Study Subjects

We retrospectively analyzed 74 patients with severe isolated TR between March 1997 and January 2007 at Severance Cardiovascular Hospital (Seoul, Korea). We excluded patients with significant left-sided valvular diseases such as moderate and severe stenosis or regurgitation in the mitral or aortic valves. Patients with pulmonary artery systolic pressures > 40 mm Hg or histories of valve operation irrespective of current prosthetic valve function were also excluded. Patients with shunt disease, such as atrial septal defect, Eisenmenger syndrome, right ventricular (RV) dysplasia, as well as hyperthyroidism and other cardiomyopathies were also excluded from this study. None of the patients had left ventricular systolic dysfunction All patients fulfilled the following criteria for severe TR: (1) TR jet area > 30% of right atrial (RA) area or TR jet area > 10 cm ² and (2) a plethora of inferior vena cava or systolic flow reversal of the hepatic vein. This study was approved by the institutional ethics committee and complied with the Declaration of Helsinki.

Echocardiography

Two-dimensional measurements were obtained using standard methods according to the guidelines of the American Society of Echocardiography. Left ventricular end-diastolic and end-systolic diameters were measured by M-mode echocardiography in the parasternal short-axis view at the papillary muscle level. Left ventricular ejection fraction was calculated using the biplane method. RV end-diastolic and end-systolic areas and dimensions were measured in the apical four-chamber view, and RV fractional area change (FAC) was calculated. RV long-axis length and mid-RV diameter were used to calculate the RV sphericity index at end-systole and end-diastole. Both end-systolic and end-diastolic RV eccentricity indices were calculated in the parasternal short-axis view at the left ventricular papillary muscle level. RA end-diastolic and end-systolic areas were also measured in the apical four-chamber view, and RA FAC was calculated. The peak TR velocity was measured using continuous-wave Doppler, and pulmonary arterial systolic pressure was estimated by measurement of the systolic TR flow velocity and RA pressure. RA pressure was estimated from the inferior vena cava with respiratory variation. TV tethering distance was measured from the annular plane to the coaptation point, and the tenting area was calculated by tracing the leaflets from the annular plane at the midsystolic phase. The TR jet area by color Doppler was measured with a sector allowing visualization of the entire right atrium, and planimetry of the maximal aliasing area of the regurgitant jet was performed. The ratio of the maximal TR jet area to the RA area at the time of jet measurement was also calculated. The effective regurgitant orifice (ERO) area and vena contracta width (VCW) were measured at a Nyquist limit of 50 to 65 cm/sec using a zoom mode according to the published guidelines of the American Society of Echocardiography. In patients with atrial fibrillation, these parameters were measured during relatively regular rhythm and calculated as the mean value over five consecutive beats. Two investigators reviewed all the images and double-checked the severity of TR. Measurements were carried out offline by a single investigator who was unaware of the status of the study patients.

Clinical Follow-Up

Follow-up data were obtained by reviewing medical records, telephone interviews, and the National Health Insurance Corporation Death Index. The end point was cardiovascular events, defined as hospitalization for worsening heart failure (HF), TV surgery, or cardiovascular death (classified as sudden death or death due to refractory HF). Sudden cardiac death was defined as unexpected sudden cardiac collapse within 1 hour of new symptoms or nocturnal death with no antecedent history of worsening symptoms. HF-related death was defined as death preceded by signs or symptoms of HF.

Statistical Analysis

Continuous variables are expressed as mean ± SD and categorical variables as number of patients (percentage). Cox regression analysis was performed to identify the major determinants of cardiovascular events (aggravation of HF, TV surgery, and cardiovascular death). After unadjusted models were fit, we developed pruned multivariate models using the following procedure. We chose independent variables that were related to the outcomes in bivariate specifications ( P < .10). Nonsignificant ( P ≥ .20) covariates whose elimination did not change the estimated coefficient of the exposure variable by >10% were sequentially removed. Age and sex were adjusted for irrespective of their association. Because our models may be overspecified for small numbers of patients and events, we estimated reduced form models with covariates that showed statistical significance in the pruned adjusted models. The proportional-hazards assumption was evaluated for proper reduced form model. Survival data were estimated using the Kaplan-Meier method, and survival curves were analyzed using the log-rank test. P values ≤ .05 were considered statistically significant.

