Abstract
Background:
Aortic valve area (AVA) ≤1.0cm2 is a defining characteristic of severe aortic stenosis (AS). AVA can be underestimated at low transvalvular flow rate. Yet, the impact of flow rate on prognostic value of AVA ≤1.0cm2 is unknown and is not incorporated into AS assessment.
Objectives:
We aimed to evaluate the effect of flow rate on prognostic value of AVA in AS.
Methods:
We studied 1,131 patients with moderate or severe AS and complete clinical follow up as part of a longitudinal database. We evaluated effect of flow rate (ratio of stroke volume to ET) on prognostic value of AVA ≤1.0cm2 for time to death, adjusting for confounders. Sensitivity analysis was performed to identify the optimal cutoff for prognostic threshold of AVA. We validated findings in a separate external longitudinal cohort of 939 patients.
Results:
Flow rate had a significant effect on prognostic value of AVA. AVA ≤1.0cm2 was not prognostic for mortality (p=0.15) if AVA was measured at flow rates below median (≤242mL/s). In contrast, AVA ≤1.0cm2 was highly prognostic for mortality (p=0.003) if AVA was measured at flow rates above median (>242mL/s). Findings were irrespective of multivariable adjustment for age, sex and SAVR/TAVR (as time-dependent covariates), comorbidities, medications and echocardiographic features. AVA ≤1.0cm2 was also not an independent predictor of mortality below median flow rate in the validation cohort. The optimal flow rate cutoff for prognostic threshold was 210mL/s.
Conclusions:
Transvalvular flow rate determines prognostic value of AVA in AS. AVA measured at low flow rate is not a good prognostic marker and therefore not a good diagnostic marker for truly severe AS. Flow rate assessment should be incorporated into clinical diagnosis, classification and prognosis of AS.
Keywords: aortic stenosis, low gradient, low flow, flow rate, prognosis, outcome
Condensed Abstract
The impact of transvalvular flow rate on prognostic value of aortic valve area (AVA) is unknown and is not incorporated into AS assessment. In 1,131 patients with moderate or severe AS and complete clinical follow up, flow rate had a significant effect on AVA’s prognostic value, independent of confounders. AVA ≤1.0cm2 was not prognostic for mortality if measured at low flow rate. In contrast, AVA ≤1.0cm2 was highly prognostic for mortality if measured at sufficient flow rate (optimal threshold 210 mL/s). Findings were reproduced in a separate longitudinal cohort (n=939). Transvalvular flow rate determines prognostic value of AVA in AS.
Introduction
Aortic stenosis (AS) is a major cause of morbidity and mortality, and is projected to increase in prevalence in the context of aging populations.[1] With easier access to valve replacement therapy,[2] the significant uncertainty about true stenosis severity in a large proportion of AS patients, such as low gradient AS, mandates a careful approach to diagnosis and prognostication.[3] Aortic valve area (AVA), measured by Doppler echocardiography and application of the continuity equation, is a central criterion of AS assessment.[4–6] The threshold AVA to define severe AS has been set as 1.0cm2 (≤1.0cm2 in Europe and <1.0cm2 in the United States).[4,5]
Flow state is important in the assessment of AS. Current assessment of flow uses a volume-based metric (stroke volume index, SVi).[7] However, volume is fundamentally different to flow, the latter defined as volume per unit time (transvalvular flow rate).[8] AVA measurement is highly dependent on transvalvular flow rate (Q), the ratio of stroke volume (SV) to ejection time (ET).[9–11] Q represents the mean volume of blood passing through the aortic valve per unit time during ventricular ejection.
Maximal (or “true”) AVA (which would be measured under normal flow conditions) may not be induced at low Q due to inadequate valve opening. Hence, AVA at low Q is not necessarily representative of true stenosis severity. Despite this, the effect of Q on prognostic value of AVA remains unknown and thus unaccounted for in current guidelines. No study to date has evaluated the impact of flow state on the prognostic value of AVA in AS.
We aimed to evaluate the effect of Q on prognostic value of AVA for mortality in AS. We hypothesized that transvalvular Q modifies the prognostic value of AVA in AS, such that low AVA (≤1.0cm2) determined at low Q would be less prognostic than if measured at high Q. We additionally sought to validate findings in a separate, longitudinal cohort, and assess the value of quantifying flow state using Q versus stroke volume.
