Predictive value of valvular calcification for the recurrence of persistent atrial fibrillation after radiofrequency catheter ablation

Abstract Background Valvular calcification (VC) is an independent risk factor for cardiovascular diseases. The relationship between VC and atrial fibrillation is not clear. Hypothesis We treated the aortic valve, mitral valve, and tricuspid valve as a whole and considered the possible association between VC and recurrence of persistent atrial fibrillation (PsAF) after radiofrequency catheter ablation (RFCA). Methods This study involved 2687 PsAF patients who underwent RFCA. Data were collected to explore the relationship between VC and outcome. VC was defined by echocardiography in aortic valve, mitral valve, or tricuspid valve. After 1 year follow‐up, subgroup analysis, mixed model regression analysis, and score system analysis were performed. The external validation of 133 patients demonstrated the accuracy of this clinical prediction model. Results Overall, 2687 inpatients were assigned to the recurrence group (n = 682) or the no recurrence group (n = 2005) with or without VC. Compared to patients with no recurrence, the incidence of VC was higher in recurrence patients. Recurrence was present in 18.5%, 34.9%, 39.3%, and 52.0% of the four groups, which met VC numbers of 0, 1, 2, and 3, respectively. After adjustment for potential confounding factors, VC was an independent risk factor for AF recurrence in several models. For multivariable logistic regression, a scoring system was established based on the regression coefficient. The receiver operating characteristic area of the scoring system was 0.787 in the external validation cohort. Conclusions VC was an independent risk factor for AF recurrence in PsAF after RFCA. The scoring system may be a useful clinical tool to assess AF recurrence.

As a common arrhythmia, atrial fibrillation (AF) is typified by a heart rate (HR) that is irregular and typically rapid.Over the past decade, the heightened occurrence of AF has been an important public health challenge. 1Radiofrequency catheter ablation (RFCA) has become an important treatment for AF, especially in heart failure (HF). 2 As a type of AF, persistent AF (PsAF) was defined as AF lasting more than 7 days.Due to the complex pathogenesis, myocardial fibrosis and disorder of electrical activity, it is also challenging to maintain sinus rhythm after RFCA in PsAF. 3 Valvular calcification (VC) is characterized by calcium deposition, osteogenic lesions, and fibrocalcific changes in the valve leaflet, which are also tightly associated with cardiovascular diseases. 4Fashanu et al. revealed that VC was associated with the incidence of HF and left ventricular function. 5A cohort study found that aortic valve calcification (AVC) showed predictive value for the incidence of major adverse cardiovascular events. 6tients with valvular diseases were associated with the incidence of AF.In addition, VC was also an independent predictor of the incidence of AF.In the Framingham study, there were 42 individuals with incident AF, and the hazard ratio was 1.6 after an analysis. 7e RFCA of PsAF was also a challenge.Nevertheless, the relationship between the outcome of PsAF RFCA and VC is still unknown.We investigated the association of VC with the recurrence of PsAF after RFCA.In addition, we explored the influencing factors and established a scoring system to identify high-risk patients.

| Study cohort
A total of 2687 inpatients with PsAF who had undergone RFCA were consecutively enrolled in this study from January 2018 to 2022 at The Anzhen Hospital.In addition, as external validation, 133 patients were enrolled between February 2022 and May 2022, and the predictive value of the scoring system was explored.
According to the VC by echocardiography, the patients were assigned to the calcification group (n = 327) or noncalcification group (n = 2360).PsAF was defined as a period of rapid, irregular atrial rhythm lasting at least 7 consecutive days. 8VC was defined as the presence of bright echoes on the aortic valve, mitral valve, or tricuspid valve. 9The major exclusion criteria included the following: paroxysmal AF, history of AF ablation, rheumatic heart disease, severe stenosis or regurgitation of the heart valve, and severe disease in other systems.The detailed recruitment process is shown in Figure S1.The study protocol was approved by the Institutional Review Board of The Anzhen Hospital, Beijing, China.

| Data collection
Data regarding demographic characteristics, clinical features, and laboratory examinations were collected for all subjects, such as sex, age, past medical history, smoking status, body mass index (BMI), blood pressure, HR, systolic blood pressure (SBP), left ventricular ejection fraction (LVEF), and albumin.The diagnostic criteria of the classical risk factors, including coronary artery disease (CAD), 10 HF, 11 stroke, 12 and diabetes mellitus (DM), 13 were followed according to the authoritative international guidelines.

