Impact of Renal Dysfunction on Left Atrial Structural Remodeling and Recurrence After Catheter Ablation for Atrial Fibrillation　― A Propensity Score Matching Analysis ―

Yuya Takahashi; Takanori Yamaguchi; Akira Fukui; Toyokazu Otsubo; Kei Hirota; Yuki Kawano; Kana Nakashima; Mai Tahara; Takayuki Kitai; Atsushi Kawaguchi; Naohiko Takahashi; Koichi Node

doi:10.1253/circj.CJ-20-0149

Abstract

Background: Renal dysfunction coexists with other known risk factors of left atrial (LA) structural remodeling, expressed as low-voltage zones (LVZs), and the recurrence of atrial fibrillation (AF) after ablation. This study aimed to determine whether renal dysfunction had an independent effect on the presence of LVZs and recurrence after AF ablation, using propensity score (PS) matching analysis.

Methods and Results: 448 consecutive patients who underwent their initial AF ablation were enrolled. Chronic kidney disease (CKD) was defined as an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m², with 126 (28%) patients having CKD. Using PS matching analysis, new subsets (CKD and non-CKD group, n=103 each) were obtained, matched for age, sex, AF type, and LA volume. The presence of LVZs defined as bipolar voltage <0.5 mV was higher in the CKD group than in the non-CKD group (31% vs. 17%, P=0.034). Multivariate analysis showed eGFR was an independent predictor of the presence of LVZs (odds ratio 1.31 per 10-mL/min/1.73 m² decrease, P=0.029). AF-free survival rate was significantly lower in the CKD patients during 20±9 months of follow-up (63% vs. 82%, P=0.019), and eGFR was shown to be an independent predictor of recurrence (hazard ratio 1.29 per 10-mL/min/1.73 m² decrease, P=0.006), but the presence of LVZs did not predict recurrence.

Conclusions: Renal dysfunction independently predicted not only the recurrence of AF after ablation but also the presence of LVZs.

Catheter ablation is an established procedure for maintaining sinus rhythm (SR) in patients with atrial fibrillation (AF). However, its efficacy is still limited in some patients.¹^,² The presence of low-voltage zones (LVZs), which represent structural remodeling of the left atrium (LA), is known to be a strong predictor for the recurrence of AF after ablation.²^–⁵ It has been suggested that the primary mechanism of LVZs is atrial fibrosis,⁶ associated with a slowing of conduction and shortening of the refractory period, which facilitate the development of AF.⁷

Chronic kidney disease (CKD) is not only a risk factor for new onset of AF,⁸ but also a risk factor for recurrence of AF after ablation.⁹ Chao et al reported that a decreased estimated glomerular filtration rate (eGFR) was associated with a reduction in LA bipolar voltage and a high rate of recurrence after ablation in patients with paroxysmal AF (PAF).¹⁰ Recently, Matsuda et al also reported an association between renal dysfunction and the presence of LVZs in the LA of patients in both PAF and non-PAF populations.¹¹ However, the association between renal dysfunction and the presence of LVZs and recurrence of AF after ablation generally coexists with other known risk factors such as age, female sex, LA volume, and non-PAF type.²^–⁵^,¹⁰^,¹¹ These cofounding factors were not fully adjusted and accounted for in previous studies.

In order to clarify the sole effect of renal dysfunction on the presence of LVZs and recurrence of AF after ablation we used propensity score (PS) matching, a method commonly used to adjust for confounding factors and reduce differences in the clinical characteristics between patients with and without a specific condition.

