Effect of preoperative vitamin D on postoperative atrial fibrillation incidence after coronary artery bypass grafting.

BACKGROUND: Post-operative atrial fibrillation (POAF) is associated with adverse long-term cardiovascular events. OBJECTIVES: This study investigated the effects of a high-dose vitamin D administered preoperatively on the postoperative atrial fibrillation (POAF) incidence in patients with vitamin D deficiency following coronary artery bypass grafting (CABG) surgery. METHODS: This randomized controlled clinical trial was conducted on 246 CABG patients with vitamin D deficiency. All patients were randomly divided into intervention and control groups including 123 cases for each group. In the intervention group, from 3 days before surgery, they received a daily dose of 150,000 units of vitamin D orally (50,000 units of Vit D tablet three times a day) and the patients in the control group received placebo tablets before surgery. All patients in the intervention group were assessed continuously for the occurrence of POAF during the recovery period. RESULTS: In terms of gender, age, and BMI there were no significant differences between intervention and control groups. Our findings showed that the use of vitamin D supplements did not cause a significant change in the duration of intubation and hospitalization. The ratio of POAF following CABG surgery in the control and treatment groups was 26% and 11.4%, respectively (odds ratio = 0.36; 95% CI = 0.18-0.72; P = 0.003). CONCLUSIONS: Our findings revealed that high-dose vitamin D supplementation before CABG surgery significantly reduced the incidence of POAF. Further multicenter randomized trials with larger sample sizes are certainly warranted to confirm our results.

Reliable focal and rotational activations in CARTOFINDER mapping using the OctaRay catheter.

INTRODUCTION: The aim of the current study was to elucidated the reliable atrial fibrillation (AF) drivers identified by CARTOFINDER using OctaRay catheter. METHODS AND RESULTS: The reliability of focal and rotational activations identified by CARTOFINDER using OctaRay catheter was assessed by the sequential recordings in each site of both atrium before and after pulmonary vein isolation (PVI) in 10 persistent AF patients. The outcome measures were the reproducibility rate during the sequential recordings and the stability rate between pre- and post-PVI as reliable focal and rotational activations. The study results were compared with those under use of PentaRay catheter (N = 18). Total 68928 points of 360 sites in OctaRay group and 24 177 points of 311 sites in PentaRay were assessed. More focal activation sites were identified in OctaRay group than PentaRay group (7.9% vs. 5.7%, p < .001), although the reproducibility rate and the stability rate were significantly lower in OctaRay group (45.3% vs. 58.9%, p < .001; 11.2% vs. 28.4%, p < .001). Meanwhile, the prevalence of reproducible focal activation sites among overall points was comparable (3.6% vs. 3.3%, p = .08). Regarding rotational activation, more rotational activation sites were identified in OctaRay group (5.1% vs. 0.2%, p < .001), and the reproducibility rate and the stability rate were significantly higher in OctaRay group (45.2% and 12.5% vs. 0.0%, p < .001). Both reliable focal and rotational activation sites were characterized by significantly shorter AF-cycle length (CL) and higher repetition of focal and rotational activations during the recordings compared with the sites of non or unreliable focal and rotational activations. CONCLUSION: In CARTOFINDER, OctaRay catheter could identify reliable focal activation with high resolution and reliable rotational activation compared with PentaRay catheter. The repetitive focal and rotational activations with short AF-CL could be the potential target during ablation.

The Possible Influence of Vitamin D Levels on the Development of Atrial Fibrillation-An Update.

Atrial fibrillation (AF) is a severe and most common supraventricular arrhythmia in humans, which, if left untreated or treated ineffectively, can lead to ischemic stroke or heart failure. It has been suggested that serum vitamin D (VitD) deficiency may be one of the critical factors influencing the onset of AF, especially in the period after cardiac surgery, such as coronary artery bypass grafting. Several papers have indicated that VitD supplementation reduces the risk of AF, significantly reducing the proportion of patients between the control and study groups in both the pre- and postoperative periods. Factors that increase the risk of AF from VitD deficiency are also further indicated, and these are age, gender, weight, season or comorbidities. In addition, the cardiodepressive mechanism of VitD is not fully understood; however, it is suggested that it acts through at least two pathways. The first indicates a direct effect of VitD on atrial muscle degradation, while the second is related to the modulation of cardiovascular depression factors. Despite many reports showing correlations between no VitD concentrations on the development of AF, this topic is still widely debated and the results from these papers are still subject to doubt. Therefore, this review aims at describing in detail the problem of correlation between VitD deficiency and the development of AF associated mainly with the postoperative period, i.e., after cardiac surgery, especially pathogenesis, and results of this correlation, taking into account recent studies, limitations and future perspectives. Due to the fact that this is still a topical problem, we believe that the collection of the latest reports and a detailed description of the problem is most appropriate in this case.

