Association between atrial fibrillation/flutter and left ventricular failure: A bidirectional Mendelian randomization study

Association between atrial fibrillation/flutter and left ventricular failure: A bidirectional Mendelian randomization study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Association between atrial fibrillation/flutter and left ventricular failure: A bidirectional Mendelian randomization study Tiantian Chen, Zhou Fan This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4156657/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background ：atrial fibrillation(AF) and heart failure(HF) share common pathophysiological mechanisms, thus frequently coexisting and mutually influencing disease progression.The combination of these conditions is associated with heightened mortality rates and unfavorable prognosis. Significant progress has been made in the study of AF-HF, but it remains unclear which approach provides the best long-term efficacy. In this study, our objective is to employ Mendelian randomization studies in order to investigate the causal relationship between atrial fibrillation/atrial flutter(AFL) and left ventricular failure(LVF), explore potential therapeutic targets for clinical application, and optimize the management and clinical outcomes of patients with AF/AFL and HF. Methods: The data of AF/AFL from the IEU OpenGWAS project.These data derive from a European population consisting of 463,010 participants drawn from the UK Biobank. Among them, 5,669 individuals had AF/AFL, and a total of 9,851,867 SNPs were considered.To ensure a matching number of SNPs between LVF and minimize population overlap effects, we implemented the most recent and largest genome-wide association study meta-analysis from the IEU OpenGWAS project. A total of 2046 cases and 460,964 controls were investigated,within a total of 9,851,867 SNPs. We adopted inverse variance weighted (IVW) as the main way to estimate the Mendelian randomization analysis. Results ：The preliminary results of IVW revealed postive causal effect of AF/AFL on LVF [OR =1.053, 95% CI: 1.023-1.084, P = 0.0006] Cochran's IVW Q test results show no significant heterogeneity among these IVs. The results of the MR-Egger regression intercept analysis indicate no significant horizontal pleiotropy. MR-PRESSO global test results revealed no horizontal pleiotropy. Additionally, the p-values of the MR PRESSO global test for AF/AFL on LVF were all greater than 0.05.The funnel plot presents a symmetricl shap,suggesting significant heterogeneity,indicating that there is no systematic bias between the study effect and its accuracy. The leave-one-out plot is shown that each IVs does not have a serious bias effect on the overall MR results.The results of the steiger test confirmed no causal effect of LVF on AF/AFL. Conclusions： This MR study presents novel genetic evidence supporting a causal association between AF/AFL and LVF, thus contributing to the advancement of our understanding in this field.This study underscores the importance of managing HF-AF patients by incorporating AF/AFL treatment alongside conventional anti-HF therapy and ventricular rate control, aiming to enhance LV function and achieve a more favorable prognosis.In addition, this study found that LVF did not have a significant impact on AF/AFL. atrial fibrillation and flutter left ventricular failure heart failure bidirectional Mendelian randomization study Figures Figure 1 Figure 2 Figure 3 Figure 4 Introduction Atrial fibrillation (AF) and heart failure (HF) impose a substantial global health burden, with an estimated current prevalence of AF in over 30 million individuals, accounting for approximately 1% of the global population. Furthermore, it is projected that the incidence of AF will double by 2030[ 1 , 2 ]. There exists a certain degree of overlap and mutual conversion between AF and atrial flutter(AFL). In the general population, the incidence rate of AF is about ten times higher than that of AFL. Even though only a small percentage of patients with AF develop AFL (e.g.10%), most patients with AFL eventually progress to AF[ 3 ].HF represents the ultimate stage in numerous cardiovascular diseases and serves as their final battleground. Globally, more than 25 million people are estimated to be affected by HF, constituting around 2% of total healthcare expenditure[ 4 ].By 2030, this cost is expected to double to $ 70 billion[ 5 ]. Findings from an extensive UK hospital database analysis (ACALM Registry) revealed significantly higher all-cause mortality rates among patients with both HF and AF(71%) compared to those solely diagnosed with HF(64%) or AF(45%) alone. Additionally, newly developed combined cases of AF and HF exhibited the highest mortality rate during a follow-up period spanning thirteen years at 75%. Similar trends were observed regarding lengthier hospital stays among individuals presenting with HF accompanied by AF [ 6 ].As medical advancements continue alongside aging populations worldwide, it is anticipated that these two diseases' global prevalence will escalate further[ 7 ]. AF and HF share common pathophysiological mechanisms, thus frequently coexisting and mutually influencing disease progression[ 8 , 9 ]. AF is a prevalent complication of HF, with an incidence rate of 25%[ 10 ]. Conversely, HF surpasses stroke mortality by more than threefold as the leading cause of death in AF patients[ 11 ]. The combination of these conditions is associated with heightened mortality rates and unfavorable prognosis[ 12 ]. Studies have indicated a higher incidence and prevalence of HF in AFL patients compared to those with AF; But, further validation is warranted[ 13 ]. Extensive research has been conducted on AF-HF, resulting in significant advancements in comprehending the epidemiology, pathophysiology, evaluation, and treatment of AF-HF; Nevertheless, the optimal long-term efficacy approach remains uncertain[ 14 ].Numerous unresolved queries persist regarding the management of patients with AF-HF. Which rhythm control therapy should be prioritized as first-line for HF patients presenting symptomatic AF? Among HF patients with symptomatic AF, who are the most likely candidates to benefit from catheter ablation? How can the propensity for AF development in HF patients be mitigated? What strategies effectively prevent HF in individuals already diagnosed with AF? Simultaneously, certain contentious points exist. For instance, conflicting data exists regarding improved outcomes in HF and AF patients through interventions such as catheter ablation[ 15 , 16 ].To address these clinical issues and controversies, a comprehensive exploration of the underlying pathological mechanisms of AF and HF is imperative. Numerous studies have provided evidence supporting a bidirectional relationship between HF and AF[ 17 ]. While it is important to consider the various subtypes and grades of HF as well as the heterogeneity in combined AF/AFL presentations, which may lead to divergent research findings. These studies have limitations for clinical guidance. Furthermore, there remains a paucity of research investigating the association between AF/AFL and left ventricular failure(LVF), with the exact underlying mechanism still unclear.This study included SNP data for LVF as the outcome. AF and AFL are common tachyarrhythmias in patients with HF[ 18 ].A trial conducted in patients with HF-AF offers an alternative perspective on the potential overlap between AFL and AF[ 19 ]. While previous studies have often used AFL and AF interchangeably as diagnoses[ 11 , 20 ], it is important to note that more than 70% of individuals with AFL do not progress to AF, while less than 10% of those diagnosed with AF also present with AFL [ 21 , 22 ]. The consideration of overlap between AFL and AF is crucial in the planning of AFL ablation for patients with LVF, as subsequent development of AF occurs in up to 43% of patients[ 23 ]. Therefore, this study incorporated data AF/AFL as the exposure data, thereby enhancing the reliability of the results. In this study, our objective is to employ Mendelian randomization(MR) studies in order to investigate the causal relationship between AF/AFL and LVF, explore potential therapeutic targets for clinical application, and optimize the management and clinical outcomes of patients with AF/AFL and HF. Method Data source for atrial fibrillation and Atrial flutter The data of atrial fibrillation and flutter from the IEU OpenGWAS project.These data derive from a European population consisting of 463,010 participants drawn from the UK Biobank. Among them, 5,669 individuals had AF/AFL, and a total of 9,851,867 single nucleotide polymorphisms(SNPs) were considered. Data source for Left ventricular failure To ensure a matching number of SNPs between LVF and minimize population overlap effects, we implemented the most recent and largest genome-wide association study meta-analysis from the IEU OpenGWAS project. A total of 2046 cases and 460,964 controls were investigated,within a total of 9,851,867 SNPs. There would be no overlap in population selection between the exposure group and the outcome group. SNPs selection We performed a set of methods to filter valid SNPs that suit the three core MR assumptions. (1) The independent SNPs strongly linked to different circulating cytokines were selected. SNPs with P -value < 5×10 − 6 were considered to be significantly associated with circulating cytokines to obtain more SNPs as instrumental variables(IVs). (2)We adopted the clumping process to evaluate the linkage disequilibrium(LD) among the SNPs (r 2 < 0.001 and clumping distance = 10,000 kb). The SNPs with LD were removed to avoid biased results.(3)We searched all the screened SNPs on PhenoScanner V2( http://www.phenoscanner.medschl.cam.ac.uk/ )[ 24 ].PhenoScanner V2 provides the phenotypes information of SNPs,which can be used to determine whether the SNPs only affect the outcomes through exposure.The SNPs related to the confounding factors were excluded to eliminate the bias. Finally, we harmonized the exposure and outcome datasets to remove the non-concordant SNPs. The remaining SNPs were used as the genetic IVs. Statistical analysis We adopted inverse variance weighted (IVW) as the main way to estimate the MR analysis.IVW assesses the overall causal impact of exposure on the outcomes.It is the most accurate way to evaluate causality if all the selected SNPs are valid[ 25 ].We also applied other methods to analyze causal association, including Weighted Median, MR Egger,Weighted Mode, and Simple Mode methods.The Weighted Median method will generate a more potent effect when more than half of the SNPs are valid[ 26 ].MR Egger provides accurate effect estimates even if all the SNPs are invalid[ 27 ].We further conducted the MR-Egger regression and the MR Pleiotropy Residual Sum and Outlier (MR-PRESSO) test to evaluate the possible horizontal pleiotropy[ 28 , 29 ]. We used Cochran’s Q statistic and MR-egger regression to test the heterogeneities. Additionally, the leave-one-out analysis was utilized to assess the robustness and consistency of the results.All statistical analyses were performed using the R packages "two-sample MR" and "MR-PRESSO."The strength of IVs was assessed by calculating the F-statistic using the formula F = R 2 ×(N − 1−K)/(1 − R 2 )×K, where R 2 represents the proportion of variance in the exposure explained by the genetic variants,N represents sample size,and K represents the number of instruments.When the F > 10, it was considered that there was no weak IVs bias[ 30 ]. Results Details about