Methods

From November 2012 to August 2014, 143 consecutive Chinese patients with variable degrees (mild to severe) of TR secondary to left-sided heart valvular disease, aged >18 and referred to the Department of Cardiology at Queen Mary Hospital were recruited. A total of 12 patients with the following condition were excluded: poor quality echocardiography images (n = 2), congenital heart disease (n = 3), viral hepatitis B or C (n = 5), excessive alcohol intake (n = 2), acute liver failure, or other terminal illness. Accordingly, 131 patients were included in the final analysis. The study was part of the Chinese Valvular Heart Disease Study to evaluate Chinese patients with valvular heart disease in an attempt to evaluate the pattern of disease, pathophysiology, and clinical outcome in these patients. The local institutional ethics board approved the study, and all subjects gave written informed consent.

Data on baseline clinical demographics and fasting blood samples were obtained on the same day from all study subjects. The cause of valvular heart disease was recorded. New York Heart Association classification was given as class I/II and class III/IV, and the status of valvular atrial fibrillation (AF) was also recorded for each subject. Laboratory blood tests including complete blood count, liver function, renal function, and hepatitis B and C virology were measured. Body mass index and conventional cardiovascular risk factors were also documented.

Detailed transthoracic echocardiography was performed in all subjects using a commercially available echocardiography system (Vingmed E9, General Electric Vingmed Ultrasound, Milwaukee). Left ventricular (LV) and right-sided heart echocardiographic parameters were measured according to the current recommendations. From the apical 4-chamber views, right ventricular end-diastolic area (RVEDA) and RV end-systolic area (RVESA) were measured by manually tracing the RV endocardial border, and RV fractional area change was calculated from the following equation: (RVEDA−RVESA)/RVEDA × 100%. Tricuspid annular plane systolic excursion (TAPSE) was measured by the M mode. From the subcostal view, the long-axis diameter of the inferior vena cava (IVC) was measured at end expiration. Then, specific values of right atrial pressure (RAP) were estimated from the IVC diameter and respiratory changes according to the current recommendations. Finally, RV systolic pressure (RVSP) was determined from peak TR velocity by continuous-wave Doppler using simplified Bernoulli equation and combining this value with an estimate of the RAP: RVSP = 4(V) ² + RAP, where V indicates peak velocity of tricuspid regurgitation.

The severity of TR was quantified by effective regurgitant orifice (ERO) using PISA method. The PISA method, as previously described, allows accurate calculation of ERO, combining the measurement of tricuspid flow and its velocity by continuous-wave Doppler. Briefly, color Doppler images of TR proximal flow convergence were obtained from apical 4-chamber views and zoomed to the region of interest. The color-flow velocity scale was maximized, and the baseline was shifted downward until the flow convergence region was visualized clearly. The Nyquist velocity range (color scale) was selected from 0.39 to 0.60 m/s for TR. Radial distance between the first aliasing velocity (red/blue interface) and the center of the tricuspid orifice was measured to calculate regurgitant flow in mid systole. The ERO area was then calculated as the ratio of regurgitant flow to the peak velocity of the TR jet. Patients were further divided into 2 groups on the basis of their TR severity: 48 patients with mild–moderate TR (ERO <0.4 cm ² ) and 83 with severe TR (ERO ≥0.4 cm ² ).

TE was used to estimate the level of LS and performed by a professionally trained operator, blinded to clinical data, with a FibroScan (Echosens, Paris, France) using an M probe. Details of the technique and examination procedure have been reported previously. Briefly, patients were placed in a supine position with the right hand at the most abducted position for right intercostal scanning. The probe was applied with coupling gel and placed on the right intercostal space overlying the right lobe of the liver. Using time–motion ultrasound image, measurements were taken once a segment of the liver was located with a thickness of over 6 cm and was free of large vascular structures. A reliable result was defined as at least 10 valid scans, a success rate of at least 60%, and an interquartile range of <30% of the median LS value. The results were expressed in kilopascals (kPa), and the results were considered unreliable if these criteria were not met.

Because the role of TE in TR or right-sided heart failure remains uninvestigated, data published on chronic hepatitis C, in which the role of TE has been extensively evaluated, were used for analysis. Accordingly, significant LS was defined as ≥12.5 kPa, the established cut-off threshold for liver cirrhosis in chronic hepatitis C.

Data are expressed as mean ± SD for continuous variables and frequencies or proportions for categorical variables. For continuous variables, an independent sample Student t test was used for intergroup comparisons. Categorical variables were compared using Pearson chi-square test or Fisher’s exact test if more than 10% of the cells had an expected count <5. Pearson’s correlation test was used to assess the relation between LS and echocardiography parameters. Univariate linear and logistic regression analysis were performed to evaluate the association of clinical demographics and echocardiography parameters with LS (continuous variable) and significant LS (categorical variable), respectively. To detect the independent predictors of significant LS, multivariate linear and logistic regression analyses were subsequently performed with an enter regression model in which each variable with a p value <0.10 (according to the univariate analysis) was chosen. The results were reported as unstandardized regression coefficients (B) in linear regression models and odds ratio in logistic regression models; the 95% CI was also calculated. To avoid bias from multicollinearity, IVC diameter and RAP were entered into the stepwise multivariate model individually. Receiver operating characteristic curve and calculation of the area under curve (AUC) analysis were used to determine the parameters most associated with the presence of significant LS. All statistical analyses were performed using the statistical package SPSS for windows, version 16.0, (SPSS, Chicago), and p values reported are 2-sided for consistency. A p value <0.05 was considered statistically significant.

