Multimodality Imaging for Atrial Fibrosis Detection in the Era of Precision Medicine.

In recent years, atrial fibrillation (AF) has increasingly become a focus of attention because it represents the most encountered arrhythmia in clinical practice and a major cause of morbidity and mortality. Issues underlying AF have long been debated; nevertheless, electrical, contractile, and structural remodeling is demonstrated to be the pivotal contributor to arrhythmic substrate. Fibrosis is a hallmark of arrhythmogenic structural remodeling, resulting from an accumulation of fibrillar collagen deposits, as a reparative process to replace degenerating myocardium with concomitant reactive fibrosis, which causes interstitial expansion. Although the precise role of fibrosis in AF initiation and maintenance remains to be fully elucidated, a better definition of its extent and distribution may assist in designing individually tailored ablation approaches and improving procedure outcomes by targeting the fibrotic substrates with an organized strategy employing imaging resources. A deep comprehension of the mechanisms underlying atrial fibrosis could be crucial to setting up improved strategies for preventing AF-promoting structural remodeling. Imaging modalities such as echocardiography, cardiac computed tomography, and cardiac magnetic resonance, combined sometimes with invasive electroanatomical mapping, could provide valuable information for the optimal patients' management if their use is not limited to cardiac anatomy study but extended to characterize abnormal left atrial substrate. Although pulmonary vein isolation is usually efficacious in treating paroxysmal AF, it is not sufficient for many patients with nonparoxysmal arrhythmias, particularly those with longstanding persistent AF. Noninvasive imaging techniques play a pivotal role in the planning of arrhythmic substrates ablation and show a strong correlation with electro-anatomic mapping, whose novel multipolar mapping catheters allow nowadays a more precise comprehension of atrial substrate. This review aims to explore the impact of the various imaging modalities for the detection of atrial fibrosis and their role in the management of AF. Copyright:

INTRODUCTION

Atrial fibrosis is a common feature of clinical atrial fibrillation (AF), which is one of the most frequent tachyarrhythmias detected in the clinical practice, associated to an impairment of patients’ quality of life, a reduction in life expectancy, and a social financial burden.[1] Although significant progress has been made in arrhythmias treatment over the past several decades as an effect of the improvement of catheter ablations techniques and drugs choices, there is still the need to reduce procedure-related complications and above all improve long-term success rate. A better understanding of mechanisms underlying AF onset and atrial remodeling may facilitate the development of new and potentially more effective therapeutic approaches and help selection of responding patients. Furthermore, anatomic and functional tissue characterization is likely to transform even stratification methodologies to assess the need for oral anticoagulation or its safe discontinuation.

Catheter ablation with the cornerstone of pulmonary vein isolation (PVI) is an effective solution in many patients, and various factors have been proposed as the predictors of recurrence. Indeed, success rates are determined by the not only clinical type of AF but also pulmonary vein reconnection rates; rather, the underlying atrial substrate is a main character.[2]

Atrial structural remodeling is the key factor linking all the known mechanisms underlying AF, and atrial fibrosis is the most outstanding feature of this remodeling.[3] Moreover, structural, functional, biochemical, and electrophysiological abnormalities of the atria have been recently overall defined as “atrial cardiomyopathy.”[4]

Although it is well demonstrated that patients with AF who tend to maintain sinus rhythm after cardioversion use to present with significantly smaller LA size if compared with patients who revert to arrhythmia,[567] it is also known that all macroscopic structural changes, such as atria enlargement, are only late markers of the disease. The real challenge for the cardiologist is to detect functional remodeling at an early stage, before anatomical alterations occur, and to tailor the proper therapeutic strategy depending on fibrosis grade to improve efficacy, efficiency, and also safety.

FIBROSIS, REMODELING, AND ATRIAL FIBRILLATION

There are a number of studies demonstrating an entanglement between atrial fibrosis and AF, and indeed, atrial fibrosis has been shown to be associated with an increased collagen deposition, as documented in lone AF patients rather than sinus rhythm control subjects.[8] Interstitial fibrosis is the hallmark of AF-induced left atrial (LA) remodeling and is associated with chamber dilation, spherical deformation, and reduced atrial function, further promoting AF in a vicious circle conventionally defined as “AF begets AF.” Notably, in some instances, AF may be a marker of high atrial fibrosis burden rather than its cause.[9] As summarized by Sohns and Marrouche,[10] atrial fibrosis comprises diverse individual and multifactorial processes resulting from complex interactions among cellular and neurohormonal mediators and may be associated with genetic factors and predisposition. These processes result in redistribution of connective myocardial tissue, due to new conditions of pathological tissue function.

