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Abstract
Objective Many patients with aortic stenosis (AS) have coexisting aortic regurgitation (AR). However, few data exist regarding its clinical significance and prognostic value. The aim of this study was to examine the effect of concomitant significant AR on clinical outcomes in patients with non-surgically treated severe AS.
Design A single centre, retrospective cohort study.
Patients and methods We retrospectively reviewed 306 consecutive patients (age, 72±11 years) with severe AS in whom non-surgical management was primarily planned at our institution between January 1999 and December 2011. There were 74 patients with moderate or severe AR (ASR) and 232 patients without significant AR (isolated AS). Clinical outcomes were compared between the two groups.
Main outcome measures All-cause mortality and valve-related events, were defined by a composite of cardiac death and hospitalisation because of heart failure.
Results The mean follow-up period was 4.5±3.3 years. Although the overall survival was comparable between the groups (p=0.07), the event-free survival, defined as survival without cardiac death or hospitalisation because of heart failure, was significantly worse in ASR than in isolated AS (p=0.02). Concomitant AR was an independent predictor of adverse events in patients with severe AS (HR, 2.10; p=0.003). Among patients who did not eventually undergo aortic valve replacement, ASR was associated with significantly worse survival and event-free survival than isolated AS (p=0.002 and p=0.03, respectively).
Conclusions Concomitant AR might worsen the prognosis of severe AS. Greater consideration of surgery might be beneficial in patients with ASR.
- Valvular disease
- coronary artery disease
- aorta
- great vessels and trauma
- dissection
- aortitis
- cardiac surgery
- surgery-valve
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- Valvular disease
- coronary artery disease
- aorta
- great vessels and trauma
- dissection
- aortitis
- cardiac surgery
- surgery-valve
Aortic stenosis (AS) is becoming an increasingly important medical problem, with the ageing of the general population.1 ,2 Pathological changes in the aortic valve caused by AS can also create aortic regurgitation (AR). As a result, a considerable proportion of AS patients also have significant AR.3 In patients with combined AS and AR (ASR), a greater combined volume and pressure overload is imposed to the left ventricle (LV) than in isolated AS patients.4 In addition to the direct gradient effect on ventricular systolic pressure, remodelling, hypertrophy and fluid overload can also aggravate AR.3 Thus, concomitant AR might be harmful in patients with severe AS.
Aortic valve surgery is the standard of care for symptomatic severe AS, because of the dismal prognosis of the condition in non-surgically treated patients.5–9 Although the natural history of severe AS is well known, studies have excluded patients with concomitant significant AR or did not evaluate the degree of concomitant AR.8–11 Moreover, evaluation of the severity of AS is difficult in the presence of significant AR, because pressure gradients may be higher in ASR patients with increased LV stroke volume. Some investigators have indicated that concomitant AR may lead to overestimation of the severity of AS, but others do not.12 ,13 Thus, there are few data on the natural history of ASR, and the optimal timing of surgery in these patients remains a source of debate. The aim of this study was to examine the effect of concomitant AR on clinical outcomes in patients with non-surgically treated severe AS.
Methods
Study population
We retrospectively reviewed 306 consecutive patients who were diagnosed with severe AS by transthoracic echocardiography at our institution, but were not primarily referred for surgery, between January 1999 and December 2011. Their clinical characteristics and comorbidity were assessed based on independent physician assessment. The patients were divided into two groups according to their degree of concomitant AR: ASR group—patients with severe AS and moderate or severe AR; and isolated AS group—patients with severe AS with no or trivial AR.
Echocardiographic evaluation
Two-dimensional echocardiography and Doppler colour flow imaging were performed in all patients. Maximal aortic jet velocity and mean aortic pressure gradient (MPG) were determined using the modified Bernoulli equation, and the aortic valve area (AVA) was measured using the standard continuity equation.14 Maximal jet velocity was recorded using the apical, right parasternal or suprasternal window that yielded the highest velocity signal. Severe AS was defined as an AVA <1.0 cm2, and grading of the severity of AR was based on the ACC/AHA guidelines.15
Clinical follow-up
The following clinical data were obtained from medical records: age, gender, body surface area, atrial fibrillation, documented diagnosis of hypertension, dyslipidaemia, diabetes, ischaemic heart disease (history of myocardial infarction or coronary artery stenosis on coronary angiography), history of cerebral infarction and haemodialysis treatment.