Dietary ω-3 fatty acids and the incidence of atrial fibrillation in the Million Veteran Program.

BACKGROUND: Although recent large randomized clinical trials have reported an increased risk of atrial fibrillation (AF) with marine ω-3 fatty acid supplements, it is unclear whether dietary marine ω-3 fatty acids assessed through food frequency questionnaires are associated with AF risk. OBJECTIVES: We sought to test the hypothesis that dietary eicosapentaenoic acid/docosahexaenoic acid/docosapentaecnoic acid (EPA/DHA/DPA) is associated with a higher risk of AF in a large prospective cohort of US Veterans. METHODS: We analyzed data from Million Veteran Program participants who completed self-reported food frequency questionnaires. We used multivariable Cox regression to estimate the HRs of AF across quintiles of ω-3 fatty acid consumption and a cubic spline analysis to assess the dose-response relations between ω-3 fatty acids and AF. RESULTS: Of the 301,294 veterans studied, the median intake of ω-3 fatty acids (EPA/DHA/DPA) was 219 mg/d (IQR: 144-575), and the mean age was 64.9 y (SD: 12.0); 91% were men, and 84% were White. Consumption of EPA/DHA/DPA exhibited a nonlinear inverse relation with incident AF characterized by an initial decline to 11% at 750 mg/d of marine ω-3 fatty acid intake followed by a plateau. CONCLUSIONS: Contrary to our hypothesis, dietary EPA/DHA/DPA was not associated with a higher risk of AF but was inversely related to AF risk in a nonlinear manner.

Effect of vitamin D on postoperative atrial fibrillation in patients who underwent coronary artery bypass grafting: A systematic review and meta-analysis.

BACKGROUND: Vitamin D insufficiency/deficiency has been identified as a risk factor for postoperative atrial fibrillation (POAF) after coronary artery bypass grafting (CABG). This is associated with significantly increased morbidity and mortality leading to not only prolonged hospital and intensive care unit (ICU) stay, but increased risk of stroke, heart failure, dementia, and long-term atrial fibrillation. This analysis aims to evaluate the efficacy of vitamin D supplementation in preventing POAF in patients undergoing CABG. METHODS: We searched PubMed, Cochrane Central Register of Controlled Trials and SCOPUS from inception to June 2022 for randomized controlled trials (RCTs). The outcome of interest was the incidence of POAF. Secondarily, we analyzed the length of ICU stay, length of hospital stay, cardiac arrest, cardiac tamponade, and blood transfusion. Results were pooled using a random-effect model. Three RCTs consisting of 448 patients were included. RESULTS: Our results suggest that vitamin D significantly reduced the incidence of POAF (RR: 0.60; 95 % CI: 0.40, 0.90; p = 0.01; I2 = 8 %). It was also observed that vitamin D significantly reduced the duration of ICU stay (WMD: -1.639; 95 % CI: -1.857, -1.420; p < 0.00001). Furthermore, the length of hospital stay (WMD: -0.85; 95 % CI: -2.14, 0.43; p = 0.19; I2 = 87 %) was also reduced, however, the result was not significant. CONCLUSION: Our pooled analysis suggests that vitamin D prevents POAF. Future large-scale randomized trials are needed to confirm our results.

Do omega-3 fatty acids increase risk of atrial fibrillation?