Methods
Primary cohort
We included patients with moderate or severe AS defined by AVA <1.5cm2 or mean gradient ≥20mmHg who underwent echocardiography between 2006 and 2016. Moderate AS was included as a referent group for non-severe AS. Quantitative data were determined from values reported in the official clinical read by an attending cardiologist with level III certification in echocardiography. We excluded patients with aortic valve prostheses; left ventricular outflow tract velocity ≥1.6m/s; moderate or greater aortic regurgitation; moderate or greater mitral regurgitation; supravalvular or subvalvular aortic stenosis; aortic coarctation or aortic dissection. 3404 unique patients were identified. From this group, we evaluated patients whose primary care was longitudinally based at our center, meaning that their clinical follow up data was complete for this study. This left 1,131 patients for analysis (Figure S1–Supplement). Baseline comorbidities and medications were determined using the electronic health record (EHR). Aortic valve replacements by open surgical aortic valve replacement (SAVR) or transcatheter aortic valve replacement (TAVR) were identified using the Current Procedural Terminology (CPT) coding system. Mortality data was obtained from the EHR which integrated social security and clinical death records to identify dates of death. Despite this integrated system, date of death could not be determined in one patient. A patient’s first available echocardiogram in the study period was used to source echocardiographic data.
In each patient, we calculated the Q, which is traditionally defined by the ratio of stroke volume to ejection time: Q=SV/ET. The echocardiography database did not routinely record SV or ET; therefore we calculated Q with a mathematically equivalent method using the available data as explained in the Supplement. In brief, the derivation method utilizes the principle that Q is not only the ratio of volume to time, but also the product of area and mean velocity (Figure S2 - Supplement). We validated our derivation method against Q measured using SV and ET in our validation cohort (Figure S3–Supplement).
Statistics
Patients were stratified by Q above and below the median. We compared baseline characteristics using two-tailed t-test for normally distributed data, Mann-Whitney U test for non-normal data (assessed by skewness statistic <−0.5 or >0.5) and Chi-squared test for proportions. We compared the prognostic value of AVA ≤1.0cm2 at Q above and below the median using Cox proportional hazards models. Models for time to death (all-cause mortality) were adjusted for age, sex and aortic valve replacement (SAVR or TAVR), including time to SAVR or TAVR using time-dependent covariate analysis. We made further multivariable adjustment for baseline comorbidities, medications and echocardiographic features that were significantly different at baseline between patients with Q above and below the median.
Effect modification of Q on AVA’s prognostic value was confirmed using measurement of interaction effect for mortality prediction above and below the median Q.
Sensitivity analysis was performed to identify the lowest Q threshold above which prognostic significance of AVA ≤1.0cm2 for mortality was maintained.
Where analyses note comparisons between Qs above and below the median, exact dichotomization was such that below median represents ≤ median while above median represents > median. The same applies to the validation cohort.
Statistical analyses were performed using IBM SPSS Version 25 (IBM Corporation, Armonk, NY).
Validation cohort
The validation cohort was comprised of patients from a previously described longitudinal cohort from Quebec Heart and Lung Institute, Canada.[6] From the original 1065 patients, 116 were excluded for not meeting inclusion criteria (AVA ≤1.5 cm2 or MG ≥20 mmHg) and 10 were excluded for missing transvalvular gradient data, leaving 939 patients. Using Cox proportional hazards models, we again evaluated the impact of Q on prognostic value of AVA. In the validation cohort where both derived and measured Q were available, references to Q refer to derived Q unless otherwise specified.
Ethics Approval
Studies were approved by the Massachusetts General Hospital/Partners Institutional Review Board and the Ethics Committee of the Quebec Heart and Lung Institute. Informed consent was not required.
Results
Primary cohort
In the primary cohort (n=1,131; 60% male), mean age was 77±11 years. Q was normally distributed, with mean Q 243±52 mL/s and median Q 242mL/s (Figure S4, Supplement). Baseline characteristics are shown in Table 1 stratified by Q above and below the median. Patients with Q below median (Q≤242mL/s) were typically older and had more comorbidities. Left ventricular ejection fraction (EF) was normal in the majority of the cohort (91% of patients had EF ≥50%).
Table 1:
Baseline characteristics by flow rate.
