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. 2020 Aug;9(2):61–70. doi: 10.15420/aer.2020.13

Atrial Myopathy Underlying Atrial Fibrillation

Harold Rivner 1, Raul D Mitrani 1, Jeffrey J Goldberger 1,✉
PMCID: PMC7491052  PMID: 32983526

Abstract

While AF most often occurs in the setting of atrial disease, current assessment and treatment of patients with AF does not focus on the extent of the atrial myopathy that serves as the substrate for this arrhythmia. Atrial myopathy, in particular atrial fibrosis, may initiate a vicious cycle in which atrial myopathy leads to AF, which in turn leads to a worsening myopathy. Various techniques, including ECG, plasma biomarkers, electroanatomical voltage mapping, echocardiography, and cardiac MRI, can help to identify and quantify aspects of the atrial myopathy. Current therapies, such as catheter ablation, do not directly address the underlying atrial myopathy. There is emerging research showing that by targeting this myopathy we can help decrease the occurrence and burden of AF.

Keywords: AF, atrial myopathy, atrial fibrosis, cardiac MRI, strain echocardiography

AF is the most common sustained cardiac rhythm disturbance.[1] Worldwide, there is an estimated 33.5 million people with AF as of 2010.[2] While there are multiple estimates, the yearly incidence in the US is expected to grow, for example, from 1.2 million cases in 2010 to 2.6 million cases in 2030 and upwards of 6–12 million cases by 2050.[1,3] It is associated with increased morbidity and mortality[4] and diminished quality of life.[5] AF is associated with structural heart disease, but it may also occur in a structurally normal heart.

The clinical evaluation of patients with AF predominantly focuses on upstream risk factors, such as: hypertension, diabetes, heart failure (reduced or preserved ejection fraction), valvular heart disease, and other cardiopulmonary pathology such as pulmonary embolism.[6,7] Despite being the site of origin for this arrhythmia, the atria are not typically evaluated in any systematic manner except for atrial size and/or volume, typically evaluated on echocardiography. Furthermore, atrial size and left atrial (LA) appendage (LAA) morphology have not been incorporated into clinical decisions such as starting anticoagulation in patients with AF.[7] For example, the guideline-recommended and widely used CHA2DS2-VASc score for the evaluation of stroke risk does not include atrial size or any measure of atrial pathophysiology.[8] Ample data have shown that the atria are diseased in many patients with AF.[9,10] In this paper, we will explore the pathophysiology of atrial myopathy, the clinical evaluation of atrial fibrosis, the relationship of atrial fibrosis with thromboembolic events, and finally potential treatment approaches that might affect this atrial myopathy.

Pathophysiology of Atrial Myopathy

The development of atrial myopathy is complex with multiple factors contributing to its development. Here, we will discuss the development of atrial fibrosis, the role of obesity, the interaction of autonomic dysfunction and comorbidities on atrial myopathy, and the link between AF and atrial myopathy.

Development of Fibrosis

Fibrosis is a common pathway to injury and failure in multiple organs. Four steps in the fibrogenic cascade have been identified: initiation of the body’s response to the initial injury; activation of effector cells; elaboration of extracellular matrix (ECM); and finally the development of fibrosis with organ failure from this matrix.[11] Tissue damage initially leads to both a regenerative phase where tissue is replaced by normal tissue cells with no permanent damage, and a fibrosis stage in which normal parenchyma is replaced with fibroconnective tissue.[12] This second phase is regulated by a complex pro-inflammatory cytokineand cell-mediated system in which fibroblasts and myofibroblasts synthesise fibrotic tissue.[11,12]

This process of fibrosis after injury is well characterised, for example, in the development of ischemic ventricular cardiomyopathy after MI. The resultant necrosis from an initial MI triggers the innate immune pathway activation of nuclear factor (NF)-kB.[13] In addition, growth factors such as transforming growth factor-beta 1 (TGF-beta1), endothelin 1, and angiotensin II will cause the proliferation of fibroblasts and myofibroblasts. These processes drive the inflammatory response and lead to ECM deposition and fibrosis.[11,14] Two types of fibrosis occur in the heart: reactive fibrosis, which occurs in the perivascular space and is similar to the fibrosis seen in other tissues; and replacement fibrosis, which occurs at the site of prior myocyte loss. This fibrotic remodelling of the heart leads to the systolic and diastolic dysfunction seen in heart failure.[15,16]

There is a similar role for fibrosis in the development of atrial myopathy. The TGF-beta1/Smad signalling pathway has been identified as a key pathway in the development of atrial fibrosis. TGF-beta1 is a member of the cytokine family responsible for tissue repair and the generation of fibrosis. Smad is an additional family of proteins that can both attenuate and inhibit TGF-beta1 to help regulate this pathway.[17] In the rapid pacing animal model for AF, activated TGF-beta1 phosphorylates Smad, to form complexes that translocate into the nucleus of myofibroblasts to upregulate the production of fibrin with resultant atrial fibrosis. In addition, overexpression of TGF-beta1 decreases the production of Smad7, which is responsible for the inhibitory feedback loop of the TGF-beta1/Smad pathway.[17,18] The renin–angiotensin–aldosterone system (RAAS) has also been implicated in the development of atrial fibrosis. Studies of transgenic mice with overexpression of angiotensin-converting enzyme (ACE) have noted marked atrial dilation and fibrosis.[19,20] Furthermore, the rapid pacing of atrial myocytes has been shown to cause the expression of microRNA that alter fibroblasts to increase ECM production.[21] As discussed later in this paper, these various proteins integral to the development of atrial fibrosis can serve as both serum biomarkers and therapeutic targets.

Role of Obesity

Obesity in general has been linked to a higher incidence of the development of AF.[22–24] More specifically, epicardial adipose tissue (EAT), which refers to the layer of adipose tissue overlying the myocardium,[25] has the potential to directly affect the atrial myocardium via the release of adipokines that promote inflammation and fibrosis.[26,27] EAT has been shown to secrete activin A (a member of the TGF-beta family) that promotes the development of atrial fibrosis via a paracrine effect.[28] EAT can also serve as a source of progenitor cells that can differentiate into the myofibroblasts that are responsible for the creation of ECM and fibrosis.[29] A link between EAT and AF can be seen clinically. Patients with AF have been found to have higher levels of EAT compared with controls;[30] furthermore, subjects with chronic AF are more likely to have a higher volume of EAT than those with paroxysmal AF.[30] On multivariate analysis there was an independent association between EAT and LA volume even when controlling for BMI.[30] Obese patients have increased low-voltage areas (13.9% versus 3.4%, p<0.001) and low-voltage areas correspond to the location of EAT on MRI.[31] Furthermore, EAT has been shown to be a predictor of the success of AF ablation and the risk of recurrence.[32–35] EAT has also been shown to be an independent risk factor for AF-associated stroke.[36]

Other Components of Atrial Myopathy

The occurrence of atrial fibrosis in AF is clear. While this may play a critical part in the pathogenesis of AF via conduction slowing and the facilitation of re-entry, it is important to acknowledge that there are also other components of the atrial myopathy that may also be implicated. For example, there are autonomic innervation changes that occur after rapid pacing. Arora et al. showed that in the canine model, after rapid pacing, there is an increase in both sympathetic and parasympathetic fibres in the posterior LA and pulmonary veins. These autonomic changes cause regional shortening of the atrial effective refractory period, creating a substrate for re-entry and AF.[37–39] These changes in innervation of the cardiac autonomic ganglia are present in AF patients and are an integral part of the atrial myopathy and have been suggested as a target for ablation.[40]

The systemic diseases incorporated in the CHADS-VASc score, such as hypertension, heart failure, and diabetes, have been associated with increased risk for AF and may also play a role in the development of atrial myopathy.[10] These comorbidities have been associated with increased LA pressure in AF patients.[41] Hypertension is associated with abnormalities in the RAAS with high circulating levels of angiotensin II, ACE, and aldosterone. In addition to the fibrotic mechanism previously discussed, these components contribute to atrial myopathy by affecting ion channel structure and function and cause pro-inflammatory effects on the LA.[42] Furthermore, left ventricular hypertrophy as the result of longstanding hypertension has been associated with both LA thrombus and increased risk of stroke.[43–46] Heart failure (both preserved and reduced ejection fraction) causes increased LA pressure, increased LA size, and upregulation of RAAS.[46] Patients with diabetes have increased angiotensin II levels, TGF-beta signalling, adipose tissue, and systemic inflammation.[47] Patients with abnormal glucose metabolism have larger atrial sizes, lower atrial voltage, and higher AF recurrence after ablation.[48] It is clear that multiple pathophysiologic pathways may be implicated in the formation of the atrial myopathy depending on the upstream initiators.

Patients with atrial myopathy have been found to have endothelial dysfunction leading to increased hypercoagulability.[49] Rapid atrial pacing of pigs has been shown to increase the levels of the endothelial nitric oxide synthase inhibitor asymmetric dimethylarginine (ADMA).[50] Furthermore, in patients with persistent AF, there are higher levels of ADMA.[50] ADMA leads to endothelial dysfunction and increases the risk of stroke.[51] Additionally, von Willebrand factor levels have been associated with both AF and the risk of ischemic stroke.[52,53] These prothrombotic factors are accentuated in patients with comorbid hypertension, heart failure, and diabetes by increased oxidative stress.[40]

AF and Atrial Myopathy

Cardiac fibrosis is a key anatomic mediator creating the electrophysiologic substrate for arrhythmias.[11,54–56] This has been illustrated in the animal model in which selective creation of atrial fibrosis via overexpression of TGF-beta1 has been shown to lead to increased inducibility of AF.[57,58] Likewise, fibrosis creates a heterogenous milieu that slows intercellular conduction.[39,59–61] There is an alteration in cell–cell connections, gap junctions, and anisotropy that contributes to re-entrant pathways.[40] In patients undergoing catheter ablation for AF, atrial tissue conduction velocities were decreased in fibrotic areas defined by low voltage.[62] These areas of slowed conduction velocity were predictive of sites in which ablation either terminated AF or slowed the AF cycle length by at least 30 ms (sensitivity 72.0% with 95% CI [50.6–87.9%] and specificity 78.1% with 95% CI [71.3–80.9%]).[62] Furthermore, atrial fibrosis allows for the formation of multiple re-entry circuits that are thought to perpetuate both left-sided atrial tachycardia and AF.[61,63] Fibrosis and fatty infiltrates upregulate pro-inflammatory cytokines to enhance the pro-inflammatory state of the atrium, which in turn increases the likelihood of recurrent AF.[64,65] These processes lead to higher AF burden and further fibrosis. AF burden has been correlated with the degree of fibrosis found in postmortem tissue: those with persistent AF had a higher degree of fibrosis than those with paroxysmal AF.[66] The degree of atrial fibrosis has been associated with AF burden, AF recurrence after ablation, and cardioembolic events (as discussed later here).

