Atrial fibrillation (AF) is one of the most prevalent cardiac arrhythmias, associated with both multiple non-modifiable factors (such as age, sex, genetics, and race) and modifiable risk factors including smoking, usage of alcohol, sleep apnea, obesity, hypertension, diabetes, and lifestyle. Various cardiomyopathies contribute to the structural abnormalities in the heart that serve as substrates for the development of AF [1]. Cardiac amyloidosis (CA) results in damage in the mechanical structure of the left atrium as well as pressure overload, contributing to electrophysiologic changes, which predisposes patients to AF [2]. CA patients with AF have an increased risk of thrombosis, heart failure, sudden cardiac arrest and death [3]. Despite the increased potential hazards and high prevalence, there is limited knowledge regarding the outcomes of AF ablation and other interventions in patients with CA. Furthermore, medical therapy remains uncertain due to the limitations of the Congestive Heart Failure, Hypertension, Age $\ge$75 [Doubled], Diabetes Mellitus, Prior Stroke or Transient Ischemic Attack [Doubled], Vascular Disease, Age 65–74, Female (CHA₂DS₂-VASc) score. Therefore, we performed this review to determine the potential role of catheter ablation and other therapeutic interventions in CA patients with AF.

Amyloidosis is a collection of rare diseases caused by abnormal folding or aggregation of proteins transforming into amyloid fibers, which are deposited in extracellular tissues and contribute to abnormal cell function resulting in damage to multiple organs. The disease is commonly classified as systemic or localized and further classified in accordance with the site of precursor protein production and amyloid deposition [2, 4, 5]. There are at least 30 types of precursor proteins that have a propensity to form amyloid fibrils [5, 6, 7], and more than nine different protein fractions are considered to cause CA [8]. Among them are 2 common amyloid proteins capable of infiltrating the myocardium: monoclonal immunoglobulin light chain and transthyretin [7]. The typical categories of myocardial amyloidosis are displayed in Fig. 1.

Fig. 1.

The typical categories of myocardial amyloidosis.

Light chain (AL) amyloidosis is a rare disease caused by over-proliferation of monoclonal plasma cells that produce immunoglobulin $\kappa$ or $\lambda$ light chains that are abnormally $\beta$-folded and unable to be cleared, some of which are associated with hematologic malignancies including multiple myeloma (MM), Waldenström macroglobulinemia (WM) and non-Hodgkin’s lymphoma. Approximately 10% of amyloidosis patients have a comorbid MM [4, 9, 10, 11]. The existing study shows little geographic variation in the incidence of AL but there are large regional disparities in the rates of diagnosis [12]. From 1998–2018, approximately 74,000 cases of monoclonal immunoglobulin light chain amyloidosis were diagnosed worldwide. Globally, the prevalence rate per million people is about 51.27, with the lowest in Brazil (32.22/million) and reaching 71.08/million in Japan [11]. The median time from the onset of symptoms to the diagnosis of AL is 2.7 years, with 50% of patients visiting 5 or more physicians before the diagnosis is finally made. AL causes organ hypoplasia, multiple organ damage, and even organ failure, and about 24%–37% of patients die within 6 months of diagnosis [13, 14].

The transthyretin (TTR), known as prealbumin, is a tetrameric transport protein originally produced in the liver and consisting of 127 amino acids at 56 kDa. Following the exposure to certain factors, such as aging or genetic mutations, TTR tetrameric proteins are deconstructed into monomers and incorrectly aggregated into amyloid. Two types of transthyretin cardiac amyloidosis (ATTR-CA) are present, an aging-associated amyloidosis named wild-type transthyretin cardiac amyloidosis (ATTRwt) and a heritable type associated with a point mutation in the TTR gene at 110 known loci, hereditary transthyretin cardiac amyloidosis (hATTR) [2, 6, 8, 15, 16]. There are no precise statistics on the incidence and prevalence of ATTR-CA [16, 17, 18, 19]. The mean age of onset of ATTRwt is 75 years and the median survival after diagnosis without therapeutic intervention is only 3.5 years. The age of onset, presenting symptoms (cardiac, neurologic, or mixed lesions), and progression of hATTR are largely dependent on the type of mutation. hATTR can occur from 30 to 80 years of age, with a median survival of only 2.5 years for those who are diagnosed but refuse treatment [20]. ATTR-CA has no significant differences in gender, clinical phenotype, disease progression, and prognosis [21].

CA is a cardiomyopathy characterized by extracellular amyloid deposits throughout the heart. Deposits of amyloid can thicken the ventricular wall, leading to centripetal ventricular remodeling, resulting in ejection fraction preserved heart failure (HFpEF), as well as atrial enlargement due to increased pressure gradients. When amyloidosis involves the cardiac conduction system, it can often lead to arrhythmias such as atrial flutter, atrial fibrillation, atrial tachycardia, and atrioventricular block [2, 15, 22, 23]. Based on the significant impact of CA on the cardiovascular system, myocardial involvement is the primary morbid and lethal factor in systemic amyloidosis [22, 24].

Arrhythmias are a common complication in patients with CA. The incidence of arrhythmias in patients with CA ranges from 10% to 88%, and includes atrial flutter, atrial fibrillation, atrioventricular block, and ventricular arrhythmias. It is not uncommon for severe myocardial amyloidosis-associated arrhythmias to result in cardiac arrest or sudden cardiac death. The incidence is closely related to the severity of the disease, electrophysiologic abnormalities, and the amount of amyloid deposition [25, 26, 27, 28, 29, 30].

Atrial flutter or fibrillation is the most common type of arrhythmia in patients with CA, and approximately 40% of patients with CA have comorbid AF [31, 32]. A multicenter study by Guilio Sinigiani et al. [33] showed that the presence of any degree of intra-atrial block (IAB) significantly increased the risk of atrial fibrillation in patients with CA by approximately 2.2-fold (p = 0.041).

AF is a prevalent and significant complication of CA, often leading to severe outcomes such as heart failure and stroke. AF is as an independent predictor of mortality in CA patients [57]. The complex pathophysiology, driven by amyloid deposition and myocardial fibrosis, complicates both diagnosis and treatment. While current therapies, including pharmacological agents and interventional therapies, offer inadequate assessment, they underscore the need for treatment regimens that address both the underlying amyloid disease and the arrhythmia itself.

Future researches, focusing on developing amyloid-specific therapies or targeted therapies on CA genes to slow amyloid deposition and reduce arrhythmic burden are necessary. Although the safety and clinical benefits of catheter ablation have been demonstrated in a number of studies, its application remains somewhat controversial because of the lack of relevant evidence of better outcomes. Therefore, more convincing data, such as randomized as well as non-randomized clinical trials aimed at optimizing AF management in CA, will be critical in establishing evidence-based approaches that improve patient outcomes and quality of life.

The original contributions presented in the study are included in the article, further inquiries can be directed to the corresponding author.

RZW, XJX, YQN, FYC, JZ, HDJ, CYW and YPJ contributed greatly to the conception of the manuscript. RZW and YPJ wrote the manuscript. All authors contributed to editorial changes in the manuscript. All authors read and approved the final manuscript. All authors have participated sufficiently in the work and agreed to be accountable for all aspects of the work.

Not applicable.

This research received no external funding.

The authors declare no conflict of interest.