Sex Differences in the Outcomes of Degenerative Mitral Valve Repair

Abstract

Purpose: This study explored the sex differences in the outcomes of degenerative mitral valve repair (MVr).

Methods: From 2010 to 2019, 1069 patients who underwent MVr due to degenerative mitral disease at Beijing Anzhen Hospital were analyzed. The average patient follow-up was 5.1 years (interquartile range: 5–7 years). The primary endpoint was overall survival. Secondary endpoints were freedom from reoperation and recurrent mitral regurgitation. A propensity-matched analysis was used to compare the outcomes of males and females.

Results: Females were older, had a higher prevalence of atrial fibrillation and moderate-to-severe tricuspid regurgitation, and had smaller left atrial, left ventricular end-diastolic, and left ventricular end-systolic diameters. Males were more likely to undergo concomitant coronary artery bypass grafting and had longer cardiopulmonary bypass and aortic cross-clamp times. The in-hospital mortality was <1% (10/1,069). After propensity score matching of 331 pairs of patients, most variables were well balanced. Before and after propensity score matching, the long-term survival and freedom from reoperation rates were similar. Males had higher durability after surgery compared with females.

Conclusions: Females were referred to surgery later and had more complications than males. Long-term survival and freedom from reoperation rates were not significantly different between the sexes.

Introduction

Degenerative mitral valve disease is the most common valve disease in developed countries.¹⁾ With improvements in living conditions and the growing aging population in China, the spectrum of mitral valve disease has changed, and the incidence has increased.²⁾ Surgery is an effective treatment option for severe degenerative mitral regurgitation (DMR). Generally, mitral valve repair (MVr) is considered superior to mitral valve replacement (MVR) for DMR.³⁾

Sex differences are widespread in cardiovascular diseases.⁴⁾ Studies have reported that females have poorer outcomes after heart surgeries, such as coronary artery bypass grafting (CABG), and being female has been viewed as a risk factor for cardiovascular surgery.⁵⁾ DMR outcomes between males and females are still controversial; although more females suffer from mitral valve prolapse, more males undergo surgery. Furthermore, studies have found that females receive surgery later and have more concomitant complications,⁶⁾ which may lead to poorer outcomes in females. In this study, we retrospectively analyzed patients with DMR and compared the survival, freedom from reoperation, and freedom from recurrent mitral regurgitation (MR) rates between males and females.

Materials and Methods

Patients

The patients received oral and written information about the study and provided written informed consent prior to enrollment in the study. All enrolled patients were treated according to the standard of care for their specific medical conditions. The study was approved by the ethics committee of our institution (approval number: 2022034X).

Between January 2010 and December 2019, 1192 consecutive patients underwent MVr for severe DMR at our institution. The exclusion criteria were congenital heart disease, an age <18 years, and previous heart surgery. Patients who underwent concomitant aortic valve surgery, CABG, and concomitant tricuspid annuloplasty and Cox-Maze surgery for atrial fibrillation (AF) were included, while patients who underwent MVr were excluded.

A total of 1069 patients were ultimately enrolled in the study, including 594 males and 337 females.

Preoperative characteristics, operative details, and perioperative results were retrospectively obtained from the patients’ electronic medical records.

Surgery

Surgeries were performed through a median sternotomy by four experienced surgeons at our center, and transesophageal echocardiography (TEE) was performed preoperatively to further examine the mitral valve pathology. Generally, posterior leaflet prolapse (PLP) was repaired via quadrangular or triangular resection; however, artificial chordal implantation was also widely used, particularly in patients with chordae rupture. In patients with anterior leaflet prolapse (ALP), leaflet folding, artificial chordal implantation, and edge-to-edge techniques were used according to the degree of prolapse and pathological characteristics, and a suitable annuloplasty ring was implanted according to the mitral valve ring size. The effect of the MVr was evaluated postoperatively using TEE. The MVr was repeated if there were signs of residual moderate MR or systolic anterior motion.

Tricuspid valve repair was performed if the patient had more than moderate tricuspid regurgitation (TR) or dilation of the tricuspid annulus (>40 mm). The Maze procedure was performed in patients with persistent AF.

Follow-up

Patients were followed up in the outpatient department. The primary endpoint was overall survival, while the secondary endpoints were recurrent MR and reoperation. MR was classified as mild, moderate, or severe according to the effective regurgitant orifice area (EROA). We termed an EROA of <0.2 cm² as mild MR, 0.2–0.39 cm² as moderate MR, and ≥0.4 cm² as severe MR. Recurrent MR was defined as having more than moderate MR on postoperative echocardiography.