| Below median Q (n=566) | Above median Q (n=565) | Sig. | |
|---|---|---|---|
| Demographics | |||
| Age (mean±SD) | 78.9 ± 10.5 | 74.5 ± 11.0 | <0.001 |
| Sex (n, % male) | 269/566, 47.5% | 408/565, 72.2% | <0.001 |
| Race (n, % white) | 511/566, 90.3% | 531/565, 94.0% | NS (0.24) |
| Body surface area (m2) (mean±SD) | 1.8 ± 0.2 | 2.0 ± 0.2 | <0.001 |
| Comorbidities | |||
| Diabetes mellitus (n, %) | 160/566, 28.3% | 177/565, 31.3% | NS (0.26) |
| Hypertension (n, %) | 484/566, 85.5% | 470/565, 83.2% | NS (0.28) |
| Heart failure (n, %) | 207/566, 36.6% | 151/565, 26.7% | <0.001 |
| Coronary artery disease (n, %) | 220/566, 38.9% | 182/565, 32.2% | 0.019 |
| Myocardial infarction (n, %) | 130/566, 23.0% | 105/565, 18.6% | NS (0.07) |
| Peripheral vascular disease (n, %) | 227/566, 40.1% | 220/565, 38.9% | NS (0.69) |
| Hyperlipidemia (n, %) | 50//566, 89.8% | 504/565, 89.2% | NS (0.76) |
| Atrial fibrillation (n, %) | 199/566, 35.2% | 130/565, 23.0% | <0.001 |
| Chronic kidney disease (n, %) | 171/563, 30.4% | 126/559, 22.5% | 0.003 |
| Never smoked (n, %) | 156/483, 32.3% | 139/483, 28.7% | NS (0.42) |
| Medications | |||
| Beta blocker (n, %) | 388/566, 68.6% | 355/565, 62.8% | 0.043 |
| ACE inhibitor (n, %) | 264/566, 46.6% | 264/565, 46.7% | NS (0.98) |
| ARB (n, %) | 106/566, 18.7% | 109/565, 19.3% | NS (0.81) |
| Potassium sparing diuretics (n, %) | 30/566, 5.3% | 23/565, 4.1% | NS (0.33) |
| Calcium channel blocker | |||
| Dihydropyridine (n, %) | 168/566, 29.7% | 166/565, 29.4% | NS (0.91) |
| Non-dihydropyridine (n, %) | 56/566, 9.9% | 54/565, 9.6% | NS (0.85) |
| Nitrate (n, %) | 148/566, 26.1% | 138/565, 24.4% | NS (0.51) |
| Statin (n, %) | 433/566, 76.5% | 421/565, 74.5% | NS (0.44) |
| Antiplatelet (n, %) | 422/566, 74.6% | 415/565, 73.5% | NS (0.67) |
| Oral anticoagulant (n, %) | 164/566, 29.0% | 130/565, 23.0% | 0.022 |
| Echocardiographic data | |||
| AVA (cm2) (mean±SD) | 0.90 ± 0.23 | 1.16 ± 0.23 | <0.001 |
| Mean gradient (mmHg) (mean±SD) | 28.2 ± 14.0 | 30.8 ± 13.3 | <0.001 |
| Q (mL/s) (mean±SD) | 203.4 ± 28.8 | 283.6 ± 37.0 | <0.001* |
| Peak gradient (mmHg) (mean±SD) | 49.9 ± 22.3 | 53.7 ± 21.6 | <0.001 |
| Bicuspid (n, %) | 34/566, 6.0% | 56/565, 9.9% | 0.02 |
| LVEDD (mm) (mean±SD) | 42.6 ± 6.5 | 44.5 ± 6.2 | <0.001 |
| LVESD (mm) (mean±SD) | 28.7 ± 7.3 | 28.6 ± 5.9 | NS (0.34) |
| Ejection fraction (n, %) (mean±SD) | 62.8 ± 13.8 | 67.8 ± 9.5 | <0.001 |
| Aortic sinus diameter (mm) (mean±SD) | 31.3 ± 4.2 | 33.5 ± 3.9 | <0.001 |
| Ascending aortic diameter(mm) (mean±SD) | 33.1 ± 4.6 | 35.0 ± 4.6 | <0.001 |
| Interventricular septal thickness (mm) (mean±SD) | 12.3 ± 2.2 | 12.7 ± 2.2 | 0.006 |
| Posterior wall thickness (mm) (mean±SD) | 11.2 ± 1.9 | 11.4 ± 1.9 | NS (0.06) |
| LA anteroposterior dimension (mm) (mean±SD) | 39.3 ± 6.5 | 39.9 ± 6.2 | NS (0.11) |
| LVOT diameter (cm) (mean±SD) | 2.01 ± 0.18 | 2.17 ± 0.18 | <0.001 |
| LVOT velocity (m/s) (mean±SD) | 0.95 ± 0.19 | 1.12 ± 0.18 | <0.001 |
Median Q 242mL/s. Abbreviations: AVA: aortic valve area; ACE: angiotensin converting enzyme; ARB: angiotensin receptor blocker; LA: left atrium; LVEDD: left ventricular end-diastolic dimension; LVESD: left ventricular end-systolic dimension; LVOT: left ventricular outflow tract; Q: transvalvular flow rate.