The rapid atrial pacing model of AF simulates the rapid atrial rates seen in AF. In this model, animals undergo persistent rapid atrial pacing with atrial rates up to 900 BPM to induce AF. After a sustained period of time (6 weeks–180 days), the atrium remains in persistent AF once pacing is stopped.[65,67] Morillo et al. first showed that sustained rapid atrial pacing led to atrial myopathy with a dilated LA.[68] It is hypothesised that persistent atrial tachycardia leads to increased expression of the TGF-beta1/Smad signalling pathway with resultant atrial fibrosis as previously discussed.[17] Furthermore, there are mRNA changes that lead to an activated fibroblast phenotype that leads to increased ECM.[17,21] In a study of 26 sheep who underwent rapid atrial pacing with induction of AF, there was a significantly greater development of fibrotic fatty infiltrative tissue in the atria compared with those who received sham treatment.[65] The development of atrial fibrosis has been noted in the rabbit and canine rapid atrial pacing models, but not uniformly.[17,21,59] These findings demonstrate how persistent rapid atrial rates such as in AF may lead to atrial fibrosis. Atrial biopsies from humans with AF show similar fibrotic and fatty infiltrative changes as seen in the rapid pacing model.[69–71] After multivariate analysis of clinical risk factors in subjects with atrial fibrosis, only history of AF was a significant predictor of atrial fibrosis.[65] Furthermore, the degree of fibrosis was associated with AF burden.[65] Rapid pacing has also been shown to induce electrical remodelling with increases in dominant frequency and ion channel density.[72] These changes persisted despite mitigation of fibrosis and atrial dilation by eplerenone.[72]

It has long been accepted that “AF begets AF”.[73] Due to the cyclic nature of atrial myopathy and AF, it is difficult to ascertain which develops first. However, there is a clear association between the two with a resultant positive feedback loop with downstream effects (Figure 1).[74]

Figure 1: Progression of Atrial Myopathy and AF.

Figure 1:

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Clinical Evaluation of Myopathy

A variety of techniques have been studied to help define the atrial myopathy, including ECG, biomarkers, intracardiac voltage mapping, echocardiographic evaluation of the LA, and cardiac MRI. Here, we will explore how they can be utilised clinically to identify myopathy and potentially predict morbidity from AF and recurrence after intervention.

ECG

Analysis of the surface ECG during sinus rhythm is a readily available tool to predict the development of atrial myopathy and AF. The terminal force of the P wave during sinus rhythm in lead V1 (PTFV1) has been shown to correlate with LA abnormalities, such as enlargement and conduction defects (Figure 2).[75,76] In a large cohort study, PTFV1 >0.06 mm/s was associated with an increased risk for the development of AF (HR 1.91; 95% CI: [1.34–2.73]; p<0.001) and with mortality (HR 1.91; 95% CI [1.34–2.73]; p<0.001).[77] Ishida et al. found similar predictive abilities of PTFV1.[78] Furthermore, PTFV1 has been shown to be independently associated with cryptogenic, cardioembolic, and ischemic strokes.[79,80] PTFV1 ≥0.04 mm/s, along with P-wave duration ≥125 ms and P-wave dispersion ≥40 ms, have been shown to be predictors of AF recurrence after ablation.[81]

Figure 2: ECG Demonstrating P Terminal Force in V1.

Figure 2:

Circled P waves show a large terminal force in V1.

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The fibrillatory f wave itself has been shown to correlate with the degree of LA enlargement and myopathy. The f wave amplitude has been shown to correlate with LA size and chronicity of AF (i.e. large f waves in persistent AF).[82] Likewise, patients with coarse AF were more likely to have spontaneous contrast in the LAA and/or thrombus on echocardiogram.[83] In addition, patients with fine AF are less likely to have AF recurrence after cardioversion compared with coarse AF.[84] Frequency analysis and signal processing techniques of f waves can be predictive of clinical AF outcomes, such as response to anti-arrhythmic drugs, cardioversion, and ablation.[10,85,86] Furthermore, higher f wave dominant frequency has been found in patients with persistent AF compared with paroxysmal AF, although this may be due to electrophysiologic and/or structural remodelling as AF persists.[87] A recent study of patients presenting to the emergency room with a first episode of AF found no difference in dominant frequency between AF types.[88] Further research is needed to establish a role for fibrillatory wave analysis.

Biomarkers

Biomarkers, although not necessarily specific to atrial pathology, have been studied both for their association with AF and AF related outcomes.[45] The underlying pathophysiology represented by these biomarkers may provide an insight into the atrial myopathy. Pro-inflammatory and cardiac injury biomarkers such as C-reactive protein (CRP), interleukin-6, TGF-beta1, troponin, and N-terminal pro-Btype natriuretic peptide (NT-proBNP) have been found to be associated with the development of AF.[89–92]

Serum TGF-beta1, which was previously discussed as part of the fibrotic pathway, has a strong positive correlation with areas of low endocardial atrial voltage consistent with fibrosis (r[2]=0.93; p<0.001).[93] In addition, TGFbeta1 expression is specifically upregulated in patients with extensive low-voltage areas undergoing ablation.[94] Serum TGF-beta1 has been shown to be an independent risk factor for AF recurrence after ablation in both paroxysmal and persistent AF.[93,95] Interestingly, Kishima et al. found lower concentrations of TGF-beta1 in patients with recurrence after ablation.[96] They suggested that the discrepancy may be related to the inflammatory state of the patient. The authors concluded that in the early fibrotic phase and inflammatory stage, TGF-beta1 is higher but begins to decrease once the atrium is more heavily fibrotic.[96]

Additionally, high levels of the inflammatory cytokine CRP have been associated with higher risk of recurrence after cardioversion.[97] Decreased aldosterone concentration has been associated with longer maintenance of sinus rhythm after cardioversion.[98,99] This may reflect a reduction in the RAAS system that drives the myopathy. Elevated levels of troponin and NT-proBNP can highlight the existence of myopathy. Post-hoc analysis of the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) study, showed that patients with persistent elevation of troponin and NT-proBNP were at a higher risk for cardiovascular events and mortality during the follow-up period. Likewise, data from the Aristotle trial showed that troponin levels were significantly associated with higher risk of stroke and systemic embolism.[100] A recent study of circulating biomarkers associated with increased myocardial interstitial fibrosis noted a correlation with both the development of AF and recurrence after AF ablation.[101]

Furthermore, when added to conventional risk scoring systems, biomarkers may enhance predictive value.[100,102] For example, the age, biomarkers and clinical history (ABC) stroke score calculates risk based on age, troponin/NT-proBNP levels, and prior stroke. In a validation cohort, this scoring system had a higher C-statistic of 0.65 compared with 0.60 for the CHA2DS2-VASc score.[102] While not an exhaustive list, these initial studies of cardiac biomarkers highlight clinical associations that may serve as additional tools for risk stratification of patients with AF.

Intracardiac Electroanatomical Voltage Mapping

In patients undergoing electrophysiology studies, in particular those undergoing ablation procedures, electroanatomical voltage mapping can help identify the substrate for tachyarrhythmias. For AF, 3D electroanatomical voltage maps can help identify low-voltage areas that may represent areas of fibrosis (Figure 3).[103] Voltage mapping can be performed in patients in sinus rhythm or AF.[104] Patients with AF had significantly lower voltage in both the right atrium and LA compared with control patients with left-sided accessory pathways (right atrium: 1.7 ± 0.4 mV versus 2.9 ± 0.4 mV; LA: 1.7 ± 0.7 mV versus 33. ± 0.7 mV; p<0.001).[105]

Figure 3: Left Atrial Voltage Map.

Figure 3:

Voltage maps of a patient in persistent AF before ablation (posteroanterior and right anterior oblique views). Red corresponds to low voltage (<0.1 mV) and purple to normal voltage (>0.45 mV).

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Studies have shown that patients with persistent AF have a higher burden of low-voltage areas compared with those with paroxysmal AF.[106] Furthermore, these low-voltage areas can be directly targeted with radiofrequency (RF) ablation to perform substrate modification. This has been reported to improve ablation success rates.[106–108]

Patients with a higher burden of low-voltage areas found on pre-ablation mapping are more likely to have recurrence after ablation.[109–112] Vlachos et al. showed that patients with paroxysmal AF who have voltage less than 0.4 mV over more than 10% of the LA area were more likely to have recurrence after pulmonary vein isolation.[113]

Similar results were seen for both paroxysmal and persistent AF after ablation when using a cut-off of 0.5 mV (HR 5.89; 95% CI [2.16–16.0]; p=0.001).[114–116]

Low-voltage area burden has been associated with traditional thromboembolic risk factors such as age, female gender and LA surface area and volume.[110,117] The mean LA voltage is significantly lower in patients with higher CHA2DS2-VASc scores than in those with lower scores.[118] Furthermore, patients with a larger area of low voltage were more likely to have had previous stroke.[119]

Echocardiogram

Echocardiography allows for easy quantification of LA parameters such as diameter, area, volume, and volume index. These measurements can be used as an initial tool but they offer only a limited ability to predict the development of AF and recurrence after treatment.[120–122] Furthermore, LA diameter on M-mode echocardiography did not predict stroke (RR 1.02/mm; p=0.10).[123] Post-hoc analysis of the Atrial Fibrillation Follow-Up Investigation of Rhythm Management (AFFIRM) trial showed no association between LA size and the risk of stroke.[124] AF patients have also been found to have LA dysfunction despite normal size.[125] Therefore, current guidelines do not include LA size in the decision to start anticoagulation.[7]

Other echocardiographic markers are now being investigated. Diastolic early transmitral flow velocity/mitral annular velocity (E/E’; a noninvasive surrogate marker for LA end-diastolic pressure) has been found to correlate with low-voltage areas on mapping and recurrence after ablation.[126] Additional information that can be obtained from transoesophageal echocardiography include LAA velocity measured on Doppler and spontaneous echocardiographic contrast, which can be predictive of future LA thrombus formation.[127,128]

