Degenerative AS is a progressive disease with a spectrum ranging from mild aortic valve thickening without obstruction to left ventricular outflow, termed aortic valve sclerosis, to severe valve calcification with outflow obstruction requiring valve replacement [1, 2]. AS is the most common type of valvular heart disease requiring valve replacement [1, 2]. Epidemiologic data from the Tromsø study in Norway has demonstrated that the prevalence of AS increases with age, being 0.2% in general population <60 years of age, 3.9% among subjects aged 70–79 years and 9.8% among subjects >80 years of age [3]. From the Cardiovascular Health study in the US, it was demonstrated that among subjects over 65 years of age, aortic valve calcification was 50% less common in women than in men, and progression from aortic valve sclerosis to AS was also less common in women [4]. In their study, the association of cardiovascular (CV) risk factors and incident AS was also demonstrated: smoking and hypertension were associated with a 35% respectively 20% increased risk for incident AS [4]. Aortic stenosis due to congenital abnormality is three times more common among men than women [5], while degenerative AS is more common among women with a women to men ratio of 1–0.76 [6].

In AS progressive calcification of the valve cusps lead to increasing obstruction of left ventricular(LV) outflow tract with secondary left ventricular hypertrophy [1, 2]. In AS patient with concomitant hypertension or obesity, LV hypertrophy may be present even in subjects with mild AS [7, 8]. Presence of left ventricular hypertrophy (LVH) was recently demonstrated as an independent marker of impaired prognosis in AS, independent of the severity of the disease [9]. Aortic stenosis is clinically suspected when a systolic ejection murmur is heard parasternally, typically in the second right intercostal space, and often radiating to the carotid arteries. A severe AS may be suspected from auscultation if the second heart sound is attenuated or absent in subjects >70 years.

Echocardiography is the first line test to confirm the diagnosis and grade the severity of the AS, thereby making the foundation for further management of the individual patient [1, 2]. By echocardiography, peak aortic jet velocity, mean transvalvular gradient and effective valve opening area are used for grading of AS severity [1, 2]. In subjects with small body size, indexation of the valve opening area for body surface area is recommended to avoid overestimation of AS severity, while in obese subjects, such indexation may lead to overestimation of the AS severity [10]. The recommended cut-off values for mild, moderate and severe AS are similar for women and men.

The dimension of the aortic root may significantly impact the accuracy of the severity grading of AS [11]. The impact of a small aortic root on grading of AS is most prominent in milder degree of AS, and diminishes with increasing AS severity [11]. Women have a smaller aortic root dimension than men in normal population [12, 13], and a small aortic root is particularly common among elderly women with AS, and also associated with atherosclerosis in the proximal aorta [12]. In patients with mild AS and a small aortic root dimension, the actual AS severity may be overestimated by 30% if the aortic valve area is not adjusted for post-stenotic pressure recovery. The improved CV risk prediction in AS patients by pressure recovery adjusted aortic valve area (energy loss index) is well demonstrated [14]. However, irrespective of the AS severity, presence of a small aortic root is associated with increased risk for CV events and death in patients with asymptomatic AS [12]. The typical AS patient with a small aortic root is an elderly woman with atherosclerosis and reduced systemic arterial compliance.

In patients with AS, progression rate of the disease does not differ between women and men [15]. However, there is a large variation in individual disease progression rate among AS patients, and in particular comorbidities like diabetes, atherosclerosis and renal disease may all lead to more rapid progression. Serial assessment of disease severity by echocardiography is therefore recommended in the guidelines [2].

As a consequence of AS progression, increasing pressure overload of the LV occurs with compensatory structural changes in LV. Typically, concentric LVH is the most common LV geometric pattern in severe AS [15]. Distinct sex-differences in LV adaptation during progression of AS have been described in patients with severe, symptomatic AS, including women having larger LV wall thicknesses and more concentric LV geometry with smaller internal cavity and larger relative wall thickness than men [16]. However, these differences were not found in patients with moderate, asymptomatic AS [17]. It is well documented that women, independently of LV size, also preserve better LV systolic function than men during progression of AS, whether measured as ejection fraction, midwall function or global longitudinal strain [16–19]. These sex-specific clinical and echocardiographic findings are mirrored by findings in experimental studies in AS, documenting more endocardial fibrosis and abnormal collagen architecture with increased cross-hatching in men [19], and sex-specific activation of pro-fibrotic genes resulting in more interstitial fibrosis in men [20]. Furthermore, a sex- and estrogen-dependent regulation of a fibrosis-related miRNA network was reported in a pressure overload model in mice [21].

While most women with AS may be accurately diagnosed by echocardiography, discordant grading (moderate AS by mean gradient and severe AS by aortic valve area) may occur in up to 30% of individuals [11]. In these patients, low transvalvular flow is often present, whether assessed by stroke volume index <35 mL/m² or by trans-aortic flow rate <200 mL/s [1, 22]. In such patients, additional tests including exercise testing, pharmacological stress-echocardiography and multidetector computed tomography (CT) scanning of the aortic valve may be indicated for accurate grading of AS severity and presence of symptoms. Such advanced diagnostic testing in AS is best performed at experienced heart valve centres.

