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Reduction in atrial and pulmonary vein stretch as a therapeutic target for prevention of atrial fibrillation

  • Lisa A. Gottlieb
    Affiliations
    Department of Cardiology, University Hospital Copenhagen – Bispebjerg, Copenhagen, Denmark

    AUMC, location Academic Medical Centre, Department of Experimental Cardiology, Amsterdam, The Netherlands

    IHU Liryc, Electrophysiology and Heart Modeling Institute, University of Bordeaux, Bordeaux, France
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  • Author Footnotes
    1 Shared last authorship.
    Ruben Coronel
    Correspondence
    Address reprint requests and correspondence: Dr Ruben Coronel, AUMC, location Academic Medical Centre, Department of Experimental Cardiology, Amsterdam, The Netherlands.
    Footnotes
    1 Shared last authorship.
    Affiliations
    AUMC, location Academic Medical Centre, Department of Experimental Cardiology, Amsterdam, The Netherlands

    IHU Liryc, Electrophysiology and Heart Modeling Institute, University of Bordeaux, Bordeaux, France
    Search for articles by this author
  • Author Footnotes
    1 Shared last authorship.
    Lukas R.C. Dekker
    Footnotes
    1 Shared last authorship.
    Affiliations
    Department of Biomedical Engineering, Eindhoven University of Technology, The Netherlands
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  • Author Footnotes
    1 Shared last authorship.
Open AccessPublished:October 17, 2022DOI:https://doi.org/10.1016/j.hrthm.2022.10.009
      Atrial fibrillation (AF) is a common cardiac arrhythmia that is associated with increased mortality. Heart failure, hypertension, valvular disease, and obstructive sleep apnea are risk factors for incident AF. A common characteristic of these diseases is that they increase atrial wall stretch. Multiple experimental studies confirm a proarrhythmic effect of atrial stretch. Conversely, a reduction in stretch is antiarrhythmic. A therapeutic target for AF, therefore, lies in local reduction of atrial stretch. This review focuses on atrial stretch and its clinical associations in patients with AF and its downstream effects on electrophysiology. We discuss the possible application of targeted atrial stretch reduction in AF prevention. We conclude that a reduction in local atrial stretch should be considered an essential element in rhythm control.

      Graphical abstract

      Keywords

      A. Introduction

      Atrial fibrillation (AF) is a common cardiac arrhythmia that increases morbidity and mortality.
      • Zwartkruis V.W.
      • Geelhoed B.
      • Suthahar N.
      • et al.
      Atrial fibrillation detected at screening is not a benign condition: outcomes in screen-detected versus clinically detected atrial fibrillation: results from the Prevention of Renal and Vascular End-stage Disease (PREVEND) study.
      Ablation therapy is considered when pharmacological therapy fails to prevent AF.
      • Calkins H.
      • Hindricks G.
      • Cappato R.
      • et al.
      2017 HRS/EHRA/ECAS/APHRS/SOLAECE expert consensus statement on catheter and surgical ablation of atrial fibrillation.
      A single ablation treatment prevents AF in ∼60% and 40% of patients with paroxysmal AF (subsequent AF episodes shorter than 1 week) and persistent AF (episodes of AF longer than 1 week), respectively.
      • Kis Z.
      • Muka T.
      • Franco O.H.
      • et al.
      The short and long-term efficacy of pulmonary vein isolation as a sole treatment strategy for paroxysmal atrial fibrillation: a systematic review and meta-analysis.
      ,
      • Clarnette J.A.
      • Brooks A.G.
      • Mahajan R.
      • et al.
      Outcomes of persistent and long-standing persistent atrial fibrillation ablation: a systematic review and meta-analysis.
      Innovative treatment strategies for AF are, therefore, needed.
      The pathophysiology of AF is complex and includes stretch of atrial tissue (graphical abstract). Common comorbitidies of AF causes atrial stretch and are risk factors for AF.
      • Benjamin E.J.
      • Levy D.
      • Vaziri S.M.
      • D’Agostino R.B.
      • Belanger A.J.
      • Wolf P.A.
      Independent risk factors for atrial fibrillation in a population-based cohort: the Framingham Heart Study.
      ,
      • Gami A.S.
      • Hodge D.O.
      • Herges R.M.
      • et al.
      Obstructive sleep apnea, obesity, and the risk of incident atrial fibrillation.
      The proarrhythmic nature of atrial stretch is confirmed by experimental studies.
      • Ravelli F.
      • Allessie M.
      Effects of atrial dilatation on refractory period and vulnerability to atrial fibrillation in the isolated Langendorff-perfused rabbit heart.
      • Satoh T.
      • Zipes D.P.
      Unequal atrial stretch in dogs increases dispersion of refractoriness conducive to developing atrial fibrillation.
      • Eijsbouts S.C.
      • Majidi M.
      • van Zandvoort M.
      • Allessie M.A.
      Effects of acute atrial dilation on heterogeneity in conduction in the isolated rabbit heart.
      • Bode F.
      • Sachs F.
      • Franz M.R.
      Tarantula peptide inhibits atrial fibrillation.
      • Verheule S.
      • Wilson E.
      • Everett Tt
      • Shanbhag S.
      • Golden C.
      • Olgin J.
      Alterations in atrial electrophysiology and tissue structure in a canine model of chronic atrial dilatation due to mitral regurgitation.
      Moreover, atrial stretch decreases the efficacy of preventive AF treatment.
      • Sramko M.
      • Wichterle D.
      • Melenovsky V.
      • et al.
      Resting and exercise-induced left atrial hypertension in patients with atrial fibrillation: the causes and implications for catheter ablation.
      • Lee J.H.
      • Kwon O.S.
      • Shim J.
      • et al.
      Left atrial wall stress and the long-term outcome of catheter ablation of atrial fibrillation: an artificial intelligence-based prediction of atrial wall stress.
      • Okumura Y.
      • Watanabe I.
      • Nakai T.
      • et al.
      Impact of biomarkers of inflammation and extracellular matrix turnover on the outcome of atrial fibrillation ablation: importance of matrix metalloproteinase-2 as a predictor of atrial fibrillation recurrence.
      • Bollmann A.
      • Binias K.H.
      • Toepffer I.
      • Molling J.
      • Geller C.
      • Klein H.U.
      Importance of left atrial diameter and atrial fibrillatory frequency for conversion of persistent atrial fibrillation with oral flecainide.
      • Brodsky M.A.
      • Allen B.J.
      • Capparelli E.V.
      • Luckett C.R.
      • Morton R.
      • Henry W.L.
      Factors determining maintenance of sinus rhythm after chronic atrial fibrillation with left atrial dilatation.
      • Arya A.
      • Hindricks G.
      • Sommer P.
      • et al.
      Long-term results and the predictors of outcome of catheter ablation of atrial fibrillation using steerable sheath catheter navigation after single procedure in 674 patients.
      Conversely, a reduction in atrial stretch is antiarrhythmic.
      • Ravelli F.
      • Allessie M.
      Effects of atrial dilatation on refractory period and vulnerability to atrial fibrillation in the isolated Langendorff-perfused rabbit heart.
      ,
      • Coronel R.
      • Langerveld J.
      • Boersma L.V.
      • et al.
      Left atrial pressure reduction for mitral stenosis reverses left atrial direction-dependent conduction abnormalities.
      A potential therapeutic option for AF, therefore, lies in the reduction of atrial stretch.
      This review focuses on atrial stretch and its clinical associations with AF and its downstream effects on electrophysiology as well as targeted ablation therapy. Improved rates of ablation success may be achieved by developing stretch-reducing ablation lesions.

