The outcome of tricuspid regurgitation (TR) remains unclear because of heterogeneity of etiology and the contradictory results of outcome studies. The aim of this study was to evaluate the clinical outcomes of TR in patients with pulmonary hypertension (PH) and normal left systolic function, stratified to patients with post- or precapillary PH.
In patients with no left valvar disease (isolated) functional TR, preserved left systolic function (ejection fraction ≥ 50%), and PH (systolic pulmonary pressure > 50 mm Hg), TR was assessed both qualitatively (grade) and semiquantitatively using the vena contracta method, and retrospective analysis of long-term outcomes was conducted. Patients with severe comorbid diseases were excluded.
The study included 245 patients (age 80.5 years, 37% men, ejection fraction 57%, all with pulmonary systolic pressure > 50 mm Hg). At least moderate to severe TR was diagnosed in 178 patients, and their outcomes were compared with those of 67 patients with the same characteristics and less than mild TR. At least moderate to severe TR was associated with lower survival, independent of all characteristics, right ventricular size or function, comorbidity, or pulmonary pressure ( P = .03 for grade and P = .02 for vena contracta). Cox proportional-hazard analysis with interaction terms for TR severity and etiology of PH (post- vs precapillary) showed that the etiology of PH did not affect the association of TR with outcome ( P = .90 for the interaction term).
At least moderate to severe isolated TR is independently associated with excess mortality in patients with preserved systolic function and PH, warranting heightened attention to diagnosis and grading. This is irrespective of etiology (pre- or postcapillary) of PH. Semiquantitative assessment of TR by vena contracta is an independent associate of outcome, superior to standard qualitative assessment.
In patients with preserved EF and PH, moderate to severe TR is associated with mortality.
This adverse association is irrespective of whether PH is post- or precapillary.
Vena contracta is superior to qualitative grading.
TAPSE is superior to all other measures of RV function.
No adverse consequence could be detected regarding vena contracta < 6.
Tricuspid regurgitation (TR) is a prevalent condition, but management guidelines remain vague because of a paucity of outcome studies and their contradictory results. The etiology of TR is very heterogeneous, but commonly, the tricuspid valve is anatomically preserved, and significant regurgitation is mostly secondary to right ventricular (RV) enlargement (functional TR), resulting in tricuspid annular dilation or leaflet tethering. The prognostic impact of TR was shown to be substantial in a large heterogeneous group, implying that tricuspid valve repair or replacement may lead to survival benefit. However, because mortality and morbidity are influenced by the same comorbidities affecting the tricuspid valve, concern was raised that the supposed harmful effect of TR may be just a surrogate marker for other cardiac or systemic comorbidities. Recent studies have tried to isolate TR from potential confounders and to assess outcomes for individual etiologies of TR separately. The results of these studies were surprising. On one hand, TR caused by flail leaflets, TR associated with mitral rheumatic disease, and isolated or idiopathic TR (functional TR with no left-sided valvular pathologies, preserved left ventricular ejection fraction [LVEF], but without pulmonary hypertension [PH]) significantly influenced survival. On the other hand, TR after left heart valve procedures, following transcatheter aortic valve replacement, or associated with systolic heart failure was not associated with excess events after adjustment for comorbidities and RV dysfunction, suggesting that in these contexts it is just a surrogate marker for the associated comorbidities.
Patients with preserved LV systolic function and PH are separated into those with postcapillary PH due to heart failure with preserved LVEF and those with precapillary PH due to lung disease. They constitute a large proportion of patients with functional TR. In trying to assess whether TR is this clinical context is an independent associate of outcome (as in patients with idiopathic TR 10 ), suggesting a possible role for a “TR-focused” intervention, or just a surrogate marker of their primary disease (as in patients with systolic heart failure ), we confined the present analysis to the well-defined, limited group of patients with preserved LVEF, PH, no left-sided valvular disease, and no other life expectancy–limiting conditions.
We retrospectively retrieved 2,381 consecutive echocardiogram from the Tel Aviv Medical Center cardiology unit performed between November 2011 and November 2014 fulfilling the following inclusion criteria: normal or preserved LVEF (≥50%) and significant PH, defined as pulmonary artery systolic pressure ≥ 50 mm Hg. We excluded patients with significant valvular disease (any other native valve disease of grade moderate or greater, any rheumatic disease, any valvular surgery), any congenital heart disease, or severe comorbidities with limited life expectancy (end-stage kidney or liver disease, metastatic cancer). We also excluded repeat examinations of the same patient. The patient selection process is shown in Figure 1 . The final cohort consisted of 178 patients with at least moderate to severe TR compared with 67 patients with LVEF ≥ 50%, pulmonary systolic pressure ≥ 50 mm Hg, and less than mild TR. All valvular abnormalities were graded using the recent American Society of Echocardiography guidelines criteria.
