Atrial amyloidosis identified by biopsy in atrial fibrillation: prevalence and clinical presentation

Kodai Shinzato; Yuya Takahashi; Takanori Yamaguchi; Toyokazu Otsubo; Kana Nakashima; Goro Yoshioka; Kensuke Yokoi; Kotaro Tsuruta; Ryosuke Osako; Shigeki Shichida; Yuki Nishimura; Makoto Edayoshi; Yuki Kawano; Yukako Shintani-Domoto; Kai Miyazaki; Akira Fukui; Atsushi Kawaguchi; Shigehisa Aoki; Seitaro Nomura; Naohiko Takahashi; Kaoru Ito; Koichi Node

doi:10.1093/eurheartj/ehaf332

. 2025 May 20;46(35):3437–3449. doi: 10.1093/eurheartj/ehaf332

Atrial amyloidosis identified by biopsy in atrial fibrillation: prevalence and clinical presentation

Kodai Shinzato ^1,^#, Yuya Takahashi ^2,^#, Takanori Yamaguchi ^3,^✉,^#, Toyokazu Otsubo ^4,^#, Kana Nakashima ^5,^#, Goro Yoshioka ^6,^#, Kensuke Yokoi ⁷, Kotaro Tsuruta ⁸, Ryosuke Osako ⁹, Shigeki Shichida ¹⁰, Yuki Nishimura ¹¹, Makoto Edayoshi ¹², Yuki Kawano ¹³, Yukako Shintani-Domoto ¹⁴, Kai Miyazaki ¹⁵, Akira Fukui ¹⁶, Atsushi Kawaguchi ¹⁷, Shigehisa Aoki ¹⁸, Seitaro Nomura ^19,²⁰, Naohiko Takahashi ²¹, Kaoru Ito ²², Koichi Node ²³

¹ Department of Cardiovascular Medicine, Saga University, 5-1-1, Nabeshima, Saga 849-8501, Japan

² Department of Cardiovascular Medicine, Saga University, 5-1-1, Nabeshima, Saga 849-8501, Japan

³ Department of Cardiovascular Medicine, Saga University, 5-1-1, Nabeshima, Saga 849-8501, Japan

⁴ Department of Cardiovascular Medicine, Saga University, 5-1-1, Nabeshima, Saga 849-8501, Japan

⁵ Department of Cardiovascular Medicine, Saga University, 5-1-1, Nabeshima, Saga 849-8501, Japan

⁶ Department of Cardiovascular Medicine, Saga University, 5-1-1, Nabeshima, Saga 849-8501, Japan

⁷ Department of Cardiovascular Medicine, Saga University, 5-1-1, Nabeshima, Saga 849-8501, Japan

⁸ Department of Cardiovascular Medicine, Saga University, 5-1-1, Nabeshima, Saga 849-8501, Japan

⁹ Department of Cardiovascular Medicine, Saga University, 5-1-1, Nabeshima, Saga 849-8501, Japan

¹⁰ Department of Cardiovascular Medicine, Saga University, 5-1-1, Nabeshima, Saga 849-8501, Japan

¹¹ Department of Cardiovascular Medicine, Saga University, 5-1-1, Nabeshima, Saga 849-8501, Japan

¹² Department of Cardiovascular Medicine, Saga University, 5-1-1, Nabeshima, Saga 849-8501, Japan

¹³ Division of Cardiology, Saiseikai Futsukaichi Hospital, Chikushino, Japan

¹⁴ Department of Integrated Diagnostic Pathology, Nippon Medical School, Tokyo, Japan

¹⁵ Department of Integrated Diagnostic Pathology, Nippon Medical School, Tokyo, Japan

¹⁶ Department of Cardiology and Clinical Examination, Faculty of Medicine, Oita University, Yufu, Japan

¹⁷ Faculty of Medicine, Education and Research Center for Community Medicine, Saga University, Saga, Japan

¹⁸ Department of Pathology and Microbiology, Saga University, Saga, Japan

¹⁹ Department of Cardiovascular Medicine, The University of Tokyo, Tokyo, Japan

²⁰ Department of Frontier Cardiovascular Science, The University of Tokyo, Tokyo, Japan

²¹ Department of Cardiology and Clinical Examination, Faculty of Medicine, Oita University, Yufu, Japan

²² Laboratory for Cardiovascular Genomics and Informatics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan

²³ Department of Cardiovascular Medicine, Saga University, 5-1-1, Nabeshima, Saga 849-8501, Japan

^✉

Corresponding author. Tel: +81 952 34 2364, Fax: +81 952 34 2089, Email: takanori@cc.saga-u.ac.jp

Kodai Shinzato, Yuya Takahashi, Takanori Yamaguchi, Toyokazu Otsubo, Kana Nakashima and Goro Yoshioka contributed equally to the study.

PMCID: PMC12448450 PMID: 40392565

Abstract

Background and Aims

This study aimed to assess the prevalence of cardiac amyloidosis (CA) in patients with non-valvular atrial fibrillation (AF) and to test the hypothesis that early-stage CA can be identified through atrial biopsy.

Methods

Atrial biopsy was performed on 578 patients during AF ablation, with right ventricular (RV) biopsy conducted in 385 patients. The amyloid type was assessed using immunohistochemistry. Patients were classified into groups of atrial biopsy–detected CA (abio-CA) and non-CA, with an additional 58 patients clinically diagnosed with CA comprising the clinical CA group.

Results

Amyloid deposits were identified in atrial samples from 40 patients (7%), including 25 amyloid transthyretin (ATTR) types. Prevalence increased to 20%–40% with advancing age, left ventricular (LV) hypertrophy, and the presence of low-voltage areas in the left atrium. The abio-CA group exhibited a thinner LV posterior wall (11.3 ± 2.2 vs 15.3 ± 4.6 mm, P < .001) compared with the clinical CA group. The abio-CA group displayed a thicker LV posterior wall (11.3 ± 2.2 vs 9.6 ± 1.4 mm, P < .001) and a higher frequency of low-voltage areas defined as <0.5 mV (45% vs 13%, P < .001) compared with the non-CA group. Right ventricular biopsy identified amyloid deposits in 13 patients (3%), comprising 11 ATTR and 2 light-chain types. Among the 26 patients in the abio-CA group who underwent RV biopsy, 13 had no amyloid deposits in RV samples, indicating confined atrial amyloidosis.

Conclusions

Atrial biopsy revealed amyloid deposits in 7% of patients undergoing AF ablation, identifying early-stage CA.

Keywords: Atrial biopsy, Atrial cardiomyopathy, Atrial fibrillation, Cardiac amyloidosis, Catheter ablation

Structured Graphical Abstract

See the editorial comment for this article ‘Diagnosis of early-stage cardiac amyloidosis: is atrial biopsy a new opportunity?’, by A. Saljic et al., https://doi.org/10.1093/eurheartj/ehaf455.

Introduction

Cardiac amyloidosis (CA) is a progressive disease associated with a high incidence of heart failure and arrhythmias and has a poor prognosis.^1,2 Atrial fibrillation (AF), the most common arrhythmia, is also associated with cardiovascular events such as heart failure, stroke, and death.³ Atrial fibrillation is common in patients with CA, having a prevalence of 30%–50%^4,5; however, the prevalence of CA in patients with non-valvular AF has not been well examined. Cardiac amyloidosis is often advanced at the time of the diagnosis.^1,6 Therefore, its early diagnosis will have a significant prognostic effect on life expectancy.⁷

Fibrosis has traditionally been considered the primary cause of the substrate for AF.⁸ Recently, we have developed an intracardiac echocardiography–guided atrial biopsy technique in patients undergoing AF ablation.^9,10 Histological factors associated with atrial structural remodelling, represented as a reduction in atrial bipolar voltage, include not only fibrosis but also increases in intercellular space preceding fibrosis, myofibrillar loss, and a decrease in the myocardial nuclear density.^10,11 Amyloid deposition was also identified and associated with severe atrial structural remodelling.¹⁰ However, the prevalence and clinical features of amyloid deposition in non-valvular AF and its significance on the outcomes after ablation are still unknown.

