Sex-Specific Left Ventricular and Aorta Size Cut-Off Values for Hemodynamically Significant Chronic Aortic Regurgitation　― Implications for Treatment in Asian Populations ―

Abstract

Background: There are no sex-specific guidelines for chronic aortic regurgitation (AR). This retrospective study examined sex-specific differences and propose treatment criteria from an Asian AR cohort.

Methods and Results: Consecutive 1,305 patients with moderate-severe AR or greater at 3 tertiary centers in Taiwan and Japan (2008–2022) were identified. Study endpoints were aortic valve surgery (AVS), all-cause death (ACD), and cardiovascular death (CVD). The median follow up was 3.9 years (interquartile range 1.3–7.1 years). Compared with men (n=968), women (n=337) were older, had more advanced symptoms, more comorbidities, larger indexed aorta size (iAorta_max) and indexed left ventricular (LV) end-systolic dimension (LVESDi; P<0.001 for all). Symptomatic status was poorly correlated with the degree of LV remodeling in women (P≥0.18). Women received fewer AVS (P≤0.001) and men had better overall 10-year survival (P<0.01). Ten-year post-AVS survival (P=0.9) and the progression of LV remodeling were similar between sexes (P≥0.16). Multivariable determinants of ACD and CVD were age, advanced symptoms, iAorta_max, LV ejection fraction (LVEF), LVESDi, LV end-systolic volume index (LVESVi), and Taiwanese ethnicity (all P<0.05), but not female sex (P≥0.05). AVS was associated with better survival (P<0.01). Adjusted LVEF, LVESDi, LVESVi, and iAorta_max cut-off values for ACD were 53%, 24.8 mm/m², 44 mL/m², and 25.5 mm/m², respectively, in women and 52%, 23.4 mm/m², 52 mL/m², and 23.2 mm/m², respectively, in men.

Conclusions: Early detection and intervention using sex-specific cut-off values may improve survival in women with AR.

The prevalence of valvular heart disease (VHD) is projected to double by 2050, posing an epidemiological burden for aging societies.¹ It is well known that there are sex-specific differences in VHD in terms of epidemiology, manifestations, treatments, and outcomes.² For example, in aortic stenosis, women tend to have less calcium deposition, more fibrosis,³ and a lower pressure gradient than men.⁴ Women are more prone to mitral valve prolapse and mitral regurgitation, and men have a higher prevalence of aortic regurgitation (AR).³ Previous studies have also reported delayed surgical referrals among women with VHD compared with men, probably due to the underuse of left ventricular (LV) dimensions normalized by body surface area (BSA), resulting in unfavorable postoperative outcomes.³ Current guidelines do not have sex-specific disease criteria,^5–7 although it is common knowledge that healthy men and women have different LV chamber and aorta sizes.⁸ AR, the third most common VHD,¹ is male predominant (75–86% of patients are men), probably due to higher prevalence of bicuspid aortic valve (BAV) in male.^3,9,10 Women are particularly underrepresented in all AR landmark studies from which the diagnostic criteria, management strategies, and surgical cut-off values have been derived and adopted in current guidelines.^5,6,11 In addition, sex-specific differences in LV responses to AR have been noted in both asymptomatic and symptomatic patients,¹² indicating that more data on sex differences in AR are urgently needed.

To date, only 2 studies have addressed sex differences in AR, both conducted in Western cohorts.^12,13 Few studies have been published on ethnic disparities among patients with aortic disease such as AR. The World Alliance of Societies of Echocardiography Normal Values Study (WASE) study¹⁴ showed interethnic differences regarding LV indices even after BSA adjustment. Therefore, we conducted the present study in an Asian cohort with hemodynamically significant AR to understand sex differences in presentation, the incidence of aortic valve surgery (AVS), survival, and sex-specific LV and aorta thresholds indicative of poor prognosis.

Methods

Study Population and Clinical Data

Between 2008 and 2022, all consecutive patients aged ≥18 years with moderate-severe or greater chronic AR diagnosed by transthoracic echocardiography (TTE) were retrospectively identified from the electronic echocardiographic databases of 3 university-affiliated hospitals (National Taiwan University Hospital [Taipei, Taiwan], National Cerebral and Cardiovascular Center [Osaka, Japan], and the University of Occupational and Environmental Health [Kitakyushu, Japan]; Supplementary Figure 1). In all cases, patient files were reviewed afresh to determine eligibility for inclusion in the study. Patients with no research authorization in their file, prior mitral or aortic valve surgery, more than mild mitral stenosis or regurgitation or aortic stenosis, complex cyanotic congenital heart disease, carcinoid heart disease, and acute AR were excluded from the study.

The final study cohort consisted of 1,305 patients, all of whom had undergone comprehensive cardiology and/or cardiovascular surgery evaluations within 30 days of TTE. Information on New York Heart Association (NYHA) functional class, symptomatic status (i.e., symptomatic vs. asymptomatic), and comorbid conditions was extracted from electronic medical records and paper charts; this information was independently and prospectively recorded by treating physicians. The Charlson comorbidity index (CCI) was computed for all patients.^15,16

This study was approved by institutional review boards (IRBs) at all 3 study sites: National Taiwan University Hospital (IRB no. 20211,126RINA), the National Cerebral and Cardiovascular Center (IRB no. R21009-3), and the University of Occupational and Environmental Health (IRB no. UOEHCRB21-097). The requirement for informed consent was waived due to the retrospective nature of the study. The datasets and study materials used in this study cannot be made available to outside parties due to confidentiality issues.

