2022 Volume 86 Issue 3 Pages 383-390
Background: Coexistent pulmonary hypertension with severe aortic stenosis confers a greater risk of mortality for patients undergoing transcatheter aortic valve replacement (TAVR). In this patient population, the impact of significant decoupling between pulmonary artery diastolic and pulmonary capillary wedge, as it relates to clinical risk, remained uncertain.
Methods and Results: Patients with severe aortic stenosis who underwent TAVR and completed pre-procedural and post-procedural invasive hemodynamic assessments with right heart catheterization were retrospectively assessed. The impact of post-TAVR decoupling, defined as a pressure difference ≥3 mmHg, on 2-year all-cause mortality or risk of heart failure admission was analyzed. Among 77 included patients (median age 86 years, 23 men), 16 had post-TAVR decoupling. The existence of post-TAVR decoupling was associated with a higher cumulative incidence of the primary endpoint (44% vs. 7%, P=0.001), with an adjusted hazard ratio of 5.87 (95% confidence interval 1.58–21.9, P=0.008).
Conclusions: A greater risk of worse outcomes in those with post-TAVR decoupling was observed. A therapeutic strategy for post-TAVR decoupling and its clinical implication need to be created and investigated in the future.
Clinical outcomes for patients with severe aortic stenosis have improved in the era of transcatheter aortic valve replacement (TAVR), as higher-risk cohorts can undergo corrective valve interventions without the clinical risk associated with surgical aortic valve replacement (SAVR).1 Recent data have also suggested equipoise in between SAVR and TAVR in those with low operative risk.2 Nevertheless, several comorbidities are associated with worse clinical outcomes following TAVR that have remain unsolved thus far.3
Editorial p 391
Pulmonary hypertension is known to be associated with an increased risk of adverse events post-TAVR.4–6 Improvement in left ventricular diastolic function following TAVR may decrease the burden of secondary pulmonary hypertension leading to better outcomes, whereas patients with persistent pulmonary hypertension generally do worse.7–9
Exaggerated elevations in diastolic pulmonary artery pressure over measured pulmonary capillary wedge are referred to as the diastolic pressure gradient (DPG). A significant gradient here is indicative of abnormal pulmonary vasculature remodeling.10 Our group previously demonstrated that the existence of decoupling, defined as an elevated DPG level, was associated with higher morbidity and mortality in patients who have had durable ventricular assist devices implanted.11
Interestingly, decoupling was observed irrespective of the level of mean pulmonary artery pressure and is a more useful prognostic variable over the conventional parameters associated with pulmonary hypertension.11 However, the clinical implications of decoupling following TAVR remain unknown. In this study, we inspected the prognostic impact of post-TAVR pulmonary artery pressure decoupling.
Patients with severe aortic stenosis who received TAVR at our institute between October 2017 and October 2019 and who underwent invasive hemodynamic assessment within 1 week before and 1 week after TAVR were prospectively included in our institutional registry. All patients were followed for 2 years or until May 2021. All patients gave written informed consent before inclusion into the study. The institutional ethical review board approved this study.
TAVR ProcedureTAVR, in general, was indicated for those with symptomatic severe AS, defined as a peak velocity at the aortic valve of >4.0 m/s and a mean pressure gradient of >40 mmHg. The procedural approach was determined by the heart valve team, which consisted of cardiologists, anesthesiologists, and cardiovascular surgeons.12 Patients received either self-expandable valves (Corevalve or Evolut R; Medtronic plc., Minneapolis, MN, USA) or balloon-expandable valves (Sapien XT or Sapien 3; Edwards Lifesciences Inc., Irvine, CA, USA) via a trans-femoral or trans-apical approach under general anesthesia.
Hemodynamic AssessmentInvasive hemodynamic assessments were performed using right heart catheterization at the catheter laboratory by heart failure cardiologists using a standard technique within 1 week before and after TAVR. As a primary independent variable, DPG was calculated as the difference between pulmonary artery diastolic and pulmonary capillary wedge pressure.10 A DPG ≥3 mmHg was defined as decoupling given the finding of the below-described analysis.
