Right ventricular (RV) dysfunction and tricuspid regurgitation (TR) may coexist with aortic stenosis. The aim of this study was to assess the association between RV dysfunction, TR, associated comorbidities, and outcomes following transcatheter aortic valve replacement (TAVR).
A retrospective analysis was conducted of baseline and 6-month clinical and echocardiographic parameters, including TR grade, RV size (grade, end-diastolic and end-systolic areas, annular diameter), and function (grade, tricuspid annular plane systolic excursion [TAPSE], fractional area change, Tei index), in 519 consecutive TAVR patients.
The prevalence of moderate or greater TR was 11% ( n = 59). Although TR was associated with increased mortality ( P = .02) in unadjusted analysis, it did not demonstrate an independent association with outcome when adjusted for RV dysfunction (TAPSE; P = .30) or multiple clinical parameters ( P ≥ .20). RV parameters associated with poor outcomes included TAPSE ( P = .006) and Tei index ( P = .005). TAPSE was associated with lower survival even when adjusted for TR ( P = .009) and all clinical parameters ( P = .01). Persistence of moderate or greater TR 6 months after TAVR seemed to be associated with lower survival ( P = .02), even when adjusted for clinical and RV parameters ( P = .07).
TR in association with aortic stenosis is frequently progressive despite TAVR but is not independently associated with outcomes. RV function is a stronger driver of adverse outcomes compared with TR itself, and RV quantitative rather than qualitative evaluation is the key to stratify these patients.
Tricuspid regurgitation (TR) is common in patients with left-sided valvular disease, and its presence has been associated with increased morbidity and mortality after surgery. Recently, guidelines have been issued for the management of TR in the context of left-sided valvular surgery, but most studies have been confined to TR associated with mitral valve disease, not with aortic stenosis (AS). In patients with AS, TR is considered to be a manifestation of right ventricular (RV) failure, enlargement, pulmonary hypertension and/or atrial fibrillation. Whether management of TR associated with AS should be undertaken at the time of aortic valve surgery just as is done for TR in mitral valve disease is controversial, because its clinical significance and natural history are less known.
Over the past decade, transcatheter aortic valve replacement (TAVR) has emerged as a less invasive option to surgical valve replacement. Although it was first performed only in patients with severe AS and no surgical option, or very high surgical risk, TAVR is increasingly being used to treat patients with severe AS and lower risk. Because as opposed to surgical aortic valve replacement, patients who undergo TAVR cannot undergo concomitant tricuspid surgery, it has become imperative to know the impact of TR on outcomes after TAVR, and the impact of successful TAVR on TR, to help decide whether TR associated with severe AS deserves concomitant surgical tricuspid repair or may be treated with TAVR alone.
Our goals in the present study were to (1) evaluate the association between RV dysfunction, TR severity, other comorbidities, and outcomes following TAVR; (2) observe the changes in TR and RV size and function following TAVR; and (3) report the association between improvement or lack of improvement of TR following TAVR and outcomes. We also tried to identify the factors associated with late progression of TR during the follow-up period.
Between March 2009 through June 2014, 564 consecutive patients with severe symptomatic native AS (aortic valve area < 1 cm 2 ) underwent TAVR at our hospital and were included in our ongoing single-center prospective registry of TAVR. All patients were considered high risk for valve surgery by our institutional heart team. Clinical details were prospectively recorded for all patients at baseline, 1-month, 6-month, and yearly clinical assessments. Echocardiographic data were recorded at baseline and 6 months after TAVR. We excluded patients who had incomplete preprocedural echocardiographic data. Finally, 519 TAVR patients (92%) were included in the study. Patients with other valvular diseases, including mitral diseases, were included in the study. The study protocol was performed in accordance with the institutional ethics committees at our center, and all patients gave informed written consent for the procedures.
Baseline, Follow-Up, and Clinical Outcomes
Baseline clinical data were collected by interviewing the patients and reviewing medical files. Clinical follow-up was obtained by interviewing the patients and by review of medical records. The study end point included all-cause mortality and a combined cardiac outcome including death and heart failure hospitalization. The criteria used to determine if an admission was due to heart failure included the following: presence of at least two major criteria (paroxysmal nocturnal dyspnea, neck-vein distention, rales, cardiomegaly, pulmonary edema, S3 gallop, hepatojugular reflux, or laboratory evidence of visceral congestion) or one major criterion with two minor criteria (ankle edema, dyspnea on ordinary exertion, hepatomegaly, pleural effusion, or tachycardia [heart rate < 120 beats/min]). In equivocal cases, we used the results of echocardiography to aid in determining if an admission was due to heart failure by looking at mitral inflow and tissue Doppler parameters. Whenever mitral inflow was associated with elevated left heart filling pressure, the admission was considered related to heart failure.