Echocardiography

The first eligible TTE for each patient was used as the baseline. TTE was performed by trained sonographers using commercially available echocardiography systems and reviewed afresh by cardiologists with Level III echocardiography training, during which AR severity and the adequacy of LV quantifications were reconfirmed and remeasured if necessary. Chamber quantification was performed based on guideline suggestions.^8,17 LV volumes were derived from the biplane disk-summation method or a single plane (n=153; 12%) if the biplane disk-summation method was not feasible. To determine AR severity, an integrated, comprehensive approach was used that included quantitative (proximal isovelocity surface area quantification) and semiquantitative measurements (vena contracta width, pressure half-time) as per current guidelines.^11,18 LV filling pressure was estimated by the mitral inflow velocity to early diastolic mitral annular velocity ratio (E/e´). Our approach to ensure the consistency of AR severity classification has been reported previously.¹⁵ The rhythm was discerned from baseline TTE electrocardiograms.

Outcomes

The primary endpoints in this study were: (1) all-cause death (ACD) under medical surveillance, where the observation time was censored at AVS in surgical patients and censored at the time of death or last follow-up in non-surgical patients; and (2) ACD during the total follow-up, where the observation time was censored at the time of death or last follow-up. Our secondary endpoint was cardiovascular death (CVD) under medical surveillance.

We also analyzed determinants of AVS, post-AVS survival, and the progression of LV remodeling before AVS (defined as the annual change between baseline TTE and last available TTE before surgery) among LV end-diastolic dimension (LVEDD), LV end-systolic dimension (LVESD), the LVESD index (LVESDi), and LV ejection fraction (LVEF). In addition, we analyzed determinants of LV reverse remodeling after AVS. LV reverse remodeling was defined as the percentage change in LVEDD, LVESD, and LVESDi (i.e., calculated as [presurgical value − post-surgical value] / presurgical value × 100).

Post-surgical TTE within 6–18 months after AVS was used for analysis. Mortality status and the dates and causes of death were retrieved from medical records, mailed questionnaires, and Taiwan’s National Health Insurance Research Database; the last query was made in June 2022. In Taiwan, the National Health Insurance program is a government-run, single-payer insurance plan that delivers universal coverage (99.5% of the whole population) for all citizens and is linked to other national databases, such as death registries.

Sex-Specific Comparisons Between Asian and US Cohorts

We compared baseline characteristics, echocardiographic features, surgical indications, and survival for both sexes in Asian and US cohorts to determine whether there were any differences associated with ethnicity between the 2 cohorts. The US cohort used for comparison was from our previous publication,¹² which was an extended cohort from a prior study¹⁰ in which only 1% of the study population was Asian. The US cohort included 1,072 consecutive patients (189 [18%] women, 883 [82%] men) with isolated moderately severe or severe AR identified from February 21, 2004, through April 29, 2019. The inclusion and exclusion criteria of the US cohort were identical to those used in the present study.¹²

Statistical Analysis

Continuous variables are expressed as the mean±SD or as the median with interquartile range (IQR) depending on their distribution, and were compared using Student’s t-test or the Wilcoxon rank-sum test, as appropriate. Categorical data are presented as counts and percentages, and were compared using the χ² and/or Fisher’s exact tests. Survival rates were estimated using the Kaplan-Meier method and were compared using the log-rank test. The primary and secondary endpoints of mortality were analyzed using the Cox proportional hazard model, where variables with clinical relevance plus variables with P<0.05 in the univariable analysis were chosen for multivariable analyses. The time-dependent effect of AVS was also estimated. Restricted cubic splines adjusted for AVS and Japanese or Taiwanese ethnicity were used to illustrate the risk of mortality over the range of LV indices and aorta sizes.¹⁹ Multivariable linear regression models adjusted for age, CCI, NYHA, and presurgical LV dimensions were used to investigate the determinants of percentage changes in LVEDD, LVESD and LVESDi. To enable comparisons between the Asian and US cohorts, we extracted mean values, standard deviations, and the number of study subjects from the 2 cohorts and performed Welch’s t-test.

Statistical analyses were performed using a combination of commercially available software (JMP 16, SAS 9.4 [SAS Institute Inc., Cary, NC, USA], and R version 4.3.1 [R Foundation for Statistical Computing, Vienna, Austria]). Two-sided P<0.05 was considered statistically significant.

Results

Baseline Characteristics

Baseline characteristics are presented in Table 1. Of the 1,305 patients in our cohort, 337 (26%) were women. The female-to-male ratio was 1 : 2.9, with a higher prevalence of BAV in men than women, as anticipated (23% vs. 7%; P<0.001).²⁰

Table 1.