This study aimed to evaluate the prevalence of amyloid deposition in patients with non-valvular AF undergoing AF ablation and to test the hypothesis that atrial biopsy can identify an earlier stage of CA in this cohort.

Methods

Study design and population

This study was performed as part of the Histological Evaluation of Atrial Fibrillation Substrate Based on Atrial Septum Biopsy (Japanese UMIN Clinical Trial Registration UMIN000040781 and UMIN000044943; HEAL-AF, n = 103 and HEAL-AF2, n = 300, respectively) and Follow-up Study of Patients Undergoing Catheter Ablation for Atrial Fibrillation: Evaluation of Long-term Outcomes and Predictive Factors Based on Genetic Predisposition–Subgroup Analysis in Patients with Atrial Biopsy and Proteomics (FUTURE-AF-S, n = 400; Japanese UMIN Clinical Trial Registration UMIN000050841) studies. These are ongoing observational studies evaluating the 3-year outcomes based on atrial biopsy after catheter ablation of non-valvular AF. Among 803 Japanese patients enrolled in these studies, the present study included 581 consecutive patients with at least 12 months of follow-up after the catheter ablation between June 2020 and April 2023. After excluding 3 patients in which an atrial biopsy could not be performed because of anatomical reasons such as scoliosis, 578 patients were enrolled in this study (atrial biopsy cohort). No patients were previously diagnosed with CA or had undergone prior open-heart surgery. Of the 578 patients, 83 had a history of pulmonary vein isolation without additional ablation. Patients with and without amyloid deposition in the atrial samples were classified into atrial biopsy–detected CA (abio-CA) and non-CA groups, respectively. For the initial 385 patients included in the HEAL-AF and HEAL-AF2 studies, endomyocardial right ventricular (RV) biopsies were concomitantly performed during ablation. Additionally, 58 patients clinically diagnosed with CA based on RV biopsy in our institutes between 2002 and 2022 were retrospectively examined (clinical CA group). Patients diagnosed with CA by modalities other than RV biopsy were excluded. Details of the data collection in the clinical CA group are provided in the Supplementary Material. The study protocol was approved by the Ethics Committee of Saga University Hospital (approval reference numbers: 20200101 for HEAL-AF, 20200901 for HEAL-AF2, and 202200401 for FUTURE-AF-S). All patients provided written informed consent. This study conformed to the principles of the Declaration of Helsinki. Definitions of AF types (paroxysmal, persistent, and long-standing persistent AF) and heart failure classifications (reduced, mid-range, and preserved ejection fraction) are detailed in the Supplementary Material.

We defined amyloidosis as atrial amyloidosis, any amyloid deposition in the atrium; ventricular amyloidosis, any amyloid deposition in the ventricles; CA, any amyloid deposition in either or both atria or ventricles; confined atrial amyloidosis, any amyloid deposition in the atria but not in the ventricles; and confined ventricular amyloidosis, any amyloid deposition in the ventricles but not in the atria.

Atrial tissue sampling and processing for histology

Biopsy and ablation procedures were performed under general anaesthesia or deep sedation. Venous accesses were obtained via femoral veins. Atrial biopsy samples were collected from the limbus of the fossa ovalis in the right atrium under intracardiac echocardiography and fluoroscopy guidance before catheter ablation.^9,10 Under fluoroscopy guidance, RV samples were also obtained from the RV septum. Details of biopsy procedures and histology processing are described in the Supplementary Material and Supplementary data online, Figures S1–S6. Up to 5 atrial samples with a sample size of 1–3 mm were successfully obtained from all 578 patients. Patients with <100 000 µm² of myocardial tissue in the histological sections were defined as the insufficient myocardial sample group, and those with ≥100 000 µm² as the sufficient myocardial sample group.¹⁰ Two or 3 RV samples were also successfully obtained from 385 patients. Biopsy-associated complications, including acute swelling of the atrial septum, cardiac perforation, atrioventricular block, and right bundle branch block, were monitored by intracardiac echocardiography and a 12-lead electrocardiogram.

Histological assessments

The embedded paraffin blocks of the biopsy samples were sectioned at a thickness of 5 μm, and deparaffinized sections were stained with haematoxylin and eosin (H&E), Masson's trichrome, and Congo red (see Supplementary data online, Figure S7). Amyloid deposition was histologically confirmed by H&E staining, revealing amorphous eosinophilic material, and by Congo red staining, demonstrating apple-green birefringence under polarized light. Histological factors, including fibrosis extent (%Fibrosis), intercellular space extent (%Intercellular space), and myofibrillar loss severity (%Myofibrillar loss), were quantitatively assessed using HALO^® and HALO AI image analysis platform version 4.0.5107 (Indica Labs, Albuquerque, NM, USA) based on Masson's trichrome staining in cases where sufficient atrial myocardium was obtained, excluding 13 cases of advanced amyloid deposition. Myocardial nuclear density, a surrogate for cardiomyocyte number, was manually quantified as previously reported based on H&E staining.¹⁰ Details of the histological quantification and the immunohistochemical typing of amyloid depositions are provided in the Supplementary Material and Supplementary data online, Figure S8.

The severity of amyloid deposition was semi-quantitatively assessed based on Congo red–stained atrial tissue sections. Mild deposition was defined as focal or filamentous deposits in <10% of atrial tissue. Moderate deposition fell between mild and severe. Severe deposition was characterized by multiple focal or diffuse amyloid deposits in >30% of atrial tissue. The severity in RV sections was similarly assessed.

Electroanatomic mapping and catheter ablation

Electrophysiological procedures were performed after biopsy procedures. High-density voltage mapping was performed during high right atrial (RA) pacing at 100 b.p.m. using a 3D electroanatomical mapping system (EnSite Precision™ or EnSite X™, Abbott, St. Paul, MN, USA) and a grid mapping catheter (Advisor™ HD Grid, Abbott). Details of voltage mapping are described in the Supplementary Material. Briefly, the global left atrial (LA) voltage was evaluated with the mean of the highest voltage at a sampling density of 1 cm². The voltage at the biopsy site was evaluated with the mean of the highest voltage at a sampling density of 0.25 cm² in HEAL-AF and HEAL-AF2 patients. Low-voltage area (LVA) was defined using two criteria: an area of <0.5 mV and ≥3.0 cm² (LVA_0.5) or a less stringent definition of an area of <1.0 mV and ≥3.0 cm² (LVA_1.0).⁹ For catheter ablation, pulmonary vein isolation was performed in all cases using either a contact force–sensing catheter (TactiCath Quartz™ or TactiFlex™; Abbott) or a cryoballoon (Arctic Front Advance Pro™; Medtronic, Minneapolis, MN, USA). If LA macro-reentrant tachycardia and/or cavotricuspid isthmus–dependent atrial flutter were induced, additional ablation procedures were implemented. Details of catheter ablation are provided in the Supplementary Material. Blood samples were collected prior to ablation for Troponin T measurement, with details of the method provided in the Supplementary Material. Follow-up was performed at 1, 3, and 6 months and then every 6 months with 12-lead electrocardiograms. Twenty-four-hour Holter monitoring was performed at 12 months. Antiarrhythmic medications and anticoagulants were managed per physician preference and current guidelines. Atrial tachyarrhythmia recurrence was defined as documented episodes lasting ≥30 s beyond the 3-month blanking period. Persistent AF recurrence was defined as AF or atrial tachycardia persisting ≥7 days post-ablation or requiring direct current cardioversion. The clinical outcomes were evaluated as a composite endpoint, including all-cause mortality, stroke, and hospitalization for heart failure, following catheter ablation in both the abio-CA and non-CA groups.

