*Article* **Isolated Atrial Fibrillation, Inflammation and Efficacy of Radiofrequency Ablation: Preliminary Insights Based on a Single-Center Endomyocardial Biopsy Study**

**Roman E. Batalov 1, Mikhail S. Khlynin 1,\*, Yulia V. Rogovskaya 1, Svetlana I. Sazonova 1, Roman B. Tatarskiy 2, Nina D. Anfinogenova <sup>1</sup> and Sergey V. Popov <sup>1</sup>**


**Abstract:** The aim of the study was to evaluate the inflammatory changes in the myocardium, based on endomyocardial biopsy (EMB) data in patients undergoing radiofrequency ablation (RFA) for idiopathic atrial fibrillation (AF). A total of 67 patients with idiopathic AF were enrolled in the study. Patients underwent the intracardiac examination, RFA of AF, and EMB with histological and immunohistochemical studies. The catheter-treatment effectiveness, and occurrence of early and late recurrences of atrial tachyarrhythmias, were assessed depending on the identified histological changes. Nine patients (13.4%) did not have any histological changes in the myocardium according to EMB. Fibrotic changes were detected in 26 cases (38.8%). Inflammatory changes according to the Dallas criteria were observed in 32 patients (47.8%). The follow-up period for patients averaged 19.3 ± 3.7 months. The effectiveness rates of primary RFA were 88.9% in patients with the intact myocardium, 46.2% in patients with fibrotic changes of varying severity, and 34.4% in patients with the presence of criteria for myocarditis. No early recurrence of arrhythmias was observed in patients with unchanged myocardia. The presence of inflammatory and fibrotic changes in the myocardium increased the rates of early and late arrhythmia recurrences and accordingly halved the effectiveness RFA of AF.

**Keywords:** atrial fibrillation; inflammation; histological myocarditis; endomyocardial biopsy; radiofrequency ablation

#### **1. Introduction**

The introduction should briefly place the study in a broad context and highlight atrial fibrillation (AF) as the most common arrhythmia with heterogeneous clinical manifestations often observed in clinical practice. AF is the cause of one-third of hospitalizations for cardiac arrhythmias. Current clinical guidelines recommend avoiding the term "lone" or isolated AF. However, in clinical practice, there are patients without any clinical and echocardiographic signs of cardiovascular and pulmonary disease, and conditions such as acute infections, recent cardiac surgery, thoracic or abdominal operations, and systemic inflammatory diseases [1].

It Is known that an essential element of AF pathophysiology is atrial remodeling, which has three main components: structural, electrical, and mechanical [2]. Inflammation is an important factor in structural remodeling. Indeed, Lau et al. showed that the inflammatory infiltration in the atrial myocardium was detected in patients with isolated AF. Further evidence for the association between AF and inflammation is increased concentrations of serum inflammatory markers, such as C-reactive protein (CRP), TNF-α, interleukins, and cytokines [3]. Besides, the level of serum inflammatory markers increases in patients

**Citation:** Batalov, R.E.; Khlynin, M.S.; Rogovskaya, Y.V.; Sazonova, S.I.; Tatarskiy, R.B.; Anfinogenova, N.D.; Popov, S.V. Isolated Atrial Fibrillation, Inflammation and Efficacy of Radiofrequency Ablation: Preliminary Insights Based on a Single-Center Endomyocardial Biopsy Study. *J. Clin. Med.* **2023**, *12*, 1254. https://doi.org/10.3390/ jcm12041254

Academic Editors: Antonio Curnis, Gianfranco Mitacchione, Giovanni Battista Forleo and Peter Seizer

Received: 21 December 2022 Revised: 21 January 2023 Accepted: 31 January 2023 Published: 4 February 2023

**Copyright:** © 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

with both isolated AF and AF associated with the underlying disease [4]. However, it is challenging to explain the occurrence of cellular infiltration and an increase in inflammatory markers only by the fact of AF without the presence of an infectious agent.

The diagnosis of idiopathic AF often suggests the presence of unrecognized myocardial lesion with a certain etiology. One of the most common causes for idiopathic AF is chronic myocarditis occurring without vivid clinical manifestation [5]. Endomyocardial biopsy (EMB)-based confirmation of active myocarditis, which can initially be suspected in patients with a combination of minimal clinical and laboratory-instrumental signs, provides the basis for successful administration of anti-inflammatory and immunosuppressive therapy.

Myocarditis can be difficult to diagnose, primarily due to the heterogeneity of its clinical manifestations. Data on the prevalence of myocarditis are limited, and there are no studies on the subclinical course of this disease. Available studies of myocardial biopsies in young people who suddenly died suggest the presence of myocarditis in 2 to 42% of cases [6,7]. The absence of a specific clinical picture, clear association with the previous infection, changes in exercise tolerance, and changes in ECG and echocardiography data often do not allow suspicion of the presence of myocarditis; spontaneous recovery completely excludes further diagnostic searches in this direction. However, the evolution of viruses, their rapid spread, tendency to chronicity, and the onset of an autoimmune component increase the number of patients with progressive cardiac dilatation and a poor prognosis. Currently, myocarditis is commonly defined as an inflammatory heart disease where diagnosis is established according to the histological (Dallas criteria), immunological, and immunohistochemical criteria (14 or more lymphocytes per square mm, including up to four monocytes and seven or more CD3+ T-lymphocytes). The cause of myocarditis often remains unknown. It is believed that the cause of myocardial damage in most cases is a viral infection. Therefore, polymerase chain reaction of the myocardial tissue sample allows detection of enterovirus, adenovirus, parvovirus B19, herpes simplex virus types 1, 2, and 6, cytomegalovirus, and Epstein-Barr virus during histological and immunological studies [8]. Delayed acute viral disease and occurrence as a result of latent subacute myocarditis is probably not uncommon in the modern world, but the occurrence spontaneously resolves without consequences in most patients. In some cases, myocarditis persists and leads to the development of fibrosis, onset of tachyarrhythmias and/or heart failure. AF represents one of these manifestations. Current treatment for AF mainly involves the use of interventional techniques such as radiofrequency isolation of the pulmonary veins, application of multiple damage lines, etc. At the same time, intracardiac intervention allows an EMB to be performed to confirm inflammatory or degenerative myocardial disease. Therefore, we set a goal to evaluate the contribution of inflammation to the clinical outcomes of the radiofrequency ablation (RFA) of AF.