Methods

Study Design and Patient Population

This study initially enrolled 448 consecutive Japanese patients who had undergone AF ablation for the first time between April 2014 and May 2017 after excluding the following: <20 years old; previous open-heart surgery; previous ablation in the LA; severe valvular heart disease; history of kidney transplantation; and hemodialysis (HD); 2 patients who failed SR restoration by external cardioversion were also excluded. CKD was defined as an eGFR <60 mL/min/1.73 m² for ≥3 months, irrespective of cause.¹² Because all the patients in the study were Japanese, eGFR was calculated using an adapted equation: eGFR (mL/min/1.73 m²)=194×serum creatinine^−1.094×age^−0.287×0.739 (if female).¹³ eGFR were calculated using serum creatinine levels measured within 7 days before ablation. The original cohort included 126 patients with CKD (28%) and 322 patients who did not have CKD (72%). The PS for CKD was generated from a multivariate logistic regression model using 4 variables strongly associated with the presence of LVZs and recurrence of AF: age, sex, AF type (PAF or non-PAF), and LA volume measured by computed tomography (CT).²^–⁵^,¹⁰^,¹¹ Patients in the 2 groups were matched on a 1:1 basis using a 4-digit nearest neighbor algorithm, resulting in 103 patient pairs (CKD and non-CKD groups). For subanalysis, the patients in the CKD group were divided into subgroups that included CKD3a defined as eGFR ≥45 and <60 mL/min/1.73 m² (n=81) and CKD3b/4/5 defined as eGFR <45 mL/min/1.73 m² (n=22). Pre- and post-ablation eGFRs were calculated using the serum creatinine level measured within 7 days before ablation and 1 year after ablation, respectively. ∆eGFR was defined as the difference between pre- and post-eGFR. Written informed consent was obtained and the study was approved by the institutional ethical review board.

PAF and non-PAF, including persistent AF and long-standing persistent AF, were defined according to the HRS/EHRA/ECAS/APHRS/SOLAECE consensus report.¹⁴ Both transthoracic and transesophageal echocardiography was performed prior to ablation to examine LA diameter, left ventricular function, and to exclude LA thrombi. LA volume was also evaluated before ablation by an ECG-gated, contrast-enhanced CT scan. When the patient’s eGFR was <30 mL/min/1.73 m², the CT was performed without contrast medium. LA volume included the measurement of the LA body, LA appendage (LAA), and pulmonary vein (PV) volume from the ostium to the first bifurcation. Antiarrhythmic drugs, with the exception of amiodarone, were discontinued for at least 5 half-lives before the ablation.

Voltage Mapping and Ablation Strategy

Electrophysiological studies and catheter ablation were performed under general anesthesia.¹⁵ The details of voltage mapping and LA voltage-based ablation have been described elsewhere.⁴^,⁵ Briefly, LA geometry and a voltage map were created during SR using a 20-pole circular mapping catheter with a 1-mm electrode length and 2-mm interelectrode spacing (Reflection HD^TM, Abbott) and a 3D-electroanatomical mapping system (EnSite NavX^TM, Abbott). The mapping catheter was manipulated through a SL0^TM (Abbott) or Agilis^TM sheath (Abbott) to prevent insufficient contact with the wall. Patients with AF at the beginning of the procedure had an external biphasic direct current cardioversion (DC) to restore SR. When restoration of SR failed even when delivering DC up to 270 J or SR could not be maintained because of frequent AF recurrence, PV isolation (PVI) was performed during on-going AF, and then DC was repeated.

A LVZ was defined as an area with a bipolar peak-to-peak voltage <0.5 mV that covered >5% of the LA surface area excluding the PV antrum and LAA.⁴^,⁵ The %LVZ was defined as the total LVZ area divided by the LA surface area. PVI using an irrigated ablation catheter (CoolFlex^TM or FlexAbility^TM, Abbott) was performed in all patients with an endpoint of entrance and exit block. No substrate modification was performed in patients without LVZs. For patients with LVZs, LVZ homogenization was performed with the endpoints set at ≥80% homogenization of the LVZs in a maximum 40% of the LA surface to prevent stiff LA syndrome.⁴^,⁵^,¹⁶ Patients with ≥40% of %LVZ underwent isolation of the LVZs and/or linear ablation across the LVZs.⁴^,⁵ Superior vena cava isolation and cavotricuspid isthmus linear ablation were performed at the operator’s discretion. Finally, focal atrial tachycardia and non-PV ectopy triggering AF induced by isoproterenol infusion were also ablated.

To examine the distribution of the LVZs, the LA was divided into 6 regions: anterior, septum, roof, posterior, inferior, and lateral wall. Mean LA voltage was calculated as the average of the bipolar voltage of all the acquired points in the 6 LA regions.

Follow-up

Follow-up was performed at 1, 3, and 6 months, and thereafter every 6 months. A 12-lead ECG was performed at each follow-up visit. 24-h Holter monitoring was performed at 3 and 12 months, and 7-day Holter monitoring at 6 and 18 months. Thereafter, 24-h Holter monitoring was performed every 6–12 months. Any atrial tachyarrhythmia documented on the ECG recordings lasting ≥30 s after the 3-month blanking period was considered as a recurrence.¹⁴ When recurrence was suspected according to symptoms or a self-pulse check, 7-day Holter monitoring was performed. Antiarrhythmic drugs were discontinued 6 months after the procedure.