      B. Atrial stretch and AF

      Strain and wall stress are indicatives of stretch. Myocardial strain (deformation) is the change in myocardial wall dimensions during the cardiac cycle, either in thickness (radial strain) or in length (longitudinal strain).
      • Lang R.M.
      • Badano L.P.
      • Mor-Avi V.
      • et al.
      Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging.
      Wall stress, defined by Laplace’s law, is dependent on intracavity pressure, wall thickness, and cavity size and reflects the force present between the adjacent cardiomyocytes.
      • Lee J.H.
      • Kwon O.S.
      • Shim J.
      • et al.
      Left atrial wall stress and the long-term outcome of catheter ablation of atrial fibrillation: an artificial intelligence-based prediction of atrial wall stress.
      Thus, increases in myocardial stretch occurs with atrial chamber dilatation.

      B.1. Atrial dilatation

      Both left atrial (LA) dilatation and right atrial (RA) dilatation are independent risk factors for AF.
      • Vaziri S.M.
      • Larson M.G.
      • Benjamin E.J.
      • Levy D.
      Echocardiographic predictors of nonrheumatic atrial fibrillation: the Framingham Heart Study.
      ,
      • Xie E.
      • Yu R.
      • Ambale-Venkatesh B.
      • et al.
      Association of right atrial structure with incident atrial fibrillation: a longitudinal cohort cardiovascular magnetic resonance study from the Multi-Ethnic Study of Atherosclerosis (MESA).
      A correlation between the LA size and the incidence and complexity of atrial arrhythmias exists in an asymptomatic elderly population.
      • Manyari D.E.
      • Patterson C.
      • Johnson D.
      • Melendez L.
      • Kostuk W.J.
      • Cape R.D.
      Atrial and ventricular arrhythmias in asymptomatic active elderly subjects: correlation with left atrial size and left ventricular mass.
      Large atria are associated with a lower success rate of pharmacological and electrical cardioversion as well as ablation therapy in patients with AF.
      • Bollmann A.
      • Binias K.H.
      • Toepffer I.
      • Molling J.
      • Geller C.
      • Klein H.U.
      Importance of left atrial diameter and atrial fibrillatory frequency for conversion of persistent atrial fibrillation with oral flecainide.
      • Brodsky M.A.
      • Allen B.J.
      • Capparelli E.V.
      • Luckett C.R.
      • Morton R.
      • Henry W.L.
      Factors determining maintenance of sinus rhythm after chronic atrial fibrillation with left atrial dilatation.
      • Arya A.
      • Hindricks G.
      • Sommer P.
      • et al.
      Long-term results and the predictors of outcome of catheter ablation of atrial fibrillation using steerable sheath catheter navigation after single procedure in 674 patients.
      Similarly, a high LA pressure, a high LA wall stress, and a high plasma level of natriuretic peptides (secreted after stretch) each predict AF recurrence after ablation therapy.
      • Sramko M.
      • Wichterle D.
      • Melenovsky V.
      • et al.
      Resting and exercise-induced left atrial hypertension in patients with atrial fibrillation: the causes and implications for catheter ablation.
      • Lee J.H.
      • Kwon O.S.
      • Shim J.
      • et al.
      Left atrial wall stress and the long-term outcome of catheter ablation of atrial fibrillation: an artificial intelligence-based prediction of atrial wall stress.
      • Okumura Y.
      • Watanabe I.
      • Nakai T.
      • et al.
      Impact of biomarkers of inflammation and extracellular matrix turnover on the outcome of atrial fibrillation ablation: importance of matrix metalloproteinase-2 as a predictor of atrial fibrillation recurrence.
      Because AF causes atrial and pulmonary vein (PV) dilatation involving loss of contractile fibers and interstitial collagen accumulation, a positive feedback mechanism is constituted.
      • Tsao H.M.
      • Yu W.C.
      • Cheng H.C.
      • et al.
      Pulmonary vein dilation in patients with atrial fibrillation: detection by magnetic resonance imaging.
      • Sanfilippo A.J.
      • Abascal V.M.
      • Sheehan M.
      • et al.
      Atrial enlargement as a consequence of atrial fibrillation: a prospective echocardiographic study.
      • Boldt A.
      • Wetzel U.
      • Lauschke J.
      • et al.
      Fibrosis in left atrial tissue of patients with atrial fibrillation with and without underlying mitral valve disease.

      B.2. Atrial wall strain

      AF is associated with atrial fibrosis and fibrofatty remodeling.
      • Huber A.T.
      • Lamy J.
      • Rahhal A.
      • et al.
      Cardiac MR strain: a noninvasive biomarker of fibrofatty remodeling of the left atrial myocardium.
      Because collagenous tissue is less compliant than the myocardium, myocardial stress in patients with AF is likely increased in more compliant (nonfibrotic) regions.
      • Connelly C.M.
      • McLaughlin R.J.
      • Vogel W.M.
      • Apstein C.S.
      Reversible and irreversible elongation of ischemic, infarcted, and healed myocardium in response to increases in preload and afterload.
      Indeed, strain of the LA is lower in patients with AF and those who later develop AF than in control subjects.
      • Habibi M.
      • Samiei S.
      • Ambale Venkatesh B.
      • et al.
      Cardiac magnetic resonance-measured left atrial volume and function and incident atrial fibrillation: results from MESA (Multi-Ethnic Study of Atherosclerosis).
      ,
      • Hwang H.J.
      • Choi E.Y.
      • Rhee S.J.
      • et al.
      Left atrial strain as predictor of successful outcomes in catheter ablation for atrial fibrillation: a two-dimensional myocardial imaging study.
      There is a parallel to ventricular arrhythmias after myocardial infarction. The border zone between the infarcted and vital ventricular myocardium deforms more than the infarcted region, but less than the vital regions.
      • Bertini M.
      • Ng A.C.
      • Borleffs C.J.
      • et al.
      Longitudinal mechanics of the periinfarct zone and ventricular tachycardia inducibility in patients with chronic ischemic cardiomyopathy.
      The strain of the border zone is lower in patients with inducible arrhythmias than in noninducible patients, thereby emphasizing that heterogeneous myocardial stretch is proarrhythmic.
      • Bertini M.
      • Ng A.C.
      • Borleffs C.J.
      • et al.
      Longitudinal mechanics of the periinfarct zone and ventricular tachycardia inducibility in patients with chronic ischemic cardiomyopathy.
      In addition to these passive changes in wall movement, during AF, the atrial contraction is lost, which is also reflected in strain curves. This complicates strain evaluation in patients with persistent AF. However, in such patients, the maximum passive atrial strain and its timing during the cardiac cycle may be used.

