Evolving Perspectives in Surgery for Mitral Regurgitation: Why Sex Matters

Abstract

There is a growing body of evidence investigating sex differences in the presentation, assessment, and outcomes of patients with mitral regurgitation (MR) undergoing mitral valve surgery. It has been shown that women present at older ages, with more comorbidities and more severe symptoms. Compared with male patients, female patients have longer intervals to surgery, lower rates of surgery, and receive fewer mitral valve repairs (as opposed to replacements). On imaging, left ventricular cavity sizes and many quantitative measures of MR severity differ significantly by sex, and current guidelines do not account for this. While sex differences in surgical outcomes have been documented, these are largely limited to primary MR and are based on older studies, underscoring the need for further research. Data on sex differences in transcatheter interventions for MR are inconclusive and heterogeneous, complicating comparisons to surgery. To address these disparities, sex‐specific thresholds for intervention in primary MR, standardization of the quantification of MR severity by sex, and further prospective studies are required. As we move into an era of precision medicine, it is critical to recognize sex as a key determinant of cardiovascular care. In patients undergoing surgery for MR, further research should evaluate whether current intervention thresholds and management pathways are appropriately tailored to female patients.

Nonstandard Abbreviations and Acronyms

CHOICE‐MI

Choice of Optimal Transcatheter Treatment for Mitral Insufficiency

COAPT

Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients With Functional Mitral Regurgitation

CSTN SIMR

Comparing the Effectiveness of Repairing Versus Replacing the Heart’s Mitral Valve in People With Severe Chronic Ischemic Mitral Regurgitation

EuroSMR

European Registry of Transcatheter Repair for Secondary Mitral Regurgitation

GDMT

guideline‐directed medical therapy

MIMVS

minimally invasive mitral valve surgery

MitraSwiss

Swiss National Registry on Percutaneous Mitral Valve Interventions

MR

mitral regurgitation

MTEER

mitral transcatheter edge‐to‐edge repair

MVr

mitral valve repair

MVR

mitral valve replacement

OCEAN‐Mitral

Optimized Catheter Valvular Intervention

PMR

primary mitral regurgitation

SMR

secondary mitral regurgitation

TMVR

transcatheter mitral valve replacement

TR

tricuspid regurgitation

TVr

Tricuspid valve repair

Mitral regurgitation (MR) is the most common valvular heart disease worldwide and has been estimated to be present in almost 2% of the adult population. ¹ Sex differences in the epidemiology of MR have been recognized for decades. ² , ³ However, the impact of sex following mitral valve (MV) interventions for MR has only been formally investigated since the late 2000s, when studies first reported that, compared with men, female patients had significantly worse prognoses after MV surgery. ⁴ , ⁵ Since then, a wealth of evidence investigating sex differences in the presentation, assessment, and outcomes of patients with MR undergoing MV surgery has been documented (Figure 1).

Figure 1. Sex differences in presentation, assessment, and outcomes in patients with MR undergoing surgery.

A wealth of sex‐related differences in MR have been reported in the literature. These can broadly be divided into differences in presentation, assessment, and outcomes. LOS indicates length of hospital stay; LV, left ventricle; MR, mitral regurgitation; MVr, mitral valve repair; MVR, mitral valve replacement; PMR, primary mitral regurgitation; SMR, secondary mitral regurgitation; TR, tricuspid regurgitation; and TVr, tricuspid valve repair.

Pathophysiology and Classification of MR

To critically review sex differences in MR, it is important to consider the classification and pathophysiology of MR. Broadly, MR can be split into 2 types: primary and secondary. Primary MR (PMR) encompasses diseases of the MV apparatus, while secondary MR (SMR) is caused by disease of the left ventricle or atrium which subsequently causes abnormal leaflet tethering forces and/or dilation of the mitral annulus. ⁶ Proper classification of MR is paramount, as PMR and SMR are fundamentally distinct phenotypes with different treatment strategies ⁷ , ⁸ and prognoses. ⁹

At the onset of PMR, the left ventricle can adapt by dilating to increase preload and stroke volume, thus maintaining forward cardiac output. However, chronic PMR can cause pathological left ventricular (LV) dilation, which in turn increases wall stress. Eventually, the left ventricle can enter a decreased contractile state, at which time irreversible dysfunction occurs. ¹⁰ , ¹¹ In contrast, SMR arises from another underlying pathology, so the pathophysiology of SMR is dependent on the underlying disease. SMR can be coarsely divided into ischemic and nonischemic pathogeneses. Ischemic SMR results from inferior LV wall motion abnormalities, often following a myocardial infarction, which subsequently causes abnormal leaflet tethering resulting in MR. ¹² Nonischemic SMR is caused by ventricular and/or atrial dilatation, which in turn leads to an abnormally large regurgitant orifice through which MR occurs. ¹³ , ¹⁴

