Tricuspid regurgitation in acute heart failure: is there any incremental risk?

Tricuspid regurgitation in acute heart failure: is there any incremental risk? Abstract Aim Significant tricuspid regurgitation (TR) is common in heart failure (HF) and portends poor prognosis. We sought to determine whether the poor outcome results from the TR itself, or whether the TR is a surrogate marker of advanced left-sided myocardial or valvular heart disease. Methods and results We studied 639 patients admitted for acute HF. The relationship between TR severity and the endpoint of readmission for HF or mortality was assessed after adjustment for multiple clinical and echocardiographic parameters. Higher TR grade was associated with higher congestion score and with other cardiac abnormalities including reduced left ventricular systolic function, moderate or severe mitral regurgitation, pulmonary hypertension (PH, defined as pulmonary artery systolic pressure ≥ 50 mmHg), and right ventricular dysfunction (all P < 0.001). Only 7% of patients with moderate or severe TR were free of other cardiac lesions. In adjusted models, moderate or severe TR was not associated with readmission for HF or mortality [hazard ratio (HR) 1.24, 95% confidence interval (95% CI) 0.97–1.57]. Patients with moderate/severe TR had similar risk for HF readmission or death compared with patients with trivial/mild TR when PH was not present (HR 1.17; 95% CI 0.78–1.75, P = 0.40) whereas the risk was higher in moderate/severe TR and PH (HR 1.78; 95% CI 1.34–2.36, P < 0.0001). Conclusion Patients presenting with symptomatic HF and significant TR have multiple coexisting cardiac abnormalities. TR provides no additive risk in the presence of normal or mildly elevated pulmonary pressures. However, it is associated with excess rehospitalizations and mortality in patients with PH. heart failure, pulmonary hypertension, functional tricuspid regurgitation Introduction Epidemiological studies have shown a high prevalence of tricuspid regurgitation (TR) in the general population1 and particularly in patients with left-sided heart disease2 or pulmonary hypertension (PH).3 Secondary or functional TR (FTR), the most frequent form of TR, occurs in 70–85% of patients. FTR is characterized by structurally normal tricuspid leaflets and caused by tricuspid annular dilatation and increased tricuspid leaflet tethering due to right ventricular (RV) remodelling, which is often due to left heart failure (HF) from myocardial or valvular causes and associated PH.4–6 Two major risk factors for FTR progression have been described; an increase in pulmonary artery systolic pressure (PASP) and atrial fibrillation (AF).7 Increase in PASP may lead to RV remodelling (both increase in volumes and change in geometry), which in turn leads to tricuspid valve (TV) leaflets tethering,4,8,9 whereas AF promotes atrial dilatation, which in turn lead to TV annular dilatation and remodelling. The prognostic role of TR associated with organic left-sided valvular heart disease is well known.10–12 However, the value of FTR in outcome stratification and the incremental prognostic significance of FTR in patients with HF are less clear. This is particularly true in patients with overt HF,2 where multiple coexisting comorbidities interact with the effect of FTR. Indeed, the complex relationship between FTR and PH and RV function is likely to affect the final clinical outcome, suggesting that these associated prognostic determinants of HF might explain the increased mortality associated with TR. Therefore, we sought to study the prognostic implications and clinical correlates of FTR in patients with acute decompensated HF (ADHF). Methods Between January 2008 and April 2015, all patients admitted to the Rambam Medical Center, Haifa, Israel with the primary diagnosis of ADHF entered a prospective registry.13 Eligible patients were those hospitalized with new-onset or worsening of pre-existing HF as the primary cause of admission. ADHF was diagnosed according to the European Society of Cardiology criteria including a brain natriuretic peptide (BNP) level > 400 pg/mL. The study was performed in accordance with the Declaration of Helsinki and approved by the institutional review committee on human research. Congestion score Assessment of congestion at hospital admission was done by the treating physician. The degree of congestion was evaluated based on a combination of several signs and symptoms as previously described.14 A composite congestion score was calculated by summing the individual scores at the time of admission and discharge (range 0–8). Echocardiographic evaluation All patients had an echocardiographic examination performed during hospital stay or within a period of 30 days prior or after the day of admission [median 2 days, interquartile range (IQR) 1–4 days]. PASP was estimated from clearly defined TR signal by continuous-wave Doppler and inferior vena cava size and respiratory variation using established criteria, as previously described.15 PH was defined using the cut-off of PASP ≥ 50 mmHg.13 TR was quantified by an integrated approach.3 First, TR was graded qualitatively using color Doppler flow mapping as follows: trivial TR (jet area ≤1.0 cm2), mild (jet area 1–5 cm2), moderate (jet area 5–10 cm2), and severe (jet area >10 cm2).8 When more than mild TR was present, severity was determined by integrating data from the following parameters: TV morphology (flail/large coaptation defect); vena contracta width when feasible (≥7 mm denoting severe TR); presence and degree of malcoaptation of the TV leaflets; tenting distance; presence of mid-to-late systolic flow reversal in the hepatic veins, and evaluation of right heart chambers.1,3,8,15 RV function was assessed qualitatively by integrating visual assessment of the contractility of the RV walls from different views and classified on an ordinal scale (normal or mildly, moderately, or severely reduced) and quantitatively by calculating the RV fractional area change, with a value <35% defined as abnormal, as previously described.5,13,16 RV dysfunction was considered to be present if at least mild systolic dysfunction was observed. The agreement in the assessment of RV function between echo readers was high (Cohen’s Kappa 0.82, 95% CI 0.67–0.97). To determine whether the type of FTR affects clinical outcome, patient with moderate or severe FTR were further divided into two subgroups based on the presence or absence of PH. Patients with PASP < 50 mmHg were labelled as non-PH related FTR (non-PH FTR) and patients with PASP ≥ 50 mm Hg as PH-FTR. Study endpoint The primary endpoint of the study was the composite of readmission for HF and mortality after hospital discharge. Following hospital discharge, clinical endpoint information was acquired by reviewing the national death registry and by reviewing the hospital records for major clinical events if the patient had been re-hospitalized. Statistical analysis Continuous variables are presented as mean ± standard deviation (SD) or medians (with IQR), and categorical variables as numbers and percentages. Baseline characteristics of the groups were compared using analysis of variance (ANOVA) for continuous variables and by the χ2 statistic for non-continuous variables. The association between moderate or severe TR and other echocardiographic or clinical parameters was determined by fitting logistic regression model. Odds ratios were calculated with their 95% confidence intervals (CIs), and the relative strength of the associations was expressed by the standardized coefficient to compare effect estimates. Survival curves were constructed for the TR categories using the Kaplan–Meier method. Stepwise Cox proportional hazards models with backward selection were used to calculate hazard ratios (HRs) and 95% CI for the TR categories. The multivariable Cox regression was adjusted for clinical, laboratory, and echocardiographic variables listed in Table 1 and the congestion score. Table 1 Baseline clinical characteristics according to the severity of tricuspid regurgitation Tricuspid regurgitation grade Characteristics Trivial (n = 133) Mild (n = 334) Moderate (n = 167) Severe (n = 75) P-value Age (years) 72 ± 13 76 ± 11 76 ± 12 74 ± 12 0.12 Female gender 57 (13) 161 (49) 89 (53) 46 (61) 0.06 hypertension 111 (83) 294 (88) 130 (79) 64 (85) 0.02 Diabetes mellitus 75 (56) 159 (48) 75 (45) 49 (65) 0.009 Chronic lung disease 28 (21) 43 (13) 31 (19) 9 (12) 0.08 Coronary artery disease 88 (66) 183 (55) 99 (59) 51 (68) 0.05 Atrial fibrillation 35 (27) 133 (40) 84 (50) 45 (60) <0.0001 Creatinine (mg/dL) 1.2 (1.0–1.7) 1.2 (1.0–1.6) 1.3 (1.0–1.7) 1.4 (1.0–1.8) 0.25 eGFR (mL min−1/1.73 m−2) 53 (36–73) 52 (38–66) 47 (34–64) 44 (31–61) 0.047 BUN (mg/dL) 27 (19–37) 24 (18–35) 29 (20–42) 32 (22–49) 0.0001 Serum sodium (mmol/L) 137 ± 5 138 ± 4 136 ± 6 137 ± 6 0.41 Aspartate transaminase (IU/L) 23 (17–36) 24 (20–37) 26 (19–41) 25 (21–33) 0.61 Alanine transaminase (IU/L) 36 (26–47) 35 (27–45) 36 (26–54) 30 (27–37) 0.12 γ-Glutamyl transferase (IU/L) 53 (30–85) 52 (33–100) 84 (38–147) 117 (62–215) 0.0001 Alkaline phosphatase (IU/L) 83 (68–115) 88 (72–114) 95 (71–142) 131 (83–168) 0.0002 Haemoglobin (g/dL) 11.7 ± 2.1 11.6 ± 2.0 11.7 ± 1.9 11.3 ± 2.0 0.58 Haematocrit (%) 36 ± 6 35 ± 6 36 ± 6 35 ± 6 0.72 BNP (ng/mL) 803 (616–1140) 851 (603–1143) 1049 (687–1631) 1119 (647–2065) 0.002 cTn I elevation (%) 42 (32) 126 (38) 65 (39) 26 (35) 0.55 Moderate/severe mitral regurgitation 19 (15) 77 (23) 66 (40) 30 (40) <0.0001 LVEF (%) 47 ± 17 49 ± 18 43 ± 20 47 ± 20 0.004 Right ventricular dysfunction 11 (8) 52 (16) 52 (31) 41 (55) <0.0001 PASP (mmHg)a 36 (30–44) 45 (40–56) 58 (48–68) 60 (52–70) <0.0001 TR parameters  Tenting area 1.4 ± 1.0 2.0 ± 0.9 0.0002  Tenting height 0.8 ± 0.4 1.1 ± 0.4 <0.001  Annular-4C diastolic diameter 3.9 ± 0.6 4.4 ± 0.5 <0.0001  Annular-4C systolic diameter 3.7 ± 0.5 4.0 ± 0.5 0.0007 Medications  Beta blockers 93 (70) 251 (75) 132 (78) 63 (84) 0.10  ACE inhibitors/ARBs 89 (67) 220 (66) 104 (62) 45 (60) 0.65  Spironolactone 25 (19) 60 (18) 47 (28) 22 (29) 0.02  Digoxin 9 (7) 22 (7) 12 (7) 8 (11) 0.67 Tricuspid regurgitation grade Characteristics Trivial (n = 133) Mild (n = 334) Moderate (n = 167) Severe (n = 75) P-value Age (years) 72 ± 13 76 ± 11 76 ± 12 74 ± 12 0.12 Female gender 57 (13) 161 (49) 89 (53) 46 (61) 0.06 hypertension 111 (83) 294 (88) 130 (79) 64 (85) 0.02 Diabetes mellitus 75 (56) 159 (48) 75 (45) 49 (65) 0.009 Chronic lung disease 28 (21) 43 (13) 31 (19) 9 (12) 0.08 Coronary artery disease 88 (66) 183 (55) 99 (59) 51 (68) 0.05 Atrial fibrillation 35 (27) 133 (40) 84 (50) 45 (60) <0.0001 Creatinine (mg/dL) 1.2 (1.0–1.7) 1.2 (1.0–1.6) 1.3 (1.0–1.7) 1.4 (1.0–1.8) 0.25 eGFR (mL min−1/1.73 m−2) 53 (36–73) 52 (38–66) 47 (34–64) 44 (31–61) 0.047 BUN (mg/dL) 27 (19–37) 24 (18–35) 29 (20–42) 32 (22–49) 0.0001 Serum sodium (mmol/L) 137 ± 5 138 ± 4 136 ± 6 137 ± 6 0.41 Aspartate transaminase (IU/L) 23 (17–36) 24 (20–37) 26 (19–41) 25 (21–33) 0.61 Alanine transaminase (IU/L) 36 (26–47) 35 (27–45) 36 (26–54) 30 (27–37) 0.12 γ-Glutamyl transferase (IU/L) 53 (30–85) 52 (33–100) 84 (38–147) 117 (62–215) 0.0001 Alkaline phosphatase (IU/L) 83 (68–115) 88 (72–114) 95 (71–142) 131 (83–168) 0.0002 Haemoglobin (g/dL) 11.7 ± 2.1 11.6 ± 2.0 11.7 ± 1.9 11.3 ± 2.0 0.58 Haematocrit (%) 36 ± 6 35 ± 6 36 ± 6 35 ± 6 0.72 BNP (ng/mL) 803 (616–1140) 851 (603–1143) 1049 (687–1631) 1119 (647–2065) 0.002 cTn I elevation (%) 42 (32) 126 (38) 65 (39) 26 (35) 0.55 Moderate/severe mitral regurgitation 19 (15) 77 (23) 66 (40) 30 (40) <0.0001 LVEF (%) 47 ± 17 49 ± 18 43 ± 20 47 ± 20 0.004 Right ventricular dysfunction 11 (8) 52 (16) 52 (31) 41 (55) <0.0001 PASP (mmHg)a 36 (30–44) 45 (40–56) 58 (48–68) 60 (52–70) <0.0001 TR parameters  Tenting area 1.4 ± 1.0 2.0 ± 0.9 0.0002  Tenting height 0.8 ± 0.4 1.1 ± 0.4 <0.001  Annular-4C diastolic diameter 3.9 ± 0.6 4.4 ± 0.5 <0.0001  Annular-4C systolic diameter 3.7 ± 0.5 4.0 ± 0.5 0.0007 Medications  Beta blockers 93 (70) 251 (75) 132 (78) 63 (84) 0.10  ACE inhibitors/ARBs 89 (67) 220 (66) 104 (62) 45 (60) 0.65  Spironolactone 25 (19) 60 (18) 47 (28) 22 (29) 0.02  Digoxin 9 (7) 22 (7) 12 (7) 8 (11) 0.67 ACE, angiotensin converting enzyme; ARB, angiotensin receptor blockers; BNP, brain natriuretic peptide; eGFR, estimated glomerular filtration rate; LVEF, left ventricular ejection fraction; PASP, pulmonary artery systolic pressure; TR, tricuspid regurgitation. a Data of 639 patients with estimable PASP. Table 1 Baseline clinical characteristics according to the severity of tricuspid regurgitation Tricuspid regurgitation grade Characteristics Trivial (n = 133) Mild (n = 334) Moderate (n = 167) Severe (n = 75) P-value Age (years) 72 ± 13 76 ± 11 76 ± 12 74 ± 12 0.12 Female gender 57 (13) 161 (49) 89 (53) 46 (61) 0.06 hypertension 111 (83) 294 (88) 130 (79) 64 (85) 0.02 Diabetes mellitus 75 (56) 159 (48) 75 (45) 49 (65) 0.009 Chronic lung disease 28 (21) 43 (13) 31 (19) 9 (12) 0.08 Coronary artery disease 88 (66) 183 (55) 99 (59) 51 (68) 0.05 Atrial fibrillation 35 (27) 133 (40) 84 (50) 45 (60) <0.0001 Creatinine (mg/dL) 1.2 (1.0–1.7) 1.2 (1.0–1.6) 1.3 (1.0–1.7) 1.4 (1.0–1.8) 0.25 eGFR (mL min−1/1.73 m−2) 53 (36–73) 52 (38–66) 47 (34–64) 44 (31–61) 0.047 BUN (mg/dL) 27 (19–37) 24 (18–35) 29 (20–42) 32 (22–49) 0.0001 Serum sodium (mmol/L) 137 ± 5 138 ± 4 136 ± 6 137 ± 6 0.41 Aspartate transaminase (IU/L) 23 (17–36) 24 (20–37) 26 (19–41) 25 (21–33) 0.61 Alanine transaminase (IU/L) 36 (26–47) 35 (27–45) 36 (26–54) 30 (27–37) 0.12 γ-Glutamyl transferase (IU/L) 53 (30–85) 52 (33–100) 84 (38–147) 117 (62–215) 0.0001 Alkaline phosphatase (IU/L) 83 (68–115) 88 (72–114) 95 (71–142) 131 (83–168) 0.0002 Haemoglobin (g/dL) 11.7 ± 2.1 11.6 ± 2.0 11.7 ± 1.9 11.3 ± 2.0 0.58 Haematocrit (%) 36 ± 6 35 ± 6 36 ± 6 35 ± 6 0.72 BNP (ng/mL) 803 (616–1140) 851 (603–1143) 1049 (687–1631) 1119 (647–2065) 0.002 cTn I elevation (%) 42 (32) 126 (38) 65 (39) 26 (35) 0.55 Moderate/severe mitral regurgitation 19 (15) 77 (23) 66 (40) 30 (40) <0.0001 LVEF (%) 47 ± 17 49 ± 18 43 ± 20 47 ± 20 0.004 Right ventricular dysfunction 11 (8) 52 (16) 52 (31) 41 (55) <0.0001 PASP (mmHg)a 36 (30–44) 45 (40–56) 58 (48–68) 60 (52–70) <0.0001 TR parameters  Tenting area 1.4 ± 1.0 2.0 ± 0.9 0.0002  Tenting height 0.8 ± 0.4 1.1 ± 0.4 <0.001  Annular-4C diastolic diameter 3.9 ± 0.6 4.4 ± 0.5 <0.0001  Annular-4C systolic diameter 3.7 ± 0.5 4.0 ± 0.5 0.0007 Medications  Beta blockers 93 (70) 251 (75) 132 (78) 63 (84) 0.10  ACE inhibitors/ARBs 89 (67) 220 (66) 104 (62) 45 (60) 0.65  Spironolactone 25 (19) 60 (18) 47 (28) 22 (29) 0.02  Digoxin 9 (7) 22 (7) 12 (7) 8 (11) 0.67 Tricuspid regurgitation grade Characteristics Trivial (n = 133) Mild (n = 334) Moderate (n = 167) Severe (n = 75) P-value Age (years) 72 ± 13 76 ± 11 76 ± 12 74 ± 12 0.12 Female gender 57 (13) 161 (49) 89 (53) 46 (61) 0.06 hypertension 111 (83) 294 (88) 130 (79) 64 (85) 0.02 Diabetes mellitus 75 (56) 159 (48) 75 (45) 49 (65) 0.009 Chronic lung disease 28 (21) 43 (13) 31 (19) 9 (12) 0.08 Coronary artery disease 88 (66) 183 (55) 99 (59) 51 (68) 0.05 Atrial fibrillation 35 (27) 133 (40) 84 (50) 45 (60) <0.0001 Creatinine (mg/dL) 1.2 (1.0–1.7) 1.2 (1.0–1.6) 1.3 (1.0–1.7) 1.4 (1.0–1.8) 0.25 eGFR (mL min−1/1.73 m−2) 53 (36–73) 52 (38–66) 47 (34–64) 44 (31–61) 0.047 BUN (mg/dL) 27 (19–37) 24 (18–35) 29 (20–42) 32 (22–49) 0.0001 Serum sodium (mmol/L) 137 ± 5 138 ± 4 136 ± 6 137 ± 6 0.41 Aspartate transaminase (IU/L) 23 (17–36) 24 (20–37) 26 (19–41) 25 (21–33) 0.61 Alanine transaminase (IU/L) 36 (26–47) 35 (27–45) 36 (26–54) 30 (27–37) 0.12 γ-Glutamyl transferase (IU/L) 53 (30–85) 52 (33–100) 84 (38–147) 117 (62–215) 0.0001 Alkaline phosphatase (IU/L) 83 (68–115) 88 (72–114) 95 (71–142) 131 (83–168) 0.0002 Haemoglobin (g/dL) 11.7 ± 2.1 11.6 ± 2.0 11.7 ± 1.9 11.3 ± 2.0 0.58 Haematocrit (%) 36 ± 6 35 ± 6 36 ± 6 35 ± 6 0.72 BNP (ng/mL) 803 (616–1140) 851 (603–1143) 1049 (687–1631) 1119 (647–2065) 0.002 cTn I elevation (%) 42 (32) 126 (38) 65 (39) 26 (35) 0.55 Moderate/severe mitral regurgitation 19 (15) 77 (23) 66 (40) 30 (40) <0.0001 LVEF (%) 47 ± 17 49 ± 18 43 ± 20 47 ± 20 0.004 Right ventricular dysfunction 11 (8) 52 (16) 52 (31) 41 (55) <0.0001 PASP (mmHg)a 36 (30–44) 45 (40–56) 58 (48–68) 60 (52–70) <0.0001 TR parameters  Tenting area 1.4 ± 1.0 2.0 ± 0.9 0.0002  Tenting height 0.8 ± 0.4 1.1 ± 0.4 <0.001  Annular-4C diastolic diameter 3.9 ± 0.6 4.4 ± 0.5 <0.0001  Annular-4C systolic diameter 3.7 ± 0.5 4.0 ± 0.5 0.0007 Medications  Beta blockers 93 (70) 251 (75) 132 (78) 63 (84) 0.10  ACE inhibitors/ARBs 89 (67) 220 (66) 104 (62) 45 (60) 0.65  Spironolactone 25 (19) 60 (18) 47 (28) 22 (29) 0.02  Digoxin 9 (7) 22 (7) 12 (7) 8 (11) 0.67 ACE, angiotensin converting enzyme; ARB, angiotensin receptor blockers; BNP, brain natriuretic peptide; eGFR, estimated glomerular filtration rate; LVEF, left ventricular ejection fraction; PASP, pulmonary artery systolic pressure; TR, tricuspid regurgitation. a Data of 639 patients with estimable PASP. Survival analyses were also performed to determine whether the type of FTR affects clinical outcome beyond TR severity. Because in previous studies2 and the present study the outcome of patients with trivial and mild TR was similar and moderate and severe TR was also similar, these TR categories were combined into two groups (trivial/mild and moderate/severe TR) and further classified into those with or without PH. The existence of an interaction between TR severity and PH was assessed using a Cox proportional hazards regression model incorporating terms for the main effect of TR severity, the main effect of PH, and the interaction between TR severity and PH. Because the echocardiographic and clinical characteristics of patients with trivial/mild TR differed markedly from those with moderate/severe TR, propensity score estimates representing the probability of a patient being in the moderate/severe TR were generated using a non-parsimonious multiple logistic regression model derived from echocardiographic and clinical variables. Following propensity score generation, patients were matched by using 1:1 nearest neighbour (Greedy-type) matching without replacement and a calliper width of a 0.2 SD of the propensity score logit. We assessed the success of the matches by examining standardized differences (measured in percentage points) in the observed confounders between the matched trivial/mild TR and moderate/severe TR groups. Small (<10%) standardized differences support the assumption of balance between groups based on observed confounders. Following the matching procedure, Cox proportional hazards model accounting for frailty effects within matched pairs (to account for dependence among matched subjects) was used to assess the risk of the primary endpoint for patients with trivial/mild FTR vs. moderate/severe FTR. Differences were considered statistically significant at the two-sided P < 0.05 level. Statistical analyses were performed using STATA Version 13.1 (College Station, TX, USA). Results During the study period, 709 patients who met the inclusion criteria were recruited. Moderate or severe TR was observed in 242 patients (34%) and trivial or mild TR in 467 patients (66%). PASP could be estimated in 639 patients (90%). Demographic and clinical characteristics of the 709 patients with TR data are shown in Table 1. Higher TR grade was associated with worse renal function and with higher diabetes and AF rates. Patients with higher TR grade were more likely to have RV dysfunction, and more mitral regurgitation (MR) and higher pulmonary pressures. Compared with patients with moderate TR, patients with severe TR had higher annular dimensions, higher tenting area, and tenting height. Increasing TR severity was associated with higher BNP levels (Figure 1A) and among the liver function tests, γ-glutamyl transferase, and alkaline phosphatase increased with increasing TR grade (Figure 1B). There was a graded increase in the congestion score at admission with increasing TR severity (Figure 1C). Figure 1 View largeDownload slide relationship between TR grade and (A) BNP levels (B) liver function tests (C) mean number of signs and symptoms of congestion (D) pulmonary artery systolic pressure (circles indicate individual PASP values). BNP, brain natriuretic peptide; PASP, pulmonary artery systolic pressure; TR, tricuspid regurgitation. Figure 1 View largeDownload slide relationship between TR grade and (A) BNP levels (B) liver function tests (C) mean number of signs and symptoms of congestion (D) pulmonary artery systolic pressure (circles indicate individual PASP values). BNP, brain natriuretic peptide; PASP, pulmonary artery systolic pressure; TR, tricuspid regurgitation. In the 639 (90%) patients with estimable PASP, there was a graded increase in PASP with increasing TR grade, albeit with large overlap (Figure 1D). The median PASP was 55 and 60 mmHg in patients with moderate and severe TR, respectively. Figure 2 summarizes the association of TR grade and several clinically significant cardiac lesions [left ventricular ejection fraction (LVEF) < 45%, moderate or severe MR, RV dysfunction, and PASP ≥ 50 mmHg]. The number of associated cardiac abnormalities increased with increasing TR grade, with ∼93% of patients with moderate and or severe TR having at least one additional clinically important cardiac abnormality (Figure 2). Figure 2 View largeDownload slide mosaic plot depicting the proportion of associated cardiac abnormalities for each TR grade. TR, tricuspid regurgitation. Figure 2 View largeDownload slide mosaic plot depicting the proportion of associated cardiac abnormalities for each TR grade. TR, tricuspid regurgitation. In multivariable logistic regression analyses, PASP, RV dysfunction, moderate or severe MR, AF, hyponatremia, and blood urea nitrogen were independently associated with moderate or severe TR (Table 2). The c-statistic of the model was 0.81 (95% CI 0.77–0.84), indicating excellent discrimination. By multivariate analysis, PASP was most closely related to moderate or severe TR, with a standardized coefficient higher than RV dysfunction or AF (Table 2). Finally, a more parsimonious model that included only echocardiographic variables (PASP, RV function, LVEF, and MR) had a c-statistic of 0.77 (95% CI 0.73–0.81). Table 2 Multivariable logistic regression analysis of determinants of moderate or severe TR Variable Wald χ2 Adjusted OR (95% CI) P-value Standardized β-coefficienta PASP (per 10 mmHg increase) 58.7 1.68 (1.46–1.93) <0.0001 2.38 RV dysfunction 13.7 2.68 (1.74–4.13) <0.0001 1.43 Moderate–severe MR 6.6 1.93 (1.30–2.97) 0.001 1.27 Hyponatremia 7.9 1.72 (1.15–2.58) 0.008 1.30 LVEF <45% 7.1 1.73 (1.16–2.60) 0.008 1.32 Atrial fibrillation 19.3 2.15 (1.48–3.13) <0.0001 1.53 BUN (per 10 mg/dL increase) 7.3 1.15 (1.04–1.28) 0.007 1.30 Variable Wald χ2 Adjusted OR (95% CI) P-value Standardized β-coefficienta PASP (per 10 mmHg increase) 58.7 1.68 (1.46–1.93) <0.0001 2.38 RV dysfunction 13.7 2.68 (1.74–4.13) <0.0001 1.43 Moderate–severe MR 6.6 1.93 (1.30–2.97) 0.001 1.27 Hyponatremia 7.9 1.72 (1.15–2.58) 0.008 1.30 LVEF <45% 7.1 1.73 (1.16–2.60) 0.008 1.32 Atrial fibrillation 19.3 2.15 (1.48–3.13) <0.0001 1.53 BUN (per 10 mg/dL increase) 7.3 1.15 (1.04–1.28) 0.007 1.30 95% CI, 95% confidence interval; LVEF, left ventricular ejection fraction; PASP, pulmonary artery systolic pressure; RV, right ventricular. a The relative strength of the associations was expressed by the standardized coefficient. Table 2 Multivariable logistic regression analysis of determinants of moderate or severe TR Variable Wald χ2 Adjusted OR (95% CI) P-value Standardized β-coefficienta PASP (per 10 mmHg increase) 58.7 1.68 (1.46–1.93) <0.0001 2.38 RV dysfunction 13.7 2.68 (1.74–4.13) <0.0001 1.43 Moderate–severe MR 6.6 1.93 (1.30–2.97) 0.001 1.27 Hyponatremia 7.9 1.72 (1.15–2.58) 0.008 1.30 LVEF <45% 7.1 1.73 (1.16–2.60) 0.008 1.32 Atrial fibrillation 19.3 2.15 (1.48–3.13) <0.0001 1.53 BUN (per 10 mg/dL increase) 7.3 1.15 (1.04–1.28) 0.007 1.30 Variable Wald χ2 Adjusted OR (95% CI) P-value Standardized β-coefficienta PASP (per 10 mmHg increase) 58.7 1.68 (1.46–1.93) <0.0001 2.38 RV dysfunction 13.7 2.68 (1.74–4.13) <0.0001 1.43 Moderate–severe MR 6.6 1.93 (1.30–2.97) 0.001 1.27 Hyponatremia 7.9 1.72 (1.15–2.58) 0.008 1.30 LVEF <45% 7.1 1.73 (1.16–2.60) 0.008 1.32 Atrial fibrillation 19.3 2.15 (1.48–3.13) <0.0001 1.53 BUN (per 10 mg/dL increase) 7.3 1.15 (1.04–1.28) 0.007 1.30 95% CI, 95% confidence interval; LVEF, left ventricular ejection fraction; PASP, pulmonary artery systolic pressure; RV, right ventricular. a The relative strength of the associations was expressed by the standardized coefficient. Effect of TR on mortality and rehospitalization Patients were followed for up to 2 years after hospital discharge (median 19 months). During the follow-up period, 242 patients (34.1%) died and 174 (24.5%) were readmitted for HF. The Kaplan–Meier survival curves demonstrated similar outcome for patients with trivial or mild TR and for patients with moderate or severe TR (Figure 3). Further analyses therefore compared the effect of moderate and severe TR to mild and trivial TR. Figure 3 View largeDownload slide the Kaplan–Meier survival plot of mortality or readmission for HF in subgroups defined by TR severity (log-rank