatory, immunomodulatory, and neuroprotective properties. Previous studies have shown that C. cicadae mycelial extracts improve dry eye disease and reduce intraocular pressure in animal models. Additionally, C. cicadae possesses antioxidant properties, which are beneficial for combating cataract formation. In this study, we aim to evaluate the preventive efficacy of C. cicadae mycelial extracts in UV-induced cataract development. By investigating the ameliorative effects of C. cicadae on eye diseases and its potential role in ocular health improvement, we hope to uncover new options for cataract prevention and provide insights into the mechanisms of action. The findings of this research could provide a novel approach for nutritional supplements targeting cataract prevention, offering potential benefits in the field of ocular health.

Efficacy of Cordyceps cicadae (Ascomycota) Mycelium Supplementation for Amelioration of Dry Eye Symptoms: A Randomized, Double-Blind Clinical Pilot Study.

Dry eye disease (DED), a multifactorial inflammatory ocular surface disorder, affects up to 50% of individuals over 50 years old worldwide and is one of the most common reasons for seeking ophthalmologic care. Generally, topical eye drops or oral drugs are administered to treat DED; however, the use of preservatives in eye drops or the adverse effects of oral drugs are disadvantageous for long-term therapy. Cordyceps cicadae, a traditional Chinese medicinal fungus, possesses anti-inflammatory effects without evident toxicity and is obtainable at low price. Our previous study demonstrated that C. cicadae mycelium effectively ameliorates dry eye symptoms in the benzalkonium chloride (BAC)-induced mouse dry eye model by increasing tear volume and tear film breakup time (TBUT). However, the effects of C. cicadae mycelium for human dry eye amelioration remains unknown. Thus, the present study investigated the mitigation of dry eye conditions and related discomforts through oral supplementation of fermented C. cicadae mycelium. A total of 70 healthy individuals were recruited and randomly allocated to receive a daily oral dose of 1,050 mg preparation in sachet containing either freeze-dried C. cicadae mycelium powder with 0.3 mg of adenosine and 1.5 mg of HEA per gram or placebo for 90 days. The participants were subjected to anthropometric measurements, dry eye questionnaires (DEQ), Schirmer's tests, intraocular pressure (IOP) measurements, tear film breakup time (TBUT) tests, tear osmolality measurements, and tear electrolyte analysis prior to and right after completion of the study. The results showed a significantly increased TBUT as well as a significant decrease in tear osmolarity, in parallel with the decrease of tear electrolytes, especially Na+ and Cl ions. Although significant increase of tear volume was not observed, the increased TBUT suggests mitigation of dry eye through improvement of tear quality. Therefore, C. cicadae mycelium supplementation may be used for dry eye alleviation as a novel therapeutic intervention.

Short-Term Hyperuricemia Leads to Structural Retinal Changes That Can be Reversed by Serum Uric Acid Lowering Agents in Mice.

Purpose: Metabolic disorders have been implicated in ocular diseases, such as age-related macular degeneration (AMD) and diabetic retinopathy (DR). Recently, hyperuricemia (HUA) has been proposed as another risk factor for AMD, although no cause-and-effect experimental data have been published. In this study, we investigated whether HUA would initiate AMD or related retinal damages in hyperuricemic mice. Methods: HUA was induced in male ICR mice by dietary supplements of uric acid and oxonic acid potassium salt, with or without treatments by allopurinol or benzbromarone for various durations. Serum uric acid and angiotensin II concentrations were measured by enzyme-linked immunosorbent assay (ELISA) at regular intervals. The retinal damages were assessed by hematoxylin and eosin staining, immunostaining, and TUNEL assay. The cause-and-effect of HUA was compared among the study groups. Results: The results showed that the total thickness of photoreceptor inner and outer segments, as well as the thickness of the photoreceptor outer segment alone, were reduced under HUA. Furthermore, HUA elevated serum angiotensin II, which indicated activation of the renin-angiotensin system (RAS), leading to higher matrix metalloproteinase-2 (MMP-2) expression, and glial activation in the ganglion cell layer. HUA also led to the reduction of retinal pigment epithelium gap junction protein connexin-43 and apoptosis. Uric acid lowering agents, allopurinol or benzbromarone, were effective in ameliorating the impairments. Conclusions: HUA may pose as a causative factor of retinal injuries. The reduction of serum uric acid may reduce the detrimental effects caused by HUA.