the selected IVs of AF/AFL are shown in (Supplementary Table S1 ).The MR estimates about AF/AFL on LVF of different methods are presented in (Supplementary Table S2).Specifically, the preliminary results of IVW revealed postive causal effect of AF/AFL on LVF[OR = 1.053, 95% CI: 1.023–1.084, P = 0.0006] (Fig. 1 ). Cochran's IVW Q test results show no significant heterogeneity among these IVs (Supplementary Table S3). The results of the MR-Egger regression intercept analysis indicate no significant horizontal pleiotropy(Supplementary Table S4). MR-PRESSO global test results revealed no horizontal pleiotropy(Supplementary Table S5). Additionally, the p-values of the MR PRESSO global test for AF/AFL on LVF were all greater than 0.05.The funnel plot presents a symmetricl shap,suggesting significant heterogeneity,indicating that there is no systematic bias between the study effect and its accuracy(Fig. 2 ). The leave-one-out plot is shown that each IVs does not have a serious bias effect on the overall MR results(Fig. 3 ).The scatter plot are shown in (Fig. 4 ).The results of the steiger test confirmed no causal effect of LVF on AF/AFL (Supplementary Table S6). Discussion In the present study, We found suggestive evidence that the genetically predicted AF/AFL displayed a particularly strong positive with LVF. Currently, the clinical management of HF patients with AF encounters challenges due to potential differences in optimal heart rate or rhythm control treatment between patients with and without cardiac damage. The appropriate target for heart rate in patients with AF-HF remains uncertain[ 31 , 32 ]. Moreover, there is controversy surrounding the treatment options for AF-HF. Several studies have shown that catheter ablation is associated with improvements in ejection fraction, B-type natriuretic peptide (BNP) levels, and quality of life[ 33 , 34 ]. In contrast, its effect on reducing hospitalizations for HF, mortality, and other cardiovascular events was not significant[ 35 , 36 ]. In addition, the pharmacological management of AFL poses a greater challenge compared to AF, necessitating more precise control over cardiac rhythm[ 37 ]. Electrocardioversion serves as an effective approach for restoring acute sinus rhythm. Nevertheless, considering the risk of recurrence, catheter ablation should be prioritized to mitigate the incidence of complications [ 38 ].Following AFL ablation in patients with LVF, more than 50% experienced improvement in left ventricular(LV) function, with complete restoration observed in approximately 75% of cases[ 39 , 40 ].Nevertheless, other studies have shown that HF may limit the success of catheter ablation, and a high recurrence rate has been reported[ 40 ]. Previous studies have investigated a bidirectional causal relationship between AF/AFL and LVF. Nevertheless, due to the substantial overlap of asymptomatic cases and risk factors, establishing a direct causal association between AF/AFL and LVF poses significant challenges[ 7 , 12 , 41 ]. The issues of confounding and reverse causality highlighted in conventional studies cannot be disregarded. In summary, there is currently insufficient high-level evidence to inform clinical decision-making regarding the pharmacological and non-pharmacological management of AF/AFL in patients with HF[ 42 ]. To address these challenges, we conducted a bidirectional Mendelian randomization study employing genetic IVs as proxies for the clinical phenotypes of AF/AFL and LVF. This approach enables us to mitigate confusion bias and reverse causation, thereby confirming the causal directionality within the framework of bidirectional MR study. SNPs associated with the outcome were excluded, and Steiger test was employed to bolster evidence supporting a unidirectional causal relationship between exposure and outcome. The studies have demonstrated that AF results in reduced cardiac output due to cardiomyopathy caused by an accelerated ventricular rate, loss of atrial contraction, irregular ventricular filling, and tachycardia[ 14 ]. An analysis of over 1000 patients with atrial flutter revealed that the prevalence of arrhythmia-induced cardiomyopathy was approximately 8%[ 39 ]. Atrial arrhythmias such as AF or AFL can lead to LVF. This is consistent with the results of our MR Analysis. The severity of systolic HF is directly proportional to the presence of AF. In this case, although ventricular rate in AF may not be associated with HF, the damage is actually attributed to the timing of AF itself[ 43 ]. This can be linked to impaired homeostasis of LV Ca 2+ and myocardial electrical remodeling caused by HF[ 44 ].Extensive research has consistently demonstrated the detrimental impact of AF on LV function and emphasized the advantages of rhythm control strategies. Therefore, restoring sinus rhythm appears to be a primary objective for patients with HF, preferably through catheter ablation. If sinus rhythm cannot be restored, permanent AF should be considered and timely discussion regarding potential options such as atrioventricular node ablation and cardiac resynchronization therapy implantation should take place with the patient[ 45 , 46 ].Results of the CASTLE-AF trial showed that the use of ablation for AF in patients with HF resulted in significantly lower mortality and hospitalization rates than medical therapy[ 47 ]. HF of any etiology is correlated with escalated healthcare expenditures and unfavorable prognosis.In patients with AF, the presence of HF is associated with a worse prognosis and increased rates of all-cause mortality and hospitalization[ 48 , 49 ].It is worth noting that according to our MR Analysis, Steiger test results showed that LVF did not have a significant effect on AF/AFL. Studies have demonstrated that HF increases the risk of developing AF through the elevation of acute and chronic left atrial(LA) pressure[ 14 ]. This increase in pressure and dilation can promote scarring and fibrosis, ultimately leading to conduction abnormalities such as decreased LA potential conduction velocity and anisotropy. The structural substrate of AF is atrial fibrosis, which represents the final common pathway through which HF contributes to the development of AF.Hf-induced alterations in atrial structure, encompassing modifications in extracellular matrix volume and composition, ultimately give rise to intra-atrial conduction heterogeneity, which constitutes the primary mechanism underlying the maintenance of AF[ 14 , 50 , 51 , 52 ]. The clinical significance of HF in patients with AF is that LA remodeling is more obvious, resulting in a reduced success rate of rhythm control strategies[ 53 ].Additionally, LA function serves as a predictive factor for recurrence following ablation therapy for AF[ 54 ].Notably, left atrial flutter accounts for a large proportion of persistent recurrence of symptoms after ablation of AF/AFL.Therefore, when HF patients with AF/AFL undergo radiofrequency ablation, the timing and strategy of surgery should be evaluated in combination with left atrial function[ 55 – 59 ].The likelihood of atrial flutter is reduced in cases of isolated LVF without elevated LA pressure or pathological structural changes. These findings align with the results obtained from our MR Analysis, although further validation is warranted. This study aimed to investigate the causal relationship between AF/AFL and LVF, revealing a significant impact of AF/AFL on the development of LVF. There are many advantages to this study.First, it uses MR analysis to establish causal inferences, and in order to make the study results more robust and reliable, we implemented strict SNPs screening criteria, validated our findings using multiple MR research methods, and performed sensitivity analyses to assess the impact of pleipotency.Our SNPs screening criteria included the use of large-scale GWAS meta-analysis data to ensure a strong association between IVs and exposure.We then use a variety of statistical methods to detect and correct for the pleiotropy of genetic variants, ensuring that different Mendelian randomization research methods are in the same direction.Second, to satisfy the exclusion hypothesis, we excluded SNPS associated with established confounders, which gives it a significant advantage over traditional observational studies.Third, there are currently few studies on AF/AFL and LVF, and this study reveals a new association.It is suggested that early control of AF or AFL in HF-AF patients can improve LV function, providing valuable insights into the pathogenesis of HF-AF patients. Nevertheless, it is important to recognize the limitations of this study. First of all, the tool variable we choose adopts P 10, which indicates that weak instrumental bias is less likely. Second, the focus on a single ethnic group (Europeans) limits the generality of our findings to other populations. Thirdly, while efforts have been made to mitigate confounding, it is not possible to completely rule out the existence of pleiotropy. Fourth, further studies on the relationship between LV function and AF/AFL need to be supplemented to further confirm our results. Finally, We did not examine potential mechanisms to elucidate the significant associations identified. Conclusions 1.This MR study presents novel genetic evidence supporting a causal association between AF/AFL and LVF, thus contributing to the advancement of our understanding in this field.This study underscores the importance of managing HF-AF patients by incorporating AF/AFL treatment alongside conventional anti-HF therapy and ventricular rate control, aiming to enhance LV function and achieve a more favorable prognosis.In addition, this study found that LVF did not have a significant impact on AF/AFL.Mechanistically, the substrate of AF/AFL primarily lies in the functional and structural abnormalities of the LA, rather than being attributed to LV function. Nevertheless, further experimental studies are warranted to validate the observed associations and elucidate the underlying biological mechanisms linking LVF with AF/AFL.2.Focusing solely in European race limits the generalizability of our research findings to other populations.3.Although further confirmation of the findings is required, the results provide new insights into the pathogenesis of HF-AF patients and provide hope for future research directions. Abbreviations AF:atrial fibrillation;AFL:atrial flutter;atrial flutter:B-type natriuretic peptide;GWAS:Genome-wide association study;HF: and heart failure;IVs：instrumental variables;IVW:inverse variance weighted;LVF:left ventricular failure;LV:left ventricular; LA:left atrial; LD:linkage disequilibrium;MR:Mendelian randomization; SNPs:single nucleotide polymorphisms. Declarations Acknowledgements The authors would like to express their sincere gratitude to the participants and investigators of the atrial fibrillation/flutter and left ventricular failure summary statistics from the IEU OpenGWAS. Authors’ contributions Tiantian Chen and Fan Zou are co-first authors;Tiantian Chen is corresponding author. Funding Not applicable. Data availability The datasets generated and analyzed during the current study are available from the corresponding author on reasonable request. Ethics approval and consent to participate Not applicable. Consent for publication Not applicable. Competing interests There are no competing interests to declare Author details 1 Department of Cardiothoracic Surgery,The Third Affiliated Hospital of Sun Yat-sen University, Sun Yat-sen University, Guangzhou, China. References Virani SS, Alonso A, Aparicio HJ, Benjamin EJ, Bittencourt