Low-Flow Aortic Stenosis in Asymptomatic PatientsValvular–Arterial Impedance and Systolic Function From the SEAS Substudy
Dana Cramariuc, MD*, ,*,
Giovanni Cioffi, MD ,
Åshild E. Rieck, MD*,
Richard B. Devereux, MD ,
Eva M. Staal, MD, PhD||,
Simon Ray, MD¶,
Kristian Wachtell, MD, PhD#,
Eva Gerdts, MD, PhD*,
* Institute of Medicine, University of Bergen, Bergen, Norway
Department of Heart Disease, Haukeland University Hospital, Bergen, Norway
Department of Cardiology, Cura Villa Bianca Hospital, Trento, Italy
Division of Cardiology, Weill Cornell Medical College, New York, New York
|| Department of Cardiology, Stavanger University Hospital, Stavanger, Norway
¶ Department of Cardiology, South Manchester University Hospital, Manchester, United Kingdom
# Department of Cardiology, The Heart Center, Rigshospitalet, Copenhagen, Denmark
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Abstract
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Objectives: This study sought to assess the impact of valvuloarterial impedance on left ventricular (LV) myocardial systolic function in asymptomatic aortic valve stenosis (AS).
Background: In atherosclerotic AS, LV global load consists of combined valvular and arterial resistance to LV ejection. Global load significantly impacts LV ejection fraction (EF) in symptomatic AS, but less is known about its effect on LV myocardial function in asymptomatic AS.
Methods: Echocardiograms in 1,591 patients with asymptomatic AS (67 ± 10 years, 51% hypertensive) at baseline in the SEAS (Simvastatin Ezetimibe in Aortic Stenosis) study evaluating placebo-controlled combined simvastatin and ezetimibe treatment in AS were used to assess LV global load as valvuloarterial impedance and LV myocardial function as stress-corrected midwall shortening. The study population was divided into tertiles of global load. Stress-corrected midwall shortening was considered low if <87% in men and<90% in women. Low-flow AS was defined as stroke volume index <22 ml/m2.04.
Results: Energy loss index decreased (0.85 cm2/m2 vs. 0.77 and 0.75 cm2/m2) and the prevalence of low stress-corrected midwall shortening increased (10% vs. 26% and 63%) with increasing LV global load (all p < 0.001). The EF was low in only 2% of patients. Patients with low-flow AS had higher LV global load and more often low midwall shortening than those with normal-flow AS (9.66 ± 2.23 mm Hg/ml·m2.04 and 77%, vs. 6.38 ± 2.04 mm Hg/ml·m2.04 and 30%, respectively, p < 0.001). In logistic regression analysis, LV global load was a main predictor of low stress-corrected midwall shortening independent of male sex, concentric LV geometry, LV hypertrophy (all p < 0.001), concomitant hypertension, and aortic regurgitation.
Conclusions: LV global load impacts LV myocardial function in asymptomatic AS independent of other main covariates of LV systolic function. LV myocardial systolic dysfunction is common in asymptomatic AS in particular in patients with low-flow AS and increased valvuloarterial afterload, whereas EF is generally preserved. (An Investigational Drug on Clinical Outcomes in Patients With Aortic Stenosis [Narrowing of the Major Blood Vessel of the Heart]; NCT00092677)
Key Words: echocardiography • hemodynamics • stenosis • valves • ventricles
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Abbreviations and Acronyms
| | AS = aortic stenosis | | CI = confidence interval | | EF = ejection fraction | | LV = left ventricle | | ROC = receiver-operator characteristic |
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Recent publications have suggested that aortic valve stenosis (AS) should not be regarded as an isolated valvular disease, but as part of an atherosclerotic process involving both the aortic valve and the large arteries (1,2). Thus, in atherosclerotic AS, left ventricular (LV) load reflects combined valvular and arterial resistance to LV ejection, which may be assessed by valvuloarterial impedance (2). The impact of combined valvuloarterial impedance on LV ejection fraction (EF) has been shown in patients with severe AS, but has so far not been studied in asymptomatic stages of AS (2).