Statistical Analysis

Normally distributed data are expressed as the mean±standard deviation, and non-normally distributed data as the median and interquartile range (IQR). Continuous data were analyzed using the unpaired t-test or analysis of variance for normally distributed data, the Wilcoxon rank-sum test or Kruskal-Wallis for non-normally distributed data. Categorical data were analyzed using the χ² test or Fisher’s exact test as appropriate. Subgroup analysis was performed using trend tests to compare the characteristics of the patients and the electrophysiological data between the subgroups that included non-CKD, CKD3a, and CKD3b/4/5. The Jonckheere-Terpstra test was used for continuous data and the Cochran-Armitage test for categorical data. To identify the risk factors for the presence of LVZs, multivariate logistic regression analyses were performed using variables with a P-value <0.10 in the univariate analysis. An atrial tachyarrhythmia recurrence-free survival curve was generated by the Kaplan-Meier method and compared using a log-rank test between the CKD and non-CKD group, between the subgroups including non-CKD, CKD3a, and CKD3b/4/5, and between patients without LVZs (%LVZ <5%), with moderate LVZs (%LVZ ≥5%, <20%), and with extensive LVZs (%LVZ ≥20%). For the subgroup analysis, a log-rank test for trend was also performed to compare the recurrence-free survival rate. Multivariate Cox regression analyses were also performed to assess the relationship between the variables with a P-value <0.10 in the univariate analysis and the time to recurrence of AF. The difference in eGFR between pre- and post-ablation was evaluated using the paired t-test. P<0.05 was considered statistically significant. The PS matching and statistical analyses were performed using JMP software (version 13.0, SAS Institute Inc., Cary, NC, USA). The Jonckheere-Terpstra test was performed using SPSS software (version 22, SPSS Inc., Chicago, IL, USA).

Results

Patients’ Characteristics

The patients’ characteristics before and after PS matching are shown in Table 1. Before matching, patients with CKD were significantly older, had larger LA size, lower EF, and a higher CHA₂DS₂-VASc score. After matching, no differences were observed in these variables between patients with and without CKD. We then compared the extent of structural remodeling and outcomes of ablation between the CKD and non-CKD groups. In the CKD group, 42 patients (41%) had persistent AF and 11 patients (11%) had long-standing persistent AF; in the non-CKD group, 36 patients (35%) had persistent AF and 10 patients (10%) had long-standing persistent AF (P=0.616). Regarding underlying heart disease, 19 patients in the non-CKD group comprised 10 with non-ischemic cardiomyopathy, 4 with ischemic cardiomyopathy, and 5 with hypertrophic cardiomyopathy, and 24 patients in the CKD group respectively comprised 12, 8, and 4 cases. Amiodarone was prescribed in 22 patients. All patients underwent high-density mapping of the LA during SR (1,271±554 LA surface points) before (n=204) and after PVI (n=19). The characteristics of the patients in the subgroups are shown in Table 2.

Table 1. Baseline Characteristics and Ablation Results of Pre- and Post-Propensity Score Matching Between Non-CKD and CKD Patients