Results

The baseline characteristics of patients with mild–moderate TR and severe TR are listed in Table 1 . A total of 77 patients had a native valvular lesion, and 54 patients had a history of previous valve surgery. Those with severe TR had significantly greater LS, bilirubin level, and a higher prevalence of AF than patients with mild–moderate TR. The level of platelet, hemoglobin, and albumin was also lower in patients with severe TR than in those with mild–moderate TR ( Table 1 ).

The echocardiographic parameters for patients with mild–moderate and severe TR are summarized in Table 1 . Compared with patients with mild–moderate TR, those with severe TR had larger RVEDA and RVESA, lower TAPSE, and higher RVSP. These patients also had a significantly higher TR-ERO, RAP, and larger IVC diameter ( Table 1 ).

LS was significantly correlated with TR-ERO, left ventricular ejection fraction (LVEF), RVEDA, RVESA, TAPSE, IVC diameter, and RAP ( Figure 1 ; all p <0.01). No such relation was observed between LS and RVSP ( Figure 1 ).

(A-H) Relation between LS and echocardiography parameters.

Comparison of different degrees of LS in patients with mild–moderate and severe TR is shown in Figure 2 . A total of 66% of patients (n = 55 of 83) with severe TR had significant LS, more than 3 times the number of patients with mild–moderate TR (n = 8 of 48, p <0.01). Alternatively, patients with mild–moderate TR were more likely to have insignificant LS than those with severe TR (83% vs 34%, p <0.01).

Comparison of different degrees of LS in patients with mild–moderate and severe TR.

Clinical findings in patients with and without significant LS (LS ≥12.5 kPa) are described as following: age, gender, body mass index, systolic and diastolic blood pressure, native valvular lesion and surgical details, and New York Heart Association class were similar in both groups of patients. Nonetheless, patients with significant LS had higher serum levels of bilirubin and alkaline phosphatase, and a higher prevalence of diabetes mellitus and AF than patients without significant LS (all p <0.05). The level of platelet, hemoglobin, and albumin was also significantly reduced in patients with significant LS (all p <0.01).

Univariate and multivariate analyses for predictors of LS (continuous variable) are listed Table 2 . Univariate linear regression analysis demonstrated that the LS was significantly associated with LVEF, RVEDA, RVESA, TAPSE, TR-ERO, RAP, and IVC. To avoid bias from multicollinearity, RAP and IVC diameter were entered into the stepwise regression model individually; after multivariate adjustment, only TR-ERO and RAP in the RAP model, and TR-ERO and IVC diameter in the IVC model, remained independently associated with LS.

Table 2

Predictors of increased liver stiffness (liver stiffness as continuous variable)

Variables	Univariate		Multivariate(IVC model)		Multivariate(RAP model)
	B(95%CI)	P	B(95%CI)	P	B(95%CI)	P
Age (years)	-0.04(-0.26 to 0.18)	0.73	–	–	–	–
Male	0.13(-4.42 to 4.69)	0.95	–	–	–	–
Left ventricular end-diastolic septal wall thickness (cm)	3.76(-5.61 to 13.12)	0.43	–	–	–	–
Left ventricular end-diastolic diameter (cm)	0.78(-1.58 to 3.13)	0.52	–	–	–	–
Left ventricular end-diastolic posterior wall thickness (cm)	8.53(-2.38 to 19.4)	0.12	–	–	–	–
Left ventricular end-diastolic volume (ml)	-0.01 (-0.06 to 0.05)	0.92	–	–	–	–
Left ventricular end-systolic volume (ml)	0.07(-0.02 to 0.16)	0.14	–	–	–	–
Left ventricular ejection fraction (%)	-0.58(-0.81 to -0.35)	<0.01	-0.12(-0.29 to 0.05)	0.17	-0.13(-0.31 to 0.04)	0.13
Right ventricular end-diastolic area (cm 2 )	0.87(0.61 to 1.12)	<0.01	-0.38(-0.90 to 0.13)	0.15	-0.30(-0.80 to 0.20)	0.23
Right ventricular end-systolic area (cm 2 )	1.30(0.85 to 1.76)	<0.01	0.49(-0.26 to 1.23)	0.20	0.43(-0.31 to 1.18)	0.25
Right ventricular fractional area change (%)	-0.01(-0.25 to 0.22)	0.91	–	–	–	–
Tricuspid annular plane systolic excursion (cm)	-9.41(-14.8 to -4.06)	<0.01	-2.85(-6.51 to 0.82)	0.13	-2.53(-6.27 to 1.21)	0.18
Right ventricular systolic pressure (mmHg)	0.07(-0.08 to 0.21)	0.39	–	–	–	–
Tricuspid regurgitation-effective regurgitant orifice (cm 2 )	10.49(9.05 to 11.9)	<0.01	8.94(6.85 to 11.02)	<0.01	9.46(7.47 to 11.45)	<0.01
∗ RAP (mmHg)	1.22(0.78 to 1.66)	<0.01	NI	NI	0.42(0.05 to 0.78)	0.03
∗ IVC (cm)	11.76(9.01 to 14.5)	<0.01	3.69(0.48 to 6.89)	0.02	NI	NI

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