Background
Significant mitral regurgitation (MR) may reduce a pressure gradient of aortic stenosis (AS) by decreasing forward stroke volume. The study objective was to evaluate whether significant MR can cause inconsistency when assessing the severity of AS.
Methods
Among 5,355 patients diagnosed with AS from 2000 to 2015, 68 were retrospectively found to have concomitant significant (moderate or greater) MR and normal left ventricular ejection fractions in normal sinus rhythm (AS with MR). As a control group, 136 patients with trivial or no MR were selected who were matched by age, gender, and left ventricular end-systolic volume (AS without MR). Nonlinear regression was performed for data pairs (aortic valve area [AVA] vs mean pressure gradient [MPG]) using the formula AVA = a + b /√MPG. Composite clinical events were defined as aortic valve surgery warranted by the development of symptoms or left ventricular dysfunction, admission because of heart failure, and death.
Results
The forward stroke volume index was significantly lower in the AS with MR group than in the AS without MR group (43.8 ± 8.3 vs 49.2 ± 10.2 mL/m 2 , P < .004). A significant group difference was found with respect to the relationship between (indexed) AVA and MPG (AVA, 0.02 + 4.43/√MPG vs −0.06 + 5.60/√MPG [ P for interaction = .04]; indexed AVA, 0.03 + 2.66/√MPG vs −0.03 + 3.47/√MPG [ P for interaction = .01]). An AVA of 1.0 cm 2 corresponded to MPGs of 20.3 and 28.2 mm Hg for the groups with and without MR, respectively. Conversely, an MPG of 40 mm Hg corresponded to AVAs of 0.72 and 0.83 cm 2 for the groups with and without MR, respectively. Among patients with MPGs < 40 mm Hg, clinical event rates were significantly higher in those with MR compared with those without MR ( P = .009).
Conclusions
This quantitative analysis demonstrated that AS severity assessed by MPG measurement may be underestimated, and thus AVA measurement is essential in patients with combined significant MR.
Highlights
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Lower forward stroke volume is induced by significant MR.
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Significant MR can be a cause of inconsistency when assessing AS severity.
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AS severity assessed by MPG may be underestimated in patients with AS and MR.
Aortic valve area measurement is essential in patients with AS and significant MR.
Accurate grading of the severity of aortic stenosis (AS) is crucial for the timely management of patients and is currently based on multiple hemodynamic parameters obtained from comprehensive echocardiographic measurements. Three parameters, transvalvular peak flow velocity (V peak ), mean pressure gradient (MPG), and aortic valve area (AVA), are at the center of this consideration, and Doppler evaluation of the severity of AS using these variables is well validated in human studies, showing excellent correlations with invasive hemodynamic measurements. Inherent variability of the measurements and calculations of these parameters exist, in that V peak and MPG are strongly affected by the degree of stroke volume and cardiac output, whereas AVA is far less flow dependent. Accordingly, discordance in relations between AVA and transaortic V peak or MPG could be possible, particularly in specific patient subgroups such as those with significant aortic regurgitation or reduced left ventricular (LV) function, sometimes raising uncertainty about the actual severity of AS.
In the same context, there is often discordance between echocardiographic measurements when trying to determine the severity of AS in patients with preserved LV ejection fractions (LVEFs). In addition to the technical challenges, it is now well known that inconsistent grading is quite common in patients with pronounced concentric LV remodeling, small LV size, and intrinsic myocardial dysfunction despite preserved LVEF. Apart from these conditions, hemodynamic influence provided by concomitant mitral regurgitation (MR) also has been suggested as a source of variation in grading of AS severity. However, this issue has never been systematically addressed, to our knowledge. The objective of this case-control study was to evaluate the hypothesis that significant MR can be a cause of inconsistency when assessing the severity of AS.