Baseline echocardiography was performed in all patients at baseline and 6 months after the procedure. Echocardiography was performed in a standard manner using the same equipment (iE33; Philips Medical Systems, Bothell, WA). RV qualitative size and function assessment was based on multiple views of the right ventricle (short-axis parasternal at basal, mid, and apical levels; lower parasternal RV inflow view; apical four-chamber view and, if possible, RV long-axis view; and subcostal short-axis and four-chamber views). Using these multiple views, an integrative qualitative grading was formulated by the physician responsible for the echocardiographic study. From four-chamber views encompassing the entire right ventricle, end-systolic and end-diastolic RV areas and the tricuspid annulus were measured. Apart from qualitative grading, RV function was evaluated by tricuspid annular plane systolic excursion (TAPSE), RV end-systolic area, fractional area change (FAC), and myocardial performance index (Tei index).
RV FAC was defined as (end-diastolic area − end-systolic area)/end-diastolic area and was obtained by tracing the RV endocardium in both systole and diastole from the annulus, along the free wall to the apex, and then back to the annulus, along the septum. TAPSE is a method to measure the distance of systolic excursion of the RV annular segment along its longitudinal plane, from a standard apical four-chamber window. The Tei index is a global estimate of both systolic and diastolic function of the right ventricle and was defined as [(isovolumic relaxation time + isovolumic contraction time)/ejection time]. Ejection time was measured using pulsed-wave Doppler of RV outflow (time from onset to cessation of flow), and tricuspid valve closure-opening time was measured using continuous-wave Doppler of the TR jet (time from onset to cessation of the jet). Isovolumic relaxation time and isovolumic contraction time were calculated by subtracting ejection time from TR jet time. TR severity was determined by an integrative, semiquantitative approach as recommended by the American Society of Echocardiography, including assessment of vena contracta width (79% of patients), proximal isovelocity surface area radius (9%), tricuspid valve morphology, right atrial and RV size, inferior vena cava size, jet area, jet density and contour, and hepatic vein flow (in all patients). Representative images from cases to illustrate the measurements of the different RV parameters are shown in Figure 1 .
Measurements of mitral inflow included the peak early filling (E-wave) and late diastolic filling (A-wave) velocities, the E/A ratio, and deceleration time of early filling velocity. Early diastolic mitral annular velocity (e′) was measured in the apical four-chamber view. In patients with atrial fibrillation, all measurements were averages of at least seven cardiac cycles. Left atrial volume was calculated using the biplane area-length method at end-systole. The severity of AS was defined by the aortic valve area calculated using the standard continuity equation (aortic valve area < 1.0 cm 2 ). Forward stroke volume was calculated from the left ventricular (LV) outflow tract with subsequent calculation of cardiac output and index. In patients with low gradients (mean gradient < 40 mm Hg), distinction between true severe AS and “pseudo-AS” resulting from low flow was done by low-dose dobutamine echocardiography in patients with low ejection fractions and by aortic valve calcium scoring on multidetector computed tomography in patients with preserved ejection fractions.
Continuous normally distributed parameters are presented as mean ± SD and were compared using Student’s t test. Ordinal and/or non-normally distributed data are presented as medians with interquartile ranges and were compared using the Wilcoxon rank sum test. Categorical data were compared between groups using the χ 2 test or the Fisher exact test. Multivariate analyses with TR grade as the dependent variable was performed to assess the clinical and echocardiographic factors associated with the grade of TR at baseline. The entry criterion was a univariate correlation with P value <.05.
Clinical end points were time to death and time to combined cardiac event (death or heart failure readmission). Univariate Cox proportional-hazards models for the end points allowed the calculation of hazard ratios (HR) attached to routine echocardiographic and RV parameters. To assess if TR grade, TAPSE, or improvement in TR was independently associated with outcomes, we used multivariate Cox proportional-hazards models for the end points (time to death and time to combined cardiac event), allowing the calculation of HRs attached to moderate or greater TR, TAPSE, or improvement in TR adjusted for significant clinical variables (age, gender, pacemaker, atrial fibrillation, European System for Cardiac Operative Risk Evaluation score) or significant echocardiographic variables (stroke volume index, deceleration time, systolic pulmonary pressure, TAPSE/TR grade, mitral regurgitation [MR] grade). The incremental value of TR grade versus clinical parameters, or RV functional parameters, for the assessment of time to clinical end points was tested by comparing nested models using F tests. Event distributions were calculated according to the Kaplan-Meier method and were compared by means of the log-rank test. All P values were two sided, and values of <.05 were considered to indicate statistical significance. All data were analyzed with JMP version 9.0 (SAS Institute, Cary, NC). All authors participated in designing the study, collecting and analyzing data, and drafting and revising the report.