Speckle tracking echocardiography (STE) has been proposed as a noninvasive tool to better predict atrial fibrosis.[129] STE is a non-Doppler echocardiographic method to quantify atrial deformation by calculating both the atrial strain and longitudinal strain rate of atrial segments.[130]

Reduced atrial strain, as calculated using STE, has been correlated with reduced atrial compliance and increased fibrosis.[130] Furthermore, histological analysis of patients undergoing mitral valve surgery for severe mitral valve regurgitation found a high inverse correlation between peak longitudinal atrial strain and LA fibrosis (r= −0.82, p<0.001).[131]

LA strain correlates with the risk of both the development of new onset AF and recurrence after treatment. In a study of patients after ST-elevation MI, multivariate analysis showed global longitudinal strain to be an independent predictor of the development of AF (HR 1.12; 95% CI [1–1.25]; p=0.042, per 1% decrease).[132] Furthermore, when stratified into tertiles of longitudinal strain, patients in the lowest tertile had twice the risk as compared with the highest tertile (HR 2.10; 95% CI [1.04– 4.25]).[132] Patients with lower LA total strain and global strain were found to have a higher recurrence of AF after ablation (OR 0.81; 95% CI [0.73– 0.89]; p<0.0001).[133]

LA strain on STE correlates with the CHADS2 score.[134] Moreover, there was an improvement in the prediction of hospitalisation and mortality when LA strain and indexed LA volume were combined with the CHADS2 score (p=0.003).[134] In patients with permanent AF, peak strain had an independent negative correlation with prior stroke when controlling for age, LA volume index, and ejection fraction.[135] Overall, these examples of STE highlight the interplay between atrial fibrosis and AF given that lower strain has been consistently correlated with AF severity and morbidity.

Cardiac MRI

Delayed contrast-enhanced cardiac MRI (DE-cMRI) has been applied to the assessment of atrial fibrosis.[136] Although its use in the left ventricle for scar detection is widespread, it is much more challenging to apply to the atrium due to its thinner wall and the limited resolution of MRI.[130,137] Cardiac MRI is performed by analysing the distribution of gadolinium contrast agent 10–15 minutes after it is administered. In normal cardiac tissue, the contrast agent quickly washes out. However, in fibrotic tissue it accumulates in the ECM.[136,138] A positive correlation has been shown between areas of delayed enhancement and areas of low voltage in pre-ablation atrial mapping (r[2]=0.61).[139] A similar association between cardiac MRI and voltage mapping was seen by Spragg et al.[137] The Utah classification scheme has been proposed to quantify LA fibrosis using DE-cMRI. Based on this system, patients are assigned to 4 groups: Utah I, defined as ≤5% LA wall enhancement; Utah II, 5–20%; Utah III, 20–35%; and Utah IV, >35%. This schema has been shown to be useful in predicting recurrence of AF after catheter ablation in both lone AF and non-lone AF.[140,141]

The DE-MRI Determinant of Successful Radiofrequency Catheter Ablation of Atrial Fibrillation (DECAAF) study is a large multicentre prospective trial that analysed the ability of the Utah criteria to predict recurrence after ablation.[141] This study showed an independent association between MRI-detected atrial fibrosis and recurrent arrhythmia. The hazard ratio was 1.06 (95% CI [1.03–1.08]) for every 1% increase in LA fibrosis. Furthermore, cumulative incidence of recurrence after 325 days based on Utah score was 15.3% (95% CI [7.6–29.6%]) in Utah I, 32.6% (95% CI [24.3–42.9%]) in Utah II, 45.9% (95% CI [35.5– 57.5%]) in Utah III, and 51.1% (95% CI [32.8–72.2%]) in Utah IV (Figure 4).[141]

Figure 4: Stages of Left Atrial Tissue Fibrosis on Cardiac MRI.

Figure 4:

Cardiac MRI showing atrial fibrosis in four patients with increasing percentages of atrial fibrosis. Normal left atrial myocardium is shown in blue; fibrosis is represented by green. AP = anteroposterior; PA = posteroanterior. Source: Mahnkopf et al. 2010.[140] Reproduced with permission from Elsevier.

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Similar results have been found when using DE-cMRI to evaluate fibrosis to predict thromboembolic risk. A recent retrospective study of more than 1200 patients who had undergone DE-cMRI evaluated the association of Utah stage atrial fibrosis with cerebrovascular events. It found a significant association between higher late gadolinium enhancement and the rate of cerebrovascular events (HR 3.94; 95% CI [1.72–8.98]).[142] An additional analysis of the Utah dataset found that women had a higher rate of fibrosis than men (17.5% versus 15.3%; p<0.01) which may explain the increased stroke risk in women with AF (prior stroke prevalence 15.8% versus 6.5%; p<0.001).[143] Moreover, in a prospective study of 111 patients with ischemic stroke, patients with a cryptogenic stroke after extensive stroke workup were found to have a statistically significantly higher percentage of LA fibrosis than patients with a known cause excluding AF (LA fibrosis percentage: median 18%, IQR 16% versus median 10.5%, IQR 16%; p=0.03). Patients with an unknown cause had a similar percentage of fibrosis compared with those with AF as cause (median 18%, IQR 16% versus median 25%, IQR 21%; p=0.22).[144]

Additionally, 4D flow cardiac MRI, in which 3D images are processed over time, allows for the quantification of LA velocities.[145] Subjects with AF had lower velocities than age-matched controls, and those imaged in AF had lower velocities than AF patients imaged in sinus rhythm.[145] While not a direct assessment of fibrosis, 4D flow MRI provides a surrogate index for the extent of the atrial myopathy. Reduced LA velocities have been associated with increased stasis and increased CHA2DS2-VASc score (p<0.043).[146–148]

Future directions for cMRI include 3D segmentation, quantification, and visualisation of LA fibrosis and T1 mapping of the LA to measure extracellular volume as a surrogate marker for LA fibrosis.[149,150] However, further research needs to be done to validate these techniques and their clinical utility (Table 1).

Table 1: Summary of Suggested Methods to Assess Atrial Myopathy.

ECG:

  • Sinus rhythm: P terminal force in V1

  • AF: f wave amplitude

  • AF: frequency analysis of f waves

 Biomarkers:

  • CRP

  • Interleukin-6

  • Troponin

  • NT-proBNP

  • TGF-beta1

 Electroanatomical voltage mapping:

  • Voltage

 Echocardiogram:

  • Left atrial dimension/volume

  • Left atrial appendage velocity

  • Left atrial strain

 Cardiac MRI:

  • DE-cMRI

  • 4D flow
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CRP = C-reactive protein; DE-cMRI = delayed contrast-enhanced cardiac MRI; NT-proBNP = N-terminal pro-B-type natriuretic peptide; TGF = transforming growth factor.

Guiding Therapies to Target Fibrosis

Current therapies such as anti-arrhythmic drugs and catheter ablation do not target the atrial myopathy that serves as the substrate for AF. Although catheter ablation of the pulmonary veins has a Class I indication for symptomatic AF,[7] extensive RF ablation generates additional scar in the atrium. While this scar tissue may remove arrhythmogenic areas, new extensive scarring may have untoward effects. Patients after RF ablation often have decreased LA area and volume, which may be the result of scar formation with resultant decreased compliance.[151,152] Alternatively, this may be due to reverse remodelling of the atrial myopathy. Using cardiac MRI, a correlation was seen between both the number of ablation procedures (r=0.58, p=0.002) and RF duration with the degree of post-ablation atrial scar (r=0.56, p=0.003). Additionally, post-ablation LA scar was negatively correlated with LA compliance and active LA ejection fraction.[153] Similar findings were seen in a study by Wylie et al.[154] Those authors concluded that scar will lead to a further decrease in LA compliance, which can lead to “stiff LA” syndrome.[154]

Conversely, prevention of progression and even regression of atrial myopathy has been reported after catheter ablation. There has been some evidence of atrial remodelling following catheter ablation in patients with baseline cardiomyopathies. In a subset of patients from the Catheter Ablation Versus Medical Rate Control in Atrial Fibrillation and Systolic Dysfunction (CAMERA-MRI) study, repeat electroanatomical mapping after pulmonary vein and posterior wall isolation by ablation showed an increase in right atrial voltage on repeat electroanatomical mapping at a mean time of 23.4 months after index ablation (from 1.6 mV ± 0.1 mV to 1.9 ± 0.1 mV; p=0.04). This along with reduction in atrial size and complex fractionated electrograms (21.7 ± 3.5% to 8.3 ± 1.8%; p=0.002) may indicate possible reversal of the atrial myopathy.[155] This reverse remodelling may be the result of maintenance of sinus rhythm after ablation.

There are preliminary results suggesting that therapies such as weight loss, angiotensin receptor blockers, aldosterone inhibitors, and statins may be able to reduce fibrosis to prevent and decrease AF burden.[156–161] For example, patients treated with angiotensin II receptor antagonists were found to have lower levels of TGF-beta1 than those not treated.[162] Clinically, the Routine Versus Aggressive Upstream Rhythm Control for Prevention of Early Atrial Fibrillation in Heart Failure (RACE III) trial randomised patients with persistent AF and mild–moderate heart failure to aldosterone antagonist, ACE inhibitors, statins, and cardiac rehab versus conventional therapy. At 1 year, sinus rhythm was present in 75% of the intervention group compared with 63% in the control group (OR 1.765; p=0.042).[163] There was also a decrease in markers of myopathy such as NT-proBNP. Similarly, in the Eplerenone in Mild Patients Hospitalization And SurvIval Study in Heart Failure (EMPHASISHF) trial, patients with systolic heart failure randomised to eplerenone had decreased incidence of new-onset AF (2.7% versus 4.5%; HR 0.58; 95% CI [0.35–0.96]; p=0.034).[164] Eplerenone has been shown in the sheep model to reduce atrial fibrosis and dilation, AF inducibility, and progression to persistent AF without preventing AF-induced electrical remodelling.[72] In the Aggressive Risk Factor Reduction Study for Atrial Fibrillation and Implications for the Outcome of Ablation (ARREST-AF), patients were randomised to risk factor modification guidelines as recommended by the American Heart Association/American College of Cardiology (AHA/ACC) versus conventional care. The treatment arm had an increase in arrhythmia-free survival rates as compared with the control (32.9% versus 9.7%; p<0.001) with HR of 2.3 (p<0.001). While the mechanism is unclear, improvements in atrial volume on echocardiography suggest that it may be due to reversal of the underlying cardiomyopathy.[165] As a result, the latest ACC/AHA guidelines for AF recommend weight loss in obese patients with a Class I indication.[7] Additionally, Kunamalla et al. demonstrated the use of targeted gene-based reduction of TGF-beta signalling to decrease fibrosis and AF in the canine model.[166] Other potential targets of gene therapy include modification of ion channels, gap junctions, autonomic innervation, and fibrosis.[167]

Conclusion

This review highlights the complex interplay between atrial myopathy and AF incidence, recurrence, burden, and stroke risk. Atrial myopathy consists of multiple changes to the atrium including increased fibrosis, pressure overload, autonomic derangement, endothelial dysfunction, and alterations in prothrombotic factors. While there are currently multiple modalities to assess atrial myopathy, they are not being utilised routinely when making decisions regarding therapy including anticoagulation. The additional use of these modalities may allow us to better predict outcomes and tailor therapy. Creating novel therapies that address inflammation, EAT, the autonomic nervous system and molecular pathways of atrial fibrosis are an exciting new paradigm for future AF treatment. Reducing and even reversing atrial myopathy may serve as a more durable method to treat AF and reduce its significant morbidity. Further research is needed to develop these novel strategies to address atrial fibrosis as the precursor to atrial myopathy, AF, and cardioembolic stroke.

