Chronic pressure-overload induces right ventricular (RV) adaptation to maintain RV–pulmonary arterial (PA) coupling. RV remodeling is frequently associated with secondary tricuspid regurgitation (TR) which may accelerate uncoupling. Our aim is to determine whether the non-invasive analysis of RV–PA coupling could improve risk stratification in patients with secondary TR. A total of 1,149 patients (median age 72[IQR, 63 to 79] years, 51% men) with moderate or severe secondary TR were included. RV–PA coupling was estimated using the ratio between two standard echocardiographic measurements: tricuspid annular plane systolic excursion (TAPSE) and pulmonary artery systolic pressure (PASP). The risk of all-cause mortality across different values of TAPSE/PASP was analyzed with a spline analysis. The cut-off value of TAPSE/PASP to identify RV–PA uncoupling was based on the spline curve analysis. At the time of significant secondary TR diagnosis the median TAPSE/PASP was 0.35 (IQR, 0.25 to 0.49) mm/mm Hg. A total of 470 patients (41%) demonstrated RV–PA uncoupling (<0.31 mm/mm Hg). Patients with RV–PA uncoupling presented more frequently with heart failure symptoms had larger RV and left ventricular dimensions, and more severe TR compared to those with RV–PA coupling. During a median follow-up of 51 (IQR, 17 to 86) months, 586 patients (51%) died. The cumulative 5-year survival rate was lower in patients with RV–PA uncoupling compared to their counterparts (37% vs 64%, p < 0.001). After correcting for potential confounders, RV–PA uncoupling was the only echocardiographic parameter independently associated with all-cause mortality (HR 1.462; 95% CI 1.192 to 1.793; p < 0.001). In conclusion, RV–PA uncoupling in patients with secondary TR is independently associated with poor prognosis and may improve risk stratification.
Significant (moderate or severe) tricuspid regurgitation (TR) is associated with increased morbidity and mortality. Secondary TR is the predominant mechanism of TR and is frequently due to left-sided valvular heart disease and left ventricular diastolic or systolic dysfunction. These conditions commonly result in elevated pulmonary pressures and increased right ventricular (RV) afterload, with the RV adapting to the increased load through hypertrophy and/or dilation. RV dilation is accompanied by progressive tricuspid annular dilation and papillary muscle displacement, key factors in the development of secondary TR. Quantification of RV–pulmonary arterial (PA) coupling may provide important insights into the mechanism of adaptation of RV contractility to afterload in patients with secondary TR. The ratio between RV end-systolic elastance (Ees) and pulmonary arterial elastance (Ea) estimated from invasive pressure–volume loops is the reference standard. Recently, the ratio between tricuspid annular plane systolic excursion (TAPSE) and pulmonary artery systolic pressure (PASP) measured on echocardiography has shown a good correlation with invasively estimated RV–PA coupling. A reduced TAPSE/PASP ratio suggests that RV contractility is uncoupled from its load and portends a poor prognosis in patients with pulmonary hypertension. The aim of the present study is to determine whether the noninvasive analysis of RV–PA coupling with the use of the TAPSE/PASP ratio could improve risk stratification in patients with significant secondary TR.
Methods
A query of the echocardiographic database of the Leiden University Medical Center (Leiden, The Netherlands) was performed to identify patients diagnosed with moderate or severe secondary TR between June 1995 and September 2016. Patients with primary TR (due to valve prolapse, endocarditis, rheumatic or carcinoid heart disease), congenital heart disease, and those who underwent tricuspid valve interventions after the diagnosis of significant TR were excluded. In addition, patients with incomplete data to assess RV–PA coupling (i.e., TAPSE and/or PASP) were specifically excluded. Clinical and demographic data at the time of the diagnosis of significant secondary TR were collected from the departmental Cardiology Information System (EPD-VisionVR; Leiden University Medical Centre, Leiden, The Netherlands). This retrospective analysis of clinically acquired data was approved by the institutional review board of the Leiden University Medical Centre that waived the need for patient written informed consent.