Other Clinical VariablesDemographics data were measured as baseline characteristics. The STS score and EURO II score before TAVR were calculated. Laboratory and echocardiography data were obtained before and after TAVR. Medication data at index discharge were also collected.
Follow upFollowing the index discharge, all patients were followed up in a standard manner by cardiologists. Plasma B-type natriuretic peptides were measured at index discharge and at a 1-year follow up. All patients were followed for 2 years or until May 2021.
All-cause death or heart failure readmissions requiring IV diuretic therapy during the 2-year observational period were defined as the primary composite endpoints.
Statistical AnalysisContinuous variables were expressed as median and interquartile, irrespective of their distribution and compared between the 2 groups using the Mann-Whitney U-test. Categorical variables were expressed as the number and percentage and compared between the 2 groups using Fisher’s exact test.
The primary endpoint was the composite of 2-year mortality and heart failure readmissions. We investigated the association between post-TAVR decoupling, defined as a DPG ≥3 mmHg, and the primary endpoint.
The cut-off of DPG was calculated by receiver operating characteristics analysis for the primary endpoint. The decoupling was defined according to the findings of this analysis and patients were stratified into 2 groups according to the existence of post-TAVR decoupling.
Kaplan-Meier analyses were performed to assess the cumulative incidence of the primary endpoint. Cox proportional hazard ratio regression analyses were performed to investigate the impact of post-TAVR decoupling on the primary endpoint. The impact of post-TAVR decoupling was adjusted for other variables that were assumed to have potential impact on the prognosis: age, post-TAVR cardiac index, and plasma B-type natriuretic peptide level at index discharge. A P value of <0.05 was considered statistically significant. Statistical analyses were performed using SPSS Statistics 22 (SPSS Inc., Armonk, IL, USA).
A total of 77 patients (age 86 [82, 89] years, 23 men) were included. All patients had severe AS with 4.4 (4.0, 5.0) m/s of peak velocity at the aortic valve, a 6.0 (4.3, 8.1) STS score, a 3.5 (2.4, 4.5) EURO II score, and 276 (143, 586) pg/mL of plasma B-type natriuretic peptide (Table 1). The median DPG was 0 (−1, 3) mmHg.
| Total (N=77) |
Post-TAVR decoupling (N=16) |
Control (N=61) |
P value | |
|---|---|---|---|---|
| Demographics | ||||
| Age, years | 86 (82, 89) | 86 (82, 90) | 86 (82, 88) | 0.58 |
| Men | 23 (30) | 7 (44) | 16 (26) | 0.15 |
| Body surface area, m2 | 1.38 (1.30, 1.52) | 1.52 (1.41, 1.59) | 1.35 (1.27, 1.48) | 0.024* |
| Estimated disease duration, months | 9 (6, 12) | 11 (7, 14) | 8 (5, 12) | 0.076 |
| Comorbidity | ||||
| Hypertension | 55 (71) | 12 (75) | 43 (70) | 0.57 |
