Advertisement
Canadian Journal of Cardiology

Right Ventricular Longitudinal Strain Predicts Survival in Patients With Functional Tricuspid Regurgitation

  • Marwin Bannehr
    Correspondence
    Corresponding author: Dr Marwin Bannehr, Department of Cardiology, Heart Center Brandenburg Bernau and Brandenburg Medical School, Theodor Fontane, Ladeburger Str 17, 16321 Bernau bei Berlin, Germany. Tel.: +49-3338-69-4036; fax: +49-3338-69-4644.
    Affiliations
    Department of Cardiology, Heart Center Brandenburg Bernau and Brandenburg Medical School, Bernau bei Berlin, Germany

    Faculty of Health Sciences Brandenburg, Brandenburg Medical School, Neuruppin, Germany
    Search for articles by this author
  • Ulrike Kahn
    Affiliations
    Department of Cardiology, Heart Center Brandenburg Bernau and Brandenburg Medical School, Bernau bei Berlin, Germany
    Search for articles by this author
  • Josephin Liebchen
    Affiliations
    Department of Cardiology, Heart Center Brandenburg Bernau and Brandenburg Medical School, Bernau bei Berlin, Germany
    Search for articles by this author
  • Maki Okamoto
    Affiliations
    Department of Cardiology, Heart Center Brandenburg Bernau and Brandenburg Medical School, Bernau bei Berlin, Germany
    Search for articles by this author
  • Valentin Hähnel
    Affiliations
    Department of Cardiology, Heart Center Brandenburg Bernau and Brandenburg Medical School, Bernau bei Berlin, Germany

    Faculty of Health Sciences Brandenburg, Brandenburg Medical School, Neuruppin, Germany
    Search for articles by this author
  • Christian Georgi
    Affiliations
    Department of Cardiology, Heart Center Brandenburg Bernau and Brandenburg Medical School, Bernau bei Berlin, Germany

    Faculty of Health Sciences Brandenburg, Brandenburg Medical School, Neuruppin, Germany
    Search for articles by this author
  • Victoria Dworok
    Affiliations
    Department of Cardiology, Heart Center Brandenburg Bernau and Brandenburg Medical School, Bernau bei Berlin, Germany

    Faculty of Health Sciences Brandenburg, Brandenburg Medical School, Neuruppin, Germany
    Search for articles by this author
  • Christoph Edlinger
    Affiliations
    Department of Cardiology, Heart Center Brandenburg Bernau and Brandenburg Medical School, Bernau bei Berlin, Germany

    Faculty of Health Sciences Brandenburg, Brandenburg Medical School, Neuruppin, Germany

    Department of Cardiology, Clinic of Internal Medicine II, Paracelsus Medical University of Salzburg, Salzburg, Austria
    Search for articles by this author
  • Michael Lichtenauer
    Affiliations
    Department of Cardiology, Clinic of Internal Medicine II, Paracelsus Medical University of Salzburg, Salzburg, Austria
    Search for articles by this author
  • Tanja Kücken
    Affiliations
    Department of Cardiology, Heart Center Brandenburg Bernau and Brandenburg Medical School, Bernau bei Berlin, Germany

    Faculty of Health Sciences Brandenburg, Brandenburg Medical School, Neuruppin, Germany
    Search for articles by this author
  • Siegfried Kropf
    Affiliations
    Institute for Biometrics and Medical Informatics, Medical Faculty, Otto von Guericke University Magdeburg, Magdeburg, Germany
    Search for articles by this author
  • Anja Haase-Fielitz
    Affiliations
    Department of Cardiology, Heart Center Brandenburg Bernau and Brandenburg Medical School, Bernau bei Berlin, Germany

    Faculty of Health Sciences Brandenburg, Brandenburg Medical School, Neuruppin, Germany

    Institute of Social Medicine and Health Economics, Otto von Guericke University Magdeburg, Magdeburg, Germany
    Search for articles by this author
  • Christian Butter
    Affiliations
    Department of Cardiology, Heart Center Brandenburg Bernau and Brandenburg Medical School, Bernau bei Berlin, Germany

    Faculty of Health Sciences Brandenburg, Brandenburg Medical School, Neuruppin, Germany
    Search for articles by this author
Open AccessPublished:January 12, 2021DOI:https://doi.org/10.1016/j.cjca.2021.01.006

      Abstract

      Background

      Functional tricuspid regurgitation (TR) is a frequent finding in echocardiography. Despite general consent that right ventricular (RV) dysfunction impacts outcome of patients with TR, it is still unknown which echocardiographic parameters most accurately reflect prognosis. In this study we aimed to evaluate the prevalence of RV dysfunction and its prognostic value in patients with TR.

      Methods

      Data from 1089 consecutive patients were analysed. Tricuspid annular plane systolic excursion (TAPSE), fractional area change, and right ventricular free wall longitudinal strain (RV strain) were used to define RV dysfunction. Patients were followed for 2-year all-cause mortality. For prediction of survival, reclassification and C statistics of RV functional parameters using TR grade as reference model were performed.

      Results

      Among the patients studied, 13.9% showed no TR, 61.2% had mild TR, 19.6% had moderate TR, and 5.3% had severe TR. The TR grade was associated with increased mortality (log rank, P < 0.001). Impaired RV strain and TAPSE were independent predictors for mortality (RV: hazard ratio [HR], 1.130; 95% confidence interval [CI], 1.099-1.160; P < 0.001; TAPSE: HR, 1.131; 95% CI, 1.085-1.175; P < 0.001). Both RV strain and TAPSE improved the reference model for survival prediction (RV: integrated discrimination improvement [IDI], 0.184; 95% CI, 0.146-0.221; P < 0.001; TAPSE: IDI, 0.057; 95% CI, 0.037-0.077; P < 0.001).

      Conclusions

      Echocardiographic evaluation of RV function appears to useful for patients with TR. Assessment of RV strain provides additional value for prediction of 2-year mortality.

      Résumé

      Contexte

      Une insuffisance tricuspide (IT) fonctionnelle est une observation fréquente en échocardiographie. Bien qu'il soit généralement admis que la dysfonction du ventricule droit (VD) a un impact sur le pronostic des patients atteints d'IT, on ne sait toujours pas quels sont les paramètres échocardiographiques qui reflètent le plus précisément ce pronostic. Dans cette étude, nous avons cherché à évaluer la prévalence de la dysfonction du VD et sa valeur pronostique chez les patients atteints d'IT.