test P < 0.0001). HF, heart failure. Figure 3 View largeDownload slide the Kaplan–Meier survival plot of mortality or readmission for HF in subgroups defined by TR severity (log-rank test P < 0.0001). HF, heart failure. Table 3 (left panel) displays univariable predictors of readmission for HF and mortality. In the unadjusted analysis, moderate or severe TR was associated with the composite endpoint. However, after adjustments for baseline clinical characteristics, laboratory and echocardiographic variables, moderate or severe TR was no longer an independent predictor of readmission for HF and mortality (Table 3, right panel). Table 3 Cox’s proportional hazards model for mortality and readmission for heart failure according to TR severity Unadjusted Adjusted Characteristics HR (95% CI) P-value HR (95% CI) P-value Age (per 10 years increase) 1.11 (1.01–1.38) 0.003 1.11 (1.01–1.57) 0.04 Estimated GFR (per mL min−1/1.73 m−2) decrease 1.07 (1.02–1.07) 0.005 — — BUN (per 10 mg/dL increase) 1.11 (1.06–1.16) <0.0001 1.08 (1.02–1.14) 0.005 Anaemia 1.28 (1.01–1.63) 0.04 — — Elevated cTn I 1.45 (1.16–1.82) 0.001 1.35 (1.07–1.70) 0.01 Congestion at discharge 1.55 (1.16–2.09) 0.003 1.42 (1.05–1.92) 0.005 ln BNP (per 1-SD increase)a 1.26 (1.13–1.39) <0.0001 1.17 (1.05–1.92) 0.005 RV dysfunction 1.31 (1.13–1.39) 0.03 — — ln PASP (per 1-SD increase)a 1.27 (1.14–1.40) <0.0001 1.14 (1.05–1.92) 0.02 Moderate/severe TR 1.55 (1.24–1.93) <0.0001 1.24 (0.97–1.57) 0.09 Unadjusted Adjusted Characteristics HR (95% CI) P-value HR (95% CI) P-value Age (per 10 years increase) 1.11 (1.01–1.38) 0.003 1.11 (1.01–1.57) 0.04 Estimated GFR (per mL min−1/1.73 m−2) decrease 1.07 (1.02–1.07) 0.005 — — BUN (per 10 mg/dL increase) 1.11 (1.06–1.16) <0.0001 1.08 (1.02–1.14) 0.005 Anaemia 1.28 (1.01–1.63) 0.04 — — Elevated cTn I 1.45 (1.16–1.82) 0.001 1.35 (1.07–1.70) 0.01 Congestion at discharge 1.55 (1.16–2.09) 0.003 1.42 (1.05–1.92) 0.005 ln BNP (per 1-SD increase)a 1.26 (1.13–1.39) <0.0001 1.17 (1.05–1.92) 0.005 RV dysfunction 1.31 (1.13–1.39) 0.03 — — ln PASP (per 1-SD increase)a 1.27 (1.14–1.40) <0.0001 1.14 (1.05–1.92) 0.02 Moderate/severe TR 1.55 (1.24–1.93) <0.0001 1.24 (0.97–1.57) 0.09 95% CI, 95% confidence interval; BNP, brain natriuretic peptide; GFR, glomerular filtration rate; PASP, pulmonary artery systolic pressure; RV, right ventricular; SD, standard deviation. a Hazard ratio for a 1-SD increase on the ln-transformed scale (SD ln BNP = 0.52; SD ln PASP = 0.31). For a multiple of 1 SD, raise the hazard ratio in the table to the power of that multiple. Table 3 Cox’s proportional hazards model for mortality and readmission for heart failure according to TR severity Unadjusted Adjusted Characteristics HR (95% CI) P-value HR (95% CI) P-value Age (per 10 years increase) 1.11 (1.01–1.38) 0.003 1.11 (1.01–1.57) 0.04 Estimated GFR (per mL min−1/1.73 m−2) decrease 1.07 (1.02–1.07) 0.005 — — BUN (per 10 mg/dL increase) 1.11 (1.06–1.16) <0.0001 1.08 (1.02–1.14) 0.005 Anaemia 1.28 (1.01–1.63) 0.04 — — Elevated cTn I 1.45 (1.16–1.82) 0.001 1.35 (1.07–1.70) 0.01 Congestion at discharge 1.55 (1.16–2.09) 0.003 1.42 (1.05–1.92) 0.005 ln BNP (per 1-SD increase)a 1.26 (1.13–1.39) <0.0001 1.17 (1.05–1.92) 0.005 RV dysfunction 1.31 (1.13–1.39) 0.03 — — ln PASP (per 1-SD increase)a 1.27 (1.14–1.40) <0.0001 1.14 (1.05–1.92) 0.02 Moderate/severe TR 1.55 (1.24–1.93) <0.0001 1.24 (0.97–1.57) 0.09 Unadjusted Adjusted Characteristics HR (95% CI) P-value HR (95% CI) P-value Age (per 10 years increase) 1.11 (1.01–1.38) 0.003 1.11 (1.01–1.57) 0.04 Estimated GFR (per mL min−1/1.73 m−2) decrease 1.07 (1.02–1.07) 0.005 — — BUN (per 10 mg/dL increase) 1.11 (1.06–1.16) <0.0001 1.08 (1.02–1.14) 0.005 Anaemia 1.28 (1.01–1.63) 0.04 — — Elevated cTn I 1.45 (1.16–1.82) 0.001 1.35 (1.07–1.70) 0.01 Congestion at discharge 1.55 (1.16–2.09) 0.003 1.42 (1.05–1.92) 0.005 ln BNP (per 1-SD increase)a 1.26 (1.13–1.39) <0.0001 1.17 (1.05–1.92) 0.005 RV dysfunction 1.31 (1.13–1.39) 0.03 — — ln PASP (per 1-SD increase)a 1.27 (1.14–1.40) <0.0001 1.14 (1.05–1.92) 0.02 Moderate/severe TR 1.55 (1.24–1.93) <0.0001 1.24 (0.97–1.57) 0.09 95% CI, 95% confidence interval; BNP, brain natriuretic peptide; GFR, glomerular filtration rate; PASP, pulmonary artery systolic pressure; RV, right ventricular; SD, standard deviation. a Hazard ratio for a 1-SD increase on the ln-transformed scale (SD ln BNP = 0.52; SD ln PASP = 0.31). For a multiple of 1 SD, raise the hazard ratio in the table to the power of that multiple. To determine whether loading conditions may have confounded the study results (i.e. patients who were more congested were misclassified into the moderate or severe TR group), we tested whether the effect of TR on clinical outcomes varied with the time of TR assessment. This was done by comparing the effect of TR in patients in whom the echocardiographic evaluation was performed within 3 days from admission vs. patients with echocardiographic evaluation >3 days from admission. The proportion of moderate or severe TR was similar with echocardiographic assessment within or >3 days from admission (37.8 vs. 36.7%, P = 0.80). There was no interaction between the time of TR assessment and TR severity with regard to the risk of rehospitalization for HF or mortality (Pinteraction=0.34). In a stratified sensitivity analysis that included the 348 patients in whom the echocardiographic evaluation of TR severity was performed during the first 3 days after admission, results were comparable with the primary analyses, with similar strength of the predictors. Moderate or severe TR was not significantly associated with readmission for HF and mortality (HR 1.16, 95% CI 0.83–1.64, P = 0.38), whereas PASP (HR 1.18 per 1 SD increase in ln PASP; 95% CI 1.02–1.38, P = 0.028) remained significantly associated with readmission for HF and mortality. Similar results were seen in the subset of patients in whom the echocardiographic evaluation of TR severity was performed more than 3 days from admission (n = 291). Moderate or severe TR was not associated with clinical outcome (HR 1.17, 95% CI 0.81–1.69, P = 0.39), whereas PASP predicted increased readmission for HF and mortality (HR 1.21 per 1 SD increase in ln PASP; 95% CI 1.03–1.42, P = 0.021). Impact of concomitant PH on the association between FTR and clinical outcome Of the 639 patients with estimable PASP, 239 had moderate or severe TR, with 68 having no PH-associated TR (28%) and 171 having PH-FTR (72%). There was no significant difference between the two groups with regard to annular 4-Chamber diastolic diameter (4.0 ± 0.7 vs. 3.9 ± 0.6, P = 0.39), annular-4C systolic diameter (3.8 ± 0.6 vs. 3.7 ± 0.5, P = 0.71), tenting area (1.84 ± 1.23 vs. 1.57 ± 1.03, P = 0.11), and tenting height (0.86 ± 0.44 vs. 0.80 ± 0.40, P = 0.37). The clinical outcome of these two groups was compared with patient having trivial/mild TR with and without PH. Unadjusted rates of readmissions for HF and mortality in the four groups are shown in Figure 4. Event rates were lowest in patients without significant TR and without PH. There was a marked increase in the risk of HF or mortality in patients with both moderate–severe TR and PH, while patients with mild TR and PH had an intermediate risk. Notably, patients with moderate–severe TR but no PH were also at intermediate risk for readmission and mortality. Figure 4 View largeDownload slide the Kaplan–Meier survival plot of mortality or readmission for heart failure in subgroups defined by pulmonary hypertension and TR severity (log-rank test P < 0.0001). HF, heart failure; PH, pulmonary hypertension; TR, tricuspid regurgitation. Figure 4 View largeDownload slide the Kaplan–Meier survival plot of mortality or readmission for heart failure in subgroups defined by pulmonary hypertension and TR severity (log-rank test P < 0.0001). HF, heart failure; PH, pulmonary hypertension; TR, tricuspid regurgitation. In a Cox proportional hazards regression analysis, there was a significant interaction between TR severity and PH (Pinteraction = 0.03), such that after adjustments for other risk variables (Table 4), patients with moderate–severe TR without PH had similar outcome to that of patients with trivial/mild TR. The risk associated with moderate–severe TR appeared to be driven primarily by the presence of concomitant PH. Table 4 Cox’s proportional hazards model for mortality and readmission for heart failure according to TR and PH severity Unadjusted Adjusted Characteristics HR (95% CI) P-value HR (95% CI) P-value Trivial/mild TR—no PH 1.0 (Referent) 1.0 (Referent) Trivial/mild TR—PH 1.55 (1.16–2.08) 0.003 1.46 (1.09–1.96) 0.01 Moderate/severe TR—no PH 1.38 (0.93–2.05) 0.11 1.17 (0.78–1.75) 0.40 Moderate/severe TR—PH 2.08 (1.58–2.73) <0.0001 1.78 (1.34–2.36) <0.0001 Unadjusted Adjusted Characteristics HR (95% CI) P-value HR (95% CI) P-value Trivial/mild TR—no PH 1.0 (Referent) 1.0 (Referent) Trivial/mild TR—PH 1.55 (1.16–2.08) 0.003 1.46 (1.09–1.96) 0.01 Moderate/severe TR—no PH 1.38 (0.93–2.05) 0.11 1.17 (0.78–1.75) 0.40 Moderate/severe TR—PH 2.08 (1.58–2.73) <0.0001 1.78 (1.34–2.36) <0.0001 95% CI, 95% confidence interval; PH, pulmonary hypertension; TR, tricuspid regurgitation. Table 4 Cox’s proportional hazards model for mortality and readmission for heart failure according to TR and PH severity Unadjusted Adjusted Characteristics HR (95% CI) P-value HR (95% CI) P-value Trivial/mild TR—no PH 1.0 (Referent) 1.0 (Referent) Trivial/mild TR—PH 1.55 (1.16–2.08) 0.003 1.46 (1.09–1.96) 0.01 Moderate/severe TR—no PH 1.38 (0.93–2.05) 0.11 1.17 (0.78–1.75) 0.40 Moderate/severe TR—PH 2.08 (1.58–2.73) <0.0001 1.78 (1.34–2.36) <0.0001 Unadjusted Adjusted Characteristics HR (95% CI) P-value HR (95% CI) P-value Trivial/mild TR—no PH 1.0 (Referent) 1.0 (Referent) Trivial/mild TR—PH 1.55 (1.16–2.08) 0.003 1.46 (1.09–1.96) 0.01 Moderate/severe TR—no PH 1.38 (0.93–2.05) 0.11 1.17 (0.78–1.75) 0.40 Moderate/severe TR—PH 2.08 (1.58–2.73) <0.0001 1.78 (1.34–2.36) <0.0001 95% CI, 95% confidence interval; PH, pulmonary hypertension; TR, tricuspid regurgitation. Propensity score matching One-to-one matching on the propensity score yielded only 26 patient pairs. Before matching the standardized difference was highest for the PASP and RV function variables (Figure 5A). After propensity score matching, patients were well balanced with respect to the variables included in the propensity model (Figure 5A), with mean difference in paired propensity scores of 3.2%. Following propensity score matching, readmissions for HF and mortality were similar in patients with moderate/severe TR and trivial/mild TR (Figure 5B) with a HR of 1.0 (95% CI 0.49–2.06, P = 0.99). Figure 5 View largeDownload slide (A) covariable balance before (red circles) and after (blue circle) propensity score matching. The standardized differences after propensity matching (blue squares) are all within 10%. (B) The Kaplan–Meier survival plot of mortality or readmission for heart failure in matched patients by TR severity. AF, atrial fibrillation; BNP, brain natriuretic peptide; COPD, chronic obstructive pulmonary disease; eGFR, estimated glomerular filtration rate; HF, heart failure; LVEF, left ventricular ejection fraction; PASP, pulmonary artery systolic pressure; RV, right ventricular; TR, tricuspid regurgitation. Figure 5 View largeDownload slide (A) covariable balance before (red circles) and after (blue circle) propensity score matching. The standardized differences after propensity matching (blue squares) are all within 10%. (B) The Kaplan–Meier survival plot of mortality or readmission for heart failure in matched patients by TR severity. AF, atrial fibrillation; BNP, brain natriuretic peptide; COPD, chronic obstructive pulmonary disease; eGFR, estimated glomerular filtration rate; HF, heart failure; LVEF, left ventricular ejection fraction; PASP, pulmonary artery systolic pressure; RV, right ventricular; TR, tricuspid regurgitation. Discussion In the present study, we observed a high prevalence of haemodynamically significant TR in patients with acute HF. TR severity was associated with multiple clinical comorbidities and risk markers including worse renal function, higher BNP levels and congestion score, as well as with mitral regurgitation, AF, RV dysfunction, reduced LVEF, and PH. After careful adjustments for the associated clinical and echocardiographic variables, significant TR (moderate or severe) was associated with higher multivariable adjusted risk for readmission for HF or mortality only in the presence of concomitant PH. Previous studies described a strong impact of TR on clinical outcome in the settings of valvular heart disease especially after