#### **2. Materials and Methods**

#### *2.1. Study Population and Design*

We examined 274 patients (182 men, 66.4%) aged 30 to 55 years (mean age of 42.2 ± 18.6 years) admitted to the clinic with a diagnosis of AF. The inclusion criterion was diagnosis of idiopathic AF. The exclusion criterion was the presence of associated diseases: arterial hypertension, obesity, diabetes mellitus, dyslipidemia, cardiovascular, autoimmune, pulmonary diseases, thyroid pathology, or other diseases that could potentially cause AF. While staying in the hospital, all patients underwent the following examinations: 12-lead ECG, Holter ECG monitoring, bicycle ergometry, six-minute walking test, clinical and biochemical blood tests, 24-h blood pressure monitoring, transthoracic echocardiography, stress test to exclude coronary heart disease (myocardial perfusion scintigraphy or stress ECHO), and in case of a positive stress test, multispiral computer or invasive coronary angiography to exclude atherosclerotic changes in the coronary arteries and, accordingly, ischemic genesis of arrhythmia. If pathological changes were detected during the examination, the patient was excluded from the study. The study included 67 patients (22.9%), in whom the cause of AF was not found by any methods available to us. Of these patients, 43 individuals (64.2%) were men aged 34 to 50 years (mean age of 41.1 ± 7.6 years). Upon admission to the clinic, all these 67 patients complained of palpitations. Persistent AF was in 29 patients (43.3%), and long-term persistent (for more than one year) in 38 cases (56.7%). The duration of arrhythmic history was 5.7 ± 1.4 years. The specific pharmacotherapy before admission to the hospital was not carried out, since it was initially believed that all patients had isolated AF. All patients with the persistent AF took antiarrhythmic drugs for AF prevention at the outpatient stage (before the hospitalization): amiodarone in 73.2% of cases, sotalol in 11.3% of patients, and propafenone in the rest of patients (15.6%). For the arrhythmia-paroxysms termination, amiodarone was used as a first line and propafenoneas a second line. All patients with long-term persistent AF before hospitalization were receiving β-blockers as drugs for heart-rate control. However, it should be noted that, according to the past medical history, patients previously took all available antiarrhythmic drugs, and the average number of medications taken was 2.8. At hospital discharge, after the interventional AF treatment, all patients were prescribed with the antiarrhythmic therapy for three months at least. Amiodarone was prescribed to patients who had long-term persistent AF before AF ablation and propafenonein to the remaining patients. The anticoagulation therapy was not prescribed before AF ablation, as all patients had no more than 1 CHA2DS2-VASc score. After the ablation, all patients were with the oral anticoagulation for three months.

The study was approved by the Local Ethics Committee and conformed to the Declaration of Helsinki on Human Research. Written informed consent was obtained from every patient after explanation of the protocol, its aims, and potential risks.

All patients underwent the interventional AF treatment. Computer angiotomography with reconstruction of the left atrium, transesophageal echocardiography, and anticoagulant therapy were used as preparation for the procedure. Also cardiac magnetic resonance (MRI) with contrast and late gadolinium enhancement was performed in all patients before AF ablation with the Vantage Titan 1.5T scanner (Toshiba, Tokyo, Japan). In all cases, before ablation, electroanatomic mapping of the left atrium was performed with the reconstruction of bipolar maps and the identification of areas with reduced amplitude, as well as with an electrical "scar". The radiofrequency antral isolation of the pulmonary veins, the posterior wall of the left atrium, and the mitral isthmus of the heart were performed using the CARTO system (Biosense Webster, Irvine, CA, USA) in all cases. Vein isolation was monitored with the Lasso circular mapping catheter (Biosense Webster, Irvine, CA, USA). The sinus rhythm, if necessary, was restored by electrical cardioversion. After the sinus rhythm restoration, EMB was performed. Biopsies were taken under X-ray control from the apex, interventricular septum (IVS), and right ventricular outflow tract. Of 67 patients who underwent EMB, 47 also underwent interatrial septum (IAS) biopsy under the transesophageal ultrasound control without any complications. The obtained samples were labeled accordingly and fixed in 10% buffered neutral formalin.

#### *2.2. Histological and Immunohistochemical Studies*

Paraffin sections were stained with hematoxylin and eosin, picrofuxin, and tolluidine blue; cardiac amyloidosis was excluded in patients over 45 years old by staining with Congo red. An immunohistochemical study was carried out to determine the immunophenotype of infiltrating cells (CD3, CD45, CD68) in each fragment of the endomyocardium and to detect the expression of cardiotropic virus antigens. The following antibodies were used: rabbit polyclonal antibodies to CD3 (Spring BioScience, Pleasanton, CA, USA), mouse monoclonal antibodies to CD45R0 (MONOSAN, Uden, The Netherlands), mouse monoclonal antibodies to CD68 (DCS), rabbit polyclonal antibodies to VP-2 protein of parvovirus B19 (Dako Cytomation), mouse monoclonal antibodies to VP-1 protein of enteroviruses (MONOSAN, Uden, The Netherlands), rabbit polyclonal antibodies to herpes virus type 2 (Dako Cytomation, Glostrup, Denmark), mouse monoclonal antibodies to herpes simplex virus type 1 (Leica Microsistems, Wetzlar, Germany), mouse monoclonal antibodies to adenovirus (Leica Microsistems, Wetzlar, Germany), mouse monoclonal antibodies to

early cytomegalovirus nuclear protein (Dako Cytomation, Glostrup, Denmark), and mouse monoclonal antibodies to Epstein-Barr virus LMP antigen (Dako Cytomation, Glostrup, Denmark). High-temperature antigen unmasking was performed when performing studies with antibodies to CD3, CD68, parvovirus B19, adenovirus, cytomegalovirus, herpes simplex virus type 1, 2, and LMP antigen of Epstein-Barr virus. A multivalent horseradish peroxidase diaminobenzidine (HRP-DAB) detection system (Spring BioScience, USA) was used to visualize the studied antigens.

The study of histological preparations was carried out at the light-optical level using an AxioLab A1 Zeiss microscope (Carl Zeiss AG, Jena, Germany). The 1997 Marburg agreement was used for morphological verification of myocarditis [9]. The infiltrating cells were counted, taking into account their immunophenotype (CD3, CD45, and CD68) [10,11].

#### *2.3. Clinical Follow-Up*

All patients had sinus rhythm on discharge from the clinic. After the procedure, all patients were prescribed antiarrhythmic and anticoagulant drugs for three months. The first three months of follow-up was considered a blind period, and the effect of the procedure was not evaluated; however, the occurrence of AF episodes was considered early relapses. All episodes of AF more than 30 s recorded on ECG or 24-h ECG monitoring, as well as symptomatic paroxysms, were considered an early relapse. Follow-up included an evaluation of complaints, ECG registration biquarterly, and Holter ECG monitoring twice every six months. The results of EMB and immunohistochemical studies were immediately provided to patients, with appropriate recommendations to follow.