      Méthodes

      Les données obtenues pour 1 089 patients consécutifs ont été analysées. L'excursion systolique du plan de l'anneau tricuspide (TAPSE, de l’anglais « tricuspid annular plane systolic excursion »), la fraction de raccourcissement de surface et la déformation longitudinale de la paroi libre du ventricule droit ont été utilisées pour définir la dysfonction du VD. Les patients ont été suivis pour la mortalité à deux ans toutes causes confondues. Pour la prédiction de la survie, une reclassification et des probabilités de concordance des paramètres fonctionnels du VD en utilisant le niveau d'IT comme modèle de référence ont été réalisées.

      Résultats

      Parmi les patients étudiés, 13,9 % ne présentaient aucune IT, 61,2 % présentaient une IT légère, 19,6 % une IT modérée et 5,3% une IR sévère. Le grade d'IT était associé à une mortalité accrue (test logarithmique par rangs, P < 0,001). L'altération de la déformation du VD et du TAPSE était un facteur prédictif indépendant de mortalité (VD : rapport des risques [RR], 1,130; intervalle de confiance [IC] à 95 %, 1,099-1,160; P < 0,001; TAPSE : RR, 1,131; IC à 95 %, 1,085-1,175 ; P < 0,001). La déformation du VD et le TAPSE ont amélioré le modèle de référence pour la prédiction de la survie (déformation du VD : indice d’amélioration de la discrimination intégrée [IDI], 0,184 ; IC à 95 %, 0,146-0,221; P < 0,001; TAPSE : IDI, 0,057; IC à 95 %, 0,037-0,077 ; P < 0,001).

      Conclusions

      L'évaluation échocardiographique de la fonction du VD s’est révélée utile pour les patients atteints d'IT. L'évaluation de la déformation du VD apporte une plus-value pour la prédiction de la mortalité à 2 ans.
      Functional tricuspid regurgitation (TR) is a frequent finding in echocardiography. It is mostly secondary due to left-sided heart disease and occurs predominantly in patients with mitral and aortic valve pathologies.
      • Dreyfus G.D.
      • Martin R.P.
      • Chan K.M.
      • Dulguerov F.
      • Alexandrescu C.
      Functional tricuspid regurgitation: a need to revise our understanding.
      Although significant reflux of the tricuspid valve (TV) may be well tolerated for years, TR is often neglected, despite its association with a poor prognosis.
      • Dreyfus G.D.
      • Corbi P.J.
      • Chan K.M.
      • Bahrami T.
      Secondary tricuspid regurgitation or dilatation: which should be the criteria for surgical repair?.
      ,
      • Nath J.
      • Foster E.
      • Heidenreich P.A.
      Impact of tricuspid regurgitation on long-term survival.
      Understanding of the pathophysiology of functional TR is important to determine the optimal management strategies for these patients.
      Echocardiographic grading of TR itself is often the sole parameter used to evaluate significance. The literature suggests that TR should be considered an abnormality in relation to tricuspid annular size, right ventricular (RV) size, and particularly RV dysfunction, which altogether alter TV leaflet coaptation and cause valvular reflux.
      • Dreyfus G.D.
      • Martin R.P.
      • Chan K.M.
      • Dulguerov F.
      • Alexandrescu C.
      Functional tricuspid regurgitation: a need to revise our understanding.
      ,
      • Prihadi E.A.
      • van der Bijl P.
      • Dietz M.
      • et al.
      Prognostic implications of right ventricular free wall longitudinal strain in patients with significant functional tricuspid regurgitation.
      In turn, the probability of functional TR is very low when there is no RV dysfunction or dilation present.
      • Ubago J.L.
      • Figueroa A.
      • Ochoteco A.
      • Colman T.
      • Duran R.M.
      • Duran C.G.
      Analysis of the amount of tricuspid valve anular dilatation required to produce functional tricuspid regurgitation.
      Despite the general consent that RV dysfunction impacts the outcome of patients with TR, it is still unknown which echocardiographic parameters of RV function most accurately reflect prognosis.
      • Prihadi E.A.
      • van der Bijl P.
      • Dietz M.
      • et al.
      Prognostic implications of right ventricular free wall longitudinal strain in patients with significant functional tricuspid regurgitation.
      Measuring RV function remains challenging. The RV cavity has a crescent shape and its lateral free wall is thin and composed of predominantly transverse fibres, whereas the medial wall is formed by the left ventricular (LV) septum containing oblique helical fibres.
      • Ho S.Y.
      • Nihoyannopoulos P.
      Anatomy, echocardiography, and normal right ventricular dimensions.
      ,
      • Kocica M.J.
      • Corno A.F.
      • Carreras-Costa F.
      • et al.
      The helical ventricular myocardial band: global, three-dimensional, functional architecture of the ventricular myocardium.
      Echocardiographic assessment plays by far the most important role. Established echocardiographic parameters of RV dysfunction, such as tricuspid annular plane systolic excursion (TAPSE) and fractional area change (FAC), derived from 2-dimensional transthoracic echocardiography, rely on geometric assumptions that are load- and angle-dependent and come with certain limitations. Measurement of TAPSE in the lateral tricuspid annulus extrapolates the shortening of the entire RV wall, RV FAC reflects the change in volume without considering the direction of flow. Therefore, patients with TR can have normal values even when a significant amount of blood flow is retrograde. Strain imaging, on the contrary, analyses motion by tracking speckles in the ultrasonic image and allows assessment of myocardial function.
      • Prihadi E.A.
      • van der Bijl P.
      • Dietz M.
      • et al.
      Prognostic implications of right ventricular free wall longitudinal strain in patients with significant functional tricuspid regurgitation.
      ,
      • Leitman M.
      • Lysyansky P.
      • Sidenko S.
      • et al.
      Two-dimensional strain---a novel software for real-time quantitative echocardiographic assessment of myocardial function.
      ,
      • Perk G.
      • Tunick P.A.
      • Kronzon I.
      Non-Doppler two-dimensional strain imaging by echocardiography---from technical considerations to clinical applications.
      RV strain has shown prognostic importance in patients with pulmonary hypertension,
      • Haeck M.L.A.
      • Scherptong R.W.C.
      • Marsan N.A.
      • et al.
      Prognostic value of right ventricular longitudinal peak systolic strain in patients with pulmonary hypertension.
      • Sachdev A.
      • Villarraga H.R.
      • Frantz R.P.
      • et al.
      Right ventricular strain for prediction of survival in patients with pulmonary arterial hypertension.
      • van Kessel M.
      • Seaton D.
      • Chan J.
      • et al.
      Prognostic value of right ventricular free wall strain in pulmonary hypertension patients with pseudo-normalized tricuspid annular plane systolic excursion values.
      reduced LV ejection fraction,
      • Carluccio E.
      • Biagioli P.
      • Alunni G.
      • et al.
      Prognostic value of right ventricular dysfunction in heart failure with reduced ejection fraction: superiority of longitudinal strain over tricuspid annular plane systolic excursion.
      and severe TR.
      • Prihadi E.A.
      • van der Bijl P.
      • Dietz M.
      • et al.
      Prognostic implications of right ventricular free wall longitudinal strain in patients with significant functional tricuspid regurgitation.
      Its impact on patients with mild or moderate TR remains unclear but may be of importance because RV dysfunction is closely related to TR.
      In this study we aimed to evaluate the prevalence of RV dysfunction and its prognostic value as an echocardiographic characteristic in patients with mild to severe TR.