Table 1 shows baseline characteristics of the 519 TAVR patients stratified by severity of TR (moderate or greater or less). The prevalence of moderate or greater TR was 11% (44 patients with moderate TR and 15 with severe TR). Patients with moderate or greater TR at baseline—compared to patients with lesser grade of TR—were older and had higher European System for Cardiac Operative Risk Evaluation scores, a higher prevalence of atrial fibrillation, pacemaker, higher New York Heart Association grades, lower ejection fractions, larger left ventricles, lower cardiac output, more advanced diastolic dysfunction, and higher systolic pulmonary artery pressure. They also had larger RV size (grade, end-diastolic and end-systolic areas), larger annular diameters, worse RV function, and higher grades of MR and aortic regurgitation.
|Variable||All patients ( n = 519)||TR less than moderate ( n = 460)||TR moderate or greater ( n = 59)||P||R 2 for TR||P|
|Baseline clinical characteristics|
|Age (y)||85.6 ± 6||82.4 ± 6||84.8 ± 5||.0008||0.02||.0005|
|EuroSCORE||20.5 ± 14||22.2 ± 14||27.9 ± 13||.004||0.08||.0002|
|Risk for surgery||.02|
|Creatinine (mg/dL)||1.15 ± 0.6||1.12 ± 0.5||1.3 ± 0.8||.20||NS||NS|
|EF (%)||56.3 ± 9||56.7 ± 9||51.8 ± 11||.002||−0.03||.0002|
|EF < 50%||16||34||.002||NS||NS|
|LV EDD (mm)||46.6 ± 6||46.5 ± 6||47.8 ± 6||.10||NS||NS|
|LV ESD (mm)||29.4 ± 7||29.1 ± 6||32.0 ± 8||.02||0.02||.005|
|LV mass index (g/m 2 )||128 ± 35||127 ± 34||134 ± 42||.20||NS||NS|
|RWT||0.52 ± 0.1||0.52 ± 0.1||0.51 ± 0.1||.40||NS||NS|
|Stroke volume index (mL/m 2 )||39.9 ± 10||40.0 ± 9||39.4 ± 11||.70||NS||NS|
|Cardiac output index (L/m 2 )||2.7 ± 0.7||2.7 ± 0.8||2.5 ± 0.6||.06||NS||NS|
|LA volume index (mL/m 2 )||49.9 ± 19||48.3 ± 16||61.9 ± 31||.001||0.07||<.0001|
|E wave (m/sec)||0.98 ± 0.3||0.95 ± 0.3||1.23 ± 0.3||<.0001||0.09||<.0001|
|E deceleration time (msec)||223 ± 80||232 ± 125||182 ± 54||<.0001||−0.01||.02|
|A wave (m/sec)||0.99 ± 0.3||1.01 ± 03||0.81 ± 0.4||.004||NS||NS|
|E/A ratio||1.1 ± 0.7||1.05 ± 0.6||1.78 ± 0.8||<.0001||0.14||<.0001|
|E′ average (cm/sec)||5.3 ± 2.1||5.3 ± 2.2||5.1 ± 1.3||.40||NS||NS|
|E/E′ average||20.1 ± 8||19.4 ± 8||26.4 ± 11||.0006||0.07||<.0001|
|Peak pressure transaortic gradient (mm Hg)||76.8 ± 23||76.5 ± 22||76.7 ± 24||.90||NS||NS|
|Mean pressure transaortic gradient (mm Hg)||46.9 ± 15||46.7 ± 15||47.1 ± 16||.60||NS||NS|
|AVA (cm 2 )||0.71 ± 0.18||0.72 ± 0.2||0.66 ± 0.2||.007||−0.01||.007|
|RA pressure (mm Hg)||6.6 ± 3||5.9 ± 3||10.8 ± 5||<.0001||0.2||<.0001|
|Systolic pulmonary pressure (mm Hg)||42.5 ± 15||39.4 ± 13||61.2 ± 13||<.0001||0.29||<.0001|
|Pulmonic acceleration time (msec)||107 ± 31||94 ± 23||.01||NS||NS|
|RV size grade||.03||0.03||.001|
|RV EDA (cm 2 )||18.0 ± 4.8||20.7 ± 7||.02||0.03||.002|
|RV ESA (cm 2 )||10.6 ± 4||12.5 ± 4||.02||0.02||.03|
|Annular diameter (mm)||32.0 ± 6||38.0 ± 9||.0002||0.1||<.0001|
|RV function grade||.30||NS||NS|
|RV FAC (%)||41.0 ± 10||39.3 ± 9||.20||NS||NS|
|TAPSE (cm)||19.5 ± 4||18.4 ± 5||.20||−0.01||.01|
|Ejection time (msec)||329 ± 33||327 ± 37||.70||NS||NS|
|Tei index||0.33 ± 0.14||0.39 ± 0.17||.04||NS||NS|
Survival and Cardiac Events after TAVR
Table 2 shows the results of univariate Cox hazard analysis for factors associated with long-term mortality in the TAVR group. There were 108 deaths (20.8%) during follow-up (1.5 ± 1.17 years). Twenty-three deaths were related to cardiac causes (nine coronary events, seven vascular, two strokes, three due to heart failure related to paravalvular leak, and two due to sudden death). Deaths due to noncardiac causes were due to infections ( n = 20), bleeding ( n = 4), and cancer ( n = 11). In 50 patients, causes of death were unknown.
