Sex Differences in Imaging for Structural Heart Disease: What is Normal for Women?

The underrepresentation of women in landmark cardiovascular clinical trials is a significant concern in cardiovascular medicine, affecting confidence regarding adequate sex-specific diagnosis, follow-up and management of female patients with valvular heart disease.^1–3 Current valvular disease guidelines recommend the use of quantitative thresholds to guide appropriate timing for interventions.^4–6 Guideline recommendations stem from outcome studies that recruited a largely male-predominant population and female sex recruitment that was not reflective of disease-based prevalence.^4–6 Consequently, guideline recommendations for imaging thresholds and intervention are an extrapolation from generalised data and do not necessarily reflect a sex-specific outcome approach to the quantitative analysis of valve severity or ensure appropriate timing for referral and intervention in female patients.^4–6

The development of sex-specific guidelines related to imaging of female patients with valvular heart disease requires a thorough assessment of sex-specific pathophysiological factors that may influence incidence and progression of the disease.⁷ This is in addition to the assessment of female-specific factors that may have implications on disease treatment and timing of intervention along with appropriate device selection.⁷ Sex-specific prevalence varies by valve pathology.^8,9 Women have been reported to have more frequent involvement of mitral and tricuspid valve disease, such as mitral valve prolapse, rheumatic mitral stenosis and tricuspid regurgitation (TR) and tricuspid, while male sex has been associated with a higher prevalence in aortic valve disease, including bicuspid aortic valve and aortic stenosis.^8–10 The American Society of Echocardiography guidelines for chamber quantification suggest the use of sex-specific quantitation and encourage using indexed values to body surface area (BSA) when assessing left-ventricular (LV) and right-ventricular (RV) volumes as well as atrial dimensions and calculated LV ejection fraction (LVEF).¹¹ However, valve-specific thresholds for regurgitant volume quantitation, stenotic valve area and decline in LVEF are not delineated to outline sex-specific differences in the most recent iteration.^4–6,11 The lag in sex-specific thresholds may be a culprit for later presentation in women with mitral valve disease, presentation with AF, heart failure hospitalisation and worse surgical repair outcomes compared with their male counterparts.¹² Similarly, aortic valve disease is associated with similar outcomes in both sexes, but rates of intervention are lagging in women.^13,14 The objectives of this review are to delineate and identify normal values in women based on the available literature and to identify a practical approach to refine assessment of valve disease in women and the timing of interventions (Figure 1 ).

Imaging in Women with Aortic Valve Disorders

Tri-leaflet aortic valve disease is the most common valve disorder in high-income countries.¹³ Longer life expectancy in women in the context of an ageing population demonstrates an equal – if not higher – prevalence of aortic stenosis in women aged over 80 years than in men of a similar age group.⁹ Data from transfemoral transcatheter aortic valve intervention (TAVI) studies have sequentially demonstrated good long-term outcomes in female patients despite an increase in immediate periprocedural bleeding and vascular-related complications.^14,15

Echocardiographic Assessment

Transthoracic echocardiography (TTE) is the first-line imaging modality in patients with aortic disease. Women have been reported to have smaller hearts with lower LV mass index, smaller LV cavity size and higher ejection fraction compared with men. In a retrospective cohort of 747 patients in which 43% those enrolled were women, when the association among different forms of LV remodelling in patients with aortic stenosis and all-cause mortality was examined, concentric LV hypertrophy was associated with a worse outcome in women (p=0.001), but not in men (p=0.22).¹⁶ Data from cardiac MRI (CMR) also show women with aortic stenotic disease inherently presenting with more intramyocardial fibrosis as demonstrated by an increase in extracellular volume by CMR.¹⁷