      B.3. Interatrial gradient in pressure

      An increased LA pressure, and consequently a larger interatrial pressure gradient, is associated with atrial septal bulging toward the RA.
      • Kusumoto F.M.
      • Muhiudeen I.A.
      • Kuecherer H.F.
      • Cahalan M.K.
      • Schiller N.B.
      Response of the interatrial septum to transatrial pressure gradients and its potential for predicting pulmonary capillary wedge pressure: an intraoperative study using transesophageal echocardiography in patients during mechanical ventilation.
      This likely heterogeneously slows interatrial conduction. Conversely, a Müller maneuver (forced inspiration against closed glottis), simulating an obstructive apneic episode, increases the RA pressure and the interatrial pressure gradient.
      • Konecny T.
      • Khanna A.D.
      • Novak J.
      • et al.
      Interatrial pressure gradients during simulated obstructive sleep apnea: a catheter-based study.
      The latter change may explain, at least in part, atrial arrhythmogenesis commonly seen in patients with obstructive sleep apnea (see below).

      B.4. Heart rhythm and atrial stretch

      In sinus rhythm, the atrial pressure fluctuates throughout the cardiac cycle with peaks during atrial contraction (a wave), after atrioventricular valve closure (c wave), and immediately before valve opening (v wave). During atrial contraction, a retrograde flow into the PV occurs.
      • Maruyama T.
      • Kishikawa T.
      • Ito H.
      • Kaji Y.
      • Sasaki Y.
      • Ishihara Y.
      Augmentation of pulmonary vein backflow velocity during left atrial contraction: a novel phenomenon responsible for progression of atrial fibrillation in hypertensive patients.
      Ventricular contraction also acts mechanically on the atria and can alter atrial electrophysiology as is evident from an acceleration of the atrial flutter frequency after an increase in ventricular rate, even during autonomic nervous blockade.
      • Ravelli F.
      • Masè M.
      • Disertori M.
      Mechanical modulation of atrial flutter cycle length.
      A premature ventricular complex causes a post-extrasystolic pause, resulting in potentiated ventricular contraction in the following beat. This could ultimately lead to even higher PV flow and stretch. Indeed, retrograde blood flow into the PV has been observed during ventricular contraction with the patient in AF.
      • Chao T.H.
      • Tsai L.M.
      • Tsai W.C.
      • et al.
      Effect of atrial fibrillation on pulmonary venous flow patterns assessed by Doppler transesophageal echocardiography.
      Because during AF atrial distensibility is reduced and higher atrial pressures result,
      • White C.W.
      • Kerber R.E.
      • Weiss H.R.
      • Marcus M.L.
      The effects of atrial fibrillation on atrial pressure-volume and flow relationships.
      electrophysiological consequences are likely to ensue. Therefore, atrial and PV stretch depends on the underlying rhythm and its disturbances (including AF).

      C. AF and stretch-inducing conditions

      Comorbidities that involve wall stress changes in patients with AF are risk factors for incident AF (Figure 1).
      • Benjamin E.J.
      • Levy D.
      • Vaziri S.M.
      • D’Agostino R.B.
      • Belanger A.J.
      • Wolf P.A.
      Independent risk factors for atrial fibrillation in a population-based cohort: the Framingham Heart Study.
      ,
      • Gami A.S.
      • Hodge D.O.
      • Herges R.M.
      • et al.
      Obstructive sleep apnea, obesity, and the risk of incident atrial fibrillation.
      ,
      • Lévy S.
      Factors predisposing to the development of atrial fibrillation.
      Figure thumbnail gr1
      Figure 1Conditions that increase atrial stretch. Common cardiovascular morbidities can increase atrial pre- and afterload. Atrioventricular dyssynchrony leads to atrial contraction against closed valves and thereby temporary atrial stretch. The intrathoracic pressure fluctuates during obstructive sleep apnea, leading to stretch of the thin-walled atria. A body position from supine to left lateral recumbent causes an immediate change in pulmonary vein wall stress. Obesity is associated with elevated left atrial pressures.

      C.1. Arterial hypertension

      Arterial hypertension is a common comorbidity in patients with AF, affecting >70% of patients with AF.
      • Lip G.Y.H.
      • Coca A.
      • Kahan T.
      • et al.
      Hypertension and cardiac arrhythmias: a consensus document from the European Heart Rhythm Association (EHRA) and ESC Council on Hypertension, endorsed by the Heart Rhythm Society (HRS), Asia-Pacific Heart Rhythm Society (APHRS) and Sociedad Latinoamericana de Estimulación Cardíaca y Electrofisiología (SOLEACE).
      Patients with arterial hypertension have a 1.7-fold higher risk of AF development than do normotensive patients.
      • Lip G.Y.H.
      • Coca A.
      • Kahan T.
      • et al.
      Hypertension and cardiac arrhythmias: a consensus document from the European Heart Rhythm Association (EHRA) and ESC Council on Hypertension, endorsed by the Heart Rhythm Society (HRS), Asia-Pacific Heart Rhythm Society (APHRS) and Sociedad Latinoamericana de Estimulación Cardíaca y Electrofisiología (SOLEACE).
      The associated arterial stiffening and left ventricular overload cause retrograde mitral blood flow, thereby increasing LA pressure and stretch.
      • Dzeshka M.S.
      • Shantsila A.
      • Shantsila E.
      • Lip G.Y.H.
      Atrial fibrillation and hypertension.
      Indeed, arterial hypertension is related to enlarged PV and PV retrograde blood flow during atrial contraction is larger in progressive paroxysmal AF than in stable paroxysmal AF with arterial hypertension.
      • Maruyama T.
      • Kishikawa T.
      • Ito H.
      • Kaji Y.
      • Sasaki Y.
      • Ishihara Y.
      Augmentation of pulmonary vein backflow velocity during left atrial contraction: a novel phenomenon responsible for progression of atrial fibrillation in hypertensive patients.
      ,
      • Herweg B.
      • Sichrovsky T.
      • Polosajian L.
      • Rozenshtein A.
      • Steinberg J.S.
      Hypertension and hypertensive heart disease are associated with increased ostial pulmonary vein diameter.