| Diabetes mellitus | 14 (18) | 1 (6) | 13 (21) | 0.14 |
| Dyslipidemia | 26 (34) | 5 (31) | 21 (34) | 0.50 |
| Ischemic heart disease | 18 (23) | 5 (31) | 13 (21) | 0.32 |
| History of cardiac surgery | 2 (3) | 0 | 2 (3) | 0.62 |
| History of stroke | 20 (26) | 5 (31) | 15 (25) | 0.45 |
| Chronic obstructive pulmonary disease | 5 (6) | 0 | 5 (8) | 0.29 |
| Peripheral artery disease | 26 (34) | 5 (31) | 21 (34) | 0.50 |
| Laboratory data on admission | ||||
| Hemoglobin, g/dL | 11.4 (10.5, 12.3) | 11.2 (10.2, 12.6) | 11.4 (10.5, 12.3) | 0.72 |
| Serum albumin, g/dL | 3.8 (3.6, 3.9) | 3.8 (3.4, 3.9) | 3.8 (3.6, 4.0) | 0.14 |
| Serum sodium, mEq/L | 141 (139, 142) | 141 (137, 142) | 141 (139, 143) | 0.19 |
| eGFR, mL/min/1.73 m2 | 46.6 (36.3, 59.9) | 41.8 (25.4, 57.3) | 47.4 (37.9, 62.7) | 0.51 |
| Plasma BNP, pg/mL | 276 (143, 586) | 266 (133, 325) | 282 (144, 609) | 0.73 |
| Echocardiography data on admission | ||||
| LVDd, mm | 45 (42, 50) | 44 (42, 45) | 47 (42, 52) | 0.14 |
| LVEF, % | 65 (56, 71) | 65 (61, 76) | 65 (56, 71) | 0.72 |
| Peak velocity of aortic valve, m/s | 4.4 (4.0, 5.0) | 4.1 (3.6, 4.7) | 4.4 (4.1, 5.1) | 0.34 |
| TAPSE, mm/s | 13.3 (11.2, 15.1) | 13.2 (11.2, 14.8) | 13.5 (11.3, 15.1) | 0.14 |
| Right ventricular fractional area change, % | 31 (24, 38) | 28 (23, 35) | 32 (24, 39) | 0.087 |
| Moderate or greater TR | 10 (13) | 4 (25) | 6 (10) | 0.11 |
| Maximum IVC dilatation, mm | 12 (8, 15) | 13 (9, 15) | 12 (8, 14) | 0.54 |
| Score on admission | ||||
| STS score | 6.0 (4.3, 8.1) | 6.3 (4.9, 9.0) | 5.4 (4.2, 8.0) | 0.17 |
| EURO II score | 3.5 (2.4, 4.5) | 3.2 (2.5, 5.0) | 3.5 (2.3, 4.4) | 0.83 |
| Hemodynamic data on admission | ||||
| Systolic blood pressure, mmHg | 114 (102, 122) | 119 (110, 122) | 114 (101, 124) | 0.65 |
| Mean right atrial pressure, mmHg | 5 (4, 7) | 5 (4, 6) | 5 (3, 7) | 0.36 |
| Mean pulmonary artery pressure, mmHg | 18 (15, 23) | 18 (15, 27) | 18 (15, 23) | 0.37 |
| Pulmonary capillary wedge pressure, mmHg | 11 (8, 15) | 12 (7, 15) | 11 (8, 15) | 0.84 |
| Diastolic pressure gradient, mmHg | 0 (−1, 3) | −5 (−1, 4) | 0 (−1, 3) | 1.0 |
| Cardiac index, L/min/m2 | 2.6 (2.4, 3.0) | 2.6 (2.3, 2.8) | 2.7 (2.4, 3.1) | 0.21 |
| Pulmonary vascular resistance index, WU | 2.7 (1.9, 3.5) | 3.5 (2.1, 4.5) | 2.6 (1.9, 3.2) | 1.0 |
eGFR, estimated glomerular filtration ratio; BNP, B-type natriuretic peptide; EuroSCORE II, european system for cardiac operative risk evaluation II; IVC, inferior vena cava; LVDd, left ventricular end-diastolic diameter; LVEF, left ventricular ejection fraction; STS, society of thoracic surgeons; TAPSE, tricuspid annular plane systolic excursion; TAVR, transcatheter aortic valve replacement; TR, tricuspid regurgitation; WU, wood unit. Continuous variables are expressed as median and interquartile and compared by using the Mann-Whitney U-test. Categorical variables are expressed as numbers and percentages and compared by using Fischer’s exact test. *P<0.05.
