Clinical and pathophysiologic determinants of catheter ablation outcome in hypertrophic cardiomyopathy with atrial fibrillation

Abstract Background Hypertrophic cardiomyopathy (HCM) is frequently associated with atrial fibrillation (AF). We compared clinical, echocardiographic, and electrophysiological parameters between HCM subtypes and those without HCM at AF catheter ablation (AFCA) and analyzed post‐AFCA reverse remodeling and AF recurrence based on HCM presence and subtype. Methods Among 5161 consecutive patients who underwent de novo AFCA, we included HCM patients and control patients who were age‐, gender‐, and AF type‐matched. Between AF‐HCM patients and controls, we compared baseline values for left atrium (LA) wall thickness (LAWT), reverse remodeling at 1‐year follow‐up, and procedural outcomes over the course of follow‐up between two groups. Results A total of 122 AF‐HCM patients and 318 control patients were included. AF‐HCM patients had more frequent heart failure and higher LA diameter, E/Em, and LA pressure (all, p < .001). However, LAWT did not differ from control group. A year after AFCA, degree of LA reverse remodeling was significantly lower in AF‐HCM than in control group (ΔLA dimension, p = .025). Nonapical HCM (HR 1.71; 95% CI 1.05–2.80), persistent AF (HR 1.46; 95% CI 1.05–2.04), and LA dimension (HR 1.04; 95% CI 1.01–1.06) were independent risk factors for AF recurrence. During 78.0 months of follow‐up, nonapical HCM patients showed higher AF recurrence rate than both apical HCM (log‐rank p = .005) and control patients (log‐rank p = .002). Conclusions The presence of HCM, particularly nonapical HCM, displayed increased LA hemodynamic loading with diastolic dysfunction and had poorer rhythm outcomes after AFCA compared to both apical HCM and control group.


| INTRODUC TI ON
Hypertrophic cardiomyopathy (HCM) is a relatively common genetic cardiac disease affecting one out of every 500 individuals in the general population and accompanies sarcomeric protein mutation in about 60% of the patients. 13][4] Despite the recognition of AF catheter ablation (AFCA) as the most effective rhythm control strategy for patients with AF, most large-scale studies evaluating its outcome have excluded those with AF-HCM.This may be due to the complex interplay between AF-HCM and the left ventricular (LV) hypertrophy, resulting in LV outflow tract (LVOT) obstruction and diastolic dysfunction, which have direct implications on the left atrial (LA) hemodynamic afterload and the development of remodeling myopathy. 5,62][13][14][15][16] This disparity in findings highlights the need for further investigation into the factors that may impact the effectiveness of AFCA in AF-HCM patients.Therefore, in this study, we compared clinical, echocardiographic, and electrophysiological parameters between patients with and without HCM and among HCM subtypes (apical versus nonapical) at the time of AFCA, while also analyzing reverse remodeling and the recurrence of AF after the AFCA based on HCM presence and subtype.

| Study population
The study protocol adhered to the principles of the Declaration of Helsinki and was approved by the Institutional Review Board of the Yonsei University Health System.All patients provided written informed consent for inclusion in the Yonsei AF Ablation Cohort (NCT02138695).Among 5161 prospectively enrolled consecutive patients who underwent de novo AFCA between March 2009 and September 2022 in a single center, we enrolled 122 patients with HCM (AF-HCM group) and 318 propensity scorematched patients (control group).Patients in the control group were selected from same cohort and were matched by age, gender, and type of AF (Figure 1).The exclusion criteria were as follows: (1) AF refractory to electrical cardioversion; (2) AF with rheumatic valvular disease; (3) a prior AF ablation or cardiac surgery; and (4) less than 18 years old.All patients stopped all anti-arrhythmic drugs for a period corresponding to at least five half-lives before the AFCA.