      C.2. Pulmonary hypertension

      More than 30% of patients with pulmonary hypertension have AF.
      • Rottlaender D.
      • Motloch L.J.
      • Schmidt D.
      • et al.
      Clinical impact of atrial fibrillation in patients with pulmonary hypertension.
      Pulmonary hypertension increases RA pressure by increased afterload. The AF incidence augmented with increasing RA pressure.
      • Olsson K.M.
      • Nickel N.P.
      • Tongers J.
      • Hoeper M.M.
      Atrial flutter and fibrillation in patients with pulmonary hypertension.
      Similarly, atrial septum defects augment the RA and pulmonary artery pressures by left-to-right shunting, and adult patients with persistent septum defects often have AF before the occlusion of the shunt.
      • Gatzoulis M.A.
      • Freeman M.A.
      • Siu S.C.
      • Webb G.D.
      • Harris L.
      Atrial arrhythmia after surgical closure of atrial septal defects in adults.
      AF is likely a cause of pulmonary hypertension because 25% of 239 patients with pulmonary hypertension, but without atrial arrhythmias, develop AF or atrial flutter over a 5-year period.
      • Olsson K.M.
      • Nickel N.P.
      • Tongers J.
      • Hoeper M.M.
      Atrial flutter and fibrillation in patients with pulmonary hypertension.

      C.3. Valvular heart disease

      Atrioventricular regurgitation and stenosis are common in patients with AF and cause atrial volume overload by increased retrograde blood flow.
      • Lévy S.
      Factors predisposing to the development of atrial fibrillation.
      Mitral valve disease is associated with AF recurrence after pharmacological cardioversion in patients with AF and enlarged LA.
      • Brodsky M.A.
      • Allen B.J.
      • Capparelli E.V.
      • Luckett C.R.
      • Morton R.
      • Henry W.L.
      Factors determining maintenance of sinus rhythm after chronic atrial fibrillation with left atrial dilatation.
      Similarly, valvular heart disease is associated with poorer ablation success in the long-term.
      • Calkins H.
      • Hindricks G.
      • Cappato R.
      • et al.
      2017 HRS/EHRA/ECAS/APHRS/SOLAECE expert consensus statement on catheter and surgical ablation of atrial fibrillation.
      Acute normalization of LA pressure after balloon valvuloplasty is associated with less conduction slowing.
      • Coronel R.
      • Langerveld J.
      • Boersma L.V.
      • et al.
      Left atrial pressure reduction for mitral stenosis reverses left atrial direction-dependent conduction abnormalities.

      C.4. Arrhythmias

      Premature atrial and ventricular activation and atrioventricular block with concomitant ventricular escape rhythm can cause atrial contraction against closed valves and thereby increases in atrial stretch.
      • Ravelli F.
      • Mase M.
      • del Greco M.
      • Marini M.
      • Disertori M.
      Acute atrial dilatation slows conduction and increases AF vulnerability in the human atrium.
      Premature atrial and ventricular complexes are risk factors for AF, and the risk increases with the increasing frequency of premature complexes.
      • Durmaz E.
      • Ikitimur B.
      • Kilickiran Avci B.
      • et al.
      The clinical significance of premature atrial contractions: how frequent should they become predictive of new-onset atrial fibrillation.
      In addition, complete atrioventricular block occurs more often in patients with AF than in patients without AF, although inverse causality may be the case.
      • Zhao X.
      • Sun C.
      • Cao M.
      • Li H.
      Atrioventricular block can be used as a risk predictor of clinical atrial fibrillation.

      C.5. Obstructive sleep apnea

      Obstructive sleep apnea leads to fluctuating changes in intrathoracic pressure, which modulates atrial stretch, and is a risk factor for AF.
      • Gami A.S.
      • Hodge D.O.
      • Herges R.M.
      • et al.
      Obstructive sleep apnea, obesity, and the risk of incident atrial fibrillation.
      An applied negative tracheal pressure in pigs, resembling that in patients with obstructive apnea, increases the atrial transmural pressure gradient and atrial distension.
      • Linz D.
      • Schotten U.
      • Neuberger H.R.
      • Böhm M.
      • Wirth K.
      Negative tracheal pressure during obstructive respiratory events promotes atrial fibrillation by vagal activation.
      In patients with AF, concomitant obstructive sleep apnea is associated with larger LA than in those without apnea.
      • Dimitri H.
      • Ng M.
      • Brooks A.G.
      • et al.
      Atrial remodeling in obstructive sleep apnea: implications for atrial fibrillation.
      Obstructive sleep apnea also causes an imbalance in sympathetic nervous activity favoring AF arrhythmogenesis.
      • Linz D.
      • Linz B.
      • Hohl M.
      • Bohm M.
      Atrial arrhythmogenesis in obstructive sleep apnea: therapeutic implications.

      C.6. Positional AF

      AF paroxysms are often triggered during sleep.
      • Rosso R.
      • Sparks P.B.
      • Morton J.B.
      • et al.
      Vagal paroxysmal atrial fibrillation: prevalence and ablation outcome in patients without structural heart disease.
      In addition to obstructive sleep apnea, the physiological high vagal tone during the night and the body position play a role in nocturnal AF.
      • Accardo A.
      • Merlo M.
      • Silveri G.
      • et al.
      Influence of ageing on circadian rhythm of heart rate variability in healthy subjects.
      ,
      • Gottlieb L.A.
      • Blanco L.S.Y.
      • Hocini M.
      • Dekker L.R.C.
      • Coronel R.
      Self-reported onset of paroxysmal atrial fibrillation is related to sleeping body position.
      Twenty-two percent of patients with symptomatic paroxysmal AF report that taking a specific body position triggers their arrhythmia symptoms, with supine and left lateral recumbent positions being the most frequent.
      • Gottlieb L.A.
      • Blanco L.S.Y.
      • Hocini M.
      • Dekker L.R.C.
      • Coronel R.
      Self-reported onset of paroxysmal atrial fibrillation is related to sleeping body position.
      A change in body position from supine to the left lateral recumbent position increases wall stress in the PV, but not in the LA.
      • Gottlieb L.A.
      • El Hamrani D.
      • Naulin J.
      • et al.
      A left lateral body position increases pulmonary vein stress in healthy humans.
      Therefore, “positional” AF is likely influenced by heterogeneous atrial stretch.