Substrate Characterization and Outcome of Catheter Ablation of Ventricular Tachycardia in Patients With Nonischemic Cardiomyopathy and Isolated Epicardial Scar.

BACKGROUND: The substrate for ventricular tachycardia (VT) in left ventricular (LV) nonischemic cardiomyopathy may be epicardial. We assessed the prevalence, location, endocardial electrograms, and VT ablation outcomes in LV nonischemic cardiomyopathy with isolated epicardial substrate. METHODS: Forty-seven of 531 (9%) patients with LV nonischemic cardiomyopathy and VT demonstrated normal endocardial (>1.5 mV)/abnormal epicardial bipolar low-voltage area (LVA, <1.0 mV and signal abnormality). Abnormal endocardial unipolar LVA (≤8.3 mV) and endocardial bipolar split electrograms and predictors of ablation success were assessed. RESULTS: Epicardial bipolar LVA (27.3 cm2 [interquartile range, 15.8-50.0]) localized to basal (40), mid (8), and apical (3) LV with basal inferolateral LV most common (28/47, 60%). Of 44 endocardial maps available, 40 (91%) had endocardial unipolar LVA (24.5 cm2 [interquartile range, 9.4-68.5]) and 29 (67%) had characteristic normal amplitude endocardial split electrograms opposite the epicardial LVA. At mean of 34 months, the VT-free survival was 55% after one and 72% after multiple procedures. Greater endocardial unipolar LVA than epicardial bipolar LVA (hazard ratio, 10.66 [CI, 2.63-43.12], P=0.001) and number of inducible VTs (hazard ratio, 1.96 [CI, 1.27-3.00], P=0.002) were associated with VT recurrence. CONCLUSIONS: In patients with LV nonischemic cardiomyopathy and VT, the substrate may be confined to epicardial and commonly basal inferolateral. LV endocardial unipolar LVA and normal amplitude bipolar split electrograms identify epicardial LVA. Ablation targeting epicardial VT and substrate achieves good long-term VT-free survival. Greater endocardial unipolar than epicardial bipolar LVA and more inducible VTs predict VT recurrence.

Health-related quality of life in patients with recurrent pericarditis: results from a phase 2 study of rilonacept.

BACKGROUND: Impact of recurrent pericarditis (RP) on patient health-related quality of life (HRQoL) was evaluated through qualitative patient interviews and as an exploratory endpoint in a Phase 2 trial evaluating the efficacy and safety of rilonacept (IL-1α/IL-1ß cytokine trap) to treat RP. METHODS: Qualitative interviews were conducted with ten adults with RP to understand symptoms and HRQoL impacts, and the 10-item Patient-Reported Outcomes Measurement Information System Global Health (PROMIS GH) v1.2 was evaluated to determine questionnaire coverage of patient experience. The Phase 2 trial enrolled participants with active symptomatic RP (A-RP, n = 16) and corticosteroid-dependent participants with no active recurrence at baseline (CSD-RP, n = 9). All participants received rilonacept weekly during a 6-week base treatment period (TP) plus an optional 18-week extension period (EP). Tapering of concomitant medications, including corticosteroids (CS), was permitted during EP. HRQoL was assessed using the PROMIS GH, and patient-reported pain and blood levels of c-reactive protein (CRP) were collected at Baseline and follow-up periods. A secondary, descriptive analysis of the Phase 2 trial efficacy results was completed using HRQoL measures to characterize both the impact of RP and the treatment effect of rilonacept. RESULTS: Information from qualitative interviews demonstrated that PROMIS GH concepts are relevant to adults with RP. From the Phase 2 trial, both participant groups showed impacted HRQoL at Baseline (mean PROMIS Global Physical Health [GPH] and Global Mental Health [GMH], were lower than population norm average). In A-RP, GPH/MPH improved by end of base TP and were sustained through EP (similar trends were observed for pain and CRP). Similarly, in CSD-RP, GPH/MPH improved by end of TP and further improved during EP, during CS tapering or discontinuation, without disease recurrence (low pain scores and CRP levels continued during the TP and EP). CONCLUSION: This is the first study demonstrating impaired HRQoL in RP. Rilonacept treatment was associated with HRQoL improvements using PROMIS GH scores. Maintained/improved HRQoL during tapering/withdrawal of CS without recurrence suggests that rilonacept may provide an alternative to CS. TRIAL REGISTRATION: ClinicalTrials.Gov; NCT03980522; 5 June 2019, retrospectively registered; https://clinicaltrials.gov/ct2/show/NCT03980522 .

