Focus Issue: Atrial FibrillationExperimentalArterial hypertension drives arrhythmia progression via specific structural remodeling in a porcine model of atrial fibrillation
Introduction
Atrial fibrillation (AF) is the most common sustained arrhythmia and is associated with an increased risk of stroke, morbidity, and death. The natural time course of the disease is often characterized by short episodes in the beginning (paroxysmal), which evolve to more stable and frequent episodes. AF progression is favored by risk factors such as arterial hypertension (HT), vascular disease, heart failure, valvular disease, or diabetes mellitus.1, 2, 3
Recurrent episodes of AF lead to atrial electrical remodeling (ie, shortening and loss of rate adaption of atrial effective refractory periods [AERPs] and shortening of action potential duration [APD]) favoring arrhythmia stability (“AF begets AF”).4, 5 During the progression from paroxysmal to permanent AF, the substrate (ie, alteration of extracellular matrix composition, changes in atrial architecture, and endo-epicardial dissociation) gains in importance over the initiating triggers.5, 6 However, while extensive research has been conducted to describe the “second factor” besides electrical remodeling that contributes to AF progression, it is not known how exactly the proposed structural and ultrastructural changes caused by risk factors such as HT affect atrial conduction or AF stability.
HT is found in 60%–80% of patients with AF, is an independent predictor of new-onset AF, and contributes to AF progression via unknown mechanisms.7 It has been shown previously that HT leads to structural atrial remodeling, favors the development of AF, and accelerates the transition from paroxysmal to permanent AF.8, 9
We previously established a porcine model of rapid atrial pacing (RAP)–induced AF.10 In this model, we have shown that HT increased the stability of AF already after 2 weeks. In the present study, we sought to investigate the underlying electrical and structural changes favoring the stability and progression of AF in hypertensive heart disease.
Section snippets
Methods
A porcine model of AF and hypertensive heart disease was used (see the Supplemental Material for further details).10 The experimental protocol was approved by the local bioethics committee of Vienna, Austria (BMWFW-66.010/0050-WF/II/3b/2014), and conformed to the “European Convention for the Protection of Vertebrate Animals Used for Experimental and other Scientific Purposes” (Council of Europe, European Treaty Series No. 123, Strasbourg, 18.III.1986).
Results
One animal in the AF group was excluded because of dislocation of the PM lead. At the final experiment, both groups had comparable body weights (46.3 ± 6.1 kg in AF+HT and 44.9 ± 4.5 kg in AF; P = .6). More animals in the AF+HT group (5 of 9, 55.6%) than in the AF group (1 of 8, 12.9%) were in AF for longer than 1 hour after PM deactivation (P < .001) (Figure 1A). The median (interquartile range) AF duration after PM deactivation was 76.7 (0–210) minutes in the AF+HT group vs 18.8 (0–150)
Discussion
We studied the effect of HT on early arrhythmia progression in a porcine model with RAP-induced AF. The present study demonstrates that increased AF stability is not supported by electrophysiological changes. The main change caused by HT was atrial dilatation, which seems to be sufficient to increase AF stability. In this early phase of AF stabilization, HT facilitates AF by atrial dilatation.
Previous animal studies have shown that remodeling during the development and progression of AF
Conclusion
DOCA-induced HT favors AF progression by increasing AF stability via early structural remodeling including atrial dilatation and fibrosis, but not by atrial cardiomyocyte hypertrophy, changes in refractory periods, APDs, or AF complexity.
Acknowledgments
We thank Alexandra Budal, MSc, Siegfried Edlinger, MSc, Reinhard Rodler, Manfred Knaus, Philipp Raab, and Vladimir Bubalo, MSc, for their excellent technical assistance.
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This work was supported by the Netherlands Heart Foundation (grant no. CVON2014-09, RACE V: Reappraisal of Atrial Fibrillation: Interaction Between HyperCoagulability, Electrical Remodeling, and Vascular Destabilisation in the Progression of Atrial Fibrillation) and by the European Union (grant no. 261057, European Network for Translational Research in Atrial Fibrillation [EUTRAF]; grant no. 633196, CATCH ME [Characterizing Afib by Translating its Causes into Health Modifiers in the Elderly]; grant no. 675351, the ITN Network AFib TrainNet; grant no. PITN-GA-2012-316738, the ITN Network RADOX: RADical reduction of OXidative stress in cardiovascular diseases; and the ERACoSysMed H2020 ERA-NET Cofund project Systems medicine for diagnosis and stratification of atrial fibrillation) (to Dr Schotten). PhD candidate M.M. received funding from the Medical University of Graz within the PhD Program Molecular Medicine and the Austrian Society of Cardiology.