Methods
Subjects
From 2000 to 2015, all patients who underwent echocardiography at Asan Medical Center were retrospectively assessed for their eligibility. Inclusion criteria for the case group (AS with MR) were patients diagnosed with AS (calculated AVA ≤ 2.0 cm 2 ) with normal sinus rhythm, normal LV systolic function (defined as LVEF ≥ 50%), and at least a moderate extent of MR. The severity of MR was assessed comprehensively by using effective regurgitant orifice area, jet area, and vena contracta, as recommended in the American Society of Echocardiography and European Association of Cardiovascular Imaging guidelines. Patients with any regional wall motion abnormalities, mitral stenosis (defined as mitral valve area < 2.0 cm 2 ), more than mild aortic regurgitation, and incomplete data to calculate AVA or stroke volume were excluded. In patients with more than one adequate study, only the earliest study was used for analysis, and the following studies were excluded. As a potential control, patients with AS with trivial or no MR, confirmed by multiple echocardiographic windows, were selected from the database. Among them, individual 1:2 matching to the cases on the basis of age (±5 years), sex (identical), and LV end-systolic volume (±10 mL) was performed by an independent statistician (S.H.) to create the control group (AS without MR). Digitally stored echocardiographic images of the eligible patients were reviewed again by experienced echocardiography specialists (J.M.S., B.J.S., and J.A.H.) for study inclusion. The classification of the main cause of AS or MR was done according to the consensus of these specialists. Approval was obtained from the local institutional ethics committee before data collection.
Echocardiographic Evaluation
Comprehensive two-dimensional and Doppler echocardiographic examinations were performed on all patients according to the guidelines for the clinical application of echocardiography. LV end-systolic volume and end-diastolic volume and LVEF were obtained using the biplane Simpson method. V peak was recorded by achieving parallel alignment of the continuous-wave beam with the direction of the stenotic jet flow using the apical, right parasternal, or suprasternal window, and the value that yielded the highest velocity signal was selected. The MPG across the aortic valve was calculated automatically using the velocity profile tracing and modified Bernoulli equation.
LV forward stroke volume was estimated using the product of time-velocity integral (TVI) measured by pulsed-wave Doppler and the cross-sectional area (CSA) of the LV outflow tract (LVOT), which was obtained by measuring the diameter ( d ) of the LVOT (CSA LVOT = π × [ d LVOT /2] 2 ). Forward stroke volume was indexed to body surface area. AVA was calculated from the continuity equation using these measurements (AVA = CSA LVOT × TVI LVOT /TVI AS ). Severe AS was defined as AVA < 1.0 cm 2 or indexed AVA < 0.6 cm 2 /m 2 .
Clinical Follow-up
Clinical outcomes of patients were evaluated by review of medical records and telephone communication, and composite clinical events were defined as aortic valve surgery warranted by the development of symptoms or LV dysfunction, admission for heart failure, and death.
Statistical Analysis
Complete clinical and echocardiographic data were collected by careful analysis of in-hospital medical records. Numeric variables are summarized as mean ± SD and nominal variables as proportions. Between-group comparisons were performed using generalized estimating equations for the matched case-control data set. Nonlinear regression was used to generate a fitted curve for data pairs of AVA and MPG using the formula AVA = a + b /√MPG. Linear regression was used to generate a fitted line for data pairs of MPG and maximal pressure gradient using the formula MPG = a + b × maximal pressure gradient. Nonlinear regression was used to generate a fitted curve for data pairs of MPG and V peak using the formula MPG = a × (V peak ) b . To assess the study hypothesis, generalized estimating equations were used to evaluate whether there were between-group differences in the fitted curves.
Cumulative incidence curves were generated according to the Kaplan-Meier method and compared using the log-rank test. Each patient was censored at the date of his or her final follow-up or at 2 years, whichever came first.
All reported P values are two-sided, and P values < .05 were considered to indicate statistical significance. R version 3.32 (R Foundation for Statistical Computing, Vienna, Austria) was used for statistical analyses.