The most crucial step in the quantitative analysis of aortic stenosis is reliant on adequate measurement and accuracy of the LV outflow tract (LVOT) diameter (LVOTd). Women reportedly have a smaller LVOTd than men.¹⁸ LVOTd derived from a linear regression linked to BSA independently of sex provided an acceptable approximation of the aortic valve area in patients with aortic stenosis.¹⁸ To ensure accuracy of quantitation, one method would be to ensure measured LVOTd is within range of a calculated LVOTd from the regression equation linked to BSA. The most recent iteration of the guideline uses an indexed stroke volume that is non-sex-specific with a cutoff value of 35 ml/m² to classify flow state within the LV.⁴ Data from the WASE study demonstrated lower stroke volume and cardiac output values in females compared with age-matched males, even when these values were indexed to BSA.¹⁹ This suggests that cutoff values for women to classify indexed stroke volumes should be sex-specific and the use of unified values may lead to errors in the classification of low flow low gradient aortic stenosis. Guzzetti et al. reported an increase in mortality in women with the use of the guideline-recommended threshold of 35 ml/m², but this was not observed in men.²⁰ This prospective study identified sex-specific indexed stroke volumes that correlated with sex-specific outcomes in patients with aortic stenosis. A stroke volume index of 32 ml/m² was associated with worse outcomes in women and a stroke volume index of 40 ml/m² correlated with unfavourable outcomes in men.²⁰

Another well-validated parameter used in the assessment flow is transvalvular flow rate (stroke volume divided by systolic ejection time).^21,22 A non-sex-specific transvalvular flow rate of 200 ml/s has been accepted as the generalisable threshold, and lower transvalvular flow rates have been associated with worse outcomes in patients with severe aortic stenosis.²¹ In a prospective cohort of 1,564 patients with severe aortic stenosis (51% men and 49% women), when transaortic flow rate was categorised according to the established cutoff of 200 ml/s, flow rate <200 ml/s was associated with a 57% higher risk of all-cause mortality (HR 1.57; 95% CI [1.11–2.22]; p=0.011).²² The best cutoff value of transvalvular flow rate for prediction of all-cause mortality was 179 ml/s in women and 209 ml/s in men, suggesting that sex-specific flow rate may be an important predictor of adverse cardiac events (Table 1 ).²²

The Role of Cardiac CT

If TTE data are discordant, alternative imaging modalities such as transoesophageal echocardiography (TOE), stress echocardiography, cardiac CT and CMR are useful adjunctive assessment tools that may be used to assess the severity of aortic stenosis and regurgitation. Imaging and histopathological studies have all demonstrated a lower calcium burden in females compared with their male counterparts, with similar severity in mean gradients inferring that lower calcium score thresholds should be applied in females with aortic stenosis to assess severity.²³ Calcium burden has also been correlated with worse outcomes.²³ When aortic valve calcium score is used to assess aortic valve severity, sex-specific ranges are recommended by the current guidelines.^4–6 An aortic valve calcium score of 1,300 Agatston units is used as an indicator of severe aortic valve stenosis in female patients and 2,000 Agatston units in males, both values correlating with an indexed aortic valve area of less than 0.6 cm² as calculated by Doppler echocardiography parameters.²⁴ Explanted valves from females showed more fibrosis compared with explanted valves from males, which were calcium-rich.²⁴ Despite male valves being calcium dense, available studies validated the finding of rapid annualised calcium progression in females compared with males with aortic stenosis, suggesting more rapid progression and a need for careful follow-up imaging in women.²⁴

Pre-transcatheter Aortic Valve Intervention Imaging

Findings from pre-TAVI imaging have identified sex-specific characteristics in women.²³ Findings from a patient level meta-analysis that included over 11,000 patients in which 48.6% of the cohort were female, reported a mean annular size of 20.7 ± 3.6 mm in females and 22.8 ± 5.1 mm in male patients.²⁵ Smaller annuli have been postulated to be a clinically significant marker of post-procedural paravalvular regurgitation (PVR) this finding was plausibly a causative effect of oversizing in the context of small anatomy.²⁶ An analysis from the PARTNER trial found more prevalent PVR in patients with large aortic annuli compared with patients with small aortic annuli.²⁶ The incidence of patient prosthesis mismatch with TAVI was also less evident in patients with small annuli, differing from previous surgical data that showed higher rates of patient prosthesis mismatch with surgical valves in this subgroup of patients.²⁶

Another element of difference in women is the finding of less calcific burden, which is likely another major player in reducing the incidence of PVR in females compared with males undergoing TAVI.²⁷ Rodés-Cabau et al. reported on the implications of small annuli on valve haemodynamics. In patients with small annuli who underwent TAVI, patient–prosthesis mismatch was less frequent.²⁶ Patient–prosthesis mismatch has not been directly associated with a difference in overall mortality; however, patient–prosthesis mismatch has been reported to be associated with less regression of LV hypertrophy.²⁶