The translational mechanisms of cardiac fibrosis should be analyzed: cardiac fibroblast and myoblast, the transforming growth factor B1 signaling for collagen synthesis, matrix metalloproteinases and tissue inhibitors of matrix metalloproteinases for coordinated degradation of the extracellular matrix (ECM) proteins, aging, and inflammation are involved.[11] Cardiac fibroblasts play a pivotal role in the formation of ECM as they are numerous within the myocardium accounting for up 60% of cells in the muscle and even outnumber cardiomyocytes. Histologically, we can observe changes in collagen subtype distribution between normal hearts and atrial tissue undergoing fibrosis. cardiac fibroblasts are basically nonexcitable cells, but they are able to transfer currents between cardiomyocytes via connexins. This action can result in heterogeneity of current conduction, shortening of action potentials, depolarization of resting cardiomyocytes, and induction of spontaneous phase 4 depolarization.[12] Consequently, atrial fibrosis might be the underlying substrate and directly involved in the occurrence and perpetuation of focal and re-entry arrhythmia mechanisms.

The relationship between atrial ultrastructural changes, cellular electrophysiological derangements, and clinical hemodynamic phenomena has been initially demonstrated in animal models.[138] Patients with paroxysmal AF may progress to permanent arrhythmias as consequence of this process of remodeling;[1415] on the other hand, knowing the extent of preablation fibrosis can be used to identify patients with a higher risk to develop a recurrence after a PVI procedure.[16] Indeed, Kottkamp et al.[17] proposed a patient-tailored ablation strategy defined as “box isolation of fibrotic areas,” which involves the circumferential isolation of substantially affected fibrosis areas, providing a new-fashioned selection criterion for PVI-only ablation subjects with nonparoxysmal AF. Likewise, Rolf et al.[18] also demonstrated a tailored substrate modification based on voltage criteria, and Yamaguchi et al.[19] described an approach of homogenizing areas of substantial fibrosis.

Atrial remodeling influences the natural course of AF: it is responsible for the perpetuation of the arrhythmia and its recurrence, characterizing patients’ typical clinical course. Moreover, there is now increasing evidence that even in patients with so-called lone or idiopathic AF, the AF itself is an arrhythmic manifestation of a structural atrial disease, recently described as “fibrotic atrial cardiomyopathy.”[20] In fact, there is substantial evidence that the majority of the patients without overt structural heart disease have a chronic fibrotic biatrial substrate, and a higher expression of fibrosis is detected in patients with persistent forms compared with those with paroxysmal AF. However, a high variability in extend of fibrosis certainly exists with part of paroxysmal AF patients having massive fibrosis, as well as part of persistent AF patients showing mild fibrosis. Thus, these data do not support a causal relationship that AF produces fibrosis in the sense of “AF begets AF” instead of being a consequence of the fibrotic process in fibrotic atrial cardiomyopathy.[2122]

DETECTION OF ATRIAL FIBROSIS

The use of cardiac imaging modalities has evolved from simple report of LA anatomy to identification of arrhythmogenic substrate and ablation outcomes. In particular, detection of atrial fibrosis could be approached by invasive or noninvasive methods of imaging [Figure 1].

Figure 1

How to detect atrial fibrosis: Invasive and noninvasive imaging methods

Invasive techniques rely on the electrophysiological approach to perform an electroanatomical mapping (EAM) with the aim to identify low-voltage and abnormal electrograms areas, which are possible sites of atrial fibrosis. Endomyocardial atrial biopsy is rarely performed in clinical practice, and it is a technique which can reach and evaluate only limited atrial zones, especially due to the relatively small thickness of the atrial wall. On the other hand, noninvasive methods, consisting of all imaging systems, have enable the heart to be imaged with better temporal and spatial resolution with the advantage to be easily performed and suitable for follow-up investigations and serial monitoring.

This review aims to examine the impact of the various imaging modalities for the detection of atrial fibrosis and their pivotal role in the management of AF.