Propensity score–matched cohort study

Propensity score matching using a logistic regression model that incorporates age, sex, and AF type (paroxysmal vs non-paroxysmal AF) was performed in comparison with the clinical characteristics between the abio-CA and non-CA groups. To find individuals with a similar propensity score in the abio-CA cases and non-CA control, 1:2 (case:control) nearest neighbour matching without replacement was performed. Survival analysis was performed based on only those patients who were successfully matched. The propensity score–matched cohort included a total of 108 patients including 36 abio-CA and 72 non-CA patients.

Statistical analysis

Normally distributed variables are presented as the means ± standard deviations, while non-normally distributed variables are presented as medians and inter-quartile ranges (IQRs). Continuous data were analysed using the unpaired t-test for normal distribution and the Wilcoxon rank-sum test for non-normal distribution. Categorical data were analysed using the χ² test or Fisher's exact test, as appropriate. The 95% confidence interval (95% CI) for the prevalence of CA was calculated using the Wilson score method. Standardized differences were calculated to assess the balance across variables in the propensity score–matched cohort. Pearson's correlation coefficients (r) assessed associations between continuous variables, and Spearman's rank correlation coefficient evaluated between-group trends. Multivariable logistic regression analysis was performed to identify clinical factors associated with amyloid deposition in atrial samples and to construct logistic regression models. Model selection was conducted based on the concordance index (C-index) and Akaike Information Criterion (AIC), where a higher C-index and lower AIC indicated a better model fit. The free survival time for atrial tachyarrhythmia recurrence and composite endpoint was determined using Kaplan–Meier methods, with comparisons between groups made using the log-rank test. The atrial biopsy cohort was classified into quartiles based on global LA voltage (Q1–Q4), excluding the 40 atrial amyloidosis patients, who were analysed separately as an abio-CA group. Histological factors were compared across the quartiles using trend tests with Spearman's rank correlation coefficient, while comparisons between the abio-CA group and Q1 were performed using Student's t-test. Cox regression evaluated the association between atrial tachyarrhythmia recurrence and patient categories (abio-CA, Q1–Q4), treating patient categories as categorical variables. Hazard ratios were calculated for abio-CA, Q1, Q2, and Q3 relative to Q4, with trend analysis for non–abio-CA categories. To examine the abio-CA group's association with composite outcomes (all-cause death, stroke, and heart failure hospitalization after catheter ablation), multiple Cox proportional hazards regression models were employed using abio-CA, age, paroxysmal AF type, and global LA voltage as covariates. All variables underwent Z-score normalization, and hazard ratios for each were calculated. The proportional hazards assumption was assessed using scaled Schoenfeld residual plots against follow-up time and the χ² test for non-zero slopes. All tests were two sided, with significance set at P < .05. Analyses were conducted using JMP version 16.1.0 (SAS Institute Inc., Cary, NC, USA) and the R package MatchIt (version 4.5.5) for propensity score matching.

Results

Patient characteristics and prevalence of cardiac amyloidosis

Amyloid deposition was identified in atrial samples from 40 patients (abio-CA) (7%, 95% CI: 5%–9%) within the atrial biopsy cohort and in RV samples from 13 patients (3%, 95% CI: 2%–6%) out of 385 who underwent concomitant RV biopsy (Figure 1). The clinical characteristics of the abio-CA, non-CA, and clinical CA groups are shown in Table 1. No patients had a history of polyneuropathy or a family history of CA. The abio-CA group had lower Troponin T levels and lesser LV hypertrophy compared with the clinical CA group. Conversely, the abio-CA group was older and showed higher Troponin T and N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels, more advanced LV hypertrophy, and more advanced atrial remodelling, indicated by reduced global LA voltage and the presence of LVA, and a higher prevalence of heart failure with preserved ejection fraction compared to the non-CA group. The clinical characteristics of the propensity score–matched cohort are presented in Supplementary data online, Table S1. In this cohort, the abio-CA group exhibited higher NT-proBNP levels, more advanced LV and atrial remodelling, and more frequent history of heart failure than the non-CA group.

Workflow and results of amyloid typing. (A) Workflow for amyloid typing. (B) Results of the typing. Among the 578 atrial biopsies, amyloid deposition was identified in 40 cases. In the 385 cases that underwent concomitant right ventricular biopsy, amyloid deposition was detected in 26 atrial samples, of which 13 samples also exhibited amyloid deposition in the right ventricular samples. The remaining 13 cases demonstrated amyloid deposition confined solely to the right atrium and were diagnosed as ‘confined atrial amyloidosis’. Among the 40 cases with amyloid deposition, typing was not possible in four instances. AA, serum amyloid; Aβ2m, Aβ2-microglobulin; ud, undetermined

Table 1.

Patient characteristics

Variables	Clinical CA group N = 58	Abio-CA group N = 40	Non-CA group N = 538	P-value, clinical vs abio-CA	P-value, Abio-CA vs non-CA
Age, years	75 ± 6	77 ± 7	67 ± 11	.199	<.001
Female, n (%)	6 (10)	12 (30)	168 (31)	.018	.872
Systolic BP, mmHg	122 ± 30	120 ± 19	123 ± 17	.564	.208
Heart failure, n (%)
HFrEF, n (%)	11 (19)	5 (13)	63 (12)	.022	.159
HFmrEF, n (%)	16 (28)	3 (8)	14 (3)
HFpEF, n (%)	9 (16)	14 (35)	65 (12)
NYHA class, n (%)
II	39 (67)	8 (20)	139 (26)	<.001	.529
III/VI	9 (16)	6 (15)	12 (2)	.944	.001
Hypertension, n (%)	34 (59)	29 (73)	305 (57)	.200	.067
Diabetes mellitus, n (%)	7 (12)	8 (20)	94 (17)	.393	.669
Ischaemic stroke, n (%)	7 (12)	5 (13)	48 (8)	1.000	.399
Atrial fibrillation, n (%)	21 (36)	40 (100)	538 (100)
PAF, n (%)	13 (22)	19 (48)	232 (43)	<.001	.383
PeAF, n (%)	8 (14)	16 (40)	189 (35)
LS-PeAF, n (%)	0	5 (13)	117 (22)
Coronary artery disease, n (%)	8 (14)	5 (13)	39 (7)	1.000	.217
PPM/ICD, n (%)	4 (7)	3 (8)	18 (3)	1.000	.172
Carpal tunnel syndrome, n (%)	17 (30)	2 (5)	–	.003	–
Spinal stenosis, n (%)	15 (26)	1 (3)	–	.002	–
NT-proBNP, pg/mL (IQR)	1849 (708–3852)	1700 (719–3051)	556 (201–1201)	.910	.035
Troponin T, ng/L (IQR)	51.0 (41.5–99.0)	23.0 (15.3–37.3)	13.6 (8.1–28.0)	<.001	.001
eGFR, mL/min/1.73 m²	50.3 ± 17.2	54.0 ± 15.1	61.7 ± 17.3	.274	.006
Echocardiographic parameters
IVS, mm	14.7 ± 2.6	11.2 ± 2.4	9.8 ± 2.0	<.001	<.001
LVPW, mm	15.3 ± 4.6	11.3 ± 2.2	9.6 ± 1.4	<.001	<.001
LVEF, %	49 ± 11	58 ± 11	60 ± 13	<.001	.134
Medication
Loop diuretic, n (%)	32 (55)	2 (5)	50 (9)	<.001	.566
Thiazide diuretic, n (%)	5 (9)	3 (7)	15 (3)	1.000	.121
MRA, n (%)	22 (38)	2 (5)	25 (5)	<.001	.710
ACE inhibitor, n (%)	10 (17)	7 (18)	76 (14)	1.000	.492
ARB, n (%)	15 (26)	12 (30)	130 (24)	.654	.446
Beta-blocker, n (%)	24 (41)	3 (8)	97 (18)	<.001	.126
Amyloid type
ATTR, n (%)	54 (93)	25 (63)		<.001
AL, n (%)	4 (7)	6 (15)
ANP, n (%)	0 (0)	5 (13)
Undetermined, n (%)		4 (10)
LVA_0.5, n (%)		18 (45)	69 (13)		<.001
LVA_1.0, n (%)		29 (73)	184 (34)		<.001
V_GLA, mV		3.4 ± 1.6	5.6 ± 2.2		<.001