Characterization of Structural Changes in Arrhythmogenic Right Ventricular Cardiomyopathy With Recurrent Ventricular Tachycardia After Ablation: Insights From Repeat Electroanatomic Voltage Mapping.

BACKGROUND: Data characterizing structural changes of arrhythmogenic right ventricular (RV) cardiomyopathy are limited. METHODS: Patients presenting with left bundle branch block ventricular tachycardia in the setting of arrhythmogenic RV cardiomyopathy with procedures separated by at least 9 months were included. RESULTS: Nineteen consecutive patients (84% males; mean age 39±15 years [range, 20-76 years]) were included. All 19 patients underwent 2 detailed sinus rhythm electroanatomic endocardial voltage maps (average 385±177 points per map; range, 93-847 points). Time interval between the initial and repeat ablation procedures was mean 50±37 months (range, 9-162). No significant progression of voltage was observed (bipolar: 38 cm2 [interquartile range (IQR), 25-54] versus 53 cm2 [IQR, 25-65], P=0.09; unipolar: 116 cm2 [IQR, 61-209] versus 159 cm2 [IQR, 73-204], P=0.36) for the entire study group. There was a significant increase in RV volumes (percentage increase, 28%; 206 mL [IQR, 170-253] versus 263 mL [IQR, 204-294], P<0.001) for the entire study population. Larger scars at baseline but not changes over time were associated with a significant increase in RV volume (bipolar: Spearman ρ, 0.6965, P=0.006; unipolar: Spearman ρ, 0.5743, P=0.03). Most patients with progressive RV dilatation (8/14, 57%) had moderate (2 patients) or severe (6 patients) tricuspid regurgitation recorded at either initial or repeat ablation procedure. CONCLUSIONS: In patients with arrhythmogenic RV cardiomyopathy presenting with recurrent ventricular tachycardia, >10% increase in RV endocardial surface area of bipolar voltage consistent with scar is uncommon during the intermediate term. Most recurrent ventricular tachycardias are localized to regions of prior defined scar. Voltage indexed scar area at baseline but not changes in scar over time is associated with progressive increase in RV size and is consistent with adverse remodeling but not scar progression. Marked tricuspid regurgitation is frequently present in patients with arrhythmogenic RV cardiomyopathy who have progressive RV dilation.

Catheter ablation of premature ventricular complexes with low intraprocedural burden guided exclusively by pace-mapping.

BACKGROUND: Catheter ablation (CA) of idiopathic premature ventricular complexes (PVCs) is typically guided by both activation and pace-mapping, with ablation ideally delivered at the site of the earliest local activation. However, activation mapping requires sufficient intraprocedural quantity of PVCs. This study aimed to investigate the outcome of CA of infrequent PVCs guided exclusively by pace-mapping. METHODS: We retrospectively analyzed all patients undergoing CA of idiopathic PVCs between 2014 and 2017. RESULTS: Among 327 patients, 24 (7.3%) had low intraprocedural PVC burden despite isoproterenol, including two patients with zero PVCs, rendering activation mapping impractical/impossible. All 24 had a history of symptomatic PVCs. During ablation, a median of 27 (17-55) pace-maps were performed, with best median PASO score of 97 (96-98)%. A median of 12 (8.75-18.75) radiofrequency (RF) lesions were delivered with 11.4 (8.5-17.6) minutes of total RF time. Clinical success, defined as more than 80% reduction in the burden of previously frequent PVCs and/or absence of symptoms as well as any documented clinical PVCs among those with infrequent or exercise-induced PVCs, was achieved in 19 (79%) patients over 9.2 (2.0-15.0) months of follow-up. CONCLUSIONS: When activation mapping cannot be performed due to inadequate intraprocedural PVC burden, detailed pace-mapping can frequently identify the precise arrhythmia site of origin, thereby guiding successful CA.

Comparison of the Ventricular Tachycardia Circuit Between Patients With Ischemic and Nonischemic Cardiomyopathies: Detailed Characterization by Entrainment.

