Stiff but keeping the beat: catheter ablation for atrial fibrillation in cardiac amyloidosis and sarcoidosis

This editorial refers to ‘Catheter ablation of atrial fibrillation in patients with cardiac amyloidosis and sarcoidosis: procedural findings and outcomes’ by A. Oraii et al., https://doi.org/10.1093/europace/euaf100 Atrial fibrillation (AF) is increasingly recognized as a hallmark of early cardiac involvement in infiltrative cardiomyopathies, particularly cardiac amyloidosis and sarcoidosis, with a prevalence of up to 15–30% in cardiac sarcoidosis and 50–70% in cardiac amyloidosis.1,2 These conditions, once considered rare and typically diagnosed at advanced stages, are now more frequently identified due to enhanced multimodal imaging, serum biomarkers, and clinical vigilance. Importantly, AF in this context often reflects direct atrial involvement related to an atrial cardiomyopathy rather than merely being a secondary consequence of elevated filling pressures or ventricular dysfunction.3 In cardiac amyloidosis, particularly the transthyretin (ATTR) and light-chain (AL) subtypes, atrial myopathy is a well-documented and early manifestation of the disease. Amyloid fibrils deposit within the atrial myocardium, disrupting myocyte structure, increasing stiffness, and leading to electromechanical dissociation.3 These changes create a highly arrhythmogenic substrate, as demonstrated by reduced atrial strain, left and right atrial enlargement, and a high prevalence of low-voltage areas (LVAs) on electroanatomic mapping. Notably, atrial infiltration can precede left ventricular involvement, with left atrial reservoir strain emerging as a powerful prognostic marker—predicting mortality and thromboembolic events even in sinus rhythm.4 Cardiac sarcoidosis, on the other hand, produces a distinct arrhythmogenic profile. Unlike the diffuse infiltration seen in amyloidosis, sarcoidosis involves patchy granulomatous inflammation, which can cause scattered atrial fibrosis and scarring. While ventricular arrhythmias and conduction disturbances dominate the clinical picture of cardiac sarcoidosis, AF and other atrial arrhythmias are increasingly recognized.5 Thus, pivotal autopsy findings suggest that atrial involvement may occur in up to 22% of symptomatic cardiac sarcoidosis cases.6 The mechanisms of AF in sarcoidosis are multifactorial: granulomatous infiltration of the atria leads to localized fibrosis and conduction heterogeneity, while elevated filling pressures from ventricular dysfunction contribute to atrial remodelling. In addition, speckle tracking studies have shown early impairment of atrial reservoir function, supporting the presence of a primary atrial myopathy even before overt ventricular disease becomes evident.7 When it comes to AF management in these subsets, emerging evidence suggests that rhythm control strategies, including catheter ablation, may provide symptom relief and even prognostic benefits in this unique population.8 In this issue of Europace, Oraii et al.9 present a comprehensive procedural analysis of AF ablation in patients with cardiac amyloidosis and sarcoidosis, offering novel insights into arrhythmia mechanisms and outcomes in these infiltrative cardiomyopathies. The authors should be commended for assembling one of the largest cohorts of these rare patient subsets to date and for incorporating a well-matched control group of patients without infiltrative cardiomyopathy using propensity matching. Their study highlights key procedural differences and clinical challenges when performing AF ablation in the setting of cardiac amyloidosis or sarcoidosis. One particularly compelling observation is the significantly higher prevalence of left atrial LVAs in patients with both conditions, suggesting extensive atrial myopathy and supporting the hypothesis of more advanced substrate disease. In cardiac amyloidosis, 62.5% of patients exhibited LVAs compared to 17.3% in controls; in cardiac sarcoidosis, this figure was 54.5% vs. 12.2%. This raises the important question of whether more extensive ablation strategies beyond pulmonary vein isolation (PVI), such as posterior wall isolation (PWI), might improve outcomes in these patients. While the study notes the prevalence of identified non-PV triggers and left atrial macro-reentrant flutters, it does not detail outcomes for patients who underwent additional substrate modification or received PWI. Specifically, in patients with persistent AF (62.5% in this study), there is conflicting evidence as to whether targeting left atrial LVAs might improve ablation outcomes. Indeed, both the STAR AF II10 and the DECAAF II11 trials failed to demonstrate a reduction in the rate of recurrent AF when either linear ablation, ablation of complex fractionated electrograms, or MRI-guided fibrosis ablation was performed in addition to PVI. On the other hand, Jadidi et al.12 demonstrated that a strategy combining PVI with selective ablation of LVAs displaying complex activation patterns (fractionated signals, rotational or rapid local activity) led to significantly higher single-procedure arrhythmia freedom compared to PVI alone (69% vs. 47%, P < 0.001). Notably, patients with minimal low-voltage burden (<10% of the atrial surface) achieved comparable outcomes with PVI-only, underscoring the need for individualized strategies based on substrate extent. In this study conducted by Oraii et al.,9 both amyloidosis and sarcoidosis patients exhibited a 2- to 4-fold higher prevalence of non-PV triggers and focal atrial tachycardias, findings that align with prior single-arm studies.8,13 These findings, along with the nature of atrial myopathy in infiltrative cardiomyopathies patients, may theoretically support the notion that more extensive and tailored ablation can enhance procedural