Baseline pulmonary hypertension (PH) is a predictor of poor outcomes in patients with severe aortic stenosis (AS). Surgical aortic valve replacement is thought to alleviate PH. The aim of this study was to determine the prognostic impact of PH in patients who underwent transcatheter aortic valve replacement (TAVR). An observational cohort study was conducted using prospectively collected data on 277 consecutive patients with severe AS who underwent TAVR at the Mayo Clinic (Rochester, Minnesota) from November 1, 2008, to June 31, 2013. Clinical and echocardiographic data, pulmonary function characteristics, and outcomes stratified by tertiles of pulmonary artery systolic pressure (PASP) were analyzed. From 277 patients who underwent TAVR, 251 patients had PASP assessment at baseline. Those in the highest PASP tertile (PASP ≥49 mm Hg) had more severe chronic lung disease and worse diastolic dysfunction. Being in the highest PASP tertile was an independent predictor of long-term mortality (hazard ratio 2.88, 95% confidence interval 1.15 to 7.23). Patients in the highest PASP tertile had longer lengths of hospital stay, while other short-term outcomes (30-day mortality and readmission, stroke, prolonged ventilation, and reoperation for bleeding) were similar across PASP tertiles. TAVR was associated with a decrease in PASP in the highest PASP tertile at 1 week after the procedure (−8 ± 14 mm Hg) and at 3 months (−7 ± 15 mm Hg) compared with baseline. In conclusion, among patients with severe AS who underwent TAVR, higher baseline PASP was strongly associated with diastolic dysfunction and chronic lung disease. Patients with higher baseline PASP tolerated TAVR relatively well in the early postprocedural phase, with diminished long-term survival. PH should not disqualify patients with severe AS from consideration for TAVR.
In this study, we sought to describe the prognostic significance of pulmonary artery systolic pressure (PASP) in patients who underwent transcatheter aortic valve replacement (TAVR) for severe symptomatic aortic stenosis (AS).
Methods
This was an observational cohort study of prospectively collected data on 277 consecutive patients with symptomatic severe AS who underwent TAVR at the Mayo Clinic (Rochester, Minnesota) from November 1, 2008, to June 31, 2013. This study was approved by the Mayo Clinic Institutional Review Board, and the requirement for informed consent was waived.
Clinical data on patients’ baseline characteristics and hospital stays were prospectively collected. The index echocardiographic examination was defined as the last transthoracic echocardiographic study before TAVR. The transthoracic echocardiogram obtained during the first week after TAVR and from 3 to 6 months after TAVR were used to assess early and late changes in PASP, respectively. Although every patient underwent baseline transthoracic echocardiography, those without adequate tricuspid regurgitation (TR) signals for the estimation of PASP were excluded from this study (n = 26). Follow-up information included vital status at the time of the last clinic visit or telephone contact. Perioperative death was defined as death within 1 month after TAVR or during the same hospitalization.
All echocardiographic studies were performed by registered diagnostic cardiac sonographers using standardized instruments and protocols. Standard M-mode, 2-dimensional, and color Doppler imaging; continuous-wave Doppler examination of tricuspid flow; pulsed-wave Doppler examination of mitral inflow; and Doppler tissue imaging of the lateral mitral annulus were performed in each subject, as previously described. The medial mitral annular tissue Doppler signal was not used, to avoid the effect of heavy calcification in the region in the setting of calcific AS. Aortic valve area (AVA) was derived from the continuity equation: AVA = left ventricular (LV) outflow tract (LVOT) area × ratio of LVOT to aortic valve time-velocity integral, where LVOT area is the cross-sectional area of the LVOT. AVA was indexed to the patient’s body surface area.
PASP was estimated using Doppler echocardiography by calculating the right ventricular–to–right atrial pressure gradient during systole, approximated by the modified Bernoulli equation as 4V 2 , where V is the velocity of the TR jet in meters per second. No patient had 2-dimensional or Doppler evidence of pulmonary valve stenosis or right ventricular outflow tract obstruction, and hence estimated right ventricular systolic pressure was equal to PASP. Right atrial pressure, estimated on the basis of echocardiographic characteristics of the inferior vena cava and assigned a standardized value, was subsequently added to the calculated gradient to estimate PASP.