#### *2.4. Statistical Analysis*

Statistical analysis was performed using the Statistica 10.0 software package and MedCalc 13. Continuous variables were expressed as mean ± standard deviation. The Shapiro-Wilk test was used to assess the normality of variable distribution. To assess the differences between the variables, the non-parametric Mann-Whitney test for independent samples was used. The Spearman test was used to estimate the correlation coefficient between quantitative variables. Efficacy analysis was performed using logistic regression analysis. To evaluate the independent predictors of CRT response, forward-stepwise logistic regression analysis was used with an entry criterion of *p* < 0.05 and a removal criterion of *p* > 0.1. Receiver-operating characteristic (ROC) analysis was used to determine the diagnostic efficiency of the methods. Intra- and inter-observer reproducibility was assessed with intraclass correlation coefficients (ICC): *p*-value < 0.05 was considered significant.

#### **3. Results**

According to EMB results, no histological changes in the myocardium of the right ventricle (RV) were found in nine patients (13.4%). Fibrotic changes in the myocardium were detected in 26 cases (38.8%) including in predominantly perivascular fibrosis in 11 patients (42.3%), small focal fibrosis in eight patients (30.8%), and perimuscular fibrosis in seven patients (26.9%) (Figures 1–3).

Inflammatory changes in the myocardium were detected in 32 patients (47.8%), including nine patients (28.1%) with lymphocytic infiltration of less than 14 lymphocytes per mm2 (Figures 4 and 5). The data obtained with EMB from RV and IAS were comparable. Inflammatory changes in RV correspond to a similar finding in IAS, while fibrotic changes in RV correspond to the same evidence in IAS. According to the results of immunohistochemical analysis, the virus expression was detected in one of these patients (3.1%). A combination of human herpes simplex virus type 2 and Epstein-Barr was found. No virus expression was detected in the remaining patients.

According to the Dallas criteria, the presence of histological myocarditis was revealed in 23 patients (34.3%) (Figure 6). Moreover, the virus expression was detected in 18 of these patients (78.3%), according to the results of immunohistochemical analysis. One patient (5.6%) was found to express three viruses: enterovirus, human herpes simplex virus type 1, and Epstein-Barr virus; six patients (33.3%) had the presence of two viruses: one patient had a combination of parvovirus and herpes simplex virus type 2; three patients had a combination of enterovirus and herpes simplex virus type 1; and two patients had a combination of Epstein-Barr virus and human herpes simplex virus type 2. The presence of one viral antigen was detected in 11 cases (61.1%), including five patients (27.8%) with Epstein-Barr virus, three patients (16.7%) with enterovirus (Figure 7), two patients (11.1%) with human herpes simplex virus, and one patient (5.6%) with parvovirus. Another five patients (21.7%) did not have viral infection.

**Figure 1.** Perimuscular fibrosis in IVS, ×100, staining according to Van Gieson. The arrows indicate the connective tissue proliferation.

**Figure 2.** Small focal fibrosis in IVS ×200, staining according to Van Gieson. The arrow indicates the focus of connective tissue proliferation.

When comparing the results of EMB from IAS and electroanatomic mapping, the results of both studies largely coincided. If there was an intact myocardium according to the EMB data, then no areas with reduced amplitude, and no electrical "scar", were

detected according to the bipolar voltage map. If fibrosis was diagnosed by EMB, then according to the bipolar voltage map, areas with reduced amplitude as well as an electrical "scar" were detected (Figure 8).

**Figure 3.** Fibrosis in IAS ×200, staining according to Van Gieson. The arrows indicate the foci of connective tissue proliferation.

**Figure 4.** Endomyocardial infiltration with CD3+ lymphocytes. Immunohistochemical study, antibodies to the Epstein-Barr virus, ×200.

According to the 16–28-month follow-up results (on average 19.3 ± 3.7 months), the patients were divided into two groups. Group 1 comprised individuals who had no AF recurrence during follow-up according to the objective and subjective examinations. Group 2 comprised patients with reported relapses of AF or other atrial tachyarrhythmias. Data are presented in Table 1.

Considering that 35 patients did not have arrhythmia paroxysms (group 1), the overall efficiency of a single procedure was 52.2%. Early relapses were reported in 26 (41.3%) cases: in 14 patients (22.2%) with fibrotic changes and in 12 patients (19.1%) with inflammatory signs. During further follow-up, the paroxysms of arrhythmias were recorded in 27 patients (42.9%), of whom one patient (1.6%) had an intact myocardium, nine patients (14.3%) had fibrotic changes, and 17 patients (26.9%) had inflammatory signs.

**Figure 5.** Endomyocardial infiltration of IAS with lymphocytes, ×200. Hematoxylin-Eosin Staining.

**Figure 6.** Active lymphocytic histological myocarditis, ×100. Hematoxylin-Eosin staining.

**Figure 7.** Expression of the enterovirus antigen VP1 in the myocardium. Immunohistochemical study, monoclonal mouse antibodies, ×400.

**Figure 8.** Bipolar voltage map of a patient with the ineffective RFA of AF and fibrosis identified by IAS biopsy. Posterior and right oblique projections. Notes: red-color areas of the atrial signal amplitude less than 0.5 V; magenta areas of the atrial signal amplitude more than 1.5 V; gradient color signals - a transition zone. Purple dots indicate the PV ostiums.


**Table 1.** Effectiveness of RFA AF in various histological changes in the myocardium.


#### **4. Discussion**

On one hand, the introduction of the RFA AF method into clinical practice, as described by M. Haissaguerre in 1998, opened up the possibility of eliminating arrhythmia. On the other hand, the diagnostic search in many cases was limited by routine ECG registration of tachycardia [12]. The use of endocardial interventions for AF has become globally widespread. However, the overall effectiveness of procedures, according to different authors, rarely exceeds 80% [13]. Changing techniques, and creating additional lines and areas of damage, can increase the efficiency, but to a rather moderate degree. Most likely, the limitations are not caused by a low efficiency of procedure itself, but rather they are due to the fact that a purely mechanistic-anatomical approach is used, as a rule, during the interventional treatment when the veins are electrically isolated and lines are applied without paying attention to the causes of AF. However, the etiology and pathophysiology of AF are multifaceted, and subclinical inflammation, and its consequences including the development of fibrotic changes, may play an essential role in AF development.