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ACE, angiotensin-converting enzyme; AF, atrial fibrillation; ARB, angiotensin receptor blocker; BP, blood pressure; eGFR, estimated glomerular filtration rate; HFmrEF, heart failure with mid-range ejection fraction; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; ICD, implantable cardioverter defibrillator; IVS, interventricular septum; LS-PeAF, long-standing persistent AF; LVEF, LV ejection fraction; NYHA, New York Heart Association; MRA, mineralocorticoid receptor antagonist; PAF, paroxysmal AF; PeAF, persistent AF; PPM, permanent pacemaker; V_GLA, global LA voltage.

The prevalence of atrial and ventricular amyloidosis increased with age (Figure 2; see Supplementary data online, Figure S9), reaching 30%–40% in subgroups with LVA_0.5 and/or a LV posterior wall (LVPW) ≥12 mm. In patients aged 60 years and older, the sensitivity and specificity for detecting atrial and ventricular amyloidosis with LVPW ≥ 12 mm and LVA_0.5 were 20% and 98%, and 31% and 97%, respectively. When applying the more lenient criteria of LVPW ≥ 11 mm and LVA_1.0, the sensitivity increased to 43% and 69%, respectively, while the specificity values were 92% in both cases. The sensitivity and specificity of atrial amyloidosis, ventricular amyloidosis, and atrial amyloidosis specific to amyloid transthyretin (ATTR), based on LVPW and LVA for each decade, are presented in Table 2 and Supplementary data online, Tables S2 and S3, along with their 95% CIs.

The prevalence of amyloid deposition in atrial samples. Examples of amyloid deposition across different amyloid types are presented, along with a voltage map showing low-voltage areas defined as <0.5 mV. Areas not coloured in purple indicate a voltage amplitude of <0.5 mV. The prevalence increased to 20%–40% in association with age, the presence of low-voltage area, and left ventricular hypertrophy

Table 2.

Sensitivity and specificity for detecting atrial amyloidosis based on left ventricular wall thickness and the presence of a low-voltage area in the left atrium

	TP (n)	FP (n)	FN (n)	TN (n)	PPV %, (95% CI)	NPV %, (95% CI)	Sensitivity %, (95% CI)	Specificity %, (95% CI)
All cohort (N = 578)
LVPW ≥ 11 mm	21	108	19	430	16 (11–24)	96 (93–97)	53 (38–67)	80 (76–83)
LVPW ≥ 12 mm	17	44	23	494	28 (18–40)	96 (93–97)	43 (29–58)	92 (89–94)
LVPW ≥ 13 mm	11	13	29	525	46 (28–65)	95 (93–96)	28 (16–43)	98 (96–99)
LVA_0.5 (+)	18	69	22	469	21 (14–30)	96 (93–97)	45 (31–60)	87 (84–90)
LVA_1.0 (+)	29	184	11	354	14 (10–19)	97 (95–98)	73 (57–84)	66 (62–70)
LVPW ≥ 11 mm and LVA_0.5	12	17	28	521	41 (26–59)	95 (93–96)	30 (18–45)	97 (95–98)
LVPW ≥ 12 mm and LVA_0.5	8	11	32	527	42 (23–64)	94 (92–96)	20 (11–35)	98 (96–99)
LVPW ≥ 13 mm and LVA_0.5	5	5	35	533	50 (24–76)	94 (92–96)	13 (5–26)	99 (98–100)
LVPW ≥ 11 mm and LVA_1.0	17	40	23	498	30 (20–43)	96 (93–97)	43 (29–58)	93 (90–94)
LVPW ≥ 12 mm and LVA_1.0	13	19	27	519	41 (26–58)	95 (93–97)	33 (20–48)	96 (95–98)
LVPW ≥ 13 mm and LVA_1.0	10	6	30	532	63 (39–82)	95 (92–96)	25 (14–40)	99 (98–99)
≥60 years old (N = 476)
LVPW ≥ 11 mm	21	90	19	346	19 (13–27)	95 (92–97)	53 (38–67)	79 (75–83)
LVPW ≥ 12 mm	17	34	23	402	33 (22–47)	95 (92–96)	43 (29–58)	92 (89–94)
LVPW ≥ 13 mm	11	11	29	425	50 (31–69)	94 (91–96)	28 (16–43)	97 (96–99)
LVPW ≥ 11 mm and LVA_0.5	12	16	28	420	43 (27–61)	94 (91–96)	30 (18–45)	96 (94–98)
LVPW ≥ 12 mm and LVA_0.5	8	10	32	426	44 (25–66)	93 (90–95)	20 (11–35)	98 (96–99)
LVPW ≥ 13 mm and LVA_0.5	5	5	35	431	50 (24–76)	92 (90–95)	13 (5–26)	99 (97–100)
LVPW ≥ 11 mm and LVA_1.0	17	36	23	400	32 (21–45)	95 (92–96)	43 (29–58)	92 (89–94)
LVPW ≥ 12 mm and LVA_1.0	13	17	27	419	43 (27–61)	94 (91–96)	33 (20–48)	96 (94–98)
LVPW ≥ 13 mm and LVA_1.0	10	6	30	430	63 (39–82)	93 (91–95)	25 (14–40)	99 (97–99)
≥70 years old (N = 294)
LVPW ≥ 11 mm	18	50	18	208	26 (17–38)	92 (88–95)	50 (34–66)	81 (75–85)
LVPW ≥ 12 mm	14	20	22	238	41 (26–58)	92 (88–94)	39 (25–55)	92 (88–95)
LVPW ≥ 13 mm	9	8	27	250	53 (31–74)	90 (86–93)	25 (14–41)	97 (94–98)
LVPW ≥ 11 mm and LVA_0.5	11	14	25	244	44 (27–63)	91 (87–94)	31 (18–47)	95 (91–97)
LVPW ≥ 12 mm and LVA_0.5	7	8	29	250	47 (25–70)	90 (85–93)	19 (10–35)	97 (94–98)
LVPW ≥ 13 mm and LVA_0.5	4	4	32	254	50 (22–78)	89 (85–92)	11 (4–25)	98 (96–99)
LVPW ≥ 11 mm and LVA_1.0	15	29	21	229	34 (22–49)	92 (88–94)	42 (27–58)	89 (84–92)
LVPW ≥ 12 mm and LVA_1.0	11	12	25	246	48 (29–67)	91 (87–94)	31 (18–47)	95 (92–97)
LVPW ≥ 13 mm and LVA_1.0	8	4	28	254	67 (39–86)	90 (86–93)	22 (12–38)	98 (96–99)

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FN, false negative; FP, false positive; NPV, negative predictive values; PPV, positive predictive value; TN, true negative; TP, true positive.

Logistic regression analysis was performed to construct multiple models, confirming that age, LVPW, and the presence of LVA_0.5 were independently associated with amyloid deposition in the atrial biopsy cohort (Table 3). Model performance was assessed using the C-index and AIC, demonstrating that Model 2, which incorporates age, LVPW, and the presence of LVA_0.5, exhibited superior performance. This model is presented as a nomogram in Figure 3. Additionally, the nomogram for Model 3, which incorporates only age and LVPW, is provided in Supplementary data online, Figure S10.