Predicting the Risk of Annular Rupture and Coronary Obstruction in Women

Small annuli have been associated with an increased risk of annular rupture, particularly in female patients.²⁸ Some findings associated with this increased risk on imaging are the presence of subannular calcium and the oversizing of balloon expandable valves by over 20% of the measured area.²⁸ Within this cohort of patients who experienced annular rupture, 74% were women, suggesting that intrinsic female tissue characteristics, such as the presence of friable tissue, may be a key risk factor for this complication.²⁸ Subannular calcium, as quantified by non-contrast multidetector CT in patients with aortic root rupture, had a higher burden of LVOT and/or subannular calcification (calcium score, 181.2 ± 211.0 versus 22.5 ± 3 7.6; p<0.001), whereas no difference in the rate of aortic cusp calcification was noted (83.9% versus 87.1%; p=0.892).²⁸ When present, localisation of LVOT calcification below the left coronary cusp (69.6% versus 66.7%; p=0.563) and the noncoronary cusp (60.9% versus 46.7%; p=0.389) was not significantly different between groups; LVOT calcification localised below the right coronary cusp was present only in patients experiencing annular rupture (30.4% versus 0.0%; p=0.019).²⁸ Both groups showed similar annular eccentricity (eccentricity index: 21.3 ± 6.4 versus 22.9 ± 5.4; p=0.328).²⁸

Ribeiro et al. reported that a significantly higher proportion (>80%) of patients who developed coronary obstruction were women, despite relatively equal sex representation in their registries.²⁹ Lower coronary heights and smaller sinus of valsalva dimensions are observed in women presenting for transcatheter aortic valve replacement compared with men, posing an increase in the risk of coronary obstruction.²⁹

Cardiac MRI in the Assessment of Aortic Disease

CMR is increasingly being recognised as the gold standard imaging modality for quantitation of chamber dimensions and regurgitant volume.³⁰ In patients with aortic disease, the use of CMR has been proven to be a more reproducible tool when assessing LV dimensions.³⁰ Similar to echocardiography, women have smaller documented chamber volumes and current guidelines recommend the use of sex-specific reference values when assessing chamber enlargement and follow-up.³⁰ In patients with aortic regurgitation, women had an increase in extracellular volume despite smaller regurgitant volumes.³⁰ In addition to the latter, non-contrast CMR can provide useful information in female patients with aortic disease during pregnancy, and it has been used as an alternative modality for valve sizing and assessing aortic dimensions prior to decision-making and intervention.

Imaging for Women with Mitral Valve Disease

Mitral valve disease is globally the most common valvular heart disease, with mitral regurgitation (MR) being more prevalent than mitral stenosis.³¹ MR affects 1–2% of the world’s population and incrementally increases with age to 7–9% of those aged >75 years.³² Myxomatous mitral disease has a predilection for female sex; it affects 2–3% of the population and has been identified as the most common cause of mitral disease in developed countries.¹⁰ Rheumatic heart disease is prevalent among all age groups of women globally and is the most common cause of mitral disease in developing nations.⁹ Mitral valve prolapse has an autosomal dominant pattern, with DCHS1 and DZIP1 mutations shown to have sex-dependent gene expression.³³

In a retrospective cohort comparing sex differences in morphology and outcomes of patients with mitral valve prolapse compared with men, women had less posterior prolapse (22% versus 31%), less flail (2% versus 8%), more leaflet thickening (32% versus 28%) and less frequent severe regurgitation (10% versus 23%; p<0.001 for all comparisons; Figure 2).³³ Regardless of the severity of regurgitation, LV and atrial diameters were smaller in women than in men but were larger in women after normalisation to BSA. At 15 years, women with no or mild MR had better odds of survival than men (87% versus 77%; adjusted risk ratio 0.82; 95% CI [0.76–0.89]), but those with severe regurgitation had worse survival than men (60% versus 68%; adjusted risk ratio 1.13;95% CI [1.01–1.26]). The survival rate 10 years after surgery was similar in women and men (77% versus 79%; p=0.14). This suggests that timing of referral in women may be delayed due to adherence to guideline-directed regurgitant volume, fraction and chamber size cutoffs that are derived from largely male-dominant studies. Other sex differences in imaging of patients with mitral disease include the findings of mitral annular calcification being associated with female sex and of posterior leaflet involvement as a male-predominant feature.^34,35