In our study, using standard examination methods only in 67 (24.5%) out of 274 patients admitted to the clinic with a diagnosis of idiopathic AF we were unable to detect cardiovascular or other diseases that could potentially explain the onset of arrhythmias. Among these 67 patients with idiopathic AF with no clinical and anamnestic data for the presence of inflammation, almost half (47.8%) of them had the inflammatory changes in the myocardium with the cellular infiltration or criteria for histological myocarditis. Immunohistochemical study allowed detection of the virus expression in the myocardium of most of these patients (59.4%). It should be noted, however, that the lack of data for the presence of a viral infection in negative patients does not exclude the potential presence of other viruses, which could not be detected by the virus-specific diagnostic kits used in our study.

The role of inflammation in the pathogenesis of isolated AF remains equivocal and limited. It is well known that the information regarding the presence of myocarditis and fibrosis could be obtained non-invasively using MRI. In our study, MRI performed in all patients did not disclose any finding consistent with biopsy results. The controversial nature of our data may be explained by the fact that this type of examination is highly dependent on the type of scanner and the doctor who conducts the study. Another important method in the non-invasive diagnostics of inflammation is the assessment of systemic concentrations of inflammatory biomarkers. In several studies, the association of inflammation markers and AF occurrence has been demonstrated. In 2018, we published an article in which we showed that in patients with isolated AF, the plasma levels of TNF-a, IL-1ß, IL-6, IL-8, neopterin, and high-sensitivity C-reactive protein exceeded that in comparison with healthy volunteers, while the concentration of IL-10 did not differ. Markers of renin-angiotensin-aldosterone system, particularly plasma renin activity and aldosterone concentration, were within the range of reference values. In this study, a specific serum marker of the latent myocarditis in patients with AF was IL-6 at a concentration of more than 1.6 pg/mL, and the marker of latent viral myocardial infection was neopterin at concentrations >13.2 nmol/L [14]. The increased levels of these markers can serve as a sign of latent viral myocarditis in AF of unclear etiology.

While assessing the effectiveness of the intervention based on the results of histological examination, we found that the effectiveness of primary RFA in patients with the intact myocardium was 88.9%. However, the effectiveness of primary RFA dropped to 46.2% in patients with fibrotic changes of varying severity and was only 34.4% in the presence of criteria for histological myocarditis. Early recurrences of arrhythmias were absent in patients with unchanged myocardium. Patients with the presence of fibrotic changes more often (53.8%) had early relapses and less often late relapses (34.6%), which, to some extent, can be considered associated with a favorable prognosis, despite the presence of fibrotic changes in the myocardium. We observed the inverse relationship in patients with the presence of inflammatory changes: late relapses were detected more often (53.1%) whereas early relapses were found less often (37.5%). This observation most likely indicates the presence of a persisting and ongoing inflammatory process underlying the onset of recurrent arrhythmias. This portion of patients requires more thorough diagnostics, monitoring, and specific treatment.

Unfortunately, the amount of data on available approaches to diagnose atrial myocardial inflammation in vivo is limited to date. Atrial EMB may be dangerous due to the risk of potential complications, but other diagnostic modalities are not always justified in otherwise absolutely-healthy patients, primarily because it is hard to suspect myocarditis if AF is the only symptom of disease. On the one hand, inflammatory changes occurring in the atria are less dangerous and cannot be the primary cause of sudden cardiac death or heart failure. On the other hand, the capabilities of detecting atrial inflammation are limited. Meanwhile, the atria in comparison with the ventricles are more vulnerable to fibrosis and connective-tissue proliferation due to the lower myocardial mass, which ultimately results in the anisotropic propagation of excitation and the occurrence of atrial tachyarrhythmias.

However, according to the published data, Yamaguchi et al. performed the intracardiac ECHO-guided endocardial biopsy in patients with AF. The authors have shown that biopsy from the right atrium (RA) septum seems to be a feasible and safe technique, although the significance of the RA biopsy in clinical practice is still unclear. Also Yamaguchi et al. detected an inverse relationship between bipolar voltage and fibrosis. However, there was variation in fibrosis, especially in patients whose voltage was in the middle range. At the end of the article, the authors concluded that factors other than fibrosis could affect voltage, e.g., myocyte cell size, myocyte disarray, intercellular-spacing, myofibrillar loss, infiltration with adipocytes. However, the impacts of these factors on voltage have not been analyzed, and future studies are warranted [15]. In our study, we conducted endocardial biopsies from IAS with the transesophageal ECHO control. We agree that this procedure seems to be a feasible and safe technique, however, when comparing the results of EMB from IAS and electroanatomic mapping, in our case the results of both studies have largely coincided. Thus, the significance of the RA biopsy in clinical practice requires additional justification. Moreover, it is well known that Mitrofanova et al. in the article "Histological evidence of inflammatory reaction associated with fibrosis in the atrial and ventricular walls in a case-control study of patients with history of atrial fibrillation" have shown that histological signs of chronic inflammation affecting ventricular myocardium are strongly associated with AF and demonstrate significant correlation with fibrosis extent that cannot be explained by cardiovascular comorbidities otherwise [16].

The inflammatory changes in the atrial myocardium identified in our study raise more questions than answers. First of all, this work using an EMB-based approach represents an investigative study and should not be extended to widespread clinical practice. However, the identified inflammatory changes in the atrial myocardium in AF patients require further comprehensive investigation and, above all, the search for the ways of non-invasive or minimally invasive diagnostics. On the other hand, the implementation of such methods in clinical practice would require baseline data, which prompt a clinician to suspect the presence of myocarditis.

The second question is whether the presence of subclinical inflammation and viral infection in the cardiomyocytes of otherwise healthy patients requires therapy. If so, what should be the treatment goal: the elimination of arrhythmia as the leading symptom or the virus elimination? If the arrhythmia is eliminated, will this mean that the myocardium is healthy and there is no viral infection and subacute myocarditis, which could lead to sudden cardiac death or the development of inflammatory cardiomyopathy and heart failure after an indefinite time? If the treatment goal is to eliminate the virus, then comprehensive etiotropic therapy, which, as a rule, takes longer than one month, would be a priority without a doubt. However, it may be challenging to convince otherwise-healthy patients of treatment necessity. The most important question is how to monitor the effectiveness of the therapy: via the second biopsy or other diagnostic modalities? Will these methods allow study of the processes occurring in the myocardium? The infection consequences, i.e. the amount and extent of fibrous tissue in the atria and ventricles, remains an essential problem as they are known to lead to the onset and progression of atrial and ventricular remodeling.

Only nine (13.4%) of a rather small group of patients included in the study had no histological changes. These cases perhaps may be considered a variant of true electrical heart disease manifested in the form of AF. However, this statement is limited by the capabilities of diagnostic methods used in the study.

