Implantable cardioverter defibrillator use in arrhythmogenic right ventricular cardiomyopathy in North America and Europe.

BACKGROUND AND AIMS: Implantable cardioverter-defibrillators (ICDs) are critical for preventing sudden cardiac death (SCD) in arrhythmogenic right ventricular cardiomyopathy (ARVC). This study aims to identify cross-continental differences in utilization of primary prevention ICDs and survival free from sustained ventricular arrhythmia (VA) in ARVC. METHODS: This was a retrospective analysis of ARVC patients without prior VA enrolled in clinical registries from 11 countries throughout Europe and North America. Patients were classified according to whether they received treatment in North America or Europe and were further stratified by baseline predicted VA risk into low- (<10%/5 years), intermediate- (10%-25%/5 years), and high-risk (>25%/5 years) groups. Differences in ICD implantation and survival free from sustained VA events (including appropriate ICD therapy) were assessed. RESULTS: One thousand ninety-eight patients were followed for a median of 5.1 years; 554 (50.5%) received a primary prevention ICD, and 286 (26.0%) experienced a first VA event. After adjusting for baseline risk factors, North Americans were more than three times as likely to receive ICDs {hazard ratio (HR) 3.1 [95% confidence interval (CI) 2.5, 3.8]} but had only mildly increased risk for incident sustained VA [HR 1.4 (95% CI 1.1, 1.8)]. North Americans without ICDs were at higher risk for incident sustained VA [HR 2.1 (95% CI 1.3, 3.4)] than Europeans. CONCLUSIONS: North American ARVC patients were substantially more likely than Europeans to receive primary prevention ICDs across all arrhythmic risk strata. A lower rate of ICD implantation in Europe was not associated with a higher rate of VA events in those without ICDs.

A major lineage of non-tailed dsDNA viruses as unrecognized killers of marine bacteria.

The most abundant viruses on Earth are thought to be double-stranded DNA (dsDNA) viruses that infect bacteria. However, tailed bacterial dsDNA viruses (Caudovirales), which dominate sequence and culture collections, are not representative of the environmental diversity of viruses. In fact, non-tailed viruses often dominate ocean samples numerically, raising the fundamental question of the nature of these viruses. Here we characterize a group of marine dsDNA non-tailed viruses with short 10-kb genomes isolated during a study that quantified the diversity of viruses infecting Vibrionaceae bacteria. These viruses, which we propose to name the Autolykiviridae, represent a novel family within the ancient lineage of double jelly roll (DJR) capsid viruses. Ecologically, members of the Autolykiviridae have a broad host range, killing on average 34 hosts in four Vibrio species, in contrast to tailed viruses which kill on average only two hosts in one species. Biochemical and physical characterization of autolykiviruses reveals multiple virion features that cause systematic loss of DJR viruses in sequencing and culture-based studies, and we describe simple procedural adjustments to recover them. We identify DJR viruses in the genomes of diverse major bacterial and archaeal phyla, and in marine water column and sediment metagenomes, and find that their diversity greatly exceeds the diversity that is currently captured by the three recognized families of such viruses. Overall, these data suggest that viruses of the non-tailed dsDNA DJR lineage are important but often overlooked predators of bacteria and archaea that impose fundamentally different predation and gene transfer regimes on microbial systems than on tailed viruses, which form the basis of all environmental models of bacteria-virus interactions.

Increasing time between first diagnosis of atrial fibrillation and catheter ablation adversely affects long-term outcomes in patients with and without structural heart disease.