	Pre-propensity score matching			Post-propensity score matching
	Non-CKD (n=322)	CKD (n=126)	P value	Non-CKD (n=103)	CKD (n=103)	P value
Age, years	63±10	70±9	<0.001*	69±8	69±8	0.993
Female sex, n (%)	94 (29)	38 (30)	0.840	44 (43)	35 (34)	0.197
LA volume, mL, median (IQR)	125 (103–158)	144 (115–167)	0.004*	135 (109–170)	140 (114–161)	0.809
Non-PAF, n (%)	134 (42)	64 (51)	0.079	46 (45)	53 (51)	0.329
BMI, kg/m²	24.0±3.7	24.5±3.3	0.253	23.7±3.1	24.4±3.6	0.163
Underlying heart disease, n (%)	43 (13)	35 (28)	<0.001*	19 (18)	24 (23)	0.493
CHA₂DS₂-VASc score, median (IQR)	2 (1–3)	3 (1–4)	<0.001*	2 (1–3)	2 (1–4)	0.231
LVEF, %, median (IQR)	67 (61–71)	64 (59–70)	0.049*	68 (60–71)	65 (59–70)	0.120
LVDd, mm, median (IQR)	48 (43–51)	48 (44–51)	0.703	47 (43–51)	48 (44–51)	0.207
LA diameter, mm, median (IQR)	40 (36–44)	42 (39–45)	0.003*	41 (36–44)	41 (38–45)	0.130
Procedure time, min	153±35	154±40	0.867	154±35	154±40	0.973
CTI ablation, n (%)	241 (75)	94 (75)	1.000	81 (79)	78 (76)	0.618
SVC isolation, n (%)	197 (61)	64 (51)	0.055	65 (63)	52 (50)	0.067
Non-PV foci ablation, n (%)	45 (14)	19 (15)	0.765	17 (16)	17 (16)	1.000
LA mean voltage, mV	n/a	n/a	n/a	1.32 (0.96–1.79)	1.22 (0.87–1.66)	0.084
Presence of LVZs, n (%)	44 (14)	36 (29)	<0.001*	18 (17)	32 (31)	0.034*
LVZ area, cm², median (IQR)	13.8 (9.5–21.0)	15.8 (7.5–26.2)	0.744	7.3 (4.0–17.2)	14.5 (5.9–25.7)	0.019*
%LVZ,^† %, median (IQR)	15.8 (9.9–26.5)	16.8 (8.2–28.4)	0.772	9.5 (4.9–19.3)	16.2 (8.8–28.1)	0.017*
eGFR, mL/min/1.73 m², median (IQR)	75 (67–84)	52 (46–55)	<0.001*	70.6 (65.1–78.9)	51.9 (46.1–55.5)	<0.001*

*Significant value (P<0.05). ^†%LVZ (%)=LVZ area/LA surface area. AF, atrial fibrillation; BMI, body mass index; CKD, chronic kidney disease; CTI, cavotricuspid isthmus; eGFR, estimated glomerular filtration rate; IQR, interquartile range; LA, left atrium; LVDd, left ventricular end-diastolic diameter; LVEF, left ventricular ejection fraction; LVZ, low-voltage zone; PAF, paroxysmal atrial fibrillation; PV, pulmonary vein; SVC, superior vena cava.

Table 2 Baseline Characteristics and Ablation Results of Subgroups

	Non-CKD (n=103)	CKD3a (n=81)	CKD3b/4/5 (n=22)	P value CKD3a vs. CKD3b/4/5	P for trend
Age, years	69±8	69±8	69±7	0.911	0.969
Female sex, n (%)	44 (43)	27 (33)	8 (36)	0.791	0.293
LA volume, mL, median (IQR)	135 (109–170)	135 (109–159)	153 (124–183)	0.019*	0.375
Non-PAF, n (%)	46 (45)	41 (51)	12 (55)	0.744	0.307
BMI, kg/m²	23.7±3.1	24.4±3.5	24.2±4.0	0.827	0.166
Underlying heart disease, n (%)	19 (18)	16 (20)	8 (36)	0.115	0.132
CHA₂DS₂-VASc score, median (IQR)	2 (1–3)	2 (1–3)	3 (2–4)	0.023*	0.064
LVEF, %, median (IQR)	68 (60–71)	65 (60–71)	64 (46–68)	0.274	0.072
LVDd, mm, median (IQR)	47 (43–51)	47 (44–50)	50 (45–55)	0.078	0.088
LA diameter, mm, median (IQR)	41 (36–44)	41 (38–45)	44 (41–46)	0.005*	0.025*
Procedure time, min	154±35	154±39	152±45	0.824	0.754
CTI ablation, n (%)	81 (79)	59 (73)	19 (86)	0.169	0.898
SVC isolation, n (%)	65 (63)	40 (49)	12 (54)	0.667	0.143
Non-PV foci ablation, n (%)	17 (16)	14 (17)	3 (14)	0.677	0.860
LA mean voltage, mV	1.32 (0.96–1.79)	1.23 (0.88–1.69)	1.11 (0.70–1.63)	0.217	0.044*
Presence of LVZs, n (%)	18 (17)	21 (26)	11 (50)	0.035*	0.002*
LVZ area, cm², median (IQR)	7.3 (4.0–17.2)	14.5 (5.9–25.7)	15.2 (8.8–30.7)	0.294	0.001*
%LVZ,^† %, median (IQR)	9.5 (4.9–19.3)	16.4 (6.7–27.9)	16.2 (11.8–33.6)	0.434	0.001*
eGFR, mL/min/1.73 m², median (IQR)	70.6 (65.1–78.9)	53.3 (49.9–56.6)	36.8 (25.9–42.5)	<0.001*	<0.001*

*Significant value (P<0.05). ^†%LVZ (%)=LVZ area/LA surface area. Abbreviations as in Table 1.

