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Long-term amelioration of an early-onset familial atrial fibrillation model with AAV-mediated in vivo gene therapy.

ABSTRACT: Atrial fibrillation (AF) is a common cardiac disease with high prevalence in the general population. Despite a mild manifestation at the onset stage, it causes serious consequences, including sudden death, when the disease progresses to the late stage. Most available treatments of AF focus on symptom management or alleviation, due to a lack of fundamental knowledge and the fact that considerable variations of AF exist. With the popularisation of the next-generation sequencing technology, several causal genetic factors, including MYL4, have been discovered to contribute to AF, giving hope to developing its gene therapies. In this study, we attempted to treat a previously established rat AF model, which carried Myl4^E11K/E11K loss of function mutation, via overexpression of exogenous wild-type Myl4 by AAV9 vectors. Our results showed that delivery of Myl4 expressing AAV9 to postnatal rat models rescued the symptoms of AF, indicating the therapeutic potential that early gene therapy intervention can achieve long-term effects in treating cardiac arrhythmias caused by gene mutations.

SUBMITTER: Hu H

PROVIDER: S-EPMC11197581 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature

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Long-term amelioration of an early-onset familial atrial fibrillation model with AAV-mediated in vivo gene therapy.

Hu Handan H Wang Liren L Li Huiying H Li Hailing H Chen Xi X Peng Wenhui W Wang Jun J Zhao Yongxiang Y Liu Mingyao M Li Dali D

Fundamental research 20220514 6

Atrial fibrillation (AF) is a common cardiac disease with high prevalence in the general population. Despite a mild manifestation at the onset stage, it causes serious consequences, including sudden death, when the disease progresses to the late stage. Most available treatments of AF focus on symptom management or alleviation, due to a lack of fundamental knowledge and the fact that considerable variations of AF exist. With the popularisation of the next-generation sequencing technology, several ...[more]

PMID: 38933375

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Project description:CONTEXT:Although the heritability of atrial fibrillation (AF) is established, the contribution of familial AF to predicting new-onset AF remains unknown. OBJECTIVE:To determine whether familial occurrence of AF is associated with new-onset AF beyond established risk factors. DESIGN, SETTING, AND PARTICIPANTS:The Framingham Heart Study, a prospective community-based cohort study started in 1948. Original and Offspring Cohort participants were aged at least 30 years, were free of AF at the baseline examination, and had at least 1 parent or sibling enrolled in the study. The 4421 participants in this analysis (mean age, 54 [SD, 13] years; 54% women) were followed up through December 31, 2007. MAIN OUTCOME MEASURES:Incremental predictive value of incorporating different features of familial AF (any familial AF, premature familial AF [onset ?65 years old], number of affected relatives, and youngest age of onset in a relative) into a risk model for new-onset AF. RESULTS:Across 11,971 examinations during the period 1968-2007, 440 participants developed AF. Familial AF occurred among 1185 participants (26.8%) and premature familial AF occurred among 351 participants (7.9%). Atrial fibrillation occurred more frequently among participants with familial AF than without familial AF (unadjusted absolute event rates of 5.8% and 3.1%, respectively). The association was not attenuated by adjustment for AF risk factors (multivariable-adjusted hazard ratio, 1.40; 95% confidence interval [CI], 1.13-1.74) or reported AF-related genetic variants. Among the different features of familial AF examined, premature familial AF was associated with improved discrimination beyond traditional risk factors to the greatest extent (traditional risk factors, C statistic, 0.842 [95% CI, 0.826-0.858]; premature familial AF, C statistic, 0.846 [95% CI, 0.831-0.862]; P = .004). Modest changes in integrated discrimination improvement were observed with premature familial AF (2.1%). Net reclassification improvement (assessed using 8-year risk thresholds of <5%, 5%-10%, and >10%) did not change significantly with premature familial AF (index statistic, 0.011; 95% CI, -0.021 to 0.042; P = .51), although categoryless net reclassification was improved (index statistic, 0.127; 95% CI, 0.064-0.189; P = .009). CONCLUSIONS:In this cohort, familial AF was associated with an increased risk of AF that was not attenuated by adjustment for AF risk factors including genetic variants. Assessment of premature familial AF was associated with a very slight increase in predictive accuracy compared with traditional risk factors.