MS, Callaway CW, Carson AP, Chamberlain AM, Cheng S, Delling FN et al : Heart Disease and Stroke Statistics-2021 Update: A Report From the American Heart Association . Circulation 2021, 143 (8):e254-e743. Patel RB, Vaduganathan M, Shah SJ, Butler J: Atrial fibrillation in heart failure with preserved ejection fraction: Insights into mechanisms and therapeutics . Pharmacol Ther 2017, 176 :32-39. Naccarelli GV, Varker H, Lin J, Schulman KL: Increasing prevalence of atrial fibrillation and flutter in the United States . Am J Cardiol 2009, 104 (11):1534-1539. Klein L: Treating Hemodynamic Congestion Is the Key to Prevent Heart Failure Hospitalizations . JACC Heart Fail 2016, 4 (5):345-347. Savarese G, Lund LH: Global Public Health Burden of Heart Failure . Card Fail Rev 2017, 3 (1):7-11. Chugh SS: Heart failure and atrial fibrillation: Can we break this nexus? Int J Cardiol 2018, 252 :142-143. Zhang Z, Li L, Hu Z, Zhou L, Zhang Z, Xiong Y, Yao Y: Causal effects between atrial fibrillation and heart failure: evidence from a bidirectional Mendelian randomization study . BMC Med Genomics 2023, 16 (1):187. Prabhu S, Voskoboinik A, Kaye DM, Kistler PM: Atrial Fibrillation and Heart Failure - Cause or Effect? Heart Lung Circ 2017, 26 (9):967-974. Mulder BA, Rienstra M, Van Gelder IC, Blaauw Y: Update on management of atrial fibrillation in heart failure: a focus on ablation . Heart 2022, 108 (6):422-428. Lardizabal JA, Deedwania PC: Atrial fibrillation in heart failure . Med Clin North Am 2012, 96 (5):987-1000. Healey JS, Oldgren J, Ezekowitz M, Zhu J, Pais P, Wang J, Commerford P, Jansky P, Avezum A, Sigamani A et al : Occurrence of death and stroke in patients in 47 countries 1 year after presenting with atrial fibrillation: a cohort study . Lancet 2016, 388 (10050):1161-1169. Wang TJ, Larson MG, Levy D, Vasan RS, Leip EP, Wolf PA, D'Agostino RB, Murabito JM, Kannel WB, Benjamin EJ: Temporal relations of atrial fibrillation and congestive heart failure and their joint influence on mortality: the Framingham Heart Study . Circulation 2003, 107 (23):2920-2925. Diamant MJ, Andrade JG, Virani SA, Jhund PS, Petrie MC, Hawkins NM: Heart failure and atrial flutter: a systematic review of current knowledge and practices . ESC Heart Fail 2021, 8 (6):4484-4496. Carlisle MA, Fudim M, DeVore AD, Piccini JP: Heart Failure and Atrial Fibrillation, Like Fire and Fury . JACC Heart Fail 2019, 7 (6):447-456. Roy D, Talajic M, Nattel S, Wyse DG, Dorian P, Lee KL, Bourassa MG, Arnold JM, Buxton AE, Camm AJ et al : Rhythm control versus rate control for atrial fibrillation and heart failure . N Engl J Med 2008, 358 (25):2667-2677. Di Biase L, Mohanty P, Mohanty S, Santangeli P, Trivedi C, Lakkireddy D, Reddy M, Jais P, Themistoclakis S, Dello Russo A et al : Ablation Versus Amiodarone for Treatment of Persistent Atrial Fibrillation in Patients With Congestive Heart Failure and an Implanted Device: Results From the AATAC Multicenter Randomized Trial . Circulation 2016, 133 (17):1637-1644. Santhanakrishnan R, Wang N, Larson MG, Magnani JW, McManus DD, Lubitz SA, Ellinor PT, Cheng S, Vasan RS, Lee DS et al : Atrial Fibrillation Begets Heart Failure and Vice Versa: Temporal Associations and Differences in Preserved Versus Reduced Ejection Fraction . Circulation 2016, 133 (5):484-492. Bamimore A, Mounsey P: Ablation of atrial tachycardia and atrial flutter in heart failure . Heart Fail Clin 2013, 9 (4):501-514. Malhi N, Hawkins NM, Andrade JG, Krahn AD, Deyell MW: Catheter ablation of atrial fibrillation in heart failure with reduced ejection fraction . J Cardiovasc Electrophysiol 2018, 29 (7):1049-1058. Schmidt M, Ulrichsen SP, Pedersen L, Bøtker HE, Nielsen JC, Sørensen HT: 30-year nationwide trends in incidence of atrial fibrillation in Denmark and associated 5-year risk of heart failure, stroke, and death . Int J Cardiol 2016, 225 :30-36. Gula LJ, Redfearn DP, Jenkyn KB, Allen B, Skanes AC, Leong-Sit P, Shariff SZ: Elevated Incidence of Atrial Fibrillation and Stroke in Patients With Atrial Flutter-A Population-Based Study . Can J Cardiol 2018, 34 (6):774-783. Lin YS, Chen YL, Chen TH, Lin MS, Liu CH, Yang TY, Chung CM, Chen MC: Comparison of Clinical Outcomes Among Patients With Atrial Fibrillation or Atrial Flutter Stratified by CHA2DS2-VASc Score . JAMA Netw Open 2018, 1 (4):e180941. Paydak H, Kall JG, Burke MC, Rubenstein D, Kopp DE, Verdino RJ, Wilber DJ: Atrial fibrillation after radiofrequency ablation of type I atrial flutter: time to onset, determinants, and clinical course . Circulation 1998, 98 (4):315-322. Kamat MA, Blackshaw JA, Young R, Surendran P, Burgess S, Danesh J, Butterworth AS, Staley JR: PhenoScanner V2: an expanded tool for searching human genotype-phenotype associations . Bioinformatics 2019, 35 (22):4851-4853. Bowden J, Del Greco MF, Minelli C, Zhao Q, Lawlor DA, Sheehan NA, Thompson J, Davey Smith G: Improving the accuracy of two-sample summary-data Mendelian randomization: moving beyond the NOME assumption . Int J Epidemiol 2019, 48 (3):728-742. Bowden J, Davey Smith G, Haycock PC, Burgess S: Consistent Estimation in Mendelian Randomization with Some Invalid Instruments Using a Weighted Median Estimator . Genet Epidemiol 2016, 40 (4):304-314. Bowden J, Davey Smith G, Burgess S: Mendelian randomization with invalid instruments: effect estimation and bias detection through Egger regression . Int J Epidemiol 2015, 44 (2):512-525. Verbanck M, Chen CY, Neale B, Do R: Detection of widespread horizontal pleiotropy in causal relationships inferred from Mendelian randomization between complex traits and diseases . Nat Genet 2018, 50 (5):693-698. Burgess S, Thompson SG: Interpreting findings from Mendelian randomization using the MR-Egger method . Eur J Epidemiol 2017, 32 (5):377-389. Burgess S, Thompson SG: Avoiding bias from weak instruments in Mendelian randomization studies . Int J Epidemiol 2011, 40 (3):755-764. Hindricks G, Potpara T, Dagres N, Arbelo E, Bax JJ, Blomström-Lundqvist C, Boriani G, Castella M, Dan GA, Dilaveris PE et al : 2020 ESC Guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS): The Task Force for the diagnosis and management of atrial fibrillation of the European Society of Cardiology (ESC) Developed with the special contribution of the European Heart Rhythm Association (EHRA) of the ESC . Eur Heart J 2021, 42 (5):373-498. Atherton JJ, Sindone A, De Pasquale CG, Driscoll A, MacDonald PS, Hopper I, Kistler PM, Briffa T, Wong J, Abhayaratna W et al : National Heart Foundation of Australia and Cardiac Society of Australia and New Zealand: Guidelines for the Prevention, Detection, and Management of Heart Failure in Australia 2018 . Heart Lung Circ 2018, 27 (10):1123-1208. Prabhu S, Taylor AJ, Costello BT, Kaye DM, McLellan AJA, Voskoboinik A, Sugumar H, Lockwood SM, Stokes MB, Pathik B et al : Catheter Ablation Versus Medical Rate Control in Atrial Fibrillation and Systolic Dysfunction: The CAMERA-MRI Study . J Am Coll Cardiol 2017, 70 (16):1949-1961. Jones DG, Haldar SK, Hussain W, Sharma R, Francis DP, Rahman-Haley SL, McDonagh TA, Underwood SR, Markides V, Wong T: A randomized trial to assess catheter ablation versus rate control in the management of persistent atrial fibrillation in heart failure . J Am Coll Cardiol 2013, 61 (18):1894-1903. Packer DL, Piccini JP, Monahan KH, Al-Khalidi HR, Silverstein AP, Noseworthy PA, Poole JE, Bahnson TD, Lee KL, Mark DB: Ablation Versus Drug Therapy for Atrial Fibrillation in Heart Failure: Results From the CABANA Trial . Circulation 2021, 143 (14):1377-1390. Sossalla S, Vollmann D: Arrhythmia-Induced Cardiomyopathy . Dtsch Arztebl Int 2018, 115 (19):335-341. Katritsis DG, Boriani G, Cosio FG, Hindricks G, Jaïs P, Josephson ME, Keegan R, Kim YH, Knight BP, Kuck KH et al : European Heart Rhythm Association (EHRA) consensus document on the management of supraventricular arrhythmias, endorsed by Heart Rhythm Society (HRS), Asia-Pacific Heart Rhythm Society (APHRS), and Sociedad Latinoamericana de Estimulación Cardiaca y Electrofisiologia (SOLAECE) . Europace 2017, 19 (3):465-511. Brembilla-Perrot B, Ferreira JP, Manenti V, Sellal JM, Olivier A, Villemin T, Beurrier D, De Chillou C, Louis P, Brembilla A et al : Predictors and prognostic significance of tachycardiomyopathy: insights from a cohort of 1269 patients undergoing atrial flutter ablation . Eur J Heart Fail 2016, 18 (4):394-401. Pizzale S, Lemery R, Green MS, Gollob MH, Tang AS, Birnie DH: Frequency and predictors of tachycardia-induced cardiomyopathy in patients with persistent atrial flutter . Can J Cardiol 2009, 25 (8):469-472. Landolina M, Cantù F, De Ferrari GM, Foresti S, Tavazzi L: The role of invasive electrophysiology in the management of patients with chronic heart failure . Heart Fail Monit 2002, 3 (2):49-59. Grace AA, Narayan SM: Common threads in atrial fibrillation and heart failure . Heart Fail Clin 2013, 9 (4):373-383, vii. Niforatos JD, Ehmann MR, Balhara KS, Hinson JS, Ramcharran L, Lobner K, Weygandt PL: Management of atrial flutter and atrial fibrillation with rapid ventricular response in patients with acute decompensated heart failure: A systematic review . Acad Emerg Med 2023, 30 (2):124-132. Shalaby AA: Atrial Fibrillation and Congestive Heart Failure: A Wicked Alliance About to Unravel . JACC Clin Electrophysiol 2022, 8 (11):1367-1368. Pabel S, Knierim M, Stehle T, Alebrand F, Paulus M, Sieme M, Herwig M, Barsch F, Körtl T, Pöppl A et al : Effects of Atrial Fibrillation on the Human Ventricle . Circ Res 2022, 130 (7):994-1010. Parkash R, Wells GA, Rouleau J, Talajic M, Essebag V, Skanes A, Wilton SB, Verma A, Healey JS, Sterns L et al : Randomized Ablation-Based Rhythm-Control Versus Rate-Control Trial in Patients With Heart Failure and Atrial Fibrillation: Results from the RAFT-AF trial . Circulation 2022, 145 (23):1693-1704. Brignole M, Pentimalli F, Palmisano P, Landolina M, Quartieri F, Occhetta E, Calò L, Mascia G, Mont L, Vernooy K et al : AV junction ablation and cardiac resynchronization for patients with permanent atrial fibrillation and narrow QRS: the APAF-CRT mortality trial . Eur Heart J 2021, 42 (46):4731-4739. Marrouche NF, Brachmann J, Andresen D, Siebels J, Boersma L, Jordaens L, Merkely B, Pokushalov E, Sanders P, Proff J et al : Catheter Ablation for Atrial Fibrillation with Heart Failure . N Engl J Med 2018, 378 (5):417-427. Benjamin EJ, Blaha MJ, Chiuve SE, Cushman M, Das SR, Deo R, de Ferranti SD, Floyd J, Fornage M, Gillespie C et al : Heart Disease and Stroke Statistics-2017 Update: A Report From the American Heart Association . Circulation 2017, 135 (10):e146-e603. Gheorghiade M, Vaduganathan M, Fonarow GC, Bonow RO: Rehospitalization for heart failure: problems and perspectives . J Am Coll Cardiol 2013, 61 (4):391-403. Frustaci A, Chimenti C, Bellocci F, Morgante E, Russo MA, Maseri A: Histological substrate of atrial biopsies in patients with lone atrial fibrillation . Circulation 1997, 96 (4):1180-1184. Hanna N, Cardin S, Leung TK, Nattel S: Differences in atrial versus ventricular remodeling in dogs with ventricular tachypacing-induced congestive heart failure . Cardiovasc Res 2004, 63 (2):236-244. Nattel S, Burstein B, Dobrev D: Atrial remodeling and atrial fibrillation: mechanisms and implications . Circ Arrhythm Electrophysiol 2008, 1 (1):62-73. Liao YC, Liao JN, Lo LW, Lin YJ, Chang SL, Hu YF, Chao TF, Chung FP, Tuan TC, Te AL et al : Left Atrial Size and Left Ventricular End-Systolic Dimension Predict the Progression of Paroxysmal Atrial Fibrillation After Catheter Ablation . J Cardiovasc Electrophysiol 2017, 28 (1):23-30. Hammerstingl C, Schwekendiek M, Momcilovic D, Schueler