| Echocardiography and definition of HCM
Transthoracic echocardiography (TTE) was conducted prior to the procedure (within 3 months) and at the 1-year follow-up.The HCM diagnosis was based on echocardiographic evidence of a hypertrophied and nondilated LV with a wall thickness ≥15 mm in the absence of another cardiac or systemic disease capable of producing a similar magnitude of hypertrophy. 17One-year follow-up TTE was conducted in 362 (80 in AF-HCM group and 282 in control group) patients.We measured the echocardiographic parameters, including LA dimension, LA volume index, LV ejection fraction, and ratio of the peak mitral flow velocity of the early rapid filling to the early diastolic velocity of the mitral annulus (E/Em), and those parameters were compared between the baseline and 1-year follow-up TTE.In addition, HCM type according to the involvement location, presence of LVOT obstruction, and LV maximal thickness were evaluated in the AF-HCM patients.

| Two-dimensional speckle-tracking strain analysis
Speckle-tracking strain analysis was performed using a dedicated semi-automated software (AutoSTRAIN, TOMTEC-ARENA, Munich, Germany) to assess LA function. 18LA strain was obtained from apical four-and two-chamber images by semi-automatic endocardial border tracking and manual adjustment to optimize tracking. 19ong the three phases of atrial strain (reservoir, conduit, and contractile), we investigate LA reservoir strain (LASr) at baseline and 1year follow-up echocardiography to evaluate LA diastolic function in AF-HCM patients.

| Measurements of the LA wall thickness and LA pressure
Using pre-AFCA cardiac computed tomography (CT), LA wall thickness (LAWT) was assessed by specialized software (AMBER, Laonmed Inc., Seoul, Korea). 20,21The methodology and principles of this software have been previously described and have been validated through testing with a 3D printed phantom and in 120 patients. 20,21In brief, the endocardium of the LA was semiautomatically divided using the edge detector on the cardiac CT.
The LA wall was then extracted with an overlapped area using morphology operations after separation from other tissues using the multi-Otsu threshold algorithm in the Hounsfield unit histogram.After solving the vector field with Laplace's equation, the LAWT was calculated as a numerical streamline connecting the endocardium and epicardium using the Euler method.The thickness of the LA wall was measured at each segmented region (anterior wall, posterior wall, posterior-inferior wall, interatrial septum, left lateral isthmus, and LA appendage) as well as in the overall LA chamber.
During the AFCA procedure, LA pressure was measured during sinus rhythm and AF immediately after trans-septal puncture as described in previous studies.If the initial rhythm was AF, we terminated the AF rhythm by internal cardioversion, allowed the atrium at least 3 min to recover from the cardioversion's atrial stunning, and then assessed LA pressure during the ensuing sinus rhythm. 22,23We excluded those patients in whom LA pressure during sinus rhythm could not be measured due to frequent re-initiations of AF after electrical cardioversion.

| Electrophysiological studies and catheter ablation
The electrophysiological mapping method and AFCA technique/ strategy used during the study period were consistently performed as described previously. 24In brief, radiofrequency energy was delivered for the ablation under 3D electroanatomical mapping (NavX, Abbott, Inc., Minnetonka, MN, USA; CARTO system, Biosense Webster, Diamond Bar, CA, USA) using an open irrigated-tip catheter (Flexibility, Abbott, USA; Smarttouch, Celsius, ThermoCool, ThermoCool SF, Biosense Webster Inc., Diamond Bar, CA, USA).During high right atrial pacing at 500 ms, high-quality voltage maps were obtained utilizing a circumferential mapping catheter.We collected 500-1000 direct contact bipolar electrograms from the LA endocardium and used peak-to-peak amplitude analysis to determine the mean LA electrogram voltage.An initial circumferential pulmonary vein (PV) isolation was performed on each patient.The roof line, posterior-inferior line, anterior line, cavotricuspid isthmus line, superior vena cava to the septal line, or complex fractionated atrial electrogram-guided ablation were added at the discretion of the operator.After cardioversion with isoproterenol infusion (5-20 μg/min; target heart rate, 120 bpm), the operation was deemed successful if there was no immediate return of AF.
Extra-PV foci for mappable AF triggers were mapped and abated to the greatest extent.