|HR (interquartile range)||P||HR (interquartile range)||P|
|Age||1.05 (1.01–1.09)||.006||1.02 (0.99–1.06)||.06|
|Gender (male)||1.47 (1.00–2.1)||.05||1.78 (1.3–2.4)||.0003|
|HTN||1.4 (0.8–2.8)||.20||1.6 (0.95–2.8)||.08|
|NIDDM||1.12 (0.8–1.6)||.40||1.12 (0.8–1.5)||.50|
|Hypercholesterolemia||0.8 (0.5–1.2)||.30||0.8 (0.6–1.2)||.30|
|PVD||1.18 (0.6–2.1)||.60||0.9 (0.5–1.6)||.80|
|Prior pacemaker||1.9 (1.08–3.2)||.03||1.8 (1.14–2.7)||.01|
|CAD||0.83 (0.6–1.2)||.40||1.1 (0.75–1.45)||.60|
|Atrial fibrillation||1.61 (1.02–2.5)||.04||1.55 (1.06–2.2)||.02|
|CABG||1.3 (0.8–2.0)||.30||1.5 (1.04–2.1)||.03|
|CVA||1.15 (0.7–2.0)||.60||0.99 (0.6–1.6)||.90|
|COPD||1.2 (0.9–2.0)||.30||1.33 (0.9–1.9)||.14|
|NYHA||1.6 (1.12–2.3)||.01||1.8 (1.35–2.45)||.0001|
|EuroSCORE||1.023 (1.02–1.05)||.0001||1.03 (1.02–1.03)||.0001|
|Frailty||1.9 (1.16–2.9)||.01||1.55 (1.03–2.25)||.03|
|Creatinine||1.3 (1.03–1.6)||.03||1.3 (1.06–1.6)||.01|
|EF||0.98 (0.97–1.00)||.10||0.98 (0.97–0.99)||.04|
|LV EDD||1.01 (0.98–1.04)||.50||1.02 (0.99–1.06)||.10|
|LV ESD||1.03 (1.00–1.06)||.04||1.03 (1.01–1.06)||.001|
|IVSd||1.04 (0.9–1.13)||.30||1.01 (0.95–1.09)||.60|
|PWd||1.03 (0.9–1.14)||.50||1.02 (0.92–1.1)||.70|
|LV mass index||1.00 (0.99–1.01)||.07||1.00 (0.99–1.00)||.10|
|RWT||1.2 (0.3–4.4)||.80||0.8 (0.3–2.4)||.70|
|Stroke volume index||0.96 (0.94–0.98)||.0003||0.97 (0.95–0.99)||.001|
|Cardiac output index||0.8 (0.6–1.06)||.10||1.04 (0.9–1.07)||.06|
|LA volume index||1.01 (1.00–1.02)||.01||1.01 (1.00–1.02)||.007|
|E wave||1.32 (0.75–2.3)||.30||2.3 (1.44–3.7)||.0006|
|E deceleration time||0.97 (0.94–0.99)||.01||0.97 (0.95–0.99)||.0003|
|E/A ratio||1.13 (0.8–1.5)||.30||1.58 (1.26–1.95)||.0001|
|E’ average||1.05 (0.97–1.10)||.10||1.04 (0.98–1.09)||.10|
|E/E’ average||1.00 (0.97–1.03)||.60||1.01 (0.98–1.03)||.30|
|Peak pressure transaortic gradient||0.98 (0.97–0.99)||.003||0.98 (0.97–0.99)||.002|
|Mean pressure transaortic gradient||0.98 (0.96–0.99)||.004||0.98 (0.97–0.99)||.0008|
|AVA||0.7 (0.23–2.0)||.50||1.2 (0.5–42.8)||.70|
|RA pressure||1.01 (0.96–1.07)||.50||1.05 (1.01–1.09)||.009|
|Systolic pulmonary pressure||1.01 (0.99–1.03)||.055||1.02 (1.00–1.03)||.001|
|MR moderate or greater||2.4 (0.85–5.3)||.09||1.6 (0.6–3.5)||.30|
|Aortic regurgitation grade||4.8 (0.8–15)||.08||2.5 (0.4–7.8)||.30|
|Tricuspid regurgitation moderate or greater||1.84 (1.09–2.95)||.02||2.0 (1.3–2.9)||.002|
|Tricuspid annulus||0.99 (0.96–1.03)||.90||1.02 (0.98–1.05)||.20|
|RV size moderate or greater||1.43 (0.84–2.36)||.10||1.35 (0.86–2.06)||.10|
|RV EDA||1.03 (0.98–1.07)||.15||1.05 (1.01–1.09)||.007|
|RV ESA||1.04 (0.98–1.09)||.20||1.06 (1.02–1.11)||.006|
|RV dysfunction moderate or greater||1.45 (0.95–2.16)||.07||1.36 (0.9–1.8)||.08|
|RV FAC||0.42 (0.03–5.5)||.50||0.14 (0.02–1.19)||.07|
