Impact of Clinical Characteristics and Biomarkers on Asthma Impairment and Risk Questionnaire Exacerbation Prediction Ability.

BACKGROUND: Complex models combining impairment-based control assessments with clinical characteristics and biomarkers have been developed to predict asthma exacerbations. The composite Asthma Impairment and Risk Questionnaire (AIRQ) with adjustments for demographics (age, sex, race, and body mass index) predicts 12-month exacerbation occurrence similarly to these more complex models. OBJECTIVE: To examine whether AIRQ exacerbation prediction is enhanced when models are adjusted for a wider range of clinical characteristics and biomarkers. METHODS: Patients aged 12 years and older completed monthly online surveys regarding exacerbation-related oral corticosteroid use, emergency department or urgent care visits, and hospitalizations. Univariate logistic regressions to predict exacerbations were performed with sociodemographics, comorbidities, exacerbation history, lung function, blood eosinophils, IgE, and FeNO. Significant (P ≤ .05) variables were included in multivariable logistic regressions with and without AIRQ control categories to predict 12-month exacerbations (log odds ratio [95% Wald confidence interval]). Model performances were compared. RESULTS: Over 12 months, 1,070 patients (70% female; mean [SD] age, 43.9 [19.4] years; 22% non-White; body mass index [SD], 30.6 [8.7]) completed one or more survey (mean [SD], 10.5 [2.8] surveys). In the multivariable analysis, AIRQ control category adjusted for significant clinical characteristics and biomarkers was predictive of one or more exacerbations: odds ratio (95% CI) not well-controlled versus well-controlled: 1.93 (1.41-2.62), very poorly controlled versus well-controlled: 3.81 (2.65-5.47). Receiver operating characteristic area under the curve (AUC) for this more complex model of exacerbation prediction (AUC = 0.72) did not differ from AIRQ (AUC = 0.70). Models with AIRQ performed better than those without AIRQ (AUC = 0.67; P < .05). CONCLUSION: Costly and time-consuming complex modeling with clinical characteristics and biomarkers does not enhance the strong exacerbation prediction ability of AIRQ.

Asthma control in the United States: relationships between short-acting ß2-agonist and systemic corticosteroid use.

BACKGROUND: Asthma control assessment is based on impairment (current symptoms) and risk (exacerbation history). OBJECTIVE: To understand the extent of uncontrolled asthma, we assessed relationships between prescription fills for systemic corticosteroids (SCS) and short-acting ß2-agonists (SABA) as risk and impairment markers, respectively. METHODS: Annual SCS and SABA fills among US patients with asthma were evaluated by a retrospective analysis of IQVIA Longitudinal Access and Adjudication Data. Patient severity was assigned based on GINA step-therapy level. Exacerbations were evaluated by SCS fills within 12 months of a first asthma prescription fill. Uncontrolled asthma was defined as ≥2 SCS and/or ≥3 SABA fills annually. Individual patient relationships between SCS and SABA fills were assessed by Pearson's correlation coefficient. RESULTS: 4,506,527 patients were included: 15% had ≥2 SCS fills, 29% had ≥3 SABA fills, 37% fulfilled either or both criteria. If only SCS were assessed, 22% treated as mild-to-moderate and 27% as severe asthma would have been misclassified as controlled. If only SABA use was evaluated, 8% treated as mild-to-moderate and 11% as severe asthma would have been misclassified. Overall, 81% of uncontrolled asthma occurred in patients treated for mild-to-moderate disease. Among patients with ≥2 SCS fills, mean SABA fills were 2.9; the correlation between SCS and SABA fills per patient was significant but weak (r=0.18; p<0.001). CONCLUSION: High symptom burden and SCS exposures are not limited to severe asthma but are also characteristic in patients treated for mild-to-moderate disease. Both impairment and risk assessments are required to understand the full extent of uncontrolled asthma across disease severities.