Differences in Presentation

It has been demonstrated that, compared with male patients, female patients present at older ages, ¹⁵ , ¹⁶ , ¹⁷ , ¹⁸ , ¹⁹ , ²⁰ , ²¹ , ²² , ²³ with more comorbidities, ¹⁵ , ²⁰ , ²³ , ²⁴ more severe symptoms, ¹⁹ , ²¹ , ²³ , ²⁴ , ²⁵ , ²⁶ and comprise the majority of patients with PMR but the minority of patients with SMR. ¹⁵ , ¹⁶ In a large cohort study of >300 000 patients admitted with a diagnosis of MR in Spain by Zamorano et al, ¹⁵ female patients were significantly older (80 years versus 75 years; P<0.001); had significantly higher Charlson comorbidity indexes, a measure of an individual’s burden of comorbidities (6.00 versus 5.00; P<0.001); and formed a greater proportion of PMR cases (112 650 versus 70 355; P<0.001) and a smaller proportion of SMR cases (47 036 versus 77 242; P<0.001) compared with male patients. Interestingly, the authors found that, within the SMR cohort, female patients made up a greater proportion of atrial SMR cases (4358 versus 3036, P<0.001), while men made up a greater proportion of ventricular SMR cases, a finding that has also been reported by other groups. ⁹ , ²⁷ The evidence for female patients presenting with more severe symptoms is extensive in PMR. ²¹ , ²⁵ , ²⁸ , ²⁹ However, in SMR, it is limited to 1 post hoc analysis of the CSTN SIMR (Comparing the Effectiveness of Repairing Versus Replacing the Heart’s Mitral Valve in People With Severe Chronic Ischemic Mitral Regurgitation) trial in which women had significantly worse self‐reported Minnesota Living With Heart Failure questionnaire scores (53.1 versus 45.0; P=0.03), although it should be noted that there was no significant difference in New York Heart Association class. ²⁴

Differences in Assessment

Sex differences have been reported in key aspects of the assessment of patients undergoing MV surgery, particularly in referral patterns and cardiac imaging. These are particularly important, as both referral to the heart team and findings on cardiac imaging are cornerstones of guidelines on the management of MR. ⁷ , ⁸

Female patients presenting with MR have been noted to have longer intervals to intervention than male patients ²⁹ , ³⁰ , ³¹ alongside having overall lower rates of intervention for MR. ¹⁵ , ²⁰ , ²⁹ , ³¹ In addition to this, Waldron et al demonstrated that female patients presenting with PMR and meeting class I indications for intervention ⁸ (severe symptomatic MR or severe asymptomatic MR with an LV end‐systolic diameter [LVESD] >40 mm and/or LV ejection fraction [LVEF] <60%) were significantly less likely to undergo multidisciplinary team evaluation, even after adjustment for relevant covariates (odds ratio, 0.27 [95% CI, 0.15–0.47]; P<0.001). ³² This is particularly concerning, as this may further delay treatment in female patients. It may also have an impact on whether female patients are considered for less invasive surgical and transcatheter therapies. This was demonstrated by Dębski et al, who studied a cohort of patients undergoing minimally invasive MV surgery (MIMVS) and found that women were less likely to be considered for MIMVS ¹⁸ despite having similar long‐term outcomes after MIMVS to male patients. ¹⁸ , ³³ Another possible explanation for this discrepancy may be that if women broadly present with more advanced mitral disease, it may be more challenging to use MIMVS. ³⁴

Cardiac imaging, namely, echocardiography, is necessary for the assessment of the severity and pathogenesis of MR. ⁷ Many differences have been reported between male and female patients on multiple imaging modalities regarding the quantification of cardiac chambers and MR severity.

Numerous groups have demonstrated differences in LV cavity sizes, on both diametric and volumetric assessment, between men and women presenting with MR, with female patients having significantly smaller LV cavity sizes.^* This is convincingly demonstrated by Altes et al, ²⁵ who performed a multimodality study on patients with PMR including transthoracic echocardiography and cardiac magnetic resonance (CMR) imaging, the gold‐standard method for assessing cardiac chamber size, ⁴⁰ and found that female patients had significantly smaller end‐diastolic and end‐systolic LV volumes, even when indexed to body surface area (BSA). The same pattern was seen on transthoracic echocardiography LV volumetric and diametric assessment. Similar evidence has been documented in SMR. ²⁴ , ⁴¹ It has also been reported that female patients present with higher LVEFs, ¹⁷ , ²⁰ , ²² , ²⁵ , ²⁹ a finding corroborated by the aforementioned study by Altes et al, although it should be noted that the evidence for significantly different LVEF between sexes is mixed. ²³ , ²⁶ , ³⁶ , ³⁷ , ³⁸ , ³⁹ Sex differences have also been reported in left atrial (LA) assessment, with Berg‐Hansen et al demonstrating that women with PMR have relatively greater LA stiffness and impaired LA reservoir mechanics compared with men despite having similar LA sizes when indexed to BSA. ³⁷