Clinical characteristics included cardiovascular risk factors, comorbidities, New York Heart Association (NYHA) functional class, medical therapy, and the presence of cardiac devices. Transthoracic echocardiographic data were acquired with patients at rest in the left lateral decubitus position using available ultrasound systems (Vivid 7, E9, and E95 systems; GE-Vingmed) equipped with 3.5 MHz or M5S transducers. Data were stored digitally in a cine-loop format for offline analysis with the EchoPac software (EchoPac version 203 and 204, GE-Vingmed). The digitized echocardiographic data were retrospectively reanalyzed taking into account current guidelines and therefore, the present study does not simply concern tabulation of descriptive data included in the clinical reports. RV dimensions were measured on an RV-focused apical view and included end-diastolic basal and mid diameter, end-diastolic base-to-apex length, end-diastolic, and end-systolic areas. RV systolic function was estimated based on TAPSE measured on M-mode recordings of the lateral tricuspid annulus. RV fractional area change was also calculated with the following formula: (end-diastolic area – end-systolic area)/end-diastolic area × 100. TR grade was assessed by a multiparametric approach, including qualitative, semi-quantitative, and quantitative parameters. PASP was estimated from the TR jet peak velocity applying the simplified Bernoulli equation and adding mean right atrial pressure. Mean right atrial pressure was derived based on the inferior vena cava diameter and collapsibility during inspiration. . Left ventricular ejection fraction (LVEF) was calculated using the biplane Simpson method. RV–PA coupling was estimated non-invasively using the ratio between two standard echocardiographic measurements: TAPSE and PASP. TAPSE/PASP ratio is a surrogate for Ees/Ea, based on the assumption that TAPSE provides an estimate of RV contractility and PASP an estimate of RV afterload. , Moreover, it was recently demonstrated that TAPSE/PASP is the only echocardiographic index that is independently associated with the gold standard invasive measurement of RV–PA coupling (i.e., Ees/Ea).
The primary endpoint of this study was all-cause mortality. All patients were followed-up for the occurrence of the primary endpoint. Survival data were collected from the departmental Cardiology Information System and the Social Security Death Index.
The statistical analyses were performed using the SPSS version 25.0 (SPSS Inc, IBM Corp) and in R environment 3.6.4 (R Foundation for Statistical Computing). Categorical variables are expressed as numbers and percentages. For continuous variables, adherence to a normal distribution was verified through visual assessment, comparing a histogram of the sample data to a normal probability curve. Normally distributed continuous variables are presented as mean ± standard deviation while variables that are non-normally distributed are presented as median and interquartile range. To assess the hazard ratio (HR) change for all-cause mortality across a range of TAPSE/PASP values at baseline a spline curve analysis was performed. The cut-off value of TAPSE/PASP to define RV–PA uncoupling was chosen based on mortality excess and previously published data. Differences between RV–PA coupling versus uncoupling were analyzed using the unpaired Student t-test for normally distributed continuous variables, the Mann–Whitney U test for non-normally distributed continuous variables and the Pearson’s chi-square test for categorical variables. The 1- and 5-year cumulative survival rates were estimated with Kaplan–Meier curves and differences between groups were analyzed using the Mantel–Cox log-rank test. A multivariable Cox proportional hazard regression analysis was conducted to assess the clinical and echocardiographic features that were independently associated with all-cause mortality. Possible confounders with a p value < 0.05 at the univariable analysis were included in the multivariable Cox regression analysis. HRs and 95% confidence intervals (CIs) were calculated. Two-sided p values < 0.05 were considered statistically significant.
Results
A total of 1,149 patients with a median age of 72 (interquartile range, 63 to 79) years fulfilled the study inclusion criteria (Supplementary Figure 1). Of these, 909 (79%) had moderate TR and 240 (21%) had severe TR. To investigate the relationship between TAPSE/PASP ratio and all-cause mortality, a spline curve analysis was performed ( Figure 1 ). After an initial slow rise of HR, there was an increase in the HR of all-cause mortality for reduced values of TAPSE/PASP ratio (<0.31 mm/mm Hg). Based on this analysis and previously published data, a TAPSE/PASP value < 0.31 mm/mm Hg was used to define RV–PA uncoupling and to dichotomize the population. RV–PA uncoupling at the time of significant secondary TR diagnosis was present in 470 patients (41%). When compared to patients with RV–PA coupling, those with RV–PA uncoupling were more frequently men, had a higher prevalence of cardiovascular risk factors and coronary artery disease, worse renal function, were more symptomatic (heart failure symptoms and peripheral edema), and used diuretics more frequently ( Table 1 ). Patients with RV–PA uncoupling had significantly larger left ventricular and RV dimensions, lower LVEF, larger left atrial (LA) volumes, and more frequently had significant mitral regurgitation than those without RV–PA uncoupling ( Table 2 ). Interestingly, those with RV–PA uncoupling had larger tricuspid regurgitant volume and vena contracta width when compared to those with RV–PA coupling.