R, Sinning JM, Schrickel JW, Mittmann-Braun E, Nickenig G, Lickfett L: Left atrial deformation imaging with ultrasound based two-dimensional speckle-tracking predicts the rate of recurrence of paroxysmal and persistent atrial fibrillation after successful ablation procedures . J Cardiovasc Electrophysiol 2012, 23 (3):247-255. Calkins H, Kuck KH, Cappato R, Brugada J, Camm AJ, Chen SA, Crijns HJ, Damiano RJ, Jr., Davies DW, DiMarco J et al : 2012 HRS/EHRA/ECAS expert consensus statement on catheter and surgical ablation of atrial fibrillation: recommendations for patient selection, procedural techniques, patient management and follow-up, definitions, endpoints, and research trial design: a report of the Heart Rhythm Society (HRS) Task Force on Catheter and Surgical Ablation of Atrial Fibrillation. Developed in partnership with the European Heart Rhythm Association (EHRA), a registered branch of the European Society of Cardiology (ESC) and the European Cardiac Arrhythmia Society (ECAS); and in collaboration with the American College of Cardiology (ACC), American Heart Association (AHA), the Asia Pacific Heart Rhythm Society (APHRS), and the Society of Thoracic Surgeons (STS). Endorsed by the governing bodies of the American College of Cardiology Foundation, the American Heart Association, the European Cardiac Arrhythmia Society, the European Heart Rhythm Association, the Society of Thoracic Surgeons, the Asia Pacific Heart Rhythm Society, and the Heart Rhythm Society . Heart Rhythm 2012, 9 (4):632-696.e621. Chae S, Oral H, Good E, Dey S, Wimmer A, Crawford T, Wells D, Sarrazin JF, Chalfoun N, Kuhne M et al : Atrial tachycardia after circumferential pulmonary vein ablation of atrial fibrillation: mechanistic insights, results of catheter ablation, and risk factors for recurrence . J Am Coll Cardiol 2007, 50 (18):1781-1787. Wasmer K, Mönnig G, Bittner A, Dechering D, Zellerhoff S, Milberg P, Köbe J, Eckardt L: Incidence, characteristics, and outcome of left atrial tachycardias after circumferential antral ablation of atrial fibrillation . Heart Rhythm 2012, 9 (10):1660-1666. Mikhaylov EN, Bhagwandien R, Janse PA, Theuns DA, Szili-Torok T: Regular atrial tachycardias developing after cryoballoon pulmonary vein isolation: incidence, characteristics, and predictors . Europace 2013, 15 (12):1710-1717. Chugh A, Oral H, Lemola K, Hall B, Cheung P, Good E, Tamirisa K, Han J, Bogun F, Pelosi F, Jr. et al : Prevalence, mechanisms, and clinical significance of macroreentrant atrial tachycardia during and following left atrial ablation for atrial fibrillation . Heart Rhythm 2005, 2 (5):464-471. Additional Declarations No competing interests reported. Supplementary Files SupplementaryTable.xlsx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4156657","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":285750113,"identity":"13150d2c-93a4-4cc9-884f-4bc2951394cf","order_by":0,"name":"Tiantian Chen","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA9UlEQVRIie3PMUvEMBTA8YZAu7Q3v3DQ+wqvZBHuwMEvki51ETlxuUE0JVAX3R3Ej3FzJBCX4Cw4aHR1yCo4eO5Hc2435De/P++9LEuSfaRJ7wMuaiLN03dYQT2LJ1RxWHac9lZMwR3wRkaTYoAymPZaOYRqWLWZjhST10eFgIbcDlYgewBBJPUfLyMJe2779yUeU3ZjtDhbw2mR5ZyfjCToyN+Wed7cWaHZGs6JLPNpJNn8grQ8fPtqZHUPrdS7JUdApONZJXdI2OYwDtghkbajYIE3KvLLxBXeh5/FVS+NJeHisp4Vyn+OJVvQ/40nSZIkW/wC9nVSlcrDtyYAAAAASUVORK5CYII=","orcid":"","institution":"Third Affiliated Hospital of Sun Yat-sen University","correspondingAuthor":true,"prefix":"","firstName":"Tiantian","middleName":"","lastName":"Chen","suffix":""},{"id":285750114,"identity":"79dad25e-824c-4c24-ae0b-1b408fd866d6","order_by":1,"name":"Zhou Fan","email":"","orcid":"","institution":"Third Affiliated Hospital of Sun Yat-sen University","correspondingAuthor":false,"prefix":"","firstName":"Zhou","middleName":"","lastName":"Fan","suffix":""}],"badges":[],"createdAt":"2024-03-24 05:59:27","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4156657/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4156657/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":53886794,"identity":"d5eb0b87-a25b-4b5c-a8e2-0df8510479e8","added_by":"auto","created_at":"2024-04-01 19:40:59","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":78868,"visible":true,"origin":"","legend":"\u003cp\u003eForest plot for the Mendelian randomization\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-4156657/v1/f000c2b68fa7e14cf9941bb9.png"},{"id":53886649,"identity":"f6b3958a-8655-4e26-9307-22f5e395f2f3","added_by":"auto","created_at":"2024-04-01 19:32:59","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":13079,"visible":true,"origin":"","legend":"\u003cp\u003eThe MR funnel plot of atrial fibrillation and flutter on LVF .\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-4156657/v1/06c728afc0f0c5870a1481d3.png"},{"id":53886651,"identity":"a1ecf7e0-b021-40ec-9b44-1add9ca80369","added_by":"auto","created_at":"2024-04-01 19:32:59","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":30046,"visible":true,"origin":"","legend":"\u003cp\u003eThe leave One Out plot of AF/AFL on LVF .\u003c/p\u003e","description":"","filename":"Figure3.png","url":"https://assets-eu.researchsquare.com/files/rs-4156657/v1/ace2740a77f2ba305466a600.png"},{"id":53886795,"identity":"ce164d0e-ba9f-41f0-8e38-ec7e1a61d231","added_by":"auto","created_at":"2024-04-01 19:40:59","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":29446,"visible":true,"origin":"","legend":"\u003cp\u003eThe scatter plot of AF/AFL on LVF .\u003c/p\u003e","description":"","filename":"Figure4.png","url":"https://assets-eu.researchsquare.com/files/rs-4156657/v1/5ce0073609ed6977446692ef.png"},{"id":72311965,"identity":"33601777-6f5d-49e8-9a48-addf44362420","added_by":"auto","created_at":"2024-12-25 06:38:39","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2308799,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4156657/v1/c2bda212-1c1e-47ba-84d5-01cfa4b9e837.pdf"},{"id":53886652,"identity":"283e305b-8a68-4844-ba48-640858b46bf7","added_by":"auto","created_at":"2024-04-01 19:32:59","extension":"xlsx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":24222,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryTable.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-4156657/v1/6a6bf2c1e083ce4f15fa8f1a.xlsx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Association between atrial fibrillation/flutter and left ventricular failure: A bidirectional Mendelian randomization study","fulltext":[{"header":"Introduction","content":"\u003cp\u003eAtrial fibrillation (AF) and heart failure (HF) impose a substantial global health burden, with an estimated current prevalence of AF in over 30\u0026nbsp;million individuals, accounting for approximately 1% of the global population. Furthermore, it is projected that the incidence of AF will double by 2030[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. There exists a certain degree of overlap and mutual conversion between AF and atrial flutter(AFL). In the general population, the incidence rate of AF is about ten times higher than that of AFL. Even though only a small percentage of patients with AF develop AFL (e.g.10%), most patients with AFL eventually progress to AF[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e].HF represents the ultimate stage in numerous cardiovascular diseases and serves as their final battleground. Globally, more than 25\u0026nbsp;million people are estimated to be affected by HF, constituting around 2% of total healthcare expenditure[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e].By 2030, this cost is expected to double to \u003cspan\u003e$\u003c/span\u003e70 billion[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Findings from an extensive UK hospital database analysis (ACALM Registry) revealed significantly higher all-cause mortality rates among patients with both HF and AF(71%) compared to those solely diagnosed with HF(64%) or AF(45%) alone. Additionally, newly developed combined cases of AF and HF exhibited the highest mortality rate during a follow-up period spanning thirteen years at 75%. Similar trends were observed regarding lengthier hospital stays among individuals presenting with HF accompanied by AF [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e].As medical advancements continue alongside aging populations worldwide, it is anticipated that these two diseases' global prevalence will escalate further[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAF and HF share common pathophysiological mechanisms, thus frequently coexisting and mutually influencing disease progression[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. AF is a prevalent complication of HF, with an incidence rate of 25%[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Conversely, HF surpasses stroke mortality by more than threefold as the leading cause of death in AF patients[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. The combination of these conditions is associated with heightened mortality rates and unfavorable prognosis[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Studies have indicated a higher incidence and prevalence of HF in AFL patients compared to those with AF; But, further validation is warranted[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eExtensive research has been conducted on AF-HF, resulting in significant advancements in comprehending the epidemiology, pathophysiology, evaluation, and treatment of AF-HF; Nevertheless, the optimal long-term efficacy approach remains uncertain[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e].Numerous unresolved queries persist regarding the management of patients with AF-HF. Which rhythm control therapy should be prioritized as first-line for HF patients presenting symptomatic AF? Among HF patients with symptomatic AF, who are the most likely candidates to benefit from catheter ablation? How can the propensity for AF development in HF patients be mitigated? What strategies effectively prevent HF in individuals already diagnosed with AF? Simultaneously, certain contentious points exist. For instance, conflicting data exists regarding improved outcomes in HF and AF patients through interventions such as catheter ablation[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e].To address these clinical issues and controversies, a comprehensive exploration of the underlying pathological mechanisms of AF and HF is imperative.\u003c/p\u003e \u003cp\u003eNumerous studies have provided evidence supporting a bidirectional relationship between HF and AF[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. While it is important to consider the various subtypes and grades of HF as well as the heterogeneity in combined AF/AFL presentations, which may lead to divergent research findings. These studies have limitations for clinical guidance. Furthermore, there remains a paucity of research investigating the association between AF/AFL and left ventricular failure(LVF), with the exact underlying mechanism still unclear.This study included SNP data for LVF as the outcome.\u003c/p\u003e \u003cp\u003eAF and AFL are common tachyarrhythmias in patients with HF[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e].A trial conducted in patients with HF-AF offers an alternative perspective on the potential overlap between AFL and AF[\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. While previous studies have often used AFL and AF interchangeably as diagnoses[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e], it is important to note that more than 70% of individuals with AFL do not progress to AF, while less than 10% of those diagnosed with AF also present with AFL [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe consideration of overlap between AFL and AF is crucial in the planning of AFL ablation for patients with LVF, as subsequent development of AF occurs in up to 43% of patients[\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. Therefore, this study incorporated data AF/AFL as the exposure data, thereby enhancing the reliability of the results.