Pulmonary function testing, including spirometry, was performed in accordance with recommended techniques. Measurements were standardized as percentages of predicted normal values. The electronic medical reports of chest computed tomographic studies performed as part of the workup for TAVR were reviewed for a diagnosis of pulmonary edema, emphysema, or pulmonary fibrosis.
All patients were followed until death (all-cause mortality) or last contact, at which time they were censored. Follow-up was 100% complete, with vital status (February 2014) determined from the Mayo Clinic registration database.
Patients were stratified by baseline PASP tertiles: <36 mm Hg, 36 mm Hg ≥PASP <49 mm Hg, and PASP ≥49 mm Hg (tertiles 1, 2, and 3, respectively). Categorical variables are presented as frequencies with their respective percentages and were compared by using chi-square tests. Column proportions for individual categories were compared using Z tests and Bonferroni’s correction for multiple comparisons. Continuous variables are presented as means ± SD and were compared using one-way analysis of variance with post hoc testing using Bonferroni’s method for multiple comparisons. Analysis of change in PASP was compared using paired-samples Student’s t test. The baseline clinical characteristics of patients who did not have sufficient TR signals for estimating PASP were compared to exclude the risk for bias due to missing data. Kaplan-Meier survival curves for time-to-event variables were constructed on the basis of all available follow-up data and compared using the log-rank test. Patients were censored according to the time of their last follow-up or death. The date of TAVR was considered the start date. Multivariate stepwise backward selection Cox regression analysis was performed to determine the independent predictive value of PASP on long-term mortality. The multivariate analysis incorporated age, gender, and baseline clinical variables related to 2-year mortality with a significance level of p ≤0.10. Data for variables entered in the model were complete except for 18 patients who did not undergo assessment of forced expiratory volume in 1 second before TAVR. Missing data were replaced by the linear trend for using the RMV (replace missing value) function in SPSS (IBM Corporation, Armonk, NY). A 2-sided α level of 0.05 was used for significance testing. All statistical analyses were performed using SPSS version 19.
Results
From November 1, 2008, to June 30, 2013, 277 patients underwent TAVR. Baseline transthoracic echocardiograms were available for all 277 patients, and PASP estimates were available in 251 patients (91%). Patients who did not have sufficient TR signals to estimate PASP (26 patients [9%]) were similar in baseline characteristics, except for more frequent obesity, compared with those who had adequate TR signals ( Supplementary Table A ).
The mean age of the study population was 81 ± 8 years, and 56% were men (n = 155). Eighty patients had PASP <36 mm Hg (tertile 1), 87 patients had PASP ≥36 mm Hg and <49 mm Hg (tertile 2), and 84 patients had PASP ≥49 mm Hg (tertile 3). Baseline characteristics according to PASP tertiles are listed in Table 1 .
| Variable | Pulmonary Artery Systolic Pressure (mmHg) | |||
|---|---|---|---|---|
