The aim of this study was to assess differences in etiology, comorbidities, echocardiographic parameters, and prognosis between men and women with significant tricuspid regurgitation (TR). Clinical and echocardiographic characteristics of 1569 patients (age 71 [62 to 78] years) at first diagnosis of significant TR were compared between men and women. Patients with congenital heart disease or previous tricuspid valve surgery were excluded. TR etiologies were defined as primary, left valvular disease related, left ventricular (LV) dysfunction related, pulmonary hypertension related, or isolated. The primary endpoint was all-cause mortality. Sex-specific differences in outcomes were compared in the total population and after propensity score matching. There were 798 (51%) women and 771 (49%) men in the study population. Women were diagnosed with significant TR at an older age compared with men (72 [62 to 79] years vs. 70 [61 to 77] years; p = 0.003). The TR etiology in women was more often left valvular disease related and isolated whereas men more often had LV dysfunction related TR. In the total population women had better 10-year survival compared with men (49% vs. 39%; p=0.001). After propensity score matching, the influence of sex on survival was neutralized (p = 0.228) but the TR etiologies remained significantly associated with all-cause mortality. Patients with left valvular disease or LV dysfunction related TR had lower survival compared with patients with primary TR (p = 0.004 and p = 0.019, respectively). In conclusion, long-term survival of patients with significant TR was similar between men and women after propensity score matching, while the etiology of TR remained significantly associated with all-cause mortality.
The prevalence of tricuspid regurgitation (TR) increases with age and is higher in women than in men in the general population. Multiple studies have demonstrated the impact of significant (moderate and severe) TR on prognosis, but differences between men and women remain unclear. , TR is a heterogeneous disease with different characteristics, treatment and prognosis depending on the etiology. The prevalence of the cardiac diseases that may cause TR, such as ischemic heart disease, left valvular disease or atrial fibrillation, vary between men and women. Recent studies have demonstrated differences in the distribution of the various TR etiologies between sexes. , , Consequently, differences between men and women in clinical and echocardiographic characteristics may be expected. It is important to clarify these sex-specific differences in presentation of TR and their prognostic implications to improve risk stratification and treatment. However, differences between men and women in characteristics, etiology and prognosis in the natural history of TR have not been extensively studied. Therefore, the aim of our study was (1) to describe sex-specific differences in clinical characteristics, echocardiographic parameters and etiology in patients with significant TR and (2) to assess the association between sex and prognosis in the overall population and a propensity score matched population of patients with significant TR.
Methods
The data that support the findings of this study are available on reasonable request to the corresponding author. Patients diagnosed with significant (moderate and severe) TR at the Leiden University Medical Center (Leiden, the Netherlands) between June 1995 and September 2016 were identified by performing a query in the departmental echocardiographic database. TR was evaluated in all patients by transthoracic echocardiography using a multiparametric approach as recommended by the current guidelines. Patients with previous surgery of the tricuspid valve and patients with congenital heart disease were excluded. Demographics and clinical data were retrospectively obtained and analyzed from the departmental Cardiology Information System (EPD-vision; Leiden University Medical Center). The institutional review board of the Leiden University Medical Center approved this observational design and retrospective analysis of clinically acquired anonymized data and waived the need for patient written informed consent.
Baseline was determined at the moment of first diagnosis of significant TR by transthoracic echocardiography. Clinical and echocardiographic characteristics and TR etiology were compared between men and women. Clinical data included demographics, cardiovascular risk factors and co-morbidities, diuretic use and glomerular filtration rate, which was calculated by the Modification of Diet in Renal Disease formula.