\u003c/p\u003e \u003cp\u003eIn this study, our objective is to employ Mendelian randomization(MR) studies in order to investigate the causal relationship between AF/AFL and LVF, explore potential therapeutic targets for clinical application, and optimize the management and clinical outcomes of patients with AF/AFL and HF.\u003c/p\u003e"},{"header":"Method","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eData source for atrial fibrillation and Atrial flutter\u003c/h2\u003e \u003cp\u003eThe data of atrial fibrillation and flutter from the IEU OpenGWAS project.These data derive from a European population consisting of 463,010 participants drawn from the UK Biobank. Among them, 5,669 individuals had AF/AFL, and a total of 9,851,867 single nucleotide polymorphisms(SNPs) were considered.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eData source for Left ventricular failure\u003c/h2\u003e \u003cp\u003eTo ensure a matching number of SNPs between LVF and minimize population overlap effects, we implemented the most recent and largest genome-wide association study meta-analysis from the IEU OpenGWAS project. A total of 2046 cases and 460,964 controls were investigated,within a total of 9,851,867 SNPs. There would be no overlap in population selection between the exposure group and the outcome group.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eSNPs selection\u003c/h2\u003e \u003cp\u003eWe performed a set of methods to filter valid SNPs that suit the three core MR assumptions. (1) The independent SNPs strongly linked to different circulating cytokines were selected. SNPs with \u003cem\u003eP\u003c/em\u003e-value\u0026thinsp;\u0026lt;\u0026thinsp;5\u0026times;10\u003csup\u003e\u0026minus;\u0026thinsp;6\u003c/sup\u003e were considered to be significantly associated with circulating cytokines to obtain more SNPs as instrumental variables(IVs). (2)We adopted the clumping process to evaluate the linkage disequilibrium(LD) among the SNPs (r\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001 and clumping distance\u0026thinsp;=\u0026thinsp;10,000 kb). The SNPs with LD were removed to avoid biased results.(3)We searched all the screened SNPs on PhenoScanner V2(\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://www.phenoscanner.medschl.cam.ac.uk/\u003c/span\u003e\u003cspan address=\"http://www.phenoscanner.medschl.cam.ac.uk/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e)[\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e].PhenoScanner V2 provides the phenotypes information of SNPs,which can be used to determine whether the SNPs only affect the outcomes through exposure.The SNPs related to the confounding factors were excluded to eliminate the bias. Finally, we harmonized the exposure and outcome datasets to remove the non-concordant SNPs. The remaining SNPs were used as the genetic IVs.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eWe adopted inverse variance weighted (IVW) as the main way to estimate the MR analysis.IVW assesses the overall causal impact of exposure on the outcomes.It is the most accurate way to evaluate causality if all the selected SNPs are valid[\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e].We also applied other methods to analyze causal association, including Weighted Median, MR Egger,Weighted Mode, and Simple Mode methods.The Weighted Median method will generate a more potent effect when more than half of the SNPs are valid[\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e].MR Egger provides accurate effect estimates even if all the SNPs are invalid[\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e].We further conducted the MR-Egger regression and the MR Pleiotropy Residual Sum and Outlier (MR-PRESSO) test to evaluate the possible horizontal pleiotropy[\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. We used Cochran\u0026rsquo;s Q statistic and MR-egger regression to test the heterogeneities. Additionally, the leave-one-out analysis was utilized to assess the robustness and consistency of the results.All statistical analyses were performed using the R packages \"two-sample MR\" and \"MR-PRESSO.\"The strength of IVs was assessed by calculating the F-statistic using the formula \u003cem\u003eF\u003c/em\u003e\u0026thinsp;=\u0026thinsp;R \u003csup\u003e2\u003c/sup\u003e\u0026times;(N\u0026thinsp;\u0026minus;\u0026thinsp;1\u0026minus;K)/(1\u0026thinsp;\u0026minus;\u0026thinsp;R\u003csup\u003e2\u003c/sup\u003e)\u0026times;K, where R\u003csup\u003e2\u003c/sup\u003e represents the proportion of variance in the exposure explained by the genetic variants,N represents sample size,and K represents the number of instruments.When the \u003cem\u003eF\u003c/em\u003e\u0026thinsp;\u0026gt;\u0026thinsp;10, it was considered that there was no weak IVs bias[\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eDetails about the selected IVs of AF/AFL are shown in (Supplementary Table \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e).The MR estimates about AF/AFL on LVF of different methods are presented in (Supplementary Table S2).Specifically, the preliminary results of IVW revealed postive causal effect of AF/AFL on LVF[OR\u0026thinsp;=\u0026thinsp;1.053, 95% CI: 1.023\u0026ndash;1.084, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.0006] (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eCochran's IVW Q test results show no significant heterogeneity among these IVs (Supplementary Table S3). The results of the MR-Egger regression intercept analysis indicate no significant horizontal pleiotropy(Supplementary Table S4). MR-PRESSO global test results revealed no horizontal pleiotropy(Supplementary Table S5). Additionally, the p-values of the MR PRESSO global test for AF/AFL on LVF were all greater than 0.05.The funnel plot presents a symmetricl shap,suggesting significant heterogeneity,indicating that there is no systematic bias between the study effect and its accuracy(Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). The leave-one-out plot is shown that each IVs does not have a serious bias effect on the overall MR results(Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).The scatter plot are shown in (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e).The results of the steiger test confirmed no causal effect of LVF on AF/AFL (Supplementary Table S6).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn the present study, We found suggestive evidence that the genetically predicted AF/AFL displayed a particularly strong positive with LVF.\u003c/p\u003e \u003cp\u003eCurrently, the clinical management of HF patients with AF encounters challenges due to potential differences in optimal heart rate or rhythm control treatment between patients with and without cardiac damage. The appropriate target for heart rate in patients with AF-HF remains uncertain[\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e, \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]. Moreover, there is controversy surrounding the treatment options for AF-HF. Several studies have shown that catheter ablation is associated with improvements in ejection fraction, B-type natriuretic peptide (BNP) levels, and quality of life[\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e, \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]. In contrast, its effect on reducing hospitalizations for HF, mortality, and other cardiovascular events was not significant[\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e, \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn addition, the pharmacological management of AFL poses a greater challenge compared to AF, necessitating more precise control over cardiac rhythm[\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e]. Electrocardioversion serves as an effective approach for restoring acute sinus rhythm. Nevertheless, considering the risk of recurrence, catheter ablation should be prioritized to mitigate the incidence of complications [\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e].Following AFL ablation in patients with LVF, more than 50% experienced improvement in left ventricular(LV) function, with complete restoration observed in approximately 75% of cases[\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e, \u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e].Nevertheless, other studies have shown that HF may limit the success of catheter ablation, and a high recurrence rate has been reported[\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e].\u003c/p\u003e \u003cp\u003ePrevious studies have investigated a bidirectional causal relationship between AF/AFL and LVF. Nevertheless, due to the substantial overlap of asymptomatic cases and risk factors, establishing a direct causal association between AF/AFL and LVF poses significant challenges[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e]. The issues of confounding and reverse causality highlighted in conventional studies cannot be disregarded. In summary, there is currently insufficient high-level evidence to inform clinical decision-making regarding the pharmacological and non-pharmacological management of AF/AFL in patients with HF[\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eTo address these challenges, we conducted a bidirectional Mendelian randomization study employing genetic IVs as proxies for the clinical phenotypes of AF/AFL and LVF. This approach enables us to mitigate confusion bias and reverse causation, thereby confirming the causal directionality within the framework of bidirectional MR study. SNPs associated with the outcome were excluded, and Steiger test was employed to bolster evidence supporting a unidirectional causal relationship between exposure and outcome.\u003c/p\u003e \u003cp\u003eThe studies have demonstrated that AF results in reduced cardiac output due to cardiomyopathy caused by an accelerated ventricular rate, loss of atrial contraction, irregular ventricular filling, and tachycardia[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. An analysis of over 1000 patients with atrial flutter revealed that the prevalence of arrhythmia-induced cardiomyopathy was approximately 8%[\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e]. Atrial arrhythmias such as AF or AFL can lead to LVF. This is consistent with the results of our MR Analysis.