Following TAVR, the peak velocity of the aortic valve was 2.1 (1.8, 2.4) m/s and plasma B-type natriuretic peptide was a median of 110 (52, 233) pg/mL (Table 2). The median DPG was 1 (0, 2) mmHg.
| Total (N=77) |
Post-TAVR decoupling (N=16) |
Control (N=61) |
P value | |
|---|---|---|---|---|
| Laboratory data at index discharge | ||||
| Hemoglobin, g/dL | 10.3 (9.7, 11.0) | 10.2 (9.3, 11.0) | 10.5 (9.9, 11.1) | 0.49 |
| Serum albumin, g/dL | 3.5 (3.2, 3.7) | 3.3 (3.1, 3.6) | 3.5 (3.2, 3.7) | 0.10 |
| Serum sodium, mEq/L | 140 (138, 141) | 139 (138, 141) | 140 (137, 141) | 0.77 |
| eGFR, mL/min/1.73 m2 | 48.6 (38.8, 64.3) | 47.5 (28.1, 70.7) | 51.8 (39.0, 64.3) | 0.77 |
| Plasma BNP, pg/mL | 110 (52, 233) | 70 (19, 329) | 60 (24, 186) | 0.47 |
| Echocardiography data at index discharge | ||||
| LVDd, mm | 45 (42, 50) | 44 (42, 49) | 47 (41, 50) | 0.48 |
| LVEF, % | 63 (55, 71) | 69 (61, 74) | 63 (55, 70) | 0.18 |
| Peak velocity of aortic valve, m/s | 2.1 (1.8, 2.4) | 2.1 (1.8, 2.4) | 2.0 (1.8, 2.4) | 1.0 |
| TAPSE, mm/s | 13.2 (11.1, 14.8) | 12.7 (11.0, 14.5) | 13.3 (11.2, 14.8) | 0.094 |
| Right ventricular fractional area change, % | 30 (22, 37) | 26 (21, 33) | 31 (22, 37) | 0.079 |
| Moderate or greater TR | 7 (9) | 3 (19) | 4 (7) | 0.13 |
| Maximum IVC dilatation, mm | 10 (7, 14) | 11 (8, 13) | 10 (7, 14) | 0.48 |
| Hemodynamic data at index discharge | ||||
| Mean right atrial pressure, mmHg | 5 (3, 6) | 6 (4, 8) | 4 (3, 6) | 0.13 |
| Mean pulmonary artery pressure, mmHg | 16 (15, 19) | 18 (15, 24) | 16 (14, 19) | 0.08 |
| Pulmonary capillary wedge pressure, mmHg | 9 (7, 13) | 9 (8, 17) | 9 (7, 13) | 0.35 |
| Diastolic pressure gradient, mmHg | 1 (0, 2) | 3 (3, 4) | 1 (−1, 2) | <0.001* |
| Cardiac index, L/min/m2 | 2.6 (2.4, 3.0) | 2.6 (2.4, 2.9) | 2.6 (2.4, 3.0) | 0.66 |
| Pulmonary vascular resistance index, WU | 2.7 (2.1, 3.5) | 3.8 (3.4, 4.6) | 2.6 (2.1, 3.0) | 0.001* |
| Medication data at index discharge | ||||
| β-blocker | 25 (32) | 4 (25) | 21 (34) | 0.33 |
| Renin angiotensin system inhibitor | 54 (70) | 13 (81) | 41 (67) | 0.25 |
| Diuretics | 38 (49) | 10 (63) | 28 (46) | 0.26 |
Continuous variables are expressed as median and interquartile and compared by using the Mann-Whitney U-test. Categorical variables are expressed as numbers and percentages and compared by using Fischer’s exact test. *P<0.05. Abbreviations as in Table 1.
Before TAVR, 21/77 patients had decoupling defined as DPG ≥3 mmHg (Figure 1A). Following TAVR, 16/77 had decoupling. Of them, 6 were due to persistent decoupling and the other 10 were cases of de novo decoupling. Post-TAVR decoupling distributed widely irrespective of the values of mean pulmonary artery pressure (Figure 1B).
Prevalence of decoupling before and after transcatheter aortic valve replacement (TAVR) (A) and the correlation between diastolic pressure gradient (DPG) and mean pulmonary artery pressure (B).
A cut-off of post-TAVR DPG to predict the primary endpoint was calculated to be 3 mmHg (Supplementary Figure). This is the rationale behind why we defined decoupling as DPG ≥3 mmHg.