The quantification of MR severity is complex and requires a multimodal approach, with many different measurements available. ⁴⁰ Nevertheless, sex differences in quantitative measurements have consistently been documented including effective regurgitant orifice area, proximal isovelocity surface area radius, and regurgitant volume on both echocardiography and CMR. ²⁵ , ²⁹ , ³⁶ , ³⁸ Interestingly, although women tend to present with more severe symptoms, these quantitative measures tend to underestimate MR severity. One notable exception to these discrepancies is indexing regurgitant volume to either total LV stroke volume (regurgitant fraction) ²⁵ or to LV end‐diastolic volume, ³⁶ which has been shown to eliminate sex discrepancies in MR assessment. It should be noted that current international guidelines for MR do not include CMR thresholds for determining MR severity, although recent work has aimed to bridge this gap. ⁴²

Differences in Outcomes

In recent years, many studies have sought to determine if there are sex differences in outcomes after MV surgery for MR. These are summarized in the Table 1. As discussed earlier, patients with PMR and patients with SMR have fundamentally distinct prognoses, so it is important to consider outcomes separately for each of these MR subtypes.

Table 1.

Overview of Studies Reporting Sex‐Specific Outcomes After Surgery for MR

Author, year	Women, n (%)	Men, n (%)	MR type	Surgical intervention	Inclusion period	Follow‐up, y	Outcome(s)
Avierinos et al, 5 2008	4461 (54)	3768 (46)	PMR	NR	January 1989 to December 1998	11.7±4.4	At 15 y, women with no or mild mitral regurgitation had better odds of survival than men. At 15 y, women with severe regurgitation had worse survival than men. The survival rate 10 y after surgery was similar in women and men.
Song et al, 4 2008	12 384 (51)	12 629 (49)	NR	MVR/MVr	January 2002 to June 2005	In‐hospital	In patients aged 40–59 y, the in‐hospital mortality rate of mitral valve operation is ≈2.5 times higher in women compared with men with similar risk factors.
Vassileva et al, 52 2011	32 964 (51)	31 060 (49)	NR	MVR/MVr	January 2005 to December 2008	In‐hospital	Among patients who underwent mitral valve repair, women had a higher in‐hospital mortality rate. After adjustment for propensity scores and concomitant procedures, this relationship was no longer statistically significant.
Seeburger et al, 44 2012	1637 (44)	2124 (56)	PMR and SMR	MIMVS	January 1999 to December 2011	10	Male patients showed significantly better postoperative long‐term survival than female patients after 1, 5, and 10 y.
Vassileva et al, 45 2013	28 879 (61)	18 723 (39)	NR	MVR/MVr	January 2000 to December 2009	5.0 [2.7–7.7]	Elderly women had a higher operative mortality rate and lower long‐term survival. Mitral repair appeared to restore normal life expectancy for men but not for women.
Chan et al, 47 2016	208 (28)	535 (72)	PMR	MVr	January 2001 to December 2014	3.1±2.8	Although there was no difference in early or late survival between groups, women were more likely to develop recurrent MR ≥2+ over the course of follow‐up.
Mokhles et al, 53 2016	1434 (42)	1977 (58)	…	MVR/MVr	January 2007 to December 2011	In‐hospital	No significant difference between sexes for in‐hospital death.
Chan et al, 21 2019	227 (24)	735 (76)	PMR	MVr	January 2002 to December 2017	5.1±3.8	Female patients were less likely to experience a postoperative decrease in indexed LV end‐systolic dimensions.
Giustino et al, 24 2019	96 (38)	155 (62)	Ischemic SMR	MVR/MVr	January 2009 to December 2012	2	Female patients experienced a higher mortality rate and worse quality of life after MV surgery. No significant differences in the degree of LV reverse remodeling between sexes.
Kislitsina et al, 20 2019	600 (42)	836 (58)	PMR and SMR	MVR/MVr	April 2004 to June 2017	5.2±3.5	The mortality rate was comparable between sexes, including in separate PMR and SMR subgroup analyses.
Hirji et al, 56 2020	947 (38)	1516 (62)	PMR and SMR	MVr	January 2002 to December 2016	8.2 (4.7–11.7)	In unadjusted analysis, female patients had significantly lower freedom from MV reoperation at 1, 5, and 10 y. No significant differences in mortality rate between sexes in adjusted analysis.
Muñoz‐Rivas et al, 16 2020	Total: 44340		PMR and SMR	MVR	January 2001 to December 2015	In‐hospital	Male sex was independently associated with a higher mortality rate after bioprosthetic MVR.
El‐Andari et al, 50 2021	200 (29)	501 (71)	NR	MVr	January 2004 to December 2018	7.6	No significant difference in mortality between sexes. No significant difference in cardiac remodeling between sexes.