PURPOSE OF THE REVIEW: To summarize the findings from recent observational follow-up studies and randomized trials of plant- and marine omega-3 fatty acids on the risk of atrial fibrillation (AF). RECENT FINDINGS: Recent randomized cardiovascular outcome trials have indicated that supplements with marine omega-3 fatty acids may be associated with a higher risk of AF, and a meta-analysis has suggested that marine omega-3 fatty acid supplements were associated with a 25% higher relative risk of AF. Also, a recent large observational study reported a modest higher risk of AF in habitual users of marine omega-3 fatty acid supplements. However, recent observational biomarker studies of circulating and adipose tissue content of marine omega-3 fatty acids have in contrast reported a lower risk of AF. Very limited knowledge exists on the role of plant-derived omega-3 fatty acids and AF. SUMMARY: Marine omega-3 fatty acid supplements may increase the risk of AF, whereas biomarkers reflecting consumption of marine omega-3 fatty acids have been linked to a lower risk of AF. Clinicians should inform patients that marine omega-3 fatty acid supplement may increase AF risk, and this should be taking into account when discussing pros and cons of taking supplements with marine omega-3 fatty acids.

Reproducibility and stability of atrial fibrillation drivers identified by an automated algorithm: CARTOFINDER.

BACKGROUND: The characteristics of atrial fibrillation (AF) drivers identified by CARTOFINDER have not been thoroughly evaluated. Therefore, the current study was sought to validate the reliability of AF drivers. METHODS: The reliability of focal and rotational activation identified by CARTOFINDER during AF was assessed by the sequential recordings in each site before and after pulmonary vein isolation (PVI) in 27 persistent AF patients. The primary outcome measures were the reproducibility rate during the sequential recordings and the stability rate between pre- and post-PVI. RESULTS: Among 32,135 points in 509 sites, focal activation was identified in 1775 points (5.5%) with a repetition of 11 (6-26) times during the recording. Rotational activation was identified in 132 points (0.4%) with a repetition number of 21 (14-21) times. AF drivers had significantly higher voltage and shorter AF cycle length than non-AF driver sites. The reproducibility rate of focal activation during the sequential recordings was 57.8% and increased with the repetition number. The reproducibility rate of rotational activation was 37.4%. The prevalence and the reproducibility rate of focal activation in post-PVI were significantly lower than pre-PVI (5.3% versus 6.0%, P = 0.02; 53.4% versus 63.6%, P < 0.001). The stability rate of focal activation between pre- and post-PVI was only 28.3% but increased with the repetition number. There was no stable rotational activation between pre- and post-PVI. CONCLUSIONS: The reproducibility of AF drivers, especially focal activation, identified by CARTOFINDER is relatively favorable, but the stability between pre- and post-PVI was poor. These results depended on the repetition number during the recording.

The effects of vitamin D supplementation on postoperative atrial fibrillation after coronary artery bypass grafting in patients with vitamin D deficiency.

INTRODUCTION: Postoperative atrial fibrillation (POAF) as a common complication of coronary artery bypass grafting (CABG) surgery is associated with increased mortality and morbidity rates. Vitamin D deficiency increases the prevalence of POAF; however, the effects of vitamin D supplementation on the incidence of POAF have not yet been completely elucidated. METHODS: In this prospective, open-label, randomized clinical trial the level of 25-hydroxy vitamin D (25(OH) D) was measured in patients undergoing CABG surgery. Patients with vitamin D insufficiency (defined as 25(OH) D level < 30 ng/ml) were included and randomly assigned to control group to receive either the general standard of care (Group A) or to study group to receive the general standard of care plus oral vitamin D3 , 600,000 IU 5 days before surgery (Group B). The primary outcome of our study was the occurrence of POAF during the first 5 days after CABG surgery. RESULTS: Totally, 93 patients in group B and 103 patients in group A completed the study. The occurrence of POAF was significantly lower in group B as compared to group A (9.68% vs. 20.39%, p = .038). The length of intensive care unit (ICU) stay and hospital stay were reduced in group B patients (2.21 vs. 3.86 days, p < .001 and 7.40 vs. 9.58 days, p = .022, respectively). CONCLUSION: Our study demonstrated that vitamin D supplementation reduces the incidence of POAF, duration of ICU, and hospital stay following CABG surgery.

Shensong Yangxin attenuates metabolic syndrome-induced atrial fibrillation via inhibition of ferroportin-mediated intracellular iron overload.