Table 3.

Multivariable logistic regression analysis for the presence of cardiac amyloidosis

Variables	Std. Coeff	Std. Error	P-value	Std. Coeff	Std. Error	P-value	Std. Coeff	Std. Error	P-value	Std. Coeff	Std. Error	P-value
	Univariate			Model 1			Model 2			Model 3
Age, years	1.360	0.257	<.001	1.206	0.286	<.001	1.192	0.283	<.001	1.327	0.272	<.001
Sex, %	0.027	0.166	.872	–	–	–	–	–	–	–	–	–
PeAF or LS-PeAF, %	−0.086	0.163	.597	–	–	–	–	–	–	–	–	–
LVPW, mm	0.931	0.150	<.001	0.863	0.164	<.001	0.862	0.164	<.001	0.924	0.164	<.001
Troponin T, ng/L	−0.005	0.168	.975	–	–	–	–	–	–	–	–	–
NT-proBNP, pg/mL	0.168	0.097	.083	0.130	0.119	.272	–	–	–	–	–	–
LVA_0.5, %	0.614	0.123	<.001	0.290	0.145	.045	0.314	0.142	.027	–	–	–
C-index				0.875			0.875			0.864
AIC				221.9			220.8			223.5

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LS-PeAF, long-standing persistent atrial fibrillation; PeAF, persistent atrial fibrillation; Std. Coeff, standardized coefficient; Std. Error, standardized error.

A nomogram for predicting cardiac (atrial) amyloidosis in patients with atrial fibrillation. To use this nomogram, locate each variable (age, left ventricular posterior wall, and the presence of low-voltage area defined as <0.5 mV in the left atrium), draw a vertical line to the ‘Points’ axis, and note the score. Sum the points from all variables. Finally, use the ‘Total Points’ axis to estimate the probability of cardiac amyloidosis

The prevalence of atrial amyloidosis by AF type was as follows: paroxysmal AF 8%, persistent AF 8%, and long-standing persistent AF 4%. Regarding heart failure types, the prevalence was as follows: heart failure with reduced ejection fraction 7%, heart failure with mid-range ejection fraction 18%, and heart failure with preserved ejection fraction 18% (see Supplementary data online, Figure S1 1).

Atrial and ventricular biopsy procedures

Atrial biopsy was successfully completed within 10 min in all patients; however, as noted above, three patients (0.5%) were excluded from the atrial biopsy cohort due to difficulties in obtaining samples for anatomical reasons. Analysis of the histological sections of atrial samples revealed that 111 patients (19%) did not have sufficient myocardial tissue for histological assessment, defined as ≥100 000 µm², and only the atrial endocardium or a small amount of myocardial tissue just beneath the endocardium was observed (see Supplementary data online, Figure S7). A comparison of the clinical characteristics of patients with and without sufficient myocardial samples is shown in Supplementary data online, Table S4. Patients with insufficient myocardial samples had a larger LA and more frequently utilized 5.5 Fr bioptome. The rate of obtaining sufficient myocardial samples with each biopsy size is presented in Supplementary data online, Figure S1 2. Right ventricular biopsies were also successfully performed via the femoral vein in all 385 patients.

Evaluation of voltage at the biopsy site and global left atrial voltage

Voltage maps of the LA were created for all patients in the atrial biopsy cohort, and global LA voltage was calculated. The voltage at the biopsy site was recorded in 345 patients. A positive correlation was observed between the voltage at the biopsy site and global LA voltage in both the abio-CA and non-CA groups (see Supplementary data online, Figure S1 3), indicating that voltage reduction is a diffuse process manifesting not only in the non-CA group but also in the abio-CA group. The atrial biopsy cohort was divided into quartiles (Q1–Q4) based on global LA voltage, and the corresponding quartile for the abio-CA group was assessed. Twenty-five patients (63%) in the abio-CA group were classified into Q1, while only four patients (10%) were classified into either Q3 or Q4 (see Supplementary data online, Figure S14).

Biopsy and ablation procedures and complications

No atrial biopsy–related complications were noted, except for transient acute local swelling at the biopsy site in two patients (see Supplementary data online, Figure S6). No major complications were observed following RV biopsy; however, right bundle branch block was noted in eight patients, 6 (1.6%) continued to have right bundle branch block at the 1-year follow-up. Voltage mapping and pulmonary vein isolation were successfully performed in all patients after biopsy. Left atrial macro-reentrant tachycardia was more frequently induced and ablated in the abio-CA group than in the non-CA group (n = 16, 40% vs n = 47, 9%, P < .001). Ablation-related complications were observed in three cases, including phrenic nerve paralysis in one patient and cardiac perforation in two patients, which were not associated with the biopsy.

Amyloid typing and characteristics of each type

Amyloid phenotyping of the atrial samples identified ATTRs in 25 patients (63%), light-chain amyloidosis (AL) in 6 patients (15%), and atrial natriuretic peptide (ANP) in 5 patients (13%). The amyloid type could not be determined in four patients (10%) due to a minimal amount of amyloid deposits (Structured Graphical Abstract; Figure 1). For the RV samples, the amyloid type was ATTR in 11 patients (85%) and AL in 2 patients (15%). The patient characteristics for each type based on atrial amyloidosis are presented in Supplementary data online, Table S5. Clinical information for patients with AL is noted in Supplementary data online, Table S6. Examples of each amyloid type are shown in Supplementary data online, Figure S15.

Patients were classified as having mild (n = 20) or moderate/severe amyloid deposition (n = 20) based on the histological assessment of atrial samples. Patients with mild amyloid deposition less frequently had heart failure with preserved ejection fraction and exhibited lesser LV hypertrophy, whereas age and LA voltage were similar between the two groups (see Supplementary data online, Table S7). All patients with ATTR had amyloid deposition in at least the endocardium of the atria. Of the 25 patients with ATTR, 7 had histological sections of atrial samples that contained only the endocardium and lacked myocardial layers, possibly due to insufficient tissue sampling from the thick, stiff endocardium. Among the 25 patients with ATTR, 18 (72%) had myocardial layers present in the histological sections of the atrial samples, while 6 (24%) exhibited amyloid deposition solely in the atrial endocardium. Patients with mild amyloid deposition were more likely to have no or mild amyloid deposition in the RV samples compared with those with moderate/severe amyloid deposition (see Supplementary data online, Table S7). There were no cases of confined ventricular amyloidosis. An example of confined atrial amyloidosis, where ATTR was detected only in the atrial endocardium but not in the atrial myocardial layer or RV samples, is shown in Supplementary data online, Figure S16. Technetium-99m pyrophosphate scintigraphy revealed no cardiac uptake in this case. An example of ANP type amyloidosis is also presented in Supplementary data online, Figure S17.

Confined atrial amyloidosis vs ventricular amyloidosis

The clinical factors associated with CA were compared among three groups: confined atrial amyloidosis, atrial and ventricular amyloidosis, and the clinical CA group. Age and history of heart failure were similar across the groups, whereas Troponin T levels and LV hypertrophy were lower in the confined atrial amyloidosis group (see Supplementary data online, Table S8).

Histological quantification of atrial structural remodelling

%Fibrosis, %Intercellular space, and %Myofibrillar loss increased, while nuclear density decreased as the quartiles based on global LA voltage progressed downward (Figure 4). The abio-CA group exhibited a lower %Fibrosis compared with the Q1 quartile of non-CA group, while other histological factors were comparable between the abio-CA group and the Q1 quartile. Global LA voltage and myocardial nuclear density of the atrial samples showed a linear decrease with age; however, no clear linear relationship was observed between age and %Fibrosis, %Intercellular space, or %Myofibrillar loss (see Supplementary data online, Figure S18).