Clinical Perspective

  • AF and atrial myopathy form a complex cycle in which each contributes to the other

  • Current risk stratification schema and management strategies do not consider the underlying myopathy of AF

  • By identifying atrial myopathy, we may be able to better risk stratify and treat patients with AF.

References

  • 1.Colilla S, Crow A, Petkun W et al. Estimates of current and future incidence and prevalence of atrial fibrillation in the U.S. adult population. Am J Cardiol. 2013;112:1142–7. doi: 10.1016/j.amjcard.2013.05.063. [DOI] [PubMed] [Google Scholar]
  • 2.Chugh SS, Havmoeller R, Narayanan K et al. Worldwide epidemiology of atrial fibrillation: a global burden of disease 2010 study. Circulation. 2014;129:837–47. doi: 10.1161/CIRCULATIONAHA.113.005119. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3.Morillo CA, Banerjee A, Perel P et al. Atrial fibrillation: the current epidemic. J Geriatr Cardiol. 2017;14:195–203. doi: 10.11909/j.issn.1671-5411.2017.03.011. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4.Sankaranarayanan R, Kirkwood G, Visweswariah R et al. How does chronic atrial fibrillation influence mortality in the modern treatment era? Curr Cardiol Rev. 2015;11:190–8. doi: 10.2174/1573403X10666140902143020. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5.Thrall G, Lane D, Carroll D et al. Quality of life in patients with atrial fibrillation: a systematic review. Am J Med. 2006;119:448e1–19. doi: 10.1016/j.amjmed.2005.10.057. [DOI] [PubMed] [Google Scholar]
  • 6.Reiffel JA. If it were only that simple. Eur Heart J. 2016;37:1603–5. doi: 10.1093/eurheartj/ehw014. [DOI] [PubMed] [Google Scholar]
  • 7.January CT, Wann LS, Calkins H et al. 2019 AHA/ACC/HRS focused update of the 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society in collaboration with the Society of Thoracic Surgeons. Circulation. 2019;140:e125–51. doi: 10.1161/CIR.0000000000000665. [DOI] [PubMed] [Google Scholar]
  • 8.Lip GYH, Nieuwlaat R, Pisters R et al. Refining clinical risk stratification for predicting stroke and thromboembolism in atrial fibrillation using a novel risk factor-based approach: the Euro Heart Survey on Atrial Fibrillation. Chest. 2010;137:263–72. doi: 10.1378/chest.09-1584. [DOI] [PubMed] [Google Scholar]
  • 9.Kallergis EM, Goudis CA, Vardas PE. Atrial fibrillation: a progressive atrial myopathy or a distinct disease? Int J Cardiol. 2014;171:126–33. doi: 10.1016/j.ijcard.2013.12.009. [DOI] [PubMed] [Google Scholar]
  • 10.Goldberger JJ, Arora R, Green D et al. Evaluating the atrial myopathy underlying atrial fibrillation: identifying the arrhythmogenic and thrombogenic substrate. Circulation. 2015;132:278–91. doi: 10.1161/CIRCULATIONAHA.115.016795. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11.Rockey DC, Bell PD, Hill JA. Fibrosis: a common pathway to organ injury and failure. N Engl J Med. 2015;372:1138–49. doi: 10.1056/NEJMra1300575. [DOI] [PubMed] [Google Scholar]
  • 12.Wynn TA. Cellular and molecular mechanisms of fibrosis. J Pathol. 2008;214:199–210. doi: 10.1002/path.2277. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13.Frangogiannis NG. Regulation of the inflammatory response in cardiac repair. Circ Res. 2012;110:159–73. doi: 10.1161/CIRCRESAHA.111.243162. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14.Burchfield JS, Xie M, Hill JA. Pathological ventricular remodeling: mechanisms: part 1 of 2. Circulation. 2013;128:388–400. doi: 10.1161/CIRCULATIONAHA.113.001878. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15.Hill JA, Olson EN. Cardiac plasticity. N Engl J Med. 2008;358:1370–80. doi: 10.1056/NEJMra072139. [DOI] [PubMed] [Google Scholar]
  • 16.Kong P, Christia P, Frangogiannis NG. The pathogenesis of cardiac fibrosis. Cell Mol Life Sci. 2014;71:549–74. doi: 10.1007/s00018-013-1349-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17.He X, Zhang K, Gao X et al. Rapid atrial pacing induces myocardial fibrosis by down-regulating Smad7 via microRNA-21 in rabbit. Heart Vessels. 2016;31:1696–1708. doi: 10.1007/s00380-016-0808-z. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18.Gramley F, Lorenzen J, Koellensperger E et al. Atrial fibrosis and atrial fibrillation: the role of the TGF-β1 signaling pathway. Int J Cardiol. 2010;143:405–13. doi: 10.1016/j.ijcard.2009.03.110. [DOI] [PubMed] [Google Scholar]
  • 19.Xiao HD, Fuchs S, Campbell DJ et al. Mice with cardiacrestricted angiotensin-converting enzyme (ACE) have atrial enlargement, cardiac arrhythmia, and sudden death. Am J Pathol. 2004;165:1019–32. doi: 10.1016/S0002-9440(10)63363-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20.Burstein B, Nattel S. Atrial fibrosis: mechanisms and clinical relevance in atrial fibrillation. J Am Coll Cardiol. 2008;51:802–9. doi: 10.1016/j.jacc.2007.09.064. [DOI] [PubMed] [Google Scholar]
  • 21.Burstein B, Qi X-Y, Yeh Y-H et al. Atrial cardiomyocyte tachycardia alters cardiac fibroblast function: a novel consideration in atrial remodeling. Cardiovasc Res. 2007;76:442–52. doi: 10.1016/j.cardiores.2007.07.013. [DOI] [PubMed] [Google Scholar]
  • 22.Wang TJ, Parise H, Levy D et al. Obesity and the risk of newonset atrial fibrillation. JAMA. 2004;292:2471–7. doi: 10.1001/jama.292.20.2471. [DOI] [PubMed] [Google Scholar]
  • 23.Frost L, Hune LJ, Vestergaard P. Overweight and obesity as risk factors for atrial fibrillation or flutter: the Danish diet, cancer, and health study. Am J Med. 2005;118:489–95. doi: 10.1016/j.amjmed.2005.01.031. [DOI] [PubMed] [Google Scholar]
  • 24.Magnani JW, Hylek EM, Apovian CM. Obesity begets atrial fibrillation: a contemporary summary. Circulation. 2013;128:401–5. doi: 10.1161/CIRCULATIONAHA.113.001840. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 25.Wong CX, Mahajan R, Pathak R et al. the role of pericardial and epicardial fat in atrial fibrillation pathophysiology and ablation outcomes. J Atr Fibrillation. 2013;5:790. doi: 10.4022/jafib.790. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 26.Hatem SN, Sanders P. Epicardial adipose tissue and atrial fibrillation. Cardiovasc Res. 2014;102:205–13. doi: 10.1093/cvr/cvu045. [DOI] [PubMed] [Google Scholar]
  • 27.Mazurek T, Zhang L, Zalewski A et al. Human epicardial adipose tissue is a source of inflammatory mediators. Circulation. 2003;108:2460–6. doi: 10.1161/01.CIR.0000099542.57313.C5. [DOI] [PubMed] [Google Scholar]
  • 28.Venteclef N, Guglielmi V, Balse E et al. Human epicardial adipose tissue induces fibrosis of the atrial myocardium through the secretion of adipo-fibrokines. Eur Heart J. 2015;36:795–805. doi: 10.1093/eurheartj/eht099. [DOI] [PubMed] [Google Scholar]
  • 29.Zuk PA, Zhu M, Mizuno H et al. multilineage cells from human adipose tissue: implications for cell-based therapies. Tissue Eng. 2001;7:211–28. doi: 10.1089/107632701300062859. [DOI] [PubMed] [Google Scholar]
  • 30.Shin SY, Yong HS, Lim HE et al. Total and interatrial epicardial adipose tissues are independently associated with left atrial remodeling in patients with atrial fibrillation. J Cardiovasc Electrophysiol. 2011;22:647–55. doi: 10.1111/j.1540-8167.2010.01993.x. [DOI] [PubMed] [Google Scholar]
  • 31.Mahajan R, Nelson A, Pathak RK et al. Electroanatomical remodeling of the atria in obesity. JACC Clin Electrophysiol. 2018;4:1529–40. doi: 10.1016/j.jacep.2018.08.014. [DOI] [PubMed] [Google Scholar]
  • 32.Tsao H-M, Hu W-C, Wu M-H et al. Quantitative analysis of quantity and distribution of epicardial adipose tissue surrounding the left atrium in patients with atrial fibrillation and effect of recurrence after ablation. Am J Cardiol. 2011;107:1498–1503. doi: 10.1016/j.amjcard.2011.01.027. [DOI] [PubMed] [Google Scholar]
  • 33.Chao T-F, Hung C-L, Tsao H-M et al. Epicardial adipose tissue thickness and ablation outcome of atrial fibrillation. PLoS One. 2013;8:e74926. doi: 10.1371/journal.pone.0074926. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 34.Maeda M, Oba K, Yamaguchi S et al. Usefulness of epicardial adipose tissue volume to predict recurrent atrial fibrillation after radiofrequency catheter ablation. Am J Cardiol. 2018;122:1694–1700. doi: 10.1016/j.amjcard.2018.08.005. [DOI] [PubMed] [Google Scholar]
  • 35.Sepehri Shamloo A, Dagres N, Dinov B et al. Is epicardial fat tissue associated with atrial fibrillation recurrence after ablation? A systematic review and meta-analysis. Int J Cardiol Heart Vasc. 2019;22:132–8. doi: 10.1016/j.ijcha.2019.01.003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 36.Tsao H-M, Hu W-C, Tsai P-H et al. The abundance of epicardial adipose tissue surrounding left atrium is associated with the occurrence of stroke in patients with atrial fibrillation. Medicine. 2016;95:e3260. doi: 10.1097/MD.0000000000003260. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 37.Arora R, Ng J, Ulphani J et al. Unique autonomic profile of the pulmonary veins and posterior left atrium. J Am Coll Cardiol. 2007;49:1340–8. doi: 10.1016/j.jacc.2006.10.075. [DOI] [PubMed] [Google Scholar]