INTRODUCTION: Atrial Fibrillation (AF) is a common arrhythmia often comorbid with systolic or diastolic heart failure (HF). Catheter ablation is a more effective treatment for AF with concurrent left ventricular dysfunction, however, the optimal timing of use in these patients is unknown. METHODS: All patients that received a catheter ablation for AF(n = 9979) with 1 year of follow-up within the Intermountain Healthcare system were included. Patients with were identified by the presence of structural disease by ejection fraction (EF): EF ≤ 35% (n = 1024) and EF > 35% (n = 8955). Recursive partitioning categories were used to separate patients into clinically meaningful strata based upon time from initial AF diagnosis until ablation: 30-180(n = 2689), 2:181-545(n = 1747), 3:546-1825(n = 2941), and 4:>1825(n = 2602) days. RESULTS: The mean days from AF diagnosis to first ablation was 3.5 ± 3.8 years (EF > 35%: 3.5 ± 3.8 years, EF ≤ 35%: 3.4 ± 3.8 years, p = .66). In the EF > 35% group, delays in treatment (181-545 vs. 30-180, 546-1825 vs. 30-180, >1825 vs. 30-180 days) increased the risk of death with a hazard ratio (HR) of 2.02(p < .0001), 2.62(p < .0001), and 4.39(p < .0001) respectively with significant risks for HF hospitalization (HR:1.44-3.69), stroke (HR:1.11-2.14), and AF recurrence (HR:1.42-1.81). In patients with an EF ≤ 35%, treatment delays also significantly increased risk of death (HR 2.07-3.77) with similar trends in HF hospitalization (HR:1.63-1.09) and AF recurrence (HR:0.79-1.24). CONCLUSION: Delays in catheter ablation for AF resulted in increased all-cause mortality in all patients with differential impact observed on HF hospitalization, stroke, and AF recurrence risks by baseline EF. These data favor earlier use of ablation for AF in patients with and without structural heart disease.

Arrhythmic risk prediction in arrhythmogenic right ventricular cardiomyopathy: external validation of the arrhythmogenic right ventricular cardiomyopathy risk calculator.

AIMS: Arrhythmogenic right ventricular cardiomyopathy (ARVC) causes ventricular arrhythmias (VAs) and sudden cardiac death (SCD). In 2019, a risk prediction model that estimates the 5-year risk of incident VAs in ARVC was developed (ARVCrisk.com). This study aimed to externally validate this prediction model in a large international multicentre cohort and to compare its performance with the risk factor approach recommended for implantable cardioverter-defibrillator (ICD) use by published guidelines and expert consensus. METHODS AND RESULTS: In a retrospective cohort of 429 individuals from 29 centres in North America and Europe, 103 (24%) experienced sustained VA during a median follow-up of 5.02 (2.05-7.90) years following diagnosis of ARVC. External validation yielded good discrimination [C-index of 0.70 (95% confidence interval-CI 0.65-0.75)] and calibration slope of 1.01 (95% CI 0.99-1.03). Compared with the three published consensus-based decision algorithms for ICD use in ARVC (Heart Rhythm Society consensus on arrhythmogenic cardiomyopathy, International Task Force consensus statement on the treatment of ARVC, and American Heart Association guidelines for VA and SCD), the risk calculator performed better with a superior net clinical benefit below risk threshold of 35%. CONCLUSION: Using a large independent cohort of patients, this study shows that the ARVC risk model provides good prognostic information and outperforms other published decision algorithms for ICD use. These findings support the use of the model to facilitate shared decision making regarding ICD implantation in the primary prevention of SCD in ARVC.

Long-term outcomes in patients treated with flecainide for atrial fibrillation with stable coronary artery disease.

BACKGROUND: Class 1C antiarrhythmic drugs (AAD) have been associated with harm in patients treated for ventricular arrhythmias with a prior myocardial infarction. Consensus guidelines have advocated that these drugs not be used in patients with stable coronary artery disease (CAD). However, long-term data are lacking to know if unique risks exist when these drugs are used for atrial fibrillation (AF) in patients with CAD without a prior myocardial infarction. METHODS: In 24,315 patients treated with the initiation of AADs, two populations were evaluated: (1) propensity-matched AF patients with CAD were created based upon AAD class (flecainide, n = 1,114, vs class-3 AAD, n = 1,114) and (2) AF patients who had undergone a percutaneous coronary intervention or coronary artery bypass graft (flecainide, n = 150, and class-3 AAD, n = 1,453). Outcomes at 3 years for mortality, heart failure (HF) hospitalization, ventricular tachycardia (VT), and MACE were compared between the groups. RESULTS: At 3 years, mortality (9.1% vs 19.3%, P < .0001), HF hospitalization (12.5% vs 18.3%, P < .0001), MACE (22.9% vs 36.6%, P < .0001), and VT (5.8% vs 8.5%, P = .02) rates were significantly lower in the flecainide group for population 1. In population 2, adverse event rates were also lower, although not significantly, in the flecainide compared to the class-3 AAD group for mortality (20.9% vs 25.8%, P = .26), HF hospitalization (24.5% vs 26.1%, P = .73), VT (10.9% vs 14.7%, P = .28) and MACE (44.5% vs 49.5%, P = .32). CONCLUSIONS: Flecainide in select patients with stable CAD for AF has a favorable safety profile compared to class-3 AADs. These data suggest the need for prospective trials of flecainide in AF patients with CAD to determine if the current guideline-recommended exclusion is warranted.