Results
Clinical and Echocardiographic Characteristics
A total of 76 patients were found to be eligible for the case group in this study. Among them, matched control subjects could not be found in eight cases because of extremes of age or LV end-systolic volume, and consequently these patients were excluded ( Figure 1 ). Among 2,882 candidates with trivial or no MR, 136 patients (AS without MR) were randomly matched as control subjects by age, sex, and LV end-systolic volume to the final 68 case patients (AS with MR). Fifty patients with moderate MR and 18 patients with severe MR were included in the group of AS with MR. The indications of echocardiographic examinations in these patients were dyspnea in 32 (47.1%), chest pain in 16 (23.5%), syncope in two (2.9%), and abnormal electrocardiographic or chest radiographic findings in the remaining 18 (26.5%). The main causes of MR were rheumatic ( n = 19), functional ( n = 17), and degenerative ( n = 32). Of note, two patients with rheumatic AS were each classified as having functional and degenerative MR, while one with bicuspid AS had rheumatic MR. Baseline clinical data of our study population are summarized in Table 1 . The groups did not differ significantly in terms of age, gender ratio, or cardiovascular risk factors. No patients had thyroid disease or were receiving dialysis for the end-stage renal disease. One hundred twenty-four patients (61%) were previously diagnosed with hypertension, and there was no difference in blood pressure, which was measured at the time of the index echocardiography, between the two groups. Forty-two patients (21%) who had histories of coronary artery disease were previously diagnosed with stable angina. Significant dyspnea (New York Heart Association functional class ≥ III) was present in 46 patients (23%) and was more frequent in the AS with MR group than in the AS without MR group (32% vs 18%, P = .03). Fourteen patients (7%) had experienced syncope, and the proportions did not differ (9% vs 6%, P = .62) between groups.
| Variable | Total | AS with MR | AS without MR | P ∗ |
|---|---|---|---|---|
| ( N = 204) | ( n = 68) | ( n = 136) | ||
| Demographics | ||||
| Age (y) | 70.0 ± 11.8 | 70.2 ± 12.0 | 69.9 ± 11.7 | .85 |
| Men | 69 (33.8) | 23 (33.8) | 46 (33.8) | ≥.99 |
| Body surface area (m 2 ) † | 1.75 ± 0.4 | 1.71 ± 0.5 | 1.77 ± 0.4 | .19 |
| Systolic blood pressure (mm Hg) | 127 ± 18 | 124 ± 22 | 128 ± 16 | .17 |
| Diastolic blood pressure (mm Hg) | 72 ± 12 | 71 ± 12 | 72 ± 11 | .31 |
| Mean blood pressure (mm Hg) | 90 ± 12 | 89 ± 14 | 91 ± 12 | .19 |
| Heart rate (beats/min) ‡ | 69 ± 13 | 68 ± 13 | 69 ± 13 | .78 |
| Coexisting conditions | ||||
| Hypertension | 124 (60.8) | 37 (54.4) | 87 (64.0) | .20 |
| Diabetes mellitus | 49 (24.0) | 12 (17.6) | 37 (27.2) | .15 |
| Hyperlipidemia | 62 (30.4) | 23 (33.8) | 39 (28.7) | .45 |
| History of smoking | 41 (20.1) | 14 (20.6) | 27 (19.9) | .32 |
| History of coronary artery disease | 42 (20.6) | 17 (25.0) | 25 (18.4) | .30 |
| History of ischemic stroke | 24 (11.8) | 11 (16.2) | 13 (9.6) | .16 |
| Chronic kidney disease | 21 (10.3) | 7 (10.3) | 14 (10.3) | ≥.99 |
| Laboratory data | ||||
| Hemoglobin (g/dL) | 12.0 ± 2.2 | 11.5 ± 2.2 | 12.2 ± 2.2 | .07 |
| Creatinine (mg/dL) | 1.3 ± 1.2 | 1.3 ± 1.1 | 1.3 ± 1.3 | .72 |
| Medications | ||||
| Calcium channel blocker | 77 (38.7) | 25 (37.9) | 52 (39.1) | .84 |
| β-blocker | 61 (30.7) | 23 (34.8) | 38 (28.6) | .40 |
| Renin-angiotensin system inhibitor | 84 (41.2) | 26 (38.2) | 58 (42.6) | .55 |
∗ P values are based on generalized estimating equations for the matched case-control data.
† Body surface area was calculated using the Du Bois formula.