Clinical follow-up data were obtained from patients either in person or by telephone interviews. Overall survival and survival free from adverse events, defined as a composite of cardiac death and hospitalisation because of heart failure, were compared between the groups.
Statistical analysis
Categorical variables are presented as number and per cent, and compared using the χ2 test or Fisher's exact test, as appropriate. Continuous variables are described as the mean ± SD. Survival analysis was performed using the by Kaplan–Meier method and differences between groups were tested using the log-rank test. To determine the predictors of adverse events, a Cox proportional hazards model was used to estimate the risks associated with the following variables: age, gender, concomitant AR, LV ejection fraction (LVEF), hypertension, diabetes mellitus, dyslipidaemia, ischaemic heart disease, prior cerebral infarction and haemodialysis treatment. Log (time) versus log (−log (survival)) stratified by each significant risk factor was plotted and the relative slopes of the plotted lines were evaluated. Variables for which probability values were <0.20 on univariable analysis and proportional assumptions were generally fair were included in the multivariable analysis. All analyses were performed using the statistical software JMP V.7.02 (SAS Institute).
Results
Patient characteristics
The patients comprised 122 men and 184 women with a mean age of 72±11 years. The mean AVA was 0.8±0.2 cm2, maximal jet velocity was 4.1±0.8 m/s, and the MPG was 40±16 mm Hg. There were 74 patients with ASR and 232 patients with isolated AS. The baseline clinical and echocardiographic characteristics of patients with ASR and those with isolated AS are shown in table 1. Although AVA and AVA index were comparable between the groups, maximal jet velocity and MPG were significantly higher in ASR patients. The group had comparable LVEF, but the dimensions of the LV were significantly greater in patients with ASR. Thirty-three patients (45%) with ASR and 111 patients (48%) with isolated AS were asymptomatic. Among the symptomatic patients, 69 patients (42%) refused surgery and 31 patients (19%) were not recommended aortic valve replacement (AVR) because of prohibitive comorbidity, or physician's unrecognition (21%).
Patient characteristics, comorbid conditions, and echocardiographic parameters
Mortality and adverse cardiac events
The mean follow-up period was 4.5±3.3 years. There were 37 non-cardiac deaths; 18 patients with cancer, seven with pneumonia, six with stroke, and six with other causes, and 62 cardiac deaths; seven patients with acute myocardial infarction, 13 with significant cardiac arrhythmia, 18 with refractory congestive heart failure, and 24 with sudden cardiac death. Fifty-five patients were admitted with severe heart failure because of AS. Although the overall survival was comparable between the groups (p=0.07, figure 1A), event-free survival was significantly worse in ASR than in isolated AS (p=0.02, figure 1B).
(A) Comparison of actuarial survival between patients with isolated severe aortic stenosis (AS) and patients with severe AS with concomitant aortic regurgitation (AR). (B) Comparison of freedom from adverse events in patients with isolated AS and patients with combined AS and AR. Adverse events are a composite of cardiac death and admission because of heart failure.
During follow-up, AVR was eventually performed in 105 patients. Among patients who did not undergo AVR, those with ASR had significantly worse survival and event-free survival than those with isolated AS (p=0.002 and p=0.03, respectively, figure 2).
Comparison of actuarial survival (A) and freedom from adverse events between patients with isolated severe aortic stenosis (AS) and patients with severe AS with concomitant aortic regurgitation (AR), among non-surgically treated patients. Adverse events are a composite of cardiac death and admission because of heart failure.