BACKGROUND: There has been increasing awareness of the 3-dimensional nature of ventricular tachycardia (VT) circuits. VT circuits in patients with ischemic cardiomyopathies (ICM) and non-ICM (NICM) may differ in this regard. METHODS: Among patients with structural heart disease and at least 1 hemodynamically tolerated VT undergoing ablation, we retrospectively analyzed responses to all entrainment maneuvers. RESULTS: Of 445 patients (ICM 228, NICM 217) undergoing VT ablation, detailed entrainment mapping of at least 1 tolerated VT was performed in 111 patients (ICM 71, NICM 40). Of 89 ICM VTs, the isthmus could be identified by endocardial entrainment in 55 (62%), compared with only 8 of 47 (17%) NICM VTs ( P<0.01). With combined endocardial and epicardial mapping, the isthmus could be identified in 56 (63%) ICM VTs and 12 (26%) NICM VTs ( P<0.01), whereas any critical component (defined as entrance, isthmus or exit) could be identified in 76 (85%) ICM VTs and 37 (79%) NICM VTs ( P=0.3). Complete success (no inducible VT at the end of ablation, 82% versus 65%, P=0.04) and 1-year, single-procedure VT-free survival (82% versus 55%, P<0.01) were both higher among patients with ICM. CONCLUSIONS: Among mappable ICM VTs, critical circuit components can usually be identified on the endocardium. In contrast, among mappable NICM VTs, although some critical component can typically be identified with the addition of epicardial mapping, the isthmus is less commonly identified, possibly due to midmyocardial location.

Electrocardiographic and Electrophysiologic Characteristics of Idiopathic Ventricular Arrhythmias Originating From the Basal Inferoseptal Left Ventricle.

OBJECTIVES: This study sought to characterize ventricular arrhythmia (VA) ablated from the basal inferoseptal left ventricular endocardium (BIS-LVe) and identify electrocardiographic characteristics to differentiate from inferobasal crux (IBC) VA. BACKGROUND: The inferior basal septum is an uncommon source of idiopathic VAs, which can arise from its endocardial or epicardial (crux) aspect. Because the latter are often targeted from the coronary venous system or epicardium, distinguishing between the 2 is important for successful ablation. METHODS: Consecutive patients undergoing ablation of idiopathic VA from the BIS-LVe or IBC from 2009 to 2018 were identified and clinical characteristics and electrocardiographs of VA were compared. RESULTS: Of 931 patients undergoing idiopathic VA ablation, Virginia was eliminated from the BIS-LVe in 19 patients (2%) (17 male, age 63.7 ± 9.2 years, LV ejection fraction: 45.0 ± 9.3%). QRS complexes typically manifested right bundle branch block morphology with "reverse V2 pattern break" and left superior axis (more negative in lead III than II). VA elimination was achieved after median of 2 lesions (interquartile range [IQR]: 1-6; range 1 to 20) (radiofrequency ablation time: 123 s [IQR: 75-311]). Compared with 7 patients with IBC VA (3 male, age 51.9 ± 20.1 years, LV ejection fraction: 51.4 ± 17.7%), BIS-LVe VA less frequently had initial negative forces (QS pattern) in leads II, III, and/or aVF (p < 0.001), R-S ratio <1 in lead V1 (p = 0.005), and notching in lead II (p = 0.006) were narrower (QRS duration: 178.2 ± 22.4 vs. 221.1 ± 41.9 ms; p = 0.04) and more frequently had maximum deflection index of <0.55 (p < 0.001). CONCLUSIONS: The BIS-LVe region is an uncommon source of idiopathic VA. Distinguishing these from IBC VA is important for procedural planning and ablation success.

Long term follow-up after ventricular tachycardia ablation in patients with congenital heart disease.

BACKGROUND: Ventricular tachycardia (VT) is frequently encountered in patients with repaired and unrepaired congenital heart disease (CHD), causing significant morbidity and sudden cardiac death. Data regarding underlying VT mechanisms and optimal ablation strategies in these patients remain limited. OBJECTIVE: To describe the electrophysiologic mechanisms, ablation strategies, and long-term outcomes in patients with CHD undergoing VT ablation. METHODS: Forty-eight patients (mean age 41.3 ± 13.3 years, 77.1% male) with CHD underwent a total of 57 VT ablation procedures at two centers from 2000 to 2017. Electrophysiologic and follow-up data were analyzed. RESULTS: Of the 77 different VTs induced at initial or repeat ablation, the underlying mechanism in 62 (81.0%) was due to scar-related re-entry; the remaining included four His-Purkinje system-related macrore-entry VTs and focal VTs mainly originating from the outflow tract region (8 of 11, 72.7%). VT-free survival after a single procedure was 72.9% (35 of 48) at a median follow-up of 53 months. VT-free survival after multiple procedures was 85.4% (41 of 48) at a median follow-up of 52 months. There were no major complications. Three patients died during the follow-up period from nonarrhythmic causes, including heart failure and cardiac surgery complication. CONCLUSION: While scar-related re-entry is the most common VT mechanism in patients with CHD, importantly, nonscar-related VT may also be present. In experienced tertiary care centers, ablation of both scar-related and nonscar-related VT in patients with CHD is safe, feasible, and effective over long-term follow-up.

