Influence of Preoperative Left Ventricular Contractile Reserve on Postoperative Ejection Fraction in Low-Gradient Aortic Stenosis
Background— Dobutamine stress hemodynamics (DSH) has the potential to stratify operative risk in low-gradient aortic stenosis (AS), but little is known about the relation between left ventricle contractile reserve and postoperative left ventricular ejection fraction (LVEF). We sought to assess the value of DSH to predict postoperative improvement in LVEF.
Methods and Results— Sixty-six consecutive patients with symptomatic severe AS (aortic valve area ≤1 cm2), LVEF ≤40%, and mean pressure gradient ≤40 mm Hg prospectively enrolled in the French multicenter study on low-gradient AS and who survived to aortic valvular replacement (AVR) were included. Preoperative contractile reserve was present in 46 patients (group I; 70%) and absent in 20 patients (group II; 30%). In the overall sample, 58% of patients improved by 2 New York Heart Association (NYHA) classes after AVR. Mean LVEF improved from 29±6% to 47±11% (P<0.0001). LVEF improved by ≥10 EF units in 38 patients (83%) in group I and in 13 patients (65%) in group II. Mean LVEF improvement was similar in the 2 groups (19±10% versus 17±11%; P=0.54). On multivariable analysis, multivessel coronary artery disease (P=0.05) and baseline mean transaortic pressure gradient (P=0.01) were related to LVEF improvement, whereas contractile reserve was not.
Conclusions— LVEF increases in the majority of patients with low-gradient AS who survive after AVR. Although the absence of contractile reserve on DSH is related to high operative mortality, it does not predict the absence of LVEF recovery in patients surviving to AVR. These data further support the concept that surgery should not be contraindicated on the basis of absence of contractile reserve alone.
Received June 15, 2005; revision received December 9, 2005; accepted January 20, 2006.
Dobutamine stress hemodynamics (DSH) has the potential to stratify operative risk in the setting of low-flow/low-gradient aortic stenosis (AS).1,2 According to a recent multicenter study, patients with left ventricular (LV) contractile reserve by DSH have a relatively low operative risk (5%), whereas patients without contractile reserve have a high operative mortality (32%).1 Operative mortality also depends on other parameters such as baseline mean transaortic pressure gradient (MPG), associated coronary artery disease, and associated comorbidities.1,3
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Clinical Perspective p 1744
In most patients with low-gradient AS who survive after aortic valve replacement (AVR), postoperative LV ejection fraction (LVEF) improves, probably because preoperative LV systolic dysfunction was primarily related to afterload mismatch.4–6 However, in some patients LVEF remains unchanged because of extensive myocardial fibrosis, associated cardiomyopathy, or associated coronary artery disease.3 Improvement in LVEF after AVR has been reported to be positively related to female gender, presence of syncope, absence of hypertension, and preoperative mean gradient and inversely related to preoperative aortic valve area and presence of coronary artery disease.5–8 However, dobutamine hemodynamics was not systematically performed before surgery in the latter studies.5–8 On the other hand, the issue of postoperative LVEF was not addressed in other studies in which DSH was systematically performed.1,2 Therefore, we sought to assess the relation between LV contractile reserve by DSH and postoperative LVEF in patients with AS, low transvalvular gradient, and LV dysfunction.
Eighty patients with low-gradient (MPG ≤40 mm Hg), symptomatic severe AS (aortic valve area ≤1 cm2) with an EF ≤40% prospectively enrolled in the French multicenter study described previously1 underwent valvular replacement. All patients had a preoperative dobutamine Doppler hemodynamic study. Thirteen patients (16%) died during the postoperative period: 3 of 50 patients with contractile reserve died (2 of cardiogenic shock), and 10 of 30 patients without contractile reserve died (8 of cardiogenic shock). Patients who survived after the operative period and had postoperative evaluation of LVEF were included in the present study. Sixty-seven patients survived to the postoperative period. All had postoperative evaluation of LVEF except 1 who was lost to follow-up. Thus, 66 patients who survived to the 30-day period after AVR and had postoperative evaluation of LVEF form the sample of the present study. Thirty-seven patients (56%) received a mechanical prosthesis, 28 patients (42%) received a biological prosthesis, and 1 patient (2%) received a homograft. Seventeen patients (26%) underwent concomitant coronary artery bypass grafting. The study was approved by local institutional review boards, and informed consent was obtained from the patients before all procedures.