| RFCA procedure
Before RFCA, oral anticoagulation was given for at least 4 weeks.
Transesophageal echocardiography or intracardiac echocardiography was performed to exclude left atrial thrombus.During RFCA, heparin was administered to maintain an activated clotting time of more than 300 s.After RFCA, antiarrhythmic drugs and oral anticoagulation were given for at least 3 months.Under the CARTO mapping system (CARTO; Biosense Webster Inc.), RFCA was performed at a maximum temperature of 45°C, maximum power of 50 W, and flow rate of 15 mL/min, and included circumferential pulmonary vein isolation, linear ablations, or complex fractionated atrial electrograms.The end point was defined as the isolation of the pulmonary vein and restoration of sinus rhythm.

| Follow-up
Follow-up was performed by telephone and outpatient clinics.
Twenty-four-hour Holter monitoring was performed at 1, 2, 3, 6, and 12 months after discharge.In addition, if patients felt serious symptoms of arrhythmia, they were also required to undergo an electrocardiogram at the closest hospital.AF recurrence was defined as documented atrial tachycardia, atrial flutter, or AF for at least 30 s during the 1-year follow-up.The final diagnosis of recurrence was reviewed by two cardiologists.

| Statistical analyses
The statistical computations were performed using SPSS software, version 26.0 (IBM Corp.).Continuous variables are reported as the means ± standard deviations for normally distributed data or medians and quartiles (quartile 1; quartile 3) for nonnormally distributed data and were compared using Student's t-test for normally distributed data or Mann−Whitney U test for nonnormally distributed data; the Kolmogorov−Smirnov test was used to check normality.Discrete variables are expressed as frequencies and percentages and were compared using the χ 2 test.Multivariable logistic regression analyses were performed to detect the relationship between AF recurrence and VC after adjusting for potential confounding variables.There were seven mixed-model regressions, which were adjusted for age, sex, ascending aorta inner diameter, left atrial diameter, LVEF, course of AF, BMI, HT, HF, CAD, DM, stroke, history of alcohol intake, SBP, DBP, HR, white blood cell, red blood cell, platelet, hemoglobin, lymphocytes, neutrophils, monocytes, alanine transaminase, aspartate aminotransferase, triglycerides, total cholesterol, high-density lipoprotein, low-density lipoprotein, urea, creatinine, uric acid, blood glucose, Na, K, total protein, albumin, CPVA, Roofline, mitral isthmus line, CTI, CFAE, superior vane cava, and others.These predictors of AF recurrence were assigned corresponding points based on their regression coefficient and produced a score system.Receiver operating characteristic (ROC) curves were constructed, and the areas under the curves (AUCs) were calculated to assess the discriminatory power of the scoring system.A two-sided p value < 0.05 was considered statistically significant.

| Baseline characteristics
According to the 1-year follow-up, 2687 patients were classified into a recurrence group (n = 682) and a no recurrence group (n = 2005).
The ages were 61.3 ± 10.3 and 60.8 ± 10.3, respectively.For VC, there were 122 patients (21.8%) in the recurrence group and 205 patients (9.6%) in the no recurrence group (p < 0.001).Compared to no recurrence, the BMI, course of AF and LA were higher in recurrence for all patients (all p < 0.05).The incidence of DM and alcohol consumption were significantly higher in recurrence for all patients (all p < 0.05).The FBG, TG, TC, and LDL-C levels were more elevated in patients with recurrence for all patients (all p < 0.001).In subgroup analysis, BMI, course of AF and LA were higher in recurrence patients for the VC subgroup and non-VC calcification subgroup (all p < 0.001).Similarly, the recurrence group showed significantly higher FBG, TG, and TC levels than the no recurrence group for the calcification subgroup (all p < 0.05).Furthermore, there were no significant differences in ablation procedures in the overall group and subgroups (Table 1).

