Cristina Aurigemma¹, Francesco Burzotta^1,2, Carlo Trani^1,2      

¹Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy   

²Universita Cattolica del Sacro Cuore, Rome, Italy    

Abstract   

Available data have demonstrated important sex-related differences in patients with valvular heart  disease, regarding clinical presentation, treatment, and outcomes. Although the calcific aortic  stenosis (AS) is more frequent in men compared to women, the majority of AS patients over 80  years old are women, in whom fibrotic remodeling of aortic valve is typically found. Mitral valve  disease is more common in women. However females are under-referred or delayed referrals to  treatment, probably due to the absence of sex-based LV dimension values guiding surgical timing.  The development of transcatheter devices have revolutionized the treatment of valvular heart disease and increased the interest in this topic.

In this context, the consideration of gender differences in presentation, diagnosis, treatment success, and prognosis is of great importance.    

Key words: gender, heart valve, transcatheter treatment, aortic valve, mitral valve, tricuspid valve   

Introduction    

The majority of valve heart disease (VHD) is diagnosed in patients greater than 65 years old, indeed the incidence of VHD increases with age. VHD may equally affect men and women, but sex specific differences in prevalence of valve disease type are described in literature (1-3).  Furthermore available data have demonstrated a different risk profiles in women and men affected  by heart valve disease, with a significant impact on treatment outcomes and prognosis (4-5).  Recently the development of transcatheter devices offers new treatment options for VHD. In this  context, although women have been historically underrepresented in most trials investigating  transcatheter treatment, the consideration of gender differences in treatment success, and prognosis  is of great importance.

This review is an overview of gender-related differences in patients with  VHD, regarding incidence, clinical presentation, treatment, and outcomes in the era of transcatheter  treatment. 

Aortic valve disease

In developed countries, the more common treated VHD is the aortic valve, with the majority of  aortic valve disease represented by aortic stenosis. In these countries calcific degeneration of  tricuspid aortic valve represents the more common mechanism of aortic stenosis.

In women aortic  valve calcium, even after indexing to body surface area or aortic annulus area, is lower compared to  men (6-8). Sex-specific hormonal differences are proposed as possible explanation of more  calcified aortic valve stenosis in men, in particular testosterone may be involved in greater calcific  deposition in the aortic sinus (9). Instead valvular fibrosis is involved in women with hemodynamically severe aortic stenosis, in which a lower degree of aortic valve calcification is  typically found (10).

The intramyocardial fibrosis is also more frequent in women compared to men  (Fig. 1).

Some gender differences are also found in clinical presentation of aortic stenosis. In  particular at presentation, women are older and have worse symptom burden, including more exercise dizziness and more advanced New York Heart Association class (11) (Fig. 1).

The aortic regurgitation has more marked sex differences than aortic stenosis and is more common  among men (12), probably due to the higher incidence of bicuspid aortic valve in male (male- female sex ratio 2:1) (13) and endocarditis (14) (Fig. 1). Similarly to aortic stenosis, a trend of greater symptomatology has also been found in women with aortic regurgitation compared to men (15)  (Fig. 1). 

Echocardiographic assessment based on sex specific criteria (stroke volume index, size specific left  ventricular dimensions and aortic regurgitation) should be considered in order to avoid an  underestimation of the severity of valve disease and undertreatment of female patients (Fig. 1).  

Figure 1. Gender differences in aortic valve disease. Gender-related differences in aortic valve  disease regarding incidence, clinical presentation, treatment, and outcomes  

SAVR - surgical aortic valve replacement; TAVI - transcatheter aortic valve implantation     

Furthermore the fibrotic remodeling of the aortic valve typically of aortic stenosis in women highlights the importance of sex-specific thresholds of aortic valve calcification by cardiac imaging.   Historically the gold standard treatment of aortic stenosis was surgical aortic valve replacement  (SAVR).

In the past decade the clinical outcomes of SAVR have improved significantly, but conflicting results on differential sex impact on outcomes are reported by several studies. Data from  Nationwide Inpatient Sample, including 166.809 patients (63% male and 37% female) underwent  SAVR between 2003 and 2014 have demonstrated a worse in-hospital mortality following SAVR in  women compared to men (5.6% versus 4%, p<0.001). After propensity matching, in-hospital  mortality remained significantly higher in women than in men (3.3% versus 2.9%, p=0.001) (16).  