Baseline Characteristics in 1,305 Patients

	Women (n=337)	Men (n=968)	P value
Age (years)	69±16	63±17	<0.001*
BSA (m2)	1.47±0.15	1.73±0.18	<0.001*
Body weight (kg)	51.7±10.7	65.7±12.9	<0.001*
Body height (cm)	153.3±7.3	167.4±8.1	<0.001*
Body mass index (kg/m2)	21.9±4.1	23.4±3.8	<0.001*
Systolic blood pressure (mmHg)	137±23	134±19	0.03*
Diastolic blood pressure (mmHg)	66±14	65±12	0.25
Pulse pressure (mmHg)	72±21	70±19	0.12
Heart rate (beats/min)	71±13	69±13	0.05
Hypertension	208 (62)	606 (63)	0.77
Hyperlipidemia	86 (26)	197 (20)	0.05
Diabetes	27 (8)	80 (8)	0.88
Connective tissue disease	51 (16)	44 (5)	<0.001*
Coronary artery disease	40 (12)	175 (18)	0.006*
Charlson comorbidity index	1.47±1.69	1.23±1.71	0.02*
Atrial fibrillation	21 (6)	80 (8)	0.22
Japanese ethnicity	156 (46)	359 (37)	0.003*
NYHA functional class (n=324/922)			0.02*
I	165 (51)	536 (58)
II	115 (35)	303 (33)
III+IV	44 (14)	83 (9)
BAV	25 (7)	224 (23)	<0.001*
BAV fusion typeA (n=24/224)			0.07
RL	14 (56)	167 (75)
RN	10 (40)	42 (19)
LN	1 (4)	14 (6)
LVEF (%)	56±11	55±11	0.39
LVEDD (mm)	56±7	62±7	<0.001*
LVEDDi (mm/m2)	38.1±5.6	35.9±5.0	<0.001*
LVESD (mm)	37±7	42±9	<0.001*
LVESDi (mm/m2)	25.6±5.7	24.2±5.7	0.001*
LVESDi
<20 mm/m2	40 (12)	230 (24)	<0.001*
20–25 mm/m2	154 (46)	383 (40)
≥25 mm/m2	143 (42)	352 (36)
LVEDV (mL; n=333/960)	140±5	194±71	<0.001*
LVEDVi (mL/m2; n=333/960)	95.6±35.4	111.8±39.5	<0.001*
LVESV (mL; n=333/958)	64±38	90±49	<0.001*
LVESVi (mL/m2; n=333/958)	43.7±25.5	51.9±28.4	<0.001*
LAVi (mL/m2; n=324/932)	39.5±18.5	37.2±16.8	0.05
E/e′ (n=276/753)	14.3±7.0	12.6±5.7	<0.001*
RVSP (n=305/834)	31.6±10.6	29.5±9	0.002*
AR vena contracta (mm; n=309/806)	6.2±1.5	6.7±1.7	<0.001*
AR vena contracta index (mm/m2; n=309/806)	4.3±1.0	3.9±1.1	<0.001*
AR pressure half-time (n=191/444)	382±102	382±109	0.97
AR effective regurgitant orifice (cm2; n=141/333)B	0.28±0.10	0.28±0.09	0.10
AR regurgitant volume (mL; n=141/328)B	56±15	60±13	0.005*
AR regurgitant volume index (mL/m2; n=141/328)	39±11	35±8	<0.001*
AR regurgitant volume/LVEDV (%; n=141/327)	39±13	32±12	<0.001*
Aorta dimensions
Annulus (mm; n=333/945)	21.3±2.5	24.1±3.1	<0.001*
Indexed annulus (mm/m2; n=333/945)	14.6±2.1	14.0±1.9	<0.001*
Sinus of Valsalva (mm; n=329/948)	36.9±8.2	41.6±7.7	<0.001*
Indexed sinus of Valsalva (mm/m2; n=329/948)	25.2±5.2	24.1±4.7	<0.001*
Mid-ascending aorta (mm; n=249/666)	39.6±8.0	40.6±8.2	0.12
Indexed mid-ascending aorta (mm/m2; n=249/666)	27.3±5.7	23.6±5.0	<0.001*
Maximal aorta size (mm; n=320/923)	40±9	43±8	<0.001*
Indexed maximal aorta size (mm/m2; n=320/923)	27.3±6.0	25.0±5.0	<0.001*
AV surgery (n=90/407)	90 (27)	407 (42)	<0.001*
Surgery and surgical indicationsC (n=495)			0.56
Symptoms	56 (63)	239 (59)
LVEF <50%	7 (8)	42 (10)
LVESD >50 mm (LVESDi >25 mm/m2)	16 (18)	60 (15)
Aortic aneurysm	4 (4)	17 (4)
LVEDD >65 mm	3 (3)	33 (8)
Early surgery	3 (3)	15 (4)
Class I indications for surgery	67 (75)	298 (73)	0.71
Aortic valve repair (n=6/19)	6 (7)	19 (5)	0.44
BioprosthesisD (n=61/278)	61 (73)	278 (72)	0.75
Concomitant aorta surgery (n=26/127)C	32 (36)	142 (35)	0.86
Concomitant CABG (n=7/41)C	7 (8)	42 (10)	0.46

Unless indicated otherwise, data are given as the mean±SD, n (%), or median [interquartile range]. *Under two-tailed tests, P<0.05 was considered statistically significant. ^AExcluding 1 patient with an unknown phenotype. ^BImages stored for proximal isovelocity surface area quantification were not routinely obtained in Taiwan before 2021. ^CTwo patients underwent surgery elsewhere, and details regarding surgical indications and concomitant surgery were unknown. Thus, these 2 patients were excluded from analysis. ^DTwo patients were excluded (heart transplantation in 1; unknown whether a bioprosthesis was used in the other). AR, aortic regurgitation; AV, aortic valve; BAV, bicuspid aortic valve; BSA, body surface area; CABG, coronary artery bypass grafting; E/e′, peak mitral inflow velocity to early diastolic mitral annular velocity ratio; LAVi, left atrial volume index; LN, left-non-coronary cusp fusion; LVEDD, left ventricular end-diastolic dimension; LVEDV, left ventricular end-diastolic volume; LVEF, left ventricular ejection fraction; LVESD(i), left ventricular end-systolic dimension (index); LVESV, left ventricular end-systolic volume; NYHA, New York Heart Association; RL, right-left coronary cusp fusion; RN, right-non-coronary cusp fusion; RVSP, right ventricular systolic pressure.