P-wave morphology and multipolar intracardiac atrial activation to facilitate nonpulmonary vein trigger localization.

INTRODUCTION: Nonpulmonary vein (non-PV) triggers of atrial fibrillation (AF) are targets for ablation but their localization remains challenging. The aim of this study was to describe P-wave (PW) morphologic characteristics and intra-atrial activation patterns and timing from multipolar coronary sinus (CS) and crista terminalis (CT) catheters that localize non-PV triggers. METHODS AND RESULTS: Selective pacing from six right and nine left atrial common non-PV trigger sites was performed in 30 consecutive patients. We analyzed 12 lead ECG features based on PW duration, amplitude and morphology, and patterns and timing of multipolar activation for all 15 sites. Regionalization and then precise localization required criteria present in at least 70% of assessments at each pacing site. The algorithm was then prospectively evaluated by four blinded observers in a validation cohort of 18 consecutive patients undergoing the same pacing protocol and 60 consecutive patients who underwent successful non-PV trigger ablation. The algorithm for site regionalization included 1) negative PW in V1, ≥30 µV change in PW amplitude across the leads V1-V3, and PW duration ≤100 milliseconds in lead 2 and 2) unique intra-atrial activation patterns and timing noted in the multipolar catheters. Specific ECG and intra-atrial activation timing characteristics included in the algorithm allowed for more precise site localization after regionalization. In the prospective evaluation, the algorithm identified the site of origin for 72% of paced and 70% of spontaneous non-PV trigger sites. CONCLUSION: An algorithm based on PW morphology and intra-atrial multipolar activation pattern and timing can help identify non-PV trigger sites of origin.

Feasibility of complex transfemoral electrophysiology procedures in patients with inferior vena cava filters.

BACKGROUND: The presence of inferior vena cava filters (IVCFs) has been considered a relative contraindication to electrophysiology (EP) procedures that require transfemoral venous placement of multiple catheters and/or long sheaths. There are inadequate data related to complex EP procedures in this population. OBJECTIVE: The purpose of this study was to describe the experience of a single high-volume center with respect to complex EP procedures in patients with IVCFs. METHODS: Patients with IVCFs undergoing complex EP procedures between 2004 and 2018 were identified. Clinical characteristics, IVCF type, procedural findings, and complications were analyzed. RESULTS: Fifty complex ablation procedures were performed in 40 patients (mean age 63.8 ± 10.9 years; 68% men). The mean IVCF dwell time was 69.1 ± 19.1 months, and 48 patients (96%) were on chronic oral anticoagulation. Procedures included ablation of atrial fibrillation (n = 21), ventricular tachycardia (n = 20), supraventricular tachycardia (n = 3), cavotricuspid isthmus flutter (n = 3), supraventricular tachycardia and cavotricuspid isthmus flutter (n = 1), and transvenous lead extraction (n = 3). Twenty procedures included quadripolar catheters (mean 1.4 ± 0.75), and 33 procedures involved deflectable decapolar catheters (mean 1.7 ± 0.47). Long sheaths were used in 35 cases (mean 1.63 ± 0.49) and intracardiac echocardiography in 38. In 4 cases (involving 3 patients), the IVCF was occluded and could not be crossed. There were no procedural complications related to the IVCF. CONCLUSION: The substantial majority of IVCFs in patients presenting for complex EP procedures were patent and easily crossed under fluoroscopic guidance. The presence of an IVCF should not discourage operators from performing procedures that require transfemoral deployment of multiple catheters and/or sheaths.

Importance of the Interventricular Septum as Part of the Ventricular Tachycardia Substrate in Nonischemic Cardiomyopathy.