The introduction and widespread adoption of transcatheter aortic valve implantation (TAVI) have revolutionized the treatment of aortic stenosis. The clinical outcomes of the 353 women enrolled in  the CoreValve US High Risk Pivotal Trial have demonstrated a lower 1-year cardiovascular  mortality and a lower 1-year all-cause mortality or major stroke in women undergoing TAVI  compared with women undergoing SAVR. Furthermore, as expected, the mean gradient was lower (8.92 (4.17) mmHg vs 12.24 (5.39) mm Hg; p <0.001) and the effective orifice area (EOA) was greater (1.80 (0.53) cm² vs 1.44 (0.47) cm²; p <0.001) in TAVI compared with SAVR. The rate of  prosthesis-patient mismatch was lower in female TAVI versus SAVR at 30 days (8.8% vs 29.3%),  6 months (8.1% vs 24.5%), and 1 year (6.9% vs 29.8%) (17).

Several studies have reported superior outcomes with TAVI in women compared to men, partially due to longer life expectancy in  women. In SAPIEN 3 Aortic Bioprosthesis European Outcome (SOURCE 3) registry all-cause  mortality trended lower in women than men at 4 years post TAVI (18).

An analysis of a  contemporary cohort of patients treated with balloon-expandable and self-expandable transcatheter  valves found similar rates of in-hospital mortality, stroke, moderate/severe paravalvular leak and  pacemaker implantation in women and men (19). Data from Transcatheter Valve Therapy (TVT)  registry of the STS/American College of Cardiology (ACC), including 11.808 (49.9%) women and  11.844 (51.1%) men underwent TAVI from 2011-2014 have demonstrated a different risk profile  between woman and men and 1-year adjusted survival was superior in female patients,  notwithstanding a greater adjusted risk for in-hospital vascular complications (20). Indeed, in TAVI  procedure major vascular complications are experienced more frequent in women, probably related  to low body surface area and smaller peripheral vessels (21). In WIN TAVI (Women’s International  Transcatheter Aortic Valve Implantation), an international, multicenter, prospective observational registry of 1019 female patients undergoing TAVI, the Valve Academic Research Consortium 2  (VARC-2) early safety end point (composite of mortality, stroke, major vascular complications,  life-threatening bleeding, stage 2 or 3 acute kidney injury, coronary artery obstruction, or repeat  procedure for valve-related dysfunction) is reported in 14% and it is manly driven by vascular  complications (7.7%) (22) (Fig. 1).

 Further information will come from the ongoing Randomized  Research in Women All Comers With Aortic Stenosis (RHEIA) trial, a prospective, randomized  multicenter study that tests non inferiority and, eventually, the superiority of TAVI versus surgical  aortic valve replacement in women with severe aortic stenosis (NCT04160130) (23).   

Mitral valve disease  

Mitral valve disease represents a quarter of valve heart disease in the developed countries, with  mitral regurgitation more common than mitral stenosis. Globally the most common valve disease is  the mitral regurgitation, which affected 1-2% of world’s population. Rheumatic and non-rheumatic degenerative mitral valve disease is also more common in women compared to men (24).  Furthermore women are predisposed to bileaflet mitral valve prolapse, due to more myxomatous  valve related to sex-based differences in extracellular matrix remodeling. The posterior mitral valve  prolapse with flail is more common in men. Due to these valve morphology differences women  with mitral valve prolapse have less frequently severe mitral valve regurgitation (25). Conversely,  secondary mitral regurgitation, as a consequence of myocardial infarction or coronary artery  disease, occurred more frequent in women compared to men (26).

Gender difference have also  been reported in the pathophysiology of mitral apparatus calcification, with posterior leaflet calcification  more common in men and mitral annular calcification in women (27) (Fig. 2). Available data have demonstrated gender difference in clinical presentation of mitral valve disease. Postcapillary  pulmonary hypertension as expression of adverse pulmonary vascular remodeling is more common  in women affected by mitral stenosis (28). Although less dilated ventricles and less severe mitral  regurgitation worse heart failure symptoms are more common in women with mitral regurgitation  (29) (Fig. 2).