It is well known that EF may remain normal during chronic pressure overload despite reduced myocardial contractility by use of the preload reserve (3) or by changes in LV geometry (4), and despite impaired LV long-axis function shown by tissue Doppler (5). In essential hypertension, LV midwall shortening, reflecting myocardial function and not merely endocardial displacement, has been suggested as a more sensitive marker of LV systolic function (6) and has proven prognostic value (7). Furthermore, stress-corrected LV midwall shortening has recently been shown to be independently associated with the presence of symptoms in symptomatic aortic stenosis (8). Among patients with severe AS, a group characterized by low-flow low-gradient and reduced survival despite preserved EF has recently been described (9). It is currently unknown whether this phenomenon may be present also in asymptomatic and milder degrees of AS.
Thus, the aim of the present analysis was to evaluate the impact of global LV load on LV systolic function measured as EF and stress-corrected midwall shortening in asymptomatic patients with normal versus low-flow AS recruited in the SEAS (Simvastatin Ezetimibe in Aortic Stenosis) study.
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Methods
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Study population.
The SEAS study randomized 1,873 patients (ages 45 to 85 years, 38.6% women) with asymptomatic AS to a 4-year, double-blind, placebo-controlled treatment with combined simvastatin and ezetimibe versus placebo to evaluate the effect on AS progression and cardiovascular morbidity and mortality (10). Eligible patients had asymptomatic AS defined as aortic valve thickening accompanied by a peak transaortic velocity  2.5 and  4.0 m/s measured at the field centers. Patients with coronary heart disease, heart failure, diabetes, history of stroke or peripheral vascular disease, clinically significant mitral valve disease, severe or predominant aortic regurgitation, rheumatic valvular disease, aortic valve prosthesis or renal insufficiency, and patients already on lipid-lowering therapy were not included in the SEAS study. Baseline patient characteristics and SEAS study design have recently been published (10). The present population included the 1,591 of the 1,873 SEAS patients included in the SEAS study in whom LV global load could be calculated from the baseline (pre-randomization) echocardiogram. Compared with the nonselected patients, the present study population did not differ in age, sex, concomitant hypertension, or severity of AS. Hypertension was defined as history of hypertension reported by the attending physician. Blood pressure was measured at clinical visits. Pulse pressure was defined as the difference of systolic to diastolic blood pressure. The SEAS study was approved by the regional ethics committees in all participating countries. All patients gave written informed consent to participate in the SEAS study.
Echocardiographic measurements.
Baseline examinations were performed at the 173 SEAS study sites following a standard protocol. Images were stored on VHS video tapes, CDs, or MO disks and forwarded for final reading to the SEAS Echocardiography Core Laboratory at Haukeland University Hospital, Bergen, Norway. The SEAS echocardiographic protocol has recently been published (11). All study echocardiograms were initially read by a junior member of the SEAS Echocardiography Core Laboratory staff and later proofread by a senior investigator; 93% of final readings were performed by 1 highly experienced reader (E.G.). All reading was done using off-line digital workstations with Image Arena software (TomTec Imaging Systems GmbH, Unterschleissheim, Germany).
Assessment of AS severity.
The Doppler echocardiographic assessment of the severity of AS included measurement of peak and mean transaortic velocities and gradients, and energy loss index calculated by a previously validated formula (12). Severe AS was defined as energy loss index 0.55 cm2/m2 (2). In severe AS, a mean transaortic gradient <30 mm Hg was considered low (13).
Indices of LV systolic function.