| Postablation management and follow-up
All patients visited the outpatient clinic at 1, 3, 6, and 12 months after the AFCA and every 6 months thereafter or whenever symptoms occurred.All patients underwent electrocardiography at every visit and 24-h Holter recording at 3 and 6 months, then every 6 months for 2 years, annually at 2-5 years, and then biannually after 5 years according to the modified 2012 HRS/EHRA/ ECAS expert consensus statement guidelines. 25AF recurrence was defined as any episode of AF or atrial tachycardia lasting at least 30 s.Any electrocardiographic documentation of AF recurrence 3 months after the blanking period was identified as clinical recurrence.

| Statistical analysis
We used a propensity score approach to control confounding factors that might influence both group assignment and outcome.Age, gender, and type of AF were considered in the propensity score matching.We used a 1:3 matching algorithm, and the primary analysis was performed with selected subjects.Continuous variables are expressed as the mean ± standard deviation for normally distributed variables and as the median (interquartile range) for nonnormally distributed variables and were compared using Student's t-test and Wilcoxon rank-sum test, respectively.We used the chi-square or

| Intraprocedural and procedural findings of AF-HCM
During the procedure, we investigated intraprocedural values in two groups.AF-HCM group had higher LA peak pressure (p < .001)and mean LA voltage (p = .011)than control group, but the existence of extra-PV foci did not differ between two groups (p = .475,Table 2).
Empirical extra-PV LA ablation was more conducted in control group TA B L E 1 Baseline clinical characteristics between AF-HCM and control groups.than AF-HCM group (p < .001,Table 2).Furthermore, procedurerelated complication rate (p = .981)and incident stroke rate during follow-up periods (p = .876)did not differ between the AF-HCM and control groups (Table 3).

| Atrial reverse remodeling in HCM
We compared echocardiographic parameters between baseline and 1-year after the procedure between AF-HCM and control groups.
Although AFCA reduced LA dimension significantly a year after the procedure in both AF-HCM and control groups (Figure 2A,B), the degree of the LA size reduction was significantly lower in the AF-HCM group than control group (−2.0 [−4.5-0] vs. −3.0[−6.0-0], p = .025; Table 3; Figure 2C).Similarly, E/Em was increased a year after the procedure in both groups (Figure 2D,E), but the degree of the E/Em increase was significantly higher in the AF-HCM group than control group (1.0 [−1.1-4.0] vs. 0 [−1.9-2.0],p = .035;Table 3; Figure 2F).
We further assessed LA reverse remodeling between two groups based on the recurrence of AF.In subjects without AF recurrence, the extent of the LA size reduction was significantly lower in the AF-HCM group compared to the control group.However, in subjects with AF recurrence, there was no significant difference in LA reverse remodeling between the two groups (Tables S2 and S3).

| AFCA rhythm outcome and associated factors with AF recurrence
During a median follow-up of 78.0 (IQR 36.3-120.8)months, clinical recurrence was observed in 46.6% of patients.The rate of clinical recurrence between the AF-HCM and control groups was comparable (log-rank p = .308;Figure 3A).Yet, when HCM was divided into apical and nonapical types, the nonapical HCM group had a significantly higher recurrence rate than both control (log-rank p = .002)and apical HCM groups (log-rank p = .005)(Figure 3B).Importantly, there was no significant difference in the AF recurrence rate between the apical HCM and the control group (log-rank p = .611).
In  Abbreviations: AF-HCM, atrial fibrillation with hypertrophic cardiomyopathy; AFCA, atrial fibrillation catheter ablation; AT, atrial tachycardia; E/Em, ratio of the peak mitral flow velocity of the early rapid filling to the early diastolic velocity of the mitral annulus; LA, left atrium; LV, left ventricular.