| Baseline characteristics between the two groups
According to the presence of VC, PsAF patients were classified into two groups: the calcification group (n = 327) and the no calcification group (n = 2360).There were 239 male patients in the calcification group and 1679 male patients in the no calcification group (p = 0.466).The incidence of DM, alcohol consumption, and AF recurrence were significantly higher in the calcification group than in the no calcification group (all p < 0.05).Similarly, the calcification group had significantly higher FBG, TG, TC, and LDL-C levels than the control group (all p < 0.05).However, no significant differences were detected in the ablation methods between the two groups.In addition, there was a significant difference between the groups in terms of age, 63.0 ± 9.9 versus 60.7 ± 10.3 (p < 0.001, Table 2).
For comparison among groups, the difference was the most in FBG (all p < 0.001, Table 3).

| VC and recurrence
Table 4 shows the results of multivariate logistic regression for the association between the incidence of recurrence and VC.There were seven models after adjusting for age, sex, ascending aorta inner  4).5).Overall, 133 patients were included between February 2022 and May 2022.ROC analyses were used to evaluate the discrimination of the model; the AUC was 0.787 (95% confidence interval [CI]: 0.700−0.873).The optimal cutoff value was 7. In addition, the sensitivity was 70.3%, and the specificity was 71.9% (Figure S3).| 7 of 11 In this prospective study, we considered VC as a whole and explored the association of VC with the recurrence of PsAF.In addition, we deduced the scoring system for diagnosis and risk assessment in the clinical setting.Moreover, we demonstrated an increased risk of PsAF recurrence with an increase in the VC number.In addition, the scoring system exhibited excellent prediction ability regarding PsAF recurrence, which contributes to interventional strategies and individualizing treatments for doctors and is expected to provide new insights concerning prognosis.
As a progressive disease, VC is characterized by ectopic calcification in the aortic valvular, mitral valve, and tricuspid valve, which is also associated with the incidence of cardiovascular diseases such as HF and CAD. 14The pathogenic mechanism for VC is not yet fully understood.Altered shear forces are initiated in valvular tissue, which might cause an imbalance between oxidative stress and antioxidants. 15In addition, the dysfunction of endothelial structure precedes calcific mineral deposition with a series of inflammatory reactions. 16Besides, apoptosis also plays a critical role in the VC process, which releases calcium and forms calcified nodules. 17For the aortic valve, there are two cell types in valve leaflets, valvular endothelial cells and valvular interstitial cells, which are influenced by blood flow and shear stress. 18With stronger shear stress, valvular endothelial cells trigger a series of signaling pathways, such as oxidative stress, inflammatory infiltration, and lipid deposition. 19 clinical practice, VC is asymptomatic and usually discovered incidentally in physical examination.Recent studies have proven the association between VC and cardiovascular diseases, especially arrhythmia.As early as 1994, mitral annular calcification (MAC) was linearly correlated with a higher prevalence of atrioventricular block and bundle branch block. 20A total of 342 participants who had undergone transcatheter aortic valve implantation were stratified into two groups according to whether atrioventricular block occurred.After multivariate analysis, AVC was observed to be an independent risk factor for atrioventricular block. 21garding AF, numerous studies have found that MCV was associated with the incidence of AF.In the Multi-Ethnic Study of Atherosclerosis, 5683 patients were classified into the MAC progression group and the no MAC progression group.After a median of 8.6 years of follow-up, MAC progression was associated with an increased risk for AF. 22A meta-analysis confirmed the prognostic value of MAC for predicting AF.In addition, AF patients with MAC had a higher risk of adverse events. 23It is speculated that this may be related to left atrial enlargement.The underlying mechanism is likely related to the sharing of numerous biological characteristics.However, most VC studies have focused on MAC, and there have been few studies on AVC and tricuspid valve calcification (TVC).As a type of AF, valvular AF has been gradually emphasized.
The underlying mechanisms of VC formation also have many commonalities, such as oxidative stress and lipid deposits.Thus, we speculated that AVC and TVC may also be associated with AF.
In our study, VC was an independent risk factor for PsAF recurrence after RFCA.In our study, we explored VC integrally for the first time.With the increase in VC, the incidence of AF recurrence increased.We speculated that the burden of the dysfunction state was higher in the three valve calcifications.
There are several means of detecting VC, such as echocardiography, coronary computed tomography angiography (CCTA), and cardiac magnetic resonance imaging.For CCTA, VC was defined as a cutoff of 130 Hounsfield units of valve by the Agatston method. 25A recent study found that the quantitative analysis of VC might provide more information associated with death or valve replacement. 26As an invasive method, it is not used widely in clinical practice.Echocardiography not only accurately assesses cardiac structure but also provides semiquantitative VC.Global cardiac calcium scores and echocardiographic calcium scores were assessed by echocardiography.After analysis, higher calcium scores were significantly associated with the incidence of AF. 27 In the Framingham study, MAC was also assessed by echocardiography. 7As an inexpensive and radiation-free tool, echocardiography can precisely present calcification of valve leaves.Therefore, we chose echocardiography, which may be more suitable in our study.
There are many factors which could influence VC, such as aged, fibrotic underlying processes.In elderly patients with cardiovascular disease, the prevalence of MAC was 42%. 280][31] A meta analysis enrolled the 26 studies which found that BMI was associated with the AF recurrence. 32A recent study found that the level of TC and FBG were higher in recurrence group. 33For the model, those factors might reflect the state of inflammatory, atrial fibrosis, lipid metabolism in PsAF patients, which provided individualized assessments in clinical practice.

