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Vena Contracta Width as a Predictor of Adverse Outcomes in Patients with Severe Isolated Tricuspid Regurgitation
Vena Contracta Width as a Predictor of Adverse Outcomes in Patients with Severe Isolated Tricuspid Regurgitation Woo-In Yang, MD, Chi-Young Shim, MD, PhD, Min-Kyung Kang, MD, Hyuk-Jae Chang, MD, PhD, Namsik Chung, MD, PhD, Seung-Yun Cho, MD, PhD, and Jong-Won Ha, MD, PhD, Seoul, South Korea
Background: The clinical outcomes and predictors of outcomes in isolated tricuspid regurgitation (TR) are poorly defined. The aim of this study was to investigate the determinants of outcomes in severe isolated TR. Methods: Seventy-four patients (mean age, 63 6 12 years; 34 men) with severe isolated TR who satisfied the criteria of (1) TR jet area > 30% of right atrial area or TR jet area > 10 cm2 and (2) a plethora of inferior vena cava or systolic flow reversal of the hepatic vein were retrospectively analyzed. The primary end points were hospitalization for worsening heart failure, tricuspid valve (TV) surgery, and cardiovascular death. Results: During the median follow-up period of 53 months, 25 events occurred (three cardiovascular deaths, nine TV surgeries, and 13 hospitalizations for worsening heart failure). Univariate Cox analysis showed that younger age, female gender, larger effective regurgitant orifice, vena contracta width (VCW), and increased right atrial and right ventricular size were associated with 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 < 0.01) was an independent predictor of cardiovascular events. Compared with patients with VCW # 7 mm, those with VCW > 7 mm had poorer long-term outcomes (adjusted hazard ratio, 19.9; P < .01). Increased VCW was also an independent predictor of cardiovascular death and TV surgery (hazard ratio, 1.2; 95% confidence interval, 1.00–1.45; P = .04). Conclusions: In severe isolated TR, VCW is a powerful independent predictor of adverse outcomes. Adverse outcomes were considerable for VCW > 7 mm, which suggests that quantification of TR by Doppler echocardiography is crucial for estimating prognosis. TV surgery might be considered for patients with severe isolated TR with VCW > 7 mm. (J Am Soc Echocardiogr 2011;24:1013-9.) Keywords: Vena contracta, Tricuspid regurgitation, Prognosis
Tricuspid regurgitation (TR) is a common finding that is present in 80% to 90% of the general population.1,2 The importance of a competent tricuspid valve (TV) has long been neglected, as evidenced by recommendations for tricuspid valvectomy in patients with infective endocarditis.3 However, recent studies have demonstrated the prognostic significance of TR.1 TR occurs mainly because of left-sided heart disease, but it can occur in isolation secondary to a primary TV or TV apparatus problem.4-6 TV surgery may be considered in patients with significant TR when left-sided valve surgery is performed.7 However, in cases of severe isolated TR, TV surFrom the Cardiology Division, Severance Cardiovascular Hospital (W.-I.Y., C.-Y.S., M.-K.K., H.-J.C., N.C., S.-Y.C.), Severance Biomedical Science Institute (J.-W.H.), Yonsei University College of Medicine, Seoul, Korea.
gery is not routinely done because the morbidity and mortality of TV surgery have been considered high,8,9 and the prognosis of isolated TR is not well characterized. Because most studies regarding outcomes of TR were in patients with left-sided heart disease, few data are available regarding clinical outcomes of isolated TR not associated with left-sided heart disease. In addition, there is a belief that severe isolated TR could be tolerated well, but evidence from clinical data is weak.10 Current practice guidelines recommend TV surgery only in cases of symptomatic severe isolated TR.7 Therefore, we sought to investigate the clinical outcomes of severe isolated TR and to determine the major determinants of outcomes in these patients.
This work was supported by grant M10642120001-06N4212-00110 from the Korea Science and Engineering Foundation, funded by the Korean government.
METHODS
Reprint requests: Jong-Won Ha, MD, PhD, Cardiology Division, Severance Biomedical Science Institute, Yonsei University College of Medicine, 134 Shinchondong, Seodaemun-gu, Seoul 120-752, Korea (E-mail: [email protected]).
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 leftsided valvular diseases such as moderate and severe stenosis or regurgitation in the mitral or aortic valves. Patients with pulmonary artery 1013
0894-7317/$36.00 Copyright 2011 by the American Society of Echocardiography. doi:10.1016/j.echo.2011.06.015
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systolic pressures > 40 mm Hg or histories of valve operation irreERO = Effective regurgitant spective of current prosthetic orifice valve function were also excluded. Patients with shunt disFAC = Fractional area change ease, such as atrial septal defect, HF = Heart failure Eisenmenger syndrome, right ventricular (RV) dysplasia, as RA = Right atrial well as hyperthyroidism and RV = Right ventricular other cardiomyopathies were also excluded from this study. TR = Tricuspid regurgitation None of the patients had left TV = Tricuspid valve ventricular systolic dysfunction VCW = Vena contracta width All patients fulfilled the following criteria for severe TR: (1) TR jet area > 30% of right atrial (RA) area or TR jet area > 10 cm2 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. Abbreviations
Echocardiography Two-dimensional measurements were obtained using standard methods according to the guidelines of the American Society of Echocardiography.11,12 Left ventricular end-diastolic and endsystolic 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 enddiastole. 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.13 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
Journal of the American Society of Echocardiography September 2011
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 6 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.