The existence of pre-TAVR decoupling was not associated with the primary endpoint (P>0.05), whereas post-TAVR decoupling was an independent predictor of the primary endpoint (hazard ratio 5.87, 95% confidence interval 1.58–21.9, P=0.008) adjusted for age, post-TAVR cardiac index, and plasma B-type natriuretic peptide at index discharge (Table 3).
| Univariate analysis | Multivariate analysis | |||
|---|---|---|---|---|
| HR (95% CI) | P value | HR (95% CI) | P value | |
| Decoupling on admission | 2.86 (0.83–9.87) | 0.097 | 1.90 (0.46–7.88) | 0.38 |
| Decoupling at index discharge | 6.90 (1.94–24.5) | 0.003* | 5.87 (1.58–21.9) | 0.008* |
Multivariate analyses were performed by adjusting for age, post-transcatheter aortic valve replacement; cardiac index, and plasma B-type natriuretic peptide level at index discharge. *P<0.05 by Cox proportional HR regression analyses. HR, hazard ratio.
The patients with post-TAVR decoupling had a higher cumulative incidence of the primary endpoint (44% vs. 7%, P=0.001; Figure 2). The proportion of patients who had heart failure readmission was 33% in the decoupling group vs. 7% in the control group (P=0.019). Mortality was 15% in the decoupling group vs. 4% in the control group (P=0.10).
Cumulative incidence of the primary outcome stratified by the existence of post- transcatheter aortic valve replacement (TAVR) decoupling. The primary outcome was defined as all-cause death or heart failure readmissions. *P<0.05 by log-rank test.
Plasma B-type natriuretic peptide levels were not significantly different between the 2 groups at index discharge, 1, and 2 years later (P>0.05 for all; Table 4).
| Post-TAVR decoupling (N=16) |
Post-TAVR control (N=61) |
P value | |
|---|---|---|---|
| At index discharge, pg/mL | 157 (70, 334) | 110 (49, 216) | 0.47 |
| At 1-year follow up, pg/mL | 101 (64, 269) | 98 (42, 165) | 0.076 |
| At 2-year follow up, pg/mL | 114 (57, 269) | 93 (47, 176) | 0.45 |
Variables were compared by using the Mann-Whitney U-test. TAVR, transcatheter aortic valve replacement.
Assessing the pre-TAVR data, there was no statistically significant difference between those with post-TAVR decoupling and those without, except for higher body surface area in the decoupling group (Table 1).
When we evaluated the post-TAVR data, the patients with decoupling tended to have higher mean pulmonary artery pressure (P=0.08; Table 2), but other parameters did not significantly differ between the 2 groups.
Changes in Decoupling Following TAVR and Clinical OutcomesAmong 21 patients with pre-TAVR decoupling, 6/21 patients with persistent decoupling had a higher incidence of the primary endpoint than 15/21 patients with improvement in decoupling (73% vs. 15%, P=0.044; Figure 3A).
Cumulative incidence of the primary outcome among patients with pre- transcatheter aortic valve replacement (TAVR) decoupling (A) and among those without (B). Persistent decoupling and de novo decoupling were associated with higher incidence. *P<0.05 by log-rank test.
Among 56 patients without pre-TAVR decoupling, 10/56 patients with de novo decoupling had a higher incidence of the primary endpoint than 46/56 patients without persistent decoupling (31% vs. 5%, P=0.008; Figure 3B).
Association Between Pulmonary Artery Diastolic Pressure and Pulmonary Capillary Wedge PressureAmong 10 patients with de novo decoupling, pulmonary capillary wedge pressure tended to decrease and pulmonary artery diastolic pressure tended to increase following TAVR (Figure 4A). As a result, DPG increased following TAVR.
Peri-procedural changes in dPAP and PCWP among patients with de novo decoupling (A) and among those with normalization in decoupling (B). Both dPAP and PCWP remained unchanged following transcatheter aortic valve replacement (TAVR) in patients with de novo decoupling (A). dPAP decreased significantly following TAVR in patients with normalized decoupling (B). dPAP, diastolic pulmonary artery pressure; PCWP, pulmonary capillary wedge pressure. *P<0.05 by Wilcoxon signed-rank test.