Compared with male patients, female patients were older, had smaller BSA, higher systolic blood pressure, more connective tissue disease, higher CCI, more advanced NYHA functional class, higher right ventricular systolic pressure, and higher LV filling pressure (all P<0.05). The prevalence of atrial fibrillation (6% in women, 8% in men) was similar to the rates reported previously.¹⁰ Women also had smaller absolute LV dimensions than men, but larger LV dimensions normalized by BSA (i.e., LVESDi and LVEDDi; P≤0.001). Furthermore, women had a smaller LV end-diastolic volume index and a smaller LV end-systolic volume index (LVESVi; P<0.001), which we considered to be a reasonable finding.⁸ Women had significantly smaller absolute annulus, sinus of Valsalva, and ascending aorta sizes, but larger indexed aorta values than men (P<0.001; Table 1). Although women were less likely to receive AVS (P<0.001), surgical indications between the sexes were similar (P=0.56). Regarding AR quantification, women had smaller vena contracta and regurgitant volume (RVol) than men (P<0.001), but once body sizes were taken into account, women were found to have larger indexed values as well as a larger RVol-to-LV end-diastolic volume ratio (P<0.01; Table 1). Comparisons between the Japanese and Taiwanese cohorts for both sexes are presented in Supplementary Table 1.

Baseline LV Remodeling in Symptomatic and Asymptomatic AR in Men and Women

In women, the degree of LV remodeling in terms of dimensions and volumes was similar regardless of symptomatic status (P=NS). However, the degree of LV remodeling was worse in symptomatic than asymptomatic men (P≤0.001; Table 2). In addition, effective regurgitant orifice area (EROA) values in women were not associated with symptomatic status (P=0.20), but EROA was significantly larger in symptomatic than asymptomatic men (P=0.002). In both sexes, symptomatic patients had larger E/e′, left atrial volume index (LAVi), and right ventricular systolic pressure than asymptomatic patients (RVSP; P<0.05 for all), which seems to imply that the development of heart failure symptoms in women may be related to diastolic dysfunction.

Table 2.

Characteristics in Asymptomatic and Symptomatic Male and Female Patients (n=1,246)^A

	Women			Men
	Asymptomatic (n=165)	Symptomatic (n=159)	P value	Asymptomatic (n=536)	Symptomatic (n=386)	P value
Age (years)	64±17	73±13	<0.0001	59±17	67±16	<0.0001
BSA (m2)	1.46±0.15	1.47±0.15	0.42	1.75±0.16	1.71±0.20	0.0002
LVEF (%)	57±9	54±12	0.006	58±9	52±12	<0.0001
LVESD (mm)	37±7	38±8	0.20	40±7	44±11	<0.0001
LVESDi (mm/m2)	25.5±5.3	26.0±6.1	0.38	22.9±4.2	26.2±6.8	<0.0001
LVESDi
<20 mm/m2	17 (10)	19 (12)	0.39	152 (28)	64 (17)	<0.0001
20–25 mm/m2	82 (50)	67 (42)		231 (43)	133 (34)
>25 mm/m2	66 (40)	73 (46)		152 (28)	189 (49)
LVESV (mL)	61±39	67±36	0.18	82±38	102±61	<0.0001
LVESVi (mL/m2)	42.2±26.3	45.8±24.9	0.21	46.7±20.5	60.1±35.6	<0.0001
EROA (cm2)	0.27±0.09	0.29±0.10	0.20	0.28±0.10	0.31±0.10	0.002
RVol (mL)	55±16	58±16	0.19	62±20	62±14	0.96
E/e′	13.2±6.5	15.2±7.4	0.023	11.6±4.4	14.0±6.9	<0.0001
LAVi (mL/m2)	36.6±14.3	42.8±22.1	0.003	34.9±14.6	40.0±19.0	<0.0001
RVSP (mmHg)	28±7	35±12	<0.0001	27±7	34±10	<0.0001

Unless indicated otherwise, data are given as the mean±SD or n (%). ^AFifty-nine patients whose symptomatic status was unknown were excluded from this table. EROA, effective regurgitant orifice area; LVESVi, left ventricular end-systolic volume index; Rvol, regurgitant volume. Other abbreviations as in Table 1.

Surgical Management, Surgical Indications, and Predictors of AVS

Across the entire study cohort, patients were followed for a median of 3.9 years (IQR 1.3–7.1 years) and 497 patients received AVS at a median of 3.0 month (IQR 1.0–18.5 months) after baseline TTE (50% of all AVS occurred within 3 months). The median time to surgery was similar among women and men (2.9 [IQR 1.0–20.5] vs. 2.9 [IQR 0.9–18.2] months, respectively; P=0.65). Women had a lower 10-year incidence of AVS than men (42±5% vs. 56±2%; P<0.0001; Figure 1A), but 10-year post-AVS survival (median time post-AVS follow-up 3.6 years [IQR 1.6–6.5 years]) was similar between the sexes (89±4% vs. 81±4% for women and men, respectively; P=0.9; Figure 1B). There were 6 deaths (3 men, 3 women) within the 30-day period after AVS. Both sexes had similar rates of concomitant coronary artery bypass grafting, concomitant aorta surgery, and the use of bioprostheses (Table 1).