The assessment of the mitral valve anatomy, function and mechanism of  abnormalities are performed by echocardiography. Sex and sizes specific parameters should be  considered to evaluate left ventricle dilation in the setting of mitral regurgitation. Transesophageal  echocardiography is used in pre-procedure assessment and guidance of percutaneous procedures  including both repair and replacement (Fig.2).

Figure 2. Gender differences in mitral valve disease. Gender-related differences in mitral valve disease regarding incidence, clinical presentation, treatment, and outcomes   

Although mitral valve (MV) disease is more common  in women compared to men, women are referred for mitral valve intervention at fewer rates and  later in the disease course (30). The delayed referral, probably due to cut-off values based primarily  on a predominantly male population without sex-based differences, partially explains the worse  clinical outcomes after mitral surgery in women (31).

Furthermore in women undergoing surgery  for primary or degenerative mitral regurgitation, mitral repair was less performed. Indeed in women  MV replacement is performed more frequently  compared to men (32). Since MV  repair is preferred to replacement for early and late better clinical survival (33), the mortality after  MV surgery is higher in women compared to men (32). These differences in intervention  and outcomes may be related to frailty, differences in the prevalence and severity of secondary  mitral regurgitation, rheumatic valve disease, and mitral annular calcification. Indeed in a propensity score-matched analysis of 846 patients the surgical approaches for men and women were  similar and mortality was comparable (34). These results underlines that the clinical outcomes are  dependent upon the later referral, the severity of the mitral disease and associated co-morbidities at  the time of surgery (Figure 2).   

Rheumatic mitral stenosis is more frequent in women, and data on outcomes after percutaneous balloon  mitral valvuloplasty are mixed and it is unclear if there are sex-based differences in outcomes after  balloon valvuloplasty (35).

The incident mitral annulus calcification is more frequent in women,  therefore in Mitral Annulus Calcification Global Registry 68% of patients were women (36).

Data  on percutaneous valve replacement in mitral annulus calcification have demonstrated a worse  clinical outcome compared to valve-in-valve and valve-in-ring procedures (37).   After transcatheter edge-to-edge repair (TEER) reverse left ventricle remodeling is revealed more frequent in female gender (38).

Nonetheless, the clinical improvements in women treated with TEER seem to be no better compared to men. Indeed studies investigated sex  difference in clinical outcomes after TEER have reported contrasting  results. The Transcatheter Mitral Valve Interventions (TRAMI) registry (39) and the Getting  Reduction of Mitral Insufficiency by Percutaneous Clip Implantation in Italy (GRASP) registry (40)  have reported less improvement in New York Heart Association Class in women compared to men,  while the European Registry of Transcatheter Repair for Secondary Mitral Regurgitation  (EuroSMR) study have shown equivalent quality of life and symptomatic improvements in both  women and men (41).

Women represented only 36% of patients in Cardiovascular Outcomes  Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients with Functional  Mitral Regurgitation (COAPT) trial (42) and only 25% of patients in the Percutaneous Repair With the  MitraClip Device for Severe Functional/Secondary Mitral Regurgitation (MITRA-FR trial) trial (43);  this underrepresentation raises questions about the applicability of results to women. In a sex- specific outcomes subanalysis of the COAPT TEER resulted in improved  clinical outcomes compared with guideline-directed medical therapy alone, irrespective of sex.  However, the reduction in heart failure hospitalizations was less pronounced in women compared  to men beyond the first year after treatment (44). Instead data from the Society of Thoracic  Surgery/ACC Transcatheter Valve Therapy registry (5.295 patients,  47.6% women enrolled from 2011 to 2017), have demonstrated sex differences in outcomes after  TEER, with female sex associated with lower adjusted 1-year risk of all- cause mortality (45). Similarly a meta-analysis of eleven studies with a total of 24.905 patients (45.6%  women) have reported that female sex is associated to lower adjusted mortality on long-term  follow-up (46).

Further studies are need to confirm sex differences in outcomes after transcatheter  edge-to-edge repair (Fig. 2).  

Tricuspid valve  

According to etiology and mechanism, tricuspid regurgitation (TR) is classified in primary and secondary  (47). Primary TR is less common and it is due to congenital and genetic  anomalies (Ebstein’s anomaly, tricuspid dysplasia, and myxomatous degeneration leading to  tricuspid valve prolapse) or due to acquired valve disease (endocarditis, carcinoid, rheumatic  involvement). In primary TR the dominant mechanism is tricuspid leaflet  abnormalities with variable leaflets mobility and dilatation of tricuspid annulus, right ventricle and  right atrium.

