|Year : 2021 | Volume
| Issue : 3 | Page : 464-468
|Histopathological changes in the right atrial appendages triggering atrial fibrillation: A tertiary care center study
Saloni Naresh Shah1, Renu G' Boy Varghese2, Sanjay Theodore3
1 Department of Histopathology, Apollo Hospitals, Chennai, Tamil Nadu, India
2 Department of Pathology, Pondicherry Institute of Medical Sciences, Kalapet, Puducherry, India
3 Department of Cardiovascular and Thoracic Surgery, Chettinad Health City, Chennai, Tamil Nadu, India
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|Date of Submission||19-Apr-2020|
|Date of Decision||24-Apr-2020|
|Date of Acceptance||09-Jul-2020|
|Date of Web Publication||28-Jul-2021|
| Abstract|| |
Background: Atrial fibrillation(AF) is as an abnormal irregular rhythm with chaotic generation of electrical signals in the atria of the heart. Various studies in the West have proved that atrial substrates, like isolated atrial amyloidosis can trigger the development of atrial fibrillation. In India, these structural changes have been analyzed on autopsied hearts. Aim: To determine the role of Atrial Amyloid as a substrate for Atrial fibrillation in ante mortem hearts. Methods and Results: Atrial appendages were obtained from seventy five patients undergoing open heart surgery at a tertiary care hospital in south India. They were stained with Hematoxylin &Eosin, Masson's Trichrome and Congo red stains and were examined for myocarditis, fibrosis and amyloidosis, respectively. 30 (40%) patients were in AF. Amyloid deposits were seen in 3 cases. All the three were in AF and had undergone mitral valve replacement (MVR) (P<0.05). 2 out of the 3 amyloid-positive cases showed active myocarditis and severe scarring but there was no statistically significant correlation between these factors. Conclusion: Amyloid and myocarditis, independently act as an arrythmogenic substrates in the development of atrial fibrillation and are also increasingly associated with female gender and MVR. We hypothesize that the amyloid deposits are due to isolated atrial amyloidosis as they were seen only in young individuals. Some patients in sinus rhythm (SR) had large left atria and myocarditis and probably are at a higher risk for developing AF. Hence, follow-up of these patients is required for prevention of severe organ damage and timely therapeutic intervention.
Keywords: Amyloidosis, Atrial fibrillation, Myocarditis, Atria, India
|How to cite this article:|
Shah SN, Varghese RB, Theodore S. Histopathological changes in the right atrial appendages triggering atrial fibrillation: A tertiary care center study. Indian J Pathol Microbiol 2021;64:464-8
|How to cite this URL:|
Shah SN, Varghese RB, Theodore S. Histopathological changes in the right atrial appendages triggering atrial fibrillation: A tertiary care center study. Indian J Pathol Microbiol [serial online] 2021 [cited 2021 Sep 27];64:464-8. Available from: https://www.ijpmonline.org/text.asp?2021/64/3/464/322394
| Introduction|| |
Atrial fibrillation (AF) is the most sustained cardiac arrhythmia with life-threatening clinical sequelae, increased mortality, and many associated complications., It is characterized by temporally and spatially disorganized, rapid atrial activity. Various factors contribute to the development of AF like age, sex, presence of mitral valve diseases, large left atrial size, presence of myocardial substrates such as amyloid, fibrosis and myocarditis, postoperative status, and other noncardiac causes.,,, Literature search revealed few studies associating the presence of the histopathological changes such as amyloidosis, fibrosis, and myocarditis, with the development of AF, mostly in autopsies or on endomyocardial biopsies only.,,,,,, To the best of our knowledge, this is the first Indian study substantiating the arrhythmogenic potential of histological changes in cardiac atria and determining their role in the development of AF.
| Subjects and Methods|| |
The current study was carried out in the Department of Pathology in collaboration with the Department of Cardio-thoracic and vascular surgery at a tertiary care hospital after obtaining approval from the Ethical Research Committee. A total of 75 adult patients who underwent open-heart surgery for cardiac bypass surgery, valve replacements, and other cardiac disorders in the department of Cardio-thoracic and Vascular Surgery were included in the study. Patients with history of systemic amyloidosis and chronic renal/hepatic diseases were excluded from the study.