El‐Andari et al, 51 2021	476 (44%)	596 (56%)	NR	MVr	January 2004 to December 2018	1	No significant differences in mortality rate between sexes. Men showed significantly improved remodeling of LV and LA, whereas women only had significant remodeling of LA.
Kandula et al, 39 2021	328 (33)	767 (67)	PMR	MVR/MVr	April 2004 to June 2017	10	Male and female patients had similar survival at 1, 5, and 10 y.
Namazi et al, 41 2021	227 (33)	471 (67)	SMR	MVR/MVr	January 1999 to December 2018	4.8 (2.4–9.2)	SMR is associated with increased mortality rate in male patients.
Dębski et al, 18 2022	424 (44)	532 (56)	PMR and SMR	MIMVS/ MVR/MVr	January 2007 to December 2019	4.9 (2.3–8.2)	Neither sex nor surgical approach was associated with worse survival.
Al‐Zubaidi et al, 19 2023	7977 (35)	14 681 (65)	PMR	MVR/MVr	January 2000 to March 2019	In‐hospital	Female sex is an independent predictor of in‐hospital death.
Liu et al, 49 2023	337 (36)	594 (64)	PMR	MVr	January 2019 to December 2019	5.1 (5–7)	Long‐term survival and freedom from reoperation rates were not significantly different between sexes.
Abadie et al, 35 2024	1825 (40)	2764 (60)	PMR	MVr	January 1994 to December 2016	7.2	After MVr, women have a higher risk for all‐cause death at lower LVESD and LVESD indexed to BSA and higher ejection fraction.
Avierinos et al, 5 2024	650 (28)	1660 (72)	PMR	MVR/MVr	March 1980 to December 2005	9.82	Female sex was associated with increased postoperative death in univariable analysis but not when adjusting for baseline covariates in multivariable analysis.
Chang et al, 43 2024	8404 (45)	10 168 (55)	PMR and SMR	MVR/MVr	January 2001 to December 2018	5.6	Female patients have a higher risk of in‐hospital death. No significant sex differences in long‐term all‐cause death.
Cheng et al, 48 2024	161 (42)	220 (58)	…	MVr	January 2019 to December 2022	2.1±1.1	No sex differences in early and late survival, reoperation, and freedom from late moderate or severe MR.
Liu et al, 46 2024	371 (35)	698 (65)	PMR	MVr	January 2010 to December 2019	4.7±2.6	Sex is not an independent predictor of long‐term all‐cause death. Female sex is an independent predictor for recurrent MR.
Malik et al, 28 2024	147 (30)	343 (70)	PMR	MVr	May 2008 to February 2023	5.4 (3.1–8.4)	No significant difference in all‐cause death between sexes.
Van Kampen et al, 17 2024	314 (33)	649 (67)	PMR	MVR/MVr	January 2013 to December 2021	2.2	Female patients had longer length of hospital stays. No significant difference in long‐term reoperation‐free survival.
Wagner et al, 32 2024	214 (55)	174 (45)	PMR	MVR/MVr	January 2014 to December 2023	1.3 [1.1–1.5]	Among patients who do not receive concomitant tricuspid valve repair during MV surgery, severe TR is more likely to develop in female patients, and female patients are more likely to require a valve‐related reoperation.
Waldron et al, 30 2024	180 (46)	211 (54)	PMR	MVR/MVr	January 2016 to December 2020	2	Survival in male and female patients is comparable after accounting for age and comorbidities.
Kwak et al, 22 2025	598 (35)	1088 (65)	PMR	MVR/MVr	January 2006 to January 2020	8.2 [5.3–12.2]	Female patients have an earlier increase in mortality risk associated with LV systolic dysfunction (LVEF and LV‐GLS).
Long et al, 26 2025	76 (53)	67 (47)	PMR and SMR	MVR/MVr	January 2017 to December 2018	6.67 [6.15–7.36]	There was no significant difference in the long‐term mortality rate between sexes. Concomitant tricuspid intervention and urgent operation associated with a higher mortality rate in women.
Bernard et al, 23 2025	661 (37)	1143 (63)	PMR	MVR/MVr	January 2002 to December 2019	6.1 (3.1–10.1)	Women have a higher risk of early stroke/transient ischemic attack after surgery but a lower risk of myocardial infarction, de novo atrial fibrillation, and atrioventricular block. Women have a higher long‐term mortality rate than men after MVr but not after MVR.

Follow‐up is shown as median, median (interquartile range), or mean±SD. AF indicates atrial fibrillation; BSA, body surface area; LA, left atrium; LV, left ventricle; LVEF, left ventricular ejection fraction; LVESD, left ventricular end‐systolic diameter; LV‐GLS, left ventricular global longitudinal strain; MIMVS, minimally invasive mitral valve surgery; MR, mitral regurgitation; MVr, mitral valve repair; MVR, mitral valve replacement; NR, not reported; PMR, primary mitral regurgitation; SMR, secondary mitral regurgitation; and TR, tricuspid regurgitation.