| Characteristics and outcome according to the type of HCM
Since nonapical type HCM was an independent factor for AF recurrence, we investigated clinical factors and procedural outcomes in the AF-HCM subset according to the type of HCM.The nonapical HCM group had a higher proportion of heart failure (p = .012),LVOT obstruction (<.001), a higher LA dimension (p = .028),E/ Em (p = .001),LV max thickness (p = .001),and LA peak pressure (p = .003)than apical HCM (Table 5).Importantly, LASr was Changes in the echocardiography parameters before and 1 year after the AFCA depending on the presence of HCM.Although LA dimension was significantly reduced 1-year after the AFCA in both the AF-HCM group (A) and control group (B), the change in the LA dimension was significantly lower in the AF-HCM group than control group (C).E/Em was increased in both the AF-HCM group (D) and control group (E), but the degree of the E/Em increase was significantly higher in the AF-HCM (F).AF, atrial fibrillation; AFCA, atrial fibrillation catheter ablation; E/Em, ratio of the peak mitral flow velocity of the early rapid filling to the early diastolic velocity of the mitral annulus; HCM, hypertrophic cardiomyopathy; LA, left atrium.

F I G U R E 3
Kaplan-Meier curve for the clinical recurrence of AF after de novo and repeat procedure.(A) AF recurrence rate did not differ between AF-HCM and control groups (log-rank p = .308).(B) AF recurrence rate was significantly higher in the nonapical type HCM group than both apical type HCM group (log-rank p = .005)and control group (log-rank p = .002).AF, atrial fibrillation; AFCA, atrial fibrillation catheter ablation; HCM, hypertrophic cardiomyopathy.
We further examined the recurrence rate based on the type of AF within the HCM population.Within the AF-HCM group, clinical recurrence rate was significantly higher in those with persistent AF than paroxysmal AF (log-rank p = .016;Figure S1).For those with persistent AF, the recurrence rate across the three groups-apical HCM, nonapical HCM, and the control group-was consistent with the statistically significant results of the overall study groups.However, for paroxysmal AF, while the recurrence rate trended similarly, it did not achieve statistical significance (Figure S2A,B).Mean LA voltage (mV) 1.4 (0.9-1.9) 1.4 (0.7-2.1) .754
Abbreviations: AF, atrial fibrillation; AF-HCM, atrial fibrillation with hypertrophic cardiomyopathy; CFAE, complex fractionated atrial electrograms; CPVI, circumferential pulmonary vein isolation; E/Em, ratio of the peak mitral flow velocity of the early rapid filling to the early diastolic velocity of the mitral annulus; LA, left atrium; LV, left ventricular; PV, pulmonary vein; TIA, transient ischemic attack.a Mid-ventricular obstruction.
nonapical type] and 18 in the control group, Table S5).Time interval between de novo and repeat procedures (p = .517),PV reconnection rate (p = .755),and the existence of extra-PV triggers (p = .546)did not differ between the two groups (Table S5).There was no significant difference in AF recurrence rate between the two groups during a 19.0 (12.0-27.5)month follow-up period (log-rank p = .495;Figure S3).

| Main findings
In this prospective registry data on AFCA, we sought to explore the differences in clinical, echocardiographic, and electrophysiological parameters between patients with HCM and those without, and among HCMP subtypes.We also examined the patterns of clinical

| Rhythm control for AF-HCM
Rhythm control in AF-HCM patients is a valuable option, but there is controversy whether the effect of AFCA is inferior to that in non-HCM patients.13][14]16 Contrary to the previous reports, we observed similar rhythm outcomes after the AFCA in patients with HCM as compared to those without.In addition, our study showed that the presence of HCM did not affect wall thickness of LA, which was consistent with a previous study by Hayashi et al. 15 Furthermore, our study examined the impact of the type of HCM on the rhythm outcome, and surprisingly, the recurrence rate between the apical HCM group and the control group did not differ significantly, while we observed that nonapical HCM patients had a worse rhythm outcome than both the apical HCM and control groups.The relatively high proportion of apical HCM patients in our cohort may have contributed to the similar rhythm outcome between the HCM and non-HCM groups.Although we adjusted for some potential confounding factors during comparison between the AF-HCM group and the control group, we still observed that nonapical HCM type is independent factors for AF recurrence.These findings suggest that the type of HCM may play an important role in predicting the rhythm outcome after AFCA.