      C.7. Heart failure and acute ischemia

      AF often coexists with heart failure and acute ischemia.
      • Lévy S.
      Factors predisposing to the development of atrial fibrillation.
      These are stretch-related morbidities. Heart failure results in higher intracardiac pressures and atrial dilatation. In the days after acute ventricular myocardial infarction, AF occurs in 2%–21% of patients.
      • González-Pacheco H.
      • Márquez M.F.
      • Arias-Mendoza A.
      • et al.
      Clinical features and in-hospital mortality associated with different types of atrial fibrillation in patients with acute coronary syndrome with and without ST elevation.
      Acute ischemia causes an increase in LA pressure potentially caused by ventricular dysfunction.
      • Alasady M.
      • Shipp N.J.
      • Brooks A.G.
      • et al.
      Myocardial infarction and atrial fibrillation: importance of atrial ischemia.
      However, AF vulnerability also appears to depend on concomitant atrial ischemia.
      • Alasady M.
      • Shipp N.J.
      • Brooks A.G.
      • et al.
      Myocardial infarction and atrial fibrillation: importance of atrial ischemia.

      D. Electrophysiological response to atrial stretch

      Cellular ionic and extracellular matrix changes after stretch are described in the Online Supplement.

      D.1. Focal origin and automaticity

      Inflation of a balloon in the LA of explanted guinea pig hearts causes early afterdepolarizations and spontaneous premature atrial complexes.
      • Nazir S.A.
      • Lab M.J.
      Mechanoelectric feedback in the atrium of the isolated guinea-pig heart.
      Stretching of isolated PV increases the frequency of spontaneous activity and the incidence of early and delayed afterdepolarization in the PV myocardium in a stretch intensity–dependent manner.
      • Chang S.L.
      • Chen Y.C.
      • Chen Y.J.
      • et al.
      Mechanoelectrical feedback regulates the arrhythmogenic activity of pulmonary veins.
      ,
      • Hamaguchi S.
      • Hikita K.
      • Tanaka Y.
      • Tsuneoka Y.
      • Namekata I.
      • Tanaka H.
      Enhancement of automaticity by mechanical stretch of the isolated guinea pig pulmonary vein myocardium.
      Focal arrhythmias from the PV myocardium can trigger AF in patients with paroxysmal AF.
      • Haissaguerre M.
      • Jais P.
      • Shah D.C.
      • et al.
      Spontaneous initiation of atrial fibrillation by ectopic beats originating in the pulmonary veins.
      AF inducibility by programmed stimulation and the duration of AF increase with RA and LA pressures >5 mm Hg.
      • Ravelli F.
      • Allessie M.
      Effects of atrial dilatation on refractory period and vulnerability to atrial fibrillation in the isolated Langendorff-perfused rabbit heart.
      ,
      • Satoh T.
      • Zipes D.P.
      Unequal atrial stretch in dogs increases dispersion of refractoriness conducive to developing atrial fibrillation.
      ,
      • Bode F.
      • Sachs F.
      • Franz M.R.
      Tarantula peptide inhibits atrial fibrillation.
      Others show that AF is induced only in high atrial pressures when the pericardium is removed, suggesting that atrial stretch, rather than atrial pressure alone, exerts the proarrhythmic effect.
      • Ninio D.M.
      • Saint D.A.
      Passive pericardial constraint protects against stretch-induced vulnerability to atrial fibrillation in rabbits.
      Also, simultaneous atrial and ventricular pacing (causing increased atrial dimensions and stretch) initiates AF in 6 of 10 patients with paroxysmal AF, but not during sole atrial pacing.
      • Ravelli F.
      • Mase M.
      • del Greco M.
      • Marini M.
      • Disertori M.
      Acute atrial dilatation slows conduction and increases AF vulnerability in the human atrium.
      Thus, acute increases in atrial stretch provides triggers and facilitates AF initiation (Figure 2).
      Figure thumbnail gr2
      Figure 2Proarrhythmic responses to atrial stretch. Early and delayed afterdepolarizations occur upon stretching of the atrial myocardium and can generate triggered activity. Stretch causes heterogeneous conduction slowing and shortening or prolongation of the refractory period, dependent on the timing of the stretch stimulus. This ultimately can lead to unidirectional block and reentry. Atrial stretch augments the inducibility of atrial fibrillation.

      D.2. Substrate for reentry

      Maintenance of AF depends on reentrant activation in an arrhythmogenic substrate, most often involving the atrial bodies.
      • Allessie M.A.
      • Lammers W.J.
      • Bonke I.M.
      • Hollen J.
      Intra-atrial reentry as a mechanism for atrial flutter induced by acetylcholine and rapid pacing in the dog.
      A short atrial refractory period and slow conduction promote reentry.

      D.2.1. Atrial refractoriness

      The effect of stretch on refractoriness is equivocal. A high atrial pressure shortens refractoriness in the RA and LA of explanted rabbit hearts.
      • Ravelli F.
      • Allessie M.
      Effects of atrial dilatation on refractory period and vulnerability to atrial fibrillation in the isolated Langendorff-perfused rabbit heart.
      However, volume loading in anesthetized animals either prolongs atrial refractoriness (atrial pressure increase of 1.2 mm Hg) or does not change refractoriness (atrial pressure increase of 4.5 mm Hg).
      • Satoh T.
      • Zipes D.P.
      Unequal atrial stretch in dogs increases dispersion of refractoriness conducive to developing atrial fibrillation.
      ,
      • Wijffels M.C.
      • Kirchhof C.J.
      • Dorland R.
      • Power J.
      • Allessie M.A.
      Electrical remodeling due to atrial fibrillation in chronically instrumented conscious goats: roles of neurohumoral changes, ischemia, atrial stretch, and high rate of electrical activation.
      Concomitant hypertension does not have an effect on atrial refractoriness in pigs with AF.
      • Manninger M.
      • Zweiker D.
      • van Hunnik A.
      • et al.
      Arterial hypertension drives arrhythmia progression via specific structural remodeling in a porcine model of atrial fibrillation.
      High atrial pressures decrease the duration of the monophasic atrial action potential at 50% and 70% of repolarization, but increase at 90% repolarization.
      • Ravelli F.
      • Allessie M.
      Effects of atrial dilatation on refractory period and vulnerability to atrial fibrillation in the isolated Langendorff-perfused rabbit heart.
      ,
      • Nazir S.A.
      • Lab M.J.
      Mechanoelectric feedback in the atrium of the isolated guinea-pig heart.
      Others observe no change in PV repolarization during PV stretching.
      • Hamaguchi S.
      • Hikita K.
      • Tanaka Y.
      • Tsuneoka Y.
      • Namekata I.
      • Tanaka H.
      Enhancement of automaticity by mechanical stretch of the isolated guinea pig pulmonary vein myocardium.
      The diverging stretch-induced changes in atrial action potential may be explained by the variation in the timing, duration, intensity, modality, and repetitive pattern of the experimental stretch stimulus but also by differences in wall thickness (see below).
      The diverging stretch-induced changes in atrial action potential may be explained by the variation in the timing and duration of the stretch stimulus (related to the reversal potential of stretch-activated ion channels; see Online Supplement). Moreover, not only the intensity, modality, and repetitive pattern of the stretch stimulus but also the wall thickness may play a role (see below).