Histopathological quantification of atrial samples. Histological factors, including the extent of fibrosis (%Fibrosis, A), the extent of intercellular space (%Intercellular space, B), the severity of myofibrillar loss (%Myofibrillar loss, C), and myocardial nuclear density (D), were quantitatively assessed using the HALO^® and HALO AI image analysis platform. The atrial biopsy cohort was classified into quartiles based on the global left atrial voltage (Q1–Q4 groups). In the comparison of histological factors across each quartile group, the 40 patients with atrial amyloidosis were excluded from each quartile group and analysed independently as a separate atrial biopsy–detected cardiac amyloidosis group. Each histological factor was compared between the Q1 quartile group and the atrial biopsy–detected cardiac amyloidosis group. In the atrial biopsy–detected cardiac amyloidosis group, red dots represent cases with mild amyloid deposition, while black dots denote cases with moderate or severe amyloid deposition. (A–C) Histological images and quantification based on Masson's trichrome staining are shown (A, %Fibrosis: 8.2%; B, %Intercellular space: 21.9%; and C, %Myofibrillar loss: 5.6%). (D) Examples of nuclear density evaluation based on haematoxylin and eosin staining are presented (a case from the non-cardiac amyloidosis group displaying 770 nuclei/mm² and a case from the atrial biopsy–detected cardiac amyloidosis group exhibiting 177 nuclei/mm²)

Outcomes after catheter ablation

The mean follow-up period was 33 ± 10 months following catheter ablation, and 322 patients (56%) were receiving antiarrhythmic drugs at the final follow-up, including amiodarone for 33 patients, bepridil for 226 patients, and Class I antiarrhythmic drugs for 63 patients. In the overall cohort, atrial tachyarrhythmia recurrence and persistent AF recurrence-free survival were comparable between the abio-CA and non-CA groups (see Supplementary data online, Figure S19). When stratified by global LA voltage quartiles, recurrence rates increased as the quartile decreased, while the recurrence rate in the abio-CA group was similar to that of the Q1 quartile (see Supplementary data online, Figures S19 and S20). During the follow-up period, the abio-CA group experienced 7 hospitalizations for heart failure, 1 stroke, and 4 deaths (all cardiovascular), while the non-CA group had 8 heart failure hospitalizations, 7 strokes, and 14 deaths, including 3 cardiovascular deaths. The composite endpoint was higher in the abio-CA group compared with the non-CA group (Figure 5). In multivariable regression models, abio-CA was independently associated with the composite outcome in the overall cohort [age-paroxysmal AF-global LA voltage-adjusted hazard ratio: 2.71 (95% CI 1.10–6.70)] (Figure 5). In the propensity score–matched cohort, no significant difference was observed between the abio-CA and non-CA groups regarding recurrence or the composite endpoint (see Supplementary data online, Figure S2 1). Tafamidis was prescribed for seven cases of ATTR ventricular amyloidosis in accordance with the statement on the appropriate administration of tafamidis in patients with transthyretin CA issued by Japanese Circulation Society.¹² Other cases of ATTR did not meet the criteria outlined in this statement, and tafamidis was not administered. In contrast, chemotherapy was administered in two cases of AL ventricular amyloidosis.

The composite endpoint in the overall cohort. Kaplan–Meier curve analysis was performed for the composite endpoint in the overall cohort (A). The composite endpoint-free survival time was determined using Kaplan–Meier estimation and compared between the groups using the log-rank test. Multiple Cox proportional hazards regression models incorporating atrial biopsy–detected cardiac amyloidosis group, age, paroxysmal atrial fibrillation type, and global left atrial voltage are presented (B). Atrial biopsy–detected cardiac amyloidosis was independently associated with the endpoint after covariate adjustments

Discussion

Major findings

To the best of our knowledge, this is the first study to investigate the prevalence of amyloid deposition through antemortem atrial biopsy in a prospective cohort of 578 patients undergoing catheter ablation for non-valvular AF. Right ventricular biopsy was performed concomitantly in 385 patients. The major findings were as follows: (i) amyloid deposition was observed in 7% of atrial biopsy samples and in 3% of ventricular biopsy samples; (ii) prevalence increased to 20%–40% with advancing age, LV hypertrophy, and the presence of LVA in the left atrium; (iii) the abio-CA group exhibited less LV hypertrophy and lower Troponin T levels compared with the clinically diagnosed CA, indicating that atrial biopsy can identify early-stage CA; and (iv) histological quantification of the atrial samples revealed that patients with CA demonstrate advanced atrial cardiomyopathy, even in cases of early-stage ventricular amyloidosis.

An early diagnosis of cardiac amyloidosis

A study of wild-type ATTR CA found a median survival of 3.9 years and a 5-year survival rate of 35.7%.¹ Late diagnosis worsens prognosis, particularly for patients diagnosed more than 6 months after symptoms appear.¹³ The ATTR-ACT (The Transthyretin Amyloidosis Cardiomyopathy Clinical Trial) trial showed that tafamidis significantly reduced mortality and hospitalizations in New York Heart Association Class I or II patients,^14,15 emphasizing the need for early diagnosis and treatment. For AL amyloidosis, prognosis depends on disease stage, and early therapy with a targeted plasma cell therapy can improve outcomes.¹⁶ Despite the high incidence of AF in patients with ATTR-CA, technetium-99m pyrophosphate scintigraphy identified ATTR-CA in only 1.7% of individuals over 60 years with LV hypertrophy.¹⁷ A recent study employing early screening and computed tomography–based myocardial extracellular volume reported a prevalence of 1.8% among patients undergoing AF ablation.¹⁸ Most cases in both studies had a LVPW thickness of 15 mm or more. Current imaging techniques may not be sensitive enough for early detection of ATTR-CA, often resulting in late-stage identification.

Clinical significance of atrial natriuretic peptide atrial amyloidosis

Amyloid deposits in the heart, including the atria, are commonly reported in post-mortem studies involving elderly patients.^19,20 Half a century ago, Hodkinson and Pomerance²¹ indicated that the prevalence of senile CA was ∼50% in a cohort of 244 autopsied cases involving individuals aged 60 years and older, with nearly half exhibiting amyloid deposits confined to the atria. The prevalence of CA increases with age, and as atrial amyloidosis progresses, the prevalence of ventricular amyloidosis also rises. Subsequently, isolated atrial amyloidosis was proposed as a distinct form of amyloidosis, with ANP identified as the fibril protein involved.^22–24 Since then, the term ‘isolated atrial amyloidosis’ has been employed as a synonym for the ANP type. In this study, we identified CA restricted to the atria that was not of the ANP type; therefore, we have used the term ‘confined atrial amyloidosis’ as a general descriptor. The primary evidence for isolated atrial amyloidosis comes from autopsy cases and studies conducted on patients undergoing open-heart surgery patients.^25–29 The prevalence of isolated atrial amyloidosis has been reported in up to 91% of atrial tissue specimens, particularly in elderly patients with AF and mitral valve disease.²⁶ In the present study, the frequency of ANP amyloidosis was found to be remarkably low, representing only 0.7% of the overall cohort and 10% of patients with atrial amyloidosis. Differences in the prevalence of ANP amyloidosis between our study and other reports may be attributed to variations in patient age ranges, the presence of valvular disease, sample size and number, as well as the sites of atrial specimen collection, with the atrial appendage serving as the primary site during open-heart surgery. Additionally, it has been reported that the frequency of amyloid deposition in the right atrium is lower than that in the left atrium,^20,26,28,29 raising the possibility that RA biopsies may result in under-diagnosis. Furthermore, the co-existence of ATTR with ANP amyloidosis^29,30 suggests that the ANP amyloidosis may have been underdiagnosed within the amyloid typing framework of this study. However, isolated atrial amyloidosis has not been sufficiently studied regarding its clinical significance beyond its association with ageing, valvular disease, and AF, and no pharmacological therapies have yet been developed.

