Gender differences

Current evidence on gender differences in interventional valve therapy indicates that the patient pathway of aortic valve stenosis requires awareness regarding symptomatology, diagnosis, prosthesis selection, and life-time management in women. In addition, sex-specific predictors and thresholds appear to be relevant to mortality, particularly in interventional therapy for tricuspid regurgitation.

“Women’s hearts beat differently” has been known for more than a decade of cardiovascular health research. Today, it is undisputed that biological, socioeconomic, and sociocultural differences exist between the sexes, and it is also known that these differences can have a significant impact on disease progression, therapy, and prognosis. A good body of data regarding gender differences already exists in the area of coronary heart disease and heart failure and is also centrally funded and prioritized in the context of health research (e.g., Federal Ministry of Health).

But what about with regard to interventional valve therapy? Are there any significant differences at all, and if so, what are their effects and how can they be compensated for? The aim of this review is to summarize the current evidence on gender differences in interventional valve therapy and to highlight remaining knowledge gaps.

What is the common denominator of gender differences in valvular diseases?

Valvular disease (VHD) is one of the most common conditions in cardiovascular care, with increasing incidence corresponding to demographic change as well as increasing options for interventional care even in old age. Women with VHD have been underrepresented in many guideline-shaping studies for a variety of reasons [1]. Consequently, this also means that all our knowledge regarding pathophysiology, diagnostics, therapy, and outcome is largely related to male populations and has so far been extrapolated to female patients. For example, a good example of this is the use and transferred scope of parameters as treatment indicators that are not body area adjusted. With a smaller female anatomy, this also regularly leads to the fact that women are already more symptomatic at the time of (delayed) diagnosis and may consequently also have a worse prognosis. Psychological components, role perception and social norms also frequently contribute to delayed diagnosis and/or treatment ( Fig. 1) . This is further aggravated by the fact that the majority of physicians in the care pathway are male, who tend to attribute the sometimes atypical complaints of female patients to psychological factors. Only about 15% of cardiologists and <5% of interventional cardiologists represent women to date, so diagnosis and treatment pathways have been subject to an un(ter)conscious confounding mechanism for decades.

Aortic valve stenosis and interventional therapy

Although aortic stenosis (AS) is the most common valvular heart disease in industrialized countries [2] in late adulthood, its diagnosis is still considered underestimated and so are the potential differences in gender-specific course and prognosis. Based on current knowledge, the incidence of AS in elderly patients (>75 years) seems to be higher for women than for men [3]. Also known is that biological sex influences cardiac remodeling and fibrosis in AS [4] and that women can achieve a degree of stenosis equivalent to men with less valvular calcification [5] and still have a faster rate of progression. Equivalent to other valvular diseases, women are often more symptomatic at diagnosis. The procedural success of interventional aortic valve replacement (TAVI) is the same in both sexes, but women are more likely to show severe vascular complications and bleeding. Because anatomy is often smaller and life expectancy is longer than in men, challenges also arise regarding the most appropriate valve selection (cue patient prosthesis mismatch; LV and annulus perforations, coronary obstruction). This is particularly relevant in the long term when a new valve intervention (valve-in-valve procedure) is planned, so treatment planning should ideally be proactive. Nevertheless, mortality is so far significantly higher than in men only in female risk groups (e.g. frailty, pulmonary hypertension, heart failure).

Mitral valve regurgitation and interventional therapy

Mitral valve disease accounts for about a quarter of VHD, with mitral regurgitation (MI) being the dominant vitium [2], with an increasing incidence over the age of 75 years. Both rheumatic and nonrheumatic etiologies of mitral valve pathology are more common in women of all ages. The same is true for mitral valve prolapse. Here, it was found that females have thicker sails, less frequent posterior prolapse, and less frequent flail morphology compared to males [6]. It appears that sex-specific differences in the extracellular matrix are prominent here, leading more frequently to myxomatous morphology and associated pathologies. Furthermore, women are more likely to develop functional or secondary MI after myocardial infarction or with compromising coronary artery disease, as well as marked mitral valve annular calcification with degenerative disease. Again, there are differences in timing of therapy and prognosis that may lead to poorer outcomes in the female patient population when treated later.

Regarding the study situation in the transcatheter edge-to-edge procedure (TEER), it should be mentioned that only 36% of patients in COAPT and only 25% of patients in MITRA-FR were female, which raises questions about the applicability of the study results to women. For example, in a sub-analysis of the COAPT study [7], significant differences in baseline characteristics were found: Women were younger than men and had fewer comorbidities but already reduced quality of life and functional capacity at baseline. Although TEER resulted in improved clinical outcomes compared with guideline-directed drug therapy alone, regardless of gender, the impact on heart failure rehospitalization rates was less pronounced in women compared with men beyond the first year after treatment. To date, studies disagree on gender differences in clinical improvement, a.e. they appear equivalent for women as well as for men [8].

