ORIGINAL RESEARCH published: 10 November 2021 doi: 10.3389/fcvm.2021.720643 Importance of Tricuspid Regurgitation Velocity Threshold in Risk Assessment of Pulmonary Hypertension-Long-Term Outcome of Patients Submitted to Aortic Valve Replacement Cora Garcia-Ribas 1,2*, Mirea Ble 1 , Miquel Gómez 1,2,3 , Aleksandra Mas-Stachurska 1 , Núria Farré-López 1,2,3 and Mercè Cladellas 1,2,3 1 Department of Cardiology, Hospital del Mar, Barcelona, Spain, 2 Department of Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain, 3 IMIM-Hospital del Mar Medical Research Institute, Barcelona, Spain Edited by: Background: The upper physiological threshold for tricuspid regurgitation velocity Leonid Goubergrits, Charité–Universitätsmedizin (TRV) of 2.8 m/s proposed by the Pulmonary Hypertension (PH) guidelines had been Berlin, Germany questioned. The aim of this study was to evaluate the prognostic significance of Reviewed by: preoperative PH in patients with aortic stenosis, long-term after valve replacement, using Renzo Cecere, two different TRV thresholds (2.55 and 2.8 m/s). McGill University, Canada Dan Rusinaru, Methods: Four hundred and forty four patients were included (mean age 73 ± 9 years; University Hospital Center (CHU), France 55% male), with a median follow-up of 5.8 years (98% completed). Patients were divided *Correspondence: into three PH probability groups according to guidelines (low, intermediate and high) for Cora Garcia-Ribas both thresholds (TRV ≤ 2.8 m/s and TRV ≤ 2.55 m/s), using right atrial area>18 cm2 coragarciaribas@gmail.com and right ventricle/left ventricle ratio>1 as additional echocardiographic variables. orcid.org/0000-0002-3589-7597 Results: In patients with measurable TRV (n = 304), the low group mortality rate was Specialty section: 25% and 30%, respectively for 2.55 and 2.8 m/s TRV thresholds. The intermediate group This article was submitted to Cardiovascular Imaging, with TRV > 2.55 m/s was an independent mortality risk factor (HR 2.04; 95% CI: 1.91 a section of the journal to 3.48, p = 0.01), in contrast to the intermediate group with TRV>2.8 m/s (HR 1.44; Frontiers in Cardiovascular Medicine 95% CI: 0.89 to 2.32, p = 0.14). Both high probability groups were associated with an Received: 04 June 2021 increased mortality risk, as compared to their respective low groups. When including all Accepted: 27 September 2021 Published: 10 November 2021 patients (with measurable and non-measurable TRV), both intermediate groups remained Citation: independently associated with an increased mortality risk: HR 1.62 (95% CI 1.11 to 2.35 Garcia-Ribas C, Ble M, Gómez M, p = 0.01) for the new cut-off point; and HR 1.43 (95% CI: 0.96 to 2.13, p = 0.07) for Mas-Stachurska A, Farré-López N and Cladellas M (2021) Importance of guidelines threshold. Tricuspid Regurgitation Velocity Conclusion: A TRV threshold of 2.55 m/s, together with right cavities measures, allowed Threshold in Risk Assessment of Pulmonary Hypertension-Long-Term a better risk assessment of patients with PH secondary to severe aortic stenosis, with or Outcome of Patients Submitted to without tricuspid regurgitation. Aortic Valve Replacement. Front. Cardiovasc. Med. 8:720643. Keywords: pulmonary hypertension, echocardiography, tricuspid regurgitation threshold, aortic stenosis (AS), left doi: 10.3389/fcvm.2021.720643 heart valve disease Frontiers in Cardiovascular Medicine | www.frontiersin.org 1 November 2021 | Volume 8 | Article 720643 Garcia-Ribas et al. Importance of Tricuspid Regurgitation Threshold INTRODUCTION Endpoints and Definitions The main aim of this study was to investigate the prognostic Pulmonary hypertension (PH) is a potential complication of significance of preoperative PH secondary to severe aortic many cardiovascular and respiratory diseases. Transthoracic stenosis, long-term after aortic valve replacement, using two Doppler echocardiography remains the most important non- different TRV thresholds (TRV ≤ 2.55 m/s and TRV ≤ 2.8 m/s), invasive screening tool due to its widespread availability and together with right cavities measurements. ease of use. The current guidelines from the European Society In order to assess all-cause mortality following aortic valve of Cardiology and the European Respiratory Society (ESC/ERS) replacement, patients were divided into three PH probability (1) recommend grading PH probability based on tricuspid groups as proposed by ESC/ERS guidelines (low, intermediate, regurgitation velocity (TRV) peak at rest and on additional and high), for both thresholds. Right atrial area (RAA) >18 echocardiographic signs suggestive of PH. PH probability is cm2 and right ventricle (RV)/left ventricle ratio >1 were used as thus classified as low (TRV ≤2.8 m/s), intermediate (TRV additional echocardiographic variables (Table 1). The presence 2.9–3.4 m/s) and high (TRV >3.4 m/s). However, certain of a single echocardiographic sign did not change the PH authors have suggested that PH estimation may often be probability level. misclassified by traditional thresholds (2), and that current In a first analysis, only patients with measurable tricuspid cut-off points may need to be reconsidered, since small regurgitation (TR) were studied. Same analyses were increases in TRV, even at values considered normal, are subsequently performed including all patients. All groups independently associated with an increased mortality (3–5). In were compared to their respective low PH probability group, this regard, an interesting investigation by Marra et al. (6) considered the reference group. Finally, the association between proposed that TRV cut-off should be lowered to 2.55 m/s in TRV and right cavities measurements was explored. healthy individuals. PH is an important contributor to morbidity and mortality in Study Protocol patients with aortic stenosis (7). Previous reports showed that a Preoperative variables included classic cardiovascular risk high PH probability was related to an increased morbidity and factors, history of myocardial infarction, atrial fibrillation or mortality (8, 9). In these studies, the intermediate probability flutter, stroke, New York Heart Association functional class III or groups were also associated with worse outcomes, but did IV, left ejection fraction <50%, chronic obstructive pulmonary not reach significance on multivariate analysis. On another disease (COPD) when FEV1 was <70%, or if the diagnosis was hand, a recent study showed that the incorporation of right previously made by a physician. All patients underwent coronary cavities measurements as additional echocardiographic signs angiography before surgery and the European System for Cardiac to TRV, allowed a better prognostic classification of patients Operative Risk Evaluation score was recorded for each one. with severe aortic stenosis after valve replacement (10). Thus, Definitions of risk factors have been previously described (11). according to the current ESC/ERS guidelines, the aim of the present study was to evaluate the preoperative PH prognosis Clinical Follow-Up of patients with severe aortic stenosis, by using two different After aortic valve replacement, clinical appointments were TRV thresholds: the 2.8 m/s proposed by current guidelines carried out at discharge, and later on at 3 and 12 months. and a new cut-off point of 2.55 m/s, together with right After this period, follow-up appointments were performed cavities measurements. once a year by a cardiologist or when the patient requested it at our institution. All clinical events were recorded in a METHODS computerized database. Research Question and Study Design Doppler Echocardiographic Methods An observational cohort with severe aortic stenosis undergoing A standard 2D echocardiography was performed in all patients aortic valve replacement was included from January 2005 before undergoing surgery, in order to evaluate TR degree and to June 