      D.2.2. Atrial conduction

      Stretching of atrial tissue in patients with AF and patients with cardiac disease increases the extent of conduction block.
      • Ravelli F.
      • Mase M.
      • del Greco M.
      • Marini M.
      • Disertori M.
      Acute atrial dilatation slows conduction and increases AF vulnerability in the human atrium.
      ,
      • Elvan A.
      • Adiyaman A.
      • Beukema R.J.
      • Sie H.T.
      • Allessie M.A.
      Electrophysiological effects of acute atrial stretch on persistent atrial fibrillation in patients undergoing open heart surgery.
      Conduction block correlates linearly with the applied stretch in the isolated rat PV.
      • Egorov Y.V.
      • Lang D.
      • Tyan L.
      • et al.
      Caveolae-mediated activation of mechanosensitive chloride channels in pulmonary veins triggers atrial arrhythmogenesis.
      Conduction slowing in the atrial-PV junction occurs with an increase in atrial pressure (2.5 mm Hg) in patients.
      • Walters T.E.
      • Lee G.
      • Spence S.
      • et al.
      Acute atrial stretch results in conduction slowing and complex signals at the pulmonary vein to left atrial junction: insights into the mechanism of pulmonary vein arrhythmogenesis.
      Similarly, RA dilatation decreases the conduction velocity and increases spatial heterogeneity in conduction.
      • Eijsbouts S.C.
      • Majidi M.
      • van Zandvoort M.
      • Allessie M.A.
      Effects of acute atrial dilation on heterogeneity in conduction in the isolated rabbit heart.
      The dilatation-induced heterogeneity in conduction can be a result of heterogeneous distribution of wall stress because thinner atrial regions stretch more than thicker regions during volume expansion.
      • Satoh T.
      • Zipes D.P.
      Unequal atrial stretch in dogs increases dispersion of refractoriness conducive to developing atrial fibrillation.
      Indeed, refractoriness prolongs more in thinner than in thicker atrial regions when subjected to dilatation.
      • Satoh T.
      • Zipes D.P.
      Unequal atrial stretch in dogs increases dispersion of refractoriness conducive to developing atrial fibrillation.
      Taken together, LA and RA stretch augments heterogeneity in conduction and refractoriness in atrial and PV tissue while providing a triggering mechanism and facilitating reentry.

      E. Therapeutic reduction in atrial stretch

      While an increase in atrial stretch promotes AF, a reduction in atrial stretch is antiarrhythmic.
      • Ravelli F.
      • Allessie M.
      Effects of atrial dilatation on refractory period and vulnerability to atrial fibrillation in the isolated Langendorff-perfused rabbit heart.
      ,
      • Coronel R.
      • Langerveld J.
      • Boersma L.V.
      • et al.
      Left atrial pressure reduction for mitral stenosis reverses left atrial direction-dependent conduction abnormalities.
      ,
      • Ishikawa K.
      • Watanabe S.
      • Lee P.
      • et al.
      Acute left ventricular unloading reduces atrial stretch and inhibits atrial arrhythmias.
      In addition, increased atrial stretch decreases the efficacy of AF therapy and therefore the preventive treatment of AF should include reduction of atrial stretch (Figure 3).
      • Sramko M.
      • Wichterle D.
      • Melenovsky V.
      • et al.
      Resting and exercise-induced left atrial hypertension in patients with atrial fibrillation: the causes and implications for catheter ablation.
      • Lee J.H.
      • Kwon O.S.
      • Shim J.
      • et al.
      Left atrial wall stress and the long-term outcome of catheter ablation of atrial fibrillation: an artificial intelligence-based prediction of atrial wall stress.
      • Okumura Y.
      • Watanabe I.
      • Nakai T.
      • et al.
      Impact of biomarkers of inflammation and extracellular matrix turnover on the outcome of atrial fibrillation ablation: importance of matrix metalloproteinase-2 as a predictor of atrial fibrillation recurrence.
      • Bollmann A.
      • Binias K.H.
      • Toepffer I.
      • Molling J.
      • Geller C.
      • Klein H.U.
      Importance of left atrial diameter and atrial fibrillatory frequency for conversion of persistent atrial fibrillation with oral flecainide.
      • Brodsky M.A.
      • Allen B.J.
      • Capparelli E.V.
      • Luckett C.R.
      • Morton R.
      • Henry W.L.
      Factors determining maintenance of sinus rhythm after chronic atrial fibrillation with left atrial dilatation.
      • Arya A.
      • Hindricks G.
      • Sommer P.
      • et al.
      Long-term results and the predictors of outcome of catheter ablation of atrial fibrillation using steerable sheath catheter navigation after single procedure in 674 patients.
      Measures of atrial stretch (volume, regional strain) can serve to monitor the effectiveness of AF therapy. Table 1 lists pharmacological agents that can modulate stretch-related atrial arrhythmogenesis (experimental and clinical).
      Figure thumbnail gr3
      Figure 3Pharmacological and interventional therapies for stretch-induced arrhythmogenesis. Pharmacological and interventional therapies can attenuate the proarrhythmic effects of atrial stretch. The stretch-induced shortening in refractoriness can be counteracted by antiarrhythmic drugs. Antagonism of the renin-angiotensin-aldosterone system (RAAS) decreases the interstitial collagen and the circulating volume. Surgical repair and replacement of atrioventricular valves and continuous positive airway pressure (CPAP) reduce stretch mechanisms in the corresponding pathologies. Cox Maze surgery may reduce atrial stretch by a stiffening of the atria by scar formation. Similarly, stretch reduction may be gained by catheter-based ablation and subsequent ablation scar formation in the atria. Ang II = angiotensin II; SACK = potassium-selective stretch-activated ion channels; SACNS = cation non-selective stretch-activated ion channels.
      Table 1Pharmacological modulation of stretch-related atrial arrhythmogenesis
      Drug classNameMechanism of actionDosagePotential antiarrhythmic effect
      AAD class IMexiletineTREK-1 channel blocker + sodium channel (late current) blocker167–501 mg/d
      Approved clinical dosages for on-label conditions.
      ↓Human TREK-1 current in vitro (173 μmol/L).
      • Schmidt C.
      • Wiedmann F.
      • Schweizer P.A.
      • Becker R.
      • Katus H.A.
      • Thomas D.
      Class I antiarrhythmic drugs inhibit human cardiac two-pore-domain K+ (K2 ₂p) channels.
      Potentially causing action potential prolongation
      PropafenoneTREK-1 channel blocker + sodium channel (early current) blocker450–600 mg/d
      Approved clinical dosages for on-label conditions.
      ↓Human TREK-1 current in vitro (7.6 μmol/L).
      • Schmidt C.
      • Wiedmann F.
      • Schweizer P.A.
      • Becker R.
      • Katus H.A.
      • Thomas D.
      Class I antiarrhythmic drugs inhibit human cardiac two-pore-domain K+ (K2 ₂p) channels.
      Potentially causing action potential prolongation
      AAD class IICarvedilolTREK-1 channel blocker + β-receptor blocker12.5–100 mg/d
      Approved clinical dosages for on-label conditions.
      ↓Human TREK-1 current in vitro (20.3 μmol/L).
      • Kisselbach J.
      • Seyler C.
      • Schweizer P.A.
      • et al.
      Modulation of K2P2.1 and K2P10.1 K+ channel sensitivity to carvedilol by alternative mRNA translation initiation.
      Potentially causing action potential prolongation
      AAD class IIIDronedaroneTREK-1 channel blocker + potassium, sodium, L-type calcium channel blocker + α/β-receptor blocker800 mg/d
      Approved clinical dosages for on-label conditions.
      ↓Human TREK-1 current in vitro (26.7 μmol/L).
      • Schmidt C.
      • Wiedmann F.
      • Schweizer P.A.
      • Becker R.
      • Katus H.A.
      • Thomas D.
      Novel electrophysiological properties of dronedarone: inhibition of human cardiac two-pore-domain potassium (K2P) channels.
      Potentially causing action potential prolongation
      VernakalantTREK-1 channel blocker + potassium, sodium, L-type calcium channel blocker3–5 mg/(kg·d)
      Approved clinical dosages for on-label conditions.
      ↓Human TREK-1 current in vitro (13.3 μmol/L).
      • Seyler C.
      • Li J.
      • Schweizer P.A.
      • Katus H.A.
      • Thomas D.
      Inhibition of cardiac two-pore-domain K+ (K2P) channels by the antiarrhythmic drug vernakalant—comparison with flecainide.
      Potentially causing action potential prolongation
      AntibioticsStreptomycinSelective SACNS and SACK blockers at low concentration in vitro. L-type calcium channel also blocked at higher concentrations
      • Quinn T.A.
      • Kohl P.
      Cardiac mechano-electric coupling: acute effects of mechanical stimulation on heart rate and rhythm.
      20–40 mg/(kg·d)
      Approved clinical dosages for on-label conditions.
      ↓Stretch-induced PV ectopy (10–400 μmol/L perfusate concentration)
      • Chang S.L.
      • Chen Y.C.
      • Chen Y.J.
      • et al.
      Mechanoelectrical feedback regulates the arrhythmogenic activity of pulmonary veins.
      ,
      • Hamaguchi S.
      • Hikita K.
      • Tanaka Y.
      • Tsuneoka Y.
      • Namekata I.
      • Tanaka H.
      Enhancement of automaticity by mechanical stretch of the isolated guinea pig pulmonary vein myocardium.
      AntihypertensivesEnalaprilAngiotensin-converting enzyme inhibitor5–20 mg/d
      Approved clinical dosages for on-label conditions.
      ↓Vasoconstriction→↓blood pressure→↓retrograde blood flow to the LA
      CandesartanAngiotensin II receptor blocker8–32 mg/d
      Approved clinical dosages for on-label conditions.
      ↓Vasoconstriction→↓blood pressure→↓retrograde blood flow to the LA