  • 38.Arora R. Recent insights into the role of the autonomic nervous system in the creation of substrate for atrial fibrillation: implications for therapies targeting the atrial autonomic nervous system. Circ Arrhythm Electrophysiol. 2012;5:850–9. doi: 10.1161/CIRCEP.112.972273. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 39.Shen MJ, Arora R, Jalife J. Atrial myopathy. JACC Basic Transl Sci. 2019;4:640–54. doi: 10.1016/j.jacbts.2019.05.005. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 40.Goette A, Kalman JM, Aguinaga L et al. EHRA/HRS/APHRS/SOLAECE expert consensus on atrial cardiomyopathies: definition, characterisation, and clinical implication. J Arrhythm. 2016;32:247–78. doi: 10.1016/j.joa.2016.05.002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 41.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. JACC Clin Electrophysiol. 2017;3:461–9. doi: 10.1016/j.jacep.2016.12.010. [DOI] [PubMed] [Google Scholar]
  • 42.Ogunsua AA, Shaikh AY, Ahmed M, McManus DD. Atrial fibrillation and hypertension: mechanistic, epidemiologic, and treatment parallels. Methodist Debakey Cardiovasc J. 2015;11:228–34. doi: 10.14797/mdcj-11-4-228. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 43.Boyd AC, McKay T, Nasibi S et al. Left ventricular mass predicts left atrial appendage thrombus in persistent atrial fibrillation. Eur Heart J Cardiovasc Imaging. 2013;14:269–75. doi: 10.1093/ehjci/jes153. [DOI] [PubMed] [Google Scholar]
  • 44.Truelsen T, Lindenstrøm E, Boysen G. Comparison of probability of stroke between the Copenhagen City Heart Study and the Framingham Study. Stroke. 1994;25:802–7. doi: 10.1161/01.STR.25.4.802. [DOI] [PubMed] [Google Scholar]
  • 45.Kirchhof P, Breithardt G, Aliot E et al. Personalized management of atrial fibrillation: proceedings from the Fourth Atrial Fibrillation Competence NETwork/European Heart Rhythm Association Consensus Conference. Europace. 2013;15:1540–56. doi: 10.1093/europace/eut232. [DOI] [PubMed] [Google Scholar]
  • 46.Novo G, Guttilla D, Fazio G et al. The role of the reninangiotensin system in atrial fibrillation and the therapeutic effects of ACE-Is and ARBS. Br J Clin Pharmacol. 2008;66:345–51. doi: 10.1111/j.1365-2125.2008.03234.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 47.Bohne LJ, Johnson D, Rose RA et al. The association between diabetes mellitus and atrial fibrillation: clinical and mechanistic insights. Front Physiol. 2019;10:135. doi: 10.3389/fphys.2019.00135. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 48.Chao T-F, Suenari K, Chang S-L et al. Atrial substrate properties and outcome of catheter ablation in patients with paroxysmal atrial fibrillation associated with diabetes mellitus or impaired fasting glucose. Am J Cardiol. 2010;106:1615–20. doi: 10.1016/j.amjcard.2010.07.038. [DOI] [PubMed] [Google Scholar]
  • 49.Sajeev JK, Kalman JM, Dewey H et al. The atrium and embolic stroke: myopathy not atrial fibrillation as the requisite determinant? JACC Clin Electrophysiol. 2020;6:251–61. doi: 10.1016/j.jacep.2019.12.013. [DOI] [PubMed] [Google Scholar]
  • 50.Goette A, Hammwohner M, Bukowska A et al. The impact of rapid atrial pacing on ADMA and endothelial NOS. Int J Cardiol. 2012;154:141–6. doi: 10.1016/j.ijcard.2010.09.004. [DOI] [PubMed] [Google Scholar]
  • 51.Willeit P, Freitag DF, Laukkanen JA et al. Asymmetric dimethylarginine and cardiovascular risk: systematic review and meta-analysis of 22 prospective studies. J Am Heart Assoc. 2016;4:e001833. doi: 10.1161/JAHA.115.001833. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 52.Scridon A, Girerd N, Rugeri L et al. Progressive endothelial damage revealed by multilevel von Willebrand factor plasma concentrations in atrial fibrillation patients. Europace. 2013;15:1562–6. doi: 10.1093/europace/eut121. [DOI] [PubMed] [Google Scholar]
  • 53.Wieberdink RG, van Schie MC, Koudstaal PJ et al. High von Willebrand factor levels increase the risk of stroke. Stroke. 2010;41:2151–6. doi: 10.1161/STROKEAHA.110.586289. [DOI] [PubMed] [Google Scholar]
  • 54.Spach MS, Boineau JP. Microfibrosis produces electrical load variations due to loss of side-to-side cell connections: a major mechanism of structural heart disease arrhythmias. Pacing Clin Electrophysiol. 1997;20:397–413. doi: 10.1111/j.1540-8159.1997.tb06199.x. [DOI] [PubMed] [Google Scholar]
  • 55.Miragoli M, Gaudesius G, Rohr S. Electrotonic modulation of cardiac impulse conduction by myofibroblasts. Circ Res. 2006;98:801–10. doi: 10.1161/01.RES.0000214537.44195.a3. [DOI] [PubMed] [Google Scholar]
  • 56.Miragoli M, Salvarani N, Rohr S. Myofibroblasts induce ectopic activity in cardiac tissue. Circ Res. 2007;101:755–8. doi: 10.1161/CIRCRESAHA.107.160549. [DOI] [PubMed] [Google Scholar]
  • 57.Verheule S, Sato T. Everett T 4th, et al Increased vulnerability to atrial fibrillation in transgenic mice with selective atrial fibrosis caused by overexpression of TGF-beta1. Circ Res. 2004;94:1458–65. doi: 10.1161/01.RES.0000129579.59664.9d. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 58.Polejaeva IA, Ranjan R, Davies CJ et al. Increased susceptibility to atrial fibrillation secondary to atrial fibrosis in transgenic goats expressing transforming growth factor-β1. J Cardiovasc Electrophysiol. 2016;27:1220–9. doi: 10.1111/jce.13049. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 59.Li D, Fareh S, Leung TK et al. Promotion of atrial fibrillation by heart failure in dogs: atrial remodeling of a different sort. Circulation. 1999;100:87–95. doi: 10.1161/01.CIR.100.1.87. [DOI] [PubMed] [Google Scholar]
  • 60.de Jong S, van Veen TAB, van Rijen HVM et al. Fibrosis and cardiac arrhythmias. J Cardiovasc Pharmacol. 2011;57:630–8. doi: 10.1097/FJC.0b013e318207a35f. [DOI] [PubMed] [Google Scholar]
  • 61.Platonov PG. Atrial fibrosis: an obligatory component of arrhythmia mechanisms in atrial fibrillation? J Geriatr Cardiol. 2017;14:233–7. doi: 10.11909/j.issn.1671-5411.2017.04.008. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 62.Honarbakhsh S, Schilling RJ, Orini M et al. Structural remodeling and conduction velocity dynamics in the human left atrium: relationship with reentrant mechanisms sustaining atrial fibrillation. Heart Rhythm. 2019;16:18–25. doi: 10.1016/j.hrthm.2018.07.019. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 63.Markowitz SM, Thomas G, Liu CF et al. Atrial tachycardias and atypical atrial flutters: mechanisms and approaches to ablation. Arrhythm Electrophysiol Rev. 2019;8:131–7. doi: 10.15420/aer.2019.17.2. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 64.Hu Y-F, Chen Y-J, Lin Y-J et al. Inflammation and the pathogenesis of atrial fibrillation. Nat Rev Cardiol. 2015;12:230–43. doi: 10.1038/nrcardio.2015.2. [DOI] [PubMed] [Google Scholar]
  • 65.Haemers P, Hamdi H, Guedj K et al. Atrial fibrillation is associated with the fibrotic remodelling of adipose tissue in the subepicardium of human and sheep atria. Eur Heart J. 2017;38:53–61. doi: 10.1093/eurheartj/ehv625. [DOI] [PubMed] [Google Scholar]
  • 66.Platonov PG, Mitrofanova LB, Orshanskaya V et al. Structural abnormalities in atrial walls are associated with presence and persistency of atrial fibrillation but not with age. J Am Coll Cardiol. 2011;58:2225–32. doi: 10.1016/j.jacc.2011.05.061. [DOI] [PubMed] [Google Scholar]
  • 67.Lenaerts I, Bito V, Heinzel FR et al. Ultrastructural and functional remodeling of the coupling between Ca2+ influx and sarcoplasmic reticulum Ca2+ release in right atrial myocytes from experimental persistent atrial fibrillation. Circ Res. 2009;105:876–85. doi: 10.1161/CIRCRESAHA.109.206276. [DOI] [PubMed] [Google Scholar]
  • 68.Morillo CA, Klein GJ, Jones DL et al. Chronic rapid atrial pacing. Structural, functional, and electrophysiological characteristics of a new model of sustained atrial fibrillation. Circulation. 1995;91:1588–95. doi: 10.1161/01.CIR.91.5.1588. [DOI] [PubMed] [Google Scholar]
  • 69.Frustaci A, Chimenti C, Bellocci F et al. Histological substrate of atrial biopsies in patients with lone atrial fibrillation. Circulation. 1997;96:1180–4. doi: 10.1161/01.CIR.96.4.1180. [DOI] [PubMed] [Google Scholar]
  • 70.Kostin S, Klein G, Szalay Z et al. Structural correlate of atrial fibrillation in human patients. Cardiovasc Res. 2002;54:361–79. doi: 10.1016/S0008-6363(02)00273-0. [DOI] [PubMed] [Google Scholar]