Figure 1.

Surgical incidence and survival. (A,B) The 10-year rate of surgery was lower among women than men (A), but 10-year post-surgical survival was similar between the sexes (B). (C,D) Ten-year survival for all-cause (C) and cardiovascular (D) deaths was poorer among women than men. Solid lines show relative risks (RR), shaded areas show 95% confidence intervals (CI). ACD, all-cause death; CVD, cardiovascular death.

As expected, factors associated with AVS included female sex (hazard ratio [HR] 0.53), younger age (HR 0.97), lower CCI (HR 0.84), the presence of symptoms (HR 2.9 for NYHA Class III/IV vs. Class I), reduced LVEF (HR 0.89 per 10% increase), larger LVESDi HR, 1.03), larger LVESVi (HR 1.06), and larger aorta size (HR 1.06–1.07). Japanese patients tended to have a higher incidence of AVS (HR 1.55–1.69; Supplementary Table 2).

Survival

The median total follow-up period was 3.9 years (IQR 1.3–7.1 years), ranging up to 12.9 years (>5 years in 539 [41%] patients). During the follow-up period, there were 240 ACDs (201 deaths under medical surveillance, 39 deaths after AVS) and 94 CVDs. Overall 10-year freedom from ACD and CVD was better among men than women (log-rank P<0.01; Figure 1C,D).

For the primary endpoint of ACD under medical surveillance, univariable analysis showed that female sex (HR 1.53), older age (HR 1.07), higher CCI (HR 1.43), advanced NYHA functional class (HR 6.84 for NYHA Class III/IV vs. Class I), larger indexed maximal ascending aorta (HR 1.09 per 1-mm/m² increase), larger LVESDi (HR 1.05 per 1-mm/m² increase), LVESVi (HR 1.01 per 10 mL/m² increase), and reduced LVEF (HR 0.71 per 10% increase) were all associated with mortality (P<0.05), whereas time-dependent AVS had a protective effect on survival (HR 0.39; 95% confidence interval 0.28–0.56; P<0.0001). Multivariable analysis (Table 3) showed that female sex per se no longer predicted mortality after adjusting for covariates that differed between the sexes. Independent factors associated with ACD under medical surveillance and during total follow-up were similar, and included older age (HR 1.06), higher CCI (HR 1.27–13.1), larger indexed aorta size (HR 1.04–1.06), NYHA functional class (HR 1.73–1.97 for NYHA Class III/IV vs. Class I), reduced LVEF (HR 0.80–0.81 per 10% increase), and increased LVESDi (HR 1.02–1.03 per 1-mm/m² increase) and LVESVi (HR 1.07–1.08 per 1-mm/m² increase). The presence of AVS was again found to have a protective effect on survival (HR 0.54–0.56; Table 3).

Table 3.

Multivariable Cox Regression Analysis for Determinants of All-Cause Death^A

	LVEF model		LVESDi model		LVESVi model
	HR (95% CI)	P value	HR (95% CI)	P value	HR (95% CI)	P value
Death under medical treatment
Univariable analysis
Female sex	1.53 (1.14–2.05)	0.004*	1.53 (1.14–2.05)	0.004*	1.53 (1.14–2.05)	0.004*
Multivariable analysis
Female sex	1.23 (0.89–1.71)	0.19	1.18 (0.85–1.62)	0.30	1.32 (0.95–1.84)	0.10
Age	1.06 (1.04–1.07)	<0.001*	1.06 (1.04–1.07)	<0.001*	1.06 (1.04–1.08)	<0.001*
CCI	1.27 (1.18–1.36)	<0.001*	1.29 (1.20–1.38)	<0.001*	1.29 (1.21–1.38)	<0.001*
iAortamax	1.06 (1.02–1.09)	<0.001*	1.05 (1.02–1.09)	0.001*	1.05 (1.01–1.08)	0.004*
NYHA functional class (Class I as reference)
Class II	0.96 (0.68–1.35)	0.84	1.00 (0.72–1.40)	0.96	0.95 (0.68–1.34)	0.80
Class III/IV	1.73 (1.09–2.75)	0.02*	1.92 (1.23–3.00)	0.004*	1.79 (1.14–2.81)	0.01*
LVEF per 10% increase	0.81 (0.71–0.93)	0.003*	–	–	–	–
LVESDi	–	–	1.02 (1.00–1.05)	0.03*	–	–
LVESVi per 10-mL/m2 increase	–	–	–	–	1.08 (1.03–1.14)	0.003*
Death during total follow-up
Univariable analysis
Female sex	1.53 (1.16–2.01)	0.002*	1.53 (1.16–2.01)	0.002*	1.53 (1.16–2.01)	0.002*
Multivariable analysis
Female sex	1.27 (0.94–1.71)	0.12	1.23 (0.91–1.64)	0.20	1.31 (0.96–1.78)	0.08
Age	1.06 (1.05–1.07)	<0.001*	1.06 (1.05–1.07)	<0.001*	1.06 (1.05–1.08)	<0.001*
CCI	1.29 (1.21–1.38)	<0.001*	1.31 (1.23–1.39)	<0.001*	1.31 (1.23–1.40)	<0.001*
iAortamax	1.04 (1.02–1.07)	0.002*	1.04 (1.01–1.07)	0.005*	1.04 (1.01–1.07)	0.005*
NYHA functional class (Class I as reference)
Class II	1.02 (0.75–1.39)	0.90	1.10 (0.81–1.49)	0.55	1.04 (0.76–1.43)	0.78
Class III/IV	1.75 (1.15–2.67)	0.009*	1.97 (1.31–2.96)	0.001*	1.89 (1.25–2.86)	0.002*
LVEF per 10% increase	0.80 (0.71–0.90)	<0.001*	–	–	–	–
LVESDi	–	–	1.03 (1.00–1.05)	0.02*	–	–
LVESVi per 10-mL/m2 increase	–	–	–	–	1.07 (1.02–1.12)	0.008*
Time-dependent aortic valve surgery	0.56 (0.37–0.82)	0.003*	0.56 (0.38–0.82)	0.003*	0.54 (0.36–0.80)	0.002*