Transthoracic Echocardiography for the Assessment of Mitral Regurgitation

In an analysis by Giustino et al. looking at sex differences in patients with ischaemic MR undergoing surgical mitral repair versus mitral valve replacement, women were found to have smaller effective regurgitant orifice areas (EROA; 0.36 ± 0.12 cm² versus 0.41 ± 0.16 cm²), mitral valve annulus area, mitral leaflet tethering area and shorter interpapillary muscle distance compared with males. However, the EROA to LV end diastolic volume ratios were greater in women than in men (0.24 ± 0.09 versus 0.20 ± 0.09, respectively; p<0.002).³⁶ Left atrial volume was lower in women than in men, whereas the MR jet to left atrial area ratios were greater in women.³⁶ Two-year outcomes from this study showed a significant increase in mortality associated with female sex, increase in risk of MR reoccurrence and lower reported symptom scores compared with males.³⁶ There was a similar reduction in indexed LV end systolic dimensions from baseline to 2 years follow-up.³⁶

Kosimudo et al. examined sex-specific outcomes in patients with secondary MR who were enrolled in the COAPT trial.³⁷ Similar findings were noted, with women having smaller chamber dimensions, similar regurgitant fractions to those of men and similar pulmonary pressures with more female patients presenting with concomitant severe TR. In a quantitative study by Tribouilloy et al., sub-analysis of the echocardiographic data to determine sex differences showed that women had less severe regurgitation than men in MR (EROA 32 ± 28 versus 52 ± 37 mm², p=0.006; regurgitant volume 50 ± 35 versus 81 ± 48 ml/beat; p=0.0006).³⁸ Differences in CMR-related regurgitant volume were also noted in a quantitative study by House et al. where a regurgitant fraction of 40% correlated with a regurgitant volume of 59 ml in men and 39.5 ml in women, while a regurgitant fraction of 50% correlated with a regurgitant volume of 76.2 ml in men and 49.6 ml in women.³⁹ In a study by Mantovani et al. examining outcomes of primary MR in women, baseline echocardiographic quantitation reported a mean EROA of 0.49 ± 0.24 in women and 0.61 ± 0.31 in men, regurgitant volume 90 ± 35 ml in women and 98 ± 47 ml in men.⁴⁰ When quantitative values were indexed to BSA, women demonstrated larger normalised LV and left atrium versus men; BSA-normalised regurgitant volume showed no difference between men and women.⁴⁰

Regurgitant fraction, determined by CMR, provided a sex-independent assessment of primary mitral insufficiency suggesting that regurgitant volume thresholds for severe primary mitral insufficiency may be lower in women.⁴⁰

Rheumatic mitral disease is a disease primarily affecting women. Studies that validated and correlated echocardiographic Doppler methodologies enrolled mainly female patients, 2D planimetry correlated best with directly measured mitral valve area.^41,42 This method eliminates assumptions related to flow and chamber haemodynamics.^41,42

Procedural Imaging for Mitral Interventions

TOE is crucial in preprocedural and intraprocedural imaging for mitral interventions. The high temporal resolution offered by echocardiography allows for high definition of detailed valve anatomy, accurate quantitation of valve area and regurgitant jet quantitation by both 2D biplane and 3D multiplanar reconstruction. In procedural planning for transcatheter edge-to-edge repair (TEER) some of the important screening parameters include ensuring adequate preprocedural valve area to allow for device implant for a hemodynamically significant result in MR reduction without inducing significant mitral stenosis. Current recommendations for area are not sex-specific and are not indexed for body size or surface area.⁴¹ Women have smaller body habitus and smaller chamber dimensions and cardiac output.⁴¹ Non-sex-specific cutoffs may be a source for later referral in females and, in some instances, withholding of beneficial therapy or consideration of alternative approaches. Other important considerations that influence post-procedural stenosis include a combination of valve compliance, device size selection, area of grasping with central tissue bridges being quoted to cause at least 50% reduction in annulus size.⁴¹ Creating a double orifice valve was associated with a larger valve area post-TEER than a triple orifice valve, and commissural tissue bridges were found to cause the least degree of stenosis.⁴³ Some of these strategies should be taken into account when selecting appropriate females for TEER rather than a crude cutoff of <4 cm². Women with mitral valve prolapse have been found to have multi-segment/scallop prolapse and more anterior leaflet involvement compared with male patients.⁴³ These findings also pose challenges to TEER since the presence of multiple jets may create a need for deployment of multiple devices for appropriate MR reduction and to create a stable tissue bridge. An increase in tissue redundancy seen with Barlow’s disease predisposes women to a higher risk of single leaflet detachment.⁴³

