The aim of this study was to determine the risk factors for tricuspid regurgitation (TR) progression in a contemporary population of patients referred for echocardiography. In a case-control study, we compared 100 consecutive patients with TR progression on serial echocardiograms (trivial or mild TR on the first echocardiogram and moderate or severe functional TR on a follow-up echocardiogram) with 100 patients matched for age and gender, having mild TR at baseline and no TR progression. Mean age was 72 ± 10 years, 55% were males, and time to TR progression was 5.3 ± 2.9 years. Less than 10% had rheumatic heart disease. Left ventricular ejection fraction was preserved (≥50%) in 85% of the TR progression group and in 74% of the control group (p = 0.06). Pulmonary artery systolic pressure increased from 41 ± 16 to 56 ± 18 mm Hg in the TR progression group and decreased from 44 ± 13 to 41 ± 11 mm Hg in the control group (p <0.0001). Independent risk factors for TR progression were pulmonary artery systolic pressure change during follow-up (odds ratio per 1 mm Hg 1.14, 95% confidence interval 1.06 to 1.23, p <0.0001), permanent atrial fibrillation (odds ratio 14.3, 95% confidence interval 4.6 to 44.2, p <0.0001), and coronary artery disease (odds ratio 5.7, 95% confidence interval 1.4 to 22.8, p = 0.015). All-cause mortality at 3 years was 20% for patients without TR progression, 42% for moderate TR, and 63% for severe TR, p <0.0001. Progression-to-severe TR independently predicted subsequent mortality. In conclusion, in patients with low prevalence of rheumatic heart disease and preserved left ventricular ejection fraction, pulmonary artery systolic pressure increase and permanent atrial fibrillation were the most powerful risk factors for TR progression. Progression-to-severe TR was an independent predictor of subsequent mortality.
The tricuspid valve (TV), once called “the forgotten valve,” has been the focus of increasing interest and research in recent years. Moderate or severe tricuspid regurgitation (TR) has been reported in 15.6% of patients referred for echocardiography. TR is associated with heart failure (HF), reduced functional capacity, and death. Most often, TR is functional and results from TV annular dilation and right ventricular (RV) remodeling. There are limited data regarding predictors and risk factors associated with TR progression. Previous studies have focused primarily on patients with mitral valve (MV) disease after MV surgery or balloon mitral valvuloplasty. These studies identified rheumatic heart disease (RHD), ischemic mitral regurgitation, baseline TR severity, atrial fibrillation (AF), and a large left atrium as predictors of TR progression. Data regarding risk factors associated with the evolution of TR and its consequences in a contemporary patient population referred for echocardiography are virtually nonexistent. The aim of the present study was to identify risk factors for TR progression in contemporary patients referred for echocardiography.
Methods
This case-control study was based on the Lady Davis Carmel Medical Center echocardiography laboratory database. The echocardiography laboratory serves both inpatients and outpatients and functions both as a tertiary center and as a community service.
The study group comprised 100 consecutive patients who had TR progression on serial echocardiograms performed from January 2000 to December 2012. All patients had either trivial or mild TR on echo 1 (defined as the first available echocardiogram) and at least moderate TR on echo 2 (defined as the first follow-up echo showing the maximal degree of TR, namely moderate or severe).
The control group consisted of 100 patients matched for age and gender, who had serial echocardiograms showing no TR progression. The first and last echocardiograms were at least 1 year apart, and were performed during the same period as in the TR progression group. Echo 1 was defined as the first available echocardiogram showing mild TR, and echo 2 was defined as the last available echocardiogram showing no more than mild TR. Patients were excluded if they had TV repair or replacement before echo 2 or if they had organic TV disease other than RHD.
We reviewed medical records for relevant clinical data. The occurrence and time of onset of paroxysmal or permanent AF and HF and time of cardiac surgery and insertion of RV permanent pacemaker leads were recorded. We determined the vital status of all patients at 3 years after the second echocardiogram. The study protocol was approved by the local ethics committee.
Transthoracic echocardiography was performed using one of several commercially available echocardiographic systems (Philips Sonos 5500 or IE33; Eindhoven, Netherlands, or General Electric VIVID Q or VIVID S6; GE Vingmed Ultrasound AS, Horten, Norway). A complete echocardiographic study was performed using standard views and techniques.
Left ventricular (LV) end-diastolic and end-systolic diameters and end-systolic left atrial diameter were determined from the parasternal long-axis view. LV ejection fraction (LVEF) was visually estimated (eyeballing method) from all available views by experienced readers. The 2-dimensional biplane method of discs was used in equivocal cases at the discretion of the reading physician. Mitral and aortic valve disease severities were determined according to the published guidelines.
TR severity was determined based on color-flow Doppler imaging, TV leaflets anatomy, and hepatic venous flow pattern, using the parasternal RV inflow, parasternal short-axis, apical 4-chamber, and the subcostal views. Mild TR was defined as a small central jet, moderate TR as an intermediate jet, and severe TR as a large jet, or in the presence of significant TV leaflets malcoaptation or systolic flow reversal in the hepatic veins.