BACKGROUND: Shensong Yangxin (SSYX) is a traditional Chinese medicine been widely used clinically to treat various arrhythmias including atrial fibrillation (AF). However, the role and precise mechanism of SSYX in MS-induced AF have not yet been elucidated. PURPOSE: To elucidate the protective effects of SSYX on MS-induced AF and its possible mechanisms of action. METHODS: Male Wistar rats (180-220 g) were fed a 16-week high-carbohydrate, high-fat (HCHF) diet together with 25% fructose in drinking water to produce a MS model. Low-concentration (SSYX-L, 0.4 g/kg) and high-concentration (SSYX-H, 0.8 g/kg) of SSYX were given by daily gavage 8-weeks following HCHF diet for 8-weeks. In vivo electrophysiological study, histological analysis, RNA-sequence (RNA-Seq) and gene ontology (GO) analysis, qRT-PCR and western blot were performed. RESULTS: Both low-concentration and high-concentration of SSYX could inhibit MS-induced AF susceptibility, electrical remodeling and structural remodeling. Results from RNA-sequence analysis revealed intracellular iron homeostasis mediated the protective effect of SSYX against MS. In vivo and in vitro experiments both demonstrated that SSYX up-regulated ferroportin (Fpn) expression and ameliorated intracellular iron overload induced by MS. To verified whether Fpn is the target of SSYX and intracellular iron overload mediated the protective effect of SSYX against MS, adeno-associated virus type 9 (AAV9) delivery system was used. Knocking down Fpn (AAV9-shFpn) markedly aggravated the reactive oxygen species (ROS) production, electrical remodeling and atrial fibrosis induced by MS, leading to a further increase of AF susceptibility induced by MS. CONCLUSION: Our study demonstrated for the first time that SSYX reduced AF susceptibility, inhibited electrical remodeling and structural remodeling via up-regulating Fpn, decreasing intracellular iron overload and reducing ROS production. These results suggest that SSYX might be a potential therapeutic agent for the treatment of MS-induced AF.

Vitamin D supplementation and postoperative atrial fibrillation.

Vitamin D is an important vitamin that has hormone-like effects in the human body. 1,25-dihydroxy vitamin D (1,25(OH)2 D) is known as the active form of vitamin D. Activated vitamin D can affect cellular proliferation, apoptosis, cellular membrane transport, immune system, and aging through genes. Postoperative atrial fibrillation (PoAF) is an important problem that increases mortality and morbidity rates after cardiac surgery operations. Various studies have been conducted on the relationship between vitamin D and PoAF. Although there are studies in the literature showing that vitamin D supplementation reduces cardiovascular mortality and morbidity in different study types (randomized vs. observational), there are also studies showing that it has no effect on clinical outcomes. Since the subject is atrial fibrillation, the conditions of the study groups such as age, the prevalence of coronary artery disease, degree of hypertension, and lung disease should be analyzed well. On the other hand, vitamin D supplementation should be carefully determined for which patient, for how long, and at what dose.

Dietary ω-3 fatty acids reduced atrial fibrillation vulnerability via attenuating myocardial endoplasmic reticulum stress and inflammation in a canine model of atrial fibrillation.

BACKGROUND: Dietary consumption of ω-3 fatty acids is correlated with a reduced incidence of cardiovascular events. Here, we investigated the effect of dietary ω-3 fatty acids on atrial fibrillation (AF) vulnerability in a canine model of AF and explored the related mechanisms. METHODS: Twenty four male beagle dogs (weight, 8-10 kg) were randomly divided into four groups: (a) sham-operated group (normal chow); (b) AF+FO [AF and normal chow supplemented with fish oil (FO): 0.6 g n-3 polyunsaturated fatty acids (ω-3 PUFA) /kg/day]; (c) AF group (normal chow); (d) sham-operated FO group (chow supplemented with FO: 0.6 g ω-3 PUFA/kg/day). AF was induced by rapid atrial pacing (RAP: 400 bpm for 4 weeks). Daily oral administration of FO was initiated 1 week before surgery and continued for 4 weeks post operation. RESULTS: Atrial electric remodeling was significantly attenuated and AF vulnerability were significantly reduced in AF+FO group compared to AF group. Endoplasmic reticulum (ER) stress-related protein expression levels of glucose-regulated protein78, C/EBP homologous protein, cleaved-Caspase12, and phosphorylation of protein kinase R-like ER kinase as well as inflammatory cytokines interleukin-1ß, interleukin-6, tumor necrosis factor-α in left atrium (LA) were significantly downregulated in AF+FO group than in AF group (all p<0.05). In addition, Masson staining revealed lower extent of LA interstitial fibrosis in AF+FO group than in AF group (p<0.01). Myocardial apoptosis was also significantly reduced in AF+FO group than in AF group (p<0.05). CONCLUSIONS: Dietary ω-3 fatty acids could significantly reduce RAP-induced AF vulnerability, possibly via attenuating myocardial ER stress, inflammation, and apoptosis in this canine model of AF.