The primary measure of LV systolic function was stress-corrected midwall shortening assessed as the ratio of actual to predicted midwall shortening for the actual circumferential end-systolic stress (14). The LV midwall shortening was calculated based on 2-dimensional measurements according to the current recommendations for cardiac chamber quantification (15). Circumferential end-systolic stress was calculated at midwall using a cylindrical model (16). Stress-corrected midwall shortening was considered low if <87% in men and <90% in women (17). The EF was measured by the biplane method of disks (15) and considered low if <50%.
Stroke volume was measured using the Teichholz correction of the cube formula (18) and normalized for height at the allometric power of 2.04 to account for its nonlinear variation with body size (19). The AS was defined as low flow when stroke volume index was <22 ml/m2.04, which corresponds to the previous cutoff of 35 ml/m2 when correcting for body surface area, and normal flow if above this threshold (9). The ratio of stroke volume index to pulse pressure was used as an indirect measure of total systemic arterial compliance (20).
Assessment of global LV load.
Global LV load was assessed by the valvuloarterial impedance as proposed by Briand et al. (2), taking into account the net mean transaortic gradient and thus the phenomenon of pressure recovery downstream to the stenotic valve (21):
Valvuloarterial impedance = (systolic arterial pressure + mean net transaortic gradient)/(stroke volume/height2.04)
Assessment of LV geometry.
The LV dimensions were measured in the 2-dimensional parasternal long-axis view following the American Society of Echocardiography guidelines (15). Left ventricular hypertrophy was assessed by LV mass/height2.7 (cutoffs 46.7 g/m2.7 in women and 49.2 g/m2.7 in men) (22). Relative wall thickness (end-diastolic posterior LV wall thickness/end-diastolic LV internal radius) defined concentric LV geometry if 0.43.
Statistical analysis.
Reproducibility of measurements of midwall shortening was assessed by intraclass correlation coefficients. The study population was divided into tertiles of global LV load. The chi-square test was used to compare categorical variables and full-factorial 2-way analysis of variance with the Sidak post hoc test to compare continuous variables, as appropriate. Bivariate correlations were assessed using the Pearson correlation coefficients with log transformation of LV global load to satisfy the assumption of normal distribution. Receiver-operator characteristic (ROC) analysis was used to identify the value of global LV load with best sensitivity and specificity in predicting low stress-corrected midwall shortening. The independent covariates of low stress-corrected midwall shortening and EF were identified by binary logistic regression analysis with forced entry of covariates. Results are given as Wald statistic and odds ratios with 95% confidence intervals (CIs). A weighted risk score was calculated based on regression coefficients of independent covariates of low stress-corrected midwall shortening identified in multivariate logistic regression analysis. The individual beta coefficients were converted into scores (multiplied by 10 and rounded off to the nearest whole number) and added to obtain an aggregated score. The discriminative power of the risk score was assessed with a ROC curve. A 2-tailed value of p 0.05 was considered significant in both univariate and multivariate analyses.
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Results
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Patient characteristics.
Patient age, heart rate, and systolic and diastolic blood pressure, and the proportions of women and hypertensive patients increased with higher global LV load, whereas body mass index decreased (all p < 0.01) (Table 1). All of the 51% of hypertensive patients were taking an antihypertensive treatment. The average number of antihypertensive drugs and the number of patients taking beta-blockers did not differ between tertiles.
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Table 1 Clinical and Biochemical Characteristics of Patients in the Total Study Population and Divided in Tertiles of Global LV Load
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AS severity and systemic arterial compliance.
Peak and mean transvalvular gradients, including the net mean transvalvular gradient, increased, whereas energy loss index decreased in higher tertiles of global LV load (all p < 0.001) (Table 2). Low systemic arterial compliance was present in 40% of the total study population and increased significantly from 3% in tertile 1 to 35% in tertile 2 and 83% in tertile 3 (p < 0.001) (Table 2). Global LV load was significantly correlated with the energy loss index (r = –0.13 and –0.16) and with systemic arterial compliance (r = –0.78 and –0.80) both in normotensive and hypertensive patients, respectively, all p < 0.001.