Low voltage-guided ablation of posterior wall improves 5-year arrhythmia-free survival in persistent atrial fibrillation.

INTRODUCTION: The posterior wall (PW) has been proposed as a standard target for ablation beyond pulmonary vein antral isolation (PVI) in patients with persistent atrial fibrillation (AF). However, studies have shown inconsistent outcomes with the addition of PW ablation. The presence or absence of low voltage on the PW may explain these inconsistencies. We evaluated whether PW ablation based on the presence or absence of low voltage improves long-term arrhythmia-free outcomes. METHODS: We retrospectively reviewed 5-year follow-up in 152 consecutive patients who received either standard ablation (SA) with PVI alone or PVI + PW ablation (PWA) based on physician discretion (n = 77) or voltage-guided ablation (VGA) with PVI and addition of PWA only if low voltage was present on the PW (n = 75). RESULTS: The two groups were well matched for baseline characteristics. At 5-year follow-up, 64% of patients receiving VGA were atrial tachyarrhythmia (AT)/AF free compared to 34% receiving SA (HR 0.358 p < .005). PWA had similar AF recurrence in SA and VGA groups (0.30 vs. 0.27 p = .96) but higher AT recurrence when comparing SA and VGA groups (0.39 vs. 0.15 p = .03). In multivariate analysis, both VGA and PWA predicted AF arrhythmia-free survival (HR 0.33, p = .001 and HR 0.20, p = .008, respectively). For AT, VGA predicted arrhythmia-free survival (HR 0.22, p = .028), while PWA predicted AT recurrence (HR 4.704, p = .0219). CONCLUSION: VGA of the posterior wall ablation beyond PVI in persistent AF significantly improves long-term arrhythmia-free survival when compared with non-voltage-guided ablation. PW ablation without voltage-guidance reduced AF recurrence but at the cost of a higher incidence of AT.

Five-year impact of catheter ablation for atrial fibrillation in patients with a prior history of stroke.

BACKGROUND: Catheter ablation of atrial fibrillation (AF) is an established therapeutic rhythm approach. Patients with a prior history of a stroke (CVA) represent a unique high-risk population for recurrent thromboembolic events. The role of antiarrhythmic treatment on the natural history of stroke recurrence in these patients is not fully understood. METHODS: Three patient groups with a prior CVA and 5 years of follow-up were matched 1:3:3 by propensity score (±0.01): AF ablation patients receiving their first ablation (n  =  139), AF patients that did not receive an ablation (n  =  416), and CVA patients without clinical AF (n  =  416). Prior CVA was determined by medical chart review. Patients were followed for outcomes of recurrent CVA, heart failure, and death. RESULTS: The average age of the population was 69 ± 11 years and 51% male. AF ablation patients had higher rates of hypertension and heart failure (P < 0.0001), but diabetes prevalence was similar between the groups (P  =  0.5). Note that 5-year risk of CVA (HR  =  2.26, P < 0.0001) and death (HR  =  2.43, P < 0.0001) were higher in the AF, no ablation group compared those that were ablated. When comparing AF, ablation to no AF patients, there was not a significant difference in 5-year risk of for CVA (HR  =  0.82, P  =  0.39) and death (HR  =  0.92, P  =  0.70); however, heart failure risk was increased (HR  =  3.08, P  =  0.001). CONCLUSION: In patients with AF and a prior CVA, patients undergoing ablation have lower rates of recurrent stroke compared to AF patients not ablated. Although the full mechanisms of benefit are unknown, as CVA rates are similar to patients without AF these data are suggestive of a potential altering of the natural history of disease progression.

Vagus nerve injury symptoms after catheter ablation for atrial fibrillation.

