Abstract
Objective
To compare the distribution, aetiology, treatment patterns and 2-year outcomes of moderate to severe valvular heart disease (VHD) between men and women in China.
Design
Nationwide, prospective, multicentre cohort study.
Setting
46 tertiary hospitals across China, representing a mix of primary and secondary care settings.
Participants
A total of 13 917 adult patients with moderate-to-severe VHD were enrolled between April and June 2018. Of these, 6296 (45.24%) were women. Inclusion criteria included moderate or severe native valve disease, infective endocarditis or prior valve intervention.
Interventions
Patients received either conservative therapy or valve interventions, including surgical repair/replacement or transcatheter procedures. Intervention decisions were based on clinical assessment.
Main outcome measures
2-year all-cause mortality, cardiovascular mortality, heart failure hospitalisation and major adverse cardiovascular events. Multivariable Cox and logistic regression analyses were conducted to identify outcome predictors.
Results
The overall intervention rate was 31.72%, with no gender difference (men: 31.26% vs women: 32.27%). Among the 5427 patients with severe symptomatic VHD, 49.11% received interventional therapy. The sex-specific pattern was particularly significant in severe symptomatic multiple valvular heart disease, where women had a higher propensity for intervention (p<0.001, OR: 1.19–1.66). In severe symptomatic aortic regurgitation patients, women were less likely to receive valve replacement (p=0.03, OR: 0.39–0.95).
The 2-year survival rate was 90.85% with no gender difference (men: 90.41% vs women: 91.38%, p=0.086). Valve intervention improved survival to 97.0%, with no gender disparity (men: 96.92% vs women: 97.01%, p=0.87). Multivariate Cox regression confirmed no significant gender effect (p>0.05).
Conclusions
Significant gender differences exist in VHD aetiology and subtypes in China. Women had more rheumatic VHD, while men had more degenerative and functional VHD. Intervention improved survival, with no gender disparity. Age and VHD subtype influenced intervention rates and prognosis, supporting individualised, sex- and age-stratified management strategies.
Trial registration number
Keywords: Valvular heart disease, Treatment Outcome, China
STRENGTHS AND LIMITATIONS OF THIS STUDY.
This prospective, multicentre, hospital-based cohort enrolled adults with echocardiography-defined moderate-to-severe valvular heart disease from 46 tertiary and regional referral centres across China.
Standardised definitions and echocardiographic severity criteria were applied across participating centres.
Multivariable models were employed to adjust for major confounders, though the possibility of residual confounding cannot be fully excluded.
The 2-year follow-up period may be insufficient to evaluate long-term outcomes.
Aetiology was recorded as a single dominant category, and reasons for non-intervention were not systematically documented, limiting detailed classification and causal interpretation.
Introduction
Valvular heart disease (VHD) represents a significant component of the global cardiovascular disease burden. The epidemiology of VHD varies markedly worldwide. In developed countries, degenerative and functional valvular diseases dominate due to population ageing. In contrast, developing nations continue to face a substantial burden of rheumatic heart disease (RHD). Globally, an estimated 46.36 million RHD cases were reported in 2022, resulting in 386 947 deaths.1 Unlike Western countries, China exhibits a higher prevalence of RHD among older populations compared with younger cohorts. The prevalence of RHD in the elderly group (2.64% in men, 3.71% in women) significantly exceeds that in the 35–54 age group (0.79% in men, 1.33% in women). However, China is in a transition period of socioeconomic advancements and ageing. With improved survival rates and ageing demographics, the prevalence of VHD, particularly degenerative VHD, is rising. Recent surveys indicate that 55.1% of VHD cases in China remain rheumatic in origin, while degenerative lesions account for 21.3%, increasing with age from 18.2% in those aged 55–64 years to 42.5% in individuals≥75 years.2
Previous studies have identified sex-based differences in the incidence and intervention rates of VHD subtypes. The European Society of Cardiology – EURObservational Research Programme Valvular Heart Disease II Registry (ESC-EORP VHD II) survey, involving 5219 patients with severe primary VHD across 208 centres in Europe and North Africa, revealed that aortic valve diseases (regurgitation, bicuspid valve anomalies) predominated in males, whereas mitral valve pathologies and secondary tricuspid regurgitation (TR) were more common in females.3 A UK study spanning two decades reported higher aortic stenosis (AS) incidence in males,4 while mitral valve diseases were more frequent in females. Gender-based disparities in diagnosis and treatment persist. Most pivotal VHD studies have focused on male-dominated cohorts, potentially leading to underestimation of disease severity in females, suboptimal treatment and increased mortality.5 Similarly, the China-Degenerative Valvular Disease Study (DVD) study reported no significant sex differences in perioperative complications, in-hospital outcomes or mid-term prognosis,6 yet disparities in surgical rates and in-hospital mortality were observed among patients undergoing aortic valve procedures.
While sex-based variations in clinical characteristics and hospitalisation outcomes of VHD have been well-documented in Western populations, significant research gaps remain within China’s unique epidemiological context. This study preliminarily explores sex-specific differences in clinical profiles, treatment approaches and prognoses among Chinese patients with moderate-to-severe VHD, aiming to inform tailored therapeutic strategies.
Methods
Study design and population
The China-VHD study (NCT03484806) is a prospective, multicentre hospital-based cohort of adults with moderate-to-severe VHD, enrolling 13 917 patients from 46 tertiary hospitals and regional cardiovascular referral centres across multiple provinces and major geographic regions of China between April and June 2018. The registry was designed to reflect patients receiving inpatient care in tertiary and referral institutions rather than to serve as a population-based surveillance system. Inclusion criteria comprised (1) moderate/severe stenosis/regurgitation, (2) infective endocarditis or (3) prior valvular interventions. The study protocol, approved by Fuwai Hospital’s Institutional Review Board (Approval No. 2017–968), adhered to the Declaration of Helsinki, with written consent obtained from all participants. All participants were enrolled based on echocardiography-defined moderate-to-severe VHD according to prespecified criteria. For analyses involving severe VHD, patients were classified as severe if any valve lesion met echocardiographic criteria for severe disease.