All patients underwent a comprehensive Doppler echocardiographic study with the use of commercially available ultrasound systems. Details of the dobutamine stress Doppler study have been described previously.9 Briefly, after the baseline measurements, a dobutamine infusion was begun at 5 μg/kg body wt per minute and titrated upward to a maximal dose of 20 μg/kg per minute. LV outflow tract diameter was assumed to be constant at different flow states, and the baseline value was used to calculate stroke volume at baseline and during dobutamine infusion according to standard formulae.10 Transaortic gradients were calculated with the use of the simplified Bernoulli equation.11 Aortic valve area was calculated by the continuity equation.12 LVEF was calculated in all 66 patients before AVR and after the 30-day postoperative period according to biplane Simpson’s rule13 in 55 cases and was assessed visually14 in 11 cases.
Dobutamine echocardiographic studies were evaluated offline in each center by a single experienced echocardiographer. Patients were classified into 2 groups according to the presence (group I) or absence (group II) of contractile reserve by DSH, defined by an increase in stroke volume of ≥20% compared with baseline value.1,2,9 All patients with contractile reserve had fixed AS, defined by an increase in valve area <0.3 cm2 with a final valve area ≤1 cm2 on dobutamine echocardiography.9,15 There were 46 patients with contractile reserve (group I; 70%) and 20 without contractile reserve (group II; 30%).
Follow-up clinical data were obtained in all patients at a mean interval of 26±20 months. The end points evaluated at follow-up were survival, New York Heart Association (NYHA) functional class, and LVEF. Follow-up echocardiographic LVEF after AVR was obtained in all patients at a mean interval of 16±15 months (range, 1 to 62 months). The physicians who performed the postoperative echocardiography were blinded to previous dobutamine findings.
Continuous data are presented as mean±SD values. Dichotomous data are presented as percentages. Univariate analysis was performed with the use of nonparametric statistical tests or parametric tests as needed. The χ2 test or the Fisher exact test was applied for dichotomous and categorical data. For continuous variables, a simple linear regression analysis was performed. Change in stroke volume and variables that were associated on univariate analysis (P<0.10) with change in LVEF and with postoperative NYHA class after AVR were entered into linear stepwise regression models allowing the determination of predictors of change in LVEF. Survival rates after AVR of patients with and without contractile reserve were estimated by the Kaplan-Meier method, and difference was tested with the log-rank test. Two-tailed probability values <0.05 were considered statistically significant.
The authors had full access to the data and take full responsibility for its integrity. All authors have read and agree to the manuscript as written.
The study sample included 19 women and 47 men with a mean age of 68±9 years; mean aortic valve area, 0.68±0.16 cm2; mean indexed valve area, 0.38±0.1 cm2/m2; mean cardiac index, 2.28±0.57 L/min per square meter; MPG, 31±6 mm Hg; and mean LVEF, 29±6%. Twenty-nine patients (44%) had a MPG ≤30 mm Hg, and 35 patients (53%) had an EF ≤30% preoperatively.
All 66 patients complained of dyspnea at the first visit, and 59 patients (89%) were classified as NYHA class III or IV. Four patients had associated angina, and 1 had a history of syncope. Preoperative coronary angiography was performed in all patients. One, 2, or 3-vessel disease was present in 10, 4, and 8 patients, respectively. Forty-four patients (67%) had no significant coronary artery disease or normal coronary angiography. Eleven patients (17%) had a history of myocardial infarction, and 4 patients (6%) had previously undergone coronary artery bypass grafting.
Baseline Clinical and Hemodynamic Data
DSH studies were well tolerated in all cases. Dobutamine peak doses were strictly comparable in the 2 groups. The baseline clinical and hemodynamic data as well as stress hemodynamics data in each group are presented in Table 1.
Postoperative Functional Improvement
In the total sample, 94% of patients (62/66) improved after AVR by ≥1 NYHA functional class at follow-up, and 58% (38/66) improved by ≥2 NYHA functional classes. After AVR, 91% (60/66) were classified as NYHA class I or II, whereas 9% (6/66) remained in class III or IV. Five of the 60 patients in NYHA class I or II after AVR died during follow-up, 2 of sudden death and 3 of noncardiac causes. Four of the 6 patients in NYHA class III or IV after AVR died during follow-up, 3 of heart failure and 1 of respiratory failure.
In group I, 96% of patients (44/46) improved by ≥1 NYHA functional class after AVR, and 59% (27/46) improved by ≥2 NYHA functional classes. During follow-up, 93% (43/46) were classified as NYHA class I or II. In group II, 90% of patients (18/20) improved by ≥1 NYHA functional class after AVR (P=0.35 versus group I), and 55% (11/20) improved by ≥2 NYHA functional classes (P=0.50 versus group I). During follow-up, 85% (17/20) were classified as NYHA class I or II (P=0.36 versus group I).