| Tertile 1 | Tertile 2 | Tertile 3 | p-Value | |
| <36 | ≥36, <49 | ≥49 | ||
| (n = 80) | (n = 87) | (n = 84) | ||
| Age (years) | 80 ± 8 | 82 ± 7 | 81 ± 8 | 0.11 |
| Men | 51 (64%) | 38 (44%) ∗ | 49 (58%) | 0.03 |
| Body mass index (kg/m 2 ) | 30 ± 7 | 30 ± 8 | 30 ± 7 | 0.89 |
| Systolic blood pressure (mmHg) | 128 ± 22 | 127 ± 19 | 123 ± 22 | 0.23 |
| Diastolic blood pressure (mmHg) | 65 ± 10 | 66 ± 12 | 65 ± 10 | 0.72 |
| Heart rate (beats per minute) | 65 ± 12 | 70 ± 12 ∗ | 71 ± 13 ∗ | 0.004 |
| Diabetes mellitus | 29 (36%) | 34 (39%) | 36 (43%) | 0.64 |
| Hypertension | 71 (89%) | 75 (86%) | 72 (87%) | 0.88 |
| Dyslipidemia | 74 (93%) | 75 (86%) | 73 (88%) | 0.42 |
| Chronic lung disease | ||||
| None or mild | 63 (39%) | 54 (34%) | 44 (27%) ∗ | 0.002 |
| Moderate or severe | 17 (19%) | 33 (37%) | 39 (44%) ∗ | |
| Peripheral vascular disease | 44 (55%) | 48 (55%) | 50 (60%) | 0.74 |
| Cerebrovascular disease | 26 (33%) | 19 (22%) | 27 (33%) | 0.21 |
| Previous myocardial infarction | 33 (41%) | 27 (31%) | 23 (28%) | 0.16 |
| Congestive heart failure | 48 (60%) | 43 (49%) | 55 (66%) | 0.08 |
| NYHA symptom classification | ||||
| Class I & II | 14 (41%) | 17 (50%) | 3 (9%) ∗ † | 0.005 |
| Class III & IV | 66 (31%) | 70 (81%) | 80 (96%) ∗ † | |
| Creatinine (mg/dL) | 1.2 ± 0.4 | 1.3 ± 0.6 | 1.4 ± 0.8 | 0.09 |
| Digoxin | 5 (6%) | 11 (13%) | 10 (12%) | 0.33 |
| Beta-blocker | 50 (63%) | 60 (69%) | 63 (76%) | 0.18 |
| ACE-I | 29 (49%) | 22 (34%) | 21 (38%) | 0.22 |
| Nitrate | 20 (25%) | 11 (13%) | 10 (12%) | 0.04 |
| Diuretics | 31 (39%) | 42 (48%) | 50 (60%) ∗ | 0.02 |
Baseline echocardiographic and pulmonary function characteristics, according to PASP tertiles, are listed in Tables 2 and 3 . Patients in tertile 3 had significantly lower LV ejection fractions, more severe diastolic dysfunction (larger left atrial volume indexes, shorter mitral valve deceleration times, and higher E/A and E/e′ ratios), right ventricular dysfunction, and higher grades of TR. On pulmonary function testing, forced expiratory volume in 1 second (percentage predicted) was lower in tertiles 2 and 3 compared with tertile 1. Forced vital capacity was higher in tertile 3 compared with tertile 1. Diffusing capacity for carbon monoxide (percentage predicted) was lower in tertiles 2 and 3 compared with tertile 1. The frequency of radiographic abnormalities on chest computed tomography was similar across PASP tertiles.
| Variables | Pulmonary Artery Systolic Pressure (mmHg) | |||
|---|---|---|---|---|
| Tertile 1 | Tertile 2 | Tertile 3 | p-Value | |
| <36 | ≥36, <49 | ≥ 49 | ||
| (n = 80) | (n = 87) | (n = 84) | ||
| Septum thickness (mm) | 13 ± 2 | 12 ± 2 | 13 ± 2 | 0.77 |
| Posterior wall thickness (mm) | 12 ± 2 | 12 ± 2 | 12 ± 2 | 0.94 |
| Mass index (g/m 2 ) | 123 ± 33 | 127 ± 40 | 130 ± 34 | 0.5 |
| Internal diastolic dimension (mm) | 49 ± 6 | 50 ± 6 | 51 ± 6 | 0.08 |
| Internal systolic dimension (mm) | 33 ± 7 | 33 ± 8 | 36 ± 9 | 0.03 |
| Left Ventricle ejection fraction (%) | 60 ± 12 | 58 ± 13 | 53 ± 15 ∗ † | 0.002 |
| Left Ventricle ejection fraction <40% | 8 (11%) | 7 (9%) | 14 (19%) | 0.16 |
| Stroke volume index (cc/m 2 ) | 48 ± 7 | 47 ± 10 | 44 ± 12 | 0.08 |
| Cardiac index (L/min/m 2 ) | 3.0±0.5 | 3.2±0.6 | 3.1 ± 0.8 | 0.17 |
| Left atrium volume index (cc/m 2 ) | 43 ± 12 | 54 ± 15 ∗ | 59 ± 19 ∗ | <0.001 |