A detailed history with relevant investigations was recorded. Under cardioplegia, right atrial appendages were obtained by the attending surgeon, fixed in 10% formalin and processed routinely in the histopathology laboratory. The sections were stained with hematoxylin and eosin (H&E), Masson's trichrome, and Congo red stains. The histological changes were subsequently graded and their presence was correlated with the development of AF. Myocarditis and fibrosis were studied in H&E and Masson's trichrome stained sections, respectively, by light microscopy and amyloid deposits were detected by Congo red-stained sections under a polarizing microscope. The grading of amyloidosis and fibrosis was done semiquantitatively: grade 0-absent, grade 1-mild, grade 2-moderate, and grade 3-severe deposits. Myocarditis was graded by DALLAS criteria: active myocarditis [the presence of inflammatory infiltrate with necrosis and/or degeneration of adjacent myocytes, not typical of the ischemic damage] [Image 1]a, borderline myocarditis [the presence of an inflammatory infiltrate without necrosis or degeneration of adjacent myocytes] [Image 1]b, and as no myocarditis. We were unable to perform immunohistochemistry on biopsies with amyloid deposits, due to the unavailability of the reagents for transthyretin and atrial natriuretic peptide.
This proposal has been reviewed and approved by the institutional Ethical Review Committee.
We used percentages and Chi-square test for statistical analysis of the data.
| Results|| |
Seventy-five atrial appendageal biopsies from patients above 18 years of age undergoing open-heart surgery were obtained. The mean age of the patients was 44.5 ± 15 SD with a range of 18 years to 75 years with most patients within 49 to 58 years of age. The histological abnormalities were then grouped age-wise. 54 out of 75 patients showed one or more of the three histological abnormalities. The histopathological changes were also distributed according to the sex. 62% of the females showed one or more of the three histological parameters as against 45% of the males. The patients were then categorized into two groups according to the presence/absence of AF. The patients in sinus rhythm (SR) constituted the control group. Out of the 75 patients, 30 were in AF and 45 in SR. The histopathological changes were grouped according to their rhythm distribution. All the 30 (100%) patients with AF showed the presence of one or more of the three abnormalities in their atria as opposed to only 25 (55%) out of the 45 patients in SR. 03 of 75 patients showed predominantly interstitial amyloid deposits [Image 2] and all of them had developed AF. Active myocarditis was seen in 38% of the patients in AF as opposed to only 18% in SR. The presence of myocarditis and amyloid was significantly associated with the development of AF. Fibrosis was not a statistically significant factor in the causation of AF; however, 62% of the patients in AF showed moderate to large deposits of collagen in them [Table 1], [Figure 1] and [Image 3].
|Table 1: Patient characteristics matched with atrial fibrillation and amyloid deposits|
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Similarly, the presence of amyloid in the atrial appendages was also independently matched with gender, type of heart surgery, size of atria on ECHO and with the other two histological substrates. The three amyloid positive patients were less than 48 years of age, excluding the possibility of senile amyloidosis. All the three patients had undergone mitral valve replacement surgery, had large left atria, and had developed AF subsequently. There was no significant sex predilection. Patients who underwent coronary artery bypass grafting (CABG) did not show evidence of amyloid in their biopsies. Amyloid deposits were not detected in the biopsies of the patients in SR. Two of the three patients with amyloid also showed the presence of high-grade fibrosis and active myocarditis independently; however, their association was not statistically significant. The female gender and type of heart surgery were significantly associated with active myocarditis. 40% of the patients in AF showed markedly significant active myocarditis [Image 1a], while the majority of the patients in SR had no evidence of inflammation. 43% of the patients with high-grade fibrosis also had active myocarditis. The presence of fibrosis showed no statistical significance with any of the parameters [Table 1].
Hence, the development of AF and amyloid deposits significantly correlated with the female sex, large left atrial size, mitral valve replacement (MVR) surgeries and with each other. Patients with AF also showed significantly active myocarditis independent of the amyloid deposits. Severe fibrosis was also present along with amyloidosis and active myocarditis but did not significantly contribute to the development of the AF.