      Methods

      Patient population

      In this retrospective observational cohort study, we analysed data from 1089 consecutive patients undergoing transthoracic echocardiography, irrespective of the indication, at a single tertiary care center from 2010 to 2016. Cases were identified via automated query of the echocardiography database. Patients with complete echocardiographic examinations were included and followed for 2-year all-cause mortality. Patients’ flow is shown in Supplemental Figure S1.

      Data collection and outcome definition

      Demographics and clinical data, including relevant comorbidities and laboratory results, were collected retrospectively from the hospital database.
      Echocardiographic examinations were performed with commercially available ultrasound systems (Vivid 7 and E9, GE-Vingmed, Horten, Norway) by trained physicians. Complete echocardiograms included 2-dimensional, pulsed-wave, continuous-wave, and color Doppler imaging. The original images were prospectively reanalysed. The images of 1 patient were analysed by 1 investigator. Investigators were blinded with regard to the endpoint. Standard echocardiographic measurements for evaluation of left atrial (LA) size and LV geometry and function were performed according to the guidelines of the American Society of Echocardiography.
      • Lang R.M.
      • Badano L.P.
      • Mor-Avi V.
      • et al.
      Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging.
      TR determination was conducted in line with current recommendations and guidelines using color flow Doppler jet area, vena contracta, and proximal isovelocity area/effective regurgitant orifice area measurement. TR was graded in 4 stages: none, mild, moderate, and severe.
      • Nishimura R.A.
      • Otto C.M.
      • Bonow R.O.
      • et al.
      2014 AHA/ACC guideline for the management of patients with valvular heart disease: Executive summary: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines.
      ,
      • Vahanian A.
      • Alfieri O.
      • Andreotti F.
      • et al.
      Guidelines on the management of valvular heart disease (version 2012).
      TAPSE was calculated on M-mode recordings. On a 2-dimensional RV-focussed 4-chamber view RV FAC and RV free wall longitudinal strain measurements were performed (Q-Analysis, EchoPAC version 202, GE-Vingmed). Echocardiographic measurements of RV strain, TAPSE, and FAC are shown in Supplemental Figure S2.
      Data for survival rates were collected from the hospital database and from primary care physicians via telephone interview. Patients were followed for 2-year all-cause mortality. The primary endpoint was defined as prevalence of RV dysfunction according to the 3 different echocardiographic approaches (TAPSE, FAC, and RV strain) and their prognostic value for survival in patients with TR.
      Chronic kidney disease was defined according to kidney damage with glomerular filtration rate < 60 mL/min per 1.73 m2 using the Chronic Kidney Disease‒Epidemiology Collaboration creatinine equation for estimation, irrespective of cause.
      • Levey A.S.
      • Eckardt K.U.
      • Tsukamoto Y.
      • et al.
      Definition and classification of chronic kidney disease: a position statement from Kidney Disease: Improving Global Outcomes (KDIGO).
      ,
      • Levey A.S.
      • Stevens L.A.
      Estimating GFR using the CKD Epidemiology Collaboration (CKD-EPI) creatinine equation: more accurate GFR estimates, lower CKD prevalence estimates, and better risk predictions.
      Our study was approved by the local ethics committee of the State of Brandenburg (AS 155(bB)/2017) and conducted in accordance with the Declaration of Helsinki. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) recommendations for reporting observational studies were applied.
      • von Elm E.
      • Altman D.G.
      • Egger M.
      • Pocock S.J.
      • Gotzsche P.C.
      • Vandenbroucke J.P.
      The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies.

      Statistics

      Continuous variables are reported as mean and standard deviation (SD), if normally distributed, or median with interquartile range (IQR), respectively, if not normally distributed. Categorical variables are expressed as absolute numbers and/or percentages. Unpaired Student t test, Mann-Whitney U test, and the χ2 test were used when appropriate to test for differences between groups. Pearson correlation coefficients were calculated to measure the strength of association between variables.
      Univariate analysis was performed to assess the association of demographic and echocardiographic parameters and comorbidities with 2-year mortality. This analaysis included RV strain, TAPSE, FAC, LV ejection fraction (LVEF) < 50%, aortic stenosis (AS), mitral regurgitation, TR Vmax as surrogate for pulmonary hypertension, sex, and age. Variables with a univariate P < 0.2 were included in the multivariable analysis with Cox regression comprised of RV strain, TAPSE, FAC, LVEF < 50%, AS, sex, and age. Results are presented as adjusted hazard ratio (HR) with 95% confidence interval (CI).
      Optimal cutoffs for sensitivity and specificity of RV strain, TAPSE, and FAC were chosen using C statistics with receiver-operator characteristics (ROC) and calculation of the area under the curve (AUC). As additional analyses for model improvement, category-free net reclassification (cfNRI), and integrated discrimination improvement (IDI) were assessed. Both cfNRI and IDI are based on predicted probabilities for survival from logistic regression analyses with TR grade alone (as nominal variable, reference model) compared with the extended model with TR grade plus parameters of RV function. Whereas cfNRI expresses the model improvement as rate of patients with improvements in the predicted probabilities (independent of the amount of improvement in the single person), IDI assesses the mean change in the individual predicted probabilities (see Supplemental Appendix S1). Kaplan-Meier curves were used to display survival.
      P ≤ 0.05 was considered statistically significant. Statistical analysis was performed using SPSS Statistics version 26.0 (IBM Corp, Armonk, NY) with the Matrix extension.