INVASIVE IMAGING METHODS

The role of EAM for the detection of atrial fibrosis has been consistently growing with the development of mapping systems. Briefly, EAM consists of a precise nonfluoroscopic visualization of mapping catheters and a reconstruction of three-dimensional (3D) volumes of interest that are created by the manipulation of the catheter. The resulting model is illustrated as a shell representing the cardiac structure of interest and can be more accurate by increasing the number of sampled points. The most established mapping techniques include color-coded display of the electrical activation sequence known as “activation mapping,” and mapping of unipolar/bipolar electrograms as part of “fractionation mapping” and “voltage mapping” on the model surface.[23] Voltage signals recorded from each electrodes are then converted by contemporary electro-anatomic systems into color-coded voltage maps, providing a static representation of time-dependent electrical activation of the atrium.

Contemporary electro-anatomic mapping platform used during AF ablation allows a very high number of voltage points to be mapped onto a geometric model of the atrial endocardium.

As mentioned by Sim et al.,[24] a major challenge in evaluating the diagnostic performance of voltage mapping is the lack of a clear consensus of the form of the substrate. Histological validation between low-voltage areas and native atrial fibrosis is currently defective: cardiac magnetic resonance (CMR) with late gadolinium enhancement (LGE) has been correlated with atrial fibrosis by histological assessment in a small number of patients,[25] and several studies have compared bipolar voltage with LGE.[26272829]

Previous studies have attempted to characterize voltage cutoffs to represent the spectrum of atrial fibrosis: In general, these studies used either ablation catheters with 4 mm electrodes,[1530] or multi-electrode catheters[1718] with 1–2 mm electrodes and 2–6 mm electrode spacing. The voltage level of <0.5 mV is used as specific for abnormal tissue during sinus rhythm or atrial stimulation;[31] however, when assessing atrial voltage during AF, it is accepted to reduce this cutoff.[32] Newer multi-electrode catheters have been developed with a specific orthogonal grid and high-density baskets with smaller electrodes, with the specific potential to overcome discrepancies due to the characteristics of the recording catheter, but with still to validate cutoff.

Anter et al.[33] examined patients with atrial scar due to prior radiofrequency ablation and found that the mean bipolar voltage amplitude was significantly higher in areas of low voltage when using multi-electrode Pentaray (1-mm electrode size; Biosense Webster, Diamond Bar, CA, USA) catheter compared with the 3.5 mm electrode on the Thermocool (Biosense Webster, Diamond Bar, CA, USA) catheter.[33] This voltage difference could be explaining as a higher mapping resolution with smaller electrode surface, which can detect even small surviving myocardial fibers in regions of LA scar.

Moreover, areas of remodeling or fibrosis will display a fractionated electrogram due to underlying conduction abnormalities.[34] According to this, atrial fibrosis is proposed to be associated not only with slower and more organized electrical activity but also with lower voltage than healthy atrial areas. Nevertheless, patients with paroxysmal and persistent AF could show varying degrees of fibrosis and a wide variation of voltage distribution.

It is pivotal to remember that EAM is an invasive procedure, performed during catheter ablation after placing electrodes into the heart chambers. Therefore, EAM cannot be used neither for patient selection nor for preprocedural prognostic evaluation. Moreover, creating potential maps is time-consuming and the voltage measured depends various factors, as heart rate, electrical activation, contact between the electrode and atrial tissue, as well as the thickness of myocardium.

Attempts have been made to correlate complex fractionated atrial electrograms (CFAEs) with areas of delayed enhancement on magnetic resonance imaging following ablation with a reasonably acceptable concordance between CFAEs with areas demonstrating LGE.[3530] As the substrate evolves toward longstanding persistent AF, complex CFAE repetitiveness is more uniformly distributed at disparate sites. Moreover, Jadidi et al.[14] correlated CFAE with delayed enhancement CMR areas of atrial fibrosis. They resulted that atrial fibrosis is associated with slower and more organized electrical activity but with lower voltage than expected in healthy atrial areas.

Notwithstanding, electro-anatomic mapping has the limitations of being an invasive procedure and therefore not suitable for diagnostic follow-up investigations.