2018 at the Department of Cardiology of the velocity using continuous and color Doppler, and to assess Hospital del Mar (Barcelona, Spain). The database contains RV function by tricuspid annular plane systolic excursion detailed clinical information of risk factors, number of (TAPSE) using the M-mode technique. TAPSE <17 mm was replaced valves, postoperative complications, and an indicative of RV systolic dysfunction (12). Echocardiographic annual follow-up. All patients underwent surgery (aortic exams were performed with commercially available ultrasound valve replacement) at our reference hospital (Hospital de systems (Vivid 7 and E9 GE Healthcare Vingmed, Trodheim) la Santa Creu i Sant Pau). Patients with isolated aortic according to the American Society of Echocardiography and insufficiency or double valve replacement, and patients the European Association of Cardiovascular Imaging guidelines submitted to transcatheter aortic valve replacement (12). TRV peak was recorded in multiple views using continuous were excluded. Doppler to obtain the optimal appearing tricuspid regurgitant jet The study was approved by the institutional review boards (most frequently from the apical 4-chamber view). TR severity at the CEIm-Parc de Salut Mar institution (approval number was graded as mild, moderate, severe or non-measurable (trivial 2019/8278) and was conducted in accordance with the amended or absent) based on TR jet size by color flow imaging. RAA was Declaration of Helsinki. measured in the apical four-chamber view at end-systole. RV Frontiers in Cardiovascular Medicine | www.frontiersin.org 2 November 2021 | Volume 8 | Article 720643 Garcia-Ribas et al. Importance of Tricuspid Regurgitation Threshold TABLE 1 | Echocardiographic probability of pulmonary hypertension according to current ESC/ERS guidelines and the new cut-off point. Tricuspid regurgitation velocity Tricuspid regurgitation velocity RAA (end-systole) >18 cm2 Echocardiographic pulmonary peak (m/s) New cut-off value* peak (m/s) Guidelines-2015 RV/LV basal diameter ratio >1 hypertension probability ≤ 2.55 or not measurable ≤ 2.8 or not measurable No Low ≤ 2.55 or not measurable ≤ 2.8 or not measurable Yes Intermediate 2.6–3.4 2.9–3.4 No 2.6–3.4 2.9–3.4 Yes High > 3.4 > 3.4 Not required *Marra et al. (6). RAA, right atrial area; RV, right ventricle; RV, left ventricle. and left ventricle basal diameter were measured from the apical the low group were reclassified to the intermediate group, and 4-chamber view obtained at the end-diastole. nine patients from the intermediate group were relocated into the high group. Thus, with the new cut-off point, the followings Statistical Analysis groups were observed: low (n = 209, 47%), intermediate (n = Continuous data are presented as mean ± standard deviation 157, 35%) and high (n = 78, 18%). (SD) or median (25–75th percentile range). Categorical variables are shown as frequencies and percentages. Relationships among continuous variable groups were explored using 2-tailed t-tests Baseline Characteristics and Clinical (for normally distributed variables) or Mann-Whitney U-tests Outcomes of Patients With Tricuspid (for non-normally distributed variables). Chi square tests and Regurgitation Fisher’s exact tests were used to examine the association between In the 304 patients with TR, the statistically significant differences groups and baseline categorical variables. The association observed between the intermediate and high probability groups between TVR and right cavities measurements was assessed by as compared to their respective low group were similar for both Spearman’s correlation. cut-off points (Table 2). Likewise, in the Kaplan Meier curves Kaplan-Meier survival curves to time-to-event data were to time-to-event data, no differences were observed in terms of compared with the Log-rank test, taking as reference the low mortality rate between the three groups, for both cut-off points