RESULTS Characteristics of Patients Seventy-four patients (mean age, 63 6 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 6 10 vs 56 6 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 b 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 6 10%. The mean VCW and ERO area were 7.5 6 2.7 mm and 88.6 6 41.5 mm2, 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
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Table 1 Baseline characteristics of patients with severe isolated TR with or without cardiovascular events Clinical finding
Age (y) Men NYHA class III and IV Diabetes mellitus Hypertension Coronary artery disease Renal failure Atrial fibrillation Organic TV problem TV prolapse Thickened and restricted TV Laboratory findings Urea nitrogen (mg/dL) Creatinine (mg/dL) Albumin (mg/dL) Hemoglobin (g/dL) Platelets (per mm3) Echocardiographic findings LVEF (%) PASP (mm Hg) VCW (mm) ERO (mm2) TR jet area (cm2) TR jet percentage RV end-diastolic area (cm2) RV end-systolic area (cm2) RV FAC (%) RV sphericity index, diastolic RV eccentricity index, diastolic RA area (cm2) RA FAC (%) TV annular EDD (mm) TV annular contraction (%) TV tethering distance (mm) TV tethering area (cm2)
Total (n = 74)
Without events (n = 49)
With events (n = 25)
P
63 6 12 34 (46%) 4 (5%) 14 (19%) 26 (35%) 13 (18%) 4 (5%) 59 (80%) 23 (31%) 12 (16%) 11 (15%)
66 6 9 28 (57%) 2 (4%) 8 (17%) 18 (39%) 8 (17%) 2 (5%) 39 (80%) 10 (20%) 6 (12%) 4 (8%)
58 6 15 6 (24%) 2 (8%) 6 (26%) 8 (35%) 5 (22%) 2 (7%) 20 (80%) 13 (52%) 6 (24%) 7 (28%)
.01 <.01 .60 .40 .73 .66 .67 1.00 <.01 .31 .04
18 6 7 1.0 6 0.3 4.3 6 0.5 13 6 2 198 6 79
17 6 7 1.0 6 0.3 4.4 6 0.4 13.3 6 1.9 197 6 78
19 6 7 1.0 6 0.3 4.2 6 0.5 12.7 6 2.1 202 6 82
.15 .84 .16 .32 .81
65 6 7 34 6 4 7.5 6 2.7 88.6 6 41.5 13.6 6 5.4 43 6 10 20.3 6 7.3 11.3 6 5.0 45 6 9 1.7 6 0.2 2.3 6 0.4 28.6 6 10.0 21 6 8 41.0 6 6.2 16 6 7 8.5 6 2.1 1.8 6 0.6
65 6 8 346 5 6.6 6 1.8 77.6 6 38.2 12.8 6 4.8 41.4 6 9.2 19.7 6 7.0 11.2 6 5.2 44 6 9 1.7 6 0.3 2.3 6 0.4 26.6 6 7.7 20 6 7 40.1 6 5.2 15 6 7 8.3 6 2.1 1.7 6 0.6
64 6 7 35 6 4 9.2 6 3.2 110.2 6 40.0 15.2 6 6.3 45.2 6 11.0 21.4 6 8.0 11.3 6 4.6 47 6 9 1.6 6 0.2 2.2 6 0.3 32.4 6 12.7 22 6 10 42.8 6 7.6 17 6 8 9.0 6 2.0 2.0 6 0.6
.41 .24 <.01 <.01 .10 .15 .34 .95 .17 .25 .45 .02 .18 .11 .22 .15 .05
EDD, End-diastolic diameter; LVEF, left ventricular ejection fraction; NYHA, New York Heart Association; PASP, pulmonary artery systolic pressure. Data are expressed as mean 6 SD or as number (percentage).
echocardiographic parameters, including TR jet area (r = 0.80, P < .01; Figure 1), RA end-systolic area (r = 0.71, P < .01), RV enddiastolic 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.
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). The receiver operating characteristic curve showed that VCW > 7 mm was a potent predictor of poor outcomes, and this cutoff value had 80% sensitivity and 77% specificity for predicting cardiovascular events (area under the curve, 0.81; 95% confidence interval, 0.70–
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Figure 1 Correlation between the TR jet area and (A) VCW (r = 0.80, P < .01) and (B) ERO area (r = 0.62, P < .01).
Table 2 Cox proportional-hazards regression analysis for time to occurrence of cardiovascular events Univariate analysis
Variable
Unadjusted HR
Female sex Age (y) RA end-systolic area TV tethering area LV EDD TR etiology VCW
2.75 0.97 1.03 2.29 0.90 0.34 1.21
95% CI
Multivariate analysis P
1.10–6.90 .03 0.95–1.00 .03 1.00–1.06 .03 1.2–4.38 .01 0.83–0.97 <.01 0.13–0.87 .02 1.11–1.33 <.01
Adjusted HR
P
2.44 0.99 0.91 0.52 0.97 0.98 1.72
.16 .54 .07 .23 .58 .99 <.01
CI, Confidence interval; EDD, end-diastolic diameter; HR, hazard ratio.
