Multivalvular disease (MVD), defined as the combination of stenotic or regurgitant lesions of two or more cardiac valves, is increasingly frequent in clinical practice, presenting in 10% of patients undergoing valvular surgery. Nevertheless, it is still poorly studied (1). Aortic stenosis (AS) is the second most common valvular disease in the western world after mitral regurgitation (MR), affecting 2% of the population between 65 and 75 years and 6% of those older than 75 years (2), and is frequently associated combined with other valvular disease or mixed with some degree of aortic regurgitation (AR), with physio-pathological and clinical implications.

Nowadays, degenerative etiology comprises the vast majority of cases; however, when associated with other valve diseases, rheumatic heart disease should be considered as it is the most common cause of MVD worldwide; typically, rheumatic heart disease affects younger patients (2) and has a faster progression than the degenerative counterpart, involving almost invariably the mitral valve (3). The clinical impact of combined valve disease depends on hemodynamic interactions between the valve lesions and, more specifically, on the severity, combination, and chronicity of each valvular defect. All these factors may alter loading conditions and ventricular function with relevant consequences when assessing the severity of valvulopathies, currently based on the concept of excess mortality threshold. Indeed, in some settings, apparently non-severe lesions may lead to severe hemodynamic imbalance when combined with other valvular defects with important clinical implications (4). Methods commonly used for the quantification of stenosis or regurgitation have been validated in patients with single-valve disease, and until today the major treatment trials often excluded concomitant relevant valvular disease. In addition, one of the most pivotal issues in the management of patients with MVD is to identify the optimal timing for intervention when the benefits of the procedure most outweigh the risks, considering that these patients generally have many comorbidities and that surgery in these patients is associated with high operative mortality (5). Expertise in cardiac surgery, transcatheter interventions, and cardiac imaging is critical in this field. In the past, the surgical indication represented the crucial decision moment in which cardiologists used to indicate whether one or more valves needed to be treated. Now things have changed, and thanks to percutaneous procedures, it is possible to treat one valve at a time, evaluating the new hemodynamic balance from time to time and giving the opportunity better to understand the physiopathology of combined valvulopathies (6).

The aim of this review is to summarize the most important pathophysiological mechanisms underlying AS when associated with MR, MS, AR, and tricuspid regurgitation (TR). We will focus on echocardiography, clinical implications, and the most important treatment strategies. Although helpful in diagnosis and prognosis in selected cases of multivalvular diseases, this review does not discuss the application of multimodality imaging (TC, MRI, stress echocardiography).

According to different studies, MR is reported in 20–80% of patients with AS. In the PARTNER trial, about 20% of patients undergoing transcatheter or surgical aortic valve replacement for severe AS presented concomitant moderate to severe MR (7). In most cases, MR in these patients is not evaluated severely, and until the last decades, the pathophysiological and clinical interaction between these two entities was not fully understood. Things have changed as some studies described essential consequences in morbidity and mortality (8).

Functional MR is present in 63% of patients with AS (9) and is likely to improve after aortic valve replacement more significantly than degenerative MR. Thus, a careful evaluation of the MR mechanism is crucial for the decision of whether a simultaneous operation on the mitral valve is necessary (10) considering that mixed mechanisms are frequent, especially in older patients with heavy mitral calcification and wall motion defects, not uncommon in patients with AS. By note, attention should be paid to obstructive hypertrophic cardiomyopathy that may present with high gradients in the LVOT and MR secondary to systolic anterior movement (11).

AS is a condition classically associated with increased afterload, but when concomitant MR is present, the left ventricle is somewhat larger as volume overload is also present. MR reduces afterload and reduces stroke volume significantly, causing a low flow-low gradient condition with the risk of underestimating the severity of AS (12, 13). Rossi et al. showed that MR was generally mild in severity when functional in origin, with an effective regurgitant orifice (ERO) smaller than 0.2 cm² in 91% of the cases. Anyway, the presence of MR may falsely underestimate the transvalvular aortic valvular gradient even if volumetrically not relevant (9).

An ERO as low as 0.2 mm² carries a probability of 30% developing a low-flow low-gradient condition, with the risk increasing with the MR severity (12). Simultaneously, the presence of MR reduces total afterload, increasing the ejection fraction which may hide subclinical myocardial dysfunction (14).

The impact of functional MR in AS was also studied with an artificial model that allowed to regulate the flow and the aortic valve area, demonstrating that both the mean pressure gradient and maximal velocity are significantly reduced by a reduction of forward stroke volume from concomitant severe MR. However, the functional aortic valve area appeared to be a reliable even in case of severe MR (15).

Subsequently, these patients may also develop atrial fibrillation with preload impairment due to loss of the “atrial kick,” a poorly hemodynamically tolerated condition in these patients per se associated with left atrial enlargement and MR progression. Generally, symptoms do not always correlate with the AS severity and LV function (16, 17); concomitant MR is associated with poorer outcomes (9).