| LIMITATIONS
Our study has some limitations.First, AF recurrence is complex and multifactorial.The single-center nature of this study and the relatively small number of enrolled patients may have introduced selection bias.Second, VC was qualitatively evaluated in our study.
Quantitative assessment will be performed for further justification.
Furthermore, pulmonary valve calcification was not assessed in our study.What remains to be determined is whether the two are connected.

| FUTURE DIRECTIONS
Our study suggested that VC can predict the PsAF recurrence.
However, future studies are needed to explore relationship between the severity of VC and AF recurrence.Besides, the the mechanism of VC in the pathogenesis of AF will decipher.

| CONCLUSIONS
In PsAF, VC was an independent risk factor for recurrence after RFCA.With the increase in VC number, the incidence of recurrence was higher.The scoring system had better predictive value based on VC.

3. 5 |
Score system of AF recurrence and ROC Multivariate logistic regression analyses were used to explore the association of risk factors with AF recurrence.There were seven independent risk factors for AF recurrence: VC, LA, course of AF, BMI, TC, FBG, and alcohol consumption.ROC curves were generated and sensitivity and specificity were calculated.The cut-off value of LA, course of AF, BMI, TC, and FBG was obtained by the maximum Jordan index.According to the cut-off value, the continuous variables were divided into the categorical variables.Based on the regression coefficient, points were assigned to those factors and subsequently summed to obtain a predictive score of AF recurrence.The points were as follows: VC-3, LA > 37 mm-3, course of AF > 19 months-2, BMI > 26.99-2, TC > 3.65 mmol/L-1, FBG > 7.10 mmol/L-1, and alcohol consumption-2 (Table

T A B L E 1
Clinical characteristics in valvular calcification and no valvular calcification patients with recurrence and no recurrence.
AF" hypothesis, frequent AF attacks might lead to the remodeling of structural and electrical and the perpetuation AF.Due to the similar of the underlying mechanisms between AF and CV, this may be the "CV begets AF."In our model, VC, LAD, course of AF, BMI, TC, FBG, and alcohol consumption were the independent risk factors for AF recurrence, which indicated that the model had the excellent predictive value.As the classical factors, LAD, course of AF, and alcohol consumption reflect the the extent of atrial fibrosis, which AF, atrial fibrilltion; Alb, albumin; ALT, alanine transaminase; AST, aspartate transaminase; BMI, body mass index; CAD, coronary artery disease; CFAE, complex fractionated atrial electrograms; Cr, creatinine; CPVA, circumferential pulmonary vein ablation; CTI, cavotricuspid isthmus; DBP, diastolic blood pressure; DM, diabetes mellitus; FBG, fast blood glucose; HDL, high-density lipoprotein cholesterol; HGB, hemoglobin; HF, heart failure; HR, heart rate; HT, hypertension; LA, left atrium; LDL, low-density lipoprotein cholesterol; LVEF, left ventricular ejection fraction; MI, mitral isthmus; PLT, platelet; RBC, red blood cell; SBP, systolic blood pressure; SVC, Superior vena cava; TC, total cholesterol; TG, triglyceride; TP, total protein; UA, uric acid; WBC, white blood cell.Clinical characteristics between calification and no valvular calcification.Baseline characteristics of the number of valvular calcification.
T A B L E 2 T A B L E 3 Odds ratio and 95% confidence interval for recurrence.The logistic multivariable logistic regression analyses of AF recurrence.