      Results

      Baseline characteristics

      Of all 1089 consecutive patients, 151 (13.9%) patients showed no TR, 667 (61.2%) mild TR, 213 (19.6%) moderate TR, and 58 (5.3%) severe functional TR (Supplemental Table S1).
      Patients were predominantly male (58.6% male) and overweight (body mass index, 27.9 ± 5.0 kg/m2). LV systolic function was impaired (ie, LVEF < 55%) in approximately half of the patients in the study cohort (50.8%). A significant number of patients suffered from aortic and mitral valve disease. Pulmonary hypertension was possible or likely in almost half of the patients according to echocardiographic assessment.
      Of the patients, 58.8% had a history of coronary artery disease, 50.8% of atrial fibrillation, and 69.5% of dyslipidemia. Arterial hypertension was seen in 92.1% and impaired kidney function in 45.9% of the patients.
      Median N-terminal pro‒brain natriuretic peptide (IQR, 2107-3991 pg/mL) and mean creatinine serum levels (96.2 μmol/L; SD, 60.1 μmol/L) were elevated.
      One hundred sixty-six (15.2%) patients died within the study period. Mean follow-up duration was 672 (95% CI, 663-681) days. Nonsurvivors were older and more often had impaired LV and RV function as well as dilated cardiac chambers, and more frequently exhibited TR, AS, mitral regurgitation, and pulmonary hypertension. N-terminal pro‒brain natriuretic peptide and creatinine levels were higher in patients who died within in the study period. Patients’ characteristics are shown in detail in Supplemental Table S1.
      Cutoffs for optimal sensitivity and specificity of RV functional parameters were chosen as: RV strain > −18%; TAPSE <18.5 mm, and FAC < 35%. Accordingly, the number of patients with RV dysfunction as defined using determined cutoff values varied regarding the different echocardiographic parameters: TAPSE, n = 450 of 1089 (41.3%); FAC, n = 462 of 1074 (42.4%); and RV strain, n = 279 of 757 (36.9%).