Confined atrial amyloidosis with light-chain amyloidosis and transthyretin amyloidosis

Regarding AL amyloidosis, reports of confined atrial amyloidosis of the AL type are exceedingly rare. Our literature review identified only one documented case involving the development of spontaneous intramural LA haemorrhage, in which AL amyloid was exclusively localized to the left atrium.³¹ The clinical significance of AL-type confined atrial amyloidosis, as revealed by atrial biopsy, requires further investigation. There is a possibility that a plasma cell disorder is being under-estimated or may manifest clinically in the future. However, early pharmacological treatment should be initiated as needed for AL-type ventricular amyloidosis. Regarding ATTR atrial amyloidosis, which is the predominant type of atrial amyloidosis in this study, a disease-modifying therapy would theoretically be applicable from the early stages. It is not yet known whether or how rapidly patients with atrial amyloidosis will progress to ventricular amyloidosis during their lifetime and develop clinical CA. Alternatively, it may remain as confined atrial amyloidosis throughout their life. We need to follow these cases closely and assess their natural history. At present, a careful decision must be made regarding whether early-stage CA, without evident clinical manifestations other than AF, should be treated with disease-modifying therapy.^14,32

Atrial amyloidosis and atrial cardiomyopathy

Atrial fibrillation is associated with the development and progression of atrial cardiomyopathy and structural remodelling. In particular, fibrosis is thought to play a major role in sustaining AF from a histopathological perspective.^11,33 The progression of atrial cardiomyopathy can be evaluated through LA size and atrial voltage evaluated during catheter ablation.^9–11,33 Our previous report and the present study have demonstrated that, in addition to fibrosis, other histological factors, including an increase in the intercellular space, a decrease in myocardial nuclear density, and the presence of atrial amyloidosis, contribute to the progression of atrial cardiomyopathy.^9–11 In this study, histological quantification of the atrial samples revealed that patients with atrial amyloidosis exhibit severe histological degeneration, including a decrease in myocardial nuclear density, an increase in intercellular space, and severe myofibrillar loss, even in those with mild amyloid deposition. However, the extent of fibrosis is relatively lower, consistent with a previous report.²⁷ Histological quantification of the atrial samples from patients in the abio-CA group revealed advanced atrial cardiomyopathy, even in patients with early-stage ventricular amyloidosis. The exact mechanisms remain unclear, and the causal relationship between amyloid deposition and the underlying histological degeneration is still unknown. Nonetheless, elucidating these mechanisms will be crucial for identifying therapeutic approaches for atrial amyloidosis and its associated histological changes.

Advantages of an atrial biopsy

Atrial biopsy may seem a high-risk procedure; however, intracardiac echocardiography–guided atrial septal biopsy is accurate, with no complications noted in the 803 patients included in this study. Transoesophageal echocardiography–guided atrial biopsy is also feasible.³⁴ However, ∼10% of cases using a 7 Fr biopsy bioptome yielded insufficient myocardial tissue due to the thick, stiff endomyocardium. Nonetheless, for diagnosing ATTR, where amyloid deposits are found in the atrial endocardium, an atrial biopsy is beneficial. Atrial biopsy guided by intracardiac or transoesophageal echocardiography, in conjunction with procedures like AF ablation or an LA appendage closure, may be a viable option.

Limitations

First, amyloid deposits other than ATTR may have been overlooked in cases in which insufficient myocardial tissue. Second, as atrial biopsies were performed solely on the RA septum, relying exclusively on RA samples may have resulted in under-diagnosis, particularly of early focal amyloid lesions or LA lesions. Furthermore, the lack of technetium-99m pyrophosphate scintigraphy in all cases raises the possibility of underdiagnosing ventricular amyloidosis. Third, the follow-up period post-ablation and biopsy was relatively short, and the atrial tachyarrhythmia recurrence and cardiovascular events were not thoroughly assessed. Fourth, the application of atrial biopsy in routine clinical practice remains challenging due to the requirement for intracardiac echocardiography, although transoesophageal echocardiography may provide an alternative. Fifth, the clinical CA group was based on a retrospective analysis.

Conclusions

Atrial biopsy revealed amyloid deposition in 7% of the patients undergoing AF ablation. Atrial biopsy identified early-stage CA, including confined atrial amyloidosis. Even if the identified ventricular amyloidosis is at an early stage, the presence of atrial amyloidosis indicates advanced atrial cardiomyopathy.

Supplementary Material

ehaf332_Supplementary_Data

ehaf332_supplementary_data.docx^{(6.6MB, docx)}

Acknowledgements

We acknowledge the assistance of Kaori Yamaguchi, Yuriko Susuki, Junko Marugami, Yumeka Mine, and Yumiko Tsugitomi for the data analysis and sample processing and the Amyloidosis Center, Kumamoto University Hospital, for the histological assessment of the amyloid deposition. We would like to thank John Martin for the English language editing.

Contributor Information

Kodai Shinzato, Department of Cardiovascular Medicine, Saga University, 5-1-1, Nabeshima, Saga 849-8501, Japan.

Yuya Takahashi, Department of Cardiovascular Medicine, Saga University, 5-1-1, Nabeshima, Saga 849-8501, Japan.

Takanori Yamaguchi, Department of Cardiovascular Medicine, Saga University, 5-1-1, Nabeshima, Saga 849-8501, Japan.

Toyokazu Otsubo, Department of Cardiovascular Medicine, Saga University, 5-1-1, Nabeshima, Saga 849-8501, Japan.

Kana Nakashima, Department of Cardiovascular Medicine, Saga University, 5-1-1, Nabeshima, Saga 849-8501, Japan.

Goro Yoshioka, Department of Cardiovascular Medicine, Saga University, 5-1-1, Nabeshima, Saga 849-8501, Japan.

Kensuke Yokoi, Department of Cardiovascular Medicine, Saga University, 5-1-1, Nabeshima, Saga 849-8501, Japan.

Kotaro Tsuruta, Department of Cardiovascular Medicine, Saga University, 5-1-1, Nabeshima, Saga 849-8501, Japan.

Ryosuke Osako, Department of Cardiovascular Medicine, Saga University, 5-1-1, Nabeshima, Saga 849-8501, Japan.

Shigeki Shichida, Department of Cardiovascular Medicine, Saga University, 5-1-1, Nabeshima, Saga 849-8501, Japan.

Yuki Nishimura, Department of Cardiovascular Medicine, Saga University, 5-1-1, Nabeshima, Saga 849-8501, Japan.

Makoto Edayoshi, Department of Cardiovascular Medicine, Saga University, 5-1-1, Nabeshima, Saga 849-8501, Japan.

Yuki Kawano, Division of Cardiology, Saiseikai Futsukaichi Hospital, Chikushino, Japan.

Yukako Shintani-Domoto, Department of Integrated Diagnostic Pathology, Nippon Medical School, Tokyo, Japan.

Kai Miyazaki, Department of Integrated Diagnostic Pathology, Nippon Medical School, Tokyo, Japan.

Akira Fukui, Department of Cardiology and Clinical Examination, Faculty of Medicine, Oita University, Yufu, Japan.

Atsushi Kawaguchi, Faculty of Medicine, Education and Research Center for Community Medicine, Saga University, Saga, Japan.

Shigehisa Aoki, Department of Pathology and Microbiology, Saga University, Saga, Japan.

