MINI REVIEW published: 13 June 2022 doi: 10.3389/fcvm.2022.877592 Atrial Mitral and Tricuspid Regurgitation: Sex Matters. A Call for Action to Unravel the Differences Between Women and Men Francisco Gual-Capllonch 1*, José Ignacio Sáenz de Ibarra 1,2 , Antoni Bayés-Genís 3,4,5 and Victoria Delgado 3 1 Heart Institute, Clínica Rotger, Palma, Spain, 2 Cardiac Surgery Department, Clínica Rotger, Palma, Spain, 3 Heart Institute, Hospital Universitari Germans Trias i Pujol, Barcelona, Spain, 4 Department of Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain, 5 CIBERCV, Instituto de Salud Carlos III, Madrid, Spain Atrial functional regurgitation is caused by atrioventricular annulus dilation, with normal leaflets and ventricular dimensions and function within the normal range. Its occurrence, in both mitral and tricuspid valves, implies a worse prognosis due to the hemodynamic derangement they produce, but also constitutes a marker of greater comorbidity and more advanced disease. Predisposing conditions for these heart valve dysfunctions are mainly atrial fibrillation and heart failure with preserved ejection fraction. However, other factors like female sex also may be involved and influence their incidence, especially for atrial tricuspid regurgitation. In the present review, we analyze sex differences Edited by: Matteo Cameli, in the reported prevalence of atrial mitral and tricuspid regurgitation, and suggest University of Siena, Italy possible mechanisms involved. Finally, we underline potential therapeutic and preventive Reviewed by: strategies to reduce the burden of these heart valve disorders and discuss research gaps. Maria Concetta Pastore, Università del Piemonte Orientale, Italy Keywords: female sex, atrial mitral regurgitation, atrial tricuspid regurgitation, heart failure, atrial fibrillation *Correspondence: Francisco Gual-Capllonch fgualc@gmail.com Secondary regurgitation of atrioventricular valves is characterized by geometric changes of the valvular apparatus secondary to dilation and/or dysfunction of the ventricles or atria. In contrast to Specialty section: primary atrioventricular regurgitation, the leaflets of the mitral and tricuspid valves are structurally This article was submitted to normal. Accordingly, the management of secondary atrioventricular valve regurgitation differs Heart Failure and Transplantation, significantly from that of primary regurgitation since it needs to target the underlying mechanism a section of the journal first rather than fixing directly the anatomy and competence of the atrioventricular valve (1). Frontiers in Cardiovascular Medicine Secondary atrioventricular valve regurgitation due to dilation and dysfunction of the left or Received: 16 February 2022 right ventricles are associated with an excess of mortality (2–5). Additionally, it is increasingly Accepted: 23 May 2022 recognized a specific type of secondary atrioventricular regurgitation caused by mitral or Published: 13 June 2022 tricuspid valve annulus dilation but with left and right ventricular dimensions and function Citation: within the normal range. This type of secondary atrioventricular valve regurgitation is known Gual-Capllonch F, Sáenz de Ibarra JI, as atrial mitral regurgitation (AMR) (6) and atrial tricuspid regurgitation (ATR) (7), and is Bayés-Genís A and Delgado V (2022) characterized by normal leaflet motion -type I of the Carpentier classification- and a diminished Atrial Mitral and Tricuspid coaptation surface caused by atrial and subsequent atrioventricular annulus valve dilation. The Regurgitation: Sex Matters. A Call for Action to Unravel the Differences characteristics of the patients with significant AMR and ATR have been described in a few Between Women and Men. cohort-based studies (6, 7). Patients are characterized for being elderly, having a high prevalence Front. Cardiovasc. Med. 9:877592. of atrial fibrillation (AF) (8, 9) and heart failure with preserved ejection fraction (HFpEF) doi: 10.3389/fcvm.2022.877592 (10, 11). Both AF and HFpEF are associated with atrial cardiomyopathy and/or atrial failure (12) Frontiers in Cardiovascular Medicine | www.frontiersin.org 1 June 2022 | Volume 9 | Article 877592 Gual-Capllonch et al. Atrioventricular Functional Regurgitation and Sex and increased pressure overload of the atria leading to dilation and dysfunction of these cardiac chambers (13). Furthermore, the volume overload imposed by atrioventricular regurgitation may aggravate the atrial and atrioventricular valvular annulus dilation, leading to more advanced atrial myopathy and impairment of atrioventricular valve regurgitation. The excess of mortality and heart failure complications associated to the presence of significant AMR and ATR has been demonstrated in patients with AF and HFpEF (14–17). While it is well known that women with AF and/or HFpEF (which are associated with AMR and ATR) present at a more advanced course of the disease as compared to men and the implementation of the available therapies may differ between