| Discussion|| |
AF is the commonest cardiac arrhythmia. The prevalence of AF increases with age and it is more commonly seen in men than women. In our study, AF predominantly developed in patients between 46 and 60 years of age and was seen in 58% of the females as compared to 31% of the males. This can be subjected to the fact that men outnumbered the women in our study. Valvular heart diseases have also been major contributors in the development of AF,, especially mitral valve disease. The valvular obstruction elevates the left atrial pressure, subsequently increasing the size of the left atrium which further causes thinning of the myocardium and deposition of collagen ultimately leading to AF. The development of AF is increased in mitral valve disease and aortic stenosis. In our setting, the presence of mitral valve diseases and the mitral valve replacement surgeries were significantly associated with the development of AF. 19 (73%) of the patients who had mitral valve replacement surgeries developed AF in contrast to only 3 (9%) of those undergoing CABG. Other types of cardiac surgeries like aortic valve replacement, tricuspid valve replacement, atrial septal defect repair, etc., had 50% chances of developing AF. There were 25 (55%) patients in SR who also showed one or more of the three histological changes. These asymptomatic patients with atrial substrates were more susceptible to develop AF and, hence, follow-up is required for timely therapeutic intervention.
Cardiac amyloidosis is a cause of restrictive cardiomyopathy with poor prognosis. The two major subtypes associated with it are immunoglobulin light chain type and transthyretin (ATTR) type. Isolated atrial amyloidosis (IAA) is a common postmortem finding in the elderly and has been reported to occur in as many as 90% of patients above 90 years of age. IAA first appears in the third decade and its prevalence increases by 15%–20% with every decade. However, the prevalence of IAA was found to be significantly higher in the chronic rheumatic heart and mitral valve disease. Atrial natriuretic peptide (ANP) is the major protein subunit of the amyloid fibril in IAA, while transthyretin is seen in senile cardiac amyloidosis. Although the clinical relevance of IAA is not clear, patients with IAA are more likely to develop AF.
Rocken et al. studied 245 right atrial appendages from patients undergoing open-heart surgery. The presence of amyloid was more prevalent in women, similar to our study, the difference being the women in their study belonged to a higher age group. Leone et al. also found that the female gender was independently related to amyloidosis of the heart. Looi and Rocken quoted that IAA is associated with mitral valve diseases/replacement. , The patients with amyloid deposits in our study had a history of chronic rheumatic heart disease with underlying mitral valve disorder.
The association of AF with amyloidosis has been extensively debated over the last few decades [Table 2]. Amyloid deposition in the atria either alters or blocks the cardiac impulses thus slowing or discontinuing them. There is extracellular matrix disruption in amyloidosis which stiffens the myocardium resulting in improper contraction and conduction followed by free radical injury and apoptosis. This is reflected by the presence of prolongation of P-waves on an electrocardiogram. Presence of diffuse or multifocal amyloid deposits would create multiple foci of irregular conduction abnormalities, thus explaining the development of AF.,, Rocken et al. found that 40 (16%) of the 245 biopsies had amyloid deposits, of which 14 (33%) developed persistent AF. Leone and his colleagues divided their patients into two groups: one with AF and the other in SR (control). 46% of the first group patients had amyloid, while only 12% of the control group showed the same. Ariyarajah et al. conducted a study in 27 autopsied hearts where 10 out of the 14 amyloid positive hearts showed a premortem atrial tachycardia. Steiner et al. obtained myocardial sleeves from 100 autopsied hearts out of which half the patients had antemortem AF. 58.5% of these patients also had the presence of amyloid in their hearts. However, no statistical significance could be established. We had three patients with amyloid positivity and all three of them had persistent AF. 10% of the cases in AF had amyloid in their biopsies.
|Table 2: Comparison of various studies in the literature with the current study|
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Amyloid was diagnosed by polarizing microscopy, along with the use of ancillary studies such as immunohistochemistry in some studies., One group of authors performed Congo Red birefringence, Congo red fluorescence, and immunohistochemistry in the cardiac biopsies and demonstrated that concurrent use of birefringence and fluorescence studies rather than just one method is superior in detecting low amounts of amyloid.
Atrial myocarditis has been recognized as a precursor of AF and results in sudden cardiac death, especially in younger patients.,, The inflammatory cells release local and systemic proinflammatory cytokines which have been implicated in the pathophysiology of AF.,,, 67% of the patients in AF in the current study demonstrated borderline or active myocarditis with an occasional biopsy showing granulomatous inflammation. Also, all patients with amyloid deposits showed myocarditis with a significant correlation between the two and both these findings were independently associated with the development of AF.