The relationship between patients’ characteristics and functional status at follow-up on univariate analysis is shown in Table 2. Preoperative relative change in stroke volume with dobutamine was similar in patients in NYHA class I or II at follow-up and in those in NYHA class III or IV. Thus, presence or absence of contractile reserve was not related to functional status in the survivors after AVR. The only parameter related to functional status at follow-up was increase in LVEF after AVR. The mean increase in LVEF after AVR was 19±10% in patients in NYHA class I or II at follow-up compared with 8±11% in patients in class III or IV (P=0.013). LVEF at follow-up was 48±10% in patients in NYHA class I or II at follow-up and was 34±14% in patients in class III or IV at follow-up (P=0.005). On multivariable analysis, the only predictor of functional status at follow-up was postoperative increase in LVEF (P=0.009).
Postoperative Increase in EF
In the total sample, LVEF increased at follow-up from 29±6% preoperatively to 47±11% after AVR (P<0.0001), representing a mean increase of 18±10%.
In group I, LVEF significantly increased after AVR from 28±6% to 47±11% (P<0.0001), with a mean increase of 19±10%. In group II, LVEF increased after AVR from 31±6% to 48±11% (P=0.0001), with a mean increase of 17±11%. Postoperative increase in LVEF was similar in groups I and II (P=0.54) (Figure).
In group I, 38 of 46 patients (83%) obtained ≥10% improvement of LVEF after AVR compared with 13 of 20 patients (65%) in group II (P=0.20). The presence of contractile reserve had a positive predictive value for LV recovery (LVEF improvement ≥10%) of 83%, but the absence of contractile reserve had a negative predictive value for LV recovery of only 35%.
The relationships between preoperative characteristics and change in LVEF after AVR are shown in Table 3. LVEF increase after AVR was not significantly related to contractile reserve (19±10% and 17±11%; P=0.54). Increase in LVEF was lower in women, in the presence of a baseline mean gradient <30 mm Hg, and in the presence of multivessel coronary artery disease. On simple linear regression analysis, increase in LVEF after AVR was positively related to baseline mean gradient and to aortic valve area increase with dobutamine but was not significantly related to increase in stroke volume on preoperative DSH (P=0.91) (Table 4). On multivariable analysis, baseline mean gradient <30 mm Hg and presence of multivessel coronary disease were inversely related to LVEF increase after AVR (Table 5), whereas change in stroke volume with dobutamine was not related to LVEF increase after AVR (β=0.027; t=0.234; P=0.82). Increase in LVEF (17.0±10% versus 17.3±11%; P=0.92) was similar in the lowest tertile compared with the highest tertile of dobutamine responses defined by the stroke volume increase.
Twenty-one patients had a preoperative LVEF <31% and a MPG <31 mm Hg (MPG, 25±4 mm Hg; mean LVEF, 24±5%). In this subset of patients, increase in LVEF after AVR was similar in patients with or without contractile reserve (14.7±7.7% versus 13.2±11%; P=0.56), and change in LVEF after AVR was not related to change in stroke volume on preoperative DSH (r=0.04; P=0.86).
There were 9 deaths during the follow-up. Although operative mortality was extremely high in patients without contractile reserve compared with patients with contractile reserve (33% versus 6%), postoperative survival rates at 2 years (90±5% versus 92±7%; P=0.63) were not significantly different in patients with and without contractile reserve on preoperative DSH.
In patients with low-gradient AS, assessment of contractile reserve by DSH has the potential for operative risk stratification.1 The present study confirms that LVEF improves after AVR by ≥10% in 83% of patients with contractile reserve with an improvement in functional status in almost all of these patients (96%). However, the main result of this study is that exhausted contractile reserve is not systematically related to persistent LV dysfunction. In patients without contractile reserve who survive to the postoperative period, LVEF improved ≥10% in 65% of cases, and clinical status improved in 90% of cases.
Contractile Reserve and Postoperative Functional Status
Our results show that postoperative functional class NYHA is not related to preoperative LV contractile reserve. This is consistent with the other result that postoperative functional class is primarily related to increase in postoperative LVEF, which itself is not primarily determined by preoperative DSH.
Predictors of Increase in Postoperative LVEF
In patients with AS and LV dysfunction, improvement in LVEF after AVR has been reported to be associated with a better survival.16 Our results confirm the clinical importance of postoperative increase in LVEF in patients with low-gradient AS, which is related to functional status at follow-up. Previous reports suggest that a higher preoperative MPG is predictive of better postoperative ventricular function in patients with AS and low preoperative LVEF.6,8 In our study, postoperative improvement of LVEF was significantly greater in patients with higher preoperative MPG. According to our results, the influence of preoperative MPG on postoperative LV function therefore remains significant even in patients already selected by their low preoperative gradient. Coronary artery disease has been reported to be associated with a lower postoperative LVEF and a lower survival after AVR.3,6,8,16,17 In our study, the improvement of LVEF after AVR was lower in patients with multivessel coronary disease. Our results therefore suggest that in patients with low-gradient AS, the poorer postoperative prognosis associated with coronary disease could in part be due to a negative influence of coronary disease on the course of LV function after AVR.