^AModels were adjusted for ethnicity. *Under two-tailed tests, P<0.05 was considered statistically significant. CCI, Charlson comorbidity index; CI, confidence interval; HR hazard ratio; iAorta_max, indexed maximal aorta size. Other abbreviations as in Table 1.

For the secondary endpoint of CVD under medical surveillance (n=74; Supplementary Table 3), female sex was associated with poor survival in univariable analysis (P=0.007), but not in multivariable analysis (P=NS). The comparison between observed and expected survival is shown in Supplementary Figure 2.

Sex-Specific Cutoffs of LVEF, LVESDi, LVESVi, and Indexed Aorta Size

Spline curves adjusted for AVS and race (Taiwanese and Japanese) depict the continuous risk of death for associated parameters. There was a non-linear relationship between mortality and LVEF, LVESDi, LVESVi, and indexed aorta size (Figure 2; Supplementary Figure 3). For ACD in women, the mortality risk started to increase when LVEF was below 53%, LVESDi above 24.8 mm/m², LVESVi above 44 mL/m², and indexed aorta size above 25.5 mm/m² (Figure 2A–D). In men, the mortality risk started to increase when LVEF was below 52%, LVESDi above 23.4 mm/m², LVESVi above 52 mL/m², and indexed aorta size above 23.2 mm/m² (Figure 2E–H). For CVD in women, the mortality risk started to increase when LVEF was below 52%, LVESDi above 24.1 mm/m², LVESVi above 46 mL/m², and indexed aorta size above 27.8 mm/m² (Supplementary Figure 3A–D). In men, the mortality risk started to increase when LVEF was below 53%, LVESDi above 23.6 mm/m², LVESVi above 49 mL/m², and indexed aorta size above 23.7 mm/m² (Supplementary Figure 3E–H).

Figure 2.

Adjusted spline curves for the risk of all-cause death during the total follow-up in women and men. The hazard ratio (HR)=1 line represents average cohort mortality, with excess mortality for values >1. (A–D) In women, spline curves adjusted for aortic valve surgery and race (Japanese or Taiwanese) showed increased all-cause death when left ventricular ejection fraction (LVEF) was below 53% (A), the left ventricular (LV) end-systolic dimension index (LVESDi) was above 24.8 mm/m² (B), the LV end-systolic volume index (LVESVi) above 44 mL/m² (C), and the indexed maximal ascending aorta size (AoDi) was above 25.5 mm/m² (D). (E–H) In men, the corresponding cut-off values were 52% for LVEF (E), 23.4 mm/m² for LVESDi (F), 52 mL/m² for LVESVi (G), and 23.2 mm/m² for AoDi (H).

AR Progression-Related LV Remodeling at Follow-up

In the present cohort, 416 patients had undergone another TTE at least 6 months after baseline (median 36 months [IQR 17.1–67.3 months] later). The annual changes in LVEDD, LVESD, LVESDi, and LVEF compared with baseline TTE were 0.71±2.93 mm, 1.02±3.70 mm, 1.55±2.09 mm/m², and −1.39±7.67%, respectively, in women and 1.10±2.95 mm, 1.20±3.50 mm, 1.23±1.73 mm/m², and −0.93±5.87%, respectively, in men. There were no between-sex differences associated with annual changes in LV remodeling parameters (all P=NS).

Determinants of LV Reverse Remodeling After AVS

Of 497 patients undergoing AVS, 337 (68%) had post-surgical TTEs within 6–18 months. Of these, the mean pre- vs. post-surgical LVEDD, LVESD, LVESDi and LVEF were 66±7 vs. 49±7 mm, 46±9 vs. 33±8 mm, 26.9±5.5 vs. 19.1±4.4 mm/m², and 55±11% vs. 60±11%, respectively (all P<0.0001). Compared with male sex, female sex was independently associated with a larger percentage change in LVEDD (β coefficient 0.39%; P=0.02) and LVESD (β coefficient 0.39%; P=0.02), but not in LVESDi or LVEF.

Sex-Specific Comparisons Between Asian and US Cohorts

Compared with the US cohort, the Asian cohort comprised patients who were older, had less BAV, had larger indexed LV and indexed aorta size, were more likely to undergo surgery for LVESD >50 mm (LVESDi >25 mm/m²), and were less likely to undergo AVS (Supplementary Table 4). These findings were true for both sexes in the US and Asian cohorts. Women in both cohorts had a lower rate of AVS and poorer survival compared with men, but both sexes had similar post-AVS survival (Supplementary Table 4).