Thus, early diagnosis and intervention are warranted to prevent advanced organ damage in these patients.
| Conclusion|| |
We analyzed the histological changes like amyloidosis, fibrosis, and myocarditis, in the atrial biopsies and determined associations of these with the development of AF. This was done after the elimination of other noncardiogenic cause of AF and excluding the patients with systemic amyloidosis. Our study provides the evidence that atrial fibrillation is more commonly associated with women and is statistically significant in those undergoing mitral valve replacement surgeries. We strongly believe that amyloid deposits and myocarditis, independently act as arrhythmogenic substrates in the development of AF. They are also increasingly associated with female gender, large left atria, and MVR. Amyloid was seen in the younger age group and, therefore, we suspect the amyloid deposits are most probably IAA. Very few patients in SR also had large left atria. These patients probably are at a higher risk of developing AF. Hence, follow-up of these patients is required for the prevention of severe organ damage and timely therapeutic intervention. To the best of our knowledge, this is the first Indian study correlating the development of AF with the relevant clinical parameters and with the presence of histological substrates in atrial appendageal biopsies.
The lack of significant correlation of atrial fibrosis with the occurrence of AF and the other clinical parameters is attributed to the small sample size. Larger number of biopsies are required to determine that amyloidosis increases the susceptibility of development of AF which in turn modulates further amyloid deposition. Interatrial distribution of histological changes influencing the development of AF could not be commented upon as we did not biopsy left atrial appendages. ANP levels in the plasma were not estimated. High levels of ANP inversely correlate with atrial collagen volume and are direct evidence of amyloid deposition. Therefore, the association of IAA, AF, and mitral valve disease could not be correlated. Immunohistochemistry for classifying the type of amyloid by staining with antibodies to ATTR and ANP was not done due to unavailability of these antigens in our country. However, as the amyloid positive cases in our study were young adults with no prior diagnoses of systemic amyloidosis, we infer that these deposits are isolated (IAA) in nature.
This proposal has been reviewed and approved by the Ethical Review Committee of Pondicherry Institute of Medical Sciences (PIMS), Kalapet, Pondicherry, which is a committee to make sure that research subjects are protected from harm.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form, the patients have given their consent for their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
The authors would like to acknowledge the contribution of Dr. Venkatachalam MD and Dr Suguna. E MD for the statistical analysis of the data in this study and Ms. Rekha and Mr. Govind for the technical support.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Benjamin EJ, Blaha MJ, Chiuve SE, Cushman M, Das SR, Deo R, et al
. Heart disease and stroke statistics-2017 update: A report from the American Heart Association. Circulation 2017;135:e146-603.
Chen LY, Shen WK. Epidemiology of atrial fibrillation: A current perspective. Heart Rhythm 2007;48:779-86.
In: Fuster V, Walsh RA, Harrington RA, editors. Hurst's The Heart. 13th
ed. The United States: The McGraw-Hill Companies. Inc ; s2011. p. 963-86.
Rocken C, Peters B, Juenemann G, Saeger W, Klein H, Huth C, et al
. Atrial amyloidosis: An arrythmogenic substrate for persistent atrial fibrillation. Circulation 2002;106:2091-7.
Krishnappa D, Dykoski R, Can I, Mbai M, Anand IS, Florea V, et al
. Atrial fibrillation in the elderly: The role of sub-clinical isolated cardiac amyloidosis. Sci Rep 2019;9:16584.
Donnellan E, Wazni O, Kanj M, Elshazly MB, Hussein A, Baranowski B, et al
. Atrial fibrillation ablation in patients with transthyretin cardiac amyloidosis. EP Eur 2020;22:259-64.
Henein MY, Suhr OB, Arvidsson S, Pilebro B, Westermark P, Hörnsten R, et al
. Reduced left atrial myocardial deformation irrespective of cavity size: a potential cause for atrial arrhythmia in hereditary transthyretin amyloidosis. Amyloid 2018;25:46-53.
Rapezzi C, Merlini G, Quarta CC, Riva L, Longhi S, Leone O, et al
. Clinical perspective. Circulation 2009;120:1203-12.
Staerk L, Sherer JA, Ko D, Benjamin EJ, Helm RH. Atrial fibrillation: Epidemiology, pathophysiology, and clinical outcomes. Circ Res 2017;120:1501-17.