The data presented in this table are dichotomized by median flow rate, therefore the p-value for this variable is shown for illustrative purposes only.
In patients with low gradient severe AS, Q was below median in 312/383 (82%) of cases, compared to only 51% of cases with high gradient severe AS (p<0.001) (Figure 1). Q was lower overall in women vs. men (225.9±45.8mL/s vs. 255.3±52.7mL/s, p<0.001). In women, Q was below median in 65% of cases, compared to in only 40% of men (p<0.001) (Figure 2). Women also had smaller ventricular dimensions (40.4±5.7mm vs. 45.6±6.0mm, p<0.001).
Figure 1: Relationship between aortic stenosis subgroups and flow rate (Q). Panel A: Subgroups of AS by flow rate; Panel B: Flow rates in high gradient vs. low gradient severe AS.
101/197 (51%) of high gradient severe AS had Q ≤ median. 312/383 (82%) of low gradient AS had Q ≤ median (≤242mL/s). Abbreviations: Sev AS HG: high gradient severe AS (n=197); Mod AS LG: moderate AS with low gradient (n=536); Sev AS LG: low gradient severe AS (n=383); Mod AS HG: moderate AS with high gradient (n=15); Q: transvalvular flow rate.
Figure 2: Flow rate by sex.
297/454 (65%) female patients had Q ≤ median (≤242mL/s). 269/677 (40%) of male patients had Q ≤ median. Abbreviation: Q: transvalvular flow rate.
Median follow up time was 3.9 years (maximum 7.3 years). There were 395/1131 (34.9%) deaths in follow up, with a median time to death of 1.9 years. Patients with Q below the median had worse survival than those with Q above the median (Figure 3). Median time to SAVR/TAVR was 0.8 years. Rates of mortality and aortic valve replacement by subgroup of Q are reported in Table 2.
Figure 3: Survival in aortic stenosis stratified by resting transvalvular flow rate below and above the median.
Patients with flow rate below the median (≤242mL/s) had worse overall survival than patients with flow rate above the median. Abbreviation: Q: transvalvular flow rate.
Table 2:
Mortality rate and intervention rate by flow rate.
| Below median Q (n=566) | Above median Q (n=565) | Sig. | |
|---|---|---|---|
| Death | 232/566 (41%) | 163/565 (29%) | <0.001 |
| Aortic valve replacement (SAVR or TAVR) | 166/566 (29%) | 188/565 (33%) | NS |
Median Q 242mL/s. Significance testing by Chi-square. Abbreviations: SAVR: surgical aortic valve replacement; TAVR: transcatheter aortic valve replacement; Q: transvalvular flow rate.
Q determined the prognostic value of AVA. If AVA was measured below median Q, AVA ≤1.0cm2 was not prognostic for mortality (HR 1.25, 95% CI 0.92–1.68, p=0.15). In contrast, if AVA was measured at a Q above median, AVA ≤1.0cm2 was highly prognostic for mortality (HR 1.66, 95% CI 1.19–2.33, p=0.003) (Table 3). These findings were irrespective of age, sex and valve replacement with SAVR or TAVR (as time-dependent covariates). Findings persisted after further multivariable adjustment for potential confounder variables (comorbidity, medication and echocardiographic) which were significantly different at baseline between patients with Qs above or below the median (Table 4).
Table 3:
Prognostic value of AVA ≤1.0cm2 by flow rate.
| Hazard ratio for death* of AVA ≤ 1.0cm2 | 95% CI for HR | Sig. | |
|---|---|---|---|
| Below median Q | 1.25 | 0.92–1.68 | NS (0.15) |
| Above median Q | 1.66 | 1.19–2.33 | 0.003 |
Median Q 242mL/s.
Cox proportional hazards model for time to death (all-cause mortality), adjusted for age, sex and surgical or transcatheter aortic valve replacement (as time-dependent covariates). Abbreviations: AVA: aortic valve area; Q: transvalvular flow rate.
Table 4:
Prognostic value of AVA ≤1.0cm2 by flow rate after additional multivariable adjustment for comorbidity, medication and echocardiography variables.
| Hazard ratio for death* of AVA ≤ 1.0cm2 | 95% CI for HR | Sig. | |
|---|---|---|---|
| Below median Q | 1.06 | 0.70–1.60 | NS (0.80) |
| Above median Q | 2.49 | 1.41–4.37 | 0.002 |
Median Q 242mL/s.