Differences in Structural Remodeling

Figure 1 shows examples of voltage maps in the LA. LVZs in the LA were more frequently identified in the CKD group than in the non-CKD group (Table 1). Subgroup analysis showed that the presence of LVZs increased as renal function deteriorated (Table 2). Although the difference in the LA mean voltage was not significant between the CKD and non-CKD groups (P=0.084, Table 1), subgroup analysis showed a trend of a decrease in LA mean voltage as renal function deteriorated (Table 2). Both total LVZ area and %LVZ were significantly higher in the CKD group (Table 1), with subgroup analysis showing that total LVZ area and %LVZ increased as renal function decreased (Table 2). The distribution of LVZs was similar in the non-CKD and CKD groups (anterior, 100% vs. 100%; septal, 61% vs. 81%; roof, 44% vs. 53%; posterior, 44% vs. 31%, inferior, 17% vs. 22%; lateral, 22% vs. 12%, all P>0.05). The presence of LVZs was higher in non-PAF compared with PAF (37% vs. 12%, P<0.001). However, there was no significant difference in the presence of LVZs between persistent and long-standing persistent AF (37% vs. 38%, P=0.939). Multivariate analyses showed that eGFR was independently associated with the presence of LVZs as well as age, female sex, LA volume, and non-PAF type (Table 3).

Figure 1.

Examples of a voltage map in patients without (A) and with (B) LVZs in the LA. LA, left atrium; LVZ, low-voltage zone.

Table 3. Predictors of the Presence of LVZs

Variables	Univariate		Multivariate
Variables	OR (95% CI)	P value	OR (95% CI)	P value
Age (per 10-years increase)	1.99 (1.26–3.15)	0.002*	2.25 (1.31–3.86)	0.002*
Female sex	3.67 (1.89–7.13)	<0.001*	6.35 (2.69–15.00)	<0.001*
LA volume (per 10-mL increase)	1.13 (1.04–1.22)	0.002*	1.17 (1.04–1.31)	0.006*
Non-PAF	4.31 (2.12–8.76)	<0.001*	3.30 (1.38–7.87)	0.007*
Underlying heart disease	2.14 (0.98–4.65)	0.060	1.13 (0.43–2.97)	0.810
Hypertension	0.90 (0.47–1.74)	0.764
Diabetes mellitus	1.23 (0.50–3.03)	0.655
eGFR (per 10-mL/min decrease)	1.30 (1.06–1.60)	0.010*	1.31 (1.02–1.69)	0.029*
AUC			0.827

*Significant value (P<0.05). AUC, area under the curve; CI, confidence interval; OR, odds ratio. Other abbreviations as in Table 1.

Outcomes After Ablation

All patients successfully completed PVI, and patients with LVZs underwent LVZ homogenization. Procedure-related complications were noted in 1 patient in the non-CKD group (1%) and 6 patients in the CKD group (6%): cardiac tamponade (n=1), PV stenosis (n=1), transient phrenic nerve injury (n=2), esophageal ulcer (n=1), and vascular-related complications (n=2). There was no significant difference in ∆eGFR between patients with (n=49) or without recurrence (n=157) at 1 year after ablation [0 (−5.3–6.5) vs. −0.3 (−6.0–5.8) mL/min/1.73 m², P=0.971]. However, in patients with non-PAF, eGFR did not tend to worsen in patients without recurrence (n=69) compared with those with recurrence (n=30) [∆eGFR, −2.2 (−8.0–2.2) vs. 4.0 (−4.4–7.5) mL/min/1.73 m², P=0.149]. This difference was not statistically significant. The atrial tachyarrhythmia recurrence-free survival rate was significantly lower in the CKD group during 20±9 months of follow-up (63% vs. 82%, P=0.019, Figure 2A). Subgroup analysis also showed trends of a decrease in recurrence-free survival rate as renal function deteriorated (Figure 2B). When the recurrence-free rate was compared between patients without LVZs (%LVZ <5%, n=156), with moderate LVZs (%LVZ ≥5%, <20%, n=29) and with extensive LVZs (%LVZ ≥20%, n=21), the recurrence-free rate decreased as the extent of LVZs increased (Figure 2C). Univariate and multivariate Cox regression analyses showed that eGFR was an independent predictor of recurrence (hazard ratio 1.29 per 10-mL/min/1.73 m² decrease, 95% confidence interval 1.08–1.56, P=0.006) as well as LA volume (Table 4). Interestingly, neither the presence of LVZs (multivariate model 1) nor LA mean voltage (multivariate model 2) was shown to predict recurrence of AF.