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Table 2 Indices of AS Severity and LV Systolic Function in the Whole Population and in Tertiles of Global LV Load
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Low-flow AS.
Among the 359 patients with energy loss index 0.55 cm2/m2 in the present study population, 100 (28%) had a low stroke volume index (22 ml/m2.04). These patients had excessive global LV load compared with patients with severely reduced energy loss index but normal-flow AS (9.66 ± 2.23 mm Hg/ml·m2.04 vs. 6.01 ± 1.22 mm Hg/ml·m2.04, p < 0.001) or compared with the remaining population (Table 3). They also included more women, had a higher heart rate, had lower LV volumes and LV mass index, and had higher relative wall thickness (Table 3) and thus more concentric geometry (43% vs. 17%) (all p < 0.05).
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Table 3 Clinical and Echocardiographic Characteristics of Patients With Low-Flow AS and Severely Reduced Energy Loss Index Versus the Remaining Study Population
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LV Systolic Function.
Prevalence of low LV systolic function
Reproducibility of measurement of midwall shortening was tested in a subset of 98 patients. The reproducibility was excellent, with an intraclass correlation coefficient 0.92 (95% CI: 0.87 to 0.96) for intraobserver variability, and 0.98 (95% CI: 0.89 to 0.99) for interobserver variability (both p < 0.001). In the total study population, 33% of patients had low stress-corrected midwall shortening, whereas only 2% had low EF. Among patients with low stress-corrected midwall shortening, only 3% also had low EF. The EF did not differ between tertiles of global LV load, whereas stress-corrected midwall shortening and stroke volume index decreased significantly with increasing load (p < 0.001) (Table 2). Prevalence of low stress-corrected midwall shortening increased with increasing global load, reaching 63% in the highest tertile (Fig. 1). Adjustment for LV geometry did not change the results.
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Figure 1 Systolic Function in Tertiles of Global Load
Prevalence of low stress-corrected midwall shortening (scMWS) and low ejection fraction (EF) in tertiles of global left ventricular (LV) load. p < 0.001 for scMWS between tertiles of global LV load.
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Impact of global LV load on systolic function in the general study population
Lower stress-corrected midwall shortening was significantly associated with higher global LV load (r = –0.60, p < 0.001), this negative correlation being present both in patients with normal and in patients with low stress-corrected midwall shortening (Fig. 2). In ROC analysis, valvuloarterial impedance = 7 mm Hg/ml·m2.04 (corresponding to 4.48 mm Hg/ml·m2 when indexing stroke volume for body surface area) was the threshold value with the best specificity (80%) and sensitivity (65%) in predicting low stress-corrected midwall shortening (area under the curve 0.803, p < 0.001) (Fig. 3). A low but statistically significant univariate correlation was also found between EF and global LV load (r = –0.07, p < 0.05).
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Figure 2 Midwall Shortening in Correlation With Global Load
Global left ventricular (LV) load (log-transformed global load, horizontal axis) has strong negative relations with stress-corrected midwall shortening (vertical axis) in the whole population (A) and in patients with normal (B) or with low (C) left ventricular systolic function. (A) The x reference line indicates the value of log-transformed global LV load with best sensitivity and specificity in predicting low stress-corrected midwall shortening. Pearson correlation coefficient r = –0.60, p < 0.001. (B, C) The x reference line indicates the mean value of log-transformed global load in patients with normal/low stress-corrected midwall shortening. Both Pearson correlation coefficients r = –0.40, p < 0.001.
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Figure 3 Predictive Cutoffs of Low Midwall Shortening
Receiver-operator characteristic (ROC) curves for the cutoff level of global left ventricular (LV) load (A) and of the clinical risk score (B) with best sensitivity and specificity in predicting low-stress corrected midwall shortening. The cutoffs of global LV load (7 mm Hg/ml·m2.04) and risk score (14 points) identified by ROC analysis are indicated by arrows. AUC = area under the curve with the 95% confidence interval.