Advancing assessment of asthma control with a composite tool: The Asthma Impairment and Risk Questionnaire.

BACKGROUND: National and international asthma guidelines and reports do not include control tools that combine impairment assessment with exacerbation history in one instrument. OBJECTIVE: To analyze the performance of the composite Asthma Impairment and Risk Questionnaire (AIRQ) in assessing both domains of control and predicting exacerbation risk compared with the Global Initiative for Asthma (GINA) 4-question symptom control tool (GINA SCT), Asthma Control Test (ACT), and physician expert opinion (EO) informed by GINA SCT responses and appraisal of GINA-identified risk factors for poor asthma outcomes. METHODS: Multivariable logistic regressions evaluated AIRQ and GINA SCT as predictors of ACT. McNemar's test compared the proportion of patients categorized at baseline as completely or well-controlled by each assessment but with current impairment or previous-year and subsequent-year exacerbations. RESULTS: The analysis included 1064 patients aged 12 years or older; mean (SD) age 43.8 years (19.3); 70% female; 79% White; and 6% Hispanic or Latino. AIRQ and GINA SCT were highly predictive of ACT well-controlled vs not well-controlled and very poorly controlled (receiver operator characteristic area under curve AIRQ = 0.90, GINA SCT = 0.86, P = .03 AIRQ vs GINA SCT) and ACT very poorly controlled vs well-controlled and not well-controlled asthma (receiver operator characteristic area under curve AIRQ = 0.91, GINA SCT = 0.87, P = .01 AIRQ vs GINA SCT). AIRQ rated fewer patients as having completely or well-controlled asthma who had current impairment (P < .01) or with previous-year and subsequent-year exacerbations (P < .001) than did GINA SCT, ACT, and EO. CONCLUSION: AIRQ performs better in assessing both domains of current control and predicting exacerbation risk than do control tools and EO informed by GINA SCT and risk factors for poor asthma outcomes.

Assessing meaningful change in the Asthma Impairment and Risk Questionnaire.

BACKGROUND: The Asthma Impairment and Risk Questionnaire (AIRQ) is a 10-item, yes/no, equally weighted control tool. Lower scores indicate better control. Moreover, 7 impairment items reflect previous 2-week symptoms, and 3 risk items assess previous 12-month exacerbations. The Follow-up AIRQ for use between annual assessments has a 3-month recall period for exacerbation items. OBJECTIVE: To evaluate the responsiveness of the AIRQ over time and identify a minimal important difference (MID). METHODS: The AIRQ longitudinal study data were analyzed from patients with asthma aged 12 years and older. Anchor-based methods assessed differences in AIRQ scores relative to Patient Global Impression of Change, the accepted MIDs for St. George's Respiratory Questionnaire and Asthma Control Test, and exacerbation occurrence over 12 months. Baseline and 12-month data reflected 12-month recall AIRQ scores; Follow-up AIRQ scores were used for 3-, 6-, and 9-month analyses. RESULTS: A total of 1070 patients were included. The Patient Global Impression of Change rating of "much improved" was associated with AIRQ mean score changes from baseline to months 3, 6, 9, and 12 of -2.0, -1.9, -1.9, and -1.8, respectively. The mean AIRQ score change among patients who met the St. George's Respiratory Questionnaire MID (≥4-point decrease) was -1.8 at 6 and 12 months. The AIRQ mean scores decreased from baseline by -2.2 to -2.5 points at months 3, 6, 9, and 12 for patients who met the Asthma Control Test MID (≥ 3-point increase). A 2-point higher baseline AIRQ score was associated with a 1.7 odds ratio of 12-month exacerbation occurrence (95% CI, 1.53-1.89). CONCLUSION: A change score of 2 is recommended as the AIRQ MID.

Impact of Lung Function on Asthma Exacerbation Rates in Children Treated with Dupilumab: The VOYAGE Study.