the two sexes (18, 19), the sex differences in AMR and ATR have not been extensively investigated. In the present review article we provide an overview of the sex differences in the prevalence and pathophysiology of AMR and ATR and discuss the potential gaps in knowledge from the diagnostic and therapeutic point of view FIGURE 1 | Differents factors contribute to the occurrence of AMR and ATR. that need further research in order to improve the outcomes of The most frequent substrate is AF, which leads to atrial and atrioventricular men and women (Figure 1). annulus dilation. HFpEF also elicits AMR and ATR, due to left and right atrial dilation as a result of pressure overload, and also constitutes a frequent trigger for AF. * denotes other variables or mechanisms, which may contribute to the occurrence of AMR, like hypervolemia, hamstringing of the posterior mitral DIFFERENCES IN PREVALENCE OF AMR leaflet or insufficient leaflet growth. # denotes other variables or mechanisms, BETWEEN WOMEN AND MEN which may contribute to the occurrence of ATR, like older age, hypervolemia, pulmonary hypertension, intracardiac lead or insufficient leaflet growth. Women have a distinct etiologic spectrum of mitral valve disease Prevalence data and suggested pathophysiologic mechanisms indicate that female patients are at higher risk for these heart valve disorders. AMR, atrial compared to men, with a higher prevalence of mitral valve mitral regurgitation; ATR, atrial tricuspid regurgitation; AF, atrial fibrillation; prolapse and rheumatic mitral valve regurgitation and lower HFpEF, heart failure with preserved ejection fraction; PH, prevalence of ischemic mitral regurgitation (20, 21). However, pulmonary hypertension. differences in prevalence of AMR between sexes is not clearly established, since the definition of AMR is relatively new and not consistent across the various observational studies and there are potential selection biases inherent to the design of the studies. mitral regurgitation among patients hospitalized for acute Nonetheless, a number of studies have shown a higher frequency decompensated heart failure showed that among 9,104 patients of AMR in women as compared to men. In a community study with HFpEF, 2,501 had significant mitral regurgitation and 4,437 from Olmsted County, 67% of patients with AMR were women had AF. Although the mechanism of mitral regurgitation was whereas only 41% of patients with secondary mitral regurgitation not specified, most probably the majority of the patients had due to left ventricular dilation and/or dysfunction (ventricular AMR since patients with primary mitral regurgitation would functional regurgitation) and 49% of patients with primary mitral have been excluded as per study design. The proportion of regurgitation were women (22). In a study evaluating the etiology female was comparable among patients with and without AF of mitral valve regurgitation of patients referred for surgical (67 vs. 65%, respectively) and the frequency of AF increased mitral valve repair, Glower et al observed that 78% of the patients with increasing severity of mitral regurgitation (28). Therefore, with isolated mitral annular dilation causing significant mitral it could be inferred that the prevalence of AMR would be higher regurgitation (surrogate definition of AMR) were women (23). in women than in men. In the prospective All Nippon AF In Additionally, a study of 378 consecutive patients with significant the Elderly (ANAFIE) registry, the echocardiographic substudy secondary mitral regurgitation demonstrated a higher frequency including 1,494 elderly patients with non-valvular AF showed of women with AMR compared to women with ventricular that 41% of patients were female and that the proportion of functional regurgitation (64 vs. 35%, p < 0.001) (24). In an significant AMR was 14%. However, it was not specified if among attempt to understand the efficacy of transcatheter edge-to-edge patients with significant AMR there were more women than mitral valve repair, various studies have analyzed the subgroups men (29). of patients with AMR and have shown that the frequency of women with AMR was larger than the frequency of men with DIFFERENCES IN PREVALENCE OF ATR AMR (25–27). BETWEEN WOMEN AND MEN When analyzing the frequency of AMR from the underlying pathophysiology point of view, the sex differences are less Several observational studies have shown that tricuspid clear. A substudy of the Atherosclerosis Risk in Communities regurgitation is more prevalent in women than in men (ARIC) Study investigating the association between AF and (30–32). It was also demonstrated in a retrospective cohort Frontiers in Cardiovascular Medicine | www.frontiersin.org 2 June 2022 | Volume 9 | Article 877592 Gual-Capllonch et al. Atrioventricular Functional Regurgitation and Sex study of 1,552 patients (49% of women), in which female CLINICAL PERSPECTIVE AND FORWARD sex, as well as age, AF, heart failure and right ventricular THINKING. A CALL FOR ACTION systolic