In PMR, there is evidence that female patients have longer postoperative length of hospital stay, ¹⁷ , ²⁰ , ²⁶ , ⁴³ greater in‐hospital death, ⁴ , ¹⁹ and higher risk of early stroke, ²³ although whether this can be explained by their more advanced presentation at baseline is unclear. In terms of the impact on long‐term outcomes, certain studies have found that female patients have a higher mortality rate. ⁵ , ⁴⁴ , ⁴⁵ This includes a cohort study of >47 000 patients in the United States, which concluded that mitral surgery restored life expectancy for women but not men. ⁴⁵ It has also been documented that women with PMR may experience less positive cardiac remodeling ²¹ and be at greater risk of recurrent MR after MV repair (MVr). ⁴⁶ However, a number of more recent studies have not found any significant differences in death between sexes,^† suggesting that improvements in surgical techniques may have helped reduce any discrepancies.

There is emerging evidence of sex discrepancies in outcomes after concomitant tricuspid valve repair (TVr). Wagner et al demonstrated that female patients with moderate or greater tricuspid regurgitation (TR) undergoing MV surgery were less likely to receive concomitant tricuspid valve repair TVr (odds ratio, 0.48 [95% CI, 0.29–0.81]; P=0.006) and that, among patients who did not receive concomitant TVr, female patients required a greater proportion of valve‐related reoperations at 4 years compared with male patients. ³² Moreover, our group also demonstrated that concomitant TVr was associated with an increased long‐term mortality rate in women compared with men. ²⁶ It is also interesting to note that many studies have documented a greater overall proportion of concomitant TVr in women. ¹⁶ , ¹⁷ , ¹⁸ , ¹⁹ , ²⁰ , ²³ , ⁴³ , ⁴⁴ , ⁵² This evidence raises the possibility that differences in the management of MR with concomitant TR could contribute to sex differences in outcomes.

There is much less data available on outcomes after surgery for SMR, perhaps due to SMR representing a minority of patients with MR ¹⁵ and the variation in practice in managing these patients, and the data is conflicting. Giustino et al found that women had a worse quality of life and lower survival after surgery, ²⁴ while, conversely, Namazi et al demonstrated that male patients had a worse prognosis after surgery for SMR. These discordant results may be explained by the first study only including patients with ischemic SMR, whereas around half of the patients in the second study had a nonischemic SMR pathogenesis. ⁴¹ Two studies with mixed PMR and SMR patients which provided subgroup analyses of patients with SMR reported no significant differences in death between male and female patients. ²⁰ , ⁴³

Importantly, there are numerous studies that have found that fewer female patients undergo MVr compared with male patients.^‡ Indeed, this may also be related to the fact that female patients present later, after which point the valve may be less amenable to repair. Considering that MVr is associated with superior long‐term survival than MV replacement (MVR) in PMR, ⁵⁴ , ⁵⁵ this is a factor that may potentially influence outcomes. However, in a recent study by Bernard et al²³ investigating 1804 patients with PMR undergoing MV surgery, the authors found that female patients, compared with male patients, had a higher long‐term mortality rate after MVr (hazard ratio [HR], 1.62 [95% CI, 1.14–2.30]; P=0.007) but not after MVR (HR, 0.91 [95% CI, 0.71–1.17]; P=0.47). It is worth noting that this study included patients from 2002 to 2019, during which surgical techniques may have improved, and was not able to fully match male and female patients, but nevertheless demonstrates the possibility of sex differences in long‐term outcomes related to the choice of MV repair versus replacement, which warrant further investigation. Concerning other concomitant procedures, it has consistently been reported that men undergo a greater proportion of concomitant coronary artery bypass grafting,^§ whereas evidence on sex differences in the incidence of concomitant atrial ablation is mixed, with some studies documenting a greater proportion in women ²⁰ , ⁴³ , ⁴⁹ , ⁵² , ⁵⁶ and others showing no significant difference between sexes. ¹⁷ , ¹⁹ , ²² , ²³ , ²⁴ , ⁴⁷ Considering that female patients have been shown to have worse outcomes after CABG, ⁵⁷ yet men appear to receive more CABG during MV surgery, it appears unlikely that concomitant CABG would drive observed sex differences in outcomes after MV surgery. Nonetheless, this illustrates the importance of performing analyses in cohorts undergoing similar procedures to mitigate this potentially confounding factor.

A meta‐analysis in 2022 by El‐Andari et al concluded that female patients had significantly increased 1‐year mortality rates ⁵⁸ ; however, this meta‐analysis grouped patients with PMR and patients with SMR, and numerous studies have been published more recently (see Table 1), so these results should be interpreted with caution.