Figure 2.

Kaplan-Meier curves of atrial tachyarrhythmia-free survival rate after voltage-based ablation in patients in the non-CKD and CKD groups (A), non-CKD, CKD3a, and CKD3b/4/5 groups (B), and %LVZ <5%, %LVZ <20%, and %LVZ ≥20% groups (C). *Significant value (P<0.05). CKD, chronic kidney disease; LVZ, low-voltage zone.

Table 4. Predictors of Recurrence after AF Ablation

Variables	Univariate		Multivariate model 1		Multivariate model 2
Variables	HR (95% CI)	P value	HR (95% CI)	P value	HR (95% CI)	P value
Age (per 10-years increase)	0.89 (0.64–1.27)	0.533
Female sex	1.37 (0.76–2.55)	0.296
LA volume (per 10-mL increase)	1.14 (1.07–1.21)	<0.001*	1.10 (1.03–1.17)	0.007*	1.10 (1.03–1.18)	0.003*
Non-PAF	1.85 (1.05–3.35)	0.033*	1.08 (0.56–2.09)	0.821	1.03 (0.50–2.14)	0.924
Underlying heart disease	1.75 (0.87–3.26)	0.108
Hypertension	1.37 (0.76–2.55)	0.294
Diabetes mellitus	2.20 (1.12–4.05)	0.023*	1.73 (0.89–3.36)	0.105	1.83 (0.86–3.61)	0.110
Presence of LVZs	1.94 (1.08–3.47)	0.025*	1.28 (0.67–2.41)	0.452
LA mean voltage (per 0.1% decrease)	1.07 (1.01–1.14)	0.019*			1.02 (0.96–1.09)	0.546
eGFR (per 10-mL/min/1.73 m² decrease)	1.43 (1.19–1.71)	<0.001*	1.29 (1.08–1.56)	0.006*	1.34 (1.10–1.62)	0.003*

*Significant value (P<0.05). HR, hazard ratio. Other abbreviations as in Tables 1,3.

Discussion

Major Findings

The present study used PS matched cohorts to show that renal dysfunction predicts the presence of LVZs and recurrence of AF after ablation. Interestingly, neither the presence of LVZs nor LA mean voltage was shown to predict recurrence of AF during 20±9 months of follow-up.

Previous Study

A population-based study that examined the association between ECG-documented AF and renal function in patients without HD dependency reported that the prevalence of AF increased in a dose-dependent fashion as renal function worsened. The prevalence of AF was 1.0% in adults without CKD and 2.8%, 2.7%, and 4.2% in adults with an eGFR ≥60 mL/min/1.73 m², albuminuria ≥30 and <60, or eGFR <30 mL/min/1.73 m², respectively.¹⁷ Chao et al¹⁰ reported that a decreased eGFR was associated with a reduction in LA peak-to-peak voltage and a high recurrence rate of catheter ablation in patients with PAF. In that study, the patient characteristics such as age, sex, and LA size were very different between patients with and without CKD, and these cofounding factors might have influenced the results, although the data were adjusted using a multivariate Cox regression analysis. Matsuda et al¹¹ also reported recently on the relationship between CKD and the presence of LVZs in patients undergoing AF ablation and the higher recurrence rate that occurred in CKD patients. However, no adjustment for cofounding risk factors for AF was made in their study. The present study used PS matching, the most commonly used method for adjustment of confounding factors, which reduced differences in the clinical characteristics between patients with and without CKD. The study showed an independent effect of renal dysfunction on the outcomes of ablation.