#### *4.1. Study Limitations*

The present study had some limitations. Our study was single-center and included a small group of patients with isolated AF. Because of this, this study is underpowered and its findings are only hypothesis-generating. Therefore, future research requires larger scale multicenter studies. In our work, we did not assess the adverse cardiac events such as thromboembolic events or heart failure during follow-up. Moreover, we used RFA as a treatment for AF, but we did not treat underlying histological myocarditis. We did not perform the high-density mapping using a multi-pole diagnostic catheter for bipolar voltage maps of the left atrium, but performed mapping with an ablation catheter.

#### *4.2. New Knowledge Gained*

The significance of EMB is supported by its ability to reveal the etiology of histological myocarditis and AF, specifically, in MRI negative patients. EMB results confirm the presence of histological myocarditis and, accordingly, may help in choosing etiotropic treatment.

#### **5. Conclusions**

The diagnostic term "idiopathic AF" is used unreasonably often in clinical practice. According to our data obtained during a standard examination, only 24.5% of patients had no diseases, which could potentially lead to the development of arrhythmia. The histological findings showed that only about 10% of AF patients had a true idiopathic form of arrhythmia, while half of AF patients had latent inflammatory changes in the myocardium and the remaining patients had fibrotic changes as a result of inflammation. Our findings indicate that the presence of inflammatory and fibrotic changes in the myocardium may increase the rates of early- and late-arrhythmia recurrences in patients undergoing RFA for AF. However, further studies are warranted to investigate in-depth this possible relationship.

**Author Contributions:** R.E.B.: study concept, study design, enrollment of patients, performing intracardiac examination, ARF of AF, and EMB, patient follow up, data analysis and interpretation, writing the original manuscript, manuscript revision, and approval for publication; M.S.K.: performing intracardiac examination, ARF of AF, and EMB, patient follow up manuscript revision, and approval for publication; Y.V.R.: performing histological and immunohistochemical studies, data analysis and interpretation, manuscript revision, and approval for publication; S.I.S.: patient examination, manuscript revision, and approval for publication; R.B.T.: patient examination, manuscript revision, and approval for publication; N.D.A.: manuscript revision, preparation, and approval for publication; S.V.P.: overall supervision of research, study concept, study design, manuscript revision, and approval for publication. All authors have read and agreed to the published version of the manuscript.

**Funding:** The study was supported by state federal budget #AAAA-A20-120041090006-1.

**Institutional Review Board Statement:** The study was conducted in accordance with the Declaration of Helsinki, and approved by the Institutional Ethics Committee of Cardiology Research Institute, Tomsk National Research Medical Center, Russian Academy of Science (protocol code 163 and 08/11/2017).

**Informed Consent Statement:** Informed consent was obtained from all subjects involved in the study. Written informed consent has been obtained from the patients to publish paper in an anonymous form.

**Data Availability Statement:** According to the internal regulations of the Institute, all data are the property of the Institute and can only be provided anonymously after an official request.

**Conflicts of Interest:** The authors declare no conflict of interest.

#### **References**


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## *Review* **Catheter Ablation for Atrial Fibrillation in Structural Heart Disease: A Review**

**Francesco Maria Angelo Brasca 1, Roberto Menè 1,2 and Giovanni Battista Perego 1,\***


**Abstract:** Atrial fibrillation (AF) is the most common arrhythmia encountered in clinical practice. Patients with structural heart disease (SHD) are at an increased risk of developing this arrhythmia and are particularly susceptible to the deleterious hemodynamic effects it carries. In the last two decades, catheter ablation (CA) has emerged as a valuable strategy for rhythm control and is currently part of the standard care for symptomatic relief in patients with AF. Growing evidence suggests that CA of AF may have potential benefits that extend beyond symptoms. In this review, we summarize the current knowledge of this intervention on SHD patients.

**Keywords:** atrial fibrillation; catheter ablation; structural heart disease

#### **1. Introduction**

Atrial fibrillation (AF) is the most prevalent arrhythmia in clinical practice [1] and it is even more frequent in patients with structural heart disease (SHD) [2].

SHD encompasses a heterogeneous group of patients that share some important features, whatever the underlying disease. First, they are characterized by reduced hemodynamic tolerance to elevated heart rates and/or to the loss of atrial contribution to LV filling, which are associated with AF; second, in this population, the choice of anti-arrhythmic drugs (AADs) is limited, owing to possible side-effects; and third, the probability of rhythm control success on AADs is lower than in non-SHD patients [3]. Additionally, SHD patients are less represented in large clinical trials on AF catheter ablation (CA); therefore, except for a suggested higher recurrence rate [4], little evidence is available concerning interventional management of these patients.

The purpose of this article is to briefly review the clinical knowledge on interventional treatment of AF in this population.

#### *Structural Heart Disease Definition*

"Structural heart disease" (SHD) is an over-reaching term first introduced by Martin Leon at the 1999 Transcatheter Cardiovascular Therapeutics Meeting to encompass all cardiac disease processes [5].

The European Society of Cardiology (ESC) guidelines identify AF as secondary to SHD when a left ventricle (LV) systolic or diastolic dysfunction is demonstrated or LV hypertrophy, valvular disease, and/or other SHDs are documented [6]. Subsequent literature evolved the nomenclature so that, currently, SHD includes: (a) heart failure with reduced ejection fraction (HFrEF, previously severe or moderate LV systolic dysfunction); (b) heart failure with preserved ejection fraction (HFpEF, previously LV diastolic dysfunction); (c) valvular heart disease (VHD), ranging from prosthetic valves to rheumatic ones; and (d) specific cardiomyopathies, such as hypertrophic cardiomyopathy (HCM) [7].

According to the ESC Guidelines definition, criteria to identify SHD patients are based on non-specific parameters [7]. Thus, the SHD impact on AF prevalence and patient's

**Citation:** Brasca, F.M.A.; Menè, R.; Perego, G.B. Catheter Ablation for Atrial Fibrillation in Structural Heart Disease: A Review. *J. Clin. Med.* **2023**, *12*, 1431. https://doi.org/10.3390/ jcm12041431

Academic Editor: Alessandro Sciahbasi

Received: 19 January 2023 Revised: 2 February 2023 Accepted: 7 February 2023 Published: 10 February 2023

**Copyright:** © 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

prognosis could be different according to the underlying pathology and the severity of the disease.

In studies dealing with AF, specific biomarkers to assess hemodynamic status (e.g., natriuretic peptides) are rarely available and seldom reported and the degree of atrial remodeling is not uniformly defined because of the use of different parameters and imaging techniques (e.g., echocardiography or magnetic resonance).