\u003c/p\u003e \u003cp\u003eThe severity of systolic HF is directly proportional to the presence of AF. In this case, although ventricular rate in AF may not be associated with HF, the damage is actually attributed to the timing of AF itself[\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e]. This can be linked to impaired homeostasis of LV Ca\u003csup\u003e2+\u003c/sup\u003e and myocardial electrical remodeling caused by HF[\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e].Extensive research has consistently demonstrated the detrimental impact of AF on LV function and emphasized the advantages of rhythm control strategies. Therefore, restoring sinus rhythm appears to be a primary objective for patients with HF, preferably through catheter ablation. If sinus rhythm cannot be restored, permanent AF should be considered and timely discussion regarding potential options such as atrioventricular node ablation and cardiac resynchronization therapy implantation should take place with the patient[\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e, \u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e].Results of the CASTLE-AF trial showed that the use of ablation for AF in patients with HF resulted in significantly lower mortality and hospitalization rates than medical therapy[\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eHF of any etiology is correlated with escalated healthcare expenditures and unfavorable prognosis.In patients with AF, the presence of HF is associated with a worse prognosis and increased rates of all-cause mortality and hospitalization[\u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e, \u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e].It is worth noting that according to our MR Analysis, Steiger test results showed that LVF did not have a significant effect on AF/AFL.\u003c/p\u003e \u003cp\u003eStudies have demonstrated that HF increases the risk of developing AF through the elevation of acute and chronic left atrial(LA) pressure[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. This increase in pressure and dilation can promote scarring and fibrosis, ultimately leading to conduction abnormalities such as decreased LA potential conduction velocity and anisotropy. The structural substrate of AF is atrial fibrosis, which represents the final common pathway through which HF contributes to the development of AF.Hf-induced alterations in atrial structure, encompassing modifications in extracellular matrix volume and composition, ultimately give rise to intra-atrial conduction heterogeneity, which constitutes the primary mechanism underlying the maintenance of AF[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e, \u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e, \u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e52\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe clinical significance of HF in patients with AF is that LA remodeling is more obvious, resulting in a reduced success rate of rhythm control strategies[\u003cspan citationid=\"CR53\" class=\"CitationRef\"\u003e53\u003c/span\u003e].Additionally, LA function serves as a predictive factor for recurrence following ablation therapy for AF[\u003cspan citationid=\"CR54\" class=\"CitationRef\"\u003e54\u003c/span\u003e].Notably, left atrial flutter accounts for a large proportion of persistent recurrence of symptoms after ablation of AF/AFL.Therefore, when HF patients with AF/AFL undergo radiofrequency ablation, the timing and strategy of surgery should be evaluated in combination with left atrial function[\u003cspan additionalcitationids=\"CR56 CR57 CR58\" citationid=\"CR55\" class=\"CitationRef\"\u003e55\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR59\" class=\"CitationRef\"\u003e59\u003c/span\u003e].The likelihood of atrial flutter is reduced in cases of isolated LVF without elevated LA pressure or pathological structural changes. These findings align with the results obtained from our MR Analysis, although further validation is warranted.\u003c/p\u003e \u003cp\u003eThis study aimed to investigate the causal relationship between AF/AFL and LVF, revealing a significant impact of AF/AFL on the development of LVF.\u003c/p\u003e \u003cp\u003eThere are many advantages to this study.First, it uses MR analysis to establish causal inferences, and in order to make the study results more robust and reliable, we implemented strict SNPs screening criteria, validated our findings using multiple MR research methods, and performed sensitivity analyses to assess the impact of pleipotency.Our SNPs screening criteria included the use of large-scale GWAS meta-analysis data to ensure a strong association between IVs and exposure.We then use a variety of statistical methods to detect and correct for the pleiotropy of genetic variants, ensuring that different Mendelian randomization research methods are in the same direction.Second, to satisfy the exclusion hypothesis, we excluded SNPS associated with established confounders, which gives it a significant advantage over traditional observational studies.Third, there are currently few studies on AF/AFL and LVF, and this study reveals a new association.It is suggested that early control of AF or AFL in HF-AF patients can improve LV function, providing valuable insights into the pathogenesis of HF-AF patients.\u003c/p\u003e \u003cp\u003eNevertheless, it is important to recognize the limitations of this study. First of all, the tool variable we choose adopts \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;5 \u0026times;10\u003csup\u003e\u0026minus;\u0026thinsp;6\u003c/sup\u003e, which introduces the possibility of false-positive variants and subsequent bias. While it is worth noting that the IVs consistently show an F statistic\u0026thinsp;\u0026gt;\u0026thinsp;10, which indicates that weak instrumental bias is less likely. Second, the focus on a single ethnic group (Europeans) limits the generality of our findings to other populations. Thirdly, while efforts have been made to mitigate confounding, it is not possible to completely rule out the existence of pleiotropy. Fourth, further studies on the relationship between LV function and AF/AFL need to be supplemented to further confirm our results. Finally, We did not examine potential mechanisms to elucidate the significant associations identified.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003e1.This MR study presents novel genetic evidence supporting a causal association between AF/AFL and LVF, thus contributing to the advancement of our understanding in this field.This study underscores the importance of managing HF-AF patients by incorporating AF/AFL treatment alongside conventional anti-HF therapy and ventricular rate control, aiming to enhance LV function and achieve a more favorable prognosis.In addition, this study found that LVF did not have a significant impact on AF/AFL.Mechanistically, the substrate of AF/AFL primarily lies in the functional and structural abnormalities of the LA, rather than being attributed to LV function. Nevertheless, further experimental studies are warranted to validate the observed associations and elucidate the underlying biological mechanisms linking LVF with AF/AFL.2.Focusing solely in European race limits the generalizability of our research findings to other populations.3.Although further confirmation of the findings is required, the results provide new insights into the pathogenesis of HF-AF patients and provide hope for future research directions.\u003c/p\u003e\n"},{"header":"Abbreviations","content":"\u003cp\u003eAF:atrial fibrillation;AFL:atrial flutter;atrial flutter:B-type natriuretic peptide;GWAS:Genome-wide association study;HF: and heart failure;IVs：instrumental variables;IVW:inverse variance weighted;LVF:left ventricular failure;LV:left ventricular; LA:left atrial; LD:linkage disequilibrium;MR:Mendelian randomization; SNPs:single nucleotide polymorphisms.\u0026nbsp;\u003c/p\u003e\n"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors would like to express their sincere gratitude to the participants and investigators of the atrial fibrillation/flutter and left ventricular failure summary statistics from\u0026nbsp;the IEU OpenGWAS.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTiantian Chen and Fan Zou are co-first authors;Tiantian Chen is corresponding author.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets generated and analyzed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003e\u003c/strong\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThere are no competing interests to declare\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor details\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003csup\u003e1\u0026nbsp;\u003c/sup\u003eDepartment of Cardiothoracic Surgery,The Third Affiliated Hospital of Sun Yat-sen University, Sun Yat-sen University, Guangzhou, China.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eVirani SS, Alonso A, Aparicio HJ, Benjamin EJ, Bittencourt MS, Callaway CW, Carson AP, Chamberlain AM, Cheng S, Delling FN\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003eHeart Disease and Stroke Statistics-2021 Update: A Report From the American Heart Association\u003c/strong\u003e. \u003cem\u003eCirculation \u003c/em\u003e2021, \u003cstrong\u003e143\u003c/strong\u003e(8):e254-e743.\u003c/li\u003e\n\u003cli\u003ePatel RB, Vaduganathan M, Shah SJ, Butler J: \u003cstrong\u003eAtrial fibrillation in heart failure with preserved ejection fraction: Insights into mechanisms and therapeutics\u003c/strong\u003e. \u003cem\u003ePharmacol Ther \u003c/em\u003e2017, \u003cstrong\u003e176\u003c/strong\u003e:32-39.\u003c/li\u003e\n\u003cli\u003eNaccarelli GV, Varker H, Lin J, Schulman KL: \u003cstrong\u003eIncreasing prevalence of atrial fibrillation and flutter in the United States\u003c/strong\u003e. \u003cem\u003eAm J Cardiol \u003c/em\u003e2009, \u003cstrong\u003e104\u003c/strong\u003e(11):1534-1539.\u003c/li\u003e\n\u003cli\u003eKlein L: \u003cstrong\u003eTreating Hemodynamic Congestion Is the Key to Prevent Heart Failure Hospitalizations\u003c/strong\u003e. \u003cem\u003eJACC Heart Fail \u003c/em\u003e2016, \u003cstrong\u003e4\u003c/strong\u003e(5):345-347.\u003c/li\u003e\n\u003cli\u003eSavarese G, Lund LH: \u003cstrong\u003eGlobal Public Health Burden of Heart Failure\u003c/strong\u003e. \u003cem\u003eCard Fail Rev \u003c/em\u003e2017, \u003cstrong\u003e3\u003c/strong\u003e(1):7-11.\u003c/li\u003e\n\u003cli\u003eChugh SS: \u003cstrong\u003eHeart failure and atrial fibrillation: Can we break this nexus?\u003c/strong\u003e\u003cem\u003eInt J Cardiol \u003c/em\u003e2018, \u003cstrong\u003e252\u003c/strong\u003e:142-143.\u003c/li\u003e\n\u003cli\u003eZhang Z, Li L, Hu Z, Zhou L, Zhang Z, Xiong Y, Yao Y: \u003cstrong\u003eCausal effects between atrial fibrillation and heart failure: evidence from a bidirectional Mendelian randomization study\u003c/strong\u003e. \u003cem\u003eBMC Med Genomics \u003c/em\u003e2023, \u003cstrong\u003e16\u003c/strong\u003e(1):187.\u003c/li\u003e\n\u003cli\u003ePrabhu S, Voskoboinik A, Kaye DM, Kistler PM: \u003cstrong\u003eAtrial Fibrillation and Heart Failure - Cause or Effect?\u003c/strong\u003e\u003cem\u003eHeart Lung Circ \u003c/em\u003e2017, \u003cstrong\u003e26\u003c/strong\u003e(9):967-974.\u003c/li\u003e\n\u003cli\u003eMulder BA, Rienstra M, Van Gelder IC, Blaauw Y: \u003cstrong\u003eUpdate on management of atrial fibrillation in heart failure: a focus on ablation\u003c/strong\u003e. \u003cem\u003eHeart \u003c/em\u003e2022, \u003cstrong\u003e108\u003c/strong\u003e(6):422-428.\u003c/li\u003e\n\u003cli\u003eLardizabal JA, Deedwania PC: \u003cstrong\u003eAtrial fibrillation in heart failure\u003c/strong\u003e. \u003cem\u003eMed Clin North Am \u003c/em\u003e2012, \u003cstrong\u003e96\u003c/strong\u003e(5):987-1000.\u003c/li\u003e\n\u003cli\u003eHealey JS, Oldgren J, Ezekowitz M, Zhu J, Pais P, Wang J, Commerford P, Jansky P, Avezum A, Sigamani A\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003eOccurrence of death and stroke in patients in 47 countries 1 year after presenting with atrial fibrillation: a cohort study\u003c/strong\u003e. \u003cem\u003eLancet \u003c/em\u003e2016, \u003cstrong\u003e388\u003c/strong\u003e(10050):1161-1169.