probability group for both thresholds. Multivariate survival (Figure 1). analysis using Cox proportional hazards models, adjusted for Regarding the low PH probability group, 106 of the 124 age, sex and significant variables related to PH and mortality patients of the low group with the guidelines threshold did not were used to assess the independent association between PH present any sign of right cavities involvement, and of these, 32 probability and postoperative prognosis for both thresholds. The (30%) died. With the new cut-off point, 67 of the 77 patients of low PH probability group was considered the reference group in the low group did not show any right-side involvement sign, and all cases. Results were estimated for all-cause mortality and were of these, 17 (25%) patients died. No significant differences were presented as hazard ratios (HR) and 95% confidence intervals observed between the three groups when comparing prosthetic (CI). Significance was set at a p < 0.05. For multivariable models, mean gradient, 30 days and 3 months after surgery. all parameters associated with death on univariate analysis with The Kaplan Meier curves to time-to-event data (Figure 2) p < 0.10 were included. Statistical analyses were performed with showed that the intermediate group mortality with the guidelines the R software version 3.4.2. threshold did not significantly differ from the low group (Log- rank p = 0.86). Conversely, the intermediate group with RESULTS the new cut-off point showed a significantly worse survival, compared to the low group (Figure 2, Log-rank p = 0.02). Study Population When performing the multivariate analysis, after adjusting for During the study period, 444 consecutive patients were included age, sex, and significant variables related to PH and mortality, before surgery and were subsequently assessed after aortic valve the intermediate group with the new cut-off point remained replacement with a median follow-up of 5.8 years (interquartile independently associated with an increased overall mortality risk range 3.2–8.1 years), with only 2% of the patients lost during (HR 2.04; 95% CI: 1.91 to 3.48, p = 0.01), in contrast to the follow-up. Mean age was 73 ± 9 years and 55% were male. TRV intermediate group with the guidelines threshold (HR 1.44; 95% was detected as non- measurable in 140 patients (32%), mild in CI: 0.89 to 2.32, p = 0.14; Table 3). 229 patients (52%) and moderate in 75 patients (17%). No severe TR was observed. Before surgery, patients were divided into three PH Baseline Characteristics and Clinical probability groups. According to the guidelines thresholds, Outcomes With all Patients the following groups were obtained: low (n = 256, 58%), Baseline characteristics of all patients (444 patients) divided intermediate (n = 119, 27%) and high (n = 69, 15%). When the into three groups did not significantly vary from TRV patients’ new TRV threshold of 2.55 m/s was applied, 47 patients from analyses (Supplementary Table 1). Frontiers in Cardiovascular Medicine | www.frontiersin.org 3 November 2021 | Volume 8 | Article 720643 Garcia-Ribas et al. Importance of Tricuspid Regurgitation Threshold TABLE 2 | Baseline characteristics and all-cause mortality during follow-up between groups, according to current ESC/ERS guidelines and the new cut-off point thresholds, in patients with tricuspid regurgitation. ESC/ERS guidelines-2015 New cut-off point value Low Intermediate High Low Intermediate High (n = 124) (n = 111) (n = 69) (n = 77) (n = 149) (n = 78) Risk factors: Age (n ± SD) 72 ± 9* 73 ± 8 75 ± 7* 71 ± 9* 73 ± 9 76 ± 7* Male (n, %) 70 (57)* 64 (43)* 41 (59) 48 (62)* 64 (43)* 46 (59) Hypertension (n, %) 86 (69) 83 (75) 54 (78) 50 (65) 113 (76) 60 (77) Diabetes mellitus (n, %) 32 (26) 34 (31) 24 (35) 21 (27) 44 (30) 25 (32) Dyslipidemia (n, %) 79 (64) 51 (52) 38 (55) 47 (61) 87 (58) 41 (53) Current Smoking (n, %) 11 (8.9) 12 (11) 6 (8.7) 6 (7.8) 14 (9.4) 9 (12) NYHA III-IV