Background: Severe, uncontrolled asthma and asthma exacerbations in children are associated with abnormal lung function and airway development, and increased risk of chronic obstructive lung disease in adulthood. The rationale for this post hoc analysis was to explore the relationship between changes in asthma exacerbation rates and lung function in children treated with dupilumab. Methods: This post hoc analysis included children aged 6 to 11 years with uncontrolled, moderate-to-severe type 2 asthma (blood eosinophils ≥150 cells/µL or fractional exhaled nitric oxide ≥20 ppb) who received dupilumab or placebo in the phase 3 LIBERTY ASTHMA VOYAGE study (NCT02948959). Endpoints were the proportion of patients achieving clinically meaningful improvements (≥5% or ≥10%) in pre-bronchodilator percent-predicted forced expiratory volume in 1 second (ppFEV1) by Week 12, annualized severe asthma exacerbation rates from Week 12-52, and mean change from baseline in ppFEV1 to Week 12. Results: At Week 12 of VOYAGE, 141/236 (60%) of children treated with dupilumab and 57/114 (50%) of children receiving placebo showed improvements of ≥5% in ppFEV1; 106/236 (45%) children receiving dupilumab and 36/114 (32%) receiving placebo achieved improvements in ppFEV1 ≥10%. During the Week 12-52 treatment period, dupilumab vs placebo significantly reduced severe exacerbation rates in all subgroups by 52-60% (all P<0.05). Dupilumab treatment resulted in rapid and sustained improvements in ppFEV1 (Week 12 least squares mean difference [95% CI] vs placebo: 3.54 [0.30, 6.78] percentage points; P=0.03) in children who achieved improvements of ≥5%. Conclusion: Dupilumab vs placebo significantly improved pre-bronchodilator ppFEV1, with a higher proportion of patients achieving a clinically meaningful response at Week 12. Dupilumab also significantly reduced severe exacerbation rates, independent of pre-bronchodilator ppFEV1 response at Week 12. Trial Registration: NCT02948959.

Myofibroblast senescence promotes arrhythmogenic remodeling in the aged infarcted rabbit heart.

Progressive tissue remodeling after myocardial infarction (MI) promotes cardiac arrhythmias. This process is well studied in young animals, but little is known about pro-arrhythmic changes in aged animals. Senescent cells accumulate with age and accelerate age-associated diseases. Senescent cells interfere with cardiac function and outcome post-MI with age, but studies have not been performed in larger animals, and the mechanisms are unknown. Specifically, age-associated changes in timecourse of senescence and related changes in inflammation and fibrosis are not well understood. Additionally, the cellular and systemic role of senescence and its inflammatory milieu in influencing arrhythmogenesis with age is not clear, particularly in large animal models with cardiac electrophysiology more similar to humans than previously studied animal models. Here, we investigated the role of senescence in regulating inflammation, fibrosis, and arrhythmogenesis in young and aged infarcted rabbits. Aged rabbits exhibited increased peri-procedural mortality and arrhythmogenic electrophysiological remodeling at the infarct border zone (IBZ) compared to young rabbits. Studies of the aged infarct zone revealed persistent myofibroblast senescence and increased inflammatory signaling over a 12-week timecourse. Senescent IBZ myofibroblasts in aged rabbits appear to be coupled to myocytes, and our computational modeling showed that senescent myofibroblast-cardiomyocyte coupling prolongs action potential duration (APD) and facilitates conduction block permissive of arrhythmias. Aged infarcted human ventricles show levels of senescence consistent with aged rabbits, and senescent myofibroblasts also couple to IBZ myocytes. Our findings suggest that therapeutic interventions targeting senescent cells may mitigate arrhythmias post-MI with age.

The Asthma Impairment and Risk Questionnaire enhances the assessment of asthma control.