      Long-term survival

      Higher TR grades were associated with increased mortality over time (log rank, P < 0.001) (Fig. 1).
      Figure thumbnail gr1
      Figure 1Kaplan-Meier analysis according to grade of TR: none, mild, moderate, and severe. TR is associated with an increased mortality (n = 1089). TR, tricuspid regurgitation.
      After adjustment for cardiac and noncardiac risk factors, RV strain, TAPSE, and FAC were independently associated with all-cause 2-year mortality (RV strain: HR, 1.130; 95% CI, 1.099-1.160; P < 0.001; TAPSE: HR, 1.131; 95% CI, 1.085-1.175; P < 0.001; FAC: HR, 1.015; 95% CI, 1.001-1.029; P = 0.036) (Table 1). Also, LVEF < 50%, age, and aortic stenosis were independent risk factors (n = 757).
      Table 1Cox regression analysis for all-cause 2-year mortality
      VariableHazard ratio95% CIP value
      LVEF < 50%3.3202.157-5.110< 0.001
      P ≤ 0.05 (statistically significant).
      AS grade1.2991.110-1.5210.001
      P ≤ 0.05 (statistically significant).
      TAPSE, mm1.1311.085-1.175< 0.001
      P ≤ 0.05 (statistically significant).
      RV free wall longitudinal strain, %1.1301.099-1.160< 0.001
      P ≤ 0.05 (statistically significant).
      Age, years1.0381.017-1.059< 0.001
      P ≤ 0.05 (statistically significant).
      FAC, %1.0151.001-1.0290.036
      P ≤ 0.05 (statistically significant).
      Sex female0.7450.516-1.0760.117
      Cox regression analysis is shown for all-cause 2-year mortality including cardiac and noncardiac risk factors in patients with mild, moderate, and severe TR for variables with P ≤ 0.200 in the univariate analysis. Univariate analysis included RV free wall longitudinal strain, TAPSE, FAC, LVEF, AS, and MR. Tricuspid regurgitation Vmax was surrogate for pulmonary hypertension, sex, and age (n = 757).
      AS, aortic stenosis; CI, confidence interval; EF, ejection fraction; FAC, fractional area change; LV, left ventricular; LVEF, left ventricular ejection fraction; MR, mitral regurgitation; RV, right ventricular; RV strain, RV free wall longitudinal strain; TAPSE, tricuspid annulus plane systolic excursion.
      P ≤ 0.05 (statistically significant).
      Grade of TR showed a low to moderate predictive value for survival, with an AUC of 0.625 (95% CI, 0.577-0.672; P < 0.001). The AUC for RV strain was 0.823 (95% CI, 0.786-0.860; P < 0.001; TAPSE: AUC, 0.776; 95% CI, 0.740-0.812; P < 0.001; FAC: AUC, 0.569; 95% CI, 0.514-0.624; P = 0.012) (Fig. 2).
      Figure thumbnail gr2
      Figure 2Receiver-operator characteristic curves for RV strain (AUC, 0.823; 95% CI, 0.786-0.860; P < 0.001; n = 757), TAPSE (AUC, 0.776; 95% CI, 0.740-0.812; P < 0.001; n = 1,089), and FAC (AUC, 0.569; 95% CI, 0.514-0.624; P = 0.012; n = 1,074). Endpoint was 2-year all-cause mortality. AUC, area under the curve; CI, confidence interval; FAC, fractional area change; RV strain, right ventricular free wall longitudinal strain; TAPSE, tricuspid annulus plane systolic excursion.
      Reclassification analysis for survival, for events, and non-events, using cfNRI, IDI, and AUC difference showed improvement of the reference model (TR grade) for RV strain and TAPSE (Table 2). FAC improved prediction of events but not non-events. There was significant interaction between TR grade and RV strain (P < 0.001), but not TR grade and TAPSE or FAC (P = 0.361 and P = 0.533, respectively).
      Table 2Reclassification analysis for model improvement of RV functional parameters
      RV strain, n = 757TAPSE, n = 1089FAC, n = 1074
      Estimate (95% CI)P valueEstimate (95% CI)P valueEstimate (95% CI)P value
      cfNRIevents0.549 (0.407-0.691)< 0.001
      P ≤ 0.05 (statistically significant).
      0.313 (0.169-0.458)< 0.001
      P ≤ 0.05 (statistically significant).
      0.277 (0.131-0.423)< 0.001
      P ≤ 0.05 (statistically significant).
      cfNRInon-events0.353 (0.279-0.426)< 0.001
      P ≤ 0.05 (statistically significant).
      0.309 (0.247-0.370)< 0.001
      P ≤ 0.05 (statistically significant).
      0.033 (−0.032 to 0.098)0.3192
      cfNRI0.901 (0.742-1.061)< 0.001
      P ≤ 0.05 (statistically significant).
      0.622 (0.465-0.779)< 0.001
      P ≤ 0.05 (statistically significant).
      0.310 (0.150-0.470)< 0.001
      P ≤ 0.05 (statistically significant).
      IDIevents0.199 (0.163-0.235)< 0.001
      P ≤ 0.05 (statistically significant).
      0.069 (0.050-0.088)< 0.001
      P ≤ 0.05 (statistically significant).
      0.016 (0.005-0.026)0.003
      P ≤ 0.05 (statistically significant).
      IDInon-events−0.015 (−0.026 to −0.004)0.008
      P ≤ 0.05 (statistically significant).
      −0.012 (−0.019 to −0.006)< 0.001
      P ≤ 0.05 (statistically significant).
      −0.001 (−0.004 to 0.002)0.720
      IDI0.184 (0.146-0.221)< 0.001
      P ≤ 0.05 (statistically significant).
      0.057 (0.037-0.077)< 0.001
      P ≤ 0.05 (statistically significant).
      0.015 (0.004-0.026)0.006
      P ≤ 0.05 (statistically significant).
      AUCdifference0.218 ((0.170-0.265)< 0.001
      P ≤ 0.05 (statistically significant).
      0.135 (0.095-0.174)< 0.001
      P ≤ 0.05 (statistically significant).
      0.035 (0.002-0.067)0.035
      P ≤ 0.05 (statistically significant).
      The cfNRI and IDI of TR grade and TR grade plus parameters of RV function include interaction of both vs TR grade alone. Endpoint was all-cause 2-year mortality. RV functional parameters show incremental prognostic value beyond TR, with RV strain being superior to TAPSE and FAC.
      AUC, area under the curve; cfNRI, category-free net reclassification improvement; FAC, fractional area change; IDI, integrated discrimination improvement; RV, right ventricular; RV strain, RV free wall longitudinal strain; TAPSE, tricuspid annulus plane systolic excursion; TR, tricuspid regurgitation.
      P ≤ 0.05 (statistically significant).
      The greatest increase in AUC was observed for RV strain, with an AUC difference of 0.218 (95% CI, 0.170-0.265; P < 0.001), superior to TAPSE and FAC (Fig. 3). The marker-extended model also included the interaction between TR grade and RV function.
      Figure thumbnail gr3
      Figure 3AUC values for grade of TR alone (black) and improved predictive values for additional right ventricular parameters: RV strain (blue), n = 757; TAPSE (red), n = 1,089; and FAC (green), n = 1,074, respectively. Endpoint was 2-year mortality. ∗P ≤ 0.05 considered statistically significant. AUC, area under the curve; CI, confidence interval; FAC, fractional area change; RV strain, right ventricular free wall longitudinal strain; TAPSE, tricuspid annulus plane systolic excursion; TR, tricuspid regurgitation.
      Kaplan-Meier analysis revealed significantly worse survival in patients with impaired RV function, namely RV strain > −18%, TAPSE < 18.5 mm, and FAC < 35% (Fig. 4).
      Figure thumbnail gr4
      Figure 4Kaplan-Meier analysis (A) in patients with all grades of TR according to RV strain < −18% and ≥ −18% (n = 757), (B) according to TAPSE ≥ 18.5 mm and < 18.5 mm (n = 1089), and (C) according to FAC ≥ 35% and < 35% (n = 1074). Cutoff values for RV functional parameters were determined using receiver-operator characteristics. FAC, fractional area change; RV strain, right ventricular free wall longitudinal strain; TAPSE, tricuspid annulus plane systolic excursion; TR, tricuspid regurgitation.

      RV pacing

      A total of 36.5% of the patients had a cardiac implantable device. Incidences of internal cardioverter-defibrillator (ICD), pacemaker, cardiac resynchronisation therapy defibrillator/pacemaker (CRT-D/P), and subcutaneous ICD (S-ICD), as well as pacing burden data, are shown in Supplemental Table S1. There was no correlation between RV strain, TAPSE, and FAC and RV pacing (RV strain: R = −0.24, P = 0.730; TAPSE: R = −0.04, P = 0.474; FAC: R = −0.06, P = 0.263). In the univariate model, RV pacing had no significant impact on survival (R = −0.12, P = 0.051).