Figure 2 Clinical outcomes after diagnosis of severe isolated TR. Kaplan-Meier curve shows the incidence of cardiovascular events. 0.92). Characteristics of patients with VCW >7mm and those with VCW # 7mm are presented in Table 3. Compared with patients with VCW # 7 mm, those with VCW > 7 mm had poorer longterm outcomes of cardiovascular events (adjusted hazard ratio, 19.9; P < .01; Figure 3). The 10-year rates of cardiovascular events were significantly higher in patients with VCW > 7 mm than in those with VCW # 7 mm (80% vs 26%, P < .01). Kaplan-Meier analysis also showed higher event rates for cardiovascular death and TV surgery in patients with VCW > 7 mm (adjusted hazard ratio, 12.4; P < .01; Figure 3). DISCUSSION The principal finding of this study is that isolated severe TR is not a benign disease and that it often causes HF-related symptoms and cardio-
vascular death. Among various echocardiographic parameters, VCW is a powerful independent predictor of adverse outcomes. Even in patients with severe isolated TR as defined by qualitative parameters, those with more severe degrees of regurgitation identified by semiquantitative VCW (>7 mm) presented with adverse cardiovascular events more frequently. These data underscore the importance of quantifying TR severity for better risk stratification of isolated TR. Prognosis of Severe Isolated TR The prognosis of isolated TR has not been well characterized. Most studies on the prognosis of TR have included patients with leftsided heart disease or histories of left-sided valve surgery.1,2 Therefore, the results of these studies might reflect confounding factors derived from the underlying disease course. Patients with severe isolated TR are often asymptomatic. Therefore, severe isolated TR had been regarded as a benign disease despite the lack of evidence. In contrast to the general misconception, however, a considerable number of patients (34%) had cardiovascular events in our study. Although it was shown that isolated TR caused by flail leaflets has high morbidity and mortality,14 severe isolated TR can occur without definite abnormalities of the TV.15 In our study, 51
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Table 3 Characteristics of patients with VCW > 7 mm and those with VCW # 7 mm Variable
VCW > 7 mm (n = 32)
VCW # 7 mm (n = 42)
P
Age (y) Men NYHA class III and IV Hemoglobin (g/dL) TR jet area (cm2) TR jet percentage RV end-diastolic area (cm2) RV end-systolic area (cm2) RV FAC (%) RV sphericity index, diastolic RV eccentricity index, diastolic RA area (cm2) RA FAC (%) TV annular EDD (mm) TV tethering distance (mm) TV tethering area (cm2)
60 6 12 9 (28%) 3 (9%) 12.5 6 2.0 15.2 6 5.6 43.1 6 11.5 23.4 6 8.6 12.8 6 6.1 46 6 11 1.6 6 0.3 2.1 6 0.3 33.5 6 12.2 20 6 10 43.7 6 6.9 9.6 6 2.4 2.1 6 0.7
65 6 12 24 (59%) 1 (2%) 13.5 6 1.8 12.4 6 5.0 42.6 6 8.7 17.8 6 5.1 10.1 6 3.6 44 6 8 1.7 6 0.2 2.4 6 0.4 24.6 6 5.5 21 6 6 38.9 6 4.8 7.7 6 1.4 1.5 6 0.4
.13 .02 .30 .03 .03 .80 <.01 .02 .28 .07 <.01 <.01 .61 <.01 <.01 <.01
EDD, End-diastolic diameter; NYHA, New York Heart Association. Data are expressed as mean 6 SD or as number (percentage).
patients (69%) presented with severe TR without evidence of organic TV disease. Even in patients without definite evidence of organic TV disease, the outcomes were considerable (two cardiovascular deaths, two TV surgeries, and eight cases of aggravated HF despite medical treatment). Thus, patients with severe isolated TR should be considered for TV surgery irrespective of TV deformity. In our practice, surgery is usually delayed in the case of isolated TR. However, severe TR results in chronic volume overload that eventually leads to RV dysfunction. Surgical outcomes in patients with severe RV remodeling and dysfunction are poor.16 Chronic severe TR could result in liver cirrhosis, immunologic deficiency, and low cardiac output, all of which could affect outcomes.17 Therefore, it is very important to determine the optimal time for TV surgery at some point in patients with severe isolated TR. Quantification of TR Severity by VCW A previous study showed that VCW measured by color Doppler correlated closely with the severity of TR and has a high diagnostic value for severe TR.18 The American and European cardiac societies advocated for quantitative methods using Doppler echocardiography to determine the severity of TR.13 However, in many echocardiographic laboratories, TR severity has been determined by conventional semiquantitative indices, such as color jet area of TR and flow pattern in the hepatic vein jet. In this study, VCW varied widely (from 4.1 to 19.0 mm), even in patients with severe isolated TR confirmed by color jet area of TR and flow pattern of the hepatic vein. In addition, although all patients fulfilled the conventional criteria for severe TR, more than half had VCW # 7 mm. More interestingly, the magnitude of VCW was the strongest predictor of cardiovascular events among all the semiquantitative indices. These results suggest that severe TR could be further subdivided according to the amount of regurgitation, which enables further stratification of high-risk patients requiring TV surgery. Color-flow imaging has been widely used for TR grading, but the assessment of severe TR jet has important limitations, such as great de-
pendency on hemodynamic conditions or echocardiographic settings.19 Systolic flow reversal of the hepatic vein is useful for discriminating severe TR but does not provide quantitative information.20 Calculation of ERO area is helpful for acquiring quantitative information but is time consuming for routine use. VCW is the smallest regurgitant jet width just beyond the flow convergence region and directly reflects the size of the regurgitant orifice.21,22 VCW is simple to measure and relatively independent of hemodynamic conditions and instrument settings.22,23 As previously noted, VCW was closely correlated with ERO area in this study. VCW also showed correlations with TR jet area, TV tethering area, RA end-systolic area, and RV end-diastolic area. Thus, VCW closely represents the severity of TR. Prognostic implications with quantitative Doppler assessment in mitral regurgitation have already been demonstrated in many studies.24-26 However, it has not been demonstrated that quantitative Doppler assessment in TR would have prognostic significance. To the best of our knowledge, this is the first study to demonstrate the prognostic significance of VCW in severe isolated TR. In this study, a larger VCW was a potent independent predictor of adverse cardiovascular outcomes. VCW > 7 mm was correlated with markedly increased cardiovascular events. Interestingly, although all patients fulfilled the conventional criteria for severe TR, fewer than half had VCW > 7 mm. Patients with VCW > 7 mm had larger TR jet areas, right atrium, and right ventricles. The right ventricle tolerates volume overload better than the left ventricle up to a certain point. Thus, patients can have no symptoms