Effect of Atrial Substrate Properties by Renal Function

Several studies have described shared risk factors between CKD and AF. Common pathophysiologic mechanisms that may contribute to atrial fibrosis thereby increasing the risk of AF have been reported, including advanced age, heart failure, increased inflammation and sympathetic tone, activation of the renin-angiotensin-aldosterone system (RAAS),¹⁸ and abnormalities in myocardial structure and function.¹⁹ Cardiac amyloidosis may also influence LA voltage and outcomes, because deposition of the amyloid protein causes voltage reduction and a delay in conduction.²⁰

Excess extracellular phosphate due to renal dysfunction exerts cytotoxic effects, including cell death, that result from the formation of insoluble nanoparticles of calcium and fetuin-A, which interact with mineral ions to form stable colloidal complexes. These nanoparticles are referred to as calciprotein particles (CPPs),²¹ and have been reported to have a pathogenic role in extraosseous calcification and cardiac endothelial cell damage in a model of CKD.²² There is recent evidence that interaction failures in paracrine signaling between cardiac endothelial cells and cardiomyocytes induce endocardial fibrosis.²³ In addition, a decline in renal function and dietary phosphate load can increase circulating fibroblast growth factor-23 (FGF23) levels, known to be associated with ventricular hypertrophy, systolic dysfunction, and increased prevalence of AF.²⁴ Further investigation is needed to confirm that the control of serum phosphate levels from an early period may contribute to a reduction in atrial fibrosis and prevalence of AF.

Effect of Voltage-Based Ablation for CKD Patients

Our study showed clearly that the recurrence rate for atrial tachyarrhythmia was higher as renal function deteriorated and that the %LVZ also increased. Of note, eGFR was shown to be an independent risk factor for recurrence, whereas neither the presence of LVZs nor LA mean voltage influenced recurrence. The outcomes of patients with %LVZ either <20% or ≥20% were similar during the long-term follow-up period even after additional LVZ homogenization, although in the early phase of follow-up there appeared to be a significant difference. These data suggest that LA fibrosis progresses over time, especially in patients with CKD, and eventually becomes the cause of the recurrence. Whether or not renal function itself or other factors that induce renal dysfunction are the cause of LA fibrosis progression and recurrence has yet to be determined.

Effect of AF Type on the Outcomes

The presence of LVZs was higher in non-PAF than in PAF (37% vs. 12%, P<0.001), with the non-PAF type being an independent predictor of the presence of LVZs, in addition to eGFR, LA size, age, and female sex. However, there was no significant difference in the presence of LVZs between persistent and long-standing persistent AF (37% vs. 38%, P=0.939). This suggests that the presence of LVZs, the primary mechanism of which is considered to be fibrosis, is associated with whether or not AF can persist, although it may not necessarily be associated with the duration of AF. Previous studies have shown a higher recurrence rate in persistent AF compared PAF,³^,⁵ but we observed that the non-PAF type was not a predictor of recurrence. This finding is consistent with that of our previous study, which showed that LVZ was a strong independent predictor of recurrence after ablation irrespective of AF type.² However, in the present study the presence of LVZs was not a predictor of recurrence during long-term follow-up, whereas eGFR and LA size were shown to be independent predictors of recurrence. Additional LVZ ablation following PVI in patients with LVZs might have affected these results. Furthermore, in patients with a decreased eGFR and enlarged LA, fibrosis might have progressed over time independently of baseline fibrotic remodeling expressed as the presence of LVZs.

Study Limitations

This study was a retrospective cohort study. PS matching was performed for patient characteristics including sex, age, AF type, and LA volume, which are known predictors for LVZs,² although it is possible other confounding factors may have also affected the development of this condition. Voltage mapping and voltage-based catheter ablation has several limitations as previously described in detail.²^,²⁵ The follow-up methodology after catheter ablation was not stringent, although 7-day Holter monitoring was carried out at 6 and 18 months. Thus, some cases of asymptomatic recurrence might have been missed.

Conclusions

Renal dysfunction is an independent predictor for both the presence of LVZs and recurrence after AF ablation. Renal dysfunction is a stronger risk factor for recurrence after AF ablation than the presence of LVZs in the LA.

Acknowledgments

None.

Data Availability

The deidentified participant data will not be shared.

Disclosures

T.Y. received remuneration and scholarship funds from Abbott Medical Japan. T.Y. and T.O. are also affiliated with the Department of Advanced Management of Cardiac Arrhythmia, Saga University, sponsored by Abbott Medical Japan, Nihon Kohden Corporation, Japan Medtronic, Japan Lifeline, Boston Scientific Japan, and Fides-ONE Corporation. The other authors declare that they have no conflict of interest. This research did not receive a grant from any funding agency in the public, commercial, or not-for-profit sectors. N.T. and K. Node are members of Circulation Journal ’s Editorial Team.

IRB Information

Ethical Review Board of Saga-ken Medical Center Koseikan, Reference no. 18-09-02-02.

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