class (n, %) 26 (21)* 21 (19) 28 (41)* 13 (17)* 33 (22) 29 (37)* Angina (n, %) 33 (27) 20 (17) 11 (16) 16 (21) 35 (24) 12 (15) Syncope (n, %) 19 (15) 10 (9) 12 (17) 13 (17) 16 (11) 12 (15) Atrial fibrillation (n, %) 8 (6.5)‡# 23 (21)# 27 (39)‡ 3 (3.9)*‡ 20 (13)* 35 (45)‡ Glomerular filtration rate <60 mL/min/1.73 m2 27 (22)* 25 (22) 25 (36)* 14 (18)* 35 (24) 27 (35)* COPD (n, %) 49 (40)* 48 (43) 39 (57)* 33 (43) 58 (39) 45 (58) Preoperative hemoglobin (g/dL) (n ± SD) 13.5 ± 1.3 13.1 ± 1.5 13.1 ± 1.5 13.7 ± 1.2 13 ± 1.4 13.1 ± 1.4 Body mass index > 30 Kg/m2 (n, %) 34 (27) 44 (40) 23 (33) 20 (26) 54 (36) 27 (35) Body surface area (m2 ) (n ± SD) 1.76 ± 0.2 1.79 ± 0.2 1.77 ± 0.2 1.79 ± 0.2 1.76 ± 0.2 1.78 ± 0.2 Left ventricle: Peak aortic jet velocity (m/s) (n ± SD) 4.5 ± 0.6 4.5 ± 0.6 4.4 ± 0.7 4.5 ± 0.6 4.4 ± 0.6 4.5 ± 0.6 Mean gradient (mmHg) (n ± SD) 52 ± 14 54 ± 19 53 ± 15 52 ± 15 54 ± 17 53 ± 17 Indexed aortic valve area (cm2 /m2 ) (n ± SD) 0.41 ± 0.11 0.42 ± 0.13 0.41 ± 0.13 0.41 ± 0.13 0.42 ± 0.13 0.40 ± 0.13 LV ejection fraction <50% (n, %) 9 (7.3) 9 (8.1) 11 (16) 5 (6.5) 12 (8.1) 12 (15) Right ventricle: Right ventricular basal diameter (mm) (n ± SD) 29 ± 4‡ 31 ± 5‡ 34 ± 5‡ 29 ± 4‡* 30 ± 4* 35 ± 6‡ ‡* ‡ ‡ TAPSE <17 mm (n, %) 2 (1.6) 6 (5)* 12 (17) 1 (1.3) 5 (3.4) 14 (18)‡ Inferior vena cava (mm) (n ± SD) 8.2 ± 4.2‡ 9.1 ± 4 12.1 ± 5‡ 8.1 ± 4.0‡ 9.0 ± 4.5 12 ± 4.6‡ Surgical parameters: Biological prosthesis valve (n, %) 88 (71) 82 (74) 54 (78) 56 (73) 107 (72) 61 (78) Bypass (n, %) 41 (33)* 21 (19)* 19 (27) 24 (31)* 37 (25)* 20 (26) Clinical outcomes during follow-up: 30 days postoperative (n, %) 3 (2.4) 3 (2.7) 2 (2.9) 1 (1.3) 5 (3.2) 2 (2.6) All-cause mortality (n, %) 41 (33)* 39 (35) 35 (51)* 21 (27)* 54 (36) 40 (51)* *p < 0.05 individual category vs. low group. #p = 0.001 individual category vs. low group. ‡ p < 0.001 individual category vs. low group. TR was classified as non-measurable in 140 patients, and factor with an increased overall mortality compared to the low of these, 49 (35%) died during follow-up. 8 patients presented group: HR 1.62 (95% CI: 1.11–2.35, p = 0.01) for the new cut-off two echocardiographic signs of right chambers involvement, and point; and HR 1.43 (95% CI: 0.96–2.13, p = 0.07) for guidelines of these, 6 (75%) died. The remaining 132 patients showed threshold (Table 4). none or only one echocardiographic sign, and of these, 43 (33%, p = 0.02) died. Likewise patients with TR, no significant differences were observed between the three groups when Correlation Between TRV Peak and comparing prosthetic mean gradient, 30 days and 3 months Additional Echocardiographic Signs after surgery. Globally, TRV showed a weak association with RAA (r = 0.20, Similarly to the inclusion of patients with TR, the Kaplan- p = 0.001) and RV diameter (r = 0.18, p = 0.001). Conversely, a Meier survival curves correctly classified the three groups for greater association was found between RAA size and RV diameter both cut-off points (Log-Rank p < 0.001; Figure 1). When (r = 0.52, p < 0.001; Figure 3). When TRV was divided according performing the multivariate analysis, the intermediate group to TR severity degree, the association between TRV and RAA obtained for both cut-off points remained an independent risk remained weak (r = 0.14, p = 0.04) in mild TR, increasing Frontiers in Cardiovascular Medicine | www.frontiersin.org 4 November 2021 | Volume 8 | Article 720643 Garcia-Ribas et al. Importance of Tricuspid Regurgitation Threshold FIGURE 1 | Kaplan-Meier survival curves analysis of patients with tricuspid regurgitation, according to ESC/ERS guidelines and the new cut-off point thresholds. FIGURE 2 | Kaplan-Meier survival curves analysis of patients with tricuspid regurgitation and an intermediate pulmonary hypertension probability compared to the low group, according to ESC/ERS guidelines and the new cut-off point thresholds. up to r = 0.40 (p < 0.001) in moderate TR. Regarding