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In binary logistic regression analysis, including global LV load, and indicator variables for sex, presence of aortic regurgitation, LV hypertrophy, concentric LV geometry, and hypertension as independent variables, the independent covariates of low stress-corrected midwall shortening were: higher global LV load, male sex, concentric LV geometry, and LV hypertrophy (all p < 0.001, –2 log likelihood ratio: 1,080) (Table 4). Results did not change in additional models including age and heart rate among the covariates. Separate analysis in patients with low and normal stroke volume showed that global LV load as well as concentric LV geometry and LV hypertrophy all were independent covariates of low stress-corrected midwall shortening in both subpopulations (p < 0.001). Further replacing global LV load with an indicator variable for load >7 mm Hg/ml·m2.04 in a final model (–2 log likelihood ratio: 1,219) identified high global load and concentric LV geometry as major covariates of low stress-corrected midwall shortening, odds ratios 10.84 (95% CI: 7.60 to 15.46) and 13.15 (95% CI: 8.73 to 19.80) per 1% lower stress-corrected midwall shortening, respectively (both p < 0.001). Male sex (OR 1.52, 95% CI: 1.13 to 2.04) and presence of LV hypertrophy (OR 6.23, 95% CI: 4.38 to 8.87, both p < 0.01) contributed less, whereas the presence of aortic regurgitation and hypertension were not significant covariates.
A risk score was calculated based on the beta coefficients in this final multivariate logistic regression model: Risk score = 12 x (high global LV load) + 2 x (male sex) + 13 x (concentric LV geometry) + (9 x LV hypertrophy). For each parameter included in the score, a value of 1 was assigned if the variable was present or 0 if it was absent. Thus, the individual risk score varied in our study population between 0 and 36 points. Based on the ROC curve analysis, the optimal cutoff point for the prediction of low stress-corrected midwall shortening was a score of 14 points (area under the curve 0.87, specificity and sensitivity 86% and 67%, respectively) (Fig. 3).
In similar analyses, LV hypertrophy was the only independent covariate of low EF, odds ratio 5.27 for the presence of LV hypertrophy, (95% CI: 2.13 to 13.07, p < 0.001), whereas neither global LV load nor global load >7 mm Hg/ml·m2.04 were independent covariates of EF.
Impact of global LV load on systolic function in low-flow AS
Low stress-corrected midwall shortening was present in 77% of patients with low-flow severe AS compared with 30% in the remaining study population. Stress-corrected midwall shortening was lower even after correction for age, sex, concomitant hypertension, and LV geometry (adjusted means 78.4% vs. 98.7%, p < 0.001), whereas EF was in the normal range and comparable to what was found in the total population (Table 3). Lower stress-corrected midwall shortening was stronger associated with higher global LV load in this subgroup than in patients with normal-flow severe AS (Fig. 4). Despite severely reduced energy loss index, 56% of these patients had mean transaortic gradient <30 mm Hg, and the average mean gradient in this group was 29 mm Hg (Table 3).
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Figure 4 Load and Function in Low-Flow Aortic Stenosis
Global left ventricular (LV) load (log-transformed global load, horizontal axis) has a stronger negative relation with stress-corrected midwall shortening (vertical axis) in patients with low-flow severe aortic stenosis (AS) (Pearson correlation coefficient r = –0.51, p < 0.001, right panel) than in patients with normal-flow severe AS (Pearson correlation coefficient r = –0.34, p < 0.001, left panel).
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Discussion
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This study shows that increased global LV load has a significant negative impact on LV midwall mechanics in patients with asymptomatic AS, in spite of normal EF. Our findings add to previous knowledge by showing that: 1) increased global LV load is detrimental to LV myocardial systolic function in asymptomatic AS; 2) high global LV load and high prevalence of myocardial systolic dysfunction are present particularly in patients with low-flow AS (i.e., low LV output despite preserved LV ejection fraction) and severely reduced energy loss index; and 3) subclinical LV myocardial systolic dysfunction cannot be predicted from assessment of EF.