Maintenance of Serum Potassium Levels ≥3.6 mEq/L Versus ≥4.5 mEq/L After Isolated Elective Coronary Artery Bypass Grafting and the Incidence of New-Onset Atrial Fibrillation: Pilot and Feasibility Study Results.

OBJECTIVE: Serum potassium levels frequently are maintained at high levels (≥4.5 mEq/L) to prevent atrial fibrillation after cardiac surgery (AFACS), with limited evidence. Before undertaking a noninferiority randomized controlled trial to investigate the noninferiority of maintaining levels ≥3.6 mEq/L compared with this strategy, the authors wanted to assess the feasibility, acceptability, and safety of recruiting for such a trial. DESIGN: Pilot and feasibility study of full trial protocol. SETTING: Two university tertiary-care hospitals. PARTICIPANTS: A total of 160 individuals undergoing first-time elective isolated coronary artery bypass grafting. INTERVENTIONS: Randomization (1:1) to protocols aiming to maintain serum potassium at either ≥3.6 mEq/L or ≥4.5 mEq/L after arrival in the postoperative care facility and for 120 hours or until discharge from the hospital or AFACS occurred, whichever happened first. MEASUREMENTS AND MAIN RESULTS: Primary outcomes: (1) whether it was possible to recruit and randomize 160 patients for six months (estimated 20% of those eligible); (2) maintaining supplementation protocol violation rate ≤10% (defined as potassium supplementation being inappropriately administered or withheld according to treatment allocation after a serum potassium measurement); and (3) retaining 28-day follow-up rates ≥90% after surgery. Between August 2017 and April 2018, 723 patients were screened and 160 (22%) were recruited. Potassium protocol violation rate = 9.8%. Follow-up rate at 28 days = 94.3%. Data on planned outcomes for the full trial also were collected. CONCLUSIONS: It is feasible to recruit and randomize patients to a study assessing the impact of maintaining serum potassium concentrations at either ≥3.6 mEq/L or ≥4.5 mEq/L on the incidence of AFACS.

Omega-3 fatty acids in adipose tissue and risk of atrial fibrillation.

BACKGROUND: The aim of the present study was to examine the relation between adipose tissue content of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) and the risk of incident atrial fibrillation (AF). METHODS: In this case-cohort study based on data from the Danish Diet, Cancer and Health cohort, a total of 5255 incident cases of AF was identified during 16.9 years of follow-up. Adipose tissue biopsies collected at baseline from all cases and from a randomly drawn subcohort of 3440 participants were determined by gas chromatography. Data were analysed using weighted Cox regression. RESULTS: Data were available for 4741 incident cases of AF (2920 men and 1821 women). Participants in the highest vs. the lowest quintile of EPA experienced a 45% lower risk of AF (men HR 0.55 (95% CI 0.41-0.69); women HR 0.55 (0.41-0.72)). For DHA, no clear association was found in men, whereas in women, participants in the highest quintile of DHA in adipose tissue had a 30% lower risk of incident AF (HR 0.70 (0.54-0.91)) compared to participants in the lowest quintile. CONCLUSIONS: A monotonous inverse association was found for the content of EPA in adipose tissue and risk of AF in both men and women. The content of DHA was inversely associated with the risk of AF in women, whereas no clear association was found for men.

Understanding PITX2-Dependent Atrial Fibrillation Mechanisms through Computational Models.