  • 71.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. Heart. 2004;90:400–5. doi: 10.1136/hrt.2003.015347. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 72.Takemoto Y, Ramirez RJ, Kaur K et al. Eplerenone reduces atrial fibrillation burden without preventing atrial electrical remodeling. J Am Coll Cardiol. 2017;70:2893–905. doi: 10.1016/j.jacc.2017.10.014. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 73.Wijffels MC, Kirchhof CJ, Dorland R et al. Atrial fibrillation begets atrial fibrillation. A study in awake chronically instrumented goats. Circulation. 1995;92:1954–68. doi: 10.1161/01.CIR.92.7.1954. [DOI] [PubMed] [Google Scholar]
  • 74.Reiffel JA. The interaction among atrial thromboembolism, atrial fibrillation, and atrial cardiomyopathy. Am J Cardiol. 2019;124:1317. doi: 10.1016/j.amjcard.2019.07.037. [DOI] [PubMed] [Google Scholar]
  • 75.Hazen MS, Marwick TH, Underwood DA. Diagnostic accuracy of the resting electrocardiogram in detection and estimation of left atrial enlargement: an echocardiographic correlation in 551 patients. Am Heart J. 1991;122:823–8. doi: 10.1016/0002-8703(91)90531-L. [DOI] [PubMed] [Google Scholar]
  • 76.Hancock EW, Deal BJ, Mirvis DM et al. AHA/ACCF/HRS recommendations for the standardization and interpretation of the electrocardiogram. Part V: electrocardiogram changes associated with cardiac chamber hypertrophy: a scientific statement from the American Heart Association Electrocardiography and Arrhythmias Committee, Council on Clinical Cardiology; the American College of Cardiology Foundation; and the Heart Rhythm Society: endorsed by the International Society for Computerized Electrocardiology. Circulation. 2009;119:e251–61. doi: 10.1161/CIRCULATIONAHA.108.191097. [DOI] [PubMed] [Google Scholar]
  • 77.Eranti A, Aro AL, Kerola T et al. Prevalence and prognostic significance of abnormal P terminal force in lead V1 of the ECG in the general population. Circ Arrhythm Electrophysiol. 2014;7:1116–21. doi: 10.1161/CIRCEP.114.001557. [DOI] [PubMed] [Google Scholar]
  • 78.Ishida K, Hayashi H, Miyamoto A et al. P Wave and the development of atrial fibrillation. Heart Rhythm. 2010;7:289–94. doi: 10.1016/j.hrthm.2009.11.012. [DOI] [PubMed] [Google Scholar]
  • 79.Kamel H, Hunter M, Moon YP et al. Electrocardiographic left atrial abnormality and risk of stroke: Northern Manhattan Study. Stroke. 2015;46:3208–12. doi: 10.1161/STROKEAHA.115.009989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 80.Goda T, Sugiyama Y, Ohara N et al. P-wave terminal force in lead V1 predicts paroxysmal atrial fibrillation in acute ischemic stroke. J Stroke Cerebrovasc Dis. 2017;26:1912–5. doi: 10.1016/j.jstrokecerebrovasdis.2017.06.031. [DOI] [PubMed] [Google Scholar]
  • 81.Salah A, Zhou S, Liu Q et al. P wave indices to predict atrial fibrillation recurrences post pulmonary vein isolation. Arq Bras Cardiol. 2013;101:519–27. doi: 10.5935/abc.20130214. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 82.Aysha MH, Hassan AS. Diagnostic importance of fibrillatory wave amplitude: a clue to echocardiographic left atrial size and etiology of atrial fibrillation. J Electrocardiol. 1988;21:247–51. doi: 10.1016/0022-0736(88)90099-4. [DOI] [PubMed] [Google Scholar]
  • 83.Li YH, Hwang JJ, Tseng YZ et al. Clinical significance of fibrillatory wave amplitude. A clue to left atrial appendage function in nonrheumatic atrial fibrillation. Chest. 1995;108:359–63. doi: 10.1378/chest.108.2.359. [DOI] [PubMed] [Google Scholar]
  • 84.Al Aloul B, Adabag AS, Can I et al. Electrocardiographic markers of cardioversion success in patients with atrial fibrillation. South Med J. 2009;102:885–9. doi: 10.1097/SMJ.0b013e3181afe5ef. [DOI] [PubMed] [Google Scholar]
  • 85.Bollmann A, Husser D, Mainardi L et al. Analysis of surface electrocardiograms in atrial fibrillation: techniques, research, and clinical applications. Europace. 2006;8:911–26. doi: 10.1093/europace/eul113. [DOI] [PubMed] [Google Scholar]
  • 86.Raygor VP, Ng J, Goldberger JJ. Surface ECG F wave analysis of dofetilide drug effect in the atrium. J Cardiovasc Electrophysiol. 2015;26:644–8. doi: 10.1111/jce.12645. [DOI] [PubMed] [Google Scholar]
  • 87.Xi Q, Sahakian AV, Frohlich TG et al. Relationship between pattern of occurrence of atrial fibrillation and surface electrocardiographic fibrillatory wave characteristics. Heart Rhythm. 2004;1:656–63. doi: 10.1016/j.hrthm.2004.09.010. [DOI] [PubMed] [Google Scholar]
  • 88.Sharma P, Barrett TW, Ng J et al. Surface ECG F wave analysis at initial onset of paroxysmal and persistent atrial fibrillation. J Cardiovasc Electrophysiol. 2017;28:498–503. doi: 10.1111/jce.13188. [DOI] [PubMed] [Google Scholar]
  • 89.Dernellis J, Panaretou M. Effect of C-reactive protein reduction on paroxysmal atrial fibrillation. Am Heart J. 2005;150:1064. doi: 10.1016/j.ahj.2005.06.032. [DOI] [PubMed] [Google Scholar]
  • 90.Marcus GM, Whooley MA, Glidden DV et al. Interleukin-6 and atrial fibrillation in patients with coronary artery disease: data from the Heart and Soul Study. Am Heart J. 2008;155:303–9. doi: 10.1016/j.ahj.2007.09.006. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 91.Patton KK, Ellinor PT, Heckbert SR et al. N-terminal pro-B-type natriuretic peptide is a major predictor of the development of atrial fibrillation: the Cardiovascular Health Study. Circulation. 2009;120:1768–74. doi: 10.1161/CIRCULATIONAHA.109.873265. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 92.Smith JG, Newton-Cheh C, Almgren P et al. Assessment of conventional cardiovascular risk factors and multiple biomarkers for the prediction of incident heart failure and atrial fibrillation. J Am Coll Cardiol. 2010;56:1712–9. doi: 10.1016/j.jacc.2010.05.049. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 93.Tian Y, Wang Y, Chen W et al. Role of serum TGF-β1 level in atrial fibrosis and outcome after catheter ablation for paroxysmal atrial fibrillation. Medicine. 2017;96:e9210. doi: 10.1097/MD.0000000000009210. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 94.Heinzmann D, Fus S, Ungern-Sternberg SV et al. TGFβ is specifically upregulated on circulating CD14++ CD16+ and CD14+ CD16++ monocytes in patients with atrial fibrillation and severe atrial fibrosis. Cell Physiol Biochem. 2018;49:226–34. doi: 10.1159/000492873. [DOI] [PubMed] [Google Scholar]
  • 95.Wu C-H, Hu Y-F, Chou C-Y et al. Transforming growth factor-β1 level and outcome after catheter ablation for nonparoxysmal atrial fibrillation. Heart Rhythm. 2013;10:10–15. doi: 10.1016/j.hrthm.2012.09.016. [DOI] [PubMed] [Google Scholar]
  • 96.Kishima H, Mine T, Takahashi S et al. The impact of transforming growth factor-β1 level on outcome after catheter ablation in patients with atrial fibrillation. J Cardiovasc Electrophysiol. 2017;28:402–9. doi: 10.1111/jce.13169. [DOI] [PubMed] [Google Scholar]
  • 97.Malouf JF, Kanagala R, Al Atawi FO et al. High sensitivity C-reactive protein: a novel predictor for recurrence of atrial fibrillation after successful cardioversion. J Am Coll Cardiol. 2005;46:1284–7. doi: 10.1016/j.jacc.2005.06.053. [DOI] [PubMed] [Google Scholar]
  • 98.Goette A, Hoffmanns P, Enayati W et al. Effect of successful electrical cardioversion on serum aldosterone in patients with persistent atrial fibrillation. Am J Cardiol. 2001;88:906–9 A8. doi: 10.1016/S0002-9149(01)01905-1. [DOI] [PubMed] [Google Scholar]
  • 99.Wozakowska-Kaplon B, Bartkowiak R, Janiszewska G. A decrease in serum aldosterone level is associated with maintenance of sinus rhythm after successful cardioversion of atrial fibrillation: aldosterone in atrial fibrillation. Pacing Clin Electrophysiol. 2010;33:561–5. doi: 10.1111/j.1540-8159.2009.02673.x. [DOI] [PubMed] [Google Scholar]
  • 100.Hijazi Z, Oldgren J, Siegbahn A et al. Application of biomarkers for risk stratification in patients with atrial fibrillation. Clin Chem. 2017;63:152–64. doi: 10.1373/clinchem.2016.255182. [DOI] [PubMed] [Google Scholar]
  • 101.Ravassa S, Ballesteros G, Lopez B et al. Combination of circulating type I collagen-related biomarkers is associated with atrial fibrillation. J Am Coll Cardiol. 2019;73:1398–1410. doi: 10.1016/j.jacc.2018.12.074. [DOI] [PubMed] [Google Scholar]
  • 102.Oldgren J, Hijazi Z, Lindback J et al. Performance and validation of a novel biomarker-based stroke risk score for atrial fibrillation. Circulation. 2016;134:1697–1707. doi: 10.1161/CIRCULATIONAHA.116.022802. [DOI] [PubMed] [Google Scholar]
  • 103.Sanders P, Morton JB, Davidson NC et al. Electrical remodeling of the atria in congestive heart failure: electrophysiological and electroanatomic mapping in humans. Circulation. 2003;108:1461–8. doi: 10.1161/01.CIR.0000090688.49283.67. [DOI] [PubMed] [Google Scholar]