\u003c/li\u003e\n\u003cli\u003eWang TJ, Larson MG, Levy D, Vasan RS, Leip EP, Wolf PA, D\u0026apos;Agostino RB, Murabito JM, Kannel WB, Benjamin EJ: \u003cstrong\u003eTemporal relations of atrial fibrillation and congestive heart failure and their joint influence on mortality: the Framingham Heart Study\u003c/strong\u003e. \u003cem\u003eCirculation \u003c/em\u003e2003, \u003cstrong\u003e107\u003c/strong\u003e(23):2920-2925.\u003c/li\u003e\n\u003cli\u003eDiamant MJ, Andrade JG, Virani SA, Jhund PS, Petrie MC, Hawkins NM: \u003cstrong\u003eHeart failure and atrial flutter: a systematic review of current knowledge and practices\u003c/strong\u003e. \u003cem\u003eESC Heart Fail \u003c/em\u003e2021, \u003cstrong\u003e8\u003c/strong\u003e(6):4484-4496.\u003c/li\u003e\n\u003cli\u003eCarlisle MA, Fudim M, DeVore AD, Piccini JP: \u003cstrong\u003eHeart Failure and Atrial Fibrillation, Like Fire and Fury\u003c/strong\u003e. \u003cem\u003eJACC Heart Fail \u003c/em\u003e2019, \u003cstrong\u003e7\u003c/strong\u003e(6):447-456.\u003c/li\u003e\n\u003cli\u003eRoy D, Talajic M, Nattel S, Wyse DG, Dorian P, Lee KL, Bourassa MG, Arnold JM, Buxton AE, Camm AJ\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003eRhythm control versus rate control for atrial fibrillation and heart failure\u003c/strong\u003e. \u003cem\u003eN Engl J Med \u003c/em\u003e2008, \u003cstrong\u003e358\u003c/strong\u003e(25):2667-2677.\u003c/li\u003e\n\u003cli\u003eDi Biase L, Mohanty P, Mohanty S, Santangeli P, Trivedi C, Lakkireddy D, Reddy M, Jais P, Themistoclakis S, Dello Russo A\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003eAblation Versus Amiodarone for Treatment of Persistent Atrial Fibrillation in Patients With Congestive Heart Failure and an Implanted Device: Results From the AATAC Multicenter Randomized Trial\u003c/strong\u003e. \u003cem\u003eCirculation \u003c/em\u003e2016, \u003cstrong\u003e133\u003c/strong\u003e(17):1637-1644.\u003c/li\u003e\n\u003cli\u003eSanthanakrishnan R, Wang N, Larson MG, Magnani JW, McManus DD, Lubitz SA, Ellinor PT, Cheng S, Vasan RS, Lee DS\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003eAtrial Fibrillation Begets Heart Failure and Vice Versa: Temporal Associations and Differences in Preserved Versus Reduced Ejection Fraction\u003c/strong\u003e. \u003cem\u003eCirculation \u003c/em\u003e2016, \u003cstrong\u003e133\u003c/strong\u003e(5):484-492.\u003c/li\u003e\n\u003cli\u003eBamimore A, Mounsey P: \u003cstrong\u003eAblation of atrial tachycardia and atrial flutter in heart failure\u003c/strong\u003e. \u003cem\u003eHeart Fail Clin \u003c/em\u003e2013, \u003cstrong\u003e9\u003c/strong\u003e(4):501-514.\u003c/li\u003e\n\u003cli\u003eMalhi N, Hawkins NM, Andrade JG, Krahn AD, Deyell MW: \u003cstrong\u003eCatheter ablation of atrial fibrillation in heart failure with reduced ejection fraction\u003c/strong\u003e. \u003cem\u003eJ Cardiovasc Electrophysiol \u003c/em\u003e2018, \u003cstrong\u003e29\u003c/strong\u003e(7):1049-1058.\u003c/li\u003e\n\u003cli\u003eSchmidt M, Ulrichsen SP, Pedersen L, B\u0026oslash;tker HE, Nielsen JC, S\u0026oslash;rensen HT: \u003cstrong\u003e30-year nationwide trends in incidence of atrial fibrillation in Denmark and associated 5-year risk of heart failure, stroke, and death\u003c/strong\u003e. \u003cem\u003eInt J Cardiol \u003c/em\u003e2016, \u003cstrong\u003e225\u003c/strong\u003e:30-36.\u003c/li\u003e\n\u003cli\u003eGula LJ, Redfearn DP, Jenkyn KB, Allen B, Skanes AC, Leong-Sit P, Shariff SZ: \u003cstrong\u003eElevated Incidence of Atrial Fibrillation and Stroke in Patients With Atrial Flutter-A Population-Based Study\u003c/strong\u003e. \u003cem\u003eCan J Cardiol \u003c/em\u003e2018, \u003cstrong\u003e34\u003c/strong\u003e(6):774-783.\u003c/li\u003e\n\u003cli\u003eLin YS, Chen YL, Chen TH, Lin MS, Liu CH, Yang TY, Chung CM, Chen MC: \u003cstrong\u003eComparison of Clinical Outcomes Among Patients With Atrial Fibrillation or Atrial Flutter Stratified by CHA2DS2-VASc Score\u003c/strong\u003e. \u003cem\u003eJAMA Netw Open \u003c/em\u003e2018, \u003cstrong\u003e1\u003c/strong\u003e(4):e180941.\u003c/li\u003e\n\u003cli\u003ePaydak H, Kall JG, Burke MC, Rubenstein D, Kopp DE, Verdino RJ, Wilber DJ: \u003cstrong\u003eAtrial fibrillation after radiofrequency ablation of type I atrial flutter: time to onset, determinants, and clinical course\u003c/strong\u003e. \u003cem\u003eCirculation \u003c/em\u003e1998, \u003cstrong\u003e98\u003c/strong\u003e(4):315-322.\u003c/li\u003e\n\u003cli\u003eKamat MA, Blackshaw JA, Young R, Surendran P, Burgess S, Danesh J, Butterworth AS, Staley JR: \u003cstrong\u003ePhenoScanner V2: an expanded tool for searching human genotype-phenotype associations\u003c/strong\u003e. \u003cem\u003eBioinformatics \u003c/em\u003e2019, \u003cstrong\u003e35\u003c/strong\u003e(22):4851-4853.\u003c/li\u003e\n\u003cli\u003eBowden J, Del Greco MF, Minelli C, Zhao Q, Lawlor DA, Sheehan NA, Thompson J, Davey Smith G: \u003cstrong\u003eImproving the accuracy of two-sample summary-data Mendelian randomization: moving beyond the NOME assumption\u003c/strong\u003e. \u003cem\u003eInt J Epidemiol \u003c/em\u003e2019, \u003cstrong\u003e48\u003c/strong\u003e(3):728-742.\u003c/li\u003e\n\u003cli\u003eBowden J, Davey Smith G, Haycock PC, Burgess S: \u003cstrong\u003eConsistent Estimation in Mendelian Randomization with Some Invalid Instruments Using a Weighted Median Estimator\u003c/strong\u003e. \u003cem\u003eGenet Epidemiol \u003c/em\u003e2016, \u003cstrong\u003e40\u003c/strong\u003e(4):304-314.\u003c/li\u003e\n\u003cli\u003eBowden J, Davey Smith G, Burgess S: \u003cstrong\u003eMendelian randomization with invalid instruments: effect\u003c/strong\u003e\u003cstrong\u003e \u003c/strong\u003e\u003cstrong\u003eestimation and bias detection through Egger regression\u003c/strong\u003e. \u003cem\u003eInt J Epidemiol \u003c/em\u003e2015, \u003cstrong\u003e44\u003c/strong\u003e(2):512-525.\u003c/li\u003e\n\u003cli\u003eVerbanck M, Chen CY, Neale B, Do R: \u003cstrong\u003eDetection of widespread horizontal pleiotropy in causal relationships inferred from Mendelian randomization between complex traits and diseases\u003c/strong\u003e. \u003cem\u003eNat Genet \u003c/em\u003e2018, \u003cstrong\u003e50\u003c/strong\u003e(5):693-698.\u003c/li\u003e\n\u003cli\u003eBurgess S, Thompson SG: \u003cstrong\u003eInterpreting findings from Mendelian randomization using the MR-Egger method\u003c/strong\u003e. \u003cem\u003eEur J Epidemiol \u003c/em\u003e2017, \u003cstrong\u003e32\u003c/strong\u003e(5):377-389.\u003c/li\u003e\n\u003cli\u003eBurgess S, Thompson SG: \u003cstrong\u003eAvoiding bias from weak instruments in Mendelian randomization studies\u003c/strong\u003e. \u003cem\u003eInt J Epidemiol \u003c/em\u003e2011, \u003cstrong\u003e40\u003c/strong\u003e(3):755-764.\u003c/li\u003e\n\u003cli\u003eHindricks G, Potpara T, Dagres N, Arbelo E, Bax JJ, Blomstr\u0026ouml;m-Lundqvist C, Boriani G, Castella M, Dan GA, Dilaveris PE\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003e2020 ESC Guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS): The Task Force for the diagnosis and management of atrial fibrillation of the European Society of Cardiology (ESC) Developed with the special contribution of the European Heart Rhythm Association (EHRA) of the ESC\u003c/strong\u003e. \u003cem\u003eEur Heart J \u003c/em\u003e2021, \u003cstrong\u003e42\u003c/strong\u003e(5):373-498.\u003c/li\u003e\n\u003cli\u003eAtherton JJ, Sindone A, De Pasquale CG, Driscoll A, MacDonald PS, Hopper I, Kistler PM, Briffa T, Wong J, Abhayaratna W\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003eNational Heart Foundation of Australia and Cardiac Society of Australia and New Zealand: Guidelines for the Prevention, Detection, and Management of Heart Failure in Australia 2018\u003c/strong\u003e. \u003cem\u003eHeart Lung Circ \u003c/em\u003e2018, \u003cstrong\u003e27\u003c/strong\u003e(10):1123-1208.\u003c/li\u003e\n\u003cli\u003ePrabhu S, Taylor AJ, Costello BT, Kaye DM, McLellan AJA, Voskoboinik A, Sugumar H, Lockwood SM, Stokes MB, Pathik B\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003eCatheter Ablation Versus Medical Rate Control in Atrial Fibrillation and Systolic Dysfunction: The CAMERA-MRI Study\u003c/strong\u003e. \u003cem\u003eJ Am Coll Cardiol \u003c/em\u003e2017, \u003cstrong\u003e70\u003c/strong\u003e(16):1949-1961.\u003c/li\u003e\n\u003cli\u003eJones DG, Haldar SK, Hussain W, Sharma R, Francis DP, Rahman-Haley SL, McDonagh TA, Underwood SR, Markides V, Wong T: \u003cstrong\u003eA randomized trial to assess catheter ablation versus rate control in the management of persistent atrial fibrillation in heart failure\u003c/strong\u003e. \u003cem\u003eJ Am Coll Cardiol \u003c/em\u003e2013, \u003cstrong\u003e61\u003c/strong\u003e(18):1894-1903.\u003c/li\u003e\n\u003cli\u003ePacker DL, Piccini JP, Monahan KH, Al-Khalidi HR, Silverstein AP, Noseworthy PA, Poole JE, Bahnson TD, Lee KL, Mark DB: \u003cstrong\u003eAblation Versus Drug Therapy for Atrial Fibrillation in Heart Failure: Results From the CABANA Trial\u003c/strong\u003e. \u003cem\u003eCirculation \u003c/em\u003e2021, \u003cstrong\u003e143\u003c/strong\u003e(14):1377-1390.\u003c/li\u003e\n\u003cli\u003eSossalla S, Vollmann D: \u003cstrong\u003eArrhythmia-Induced Cardiomyopathy\u003c/strong\u003e. \u003cem\u003eDtsch Arztebl Int \u003c/em\u003e2018, \u003cstrong\u003e115\u003c/strong\u003e(19):335-341.\u003c/li\u003e\n\u003cli\u003eKatritsis DG, Boriani G, Cosio FG, Hindricks G, Ja\u0026iuml;s P, Josephson ME, Keegan R, Kim YH, Knight BP, Kuck KH\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003eEuropean Heart Rhythm Association (EHRA) consensus document on the management of supraventricular arrhythmias, endorsed by Heart Rhythm Society (HRS), Asia-Pacific Heart Rhythm Society (APHRS), and Sociedad Latinoamericana de Estimulaci\u0026oacute;n Cardiaca y Electrofisiologia (SOLAECE)\u003c/strong\u003e. \u003cem\u003eEuropace \u003c/em\u003e2017, \u003cstrong\u003e19\u003c/strong\u003e(3):465-511.\u003c/li\u003e\n\u003cli\u003eBrembilla-Perrot B, Ferreira JP, Manenti V, Sellal JM, Olivier A, Villemin T, Beurrier D, De Chillou C, Louis P, Brembilla A\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003ePredictors and prognostic significance of tachycardiomyopathy: insights from a cohort of 1269 patients undergoing atrial flutter ablation\u003c/strong\u003e. \u003cem\u003eEur J Heart Fail \u003c/em\u003e2016, \u003cstrong\u003e18\u003c/strong\u003e(4):394-401.\u003c/li\u003e\n\u003cli\u003ePizzale S, Lemery R, Green MS, Gollob MH, Tang AS, Birnie DH: \u003cstrong\u003eFrequency and predictors of tachycardia-induced cardiomyopathy in patients with persistent atrial flutter\u003c/strong\u003e. \u003cem\u003eCan J Cardiol \u003c/em\u003e2009, \u003cstrong\u003e25\u003c/strong\u003e(8):469-472.\u003c/li\u003e\n\u003cli\u003eLandolina M, Cant\u0026ugrave; F, De Ferrari GM, Foresti S, Tavazzi L: \u003cstrong\u003eThe role of invasive electrophysiology in the management of patients with chronic heart failure\u003c/strong\u003e. \u003cem\u003eHeart Fail Monit \u003c/em\u003e2002, \u003cstrong\u003e3\u003c/strong\u003e(2):49-59.\u003c/li\u003e\n\u003cli\u003eGrace AA, Narayan SM: \u003cstrong\u003eCommon threads in atrial fibrillation and heart failure\u003c/strong\u003e. \u003cem\u003eHeart Fail Clin \u003c/em\u003e2013, \u003cstrong\u003e9\u003c/strong\u003e(4):373-383, vii.\u003c/li\u003e\n\u003cli\u003eNiforatos JD, Ehmann MR, Balhara KS, Hinson JS, Ramcharran L, Lobner K, Weygandt PL: \u003cstrong\u003eManagement of atrial flutter and atrial fibrillation with rapid ventricular response in patients with acute decompensated heart failure: A systematic review\u003c/strong\u003e. \u003cem\u003eAcad Emerg Med \u003c/em\u003e2023, \u003cstrong\u003e30\u003c/strong\u003e(2):124-132.