mitral valve intervention,10,12 and in isolated TR.17 However, only a paucity of studies with contradictory results are currently available with regard to the prognostic significance of TR in the setting of overt HF. Two studies reported increased mortality in patients with moderate and severe TR.18,19 However, in both studies TR was not considered along with other known predictors of survival like PH. In addition, these studies lacked information on symptoms, biomarkers, and kidney function. In a more recent study, Neuhold et al.2 reported that the prognostic impact of FTR in chronic HF was significantly associated with excess mortality only in mildly or moderately reduced LV function with no additive value in more advanced disease. In contrast to these previous studies, our study population was confined to patients with symptomatic HF requiring hospitalization. There is an inherent difficulty to determine the haemodynamic consequences and clinical outcome of TR due to multiple associated comorbidities, especially in the setting of HF. In the present study, only ∼7% of the patients with moderate or severe TR were free of other important cardiac abnormalities (MR, reduced LVEF, PH, or RV dysfunction). Propensity matching procedure could match <10% of patients owing to the marked baseline differences. Although the small number of matched patients precludes us from drawing conclusions from this analysis, it demonstrates the pitfalls of comparing patients with moderate/severe TR to those with trivial/mild TR. The strong relationship between increasing TR severity and important cardiac comorbidities, contributes to the current uncertainties regarding the clinical significance and surgical management of TR, especially in the presence of severe RV or LV dysfunction, or severe PH.20 Two major forms of FTR have recently been proposed: (i) FTR that is strongly associated with aging and AF.4,7 This variant appears to result predominantly from annular enlargement leading to exhaustion of annular coverage reserve.4 (ii) PH-associated FTR which entails mainly valvular tethering with tenting and reduced coaptation,4 but can also be associated with annular dilatation6 which further contributes to increased tenting area. In the present study of patients with overt HF, there was a large overlap in annular size and tenting parameters between patients with and without PH, presumably because leaflet tethering can occur as a consequence of both RV remodelling and TV annular dilatation (coexisting PH and AF),21 and because annular dilatation can also be associated with PH.6 Although PH is not a necessary prerequisite for the development of secondary TR,1 it remains a major mechanism for TR progression, especially in patients with HF, in whom pulmonary pressure is frequently elevated and tends to increase with disease progression.7 The present study shows that the most powerful modulator of the association between TR and clinical outcome was PASP, and that PH-associated FTR portends a higher risk for readmission for HF and mortality. The present study demonstrates the inextricable link between TR severity, RV function, and PH. PASP and RV dysfunction were two key factors strongly associated with moderate or severe TR (Table 2). Most patients with moderate or severe TR had PH, and RV dysfunction was present in 31% and 55% of patients with moderate and severe TR, respectively. However, RV dysfunction was not independently associated with readmission for HF or mortality. Collectively, these data suggest that the RV volume overload alone induced by TR may be insufficient to meaningfully alter the clinical outcome. However, when volume overload is superimposed on pre-existing pressure overload, the risk for readmission for HF and mortality increases. These data reinforce the key role of PH in the pathophysiology and progression of TR in patients with HF.7 Beyond its association with cardiac abnormalities, TR was also associated with reduced renal function, greater congestion, and higher BNP levels. The association between haemodynamically significant TR and renal dysfunction has been ascribed to higher central and renal venous pressure, leading to reduced renal perfusion pressure.22 Clinical implications FTR frequently accompanies advanced stage of HF, regardless of aetiology,2 and progression to significant TR in contemporary patients is frequently not related to left-sided valvular disease.7 Therefore, an appropriate interpretation of the clinical significance of FTR in the context of patients with symptomatic HF is warranted. In the absence of other indications for cardiac surgery, current guideline consider patient with severe TR and congestive signs directly related to the TR and progressive RV dysfunction as candidates for surgery.8,20 Recent previous studies suggest that severe isolated TR adversely affects clinical outcome,17 and that TV replacement may be beneficial when performed in patients with mild or no HF.23 However, as shown in the present study, it would be difficult to view severe TR as the predominant culprit of adverse clinical outcome in the majority of patients with overt HF and fluid overload. The TR-specific impact on outcome is difficult to extricate but was not significant in the present study. Study limitations This study has limitations that need be acknowledged. The study is a single-centre study. TR severity was not assessed using quantitative methods. Quantitative methods for TR estimation have their limitations and are not widely practiced.3 As in previous studies,1,2,5–7 using a semiquantitative approach, we were able to define groups with distinct clinical presentation and echocardiographic parameters that attest to the validity of our methods. Because of the bidirectional link between congestion and TR, fluid overload secondary to worsening HF may lead to overestimation of the true TR severity. Conclusion Patients presenting with HF and significant FTR have multiple coexisting cardiac abnormalities. The impact of FTR on the clinical outcome in HF patients depends on the severity of PH. In patient with symptomatic HF, FTR provides no additive risk in the presence of normal or mildly elevated pulmonary pressures. However, it is associated with excess rehospitalizations and mortality in patients with PH. References 1 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 . Google Scholar CrossRef Search ADS PubMed 2 Neuhold S , Huelsmann M , Pernicka E , Graf A , Bonderman D , Adlbrecht C et al. Impact of tricuspid regurgitation on survival in patients with chronic heart failure: unexpected findings of a long-term observational study . Eur Heart J 2013 ; 34 : 844 – 52 . Google Scholar CrossRef Search ADS PubMed 3 Lancellotti P , Tribouilloy C , Hagendorff A , Popescu BA , Edvardsen T , Pierard LA et al. Recommendations for the echocardiographic assessment of native valvular regurgitation: an executive summary from the European Association of Cardiovascular Imaging . Eur Heart J Cardiovasc Imaging 2013 ; 14 : 611 – 44 . Google Scholar CrossRef Search ADS PubMed 4 Topilsky Y , Khanna A , Le Tourneau T , Park S , Michelena H , Suri R et al. Clinical context and mechanism of functional tricuspid regurgitation in patients with and without pulmonary hypertension . Circ Cardiovasc Imaging 2012 ; 5 : 314 – 23 . Google Scholar CrossRef Search ADS PubMed 5 Mutlak D , Aronson D , Lessick J , Reisner SA , Dabbah S , Agmon Y. Functional tricuspid regurgitation in patients with pulmonary hypertension: is pulmonary artery pressure the only determinant of regurgitation severity? Chest 2009 ; 135 : 115 – 21 . Google Scholar CrossRef Search ADS PubMed 6 Medvedofsky D , Aronson D , Gomberg-Maitland M , Thomeas V , Rich S , Spencer K et al. Tricuspid regurgitation progression and regression in pulmonary arterial hypertension: implications for right ventricular and tricuspid valve apparatus geometry and patients outcome . Eur Heart J Cardiovasc Imaging 2017 ; 18 : 86 – 94 . Google Scholar CrossRef Search ADS PubMed 7 Shiran A , Najjar R , Adawi S , Aronson D. Risk factors for progression of functional tricuspid regurgitation . Am J Cardiol 2014 ; 113 : 995 – 1000 . Google Scholar CrossRef Search ADS PubMed 8 Badano LP , Muraru D , Enriquez-Sarano M. Assessment of functional tricuspid regurgitation . Eur Heart J 2013 ; 34 : 1875 – 85 . Google Scholar CrossRef Search ADS PubMed 9 Fukuda S , Gillinov AM , McCarthy PM , Stewart WJ , Song JM , Kihara T et al. Determinants of recurrent or residual functional tricuspid regurgitation after tricuspid annuloplasty . Circulation 2006 ; 114 :I582–587. 10 Sagie A , Schwammenthal E , Newell JB , Harrell L , Joziatis TB , Weyman AE et al. Significant tricuspid regurgitation is a marker for adverse outcome in patients undergoing percutaneous balloon mitral valvuloplasty . J Am Coll Cardiol 1994 ; 24 : 696 – 702 . Google Scholar CrossRef Search ADS PubMed 11 Shiran A , Sagie A. Tricuspid regurgitation in mitral valve disease incidence, prognostic implications, mechanism, and management . J Am Coll Cardiol 2009 ; 53 : 401 – 8 . Google Scholar CrossRef Search ADS PubMed 12 Vargas Abello LM , Klein AL , Marwick TH , Nowicki ER , Rajeswaran J , Puwanant S et al. Understanding right ventricular dysfunction and functional tricuspid regurgitation accompanying mitral valve disease . J Thorac Cardiovasc Surg 2013 ; 145 :1234–41. e1235. 13 Aronson D , Darawsha W , Atamna A , Kaplan M , Makhoul BF , Mutlak D et al. Pulmonary hypertension, right ventricular function, and clinical outcome in acute decompensated heart failure . J Card Fail 2013 ; 19 : 665 – 71 . Google Scholar CrossRef Search ADS PubMed 14 Darawsha W , Chirmicci S , Solomonica A , Wattad M , Kaplan M , Makhoul BF et al. Discordance between hemoconcentration and clinical assessment of decongestion in acute heart failure . J Card Fail 2016 ; 22 : 680 – 8 . Google Scholar CrossRef Search ADS PubMed 15 Mutlak D , Carasso S , Lessick J , Aronson D , Reisner SA , Agmon Y. Excessive respiratory variation in tricuspid regurgitation systolic velocities in patients with severe tricuspid regurgitation . Eur Heart J Cardiovasc Imaging 2013 ; 14 : 957 – 62 . Google Scholar CrossRef Search ADS PubMed 16 Shahar K , Darawsha W , Yalonetsky S , Lessick J , Kapeliovich M , Dragu R et al. Time dependence of the effect of right ventricular dysfunction on clinical outcomes after myocardial infarction: role of pulmonary hypertension . J Am Heart Assoc 2016 ; 5 : e003606 . Google Scholar CrossRef Search ADS PubMed 17 Topilsky Y , Nkomo VT , Vatury O , Michelena HI , Letourneau T , Suri RM et al. Clinical outcome of isolated tricuspid regurgitation . JACC Cardiovasc Imaging 2014 ; 7 : 1185 – 94 . Google Scholar CrossRef Search ADS PubMed 18 Hung J , Koelling T , Semigran MJ , Dec GW , Levine RA , Di Salvo TG. Usefulness of echocardiographic determined tricuspid regurgitation in predicting event-free survival in severe heart failure secondary to idiopathic-dilated cardiomyopathy or to ischemic cardiomyopathy . Am J Cardiol 1998 ; 82 : 1301 – 3 . A1310. Google Scholar CrossRef Search ADS PubMed 19 Koelling TM , Aaronson KD , Cody RJ , Bach DS , Armstrong WF. Prognostic significance of mitral regurgitation and tricuspid regurgitation in patients with left ventricular systolic dysfunction . Am Heart J 2002 ; 144 : 524 – 9 . Google Scholar CrossRef Search ADS PubMed 20 Vahanian A , Alfieri O , Andreotti F , Antunes MJ , Baron-Esquivias G , Baumgartner H et al. Guidelines on the management of valvular heart disease (version 2012) . Eur Heart J 2012 ; 33 : 2451 – 96 . Google Scholar CrossRef Search ADS PubMed 21 Ubago JL , Figueroa A , Ochoteco A , Colman T , Duran RM , Duran CG. Analysis of the amount of tricuspid valve anular dilatation required to produce functional tricuspid regurgitation . Am J Cardiol 1983 ; 52 : 155 – 8 . Google Scholar CrossRef Search ADS PubMed 22 Maeder MT , Holst DP , Kaye DM. Tricuspid regurgitation contributes to renal dysfunction in patients with heart failure . J Card Fail 2008 ; 14 : 824 – 30 . Google Scholar CrossRef Search ADS PubMed 23 Topilsky Y , Khanna AD , Oh JK , Nishimura RA , Enriquez-Sarano M , Jeon YB et al. Preoperative factors associated with adverse outcome after tricuspid valve replacement . Circulation 2011 ; 123 : 1929 – 39 . Google Scholar CrossRef Search ADS PubMed Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2018. For permissions, please email: journals.permissions@oup.com. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png European Heart Journal – Cardiovascular Imaging Oxford University Press

Tricuspid regurgitation in acute heart failure: is there any incremental risk?