Clinical Characteristics and Outcomes
The records of all 245 patients were reviewed retrospectively. Comorbid conditions, medications, related physical examination findings, and demographic data were retrieved. Outcome was analyzed from an echocardiographic diagnosis until death or last follow-up to December 2016. In patients with several echocardiographic examinations, outcomes were analyzed from the first study with at least moderate to severe TR. Date of death was ascertained using the national health database, ensuring data accuracy. Cause of death was also noted. Cardiac death was defined as death related to acute coronary syndrome, heart failure, or arrhythmia. The study was powered (80%, P = .05) to detect a ≥30% mortality difference between at least moderate to severe and lesser degrees of TR. The study was institutional review board approved.
Echocardiography was performed in a standard manner using the same equipment (iE33; Philips Medical Systems, Bothell, WA). 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 index of myocardial performance (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 Doppler of RV outflow (time from the onset to the cessation of flow) and tricuspid valve closure-opening time was measured using continuous Doppler of the TR jet (time from the onset to the 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 using an integrative, semiquantitative approach as recommended by the American Society of Echocardiography. We first assessed the severity of valve regurgitation by evaluating specific signs that would point to either less than mild or severe regurgitation, including color jet area (thin small central vs large >50% jet area), vena contracta (VC) width (<0.2 cm or ≥7 mm), density of continuous Doppler jet (faint or dense and triangular), hepatic vein flow pattern (systolic dominant vs systolic reversal), transtricuspid inflow pattern (A-wave dominant or high-velocity E-wave dominant), annular diameter (normal vs dilated annulus with lack of valve coaptation), and RV and right atrial (RA) size (normal vs dilated). If all of the signs and indices were concordant, we defined TR as less than mild or severe. If the signs or values of the qualitative or semiquantitative parameters were in the intermediate range between mild and severe, we defined TR as at least moderate to severe if the majority (five or more) of the signs and indices were concordant with severe TR. 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. Cardiac structural as well as functional information was used to define whether PH was postcapillary (elevated left filling pressure) or precapillary (elevated pulmonary vascular resistance). Briefly, postcapillary PH was defined whenever left atrial maximal volume index was >34 mL/m 2 or LV mass exceeded the gender-specific normal range and E/A ratio was ≥2. Precapillary PH was defined whenever E/A ratio was ≤0.8, along with a peak E velocity < 50 cm/sec. In patients with E/A ratios ≤ 0.8 with peak E velocities > 50 cm/sec, or E/A ratios between >0.8 and < 2, postcapillary PH was defined whenever the average E/e′ ratio was >14 and left atrial maximal volume index was >34 mL/m 2 .
Continuous normally distributed parameters are presented as mean ± SD and were compared using Student’s t test. Ordinal and/or skewed data are presented as median (interquartile range) and were compared using the Wilcoxon rank sum test. Categorical data were compared between groups using the χ 2 test or Fisher exact test. Clinical end points were time to death and time to cardiac death. Univariate Cox proportional-hazard models for the end points allowed the calculation of hazard ratios (HRs) attached to routine echocardiographic and RV parameters. To assess if TR grade or VC was independently associated with outcome, we used multivariate Cox proportional-hazard models for the end points (time to death), allowing the calculation of HRs attached to at least moderate to severe TR adjusted for significant clinical variables or echocardiographic variables. The entry criterion was a univariate correlation with a P value < .05. To detect collinearity, we used correlation factor analyses to determine if any pairs of predictor variables were correlated with each other or with TR. The only highly correlated parameters (correlation coefficient > 0.9) were systolic pulmonary artery pressure and RA pressure. If any such pairs were found, the variable with the lowest univariate P value was chosen to be included in the analysis. Incremental value of VC versus TR grade, or jet area, and incremental value of TAPSE versus other RV functional parameters for assessment of time to clinical end points were tested by comparing nested models using F tests. Event distributions were calculated according to the Kaplan-Meier method and compared by means of the log-rank test. All P values were two sided, and P values < .05 were considered to indicate statistical significance. To assess thresholds of risk for TR VC, we used spline curves (of HR on the y axis vs TR VC on the x axis), whereby an HR of 1 represents the cohort’s mean risk. All data were analyzed using the JMP version 12.0 (SAS Institute, Cary, NC). All authors participated in designing the study, collecting and analyzing data, and drafting and revising the manuscript.