Global LV load.
Aortic stenosis is frequently associated with reduced arterial compliance, as recently reported (2). This was also the case in the SEAS population, which included older patients with degenerative asymptomatic AS, of whom 51% were on antihypertensive treatment, from which a high prevalence of reduced systemic arterial compliance is to be expected. An increased arterial load influences both the diagnosis and the outcome of patients with AS (1,23). As shown by our results, valvuloarterial impedance is highly correlated to systemic arterial compliance and to the severity of AS assessed by the energy loss index both in hypertensive and in normotensive individuals, and thus represents an adequate expression for the combined valvular and arterial load present in AS. We showed that increased valvuloarterial impedance significantly affects stress-corrected midwall shortening, adding support for the recent proposal to assess both the valvular and the arterial disease in AS (1).
Low-flow AS.
Among the challenging patients with low-flow severe AS (24,25), a group with low transvalvular gradient, paradoxically preserved EF and reduced survival, who seemed to benefit more from surgical than medical treatment, has recently been described (9). The criteria for this condition were also identified within the present population occurring in 28% of patients with asymptomatic AS and severely reduced energy loss index, which is consistent with the 35% reported by Hachicha et al. (9) in a study of patients with severe AS. In accordance with their results, the pattern of low-flow severe AS in the present study was associated with more pronounced LV concentric remodeling, smaller LV cavity, increased global LV load as reflected by higher valvuloarterial impedance, and reduced midwall shortening. The study by Hachicha et al. (9), however, had several limitations, including the retrospective design as well as the unknown status of symptoms at baseline. Hence, a substantial proportion of patients included in this previous study were probably symptomatic at baseline. The present prospective study confirms that an important proportion of asymptomatic patients with severe AS and preserved EF may nonetheless present with a low-flow state and thus a low gradient, which may in turn lead to an underestimation of the disease severity. Furthermore, this study confirms that these patients are, in fact, at a more advanced stage of the disease with more severely impaired intrinsic myocardial function. This finding may explain the reduced survival observed in the study by Hachicha et al. (9).
Impact of global LV load on LV systolic function.
The present study is the first to show that LV myocardial systolic function often is reduced in asymptomatic stages of AS with preserved EF. Stress-corrected midwall shortening was recently shown to be independently associated with the presence of symptoms in symptomatic aortic stenosis (8). Our result adds to this previous observation by showing that low stress-corrected midwall shortening can be found in 33% of patients with asymptomatic AS, and is most frequent in low-flow AS (77% in our study). Furthermore, stress-corrected midwall shortening decreased significantly and proportionally with higher global LV load, even after adjustment for LV geometry. The influence of high load on myocardial function was in particular much stronger in patients with low-flow AS than in those with normal-flow severe AS (r= –0.51 vs. –0.34, p < 0.001). Considering that the normal LV is functionally matched to its load (26), we show that in asymptomatic AS a mismatch between load and LV systolic function frequently occurs.
The impact of global LV load on LVEF was previously published by Briand et al. (2) in 208 patients with moderate to severe, mostly symptomatic AS, and several comorbidities (coronary artery disease in 59%, previous myocardial infarction in 28%, and diabetes in 23% of patients). We extend this previous observation by showing that, in asymptomatic stages of AS, increased global LV load significantly impacts LV myocardial systolic function, whereas no independent association with low EF was found. As shown by our multivariate analyses, increased global LV load influenced stress-corrected midwall shortening independent of LV geometry, LV hypertrophy, and sex, and the presence of an valvuloarterial index >7 mm Hg/ml·m2.04, the value most discriminative in predicting low stress-corrected midwall shortening, increased the probability of having low stress-corrected midwall shortening by 51%, adjusting for the other variables in the model. Of note, this threshold value is about 10% lower than the previously reported valvuloarterial impedance threshold for low EF of 5 mm Hg/ml·m2 (2) because indexing for height2.04 yields a higher value than indexing for body surface area.