pressure were significantly associated with tricuspid regurgitation progression (33). Specifically, the association As a result of this higher susceptibility of women for this of ATR to female sex has also been recognized (9, 34). Zhao type of atrioventricular valve regurgitation as compared to et al analyzed factors involved in determining the severity of men, strategies aimed at reducing the occurrence of AMR ATR in 170 patients with AF (56% of women), and found a and ATR may have a greater impact in women than in men. female predominance in severe ATR (percentage of women The development of AMR and ATR has been associated to 70 vs. 43% of women in non-severe ATR group, p < 0.001) worse prognosis, as it entails volume overload and decreased (35). It was also observed in an echocardiographic study of 251 stroke volume, but also because they are both markers of patients (53% of women), in which AF was strongly associated more advanced atrial remodeling due to increased AF burden, with the occurrence of significant ATR in women (OR 10.1, diastolic dysfunction, LA failure and pulmonary hypertension. p < 0.001) but not in men (OR 0.91, p < 0.87) (36). This Therefore, early diagnosis and adequate treatment of related was confirmed in a non-selected population of 432 patients conditions may impact on the burden of AMR and ATR, (49.1% of women) with AF and without primary valve disease particularly in women. For instance, it is acknowledged that or LV abnormalities. Significant ATR was present in 14.8% women with AF are diagnosed later and received less rhythm of patients, and the associated factors were female sex (OR control as compared to men, as demonstrated in the EORP- 2.61, p < 0.001), LA dilation and increasing pulmonary artery AF Pilot survey (52). Subsequently, this late diagnosis and systolic pressure (37). Regarding ATR in the context of HFpEF, underutilization of effective therapies in women with AF may a retrospective observational study of 328 patients detected 8% lead to a higher prevalence of significant AMR and ATR. of significant ATR, with 58% of female patients among this Furthermore, successful pulmonary vein ablation for AF has been group (11). associated with lower rates of significant AMR (8) and ATR (53) during follow-up. Earlier detection of HFpEF would also be POTENTIAL CAUSES FOR THE DIFFERENT expected to reduce atrial dilation and dysfunction, and decrease FREQUENCY OF AMR AND ATR BETWEEN the incidence of AMR. On the other side, timely diagnosis and effective treatment of pulmonary hypertension would WOMEN AND MEN reverse right atrial and ventricular dilation and consequently, The possible causes for the higher proportion of women with ATR and secondary tricuspid regurgitation. Additionally, an AMR and ATR as compared to men are not completely intracavitary lead may predispose to tricuspid regurgitation (54), understood and remain speculative. First, some studies point or worsen its severity when there are other pathogenic factors to distinct factors that may lead to more advanced LA like tricuspid annular remodeling or right ventricular dilatation dysfunction and more atrial fibrosis in women than in men (55). Therefore, mode of pacing should be carefully pondered (38), higher levels of the inflammatory markers (39, 40), or in women with high risk of tricuspid regurgitation, taking different electrophysiological properties (41, 42), which may into account that leadless pacing has been also unexpectedly be modulated by sex hormones (43, 44). In addition, the associated with tricuspid regurgitation progression (56). When atrioventricular annuli may have differences in composition and surgery for AMR is indicated, it has been advocated to perform cellularity according to sex. In a post-mortem study, El-Busaid simultaneously a tricuspid annuloplasty in all patients to prevent et al. analyzed 5-mm sections from the anterior and posterior future regurgitation, since right atrial enlargement is expected mitral and tricuspid valve annuli and demonstrated that the to continue as long as AF or HFpEF persist (57). In the myocardium was consistently present in all atrioventricular valve setting of other left-sided valve surgery, tricuspid repair for annuli of men but it was nearly absent in women, whereas mild or moderate tricuspid regurgitation with a dilated tricuspid the atrioventricular valve annuli of women were less elastic annulus is advocated (class IIa) (1), and should be particularly and had relatively scattered cells within the collagen matrix recommended in women with additional risk factors, in order compared to the atrioventricular valve annuli of men (45). to prevent more severe forms of ATR. Furthermore, the use Insufficient compensatory leaflet remodeling in response to of surgical ablation techniques should be considered at the mitral and tricuspid annulus dilation has been demonstrated to time of mitral valve repair/replacement in patients who are play a role in the pathophysiology of AMR (46, 47) and ATR symptomatic and may