RV DISCUSSION diameter, while no association with TRV was found in mild TR, a moderate correlation was observed (r = 0.38, p = 0.001) The main findings of this observational study are the following: in moderate TR. (1) A TRV cut-off point of 2.55 m/s, instead of the 2.8 m/s Frontiers in Cardiovascular Medicine | www.frontiersin.org 5 November 2021 | Volume 8 | Article 720643 Garcia-Ribas et al. Importance of Tricuspid Regurgitation Threshold TABLE 3 | Relative risk of all-cause mortality on multivariate analysis according to threshold of 2.8 m/s might be missing an at-risk population, in ESC/ERS and the new cut-off point thresholds, in patients with tricuspid the line with the emerging data that associated borderline PH regurgitation. with an increased mortality risk (13–16). Guidelines−2015 New cut-off point A weak association was observed between right cavities size and TRV (r = 0.20, p = 0.001 for RAA; and r = 0.18, p = HR CI P HR CI P 0.001 for RV diameter), especially in mild TR (Figure 3). These Low PH probability group Reference group Reference group results were in accordance with prior studies that demonstrated Intermediate PH probability group 1.44 0.89–2.32 0.14 2.04 1.91–3.48 0.009 that structural right- side changes, as right atrium enlargement High PH probability group 1.64 0.98–2.74 0.05 2.02 1.10–3.72 0.02 and tricuspid annulus dilatation, could be present despite mild TR degree (17, 18). The low correlation found between TRV Adjusted by age, sex, atrial fibrillation, COPD, left ventricular ejection fraction <50%, and right cavities measures may be explained by the suboptimal hypertension, diabetes mellitus, NYHA III-IV class, glomerular filtration rate < 60 sensitivity and specificity of the TR jet used in isolation. This mL/min/1.73 m2 , bypass, prosthesic valve. low association was already described in previous reports that compared PH estimation through the TR jet with right-heart TABLE 4 | Relative risk of all-cause mortality on multivariate analysis according to catheterization, as the gold standard diagnostic technique (19, ESC/ERS and the new cut-off point thresholds, in all patients. 20). In line with this concern, O’Leary et al. (21) showed, in a large Guidelines−2015 New cut-off point study of 1,262 patients, that the lack of measurable TRV could not be equated with significant PH absence, as 47% of the patients HR CI P HR CI P without TR had confirmed PH by right heart catheterization. Low PH probability group Reference group Reference group On another hand, other authors observed that patients with Intermediate PH probability group 1.43 0.96–2.13 0.07 1.62 1.11–2.35 0.01 mild PH (5) and those in whom pulmonary artery pressure was High PH probability group 1.46 0.94–2.29 0.09 1.51 0.94–2.40 0.08 underestimated by Doppler echocardiography (19) had evidence of RV dysfunction and dilation. In this regard, Mutlak et al. Adjusted by age, sex, atrial fibrillation, COPD, left ventricular, ejection fraction <50%, (22) observed that although pulmonary artery systolic pressure hypertension, diabetes mellitus, NYHA III-IV class, glomerular filtration rate < 60 mL/min/1.73 m2 , bypass, prosthesis valve. was a strong determinant of TR severity, others aspects such as demographic characteristics, mechanical factors or remodeling of the right heart cavities were also predictive of the TR jet, and threshold proposed by the ESC/ERS guidelines, together with that systolic pulmonary artery pressure was not always related to the measurements of the right cavities, allowed a better risk TR severity. assessment of patients with PH secondary to severe aortic The current study also aimed to investigate the PH prognosis stenosis, with or without TR. (2) The association between right of those patients without TR, a less evaluated group due to its cavities size and TRV peak was weak, especially in mild TR. frequent exclusion in the majority of studies. Of the 140 patients Prior studies