Data collection and outcomes
Demographics, comorbidities, treatments and clinical outcomes were systematically recorded. Follow-up at 6, 12, 18 and 24 months assessed mortality, heart failure hospitalisation (HHF) and major adverse cardiovascular events (MACE, a composite of all-cause mortality, HHF and myocardial infarction). Aetiology was determined through clinical, imaging and surgical data. Valve intervention was defined as a valve-related transcatheter procedure or surgical valve repair/replacement performed during the index hospitalisation at enrolment. Prior valve surgery and post-discharge procedures were not counted, and reasons for non-intervention were not systematically recorded. A single dominant aetiology was recorded in the case report form; mixed aetiology was not separately coded.
Statistical analysis
Patient characteristics, management and outcomes were presented and compared between men and women patients with VHD. Intervention rates were calculated for all patients, symptomatic patients with severe VHD, across different types of VHD and stratified by gender. Two-year survival post-enrolment was assessed. Continuous variables were described as mean±SD or median with IQR, analysed using one-way ANOVA or the Kruskal-Wallis H test appropriately. Categorical variables were displayed as counts (percentages) and assessed by χ2 or the Fisher’s exact test where appropriate. Logistic regression and Cox proportional hazards regression were applied. Missing data were handled using multiple imputation under the missing-at-random assumption, and estimates were pooled across imputed datasets using Rubin’s rules. Two-year survival rates were calculated using the Kaplan-Meier method with 95% CIs. A 2-tailed p value<0.05 was considered statistically significant. All statistical analyses were performed using R software.
Patient and public involvement statement
Patients and the public were not involved in the design, conduct, reporting or dissemination plans of this research.
Reporting guideline
This study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines. The completed STROBE checklist is provided in the online supplemental material.
Result
A total of 13 917 patients with moderate to severe VHD were enrolled, of whom 6296 were women (45.24%). The median age was 62 years.
Distribution and aetiology
Among 13 917 patients, 88.77% had native VHD, while 11.23% had prior interventions. Sex-specific prevalence differed: men showed higher AR (aortic regurgitation) (15.67% vs 6.62%) and MR (mitral regurgitation) (24.13% vs 19.14%), whereas women had more MS (mitral stenosis) (6.16% vs 2.14%) and TR (16.58% vs 12.28%) (figure 1). Severe VHD (43.9% of cohort) was most frequently multiple valvular heart disease (MVHD) (43.54%), with severe AR and MR more common in men (18.95% vs 8.99%; 26.4% vs 22.86%) and severe TR in women (22.59% vs 17.18%, p<0.001) (online supplemental table 1).
Figure 1. Distribution of moderate to severe VHD by sex. AR, aortic regurgitation; AS, aortic stenosis; MR, mitral regurgitation; MS, mitral stenosis; MVHD, multiple valvular heart disease; TR, tricuspid regurgitation; VHD, valvular heart disease.
Rheumatic (22.67%), degenerative (22.71%) and functional (27.18%) aetiologies predominated overall (table 1), with functional causes most prevalent in men (28.89%) and rheumatic in women (31.89%). Aortic valve diseases were primarily degenerative (AS: 55.63%; AR: 45.25%), though AR aetiology differed by sex: women had higher degenerative and rheumatic causes (48.92% vs 43.97%; 8.15% vs 5.61%), p=0.001, while men showed more congenital origins (14.74% vs 10.07%). MR aetiology varied by valve pathology: functional (33.71%) and ischaemic (20.5%) causes dominated MR, whereas rheumatic MR was significantly more prevalent in women (13.11% vs 6.53%). TR was predominantly functional (53.0%), with women exhibiting higher rheumatic and congenital aetiologies (5.36% vs 0.85%; 12.74% vs 9.29%). MVHD aetiology differed significantly: functional and degenerative causes prevailed in men (33.16%, 23.0%), while rheumatic and functional more in women (38.94%, 24.16%) (online supplemental tables 2,3).
Table 1. Valvular heart disease aetiology by gender and age group.
| Cause | Total | Gender | Age | |||
|---|---|---|---|---|---|---|
| Men | Women | 18–59 | 60–69 | 70– | ||
| Rheumatic | 3155 (22.67) | 1147 (15.05) | 2008 (31.89) | 1817 (31.15) | 987 (22.83) | 351 (9.34) |
| Degenerative | 3161 (22.71) | 1894 (24.85) | 1267 (20.12) | 666 (11.42) | 1065 (24.63) | 1430 (38.03) |
| Endocarditis | 195 (1.40) | 142 (1.86) | 53 (0.84) | 144 (2.47) | 40 (0.93) | 11 (0.29) |
| Congenital | 1147 (8.24) | 627 (8.23) | 520 (8.26) | 801 (13.73) | 263 (6.08) | 83 (2.21) |
| Ischaemic | 990 (7.11) | 671 (8.80) | 319 (5.07) | 257 (4.41) | 356 (8.23) | 377 (10.03) |
| Functional | 3783 (27.18) | 2202 (28.89) | 1581 (25.11) | 1440 (24.69) | 1127 (26.06) | 1216 (32.34) |
| Autoimmune | 37 (0.27) | 18 (0.24) | 19 (0.30) | 21 (0.36) | 10 (0.23) | 6 (0.16) |
| Other | 1180 (8.48) | 756 (9.92) | 424 (6.73) | 622 (10.66) | 400 (9.25) | 158 (4.20) |
Clinical characteristics
Baseline characteristics were categorised by gender, as shown in table 2, with 7621 men and 6296 women included. Hypertension was the most common comorbidity, affecting 5930 patients (42.61%). Many patients (83.6%) had symptoms, primarily dyspnoea on exertion (62.85%), palpitations (33.71%), chest pain (19.6%) and oedema (15.9%). Heart failure was observed in 65.47% of patients, with the majority classified as NYHA (New York Heart Association) Class I (36.24%) and Class III (27.51%). Compared with men, women had a higher prevalence of atrial fibrillation/flutter (33.82% vs 26.55%), but lower rates of hypertension, coronary artery disease, aortic disease, chronic pulmonary disease and renal insufficiency (p<0.05). In terms of symptoms, men more frequently experienced chest pain (21.06% vs 17.84%), angina (14.16% vs 10.83%) and heart failure (66.59% vs 64.12%), while women had higher rates of palpitations (38.01% vs 30.17%) and oedema (17.44% vs 14.63%). Echocardiographic parameters revealed that women had a higher mean LVEF (left ventricular ejection fraction) (56.39±11.70%) compared with men (52.30±13.84%), and men had a higher proportion of LVEF<50% (33.47% vs 20.6%). In terms of invasive examinations, 27.36% of patients underwent coronary angiography, with men significantly more likely to have this procedure than women (p<0.001), and 13.93% of patients had a transoesophageal echocardiogram.