Tricuspid regurgitation and interventional therapy

Equivalent to the mitral valve, this atrioventricular (AV) vitium can also be divided into primary and secondary etiologies. Primary tricuspid regurgitation (TI) includes a variety of congenital and genetic anomalies (e.g., Ebstein anomaly, tricuspid dysplasia, and myxomatous degeneration resulting in tricuspid valve prolapse) or acquired valve diseases (e.g., endocarditis, rheumatic involvement). Secondary TI is most often the result of right ventricular dilatation or incomplete leaflet coaptation (tethering/tendering). In principle, the anatomic variation of tricuspid valve morphologies is more pronounced than in other valves, making sex distribution difficult to map. Nevertheless, specific etiologies including congenital TI, right-sided endocarditis, carcinoid heart, and pacemaker-related TI are more common in men [1]. Women, on the other hand, appear to have a higher prevalence of relevant tricuspid regurgitation [9], which is also more rapidly progressive after initial diagnosis compared with men. Here, atrial fibrillation appears to be an independent risk factor. A possible explanatory model could lie in the anatomy of the annulus, which is more elastic in men because more myocardium is embedded. In addition, TI is more likely to be associated with left-sided vitiation in female patients, whereas LV dysfunction seems to be more often a causative factor in men.

Because outcome in secondary TI is strongly linked to left heart disease, this explains the higher and sex-independent all-cause mortality in this population. Accordingly, the majority of patients with relevant TI are thought to be at increased surgical risk and rarely undergo surgery for isolated TI, bringing the need for transcatheter tricuspid valve intervention (TTVI) to the forefront in recent years. Since this is a comparatively young interventional procedure, long-term results remain to be seen. However, initial results demonstrate a sex-independent outcome after TTVI in terms of survival, hospitalization, functional status, and reduction in first-year TI, as well as a survival advantage over drug therapy alone in both women and men [10]. This is also reflected in recent 2-year results, where despite etiologic differences, women and men have equal survival rates after TTVI. Interestingly, however, mortality predictors appear to be sex-specific and, in particular, right ventricular function and right ventricular pulmonary artery coupling (TAPSE/mPAP) appear to be relevant to mortality in women [11].

Conclusion

Due to demographic change, the proportion of valvular heart disease requiring treatment will continue to rise in the coming years, and with it the proportion of women affected, especially as they have a longer life expectancy. Interventional therapies are on the rise and offer treatment options even for patients who can no longer be operated on. A gender-based view and analysis of patient pathways, treatment options, timing, and impact on prognosis will be essential in the future to provide the best possible therapy. To achieve this, the proportion of women in clinical trials must be significantly increased and awareness of prevalence and symptoms in the clinical setting must be sustainably raised. Integration into continuing medical education is an intrinsic part of this.

Take-Home Messages

• The patient pathway of aortic valve stenosis requires awareness regarding symptomatology, diagnosis, prosthesis selection, and
  Life-time management in women.
• Size- or sex-adjusted parameters may prevent late diagnosis, but valid conclusions regarding transferability/sex-specific outcome require higher inclusion of women in randomized trials.
• Sex-specific predictors and thresholds appear to be particularly relevant to mortality in interventional therapy for tricuspid regurgitation.

Literature:

1. DesJardin JT, Chikwe J, Hahn RT, et al: Sex Differences and Similarities in Valvular Heart Disease. Circ Res 2022 Feb 18; 130(4): 455-473.
2. Nkomo VT, Gardin JM, Skelton TN, et al: Burden of valvular heart diseases: a population-based study, Lancet 368 (2006), 1005-1011.
3. Toyofuku M, Taniguchi T, Morimoto T, et al: Sex differences in severe aortic stenosis- clinical presentation and mortality, Circ J 81 (2017); 1213-1221, 10.1253/circj.CJ-16-1244.
4. Treibel TA, Kozor R, Fontana M, et al: Sex dimorphism in the myocardial response to aortic stenosis, JACC Cardiovasc. Imaging 11 (2018): 962-973.
5. Aggarwal SR, Clavel MA, Messika-Zeitoun D, et al: Sex differences in aortic valve calcification measured by multidetector computed tomography in aortic stenosis, Circ Cardiovasc. Imaging 6 (2013): 40-47.
6. Avierinos JF, Inamo J, Grigioni F, et al: Sex differences in morphology and outcomes of mitral valve prolapse. Ann Intern Med 2008; 149: 787-795.
7. Kosmidou I, Lindenfeld J, Abraham WT, et al: Sex-Specific Outcomes of Transcatheter Mitral-Valve Repair and Medical Therapy for Mitral Regurgitation in Heart Failure. JACC Heart Fail 2021 Sep; 9(9): 674-683.
8. Park SD, Orban M, Karam N, et al: EuroSMR Investigators. Sex-Related Clinical Characteristics and Outcomes of Patients Undergoing Transcatheter Edge-to-Edge Repair for Secondary Mitral Regurgitation. JACC Cardiovasc Interv 2021 Apr 26; 14(8): 819-827.
9. Singh JP, Evans JC, Levy D, et al: Prevalence and clinical determinants of mitral, tricuspid, and aortic regurgitation (the Framingham Heart Study). Am J Cardiol 1999; 83: 897-902.
10. Scotti A, Coisne A, Taramasso M, et al: Sex-related characteristics and short-term outcomes of patients undergoing transcatheter tricuspid valve intervention for tricuspid regurgitation. Eur Heart J 2023 Mar 7; 44(10): 822-832.
11. Fortmeier V, Lachmann M, Körber MI, et al: Sex-Related Differences in Clinical Characteristics and Outcome Prediction Among Patients Undergoing Transcatheter Tricuspid Valve Intervention. JACC Cardiovasc Interv 2023 Apr 24; 16(8): 909-923.

CARDIOVASC 2023; 22(3): 10-12