  • 104.Rodriguez-Manero M, Valderrabano M, Baluja A et al. Validating left atrial low voltage areas during atrial fibrillation and atrial flutter using multielectrode automated electroanatomic mapping. JACC Clin Electrophysiol. 2018;4:1541–52. doi: 10.1016/j.jacep.2018.08.015. [DOI] [PubMed] [Google Scholar]
  • 105.Stiles MK, John B, Wong CX et al. Paroxysmal lone atrial fibrillation is associated with an abnormal atrial substrate: characterizing the “second factor”. J Am Coll Cardio. 2009;53:1182–91. doi: 10.1016/j.jacc.2008.11.054. [DOI] [PubMed] [Google Scholar]
  • 106.Rolf S, Kircher S, Arya A et al. Tailored atrial substrate modification based on low-voltage areas in catheter ablation of atrial fibrillation. Circ Arrhythm Electrophysiol. 2014;7:825–33. doi: 10.1161/CIRCEP.113.001251. [DOI] [PubMed] [Google Scholar]
  • 107.Kottkamp H, Schreiber D, Moser F et al. Therapeutic approaches to atrial fibrillation ablation targeting atrial fibrosis. JACC Clin Electrophysiol. 2017;3:643–53. doi: 10.1016/j.jacep.2017.05.009. [DOI] [PubMed] [Google Scholar]
  • 108.Zhou W, Wang L, Zhou B et al. Catheter ablation of paroxysmal atrial fibrillation using high-density mapping-guided substrate modification. Pacing Clin Electrophysiol. 2018;41:1630–4. doi: 10.1111/pace.13524. [DOI] [PubMed] [Google Scholar]
  • 109.Verma A, Wazni OM, Marrouche NF et al. Pre-existent left atrial scarring in patients undergoing pulmonary vein antrum isolation: an independent predictor of procedural failure. J Am Coll Cardiol. 2005;45:285–92. doi: 10.1016/j.jacc.2004.10.035. [DOI] [PubMed] [Google Scholar]
  • 110.Wang X-H, Li Z, Mao J-L et al. Low voltage areas in paroxysmal atrial fibrillation: the prevalence, risk factors and impact on the effectiveness of catheter ablation. Int J Cardiol. 2018;269:139–44. doi: 10.1016/j.ijcard.2018.07.076. [DOI] [PubMed] [Google Scholar]
  • 111.Kumagai K, Minami K, Sugai Y et al. Evaluation of the atrial substrate based on low-voltage areas and dominant frequencies after pulmonary vein isolation in nonparoxysmal atrial fibrillation. J Arrhythm. 2018;34:230–8. doi: 10.1002/joa3.12049. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 112.Begg GA, Karim R, Oesterlein T et al. Left atrial voltage, circulating biomarkers of fibrosis, and atrial fibrillation ablation. A prospective cohort study. PLoS One. 2018;13:e0189936. doi: 10.1371/journal.pone.0189936. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 113.Vlachos K, Efremidis M, Letsas KP et al. Low-voltage areas detected by high-density electroanatomical mapping predict recurrence after ablation for paroxysmal atrial fibrillation. J Cardiovasc Electrophysiol. 2017;28:1393–1402. doi: 10.1111/jce.13321. [DOI] [PubMed] [Google Scholar]
  • 114.Masuda M, Fujita M, Iida O et al. Left atrial low-voltage areas predict atrial fibrillation recurrence after catheter ablation in patients with paroxysmal atrial fibrillation. Int J Cardiol. 2018;257:97–101. doi: 10.1016/j.ijcard.2017.12.089. [DOI] [PubMed] [Google Scholar]
  • 115.Yamaguchi T, Tsuchiya T, Fukui A et al. Impact of the extent of low-voltage zone on outcomes after voltage-based catheter ablation for persistent atrial fibrillation. J Cardiol. 2018;72:427–33. doi: 10.1016/j.jjcc.2018.04.010. [DOI] [PubMed] [Google Scholar]
  • 116.Huang D, Li J-B, Zghaib T et al. The extent of left atrial lowvoltage areas included in pulmonary vein isolation is associated with freedom from recurrent atrial arrhythmia. Can J Cardiol. 2018;34:73–9. doi: 10.1016/j.cjca.2017.10.012. [DOI] [PubMed] [Google Scholar]
  • 117.Nery PB, Al Dawood W, Nair GM et al. Characterization of lowvoltage areas in patients with atrial fibrillation: insights from high-density intracardiac mapping. Can J Cardiol. 2018;34:1033–40. doi: 10.1016/j.cjca.2018.04.008. [DOI] [PubMed] [Google Scholar]
  • 118.Park JH, Joung B, Son N-H et al. The electroanatomical remodelling of the left atrium is related to CHADS2/CHA2DS2VASc score and events of stroke in patients with atrial fibrillation. Europace. 2011;13:1541–9. doi: 10.1093/europace/eur135. [DOI] [PubMed] [Google Scholar]
  • 119.Müller P, Makimoto H, Dietrich JW et al. Association of left atrial low-voltage area and thromboembolic risk in patients with atrial fibrillation. Europace. 2018;20(Fl_3):f359–65. doi: 10.1093/europace/eux172. [DOI] [PubMed] [Google Scholar]
  • 120.Blume GG, Mcleod CJ, Barnes ME et al. Left atrial function: physiology, assessment, and clinical implications. Eur J Echocardiogr. 2011;12:421–30. doi: 10.1093/ejechocard/jeq175. [DOI] [PubMed] [Google Scholar]
  • 121.Hoit BD. Left atrial size and function: role in prognosis. J Am Coll Cardiol. 2014;63:493–505. doi: 10.1016/j.jacc.2013.10.055. [DOI] [PubMed] [Google Scholar]
  • 122.Schaaf M, Andre P, Altman M et al. Left atrial remodelling assessed by 2D and 3D echocardiography identifies paroxysmal atrial fibrillation. Eur Heart J Cardiovasc Imaging. 2017;18:46–53. doi: 10.1093/ehjci/jew028. [DOI] [PubMed] [Google Scholar]
  • 123.Atrial Fibrillation Investigators. Echocardiographic predictors of stroke in patients with atrial fibrillation: a prospective study of 1066 patients from 3 clinical trials. Arch Intern Med. 1998;158:1316–20. doi: 10.1001/archinte.158.12.1316. [DOI] [PubMed] [Google Scholar]
  • 124.Olshansky B, Heller EN, Mitchell LB et al. Are transthoracic echocardiographic parameters associated with atrial fibrillation recurrence or stroke? Results from the Atrial Fibrillation Follow-Up Investigation of Rhythm Management (AFFIRM) Study. J Am Coll Cardiol. 2005;45:2026–33. doi: 10.1016/j.jacc.2005.03.020. [DOI] [PubMed] [Google Scholar]
  • 125.Gupta DK, Shah AM, Giugliano RP et al. Left atrial structure and function in atrial fibrillation: ENGAGE AF-TIMI 48. Eur Heart J. 2014;35:1457–65. doi: 10.1093/eurheartj/eht500. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 126.Masuda M, Fujita M, Iida O et al. An E/e’ ratio on echocardiography predicts the existence of left atrial lowvoltage areas and poor outcomes after catheter ablation for atrial fibrillation. Europace. 2018;20:e60–8. doi: 10.1093/europace/eux119. [DOI] [PubMed] [Google Scholar]
  • 127.Asinger RW, Koehler J, Pearce LA et al. Pathophysiologic correlates of thromboembolism in nonvalvular atrial fibrillation: II. Dense spontaneous echocardiographic contrast (the Stroke Prevention in Atrial Fibrillation [SPAF-III] Study) J Am Soc Echocardiogr. 1999;12:1088–96. doi: 10.1016/S0894-7317(99)70106-9. [DOI] [PubMed] [Google Scholar]
  • 128.Goldman ME, Pearce LA, Hart RG et al. Pathophysiologic correlates of thromboembolism in nonvalvular atrial fibrillation: I. Reduced flow velocity in the left atrial appendage (the Stroke Prevention in Atrial Fibrillation [SPAF-III] Study) J Am Soc Echocardiogr. 1999;12:1080–7. doi: 10.1016/S0894-7317(99)70105-7. [DOI] [PubMed] [Google Scholar]
  • 129.Todaro MC, Choudhuri I, Belohlavek M et al. New echocardiographic techniques for evaluation of left atrial mechanics. Eur Heart J Cardiovasc Imaging. 2012;13:973–84. doi: 10.1093/ehjci/jes174. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 130.Lacalzada-Almeida J, García-Niebla J. How to detect atrial fibrosis. J Geriatr Cardiol. 2017;14:185–94. doi: 10.11909/j.issn.1671-5411.2017.03.008. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 131.Cameli M, Lisi M, Righini FM et al. Usefulness of atrial deformation analysis to predict left atrial fibrosis and endocardial thickness in patients undergoing mitral valve operations for severe mitral regurgitation secondary to mitral valve prolapse. Am J Cardiol. 2013;111:595–601. doi: 10.1016/j.amjcard.2012.10.049. [DOI] [PubMed] [Google Scholar]
  • 132.Olsen FJ, Pedersen S, Jensen JS et al. Global longitudinal strain predicts incident atrial fibrillation and stroke occurrence after acute myocardial infarction. Medicine. 2016;95:e5338. doi: 10.1097/MD.0000000000005338. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 133.Yasuda R, Murata M, Roberts R et al. Left atrial strain is a powerful predictor of atrial fibrillation recurrence after catheter ablation: study of a heterogeneous population with sinus rhythm or atrial fibrillation. Eur Heart J Cardiovasc Imaging. 2015;16:1008–14. doi: 10.1093/ehjci/jev028. [DOI] [PubMed] [Google Scholar]
  • 134.Saha SK, Anderson PL, Caracciolo G et al. Global left atrial strain correlates with CHADS2 risk score in patients with atrial fibrillation. J Am Soc Echocardiogr. 2011;24:506–12. doi: 10.1016/j.echo.2011.02.012. [DOI] [PubMed] [Google Scholar]
  • 135.Shih J-Y, Tsai W-C, Huang Y-Y et al. Association of decreased left atrial strain and strain rate with stroke in chronic atrial fibrillation. J Am Soc Echocardiogr. 2011;24:513–9. doi: 10.1016/j.echo.2011.01.016. [DOI] [PubMed] [Google Scholar]