for a long time, until RV dysfunction develops. However, chronic volume overload by TR would eventually exhaust the right ventricle, followed rapid deterioration in prognosis.27,28 Therefore, the decisions regarding the timing of surgery for severe, isolated TR are not easy and it must incorporate multiple factors, such as symptom status, RV systolic function, and comorbidities. The current guidelines recommend TV surgery in patients who have symptoms or diseased TV leaflets.7 Because the measurement of VCW provided the substantial prognostic significance, it might be useful in determining the appropriate time for TV surgery. Study Limitations The TV is composed of three leaflets, making a noncircular geometry of the vena contracta. In this study, VCW was measured in the apical four-chamber view to reduce errors derived by different views. However, two-dimensional echocardiography has limitations in measuring vena contracta with diverse geometry. Although threedimensional echocardiography could overestimate true orifice size due to lower spatial and temporal resolution, three-dimensional echocardiography has the advantage in evaluating elliptical convergence region. A recent study using three-dimensional echocardiography demonstrated different VCW according to different views.29 Thus, the 7-mm cutoff value for VCW presented in this study might not be appropriate in other views, and further study would be warranted to define the best two-dimensional plane for VCW measurement. Assessment of RV function and volume by two-dimensional echocardiography might not be accurate, because of the anatomic complexity of the right heart. In this study, RV function was assessed only by FAC, which is often volume dependent. Evaluation of RV function using tricuspid annular systolic velocity measured by tissue Doppler echocardiography or three-dimensional echocardiography might be more desirable but was not available in our study. The retrospective design, the small number of patients, and the relatively short duration of
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Figure 3 Kaplan-Meier analysis in patients with VCW > 7 mm and VCW # 7 mm for (A) cardiovascular events (P < .01) and (B) cardiovascular death and TV surgery (P < .01) with the log-rank test. follow-up were other limitations. However, severe isolated TR is not a common disease, and few studies have reported outcomes. Therefore, this study could be valuable despite these limitations. CONCLUSIONS In patients with severe isolated TR, irrespective of all other characteristics, the degree of TR quantified by Doppler echocardiography has an independent prognostic significance. Adverse outcomes, which were considerable for VCW > 7 mm, suggest that the quantification of TR by Doppler echocardiography is crucial in estimating prognosis. Patients with severe isolated TR with VCW > 7 mm should be considered for TV surgery. REFERENCES 1. Nath J, Foster E, Heidenreich PA. Impact of tricuspid regurgitation on longterm survival. J Am Coll Cardiol 2004;43:405-9. 2. Singh JP, Evans JC, Levy D, Larson MG, Freed LA, Fuller DL, et al. Prevalence and clinical determinants of mitral, tricuspid, and aortic regurgitation (the Framingham Heart Study). Am J Cardiol 1999;83:897-902. 3. Nihoyannopoulos P. Tricuspid valvectomy following tricuspid valve endocarditis on an intravenous drug addict. Heart 2001;86:144. 4. David TE. Functional tricuspid regurgitation: a perplexing problem. J Am Soc Echocardiogr 2009;22:904-6. 5. Hauck AJ, Freeman DP, Ackermann DM, Danielson GK, Edwards WD. Surgical pathology of the tricuspid valve: a study of 363 cases spanning 25 years. Mayo Clin Proc 1988;63:851-63. 6. Seo H, Ha J, Moon JY, Choi E, Rim S, Jang Y, et al. Right ventricular remodeling and dysfunction with subsequent annular dilatation and tethering as a mechanism of isolated tricuspid regurgitation. Circ J 2008;72:1645-9. 7. Bonow RO, Carabello BA, Chatterjee K, de Leon AC, Faxon DP, Freed MD, et al. 2008 Focused update incorporated into the ACC/ AHA 2006 guidelines for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 1998 Guidelines for the Management of Patients With Valvular Heart Disease): endorsed by the Society of Cardiovascular Anesthesiologists, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. Circulation 2008;118:e523-661.
8. Iscan ZH, Vural KM, Bahar I, Mavioglu L, Saritas A. What to expect after tricuspid valve replacement? Long-term results. Eur J Cardiothorac Surg 2007;32:296-300. 9. Ratnatunga CP, Edwards MB, Dore CJ, Taylor KM. Tricuspid valve replacement: UK Heart Valve Registry mid-term results comparing mechanical and biological prostheses. Ann Thorac Surg 1998;66:1940-7. 10. Croxson MS, O’Brien KP, Lowe JB. Traumatic tricuspid regurgitation. Long-term survival. Br Heart J 1971;33:750-5. 11. Lang RM, Bierig M, Devereux RB, Flachskampf FA, Foster E, Pellikka PA, et al. Recommendations for chamber quantification: a report from the American Society of Echocardiography’s Guidelines and Standards Committee and the Chamber Quantification Writing Group, developed in conjunction with the European Association of Echocardiography, a branch of the European Society of Cardiology. J Am Soc Echocardiogr 2005;18: 1440-63. 12. Rudski LG, Lai W, Afilalo J, Hua L, Handschumacher MD, Chandrasekaran K, et al. Guidelines for the echocardiographic assessment of the right heart in adults: a report from the American Society of Echocardiography endorsed by the European Association of Echocardiography, a registered branch of the European Society of Cardiology, and the Canadian Society of Echocardiography. J Am Soc Echocardiogr 2010;23:685-713. 13. Zoghbi WA, Enriquez-Sarano M, Foster E, Grayburn PA, Kraft CD, Levine RA, et al. Recommendations for evaluation of the severity of native valvular regurgitation with two-dimensional and Doppler echocardiography. J Am Soc Echocardiogr 2003;16:777-802. 14. Messika-Zeitoun D, Thomson H, Bellamy M, Scott C, Tribouilloy C, Dearani J, et al. Medical and surgical outcome of tricuspid regurgitation caused by flail leaflets. J Thorac Cardiovasc Surg 2004;128:296-302. 15. Mutlak D, Lessick J, Reisner SA, Aronson D, Dabbah S, Agmon Y. Echocardiography-based spectrum of severe tricuspid regurgitation: the frequency of apparently idiopathic tricuspid regurgitation. J Am Soc Echocardiogr 2007;20:405-8. 16. Kim Y, Kwon DA, Kim H, Park J, Hahn S, Kim K, et al. Determinants of surgical outcome in patients with isolated tricuspid regurgitation. Circulation 2009;120:1672-8. 17. Louie EK, Bieniarz T, Moore AM, Levitsky S. Reduced atrial contribution to left ventricular filling in patients with severe tricuspid regurgitation after tricuspid valvulectomy: a Doppler echocardiographic study. J Am Coll Cardiol 1990;16:1617-24. 18. Tribouilloy CM, Enriquez-Sarano M, Bailey KR, Tajik AJ, Seward JB. Quantification of tricuspid regurgitation by measuring the width of the vena contracta with Doppler color flow imaging: a clinical study. J Am Coll Cardiol 2000;36:472-8.