be considered in patients who are (48, 49). A distinct pattern of leaflet remodeling between sexes asymptomatic, if feasible and if it does not increase the risk of cannot be inferred from these studies yet. However, different pacemaker implantation (58). It is conceivable to hypothesize response of fibroblasts has been demonstrated according to that effective rhythm control may help to halt the progression sex (50, 51) and could explain different prevalence of AMR of atrial remodeling and reduce the risk of failure of mitral and ATR between men and women. Finally, it is possible valve repair at long-term follow-up, although this has not that more advanced stage of AF (18) and HFpEF (19) at the been demonstrated. time of diagnosis and less aggressive treatment approach may The use of new percutaneous transcatheter therapies may also account for this greater prevalence of AMR and ATR increase in the future for the treatment of symptomatic in women. and refractory significant AMR (25) and ATR (59), which Frontiers in Cardiovascular Medicine | www.frontiersin.org 3 June 2022 | Volume 9 | Article 877592 Gual-Capllonch et al. Atrioventricular Functional Regurgitation and Sex may be preferred over valve surgery due to old age or CONCLUSIONS comorbidities of these patients. In this regard, early diagnosis and treatment may be imperative in order to ensure that these AMR and ATR occur mainly in patients with AF and HFpEF and therapies are effective and the patients are not referred too are associated with higher rates of heart failure and mortality. late when the remodeling process of the atria has reached Observational data demonstrate a higher prevalence of these a point of no return. Finally, echocardiographic follow-up is heart valve diseases in women, especially for ATR. Mechanisms warranted to evaluate the development of significant AMR or involved in this sex distribution are not well-understood, and ATR in patients considered at risk, for instance, those with may be related to differences in histopathological characteristics permanent AF, HFpEF, severely dilated atria, mild-to-moderate of the atrio-ventricular annuli and leaflets and different AMR or ATR, pulmonary hypertension or those with an time-course or treatment strategies of the predisposing intracavitary lead. conditions in women compared to men. Research gaps include There is currently a growing interest in the field of AMR pathophysiological determinants and unbiased incidence of and ATR due to their increasing prevalence, prognostic both heart valve diseases, as well as differential treatment implications and novel therapeutic strategies. In this regard, strategies. Awareness of these sex-related differences from the research on sex differences in pathophysiology, clinical clinical ground to the echocardiography laboratories and the presentation and treatment approach is warranted and investigational setting may contribute to improve the knowledge could help to better understand these heart valve diseases. and better management of these valve disorders in both sexes. On the other hand, a closer attention is required to prevent sex inequity in diagnosis and treatment of AF and HFpEF AUTHOR CONTRIBUTIONS (18, 60, 61), the underlying conditions of AMR and ATR. Additionally, prompt referral to echocardiography is necessary FG-C and VD contributed to the conception and design of for an earlier diagnosis, when treatment or preventive the paper. FG-C drafted the manuscript. JS, AB-G, and VD strategies may modify the natural history of these heart contributed to the critical revision of the manuscript. 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(2015) 372:1399–409. doi: 10.1056/NEJMoa1500528 be made by its manufacturer, is not guaranteed or endorsed by the 59. Lurz P. Stephan von Bardeleben R, Weber M, Sitges M, Sorajja P, Hausleiter J, et al. Transcatheter Edge-to-Edge Repair for publisher. Treatment of Tricuspid Regurgitation. J Am Coll Cardiol. (2021) 77:229–39. doi: 10.1016/j.jacc.2020.11.038 Copyright © 2022 Gual-Capllonch, Sáenz de Ibarra, Bayés-Genís and Delgado. 60. Sotomi Y, Hikoso S, Nakatani D, Mizuno H, Okada K, Dohi T, et al. Sex This is an open-access article distributed under the terms of the Creative Commons differences in heart failure with preserved ejection fraction. J Am Heart Assoc. Attribution License (CC BY). The use, distribution or reproduction in other forums (2021) 10:e018574. doi: 10.1161/JAHA.120.018574 is permitted, provided the original author(s) and the copyright owner(s) are credited 61. Farrero M, Bellumkonda L, Gómez Otero I, Díaz Molina B. Sex and heart and that the original publication in this journal is cited, in accordance with accepted failure treatment prescription and adherence. Front Cardiovasc Med. (2021) academic practice. No use, distribution or reproduction is permitted which does not 8:630141. doi: 10.3389/fcvm.2021.630141 comply with these terms. Frontiers in Cardiovascular Medicine | www.frontiersin.org 6 June 2022 | Volume 9 | Article 877592