Seitaro Nomura, Department of Cardiovascular Medicine, The University of Tokyo, Tokyo, Japan; Department of Frontier Cardiovascular Science, The University of Tokyo, Tokyo, Japan.

Naohiko Takahashi, Department of Cardiology and Clinical Examination, Faculty of Medicine, Oita University, Yufu, Japan.

Kaoru Ito, Laboratory for Cardiovascular Genomics and Informatics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.

Koichi Node, Department of Cardiovascular Medicine, Saga University, 5-1-1, Nabeshima, Saga 849-8501, Japan.

Supplementary data

Supplementary data are available at European Heart Journal online.

Declarations

Disclosure of Interest

T.Y. received honoraria from Abbott Medical Japan and Medtronic Japan. T.Y., Y.T., 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, Medtronic Japan, Japan Lifeline, Boston Scientific Japan, and Fides-ONE Corporation. The remaining authors declare that they have no conflicts of interest.

Data Availability

Data are available upon reasonable request to the corresponding author.

Funding

This work was supported by Japan Society for the Promotion of Science (JSPS) KAKENHI Grand-in-Aid for Scientific Research (A) (JP22H00471 to S.N. and T.Y.) and for Scientific Research (C) (JP21K08056 to T.Y. and JP23K06434 to Y.S.-D.), Japan Agency for Medical Research and Development (AMED) (JP22ek0210164 and JP23ek0210164 to T.Y., K.I., and K.N.; JP18km0405209, JP23tm0724607, and JP24ek0109755 to T.Y. and S.N.), and Roche Diagnostics. K.K. provided high-sensitive Troponin T assay. This company has no other disclosures to make.

Ethical Approval

The study protocol was approved by the Ethics Committee of Saga University Hospital (approval reference numbers: 20200101 for HEAL-AF, 20200901 for HEAL-AF2, and 202200401 for FUTURE-AF-S).

Pre-registered Clinical Trial Number

Japanese UMIN Clinical Trial Registration UMIN000040781, UMIN000044943, and UMIN000050841.

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25. Looi LM. Isolated atrial amyloidosis: a clinicopathologic study indicating increased prevalence in chronic heart disease. Hum Pathol 1993;24:602–7. 10.1016/0046-8177(93)90239-D [DOI] [PubMed] [Google Scholar]
26. Kawamura S, Takahashi M, Ishihara T, Uchino F. Incidence and distribution of isolated atrial amyloid: histologic and immunohistochemical studies of 100 aging hearts. Pathol Int 1995;45:335–42. 10.1111/j.1440-1827.1995.tb03466.x [DOI] [PubMed] [Google Scholar]
27. Röcken C, Peters B, Juenemann G, Saeger W, Klein HU, Huth C, et al. Atrial amyloidosis: an arrhythmogenic substrate for persistent atrial fibrillation. Circulation 2002;106:2091–7. 10.1161/01.CIR.0000034511.06350.DF [DOI] [PubMed] [Google Scholar]
28. Leone O, Boriani G, Chiappini B, Pacini D, Cenacchi G, Martin Suarez S, et al. Amyloid deposition as a cause of atrial remodelling in persistent valvular atrial fibrillation. Eur Heart J 2004;25:1237–41. 10.1016/j.ehj.2004.04.007 [DOI] [PubMed] [Google Scholar]
29. Fayyaz AU, Bois MC, Dasari S, Padmanabhan D, Vrana JA, Stulak JM, et al. Amyloidosis in surgically resected atrial appendages: a study of 345 consecutive cases with clinical implications. Mod Pathol 2020;33:764–74. 10.1038/s41379-019-0407-5 [DOI] [PubMed] [Google Scholar]
30. Bandera F, Martone R, Chacko L, Ganesananthan S, Gilbertson JA, Ponticos M, et al. Clinical importance of left atrial infiltration in cardiac transthyretin amyloidosis. JACC Cardiovasc Imaging 2022;15:17–29. 10.1016/j.jcmg.2021.06.022 [DOI] [PMC free article] [PubMed] [Google Scholar]
31. Edibam C, Playford D, Texler M, Edwards M. Isolated left atrial amyloidosis: acute premitral stenosis secondary to spontaneous intramural left atrial hemorrhagic dissection. J Am Soc Echocardiogr 2006;19:938.e1–4. 10.1016/j.echo.2006.01.028 [DOI] [PubMed] [Google Scholar]
32. Fontana M, Berk JL, Gillmore JD, Witteles RM, Grogan M, Drachman B, et al. Vutrisiran in patients with transthyretin amyloidosis with cardiomyopathy. N Engl J Med 2025;392:33–44. 10.1056/NEJMoa2409134 [DOI] [PubMed] [Google Scholar]
33. Goette A, Corradi D, Dobrev D, Aguinaga L, Cabrera JA, Chugh SS, et al. Atrial cardiomyopathy revisited-evolution of a concept: a clinical consensus statement of the European Heart Rhythm Association (EHRA) of the ESC, the Heart Rhythm Society (HRS), the Asian Pacific Heart Rhythm Society (APHRS), and the Latin American Heart Rhythm Society (LAHRS). Europace 2024;26:euae204. 10.1093/europace/euae204 [DOI] [PMC free article] [PubMed] [Google Scholar]
34. Sepehri Shamloo A, Husser D, Buettner P, Klingel K, Hindricks G, Bollmann A. Atrial septum biopsy for direct substrate characterization in atrial fibrillation. J Cardiovasc Electrophysiol 2020;31:308–12. 10.1111/jce.14308 [DOI] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

ehaf332_Supplementary_Data

ehaf332_supplementary_data.docx^{(6.6MB, docx)}

Data Availability Statement

Data are available upon reasonable request to the corresponding author.

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PERMALINK

Atrial amyloidosis identified by biopsy in atrial fibrillation: prevalence and clinical presentation

Kodai Shinzato

Yuya Takahashi

Takanori Yamaguchi

Toyokazu Otsubo

Kana Nakashima

Goro Yoshioka

Kensuke Yokoi

Kotaro Tsuruta

Ryosuke Osako

Shigeki Shichida

Yuki Nishimura

Makoto Edayoshi

Yuki Kawano

Yukako Shintani-Domoto

Kai Miyazaki

Akira Fukui

Atsushi Kawaguchi

Shigehisa Aoki

Seitaro Nomura

Naohiko Takahashi

Kaoru Ito

Koichi Node

Abstract

Background and Aims

Methods

Results

Conclusions

Structured Graphical Abstract

Structured Graphical Abstract.

Introduction

Methods

Study design and population

Atrial tissue sampling and processing for histology

Histological assessments

Electroanatomic mapping and catheter ablation

Propensity score–matched cohort study

Statistical analysis

Results

Patient characteristics and prevalence of cardiac amyloidosis

Figure 1.

Table 1.

Figure 2.

Table 2.

Table 3.

Figure 3.

Atrial and ventricular biopsy procedures

Evaluation of voltage at the biopsy site and global left atrial voltage

Biopsy and ablation procedures and complications

Amyloid typing and characteristics of each type

Confined atrial amyloidosis vs ventricular amyloidosis

Histological quantification of atrial structural remodelling

Figure 4.

Outcomes after catheter ablation

Figure 5.

Discussion

Major findings

An early diagnosis of cardiac amyloidosis

Clinical significance of atrial natriuretic peptide atrial amyloidosis

Confined atrial amyloidosis with light-chain amyloidosis and transthyretin amyloidosis

Atrial amyloidosis and atrial cardiomyopathy

Advantages of an atrial biopsy

Limitations

Conclusions

Supplementary Material

Acknowledgements

Contributor Information

Supplementary data

Declarations

Disclosure of Interest

Data Availability

Funding

Ethical Approval

Pre-registered Clinical Trial Number

References

Associated Data

Supplementary Materials

Data Availability Statement

ACTIONS