BACKGROUND: Asthma control is often overestimated in routine practice, and despite advances in the understanding of immunopathology and the availability of new precision therapies, the burden of disease remains unacceptably high. OBJECTIVE: To compare the performance of the Asthma Impairment and Risk Questionnaire (AIRQ) with patient and physician assessments and the Asthma Control Test (ACT) in identifying asthma control. METHODS: Baseline data from a longitudinal study of the AIRQ were analyzed. Patients with asthma in the United States aged 12 years and older followed in 24 specialty practices and 1 specialty-affiliated primary care clinic were enrolled between May and November 2019. At entry, participants completed AIRQ and ACT, and participants and physicians completed 5-point Likert scale assessments of control. RESULTS: A total of 1112 participants were enrolled (mean [SD] age = 43.9 [19.3] years, 70% of the female sex, 78% White). Overall, 62% of participants rated themselves as well- or completely controlled, and 54% were rated comparably by physicians. The ACT classified 49% of participants as well-controlled, with 35% similarly categorized by AIRQ. Previous-year exacerbations were experienced by 32% of participants who self-rated as well- or completely controlled, 30% who were rated as well- or completely controlled by physicians, and 29% assessed as well-controlled by ACT, but only 15% of those classified as well-controlled by AIRQ. CONCLUSION: The burden of asthma is substantial in patients cared for by asthma specialists, and asthma control is overestimated by patients, physicians, and the symptom-based ACT. The AIRQ assesses risk in addition to symptom control and may serve to improve asthma control determination by assessing previous exacerbations.

Relationship Between Asthma Control as Measured by the Asthma Impairment and Risk Questionnaire (AIRQ) and Patient Perception of Disease Status, Health-Related Quality of Life, and Treatment Adherence.

Purpose: Critical asthma outcomes highlighted in clinical guidelines include asthma-related quality of life, asthma exacerbations, and asthma control. An easy-to-implement measure of asthma control that assesses both symptom impairment and exacerbation risk and reflects the impact of asthma on patients' lives is lacking. Hence, the objective of this study was to assess the Asthma Impairment and Risk Questionnaire (AIRQ®) construct validity relative to patient self-perception of asthma status and validated disease-specific patient-reported outcome (PRO) measures. Patients and methods: Baseline data were analyzed from patients (aged ≥ 12 years) with asthma participating in a 12-month observational study assessing the ability of AIRQ to predict exacerbations. At entry, patients completed a sociodemographic questionnaire, AIRQ, 3 questions addressing self-perceived asthma status, Saint George's Respiratory Questionnaire (SGRQ), mini-Asthma Quality of Life Questionnaire (AQLQ), and Adult Asthma Adherence Questionnaire (AAAQ). Descriptive statistics were calculated for demographic and clinical characteristics. AIRQ construct validity was evaluated by assessing correlations between total AIRQ score and patient self-assessments, SGRQ, mini-AQLQ, and AAAQ scores. Comparisons of SGRQ, mini-AQLQ, and AAAQ total and component/domain scores by AIRQ control category were performed using general linear models and Scheffe's post hoc adjustments for pairwise comparisons. Results: A total of 1112 patients were enrolled: 70% female, 78% White, mean (standard deviation) age 43.9 (19.5) years. There were highly significant correlations between AIRQ score and patient self-perception of overall control (r = 0.69; p < 0.001), total SGRQ (r = 0.74, p < 0.001), and mini-AQLQ (r = -0.78, p < 0.001) scores. As AIRQ control category worsened, so did total and domain SGRQ, mini-AQLQ, and AAAQ impediment-to-inhaled-corticosteroid-adherence scores (all pairwise comparisons p < 0.001). Conclusion: Findings demonstrate the construct validity of AIRQ relative to patient self-perception of asthma status, disease-specific PRO measures, and treatment adherence barriers. AIRQ can be a useful instrument to raise awareness of the unrecognized impacts of asthma on patients' lives.

Identifying Patients for Self-Administration of Omalizumab.

