Reduced left atrial cardiomyocyte PITX2 and elevated circulating BMP10 predict atrial fibrillation after ablation

Reyat, Jasmeet S.; Chua, Winnie; Cardoso, Victor Roth; Witten, Anika; Kastner, Peter; Kabir, S. Nashitha; Sinner, Moritz F.; Wesselink, Robin; Holmes, Andrew P.; Pavlović, Davor; Stoll, Monika; Kääb, Stefan; Gkoutos, Georgios V.; Groot, Joris R. de; Kirchhof, Paulus; Fabritz, Larissa

doi:10.1172/jci.insight.139179

Cited by 59 publications

(81 citation statements)

References 53 publications

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“…BMP10 has been very recently shown to predict recurrence of AF independently after catheter ablation in 359 patients, while NT-proBNP did not [21]. However, patients were more severely ill (47% had HF, history of stroke in 12%, NT-proBNP approximately double higher that in GISSI-AF) than those in the present study, even though absolute concentrations of BMP10 were just slightly higher.…”

Section: Discussioncontrasting

confidence: 64%

Total NT-proBNP, a novel biomarker in atrial fibrillation. A mechanistic analysis of the GISSI-AF trial

Staszewsky

Meessen

Novelli

et al. 2020

Preprint

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Objective(1) to test the association with prevalent and incident atrial fibrillation (AF), and prognosis of total N-terminal pro-B type natriuretic peptide (total NT-proBNP) and of a panel of biomarkers; (2) to assess iwhether the extent of glycosylation affects the relation of NT-proBNP with AF.MethodsIn a sub-study of the GISSI-AF trial on 382 patients in sinus rhythm with a history of AF, echocardiographic variables and eight circulating biomarkers were serially assayed over one year. The relations between circulating baseline biomarkers and AF and the risk of CV events, were assessed by Cox-analysis models adjusting the first by clinical variables, the second by clinical variables and the echocardiographic left-atrial-minimum-volume-index (LAVImin).ResultsOver a median follow-up of 365 days, 203/382 patients (53.1%) had at least one recurrence of AF and 16.3% were hospitalized for cardiovascular (CV) reasons. Total NT-proBNP, NT-proBNP, angiopoietin 2 (Ang2), myosin binding protein (MyBPC3) and bone morphogenic protein-10 (BMP-10) were strongly associated to ongoing AF. Natriuretic peptides and MyBPC3 predicted recurrent AF but this lost significance after adjustment for LAVImin. NT-proBNP and Ang2 predicted CV hospitalization even after adjustment for LAVImin, HR95%CI: 2.20 [1.02-4.80] and 5.26 [1.16-23.79].ConclusionsThe association of AF recurrence with the novel biomarker total NT-proBNP, is similar to that of NT-proBNP, suggesting no influence of glycosylation. Ang2, MyBPC3 and BMP10 were strongly associated with AF, indicating a possible role of extracellular matrix and myocardial injury. Abstract-words=233Key messagesWhat is already known on this subject?It is still complicated to predict the recurrence of AF in patients in sinus rhythm with a recent history of AF. Though several biomarkers have been associated with AF, few of them have proved to be independent predictors for recurrent AF or cardiovascular (CV) events. Their predictive sensitivity and specificity is modest at best. Previous studies showed that NT-proBNP was possibly the strongest predictor of recurrent AF and CV hospitalization. Natriuretic peptides circulate to a large extent as glycosylated molecules and a novel assay is now available to measure the glycosylated and non-glycosylated NT-proBNP in plasma, the total NT-proBNP. The extent of glycosylation varies in different diseases.What might this study add?No studies have assessed (a) the extent of NT-proBNP glycosylation in AF, or (b) the association and predictive value in patients with AF of total NT-proBNP. A multimarker approach, ratter than one based on a single biomarker, might predict AF better.The relation with AF of the novel biomarker, total NT-proBNP, is as strong as that of NT-proBNP, suggesting no-influence of glycosylation.Two biomarkers, MyBPC3, secreted few minutes after myocardial injury and Ang-2, involved in inflammation and coagulation, were strongly associated to AF.How might this impact on clinical practice?The identification of novel circulating biomarkers could have a direct impact on clinical practice when predicting the occurrence of AF, but unfortunately current data do not allow predictions based on biomarkers.The associations of different biomarkers with ongoing AF may cast light on the mechanisms of triggering and maintenance of AF.Strengths and limitations of this studyThe data came from to a multicenter randomized clinical trial with available concomitant serial echocardiographic and circulating biomarkers recorded and evaluated centrally, hence with minimal bias; AF recurrence during a 12-month follow up was checked weekly by trans-telephonic electrocardiographic monitoring, and with 12-lead ECG every six months.A comparative analysis of total NT-proBNP with other novel biomarkers and echocardiographic variables has never been done so far. The possible added value of total NT-proBNP to the benchmark biomarker NT-proBNP was assessed on the basis of different dimensions of performance, as recently proposed for new biomarkers. The main limitations are (1) the relatively small numbers of patients with AF during follow-up visits, (2) the very low prevalence of patients with other cardiac diseases such as coronary artery disease and heart failure, and (3) consequently, the low incidence of clinical events in one-year follow-up.