      ↓Atrial collagen accumulation (10 mg/(kg·d) in vivo dogs)
      • Kumagai K.
      • Nakashima H.
      • Urata H.
      • Gondo N.
      • Arakawa K.
      • Saku K.
      Effects of angiotensin II type 1 receptor antagonist on electrical and structural remodeling in atrial fibrillation.
      DiureticsFurosemideRenal sodium-potassium-chloride channel inhibitor20–500 mg/d
      Approved clinical dosages for on-label conditions.
      ↑Diuresis→↓circulating volume→↓atrial stretch
      SacubitrilNeprilysin enzyme inhibitor98–196 mg/d
      Approved clinical dosages for on-label conditions.
      ↓ANP degradation→↑ANP-mediated diuresis→ ↓circulating volume
      • Goetze J.P.
      • Bruneau B.G.
      • Ramos H.R.
      • Ogawa T.
      • de Bold M.K.
      • de Bold A.J.
      Cardiac natriuretic peptides.
      ElementsGadolinium (Gd3+)SACK and SACNS blockers12.5–100 μmol/L perfusate concentration.

      Unknown safety profile in humans
      ↓Stretch-induced afterdepolarizations in the atria and PV
      • Chang S.L.
      • Chen Y.C.
      • Chen Y.J.
      • et al.
      Mechanoelectrical feedback regulates the arrhythmogenic activity of pulmonary veins.
      ,
      • Tavi P.
      • Laine M.
      • Weckström M.
      Effect of gadolinium on stretch-induced changes in contraction and intracellularly recorded action- and afterpotentials of rat isolated atrium.


      ↓AF inducibility in a dose-dependent manner without changes in refractoriness
      • Bode F.
      • Katchman A.
      • Woosley R.L.
      • Franz M.R.
      Gadolinium decreases stretch-induced vulnerability to atrial fibrillation.
      PeptideGsMTx-4Selective SACNS blocker0.17 μmol/L perfusate concentration.

      Unknown safety profile in humans
      ↓Stretch-induced AF inducibility and duration
      • Bode F.
      • Sachs F.
      • Franz M.R.
      Tarantula peptide inhibits atrial fibrillation.
      AAD = antiarrhythmic drug; AF = atrial fibrillation; ANP = atrial natriuretic peptide; GsMTx-4 = grammastola spatulata mechanotoxin-4; LA = left atrium; PV = pulmonary vein; SAC = stretch-activated channel; SACNS = cation non-selective stretch-activated channels; SACK = potassium-selective stretch-activated channels; TREK = TWIK-related potassium channel.
      Approved clinical dosages for on-label conditions.

      E.1. Noninvasive interventions

      Noninvasive respiratory support by continuous positive air pressure ventilation in patients with obstructive sleep apnea decreases the transmural atrial pressure gradient and stretch.
      • Becker H.
      • Grote L.
      • Ploch T.
      • et al.
      Intrathoracic pressure changes and cardiovascular effects induced by nCPAP and nBiPAP in sleep apnoea patients.
      It lowers AF recurrence after ablation therapy in patients with AF and concomitant obstructive sleep apnea.
      • Congrete S.
      • Bintvihok M.
      • Thongprayoon C.
      • et al.
      Effect of obstructive sleep apnea and its treatment of atrial fibrillation recurrence after radiofrequency catheter ablation: a meta-analysis.
      Avoiding AF-triggered body positions may prevent AF as well.
      • Gottlieb L.A.
      • Blanco L.S.Y.
      • Hocini M.
      • Dekker L.R.C.
      • Coronel R.
      Self-reported onset of paroxysmal atrial fibrillation is related to sleeping body position.