| Mitral valve deceleration time (ms) | 248 ± 80 | 221 ± 71 | 175 ± 45 ∗ † | <0.001 |
| E/A | 1.0 ± 0.5 | 1.0 ± 0.6 | 1.9 ± 1.0 ∗ † | <0.001 |
| E/e′ | 15 ± 7 | 18 ± 9 | 21 ± 9 ∗ | <0.001 |
| Right atrial pressure estimate (mmHg) | 5 ± 1 | 7 ± 3 ∗ | 11 ± 5 ∗ † | <0.001 |
| Right ventricular enlargement | 7 (9%) | 16 (19%) | 45 (54%) ∗ † | <0.001 |
| Right ventricular systolic dysfunction | 14 (18%) | 14 (17%) | 39 (49%) ∗ † | <0.001 |
| Tricuspid regurgitation (≥moderate) | 2 (3%) | 13 (15%) ∗ | 37 (45%) ∗ † | <0.001 |
| Tricuspid valve annular systolic TDI velocity (m/sec) | 0.11 ± 0.03 | 0.11 ± 0.03 | 0.09 ± 0.03 ∗ † | 0.003 |
| Right ventricular systolic pressure (mmHg) | 30 ± 4 | 42 ± 4 ∗ | 62 ± 11 ∗ † | — |
| Aortic valve area (cm 2 ) | 0.8 ± 0.1 | 0.8 ± 0.2 | 0.8 ± 0.2 | 0.42 |
| Aortic valve mean systolic gradient (mmHg) | 49±12 | 50±13 | 51 ± 15 | 0.86 |
| Aortic valve peak systolic velocity (m/sec) | 4.5 ± 0.6 | 4.5 ± 0.6 | 4.5±0.7 | 0.99 |
| Pulmonary Artery Systolic Pressure (mmHg) | ||||
|---|---|---|---|---|
| Tertile 1 | Tertile 2 | Tertile 3 | p-Value | |
| <36 | ≥36, <49 | ≥49 | ||
| (n = 75) | (n = 82) | (n = 80) | ||
| Pulmonary function tests | ||||
| Forced expiratory volume (1 sec, Liters) | 1.9 ± 0.7 | 1.5 ± 0.5 ∗ | 1.5 ± 0.5 ∗ | <0.001 |
| Forced expiratory volume (1 sec, % predicted) | 73 ± 21 | 65 ± 20 ∗ | 60 ± 17 ∗ | <0.001 |
| Forced vital capacity (Liters) | 2.6 ± 0.9 | 2.2 ± 0.7 ∗ | 2.2 ± 0.7 ∗ | 0.001 |
| Forced vital capacity (% predicted) | 80 ± 20 | 74 ± 20 | 67 ± 18 ∗ | <0.001 |
| FEV1/FVC (ratio) | 69 ± 13 | 67 ± 13 | 68 ± 13 | 0.62 |
| Total lung capacity (Liters) | 7.5 ± 15.2 | 5.0 ± 1.3 | 4.8 ± 1.2 | 0.17 |
| Total lung capacity (% predicted) | 91 ± 21 | 89 ± 20 | 81 ± 17 ∗ | 0.02 |
| Residual volume (Liters) | 2.7 ± 1.1 | 2.7 ± 1.1 | 2.54 ± 0.83 | 0.43 |
| Residual volume (% predicted) | 115 ± 42 | 109 ± 49 | 103 ± 33 | 0.29 |
| Diffusing capacity for CO (mL CO/min/mmHg) | 15 ± 5 | 12 ± 4 ∗ | 12 ± 4 ∗ | <0.001 |
| Diffusing capacity for CO (% predicted) | 70 ± 18 | 62 ± 17 ∗ | 58 ± 16 ∗ | <0.001 |
| Chest CT | ||||
| Pulmonary edema | 6 (8%) | 4 (8%) | 6 (7%) | 0.72 |
| Emphysema | 12 (15%) | 15 (18%) | 15 (18%) | 0.85 |
| Fibrosis | 9 (11%) | 12 (14%) | 8 (10%) | 0.66 |
In the first week after TAVR, mean PASP change in the entire cohort was 0.2 ± 13 mm Hg. Among patients in tertile 1 and tertile 2, PASP increased by 8 ± 10 and 2 ± 10 mm Hg, respectively. However, among patients in tertile 3, PASP decreased in the first week after TAVR by −8 ± 14 mm Hg (p <0.001 vs baseline and tertiles 1 and 2), a change that was maintained at 3 months (−7 ± 14 mm Hg, p <0.001 vs baseline, pairwise comparison).
Baseline mean systolic gradient across the aortic valve was 50 ± 13 mm Hg. In the whole cohort, mean systolic gradient across the aortic valve decreased by −37 ± 14 mm Hg (p <0.001 vs baseline, pairwise comparison), a change that was similar across PASP tertiles.
Patients in the highest PASP tertile had longer lengths of hospital stay after TAVR, while other short-term outcomes, including 30-day mortality, 30-day readmission, cerebrovascular events, duration of mechanical ventilation, new-onset renal failure, and reoperation for bleeding, were similar across PASP tertiles ( Table 4 ).