Among 15 patients with normalization of decoupling, pulmonary capillary wedge pressure tended to decrease and diastolic pulmonary artery pressure decreased significantly following TAVR (Figure 4B). As a result, DPG decreased following TAVR.
In this study, we analyzed the impact of post-TAVR decoupling between pulmonary artery diastolic and pulmonary capillary wedge pressure on the 2-year all-cause mortality and heart failure readmissions. The major findings were: (1) approximately 20% of the patients had decoupling, defined as DPG ≥3 mmHg, following TAVR, irrespective of the level of mean pulmonary artery pressure; and (2) the existence of decoupling post-TAVR was associated with an increased risk of 2-year all-cause death or heart failure readmissions.
Pulmonary Hypertension and Decoupling in Aortic StenosisSecondary pulmonary hypertension related to diastolic dysfunction is common in patients with severe aortic stenosis.4 This occurs due to chronically high ventricular afterload leading to increased ventricular hypertrophy and eventually stiffness. Short-term increases in intra-cardiac pressure with mild-to-moderate aortic stenosis may gradually lead to post-capillary pulmonary hypertension, whereas long-term elevations in intra-cardiac pressure with severe aortic stenosis would sometimes cause the out-of-proportion pulmonary hypertension accompanying pre-capillary pulmonary hypertension,7 which is distinguished from pure post-capillary pulmonary hypertension by the elevated level in DPG or pulmonary vascular resistance.10 In our cohort, those with decoupling tended to have longer disease duration before TAVR.
The concept of decoupling was originally developed to assess fixed pulmonary vascular damage despite significant mechanical unloading of the left ventricle during the durable ventricular assist device support.11 The decoupling was observed irrespective of the level of mean pulmonary artery pressure.
In the same manner, decoupling was observed following TAVR, irrespective of the level of mean pulmonary artery pressure in this study. Despite normalization of ventricular afterload following TAVR, some patients had persistently elevated pulmonary artery diastolic pressures leading to de novo decoupling, probably from longstanding chronically high ventricular afterload causing fixed pulmonary vascular damage.13
Implication of Post-TAVR DecouplingSeveral prior studies have reported the risk of baseline pulmonary hypertension, defined invasively or non-invasively, with post-TAVR mortality.5–9 Pre-TAVR decoupling was not associated with the primary outcome in this study, given that many patients had drastic changes in DPG following TAVR.
Post-TAVR decoupling was significantly associated with an increased risk of all-cause death or heart failure readmissions. Of note, de novo decoupling and persistent decoupling were associated with worse clinical outcomes. Fixed pulmonary vascular damage increases the afterload on the right ventricle, eventually leading to chamber dilation and progressive tricuspid regurgitation, with a late decline in ventricular function. The existence of right ventricular failure is associated with poor long-term clinical outcomes.14 The study of potential interventions to address post-TAVR decoupling with pulmonary vasodilators is needed, though current data are lacking in supporting the routine use of these therapies for such a cohort.15
Study LimitationsThis is a retrospective study consisting of a moderate sample size cohort. In the multivariate analyses, extensive adjustment for multiple covariates was not possible due to the smaller sample size. We assessed changes in decoupling during the index hospitalization following TAVR, but are lacking long-term follow up data. We did not assess the impact of decoupling on the right heart function, despite the inherent risk of worsening function over time.
The existence of post-TAVR decoupling was associated with worse clinical outcomes. Future investigations on potential interventions to those with decoupling remains the next concern.
None.
K.K. is a member of Circulation Journal’s Editorial Board. The authors have no disclosures to declare.
The Clinical Research Review Board from University of Toyama (R2015154) approved this study.
Data are available from the corresponding authors upon reasonable request.
Please find supplementary file(s);
http://dx.doi.org/10.1253/circj.CJ-21-0573