Cox proportional hazards model for time to death (all-cause mortality), adjusted for age, sex, surgical or transcatheter aortic valve replacement (as time-dependent covariates), baseline diagnosis of heart failure, coronary artery disease, atrial fibrillation, chronic kidney disease, use of beta blocker or oral anticoagulant, body surface area, absolute transvalvular flow rate, bicuspid valve status, mean aortic valve gradient, peak aortic valve gradient, left ventricular internal dimension at end-diastole, left ventricular ejection fraction, aortic sinus diameter, ascending aorta diameter, interventricular septal thickness, left ventricular outflow tract diameter and left ventricular outflow tract velocity. Overall result pattern unchanged after removal of peak gradient from the model (due to collinearity with mean gradient) or if model run as backward stepwise regression. Abbreviations: AVA: aortic valve area; Q: transvalvular flow rate.
Interaction testing confirmed the effect of Q on AVA’s prognostic value (Table S1, Supplement). With AVA and Q binarized (≤ / >1.0 cm2 and ≤ / > median, respectively), the interaction of the two variables was significant for prediction of mortality. With AVA and Q as continuous variables, interaction testing confirmed the confounding effect of low Q on AVA’s prognostic value seen in earlier hazard models.
Sensitivity analysis was performed by reducing the threshold value by 10mL/s increments to find the lowest Q cutoff above which prognostic value of AVA was maintained (Table S2–Supplement). Prognostic value was significant above a cutoff of 242mL/s (median) through 210mL/s. We used 210mL/s as the optimal cutoff.
Validation cohort
Baseline characteristics of the validation cohort are described in Table S3–Supplement with a comparison to the primary cohort. The majority (84%) of patients had EF≥50%. Mean and median Q in the validation cohort (216.8±53.0mL/s and 211.7 mL/s, respectively) were lower than in the primary cohort (p<0.001).
The linear regression between the derived and measured Q closely approximated a line of identity providing strong validation of our Q derivation method (Figure S3–Supplement).
Follow up time was longer in the validation cohort (median follow up time 5.8 years, maximum follow up 13.5 years) than in the primary cohort. There were 482/939 (51.3%) deaths and 542/939 (57.7%) SAVRs or TAVRs in the validation cohort. Median time to death was 3.8 years. Median time to SAVR/TAVR was 0.6 years. As was the case in the primary cohort, AVA ≤1.0cm2 was not independently predictive of mortality at Q below median, while at Q above median, AVA ≤1.0cm2 was independently predictive of mortality (Table S4–Supplement).
Q provided unique information to SVi about classification of flow state. Q was below the median in 205/619 (33.1%) of patients with conventionally defined “normal flow” (SVi ≥35mL/m2) (Figure 4). In patients from the validation cohort with normal SVi (≥35mL/m2) (n=619), where AVA would traditionally be considered to have good predictive value for outcomes, AVA ≤1.0cm2 was only prognostic for mortality when Q was above median (HR 1.65, 95% CI 1.19–2.28, p=0.003). That is, despite a normal SVi, AVA ≤1.0cm2 was not prognostic for mortality when Q was below median (HR 1.28, 95% CI 0.85–1.92, p=0.24) (Table 5). Additionally, in patients with normal SVi, patients with Q below median had worse survival overall compared with patients with Q above median (HR 1.40, 95% CI 1.10–1.79, p=0.006) (Figure 5). ET was significantly longer in patients with low Q and normal SVi, compared with patients with low Q and low SVi (337.5±31.8 ms vs. 304.7±34.0 ms, p<0.001). When prognostic value of AVA was compared by SVi criteria (<35 and ≥35 mL/m2), SVi was not able to discriminate the prognostic value of AVA until Q was incorporated as a covariate (Table S5–Supplement). Receiver operating characteristics of Q and SVi are described in Table S6–Supplement.
Figure 4: Stroke volume versus flow rate classification of flow state.
While 265/320 (82.8%) of patients with low stroke volume index had flow rate below median (≤212 mL/s), 205/619 (33.1%) of patients with normal stroke volume index also had flow rate below median in the validation cohort. Abbreviation: Q: transvalvular flow rate.
Table 5:
Prognostic value of AVA ≤1.0cm2 according to transvalvular flow rate in patients with normal stroke volume index ≥35mL/m2.
| Hazard ratio for death* of AVA ≤ 1.0cm2 | 95% CI for HR | Sig. | |
|---|---|---|---|
| Below median Q | 1.28 | 0.85–1.92 | NS (0.24) |
| Above median Q | 1.65 | 1.19–2.28 | 0.003 |
Median Q 212 mL/s.
Cox proportional hazards model for time to death (all-cause mortality), adjusted for surgical or transcatheter aortic valve replacement (as time-dependent covariates). Abbreviations: AVA: aortic valve area; Q: transvalvular flow rate.