Secondary TR represents 90% of all TR and it is  characterized by normal valve leaflets with incomplete leaflet coaptation. There are two types of  secondary TR: atrial and ventricular. Atrial TR is due to atrial  fibrillation/flutter or heart failure with preserved ejection fraction. In atrial TR  the dominant mechanism is marked tricuspid valve annulus dilatation; right atrium is also dilated,  while leaflets mobility and right ventricle volume are typically normal. Ventricular TR is related to left-sided ventricular or valve disease, pulmonary hypertension, right  ventricular cardiomyopathy or infarction. In ventricular regurgitation the dominant mechanism is  marked leaflet tethering, with leaflet mobility reduction in systole and dilatation of right annulus,  right ventricle and right atrium.

The Framingham Heart Study (48) and other community-based  cross sectional studies (49) have demonstrated a female preponderance for mild or severe TR dominance with a male-to-female ratio of 1 to 1.6. Post mortem studies have revealed  sex-differences in annular anatomy, with more elastic, more cellular and smaller when correcting  for heart weight right atrioventricular annuli in men compared to women (50) (Fig. 3).  Consequently, triggers such as atrial fibrillation may cause more frequently annular dilation and  secondary TR in women. The progression from moderate to severe TR is also more  rapid in women compared to men (51). Furthermore women with secondary TR  are older and more symptomatic than men (52) (Fig. 3).

Figure 3. Gender differences in tricuspid valve disease. Gender-related differences in tricuspid  valve disease regarding incidence, clinical presentation, treatment, and outcomes

Surgical intervention for isolated  TR is a rare intervention with higher in-hospital mortality (8.8%), repair is  associated to better clinical outcome compared to replacement (53). In the analysis of data from the  National Inpatient Sample women represent the majority of patients undergoing tricuspid surgery and no gender difference is identified in clinical outcomes (54).

Recently different percutaneous  treatments for tricuspid regurgitation are proposed. Multiple technologies for transcatheter tricuspid  valve repair are available, including coaptation or annuloplasty devices. Data of safety and  feasibility trials on these devices reported promising results (55, 56).

Other current transcatheter  treatment options include heterotopic caval valve implantation and not yet commercially available  transcatheter tricuspid valve replacement with orthotopic valve implantation. The Transcatheter  Tricuspid Valve Therapies (TriValve) registry have enrolled patients with severe tricuspid  regurgitation undergoing transcatheter tricuspid valve intervention (percutaneous edge-to-edge,  annuloplasty, tricuspid replacement) from 2016 to 2021 in 24 centers (57). Data from this registry have demonstrated no difference between men and women in survival, heart failure hospitalization,  functional status, and tricuspid regurgitation reduction up to 1 year, but transcatheter tricuspid valve  intervention is associated by survival benefit compared to medical therapy alone in both women and  men (Fig. 3).  

Figure 4. Gender-related differences in heart valve disease

Conclusions  

VHD increases significantly among aging populations and important sex-related differences in  clinical presentation, treatment, and outcomes are revealed by several studies. A specific risk profile is identified in females with consequently unique challenges for the invasive treatment of the  diseased valve (Fig. 4). Implementation of sex-specific treatment criteria should be encouraged  in order to guarantee timely referral to treatment.

Future research studies on sex-related differences are  need for a tailored management with respect to the timing of intervention and treatment modality to  benefit both sexes.  

Peer-review: External  and internal

Conflicts of interest: None to declare

Authors’ disclosures: Cristina Aurigemma has been involved in advisory board activities by Abbott,  Abiomed, Medtronic and Daiichi Sankyo. Francesco Burzotta discloses to have been involved in advisory  board meetings or having received speaker’s fees from Abbott, Abiomed, Medtronic and Biotronic. Carlo  Trani discloses to have been involved in advisory board meetings or having received speaker’s fees  from Abbott, Abiomed, Medtronic and Biotronic.      

No fee was received for this work.

Authorship: C.A., F.B., and C.T.   equally contributed to the study and manuscript preparation.  

Acknowledgement and funding: None to declare