Mixed Aortic Valve Disease: A Double Trouble

Despite the relatively high prevalence of mixed aortic valve disease, i.e. combined aortic stenosis (AS) and aortic regurgitation (AR), there is very little data on the outcome and management of this entity.1Nishimura RA Otto CM Bonow RO et al.AHA/ACC focused update of the 2014 AHA/ACC guideline for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association task force on clinical practice guidelines.J Am Coll Cardiol. 2017; 70 (doi: 10.1016/j.jacc.2017.03.011.): 252-289Google Scholar, 2Zilberszac R Gabriel H Schemper M et al.Outcome of combined stenotic and regurgitant aortic valve disease.J Am Coll Cardiol. 2013; 61 (doi: 10.1016/j.jacc.2012.11.070.): 1489-1495Google Scholar, 3Egbe AC Poterucha JT Warnes CA Mixed aortic valve disease: midterm outcome and predictors of adverse events.Eur Heart J. 2016; 37 (doi: 10.1093/eurheartj/ehw079.): 2671-2678Google Scholar Indeed most previous studies that have examined the outcome of patients with AS generally excluded those with concomitant AR, and vice versa. Furthermore, the presence of concomitant AR may interact with the quantitation of AS severity, and vice versa. In a recent nationwide epidemiology study conducted in Sweden, multiple valvular heart diseases represented 10.4% of all valvular disease cases and mixed aortic valve disease accounted for 18.7% of multiple disease cases.4Andell P Li X Martinsson A et al.Epidemiology of valvular heart disease in a Swedish nationwide hospital-based register study.Heart. 2017; 103 (doi: 10.1136/heartjnl-2016-310894.): 1696-1703Google Scholar In the elegant study published in this issue of Structural Heart, Sorajja et al. retrospectively analyzed the data of 308 asymptomatic patients with moderate or severe AS and compared outcomes according to the presence and severity of concomitant AR.5Sorajja P, Nelson P, Garberich R, Bradley SM, Athappan G, Bae R, Harris K, Lesser J, Tindell L, Farivar RS, Goessl M. Clinical Impact of Chronic Aortic Regurgitation in Asymptomatic Patients with Native Aortic Valve Stenosis. Struct Heart. 2018; this issue. doi:10.1080/24748706.2018.1479078.Google Scholar For patients with moderate AS, the 4-year survival free of death, cardiac symptoms, or aortic valve replacement (AVR) was 47.1%, 30.9%, and 29.0% for none, mild, and moderate/severe AR, respectively (p = 0.02) and this association remained significant after adjustment for morbidities in multivariable analyses. Mild AR and moderate/severe AR were, respectively, associated with a 1.8- and 2.0-fold increase in the risk of adverse events in asymptomatic patients with moderate AS. On the other hand, concomitant mild or moderate/severe AR was not significantly associated with increased risk of death, symptoms, and AVR in asymptomatic patients with severe AS. This latter finding is consistent with the study by Egbe et al. where asymptomatic patients with moderate/severe mixed aortic valve disease had similar outcomes compared to those with isolated severe AS.3Egbe AC Poterucha JT Warnes CA Mixed aortic valve disease: midterm outcome and predictors of adverse events.Eur Heart J. 2016; 37 (doi: 10.1093/eurheartj/ehw079.): 2671-2678Google Scholar Hence the main message of the present article by Sorajja et al.5Sorajja P, Nelson P, Garberich R, Bradley SM, Athappan G, Bae R, Harris K, Lesser J, Tindell L, Farivar RS, Goessl M. Clinical Impact of Chronic Aortic Regurgitation in Asymptomatic Patients with Native Aortic Valve Stenosis. Struct Heart. 2018; this issue. doi:10.1080/24748706.2018.1479078.Google Scholar is that the presence of concomitant AR increases the risk of progression to symptoms and need for AVR in patients with moderate AS but not in those with severe AS. That asymptomatic patients with severe AS have comparable long-term outcomes regardless of AR severity may appear, at first glance, counter-intuitive. This intriguing finding may be related to the fact that once AS has reached the severe stage, it becomes the main determinant of outcomes and thereby occults the effect of concomitant AR. In fact, the 4-year event-free survival rate was low (~ 30%) and similar in patients with severe AS and no AR versus those with moderate AS and moderate/severe AR. Hence, the addition of a moderate/severe AR, or even a mild AR, to a moderate AS yields to outcome similar to that of isolated severe AS. On the other, the addition of AR to a severe AS does not appear to change the