Pulmonary artery systolic pressure (PASP) was estimated from the TR jet using the view showing maximal jet velocity, and the right atrial (RA) pressure was estimated from the inferior vena cava diameter and inspiratory collapse or from direct examination of the jugular veins in the echocardiography laboratory. RV or RA enlargement was determined qualitatively from the apical 4-chamber view. The RV was considered enlarged if it appeared larger than the LV in this view. RV function was visually estimated from multiple views and classified as normal or dysfunctional.
Cases (n = 100) were individually matched with controls for age (within 5 years) and gender. Univariate case-control comparisons were performed using tests for paired data, including the paired t test for normally distributed continuous variables, the Wilcoxon matched-pairs signed-rank test for non-normally distributed continuous variables, and the McNemar chi-square test for categorical variables. An exact binomial version of McNemar’s test for matched samples was used when appropriate.
Multiple conditional logistic regression models for 1:1 matched data were estimated and used to calculate odds ratios and corresponding 95% confidence intervals for potential risk factors associated with TR progression. Time-dependent events such as AF and HF were included in the analysis if they occurred before the occurrence of TR progression in the study group (as assessed by serial echocardiograms) or before echo 2 in the control group. Models were conditioned on the original matched variables, and additional covariates that may influence the risk of TR progression were included if found significant at the p <0.05 level. We sought a final parsimonious model that included only those variables that were independently associated with progression of TR in a stepwise-backward elimination procedure.
The impact of TR progression on subsequent mortality was evaluated starting at echo 2. Survival curves were constructed using the Kaplan-Meier method, and comparisons were made using the log-rank test. Stepwise Cox proportional hazards models with backward selection were used to calculate hazard ratios and 95% confidence interval for TR grade and other risk variables. Skewed variables were natural log transformed and evaluated “per 1-SD greater” to facilitate comparisons of strengths of association.
Differences were considered statistically significant at the 2-sided p <0.05 level. Statistical analyses were performed using Stata, version 12.0 (StataCorp LP, College Station, Texas).
Results
Clinical characteristics of the patients with TR progression (n = 100) and the patients in the control group, who did not have TR progression (n = 100), are listed in Table 1 . The 2 groups were well matched for age and gender. The TR progression group was slightly older, but although the difference was statistically significant, it was negligible (<1%). RHD was uncommon in both groups (<10%). Left-sided valvular heart disease was present in about a third of the patients, and less than 10% had MV surgery, with no significant difference in between groups. In both groups, most patients were hypertensive and almost 1/2 was diabetic.
| Variable | Control Group (n = 100) | TR Progression (n = 100) | p Value |
|---|---|---|---|
| Age (yrs) | 71.8 ± 9.5 | 72.4 ± 9.7 | 0.001 |
| Women | 45 | 46 | 0.3 |
| Hypertension | 85 | 86 | 0.8 |
| Diabetes mellitus | 42 | 48 | 0.4 |
| Chronic lung disease | 15 | 16 | 0.85 |
| CAD | 53 | 67 | 0.03 |
| Previous myocardial infarction | 32 | 37 | 0.4 |
| AF ∗ | 49 | 65 | 0.02 |
| Permanent AF ∗ | 19 | 53 | <0.0001 |
| Heart failure ∗ | 38 | 62 | 0.001 |
| RHD | 4 | 9 | 0.13 |
| Cardiomyopathy | 0 | 2 | 0.50 |
| Left-sided valvular heart disease † | 27 | 34 | 0.55 |
| MV prolapse | 1 | 4 | 0.25 |
| Atrial septal defect | 0 | 3 | 0.25 |
| Cardiac surgery ∗ | 37 | 41 | 0.54 |
| Coronary artery bypass surgery | 25 | 27 | 0.73 |
| Atrial septal defect repair | 0 | 1 | 1.0 |
| Aortic valve replacement | 15 | 12 | 0.53 |
| MV replacement | 2 | 7 | 0.18 |
| MV repair | 2 | 0 | 0.50 |
| Cardiac pacemaker with RV lead ∗ | 12 | 18 | 0.26 |
∗ Before the occurrence of TR progression in the TR progression group or before echo 2 in the control group.
† At least moderate mitral or aortic valve disease or previous left-sided valve surgery.
Patients with TR progression were more likely to have AF and, in particular, permanent AF. Patients in the TR progression group had significantly more HF, mostly with preserved LVEF, and they had significantly more coronary artery disease (CAD). Less than 20% of the patients had a permanent RV pacemaker lead, with no significant difference in between groups.