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19. Rivera JM, Vandervoort PM, Vazquez de Prada JA, Mele D, Karson TH, Morehead A, et al. Which physical factors determine tricuspid regurgitation jet area in the clinical setting? Am J Cardiol 1993;72:1305-9. 20. Sakai K, Nakamura K, Satomi G, Kondo M, Hirosawa K. Evaluation of tricuspid regurgitation by blood flow pattern in the hepatic vein using pulsed Doppler technique. Am Heart J 1984;108:516-23. 21. Bolger AF, Eigler NL, Pfaff JM, Resser KJ, Maurer G. Computer analysis of Doppler color flow mapping images for quantitative assessment of in vitro fluid jets. J Am Coll Cardiol 1988;12:450-7. 22. Switzer DF, Yoganathan AP, Nanda NC, Woo YR, Ridgway AJ. Calibration of color Doppler flow mapping during extreme hemodynamic conditions in vitro: a foundation for a reliable quantitative grading system for aortic incompetence. Circulation 1987;75:837-46. 23. Baumgartner H, Kratzer H, Helmreich G, Khn P. Quantitation of aortic regurgitation by colour coded cross-sectional Doppler echocardiography. Eur Heart J 1988;9:380-7. 24. Grigioni F, Enriquez-Sarano M, Zehr KJ, Bailey KR, Tajik AJ. Ischemic mitral regurgitation: long-term outcome and prognostic implications with quantitative Doppler assessment. Circulation 2001;103:1759-64.
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25. Enriquez-Sarano M, Avierinos J, Messika-Zeitoun D, Detaint D, Capps M, Nkomo V, et al. Quantitative determinants of the outcome of asymptomatic mitral regurgitation. N Engl J Med 2005;352:875-83. 26. Grayburn PA, Appleton CP, DeMaria AN, Greenberg B, Lowes B, Oh J, et al. Echocardiographic predictors of morbidity and mortality in patients with advanced heart failure: the Beta-Blocker Evaluation of Survival Trial (BEST). J Am Coll Cardiol 2005;45:1064-71. 27. Polak JF, Holman BL, Wynne J, Colucci WS. Right ventricular ejection fraction: an indicator of increased mortality in patients with congestive heart failure associated with coronary artery disease. J Am Coll Cardiol 1983; 2:217-24. 28. de Groote P, Millaire A, Foucher-Hossein C, Nugue O, Marchandise X, Ducloux G, et al. Right ventricular ejection fraction is an independent predictor of survival in patients with moderate heart failure. J Am Coll Cardiol 1998;32:948-54. 29. Song JM, Jang MK, Choi YS, Kim YJ, Min SY, Kim DH, et al. The vena contracta in functional tricuspid regurgitation: a real-time three-dimensional color Doppler echocardiography study. J Am Soc Echocardiogr 2011; 24:663-70.
Background: The clinical outcomes and predictors of outcomes in isolated tricuspid regurgitation (TR) are poorly defined. The aim of this study was to investigate the determinants of outcomes in severe isolated TR. Methods: Seventy-four patients (mean age, 63 6 12 years; 34 men) with severe isolated TR who satisfied the criteria of (1) TR jet area > 30% of right atrial area or TR jet area > 10 cm2 and (2) a plethora of inferior vena cava or systolic flow reversal of the hepatic vein were retrospectively analyzed. The primary end points were hospitalization for worsening heart failure, tricuspid valve (TV) surgery, and cardiovascular death. Results: During the median follow-up period of 53 months, 25 events occurred (three cardiovascular deaths, nine TV surgeries, and 13 hospitalizations for worsening heart failure). Univariate Cox analysis showed that younger age, female gender, larger effective regurgitant orifice, vena contracta width (VCW), and increased right atrial and right ventricular size were associated with 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 < 0.01) was an independent predictor of cardiovascular events. Compared with patients with VCW # 7 mm, those with VCW > 7 mm had poorer long-term outcomes (adjusted hazard ratio, 19.9; P < .01). Increased VCW was also an independent predictor of cardiovascular death and TV surgery (hazard ratio, 1.2; 95% confidence interval, 1.00–1.45; P = .04). Conclusions: In severe isolated TR, VCW is a powerful independent predictor of adverse outcomes. Adverse outcomes were considerable for VCW > 7 mm, which suggests that quantification of TR by Doppler echocardiography is crucial for estimating prognosis. TV surgery might be considered for patients with severe isolated TR with VCW > 7 mm. (J Am Soc Echocardiogr 2011;24:1013-9.) Keywords: Vena contracta, Tricuspid regurgitation, Prognosis
Tricuspid regurgitation (TR) is a common finding that is present in 80% to 90% of the general population.1,2 The importance of a competent tricuspid valve (TV) has long been neglected, as evidenced by recommendations for tricuspid valvectomy in patients with infective endocarditis.3 However, recent studies have demonstrated the prognostic significance of TR.1 TR occurs mainly because of left-sided heart disease, but it can occur in isolation secondary to a primary TV or TV apparatus problem.4-6 TV surgery may be considered in patients with significant TR when left-sided valve surgery is performed.7 However, in cases of severe isolated TR, TV surFrom the Cardiology Division, Severance Cardiovascular Hospital (W.-I.Y., C.-Y.S., M.-K.K., H.-J.C., N.C., S.-Y.C.), Severance Biomedical Science Institute (J.-W.H.), Yonsei University College of Medicine, Seoul, Korea.
gery is not routinely done because the morbidity and mortality of TV surgery have been considered high,8,9 and the prognosis of isolated TR is not well characterized. Because most studies regarding outcomes of TR were in patients with left-sided heart disease, few data are available regarding clinical outcomes of isolated TR not associated with left-sided heart disease. In addition, there is a belief that severe isolated TR could be tolerated well, but evidence from clinical data is weak.10 Current practice guidelines recommend TV surgery only in cases of symptomatic severe isolated TR.7 Therefore, we sought to investigate the clinical outcomes of severe isolated TR and to determine the major determinants of outcomes in these patients.