      Discussion

      In this study we have investigated the prevalence of RV dysfunction and its prognostic value for survival in patients with mild to severe functional TR. To assess RV function, we used RV strain in addition to the conventional measures of TAPSE and FAC.
      Functional TR was present in approximately 86% of patients, with moderate and severe TR in 25% of them. TR had a significant impact on survival. RV dysfunction, assessed by RV strain, was detected in approximately 40% of cases. RV strain, TAPSE, and FAC were independently associated with all-cause 2-year mortality. RV functional parameters showed incremental prognostic value beyond TR, with RV strain being superior to TAPSE and FAC.
      TR is a frequent finding in echocardiography; it has become a known risk factor for mortality in various patient cohorts.
      • Nath J.
      • Foster E.
      • Heidenreich P.A.
      Impact of tricuspid regurgitation on long-term survival.
      ,
      • Bannehr M.
      • Kahn U.
      • Okamoto M.
      • et al.
      Post-procedural tricuspid regurgitation predicts long-term survival in patients undergoing percutaneous mitral valve repair.
      • Koelling T.M.
      • Aaronson K.D.
      • Cody R.J.
      • Bach D.S.
      • Armstrong W.F.
      Prognostic significance of mitral regurgitation and tricuspid regurgitation in patients with left ventricular systolic dysfunction.
      • Coffey S.
      • Rayner J.
      • Newton J.
      • Prendergast B.D.
      Right-sided valve disease.
      • Benfari G.
      • Antoine C.
      • Miller W.L.
      • et al.
      Excess mortality associated with functional tricuspid regurgitation complicating heart failure with reduced ejection fraction.
      • Varadarajan P.
      • Pai R.G.
      Prognostic implications of tricuspid regurgitation in patients with severe aortic regurgitation: results from a cohort of 756 patients.
      • Pettersson G.B.
      • Rodriguez L.L.
      • Blackstone E.H.
      Severe tricuspid valve regurgitation is not an innocent finding to be ignored!.
      Functional TR is an abnormality in the context of tricuspid annular dilation due to RV dilation and RV dysfunction. In line with previous research, in the present study TR was secondary mainly because of left-sided heart disease.
      • Dreyfus G.D.
      • Martin R.P.
      • Chan K.M.
      • Dulguerov F.
      • Alexandrescu C.
      Functional tricuspid regurgitation: a need to revise our understanding.
      Although implantable cardiac devices were present in approximately one third of our study cohort, TR did not appear primarily due to RV-lead interference with the TV, based on echocardiographic assessment. RV pacing has been associated with adverse outcomes.
      • Kiehl E.L.
      • Makki T.
      • Kumar R.
      • et al.
      Incidence and predictors of right ventricular pacing-induced cardiomyopathy in patients with complete atrioventricular block and preserved left ventricular systolic function.
      ,
      • Sweeney M.O.
      • Hellkamp A.S.
      • Ellenbogen K.A.
      • et al.
      Adverse effect of ventricular pacing on heart failure and atrial fibrillation among patients with normal baseline QRS duration in a clinical trial of pacemaker therapy for sinus node dysfunction.
      In this study, however, RV pacing in relation to survival slightly missed the significance level.
      RV dysfunction has been shown to impact long-term survival. Diminished RV strain is associated with worse outcome in patients with pulmonary hypertension, reduced LV function, and severe TR.
      • Prihadi E.A.
      • van der Bijl P.
      • Dietz M.
      • et al.
      Prognostic implications of right ventricular free wall longitudinal strain in patients with significant functional tricuspid regurgitation.
      ,
      • Haeck M.L.A.
      • Scherptong R.W.C.
      • Marsan N.A.
      • et al.
      Prognostic value of right ventricular longitudinal peak systolic strain in patients with pulmonary hypertension.
      • Sachdev A.
      • Villarraga H.R.
      • Frantz R.P.
      • et al.
      Right ventricular strain for prediction of survival in patients with pulmonary arterial hypertension.
      • van Kessel M.
      • Seaton D.
      • Chan J.
      • et al.
      Prognostic value of right ventricular free wall strain in pulmonary hypertension patients with pseudo-normalized tricuspid annular plane systolic excursion values.
      • Carluccio E.
      • Biagioli P.
      • Alunni G.
      • et al.
      Prognostic value of right ventricular dysfunction in heart failure with reduced ejection fraction: superiority of longitudinal strain over tricuspid annular plane systolic excursion.
      However, to our knowledge, our study is the first to show that RV strain is an independent risk factor for 2-year all-cause mortality in patients with all degrees of functional TR, even mild and moderate.
      In patients with mild TR, which accounts for approximately 60% of TR patients, RV dilation cannot be expected. Significant RV enlargement was present in about 20% of patients, whereas 25% showed moderate to severe TR. This appears plausible because RV dilation primarily occurs if there is significant TR and vice versa.
      TR and RV dysfunction appear closely related---with both having an impact on survival. However, the reason for excess mortality remains to be determined. In our opinion, TR may in many cases be interpreted as an epiphenomenon of another underlying structural cardiopulmonary disease. This hypothesis is supported by the fact that many patients encountered in everyday clinical practice who, after an intervention involving the mitral valve or aortic valve, show a clear improvement in TR. Clarification of this issue in long-term, large-scale registries with hemodynamic data from right heart catheterisation would be desirable for patients undergoing left heart intervention, such as transcatheter aortic valve replacement or percutaneous mitral valve repair.
      Assessment of RV function is challenging, mostly because of the anatomy of the RV. Different echocardiographic approaches are used in clinical practice, above all TAPSE and FAC. However, these conventional measures have limited implications as they are prone to overestimate RV function in the presence of TR.
      • Leitman M.
      • Lysyansky P.
      • Sidenko S.
      • et al.
      Two-dimensional strain---a novel software for real-time quantitative echocardiographic assessment of myocardial function.
      ,
      • Perk G.
      • Tunick P.A.
      • Kronzon I.
      Non-Doppler two-dimensional strain imaging by echocardiography---from technical considerations to clinical applications.
      In contrast, RV strain allows assessment of myocardial function through analysis of deformation, setting aside geometric assumptions or extrapolations, and is therefore independent from TV reflux.
      • Leitman M.
      • Lysyansky P.
      • Sidenko S.
      • et al.
      Two-dimensional strain---a novel software for real-time quantitative echocardiographic assessment of myocardial function.
      ,
      • Perk G.
      • Tunick P.A.
      • Kronzon I.
      Non-Doppler two-dimensional strain imaging by echocardiography---from technical considerations to clinical applications.
      This may be the reason why it has appeared to be the most sensitive parameter with prognostic value in our study, especially in patients with moderate and severe TR, and has been postulated as being superior for detection of RV dysfunction in other settings, such as pulmonary hypertension.
      • Prihadi E.A.
      • van der Bijl P.
      • Dietz M.
      • et al.
      Prognostic implications of right ventricular free wall longitudinal strain in patients with significant functional tricuspid regurgitation.
      ,
      • Sachdev A.
      • Villarraga H.R.
      • Frantz R.P.
      • et al.
      Right ventricular strain for prediction of survival in patients with pulmonary arterial hypertension.
      ,
      • van Kessel M.
      • Seaton D.
      • Chan J.
      • et al.
      Prognostic value of right ventricular free wall strain in pulmonary hypertension patients with pseudo-normalized tricuspid annular plane systolic excursion values.
      RV strain also showed a stronger correlation with RVEF, according to cardiac magnetic resonance imaging (MRI), than conventional parameters, and seemed to be more sensitive in detecting myocardial dysfunction at an earlier, subclinical stage.
      • Longobardo L.
      • Suma V.
      • Jain R.
      • et al.
      Role of two-dimensional speckle-tracking echocardiography strain in the assessment of right ventricular systolic function and comparison with conventional parameters.
      ,
      • Smolarek D.
      • Gruchała M.
      • Sobiczewski W.
      Echocardiographic evaluation of right ventricular systolic function: the traditional and innovative approach.
      Although MRI may be the “gold standard” to assess RV function, it does not appear to be feasible in clinical routine. Therefore, it seems important to further explore echocardiographic approaches to accurately assess RV function.