Table 2. Clinical characteristics of valvular heart disease by gender.
| Variables | Total (13 917) | Men (7621) | Women (6296) | P |
|---|---|---|---|---|
| Baseline feature | ||||
| Age, M (Q₁, Q₃) | 62.65 (53.00, 70.86) | 62.42 (52.96, 70.69) | 63.01 (53.06, 71.03) | 0.109 |
| BMI, mean±SD | 23.38 (21.09, 25.54) | 23.70 (21.51, 25.83) | 22.86 (20.66, 25.20) | <0.001 |
| BMI group | <0.001 | |||
| <18.5 | 1272 (9.16) | 583 (7.66) | 689 (10.98) | |
| 18.5–23.9 | 6806 (49.02) | 3515 (46.21) | 3291 (52.44) | |
| 24–27.9 | 4481 (32.28) | 2740 (36.02) | 1741 (27.74) | |
| ≥28 | 1324 (9.54) | 769 (10.11) | 555 (8.84) | |
| Current smoking | 1971 (14.16) | 1839 (24.13) | 132 (2.10) | <0.001 |
| Complication | ||||
| Hypertension | 5930 (42.61) | 3465 (45.47) | 2465 (39.15) | <0.001 |
| Hyperlipidaemia | 1871 (13.44) | 1090 (14.30) | 781 (12.40) | 0.001 |
| Diabetes | 1919 (13.79) | 1073 (14.08) | 846 (13.44) | 0.274 |
| Coronary artery disease | 3782 (27.18) | 2395 (31.43) | 1387 (22.03) | <0.001 |
| Cardiomyopathy | 1002 (7.20) | 682 (8.95) | 320 (5.08) | <0.001 |
| Atrial fibrillation or flutter | 4152 (29.83) | 2023 (26.55) | 2129 (33.82) | <0.001 |
| Aortic disease | 876 (6.29) | 582 (7.64) | 294 (4.67) | <0.001 |
| Peripheral artery disease | 349 (2.51) | 208 (2.73) | 141 (2.24) | 0.066 |
| Cerebrovascular disease | 1254 (9.01) | 706 (9.26) | 548 (8.70) | 0.251 |
| Chronic lung disease | 822 (5.91) | 545 (7.15) | 277 (4.40) | <0.001 |
| Renal insufficiency | 727 (5.22) | 475 (6.23) | 252 (4.00) | <0.001 |
| Cancer | 211 (1.52) | 109 (1.43) | 102 (1.62) | 0.362 |
| Peptic ulcer | 248 (1.78) | 161 (2.11) | 87 (1.38) | 0.001 |
| Previous valve intervention | 1563 (11.23) | 738 (9.68) | 825 (13.10) | <0.001 |
| Surgical valve prosthesis | 564 (4.05) | 262 (3.44) | 302 (4.80) | <0.001 |
| Surgical valve replacement | 1249 (8.97) | 594 (7.79) | 655 (10.40) | <0.001 |
| Percutaneous balloon valvuloplasty | 116 (0.83) | 30 (0.39) | 86 (1.37) | <0.001 |
| TAVR | 17 (0.12) | 7 (0.09) | 10 (0.16) | 0.260 |
| Mitra clip | 5 (0.04) | 2 (0.03) | 3 (0.05) | 0.831 |
| Symptomatic | 11 635 (83.60) | 6338 (83.16) | 5297 (84.13) | 0.125 |
| Chest pain | 2728 (19.60) | 1605 (21.06) | 1123 (17.84) | <0.001 |
| Palpitation | 4692 (33.71) | 2299 (30.17) | 2393 (38.01) | <0.001 |
| Dyspnoea | 8747 (62.85) | 4774 (62.64) | 3973 (63.10) | 0.575 |
| Swoon | 548 (3.94) | 290 (3.81) | 258 (4.10) | 0.377 |
| Oedema | 2213 (15.90) | 1115 (14.63) | 1098 (17.44) | <0.001 |
| Angina pectoris | 1761 (12.65) | 1079 (14.16) | 682 (10.83) | <0.001 |
| Cardiac insufficiency | 9112 (65.47) | 5075 (66.59) | 4037 (64.12) | 0.002 |
| NYHA functional class | 0.015 | |||
| I | 5044 (36.24) | 2696 (35.38) | 2348 (37.29) | |
| II | 3704 (26.61) | 2069 (27.15) | 1635 (25.97) | |
| III | 3828 (27.51) | 2081 (27.31) | 1747 (27.75) | |
| IV | 1341 (9.64) | 775 (10.17) | 566 (8.99) | |
| Infective endocarditis | 203 (1.46) | 142 (1.86) | 61 (0.97) | <0.001 |
| Physical examination | ||||
| Systolic blood pressure, mean±SD（mm Hg） | 125.20±20.06 | 126.10±19.75 | 124.10±20.38 | <0.001 |
| Diastolic blood pressure, mean±SD（mm Hg） | 73.89±12.87 | 74.15±12.97 | 73.57±12.75 | 0.008 |
| Heart rate, mean±SD | 78.68±17.22 | 78.32±16.83 | 79.12±17.67 | 0.007 |
| Left atrial diameter, mean±SD | 45.66±10.11 | 45.93±9.98 | 45.34±10.27 | <0.001 |
| LVEDD, mean±SD (mm） | 53.85±10.71 | 57.21±10.87 | 49.79±8.96 | <0.001 |