This work was supported by grant M10642120001-06N4212-00110 from the Korea Science and Engineering Foundation, funded by the Korean government.
METHODS
Reprint requests: Jong-Won Ha, MD, PhD, Cardiology Division, Severance Biomedical Science Institute, Yonsei University College of Medicine, 134 Shinchondong, Seodaemun-gu, Seoul 120-752, Korea (E-mail: [email protected]).
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 leftsided valvular diseases such as moderate and severe stenosis or regurgitation in the mitral or aortic valves. Patients with pulmonary artery 1013
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systolic pressures > 40 mm Hg or histories of valve operation irreERO = Effective regurgitant spective of current prosthetic orifice valve function were also excluded. Patients with shunt disFAC = Fractional area change ease, such as atrial septal defect, HF = Heart failure Eisenmenger syndrome, right ventricular (RV) dysplasia, as RA = Right atrial well as hyperthyroidism and RV = Right ventricular other cardiomyopathies were also excluded from this study. TR = Tricuspid regurgitation None of the patients had left TV = Tricuspid valve ventricular systolic dysfunction VCW = Vena contracta width All patients fulfilled the following criteria for severe TR: (1) TR jet area > 30% of right atrial (RA) area or TR jet area > 10 cm2 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. Abbreviations
Echocardiography Two-dimensional measurements were obtained using standard methods according to the guidelines of the American Society of Echocardiography.11,12 Left ventricular end-diastolic and endsystolic 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 enddiastole. 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.13 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
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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 6 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.
RESULTS Characteristics of Patients Seventy-four patients (mean age, 63 6 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 6 10 vs 56 6 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 b 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 6 10%. The mean VCW and ERO area were 7.5 6 2.7 mm and 88.6 6 41.5 mm2, 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
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Table 1 Baseline characteristics of patients with severe isolated TR with or without cardiovascular events Clinical finding
Age (y) Men NYHA class III and IV Diabetes mellitus Hypertension Coronary artery disease Renal failure Atrial fibrillation Organic TV problem TV prolapse Thickened and restricted TV Laboratory findings Urea nitrogen (mg/dL) Creatinine (mg/dL) Albumin (mg/dL) Hemoglobin (g/dL) Platelets (per mm3) Echocardiographic findings LVEF (%) PASP (mm Hg) VCW (mm) ERO (mm2) TR jet area (cm2) TR jet percentage RV end-diastolic area (cm2) RV end-systolic area (cm2) RV FAC (%) RV sphericity index, diastolic RV eccentricity index, diastolic RA area (cm2) RA FAC (%) TV annular EDD (mm) TV annular contraction (%) TV tethering distance (mm) TV tethering area (cm2)
Total (n = 74)
Without events (n = 49)
With events (n = 25)
P
63 6 12 34 (46%) 4 (5%) 14 (19%) 26 (35%) 13 (18%) 4 (5%) 59 (80%) 23 (31%) 12 (16%) 11 (15%)
66 6 9 28 (57%) 2 (4%) 8 (17%) 18 (39%) 8 (17%) 2 (5%) 39 (80%) 10 (20%) 6 (12%) 4 (8%)
58 6 15 6 (24%) 2 (8%) 6 (26%) 8 (35%) 5 (22%) 2 (7%) 20 (80%) 13 (52%) 6 (24%) 7 (28%)
.01 <.01 .60 .40 .73 .66 .67 1.00 <.01 .31 .04
18 6 7 1.0 6 0.3 4.3 6 0.5 13 6 2 198 6 79
17 6 7 1.0 6 0.3 4.4 6 0.4 13.3 6 1.9 197 6 78
19 6 7 1.0 6 0.3 4.2 6 0.5 12.7 6 2.1 202 6 82
.15 .84 .16 .32 .81
65 6 7 34 6 4 7.5 6 2.7 88.6 6 41.5 13.6 6 5.4 43 6 10 20.3 6 7.3 11.3 6 5.0 45 6 9 1.7 6 0.2 2.3 6 0.4 28.6 6 10.0 21 6 8 41.0 6 6.2 16 6 7 8.5 6 2.1 1.8 6 0.6
65 6 8 346 5 6.6 6 1.8 77.6 6 38.2 12.8 6 4.8 41.4 6 9.2 19.7 6 7.0 11.2 6 5.2 44 6 9 1.7 6 0.3 2.3 6 0.4 26.6 6 7.7 20 6 7 40.1 6 5.2 15 6 7 8.3 6 2.1 1.7 6 0.6
64 6 7 35 6 4 9.2 6 3.2 110.2 6 40.0 15.2 6 6.3 45.2 6 11.0 21.4 6 8.0 11.3 6 4.6 47 6 9 1.6 6 0.2 2.2 6 0.3 32.4 6 12.7 22 6 10 42.8 6 7.6 17 6 8 9.0 6 2.0 2.0 6 0.6
.41 .24 <.01 <.01 .10 .15 .34 .95 .17 .25 .45 .02 .18 .11 .22 .15 .05
EDD, End-diastolic diameter; LVEF, left ventricular ejection fraction; NYHA, New York Heart Association; PASP, pulmonary artery systolic pressure. Data are expressed as mean 6 SD or as number (percentage).
echocardiographic parameters, including TR jet area (r = 0.80, P < .01; Figure 1), RA end-systolic area (r = 0.71, P < .01), RV enddiastolic 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.