showed that a high PH probability was associated with non-measurable TR, 75% (6 of 8 patients) with enlarged with an increased morbidity and mortality in patients with right chambers died during follow-up. Conversely, of the 132 severe aortic stenosis (8–10). However, data are not so conclusive remaining patients (with none or only one PH echocardiographic when it comes to lower velocities and the physiological TRV sign), 43 patients (33%, p = 0.02) died. When including all spectrum for healthy individuals remains controversial. The patients, the intermediate group obtained for both cut-off points current guidelines suggest that PH probability is unlikely if remained an independent risk factor with an increased overall TRV is <2.8 m/s and none or only one additional PH sign mortality compared to the low group: HR 1.62 (95% CI 1.11 to is present. Conversely, Marra et al. (6) observed that the 95% 2.35 p = 0.01) for the new cut-off point; and HR 1.43 (95% CI: quantile of TRV in a healthy population corresponded to 2.55 0.96 to 2.13, p = 0.07) for guidelines threshold (Table 4). m/s, without significant differences found between males and Secondary TR is caused by RV elliptical deformation and females. Moreover, in the Gladwin et al. study (4), a TRV ≥ 2.55 dysfunction, leading to valvular tethering and malcoaptation, and m/s was associated with a higher risk of death in patients with frequently only with mild tricuspid annulus enlargement (23– sickle cell disease; and Hachulla et al. (3) concluded that a TRV 27). These anatomical changes were described in the absence ≥2.55 m/s, together with symptoms of PH, effectively detected of substantial TR (23, 26). Our findings may therefore be the disease at an early stage. Finally, in a large study that included related to the different RV remodeling patterns in the PH 47,728 patients, Huston et al. (5) observed that when taking a setting, and might indicate that right cavities enlargement TRV value of 1.9 m/s as reference, the mortality risk began at a was strongly associated with worse outcomes. In this regard, TRV value of 2.3 m/s (HR 1.14; 95% CI 1.02–1.27) and doubled previous studies demonstrated the importance of right cavities at a TRV value of 2.8 m/s (HR 2.08; 95% CI 1.83–2.37). size in PH prognosis assessment (28–33). On the other hand, In the present study, the intermediate group with a TRV since the right ventricular muscle mass is lower than the one > 2.55 m/s was independently associated with a higher overall on the left ventricle, this makes RV systolic function more mortality risk (HR 2.04; 95% CI: 1.91–3.48, p = 0.01) compared load sensitive. Consequently, TR severity relies on dynamic to the low probability group. In contrast, the multivariate analysis processes as preload, afterload and RV function (23, 25, 26), for the intermediate group with TRV > 2.8 m/s did not reach making TR grading extremely labile. Moreover, TR evaluation is significance (HR 1.44; 95% CI: 0.89–2.32, p = 0.14; Table 3). echocardiographic window and respiratory dependent, leading These findings thus suggest that the current recommended TRV to PH underestimation when the regurgitant jet is not easily Frontiers in Cardiovascular Medicine | www.frontiersin.org 6 November 2021 | Volume 8 | Article 720643 Garcia-Ribas et al. Importance of Tricuspid Regurgitation Threshold FIGURE 3 | (A) Correlation between tricuspid regurgitation velocity and right atrial area. (B) Correlation between tricuspid regurgitation velocity and right ventricle diameter. (C) Correlation between right atrial area and right ventricle diameter. recorded (17). These findings thus emphasized the need to CONCLUSIONS use additional PH echocardiographic features as right-side measurements, particularly in those groups with mild or A TRV cut-off point of 2.55 m/s, instead of the 2.8 m/s absent TR. threshold suggested by the current guidelines, together with additional signs of right cavities