Finally, an LA activation study with a high-density mapping could give us further information on structural changes of myocardial wall [Figure 2 and Video 1]. Dinov et al.[36] proved that patients with AF have different LA activation patterns as well as longer LA activation times as compared to controls without history of atrial arrhythmias. In this study, authors demonstrated that most AF patients feature a specific upward LA activation pattern with the latest local activation at anterior mitral annulus and hypothesized that a prolonged atrial conduction time could be the result of a block in the Bachmann's bundle that connects the right atrium with the anterosuperior part of LA.

Figure 2

Example of normal activation mapping at the left atrium with multipolar mapping catheter. Left Panel: late activation at posterolateral aspect of left atrium (lateral projection; purple spot); Right Panel: right anterior oblique projection showing the earlier left atrium activation at anterior wall (red spot) in the region of Bachmann's bundle

NONINVASIVE IMAGING METHODS

Echocardiography

Echocardiography endures as the most widespread imaging modality in cardiology and has a central role in patients’ evaluation, especially prior catheter ablation. Advantages of echocardiography consist of its being safe, inexpensive, and easily performed; moreover, echocardiography could provide information about cardiac anatomy, ventricular function, chamber sizes, intracardiac pressure gradients, and valvular function.

All the echocardiographic approaches do not favor direct visualization of the fibrosis but are still limited to uncover the secondary effects of atrial wall fibrosis, and conventionally, the assessment for atrial remodeling has largely been limited to the assessment of atrial size. LA enlargement has been proposed to be the first detectable anatomical change before the onset of AF,[3738] and two-dimensional area or volume has been used to quantify atrial remodeling in terms of LA diameter, area, and volume. Such dimensions have been shown to be a strong predictor of AF recurrence after electrical cardioversion or radiofrequency ablation.[3940]

Echocardiography is the first-line imaging modality for assessing atrial size and function because of its relative availability, low cost, and noninvasive nature. Besides quantification of size changes, other echocardiographic-specific parameters that quantify LA function include pulsed-wave Doppler at the mitral leaflet tips and at the pulmonary veins which have been used to describe LA hemodynamic capacity.[41] More specifically, value of peak A wave and velocity time integral in late diastole have been described as indirect atrial function parameters. Furthermore, the ratio of transmitral E wave to peak septal mitral annular tissue velocity in early diastole (E/E’ ratio) is a measurement of left ventricular filling pressures which determine LA function.

Modern echocardiographic techniques, such as myocardial deformation indices such as Doppler-derived regional atrial strain, have also been successfully used to quantify atrial function.[4243] Speckle tracking echocardiography (STE) is an advanced imaging technique enabling the assessment of impairment of LA reservoir function,[44] potentially caused by reduced atrial compliance due to atrial fibrosis.

Recent studies correlated LA strain and strain rate in patients with AF with fibrosis by 3D delayed enhancement gadolinium CMR, where patients with persistent arrhythmia were found to have more LA wall fibrosis and significantly lower longitudinal strain in the mid-septal and mid-lateral walls compared with patients with paroxysmal AF.[43] These studies demonstrated that the LA lateral wall strain can be accurately imaged, is not constrained by other cardiac chambers, and may be used as a surrogate measure of LA wall fibrosis.[45]

Grading strain by speckle tracking offers the advantage of being able to assess myocardial deformation independently of the angle and rotation. Furthermore, it is also a valid measure which is less dependent on load compared with other conventional echocardiographic parameters. Specific additional advantages of using STE include an easy visualization of regional atrial contraction, which is seen as negative strain and strain rate, and LA relaxation (or peak lengthening strain during ventricular systole), represented by positive strain and strain rate. In addition, atrial contraction is absent in AF, and both atrial contraction and relaxation have been identified as important indexes of LA compliance due to fibrosis. Hence, in the clinical setting, given the close relationship between morphology and function, a reduced atrial deformation during the reservoir phase of cardiac cycle may be an early and noninvasive marker of the amount of atrial wall fibrosis. Moreover, postprocedural LA strain during reservoir phase holds promise to be a remarkably reliable predictor of successful AF ablation, allowing stratification of patients on the basis of the likelihood of maintaining sinus rhythm after the procedure.[46]

Nevertheless, assessment of atrial strain with echocardiography could be challenging for some reasons: First, the atrial wall is thinner than the left ventricle hence more difficult to trace and track accurately. Moreover, the atrium is also located in the far field of the ultrasound beam; thus, image resolution of the atria walls is also often unsatisfactory. Moreover, reliable strain imaging acquisition and measurement requires significant expertise, and is subject to high inter-observer and intra-observer variability.