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). The receiver operating characteristic curve showed that VCW > 7 mm was a potent predictor of poor outcomes, and this cutoff value had 80% sensitivity and 77% specificity for predicting cardiovascular events (area under the curve, 0.81; 95% confidence interval, 0.70–
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Figure 1 Correlation between the TR jet area and (A) VCW (r = 0.80, P < .01) and (B) ERO area (r = 0.62, P < .01).
Table 2 Cox proportional-hazards regression analysis for time to occurrence of cardiovascular events Univariate analysis
Variable
Unadjusted HR
Female sex Age (y) RA end-systolic area TV tethering area LV EDD TR etiology VCW
2.75 0.97 1.03 2.29 0.90 0.34 1.21
95% CI
Multivariate analysis P
1.10–6.90 .03 0.95–1.00 .03 1.00–1.06 .03 1.2–4.38 .01 0.83–0.97 <.01 0.13–0.87 .02 1.11–1.33 <.01
Adjusted HR
P
2.44 0.99 0.91 0.52 0.97 0.98 1.72
.16 .54 .07 .23 .58 .99 <.01
CI, Confidence interval; EDD, end-diastolic diameter; HR, hazard ratio.
Figure 2 Clinical outcomes after diagnosis of severe isolated TR. Kaplan-Meier curve shows the incidence of cardiovascular events. 0.92). Characteristics of patients with VCW >7mm and those with VCW # 7mm are presented in Table 3. Compared with patients with VCW # 7 mm, those with VCW > 7 mm had poorer longterm outcomes of cardiovascular events (adjusted hazard ratio, 19.9; P < .01; Figure 3). The 10-year rates of cardiovascular events were significantly higher in patients with VCW > 7 mm than in those with VCW # 7 mm (80% vs 26%, P < .01). Kaplan-Meier analysis also showed higher event rates for cardiovascular death and TV surgery in patients with VCW > 7 mm (adjusted hazard ratio, 12.4; P < .01; Figure 3). DISCUSSION The principal finding of this study is that isolated severe TR is not a benign disease and that it often causes HF-related symptoms and cardio-
vascular death. Among various echocardiographic parameters, VCW is a powerful independent predictor of adverse outcomes. Even in patients with severe isolated TR as defined by qualitative parameters, those with more severe degrees of regurgitation identified by semiquantitative VCW (>7 mm) presented with adverse cardiovascular events more frequently. These data underscore the importance of quantifying TR severity for better risk stratification of isolated TR. Prognosis of Severe Isolated TR The prognosis of isolated TR has not been well characterized. Most studies on the prognosis of TR have included patients with leftsided heart disease or histories of left-sided valve surgery.1,2 Therefore, the results of these studies might reflect confounding factors derived from the underlying disease course. Patients with severe isolated TR are often asymptomatic. Therefore, severe isolated TR had been regarded as a benign disease despite the lack of evidence. In contrast to the general misconception, however, a considerable number of patients (34%) had cardiovascular events in our study. Although it was shown that isolated TR caused by flail leaflets has high morbidity and mortality,14 severe isolated TR can occur without definite abnormalities of the TV.15 In our study, 51
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Table 3 Characteristics of patients with VCW > 7 mm and those with VCW # 7 mm Variable
VCW > 7 mm (n = 32)
VCW # 7 mm (n = 42)
P
Age (y) Men NYHA class III and IV Hemoglobin (g/dL) TR jet area (cm2) TR jet percentage RV end-diastolic area (cm2) RV end-systolic area (cm2) RV FAC (%) RV sphericity index, diastolic RV eccentricity index, diastolic RA area (cm2) RA FAC (%) TV annular EDD (mm) TV tethering distance (mm) TV tethering area (cm2)
60 6 12 9 (28%) 3 (9%) 12.5 6 2.0 15.2 6 5.6 43.1 6 11.5 23.4 6 8.6 12.8 6 6.1 46 6 11 1.6 6 0.3 2.1 6 0.3 33.5 6 12.2 20 6 10 43.7 6 6.9 9.6 6 2.4 2.1 6 0.7
65 6 12 24 (59%) 1 (2%) 13.5 6 1.8 12.4 6 5.0 42.6 6 8.7 17.8 6 5.1 10.1 6 3.6 44 6 8 1.7 6 0.2 2.4 6 0.4 24.6 6 5.5 21 6 6 38.9 6 4.8 7.7 6 1.4 1.5 6 0.4
.13 .02 .30 .03 .03 .80 <.01 .02 .28 .07 <.01 <.01 .61 <.01 <.01 <.01
EDD, End-diastolic diameter; NYHA, New York Heart Association. Data are expressed as mean 6 SD or as number (percentage).