| LVEF, mean±SD（%） | 54.15±13.08 | 52.30±13.84 | 56.39±11.70 | <0.001 |
| LVEF＜50% | 3848 (27.65) | 2551 (33.47) | 1297 (20.60) | <0.001 |
| LVEF≥50% | 10 069 (72.35) | 5070 (66.53) | 4999 (79.40) | |
| Ascending aorta diameter, mean±SD (mm） | 33.51±6.43 | 34.68±6.54 | 32.10±6.01 | <0.001 |
| Aortic bilobed deformity | 589 (4.23) | 408 (5.35) | 181 (2.87) | <0.001 |
| Pulmonary hypertension | 5462 (39.25) | 2721 (35.70) | 2741 (43.54) | <0.001 |
| With other heart malformations | 824 (5.92) | 346 (4.54) | 478 (7.59) | <0.001 |
| Severe AS | 815 (41.20) | 465 (43.10) | 350 (38.93) | 0.161 |
| Severe AR | 1109 (14.78) | 827 (18.95) | 282 (8.99) | <0.001 |
| Severe MS | 854 (40.30) | 252 (38.47) | 602 (41.12) | 0.234 |
| Severe MR | 2493 (24.82) | 1467 (26.40) | 1026 (22.86) | <0.001 |
| Severe TR | 1908 (19.81) | 852 (17.18) | 1056 (22.59) | <0.001 |
| Hospitalisation | 11 914 (85.61) | 6617 (86.83) | 5297 (84.13) | <0.001 |
| Selected department | <0.001 | |||
| Outpatient service | 2133 (15.33) | 1092 (14.33) | 1041 (16.53) | |
| Cardiology ward | 6985 (50.19) | 3947 (51.79) | 3038 (48.25) | |
| Cardiac surgery ward | 4717 (33.89) | 2543 (33.37) | 2174 (34.53) | |
| Emergency treatment | 82 (0.59) | 39 (0.51) | 43 (0.68) | |
| Dobutamine stimulation test | 25 (0.18) | 12 (0.16) | 13 (0.21) | 0.497 |
| Exercise stress test | 71 (0.51) | 31 (0.41) | 40 (0.64) | 0.060 |
| Right cardiac catheterisation | 289 (2.08) | 117 (1.54) | 172 (2.73) | <0.001 |
| Left heart catheterisation | 227 (1.63) | 122 (1.60) | 105 (1.67) | 0.757 |
| Transoesophageal echocardiography | 1939 (13.93) | 1051 (13.79) | 888 (14.10) | 0.595 |
| Coronary angiography | 3807 (27.36) | 2285 (29.98) | 1522 (24.17) | <0.001 |
AR, aortic regurgitation; AS, aortic stenosis; BMI, Body Mass Index; LVEDD, left ventricular end-diastolic diameters; LVEF, left ventricular ejection fraction; MR, mitral regurgitation; MS, mitral stenosis; NYHA, New York Heart Association; TAVR, transcatheter aortic valve replacement; TR, tricuspid regurgitation.
Medications and interventions
Online supplemental table 4 outlines medications prescribed and invasive interventions. The most prescribed medications were diuretics (71.24%) and beta-blockers (55.32%), followed by ACE inhibitor/angiotensin II receptor blocker (39.81%), aspirin (30.52%), digitalis (31.29%) and P2Y12 inhibitors (20.82%). Among 4152 patients with atrial fibrillation/flutter, women were more likely to receive warfarin than men (56.88% vs 48.15%, p<0.001).
All intervention rates reported below refer to valve intervention performed during the index hospitalisation at enrolment (valve-related transcatheter procedures or surgical valve repair/replacement); prior procedures and elective interventions after discharge were not counted.
During hospitalisation, 31.72% of patients underwent valve intervention (table 3), including surgical repair in 15.07%—mainly for the tricuspid (12.15%) and mitral valves (4.78%). Valve replacement was performed in 24.91% of patients, most commonly using mechanical valves (66.73%). Aortic and mitral valve replacements accounted for 14.65% and 14.81%, respectively. Percutaneous procedures, including balloon valvuloplasty, TAVR (transcatheter aortic valve replacement) and, were performed in 1.26%, 0.93% and 0.13% of patients, respectively. CABG (Coronary Artery Bypass Graft) (3.06%), aortic surgery (2.85%) and antiarrhythmic surgery (3.23%) were performed concurrently in selected cases.