Prognostic factors for adverse cardiac events
Table 2 shows the results of univariable and multivariable analyses to identify predictors of adverse clinical events. Univariable analysis showed that age >75 years, concomitant AR, LVEF <50%, diabetes mellitus, haemodialysis treatment and history of ischaemic heart disease were significant predictors. The multivariate Cox proportional hazard model revealed that concomitant AR (HR, 2.10; 95% CI 1.29 to 3.35; p=0.003), age >75 years (HR, 1.90; 95% CI 1.14 to 3.14; p=0.01) and ischaemic heart disease (HR, 2.11; 95% CI 1.30 to 3.45; p=0.003) were independent predictors.
Univariable and multivariable analysis of possible predictors of adverse events
Discussion
The main findings of this study were as follows: (1) among severe AS patients, 27% had concomitant significant AR; (2) patients with ASR had significantly worse outcomes than patients with isolated AS; and (3) concomitant AR was an independent predictor of adverse events in patients with severe AS.
AS is the most common reason for valve surgery and increases in prevalence with age.1 ,2 AVR is recommended for severe AS once symptoms appear or in the presence of LV systolic impairment.15 ,16 Definitive diagnosis of severe AS is not always easy because discrepancies are often observed between the gradient and the valve area in individual patients.17 Rosenhek et al 11 reported that aortic jet velocity may reflect the haemodynamic load on the LV more accurately than AVA in the setting of severe AS. However, conditions that increase stroke volume, including AR, tend to lead to overestimation of the severity of AS based on a higher jet velocity and pressure gradient. Moreover, there are few data available to assess whether the criteria used for severe AS could be applied to patients with ASR, despite the fact that concomitant AR is common in patients with AS.3 In the present study, a significant number of patients had coexisting AR, and those patients had poorer outcomes than those with isolated AS. Thus, a lower threshold for surgery might be reasonable and beneficial for patients with ASR.
AR represents combined volume and pressure overload on the LV. Volume overload results in neuroendocrine activation, including an augmented β-adrenergic stimulation, reduced myocyte protein synthesis and extracellular matrix degradation, leading to progressive dilation and functional deterioration of the LV.18 ,19 Krayenbuehl et al 20 have reported that the deterioration of myocardial function is more advanced in ASR than in isolated AS when the patient becomes symptomatic. Pathological analysis of endomyocardial biopsy specimens has shown that the degeneration of cardiomyocytes is more severe in ASR than in isolated AS.4 These findings seem to indicate that concomitant AR carries an increased risk of rapid clinical deterioration in patients with severe AS. In addition, LV hypertrophy, which occurs as a result of adaptation to increased afterload, and the decreased diastolic arterial pressure caused by AR result in reduced coronary flow reserve.21 Thus, concomitant AR may synergistically exacerbate the myocardial ischaemia in patients with severe AS. However, Catovic et al 22 reported that concomitant AR was not a risk factor for adverse postoperative outcomes in patients with severe AS who underwent aortic valve surgery. In the present study, concomitant AR was more strongly associated with a worse outcome in patients who did not eventually undergo AVR. Thus, because concomitant significant AR is associated with poorer outcomes but AVR may eliminate the differences in outcome after surgery, greater consideration of surgery might be appropriate in patients with ASR.
The major limitation of the present study is the retrospective design, which is prone to inherent bias. Although various statistical tools were used to minimise the effect of selection bias, it is not possible to remove all biases. In addition, the number of patients in the current study was too small to use propensity matching to obtain a fair comparison between the groups. AR quantification data was not available in mild or moderate AR patients. The study included patients who eventually underwent AVR; this could have led to underestimation of the mortality of those with severe AS who were not treated surgically, because patients who underwent AVR had better outcomes than those who did not. Besides, the exact causes of why surgery was performed eventually were not fully assessed. Further studies are needed to determine whether patients with severe AS and concomitant significant AR might benefit from early AVR.
In conclusion, concomitant AR worsens the prognosis of severe AS. Greater consideration of surgery might be beneficial in patients with ASR.
References
Footnotes
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SH and TK contributed equally to this study.
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Competing interests None.
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Ethics approval Ethics approval was provided by the Institutional Review Board of Kobe City Medical Center General Hospital.
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Provenance and peer review Not commissioned; externally peer reviewed.