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Oxford University Press
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2018. For permissions, please email: journals.permissions@oup.com.
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2047-2404
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10.1093/ehjci/jex343
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Abstract

Abstract Aim Significant tricuspid regurgitation (TR) is common in heart failure (HF) and portends poor prognosis. We sought to determine whether the poor outcome results from the TR itself, or whether the TR is a surrogate marker of advanced left-sided myocardial or valvular heart disease. Methods and results We studied 639 patients admitted for acute HF. The relationship between TR severity and the endpoint of readmission for HF or mortality was assessed after adjustment for multiple clinical and echocardiographic parameters. Higher TR grade was associated with higher congestion score and with other cardiac abnormalities including reduced left ventricular systolic function, moderate or severe mitral regurgitation, pulmonary hypertension (PH, defined as pulmonary artery systolic pressure ≥ 50 mmHg), and right ventricular dysfunction (all P < 0.001). Only 7% of patients with moderate or severe TR were free of other cardiac lesions. In adjusted models, moderate or severe TR was not associated with readmission for HF or mortality [hazard ratio (HR) 1.24, 95% confidence interval (95% CI) 0.97–1.57]. Patients with moderate/severe TR had similar risk for HF readmission or death compared with patients with trivial/mild TR when PH was not present (HR 1.17; 95% CI 0.78–1.75, P = 0.40) whereas the risk was higher in moderate/severe TR and PH (HR 1.78; 95% CI 1.34–2.36, P < 0.0001). Conclusion Patients presenting with symptomatic HF and significant TR have multiple coexisting cardiac abnormalities. TR provides no additive risk in the presence of normal or mildly elevated pulmonary pressures. However, it is associated with excess rehospitalizations and mortality in patients with PH. heart failure, pulmonary hypertension, functional tricuspid regurgitation Introduction Epidemiological studies have shown a high prevalence of tricuspid regurgitation (TR) in the general population1 and particularly in patients with left-sided heart disease2 or pulmonary hypertension (PH).3 Secondary or functional TR (FTR), the most frequent form of TR, occurs in 70–85% of patients. FTR is characterized by structurally normal tricuspid leaflets and caused by tricuspid annular dilatation and increased tricuspid leaflet tethering due to right ventricular (RV) remodelling, which is often due to left heart failure (HF) from myocardial or valvular causes and associated PH.4–6 Two major risk factors for FTR progression have been described; an increase in pulmonary artery systolic pressure (PASP) and atrial fibrillation (AF).7 Increase in PASP may lead to RV remodelling (both increase in volumes and change in geometry), which in turn leads to tricuspid valve (TV) leaflets tethering,4,8,9 whereas AF promotes atrial dilatation, which in turn lead to TV annular dilatation and remodelling. The prognostic role of TR associated with organic left-sided valvular heart disease is well known.10–12 However, the value of FTR in outcome stratification and the incremental prognostic significance of FTR in patients with HF are less clear. This is particularly true in patients with overt HF,2 where multiple coexisting comorbidities interact with the effect of FTR. Indeed, the complex relationship between FTR and PH and RV function is likely to affect the final clinical outcome, suggesting that these associated prognostic determinants of HF might explain the increased mortality associated with TR. Therefore, we sought to study the prognostic implications and clinical correlates of FTR in patients with acute decompensated HF (ADHF). Methods Between January 2008 and April 2015, all patients admitted to the Rambam Medical Center, Haifa, Israel with the primary diagnosis of ADHF entered a prospective registry.13 Eligible patients were those hospitalized with new-onset or worsening of pre-existing HF as the primary cause of admission. ADHF was diagnosed according to the European Society of Cardiology criteria including a brain natriuretic peptide (BNP) level > 400 pg/mL. The study was performed in accordance with the Declaration of Helsinki and approved by the institutional review committee on human research. Congestion score Assessment of congestion at hospital admission was done by the treating physician. The degree of congestion was evaluated based on a combination of several signs and symptoms as previously described.14 A composite congestion score was calculated by summing the individual scores at the time of admission and discharge (range 0–8). Echocardiographic evaluation All patients had an echocardiographic examination performed during hospital stay or within a period of 30 days prior or after the day of admission [median 2 days, interquartile range (IQR) 1–4 days]. PASP was estimated from clearly defined TR signal by continuous-wave Doppler and inferior vena cava size and respiratory variation using established criteria, as previously described.15 PH was defined using the cut-off of PASP ≥ 50 mmHg.13 TR was quantified by an integrated approach.3 First, TR was graded qualitatively using color Doppler flow mapping as follows: trivial TR (jet area ≤1.0 cm2), mild (jet area 1–5 cm2), moderate (jet area 5–10 cm2), and severe (jet area >10 cm2).8 When more than mild TR was present, severity was determined by integrating data from the following parameters: TV morphology (flail/large coaptation defect); vena contracta width when feasible (≥7 mm denoting severe TR); presence and degree of malcoaptation of the TV leaflets; tenting distance; presence of mid-to-late systolic flow reversal in the hepatic veins, and evaluation of right heart chambers.1,3,8,15 RV function was assessed qualitatively by integrating visual assessment of the contractility of the RV walls from different views and classified on an ordinal scale (normal or mildly, moderately, or severely reduced) and quantitatively by calculating the RV fractional area change, with a value <35% defined as abnormal, as previously described.5,13,16 RV dysfunction was considered to be present if at least mild systolic dysfunction was observed. The agreement in the assessment of RV function between echo readers was high (Cohen’s Kappa 0.82, 95% CI 0.67–0.97). To determine whether the type of FTR affects clinical outcome, patient with moderate or severe FTR were further divided into two subgroups based on the presence or absence of PH. Patients with PASP < 50 mmHg were labelled as non-PH related FTR (non-PH FTR) and patients with PASP ≥ 50 mm Hg as PH-FTR. Study endpoint The primary endpoint of the study was the composite of readmission for HF and mortality after hospital discharge. Following hospital discharge, clinical endpoint information was acquired by reviewing the national death registry and by reviewing the hospital records for major clinical events if the patient had been re-hospitalized. Statistical analysis Continuous variables are presented as mean ± standard deviation (SD) or medians (with IQR), and categorical variables as numbers and percentages. Baseline characteristics of the groups were compared using analysis of variance (ANOVA) for continuous variables and by the χ2 statistic for non-continuous variables. The association between moderate or severe TR and other echocardiographic or clinical parameters was determined by fitting logistic regression model. Odds ratios were calculated with their 95% confidence intervals (CIs), and the relative strength of the associations was expressed by the standardized coefficient to compare effect estimates. Survival curves were constructed for the TR categories using the Kaplan–Meier method. Stepwise Cox proportional hazards models with backward selection were used to calculate hazard ratios (HRs) and 95% CI for the TR categories. The multivariable Cox regression was adjusted for clinical, laboratory, and echocardiographic variables listed in Table 1 and the congestion score. Table 1 Baseline clinical characteristics according to the severity of tricuspid regurgitation Tricuspid regurgitation grade Characteristics Trivial (n = 133) Mild (n = 334) Moderate (n = 167) Severe (n = 75) P-value Age (years) 72 ± 13 76 ± 11 76 ± 12 74 ± 12 0.12 Female gender 57 (13) 161 (49) 89 (53) 46 (61) 0.06 hypertension 111 (83) 294 (88) 130 (79) 64 (85) 0.02 Diabetes mellitus 75 (56) 159 (48) 75 (45) 49 (65) 0.009 Chronic lung disease 28 (21) 43 (13) 31 (19) 9 (12) 0.08 Coronary artery disease 88 (66) 183 (55) 99 (59) 51 (68) 0.05 Atrial fibrillation 35 (27) 133 (40) 84 (50) 45 (60) <0.0001 Creatinine (mg/dL) 1.2 (1.0–1.7) 1.2 (1.0–1.6) 1.3 (1.0–1.7) 1.4 (1.0–1.8) 0.25 eGFR (mL min−1/1.73 m−2) 53 (36–73) 52 (38–66) 47 (34–64) 44 (31–61) 0.047 BUN (mg/dL) 27 (19–37) 24 (18–35) 29 (20–42) 32 (22–49) 0.0001 Serum sodium (mmol/L) 137 ± 5 138 ± 4 136 ± 6 137 ± 6 0.41 Aspartate transaminase (IU/L) 23 (17–36) 24 (20–37) 26 (19–41) 25 (21–33) 0.61 Alanine transaminase (IU/L) 36 (26–47) 35 (27–45) 36 (26–54) 30 (27–37) 0.12 γ-Glutamyl transferase (IU/L) 53 (30–85) 52 (33–100) 84 (38–147) 117 (62–215) 0.0001 Alkaline phosphatase (IU/L) 83 (68–115) 88 (72–114) 95 (71–142) 131 (83–168) 0.0002 Haemoglobin (g/dL) 11.7 ± 2.1 11.6 ± 2.0 11.7 ± 1.9 11.3 ± 2.0 0.58 Haematocrit (%) 36 ± 6 35 ± 6 36 ± 6 35 ± 6 0.72 BNP (ng/mL) 803 (616–1140) 851 (603–1143) 1049 (687–1631) 1119 (647–2065) 0.002 cTn I elevation (%) 42 (32) 126 (38) 65 (39) 26 (35) 0.55 Moderate/severe mitral regurgitation 19 (15) 77 (23) 66 (40) 30 (40) <0.0001 LVEF (%) 47 ± 17 49 ± 18 43 ± 20 47 ± 20 0.004 Right ventricular dysfunction 11 (8) 52 (16) 52 (31) 41 (55) <0.0001 PASP (mmHg)a 36 (30–44) 45 (40–56) 58 (48–68) 60 (52–70) <0.0001 TR parameters  Tenting area 1.4 ± 1.0 2.0 ± 0.9 0.0002  Tenting height 0.8 ± 0.4 1.1 ± 0.4 <0.001  Annular-4C diastolic diameter 3.9 ± 0.6 4.4 ± 0.5 <0.0001  Annular-4C systolic diameter 3.7 ± 0.5 4.0 ± 0.5 0.0007 Medications  Beta blockers 93 (70) 251 (75) 132 (78) 63 (84) 0.10  ACE inhibitors/ARBs 89 (67) 220 (66) 104 (62) 45 (60) 0.65  Spironolactone 25 (19) 60 (18) 47 (28) 22 (29) 0.02  Digoxin 9 (7) 22 (7) 12 (7) 8 (11) 0.67 Tricuspid regurgitation grade Characteristics Trivial (n = 133) Mild (n = 334) Moderate (n = 167) Severe (n = 75) P-value Age (years) 72 ± 13 76 ± 11 76 ± 12 74 ± 12 0.12 Female gender 57 (13) 161 (49) 89 (53) 46 (61) 0.06 hypertension 111 (83) 294 (88) 130 (79) 64 (85) 0.02 Diabetes mellitus 75 (56) 159 (48) 75 (45) 49 (65) 0.009 Chronic lung disease 28 (21) 43 (13) 31 (19) 9 (12) 0.08 Coronary artery disease 88 (66) 183 (55) 99 (59) 51 (68) 0.05 Atrial fibrillation 35 (27) 133 (40) 84 (50) 45 (60) <0.0001 Creatinine (mg/dL) 1.2 (1.0–1.7) 1.2 (1.0–1.6) 1.3 (1.0–1.7) 1.4 (1.0–1.8) 0.25 eGFR (mL min−1/1.73 m−2) 53 (36–73) 52 (38–66) 47 (34–64) 44 (31–61) 0.047 BUN (mg/dL) 27 (19–37) 24 (18–35) 29 (20–42) 32 (22–49) 0.0001 Serum sodium (mmol/L) 137 ± 5 138 ± 4 136 ± 6 137 ± 6 0.41 Aspartate transaminase (IU/L) 23 (17–36) 24 (20–37) 26 (19–41) 25 (21–33) 0.61 Alanine transaminase (IU/L) 36 (26–47) 35 (27–45) 36 (26–54) 30 (27–37) 0.12 γ-Glutamyl transferase (IU/L) 53 (30–85) 52 (33–100) 84 (38–147) 117 (62–215) 0.0001 Alkaline phosphatase (IU/L) 83 (68–115) 88 (72–114) 95 (71–142) 131 (83–168) 0.0002 Haemoglobin (g/dL) 11.7 ± 2.1 11.6 ± 2.0 11.7 ± 1.9 11.3 ± 2.0 0.58 Haematocrit (%) 36 ± 6 35 ± 6 36 ± 6 35 ± 6 0.72 BNP (ng/mL) 803 (616–1140) 851 (603–1143) 1049 (687–1631) 1119 (647–2065) 0.002 cTn I elevation (%) 42 (32) 126 (38) 65 (39) 26 (35) 0.55 Moderate/severe mitral regurgitation 19 (15) 77 (23) 66 (40) 30 (40) <0.0001 LVEF (%) 47 ± 17 49 ± 18 43 ± 20 47 ± 20 0.004 Right ventricular dysfunction 11 (8) 52 (16) 52 (31) 41 (55) <0.0001 PASP (mmHg)a 36 (30–44) 45 (40–56) 58 (48–68) 60 (52–70) <0.0001 TR parameters  Tenting area 1.4 ± 1.0 2.0 ± 0.9 0.0002  Tenting height 0.8 ± 0.4 1.1 ± 0.4 <0.001  Annular-4C diastolic diameter 3.9 ± 0.6 4.4 ± 0.5 <0.0001  Annular-4C systolic diameter 3.7 ± 0.5 4.0 ± 0.5 0.0007 Medications  Beta blockers 93 (70) 251 (75) 132 (78) 63 (84) 0.10  ACE inhibitors/ARBs 89 (67) 220 (66) 104 (62) 45 (60) 0.65  Spironolactone 25 (19) 60 (18) 47 (28) 22 (29) 0.02  Digoxin 9 (7) 22 (7) 12 (7) 8 (11) 0.67 ACE, angiotensin converting enzyme; ARB, angiotensin receptor blockers; BNP, brain natriuretic peptide; eGFR, estimated glomerular filtration rate; LVEF, left ventricular ejection fraction; PASP, pulmonary artery systolic pressure; TR, tricuspid regurgitation. a Data of 639 patients with estimable PASP. Table 