#### **2. Impact of SHD on AF**

Independently of the underlying disease, a common final pathway is supposed to lead to AF: elevated left atrial pressure, causing "atrial myopathy" [8]. Indeed, atrial hypertension is associated with chamber dilation, extracellular matrix remodeling, autonomic imbalance, and calcium handling defects, which have a well demonstrated proarrhythmic effect and are involved in the induction and maintenance of AF [9,10].

The actual incidence and prevalence of AF in the overall SHD population have not been assessed, but data are available for specific subgroups.

#### *2.1. HFrEF*

In 2003, Maisel estimated that the AF prevalence ranges from <10% in New York Heart Association (NYHA) functional class I patients to nearly 50% in NYHA IV patients. Overall, HF patients have a sixfold increased risk of AF in the long term [11].

Both AF and HF have a higher prevalence in the elderly, and this might partially explain the correlation between the degree of functional impairment and the occurrence of AF. Nevertheless, there are several pathophysiological reasons for why they are supposed to favor each other, leading to the concept that "AF begets HF and vice versa" [12].

In particular, myocardial inflammation and fibrosis, leading to atrial interstitial fibrosis, are present in both AF and HF. Thus, during exertion, AF itself could be less tolerated in HF patients and, thereby, may trigger clinical recognition of this condition.

In a sample from the Framingham cohort including data between 1980 and 2012, it was found that a greater proportion of individuals have AF without HF, and AF more commonly precedes HF than in cohorts studied in previous years [12]. However, different strategies to detect AF have been implemented over time, making these results hardly comparable. Regarding the temporal relationship between AF and HF onset, it has been noted that patients who develop HF first and AF later have a worse clinical progression compared with the opposite [13].

#### *2.2. HFpEF*

HFpEF often coexists with other cardiac diseases; thus, it might be difficult to isolate its specific effect. Diastolic dysfunction should be graded according to American Society of Echocardiography recommendations and the evaluation should be based on parameters that are not affected by the presence of AF [14].

In a population study by Chen et al., one-third of patients with isolated diastolic dysfunction and HF-related symptoms show AF in the ECG presentation [15].

In a longitudinal study by Tsang and colleagues, abnormal LV diastolic function is associated with new onset of AF in almost 10% of cases within 4 years. In particular, the presence of grade 2 or 3 diastolic dysfunction was associated with a 2.5-fold increase in AF recurrence risk when compared with grade 1 dysfunction or normal diastolic function [16].

#### *2.3. Valvular Heart Disease (VHD)*

The presence of rheumatic mitral stenosis, repaired mitral valve or prosthetic valve are three different conditions. The presence of just one of the three is sufficient to distinguish valvular and non-valvular AF [17].

In 1990, data from surgical series were published by Wipf et al., who reported an AF prevalence close to 75% in rheumatic heart disease (RHD) at the time of surgical treatment [18]. In addition, in early studies on patients treated with AAD, AF frequently complicated RHD, with more than 30% of patients with AF episodes over long-term followup [19].

Even if a decline in RHD prevalence was recorded in Western countries, the presence of a valvular heart disease is still associated with a 1.8–3.4-fold increased risk for AF [20], and mitral stenosis and mechanical prosthetic valves are associated with a further increase in thromboembolic risk [21].

#### *2.4. Cardiomyopathies*

Hypertrophic cardiomyopathy (HCM) is the most common hereditary cardiomyopathy [22], and thus the best investigated. The estimated prevalence of AF in HCM is 22.5% and the annual incidence is 3.1% [23].

The maintenance of sinus rhythm could be of a particular importance in HCM patients, as this is associated with a significant improvement in the New York Heart Association functional (NYHA) class and quality-of-life score [24]. These benefits seem to depend on heart rate control and atrial active contraction, which increase the LV filling, reducing outflow obstruction.

Furthermore, dyspnea and other heart failure symptoms are frequently associated with AF, which is a major cause of hemodynamic deterioration and an ominous prognostic indicator [24].

#### **3. Catheter Ablation**

Most structural heart diseases are associated with some degree of atrial hypertension, remodeling, and fibrosis. Marrouche and colleagues have reported that extensive atrial fibrosis is associated with a significant decrease in AF ablation effectiveness [25]. Thus, patients with SHD are expected to have a high rate of AF recurrence and to be less responsive to CA compared with non-SHD patients [26].

The evaluation and comparison among studies on CA in SHD is made difficult by the differences in the ablation strategy, energy sources, and endpoints.

To date, pulmonary veins' isolation (PVI) is recommended for the index procedure in both paroxysmal AF (PAF) and persistent AF (PerAF) patients [27]. More extensive ablation strategies are not supported by consistent data [28]. In particular, no evidence supports a different approach in SHD patients, even if, in this population, there is a widespread tendency to extend ablation beyond PVI, adding lines or complex fragmented atrial electrogram (CFAE) and extra-pulmonary foci ablation.

Radiofrequency is the most represented energy source in the literature on SHDs, whereas cryoballoon results have been reported only in registries [29].

Finally, studies are hardly comparable because of the differences in the assessment of AF recurrence. In many cases, AF detection is based on symptoms or on electrocardiography and/or prolonged cardiac monitoring triggered by symptoms. In some instances, loop recorders are implanted, providing continuous monitoring throughout the follow-up. In the specific setting of SHD, AF is more often symptomatic, thus symptom-based detection might be somehow more reliable than in the general population.

#### *3.1. CA in HFrEF*

AF ablation in HFrEF patients has been studied in several randomized clinical trials (RCTs). CA was compared either to other rhythm control strategies (AADs) or to rate control (drugs and/or ablate and pace). In most studies, extrapulmonary lesions, such as left atrial lines or CFAE, were added to PVI; single or multiple procedures were possible. The endpoints ranged from symptom recurrence, documented AF recurrence, and functional improvement (NYHA class, 6 min walk distance, QoL scores, peak oxygen consumption, LVEF, and BNP) to hard ones such as mortality and hospitalization.

Table 1 shows the results of the main studies, with some of them deserving specific considerations.

The CAMERA MRI trial included only idiopathic systolic dysfunction and used cardiac magnetic resonance to assess LVEF [30]. A significant improvement in LVEF (18 ± 13%) in the group of patients treated with catheter ablation and a reduction in LV end-systolic volume (−<sup>24</sup> ± 24 mL/m2 vs. −<sup>8</sup> ± 20 mL/m2, *<sup>p</sup>* < 0.0001) were observed; furthermore, extensive late gadolinium enhancement (LGE) was a negative predictor of LV functional improvement. Of note, MacDonald et al. published a similar study that failed to show an improvement in LVEF and other functional endpoints, probably owing to a larger proportion of advanced HF patients (90% NYHA III or more) [31].