BACKGROUND: Vagus nerve injury during catheter ablation for atrial fibrillation can significantly impact quality of life and result in lingering gastrointestinal symptoms. This study was designed to define risk factors of vagus nerve injury, symptoms, prevalence, and temporal resolution. METHODS: A total of 100 patients undergoing radiofrequency catheter ablation (RFCA) were enrolled and consented to participate in the study. Patients completed a 22-item questionnaire that included questions specific to vagus nerve injury symptomatology during their baseline visit and at 1 and 3 months post-RFCA. RESULTS: The average age of the population was 63 ± 10.6 years and 68% were male. A total of 100 patients completed their baseline questionnaire (90 patients completed the 1-month questionnaires and 85 patients completed the 3-month questionnaires). Symptoms rated as moderate were prevalent at baseline (trouble swallowing 13%, bloating 26%, feeling full 20%), and increased in all categories analyzed at 1 month and with the exception of trouble swallowing returned to the preablation percentages at 3 months (heartburn 22.4%, trouble swallowing 18.8%, bloating 16.5%, nausea 8.2%, vomiting 3.5%, constipation 18.8%, diarrhea 16.4%, feeling full 15.3%). Severe rated symptoms of trouble swallowing (2-5.5%), bloating (5-7.6%), and early satiety (5-9.8%) increased at 1 month and bloating and early satiety percentages remained approximately two times higher at 3 months (trouble swallowing 2.4%, bloating 8.2%, early satiety 7.1%). CONCLUSION: The majority of symptoms were resolved by 3 months, although those patients who rate bloating and early satiety at a severe rating may have persistent symptoms.

Circadian rhythms govern cardiac repolarization and arrhythmogenesis.

Sudden cardiac death exhibits diurnal variation in both acquired and hereditary forms of heart disease, but the molecular basis of this variation is unknown. A common mechanism that underlies susceptibility to ventricular arrhythmias is abnormalities in the duration (for example, short or long QT syndromes and heart failure) or pattern (for example, Brugada's syndrome) of myocardial repolarization. Here we provide molecular evidence that links circadian rhythms to vulnerability in ventricular arrhythmias in mice. Specifically, we show that cardiac ion-channel expression and QT-interval duration (an index of myocardial repolarization) exhibit endogenous circadian rhythmicity under the control of a clock-dependent oscillator, krüppel-like factor 15 (Klf15). Klf15 transcriptionally controls rhythmic expression of Kv channel-interacting protein 2 (KChIP2), a critical subunit required for generating the transient outward potassium current. Deficiency or excess of Klf15 causes loss of rhythmic QT variation, abnormal repolarization and enhanced susceptibility to ventricular arrhythmias. These findings identify circadian transcription of ion channels as a mechanism for cardiac arrhythmogenesis.

Atrial fibrillation incrementally increases dementia risk across all CHADS2 and CHA2DS2VASc strata in patients receiving long-term warfarin.

BACKGROUND: Patients with atrial fibrillation (AF) are at higher risk for developing dementia. Warfarin is a common therapy for the prevention of thromboembolism in AF, valve replacement, and thrombosis patients. The extent to which AF itself increases dementia risk remains unknown. METHODS: A total 6030 patients with no history of dementia and chronically anticoagulated with warfarin were studied. Warfarin management was provided through a Clinical Pharmacy Anticoagulation Service. Patients were stratified by warfarin indication of AF (n=3015) and non-AF (n=3015) and matched by propensity score (±0.01). Patients were stratified by the congestive heart failure, hypertension, age >75 years, diabetes, stroke (CHADS2) score calculated at the time of warfarin initiation and followed for incident dementia. RESULTS: The average age of the AF cohort was 69.3±11.2 years, and 52.7% were male; average age of non-AF cohort was 69.3±10.9 years, and 51.5% were male. Increasing CHADS2 score was associated with increased dementia incidence, P trend=.004. When stratified by warfarin indication, AF patients had an increased risk of dementia incidence. After multivariable adjustment, AF patients continued to display a significantly increased risk of dementia when compared with non-AF patients across all CHADS2 scores strata. CONCLUSIONS: In patients receiving long-term warfarin therapy, dementia risk increased with increasing CHADS2 scores. However, the presence of AF was associated with higher rates of dementia across all CHADS2 score strata. These data suggest that AF contributes to the risk of dementia and that this risk is not solely attributable to anticoagulant use. Dementia may be an end manifestation of a systemic disease state, and AF likely contributes to its progression.

Impact of Voltage Mapping to Guide Whether to Perform Ablation of the Posterior Wall in Patients With Persistent Atrial Fibrillation.