Generaux et al. propose a new staging system of AS that attributes severity considering the presence of concomitant MR, impaired left ventricular function, pulmonary hypertension, and TR (18). This system confirmed that MR provides incremental predictive value in patients with asymptomatic moderate to severe AS undergoing surgical and percutaneous aortic valve replacement (AVR) (19). An incremental prognostic value over clinical characteristics was shown by incorporating left ventricular global longitudinal strain into the staging classification (20). Pighi et al. recently reported that cardiac damage classification is significantly associated with a higher incidence of acute kidney injury following percutaneous AVR and that it is an independent predictor of 12-month all-cause mortality only in patients with advanced stages of extravalvular cardiac damage (21) (Figure 1).

TR is common in patients with left-side valvular disease and more specifically in 40% of patients with severe degenerative AS (38). Elevated left ventricular diastolic dysfunction and increased left atrial pressures due to AS reflect backward pressure to the pulmonary veins with the remodeling of the alveolar–capillary membrane and development of pulmonary hypertension (39). Chronic pulmonary congestion and pulmonary hypertension increase right ventricular afterload, and TR is caused by right atrium dilatation and leaflet mal-coaptation (40, 41). Eventually, these changes may promote atrial fibrillation, a condition per se associated with TR. In very advanced disease, backward flow and right ventricular dysfunction may cause a low-flow condition. For many years, the tricuspid valve has been regarded as the “forgotten valve” with a limited impact on hemodynamics, and management was conservative (42).

However, in the past decades, TR was found to have a negative prognostic impact in patients undergoing AVR (43–46). It is still not clear if TR is directly related to mortality or is a marker of advanced underlying disease (47). Patients with associated TR and AS usually are sicker with more comorbidities, more symptoms, and worse outcomes in terms of heart failure, hospitalization, and mortality. It is still debated if these patients would benefit from a combined intervention such as AVR and tricuspid annuloplasty or transcatheter tricuspid valve procedure (48) (Figure 1).

The association of MS and AS may be rheumatic in origin or the combination of degenerative calcific disease-causing hypomobility of the mitral valve leaflets and the aortic cusps. Finally, a variety of these causes is possible, especially in the presence of bicuspid aorta or radiation injuries (59, 60). In patients undergoing TAVI, concomitant MS is reported in 18% of patients (60).

The combination of double-valve stenosis in series is poorly hemodynamically tolerated, and usually, patients become symptomatic at an early stage of the disease (61). Mitral stenosis may severely impair preload and left ventricular filling, already damaged in a hypertrophic left ventricle, leading to a reduction in cardiac output and a paradoxical low-flow condition (62). Thus, the presence of AS may be somewhat masked. Clinical findings do not help as generally these patients present with dyspnea, a very vague symptom. Also, severe left atrial enlargement and atrial fibrillation are very common in this population.

However, the recognition of this double-valve pathology has important clinical implications as a correction of severe MS without treating AS first could impose a sudden increase in filling pressure to a small and hypertrophic left ventricle resulting in pulmonary edema.

Degenerative MS usually has a slower course than rheumatic, milder in severity MS and generally affects the aging population (63). The presence of MS associated with AS impacts mortality following both surgical AVR and TAVI (60, 64). Also, the presence of mild MS without documented secondary pulmonary hypertension or manifest valvular atrial fibrillation has a negative prognostic impact on TAVI (64) (Figure 1).

The combination of AS and AR is part of the mixed aortic valve disease. About 75% of patients with a primary diagnosis of AS have some degree of concomitant AR. Conversely, 17.9% of patients with predominant AR have AS (2). Combined AS and AR are frequently observed in cases of bicuspid anatomy and rheumatic heart disease. Current guidelines are based primarily on the natural history of isolated AS or AR. Therefore, it is difficult to select those patients who could benefit from early valvular surgery. Nowadays, the management of this condition is determined by the severity of the dominant lesion. However, this approach is certainly oversimplifying (71).

AS causes ventricular hypertrophy while the regurgitation causes volume overload and ventricular dilatation, resulting in eccentric hypertrophy depending on the severity of each lesion (76). In case of significant AR, diastolic pressure is elevated with left ventricle filling on a steeper portion of the pressure–volume curve, potentially causing earlier onset of symptoms than if concomitant AR are not present (77).

In order to keep up with the elevated stroke volume, the ventricle progressively dilatates, producing an increasing wall tension that further worsens dilatation and reduces coronary perfusion (78). All these factors may explain earlier symptoms (79). On the other hand, compared to pure AR, concomitant AS limits the degree of LV dilation in response to the volume overload and the progression of AS tends to be slower.

Of note, in these patients AS severity has a predominant role in clinical outcomes (76).

This may suggest that a small degree of AR may put the severity of the valve disease at a higher stage, meaning strict monitoring for patients with moderate mixed aortic valve disease similar to those with isolated severe AS (Figure 1).

The presentation of aortic valve stenosis in the context of multiple valve disease is a highly prevalent condition, and it will increase over time with the aging population.

The hemodynamic interactions between AS and other valve diseases depend on the specific combination of valve lesions and may result in diagnostic pitfalls at echocardiography; therefore, other imaging modalities may be helpful. The heart valve team must integrate various parameters into the diagnosis and management strategy, including suitability for single or multiple transcatheter valve procedures.

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