Project description:AimsNew-onset atrial fibrillation (NOAF) complicating acute myocardial infarction (AMI) has been associated with poor survival, but the clinical implication of NOAF on heart failure (HF) is still not well characterized. We aimed to investigate the relationship between NOAF complicating AMI and HF hospitalization.Methods and resultsAdult AMI patients identified in the New-Onset Atrial Fibrillation Complicating Acute Myocardial Infarction in Shanghai registry who, discharged alive, had complete echocardiography and follow-up data from February 2014 to March 2018 were included. Patients were divided according to the presence of NOAF. The outcome measures were HF hospitalization and death during the observational period (until 10 April 2019). Cox proportional hazard models were performed in the whole population and propensity score-matched (PSM) cohort to assess the adjusted hazard ratio (HR) and 95% confidence interval (CI). Overall, 2075 patients (mean age: 65.2 ± 12.3 years, 77.3% were men) with AMI were analysed, of whom 228 (11.0%) developed NOAF. Advanced age, admission HF (Killip II-IV), impaired renal function, decreased left ventricular ejection fraction, increased heart rate, and left atrial enlargement were independent predictors of NOAF. Over a median observational period of 2.7 years, the annual incidence rates of HF hospitalization were 18.4% and 2.8% for patients with NOAF and sinus rhythm, respectively. After adjustment for confounders, NOAF was significantly associated with HF hospitalization (HR: 3.14, 95% CI: 2.30-4.28, P < 0.001). Similar results were obtained when accounting for the competing risk of all-cause death (subdistribution HR: 3.06, 95% CI: 2.18-4.30, P < 0.001) or from the PSM cohort (HR: 2.82, 95% CI: 1.99-4.00, P < 0.001). Patients with persistent NOAF (HR: 5.81, 95% CI: 3.59-9.41) were at significantly higher risk of HF hospitalization when compared with those with transient one (HR: 2.61, 95% CI: 1.84-3.70, P interaction = 0.008). Although post-MI NOAF was significantly related to cardiovascular death (annual incidence rates for NOAF and sinus rhythm were 9.4% and 2.3%, respectively; HR: 1.97, 95% CI: 1.36-2.85, P < 0.001), such an association was attenuated when HF hospitalization (modelled as a time-varying covariate) and antithrombotic treatment were adjusted (HR: 1.37, 95% CI: 0.92-2.02, P = 0.121).ConclusionsIn patients with AMI, NOAF is strongly associated with an increased long-term risk of HF hospitalization. Our findings suggest that strengthened secondary prevention of HF should be considered in this high-risk population.

Project description:BackgroundAtrial fibrillation (AF) is prevalent in patients with type 2 diabetes mellitus (T2DM). Glycemic variability (GV) is associated with risk of micro- and macrovascular diseases. However, whether the GV can increase the risk of AF remains unknown.MethodsThe cohort study used a database from National Taiwan University Hospital, a tertiary medical center in Taiwan. Between 2014 and 2019, a total of 27,246 adult patients with T2DM were enrolled for analysis. Each individual was assessed to determine the coefficients of variability of fasting glucose (FGCV) and HbA1c variability score (HVS). The GV parameters were categorized into quartiles. Multivariate Cox regression models were employed to estimate the relationship between the GV parameters and the risk of AF, transient ischemic accident (TIA)/ischemic stroke and mortality in patients with T2DM.ResultsThe incidence rates of AF and TIA/ischemic stroke were 21.31 and 13.71 per 1000 person-year respectively. The medium follow-up period was 70.7 months. In Cox regression model with full adjustment, the highest quartile of FGCV was not associated with increased risk of AF [Hazard ratio (HR): 1.12, 95% confidence interval (CI) 0.96-1.29, p = 0.148] or TIA/ischemic stroke (HR: 1.04, 95% CI 0.83-1.31, p = 0.736), but was associated with increased risk of total mortality (HR: 1.33, 95% CI 1.12-1.58, p < 0.001) and non-cardiac mortality (HR: 1.41, 95% CI 1.15-1.71, p < 0.001). The highest HVS was significantly associated with increased risk of AF (HR: 1.29, 95% CI 1.12-1.50, p < 0.001), total mortality (HR: 2.43, 95% CI 2.03-2.90, p < 0.001), cardiac mortality (HR: 1.50, 95% CI 1.06-2.14, p = 0.024) and non-cardiac mortality (HR: 2.80, 95% CI 2.28-3.44, p < 0.001) but was not associated with TIA/ischemic stroke (HR: 0.98, 95% CI 0.78-1.23, p = 0.846). The Kaplan-Meier analysis showed significantly higher risk of AF, cardiac and non-cardiac mortality according to the magnitude of GV (log-rank test, p < 0.001).ConclusionsOur data demonstrate that high GV is independently associated with the development of new-onset AF in patients with T2DM. The benefit of maintaining stable glycemic levels to improve clinical outcomes warrants further studies.

Dataset Information

Long-term amelioration of an early-onset familial atrial fibrillation model with AAV-mediated in vivo gene therapy.

Publications

Long-term amelioration of an early-onset familial atrial fibrillation model with AAV-mediated in vivo gene therapy.

Similar Datasets

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