      Study limitations

      Our study was performed retrospectively at a single center. Parameters of RV function could not be reanalyzed in all patients. RV strain measurements are influenced by the quality of the acoustic window, limiting the generalisability of our study findings. Thus, sample size was reduced for consequent analysis. Assessment of TR grade included semiquantitative and quantitative echocardiographic parameters. TR is known to fluctuate and to be load-dependent. Standards for evaluation of TR are less robust than for mitral or aortic valve disease.
      Heart rate and blood pressure, which may impact TR, could not be obtained retrospectively. Echocardiographic images of 1 patient were reanalyzed by 1 investigator only. Interobserver differences cannot be excluded.

      Clinical implications

      Reduced RV strain appears to be a potential risk factor for long-term survival, even in patients with less-than-severe TR. If TR is present, echocardiographic evaluation of RV function appears to be of interest. Assessment of RV strain is a promising approach with prognostic implications for survival. Closer monitoring and follow-up of patients with impaired RV function according to RV strain will be informative.
      It remains unknown whether TV intervention is the best approach. Surgical TV annuloplasty has only shown promising results in the context of concomitant mitral and aortic valve surgery.
      • Goldstone A.B.
      • Howard J.L.
      • Cohen J.E.
      • et al.
      Natural history of coexistent tricuspid regurgitation in patients with degenerative mitral valve disease: implications for future guidelines.
      Isolated TV surgery has been associated with a high rate of mortality.
      • Kim J.B.
      • Jung S.H.
      • Choo S.J.
      • Chung C.H.
      • Lee J.W.
      Clinical and echocardiographic outcomes after surgery for severe isolated tricuspid regurgitation.
      ,
      • Baumgartner H.
      • Falk V.
      • Bax J.J.
      • et al.
      2017 ESC/EACTS guidelines for the management of valvular heart disease.
      Thus, the current guidelines are cautious when it comes to recommendations for TV surgery.
      • Baumgartner H.
      • Falk V.
      • Bax J.J.
      • et al.
      2017 ESC/EACTS guidelines for the management of valvular heart disease.
      Overall, data are scarce and optimal timing remains somewhat unclear. Transcatheter solutions may be a promising approach in the future as they are less invasive. However, all interventional devices are still in development and are far from incorporation into clinical practice.
      • Hahn R.T.
      Current transcatheter devices to treat functional tricuspid regurgitation with discussion of issues relevant to clinical trial design.
      In conclusion, in patients with TR, echocardiographic evaluation of RV function appears to be useful. Assessment of RV strain provides additional value for prediction of 2-year mortality. Further studies are needed to characterise the interaction between TR and RV dysfunction.

      Funding Sources

      This research was funded by the Deutsche Stiftung für Herzforschung (grant ID FKZ: F57/17).

      Disclosures

      The authors have no conflicts of interest to disclose.