1 Baseline clinical characteristics according to the severity of tricuspid regurgitation Tricuspid regurgitation grade Characteristics Trivial (n = 133) Mild (n = 334) Moderate (n = 167) Severe (n = 75) P-value Age (years) 72 ± 13 76 ± 11 76 ± 12 74 ± 12 0.12 Female gender 57 (13) 161 (49) 89 (53) 46 (61) 0.06 hypertension 111 (83) 294 (88) 130 (79) 64 (85) 0.02 Diabetes mellitus 75 (56) 159 (48) 75 (45) 49 (65) 0.009 Chronic lung disease 28 (21) 43 (13) 31 (19) 9 (12) 0.08 Coronary artery disease 88 (66) 183 (55) 99 (59) 51 (68) 0.05 Atrial fibrillation 35 (27) 133 (40) 84 (50) 45 (60) <0.0001 Creatinine (mg/dL) 1.2 (1.0–1.7) 1.2 (1.0–1.6) 1.3 (1.0–1.7) 1.4 (1.0–1.8) 0.25 eGFR (mL min−1/1.73 m−2) 53 (36–73) 52 (38–66) 47 (34–64) 44 (31–61) 0.047 BUN (mg/dL) 27 (19–37) 24 (18–35) 29 (20–42) 32 (22–49) 0.0001 Serum sodium (mmol/L) 137 ± 5 138 ± 4 136 ± 6 137 ± 6 0.41 Aspartate transaminase (IU/L) 23 (17–36) 24 (20–37) 26 (19–41) 25 (21–33) 0.61 Alanine transaminase (IU/L) 36 (26–47) 35 (27–45) 36 (26–54) 30 (27–37) 0.12 γ-Glutamyl transferase (IU/L) 53 (30–85) 52 (33–100) 84 (38–147) 117 (62–215) 0.0001 Alkaline phosphatase (IU/L) 83 (68–115) 88 (72–114) 95 (71–142) 131 (83–168) 0.0002 Haemoglobin (g/dL) 11.7 ± 2.1 11.6 ± 2.0 11.7 ± 1.9 11.3 ± 2.0 0.58 Haematocrit (%) 36 ± 6 35 ± 6 36 ± 6 35 ± 6 0.72 BNP (ng/mL) 803 (616–1140) 851 (603–1143) 1049 (687–1631) 1119 (647–2065) 0.002 cTn I elevation (%) 42 (32) 126 (38) 65 (39) 26 (35) 0.55 Moderate/severe mitral regurgitation 19 (15) 77 (23) 66 (40) 30 (40) <0.0001 LVEF (%) 47 ± 17 49 ± 18 43 ± 20 47 ± 20 0.004 Right ventricular dysfunction 11 (8) 52 (16) 52 (31) 41 (55) <0.0001 PASP (mmHg)a 36 (30–44) 45 (40–56) 58 (48–68) 60 (52–70) <0.0001 TR parameters  Tenting area 1.4 ± 1.0 2.0 ± 0.9 0.0002  Tenting height 0.8 ± 0.4 1.1 ± 0.4 <0.001  Annular-4C diastolic diameter 3.9 ± 0.6 4.4 ± 0.5 <0.0001  Annular-4C systolic diameter 3.7 ± 0.5 4.0 ± 0.5 0.0007 Medications  Beta blockers 93 (70) 251 (75) 132 (78) 63 (84) 0.10  ACE inhibitors/ARBs 89 (67) 220 (66) 104 (62) 45 (60) 0.65  Spironolactone 25 (19) 60 (18) 47 (28) 22 (29) 0.02  Digoxin 9 (7) 22 (7) 12 (7) 8 (11) 0.67 Tricuspid regurgitation grade Characteristics Trivial (n = 133) Mild (n = 334) Moderate (n = 167) Severe (n = 75) P-value Age (years) 72 ± 13 76 ± 11 76 ± 12 74 ± 12 0.12 Female gender 57 (13) 161 (49) 89 (53) 46 (61) 0.06 hypertension 111 (83) 294 (88) 130 (79) 64 (85) 0.02 Diabetes mellitus 75 (56) 159 (48) 75 (45) 49 (65) 0.009 Chronic lung disease 28 (21) 43 (13) 31 (19) 9 (12) 0.08 Coronary artery disease 88 (66) 183 (55) 99 (59) 51 (68) 0.05 Atrial fibrillation 35 (27) 133 (40) 84 (50) 45 (60) <0.0001 Creatinine (mg/dL) 1.2 (1.0–1.7) 1.2 (1.0–1.6) 1.3 (1.0–1.7) 1.4 (1.0–1.8) 0.25 eGFR (mL min−1/1.73 m−2) 53 (36–73) 52 (38–66) 47 (34–64) 44 (31–61) 0.047 BUN (mg/dL) 27 (19–37) 24 (18–35) 29 (20–42) 32 (22–49) 0.0001 Serum sodium (mmol/L) 137 ± 5 138 ± 4 136 ± 6 137 ± 6 0.41 Aspartate transaminase (IU/L) 23 (17–36) 24 (20–37) 26 (19–41) 25 (21–33) 0.61 Alanine transaminase (IU/L) 36 (26–47) 35 (27–45) 36 (26–54) 30 (27–37) 0.12 γ-Glutamyl transferase (IU/L) 53 (30–85) 52 (33–100) 84 (38–147) 117 (62–215) 0.0001 Alkaline phosphatase (IU/L) 83 (68–115) 88 (72–114) 95 (71–142) 131 (83–168) 0.0002 Haemoglobin (g/dL) 11.7 ± 2.1 11.6 ± 2.0 11.7 ± 1.9 11.3 ± 2.0 0.58 Haematocrit (%) 36 ± 6 35 ± 6 36 ± 6 35 ± 6 0.72 BNP (ng/mL) 803 (616–1140) 851 (603–1143) 1049 (687–1631) 1119 (647–2065) 0.002 cTn I elevation (%) 42 (32) 126 (38) 65 (39) 26 (35) 0.55 Moderate/severe mitral regurgitation 19 (15) 77 (23) 66 (40) 30 (40) <0.0001 LVEF (%) 47 ± 17 49 ± 18 43 ± 20 47 ± 20 0.004 Right ventricular dysfunction 11 (8) 52 (16) 52 (31) 41 (55) <0.0001 PASP (mmHg)a 36 (30–44) 45 (40–56) 58 (48–68) 60 (52–70) <0.0001 TR parameters  Tenting area 1.4 ± 1.0 2.0 ± 0.9 0.0002  Tenting height 0.8 ± 0.4 1.1 ± 0.4 <0.001  Annular-4C diastolic diameter 3.9 ± 0.6 4.4 ± 0.5 <0.0001  Annular-4C systolic diameter 3.7 ± 0.5 4.0 ± 0.5 0.0007 Medications  Beta blockers 93 (70) 251 (75) 132 (78) 63 (84) 0.10  ACE inhibitors/ARBs 89 (67) 220 (66) 104 (62) 45 (60) 0.65  Spironolactone 25 (19) 60 (18) 47 (28) 22 (29) 0.02  Digoxin 9 (7) 22 (7) 12 (7) 8 (11) 0.67 ACE, angiotensin converting enzyme; ARB, angiotensin receptor blockers; BNP, brain natriuretic peptide; eGFR, estimated glomerular filtration rate; LVEF, left ventricular ejection fraction; PASP, pulmonary artery systolic pressure; TR, tricuspid regurgitation. a Data of 639 patients with estimable PASP. Survival analyses were also performed to determine whether the type of FTR affects clinical outcome beyond TR severity. Because in previous studies2 and the present study the outcome of patients with trivial and mild TR was similar and moderate and severe TR was also similar, these TR categories were combined into two groups (trivial/mild and moderate/severe TR) and further classified into those with or without PH. The existence of an interaction between TR severity and PH was assessed using a Cox proportional hazards regression model incorporating terms for the main effect of TR severity, the main effect of PH, and the interaction between TR severity and PH. Because the echocardiographic and clinical characteristics of patients with trivial/mild TR differed markedly from those with moderate/severe TR, propensity score estimates representing the probability of a patient being in the moderate/severe TR were generated using a non-parsimonious multiple logistic regression model derived from echocardiographic and clinical variables. Following propensity score generation, patients were matched by using 1:1 nearest neighbour (Greedy-type) matching without replacement and a calliper width of a 0.2 SD of the propensity score logit. We assessed the success of the matches by examining standardized differences (measured in percentage points) in the observed confounders between the matched trivial/mild TR and moderate/severe TR groups. Small (<10%) standardized differences support the assumption of balance between groups based on observed confounders. Following the matching procedure, Cox proportional hazards model accounting for frailty effects within matched pairs (to account for dependence among matched subjects) was used to assess the risk of the primary endpoint for patients with trivial/mild FTR vs. moderate/severe FTR. Differences were considered statistically significant at the two-sided P < 0.05 level. Statistical analyses were performed using STATA Version 13.1 (College Station, TX, USA). Results During the study period, 709 patients who met the inclusion criteria were recruited. Moderate or severe TR was observed in 242 patients (34%) and trivial or mild TR in 467 patients (66%). PASP could be estimated in 639 patients (90%). Demographic and clinical characteristics of the 709 patients with TR data are shown in Table 1. Higher TR grade was associated with worse renal function and with higher diabetes and AF rates. Patients with higher TR grade were more likely to have RV dysfunction, and more mitral regurgitation (MR) and higher pulmonary pressures. Compared with patients with moderate TR, patients with severe TR had higher annular dimensions, higher tenting area, and tenting height. Increasing TR severity was associated with higher BNP levels (Figure 1A) and among the liver function tests, γ-glutamyl transferase, and alkaline phosphatase increased with increasing TR grade (Figure 1B). There was a graded increase in the congestion score at admission with increasing TR severity (Figure 1C). Figure 1 View largeDownload slide relationship between TR grade and (A) BNP levels (B) liver function tests (C) mean number of signs and symptoms of congestion (D) pulmonary artery systolic pressure (circles indicate individual PASP values). BNP, brain natriuretic peptide; PASP, pulmonary artery systolic pressure; TR, tricuspid regurgitation. Figure 1 View largeDownload slide relationship between TR grade and (A) BNP levels (B) liver function tests (C) mean number of signs and symptoms of congestion (D) pulmonary artery systolic pressure (circles indicate individual PASP values). BNP, brain natriuretic peptide; PASP, pulmonary artery systolic pressure; TR, tricuspid regurgitation. In the 639 (90%) patients with estimable PASP, there was a graded increase in PASP with increasing TR grade, albeit with large overlap (Figure 1D). The median PASP was 55 and 60 mmHg in patients with moderate and severe TR, respectively. Figure 2 summarizes the association of TR grade and several clinically significant cardiac lesions [left ventricular ejection fraction (LVEF) < 45%, moderate or severe MR, RV dysfunction, and PASP ≥ 50 mmHg]. The number of associated cardiac abnormalities increased with increasing TR grade, with ∼93% of patients with moderate and or severe TR having at least one additional clinically important cardiac abnormality (Figure 2). Figure 2 View largeDownload slide mosaic plot depicting the proportion of associated cardiac abnormalities for each TR grade. TR, tricuspid regurgitation. Figure 2 View largeDownload slide mosaic plot depicting the proportion of associated cardiac abnormalities for each TR grade. TR, tricuspid regurgitation. In multivariable logistic regression analyses, PASP, RV dysfunction, moderate or severe MR, AF, hyponatremia, and blood urea nitrogen were independently associated with moderate or severe TR (Table 2). The c-statistic of the model was 0.81 (95% CI 0.77–0.84), indicating excellent discrimination. By multivariate analysis, PASP was most closely related to moderate or severe TR, with a standardized coefficient higher than RV dysfunction or AF (Table 2). Finally, a more parsimonious model that included only echocardiographic variables (PASP, RV function, LVEF, and MR) had a c-statistic of 0.77 (95% CI 0.73–0.81). Table 2 Multivariable logistic regression analysis of determinants of moderate or severe TR Variable Wald χ2 Adjusted OR (95% CI) P-value Standardized β-coefficienta PASP (per 10 mmHg increase) 58.7 1.68 (1.46–1.93) <0.0001 2.38 RV dysfunction 13.7 2.68 (1.74–4.13) <0.0001 1.43 Moderate–severe MR 6.6 1.93 (1.30–2.97) 0.001 1.27 Hyponatremia 7.9 1.72 (1.15–2.58) 0.008 1.30 LVEF <45% 7.1 1.73 (1.16–2.60) 0.008 1.32 Atrial fibrillation 19.3 2.15 (1.48–3.13) <0.0001 1.53 BUN (per 10 mg/dL increase) 7.3 1.15 (1.04–1.28) 0.007 1.30 Variable Wald χ2 Adjusted OR (95% CI) P-value Standardized β-coefficienta PASP (per 10 mmHg increase) 58.7 1.68 (1.46–1.93) <0.0001 2.38 RV dysfunction 13.7 2.68 (1.74–4.13) <0.0001 1.43 Moderate–severe MR 6.6 1.93 (1.30–2.97) 0.001 1.27 Hyponatremia 7.9 1.72 (1.15–2.58) 0.008 1.30 LVEF <45% 7.1 1.73 (1.16–2.60) 0.008 1.32 Atrial fibrillation 19.3 2.15 (1.48–3.13) <0.0001 1.53 BUN (per 10 mg/dL increase) 7.3 1.15 (1.04–1.28) 0.007 1.30 95% CI, 95% confidence interval; LVEF, left ventricular ejection fraction; PASP, pulmonary artery systolic pressure; RV, right ventricular. a The relative strength of the associations was expressed by the standardized coefficient. Table 2 Multivariable logistic regression analysis of determinants of moderate or severe TR Variable Wald χ2 Adjusted OR (95% CI) P-value Standardized β-coefficienta PASP (per 10 mmHg increase) 58.7 1.68 (1.46–1.93) <0.0001 2.38 RV dysfunction 13.7 2.68 (1.74–4.13) <0.0001 1.43 Moderate–severe MR 6.6 1.93 (1.30–2.97) 0.001 1.27 Hyponatremia 7.9 1.72 (1.15–2.58) 0.008 1.30 LVEF <45% 7.1 1.73 (1.16–2.60) 0.008 1.32 Atrial fibrillation 19.3 2.15 (1.48–3.13) <0.0001 1.53 BUN (per 10 mg/dL increase) 7.3 1.15 (1.04–1.28) 0.007 1.30 Variable Wald χ2 Adjusted OR (95% CI) P-value Standardized β-coefficienta PASP (per 10 mmHg increase) 58.7 1.68 (1.46–1.93) <0.0001 2.38 RV dysfunction 13.7 2.68 (1.74–4.13) <0.0001 1.43 Moderate–severe MR 6.6 1.93 (1.30–2.97) 0.001 1.27 Hyponatremia 7.9 1.72 (1.15–2.58) 0.008 1.30 LVEF <45% 7.1 1.73 (1.16–2.60) 0.008 1.32 Atrial fibrillation 19.3 2.15 (1.48–3.13) <0.0001 1.53 BUN (per 10 mg/dL increase) 7.3 1.15 (1.04–1.28) 0.007 1.30 95% CI, 95% confidence interval; LVEF, left ventricular ejection fraction; PASP, pulmonary artery systolic pressure; RV, right ventricular. a The relative strength of the associations was expressed by the standardized coefficient. Effect of TR on mortality and rehospitalization Patients were followed for up to 2 years after hospital discharge (median 19 months). During the follow-up period, 242 patients (34.1%) died and 174 (24.5%) were readmitted for HF. The Kaplan–Meier survival curves demonstrated similar outcome for patients with trivial or mild TR and for patients with moderate or severe TR (Figure 3). Further analyses therefore compared the effect of moderate and severe TR to mild and trivial TR. Figure 3 View largeDownload slide the Kaplan–Meier