Real-world data from the EXPAND G4 registry were reflective of the previous findings in women.^44,45 When patients from the registry were stratified by echocardiographic suitability for TEER, men were found to have more suitable anatomy compared with women (57.1% men versus 43% women), women were more likely to be deemed at risk of procedure-related stenosis (57.1% women versus 42.9% men), women were also stratified as likely to have more residual MR (55.6% women versus 44.4% men). Findings from the registry demonstrated low risk of major adverse events in women and improvement in MR, acceptable gradients and an improvement in quality of life and patient-reported outcomes despite anticipated concerns during preprocedural assessment.^44,45

Role of Cardiac CT for Mitral Valve Assessment in Women

Cardiac CT plays a key role in preprocedural planning for transcatheter mitral valve replacement (TMVR) using either dedicated mitral platforms in native pathology or in preprocedural planning for a valve-in-valve or valve-in-ring using TAVI platforms. In a single-centre retrospective cohort by Hatab et al., TMVR screening failure in females was found to be as high as 67%.⁴⁶

A substudy from the Valve In Mitral Annular Calcification (ViMAC) registry retrospectively analysed the cohort of patients who underwent ViMAC to delineate features associated with a high risk of LVOT obstruction.⁴⁷ Female sex was a strong predictor of LVOT obstruction and 100% of patients within this cohort who developed LVOT obstruction were women.⁴⁷ Mitral annular diastolic dimensions were similar between both groups. Average mitral annular calcification (MAC) thickness (8.4 mm versus 8.3 mm; p=0.93), maximum MAC⁷ MAC thickness (11.8 versus 12.8 mm; p=0.59) and CT-based MAC scores were similar between both groups (7.9 ± 0.8 versus 7.7 ± 1.5; p=0.72). The mean length of the anterior mitral leaflet was shorter in the group with LVOT obstruction (18.6 mm versus 22.4 mm; p=0.02). The mean LVOT area in systole was lower in the group with LVOT obstruction (331.1 mm² versus 451.9 mm²; p=0.03). Similarly, the neo-LVOT (145.3 versus 270.9; p=0.006) and the indexed neo-LVOT (90.1 versus 157.4; p=0.05) were also lower in the group with LVOT obstruction, and the expected % LVOT area reduction was higher in this group (58.3% versus 42.7%; p=0.008). The virtual valve to septum distance was lower in the group with LVOT obstruction (3.1 mm versus 6.9 mm; p=0.002). The small sample size and low event rates limited analysis adjusted to sex as well as the performance of the cutoff values for LVOT obstruction predictors. The dynamic interplay between the mitral annulus, LV and outflow tract suggests that LVOT measurements should not be sole predictors of obstruction in women, rather a combination of factors to be considered include the size of the ventricle and type of mitral device implanted and specifics regarding closed or open cell technology.

Role of Cardiac MRI in Mitral Disease in Women

CMR plays a fundamental role in quantitation of MR severity, especially in the context of Barlow’s disease and in secondary MR. Quantitation by echocardiographic methods may be inaccurate when multiple or very eccentric jets are present or when image quality is suboptimal for volumetric and Doppler assessment due to either foreshortened images or misaligned Doppler signals.

Imaging for Tricuspid Valve Interventions in Women

In a community-based study examining the prevalence of TR, all-cause TR was more commonly diagnosed in women than in men after adjustment for age.⁴⁸ These findings are in line with previous findings of the Framingham Heart Study in which more than mild TR was found to be more prevalent in women with a ratio of 1.6 women:1 man.⁴⁹ In a retrospective analysis of patients from a tertiary care centre in the Netherlands, patients with the fastest development of significant TR were older, more frequently women and showed more RV dilation and dysfunction compared with patients with the slowest development of TR.⁵⁰ Rapid development of significant TR was independently associated with all-cause mortality independent of age, LVEF, RV systolic pressure, and tricuspid annular plane systolic excursion (TAPSE). This highlights the important role of the imager in identifying female patients deemed to be at high risk of progression and ensuring close follow-up imaging and defining appropriate thresholds for intervention.