Table 3. Treatment and in-hospital outcomes with valvular heart disease (VHD) patients by gender.
| Variables | Total (13 917) | Men (7621) | Women (6296) | P |
|---|---|---|---|---|
| Medication | ||||
| Warfarin | 6098 (43.82) | 3202 (42.02) | 2896 (46.00) | <0.001 |
| Aspirin | 4247 (30.52) | 2667 (35.00) | 1580 (25.10) | <0.001 |
| P2Y10 receptor inhibitors | 2898 (20.82) | 1788 (23.46) | 1110 (17.63) | <0.001 |
| Beta-blocker | 7699 (55.32) | 4437 (58.22) | 3262 (51.81) | <0.001 |
| ACEI/ARB | 5540 (39.81) | 3332 (43.72) | 2208 (35.07) | <0.001 |
| Diuretics | 9915 (71.24) | 5502 (72.20) | 4413 (70.09) | 0.006 |
| Digitalis | 4355 (31.29) | 2362 (30.99) | 1993 (31.66) | 0.402 |
| Invasive intervention | ||||
| Valvular interventions | 4414 (31.72) | 2382 (31.26) | 2032 (32.27) | 0.199 |
| Surgical valve repair, n (%) | 2097 (15.07) | 983 (12.90) | 1114 (17.69) | <0.001 |
| Surgical valve replacement | 3467 (24.91) | 1870 (24.54) | 1597 (25.37) | 0.261 |
| Prosthesis type, n (%) | 0.117 | |||
| Bio prosthesis | 1135 (33.00) | 636 (34.29) | 499 (31.50) | |
| Mechanical valve | 2295 (66.73) | 1216 (65.55) | 1079 (68.12) | |
| Bio prosthesis+mechanical valve | 9 (0.26) | 3 (0.16) | 6 (0.38) | |
| Percutaneous balloon valvuloplasty | 175 (1.26) | 64 (0.84) | 111 (1.76) | <0.001 |
| TAVR | 130 (0.93) | 73 (0.96) | 57 (0.91) | 0.748 |
| Mitra clip | 18 (0.13) | 9 (0.12) | 9 (0.14) | 0.685 |
| CABG | 426 (3.06) | 300 (3.94) | 126 (2.00) | <0.001 |
| Aortic surgery | 396 (2.85) | 284 (3.73) | 112 (1.78) | <0.001 |
| Antiarrhythmic surgery | 450 (3.23) | 180 (2.36) | 270 (4.29) | <0.001 |
| Other cardiac surgery | 658 (4.73) | 307 (4.03) | 351 (5.57) | <0.001 |
| In-hospital outcomes | ||||
| In-hospital death | 86 (0.62) | 45 (0.59) | 41 (0.65) | 0.649 |
| In-hospital causes of death | 1.000 | |||
| Cardiogenic | 67 (77.91) | 35 (77.78) | 32 (78.05) | |
| Non-cardiogenic | 6 (6.98) | 3 (6.67) | 3 (7.32) | |
| Uncertain | 8 (9.30) | 4 (8.89) | 4 (9.76) | |
| Other | 5 (5.81) | 3 (6.67) | 2 (4.88) | |
| Complications | ||||
| Stroke | 33 (0.24) | 21 (0.28) | 12 (0.19) | 0.305 |
| Cardiac insufficiency | 205 (1.47) | 128 (1.68) | 77 (1.22) | 0.026 |
| Valve reoperation | 10 (0.07) | 6 (0.08) | 4 (0.06) | 0.988 |
| MI | 30 (0.22) | 19 (0.25) | 11 (0.17) | 0.345 |
| Major bleeding | 35 (0.25) | 22 (0.29) | 13 (0.21) | 0.335 |
ACEI, ACE inhibitor; ARB, angiotensin II receptor blocker; CABG, coronary artery bypass graft; MI, myocardial infarction; TAVRt, transcatheter aortic valve replacement.
Intervention rates were significantly influenced by age, with only 11.14% of patients aged≥70 undergoing interventions. Overall, no significant sex difference in intervention rate was observed (31.26% men vs 32.27% women, online supplemental table 11), but women were more likely to receive valve repair (OR 1.45, 95% CI 1.32 to 1.59; adjusted OR 1.16, 95% CI 1.03 to 1.30, p<0.05, online supplemental table 12). Among patients with moderate to severe VHD, AS had the highest intervention rate (63.08%) with no sex difference. AR patients had a lower rate (43.27%), and men were more likely than women to receive intervention (46.98% vs 32.61%) and valve replacement (43.89% vs 28.54%). TR had the lowest intervention rate (9.29%), mostly surgical repair (online supplemental tables 5-9). As online supplemental figure 1 shows, the proportion of MVHD and TR not undergoing intervention during the index admission was higher.
Among 5427 patients with severe symptomatic VHD, 49.1% underwent intervention. As reasons for non-intervention and symptom attribution were not systematically recorded, this proportion should not be interpreted as undertreatment alone. Patients not undergoing intervention during the index admission were more likely to be ≥70 years (36.9% vs 9.3%) and had more comorbidities (online supplemental table 10). These findings suggest that clinical risk profile and comorbidity burden were important determinants of intervention decisions during the index admission. The intervention group had more palpitations, dyspnoea, heart failure and bicuspid aortic valves. No sex difference was seen in severe symptomatic VHD intervention rate (49.6% women vs 48.7% men, online supplemental table 13), but women were more likely to receive valve repair (OR 1.51, 95% CI 1.33 to 1.71; adjusted OR 1.3, 95% CI 1.11 to 1.53, p<0.01, online supplemental table 14). In AR patients, men more often underwent valve replacement (69.19% vs 57.84%) and CABG (8.56% vs 1.96%). In contrast, no sex difference was seen in AS or mitral valve disease intervention rates. In MVHD, women had higher intervention rates (45.75% vs 37.55%) and fewer concomitant procedures. TR had the lowest overall intervention rate (15.2%), and repair was the dominant approach (11.8%).