LA fibrosis, thought to be a hallmark of structural remodeling, increases LA stiffness and worsens LA function. In a recent paper, Pilichowska-Paszkiet et al.[47] noticed a stronger association between low-voltage areas and the parameters that characterized LA diastolic function than parameters characterizing LA systolic function (peak atrial contractile strain, LA appendage velocity, or A and A’). It is in accordance with the published data on LA function in paroxysmal AF, where LA enlargement and impairment of its function as a reservoir were observed, whereas LA systolic function remained unchanged.[48] Peak atrial longitudinal strain is therefore seen as an indicator of LA reservoir function, during which LA cavity is filled with blood coming from the pulmonary veins, which leads to LA extension. The presence of LA intramural fibrosis may greatly impair LA compliance and influence especially the LA reservoir phase. During AF, LA's function as a reservoir and conduit is severely impaired, and systolic function is lacking. It has been shown that LA strain is impaired and reduction of positive LA strain curve during the reservoir phase is observed in AF.[6] Decreased LA strain in AF can occur mainly due to atrial mechanical function impairment, as consequence of both lack of systole and diastolic impairment. By definition, patients with AF have lower LA strain as a result of the impairment of atrial mechanical function; therefore, LA fibrosis assessment using LA function deterioration measurement may result in lower diagnostic accuracy. In addition, the amplitude of atrial signal is dropped during AF and significantly increases in the very same place when sinus rhythm reoccurs.

The electrical dispersion that characterized the onset and maintenance of the arrhythmia is caused by the disruption of the electrical pathway. It has been demonstrated that longer atrial electromechanical coupling, inter- and intra-atrial electromechanical delay measured with tissue Doppler imaging, and greater P-wave dispersion are the well-known electrophysiological characteristics to the atria prone to fibrillation.[496]

Recently, total atrial conduction time has been proposed as a marker of atrial remodeling and a novel echocardiographic parameter based on tissue doppler imaging (TDI) has been introduced to assess it. Preliminary studies have demonstrated that a long PA-TDI interval is associated with LA low-voltage areas and long LA activation time and could influence AF ablation efficacy.[50515253] PA-TDI is obtained by calculating the time duration difference between the onset of the echocardiogram-derived P-wave and the peak of the A’ wave on the lateral mitral annulus TDI. An example of PA-TDI assessment is shown in Figure 3.

Figure 3

Correlation between echocardiography and electro-anatomic mapping: a long PA-tolerable daily intake interval is associated with extended low voltage area. Panel A: a PA-tolerable daily intake value of 187 ms recorded on the lateral mitral annulus. Panel B: anterior left atrial wall after pulmonary vein isolation (in red) with very large low-voltage areas (in red, green and yellow) in the Bachmann's bundle region and only limited area of normal-voltage myocardium

Multislice computed tomography

Computed tomography (CT) has the advantage of creating images with significantly better resolution compared with echocardiography but has largely been limited to quantification of atrial and atrial appendage dimensions and volume in a clinical setting.

Initial studies were based on the measurement of atrial wall thickness from multislice CT images between patients with paroxysmal and chronic AF, advancing the hypothesis that LA thickness may be a useful predictor to identifying patients at risk to develop permanent AF. Besides, the periatrial fat identified on CT images has also been associated with the pathogenesis of AF.[54] Even though 3D reconstruction of cardiac structures from cardiac CT data sets has revolutionized the perception of LA anatomy and facilitated the development of original AF ablation approaches, CT does not provide sufficient resolution for a correct quantification of fibrosis, especially comparing to magnetic resonance. Anyway, thickness evaluation could allow to tailored energy delivery and sometimes could be correlated with low voltage areas [Figure 4]. Regarding the limitations of CT, of primary concern is the radiation exposure associated with CT compared with other imaging modalities.

Figure 4

Panel A: Electro-anatomical mapping showing a large low voltage area (red) at the anterior wall with already isolated pulmonary veins (red); Panel B: the same projection showing a thinning (red regions) at the same sites of low-voltage areas

Ling et al.[55] proposed how to identify surrogate regions of fibrosis: in this technique, contrast-enhanced gated cardiac CT is segmented by degree of contrast attenuation and areas of low attenuation correlated with low-voltage points derived from invasive electro-anatomic bipolar voltage maps.