Figure 5: Survival stratified by flow rate in patients with normal stroke volume index (≥35mL/m2).
In the validation cohort, even in patients with normal stroke volume index, flow rate below the median (≤212mL/s) was associated with worse overall than flow rate above the median. Abbreviation: Q: transvalvular flow rate.
Discussion
Aortic valve area has poor prognostic value at low transvalvular flow rate
The main finding of this study is that the prognostic value of AVA is dependent upon the transvalvular flow rate at the time of AVA measurement. This was observed and validated using two large, longitudinal cohorts from different institutions. Our data suggest that current guideline recommendations about severity classification based on low AVA cannot be uniformly applied among AS patients. Specifically, based on poor prognostic information of AVA at low Q, our findings raise concerns about the validity of diagnoses of severe AS (using AVA) made at low Q. This is a novel finding with potential to widely impact clinical care of patients with aortic stenosis.
The mechanistic explanation for our findings is based on fundamental principles of material physics and fluid dynamics.[8] The opening of a semi-compliant orifice (stenotic aortic valve) is dependent upon the valve compliance characteristics (severity of stenosis) and the transvalvular flow rate (volume per unit time). At low Q, valve opening may be insufficient to produce the maximal effective orifice area or “true AVA”. We have shown that this phenomenon clinically translates to a poor prognostic value of low AVA, if AVA was measured at low Q.
Our observations are mechanistically supported by studies showing change in AVA with change in Q. In an in vitro model, Voelker et al. showed that changing Q from 100 to 200mL/s changed measured AVA by 24%, while there was minimal change in AVA by changing Q from 200 to 300mL/s.[9] Rask et al. showed that Q significantly altered AVA measurement by continuity equation.[10] They showed that the percentage change in AVA was roughly half (0.56) the percentage change in Q, such that a 50% change in Q (e.g. from 160mL/s to 240mL/s) could alter AVA by 25%.
Our findings are also supported by other studies that have evaluated AS severity classification at different Q in patients with impaired ejection fraction receiving dobutamine infusion. Blais et al. showed that classification of AS by AVA criteria was optimized only if the AVA was extrapolated to a “projected AVA” at a Q of 250mL/s.[11] Chahal et al. showed that classification of AS by AVA criteria in patients with impaired EF was largely sufficient on a resting echocardiogram, without needing dobutamine infusion if resting Q was ≥200mL/s, but dobutamine was needed to reclassify patients if resting Q was <200mL/s.[12] While these studies looked at classification of AS based on agreement of AVA with other echocardiographic metrics at varying Q, our study is the first to evaluate the effect of Q on the prognostic value of AVA for a clinical outcome in longitudinal data. We additionally included patients with normal EF.
The findings of our study, and those of the studies above, suggest that Q should be incorporated into the AS diagnostic and severity classification algorithm. The measurements required to determine Q are readily available in a standard echocardiographic study, and Q calculation could also be automated using routinely reported metrics (AVA, peak velocity, mean gradient) and our derivation method (Supplement, Figure S2 and S3). Specifically, in the presence of low Q and discordant metrics of severity (low AVA and low mean gradient), AVA should be recalculated above the threshold flow conditions necessary to determine the “true AVA” (Central Illustration). While current methods use dobutamine to augment stroke volume or Q in patients with impaired EF, we propose that simple bedside maneuvers could be used to augment Q as part of a standard echocardiographic workflow, even in patients with normal EF. Studies have shown that left ventricular ET can be shortened with hand squeeze exercise.[13,14] In a small supplementary study (details in Supplement), we have verified this by showing that Q could be significantly augmented after only 30 seconds of hand squeeze exercise, due to shortening of ET rather than increase in stroke volume (Figure S5, Supplement). However, this bedside technique requires further investigation. Other bedside approaches worthy of investigation might include leg raising or arm weights.[15] Using non-echocardiographic modalities, such as computed tomography calcium score, could also help clarify aortic stenosis severity in subjects with low Q.[3]
Central Illustration: Algorithm for incorporation of flow rate into assessment of Aortic Stenosis.
AVA measured at Q >210mL/s is prognostic for mortality and therefore valid as a marker of severe AS. Abbreviations: AS: aortic stenosis; AVA: aortic valve area, MG: mean gradient, Q: flow rate. *Further assessment when AVA is invalid may include augmentation of Q and/or use of alternative modalities including computed tomography calcium score.