For severe symptomatic VHD, univariate and multivariate logistic regression analysis identified age≥70, underweight (BMI<18.5), diabetes, coronary disease, cardiomyopathy, atrial fibrillation, chronic pulmonary disease, renal insufficiency, NYHA class IV and pulmonary hypertension as predictors of non-intervention. Protective factors included age<60, overweight, NYHA II–III, preserved LVEF and larger LVEDD (online supplemental table 13). For severe symptomatic MVHD, female sex was a predictor of receiving valvular intervention (p<0.001, OR: 1.19–1.66), valve replacement (p<0.001, OR: 1.18–1.67) and valve repair (p<0.001, OR: 1.39–1.99) (online supplemental table 15-17). However, after adjustment for potential confounders in multivariate logistic regression, the influence of sex was no longer statistically significant. In severe symptomatic AR, women were less likely to undergo valve replacement (p=0.03, OR: 0.39–0.95), but this association did not remain significant in the multivariate model (online supplemental table 18).
As presented in the online supplemental table 4, in-hospital mortality was low (0.62%) and predominantly attributed to cardiac causes (77.91%), with no sex difference (0.59% men vs 0.65% women, p=0.649). Men had more cardiac insufficiency (1.68% vs 1.22%, p=0.026).
Outcomes
The 2-year mortality rate of 9.15% (1058 patients), of which 6.15% (688 patients) were cardiovascular deaths (table 4). A total of 1223 patients (11.22%) were hospitalised, with an incidence of HHF at 6.47% and MACE at 14.29%. The 2-year incidence of adverse events differed by sex. Women patients had a lower 2-year mortality rate (8.62% vs 9.59%) and cardiovascular mortality rate (5.72% vs 6.5%) compared with men, but the differences were not statistically significant. However, the 2-year incidence of MI (0.43% vs 0.77%) and MACE (13.56% vs 14.89%) was significantly lower in women compared with men.
Table 4. Two-year outcomes of valvular heart disease (VHD) by gender.
| Variables | Total (13 917) | Men (7621) | Women (6296) | P |
|---|---|---|---|---|
| Death, n (%) | 1058 (9.15) | 606 (9.59) | 452 (8.62) | 0.071 |
| Cardiovascular death, n (%) | 688 (6.15) | 397 (6.50) | 291 (5.72) | 0.089 |
| MACE, n (%) | 1661 (14.29) | 946 (14.89) | 715 (13.56) | 0.043 |
| Cause of death, n (%) | 0.907 | |||
| Cardiogenic | 688 (65.03) | 397 (65.51) | 291 (64.38) | |
| Non-cardiogenic | 108 (10.21) | 65 (10.73) | 43 (9.51) | |
| Uncertain | 187 (17.67) | 103 (17.00) | 84 (18.58) | |
| Other | 73 (6.90) | 40 (6.60) | 33 (7.30) | |
| COVID-19 pneumonia | 2 (0.19) | 1 (0.17) | 1 (0.22) | |
| HHF, n (%) | 700 (6.47) | 394 (6.67) | 306 (6.23) | 0.346 |
| Rehospitalisation, n (%) | 1223 (11.22) | 694 (11.68) | 529 (10.67) | 0.098 |
| Valve reoperation, n (%) | 27 (0.25) | 18 (0.31) | 9 (0.19) | 0.206 |
| MI, n (%) | 66 (0.62) | 45 (0.77) | 21 (0.43) | 0.026 |
Bold values signifies the 2-year incidence of MACE differed significantly between men and women (p=0.043).
HHF, heart failure hospitalisation; MACE, major adverse cardiovascular events.
The survival curves are shown below (figure 2). The overall 2-year survival rate was 90.85%, with no significant gender difference (men: 90.41% vs women: 91.38%, p=0.086). The 2-year survival rate of severe VHD was 89.89% (men: 89.47% vs women: 90.39%, p=0.31). Valve intervention significantly improved survival to 97.0%, with no gender disparity (men: 96.92% vs women: 97.01%, p=0.87). Intervention also reduced the incidence of HHF, cardiovascular death and MACE, with no independent gender effect on outcomes (online supplemental table 19, figures 2,3). Multivariate Cox regression confirmed no significant gender effect on 2-year prognosis.
Figure 2. Kaplan-Meier curves of 2-year survival rates of the overall population, post-intervention, <60 years old, 60–70 years old, AR and MVHD patients by gender were shown. AR, aortic regurgitation; AS, aortic stenosis; MR, mitral regurgitation; MS, mitral stenosis; MVHD, multiple valvular heart disease; TR, tricuspid regurgitation.
Among VHD subtypes, MS had the highest 2-year survival rate (96.95%), while MVHD had the lowest (86.59%). In AR patients, men had higher 2-year survival rates (96% vs 93%, p=0.023). In MVHD patients, women had higher 2-year survival rates (87.94% vs 85.33%, p=0.031) and lower incidences of HHF, cardiovascular death and MACE (p<0.05). As shown in figure 3, women’s sex was a risk factor for 2-year survival rate in AR patients (HR 1.78, 95% CI 1.07 to 2.96, p=0.025); however, it was a protective factor for 2-year survival rate in MVHD patients (HR 0.81, 95% CI 0.67 to 0.98, p=0.031). However, after adjusting for multiple factors, gender had no significant effect on survival.
Figure 3. Univariate Cox regression analysis was used to analyse the 2-year mortality of patients with moderate to severe VHD. AR, aortic regurgitation; AS, aortic stenosis; MR, mitral regurgitation; MS, mitral stenosis; MVHD, multiple valvular heart disease; TR, tricuspid regurgitation; VHD, valvular heart disease.
Age-gender interaction analysis revealed that patients≥70 years had higher risks of MACE, cardiovascular death and HHF. Cumulative incidence curves showed men<60 years had higher MACE rates (8.18% vs 6.69% in women, p=0.046), and women aged 60–70 years had better survival (92.38% vs 90.44% in men, p=0.042) and lower MACE rates (12.24% vs 14.72% in men, p=0.031). As shown in table 5, multivariable Cox regression demonstrated no significant effect of gender on outcomes among patients with moderate-to-severe VHD (p>0.05). Independent risk factors included renal insufficiency, NYHA class III–IV, dyspnoea, age>70 years and pulmonary hypertension. In contrast, valve intervention, higher LVEF, age<60 years and the presence of palpitations were identified as protective factors (online supplemental tables 20-23).