Statistical analyses

Statistical analyses were conducted using SPSS Statistics (version 22.0; IBM Corp., Armonk, NY, USA) and R 3.6.1 (R Foundation for Statistical Computing, Vienna, Austria) software. Continuous variables were expressed as mean ± standard deviation, while differences between groups were expressed using the Student’s t-test or Mann–Whitney U test. Categorical variables were reported as counts and percentages, and differences between groups were tested using the chi-squared or Fisher’s exact probability test. The significance level for all statistical tests was bilateral (p <0.05). Missing values were processed using multiple interpolations. Kaplan–Meier analysis was used to evaluate the long-term survival, MR recurrence, and reoperation rates, and the log-rank method was used to compare differences between survival curves.

Death is a competing risk for reoperation and recurrent MR. Therefore, competing risk models were applied to assess the association of death with reoperation and recurrent MR. The corresponding 95% confidence intervals and p-values were calculated using the Fine–Gray method. The results of this competing risk analysis are presented graphically using the estimated cumulative incidence functions.

Propensity score matching

Propensity scores were estimated using logistic regression. Variables included age, body mass index (BMI), and history of hypertension, diabetes, cerebrovascular disease, coronary artery disease, and AF. Echocardiographic data included the ejection fraction (EF), left ventricular end-systolic diameter (LVESD), left ventricular end-diastolic diameter (LVEDD), left atrial diameter (LAD), segment of prolapsed leaflets, and prevalence of more than moderate TR and pulmonary hypertension.

Patients were matched 1:1 without replacement. After matching, 331 pairs were analyzed. We assessed the covariate balance using standardized mean differences, where <10% was considered acceptable for most covariates after matching, with the “MatchIt” statistical package for R 3.6.1.

Results

Perioperative data

Of the 1069 patients enrolled in this study, 594 (64%) were male and 337 (36%) were female. In total, 62 males and 28 females underwent MVR because of repair failure, which was not significantly different.

The average patient age was 54.90 ± 12.01 years. Before matching, males were younger (53.49 ± 11.47 vs. 57.08 ± 13.10 years; p <0.05) and had a higher BMI (24.88 ± 3.24 vs. 24.31 ± 3.69 kg/m²; p <0.05). Females had a higher prevalence of AF (36.9% vs. 29.7%; p <0.05). Males had a larger LAD, LVEDD, and LVESD. Females had a higher prevalence of moderate-to-severe TR. After matching, 331 pairs of patients were analyzed, and most variables were well balanced (Supplementary Figs. 1 and 2; all supplementary files are available online). The baseline characteristics are summarized in Table 1.

Table 1. Clinical characteristics of all patients.

Variables	Unmatched			Matched
	Men	Women	P-value	Men	Women	P-value
BMI	24.88 (3.24%)	24.31 (3.69%)	0.009	24.38 (3.19%)	24.32 (3.67%)	0.829
Age	53.49 ± 11.47	57.08 ± 13.10	<0.001	56.69 ± 10.85	56.48 ± 13.32	0.825
NYHA
I	23 (3.3%)	6 (1.6%)	0.126	7 (2.1%)	6 (1.8%)	0.935
II	468 (67.0%)	246 (66.3%)		227 (68.6%)	221 (66.8%)
III	196 (28.1%)	107 (28.8%)		88 (26.6%)	95 (28.7%)
IV	11 (1.6%)	12 (3.2%)		9 (2.7%)	9 (2.7%)
AF	207 (29.7%)	137 (36.9%)	0.019	113 (34.1%)	114 (34.4%)	1
CAD	75 (10.7%)	27 (7.3%)	0.084	30 (9.1%)	25 (7.6%)	0.573
CVD	23 (3.3%)	19 (5.1%)	0.194	16 (4.8%)	14 (4.2%)	0.852
DM	46 (6.6%)	29 (7.8%)	0.534	29 (8.8%)	25 (7.6%)	0.67
Hypertension	267 (38.3%)	151 (40.7%)	0.475	127 (38.4%)	137 (41.4%)	0.475
Echocardiographic data
LAD	47.85 ± 9.81	45.44 ± 8.49	<0.001	45.53 ± 8.25	45.16 ± 8.46	0.562
LVEDD	58.49 ± 7.05	53.64 ± 5.88	<0.001	54.47 ± 5.66	54.13 ± 5.80	0.453
LVESD	38.08 ± 6.29	34.56 ± 5.00	<0.001	35.15 ± 5.10	34.84 ± 5.06	0.434
EF	62.71 ± 7.11	63.27 ± 6.01	0.199	63.32 ± 6.99	63.29 ± 6.09	0.955
PHT			0.46			0.938
Mild	221 (31.7%)	133 (35.8%)		110 (33.2%)	112 (33.8%)
Moderate	66 (9.5%)	38 (10.2%)		33 (10.0%)	35 (10.6%)
Severe	24 (3.4%)	13 (3.5%)		15 (4.5%)	12 (3.6%)
MV pathology
ALP	176 (25.2%)	97 (26.1%)	0.927	83 (25.1%)	81 (24.5%)	0.981
PLP	426 (61.0%)	222 (59.8%)		201 (60.7%)	202 (61.0%)
BLP	96 (13.8%)	52 (14.0%)		47 (14.2%)	48 (14.5%)
TR	165 (23.6%)	112 (30.2%)	0.024	96 (29.0%)	92 (27.8%)	0.796
Perioperative data
TVP	457 (65.5%)	253 (68.2%)	0.407	225 (68.0%)	223 (67.4%)	0.934
Maze surgery	196 (28.1%)	126 (34.0%)	0.054	104 (31.4%)	104 (31.4%)	1
AVR	49 (7.0%)	15 (4.0%)	0.069	16 (4.8%)	12 (3.6%)	0.562
CABG	56 (8.0%)	15 (4.0%)	0.018	18 (5.4%)	15 (4.5%)	0.721
Clamping time	79.39 (32.90%)	75.01 (28.84%)	0.031	77.44 (32.02%)	73.73 (27.62%)	0.111
CPB time	112.20 (43.74%)	104.68 (38.28%)	0.005	109.45 (42.11%)	103.21 (36.87%)	0.043