patients (69%) presented with severe TR without evidence of organic TV disease. Even in patients without definite evidence of organic TV disease, the outcomes were considerable (two cardiovascular deaths, two TV surgeries, and eight cases of aggravated HF despite medical treatment). Thus, patients with severe isolated TR should be considered for TV surgery irrespective of TV deformity. In our practice, surgery is usually delayed in the case of isolated TR. However, severe TR results in chronic volume overload that eventually leads to RV dysfunction. Surgical outcomes in patients with severe RV remodeling and dysfunction are poor.16 Chronic severe TR could result in liver cirrhosis, immunologic deficiency, and low cardiac output, all of which could affect outcomes.17 Therefore, it is very important to determine the optimal time for TV surgery at some point in patients with severe isolated TR. Quantification of TR Severity by VCW A previous study showed that VCW measured by color Doppler correlated closely with the severity of TR and has a high diagnostic value for severe TR.18 The American and European cardiac societies advocated for quantitative methods using Doppler echocardiography to determine the severity of TR.13 However, in many echocardiographic laboratories, TR severity has been determined by conventional semiquantitative indices, such as color jet area of TR and flow pattern in the hepatic vein jet. In this study, VCW varied widely (from 4.1 to 19.0 mm), even in patients with severe isolated TR confirmed by color jet area of TR and flow pattern of the hepatic vein. In addition, although all patients fulfilled the conventional criteria for severe TR, more than half had VCW # 7 mm. More interestingly, the magnitude of VCW was the strongest predictor of cardiovascular events among all the semiquantitative indices. These results suggest that severe TR could be further subdivided according to the amount of regurgitation, which enables further stratification of high-risk patients requiring TV surgery. Color-flow imaging has been widely used for TR grading, but the assessment of severe TR jet has important limitations, such as great de-
pendency on hemodynamic conditions or echocardiographic settings.19 Systolic flow reversal of the hepatic vein is useful for discriminating severe TR but does not provide quantitative information.20 Calculation of ERO area is helpful for acquiring quantitative information but is time consuming for routine use. VCW is the smallest regurgitant jet width just beyond the flow convergence region and directly reflects the size of the regurgitant orifice.21,22 VCW is simple to measure and relatively independent of hemodynamic conditions and instrument settings.22,23 As previously noted, VCW was closely correlated with ERO area in this study. VCW also showed correlations with TR jet area, TV tethering area, RA end-systolic area, and RV end-diastolic area. Thus, VCW closely represents the severity of TR. Prognostic implications with quantitative Doppler assessment in mitral regurgitation have already been demonstrated in many studies.24-26 However, it has not been demonstrated that quantitative Doppler assessment in TR would have prognostic significance. To the best of our knowledge, this is the first study to demonstrate the prognostic significance of VCW in severe isolated TR. In this study, a larger VCW was a potent independent predictor of adverse cardiovascular outcomes. VCW > 7 mm was correlated with markedly increased cardiovascular events. Interestingly, although all patients fulfilled the conventional criteria for severe TR, fewer than half had VCW > 7 mm. Patients with VCW > 7 mm had larger TR jet areas, right atrium, and right ventricles. The right ventricle tolerates volume overload better than the left ventricle up to a certain point. Thus, patients can have no symptoms for a long time, until RV dysfunction develops. However, chronic volume overload by TR would eventually exhaust the right ventricle, followed rapid deterioration in prognosis.27,28 Therefore, the decisions regarding the timing of surgery for severe, isolated TR are not easy and it must incorporate multiple factors, such as symptom status, RV systolic function, and comorbidities. The current guidelines recommend TV surgery in patients who have symptoms or diseased TV leaflets.7 Because the measurement of VCW provided the substantial prognostic significance, it might be useful in determining the appropriate time for TV surgery. Study Limitations The TV is composed of three leaflets, making a noncircular geometry of the vena contracta. In this study, VCW was measured in the apical four-chamber view to reduce errors derived by different views. However, two-dimensional echocardiography has limitations in measuring vena contracta with diverse geometry. Although threedimensional echocardiography could overestimate true orifice size due to lower spatial and temporal resolution, three-dimensional echocardiography has the advantage in evaluating elliptical convergence region. A recent study using three-dimensional echocardiography demonstrated different VCW according to different views.29 Thus, the 7-mm cutoff value for VCW presented in this study might not be appropriate in other views, and further study would be warranted to define the best two-dimensional plane for VCW measurement. Assessment of RV function and volume by two-dimensional echocardiography might not be accurate, because of the anatomic complexity of the right heart. In this study, RV function was assessed only by FAC, which is often volume dependent. Evaluation of RV function using tricuspid annular systolic velocity measured by tissue Doppler echocardiography or three-dimensional echocardiography might be more desirable but was not available in our study. The retrospective design, the small number of patients, and the relatively short duration of
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Journal of the American Society of Echocardiography September 2011
Figure 3 Kaplan-Meier analysis in patients with VCW > 7 mm and VCW # 7 mm for (A) cardiovascular events (P < .01) and (B) cardiovascular death and TV surgery (P < .01) with the log-rank test. follow-up were other limitations. However, severe isolated TR is not a common disease, and few studies have reported outcomes. Therefore, this study could be valuable despite these limitations. CONCLUSIONS In patients with severe isolated TR, irrespective of all other characteristics, the degree of TR quantified by Doppler echocardiography has an independent prognostic significance. Adverse outcomes, which were considerable for VCW > 7 mm, suggest that the quantification of TR by Doppler echocardiography is crucial in estimating prognosis. Patients with severe isolated TR with VCW > 7 mm should be considered for TV surgery. REFERENCES 1. Nath J, Foster E, Heidenreich PA. Impact of tricuspid regurgitation on longterm survival. J Am Coll Cardiol 2004;43:405-9. 2. Singh JP, Evans JC, Levy D, Larson MG, Freed LA, Fuller DL, et al. Prevalence and clinical determinants of mitral, tricuspid, and aortic regurgitation (the Framingham Heart Study). Am J Cardiol 1999;83:897-902. 3. Nihoyannopoulos P. Tricuspid valvectomy following tricuspid valve endocarditis on an intravenous drug addict. Heart 2001;86:144. 4. David TE. Functional tricuspid regurgitation: a perplexing problem. J Am Soc Echocardiogr 2009;22:904-6. 5. Hauck AJ, Freeman DP, Ackermann DM, Danielson GK, Edwards WD. Surgical pathology of the tricuspid valve: a study of 363 cases spanning 25 years. Mayo Clin Proc 1988;63:851-63. 6. Seo H, Ha J, Moon JY, Choi E, Rim S, Jang Y, et al. Right ventricular remodeling and dysfunction with subsequent annular dilatation and tethering as a mechanism of isolated tricuspid regurgitation. Circ J 2008;72:1645-9. 7. Bonow RO, Carabello BA, Chatterjee K, de Leon AC, Faxon DP, Freed MD, et al. 2008 Focused update incorporated into the ACC/ AHA 2006 guidelines for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 1998 Guidelines for the Management of Patients With Valvular Heart Disease): endorsed by the Society of Cardiovascular Anesthesiologists, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. Circulation 2008;118:e523-661.
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Journal of the American Society of Echocardiography Volume 24 Number 9
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