involvement, provided a better risk stratification of PH secondary to severe aortic stenosis, with LIMITATIONS or without TR. Further prospective studies are warranted for confirmation and validation. The current study had several limitations. First, this was a single-center observational study and therefore may not reflect general practice. All data were collected prospectively, although DATA AVAILABILITY STATEMENT the analysis of the data was done retrospectively. Second, our The original contributions presented in the study are included findings concerning pulmonary pressure estimation were not in the article/Supplementary Material, further inquiries can be compared with right heart catheterization measures. Third, directed to the corresponding author. no echocardiographic contrast had been used to potentiate TR in those patients with weak signal. Fourth, only two echocardiographic signs of different categories have been ETHICS STATEMENT evaluated, easily obtainable in clinical practice, without meaning to compare the different echocardiographic signs proposed in The studies involving human participants were reviewed and ESC/ERS guidelines. approved by CEIm-Parc de Salut Mar institution (approval Frontiers in Cardiovascular Medicine | www.frontiersin.org 7 November 2021 | Volume 8 | Article 720643 Garcia-Ribas et al. Importance of Tricuspid Regurgitation Threshold number 2019/8278). The Ethics Committee waived the writing. All authors contributed to the article and approved the requirement of written informed consent for participation. submitted version. AUTHOR CONTRIBUTIONS SUPPLEMENTARY MATERIAL CG-R and MC: conceptualization, data curation, formal analysis, The Supplementary Material for this article can be found methodology, validation, writing, review, and editing. MB, online at: https://www.frontiersin.org/articles/10.3389/fcvm. MG, AM-S, and NF-L: data curation, formal analysis, and 2021.720643/full#supplementary-material REFERENCES 13. Douschan P, Kovacs G, Avian A, Foris V, Gruber F, Olschewski A, et al. Mild elevation of pulmonary arterial pressure as a predictor of mortality. Am J 1. Galiè N, Humbert M, Vachiery JL, Gibbs S, Lang I, Torbicki A, et al. Respir Crit Care Med. (2018) 197:509–16. doi: 10.1164/rccm.201706-1215OC 2015 ESC/ERS guidelines for the diagnosis and treatment of pulmonary 14. 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Right atrial size and tricuspid regurgitation severity the publisher, the editors and the reviewers. Any product that may be evaluated in predict mortality or transplantation in primary pulmonary hypertension. J this article, or claim that may be made by its manufacturer, is not guaranteed or Am Soc Echocardiogr. (2002) 15:1160–4. doi: 10.1067/mje.2002.123962 31. Raymond RJ, Hinderliter AL, Willis PW, Ralph D, Caldwell EJ, endorsed by the publisher. Williams W, et al. Echocardiographic predictors of adverse outcomes in primary pulmonary hypertension. J Am Coll Cardiol. (2002) Copyright © 2021 Garcia-Ribas, Ble, Gómez, Mas-Stachurska, Farré-López and 39:1214–9. doi: 10.1016/S0735-1097(02)01744-8 Cladellas. This is an open-access article distributed under the terms of the Creative 32. Ghio S, Pazzano AS, Klersy C, Scelsi L, Raineri C, Camporotondo Commons Attribution License (CC BY). The use, distribution or reproduction in R, et al. Clinical and prognostic relevance of echocardiographic other forums is permitted, provided the original author(s) and the copyright owner(s) evaluation of right ventricular geometry in patients with are credited and that the original publication in this journal is cited, in accordance idiopathic pulmonary arterial hypertension. Am J Cardiol. (2011) with accepted academic practice. No use, distribution or reproduction is permitted 107:628–32. doi: 10.1016/j.amjcard.2010.10.027 which does not comply with these terms. Frontiers in Cardiovascular Medicine | www.frontiersin.org 9 November 2021 | Volume 8 | Article 720643