OBJECTIVES: This study sought to characterize septal substrate in patients with nonischemic left ventricular cardiomyopathy (NILVCM) undergoing ventricular tachycardia (VT) ablation. BACKGROUND: The interventricular septum is an important site of VT substrate in NILVCM. METHODS: The authors studied 95 patients with NILVCM and VT. Electroanatomic mapping using standard bipolar (<1.5 mV) and unipolar (<8.3 mV) low-voltage criteria identified septal scar location and size. Analysis of unipolar voltage was performed and scars quantified using graded unipolar cutoffs from 4 to 8.3 mV were correlated with delayed gadolinium-enhanced cardiac magnetic resonance (DE-CMR), performed in 57 patients. RESULTS: Detailed LV endocardial mapping (mean 262 ± 138 points) showed septal bipolar and unipolar voltage abnormalities (VAs) in 44 (46%) and 79 (83%) patients, most commonly with basal anteroseptal involvement. Of the 59 patients in whom the septum was targeted, bipolar and unipolar septal VAs were seen in 36 (61%) and 54 (92%). Of the 35 with CMR-defined septal scar, bipolar and unipolar septal VAs were seen in 18 (51%) and 31 (89%). In 12 patients without CMR septal scar, 6 (50%) had isolated unipolar septal VAs on electroanatomic mapping, a subset of whom the septum was targeted for ablation (44%). In the graded unipolar analysis, the optimal cutoff associated with magnetic resonance imaging septal scar was 4.8 mV (sensitivity 75%, specificity 70%; area under the curve: 0.75; 95% confidence interval: 0.60 to 0.90). CONCLUSIONS: Septal substrate by unipolar or bipolar voltage mapping in patients with NILVCM and VT is common. A unipolar voltage cutoff of 4.8 mV provides the best correlation with DE-CMR. A subset of patients with septal VT had normal DE-CMR or endocardial bipolar voltage with abnormal unipolar voltage.

Characterization of the Electroanatomic Substrate in Cardiac Sarcoidosis: Correlation With Imaging Findings of Scar and Inflammation.

OBJECTIVES: This study sought to characterize the electroanatomic (EAM) substrate in patients with cardiac sarcoidosis (CS) and ventricular tachycardia and its relationship to imaging findings of inflammation and fibrosis. BACKGROUND: CS is characterized by coexistence of active inflammation and replacement fibrosis. METHODS: A total of 42 patients with CS based on established criteria and ventricular tachycardia underwent high-density EAM mapping. Abnormal electrograms (EGM) were collected and independently classified as multicomponent fractionated, isolated, late, and split according to standard criteria and regardless of the peak-to-peak bipolar/unipolar voltage. A total of 29 patients (69%) underwent pre-procedural cardiac magnetic resonance (CMR) and positron emission tomography (PET)/computed tomography (CT). The distribution of EAM substrate was correlated with regions of late gadolinium enhancement (LGE) on CMR and increased 18F-fluorodeoxyglucose uptake on PET/CT. RESULTS: Of 21,451 bipolar and unipolar EGM, 4,073 (19%) were classified as abnormal with a predominant distribution in the basal perivalvular segments and interventricular septum. Using the standard bipolar (<1.5 mV) and unipolar (<8.3 mV for left ventricle <5.5 mV for the right) voltage cutoff values, 40% and 22% of the abnormal EGM were located outside the EAM low-voltage areas, respectively. LGE was present in 26 of 29 patients (90%), whereas abnormal 18F-fluorodeoxyglucose uptake in 14 of 29 patients (48%) with imaging. Segments with abnormal EGM had more LGE-evident scar transmurality [median: 24% (interquartile range [IQR]: 4% to 40%) vs. median: 5% (IQR: 0% to 15%); p < 0.001] and lower metabolic activity (median: 20 g glucose [IQR: 14 g to 30 g] vs. median: 29 g glucose [IQR: 18 g to 39 g]; p < 0.001). Overall, the agreement between the presence of abnormal EGM was higher with the presence of LGE (κ = 0.51; p < 0.001) than with the presence of active inflammation (κ = -0.12; p = 0.003). CONCLUSIONS: In patients with CS and ventricular tachycardia, pre-procedural imaging with CMR and PET/CT can be useful in detecting EAM abnormalities that are potential targets for substrate ablation. Abnormal EGM were more likely located in segments with more scar transmurality (LGE) at CMR and a lower degree of inflammation on PET.