Evidence in Transcatheter Interventions

With the advent of transcatheter interventions for the treatment of MR, including mitral transcatheter edge‐to‐edge repair (MTEER) and transcatheter mitral valve replacement (TMVR), it is informative to review the evidence of sex differences in these treatment modalities.

Registry studies have found that the majority of patients treated with MTEER are male patients. ¹⁵ , ⁵⁹ , ⁶⁰ , ⁶¹ , ⁶² In an analysis of 68 028 patients who underwent MTEER from 2013 to 2023 in the Society of Thoracic Surgeons/American College of Cardiology Transcatheter Valve Therapy registry by Rozenbaum et al, the overall proportion of female patients treated was 46.2%, which was consistent in every subgroup treated with the exception of atrial SMR (women 2597 [58.6%] versus men, 1834 [41.4%]), likely due to the greater incidence of atrial SMR in women, as discussed in the section on differences in presentation. In the context of TMVR, a greater proportion of men have been screened (54.3%) and treated (63.3%) in the CHOICE‐MI (Choice of Optimal Transcatheter Treatment for Mitral Insufficiency) registry (N=746) ⁶³ and in the OCEAN‐Mitral (Optimized Catheter Valvular Intervention) registry (women, 941 [43.7%] versus men, 1209 [56.3%]). ⁶¹

With regard to outcomes in MTEER, Biasco et al performed an analysis of MitraSwiss (Swiss National Registry on Percutaneous Mitral Valve Interventions) in 2024, including >1000 patients with 5‐year mortality data. ⁶⁴ The authors demonstrated that there was no significant difference in mortality rate at 5‐year follow‐up between male and female patients, although they did note that the 30‐day mortality rate was significantly higher in male patients. Importantly, the authors provided individual analyses for both PMR and SMR and found that there was no significant difference in all‐cause death between male and female patients in either MR type (PMR (men): HR, 1.23 [95% CI, 0.83–1.32]; P=0.298; SMR (men): HR, 1.31 [95% CI, 0.96–1.78]; P=0.090). Similar results have been reported in other retrospective cohort studies, ⁶⁵ , ⁶⁶ , ⁶⁷ , ⁶⁸ , ⁶⁹ , ⁷⁰ , ⁷¹ , ⁷² although most of these studies combined patients with PMR and patients with SMR. A systematic review by Yi et al in 2023 found no sex‐related differences in short‐ and long‐term mortality rate; however, this review included mixed PMR and SMR cohorts and included only studies published before March 2021. ⁴⁹

Within the 2 studies looking at patients with SMR undergoing MTEER in isolation, a post hoc analysis of the COAPT (Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients With Functional Mitral Regurgitation) trial, which compared MTEER with guideline‐directed medical therapy (GDMT) in SMR, found that although MTEER led to clinical improvements in both sexes, female patients had less pronounced reductions in heart failure hospitalizations at 2 years. ⁷³ Conversely, an analysis of the EuroSMR (European Registry of Transcatheter Repair for Secondary Mitral Regurgitation) found that there were no sex‐related differences in clinical outcomes after 2 years of follow‐up.⁷³ These authors proposed that, as the COAPT trial excluded patients with severe LV dilation, male patients in the COAPT trial were less likely to have “end‐stage” LV disease, so the results may be biased, as opposed to a registry analysis, which would be more representative of the general MTEER population. Moreover, it should be noted that the COAPT trial was not powered to assess sex differences, and the EuroSMR registry analysis had more than twice as many patients.

TMVR is a more novel treatment modality, so there is sparse literature on sex differences in outcomes, but 2‐year results from the CHOICE‐MI registry, including 400 patients undergoing TMVR, did not find sex to be an independent predictor of death. ⁷⁴ Interestingly, women formed the majority of the patients turned down for TMVR in the CHOICE‐MI registry. ⁶³ Furthermore, of patients deemed ineligible for TMVR, a greater proportion of men received bailout MTEER (men, 124 [57.5%] versus women, 92 [42.6%]), while a greater proportion of women underwent high‐risk surgery (women, 33 [54.1%] versus men, 29 [45.9%]) or were declined for any intervention and received GDMT (women, 132 [55%] versus men, 108 [45%]). Two further studies looking at cohorts of patients screened for TMVR have also found that women are more likely to be turned down and subsequently less likely to receive bailout MTEER as opposed to GDMT. ⁷⁵ , ⁷⁶ These studies also found that GDMT was associated with worse outcomes in this population of patients. The possible reasons for the greater proportion of women, compared with men, turned down for TMVR are multifactorial and not fully understood, but may be related to female patients having smaller ventricles and more complex mitral disease, increasing the probability of anatomic ineligibility. ⁷⁵ , ⁷⁶ Whether high‐risk surgery should play a greater role in female TMVR‐ineligible patients remains to be seen, but studies of TMVR‐ineligible patients suggest that surgery offers superior outcomes compared with GDMT. ⁷⁵ , ⁷⁶ , ⁷⁷ In any event, the greater proportion of women, as opposed to men, turned down for surgery after TMVR ineligibility warrants further investigation, particularly as women subsequently appear to also be turned down more often than men for bailout MTEER.