  • 136.Siebermair J, Kholmovski EG, Marrouche N. Assessment of left atrial fibrosis by late gadolinium enhancement magnetic resonance imaging: methodology and clinical implications. JACC Clin Electrophysiol. 2017;3:791–802. doi: 10.1016/j.jacep.2017.07.004. [DOI] [PubMed] [Google Scholar]
  • 137.Spragg DD, Khurram I, Zimmerman SL et al. Initial experience with magnetic resonance imaging of atrial scar and co-registration with electroanatomic voltage mapping during atrial fibrillation: success and limitations. Heart Rhythm. 2012;9:2003–9. doi: 10.1016/j.hrthm.2012.08.039. [DOI] [PubMed] [Google Scholar]
  • 138.Bucciarelli-Ducci C, Baritussio A, Auricchio A. Cardiac MRI anatomy and function as a substrate for arrhythmias. Europace. 2016;18iv:130–5. doi: 10.1093/europace/euw357. [DOI] [PubMed] [Google Scholar]
  • 139.Oakes RS, Badger TJ, Kholmovski EG et al. Detection and quantification of left atrial structural remodeling with delayed-enhancement magnetic resonance imaging in patients with atrial fibrillation. Circulation. 2009;119:1758–67. doi: 10.1161/CIRCULATIONAHA.108.811877. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 140.Mahnkopf C, Badger TJ, Burgon NS et al. Evaluation of the left atrial substrate in patients with lone atrial fibrillation using delayed-enhanced MRI: implications for disease progression and response to catheter ablation. Heart Rhythm. 2010;7:1475–81. doi: 10.1016/j.hrthm.2010.06.030. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 141.Marrouche NF, Wilber D, Hindricks G et al. Association of atrial tissue fibrosis identified by delayed enhancement MRI and atrial fibrillation catheter ablation: the DECAAF Study. JAMA. 2014;311:498–506. doi: 10.1001/jama.2014.3. [DOI] [PubMed] [Google Scholar]
  • 142.King JB, Azadani PN, Suksaranjit P et al. Left atrial fibrosis and risk of cerebrovascular and cardiovascular events in patients with atrial fibrillation. J Am Coll Cardiol. 2017;70:1311–21. doi: 10.1016/j.jacc.2017.07.758. [DOI] [PubMed] [Google Scholar]
  • 143.Akoum N, Mahnkopf C, Kholmovski EG et al. Age and sex differences in atrial fibrosis among patients with atrial fibrillation. Europace. 2018;20:1086–92. doi: 10.1093/europace/eux260. [DOI] [PubMed] [Google Scholar]
  • 144.Fonseca AC, Alves P, Inácio N et al. Patients with undetermined stroke have increased atrial fibrosis: a cardiac magnetic resonance imaging study. Stroke. 2018;49:734–7. doi: 10.1161/STROKEAHA.117.019641. [DOI] [PubMed] [Google Scholar]
  • 145.Fluckiger JU, Goldberger JJ, Lee DC et al. Left atrial flow velocity distribution and flow coherence using fourdimensional FLOW MRI: a pilot study investigating the impact of age and pre- and postintervention atrial fibrillation on atrial hemodynamics. J Magn Reson Imaging. 2013;38:580–7. doi: 10.1002/jmri.23994. [DOI] [PubMed] [Google Scholar]
  • 146.Markl M, Carr M, Ng J et al. Assessment of left and right atrial 3D hemodynamics in patients with atrial fibrillation: a 4D flow MRI study. Int J Cardiovasc Imaging. 2016;32:807–15. doi: 10.1007/s10554-015-0830-8. [DOI] [PubMed] [Google Scholar]
  • 147.Markl M, Lee DC, Furiasse N et al. Left atrial and left atrial appendage 4D blood flow dynamics in atrial fibrillation. Circ Cardiovasc Imaging. 2016;9:e004984. doi: 10.1161/CIRCIMAGING.116.004984. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 148.Lee DC, Markl M, Ng J et al. Three-dimensional left atrial blood flow characteristics in patients with atrial fibrillation assessed by 4D flow CMR. Eur Heart J Cardiovasc Imaging. 2016;17:1259–68. doi: 10.1093/ehjci/jev304. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 149.Ravanelli D dal, Piaz EC, Centonze M et al. A novel skeleton based quantification and 3-D volumetric visualization of left atrium fibrosis using late gadolinium enhancement magnetic resonance imaging. IEEE Trans Med Imaging. 2014;33:566–76. doi: 10.1109/TMI.2013.2290324. [DOI] [PubMed] [Google Scholar]
  • 150.Beinart R, Khurram IM, Liu S et al. Cardiac magnetic resonance T1 mapping of left atrial myocardium. Heart Rhythm. 2013;10:1325–31. doi: 10.1016/j.hrthm.2013.05.003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 151.Gibson DN, Di Biase L, Mohanty P et al. Stiff left atrial syndrome after catheter ablation for atrial fibrillation: clinical characterization, prevalence, and predictors. Heart Rhythm. 2011;8:1364–71. doi: 10.1016/j.hrthm.2011.02.026. [DOI] [PubMed] [Google Scholar]
  • 152.Kim YG, Shim J, Oh S-K et al. Different responses of left atrium and left atrial appendage to radiofrequency catheter ablation of atrial fibrillation: a follow up MRI study. Sci Rep. 2018;8:7871. doi: 10.1038/s41598-018-26212-y. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 153.Cochet H, Scherr D, Zellerhoff S et al. Atrial structure and function 5 years after successful ablation for persistent atrial fibrillation: an MRI study. J Cardiovasc Electrophysiol. 2014;25:671–9. doi: 10.1111/jce.12449. [DOI] [PubMed] [Google Scholar]
  • 154.Wylie JV Jr, Peters DC, Essebag V et al. Left atrial function and scar after catheter ablation of atrial fibrillation. Heart Rhythm. 2008;5:656–62. doi: 10.1016/j.hrthm.2008.02.008. [DOI] [PubMed] [Google Scholar]
  • 155.Sugumar H, Prabhu S, Voskoboinik A et al. Atrial remodeling following catheter ablation for atrial fibrillation-mediated cardiomyopathy: long-term follow-up of CAMERA-MRI study. JACC Clin Electrophysiol. 2019;5:681–8. doi: 10.1016/j.jacep.2019.03.009. [DOI] [PubMed] [Google Scholar]
  • 156.Schneider MP, Hua TA, Böhm M et al. Prevention of atrial fibrillation by renin-angiotensin system inhibition a metaanalysis. J Am Coll Cardiol. 2010;55:2299–307. doi: 10.1016/j.jacc.2010.01.043. [DOI] [PubMed] [Google Scholar]
  • 157.Dabrowski R, Szwed H. Antiarrhythmic potential of aldosterone antagonists in atrial fibrillation. Cardiol J. 2012;19:223–9. doi: 10.5603/CJ.2012.0043. [DOI] [PubMed] [Google Scholar]
  • 158.Fauchier L, Clementy N, Babuty D. Statin therapy and atrial fibrillation: systematic review and updated meta-analysis of published randomized controlled trials. Curr Opin Cardiol. 2013;28:7–18. doi: 10.1097/HCO.0b013e32835b0956. [DOI] [PubMed] [Google Scholar]
  • 159.Parviz Y, Iqbal J, Pitt B et al. Emerging cardiovascular indications of mineralocorticoid receptor antagonists. Trends Endocrinol Metab. 2015;26:201–11. doi: 10.1016/j.tem.2015.01.007. [DOI] [PubMed] [Google Scholar]
  • 160.Nalliah CJ, Sanders P, Kottkamp H et al. The role of obesity in atrial fibrillation. Eur Heart J. 2016;37:1565–72. doi: 10.1093/eurheartj/ehv486. [DOI] [PubMed] [Google Scholar]
  • 161.Liu T, Korantzopoulos P, Shao Q et al. Mineralocorticoid receptor antagonists and atrial fibrillation: a meta-analysis. Europace. 2016;18:672–8. doi: 10.1093/europace/euv366. [DOI] [PubMed] [Google Scholar]
  • 162.Zhao S, Li M, Ju W et al. Serum level of transforming growth factor beta 1 is associated with left atrial voltage in patients with chronic atrial fibrillation. Indian Pacing Electrophysiol J. 2018;18:95–9. doi: 10.1016/j.ipej.2017.11.001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 163.Rienstra M, Hobbelt AH, Alings M et al. Targeted therapy of underlying conditions improves sinus rhythm maintenance in patients with persistent atrial fibrillation: results of the RACE 3 trial. Eur Heart J. 2018;39:2987–96. doi: 10.1093/eurheartj/ehx739. [DOI] [PubMed] [Google Scholar]
  • 164.Swedberg K, Zannad F, McMurray JJV et al. Eplerenone and atrial fibrillation in mild systolic heart failure: results from the EMPHASIS-HF (Eplerenone in Mild Patients Hospitalization And SurvIval Study in Heart Failure) Study. J Am Coll Cardiol. 2012;59:1598–1603. doi: 10.1016/j.jacc.2011.11.063. [DOI] [PubMed] [Google Scholar]
  • 165.Pathak RK, Middeldorp ME, Lau DH et al. Aggressive risk factor reduction study for atrial fibrillation and implications for the outcome of ablation: the ARREST-AF cohort study. J Am Coll Cardiol. 2014;64:2222–2231. doi: 10.1016/j.jacc.2014.09.028. [DOI] [PubMed] [Google Scholar]
  • 166.Kunamalla A, Ng J, Parini V et al. Constitutive expression of a dominant-negative TGF-β type ii receptor in the posterior left atrium leads to beneficial remodeling of atrial fibrillation substrate. Circ Res. 2016;119:69–82. doi: 10.1161/CIRCRESAHA.115.307878. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 167.Hucker WJ, Hanley A, Ellinor PT. Improving atrial fibrillation therapy: is there a gene for that? J Am Coll Cardiol. 2017;69:2088–95. doi: 10.1016/j.jacc.2017.02.043. [DOI] [PMC free article] [PubMed] [Google Scholar]

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