Increasing age is an important risk factor for AF with the prevalence of AF increasing from around 2% in patients younger than 65 years to more than 15% in patients more than 80 years of age2. This age related increase in prevalence of AF has been suggested to be not only due to the increasing prevalence of commorbidites and structural heart disease, but also due to atrial remodelling, both structural and electrophysiological, that occurs with aging per se5,15. Accordingly, while some studies have suggested an increase in atrial fibrosis with aging, others have not shown such an association7,16,17. More recently amyloid deposition in the ventricles has been described with aging predisposing to HFpEF8,9. In this study, we identified clinically undetected atrial amyloid deposits in 3.1% autopsies with the prevalence increasing to 8.2% in patients greater than 80 years of age. Further, the presence of such atrial amyloid deposits was associated with a five fold higher odds of AF as opposed to patients without such amyloid deposits after adjusting for age.

Amyloid infiltration of the heart is most commonly seen in patients with AL amyloidosis or ATTR related amyloidosis. While conduction system abnormalities and atrial fibrillation is frequently seen in these patients they are typically seen in association with restrictive cardiomyopathy with heart failure dominating the clinical presentation18,19,20. More recently, Röcken et al. demonstrated amyloid deposits in the atrium in a series of patients undergoing cardiac surgery. A significant proportion of their patients had valvular abnormalities necessitating valve replacement surgery; the increased atrial pressure consequent to the valvular lesion was postulated to increase ANP secretion and promote the progression and consequences of isolated atrial amyloidosis10. Similar findings were seen by Leone and colleagues in patients undergoing surgery for valvular heart disease11. Both these groups demonstrated an increased risk of AF in patients with amyloid deposition. By contrast, in this study, amongst patients with amyloid deposits only one patient had valvular heart disease (aortic stenosis necessitating aortic valve replacement). Further, none of these patients had clinical manifestations of restrictive cardiomyopathy or HFpEF and thus, non-valvular AF was likely the sole manifestation of cardiac amyloid deposition in these patients. These amyloid deposits were only seen in individuals greater than 60 years of age with the prevalence increasing with increasing age (Fig. 3). Such clinically undetected cardiac amyloid deposits may partly be responsible for the higher prevalence of nonvalvular AF seen with aging.

Amyloid deposition in the atrium alters impulse conduction with the occurrence of conduction slowing and conduction blocks. Slowing of conduction within the atrium manifests as prolongation of P-wave duration. In our study, patients with ICA had a trend towards longer P-wave duration though this did not reach statistical significance. Such an increase in P-wave duration was shown in an earlier study by Röcken and colleagues10. Further, amyloid tissue by virtue of being inexcitable would lead to a reduction in voltage on the surface electrocardiogram, resulting in low voltage P-waves as was seen in our study. The presence of low voltage P-waves during sinus rhythm may be useful in identifying individuals with AF with amyloid deposits in the atrium. The QRS voltage though described to be lower with amyloid infiltration of the ventricles, was however not reduced likely reflecting the milder form of disease with less diffuse ventricular involvement21.

Amyloid deposition would lead to discontinuities in conduction within the atrium leading to re-entry and wave break predisposing to AF. The presence of multifocal or diffuse atrial amyloid deposits would create multiple drivers explaining the higher incidence of persistent AF seen both in our study and in prior studies of isolated atrial amyloidosis10,11.

Rhythm control in elderly patients is challenging. Rhythm control with antiarrhythmic drugs has not been shown to be superior to a rate control strategy and is also associated with a high rate of recurrence22. Catheter ablation in the elderly is associated with a higher rate of recurrence necessitating multiple procedures, while some studies have also shown a higher rate of mortality as compared to younger patients23,24,25. The findings of our study provide an explanation for these findings with amyloid deposits creating a greater substrate for perpetuation of AF. Further, the biophysics of lesion formation during radiofrequency ablation is influenced by underlying tissue characteristics with smaller lesions forming in scar tissue as opposed to healthy myocardium. The efficacy of lesion formation in the presence of amyloid deposits has not been studied and the presence of such amyloid deposits may limit the efficacy of ablation.

A limitation of our study is the absence of immunohistochemistry in patients with amyloid deposits thereby limiting precise identification of the type of amyloid fibril. Senile systemic amyloidosis (SSA), also known as wild-type ATTR amyloidosis, is characteristed by predominant cardiac manifestations and its prevalence increases with increasing age. Given the restriction of amyloid deposits to only the heart and the presence of such deposits in both the atria and ventricles in our patients, the pattern of amyloid deposits in our patients likely represents a mild form of SSA with isolated cardiac involvement. This is likely a prevalent form of amyloidosis in the elderly population contributing to HFpEF8,9 and nonvalvular AF. A second limitation of our study is the paucity of female patients who accounted for only 0.5% of the study population. This reflects the population treated at our Institution and the results of this study can thus be extrapolated only to the male population. A third limitation, inherent to the retrospective study design, is the failure to diagnose sub-clinical AF in both group of patients. The methodology employed to detect amyloid deposition in our patients included a gross examination of both atria followed by directed biopsies from affected areas. In patients with no gross evidence of amyloid deposition, multiple samples were obtained from both atria. It is possible that this method of amyloid detection couldve missed detecting patients with focal amyloid deposits and this represents an additional limitation of this study. Since there is no other method available for identifying asymptomatic (silent) cardiac amyloid deposition we are unable to comment of the sensitivity of the method employed.

Additionally, while this is an autopsy based study and thus bears with it the concern for selection bias, there currently is no modality to identify isolated atrial amyloidosis antemortem. This report represents the first description of the role for such amyloid deposits in the elderly with AF occurring in the absence of valvular heart disease and additional studies are required to further define this entity and aid in its antemortem clinical detection.

Despite these limitations, our study identifies the presence of clinically silent cardiac amyloid deposits in a significant proportion of elderly patients and recognises a higher prevalence of persistent AF in these patients. The causality of this association needs to be evaluated in further studies.