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Section: Discussioncontrasting

confidence: 64%

Total NT-proBNP, a novel biomarker in atrial fibrillation. A mechanistic analysis of the GISSI-AF trial

Staszewsky

Meessen

Novelli

et al. 2020

Preprint

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“…TASK-like background currents, contributors to the resting membrane potential, decreased in PITX2c +/− mice [79]. In the left atrial chambers, Kir2.1 (Kcnj2) and Nav1.5 (Scn5a) channel expression are decreased [20], while Bmp10 is highly upregulated [80]. These findings support that PITX2 may control atrial chamber dimensions, because overexpression of Bmp10 plays a crucial role in regulating physiological hypertrophy.…”

Section: Membrane Effector Genes Regulated By Pitx2supporting

confidence: 54%

Understanding PITX2-dependent Atrial Fibrillation Mechanisms through Computational Models

Bai¹,

Lu²,

Zhu³

et al. 2021

Preprint

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Atrial fibrillation (AF) is a common arrhythmia. Better prevention and treatment of AF are needed to reduce AF-associated morbidity and mortality. Several major mechanisms cause AF in patients, including a genetic predisposition to develop AF. Genome-wide association studies have identified genetic variants associated with AF populations, with the strongest hits clustering on chromosome 4q25, close to the gene coding for the homeobox transcription PITX2. Because of the inherent complexity of the human heart, experimental and basic research on PITX2-dependent AF is not sufficient for understanding atrial functional proprieties. Linking PITX2 to ion channels, cells, tissues, atria and the whole heart, computational models are necessary for achieving a quantitative understanding of atrial structure and function in PITX2-dependent AF. Computational approaches are used to capture all that we know about PITX2-dependent AF and to develop improved therapies. In the present review, we discuss advances in atrial modelling and focus on the mechanistic links between PITX2 and AF. Challenges in applying models for improving patient health are described, as well as a summary of future perspectives.

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“…Recently, many AF-associated loci were identified in GWASs [ 3 , 4 , 5 , 6 , 7 , 8 , 9 ] and the most common AF susceptibility locus first identified in European, Chinese, and Japanese populations is located on chromosome 4q25 [ 10 ]. The gene-poor 4q25 region harbors paired-like homeodomain transcription factor 2 ( Pitx2 ), which has been fundamentally linked to AF [ 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 ], although the basis for this connection remains obscure. In early cardiac embryogenesis, Pitx2 suppresses left atrial automaticity and the formation of “sinus node-like structures” in the left atrium [ 21 ] and contributes to the formation of the pulmonary vein myocardium [ 13 ].…”

Section: Introductionmentioning

confidence: 99%

In Silico Assessment of Class I Antiarrhythmic Drug Effects on Pitx2-Induced Atrial Fibrillation: Insights from Populations of Electrophysiological Models of Human Atrial Cells and Tissues

Bai

Zhu

et al. 2021

IJMS

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Electrical remodelling as a result of homeodomain transcription factor 2 (Pitx2)-dependent gene regulation was linked to atrial fibrillation (AF) and AF patients with single nucleotide polymorphisms at chromosome 4q25 responded favorably to class I antiarrhythmic drugs (AADs). The possible reasons behind this remain elusive. The purpose of this study was to assess the efficacy of the AADs disopyramide, quinidine, and propafenone on human atrial arrhythmias mediated by Pitx2-induced remodelling, from a single cell to the tissue level, using drug binding models with multi-channel pharmacology. Experimentally calibrated populations of human atrial action po-tential (AP) models in both sinus rhythm (SR) and Pitx2-induced AF conditions were constructed by using two distinct models to represent morphological subtypes of AP. Multi-channel pharmaco-logical effects of disopyramide, quinidine, and propafenone on ionic currents were considered. Simulated results showed that Pitx2-induced remodelling increased maximum upstroke velocity (dVdtmax), and decreased AP duration (APD), conduction velocity (CV), and wavelength (WL). At the concentrations tested in this study, these AADs decreased dVdtmax and CV and prolonged APD in the setting of Pitx2-induced AF. Our findings of alterations in WL indicated that disopyramide may be more effective against Pitx2-induced AF than propafenone and quinidine by prolonging WL.

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Reduced left atrial cardiomyocyte PITX2 and elevated circulating BMP10 predict atrial fibrillation after ablation

Cited by 59 publications

References 53 publications

Total NT-proBNP, a novel biomarker in atrial fibrillation. A mechanistic analysis of the GISSI-AF trial

Total NT-proBNP, a novel biomarker in atrial fibrillation. A mechanistic analysis of the GISSI-AF trial

Understanding PITX2-dependent Atrial Fibrillation Mechanisms through Computational Models

In Silico Assessment of Class I Antiarrhythmic Drug Effects on Pitx2-Induced Atrial Fibrillation: Insights from Populations of Electrophysiological Models of Human Atrial Cells and Tissues

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