Atrial fibrillation (AF) is a common arrhythmia. Better prevention and treatment of AF are needed to reduce AF-associated morbidity and mortality. Several major mechanisms cause AF in patients, including genetic predispositions to AF development. Genome-wide association studies have identified a number of genetic variants in association with AF populations, with the strongest hits clustering on chromosome 4q25, close to the gene for the homeobox transcription PITX2. Because of the inherent complexity of the human heart, experimental and basic research is insufficient for understanding the functional impacts of PITX2 variants on AF. Linking PITX2 properties to ion channels, cells, tissues, atriums and the whole heart, computational models provide a supplementary tool for achieving a quantitative understanding of the functional role of PITX2 in remodelling atrial structure and function to predispose to AF. It is hoped that computational approaches incorporating all we know about PITX2-related structural and electrical remodelling would provide better understanding into its proarrhythmic effects leading to development of improved anti-AF therapies. In the present review, we discuss advances in atrial modelling and focus on the mechanistic links between PITX2 and AF. Challenges in applying models for improving patient health are described, as well as a summary of future perspectives.

Immuno-Electrophysiological Mechanisms of Functional Electrical Connections Between Recipient and Donor Heart in Patients With Orthotopic Heart Transplantation Presenting With Atrial Arrhythmias.

[Figure: see text].

L-Carnitine supplementation for the prevention of postoperative atrial fibrillation in aortic valve surgery.

OBJECTIVES: L-Carnitine, a quaternary amine, improves fatty acid metabolism in the heart and has anti-inflammatory effects. Several studies have reported the efficacy of L-carnitine for the prophylaxis of arrhythmia. We assessed the clinical effectiveness of L-carnitine in preventing postoperative atrial fibrillation (POAF) in aortic valve surgery. METHODS: Thirty patients who underwent aortic valve surgery were included. Fifteen patients had no prophylaxis other than conventional measures (control), while 15 patients received oral L-carnitine for 9 days (daily dose of 3 g). The incidence of POAF during 1 week after surgery was compared between the two groups. The multivariable logistic regression analysis for POAF was performed using the pre- and intraoperative parameters. RESULTS: Preoperative characteristics and operative data were comparable between the groups. The POAF rate was significantly lower in the L-carnitine group than in the control (20% and 60%, respectively; P = 0.025). L-Carnitine use was an independently negative predictor for POAF (odds ratio 0.067; 95% confidence interval 0.006-0.768). CONCLUSIONS: L-Carnitine administration may have potential for the prevention of POAF in aortic valve surgery.

Ablation of Atrial Fibrillation in Patients With Hypertrophic Cardiomyopathy: Treatment Strategy, Characteristics of Consecutive Atrial Tachycardia and Long-Term Outcome.

Background Atrial fibrillation (AF) is common in patients with hypertrophic cardiomyopathy (HCM) and is associated with a deterioration of clinical status. Ablation of symptomatic AF is an established therapy, but in HCM, the characteristics of recurrent atrial arrhythmias and the long-term outcome are uncertain. Methods and Results Sixty-five patients with HCM (aged 64.5±9.9 years, 42 [64.6%] men) underwent AF ablation. The ablation strategy included pulmonary vein isolation in all patients and ablation of complex fractionated atrial electrograms or subsequent atrial tachycardias (AT) if appropriate. Paroxysmal, persistent AF, and a primary AT was present in 13 (20.0%), 51 (78.5%), and 1 (1.5%) patients, respectively. Twenty-five (38.4%) patients developed AT with a total number of 54 ATs. Stable AT was observed in 15 (23.1%) and unstable AT in 10 (15.3%) patients. The mechanism was characterized as a macroreentry in 37 (68.5%), as a localized reentry in 12 (22.2%), a focal mechanism in 1 (1.9%), and not classified in 4 (7.4%) ATs. After 1.9±1.2 ablation procedures and a follow-up of 48.1±32.5 months, freedom of AF/AT recurrences was demonstrated in 60.0% of patients. No recurrences occurred in 84.6% and 52.9% of patients with paroxysmal and persistent AF, respectively (P<0.01). Antiarrhythmic drug therapy was maintained in 24 (36.9%) patients. Conclusions AF ablation in patients with HCM is effective for long-term rhythm control, and especially patients with paroxysmal AF undergoing pulmonary vein isolation have a good clinical outcome. ATs after AF ablation are frequently observed in HCM. Freedom of atrial arrhythmia is achieved by persistent AF ablation in a reasonable number of patients even though the use of antiarrhythmic drug therapy remains high.