CT of the aortic valve has revealed that calcification is more pronounced in men than in women independent of the severity of the AS [23]. With CT, calcification is measured by Agatston score. Recently, sex specific cut-off values for CT Agatston identifying severe AS (>1200 AU in women and >2000 AU in men) were prognostically validated [24]. These cut-off values may be used for detection of severe AS in patients with low flow and discordantly graded severe AS by conventional echocardiography.

Aortic stenosis is asymptomatic until severe hemodynamic pressure overload is present. When the cardinal symptoms of angina pectoris, syncope and heart failure appear in patients with severe AS, aortic valve replacement is indicated. It is well recognized that perioperative mortality and complications are higher in women than in men undergoing surgical aortic valve replacement (SAVR) [2]. This has been attributed to higher age and comorbidity burden in women including more hypertension and obesity and the usually smaller body size in women [2]. In contrast, concomitant coronary artery disease and renal impairment are more common in men than in women with AS. Nowadays transcatheter aortic valve replacement (TAVR) may be an option for AS patients who cannot be treated surgically or who have an inacceptable high operative risk [2]. The PARTNER trial recently documented that in high risk patients with AS, treatment with TAVR and SAVR had a comparable 1-year risk for combined mortality and major stroke [25]. A retrospective analysis of the 2-year outcome in the PARTNER trial documented the superior outcome with TAVR in women, in particular when femoral access was used [26]. However, men in the PARTNER trial had a higher prevalence of diabetes, renal impairment and previous coronary artery bypass grafting, all factors that may have impacted the 2-year outcome beyond the type of treatment. A smaller study in patients with severe AS, documented that lack of postoperative regression of LV hypertrophy was particularly associated with reduced survival in women [27]. Therefore, a prospective study designed to assess sex differences in outcome after TAVR is warranted.

In Europe, mitral regurgitation (MR) is the second most common valve disease requiring surgery [2]. Pathological changes in any of the mitral valve components may lead to MR.

Mitral regurgitation may be primary (due to structural disease of the valve itself) or secondary (due to regional or global functional disease in the LV or dilated left atrium) [1, 2]. The most common cause of primary MR in developed countries is a mitral valve prolapse. A mitral valve prolapse results from a disproportion between the valve’s connective elements (leaflets, annulus and chordae) and the muscular support (papillary muscle and left ventricular myocardium) [28]. Mitral valve prolapse may be a primary condition or secondary to several disorders, including heritable disorders like the Marfan syndrome or the Ehlers-Danlos syndrome, ostium secundum atrial septal defect, anorexia nervosa or cardiomyopathy [28]. Other causes of primary MR are severe myxomatous degeneration with gross redundancy of both leaflets and the chordal apparatus (Barlow’s disease) and fibro-elastic deficiency disease, in which lack of connective tissue leads to chordal rupture or less common causes like connective tissue disorders, rheumatic heart disease, cleft mitral valve, radiation heart disease, annulus calcification or infectious endocarditis [1]. Secondary MR is caused by idiopathic myocardial disease or coronary artery disease. In patients with coronary artery disease, mitral annulus dilatation secondary to post-myocardial infarction remodelling of the LV or ischemic rupture of chordae may occur.

Primary MR is more common among women, while secondary MR is more common among men. Both leaflets and annulus are normally larger in women than in men, probably explaining the somewhat higher prevalence of mild mitral valve prolapse in women [29]. Mitral regurgitation is found in around 20% of adult general population [30]. In the population based Strong Heart Study, presence of MR was independently associated with female sex, older age, lower body mass index, renal dysfunction, as well as with prior myocardial infarction or other mitral valve disease [31].

A MR is clinically suspected when a holosystolic murmur is heard at the apex of the heart and radiating to the axillary region. The MR must be at least moderate severe to be diagnosed by auscultation. Echocardiography is recommended as first test to diagnose the cause and severity of a MR. There are no sex differences in guideline recommendations for diagnosis or grading of MR [1, 2].

A combination of transthoracic (TTE) and transesophageal (TEE) echocardiography may be necessary to detect the cause of the MR as well as consequences for LV and atrial structure and function and presence of secondary pulmonary hypertension. Three-dimensional TTE is superior to conventional 2-dimensional TTE in visualization of valve structure and function. Three-dimensional TEE is used for guidance during catheter-based mitral valve procedures.

Assessment of MR involves detailed evaluation of its etiology and mechanism. The mechanism of the MR may be described by the Carpentier’s classification of leaflet motion: type 1 normal leaflet motion (e.g. annular dilatation, leaflet perforation or mitral valve cleft), type 2 excessive leaflet motion (i.e. chordal elongation or rupture, prolapse) and type 3 restricted leaflet motion (i.e. coronary artery disease, LV dilatation with leaflet tethering) [32]. In patients with type 3 MR due to posterior myocardial infarction, the regurgitation jet is usually eccentric with posterior leaflet tethering. In patients with type 3 MR due to previous anterior myocardial infarction or non-ischemic cardiomyopathy, the regurgitation jet is usually central. Multiple variables with somewhat different criteria are integrated in grading of primary and secondary MR, including qualitative (mitral valve morphology, colour and continuous wave Doppler), semiquantitative (vena contracta width, mitral inflow, pulmonary venous flow), quantitative (regurgitant volume, effective regurgitant orifice area) and supportive measurements (LV and left atrial structure and function and pulmonary arterial pressure).