Natural History of Mixed Aortic Valve Disease

Abstract & Commentary

By Andrew J. Boyle, MBBS, PhD. Assistant Professor of Medicine, Interventional Cardiology, University of California, San Francisco

Source: Zilberszac R, et al. Outcome of combined stenotic and regurgitant aortic valve disease. J Am Coll Cardiol 2013;61:1489-1495.

The prevalence and natural history of aortic stenosis (AS) are well known. However, there is a paucity of data about the natural history of combined AS and aortic regurgitation (AR). AS and AR confer differing types of stress on the left ventricle, and it stands to reason that the combination may result in worse outcomes than either AS or AR alone. To test this hypothesis, Zilberszac and colleagues prospectively followed asymptomatic patients with at least moderate AS and at least moderate AR, and preserved left ventricular (LV) function (LV ejection fraction ≥ 55%). They describe the clinical outcomes and predictors of progression to requirement for surgical aortic valve replacement (AVR).

The study involved 71 consecutive patients; 21 were women and the mean age was 52 ± 17 years. They excluded patients with concomitant moderate or severe lesions involving other valves and those with symptoms. Thirty-five patients had a bicuspid aortic valve, the rest had degenerative calcific AS; there were no cases of rheumatic valve disease. Eight patients had concomitant coronary artery disease, 31 had hypertension, 10 had diabetes, and 22 had dyslipidemia. All measurements were made by echocardiography. Multiple transducer positions were used to record aortic valve peak jet velocity (AV-Vel) and aortic valve area was calculated using the continuity equation. Severe AS was defined by an aortic valve area ≤ 1.0 cm2 and moderate AS by a valve area of 1.0-1.5 cm2. Severe AR was defined by a vena contracta of more than 6 mm and a prominent diastolic flow reversal in the descending aorta. Moderate AR was defined by a vena contracta of 3-6 mm. Importantly, when grading lesion severity, the authors took into account the effects of AS and LV hypertrophy on the measurement of AR, and the increased flow in the presence of AR on increasing AV-Vel when grading AS. The patients were followed every 6 months in a dedicated valve clinic. They were referred for valve replacement if they met criteria for valve replacement for either AS or AR, and exercise testing was used in a selected minority of patients.

The patients were followed for a median of 8.9 years. During that time, 50 patients developed an indication for AVR, and the development of symptoms was the most common indication. Forty-three actually underwent valve replacement surgery, six refused surgery, and one was denied surgery because of limited life expectancy from metastatic cancer. Overall event rates were high with an event-free survival [defined as freedom from cardiovascular death and need for valve replacement] for the entire patient population of 82 ± 5%, 62 ± 6%, 49 ± 6%, 33 ± 6%, and 19 ± 5% at 1, 2, 3, 4, and 6 years, respectively. Three patients died after they developed indications for surgery but refused. There was one noncardiac death, one operative death, and no postoperative deaths. Interestingly, aortic valve area and severity of AR did not predict progression. AV-Vel independently predicted event-free survival. Patients with AV-Vel 3.0 to 3.9 m/s who did not progress had an excellent prognosis, but rapid progression of AV-Vel and subsequent clinical events were common. Progression of AV-Vel resulted in a hazard ratio [HR] of 3.3 for clinical events (P < 0.001). The presence of concomitant coronary artery disease was the other independent predictor of events (HR 4.01; P = 0.01). The authors conclude that asymptomatic patients with combined aortic valve disease can be safely followed until surgical criteria defined for AS, AR, or the aorta are reached. However, high event rates can be expected, even in younger patients and those with only moderate disease. AV-Vel, which reflects both stenosis and regurgitant severity, provides an objective and easily assessable predictive parameter.


This study, although small, is an important contemporary view of mixed aortic valve disease. There were no cases of rheumatic valve disease in this cohort, which reflects the shifting etiology of aortic valve disease from mainly rheumatic in previous decades to predominantly degenerative. Despite the young age of this cohort and the fact that this was predominantly moderate disease, there was a high rate of progression to require surgery. Compared to historical controls with isolated AS and AV-Vel 3.0-3.9, patients with mixed AS and AR and AV-Vel 3.0-3.9 have lower event-free survival rates, suggesting more rapid progression of mixed disease.

AV-Vel predicted event-free survival, yet aortic valve area did not. In mixed aortic valve disease, the assessment of severity of either lesion can be confounded by the coexisting lesion. AV-Vel measures not only the increased velocity through the stenotic valve, but also reflects the increased volume from AR. Thus, it has contributions from both lesions, and appears to be an excellent tool in stratifying the overall hemodynamic load of combined AS and AR. My take-home messages from this study are that patients with asymptomatic, moderate, or greater mixed aortic valve disease should have close follow-up because there is a high rate of progression, and that AV-Vel is an integral part of the assessment of these patients.