survival plot of mortality or readmission for HF in subgroups defined by TR severity (log-rank test P < 0.0001). HF, heart failure. Figure 3 View largeDownload slide the Kaplan–Meier survival plot of mortality or readmission for HF in subgroups defined by TR severity (log-rank test P < 0.0001). HF, heart failure. Table 3 (left panel) displays univariable predictors of readmission for HF and mortality. In the unadjusted analysis, moderate or severe TR was associated with the composite endpoint. However, after adjustments for baseline clinical characteristics, laboratory and echocardiographic variables, moderate or severe TR was no longer an independent predictor of readmission for HF and mortality (Table 3, right panel). Table 3 Cox’s proportional hazards model for mortality and readmission for heart failure according to TR severity Unadjusted Adjusted Characteristics HR (95% CI) P-value HR (95% CI) P-value Age (per 10 years increase) 1.11 (1.01–1.38) 0.003 1.11 (1.01–1.57) 0.04 Estimated GFR (per mL min−1/1.73 m−2) decrease 1.07 (1.02–1.07) 0.005 — — BUN (per 10 mg/dL increase) 1.11 (1.06–1.16) <0.0001 1.08 (1.02–1.14) 0.005 Anaemia 1.28 (1.01–1.63) 0.04 — — Elevated cTn I 1.45 (1.16–1.82) 0.001 1.35 (1.07–1.70) 0.01 Congestion at discharge 1.55 (1.16–2.09) 0.003 1.42 (1.05–1.92) 0.005 ln BNP (per 1-SD increase)a 1.26 (1.13–1.39) <0.0001 1.17 (1.05–1.92) 0.005 RV dysfunction 1.31 (1.13–1.39) 0.03 — — ln PASP (per 1-SD increase)a 1.27 (1.14–1.40) <0.0001 1.14 (1.05–1.92) 0.02 Moderate/severe TR 1.55 (1.24–1.93) <0.0001 1.24 (0.97–1.57) 0.09 Unadjusted Adjusted Characteristics HR (95% CI) P-value HR (95% CI) P-value Age (per 10 years increase) 1.11 (1.01–1.38) 0.003 1.11 (1.01–1.57) 0.04 Estimated GFR (per mL min−1/1.73 m−2) decrease 1.07 (1.02–1.07) 0.005 — — BUN (per 10 mg/dL increase) 1.11 (1.06–1.16) <0.0001 1.08 (1.02–1.14) 0.005 Anaemia 1.28 (1.01–1.63) 0.04 — — Elevated cTn I 1.45 (1.16–1.82) 0.001 1.35 (1.07–1.70) 0.01 Congestion at discharge 1.55 (1.16–2.09) 0.003 1.42 (1.05–1.92) 0.005 ln BNP (per 1-SD increase)a 1.26 (1.13–1.39) <0.0001 1.17 (1.05–1.92) 0.005 RV dysfunction 1.31 (1.13–1.39) 0.03 — — ln PASP (per 1-SD increase)a 1.27 (1.14–1.40) <0.0001 1.14 (1.05–1.92) 0.02 Moderate/severe TR 1.55 (1.24–1.93) <0.0001 1.24 (0.97–1.57) 0.09 95% CI, 95% confidence interval; BNP, brain natriuretic peptide; GFR, glomerular filtration rate; PASP, pulmonary artery systolic pressure; RV, right ventricular; SD, standard deviation. a Hazard ratio for a 1-SD increase on the ln-transformed scale (SD ln BNP = 0.52; SD ln PASP = 0.31). For a multiple of 1 SD, raise the hazard ratio in the table to the power of that multiple. Table 3 Cox’s proportional hazards model for mortality and readmission for heart failure according to TR severity Unadjusted Adjusted Characteristics HR (95% CI) P-value HR (95% CI) P-value Age (per 10 years increase) 1.11 (1.01–1.38) 0.003 1.11 (1.01–1.57) 0.04 Estimated GFR (per mL min−1/1.73 m−2) decrease 1.07 (1.02–1.07) 0.005 — — BUN (per 10 mg/dL increase) 1.11 (1.06–1.16) <0.0001 1.08 (1.02–1.14) 0.005 Anaemia 1.28 (1.01–1.63) 0.04 — — Elevated cTn I 1.45 (1.16–1.82) 0.001 1.35 (1.07–1.70) 0.01 Congestion at discharge 1.55 (1.16–2.09) 0.003 1.42 (1.05–1.92) 0.005 ln BNP (per 1-SD increase)a 1.26 (1.13–1.39) <0.0001 1.17 (1.05–1.92) 0.005 RV dysfunction 1.31 (1.13–1.39) 0.03 — — ln PASP (per 1-SD increase)a 1.27 (1.14–1.40) <0.0001 1.14 (1.05–1.92) 0.02 Moderate/severe TR 1.55 (1.24–1.93) <0.0001 1.24 (0.97–1.57) 0.09 Unadjusted Adjusted Characteristics HR (95% CI) P-value HR (95% CI) P-value Age (per 10 years increase) 1.11 (1.01–1.38) 0.003 1.11 (1.01–1.57) 0.04 Estimated GFR (per mL min−1/1.73 m−2) decrease 1.07 (1.02–1.07) 0.005 — — BUN (per 10 mg/dL increase) 1.11 (1.06–1.16) <0.0001 1.08 (1.02–1.14) 0.005 Anaemia 1.28 (1.01–1.63) 0.04 — — Elevated cTn I 1.45 (1.16–1.82) 0.001 1.35 (1.07–1.70) 0.01 Congestion at discharge 1.55 (1.16–2.09) 0.003 1.42 (1.05–1.92) 0.005 ln BNP (per 1-SD increase)a 1.26 (1.13–1.39) <0.0001 1.17 (1.05–1.92) 0.005 RV dysfunction 1.31 (1.13–1.39) 0.03 — — ln PASP (per 1-SD increase)a 1.27 (1.14–1.40) <0.0001 1.14 (1.05–1.92) 0.02 Moderate/severe TR 1.55 (1.24–1.93) <0.0001 1.24 (0.97–1.57) 0.09 95% CI, 95% confidence interval; BNP, brain natriuretic peptide; GFR, glomerular filtration rate; PASP, pulmonary artery systolic pressure; RV, right ventricular; SD, standard deviation. a Hazard ratio for a 1-SD increase on the ln-transformed scale (SD ln BNP = 0.52; SD ln PASP = 0.31). For a multiple of 1 SD, raise the hazard ratio in the table to the power of that multiple. To determine whether loading conditions may have confounded the study results (i.e. patients who were more congested were misclassified into the moderate or severe TR group), we tested whether the effect of TR on clinical outcomes varied with the time of TR assessment. This was done by comparing the effect of TR in patients in whom the echocardiographic evaluation was performed within 3 days from admission vs. patients with echocardiographic evaluation >3 days from admission. The proportion of moderate or severe TR was similar with echocardiographic assessment within or >3 days from admission (37.8 vs. 36.7%, P = 0.80). There was no interaction between the time of TR assessment and TR severity with regard to the risk of rehospitalization for HF or mortality (Pinteraction=0.34). In a stratified sensitivity analysis that included the 348 patients in whom the echocardiographic evaluation of TR severity was performed during the first 3 days after admission, results were comparable with the primary analyses, with similar strength of the predictors. Moderate or severe TR was not significantly associated with readmission for HF and mortality (HR 1.16, 95% CI 0.83–1.64, P = 0.38), whereas PASP (HR 1.18 per 1 SD increase in ln PASP; 95% CI 1.02–1.38, P = 0.028) remained significantly associated with readmission for HF and mortality. Similar results were seen in the subset of patients in whom the echocardiographic evaluation of TR severity was performed more than 3 days from admission (n = 291). Moderate or severe TR was not associated with clinical outcome (HR 1.17, 95% CI 0.81–1.69, P = 0.39), whereas PASP predicted increased readmission for HF and mortality (HR 1.21 per 1 SD increase in ln PASP; 95% CI 1.03–1.42, P = 0.021). Impact of concomitant PH on the association between FTR and clinical outcome Of the 639 patients with estimable PASP, 239 had moderate or severe TR, with 68 having no PH-associated TR (28%) and 171 having PH-FTR (72%). There was no significant difference between the two groups with regard to annular 4-Chamber diastolic diameter (4.0 ± 0.7 vs. 3.9 ± 0.6, P = 0.39), annular-4C systolic diameter (3.8 ± 0.6 vs. 3.7 ± 0.5, P = 0.71), tenting area (1.84 ± 1.23 vs. 1.57 ± 1.03, P = 0.11), and tenting height (0.86 ± 0.44 vs. 0.80 ± 0.40, P = 0.37). The clinical outcome of these two groups was compared with patient having trivial/mild TR with and without PH. Unadjusted rates of readmissions for HF and mortality in the four groups are shown in Figure 4. Event rates were lowest in patients without significant TR and without PH. There was a marked increase in the risk of HF or mortality in patients with both moderate–severe TR and PH, while patients with mild TR and PH had an intermediate risk. Notably, patients with moderate–severe TR but no PH were also at intermediate risk for readmission and mortality. Figure 4 View largeDownload slide the Kaplan–Meier survival plot of mortality or readmission for heart failure in subgroups defined by pulmonary hypertension and TR severity (log-rank test P < 0.0001). HF, heart failure; PH, pulmonary hypertension; TR, tricuspid regurgitation. Figure 4 View largeDownload slide the Kaplan–Meier survival plot of mortality or readmission for heart failure in subgroups defined by pulmonary hypertension and TR severity (log-rank test P < 0.0001). HF, heart failure; PH, pulmonary hypertension; TR, tricuspid regurgitation. In a Cox proportional hazards regression analysis, there was a significant interaction between TR severity and PH (Pinteraction = 0.03), such that after adjustments for other risk variables (Table 4), patients with moderate–severe TR without PH had similar outcome to that of patients with trivial/mild TR. The risk associated with moderate–severe TR appeared to be driven primarily by the presence of concomitant PH. Table 4 Cox’s proportional hazards model for mortality and readmission for heart failure according to TR and PH severity Unadjusted Adjusted Characteristics HR (95% CI) P-value HR (95% CI) P-value Trivial/mild TR—no PH 1.0 (Referent) 1.0 (Referent) Trivial/mild TR—PH 1.55 (1.16–2.08) 0.003 1.46 (1.09–1.96) 0.01 Moderate/severe TR—no PH 1.38 (0.93–2.05) 0.11 1.17 (0.78–1.75) 0.40 Moderate/severe TR—PH 2.08 (1.58–2.73) <0.0001 1.78 (1.34–2.36) <0.0001 Unadjusted Adjusted Characteristics HR (95% CI) P-value HR (95% CI) P-value Trivial/mild TR—no PH 1.0 (Referent) 1.0 (Referent) Trivial/mild TR—PH 1.55 (1.16–2.08) 0.003 1.46 (1.09–1.96) 0.01 Moderate/severe TR—no PH 1.38 (0.93–2.05) 0.11 1.17 (0.78–1.75) 0.40 Moderate/severe TR—PH 2.08 (1.58–2.73) <0.0001 1.78 (1.34–2.36) <0.0001 95% CI, 95% confidence interval; PH, pulmonary hypertension; TR, tricuspid regurgitation. Table 4 Cox’s proportional hazards model for mortality and readmission for heart failure according to TR and PH severity Unadjusted Adjusted Characteristics HR (95% CI) P-value HR (95% CI) P-value Trivial/mild TR—no PH 1.0 (Referent) 1.0 (Referent) Trivial/mild TR—PH 1.55 (1.16–2.08) 0.003 1.46 (1.09–1.96) 0.01 Moderate/severe TR—no PH 1.38 (0.93–2.05) 0.11 1.17 (0.78–1.75) 0.40 Moderate/severe TR—PH 2.08 (1.58–2.73) <0.0001 1.78 (1.34–2.36) <0.0001 Unadjusted Adjusted Characteristics HR (95% CI) P-value HR (95% CI) P-value Trivial/mild TR—no PH 1.0 (Referent) 1.0 (Referent) Trivial/mild TR—PH 1.55 (1.16–2.08) 0.003 1.46 (1.09–1.96) 0.01 Moderate/severe TR—no PH 1.38 (0.93–2.05) 0.11 1.17 (0.78–1.75) 0.40 Moderate/severe TR—PH 2.08 (1.58–2.73) <0.0001 1.78 (1.34–2.36) <0.0001 95% CI, 95% confidence interval; PH, pulmonary hypertension; TR, tricuspid regurgitation. Propensity score matching One-to-one matching on the propensity score yielded only 26 patient pairs. Before matching the standardized difference was highest for the PASP and RV function variables (Figure 5A). After propensity score matching, patients were well balanced with respect to the variables included in the propensity model (Figure 5A), with mean difference in paired propensity scores of 3.2%. Following propensity score matching, readmissions for HF and mortality were similar in patients with moderate/severe TR and trivial/mild TR (Figure 5B) with a HR of 1.0 (95% CI 0.49–2.06, P = 0.99). Figure 5 View largeDownload slide (A) covariable balance before (red circles) and after (blue circle) propensity score matching. The standardized differences after propensity matching (blue squares) are all within 10%. (B) The Kaplan–Meier survival plot of mortality or readmission for heart failure in matched patients by TR severity. AF, atrial fibrillation; BNP, brain natriuretic peptide; COPD, chronic obstructive pulmonary disease; eGFR, estimated glomerular filtration rate; HF, heart failure; LVEF, left ventricular ejection fraction; PASP, pulmonary artery systolic pressure; RV, right ventricular; TR, tricuspid regurgitation. Figure 5 View largeDownload slide (A) covariable balance before (red circles) and after (blue circle) propensity score matching. The standardized differences after propensity matching (blue squares) are all within 10%. (B) The Kaplan–Meier survival plot of mortality or readmission for heart failure in matched patients by TR severity. AF, atrial fibrillation; BNP, brain natriuretic peptide; COPD, chronic obstructive pulmonary disease; eGFR, estimated glomerular filtration rate; HF, heart failure; LVEF, left ventricular ejection fraction; PASP, pulmonary artery systolic pressure; RV, right ventricular; TR, tricuspid regurgitation. Discussion In the present study, we observed a high prevalence of haemodynamically significant TR in patients with acute HF. TR severity was associated with multiple clinical comorbidities and risk markers including worse renal function, higher BNP levels and congestion score, as well as with mitral regurgitation, AF, RV dysfunction, reduced LVEF, and PH. After careful adjustments for the associated clinical and echocardiographic variables, significant TR (moderate or severe) was associated with higher multivariable adjusted risk for readmission for HF or mortality only in the presence of concomitant PH. Previous studies described a strong impact of TR on clinical outcome in the settings of valvular heart disease