Omalizumab, a recombinant anti-immunoglobulin E (IgE) monoclonal antibody, is indicated for moderate to severe allergic asthma, chronic spontaneous urticaria, and nasal polyps, and is approved for self-administration. However, specific guidance on identifying candidates with characteristics suitable for this type of administration is lacking. To help address this issue, this article provides practical considerations for the health care provider treating patients with omalizumab. We encourage health care providers to consider self-administration of omalizumab as an option for all appropriate, but not all, patients, and we recommend an individualized approach when considering self-administration of omalizumab.

The Asthma Impairment and Risk Questionnaire (AIRQ) Control Level Predicts Future Risk of Asthma Exacerbations.

BACKGROUND: The Asthma Impairment and Risk Questionnaire (AIRQ) is a 10-item, equally weighted, yes/no control tool validated in patients with asthma aged 12 years and older. OBJECTIVE: To evaluate AIRQ's ability to predict patient-reported exacerbations over 12 months. METHODS: Patients completed a baseline AIRQ during an in-person enrollment visit and reported exacerbations (ie, asthma-related courses of oral corticosteroids, emergency department/urgent care visits, and hospitalizations) via monthly online surveys. Logistic regressions were performed using AIRQ control level (well-controlled [WC], not well-controlled [NWC], very poorly controlled [VPC]), age, sex, race, and body mass index as covariates and 1 or more and 2 or more exacerbations as the dependent variables (adjusted odds ratios [OR] and 95% Wald CIs). Kaplan-Meier analyses of time to first exacerbation by AIRQ control level were performed. RESULTS: A total of 1,112 patients were enrolled; 1,070 completed 1 or more surveys over 12 months (mean ± SD 10.5 ± 2.8 months); 70.5% female; age 43.9 ± 19.3 years; 20.4% non-White; body mass index 30.6 ± 8.7 kg/m2; AIRQ: WC 35.2%, NWC 38.1%, VPC 26.6%. A total of 45.7% of patients reported 1 or more exacerbations and 26.7% 2 or more exacerbations (WC 28.4% ≥ 1, 11.1% ≥ 2; NWC 46.3% ≥ 1, 27.9% ≥ 2; VPC 67.7% ≥ 1, 45.6% ≥ 2). The ORs for 1 or more exacerbations NWC versus WC were 2.1 (CI 1.6-2.9), and VPC versus WC were 4.6 (CI 3.3-6.5). The ORs for 2 or more exacerbations NWC versus WC were 3.1 (CI 2.1-4.6), and VPC versus WC were 6.1 (CI 4.0-9.1). Kaplan-Meier curves demonstrated clear differentiation of time to first exacerbation by AIRQ control level (P < .001). CONCLUSIONS: The AIRQ control level predicts exacerbation risk over 12 months and probability of time to first exacerbation.

Evaluating construct validity of the Asthma Impairment and Risk Questionnaire using a 3-month exacerbation recall.

BACKGROUND: Recurrent assessment of asthma control is essential to evaluating disease stability and intervention impacts. An assessment that can be administered between annual clinic visits is needed. The Asthma Impairment and Risk Questionnaire (AIRQ) is a cross-sectionally validated, 10-item, yes or no, composite control tool evaluating previous 2-week symptoms and previous 12-month exacerbations. OBJECTIVE: To evaluate the construct validity of the AIRQ using a 3-month recall period for exacerbation-based risk questions and retaining the 2-week recall for symptom-based impairment items. METHODS: At baseline, patients completed the AIRQ with 12-month recall exacerbation items, Asthma Control Test (ACT), St. George's Respiratory Questionnaire (SGRQ), and global self-assessments of asthma risk, control, and symptom severity. Patient-reported exacerbations were captured monthly. The AIRQ with 3-month recall exacerbation items, ACT, and global self-assessments was administered at months 3, 6, and 9, and SGRQ at month 6. RESULTS: A total of 1112 patients aged 12 years or older were enrolled (mean [SD] age, 43.9 [19.5] years). The AIRQ and each administration of the AIRQ with 3-month recall exacerbation items classified asthma control similarly to an ACT plus exacerbation validation standard. For both AIRQ versions, SGRQ scores were higher with worsening asthma control (P < .001). At months 3, 6, and 9, worse AIRQ control levels were associated with higher proportions of patients with 1 or more and 2 or more exacerbations in the previous 3 months and patient global self-assessments indicating greater asthma morbidity (all P < .001). CONCLUSION: The AIRQ using exacerbation risk items with a 3-month recall period exhibits construct validity for classifying current asthma control and can be administered between annual AIRQ assessments.