natural evolution of the disease. Even if not statistically different, the patients with severe AS and moderate/severe AR, nonetheless, harbored numerically lower event-free survival rates compared to those with severe AS and no AR. The concomitance of severe AS and moderate/severe AR may thus increase the risk of symptoms onset and AVR in some patients. However, in the majority of asymptomatic patients with severe AS, the additional hemodynamic burden related to concomitant AR is likely occulted by the severe AS and does not alter the time to AVR in these patients. Another intriguing finding of this study5Sorajja P, Nelson P, Garberich R, Bradley SM, Athappan G, Bae R, Harris K, Lesser J, Tindell L, Farivar RS, Goessl M. Clinical Impact of Chronic Aortic Regurgitation in Asymptomatic Patients with Native Aortic Valve Stenosis. Struct Heart. 2018; this issue. doi:10.1080/24748706.2018.1479078.Google Scholar is that, in patients with asymptomatic moderate AS at baseline, a mild AR has a significant negative impact on outcomes (adjusted hazard ratio for events: 1.8), which is almost as bad as moderate/severe AR (adjusted hazard ratio: 2.2). This may be related to the fact that patients with moderate/severe AS often develop left ventricular (LV) concentric hypertrophy and advanced diastolic dysfunction with reduced LV compliance. In the present study,5Sorajja P, Nelson P, Garberich R, Bradley SM, Athappan G, Bae R, Harris K, Lesser J, Tindell L, Farivar RS, Goessl M. Clinical Impact of Chronic Aortic Regurgitation in Asymptomatic Patients with Native Aortic Valve Stenosis. Struct Heart. 2018; this issue. doi:10.1080/24748706.2018.1479078.Google Scholar the vast majority of the patients indeed harbored LV concentric remodeling or hypertrophy with relatively small LV cavities at baseline; LV diastolic function was not reported. Hence, the left ventricle of these patients with AS is primarily adapted to pressure overload and may thus not be able to tolerate an even mild aortic regurgitant volume. Figure 1 proposes an algorithm for the management of asymptomatic patients with or without concomitant AR based on the guidelines1Nishimura RA Otto CM Bonow RO et al.AHA/ACC focused update of the 2014 AHA/ACC guideline for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association task force on clinical practice guidelines.J Am Coll Cardiol. 2017; 70 (doi: 10.1016/j.jacc.2017.03.011.): 252-289Google Scholar and the data reported by Sorajja et al.5Sorajja P, Nelson P, Garberich R, Bradley SM, Athappan G, Bae R, Harris K, Lesser J, Tindell L, Farivar RS, Goessl M. Clinical Impact of Chronic Aortic Regurgitation in Asymptomatic Patients with Native Aortic Valve Stenosis. Struct Heart. 2018; this issue. doi:10.1080/24748706.2018.1479078.Google Scholar If the patient has severe AS, there is a high risk of rapid progression to symptoms or systolic heart failure regardless of the presence or absence of concomitant AR. These patients should thus receive a close clinical surveillance with: (1) an echocardiogram to assess AS progression and left ventricular ejection fraction (LVEF), and (2) an exercise treadmill test to assess symptomatic status every 3–6 months. If the patients develop symptoms or LV systolic dysfunction (LVEF< 50%), guidelines recommend to consider AVR (Class I indication). If the patient remains asymptomatic and the surgical risk is low, early “prophylactic” AVR is reasonable according to guidelines (Class IIa). In asymptomatic patients with moderate AS and none/trace AR, the risk of rapid (i.e. within 1 year) progression to symptoms or systolic heart failure is low. Nonetheless, the rate of adverse events increases substantially beyond 1 year according to the study by Sorajja et al.5Sorajja P, Nelson P, Garberich R, Bradley SM, Athappan G, Bae R, Harris K, Lesser J, Tindell L, Farivar RS, Goessl M. Clinical Impact of Chronic Aortic Regurgitation in Asymptomatic Patients with Native Aortic Valve Stenosis. Struct Heart. 2018; this issue. doi:10.1080/24748706.2018.1479078.Google Scholar Hence in these patients, it appears preferable to perform a clinical and echocardiographic follow-up every year rather than every 1–2 years as recommended in the guidelines.1Nishimura RA Otto CM Bonow RO et al.AHA/ACC focused update of the 2014 AHA/ACC guideline for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association task force on clinical practice guidelines.J Am Coll Cardiol. 