especially after mitral valve intervention,10,12 and in isolated TR.17 However, only a paucity of studies with contradictory results are currently available with regard to the prognostic significance of TR in the setting of overt HF. Two studies reported increased mortality in patients with moderate and severe TR.18,19 However, in both studies TR was not considered along with other known predictors of survival like PH. In addition, these studies lacked information on symptoms, biomarkers, and kidney function. In a more recent study, Neuhold et al.2 reported that the prognostic impact of FTR in chronic HF was significantly associated with excess mortality only in mildly or moderately reduced LV function with no additive value in more advanced disease. In contrast to these previous studies, our study population was confined to patients with symptomatic HF requiring hospitalization. There is an inherent difficulty to determine the haemodynamic consequences and clinical outcome of TR due to multiple associated comorbidities, especially in the setting of HF. In the present study, only ∼7% of the patients with moderate or severe TR were free of other important cardiac abnormalities (MR, reduced LVEF, PH, or RV dysfunction). Propensity matching procedure could match <10% of patients owing to the marked baseline differences. Although the small number of matched patients precludes us from drawing conclusions from this analysis, it demonstrates the pitfalls of comparing patients with moderate/severe TR to those with trivial/mild TR. The strong relationship between increasing TR severity and important cardiac comorbidities, contributes to the current uncertainties regarding the clinical significance and surgical management of TR, especially in the presence of severe RV or LV dysfunction, or severe PH.20 Two major forms of FTR have recently been proposed: (i) FTR that is strongly associated with aging and AF.4,7 This variant appears to result predominantly from annular enlargement leading to exhaustion of annular coverage reserve.4 (ii) PH-associated FTR which entails mainly valvular tethering with tenting and reduced coaptation,4 but can also be associated with annular dilatation6 which further contributes to increased tenting area. In the present study of patients with overt HF, there was a large overlap in annular size and tenting parameters between patients with and without PH, presumably because leaflet tethering can occur as a consequence of both RV remodelling and TV annular dilatation (coexisting PH and AF),21 and because annular dilatation can also be associated with PH.6 Although PH is not a necessary prerequisite for the development of secondary TR,1 it remains a major mechanism for TR progression, especially in patients with HF, in whom pulmonary pressure is frequently elevated and tends to increase with disease progression.7 The present study shows that the most powerful modulator of the association between TR and clinical outcome was PASP, and that PH-associated FTR portends a higher risk for readmission for HF and mortality. The present study demonstrates the inextricable link between TR severity, RV function, and PH. PASP and RV dysfunction were two key factors strongly associated with moderate or severe TR (Table 2). Most patients with moderate or severe TR had PH, and RV dysfunction was present in 31% and 55% of patients with moderate and severe TR, respectively. However, RV dysfunction was not independently associated with readmission for HF or mortality. Collectively, these data suggest that the RV volume overload alone induced by TR may be insufficient to meaningfully alter the clinical outcome. However, when volume overload is superimposed on pre-existing pressure overload, the risk for readmission for HF and mortality increases. These data reinforce the key role of PH in the pathophysiology and progression of TR in patients with HF.7 Beyond its association with cardiac abnormalities, TR was also associated with reduced renal function, greater congestion, and higher BNP levels. The association between haemodynamically significant TR and renal dysfunction has been ascribed to higher central and renal venous pressure, leading to reduced renal perfusion pressure.22 Clinical implications FTR frequently accompanies advanced stage of HF, regardless of aetiology,2 and progression to significant TR in contemporary patients is frequently not related to left-sided valvular disease.7 Therefore, an appropriate interpretation of the clinical significance of FTR in the context of patients with symptomatic HF is warranted. In the absence of other indications for cardiac surgery, current guideline consider patient with severe TR and congestive signs directly related to the TR and progressive RV dysfunction as candidates for surgery.8,20 Recent previous studies suggest that severe isolated TR adversely affects clinical outcome,17 and that TV replacement may be beneficial when performed in patients with mild or no HF.23 However, as shown in the present study, it would be difficult to view severe TR as the predominant culprit of adverse clinical outcome in the majority of patients with overt HF and fluid overload. The TR-specific impact on outcome is difficult to extricate but was not significant in the present study. Study limitations This study has limitations that need be acknowledged. The study is a single-centre study. TR severity was not assessed using quantitative methods. Quantitative methods for TR estimation have their limitations and are not widely practiced.3 As in previous studies,1,2,5–7 using a semiquantitative approach, we were able to define groups with distinct clinical presentation and echocardiographic parameters that attest to the validity of our methods. Because of the bidirectional link between congestion and TR, fluid overload secondary to worsening HF may lead to overestimation of the true TR severity. Conclusion Patients presenting with HF and significant FTR have multiple coexisting cardiac abnormalities. The impact of FTR on the clinical outcome in HF patients depends on the severity of PH. In patient with symptomatic HF, FTR provides no additive risk in the presence of normal or mildly elevated pulmonary pressures. However, it is associated with excess rehospitalizations and mortality in patients with PH. References 1 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 . Google Scholar CrossRef Search ADS PubMed 2 Neuhold S , Huelsmann M , Pernicka E , Graf A , Bonderman D , Adlbrecht C et al. Impact of tricuspid regurgitation on survival in patients with chronic heart failure: unexpected findings of a long-term observational study . Eur Heart J 2013 ; 34 : 844 – 52 . Google Scholar CrossRef Search ADS PubMed 3 Lancellotti P , Tribouilloy C , Hagendorff A , Popescu BA , Edvardsen T , Pierard LA et al. Recommendations for the echocardiographic assessment of native valvular regurgitation: an executive summary from the European Association of Cardiovascular Imaging . Eur Heart J Cardiovasc Imaging 2013 ; 14 : 611 – 44 . Google Scholar CrossRef Search ADS PubMed 4 Topilsky Y , Khanna A , Le Tourneau T , Park S , Michelena H , Suri R et al. Clinical context and mechanism of functional tricuspid regurgitation in patients with and without pulmonary hypertension . Circ Cardiovasc Imaging 2012 ; 5 : 314 – 23 . Google Scholar CrossRef Search ADS PubMed 5 Mutlak D , Aronson D , Lessick J , Reisner SA , Dabbah S , Agmon Y. Functional tricuspid regurgitation in patients with pulmonary hypertension: is pulmonary artery pressure the only determinant of regurgitation severity? Chest 2009 ; 135 : 115 – 21 . Google Scholar CrossRef Search ADS PubMed 6 Medvedofsky D , Aronson D , Gomberg-Maitland M , Thomeas V , Rich S , Spencer K et al. Tricuspid regurgitation progression and regression in pulmonary arterial hypertension: implications for right ventricular and tricuspid valve apparatus geometry and patients outcome . Eur Heart J Cardiovasc Imaging 2017 ; 18 : 86 – 94 . Google Scholar CrossRef Search ADS PubMed 7 Shiran A , Najjar R , Adawi S , Aronson D. Risk factors for progression of functional tricuspid regurgitation . Am J Cardiol 2014 ; 113 : 995 – 1000 . Google Scholar CrossRef Search ADS PubMed 8 Badano LP , Muraru D , Enriquez-Sarano M. Assessment of functional tricuspid regurgitation . Eur Heart J 2013 ; 34 : 1875 – 85 . Google Scholar CrossRef Search ADS PubMed 9 Fukuda S , Gillinov AM , McCarthy PM , Stewart WJ , Song JM , Kihara T et al. Determinants of recurrent or residual functional tricuspid regurgitation after tricuspid annuloplasty . Circulation 2006 ; 114 :I582–587. 10 Sagie A , Schwammenthal E , Newell JB , Harrell L , Joziatis TB , Weyman AE et al. Significant tricuspid regurgitation is a marker for adverse outcome in patients undergoing percutaneous balloon mitral valvuloplasty . J Am Coll Cardiol 1994 ; 24 : 696 – 702 . Google Scholar CrossRef Search ADS PubMed 11 Shiran A , Sagie A. Tricuspid regurgitation in mitral valve disease incidence, prognostic implications, mechanism, and management . J Am Coll Cardiol 2009 ; 53 : 401 – 8 . Google Scholar CrossRef Search ADS PubMed 12 Vargas Abello LM , Klein AL , Marwick TH , Nowicki ER , Rajeswaran J , Puwanant S et al. Understanding right ventricular dysfunction and functional tricuspid regurgitation accompanying mitral valve disease . J Thorac Cardiovasc Surg 2013 ; 145 :1234–41. e1235. 13 Aronson D , Darawsha W , Atamna A , Kaplan M , Makhoul BF , Mutlak D et al. Pulmonary hypertension, right ventricular function, and clinical outcome in acute decompensated heart failure . J Card Fail 2013 ; 19 : 665 – 71 . Google Scholar CrossRef Search ADS PubMed 14 Darawsha W , Chirmicci S , Solomonica A , Wattad M , Kaplan M , Makhoul BF et al. Discordance between hemoconcentration and clinical assessment of decongestion in acute heart failure . J Card Fail 2016 ; 22 : 680 – 8 . Google Scholar CrossRef Search ADS PubMed 15 Mutlak D , Carasso S , Lessick J , Aronson D , Reisner SA , Agmon Y. Excessive respiratory variation in tricuspid regurgitation systolic velocities in patients with severe tricuspid regurgitation . Eur Heart J Cardiovasc Imaging 2013 ; 14 : 957 – 62 . Google Scholar CrossRef Search ADS PubMed 16 Shahar K , Darawsha W , Yalonetsky S , Lessick J , Kapeliovich M , Dragu R et al. Time dependence of the effect of right ventricular dysfunction on clinical outcomes after myocardial infarction: role of pulmonary hypertension . J Am Heart Assoc 2016 ; 5 : e003606 . Google Scholar CrossRef Search ADS PubMed 17 Topilsky Y , Nkomo VT , Vatury O , Michelena HI , Letourneau T , Suri RM et al. Clinical outcome of isolated tricuspid regurgitation . JACC Cardiovasc Imaging 2014 ; 7 : 1185 – 94 . Google Scholar CrossRef Search ADS PubMed 18 Hung J , Koelling T , Semigran MJ , Dec GW , Levine RA , Di Salvo TG. Usefulness of echocardiographic determined tricuspid regurgitation in predicting event-free survival in severe heart failure secondary to idiopathic-dilated cardiomyopathy or to ischemic cardiomyopathy . Am J Cardiol 1998 ; 82 : 1301 – 3 . A1310. Google Scholar CrossRef Search ADS PubMed 19 Koelling TM , Aaronson KD , Cody RJ , Bach DS , Armstrong WF. Prognostic significance of mitral regurgitation and tricuspid regurgitation in patients with left ventricular systolic dysfunction . Am Heart J 2002 ; 144 : 524 – 9 . Google Scholar CrossRef Search ADS PubMed 20 Vahanian A , Alfieri O , Andreotti F , Antunes MJ , Baron-Esquivias G , Baumgartner H et al. Guidelines on the management of valvular heart disease (version 2012) . Eur Heart J 2012 ; 33 : 2451 – 96 . Google Scholar CrossRef Search ADS PubMed 21 Ubago JL , Figueroa A , Ochoteco A , Colman T , Duran RM , Duran CG. Analysis of the amount of tricuspid valve anular dilatation required to produce functional tricuspid regurgitation . Am J Cardiol 1983 ; 52 : 155 – 8 . Google Scholar CrossRef Search ADS PubMed 22 Maeder MT , Holst DP , Kaye DM. Tricuspid regurgitation contributes to renal dysfunction in patients with heart failure . J Card Fail 2008 ; 14 : 824 – 30 . Google Scholar CrossRef Search ADS PubMed 23 Topilsky Y , Khanna AD , Oh JK , Nishimura RA , Enriquez-Sarano M , Jeon YB et al. Preoperative factors associated with adverse outcome after tricuspid valve replacement . Circulation 2011 ; 123 : 1929 – 39 . Google Scholar CrossRef Search ADS PubMed Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2018. For permissions, please email: journals.permissions@oup.com. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices)

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European Heart Journal – Cardiovascular ImagingOxford University Press

Published: Sep 1, 2018

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