Cannabis-related allergies: An international overview and consensus recommendations.

Cannabis is the most widely used recreational drug in the world. Cannabis sativa and Cannabis indica have been selectively bred to develop their psychoactive properties. The increasing use in many countries has been accelerated by the COVID-19 pandemic. Cannabis can provoke both type 1 and type 4 allergic reactions. Officially recognized allergens include a pathogenesis-related class 10 allergen, profilin, and a nonspecific lipid transfer protein. Other allergens may also be relevant, and recognition of allergens may vary between countries and continents. Cannabis also has the potential to provoke allergic cross-reactions to plant foods. Since cannabis is an illegal substance in many countries, research has been hampered, leading to challenges in diagnosis since no commercial extracts are available for testing. Even in countries such as Canada, where cannabis is legalized, diagnosis may rely solely on the purchase of cannabis for prick-to-prick skin tests. Management consists of avoidance, with legal issues hindering the development of other treatments such as immunotherapy. Education of healthcare professionals is similarly lacking. This review aimed to summarize the current status of cannabis allergy and proposes recommendations for the future management of this global issue.

2020 NAEPP Guidelines Update and GINA 2021-Asthma Care Differences, Overlap, and Challenges.

The 2020 National Asthma Education and Prevention Program Coordinating Committee Expert Panel Working Group (NAEPP [2020 Focused Asthma Update]) guidelines and the Global Initiative for Asthma (GINA) 2021 strategy report are compared in this Rostrum article. The methodologies of each publication are described. Subsequently, 4 different selected pharmacological recommendations are compared in the 2 documents: step 1 for children 0 to 4 years of age with viral-induced wheezing, step 2 in ages 12 years and older with the intermittent use of inhaled corticosteroid, steps 3 and 4 with single-inhaler maintenance and reliever therapy with inhaled corticosteroids-formoterol (SMART), and steps 3, 4, and 5 with add-on long-acting muscarinic antagonist therapy. Nonpharmacological recommendations are also considered and contrasted, including for exhaled nitric oxide, environmental control, immunotherapy, and bronchial thermoplasty. Similarities and differences in these 2 documents are highlighted, and recommendations are made about harmonizing the approaches where possible.

Mapping geographic variability of severe uncontrolled asthma in the United States: Management implications.

BACKGROUND: The US population-level data on asthma morbidity and mortality are available primarily through state-level surveys. We hypothesize that considerable county-level heterogeneity may be obscured by state-level data, thus impeding focused initiatives to improve asthma outcomes. OBJECTIVE: To assess heterogeneity in the prevalence of uncontrolled, severe, and severe uncontrolled asthma by evaluating state- and county-level morbidity reflected in large administrative claims data sets and identify relationships between pharmacotherapy-based morbidity and the Centers for Disease Control and Prevention's asthma mortality data. METHODS: Asthma prevalence and morbidity were identified using medical and pharmacy claims from the IQVIA Longitudinal Access and Adjudication Data database (July 2015-June 2018). Heat maps ranked the prevalence of severe uncontrolled asthma by deciles in all 50 states and the District of Columbia, plus 2935 counties. Mortality in states (2016) and 3147 counties (1999-2018) was similarly mapped and ranked and contrasted with claims-based morbidity. RESULTS: Among 4,506,527 individuals with asthma, 640,936 (14.2%) received age-specific therapy for severe asthma. Of those with severe asthma, 144,232 (22.5%) filled 2 or more annual courses of systemic steroids and were designated as having severe uncontrolled asthma. Most states with high mortality had relatively few patients with severe uncontrolled asthma. A marked correlation between mortality and morbidity and trends by urban vs rural and metropolitan status were found at the county level. CONCLUSION: Intrastate heterogeneity in the morbidity and mortality of severe uncontrolled asthma at the county level is not evident in state-level analyses. Increased local awareness of systemic corticosteroid use as an indicator of uncontrolled asthma should prompt regional educational and public health efforts to improve outcomes.