Table 5. Univariate Cox regression analysis of 2-year outcomes of moderate to severe valvular heart disease (VHD) by women.
| Unadjusted model | Adjusted model 1 | Adjusted model 2 | ||||
|---|---|---|---|---|---|---|
| HR (95% CI) | P | HR (95% CI) | P | HR (95% CI) | P | |
| Death | 0.90 (0.80~1.02) | 0.086 | 0.99 (0.86~1.13) | 0.881 | 0.99 (0.86~1.13) | 0.890 |
| Cardiovascular death | 0.88 (0.76~1.02) | 0.100 | 1.01 (0.85~1.20) | 0.921 | 1.00 (0.84~1.19) | 0.993 |
| MACE | 0.91 (0.82~1.00) | 0.055 | 1.05 (0.95~1.18) | 0.340 | 1.05 (0.94~1.17) | 0.353 |
| HHF | 0.92 (0.80~1.07) | 0.301 | 1.16 (0.98~1.37) | 0.091 | 1.16 (0.98~1.37) | 0.091 |
HHF, heart failure hospitalisation; MACE, major adverse cardiovascular events.
Model 1 includes BMI group, hypertension, current smoking, hyperlipidaemia, coronary artery disease, diabetes, cardiomyopathy, atrial fibrillation or flutter, bicuspid aortic valve, chronic lung disease, renal insufficiency, chest pain, palpitations and dyspnoea on exertion, pulmonary hypertension, LVEF, LVEDD, NYHA functional class and invasive interventions for VHD.
Model 2 includes Model 1 and age group.
Discussion
This study provides the first comprehensive analysis of the subtypes, aetiology, clinical characteristics, management and outcomes of moderate to severe VHD in Chinese adults, highlighting an ongoing epidemiological transition. According to a 2022 report, China recorded 1.882 million hospitalised VHD cases, predominantly mitral valve lesions (45.4%), whereas aortic valve pathologies are more prevalent in Western countries. One study showed that the incidence of VHD was 13.2% in individuals over 75 years old.7 Among those aged 80–89, the incidence of AS was 9.8%.8
Rheumatic VHD remains a significant burden, affecting 22.7% of the overall cohort and 38.9% of females with MVHD. This aligns with global trends: Indigenous Australian women exhibit a higher incidence of acute rheumatic fever (228 vs 162 per 100 000 in males),9 Indonesian women were predominantly affected by RHD (70.7%),10 and Asian studies have identified childhood RHD prevalence as high as 12 per 1000.11 MS was primarily rheumatic (95.3%), consistent with RHD’s predilection for left-sided valve damage, whereas only 11.8% of mitral valve disease in Europe is of rheumatic origin.12 Among younger individuals (<60 years), rheumatic aetiology remains prominent (31.15%), while degenerative causes predominate in older adults (≥70 years, 38.03%), resembling patterns observed in high-income countries. This transition likely reflects East Asia’s rapid population ageing and an incomplete epidemiological shift, signifying a gradual transition from infectious to degenerative valvular pathology.
As a hospital-based registry enrolling patients from tertiary and regional referral centres, our findings primarily reflect individuals receiving inpatient care in major cardiovascular institutions. Although the participating centres were geographically distributed across China, the cohort was not designed as a population-based surveillance system. Therefore, extrapolation to primary care settings or untreated populations should be interpreted with caution.
AS accounted for 7.21% of cases (6.3% in women, 7.94% in men), primarily due to degenerative (55.63%), congenital (28.08%) and rheumatic (11.44%) causes. In contrast, a French national study reported AS in 61.6% of hospitalised VHD patients, with a significantly higher incidence in men than in women (73.8 vs 47.1 per 100 000).13 Rheumatic AS remains prevalent in Asia, with reported rates of 4.54 per 1000 in India and 1.86 per 1000 in China, whereas countries such as Singapore, Korea and Japan exhibit lower RHD prevalence, resembling Western patterns.14 Notably, the prevalence of congenital bicuspid aortic valves was significantly higher in young men than in women (13.15% vs 5.04%), consistent with the reported 3:1 male-to-female ratio and greater calcification burden in males.15 However, degenerative calcification is slower in the elderly, which may be related to genetic susceptibility and poor control of hypertension. Although the haemodynamic progression rate of AS does not differ by sex,16 the underlying pathological mechanisms are sex-specific: males exhibit greater calcification, whereas females rely more on fibrosis for valvular dysfunction at equivalent stenosis severity. Oestrogen may delay valvular calcification by modulating collagen metabolism and inflammatory responses, whereas androgens may promote myocardial hypertrophy and fibrosis, contributing to distinct disease progression patterns in women.17
Sex-based differences were also evident in AR. Degenerative (45.25%) and congenital (13.15% bicuspid valve) aetiologies predominated in men, whereas functional causes were more frequent in women (23.96%). The higher degenerative AR burden in men may be linked to androgen-mediated extracellular matrix remodelling and aortic root dilation,18 whereas oestrogen’s cardioprotective effects on left ventricular adaptation may delay symptom onset in women, contributing to a later clinical presentation with more advanced ventricular remodelling.19 A recent large retrospective cohort study found no sex-based difference in all-cause mortality among AS patients, but females were less likely to undergo aortic valve replacement.20 Intervention rates were significantly lower in women (OR: 0.6, 95% CI 0.4 to 0.91, p=0.002), consistent with prior findings. This therapeutic disparity may partially explain the observed sex difference in unadjusted 2-year survival (93% vs 96% in men, p=0.023). However, mortality differences attenuated after multivariable adjustment, suggesting that sex-related outcome disparities are primarily driven by variations in clinical management rather than inherent biological factors.