Contractile Reserve and Postoperative LV Function
All group I patients in the present study referred for surgery had a “fixed” AS (change in aortic valve area <0.3 cm2) indicating severe AS.15 The main mechanism for LV dysfunction in these patients is afterload mismatch18; thus, postoperative improvement in LVEF is not surprising in this group.5,9,19,20
In contrast, in patients without contractile reserve, a low-flow state may persist during the dobutamine test. Because the calculated valve area is flow dependent,21 the true severity of AS may not be fully assessed.15 Causes of LV dysfunction may include a certain degree of intrinsic, irreversible myocardial dysfunction due to fibrosis or myocardial infarction.3,22 However, our study demonstrates that absence of contractile reserve does not preclude significant improvement in LVEF after AVR, when it is considered that two thirds of survivors after AVR without preoperative contractile reserve on DSH obtained ≥10% improvement of LVEF. Perhaps the main determinant for low preoperative LVEF in these patients was an afterload mismatch that cannot be corrected by inotropic stimulation with dobutamine. Exhausted contractile reserve in low-gradient AS therefore does not systematically indicate irreversible LV dysfunction.
Limitations of the Study
Operative mortality is mostly due to cardiogenic shock and is much higher in patients without contractile reserve.1 Thus, excluding from analysis patients who died postoperatively may have led to an underestimation of the influence of exhausted contractile reserve on postoperative LV function. However, this study demonstrates that irreversible LV dysfunction is not the rule in patients without contractile reserve because in those (approximately two thirds) who survived to the operation, the majority obtained improvement in LVEF. Our study sample may have been too small to demonstrate a significant difference in the percentage of patients experiencing recovery in LV function between those with and those without contractile reserve and was not designed to study long-term survival. Further studies may be needed to address those issues. Furthermore, our results must be interpreted in light of the variability of LVEF measurements, considering that most LVEF evaluations after AVR were performed by the referring physicians. However, the strong correlation between postoperative LVEF and functional NYHA class supports the idea that postoperative LVEF as evaluated in our study is clinically relevant. Finally, our results must be considered tentative because no statistical adjustment was made to probability values to account for the large number of statistical tests.
In the setting of low-gradient AS, postoperative improvement in LVEF is not related mainly to preoperative LV contractile reserve. In the patients with absence of contractile reserve on DSH, despite high operative mortality, postoperative LVEF as well as functional status often improves provided that the patients survive the postoperative period. Therefore, the results of DSH should be integrated with all relevant parameters (including primarily associated comorbidities, coronary artery disease, and baseline MPG) when the risk/benefit ratio for each individual patient is assessed. Finally, in view of the very poor prognosis of unoperated low-gradient AS and the potential benefit of valve replacement despite a higher operative risk, surgery should not be contraindicated on the sole basis of exhausted contractile reserve.
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In the setting of low-gradient aortic stenosis (AS), patients without contractile reserve by dobutamine stress hemodynamics (DSH) have a high operative mortality compared with patients with contractile reserve. However, little is known about the relation between contractile reserve and postoperative left ventricular ejection fraction (LVEF). This study was designed to assess the value of DSH to predict postoperative improvement in LVEF. Sixty-six patients with low-gradient AS (valve area, 0.68±0.16 cm2; mean transaortic pressure gradient [MPG], 31±6 mm Hg) who survived to aortic valve replacement (AVR) were classified into 2 groups: group I with contractile reserve (n=46) and group II without contractile reserve (n=20). Improvement in LVEF after AVR was comparable in the 2 groups (19% and 17%; P=0.54). Predictors for LVEF improvement were multivessel coronary artery disease and MPG but not contractile reserve. LVEF improved by ≥10 EF units in 83% of group I and 65% of group II patients (P=0.20). New York Heart Association (NYHA) class improved after AVR in 96% of group I patients and 90% of group II patients (P=0.35). Therefore, absence of contractile reserve does not systematically indicate irreversible left ventricular dysfunction. In patients without contractile reserve on DSH, operative mortality is high, but postoperative LVEF and functional status often improve provided that the patients survive the operation. Finally, in view of the very poor prognosis of unoperated low-gradient AS, surgery should not be contraindicated on the sole basis of exhausted contractile reserve.