More recently, RCTs comparing CA to AADs for rhythm control strategy focused on hospitalization or mortality. The AATAC trial compared CA to amiodarone in patients with PerAF [32]. An implanted device was used to detect AF. CA was more effective in preventing recurrences (30% vs. 66%; *p* < 0.001), preventing unplanned HF hospitalization (31% vs. 57%; *p* < 0.001), and reducing all-cause mortality (8% vs. 18%; *p* = 0.037).

CASTLE-AF enrolled 363 HFrEF patients, randomized to PVI ablation or medical (both rate and rhythm control) therapy [33]. Patients had PAF or PerAF, LVEF < 35%, NYHA functional class equal to II or greater, an ICD or CRTD device, and should have failed a prior treatment with AAD. At 38-month follow-up, CA reduced the risk of death or HF hospitalization (28.5% vs. 44.6%, *p* = 0.006). Both all-cause mortality (13.4% vs. 25%, *p* = 0.01) and cardiovascular death (HR 0.49, *p* = 0.009) were significantly reduced in the ablation arm. Arrhythmia-free survival at 5 years was 63% in the ablation group and 22% in the medical therapy arm. Nevertheless, only 10% of screened patients were included in the study, so these results could be applied only in really selected patients.

Interestingly, in a sub-analysis of CASTLE-AF [34], Brachman and colleagues found that a reduction in AF burden below 50% after 6 months of catheter ablation was associated with a significant reduction in all-cause mortality and hospitalizations for HF. The same relationship could not be found if patients were stratified according to AF recurrence after ablation, defined by the HRS consensus statement of at least one AF episode longer than 30 s following the procedure [4]. The authors speculate that this might be explained by a survival benefit proportionate to the time spent in sinus rhythm and by the reduction in AF burden, being an epiphenomenon of reverse atrial and ventricular remodeling following ablation. Overall, these considerations may prompt a paradigm shift in how procedural efficacy is defined.

In 2019, the AMICA trial was stopped owing to futility because a similar improvement in LVEF was obtained in both the CA group and the medical therapy group [35]. Of note, LVEF improved more than expected from the literature in the control group.

Lastly, the RAFT-AF trial compared all-cause mortality and HF events in both HFrEF and HFpEF patients with AF randomized to ablation-based rhythm control or to pharmacologic rate control [36]. Despite showing a non-significant trend for improved outcomes with ablation-based rhythm control (29% relative risk reduction, *p* = 0.066), the trial was stopped early for apparent futility. It must be noted that the decision to terminate the trial was taken following the 2017 ad-interim analysis, when the available results found a trend for a worse outcome with CA, which was eventually overturned in the final results. Notwithstanding this, ablation-based therapy was associated with significantly greater gains in quality of life, 6 min walk distance, and LVEF. In addition, there was a significantly greater fall in NT-proBNP levels in the ablation group.

The results of these trials have been included in a 2020 meta-analysis that, in a population of 1112 HF patients, has demonstrated a consistent benefit of CA compared with AADs in terms of all-cause mortality (49% relative risk reduction (RRR), *p* = 0.0003), rehospitalizations (56% RRR, *p* = 0.003), LVEF improvement (mean improvement of 6.8%, *p* = 0.0004), AF/AT recurrence (96% RRR, *p* < 0.00001), and quality of life (*p* = 0.007), without significant differences concerning safety [37]. Overall, these results highlight the physiologic and clinical advantage of maintaining sinus rhythm in HF patients, as well as the effectiveness of CA in pursuing this objective. Interestingly, in the same meta-analysis, a second subset of studies comparing pharmacologic rhythm control to rate control failed

to demonstrate clinically significant benefits. This may be explained by a lower efficacy of AADs in maintaining sinus rhythm and by the neutralization of the benefits of sinus rhythm by the adverse effects of these medications.

Furthermore, any rhythm control strategy is at high risk of failure when used in too advanced stages of the disease [38].

#### *3.2. CA in HFpEF*

Few data are available on CA in patients with HFpEF because of the recent definition of this nosologic entity.

In the study by Cha et al., the 1-year arrhythmia-free survival after CA was 84% in patients with normal LV function and significantly lower when diastolic or systolic dysfunction was found at echocardiography (75% and 62%, respectively) [39]. Of note, in the diastolic dysfunction group, patients were older and more frequently had hypertension. Nevertheless, both systolic and diastolic dysfunction were significant predictors of increased AF recurrence risk, even after correction for these potential confounders.

Hu et al. showed an association between diastolic abnormality, low voltages at LA electro-anatomical map, and recurrence rates [40]. Even if limited by the low number of patients enrolled, this study suggests a pathophysiological link between extensive fibrosis and CA failure in HFpEF.

A meta-analysis on six observational studies comparing CA in HFpEF and HFrEF found no differences in terms of procedural efficacy, periprocedural adverse events, or re-hospitalizations between the groups, but highlighted a significantly lower mortality at follow-up in the HFpEF group (mean difference of 0.41; 95% CI 0.18–0.94) [41].

Using retrospective data from a national administrative database, Krishnamurthy and colleagues found that CA in patients with HFpEF, compared with patients without HF, is associated with more procedural complications, all-cause readmissions, cardiac readmissions, noncardiac readmissions, and early mortality. Nevertheless, when adjusting for age, sex, and comorbidities, only all-cause readmissions maintain a statistically significant increased risk (OR 1.52; *p* = 0.002) [42]. These results suggest that increased procedural complications, readmission, and early mortality following CA in HFpEF patients are mainly driven by concomitant risk factors, such as age and comorbidities, rather than by HFpEF itself.

Finally, a significant group of HF patients was included in the CABANA trial and randomized to catheter ablation versus drug therapy [43]. In the related sub-group analysis of 778 patients with HF [44], 91% of these had LVEF > 40% and 79% had LVEF > 50%. This sub-group analysis can thus be considered the first randomized prospective collection of data on AF ablation in HFpEF. A significant reduction in the composite outcome of death, disabling stroke, serious bleeding, and cardiac arrest (HR: 0.64, 95% CI 0.41–0.99), as well as in all-cause mortality alone (HR: 0.57, 95% CI: 0.33−0.96), was found; notably, these beneficial results were not evident in the main trial including both HF and non-HF patients. In addition, patients undergoing CA experienced a considerable improvement in quality of life indicators and, not surprisingly, a lower incidence of AF recurrence and burden in each of the 12-month follow-up assessments to the end of the 5-year observation period. Interestingly, compared with other studies, patients were randomized to treatment within a relatively short period of time from their diagnosis of AF (median 1.1 years); as it is known that rhythm control pursued early in the course of AF is associated with better outcomes and that CA is more effective than AADs in maintaining sinus rhythm [45], part of the beneficial effects seen in the CABANA subgroup may be explained by early intervention. Overall, these data reinforce the role of CA in HFpEF, especially when administered in the early stages of the disease.