|TAPSE||0.92 (0.87–0.97)||.006||0.94 (0.89–0.98)||.01|
|Ejection time||0.99 (0.98–0.99)||.01||0.99 (0.98–0.99)||.008|
|Tei index||12.4 (2.1–67)||.005||17.7 (4.4–68)||.0001|
Associations of TR in Severe AS
Table 1 shows the associations between clinical and echocardiographic parameters and the grade of TR at baseline. The only parameters that were associated with TR grade were those related to diastolic dysfunction (left atrial volume index, E/A ratio, and E/e′ ratio), pulmonary pressure (systolic pulmonary pressure), presence of other valvular diseases (mitral and aortic regurgitation), and annular dilatation (annular diameter). Multivariate analysis showed that preoperative systolic pulmonary artery pressure ( P = .0006) and annular diameter ( P = .008) were the only independent correlates of TR grade (χ 2 = 80.4, P < .0001 for the model).
TR Grade and Outcomes
Figures 2 A and 2 B show the associations of moderate or greater TR in univariate Kaplan-Meier analysis on survival ( Figure 2 A) and cardiac events ( Figure 2 B). Moderate or greater TR was not associated with 30-day mortality (odds ratio, 1.4; 95% CI, 0.12–1.9; P = .20). Moderate or greater TR was associated with long-term mortality (HR, 1.84; 95% CI, 1.09–2.95; P = .02) and higher cardiac event rate (HR, 2.0; 95% CI, 1.3–2.9; P = .002) in unadjusted analysis. However, in multivariate Cox hazard analysis adjusted for comorbidities, although TR grade remained significantly associated with increased mortality if adjusted for age alone (adjusted risk ratio, 1.68; 95% CI, 1.00–2.7; P = .05) or MR grade alone (adjusted risk ratio, 1.74; 95% CI, 1.00–2.9; P = .05), it was not when adjusted for European System for Cardiac Operative Risk Evaluation score ( P = .3), systolic pulmonary pressure, gender, presence of atrial fibrillation, or pacemaker ( P = .20), emphasizing the link among TR grade, advanced clinical stage, and adverse outcome ( Table 3 ). Patients were stratified according to the presence of RV dysfunction, MR, atrial fibrillation, and pulmonary artery systolic pressure at baseline. Cox proportional-hazards analysis with interaction terms for RV dysfunction (TAPSE ≤ 17), MR (moderate or greater), systolic pulmonary artery pressure (<50 or ≥50 mm Hg), and baseline rhythm (sinus or atrial fibrillation) with TR grade showed that TAPSE ≤ 17 ( P = .70 for interaction), moderate or greater MR ( P = .12 for interaction), pulmonary hypertension ( P = .80 for interaction), and baseline rhythm ( P = .08 for interaction) did not affect the association between TR and survival. Survival analysis in patients with or without RV dysfunction (TAPSE > or ≤ 17), and TR (less than moderate or moderate or greater) is shown in Figure 3 . RV dysfunction was associated with higher mortality irrespective of TR grade.