EF was normal in the overwhelming majority of asymptomatic AS patients, and in multivariate analyses, low EF was only associated with LV hypertrophy, not with global LV load. This finding is in accordance with previous knowledge that EF reflects LV endocardial displacement and not myocardial function and that EF often fails to diagnose LV myocardial systolic dysfunction (27,28). Low EF, as shown by Hein et al. (28) in biopsies from AS patients, is associated with myocyte death and fibrosis, which occur when myocardial compensatory mechanisms are exhausted and may continue even after excessive afterload disappears because of aortic valve replacement. Based on our results, we speculate that myocardial systolic dysfunction, reflected by low stress-corrected midwall shortening, may occur at earlier stages of degeneration, which are dominated by increased density of cellular microtubule network (29) and hypertrophy (28) in response to increased global load.
Clinical implications.
These results have potentially important implications for the evaluation of patients with asymptomatic AS. LV myocardial systolic dysfunction is a common finding in asymptomatic AS (33% of our patients), affecting particularly men, patients with concentric LV hypertrophy, and high global LV load, suggesting combined valvular and arterial disease. A simple 4-term risk score including these covariates can be clinically used in identifying patients with a high risk of low myocardial systolic function (risk score >14). Further studies are needed to evaluate the prognostic impact of measures of LV myocardial systolic dysfunction and global load in AS patients and thus the clinical benefit of calculating stress-corrected midwall shortening and global LV load in patients with asymptomatic AS.
Study limitations.
The present analysis is cross-sectional, and the impact of different levels of global LV load on LV systolic function is assessed by dividing the study population in tertiles of load. Longitudinal follow-up during the planned 4-year duration of the study will provide information about the prognostic implications of the present findings. Measurement of stress-corrected midwall shortening was based on 2-dimensional measurements according to the current recommendations (15). However, they assume homogenous wall thickness in the LV, a limitation that we attempted to avoid by measuring the average septal thickness in patients with asymmetrical hypertrophy of the septum and by excluding patients with coronary artery disease and subsequent wall motion abnormalities.
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Conclusions
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In patients with asymptomatic AS without diabetes or known artery disease recruited in the SEAS study, EF was generally preserved, whereas LV myocardial dysfunction was present in 33% of patients. LV myocardial dysfunction was particularly common in patients with increased global LV load, and especially in the subgroup with low-flow AS, and was associated with more concentric LV geometry, LV hypertrophy, and male sex. Assessing LV myocardial function may be helpful in identifying these patients with impaired intrinsic myocardial dysfunction in spite of normal EF. However, the prognostic implication of LV myocardial dysfunction in asymptomatic AS patients with normal EF is currently unknown and needs to be addressed in future research.
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Footnotes
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The SEAS (Simvastatin Ezetimibe in Aortic Stenosis) Echocardiography Core Laboratory was supported by MSP Singapore Company, LLC, Singapore, a partnership between Merck Co., Inc., and the Schering-Plough Corporation. Drs. Wachtell and Gerdts have received honoraria for occasional lectures at scientific symposia sponsored by Merck/Schering-Plough Pharmaceuticals and as members of the Scientific Steering Committee in the SEAS study. Dr. Ray has received payments for recruitment into the study and for speakers' bureau appointments. Dr. Devereux has received honoraria from and served as a consultant for Merck & Co., Inc.
* Reprint requests and correspondence: Dr. Dana Cramariuc, Department of Heart Disease, Haukeland University Hospital, NO-5021 Bergen, Norway (Email: dana.cramariuc{at}helse-bergen.no).
Manuscript received May 28, 2008;
revised manuscript received December 19, 2008,
accepted December 24, 2008.
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