| Apical vs. nonapical HCM
Apical HCM is more prevalent in Asian countries than in Western countries and is associated with a lower myocardial fibrosis burden, less diastolic dysfunction, and a benign clinical course compared to nonapical HCM. 26,27In this study, two-thirds of the patients had apical type HCM and only 13.1% of AF-HCM patients had LVOT or mid-ventricular obstruction, which has a relatively good prognosis.
Therefore, the selection bias toward apical HCM patients in our study may have influenced the rhythm outcome of AFCA in AF-HCM patients.
In this study, we measured the LASr in the HCM group to explore the potential mechanisms underlying the difference in AF recurrence between patients with apical-and nonapical HCM.LASr is a measure of the LA function that assesses the deformation of the LA wall during ventricular systole. 28Our results revealed that nonapical HCM patients had lower LASr values than apical HCM patients.Apical HCM is characterized by hypertrophy of the apex of the heart, which can lead to less myocardial fibrosis, less diastolic dysfunction, and less increased LV filling pressure compared to nonapical HCM.The difference in LASr between apical and nonapical HCM may be due to the structural and functional differences between the two types of HCM. 26 Other possible factors that may influence LASr in HCM patients include the distribution and severity of hypertrophy, the presence of genetic mutations, and comorbidities.However, more research is needed to fully understand the mechanisms underlying the differences in LASr between apical and nonapical HCM patients.

| Repeat procedure in AF-HCM
Previous studies reported that AFCA is still effective choice for maintaining sinus rhythm in HCM patients although AFCA is not as efficacious in HCM patients compared to AF patients with no structural heart disease. 14,29In this study, we investigate repeat procedural findings in AF-HCM and control groups, and the results revealed that the PV reconnection rate and the existence of extra-PV triggers during the repeat procedure did not differ between two groups.These findings might suggest that LV diastolic function may have played a more significant role in the hemodynamics and reverse remodeling of the LA and may have affected AF recurrence rate after de novo AFCA in AF patients with HCM.

| Limitations
This study had several limitations.First, this was an observational prospective cohort study of highly selected patients who underwent AFCA.Moreover, there could be selection bias because this study was not an all-comers design ablation study.We tried to resolve some limitations by selecting propensity score-matched control groups.Second, the differentiation of HCM from other infiltrative heart diseases, such as cardiac amyloidosis, was not performed in a prospective manner for all patients using methods such as CMR, genetic studies, or myocardial biopsy.Instead, these diagnostic tests were conducted at the discretion of the treating clinicians on an as-needed basis.This approach may have resulted in some patients with infiltrative heart diseases being included in the HCM group, potentially affecting the study findings.
Third, although we kept a consistent ablation protocol performed by experienced operators, the catheter and mapping technologies kept changing during the long enrollment period.Fourth, the evaluation of LA size by the LA diameter could have been limited than by the LA volume, but since all the patients underwent serial echocardiography before and 1 year after the procedure, we could evaluate the changes in LA size and compare the differences between two groups with LA diameter.Fifth, more frequently performed additional extra-PV LA ablation in control group would be one of factor that influenced AF recurrence outcome.However, we found that the apical type HCM still remained as independent factor for AF recurrence even after adjusting ablation strategy during Cox regression analysis.Sixth, previous studies reported that the proportion of the low voltage area in LA is associated with extent of atrial fibrosis and AF recurrence.However, our study evaluated LA voltage value with a parameter of mean LA voltage and this parameter would have limited value to reflect atrial fibrosis.Seventh, we have no data of pre-and postprocedural AF burden.Eighth, although HCM is a genetic disease, we did not evaluate the genetic susceptibility for HCM, genetic influence on the HCM type, or outcome of AFCA.However, recent studies reported that there has been no significant impact on genetic mutation on ablation outcomes. 12Further study including a genetic study in HCM is necessary.