Echocardiographic findings of the patients in the two groups are compared in Table 2 . Because the groups were initially matched on the basis of LV end-systolic volume and all subjects had normal LV systolic function, the indexed LV volume measurements were not significantly different between groups. Although total stroke volume measured from LV end-diastolic and end-systolic volumes was similar between groups, forward stroke volume, indexed forward stroke volume, and mean transaortic flow rate were significantly lower in the AS with MR group, mainly because of the difference in LVOT TVI, not the difference in the CSA of the LVOT. A total of 132 (65%) and 123 (60%) patients were graded as having severe AS on the basis of AVA and indexed AVA, respectively. As expected, patients with severe AS were more often included in the AS with MR group ( n = 56 [82%] by AVA) compared with the AS without MR group ( n = 76 [56%] by AVA), and consequently transaortic V peak and MPG were significantly higher, while AVA and indexed AVA were significantly smaller in the AS with MR group.
| Variable | Total | AS with MR | AS without MR | P ∗ |
|---|---|---|---|---|
| ( N = 204) | ( n = 68) | ( n = 136) | ||
| LV end-diastolic volume index (mL/m 2 ) | 66.6 ± 15.9 | 67.4 ± 16.4 | 66.2 ± 15.8 | .65 |
| LV end-systolic volume index (mL/m 2 ) | 25.1 ± 7.2 | 26.0 ± 7.3 | 24.7 ± 7.1 | .23 |
| Total stroke volume index (mL/m 2 ) | 41.5 ± 10.2 | 41.4 ± 10.7 | 41.5 ± 9.9 | .90 |
| LVEF (%) | 62.4 ± 5.1 | 61.5 ± 5.7 | 62.8 ± 4.8 | .11 |
| LV mass index (g/m 2 ) | 126.8 ± 34.8 | 148.0 ± 35.0 | 116.1 ± 29.5 | <.001 |
| Left atrial diameter (mm) | 42.8 ± 8.0 | 48.5 ± 6.5 | 40.0 ± 7.1 | <.001 |
| Tricuspid regurgitation V peak (m/sec) | 2.7 ± 0.7 | 3.2 ± 0.7 | 2.5 ± 0.5 | <.001 |
| LVOT diameter (cm) | 2.01 ± 0.12 | 2.00 ± 0.09 | 2.02 ± 0.15 | .24 |
| CSA (LVOT) (cm 2 ) | 3.35 ± 0.51 | 3.29 ± 0.47 | 3.38 ± 0.53 | .23 |
| LVOT TVI (cm) | 22.9 ± 4.2 | 21.2 ± 3.7 | 23.7 ± 4.2 | <.001 |
| Forward stroke volume (mL) | 76.1 ± 16.5 | 69.4 ± 15.0 | 79.5 ± 16.2 | <.001 |
| Forward stroke volume index (mL/m 2 ) | 47.4 ± 9.9 | 43.8 ± 8.3 | 49.2 ± 10.2 | <.001 |
| LV ejection time (msec) | 321.0 ± 34.6 | 327.2 ± 34.7 | 319.2 ± 34.3 | .15 |
| Mean transaortic flow rate (mL/sec) | 239 ± 54 | 215 ± 47 | 251 ± 53 | <.001 |
| Etiology of aortic stenosis | <.001 | |||
| Degenerative | 136 (66.7) | 40 (58.8) | 96 (70.6) | |
| Bicuspid | 43 (21.1) | 8 (11.8) | 35 (25.7) | |
| Rheumatic | 25 (12.3) | 20 (29.4) | 5 (3.7) | |
| Aortic valve V peak (m/sec) | 4.1 ± 1.2 | 4.4 ± 1.1 | 4.0 ± 1.2 | .01 |
| Aortic valve MPG (mm Hg) | 43.4 ± 26.3 | 49.7 ± 25.6 | 40.2 ± 26.1 | .01 |
| Aortic valve TVI (cm) | 97.7 ± 36.1 | 107.0 ± 37.5 | 93.1 ± 34.6 | .01 |
| Aortic valve area (cm 2 ) | 0.89 ± 0.37 | 0.73 ± 0.31 | 0.97 ± 0.38 | <.001 |
| Aortic valve area index (cm 2 /m 2 ) | 0.55 ± 0.23 | 0.46 ± 0.18 | 0.60 ± 0.24 | <.001 |
| Doppler velocity index | 0.27 ± 0.11 | 0.22 ± 0.10 | 0.29 ± 0.10 | <.001 |
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