Our study did not limit findings to patients with impaired EF. We evaluated all moderate or severe AS patients, the overwhelming majority of whom had normal EF. This is clinically important because low gradient AS with preserved EF (“paradoxical” low gradient) is a far more prevalent group than low gradient AS with reduced EF and is an area of diagnostic uncertainty in severe AS.[7,16]
In addition to the novel finding of the impact of Q on prognostic value of AVA, we have confirmed the adverse prognostic impact of low Q itself in AS (Figure 3).[17,18]
Low transvalvular flow rate explains discordant severity metrics in aortic stenosis
Low Q provides a unifying mechanism of discordance between AVA and mean gradient in AS severity assessment. Because severe AS is defined and classified by both low AVA (≤1.0cm2) and high mean gradient (≥ 40 mmHg), our findings are particularly relevant in patients where low AVA is the only echocardiographic feature that meets criteria to define severe AS – namely patients with low gradient severe AS (AVA ≤1.0cm2 and mean gradient <40 mmHg, i.e. “discordant severe AS”). Mean gradient is also dependent on Q, hence at low Q, both AVA and mean gradient can be lower than they would be under normal flow conditions.
This phenomenon explains the predominance of discordant low gradient severe AS in the below median Q group (Figure 1). Q was below the median in 82% (312/383) of patients with low gradient severe AS diagnosis. Importantly, Q assessment can help clarify prognostic value of AVA in this situation of discordance and therefore can also help clarify true AS severity in discordant AS (Central Illustration).
Transvalvular flow rate versus stroke volume index
The widespread awareness of the importance of flow state in AS commenced with appreciation of the importance of stroke volume (and SVi) in AS.[7,16] These descriptions facilitated refined classification, diagnosis, prognosis and therapeutic decision-making in AS. Notably, however, while the term flow is commonly discussed in the AS literature, it is often a volume metric (stroke volume) that is actually being measured and referred to, while true flow itself (defined as volume per unit time) is rarely quantified. The primary aim of our study was not to compare prognostic value of SVi and Q, but rather to assess the impact of flow state on prognostic value of aortic valve area. In doing so, we sought to more accurately measure the flow state in AS by directly measuring the Q, defined by the mean volume of blood passing through the aortic valve per unit time during ventricular ejection (ratio of SV to ET). Recent work from the group of Senior et al. first highlighted the value in assessing flow state in AS by Q as an alternative to SVi.[12,17,18] These studies have described both classification of AS by dobutamine echocardiography in patients with discordant low gradient AS and low EF,[12] but also the effect of flow rate on outcomes,[17] even after intervention.[18] We have sought to build upon this foundation by evaluating the effect of Q on prognostic value of AVA in AS, regardless of EF.
In our data, the classification of flow state by SVi and Q was different. Nearly a third of patients with “normal flow” defined by SVi, in fact had Q below the median (Figure 4). Moreover, Q assessment could also stratify prognosis beyond traditional SVi criteria. In patients with “normal flow” by SVi criteria, having a Q below median was associated with worse survival (Figure 5). Most importantly however, in this group with normal SVi, AVA ≤1.0cm2 was not prognostic for mortality if Q was below median, but AVA ≤1.0cm2 was highly prognostic for mortality when Q was above median (Table 5). Additionally, SVi could not independently discriminate the prognostic value of AVA until Q was considered (Table S5, Supplement). Thus, measurement of Q which incorporates volume and time adds not only to classification, but also prognostication in AS, over and above the use of the current guideline standard,[4] SVi. Volume and flow are not synonymous.
Prolongation of left ventricular ET is the mechanism of low flow rate despite normal stroke volume. This is because transvalvular flow rate is the ratio of SV to ET. Indeed, ET was significantly longer in patients with low Q and normal SVi as compared with patients with low Q and low SVi (337.5±31.8ms vs. 304.7±34.0ms, p<0.001). Prolongation of ET can occur not only due to valvular afterload, but also because of hypertension and age-related arterial stiffness,[19,20] both common in AS (“valvulo-arterial load”).[16] ET prolongation therefore provides insight into the heretofore perplexing but important clinical scenario of low gradient severe AS in the setting of normal stroke volume (a condition currently termed “normal flow low gradient AS”).[21] Indeed, recent work in a propensity matched dataset has shown that the beneficial effect of aortic valve replacement might be better guided by Q rather than SVi.[22] Vamvakidou et al. also showed that low Q, and not low SVi, was prognostic for mortality in multivariable analysis in patients undergoing aortic valve intervention.[18]
Low transvalvular flow rate is more common in women
Women more commonly have discordant metrics of severity and hence pose greater clinical challenges during AS assessment.[23] We saw important sex differences in Q distribution that can explain this observation. Q was below median in 65% of women, as compared with 40% of men (p<0.001) (Figure 2). Knowing Q at the time of AVA calculation is therefore particularly important in women with discordant severe AS.