ALDH2 deficiency induces atrial fibrillation through dysregulated cardiac sodium channel and mitochondrial bioenergetics: A multi-omics analysis.

Point mutation in alcohol dehydrogenase 2 (ALDH2), ALDH2*2 results in decreased catalytic enzyme activity and has been found to be associated with different human pathologies. Whether ALDH2*2 would induce cardiac remodeling and increase the attack of atrial fibrillation (AF) remains poorly understood. The present study evaluated the effect of ALDH2*2 mutation on AF susceptibility and unravelled the underlying mechanisms using a multi-omics approach including whole-genome gene expression and proteomics analysis. The in-vivo electrophysiological study showed an increase in the incidence and reduction in the threshold of AF for the mutant mice heterozygous for ALDH2*2 as compared to the wild type littermates. The microarray analysis revealed a reduction in the retinoic acid signals which was accompanied by a downstream reduction in the expression of voltage-gated Na+ channels (SCN5A). The treatment of an antagonist for retinoic acid receptor resulted in a decrease in SCN5A transcript levels. The integrated analysis of the transcriptome and proteome data showed a dysregulation of fatty acid ß-oxidation, adenosine triphosphate synthesis via electron transport chain, and activated oxidative responses in the mitochondria. Oral administration of Coenzyme Q10, an essential co-factor known to meliorate mitochondrial oxidative stress and preserve bioenergetics, conferred a protection against AF attack in the mutant ALDH2*2 mice. The multi-omics approach showed the unique pathophysiology mechanisms of concurrent dysregulated SCN5A channel and mitochondrial bioenergetics in AF. This inspired the development of a personalized therapeutic agent, Coenzyme Q10, to protect against AF attack in humans characterized by ALDH2*2 genotype.

Omega-3 polyunsaturated fatty acid supplementation improves lipid metabolism and endothelial function by providing a beneficial eicosanoid-pattern in patients with acute myocardial infarction: A randomized, controlled trial.

BACKGROUND & AIMS: Omega-3 polyunsaturated fatty acid (ω-3 PUFA) have been reported to have beneficial cardiovascular effects, but its mechanism of protection against acute myocardial infarction (AMI) who are under guideline-based therapy is not fully understood. Here, we used a metabolomic approach to systematically analyze the eicosanoid metabolites induced by ω-3 PUFA supplementation and investigated the underlying mechanisms. METHODS: Participants with AMI after successful percutaneous coronary intervention were randomized to 3 months of 2 g daily ω-3 PUFA and guideline-adjusted therapy (n = 30, ω-3 therapy) or guideline-adjusted therapy alone (n = 30, Usual therapy). Functional PUFA-derived eicosanoids in plasma were profiled by metabolomics. Clinical and laboratory tests were obtained before and 3 months after baseline and after the study therapy. RESULTS: By intent-to-treat analysis, the content of 11-HDoHE, 20-HDoHE and 16,17-EDP and that of epoxyeicosatetraenoic acids (EEQs), derived from docosahexaenoic acid and eicosapentaenoic acid, respectively, were significantly higher with ω-3 group than Usual therapy, whereas that of prostaglandin J2 (PGJ2) and leukotriene B4, derived from arachidonic acid, was significantly decreased. As compared with Usual therapy, ω-3 PUFA therapy significantly reduced levels of triglycerides (-6.3%, P < 0.05), apolipoprotein B (-4.9%, P < 0.05) and lipoprotein(a) (-37.0%, P < 0.05) and increased nitric oxide level (62.2%, P < 0.05). In addition, the levels of these variables were positively correlated with change in 16,17-EDP and EEQs content but negatively with change in PGJ2 content. CONCLUSIONS: ω-3 PUFA supplementation may improve lipid metabolism and endothelial function possibly by affecting eicosanoid metabolic status at a systemic level during convalescent healing after AMI. CLINICAL TRIAL REGISTRATION: URL: http://www.chictr.org.cn. Unique identifier: ChiCTR1900025859.