National Asthma Education and Prevention Program 2020 Guidelines: What's Important for Primary Care.

KEY TAKEAWAYS: • The 2020 Focused Updates to the Asthma Management Guidelines: A Report from the National Asthma Education and Prevention Program Coordinating Committee Expert Panel Working Group provides updated recommendations for 6 topics related to the management of individuals with asthma. • The classification of asthma severity and asthma control, as well as the concept of utilizing a stepwise approach to pharmacologic treatment, were not updated from the Expert Panel Report 3, released in 2007. • However, important updates in preferred therapies for intermittent and persistent asthma at treatment steps 1 through 5 were suggested. • Recommendations regarding biologic therapy were not included in the 2020 update, as only evidence and US Food and Drug Administration approvals through October 2018 were considered. • The most recent 2021 Global Initiative for Asthma guidelines are not included in this review but can be used in a complementary manner to assist primary care clinicians to optimize decisions regarding the care of patients with asthma.

CaMKII oxidation is a critical performance/disease trade-off acquired at the dawn of vertebrate evolution.

Antagonistic pleiotropy is a foundational theory that predicts aging-related diseases are the result of evolved genetic traits conferring advantages early in life. Here we examine CaMKII, a pluripotent signaling molecule that contributes to common aging-related diseases, and find that its activation by reactive oxygen species (ROS) was acquired more than half-a-billion years ago along the vertebrate stem lineage. Functional experiments using genetically engineered mice and flies reveal ancestral vertebrates were poised to benefit from the union of ROS and CaMKII, which conferred physiological advantage by allowing ROS to increase intracellular Ca2+ and activate transcriptional programs important for exercise and immunity. Enhanced sensitivity to the adverse effects of ROS in diseases and aging is thus a trade-off for positive traits that facilitated the early and continued evolutionary success of vertebrates.

Oxidized CaMKII and O-GlcNAcylation cause increased atrial fibrillation in diabetic mice by distinct mechanisms.

Diabetes mellitus (DM) and atrial fibrillation (AF) are major unsolved public health problems, and diabetes is an independent risk factor for AF. However, the mechanism(s) underlying this clinical association is unknown. ROS and protein O-GlcNAcylation (OGN) are increased in diabetic hearts, and calmodulin kinase II (CaMKII) is a proarrhythmic signal that may be activated by ROS (oxidized CaMKII, ox-CaMKII) and OGN (OGN-CaMKII). We induced type 1 (T1D) and type 2 DM (T2D) in a portfolio of genetic mouse models capable of dissecting the role of ROS and OGN at CaMKII and global OGN in diabetic AF. Here, we showed that T1D and T2D significantly increased AF, and this increase required CaMKII and OGN. T1D and T2D both required ox-CaMKII to increase AF; however, we did not detect OGN-CaMKII or a role for OGN-CaMKII in diabetic AF. Collectively, our data affirm CaMKII as a critical proarrhythmic signal in diabetic AF and suggest ROS primarily promotes AF by ox-CaMKII, while OGN promotes AF by a CaMKII-independent mechanism(s). These results provide insights into the mechanisms for increased AF in DM and suggest potential benefits for future CaMKII and OGN targeted therapies.