Defining tricuspid valve anatomy is essential to TEER planning. A novel nomenclature to define and classify tricuspid valve anatomy has recently been published. Within this series of 579 patients 54% were identified by imaging to have three leaflet morphology named as type I, 5% identified as having two-leaflet morphology named type II, 3% had four-leaflet configuration with a scalloped anterior leaflet segmented into two named IIIA, 32% of patients were found to have four leaflets with a segmented posterior leaflet named IIIB, 4% patients with a type IIIC morphology showing four leaflets with segmentation of the septal leaflet; lastly a five-leaflet configuration was identified in 3% of patients, named type IV. Within this series of patients, 50.4% of patients enrolled were female and there was no predilection in terms of leaflet configuration seen between men and women.⁵¹ A post-mortem series reported by de Gaspari et al. examined tricuspid anatomy of 127 normal patients to determine sex-based differences across different age groups.⁵² Reported median tricuspid valve circumference was 102.0 mm (women 95.5 mm; men 109.0 mm; p<0.001). The anterior leaflet was widest (median 38.0 mm), followed by the posterior (35.0 mm) and septal (28.0 mm) leaflets (p<.001 for all). Men had wider and longer anterior and posterior leaflets compared with women (p<0.001). Median leaflet lengths were as follows: anterior, 41.0 mm (men) and 35.5 mm (women); posterior, 40.0 mm (men) and 31.5 mm (women); and septal, 28.0 mm (men) and 27.5 mm (women). The most frequently encountered leaflet pattern (38.6%) was non-scalloped anterior and septal with scalloped posterior. These results corroborate findings encountered inprevious patient cohorts. Cord-free zones are important to identify for procedural planning.⁵² Within this cohort, cord-free zones were found commonly in the central portion of the anterior and posterior leaflets and along the anteroposterior commissure, with no differences identified in cord-free zones between men and women.⁵²

In tricuspid valve disease, TTE plays an imperative role in defining tricuspid valve anatomy and quantitating regurgitation severity and for the assessment of right-sided dimensions and function. Right-sided structures sit in close proximity to the chest wall and, in many circumstances, TTE can yield high-resolution images to delineate valve morphology, mechanism of TR and assess chamber enlargement. TOE can further provide clarity on subchordal structures, detailed leaflet anatomy and 3D quantitation as well as procedural feasibility (Figure 3). Thresholds for regurgitant volume, regurgitant fraction, vena contracta width, vena contracta area and coaptation gap are not sex specific as per the most recent guidelines and consensus statements.⁵³ Guidelines do recommend the use of sex-specific thresholds for right atrial and ventricular dimensions in a similar manner to that of quantitation for LV chambers.⁵³

RV wall tension is a parameter that can be used to risk-stratify patients with tricuspid valve regurgitation. RV wall tension is defined as RV base-to-apex length multiplied by pulmonary artery systolic pressure. An RV wall tension >3,300 mmHg has been associated with a two- to three-fold increase in risk of mortality in both men and women with tricuspid valve regurgitation. A recent retrospective study that investigated sex-specific differences in RV haemodynamics in patients with significant tricuspid valve regurgitation and all-cause mortality found sex-specific thresholds of RV wall tension to be an independent predictor of all-cause mortality in this specific population. A mean RV wall tension of 3,170 ± 1,220 mmHg × mm in women and 3,817 ± 1,499 mmHg × mm in men (p=0.002) were identified as predictors of outcome.⁵⁴

Multimodality cardiac imaging in the form of cardiac CT and CMR are essential to assess adjacent anatomy including the right coronary artery, coronary sinus and inferior vena cava, and to delineate the pathway of device trajectory into the right atrium.⁵⁵