#### *3.3. Valvular Heart Disease (VHD)*

Few studies on CA in patients with uncorrected VHD are available, owing to the strong indication of valvular defect correction before trying the invasive treatment of AF [46]. The results are not consistent; a study found no difference in arrhythmias recurrence between VHD patients and non-VHD patients, but, notably, the recurrence rate was higher in patients with larger left atria in both groups [47]. Nevertheless, in moderate VHD patients, AF recurrence is more frequent than in non-VHD patients after discontinuation of AADs in the long-term follow-up [48].

Surgical ablation during valve surgery is a valid option [49] and its results are superior to a subsequent single CA procedure [50], but this analysis extends beyond the aim of this paper.

Catheter ablation in patients with prosthetic valves remains challenging; lower effectiveness, higher complication rates, greater radiation exposure, and higher incidence of post-ablation atrial tachycardia were reported [50,51]. Furthermore, a possible role of non-PV foci was suggested by the evidence that a strategy including extended PVI and non-PV trigger elimination is associated with a higher 12-month and long-term arrhythmia-free survival [52].

According to a meta-analysis by Santangeli et al., CA of valvular AF is associated with an increased risk of recurrences in patients with MVR, but it is feasible and safe, despite the presence of prosthetic valves or annuloplasty rings, in experienced centers [53].

#### *3.4. Hypertrophic Cardiomyopathy (HCM)*

To date, the role of AF ablation in this setting needs to be inferred from non-randomized observational studies, because no RCT is available. The success rate of AF ablation is lower than in patients without HCM [54]. The procedural results were evaluated in a metaanalysis by Zhao et al. [55]; a single ablation procedure is frequently followed by arrhythmia relapses and antiarrhythmic drugs and/or multiple procedures could be required. In particular, the probability of 3 months' freedom from arrhythmias after a single procedure is estimated to be 79%, while at 18 months, most patients experienced AF recurrences.

The association between AF recurrence and wall thickness or left ventricle (LV) outflow tract obstruction is not predictive, while left atrial (LA) structure, diameter, and electrical features, as well as the presence of LV apical aneurysm, seem to predict post procedural outcome [55–57].

Besides the possible presence of gaps in the isolation lesions set, two interesting hypotheses are proposed to explain the higher recurrence rate seen in HCM patients: the response of hypertrophic tissue to RF is different from that of normal myocardial tissue and non-PV foci are more frequent in HCM patients. The former might be the cause of PV stenosis, which occurs more often in these patients [58]. The latter is supported by the high frequency of post-ablation non-AF atrial tachycardias (38.4%) that have either macro-reentry or localized reentry as an underlying mechanism [59]. This may be explained by the extensive structural alterations seen in HCM atria and may be a reason to pursue a non-PVI-only ablation strategy [60].

#### *3.5. CA Technique in SHD*

Following the description of pulmonary veins' isolation (PVI) as the first effective CA strategy for AF [61], different techniques have been described in terms of both energy source (e.g., radiofrequency, cryo-energy, and electroporation) and ablation targets beyond PVI (e.g., posterior wall isolation and rotor ablation). Despite a flourishing body of literature on the role of these different techniques in AF, all of the aforementioned trials have been carried out using radiofrequency as ablation energy and few studies have specifically addressed the topic of CA strategies in SHD.

Recently, a retrospective analysis of the ONE-Stop Italian registry on Cryoballoon (CB) PVI was published [29]. The procedure time, fluoroscopic time, and complication rate were not different in a subgroup of 282 SHD patients as compared with the non-SHD cohort. The recurrence rate was similar in both groups at 13-month follow-up (22.0% vs. 21.6%; *p* = 0.895) and was not related to either left atrial size or LVEF. Of interest, the percentage of SHD patients on AAD treatment decreased from 70.7% to 28.7% after CB-PVI (*p* = 0.001). Because of its retrospective nature, the study suffers from possible selection bias

and included SHD patients with minimal or no reduction in LVEF. Similar results have been found in an international cohort including 318 patients with HF; that is, procedure-related safety and long-term efficacy following PVI through cryoablation were comparable in patients with and without HF [62]. Altogether, these results suggest that CB-PVI is feasible and safe in the SHD setting and that additional benefits might be obtained through the reduction in AAD usage.

More extensive atrial remodeling is present in persistent AF (as opposed to paroxysmal) and when AF is associated with HF. Therefore, mechanisms other than PVs' firing have been hypothesized for AF initiation and maintenance in these settings. Although meta-analyses suggest a potential incremental benefit in terms of procedural efficacy for extra-PVI lesions in patients with persistent AF [63,64], no conclusive evidence has been provided to date. Furthermore, in 2014, a meta-regression analysis reported no differences in sinus rhythm maintenance between the PVI-only approach and extended left atrial ablation in patients with AF and HFrEF [65]. Interestingly, however, in a small single-center study on paroxysmal AF, non-PV triggers were found to be more frequent in patients with LVEF < 35% compared with those with LVEF > 50% (69.1% vs. 26.6%; *p* < 0.001); ablation of these triggers, in addition to PVI, resulted in improved long-term procedural success (75.0% vs. 32.2%; *p* < 0.001) [66]. Thus, further investigation is needed to definitively assess the role of additional lesions in addition to PVI in these contexts.



#### **4. Conclusions**

Catheter ablation in SHD patients could be technically challenging, but it is feasible and safe. The best ablation strategy is not well defined; although non-PV additional lesions are a common practice, a PVI-only approach might have a role even in SHD patients. Whatever the initial ablation method, multiple procedures are often needed. Evidence of the improvement in LV function and quality-of-life is available in particular for HFrEF patients, while data on hospitalization and mortality are encouraging but limited to very specific subsets. Overall, despite that, in SHD patients, CA shows a higher AF recurrence rate, the clinical benefit could be more significant in the setting of SHD.

**Author Contributions:** Writing—original draft preparation, F.M.A.B.; writing—review and editing, F.M.A.B., R.M. and G.B.P. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research was funded by the Italian Ministry of Health.

**Data Availability Statement:** No original data are presented in the current article.

**Conflicts of Interest:** Dr. G.B. Perego is member of the Medtronic European Advisory Board. The authors declare no conflict of interest.

#### **References**


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