| Variable | Overall (n = 1,149) | RV–PA coupling (TAPSE/PASP ≥ 0.31) (n = 679) | RV–PA uncoupling (TAPSE/PASP < 0.31) (n = 470) | p value |
|---|---|---|---|---|
| Age (years) | 72 (63-79) | 72 (62 to 78) | 72 (63 to 79) | 0.271 |
| Men | 582 (51%) | 317 (47%) | 265 (56%) | 0.001 |
| Body mass index (kg/m 2 ) | 26 ± 4 | 26 ± 4 | 25 ± 4 | 0.489 |
| Hypertension | 854 (81%) | 497 (80%) | 357 (83%) | 0.312 |
| Hypercholesterolemia | 501 (48%) | 266 (43%) | 235 (55%) | <0.001 |
| Diabetes mellitus | 208 (20%) | 82 (13%) | 126 (29%) | <0.001 |
| Coronary artery disease | 457 (40%) | 221 (33%) | 236 (51%) | <0.001 |
| Chronic obstructive pulmonary disease | 154 (15%) | 84 (14%) | 70 (16%) | 0.258 |
| Glomerular filtration rate (ml/min/1.73 m 2 ) | 65 ± 29 | 68 ± 28 | 59 ± 28 | <0.001 |
| Current or former smoker | 319 (31%) | 192 (31%) | 127 (30%) | 0.584 |
| Atrial fibrillation | 539 (50%) | 314 (49%) | 225 (51%) | 0.692 |
| New York Heart Association functional class III-IV | 464 (44%) | 220 (36%) | 244 (56%) | <0.001 |
| Peripheral edema | 249 (23%) | 109 (17%) | 140 (31%) | <0.001 |
| Diuretic use | 645 (58%) | 329 (50%) | 316 (69%) | <0.001 |
| Variable | Overall (n = 1,149) | RV–PA coupling (TAPSE/PASP ≥ 0.31 )(n=679) | RV–PA uncoupling (TAPSE/PASP < 0.31) (n=470) | p value |
|---|---|---|---|---|
| Left-sided heart | ||||
| Left ventricular end-diastolic diameter (mm) | 48 ± 11 | 47 ± 11 | 50 ± 12 | <0.001 |
| Left ventricular end-systolic diameter (mm) | 39 ± 13 | 37 ± 13 | 41 ± 14 | <0.001 |
| Left ventricular end-diastolic volume (ml) | 113 (80-167) | 105 (80-154) | 125 (82-190) | <0.001 |
| Left ventricular ejection fraction (%) | 44 ± 16 | 46 ± 15 | 41 ± 16 | <0.001 |
| Left atrial maximum volume (ml) | 92 (59-127) | 80 (56-119) | 104 (70-137) | <0.001 |
| Significant aortic stenosis | 263 (24%) | 145 (22%) | 118 (26%) | 0.106 |
| Significant mitral regurgitation | 304 (27%) | 155 (23%) | 149 (32%) | 0.001 |
| Right-sided heart | ||||
| RV basal diameter (mm) | 45 ± 8 | 45 ± 9 | 46 ± 8 | 0.409 |
| RV mid diameter (mm) | 35 ± 9 | 34 ± 9 | 36 ± 9 | 0.001 |
| RV longitudinal diameter (mm) | 72 ± 12 | 71 ± 13 | 74 ± 12 | <0.001 |
| RV end-diastolic area (cm 2 ) | 25 ± 12 | 25 ± 14 | 26 ± 9 | 0.025 |
| Right atrial area (cm 2 ) | 28 ± 11 | 27 ± 11 | 28 ± 10 | 0.078 |
| Fractional area change (%) | 34 ± 13 | 36 ± 14 | 31 ± 12 | <0.001 |
| Tricuspid annular plane systolic excursion (mm) | 15 ± 5 | 18 ± 5 | 12 ± 3 | <0.001 |
| PASP (mm Hg) | 44 ± 16 | 37 ± 11 | 55 ± 15 | <0.001 |
| Tricuspid valve | ||||
| Tricuspid annulus diameter (mm) | 42 ± 8 | 42 ± 8 | 42 ± 8 | 0.106 |
| Vena contracta (mm) | 11 ± 4 | 10 ± 4 | 11 ± 4 | 0.023 |
| Effective regurgitant orifice area (mm 2 ) | 68 (43-105) | 68 (41-110) | 68 (46-101) | 0.905 |
| Regurgitant volume (ml/beat) | 65 (39-104) | 59 (35-102) | 73 (46-106) | <0.001 |
| Pacemaker/Implantable cardioverter defibrillator lead | 413 (37%) | 245 (37%) | 168 (36%) | 0.887 |
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