A sex-based analysis from the TriValve registry examined sex-related baseline characteristics and early post-procedural outcomes in 556 patients, from 24 different centres in the Europe and North America who underwent transcatheter tricuspid valve intervention (TTVI).⁵⁶ A total of 316 (56.8%) patients enrolled were women. Findings from this analysis suggest relatively earlier referral of women with tricuspid valve regurgitation compared with previous studies investigating intervention in aortic disease and MR. Women enrolled had similar indexed RV dimensions compared with male counterparts, had similar measures of RV function and higher LV ejection fractions. Reported baseline echocardiographic characteristics showed similar parameters among women and men enrolled. The majority of patients were found to have centrally located TR jets (64.9% in females versus 65.2% in males), the second most common location was jet origin between the anterior and septal leaflets in both men and women. The mean TR vena contracta was 10.4 ± 4 mm in females and 10.6 ± 4 mm in males, women had numerically larger EROA of 0.7 ± 0.57 cm² versus men with a mean EROA 0.65 ± 0.47 cm² and lastly women had a similar proximal isovelocity surface area-calculated regurgitant volume compared with men (51 ± 32 ml versus 52 ± 28 ml). Indexed tricuspid annular diameter was slightly larger in females, coaptation gaps and tenting area dimensions were similar in males and females.⁵⁶ Female patients commonly needed two to three TEER devices to achieve acceptable TR reduction compared with male patients, in whom an average of three to four devices were more frequently used.

Other quantitative parameters used in TTVI trials include the assessment of RV fractional area change, TAPSE to pulmonary artery systolic pressure ratio as a marker of RV to pulmonary artery pressure coupling, RV stroke volume and cardiac output.⁵⁷ These parameters were used to assess RV function in trials enrolling patients for TEER and transcatheter tricuspid valve replacement.⁵⁷ Sex-specific thresholds were not identified from these patient cohorts; however, it is important to note that trials investigating tricuspid valve interventions achieved adequate female participation and – in some aspects, such as transcatheter valve replacement – trials enrolled more female participants than men.⁵⁷

Discussion

Advanced imaging techniques have evolved to help guide the timing of interventions for patients with valvular heart disease. Unfortunately, there has been a lag in sex-specific thresholds for quantitation of valve lesions. Advancement in 2D imaging parameters and 3D quantitative parameters such as 3D vena contracta, 3D proximal isovelocity surface area and calculated regurgitant volumes and fractions have not been validated in female patients to determine ideal thresholds. Strain imaging and speckle imaging are also lagging regarding sex-specific thresholds. Current guidelines highlight differences in quantitative analysis for different pathologies such as primary and secondary MR and acknowledge different regurgitant volumes that may be used as cutoffs for haemodynamically significant disease.⁶ However, sex-specific cutoffs are not mentioned due to a paucity of available evidence. Parameters mentioned in the current valve guidelines are largely a derivation of studies that investigated outcomes in the era of surgical intervention and are not necessarily applicable to the current age of transcatheter interventions. There are gaps in quantitating lesion severity post intervention, especially when TEER devices are being used. Assessing severity in female patients intra- and post-procedurally has not been studied and parameter such as 3D vena contracta measure from 3D multiplanar reconstruction and residual effective orifice area have not been extensively validated in women to determine acceptable effective orifice areas post-intervention. It is also important to note that echocardiographic thresholds and thresholds reported from CMR quantitation may not necessarily be interchangeable and studies reporting sex-specific thresholds are needed.^58,59 Recent CMR data comparing echocardiographic quantitation of aortic regurgitation with CMR quantitation found lower regurgitant fraction cutoffs of 33% to correlate better with clinical outcomes, suggesting that conventional cutoffs need to be considered in totality of all other quantitative parameters. Other imaging markers such as extracellular volume are also important determinants of fibrosis and should be taken into consideration by imagers and heart teams alike; methods and thresholds for quantitation are needed. Assessment of ventricular function and remodelling patterns are also better studied with CMR and measures of acceptable remodelling thresholds should be identified to help determine procedural success.

Conclusion

Sex-specific imaging studies are needed to identify outcomes-based thresholds in females with valvular heart disease, similar to the available normal values for chamber quantitation. Ensuring adequate female patient enrolment in clinical trials, registries and outcome studies is key to help mitigate inequity in outcomes between sexes. National measures include the assurance of referral pathways to valve centres of excellence to ensure detailed assessment by people with expertise in quantitation. Training and competency pathways to develop clinical and research centres for valve disease in women would help narrow the current gap in care and ensure that evidence-based options are offered to this group of patients. Finally, investment in institutional policies that help identify valve patients for early referral and assessment by a valve disease specialist with expertise in imaging women with valve pathology is needed (Figure 4 ).