AF: atrial fibrillation; ALP: anterior leaflet prolapse; AVR: aortic valve replacement; BLP: bileaflet prolapse; BMI: body mass index; CABG: coronary artery bypass grafting; CAD: coronary heart disease; CPB: cardiopulmonary bypass; CVD: cerebral vascular disease; DM: diabetes mellitus; EF: ejection fraction; LAD: left atrial diameter; LVEDD: left ventricular end diastolic diameter; LVESD: left ventricular end systolic diameter; MV: mitral valve; NYHA: New York Heart Association; PHT: pulmonary hypertension; PLP: posterior leaflet prolapse; TR: tricuspid regurgitation; TVP: tricuspid valvuloplasty

Surgical data

The most common technique for PLP repair was triangular resection; an additional 250 (39%) patients underwent leaflet folding, while other techniques such as chordal replacement, chordal shortening, and edge-to-edge repair were also adopted. For ALP repair, chordal replacement was the most common technique (18/273, 68%); 47 (17%) patients underwent leaflet folding, and 46 (17%) underwent edge-to-edge repair. For the bileaflet prolapse repair, chordal replacement, edge-to-edge repair, and triangular resection were performed (Supplementary Table 1).

Suitable annuloplasty rings and bands were implanted according to the mitral valve ring size. The mean annuloplasty ring size was 32 mm.

Before matching, CABG was used more frequently in males than in females. The use of Maze surgery for AF, tricuspid valve repair, and aortic valve replacement did not differ between the two groups. Males also had longer cardiopulmonary bypass and aortic cross-clamp durations than females. After matching, the concomitant procedures were not significantly different; however, the aortic cross-clamp time was longer for males.

The in-hospital mortality was less than 1% (10/1069), including four males and six females. Although females had a higher in-hospital mortality than males (1.6% vs. 0.57%), the difference was not significant (p = 0.09).

Follow-up results

Survival

The average follow-up duration was 5.1 years (interquartile range, 5–7 years). In total, 33 patients died during the follow-up period, of which 23 were male and 10 were female. Ten cardiac deaths occurred in the male group due to heart failure (HF) (n = 5), myocardial infarction (n = 2), infective endocarditis (n = 1), and sudden unexplained death (n = 2). In the female group, 8 patients died due to HF (n = 6), sudden unexplained death (n = 1), and infective endocarditis (n = 1). The long-term survival rates of males and females were 94 ± 1% and 94 ± 1%, respectively. The Cox regression analysis showed that older age and smaller EF were the risk factors of overall death, while sex was not (Table 2A).

Table 2. The risk factors of long-term survival and recurrent MR.