Longhi S, Quarta CC, Milandri A, Lorenzini M, Gagliardi C, Manuzzi L, et al
. Atrial fibrillation in amyloidotic cardiomyopathy: Prevalence, incidence, risk factors and prognostic role. Amyloid 2015;22:147-55.
Sartipy U, Dahlstrom U, Fu M, Lund LH. Atrial fibrillation in heart failure with preserved, mid-range, and reduced ejection fraction. JACC Heart Fail 2017;5:565-74.
Begieneman MPV, Emmens RW, Rijvers L, Kubat B, Paulus WJ, Vonk ABA, et al
. Ventricular myocarditis coincides with atrial myocarditis in patients. Cardiovasc Pathol 2016;25:141-8.
Aretz HT, Billingham ME, Edwards WD. Myocarditis: A histopathologic definition and classification. Am J Cardiovasc Pathol 1987;1:3-14.
Aronow WS, Ahn C, Gutstein H. Prevalence and incidence of cardiovascular disease in 1,160 older men and 2,464 older women in a long-term health care facility. J Gerontol Med Sci 2002;57A: M45-6.
Banerjee A, Allan V, Denaxas S, Shah A, Kotecha D, Lambiase PD, et al
. Subtypes of atrial fibrillation with concomitant valvular heart disease derived from electronic health records: Phenotypes, population prevalence, trends and prognosis. EP Eur 2019;21:1776-84.
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.
Looi LM. Isolated atrial amyloidosis: A clinicopathologic study indicating increased prevalence in chronic heart disease. Hum Pathol 1993;24:602-7.
Biolo A, Ramamurthy S, Connors LH, O'Hara CJ, Meier-Ewert HK, Soo Hoo PT, et al
. Matrix metalloproteinases and their tissue inhibitors in cardiac amyloidosis: Relationship to structural, functional myocardial changes and to light chain amyloid deposition. Circ Heart Fail 2008;1:249-57.
Ariyarajah V, Steiner I, Hájková P, Khadem A, Kvasnicka J, Apiyasawat S, et al
. The association of atrial tachyarrhythmias with isolated atrial amyloid disease: Preliminary observations in autopsied heart specimens. Cardiology 2009;113 :132-7.
Steiner I, Hajkova P, Kvasnicka J, Kholova I. Myocardial sleeves of pulmonary veins and atrial fibrillation: A post mortem histopathological study of 100 subjects. Virchows Arch 2006;449:88-95.
Millucci L, Ghezzi L, Bernardini G, Braconi D, Tanganelli P, Santucci A. Prevalence of isolated atrial amyloidosis in young patients affected by congestive heart failure. Sci World J 2012;2012:1-8.
Winkel BG, Holst AG, Theilade J, Kristensen IB, Thomsen JL, Ottesen GL, et al
. Nationwide study of sudden cardiac death in persons aged 1–35 years. Eur Heart J 2011;32:983-90.
Wang H, Yao Q, Zhu S, Zhang G, Wang Z, Li Z, et al
. The autopsy study of 553 cases of sudden cardiac death in Chinese adults. Heart Vessels 2014;29:486-95.
Yamashita T, Sekiguchi A, Iwasaki Y-K, Date T, Sagara K, Tanabe H, et al
. Recruitment of immune cells across atrial endocardium in human atrial fibrillation. Circ J 2010;74:262-70.
Marcus GM, Smith LM, Ordovas K, Scheinman MM, Kim AM, Badhwar N, et al
. Intracardiac and extracardiac markers of inflammation during atrial fibrillation. Heart Rhythm 2010;7:149-54.
Schnabel RB, Larson MG, Yamamoto JF, Kathiresan S, Rong J, Levy D, et al
. Relation of multiple inflammatory biomarkers to incident atrial fibrillation. Am J Cardiol 2009;104:92-6.
Chen M-C, Chang J-P, Liu W-H, Yang C-H, Chen Y-L, Tsai T-H, et al
. Increased inflammatory cell infiltration in the atrial myocardium of patients with atrial fibrillation. Am J Cardiol 2008;102:861-5.
Saloni Naresh Shah
Department of Histopathology, Apollo Hospitals, 21, Greams Lane, Off Greams Road, Chennai - 600 006, Tamil Nadu
Source of Support: None, Conflict of Interest: None
[Table 1], [Table 2]
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