Limitations
While the retrospective nature of our analysis carries inherent limitations, the primary cohort consisted of patients who had dedicated longitudinal follow up with complete outcome data. We believe that this type of analysis represents the most practical approach available to test our hypothesis in a large cohort. Importantly, our findings were validated in a separate, large longitudinal cohort of patients from a different center, mitigating some of the limitations of retrospective analysis. Indeed, using our approach, the optimal cutoff for prognostic threshold in the primary cohort was identical (rounded to the nearest 10mL/s) to the median for the validation cohort. This preserved our key finding in both cohorts, such that at low Q (below 210mL/s), AVA has poor prognostic value, but above 210mL/s AVA is prognostic. This is despite the fact that Q distribution was lower in the validation cohort, as compared with the primary cohort. Differences in Q distribution between cohorts may have resulted from the validation center being a recognized referral center for low gradient AS, attracting a greater than average proportion of patients with low Q.
While Q adds to the current diagnostic, prognostic and classification framework of AS, it still requires left ventricular outflow tract (LVOT) diameter measurement in its derivation, and hence is subject to be underestimated (along with AVA and SVi) if LVOT diameter is underestimated. Although LVOT diameter was lower in patients with Q below the median than in patients with Q above the median (Table 1), after adjustment for this potential confounder, our observations about the effect of Q on prognostic value of AVA were preserved (Table 4). Moreover, a low AVA and low Q resulting from LVOT underestimation would not alter our overall clinical message urging caution in this very situation (Central Illustration). Future approaches might adopt three-dimensional approaches which could obviate LVOT diameter measurement.[24] In both the primary and validation cohorts, while the presence of atrial fibrillation as a comorbidity was known, it was not known which patients were in atrial fibrillation at the time of echocardiography – a potential measurement confounder. Atrial fibrillation was more common at low Q (Table 1), however after multivariable adjustment for this (Table 4) the key findings of this study remained unchanged, which is reassuring.
Conclusions
Transvalvular flow rate alters the prognostic value of AVA in AS. AVA ≤1.0cm2 is independently prognostic for mortality at normal flow rates. In patients with low flow rates, AVA ≤1.0cm2 is not an independent predictor of mortality related to aortic stenosis and is therefore not a valid defining feature of severe aortic stenosis. Flow rate assessment should be incorporated into diagnosis, classification and prognosis schema for aortic stenosis.
Supplementary Material
Clinical Perspectives.
Competency in Patient Care and Procedural Skills:
In patients with aortic stenosis, transvalvular flow rate is an important determinant of the prognostic value of aortic valve area. Low aortic valve area measured at low flow rate does not reliably identify severe aortic stenosis, while small valve orifice area measured at sufficient flow rate identifies patients at greater risk of mortality.
Translational Outlook:
Prospective investigations are needed to clarify the diagnostic utility of measuring transvalvular flow rate in patients with aortic stenosis.
Acknowledgments
Funding: This work was presented by Dr. Namasivayam at the Samuel A. Levine Early Career Clinical Investigator Award Competition at the American Heart Association Scientific Sessions, November 2019. Dr. Namasivayam is a recipient of a travel stipend and honorarium from the American Heart Association, the St. Vincent’s Clinic Foundation Traveling Fellowship Award and is supported by a Clinical and Research Fellowship from the Division of Cardiology, Massachusetts General Hospital, Harvard Medical School. Dr. Capoulade is supported by a Connect Talent Research Chair from Région Pays de la Loire and Nantes Métropole. Dr. Pibarot is supported in part by grants FDN-143225 and MOP-114997 from Canadian Institutes of Health Research (CIHR) and a grant from the Foundation of the Quebec Heart and Lung Institute. Dr. Pibarot holds the Canada Research Chair in Valvular Heart Diseases from CIHR. Dr. Hung is supported in part by grants R01 HL092101 and U01 HL088942 from the National Heart, Lung, and Blood Institute.
Abbreviations:
- AS
aortic stenosis
- AVA
aortic valve area
- EF
ejection fraction
- ET
ejection time
- LVOT
left ventricular outflow tract
- SAVR
surgical aortic valve replacement
- SV
stroke volume
- SVi
stroke volume index
- TAVR
transcatheter aortic valve replacement
- Q
transvalvular flow rate
Footnotes
Disclosures: None from any author.
Short Tweet: Flow rate (Q) determines AVA’s prognostic value. AVA only prognostic if measured at sufficient Q. #flowratematters #echofirst
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