	Univariate analysis		Multivariate analysis
	HR (95% CI)	P value	HR (95% CI)	P value
(A) Cox regression analysis of survival
Age	1.05 (1.01–1.08)	0.019	1.04 (1.00–1.08)	0.047
AF	2.30 (1.08–4.91)	0.030
LVESD >40 mm	2.48 (1.17–5.28)	0.018
EF <60%	3.46 (1.62–7.39)	0.001	3.09 (1.43–6.65)	0.04
Maze surgery	2.60 (1.22–5.53)	0.013
(B) Risk factors of recurrent MR
Age	1.019 (1.00–1.03)	0.026	1.02 (1.00–1.04)	0.013
Sex (women)	1.71 (1.19–2.45)	<0.01	1.68 (1.10–2.32)	<0.01
BMI	0.90 (0.86–0.96)	<0.01	0.91 (0.86–0.96)	<0.01
AF	1.47 (1.01–2.12)	0.043
E wave velocity	1.01 (1.00–1.01)	<0.01	1.01 (1.00–1.01)	<0.01
Complex pathology	1.53 (1.07–2.20)	0.02	1.60 (1.10–2.32)	0.005
Pulmonary hypertension	1.36 (1.11–1.71)	0.003
Residual 1 + MR Post-surgery	1.74 (1.18–2.76)	0.014	1.68 (1.08–2.62)	0.023
CPB time	1.00 (1.00–1.01)	0.032
Aortic clamping time	1.01 (1.00–1.01)	0.018	1.01 (1.00–1.01)	0.041

AF: atrial fibrillation; BMI: body mass index; CI: confidence interval; CPB: cardiopulmonary bypass; EF: ejection fraction; HR: hazard ratio; LVESD: left ventricular end systolic diameter; MR: mitral regurgitation

After matching, eight females and nine males died. The 10-year overall survival was 96 ± 1% for males and 97.5 ± 1% for females, and the long-term survival was not significantly different (Fig. 1).

Fig. 1. Overall survival of men and women before (A) and after (B) matching. The overall survival was not significantly different between the two groups before and after matching.

Reoperation and recurrent MR

Before matching, 13 patients underwent reoperation (4 females and 9 males). Recurrent MR was observed in 119 patients, of which 55 were female and 64 were male. The 10-year freedom from reoperation and recurrent MR rates were 98 ± 1% and 86 ± 2% for males and 98 ± 1% and 72 ± 5% for females, respectively; thus, males had better long-term durability than females after MVr.

After matching, four females and two males underwent reoperation. A total of 50 female and 27 male patients developed recurrent MR; 10-year freedom from reoperation and recurrent MR rates between females and males were 98 ± 1% vs. 98 ± 2% and 88 ± 2% vs. 76 ± 5%, respectively, which were not significantly different (p = 0.76 and p = 0.24, respectively) (Figs. 2 and 3). The competitive risk model also showed that after adjusting for confounding variables, the female sex was still a risk factor for recurrent MR (Table 2B).

Fig. 2. Cumulative incidence of reoperation for men and women before (A) and after (B) matching. The cumulative incidence of reoperation was not significantly different between the two groups before and after matching.

Fig. 3. Cumulative incidence of recurrent MR of men and women before (A) and after (B) matching. Before matching and after matching, the repair was more durable in men than in women. MR: mitral regurgitation.

AF

A total of 98 patients developed AF during the follow-up period, including 68 males and 30 females. Of these, 58 patients had recurrent AF, 40 developed new-onset AF, and 18 underwent catheter ablation. After matching, 60 patients developed AF, including 34 males and 26 females, which was not significantly different.

Recurrent TR

Before matching, 40 patients (27 females and 13 males) developed moderate and severe TR during the follow-up. Of these, 24 underwent concomitant tricuspid valve surgery. After matching, 28 patients developed TR, including 20 females and 8 males, indicating that females may have a higher probability of developing moderate and severe TR after surgery.

Other outcomes

Before matching, stroke was observed in 12 patients (2 females and 10 males), bleeding in 3 patients (1 female and 2 males), percutaneous coronary intervention (PCI) for coronary heart disease in 13 patients (3 females and 10 males), catheter ablation for AF in 18 patients (5 females and 13 males), and pacemaker implantation in 16 patients (10 females and 6 males), none of which was significantly different between the two groups.

After matching, stroke was observed in 5 patients (2 females and 3 males), bleeding in 1 patient (1 male), PCI for coronary heart disease in 4 patients (4 males), catheter ablation for AF in 10 patients (3 females and 7 males), and pacemaker implantation in 13 patients (7 females and 6 males), none of which was significantly different between men and women.