Transthoracic 2-dimensional echocardiography was performed with patients at rest. Commercially available ultrasound systems (Vivid 7, E9 and E95 systems; GE-Vingmed) equipped with 3.5 MHz or M5S transducers were used to acquire images that were digitally stored for offline analysis with commercially available software (EchoPAC version 113.0.3 and 202; GE-Vingmed). M-mode, 2-dimensional, color, continuous- and pulsed-wave Doppler data were acquired on parasternal, apical and subcostal views according to the current recommendations. , Left ventricular (LV) ejection fraction was derived by the Simpson method from LV volumes that were measured on the apical 2- and 4-chamber views. Left atrial (LA) maximum volume was assessed on the apical 2- and 4-chamber views and corrected for body surface area. Significant (moderate or severe) aortic stenosis was defined by an aortic valve area ≤ 1.5 cm 2 , which was calculated by the continuity equation. Mitral regurgitation and TR severity were graded by an integrative approach based on qualitative, semiquantitative and quantitative parameters evaluated on 2-dimensional, color, continuous and pulsed wave Doppler data according to the current recommendations. The tricuspid annular diameter, right atrial (RA) and right ventricular (RV) areas were measured on a focused RV apical 4-chamber view and corrected for body surface area. RV systolic function was quantified by tricuspid annular plane systolic excursion (TAPSE) as measured on M-mode recordings of the lateral tricuspid annulus. Systolic pulmonary artery pressure (sPAP) was estimated by the simplified Bernoulli equation, derived from the tricuspid regurgitant jet peak velocity with addition of 3, 8 or 15 mmHg based on the size and collapsibility of the inferior vena cava. Quantitative parameters of TR were measured as recommended by current guidelines.
Etiology of TR was defined by a stepwise classification based on the method introduced by Topilsky and colleagues. Firstly, primary TR was defined in case of structural abnormalities of the tricuspid valve. Secondly, patients with moderate or severe (significant) left-sided valvular disease at baseline, such as mitral regurgitation, or with previous left-sided valvular surgery were classified as having left valvular disease related TR. The third category was characterized as LV dysfunction related TR, occurring in patients with a LV ejection fraction <50%. The fourth step defined TR associated with pulmonary hypertension in case of sPAP ≥50 mm Hg and the remaining patients were categorized as isolated TR.
The primary outcome of interest was all-cause mortality while on optimal medical therapy. Survival data were verified by the departmental Cardiology Information System which is linked to the Social Security Death Index. Secondary endpoints included hospitalization for heart failure, tricuspid valve surgery, any valvular surgery, coronary artery bypass grafting and the occurrence of atrial arrhythmias during follow-up. Outcome was assessed in the total population and in a subpopulation of propensity score matched pairs of men and women to account for the effect of baseline clinical and echocardiographic differences on prognosis.
Continuous variables with normal distribution are expressed as mean ± standard deviation and continuous variables with non-normal distribution as median (interquartile range). A histogram of the sample data was compared with a normal probability curve to determine the adherence to normality. Categorical variables are presented as frequencies and percentages. Baseline differences between men and women were analyzed by the unpaired T -test, the Mann-Whitney U test and the chi-square test as appropriate. To account for potential confounders in the determination of sex-related differences in prognosis, a matched subgroup for comparative outcome analysis was formed using propensity scores. Baseline variables used to calculate propensity score are presented in Supplementary Table S1. All women were entered into a nearest neighbor 1:1 variable ratio, parallel, balanced propensity score matching model using a caliper width of 0.05, and thereby matched 1:1 to men. The 1-, 5- and 10-year survival rates in the total population and in the propensity score matched population were calculated with the Kaplan Meier curves censored for tricuspid valve surgery. Differences between men and women in the primary endpoint were analyzed using the log-rank test. Sex differences in the secondary endpoints were compared using the chi-square test. Cox proportional hazards regression analysis was performed to test the association of TR etiologies with all-cause mortality in the propensity score matched population. Hazard ratios and 95% confidence intervals were calculated. All p-values were 2-sided and values <0.05 were considered significant. Statistical analyses were performed with SPSS for Windows, version 25 (SPSS Inc, IBM Corp).