Cardiac magnetic resonance

As previously described, atrial fibrosis mostly consists of disorganized myocytes and collagen and has an expanded extracellular space as compared to healthy myocardial tissues. Hence, magnetic resonance imaging is the modality with a sufficient high temporal and spatial resolution to successfully reproduce the LA. LGE CMR image contrast is based on delayed gadolinium wash-out in tissues with increased extracellular volume, for example due to fibrosis.[155657] Localization of fibrotic areas, together with anatomical reconstruction and pulmonary vein visualization, allows for precise ablation target definition and may improve outcome prediction.

Initial studies reported a correlation between areas of delayed gadolinium enhancement on CMR with LA wall fibrosis by histopathology in animals models with radiofrequency-induced lesions.[2] Similar approaches were applied to subsequent studies: CMR was performed to those patients who underwent ablation procedure and correlated areas of LGE within the atrial walls which were ablated.[258] Harrison et al.[59] exposed the first histopathological validation of LGE and endocardial voltage mapping for definition of atrial scarring by acute and chronic ablation injury by providing signal intensity threshold for both ablation types. Moreover, as seen above, it was largely demonstrated that the large fibrotic substrate detected with LGE-CMR is associated with the CFAEs, proposed as a relevant phenomenon maintaining AF.[14]

The most exploited classification system for LA fibrosis is based on the amount of delayed enhancement CMR.[2] The Utah classification divides patients into four groups according to degree of fibrosis: Utah I (<5% LA wall delayed enhancement), Utah II (5%–20% LA wall delayed enhancement), Utah III (20%–35% LA wall delayed enhancement), and Utah IV (>35%). The same classification is pivotal in predicting the likely success of catheter ablation therapy for AF. Data presented by Marrouche et al.[2] showed satisfactory suppression of the arrhythmic burden in all patients with Utah I fibrosis, 81.8% of patients with Utah II fibrosis, 62.5% of patient with Utah III, and none patients with Utah IV fibrosis. In addition, this study also demonstrated no recurrence of the arrhythmia based on the amount of fibrosis in Utah I patients and a progressively increasing rate of recurrence of the arrhythmia based on the amount of fibrosis (28% in Utah II, 35% in Utah, and 56% in Utah IV). Hence, an approach which combines novel imaging techniques such as T1 delayed gadolinium enhancement by CMR[60] and the Utah classification system may be useful in a clinical setting to risk stratify patients likely to develop recurrence. Notwithstanding, the reproducibility, sensitivity, and specificity of this approach compared to the gold standard, that is the histopathological approach, have not fully established.

Following the development of reliable strategies to characterize LA substrate, CMR evaluation of LA LGE was shown to predict successful ablation strategies with more extensive LGE predicting the need for more ablation than PVI alone and mild LGE predicting overall favorable ablation outcomes.[6162] In the DECAAF study, prospective evaluation of LA LGE before ablation was highly associated with ablation outcomes with excessive fibrosis predicting a high likelihood of recurrent arrhythmia.[63]

The role of CMR has been growing in the last years: in contrast to invasive EAM during the ablation procedure, LGE-CMR-guided fibrosis management has improved the understanding of arrhythmia substrate. Fochler et al.[63] reported that an LGE-CMR anatomically guided approach for the treatment of recurrent arrhythmias post-AF ablation is feasible and effective. Similarly, LGE-CMR-guided assessment may provide novel insights into patient-specific AF stages and treatment strategies. Nevertheless, this modality requires extensive experience, and its reproducibility is yet to be demonstrated.[10]

Kuppahally et al.[43] effectively demonstrated that a larger extension of LA enhancement on delayed enhancement CMR is related to lower atrial reservoir performance, expressed by a reduced atrial strain peak during this phase of the cardiac cycle. After dividing patients with AF according to duration of the arrhythmia (paroxysmal and persistent), the amount of fibrosis and the concordant reduction of atrial strain were significantly greater in patients with chronic AF than in those with paroxysmal AF, showing a continuum of ultrastructural abnormalities affecting the atria.

In addition, other studies have evaluated the ability of CMR to detect gaps in PVI lesions to identify PV reconnections,[64] and more recently, Quinto et al.[65] demonstrated also that the substrate characterization provided by LGE CMR is associated with shorter procedure and better clinical outcomes in repeated AF ablation procedures.