The echocardiographic findings are listed in Table 2 . At baseline (echo 1), there was no significant difference in LV size or EF between groups, and most patients had preserved LVEF (≥50%). There was also no difference in left atrial size. PASP was mildly elevated, with no significant difference in between groups. Most patients had a normal RV at baseline.
| Variable | Baseline | Follow-Up | ||||
|---|---|---|---|---|---|---|
| TR Progression | p Value | TR Progression | p Value | |||
| No (n = 100) | Yes (n = 100) | No (n = 100) | Yes (n = 100) | |||
| Left ventricular end-diastolic diameter (cm) | 4.9 ± 0.6 | 4.9 ± 0.7 | 0.37 | 5.0 ± 0.8 | 4.8 ± 0.7 | 0.12 |
| Left ventricular end-systolic diameter (cm) | 3.4 ± 0.8 | 3.3 ± 0.8 | 0.42 | 3.4 ± 0.8 | 3.6 ± 1.0 | 0.08 |
| LVEF (%) | 54 ± 13 | 55 ± 11 | 0.25 | 53 ± 14 | 51 ± 15 | 0.36 |
| LVEF ≥50% | 85 | 74 | 0.06 | 70 | 68 | 0.76 |
| Left atrial diameter (cm) | 4.4 ± 0.6 | 4.4 ± 0.7 | 0.79 | 4.5 ± 0.6 | 4.8 ± 0.7 | 0.0002 |
| Mitral stenosis ∗ | 0 | 3 | 0.83 | 0 | 5 | 0.07 |
| Mitral regurgitation ∗ | 10 | 11 | 0.82 | 8 | 29 | 0.0006 |
| Aortic stenosis ∗ | 10 | 11 | 0.82 | 10 | 11 | 0.79 |
| Aortic regurgitation ∗ | 0 | 1 | 1.0 | 2 | 2 | 1.0 |
| PASP (mm Hg) | 44 ± 13 | 41 ± 16 † | 0.21 | 41 ± 11 ‡ | 56 ± 18 † | <0.0001 |
| Right atrial pressure (mm Hg) | 6.2 ± 2.6 | 7.0 ± 2.8 | 0.06 | 6.0 ± 2.3 | 9.4 ± 4.0 | <0.0001 |
| Right ventricular enlargement | 7 | 6 | 0.78 | 8 | 46 | <0.0001 |
| Right ventricular dysfunction | 5 | 1 | 0.21 | 7 | 19 | 0.01 |
| Right atrial enlargement | 18 | 29 | 0.07 | 22 | 80 | <0.0001 |
Echo 2 was performed 4.6 ± 2.9 years after echo 1. The time interval from echo 1 to echo 2 was longer in the TR progression group than in the control group (5.3 ± 2.9 vs 4.0 ± 2.6 years; p <0.001). In the control group, 11 patients had none or trivial TR and 89 had mild TR at echo 2. In the TR progression group, 77 patients had moderate TR and 23 had severe TR at echo 2.
Similar to baseline, there was no significant difference at follow-up (echo 2) between the 2 groups in LV size or LVEF. Significantly, more patients in the TR progression group had moderate or severe mitral regurgitation at follow-up, and left atrial size was significantly larger in this group. As expected, patients with TR progression had significantly more RV and RA enlargement, RV dysfunction, and increased RA pressure at follow-up.
The main echocardiographic finding was the difference between the 2 groups in PASP change (between echo 1 and echo 2). PASP increased by 15.1 ± 15.7 mm Hg in the TR progression group (p <0.0001) but decreased by 3.36 ± 13.0 mm Hg in the control group (p = 0.014, Figure 1 ).
Univariable risk factors for TR progression included PASP change (from echo 1 to echo 2), permanent AF, HF, and CAD. In a multivariable conditional logistic regression model, PASP change, permanent AF, and CAD remained independently associated with TR progression ( Table 3 ). Receiver operating characteristic curve for PASP change as a risk factor for TR progression showed an area under the curve of 0.82 (95% confidence interval 0.76 to 0.88). An increase in PASP ≥10 mm Hg predicted TR progression with a sensitivity of 61% and a specificity of 89%. Figure 2 shows the proportion of patients with TR progression according to the presence or absence of permanent AF and PASP change above median of the whole study population (4 mm Hg). Only 12 of 72 patients (16.7%) who did not have permanent AF and had a PASP change ≤4 mm Hg had TR progression, compared with 39 of 42 patients (92.9%) who had both permanent AF and an increase in PASP >4 mm Hg during follow-up.
| Variable | Unadjusted OR (95% CI) | p Value | Adjusted OR (95% CI) | p Value |
|---|---|---|---|---|
| PASP change (per 1 mm Hg) | 1.12 (1.07–1.18) | <0.0001 | 1.14 (1.06–1.23) | <0.0001 |
| Permanent AF | 5.86 (2.63–13.06) | <0.0001 | 14.30 (4.63–44.19) | <0.0001 |
| Heart failure | 2.50 (1.40–4.46) | 0.002 | — | — |
| CAD | 2.00 (1.05–3.80) | 0.034 | 5.65 (1.40–22.80) | 0.015 |
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