Characteristics of Patients

Seventy-four patients (mean age, 63 ± 12 years; range, 37–81 years; 34 men) with severe isolated TR were enrolled in this study. Of the 74 patients, organic TV problems were observed in 23 (31%); 12 patients had prolapse of the TV, and 11 patients showed thickened and restricted TV. Of the 23 patients with TV organic problems, 10 patients underwent TV surgery; five had myxomatous degeneration, and the remaining five had severe fibrosed leaflets. Fifty-one patients (69%) had no evidence of organic TV disease or other confounding factors possibly causing TR. Only four of the 51 patients without organic TV problems presented with RV remodeling. The patients without organic TV problems were older than those with organic TV problems (66 ± 10 vs 56 ± 12 years, P < .01), and most had atrial fibrillation ( n = 46 [90%]). Patients with atrial fibrillation often had tricuspid annular dilatation, but they had smaller annular dilatation than patients with TV organic problems (39 vs 46 mm, P < .05).

Forty patients (54%) were taking diuretics, 24 (32%) were taking digitalis, and 18 (24%) were taking β blockers. Warfarin was administrated to 32 patients (43%) and aspirin to 21 (28%).

Correlations Among Echocardiographic Parameters

Echocardiographic characteristics are reported in Table 1 . The mean RA jet area percentage was 43 ± 10%. The mean VCW and ERO area were 7.5 ± 2.7 mm and 88.6 ± 41.5 mm ² , respectively. Patients with organic TV problems showed larger VCWs than those without organic TV problems (6.4 vs 9.9 mm, P < .01). There was a good correlation between VCW and ERO areas ( r = 0.81, P < .01). VCW also showed significant correlations with other echocardiographic parameters, including TR jet area ( r = 0.80, P < .01; Figure 1 ), RA end-systolic area ( r = 0.71, P < .01), RV end-diastolic area ( r = 0.63, P < .01), and TV tethering area ( r = 0.56, P < .01). There were weak correlations between VCW and diastolic RV eccentricity index ( r = −0.40, P < .01) and RV sphericity index ( r = −0.24, P = .04). However, TV annular contraction, RA FAC, and RV FAC were not significantly correlated with VCW of the TV. ERO area also showed significant correlations with TR jet area ( r = 0.62, P < .01; Figure 1 ), RA end-systolic area ( r = 0.58, P < .01), RV end-diastolic area ( r = 0.70, P < .01), and TV tethering area ( r = 0.60, P < .01). Although all patients fulfilled the conventional criteria for severe TR, more than half had VCW ≤ 7 mm. Patients with VCW > 7 mm had larger TR jet areas and larger right atria and right ventricles. Furthermore, hemoglobin levels were significantly lower in patients with VCW > 7 mm. These findings suggest that VCW would be a better parameter reflecting the severity of TR than conventional parameters.

Correlation between the TR jet area and (A) VCW ( r = 0.80, P < .01) and (B) ERO area ( r = 0.62, P < .01).

Clinical Outcomes

During the median follow-up period of 53 months, 25 cardiovascular events (34%) occurred (three cardiovascular deaths, nine TV surgeries, and 13 hospitalizations for worsening HF). Ten years after diagnosis of severe isolated TR, the incidence of cardiovascular events was 53% ( Figure 2 ). Univariate Cox analysis showed that younger age, female gender, TR with TV organic problem, larger ERO area, RA size, RV size, VCW, and decreased left ventricular end-diastolic diameter were associated with adverse cardiovascular events. Increased TV tethering distance and tethering area were also associated with cardiovascular events. In multivariate Cox regression analysis, larger VCW (hazard ratio, 1.72; 95% confidence interval, 1.15–2.57, P < .01) was an independent predictor of cardiovascular events ( Table 2 ).

Clinical outcomes after diagnosis of severe isolated TR. Kaplan-Meier curve shows the incidence of cardiovascular events.

Table 2

Cox proportional-hazards regression analysis for time to occurrence of cardiovascular events

Variable	Univariate analysis			Multivariate analysis
	Unadjusted HR	95% CI	P	Adjusted HR	P
Female sex	2.75	1.10–6.90	.03	2.44	.16
Age (y)	0.97	0.95–1.00	.03	0.99	.54
RA end-systolic area	1.03	1.00–1.06	.03	0.91	.07
TV tethering area	2.29	1.2–4.38	.01	0.52	.23
LV EDD	0.90	0.83–0.97	<.01	0.97	.58
TR etiology	0.34	0.13–0.87	.02	0.98	.99
VCW	1.21	1.11–1.33	<.01	1.72	<.01

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