Bisbal et al.[66] moved forward from the concept of LA remodeling and proposed the idea of LA sphericity, evaluated in a single-center magnetic resonance imaging study, as a shape-based remodeling parameter associated with ablation procedure success. In their study, the authors demonstrated that such sphericity is the only imaging parameter with independent predictive value for recurrence after AF ablation, even after adjusting for covariates, regardless of AF phenotype, imaging modality, energy source, and center experience, and proposed a simple clinical imaging “LA geometry and outcome” score.

There can be significant technical challenges that limit CMR broad applicability: patients can be imaged while in AF although both irregular and rapid heart rates can limit image quality or make fibrosis assessment unsatisfactory. LA thinning is a major issue for LGE images interpretation, which is variable among centers and the optimal processing technique remains to be better described.

…And beyond

Molecular imaging technologies have been impressively advancing in recent years: Targeted probes for specific molecular and cellular targets, or for relevant biological pathways, might present prospects for development of safe and noninvasive imaging techniques in the field of AF.[67] Molecular imaging refers to the use of small molecules, peptides, or antibodies tagged with an imaging reporter that recognize specific receptors, proteins, or products of biological pathways. This methodology represents a ground-breaking approach, especially now when a personalized medicine is requested. Imaging of collagen, fibroblasts, and the renin-angiotensin system, as well as matricellular proteins and matrix-degrading enzymes, could predict the extent of ECM expansion, determine the impairment of cardiac function, and enable evaluation of therapies that modulate the ECM microenvironment and the fibrotic response.[67] Notwithstanding, current examples of molecular imaging for AF scarcely exist, whereas in fact, promising probes were already developed for other cardiovascular diseases.

Clinical impact and applications

Understanding and targeting an existing atrial substrate that contributes to the maintenance of AF is a new strategy to improve success rates of catheter ablation. Although it is by now clear that PVI alone is an insufficient ablation strategy for many patients with AF, it is still unknown what additional ablation to perform and how to select those patients to be more aggressive with. The pathophysiological basis for ablation targeting recognized fibrotic areas could be similar to that observed in ventricular arrhythmias following myocardial infarction: Fibrotic tissue is associated with delayed conduction velocity and predisposition to arrhythmia. The knowledge of the individual amount and distribution pattern of fibrosis LA substrate allows a personalized path in preventing, monitoring, and targeting arrhythmic substrate in patients with AF.

Imaging modalities such as echocardiography, cardiac CT, and CMR provide valuable information for the optimal management of AF if their use is not limited to cardiac anatomy study but extended to characterize abnormal LA substrate.

The reversibility of structural remodeling, however, is questionable. In patients with really lone AF who have no underlying structural heart disease or excessive atrial fibrosis, catheter ablation can be expected to be curative with complete atrial normalization. However, in case of fibrotic atrial cardiomyopathy, intrinsic fibrotic disease process necessary for AF to occur or at least to sustain may already be very advanced when AF appears and may be independent of associated comorbidities and type of AF.[20]

CONCLUSION AND FUTURE PERSPECTIVES

The prevalence of AF worldwide highlights the need of the development of high accuracy and precision therapies aimed at preventing or reversing AF. Clinical and experimental studies have largely reported that the extent of atrial fibrosis is closely combined with the occurrence and maintenance of AF; nevertheless, the development of fibrosis is a highly complex, multifaceted, and patient-specific process, involving various levels of interactions.

Although the precise role of fibrosis in AF initiation and maintenance remains to be fully elucidated, a better definition of its extent and distribution may assist in designing individually tailored ablation approaches and improving procedure outcomes by targeting the fibrotic substrates with an organized strategy employing imaging resources. Electro-anatomical mapping of the LA is nowadays essential to guide operators for a tailored AF ablation, even though it is useless in the preoperative setting. On the other hand, preprocedural delayed enhancement CMR imaging could be a powerful tool to detect preexisting atrial fibrosis; however, until now, it is still technically challenging and not available in most centers. Finally, echocardiography is easily achievable, low cost, and radiation-free, and novel parameters as PA-TDI and techniques as speckle tracking seem to be promising, with a rising role in the clinical practice. In light of the encouraging data, the use of simple methods should be extended at least in the selection of patients to consider furthering and more complex screening.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.