      E.2. Surgery

      Valve repair and replacement and balloon valvotomy are obvious therapeutic options for atrioventricular valve disease. LA de-dilatation by mitral valvotomy in patients with mitral stenosis immediately normalizes atrial conduction.
      • Coronel R.
      • Langerveld J.
      • Boersma L.V.
      • et al.
      Left atrial pressure reduction for mitral stenosis reverses left atrial direction-dependent conduction abnormalities.
      Indeed, ∼20% of patients with AF have spontaneous AF termination 1 year after mitral valve repair.
      • Large S.R.
      • Hosseinpour A.R.
      • Wisbey C.
      • Wells F.C.
      Spontaneous cardioversion and mitral valve repair: a role for surgical cardioversion (Cox-maze)?.
      Similarly, normalization of LA pressure by left ventricular unloading (by a percutaneous left ventricular assist device) in pigs with mitral regurgitation reduces AF inducibility.
      • Ishikawa K.
      • Watanabe S.
      • Lee P.
      • et al.
      Acute left ventricular unloading reduces atrial stretch and inhibits atrial arrhythmias.
      Heart failure with preserved ejection fraction and concomitant pulmonary hypertension may be treated with an interatrial shunt to decrease LA pressure.
      • Lu D.
      • Zhu J.
      • Liao B.
      Efficacy and safety of inter-atrial shunt devices for heart failure with reduced or preserved ejection fraction: early experiences.
      Atrial shunting decreases the heart failure symptoms in 3 early studies, but the effect on AF prevention still remains to be elucidated.
      • Lu D.
      • Zhu J.
      • Liao B.
      Efficacy and safety of inter-atrial shunt devices for heart failure with reduced or preserved ejection fraction: early experiences.
      An iatrogenic atrial septal defect in patients with AF 3 months after interventional AF ablation may decrease LA stretch (especially in patients with left ventricular heart failure of hypertension), thereby exerting an antiarrhythmic effect on AF.
      • Sieira J.
      • Chierchia G.B.
      • Di Giovanni G.
      • et al.
      One year incidence of iatrogenic atrial septal defect after cryoballoon ablation for atrial fibrillation.
      LA to RA shunting may decrease LA stretch in patients with concomitant left ventricular heart failure or arterial hypertension, thereby exerting an antiarrhythmic effect on AF. Subsequent spontaneous closure of the iatrogenic septal defect can reestablish a high LA pressure and may provide an explanation for the late AF recurrences (>3 months) often observed after AF ablation in patients with arterial hypertension.
      • Gottlieb L.A.
      • Dekker L.R.C.
      • Coronel R.
      The blinding period following ablation therapy for atrial fibrillation: proarrhythmic and antiarrhythmic pathophysiological mechanisms.

      E.3. Catheter-based ablation

      Targeted delivery of ablative energy in the atrial body and PV is a common treatment of drug-refractory AF, whereby thermal or other kinds of energy are delivered in order to cease focal arrhythmias or disrupt reentrant pathways.
      • Calkins H.
      • Hindricks G.
      • Cappato R.
      • et al.
      2017 HRS/EHRA/ECAS/APHRS/SOLAECE expert consensus statement on catheter and surgical ablation of atrial fibrillation.
      PV isolation aims to electrically isolate the PV origin of the arrhythmia from the atrial body.
      • Calkins H.
      • Hindricks G.
      • Cappato R.
      • et al.
      2017 HRS/EHRA/ECAS/APHRS/SOLAECE expert consensus statement on catheter and surgical ablation of atrial fibrillation.
      However, ablation success is not immediate, but often demands several weeks to develop.
      • Mugnai G.
      • de Asmundis C.
      • Hunuk B.
      • et al.
      Second-generation cryoballoon ablation for paroxysmal atrial fibrillation: predictive role of atrial arrhythmias occurring in the blanking period on the incidence of late recurrences.
      It has been posited that ablation success depends on the formation of a mature noncompliant scar in the course of several weeks to months.
      • Gottlieb L.A.
      • Dekker L.R.C.
      • Coronel R.
      The blinding period following ablation therapy for atrial fibrillation: proarrhythmic and antiarrhythmic pathophysiological mechanisms.
      Because heterogeneous stretch (and thereby increased heterogeneity in conduction and refractoriness) is proarrhythmic for AF, not only a reduction but also a homogenization of stretch is a potential therapeutic target for AF. The success rate of connecting linear ablation lesions in the LA in addition to PV isolation is higher than that of sole PV isolation.
      • Oral H.
      • Scharf C.
      • Chugh A.
      • et al.
      Catheter ablation for paroxysmal atrial fibrillation: segmental pulmonary vein ostial ablation versus left atrial ablation.
      • Kottkamp H.
      • Hindricks G.
      • Autschbach R.
      • et al.
      Specific linear left atrial lesions in atrial fibrillation: intraoperative radiofrequency ablation using minimally invasive surgical techniques.
      • Knecht S.
      • Hocini M.
      • Wright M.
      • et al.
      Left atrial linear lesions are required for successful treatment of persistent atrial fibrillation.
      Similarly, the previously used Cox maze procedure, which compartmentalizes both atria and include complete PV isolation, leads to extensive atrial scar and a success rate in AF prevention of 93%.
      • Cox J.L.
      • Schuessler R.B.
      • Lappas D.G.
      • Boineau J.P.
      An 8 1/2-year clinical experience with surgery for atrial fibrillation.
      The antiarrhythmic effect of the Cox maze procedure was also observed only after 3 months.
      • Cox J.L.
      • Schuessler R.B.
      • Lappas D.G.
      • Boineau J.P.
      An 8 1/2-year clinical experience with surgery for atrial fibrillation.
      We speculate that a targeted reduction and homogenization of atrial stretch by ablation scar can be considered an additional concept for improving outcome in patients with drug-resistant AF.

      Conclusion

      Atrial stretch contributes significantly to the complex arrhythmogenic mechanisms of AF. AF often occurs together with atrial stretch–increasing comorbidities that attenuate the efficacy of AF treatment. Therefore, treatment of these comorbidities should be included in the standard AF treatment. Specific targeting on the downstream pathway of atrial stretch, for example, by modulation of ion channels and of collagen-producing cells, may improve rhythm control but remains to be investigated in patients with AF. A reduction and homogenization of atrial stretch can directly be achieved by ablation therapy and subsequent scar formation. Therefore, a (computer-aided, patient-specific) alternative design of stretch-reducing ablation lesions may ameliorate therapy outcomes.

      Acknowledgments

      We kindly thank C.E. Conrath, MD (University of Amsterdam, The Netherlands), for critical reading, editing, and valuable comments on the manuscript.

      Supplementary data

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