| CON CLUS ION
In this study, AF-HCM patients showed increased LA hemodynamic loading and diastolic dysfunction, but similar post-AFCA rhythm outcomes compared to the control group.Yet, nonapical HCM type is important poor prognostic factor and the nonapical HCM patients had less favorable rhythm outcome compared to both non-HCM and apical HCM patients.

CO N FLI C T O F I NTER E S T S TATEM ENT
The authors declare no conflict of interest.

A PPROVA L O F TH E R E S E A RCH PROTO CO L
The study was approved by the institutional review board.

I N FO R M ED CO N S ENT
Informed consent was obtained from all patients at admission.

R EG I S TRY A N D TH E R EG I S TR ATI O N N U M B E R
N/A.

A N I M A L S TU D I E S
N/A.

F I G U R E 1
Patient selection and included patients of the study.AF, atrial fibrillation; AFCA, atrial fibrillation catheter ablation; HCM, hypertrophic cardiomyopathy.| 481 LEE et al.

Fisher's exact
test to compare categorical variables.We conducted a Kaplan-Meier analysis test to analyze the probability of the freedom from AF recurrence after AFCA.Using Cox regression analysis, we identified predictors of AF recurrence after AFCA.The variables selected for the multivariate analysis were those with p-value <.05 in the univariate analysis.We used Statistical Package for the Social Sciences version 25.0 (IBM Corporation, Armonk, NY, USA) and R software version 3.6.2(The R Foundation for Statistical Computing, Vienna, Austria) for data analysis.
AF recurrence and post-AFCA atrial reverse remodeling based on the presence and subtype of HCM.Compared to those without HCM, AF-HCM patients exhibited a larger LA size and elevated LA pressure at the time of AFCA.AF-HCM patients demonstrated less favorable LA reverse remodeling after AFCA over a 1-year follow-up.While clinical AF recurrence did not differ based on the presence of HCM during the follow-up, patients with nonapical HCM experienced a significantly higher recurrence rate compared to the control group, which in contrast was not observed in those with apical HCM.
This work was supported by the Korea Medical Device Development Fund grant [Project number 1711174471; RS-2022-00141473] funded by the Korea government (the Ministry of Science and ICT, the Ministry of Trade, Industry and Energy, the Ministry of Health & Welfare, the Ministry of Food and Drug Safety).We would like to thank Mr. John Martin for linguistic assistance.
the multivariate Cox regression analysis to identify risk factors for AF recurrence, nonapical HCM was an independent risk factor (HR 1.71; 95% CI 1.05-2.80;p = .031),after adjusting other clinical and electrophysiological risk factors for the recur- rence such as persistent AF, LA dimension, and empirical extra-PV LA ablation (Table4).Additionally, persistent AF (HR 1.46; 95% CI 1.05-2.04;p=.025)andLAdimension (HR 1.04; 95% CI 1.01-1.06;p=.006)werealsoidentified as independent risk factors for AF recurrence.In contrast, apical HCM did not stand out as an independent predictor for AF recurrence (HR 0.83; 95% CI 0.55-1.25;p=.375).TA B L E 3Procedural outcomes during follow-up and 1-year follow-up and changes of echocardiographic findings in the AF-HCM and control groups.
Clinical and procedural characteristics in subgroups according to the type of HCM in AF-HCM group.
a HRs were adjusted for persistent AF, LA dimension, empirical extra-PV LA ablation, and nonapical type HCM those were with p-value <.05 in the univariate analysis.TA B L E 5