Functional MR and TR were common (33.71% and 53.03%, respectively), predominantly associated with hypertension (42.61%) and atrial fibrillation (33.82%). Functional MR rates were comparable to Western populations, but ischaemic MR was less common (20.5% vs 51.6% in the ESC-EORP VHD II registry), reflecting regional differences in coronary artery disease epidemiology. Rheumatic MS accounted for 95.28% of MS cases, with women comprising 79.1% of affected individuals, aligning with their higher susceptibility to rheumatic fever. Prior research suggests that although survival rates at 6-month follow-up are similar between sexes, females with MS or primary MR exhibit significantly lower intervention rates. Women with severe degenerative MR present with more severe symptoms and higher MIDA scores yet experience lower surgical referral rates and poorer outcomes.21 MVHD was the most prevalent subtype (29.04%), with women being more likely to undergo valve repair (OR=1.45), possibly due to the anatomical feasibility of repair in rheumatic disease. No significant sex-based disparity in overall intervention rates was observed, which may reflect a combination of anatomical and sociobehavioural factors.
Men exhibited larger left ventricular end-diastolic diameters (LVEDD: 58.2±8.1 mm vs 52.1±7.3 mm in women), potentially reflecting testosterone-driven myocardial remodelling.22 Conversely, women showed higher LVEF (56.39% vs 52.30%), suggesting compensatory mechanisms preserving diastolic function.23
It should be noted that enrolment occurred in 2018, and the management patterns reported here reflect real-world practice in China during that period. Since then, transcatheter therapies and guideline recommendations have evolved substantially, particularly for aortic, mitral and tricuspid valve disease. Accordingly, contemporary intervention rates and procedural composition may differ from those observed in this cohort, and our findings should be interpreted as a benchmark of hospital-based VHD management during the enrolment period.
Intervention-associated survival benefits underscore the importance of guideline-directed therapy. However, intervention rates were significantly lower in patients aged≥70 years compared with those <60 years (11.14% vs 41.2%). Previous studies indicate that 20.6% of AS patients are denied interventions due to advanced age and comorbidities. The underutilisation of TAVR in our AS cohort (8.84% vs 38.7% in EORP VHD II registry) further exacerbates therapeutic disparities. Gender-based differences were also evident in surgical approaches: women had higher rates of valvuloplasty (17.69% vs 12.90%) but lower rates of aortic valve replacement (11.91% vs 16.91%), consistent with prior studies in degenerative MR populations.24 This discrepancy may correlate with anatomical variations, as smaller aortic root dimensions in females could increase procedural complexity.
MVHD accounted for 29.04% in this study, while the Swedish registry data showed that only 4.6% of patients with VHD had MVHD.25 MVHD exhibited poorer prognosis compared with VHD (2-year survival: 86.59% vs 90.85%), reflecting cumulative haemodynamic burden. Paradoxically, female MVHD patients demonstrated superior survival (87.94% vs 85.33%, p=0.031), contrary to previous reports,26 which are potentially attributable to oestrogen’s cardioprotective properties. Established risk factors, pulmonary hypertension and renal insufficiency, aligned with multinational registry data, emphasising comorbidity-driven risk stratification. The age-sex interaction analysis showed that the risk of MACE in men over 70 years old and 60–70 years old was significantly higher than that in women of the same age, and further study is needed to explore the influencing factors of hormones and lifestyle.
Women patients exhibited significantly lower 2-year incidence of MI and MACE compared with men, which may be attributable to the higher prevalence of atherosclerotic risk factors (eg, smoking and diabetes) in men. Notably, the sex-based difference in outcomes was attenuated after adjustment for these variables in multivariate analysis. Collectively, these findings suggest that the impact of sex on VHD prognosis is contingent on VHD subtypes and treatment strategies. Sex may indirectly influence outcomes through its association with comorbidity profiles and clinical decision-making. Further studies are warranted to elucidate sex-specific pathophysiological mechanisms and evaluate gender-related disparities in therapeutic approaches, with the goal of optimising personalised management strategies for VHD patients.
Limitations of the study
Our study has several limitations. First, the analysis was based on data from an observational cohort. While we used multivariable models to adjust for key covariates, some residual confounding likely remains, which could affect our findings. Second, the 2-year follow-up was too short to adequately determine the prognostic impact of individual risk factors for some specific types of VHD; longer-term prospective studies are needed. Third, aetiology was recorded as a single dominant category, and mixed or overlapping aetiology (eg, coexisting rheumatic and degenerative changes) could not be specifically captured, introducing potential misclassification. Fourth, the registry did not systematically document reasons for non-intervention during the index admission, and symptom attribution (valvular vs non-valvular) was not adjudicated; therefore, the specific drivers of non-intervention cannot be determined. Further research is needed to explore sex differences across VHD subtypes and to evaluate whether modifying risk factors improves outcomes.
Supplementary material
Acknowledgements
We sincerely acknowledge the contributions of all team members involved in data collection, management and oversight for the China-VHD study.
Footnotes
Funding: This work was supported by the Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences (No. 2017-12M-3-002) and the National Key R&D Program of China (No. 2020YFC2008100).
Prepub: Prepublication history and additional supplemental material for this paper are available online. To view these files, please visit the journal online (https://doi.org/10.1136/bmjopen-2025-108331).
Provenance and peer review: Not commissioned; externally peer reviewed.
Patient consent for publication: Not applicable.
Ethics approval: This study involves human participants. Ethical approval for this study was obtained from the ethics committee of Fuwai Hospital, Chinese Academy of Medical Sciences (Approval No. 2017-968) (email: fuwailunli@fuwai.com). Participants gave informed consent to participate in the study before taking part.
Data availability free text: Data are available upon reasonable request from the corresponding author. Due to patient privacy and institutional regulations, the data are not publicly available.
Patient and public involvement: Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.
Data availability statement
Data are available upon reasonable request.
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