BACKGROUND: Fibrosis as a substrate for atrial fibrillation (AF) has been shown in numerous preclinical models. Voltage mapping enables in vivo assessment of scar in the left atrium (LA), which can be targeted with catheter ablation. OBJECTIVE: We hypothesized that using the presence or absence of low voltage to guide ablation beyond pulmonary vein antral isolation (PVAI) will improve atrial arrhythmia (AF/AT)-free survival in persistent AF. METHODS AND RESULTS: Single-center retrospective analysis of 2 AF ablation strategies: (1) standard ablation (SA) versus (2) voltage-guided ablation (VGA). PVAI was performed in both groups. With SA, additional lesions beyond PVAI were performed at the discretion of the operator. With VGA, additional lesions to isolate the LA posterior wall were performed if voltage mapping of this region in sinus rhythm showed scar (LA voltage < 0.5 mV). AF-/AT-free endpoint was defined as no sustained AF/AT seen off antiarrhythmic medications after a 2-month postablation blanking period. Seventy-six patients underwent SA and 65 underwent VGA. Patients were well matched for comorbidities, LVEF, and left atrial size. Posterior wall ablation was performed in 57% of patient with SA compared to 42% with VGA. VGA ablation increased 1-year AF-/AT-free survival in patients when compared to SA (80% vs. 57%; P = 0.005). In a multivariate analysis, VGA was the only independent predictor of AF-/AT-free survival (hazard ratio of 0.30; P = 0.002). CONCLUSIONS: The presence of LA posterior wall scar may be an important ablation target in persistent AF. A prospective randomized trial is needed to confirm these data.

A Comparison of Remote Magnetic Irrigated Tip Ablation versus Manual Catheter Irrigated Tip Catheter Ablation With and Without Force Sensing Feedback.

BACKGROUND: Remote magnetic navigation (RMN) and contact force (CF) sensing technologies have been utilized in an effort to improve safety and efficacy of catheter ablation. A comparative analysis of the relative short- and long-term outcomes of AF patients has not been performed. As such, we comparatively evaluated the safety and efficacy of these technologies. METHODS: A total of 627 patients who underwent catheter ablation with either a manual irrigated tip catheter: (312, 49.8%) or by RMN: (315, 50.2%) were included in this single-center cohort study. Patients treated with CF (59) were analyzed separately as well. One- and 3-year endpoints included death, HF hospitalization, stroke, TIA, and atrial flutter or AF recurrence. RESULTS: Age averaged 65.1 ± 10.7 years and 64.1% male. One- and 3-year endpoints of death, HF hospitalization, stroke, TIA, and atrial flutter or AF recurrence were statistically similar between manual and RMN treated groups. Fluoroscopy times were significantly lower in the RMN group compared to the manual ablation group (8.47 ± 0.45 vs. 9.63 ± 4.06 minutes, P < 0.0001). CF guided patients had 1-year recurrence rate of AF/atrial flutter statistically identical to patients treated with RMN (36.8% vs. 38.6%; P = 1.00). CONCLUSION: RMN results in outcomes similar to manual navigation. The addition of CF sensing catheters did not improve relative procedural outcome or safety profile in comparison to RMN guided ablation in this large observational study of AF ablation.

The Impact of Age on 5-Year Outcomes After Atrial Fibrillation Catheter Ablation.

BACKGROUND: Catheter ablation of atrial fibrillation (AF) is an established therapeutic rhythm approach in symptomatic patients. Many studies have shown that age has little to no impact on outcomes during the first year after ablation. However, AF is a disease of aging and age-based substrate for arrhythmia is likely to progress. To this regard, we examined patients with 5-year outcome data following an index AF ablation procedure to define the impact of age on long-term outcomes. METHODS: A total of 923 patients that underwent their index AF ablation and had 5 years of follow-up were studied. Patients were followed up for atrial flutter/AF recurrence, heart failure, stroke, death, and cardiac function. Patients were separated and compared in 5 age-based groups (<50, 51-60, 61-70, 71-80, >80). RESULTS: The average age of the population was 66 ± 11 years and 59% were male. The AF was paroxysmal in 55%, persistent in 27%, and longstanding persistent in 18%. Older patients were more likely female and had higher rates of cardiovascular diseases. For every 10-year increase in age there was a higher multivariate-adjusted risk of atrial flutter/AF recurrence (HR: 1.13, P = 0.01), death (HR:1.91, P < 0.0001), and major adverse cardiac events (HR: 1.09, P = 0.07). Although atrial flutter/AF recurrence rates by age were similar at 1 year, at 5 years, younger patients had significantly lower rates of recurrences. CONCLUSION: Age significantly impacts outcomes after AF ablation when analyzed with long-term follow-up. These data highlight the progressive nature of AF and the need to consider interventions early.