Overall, there is little evidence of sex‐related differences in outcomes after transcatheter MR intervention, but studies are limited by small patient cohorts and shorter follow‐up periods, likely due to the more recent widespread adoption of transcatheter therapies as an alternative to surgery. Moreover, while surgical studies often focus specifically on PMR, most transcatheter studies have analyzed patients with PMR and patients with SMR together, limiting direct comparisons. Women appear to undergo less MTEER/TMVR compared with men, except for atrial SMR, which is in line with the epidemiological and surgical evidence discussed previously. Therefore, any decreased rate of surgical intervention for women due to their higher operative risk profile does not appear to be mitigated by higher rates of transcatheter intervention. Finally, in TMVR‐ineligible patients, women appear to be more frequently turned down for surgery than men, so the role of surgery in TMVR‐ineligible women should be further investigated.

Causal Factors

Several factors may explain sex differences in outcomes after mitral surgery, and a key question is whether the delayed presentation and underestimation of MR in female patients can account for these discrepancies in outcomes or whether there may be fundamental sex differences in the response to MV surgery independent of presentation and severity.

As mentioned previously, class I indications for intervention in severe PMR in both European ⁷ and US guidelines ⁸ use absolute cutoffs for LVESD and LVEF that are not adjusted for sex. This is potentially problematic, as we have seen that female patients consistently present with smaller LV dimensions (and perhaps higher LVEFs). Therefore, waiting until female patients reach the same LVESD threshold of 40 mm and LVEF threshold of 60% as male patients could mean female patients incur a relatively greater degree of adverse remodeling, which may be irreversible by the time surgical intervention is performed. This is perhaps supported by the observation that, despite comparable mortality rates, female patients experience a greater incidence of long‐term heart failure following PMR surgery. ³⁸ Moreover, a recent study by Kwak et al in a PMR cohort of 1686 patients demonstrated that female patients had an earlier increase in mortality risk at higher LVEF values compared with male patients, supporting the lack of sex‐specific LVEF thresholds as a causal factor for sex differences in outcomes. ²² A similar pattern was also reported by Abadie et al, whereby an absolute threshold of LVEF <60% in women caused more undue long‐term harm. ³⁵ Furthermore, the lower proportion of MVr in female patients is notable, as MVR has been associated with inferior long‐term outcomes. ⁵⁴ , ⁵⁵

Support for the hypothesis that there may be fundamental sex differences in response to MV surgery is perhaps provided by emerging genetic evidence of sex‐specific determinants of right ventricular (RV) function. Harbaum et al recently demonstrated in a genome‐wide association study the presence of sex‐specific RV phenotypes, specifically in the BMPR1A (bone morphogenetic protein receptor type 1A) gene, which alters transcriptional regulation of RV tissue. ⁷⁸ They found that polymorphisms at rs140745739 had associations with cardiac performance under chronically increased afterload in female patients with pulmonary arterial hypertension. In the context of MR, the RV can also be exposed to a state of chronic afterload, as persistent regurgitant flow into the LA can eventually cause pulmonary hypertension. ⁷⁹ This raises the possibility that the response to changes in afterload caused by MR (and MR eradication during MV surgery) in the RV may be sex dependent and thus confer different outcomes. This could also explain the sex difference in outcomes for patients with MR with concomitant TR described by Wagner et al, ³² as severe TR can be a marker of more advanced MV disease ⁷⁹ and indicate that the RV has been chronically exposed to a high afterload. Differences in anthropometrics between sexes are another potential contributor to differences in outcomes. Emerging evidence suggests that differences in chest wall configuration may have an impact on cardiac function and outcomes in MV prolapse. ⁸⁰ , ⁸¹ , ⁸² It is therefore possible that inherent sex‐based differences in anthropometrics may confer a different response to MR.

Bridging the Gap

To “bridge the gap” between sexes, several key factors must be addressed: establishing sex‐specific thresholds for intervention in PMR, adopting sex‐neutral methods for quantifying MR severity, ensuring equitable inclusion of female patients in multidisciplinary teams and consideration for MVr/MIMVS, and further sex‐specific research (Figure 2).

Figure 2. Key action points required to help bridge the gap in sex‐related differences in MR.

To reduce sex differences in outcomes after mitral surgery, key factors that must be addressed are sex‐specific thresholds for intervention in primary MR, sex‐neutral methods for quantifying MR severity, equitable inclusion of female patients in multidisciplinary teams, equal consideration of women for MVr and minimally invasive approaches, and further sex‐specific research and clinical trials. MR, mitral regurgitation; MVr, mitral valve repair; and PMR, primary mitral regurgitation.