      Supplementary Material

      References

        • Dreyfus G.D.
        • Martin R.P.
        • Chan K.M.
        • Dulguerov F.
        • Alexandrescu C.
        Functional tricuspid regurgitation: a need to revise our understanding.
        J Am Coll Cardiol. 2015; 65: 2331-2336
        • Dreyfus G.D.
        • Corbi P.J.
        • Chan K.M.
        • Bahrami T.
        Secondary tricuspid regurgitation or dilatation: which should be the criteria for surgical repair?.
        Ann Thorac Surg. 2005; 79: 127-132
        • Nath J.
        • Foster E.
        • Heidenreich P.A.
        Impact of tricuspid regurgitation on long-term survival.
        J Am Coll Cardiol. 2004; 43: 405-409
        • Prihadi E.A.
        • van der Bijl P.
        • Dietz M.
        • et al.
        Prognostic implications of right ventricular free wall longitudinal strain in patients with significant functional tricuspid regurgitation.
        Circ Cardiovasc Imaging. 2019; 12e008666
        • Ubago J.L.
        • Figueroa A.
        • Ochoteco A.
        • Colman T.
        • Duran R.M.
        • Duran C.G.
        Analysis of the amount of tricuspid valve anular dilatation required to produce functional tricuspid regurgitation.
        Am J Cardiol. 1983; 52: 155-158
        • Ho S.Y.
        • Nihoyannopoulos P.
        Anatomy, echocardiography, and normal right ventricular dimensions.
        Heart. 2006; 92: i2-13
        • Kocica M.J.
        • Corno A.F.
        • Carreras-Costa F.
        • et al.
        The helical ventricular myocardial band: global, three-dimensional, functional architecture of the ventricular myocardium.
        Eur J Cardiothorac Surg. 2006; 29: S21-40
        • Leitman M.
        • Lysyansky P.
        • Sidenko S.
        • et al.
        Two-dimensional strain---a novel software for real-time quantitative echocardiographic assessment of myocardial function.
        J Am Soc Echocardiogr. 2004; 17: 1021-1029
        • Perk G.
        • Tunick P.A.
        • Kronzon I.
        Non-Doppler two-dimensional strain imaging by echocardiography---from technical considerations to clinical applications.
        J Am Soc Echocardiogr. 2007; 20: 234-243
        • Haeck M.L.A.
        • Scherptong R.W.C.
        • Marsan N.A.
        • et al.
        Prognostic value of right ventricular longitudinal peak systolic strain in patients with pulmonary hypertension.
        Circ Cardiovasc Imaging. 2012; 5: 628-636
        • Sachdev A.
        • Villarraga H.R.
        • Frantz R.P.
        • et al.
        Right ventricular strain for prediction of survival in patients with pulmonary arterial hypertension.
        Chest. 2011; 139: 1299-1309
        • van Kessel M.
        • Seaton D.
        • Chan J.
        • et al.
        Prognostic value of right ventricular free wall strain in pulmonary hypertension patients with pseudo-normalized tricuspid annular plane systolic excursion values.
        Int J Cardiovasc Imaging. 2016; 32: 905-912
        • Carluccio E.
        • Biagioli P.
        • Alunni G.
        • et al.
        Prognostic value of right ventricular dysfunction in heart failure with reduced ejection fraction: superiority of longitudinal strain over tricuspid annular plane systolic excursion.
        Circ Cardiovasc Imaging. 2018; 11 (e006894-e006894)
        • Lang R.M.
        • Badano L.P.
        • Mor-Avi V.
        • et al.
        Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging.
        J Am Soc Echocardiogr. 2015; 28 (e14): 1-39
        • Nishimura R.A.
        • Otto C.M.
        • Bonow R.O.
        • et al.
        2014 AHA/ACC guideline for the management of patients with valvular heart disease: Executive summary: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines.
        Circulation. 2014; 129: 2440-2492
        • Vahanian A.
        • Alfieri O.
        • Andreotti F.
        • et al.
        Guidelines on the management of valvular heart disease (version 2012).
        Eur Heart J. 2012; 33: 2451-2496
        • Levey A.S.
        • Eckardt K.U.
        • Tsukamoto Y.
        • et al.
        Definition and classification of chronic kidney disease: a position statement from Kidney Disease: Improving Global Outcomes (KDIGO).
        Kidney Int. 2005; 67: 2089-2100
        • Levey A.S.
        • Stevens L.A.
        Estimating GFR using the CKD Epidemiology Collaboration (CKD-EPI) creatinine equation: more accurate GFR estimates, lower CKD prevalence estimates, and better risk predictions.
        Am J Kidney Dis. 2010; 55: 622-627
        • von Elm E.
        • Altman D.G.
        • Egger M.
        • Pocock S.J.
        • Gotzsche P.C.
        • Vandenbroucke J.P.
        The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies.
        Lancet. 2007; 370: 1453-1457
        • Bannehr M.
        • Kahn U.
        • Okamoto M.
        • et al.
        Post-procedural tricuspid regurgitation predicts long-term survival in patients undergoing percutaneous mitral valve repair.
        J Cardiol. 2019; 74: 524-531
        • Koelling T.M.
        • Aaronson K.D.
        • Cody R.J.
        • Bach D.S.
        • Armstrong W.F.
        Prognostic significance of mitral regurgitation and tricuspid regurgitation in patients with left ventricular systolic dysfunction.
        Am Heart J. 2002; 144: 524-529
        • Coffey S.
        • Rayner J.
        • Newton J.
        • Prendergast B.D.
        Right-sided valve disease.
        Int J Clin Pract. 2014; 68: 1221-1226
        • Benfari G.
        • Antoine C.
        • Miller W.L.
        • et al.
        Excess mortality associated with functional tricuspid regurgitation complicating heart failure with reduced ejection fraction.
        Circulation. 2019;
        • Varadarajan P.
        • Pai R.G.
        Prognostic implications of tricuspid regurgitation in patients with severe aortic regurgitation: results from a cohort of 756 patients.
        Interact Cardiovasc Thorac Surg. 2012; 14: 580-584
        • Pettersson G.B.
        • Rodriguez L.L.
        • Blackstone E.H.
        Severe tricuspid valve regurgitation is not an innocent finding to be ignored!.
        JACC Cardiovasc Imaging. 2014; 7: 1195-1197
        • Kiehl E.L.
        • Makki T.
        • Kumar R.
        • et al.
        Incidence and predictors of right ventricular pacing-induced cardiomyopathy in patients with complete atrioventricular block and preserved left ventricular systolic function.
        Heart Rhythm. 2016; 13: 2272-2278
        • Sweeney M.O.
        • Hellkamp A.S.
        • Ellenbogen K.A.
        • et al.
        Adverse effect of ventricular pacing on heart failure and atrial fibrillation among patients with normal baseline QRS duration in a clinical trial of pacemaker therapy for sinus node dysfunction.
        Circulation. 2003; 107: 2932-2937
        • Longobardo L.
        • Suma V.
        • Jain R.
        • et al.
        Role of two-dimensional speckle-tracking echocardiography strain in the assessment of right ventricular systolic function and comparison with conventional parameters.
        J Am Soc Echocardiogr. 2017; 30 (e936): 937-946
        • Smolarek D.
        • Gruchała M.
        • Sobiczewski W.
        Echocardiographic evaluation of right ventricular systolic function: the traditional and innovative approach.
        Cardiol J. 2017; 24: 563-572
        • Goldstone A.B.
        • Howard J.L.
        • Cohen J.E.
        • et al.
        Natural history of coexistent tricuspid regurgitation in patients with degenerative mitral valve disease: implications for future guidelines.
        J Thorac Cardiovasc Surg. 2014; 148: 2802-2809
        • Kim J.B.
        • Jung S.H.
        • Choo S.J.
        • Chung C.H.
        • Lee J.W.
        Clinical and echocardiographic outcomes after surgery for severe isolated tricuspid regurgitation.
        J Thorac Cardiovasc Surg. 2013; 146: 278-284
        • Baumgartner H.
        • Falk V.
        • Bax J.J.
        • et al.
        2017 ESC/EACTS guidelines for the management of valvular heart disease.
        Eur Heart J. 2017; 38: 2739-2791
        • Hahn R.T.
        Current transcatheter devices to treat functional tricuspid regurgitation with discussion of issues relevant to clinical trial design.
        Ann Cardiothorac Surg. 2017; 6: 240-247

      Linked Article

      • Right Ventricle Longitudinal Strain: A New Tool in Functional Tricuspid Regurgitation Prognostication
        Canadian Journal of CardiologyVol. 37Issue 7
        • Preview
          The second- or middle-child syndrome is a hypothetical condition whereby the middle child feels “left out” or underappreciated. Analogous to this is how the right ventricle (RV) and tricuspid valve have been treated compared with the left ventricle and mitral valve, respectively. Although a wealth of research has demonstrated the importance of the tricuspid valve and RV remodelling and function over the past 2 decades, there remain significant knowledge and treatment gaps.1
        • Full-Text
        • PDF