Percent Time With a Supratherapeutic INR in Atrial Fibrillation Patients Also Using an Antiplatelet Agent Is Associated With Long-Term Risk of Dementia.

BACKGROUND: Patients with atrial fibrillation (AF) are at higher risk of developing dementia. AF patients treated with warfarin with poor time in therapeutic ranges are significantly more likely to develop dementia. AF patients are also frequently treated with antiplatelet agents due to coexistent vascular disease. We hypothesize that AF patients with anticoagulation and antiplatelet therapies will be at higher risk of dementia, particularly with chronic exposure to over-anticoagulation. METHODS: Chronically anticoagulated patients receiving warfarin (target INR 2-3) for AF and managed by the Intermountain Healthcare Clinical Pharmacist Anticoagulation Service (CPAS) on concurrent antiplatelet agents with no history of dementia or stroke/TIA were included. The primary outcome was the presence of dementia defined by neurologist determined ICD-9 codes. Percent time with an INR>3.0 was determined and then compared by 3 strata <10% (n = 340), 10-24% (n = 417), ≥25% (n = 235). Multivariable Cox hazard regression was utilized to determine dementia incidence by percent time. RESULTS: A total of 992 patients were studied. Patients with an INR>3 more than 25% of the time were 2.40 times more likely to develop dementia (P = 0.04). A comparison between < 10% group and 10-24.9% group with INR>3 indicated no difference in risk for the development of dementia (P = 0.74). The risk was significantly increased in patients using triple antithrombotic therapy, although the number of patients within this group was small. CONCLUSION: In AF patients receiving antiplatelet and anticoagulant therapies, the percent of time exposed to over-anticoagulation increased dementia risk. These data support the possibility of chronic cerebral injury from microbleeds as a mechanism underlying the association of AF and dementia.

Five-year outcomes of catheter ablation in patients with atrial fibrillation and left ventricular systolic dysfunction.

BACKGROUND: Catheter ablation of atrial fibrillation (AF) is an established therapy for symptomatic patients. The long-term efficacy and impact of catheter ablation among patients with severe systolic heart failure (SHF) requires additional study to understand if outcomes achieved at 1 year are maintained and mechanisms of AF recurrence. METHODS: Three groups with SHF and 5 years of follow-up were matched 1:4:4 by age (±5 years) and sex: AF ablation patients receiving their first ablation (n = 267), AF patients that did not receive an ablation (n = 1,068), and SHF patient without AF (n = 1,068). SHF was based upon clinical diagnosis and an ejection fraction (EF) ≤35%. Patients were followed for 5-year primary outcomes of AF recurrence, heart failure, stroke, death, and cardiac function. RESULTS: At 5 years, 60.7% of patients had clinical recurrence of AF. Diabetes and a prior heart attack were significant predictors of long-term risk of AF recurrence. Long-term mortality rates were 27%, 55%, 50%, in the AF ablation, AF, and no AF groups, respectively (P < 0.0001), with the lower rates attributed to lower cardiovascular mortality. At 5 years, there was no difference in EF, yet HF hospitalizations were lower following AF ablation compared to patients with AF and no ablation. Stroke rates at 5 years trended to be lower in the AF ablation group, but the difference was not statistically significant. CONCLUSION: Recurrence rates of AF in patients with SHF after ablation are common at 5 years with an anticipated ongoing increase. Long-term AF-related comorbidities tended to be less in the AF ablation group.

Aberrant S-nitrosylation mediates calcium-triggered ventricular arrhythmia in the intact heart.