An appealing approach to updating LVESD thresholds is indexing them to BSA, a method already adopted in international guidelines for aortic regurgitation. ⁷ However, work by Abadie et al studied this approach in a registry of >4500 patients with PMR who underwent MVr and found that when indexing LVESD to BSA, female and male patients did not have the same threshold of LVESD indexed to BSA associated with an increased mortality rate (women, 18 mm/m²; men, 21 mm/m²). ³⁵ Thus, the authors concluded that it may be more appropriate to implement sex‐specific thresholds for LVESD, with an LVESD cutoff of 40 mm for male patients and 36 mm for female patients. However, these sex‐specific thresholds have not been externally validated, so further studies are needed to adjudicate if these are appropriate cutoffs. It may also be worth considering the assessment of cardiac function with strain analysis, for example, with speckle‐tracking echocardiography, as strain analysis can detect more subtle and progressive changes in cardiac function and has been shown to better reflect “true” cardiac function in female patients with MR. ³⁹ As mentioned earlier, sex differences in prognosis using an LVEF cutoff of 60% have been reported, so sex specific LVEF cutoffs warrant further investigation.

The ideal approach to standardizing the quantification of MR severity would be the routine use of CMR‐derived regurgitant fraction. However, CMR is costly, time consuming, and not suitable for certain patients, ⁴² so this approach is unlikely to be feasible for widespread use in real‐world clinical practice. As transthoracic echocardiography assessment remains the first‐line investigation for MR, the method proposed by House et al of indexing regurgitant volume to LV end‐diastolic volume ³⁶ warrants further investigation as these parameters can be obtained using 3‐dimensional transthoracic echocardiography. Additionally, methods to quantify MR severity (such as effective regurgitant orifice area and proximal isovelocity surface area radius) should be reevaluated to determine whether sex‐specific thresholds are needed. Given the potential sex discrepancies in patients with MR with concomitant TR, efforts should be made to promote awareness of the American College of Cardiology and American Heart Association guidelines, which provide a BSA‐indexed measure of TR annular diameter (>21 mm/m²) above which intervention is recommended alongside the nonindexed threshold of 40 mm.⁸

It is plausible that in MR, there may be sex‐specific responses to different treatment modalities, so a clinical trial may yield novel insights and enable the optimization of therapies by sex. Given the range of procedures available for MR, a randomized trial investigating the benefit of transcatheter versus surgical intervention in female patients is warranted to comprehensively evaluate whether 1 of these modalities is superior in female patients. This has successfully been done in the context of transcatheter versus surgical valve replacement in aortic stenosis. ⁸³ As the efficacy of TMVR remains to be established in ongoing randomized clinical trials, ⁸⁴ it would be appropriate to limit the transcatheter arm to MTEER until TMVR has been established as an effective therapy for MR. Given that female patients consistently receive more MVR than MVr, it should also be investigated whether MVR in women is noninferior to MVr. Consequently, a 3‐arm trial incorporating MVR, MVr, and MTEER in female patients would allow these questions to be answered simultaneously. Such a trial should only include a single mechanism of MR, given their distinct prognostic trajectories. In an SMR trial, it may be prudent to investigate patients with atrial SMR separately, given the difference in epidemiology between sexes. It would also be crucial to include a detailed assessment of changes in quality of life alongside hard clinical outcomes, as the current evidence in women raises the possibility that these end points may not yield the same result, but both are important to patients. Moreover, assessing the degree of LV remodeling (eg, using indexed LV volumes) in women and understanding how this relates to clinical outcomes would provide insights into whether the degree of remodeling that yields benefit is different in female patients. We note completed ⁸⁵ and ongoing ⁸⁶ , ⁸⁷ trials (NCT05051033, NCT04198870, NCT03271762) comparing surgery to transcatheter treatment in MR and hope investigators will be motivated to perform posthoc analyses investigating whether sex influences trial outcomes.

Finally, given the evidence of decreased inclusion of female patients in multidisciplinary teams, care should be taken to ensure that female patients are routinely referred for discussion in multidisciplinary teams. This will also ensure that female patients are equally considered for MVR, MVr, MIMVS, concomitant TVr, MTEER, and TMVR.

Conclusions

The current review has demonstrated that sex is a key determinant of cardiovascular care in patients with MR undergoing MV surgery. There is strong evidence that, among patients with MR, women present with more advanced disease and exhibit anatomic differences that may influence both assessment and outcomes. While sex differences in surgical outcomes have been documented, these are largely limited to PMR and based on older studies, underscoring the need for further research. Data on sex differences in patients undergoing transcatheter interventions for MR are heterogeneous and inconclusive, complicating comparisons to surgery. Future work should assess whether current intervention thresholds and management pathways are appropriately tailored to female patients.

Sources of Funding

No funding was received for conducting this study.

Disclosures

None.