Discussion

In this single-center retrospective analysis, more males than females visited the hospital for surgery. Females were older and had more complications, such as AF and moderate-to-severe TR. Males had a larger LAD, LVEDD, and LVESD. Males had a higher probability of MVr than female patients, and females had a higher in-hospital mortality rate, but this difference was not statistically significant. Before and after propensity score matching, female and male patients had similar long-term survival rates. However, males had a higher rate of freedom from recurrent MR than females.

Sex differences in heart disease, especially in coronary heart disease, HF, and valvular heart disease, have been reported for many years. Females have demonstrated a higher operative risk and mortality after CABG.⁷⁾ Some risk calculators, such as those of the Society of Thoracic Surgeons and European System for Cardiac Operative Risk Evaluation (EuroSCORE), also regard being female as a risk factor before CABG.⁸⁾ Kytö et al.⁹⁾ conducted a propensity-weighted, population based study using major adverse cardiovascular events (MACEs) as composite endpoints and found that sex was not an independent predictor of long-term MACEs after CABG. However, males had a higher long-term all-cause mortality and females had a higher risk of myocardial infarction. Females may also develop ischemic MR after myocardial infarction, and HF is more prevalent in females than in males.¹⁰⁾ Sex differences have also been observed in the etiology, epidemiology, comorbidities, treatment, and outcomes of HF. Hogue et al.⁴⁾ reported that females are more likely to experience neurological events after cardiac surgery and have higher 30-day mortality than males.

The mechanisms underlying sex differences are not completely clear; chromosomes and hormones may contribute.¹¹⁾ As for valvular heart disease, males and females may have different types of valves. Males are more likely to develop aortic valve disease, and females are more likely to develop mitral valve diseases, regardless of the presence of rheumatic or degenerative diseases.¹²⁾ Studies have also reported sex-based differences in the outcomes of mitral valve surgery. Avierinos et al.¹³⁾ found that females with severe regurgitation had a worse survival than males, but females with no/mild MR had better survival. Kandula et al.¹⁴⁾ conducted a propensity score matching study and found that the outcomes of mitral valve surgeries are similar for males and females who present with the same type and degree of DMR; females underwent surgery later than males, which might be accompanied by complications and preoperative ventricular dysfunction. This may result in worse outcomes in females after mitral valve surgery. Vassileva et al.⁶⁾ used a national database to investigate the effect of sex on the outcomes of elderly patients undergoing mitral valve surgery. They found that elderly females had poor outcomes, but after risk adjustments, the survival was similar, which might have resulted from females undergoing surgery later than males. MVr appeared to restore life expectancy in males but not in females.

Basic male and female characteristics might affect the outcomes, and studies have found that males and females have similar outcomes after adjusting for covariates.¹⁵⁾ Although more females develop degenerative mitral disease, more males undergo surgery, and more females undergo surgery later. In our study, before matching, females were older and had more complications during surgery, such as AF, than males. This may also be one reason why females have worse postoperative outcomes than males. Studies have also found that females have thicker leaflets and less posterior prolapse, and are less frail than males.¹⁴⁾ In our study, the mitral valve pathology was similar between females and males. Two methods were used to eliminate the influence of covariates: Cox regression and propensity score matching. Cox regression showed that after adjusting for some covariates, sex was still a risk factor for recurrent MR after surgery. Older age and lower EF were risk factors for late death.

Before and after matching, males and females had similar long-term survival and freedom from reoperation rates. Males had a higher rate of freedom from recurrent MR than females.

For asymptomatic patients, an early surgery for patients with left ventricular dysfunction (LVESD ≥40 mm or EF ≤60%) has been recommended¹⁶⁾; however, females often have a smaller LAD, LVEDD, and LVESD, which might lead to a bias in the timing of surgery. More measurements might be considered to determine the timing of surgery in asymptomatic patients.

Transcatheter edge-to-edge MVr might be an alternative treatment for patients who cannot tolerate surgical MVr. Guddeti et al.¹⁷⁾ found that females had higher 90-day all-cause and HF readmission rates. Thus, early surgery might be a good option for females.

Study limitations

This study had some limitations. First, this was a single-center retrospective study. Additionally, we could not continuously obtain echocardiography data during the follow-up, and some patients were not regularly reexamined, thereby reducing the accuracy of the evaluations performed to determine the degree of recurrent MR.

Conclusion

Females were referred to surgery later and had more complications. Long-term survival and freedom from reoperation rates were not significantly different between males and females. However, males had higher durability after the repair.

Disclosure Statement

There are no financial conflicts of interest to disclose.