Discussion

This is the first contemporary study in an Asian cohort to investigate sex differences among patients with hemodynamically significant AR. The principal findings are that: (1) compared with men, women were older, more symptomatic, exhibited more comorbid conditions, and had higher LV filling pressure with smaller absolute LV size but larger LVEDDi, LVESDi, and indexed aorta sizes at AR presentation; (2) there was a higher correlation between AR symptoms and LV remodeling in men than in women, but symptoms correlated well with diastolic function parameters in both sexes; (3) the rate of AVS was lower among women, but post-AVS survival was comparable between the sexes; (4) cut-off values of LVEF, LVESDi, LVESVi, and indexed aorta size for ACD were 53%, 24.8 mm/m², 44 mL/m², and 25.5 mm/m², respectively, in women and 52%, 23.4 mm/m², 52 mL/m², and 23.2 mm/m², respectively, in men; (5) ACD and CVD occurred more frequently in women, but sex per se was not found to be a determinant of death after covariate adjustment; and (6) both sexes had similar degrees of LV remodeling owing to AR progression.

Because AR remains a male-predominant valvulopathy by nature,^10,12,13 women have inevitably remained underrepresented in previous studies. In AR, sex-specific differences have mostly been reported in Western populations. In 1996, a surgical cohort of patients with AR showed that women undergoing AVS presented with more advanced symptoms than men and that post-AVS survival was reduced in women.¹³ A more contemporary US AR cohort that included both surgical and non-surgical patients found that the between-sex survival gap was reduced.¹² In that study, although medically treated AR patients of both sexes still experienced a survival disadvantage compared with the expected survival of the general US population, this discrepancy was more significant among women, indicating a relatively poorer survival rate in female patients.¹²

Sex-specific differences in our Asian cohort were similar to those in the US cohort.¹² First, women were older, more symptomatic, and had higher CCI, LV filling pressure, and RVSP. Women also had larger indexed LV size, a larger AR RVol index, larger indexed aorta size, and a lower rate of AVS (Table 1; Supplementary Table 4).

Second, there was a poor correlation between symptomatic status and LV size in women from both the Asian and US cohorts (Table 2). However, there was a strong correlation between symptoms and a larger LV in men in both the Asian and US cohorts (Table 2). This may imply that women with AR have “stiffer” hearts with less distensibility that precludes LV dilatation, which may be supported by the larger AR RVol/LVEDV in women than in men. Such a phenomenon may be due, in part, to a relatively smaller physique in women; however, previous studies could further support our hypothesis. For example, Redfield et al reported that aging and female sex were associated with increased ventricular systolic and diastolic stiffness even in the absence of cardiovascular disease.²¹ Beale et al showed that women with heart failure and preserved ejection fraction tended to have higher LV filling pressure than men.²² Malahfji et al found extracellular volume fraction, a surrogate marker of advanced myocardial fibrosis, increased with AR progression in women, but not in men, suggesting different LV adaptive responses to AR-related pressure and volume overload between the sexes.²³ As such, women with AR may have reduced cardiac compliance compared with men. Hence, the occurrence of symptoms may not be completely correlated with LV size in women, but parameters associated with diastolic function (e.g., E/e′, LAVi, RVSP) may be able to provide a clearer picture regarding symptoms in women (Table 2).

Third, it seems that differences in survival between the sexes cannot be attributed to sex per se (Table 3; Supplementary Table 3), but may be caused by other disadvantages associated with female sex. We find it encouraging that post-AVS survival was comparable between the sexes in our Asian cohort, a result also seen in the US cohort, implying that surgical interventions can reverse disease courses and outcomes in both sexes regardless of ethnicity.

Despite similarities in findings for the US and Asian cohorts regarding sex-specific differences, it is important to note that, for both men and women, patients in the Asian cohort were older and had larger indexed LV and aorta size at presentation, implying that Asian patients tend to present at a later stage of AR than Western patients.

This is the first paper to report sex-specific LV and aorta cut-off values for patients with significant AR. We showed that for LVESDi (normal range 13–21 mm/m²),⁸ the cut-off values for ACD were 24.8 mm/m² in women and 23.4 mm/m² in men; the cut-off value for Asian men aligned with findings from recent Western studies,^9,10 but Asian women appeared to be able to tolerate slightly more LV remodeling (Figure 2). For LVESVi, the cut-off values for ACD were 44 mL/m² in women and 52 mL/m² in men. It is important to note that the normal range of LVESDi in the general population was similar between sexes (1.3–2.1 cm/m² in both men and women), but the normal range for LVESVi was larger in men than women (11–31 vs. 8–24 mL/m², respectively).⁸ In addition, considering that LV volumes decreased by age, relatively older women with AR (who were, on average, 6 years older than men with AR) would have even smaller normal LVESVi values. The sex-specific aorta cut-off values indicative of poor survival (i.e., ACD) in AR were larger in women (25.5 mm/m²) than men (23.2 mm/m²); this is consistent with the finding that women had larger normal values for indexed aorta size than men (16.6±2.8 vs. 15.9±2.8 mm/m², respectively), as reported by Saura et al.²⁴ Current guidelines regarding the timing of concomitant aorta replacement still focus on absolute and not indexed values;^5–7 we hypothesize that this may have resulted in the higher incidence of aortic dissection in our recent Asian study,²⁵ and emphasizes the importance of using indexed aorta size as a reference for decisions regarding the timing of surgery. In both the Asian and US cohorts (Supplementary Table 4), women had smaller absolute LV dimensions, smaller absolute LV volumes, and larger indexed LV dimensions, whereas men had larger indexed LV volumes. Potential explanations are that the LV dimension is 1-dimensional, BSA 2-dimensional, and LV volume 3-dimensional, which may affect the calculation of indexed dimensions and volumes in different ways. For example, the mean LVEDD values for women and men in the present cohort were 56 and 62 mm, respectively, and the LVEDV values derived using the Teichholz method were 152 and 195 mL, respectively. Therefore, LVEDD (1-dimensional) values for men were 10% larger than for women, whereas LVEDV (3-dimensional) values for men were 22% larger than for women.