Clinical and Echocardiographic Characteristics
Demographic laboratory and echocardiographic baseline parameters stratified by severity of TR are shown in Table 1 . Clinical parameters stratified by severity of TR are shown in Table 2 . The etiology for PH was precapillary in 74 patients (30%; connective tissue disease, n = 9; thromboembolic disease, n = 18; and chronic obstructive lung disease, n = 47) and postcapillary in 171 patients. There were no differences between the groups in etiology of PH ( Table 2 ). Compared with patients with less than mild TR, those with at least moderate to severe TR were significantly older and had increased prevalence of atrial fibrillation, increased New York Heart Association grade, reduced blood pressure, reduced cardiac output, higher pulmonary artery systolic pressure, and larger left atria. Physical examination findings indicated right heart failure more often in patients with at least moderate to severe TR. Most echocardiographic parameters of right heart dysfunction were poorer in the group with at least moderate to severe TR: larger RA area, higher estimated RA pressure, TAPSE, and larger RV area measurements. The Tei index and RV FAC values were similar in both TR groups.
|Parameter||Less than mild TR ( n = 67)||At least moderate to severe TR ( n = 178)||P|
|Age (y)||78.0 ± 10.9||81.5 ± 11.0||.03|
|Male||27 (40%)||64 (35%)||.50|
|Hemoglobin (g/dL)||11.3 ± 1.8||11.4 ± 1.8||.70|
|Creatinine (mg/dL)||1.5 ± 0.8||1.4 ± 0.8||.90|
|Bilirubin (mg/dL)||0.5 ± 0.3||0.8 ± 0.3||.0005|
|Systolic BP (mm Hg)||146.7 ± 27.1||137.8 ± 27.1||.02|
|Charlson comorbidity index||1.52 ± 1.22||1.39 ± 1.26||.50|
|LVEF (%)||57.1 ± 4.2||57.7 ± 3.5||.3|
|SPAP (mm Hg)||56.4 ± 5.4||66.2 ± 12.6||<.0001|
|Cardiac index (L/min/m 2 )||2.96 ± 0.7||2.66 ± 0.7||.009|
|LA volume index (mL/m 2 )||46.1 ± 12.9||53.1 ± 22.8||.006|
|LVDd 2D (mm)||46.2 ± 6.6||45.4 ± 6.5||.40|
|LVDs 2D (mm)||27.8 ± 5.6||27.8 ± 6.4||.90|
|MV E Vmax (m/sec)||1.1 ± 0.3||1.0 ± 0.3||.40|
|E/A ratio||1.7 ± 1.2||1.8 ± 1.2||.50|
|E/(average E′)||17.1 ± 6.2||14.8 ± 5.2||.02|
|RAP (mm Hg)||9.1 ± 4.3||13.7 ± 5.0||.0001|
|RA area (cm 2 )||19.2 ± 4.9||27.2 ± 8.1||.0001|
|Tricuspid annulus (cm)||3.3 ± 0.5||3.8 ± 0.7||<.0001|
|TAPSE (mm)||19.5 ± 5.2||16.9 ± 5.5||.0001|
|Tei index||0.3 ± 0.1||0.3 ± 0.1||.10|
|RV end-diastolic area (cm 2 )||28.9 ± 7.3||34.2 ± 8.3||.0001|
|RV end-systolic area (cm 2 )||19.5 ± 5.9||23.3 ± 7.0||.0001|
|RV FAC||33.4 ± 7.3||32.2 ± 9.9||.30|
|TR jet area (cm 2 )||1.0 ± 0.3||10.9 ± 5.6||.0001|
|TR VC (mm)||1.3 ± 1.1||7.7 ± 2.9||.0001|
|Parameter||Minimal TR||Significant TR||P|
|Anemia at baseline||21.9%||24.3%||.70|
|CKD at baseline||40.6%||35.5%||.50|
During the follow-up period (1.8 ± 1.3 years), 28 deaths occurred in the less than mild group, six of which were cardiac deaths, and 105 in the at least moderate to severe TR group, with 39 of cardiac etiology. Clinical and echocardiographic parameters associated with mortality are shown in Table 3 .
|At least moderate to severe TR||1.78||1.19–2.76||.004|
|TR jet area||1.03||1.00–1.06||.04|
|Charlson comorbidity index||0.94||0.81–1.09||.40|
|LA volume index||1.01||1.00–1.01||.07|
|MV E wave||0.87||0.47–1.61||.60|
|MV E/A ratio||0.95||0.77–1.15||.60|
|MV E/E average||1.01||0.97–1.05||.60|
|RV end-diastolic area||1.00||0.98–1.02||.80|
|RV end-systolic area||1.01||0.99–1.04||.40|