Nitric oxide (NO) derived from the activity of neuronal nitric oxide synthase (NOS1) is involved in S-nitrosylation of key sarcoplasmic reticulum (SR) Ca(2+) handling proteins. Deficient S-nitrosylation of the cardiac ryanodine receptor (RyR2) has a variable effect on SR Ca(2+) leak/sparks in isolated myocytes, likely dependent on the underlying physiological state. It remains unknown, however, whether such molecular aberrancies are causally related to arrhythmogenesis in the intact heart. Here we show in the intact heart, reduced NOS1 activity increased Ca(2+)-mediated ventricular arrhythmias only in the setting of elevated myocardial [Ca(2+)](i). These arrhythmias arose from increased spontaneous SR Ca(2+) release, resulting from a combination of decreased RyR2 S-nitrosylation (RyR2-SNO) and increased RyR2 oxidation (RyR-SOx) (i.e., increased reactive oxygen species (ROS) from xanthine oxidoreductase activity) and could be suppressed with xanthine oxidoreductase (XOR) inhibition (i.e., allopurinol) or nitric oxide donors (i.e., S-nitrosoglutathione, GSNO). Surprisingly, we found evidence of NOS1 down-regulation of RyR2 phosphorylation at the Ca(2+)/calmodulin-dependent protein kinase (CaMKII) site (S2814), suggesting molecular cross-talk between nitrosylation and phosphorylation of RyR2. Finally, we show that nitroso-redox imbalance due to decreased NOS1 activity sensitizes RyR2 to a severe arrhythmic phenotype by oxidative stress. Our findings suggest that nitroso-redox imbalance is an important mechanism of ventricular arrhythmias in the intact heart under disease conditions (i.e., elevated [Ca(2+)](i) and oxidative stress), and that therapies restoring nitroso-redox balance in the heart could prevent sudden arrhythmic death.

Inhibition of CaMKII phosphorylation of RyR2 prevents induction of atrial fibrillation in FKBP12.6 knockout mice.

RATIONALE: Abnormal calcium release from sarcoplasmic reticulum (SR) is considered an important trigger of atrial fibrillation (AF). Whereas increased Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) activity has been proposed to contribute to SR leak and AF induction, downstream targets of CaMKII remain controversial. OBJECTIVE: To test the hypothesis that inhibition of CaMKII-phosphorylated type-2 ryanodine receptors (RyR2) prevents AF initiation in FKBP12.6-deficient (-/-) mice. METHODS AND RESULTS: Mice lacking RyR2-stabilizing subunit FKBP12.6 had a higher incidence of spontaneous and pacing-induced AF compared with wild-type mice. Atrial myocytes from FKBP12.6-/- mice exhibited spontaneous Ca(2+) waves (SCaWs) leading to Na(+)/Ca(2+)-exchanger activation and delayed afterdepolarizations (DADs). Mutation S2814A in RyR2, which inhibits CaMKII phosphorylation, reduced Ca(2+) spark frequency, SR Ca(2+) leak, and DADs in atrial myocytes from FKBP12.6-/-:S2814A mice compared with FKBP12.6-/- mice. Moreover, FKBP12.6-/-:S2814A mice exhibited a reduced susceptibility to inducible AF, whereas FKBP12.6-/-:S2808A mice were not protected from AF. CONCLUSIONS: FKBP12.6 mice exhibit AF caused by SR Ca(2+) leak, Na(+)/Ca(2+)-exchanger activation, and DADs, which promote triggered activity. Genetic inhibition of RyR2-S2814 phosphorylation prevents AF induction in FKBP12.6-/- mice by suppressing SR Ca(2+) leak and DADs. These results suggest suppression of RyR2-S2814 phosphorylation as a potential anti-AF therapeutic target.

DNA phosphorothioation is widespread and quantized in bacterial genomes.

Phosphorothioate (PT) modification of DNA, with sulfur replacing a nonbridging phosphate oxygen, was recently discovered as a product of the dnd genes found in bacteria and archaea. Given our limited understanding of the biological function of PT modifications, including sequence context, genomic frequencies, and relationships to the diversity of dnd gene clusters, we undertook a quantitative study of PT modifications in prokaryotic genomes using a liquid chromatography-coupled tandem quadrupole mass spectrometry approach. The results revealed a diversity of unique PT sequence contexts and three discrete genomic frequencies in a wide range of bacteria. Metagenomic analyses of PT modifications revealed unique ecological distributions, and a phylogenetic comparison of dnd genes and PT sequence contexts strongly supports the horizontal transfer of dnd genes. These results are consistent with the involvement of PT modifications in a type of restriction-modification system with wide distribution in prokaryotes.

Clinical Management of Brugada Syndrome: Commentary From the Experts.

Although there is consensus on the management of patients with Brugada Syndrome with high risk for sudden cardiac arrest, asymptomatic or intermediate-risk patients present clinical management challenges. This document explores the management opinions of experts throughout the world for patients with Brugada Syndrome who do not fit guideline recommendations. Four real-world clinical scenarios were presented with commentary from small expert groups for each case. All authors voted on case-specific questions to evaluate the level of consensus among the entire group in nuanced diagnostic and management decisions relevant to each case. Points of agreement, points of controversy, and gaps in knowledge are highlighted.