\u003c/li\u003e\n\u003cli\u003eShalaby AA: \u003cstrong\u003eAtrial Fibrillation and Congestive Heart Failure: A Wicked Alliance About to Unravel\u003c/strong\u003e. \u003cem\u003eJACC Clin Electrophysiol \u003c/em\u003e2022, \u003cstrong\u003e8\u003c/strong\u003e(11):1367-1368.\u003c/li\u003e\n\u003cli\u003ePabel S, Knierim M, Stehle T, Alebrand F, Paulus M, Sieme M, Herwig M, Barsch F, K\u0026ouml;rtl T, P\u0026ouml;ppl A\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003eEffects of Atrial Fibrillation on the Human Ventricle\u003c/strong\u003e. \u003cem\u003eCirc Res \u003c/em\u003e2022, \u003cstrong\u003e130\u003c/strong\u003e(7):994-1010.\u003c/li\u003e\n\u003cli\u003eParkash R, Wells GA, Rouleau J, Talajic M, Essebag V, Skanes A, Wilton SB, Verma A, Healey JS, Sterns L\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003eRandomized Ablation-Based Rhythm-Control Versus Rate-Control Trial in Patients With Heart Failure and Atrial Fibrillation: Results from the RAFT-AF trial\u003c/strong\u003e. \u003cem\u003eCirculation \u003c/em\u003e2022, \u003cstrong\u003e145\u003c/strong\u003e(23):1693-1704.\u003c/li\u003e\n\u003cli\u003eBrignole M, Pentimalli F, Palmisano P, Landolina M, Quartieri F, Occhetta E, Cal\u0026ograve; L, Mascia G, Mont L, Vernooy K\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003eAV junction ablation and cardiac resynchronization for patients with permanent atrial fibrillation and narrow QRS: the APAF-CRT mortality trial\u003c/strong\u003e. \u003cem\u003eEur Heart J \u003c/em\u003e2021, \u003cstrong\u003e42\u003c/strong\u003e(46):4731-4739.\u003c/li\u003e\n\u003cli\u003eMarrouche NF, Brachmann J, Andresen D, Siebels J, Boersma L, Jordaens L, Merkely B, Pokushalov E, Sanders P, Proff J\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003eCatheter Ablation for Atrial Fibrillation with Heart Failure\u003c/strong\u003e. \u003cem\u003eN Engl J Med \u003c/em\u003e2018, \u003cstrong\u003e378\u003c/strong\u003e(5):417-427.\u003c/li\u003e\n\u003cli\u003eBenjamin EJ, Blaha MJ, Chiuve SE, Cushman M, Das SR, Deo R, de Ferranti SD, Floyd J, Fornage M, Gillespie C\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003eHeart Disease and Stroke Statistics-2017 Update: A Report From the American Heart Association\u003c/strong\u003e. \u003cem\u003eCirculation \u003c/em\u003e2017, \u003cstrong\u003e135\u003c/strong\u003e(10):e146-e603.\u003c/li\u003e\n\u003cli\u003eGheorghiade M, Vaduganathan M, Fonarow GC, Bonow RO: \u003cstrong\u003eRehospitalization for heart failure: problems and perspectives\u003c/strong\u003e. \u003cem\u003eJ Am Coll Cardiol \u003c/em\u003e2013, \u003cstrong\u003e61\u003c/strong\u003e(4):391-403.\u003c/li\u003e\n\u003cli\u003eFrustaci A, Chimenti C, Bellocci F, Morgante E, Russo MA, Maseri A: \u003cstrong\u003eHistological substrate of atrial biopsies in patients with lone atrial fibrillation\u003c/strong\u003e. \u003cem\u003eCirculation \u003c/em\u003e1997, \u003cstrong\u003e96\u003c/strong\u003e(4):1180-1184.\u003c/li\u003e\n\u003cli\u003eHanna N, Cardin S, Leung TK, Nattel S: \u003cstrong\u003eDifferences in atrial versus ventricular remodeling in dogs with ventricular tachypacing-induced congestive heart failure\u003c/strong\u003e. \u003cem\u003eCardiovasc Res \u003c/em\u003e2004, \u003cstrong\u003e63\u003c/strong\u003e(2):236-244.\u003c/li\u003e\n\u003cli\u003eNattel S, Burstein B, Dobrev D: \u003cstrong\u003eAtrial remodeling and atrial fibrillation: mechanisms and implications\u003c/strong\u003e. \u003cem\u003eCirc Arrhythm Electrophysiol \u003c/em\u003e2008, \u003cstrong\u003e1\u003c/strong\u003e(1):62-73.\u003c/li\u003e\n\u003cli\u003eLiao YC, Liao JN, Lo LW, Lin YJ, Chang SL, Hu YF, Chao TF, Chung FP, Tuan TC, Te AL\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003eLeft Atrial Size and Left Ventricular End-Systolic Dimension Predict the Progression of Paroxysmal Atrial Fibrillation After Catheter Ablation\u003c/strong\u003e. \u003cem\u003eJ Cardiovasc Electrophysiol \u003c/em\u003e2017, \u003cstrong\u003e28\u003c/strong\u003e(1):23-30.\u003c/li\u003e\n\u003cli\u003eHammerstingl C, Schwekendiek M, Momcilovic D, Schueler R, Sinning JM, Schrickel JW, Mittmann-Braun E, Nickenig G, Lickfett L: \u003cstrong\u003eLeft atrial deformation imaging with ultrasound based two-dimensional speckle-tracking predicts the rate of recurrence of paroxysmal and persistent atrial fibrillation after successful ablation procedures\u003c/strong\u003e. \u003cem\u003eJ Cardiovasc Electrophysiol \u003c/em\u003e2012, \u003cstrong\u003e23\u003c/strong\u003e(3):247-255.\u003c/li\u003e\n\u003cli\u003eCalkins H, Kuck KH, Cappato R, Brugada J, Camm AJ, Chen SA, Crijns HJ, Damiano RJ, Jr., Davies DW, DiMarco J\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003e2012 HRS/EHRA/ECAS expert consensus statement on catheter and surgical ablation of atrial fibrillation: recommendations for patient selection, procedural techniques, patient management and follow-up, definitions, endpoints, and research trial design: a report of the Heart Rhythm Society (HRS) Task Force on Catheter and Surgical Ablation of Atrial Fibrillation. Developed in partnership with the European Heart Rhythm Association (EHRA), a registered branch of the European Society of Cardiology (ESC) and the European Cardiac Arrhythmia Society (ECAS); and in collaboration with the American College of Cardiology (ACC), American Heart Association (AHA), the Asia Pacific Heart Rhythm Society (APHRS), and the Society of Thoracic Surgeons (STS). Endorsed by the governing bodies of the American College of Cardiology Foundation, the American Heart Association, the European Cardiac Arrhythmia Society, the European Heart Rhythm Association, the Society of Thoracic Surgeons, the Asia Pacific Heart Rhythm Society, and the Heart Rhythm Society\u003c/strong\u003e. \u003cem\u003eHeart Rhythm \u003c/em\u003e2012, \u003cstrong\u003e9\u003c/strong\u003e(4):632-696.e621.\u003c/li\u003e\n\u003cli\u003eChae S, Oral H, Good E, Dey S, Wimmer A, Crawford T, Wells D, Sarrazin JF, Chalfoun N, Kuhne M\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003eAtrial tachycardia after circumferential pulmonary vein ablation of atrial fibrillation: mechanistic insights, results of catheter ablation, and risk factors for recurrence\u003c/strong\u003e. \u003cem\u003eJ Am Coll Cardiol \u003c/em\u003e2007, \u003cstrong\u003e50\u003c/strong\u003e(18):1781-1787.\u003c/li\u003e\n\u003cli\u003eWasmer K, M\u0026ouml;nnig G, Bittner A, Dechering D, Zellerhoff S, Milberg P, K\u0026ouml;be J, Eckardt L: \u003cstrong\u003eIncidence, characteristics, and outcome of left atrial tachycardias after circumferential antral ablation of atrial fibrillation\u003c/strong\u003e. \u003cem\u003eHeart Rhythm \u003c/em\u003e2012, \u003cstrong\u003e9\u003c/strong\u003e(10):1660-1666.\u003c/li\u003e\n\u003cli\u003eMikhaylov EN, Bhagwandien R, Janse PA, Theuns DA, Szili-Torok T: \u003cstrong\u003eRegular atrial tachycardias developing after cryoballoon pulmonary vein isolation: incidence, characteristics, and predictors\u003c/strong\u003e. \u003cem\u003eEuropace \u003c/em\u003e2013, \u003cstrong\u003e15\u003c/strong\u003e(12):1710-1717.\u003c/li\u003e\n\u003cli\u003eChugh A, Oral H, Lemola K, Hall B, Cheung P, Good E, Tamirisa K, Han J, Bogun F, Pelosi F, Jr.\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003ePrevalence, mechanisms, and clinical significance of macroreentrant atrial tachycardia during and following left atrial ablation for atrial fibrillation\u003c/strong\u003e. \u003cem\u003eHeart Rhythm \u003c/em\u003e2005, \u003cstrong\u003e2\u003c/strong\u003e(5):464-471.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"atrial fibrillation and flutter, left ventricular failure, heart failure, bidirectional Mendelian randomization study","lastPublishedDoi":"10.21203/rs.3.rs-4156657/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4156657/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e：atrial fibrillation(AF) and heart failure(HF) share common pathophysiological mechanisms, thus frequently coexisting and mutually influencing disease progression.The combination of these conditions is associated with heightened mortality rates and unfavorable prognosis. Significant progress has been made in the study of AF-HF, but it remains unclear which approach provides the best long-term efficacy. In this study, our objective is to employ Mendelian randomization studies in order to investigate the causal relationship between atrial fibrillation/atrial flutter(AFL) and left ventricular failure(LVF), explore potential therapeutic targets for clinical application, and optimize the management and clinical outcomes of patients with AF/AFL and HF.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods: \u003c/strong\u003eThe data of AF/AFL from the IEU OpenGWAS project.These data derive from a European population consisting of 463,010 participants drawn from the UK Biobank. Among them, 5,669 individuals had AF/AFL, and a total of 9,851,867 SNPs were considered.To ensure a matching number of SNPs between LVF and minimize population overlap effects, we implemented the most recent and largest genome-wide association study meta-analysis from the IEU OpenGWAS project. A total of 2046 cases and 460,964 controls were investigated,within a total of 9,851,867 SNPs. We adopted inverse variance weighted (IVW) as the main way to estimate the Mendelian randomization analysis.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e：The preliminary results of IVW revealed postive causal effect of AF/AFL on LVF [OR =1.053, 95% CI: 1.023-1.084, P = 0.0006] Cochran's IVW Q test results show no significant heterogeneity among these IVs. The results of the MR-Egger regression intercept analysis indicate no significant horizontal pleiotropy. MR-PRESSO global test results revealed no horizontal pleiotropy. Additionally, the p-values of the MR PRESSO global test for AF/AFL on LVF were all greater than 0.05.The funnel plot presents a symmetricl shap,suggesting significant heterogeneity,indicating that there is no systematic bias between the study effect and its accuracy. The leave-one-out plot is shown that each IVs does not have a serious bias effect on the overall MR results.The results of the steiger test confirmed no causal effect of LVF on AF/AFL.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions：\u003c/strong\u003eThis MR study presents novel genetic evidence supporting a causal association between AF/AFL and LVF, thus contributing to the advancement of our understanding in this field.This study underscores the importance of managing HF-AF patients by incorporating AF/AFL treatment alongside conventional anti-HF therapy and ventricular rate control, aiming to enhance LV function and achieve a more favorable prognosis.In addition, this study found that LVF did not have a significant impact on AF/AFL.\u003c/p\u003e","manuscriptTitle":"Association between atrial fibrillation/flutter and left ventricular failure: A bidirectional Mendelian randomization study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-04-01 19:32:54","doi":"10.21203/rs.3.rs-4156657/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"2a79e3f5-db3f-44fc-93c6-22eff308cb0f","owner":[],"postedDate":"April 1st, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-12-25T06:38:08+00:00","versionOfRecord":[],"versionCreatedAt":"2024-04-01 19:32:54","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4156657","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4156657","identity":"rs-4156657","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}