success. However, given the progressive nature of these diseases—particularly cardiac amyloidosis—strategies limited to currently detectable LVAs may underestimate the true arrhythmogenic substrate. What appears as normal voltage today may evolve into fibrotic, low-voltage tissue tomorrow. In this context, a more extensive, pre-emptive ablation approach may provide better long-term rhythm control than a strictly voltage-guided strategy. Nonetheless, the long-term durability of these strategies in the setting of progressive atrial disease remains uncertain, in part because the relatively small sample size limited the study’s ability to perform meaningful comparisons between patients undergoing PVI alone and those receiving additional substrate modification. Inevitably, cardiomyopathies are not all created equal. Oraii et al.9 demonstrated that while AF recurrence rates were higher in patients with cardiac amyloidosis at 1 year (47.4% vs. 27.1%, P = 0.049), recurrence rates in those with cardiac sarcoidosis were comparable to controls. These divergent outcomes likely reflect distinct pathophysiologic substrates. Amyloid infiltration causes extensive, progressive fibrosis and electromechanical disarray within the atria, while sarcoidosis—as previously mentioned—leads to patchy granulomatous inflammation, potentially allowing for more effective ablation outcomes. Importantly, inflammation in sarcoidosis may be amenable to immunosuppressive therapy (in combination with AAD therapy), which has shown anecdotal success in reducing atrial arrhythmia burden,14 while the reversibility of amyloid deposits at the atrial level with targeted therapies, including small-interfering RNA drugs and gene editing for ATTR amyloidosis is currently object of many investigations. Although this study underscores a shared arrhythmogenic phenotype in infiltrative cardiomyopathies, both LVAs and non-PV triggers were more frequent in patients with cardiac amyloidosis compared to those with cardiac sarcoidosis (62.5% vs. 54.5% for LVAs, 29.2% vs. 17.6% for non-PV triggers). This higher prevalence of non-PV triggers in amyloidosis further supports the notion of an advanced and diffuse atrial myopathy, consistent with a more progressive atrial myopathy that may be more resistant to conventional ablation strategies. Emerging evidence suggests that early rhythm control strategies, including catheter ablation, may not only alleviate symptoms but also confer prognostic benefits by preventing progression of atrial myopathy.15 Recent studies in the general AF population support the advantages of early intervention, and this concept may be especially relevant in infiltrative cardiomyopathies, where timely ablation—before extensive remodelling—could preserve atrial function and electromechanical coupling. Again, pathophysiologic differences underscore the need for disease-specific approaches to rhythm control. Amyloidosis may require earlier and more aggressive rhythm control, associated with treatments specific for the type of amyloidosis, while in sarcoidosis, a combined approach including anti-inflammatory therapy may enhance success. Future studies comparing recurrence rates across ablation strategies and timing in sarcoidosis, as well as in the different types of amyloidosis will be critical. A key factor in interpreting the overall ablation efficacy reported by Oraii et al.9 is the use of AAD therapy post-procedure. In this study, over 40% of patients with amyloidosis and sarcoidosis remained on AADs beyond the 90-day blanking period, compared with lower rates in the control group. As a registry-based study, the continuation of AAD therapy was at the discretion of the treating physician. Post-ablation recurrence rates differed markedly between patients on and off AADs at 1-year follow-up (27.3% vs. 75.0% in cardiac amyloidosis; 22.2% vs. 50.0% in cardiac sarcoidosis). Therefore, the non-uniform post-ablation AAD strategy represents a significant confounder in assessing crude ablation success, and the true recurrence risk in these infiltrative cardiomyopathies is even more difficult to estimate and compare. Data from prior literature provide additional context. Donnellan et al.⁹ reported that catheter ablation in ATTR cardiac amyloidosis significantly reduced arrhythmic recurrences and heart failure hospitalizations and was associated with improved survival compared to medical therapy alone. In contrast, it remains unclear whether similar reductions in hospitalizations or mortality occurred in the cohort studied by Oraii et al.9 as no comparison of the pre- and post-ablation clinical course was presented. Ultimately, this study marks a significant contribution to the field of catheter ablation in complex cardiomyopathies. As the number of patients diagnosed with infiltrative disease rises—and as diagnostic tools enable earlier detection—the focus must shift toward earlier rhythm control, including ablation before irreversible atrial remodelling occurs and combination with effective therapies targeted to the systemic disease, i.e. amyloidosis or sarcoidosis, respectively. Atrial cardiomyopathy may serve as an early therapeutic target, and characterization of its extent and severity through strain imaging and high-density mapping will be the key to refining risk and guiding intervention. Rhythm control strategies, including catheter ablation, should be considered not only for symptom control but for potential benefit in terms of outcome and prevention of adverse events. Collaborative multicentre research will be essential to optimize rhythm management, in the context of integrated multidisciplinary care, taking into account the high risk and specificity of these patient populations. This research received no funding. There are no new data associated with this article.