Identification of a small molecule inhibitor of the aminoglycoside 6'-N-acetyltransferase type Ib [AAC(6')-Ib] using mixture-based combinatorial libraries.

The aminoglycoside, 6'-N-acetyltransferase type Ib [AAC(6')-Ib] is the most widely distributed enzyme among AAC(6')-I-producing Gram-negative pathogens and confers resistance to clinically relevant aminoglycosides, including amikacin. This enzyme is therefore an ideal target for enzymatic inhibitors that could overcome resistance to aminoglycosides. The search for inhibitors was carried out using mixture-based combinatorial libraries, the scaffold ranking approach, and the positional scanning strategy. A library with high inhibitory activity had pyrrolidine pentamine scaffold and was selected for further analysis. This library contained 738,192 compounds with functionalities derived from 26 different amino acids (R1, R2 and R3) and 42 different carboxylic acids (R4) in four R-group functionalities. The most active compounds all contained S-phenyl (R1 and R3) and S-hydromethyl (R2) functionalities at three locations and differed at the R4 position. The compound containing 3-phenylbutyl at R4 (compound 206) was a robust enzymatic inhibitor in vitro, in combination with amikacin it potentiated the inhibition of growth of three resistant bacteria in culture, and it improved survival when used as treatment of Galleria mellonella infected with aac(6')-Ib-harboring Klebsiella pneumoniae and Acinetobacter baumannii strains.

Long-term outcome of surgical cryoablation for refractory ventricular tachycardia in patients with non-ischemic cardiomyopathy.

Aims: Limited data exist on the long-term outcome of patients (pts) with non-ischemic cardiomyopathy (NICM) and ventricular tachycardia (VT) refractory to conventional therapies undergoing surgical ablation (SA). We aimed to investigate the long-term survival and VT recurrence in NICM pts with VT refractory to radiofrequency catheter ablation (RFCA) who underwent SA. Methods and results: Consecutive pts with NICM and VT refractory to RFCA who underwent SA were included. VT substrate was characterized in the electrophysiology lab and targeted by RFCA. During SA, previous RFCA lesions/scars were identified and targeted with cryoablation (CA; 3 min/lesion; target -150 °C). Follow-up comprised office visits, ICD interrogations and the social security death index. Twenty consecutive patients with NICM who underwent SA (age 53 ± 16 years, 18 males, LVEF 41 ± 20%; dilated CM = 9, arrhythmogenic right ventricular CM = 3, hypertrophic CM = 2, valvular CM = 4, and mixed CM = 2) were studied. Percutaneous mapping/ablation in the electrophysiology lab was performed in 18 and 2 pts had primary SA. During surgery, 4.9 ± 4.0 CA lesions/pt were delivered to the endocardium (2) and epicardium (11) or both (7). VT-free survival was 72.5% at 1 year and over 43 ± 31 months (mos) (range 1-83mos), there was only one arrhythmia-related death. There was a significant reduction in ICD shocks in the 3-mos preceding SA vs. the entire follow-up period (6.6 ± 4.9 vs. 2.3 ± 4.3 shocks/pt, P = 0.001). Conclusion: In select pts with NICM and VT refractory to RFCA, SA guided by pre-operative electrophysiological mapping and ablation may be a therapeutic option.

Lack of prognostic value of atrial arrhythmia inducibility and change in inducibility status after catheter ablation of atrial fibrillation.

BACKGROUND: Previous studies have suggested a role of atrial arrhythmia inducibility as an endpoint of catheter ablation of atrial fibrillation (AF). The prognostic value of noninducibility after ablation and of a change in inducibility status has not been investigated in large studies. OBJECTIVE: The purpose of this study was to evaluate the prognostic role of noninducibility and of a change in inducibility status after ablation of AF. METHODS: We studied 305 consecutive patients with AF (66% paroxysmal) undergoing antral pulmonary vein (PV) isolation plus non-PV triggers ablation. All patients underwent a standardized induction protocol before and after ablation from the coronary sinus and right atrium: 15-beat burst pacing at 250 ms and decrementing to 180 ms (up to 20 µg/min isoproterenol). Inducibility was defined as any sustained AF or organized atrial tachycardia (AT) lasting >2 minutes. RESULTS: A total of 197 patients (65%) had inducible AF/AT at baseline compared to 118 (39%) after ablation. One hundred seven patients (57%) changed their inducibility status from inducible preablation to noninducible postablation. After 19 ± 7 months of follow-up, 212 patients (70%) remained free from any recurrent AF/AT. Noninducibility of AF/AT postablation (log-rank P = .236) or change in inducibility status (log-rank P = .429) was not associated with reduced risk of recurrent AF/AT. Results were consistent across the paroxysmal and nonparoxysmal subgroups. CONCLUSION: Noninducibility of atrial arrhythmia or change in inducibility status after PV isolation and non-PV trigger ablation is not associated with long-term freedom from recurrent arrhythmia and should not be used as an ablation endpoint or to support the appropriateness of additional ablation lesion sets.