Results
A total of 1569 patients with significant TR (median age 71 years [62-78]) were included in the analysis. There were 798 (51%) women and 771 (49%) men. Baseline clinical characteristics of the total population and according to sex are presented in Table 1 . In per-group analysis, women were older at diagnosis of significant TR compared with men (72 years [62 to 79] vs. 70 years [61 to 77]; p = 0.003). Men were more likely to have hypercholesterolemia, diabetes mellitus and a smoking habit. Men more often had known coronary artery disease compared with women (48% vs. 28%; p <0.001) and more often had a pacemaker or implantable cardioverter-defibrillator (ICD) in situ (41% vs. 26%; p <0.001). No significant differences between the sexes were found in the presence of atrial fibrillation.
| Variable | Overall (n=1569) | Women (n=798) | Men (n=771) | p-value |
|---|---|---|---|---|
| Age (years) | 71 (62-78) | 72 (62-79) | 70 (61-77) | 0.003 |
| Body mass index (kg/m 2 ) | 26 ± 4 | 26 ± 5 | 26 ± 4 | 0.188 |
| Hypertension | 1143 (80%) | 574 (78%) | 569 (81%) | 0.182 |
| Hypercholesterolemia | 668 (47%) | 291 (40%) | 377 (54%) | <0.001 |
| Diabetes mellitus | 289 (20%) | 132 (18%) | 157 (22%) | 0.043 |
| (Ex-)smoker | 450 (31%) | 197 (27%) | 253 (36%) | <0.001 |
| Coronary artery disease | 588 (38%) | 221 (28%) | 367 (48%) | <0.001 |
| Atrial fibrillation | 739 (50%) | 373 (50%) | 366 (51%) | 0.735 |
| Pacemaker/ICD | 516 (33%) | 201 (26%) | 315 (41%) | <0.001 |
| Oral anticoagulants | 824 (58%) | 391 (54%) | 433 (62%) | 0.003 |
| Aspirin | 285 (20%) | 147 (20%) | 138 (20%) | 0.834 |
| Betablockers | 844 (59%) | 412 (57%) | 432 (62%) | 0.060 |
| ACE-inhibitors | 867 (61%) | 412 (57%) | 455 (65%) | <0.001 |
| Aldosterone antagonists | 307 (22%) | 130 (18%) | 177 (26%) | 0.001 |
| Calcium antagonists | 152 (11%) | 81 (11%) | 71 (10%) | 0.530 |
| Statins | 633 (45%) | 268 (37%) | 365 (52%) | <0.001 |
| Diuretic use | 876 (58%) | 445 (58%) | 431 (58%) | 0.811 |
| eGFR (ml/min/1.73m 2 ) | 65 (46-84) | 63 (47-81) | 66 (46-86) | 0.278 |
| Echocardiographic characteristics | ||||
| LV end diastolic volume (ml/m 2 ) | 63 (47-93) | 54 (41-75) | 78 (54-115) | <0.001 |
| LV ejection fraction (%) | 45 ± 16 | 47 ± 15 | 42 ± 16 | <0.001 |
| LA maximum volume (ml/m 2 ) | 50 (34-69) | 48 (34-67) | 51 (34-70) | 0.454 |
| Significant aortic stenosis | 314 (23%) | 185 (27%) | 129 (19%) | 0.001 |
| Significant mitral regurgitation | 457 (29%) | 232 (29%) | 225 (29%) | 0.950 |
| RV end diastolic area (mm 2 /m 2 ) | 13 (10-16) | 12 (10-14) | 14 (11-17) | <0.001 |
| TAPSE (mm) | 16 ± 5 | 16 ± 5 | 15 ± 5 | <0.001 |
| sPAP (mmHg) | 42 ± 17 | 42 ± 16 | 43 ± 18 | 0.049 |
| RA maximum area (cm 2 /m 2 ) | 15 ± 5 | 14 ± 5 | 15 ± 5 | 0.004 |
| Severe tricuspid regurgitation | 367 (23%) | 196 (25%) | 171 (22%) | 0.265 |
| Tricuspid annular diameter (mm/m 2 ) | 22 ± 4 | 22 ± 4 | 22 ± 4 | 0.956 |
| Tricuspid leaflet tenting area (mm 2 ) | 1.9 (0.0-3.9) | 1.6 (0.0-3.4) | 2.3 (0.2-4.4) | <0.001 |
| PISA radius (mm) | 11.1 ± 4.0 | 10.8 ± 3.9 | 11.3 ± 4.2 | 0.016 |
| EROA (mm 2 ) | 62 (39-99) | 59 (37-94) | 65 (41-104) | 0.020 |
| RVol (mL/beat) | 59 (35-99) | 55 (33-94) | 62 (36-103) | 0.021 |
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