2017; 70 (doi: 10.1016/j.jacc.2017.03.011.): 252-289Google Scholar In patients with moderate AS and concomitant mild or moderate/severe AR, the risk of progression to symptoms or LV systolic dysfunction is similar or close to that of severe AS and these patients should thus receive close surveillance with an echocardiogram and exercise testing every 3–6 months (Figure 1). If on the basis of the echocardiographic assessment, the overall severity of the mixed aortic valve disease is considered severe and the patient develops symptoms or LV systolic dysfunction, AVR is indicated (Class I). Some studies suggest that the best parameters to assess the overall severity of mixed aortic valve disease is the peak aortic jet velocity or the mean transaortic pressure gradient.2Zilberszac R Gabriel H Schemper M et al.Outcome of combined stenotic and regurgitant aortic valve disease.J Am Coll Cardiol. 2013; 61 (doi: 10.1016/j.jacc.2012.11.070.): 1489-1495Google Scholar,3Egbe AC Poterucha JT Warnes CA Mixed aortic valve disease: midterm outcome and predictors of adverse events.Eur Heart J. 2016; 37 (doi: 10.1093/eurheartj/ehw079.): 2671-2678Google Scholar Indeed the velocity and gradient will both increase as a result of AS and also AR (because of the increase in transvalvular flow related to the regurgitant volume). A peak velocity ≥ 4 m/s and/or a mean gradient ≥ 40 mmHg would thus suggest severe mixed aortic valve disease. If the patient harbors severe aortic valve disease according to these criteria and remains asymptomatic with preserved LVEF, AVR may be considered (Class IIa), as in asymptomatic patients with isolated severe AS (Figure 1). In the present study by Sorajja et al.5Sorajja P, Nelson P, Garberich R, Bradley SM, Athappan G, Bae R, Harris K, Lesser J, Tindell L, Farivar RS, Goessl M. Clinical Impact of Chronic Aortic Regurgitation in Asymptomatic Patients with Native Aortic Valve Stenosis. Struct Heart. 2018; this issue. doi:10.1080/24748706.2018.1479078.Google Scholar peak aortic jet velocity, surprisingly, did not come out as a predictor of events in patients with moderate or severe AS and LVEF was, with the severity of AR, the only baseline echocardiographic parameter associated with outcomes. This intriguing finding may be related, at least in part, to the fact that the authors performed separate analyses in the subset of moderate AS and in that of severe AS.5Sorajja P, Nelson P, Garberich R, Bradley SM, Athappan G, Bae R, Harris K, Lesser J, Tindell L, Farivar RS, Goessl M. Clinical Impact of Chronic Aortic Regurgitation in Asymptomatic Patients with Native Aortic Valve Stenosis. Struct Heart. 2018; this issue. doi:10.1080/24748706.2018.1479078.Google Scholar Ongoing randomized trials such as the EARLY-TAVR trial or the EvoLVeD trial are comparing the timing of AVR, i.e. early AVR versus clinical surveillance with AVR performed when symptoms develop, in patients with asymptomatic severe AS. However, the vast majority of patients with moderate AS and concomitant AR are not eligible for the EARLY-TAVR trial, which requires a peak jet velocity ≥ 4 m/s and an AVA< 1.0 cm2 for inclusion. These patients may, however, be eligible for the EvoLVeD trial that only requires a peak aortic jet velocity > 3.5 m/s as inclusion criteria. This study by Sorajja et al.5Sorajja P, Nelson P, Garberich R, Bradley SM, Athappan G, Bae R, Harris K, Lesser J, Tindell L, Farivar RS, Goessl M. Clinical Impact of Chronic Aortic Regurgitation in Asymptomatic Patients with Native Aortic Valve Stenosis. Struct Heart. 2018; this issue. doi:10.1080/24748706.2018.1479078.Google Scholar suggests that mixed aortic valve disease, i.e AS + AR, is a double trouble for both the left ventricle and the patient. The coexistence of ≥ mild AR puts the asymptomatic patients with moderate AS at the same and high risk of rapid progression to symptoms compared to those with isolated severe AS. On the other hand, the presence of concomitant AR does not appear to significantly change the natural evolution of a patient who already has reached the severe AS. These findings suggest that close clinical surveillance with echocardiographic evaluation and exercise testing every 3–6 months should be considered in asymptomatic patients with severe AS (with or without AR) as well as in those with moderate AS and ≥ mild AR. Further studies are needed to determine whether an earlier AVR would improve outcomes in patients with severe mixed aortic valve disease.