Recent Western studies in AR (75–86% men), which did not focus on finding sex-specific cut-off values, reported that cut-off values indicative of adverse events in AR were 55–60% for LVEF,^9,26 20–22 mm/m² for LVESDi,^9,10,27 and 45 mL/m² for LVESVi.²⁸ A recent study using cardiac magnetic resonance imaging to evaluate quantitative thresholds and outcomes in AR reported that LVESVi ≥43 mL/m² was associated with adverse outcomes.²⁹ Regarding sex-specific thresholds informing heightened risks of adverse events, we proposed the following cut-off values:

• LVEF <55% in both sexes, which corresponds with current guidelines^5,6

• LVESDi >20 mm/m² and <25 mm/m², regardless of sex

• LVESVi >45 mL/m² in women and >50 mL/m² in men

• indexed aorta size >25 mm/m² in women and >23 mm/m² in men.

Clinical Implications

In this study we showed that survival was reduced in women due to older age, advanced symptoms, more comorbidities, and larger indexed LV and aorta size, implying that women presented at later stages of AR. Because women tend to exhibit a combination of smaller absolute LV diameters, smaller AR vena contracta, smaller AR EROA, and smaller absolute AR RVol of AR at presentation, imagers may conclude that women have less severe AR, leading to underdiagnosis, delayed referral, greater symptom burden, and a lower rate of AVS in women, which, in turn, results in poor outcomes (Figure 1). Encouragingly, women had larger AR RVol/LVEDV than men. Therefore, it seems that AR RVol/LVEDV could serve as a better discriminator of AR severity than EROA in women. To close the mortality gap between the sexes, more sex-specific studies, increased attention on patients who are at risk of AR progression,²⁹ quantification of AR using the proximal isovelocity surface area method, using indexed values for LV size,^2,3 aorta size, and possibly for quantification parameters, and the use of sex-specific treatment thresholds may help enhance timely intervention. Overall, women had similar post-AVS survival to men, indicating that timely intervention can result in effective outcomes.

Study Limitations

This is a retrospective study of data from tertiary referral centers in Taiwan and Japan. Thus, the results of the study may not be generalizable to broader Asian populations with significant AR. In addition, generalization to other clinical settings where measurements were performed by less experienced operators should be approached with caution. We were also unable to assess sex-based disparities caused by psychological and societal factors, such as access to healthcare, health literacy, and socioeconomic status, which could contribute to the mortality gap and lower rate of AVS in women. In addition, we did not have a core laboratory for all echocardiographic measurements, so were unable to control for all variations related to measurements. Finally, because this was a retrospective study, follow-up TTEs for assessing AR progression-related LV remodeling were not arranged regularly, which may result in some bias.

Conclusions

In this multicenter Asian study of hemodynamically significant AR, we found that symptoms were correlated with diastolic parameters rather than LV dilatation in women, implying that women may have “stiffer” hearts than men. This emphasized the importance of using diastolic parameters in AR. Women also presented with older age, advanced symptoms, more comorbidities, larger indexed LV and aorta size, and a lower rate of AVS, yet had similar post-AVS survival compared with men. Our findings are similar to findings from studies in Western populations, suggesting that the delayed referral and higher mortality in women with AR could be a universal observation. In terms of ACD and CVD, we proposed sex-specific cut-off values for LV and aorta size, but further studies are needed to validate the sex-specific treatment thresholds.

Acknowledgments

The authors thank Y.H. Chen for assistance with statistical analysis on life tables and the staff of Department of medical Research, National Taiwan University Hospital for providing technical support of integrative medical database.

Sources of Funding

The study was supported by the National Science and Technology Council (NSTC 111-2314-B-002-298), Taipei, Taiwan, and National Taiwan University Hospital (113-IF 0004), Taipei, Taiwan.

Disclosures

C.I. is a member of Circulation Journal’s Editorial Team. The remaining authors have no conflicts of interest to disclose.

IRB Information

This study was approved by the research ethics committees of National Taiwan University Hospital (IRB no. 20211,126RINA), the National Cerebral and Cardiovascular Center (IRB no. R21009-3), and the University of Occupational and Environmental Health (IRB no. UOEHCRB21-097).

Data Availability

The raw data and deidentified participant data will not be shared under the Declaration of Helsinki and the Personal Data Protection Act of Taiwan.

Supplementary Files

Please find supplementary file(s);

https://doi.org/10.1253/circj.CJ-24-0095

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