Outcomes of Catheter Ablation of Idiopathic Outflow Tract Ventricular Arrhythmias With an R Wave Pattern Break in Lead V2: A Distinct Clinical Entity.

INTRODUCTION: In outflow tract ventricular arrhythmias (OT-VAs), an abrupt loss of the R wave in lead V2 compared to V1 and V3 (pattern break in V2-PBV2) suggests an origin close to the anterior interventricular sulcus (anatomically opposite to lead V2) and adjacent to proximal coronaries. We studied the outcome of catheter ablation of OT-VAs with a PBV2. METHODS AND RESULTS: Of 130 consecutive patients with idiopathic left bundle block morphology OT-VAs and transition ≤V4, 12 (9%) had PBV2. Outcomes in this group were compared to the remaining 118 patients. Patients with PBV2 were more likely to be younger (41 ± 18 vs. 50 ± 14 years, P = 0.0384) and women (11 [92%] vs. 70 [59%], P = 0.0302). The earliest activation was at the RVOT in seven, left coronary cusp (LCC) in one, anterior interventricular vein (AIV) in two and the epicardium in two. In five (42%) cases (earliest activation in the AIV in two, epicardium in two, and RVOT below the valve level in one), ablation was aborted due to proximity to the left anterior descending (LAD) coronary artery. After 36 ± 17 months and 1.3 ± 0.5 procedures, VAs elimination was achieved in 58% of patients with PBV2 compared to 89% of the reference population (P = 0.0125) with effective site in five of seven at the most anterior and leftward RVOT adjacent to the pulmonic valve (PV). CONCLUSIONS: OT-VAs with PBV2 demonstrate a unique ECG pattern and challenging catheter ablation. Proximity to LAD precludes ablation in about half. Long-term VA suppression could be achieved in only 58% of cases most commonly when the earliest site is at the anterior and leftward RVOT just under the PV.

Postoperative atrial tachycardias after mitral valve surgery: Mechanisms and outcomes of catheter ablation.

BACKGROUND: Atrial tachycardias (ATs) including atrial fibrillation are common arrhythmias occurring late after mitral valve (MV) surgery, and their management is challenging. OBJECTIVE: The purpose of this study was to determine the electrophysiological mechanisms of ATs in patients with prior MV surgery and the long-term outcomes of catheter ablation. METHODS: We studied 67 consecutive patients (mean age 59.4 ± 10.6 years; 41 men [61%]) with prior MV surgery who presented with ATs postoperatively between 2007 and 2015. RESULTS: AT was clinically documented before the electrophysiology study in 55 patients, whereas in the remaining 12 patients AT was inducible at the study. A total of 99 ATs (35 spontaneous and 64 inducible) were characterized. Overall, the right atrium (RA) was the chamber of origin in 56%. The underlying mechanism was macroreentry in 91 cases and included typical RA flutter (n = 37), mitral annular flutter (n = 21), incisional right AT (n = 16), roof-dependent reentry (n = 12), and local left atrial reentry (n = 5). Eight focal ATs were also documented: 6 from the left atrium and 2 from the RA. Left-sided ATs were more common in patients with prior Maze procedure (53%), and mitral annular flutter was twice as prevalent in this group (42% vs 21%; P = .05). The ablation was acutely successful in 98.5%. Freedom from atrial arrhythmias was 62% at 12 months, with 42% requiring more than 1 procedure. CONCLUSION: Macroreentry is the predominant AT mechanism in patients with prior MV surgery. Circuits are most often localized to the RA, with left-sided ATs more common in patients with prior Maze procedure. Repeat procedures are common and outcomes with 1 year complete AT control good.