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Right Ventricular Dimension for Heart Failure With Preserved Ejection Fraction Involving Right Ventricular-Vascular Uncoupling

Open AccessPublished:August 04, 2022DOI:https://doi.org/10.1016/j.cjco.2022.07.014

      Abstract

      Background

      Right ventricular (RV) to pulmonary artery (PA) uncoupling is known to be important for the prognosis of not only heart failure (HF) with reduced ejection fraction but also HF with preserved ejection fraction (HFpEF). We further investigated key factors in the poor prognosis for HFpEF patients with RV-PA uncoupling.

      Methods

      We studied 817 patients with HFpEF who were discharged alive in a multicentred cohort using post hoc analyses, with a primary endpoint of cardiac mortality or HF readmission. A total of 288 RV-PA uncoupled patients were observed, namely those with a tricuspid annular plane systolic excursion (TAPSE)/PA systolic pressure (PASP) ratio < 0.46 mm/mm Hg.

      Results

      Among the RV-PA uncoupled patients, 101 adverse outcomes occurred over a median of 340 days. Echocardiographic RV dimension (RVD) was significantly important for prognosis in both univariable and multivariable Cox regression testing (hazard ratio 1.044, 95% confidence interval 1.014-1.074, P = 0.0042, and hazard ratio 1.036, 95% confidence interval 1.001-1.072, P = 0.0438, respectively) considered with the covariates of age, atrial fibrillation, renal function, N-terminal pro-brain natriuretic peptide, and other echocardiographic parameters. We further divided the patients into 4 groups, first into 2 groups with a TAPSE/PASP either ≥ or < 0.46 mm/mm Hg, and then into 4 groups by RVD medians of 31.9 mm and 33.3 mm, respectively. Kaplan-Meier curve analysis showed that outcomes were worst in patients with a low TAPSE/PASP ratio and larger RVD (log-rank P < 0.0001).

      Conclusions

      This multicentre observational study highlighted the further prognostic importance of larger RVD among HFpEF patients with RV-PA uncoupling.

      Résumé

      Contexte

      On sait que le découplage entre le ventricule droit (VD) et l’artère pulmonaire (AP) est important pour établir le pronostic de l’insuffisance cardiaque à fraction d’éjection réduite, mais également celui de l’insuffisance cardiaque à fraction d’éjection préservée (ICFEP). Nous avons étudié en détail les facteurs clés liés au pronostic défavorable de l'ICFEP chez les patients présentant un découplage VD-AP.

      Méthodologie

      À partir des données d’une cohorte multicentrique, nous avons réalisé des analyses a posteriori sur 817 patients présentant une ICFEP qui sont sortis de l’hôpital en vie, avec comme critère d’évaluation principal la mortalité d’origine cardiaque ou la réadmission en raison de l’insuffisance cardiaque. Au total, 288 patients affichant un découplage VD-AP ont été observés, principalement ceux dont le rapport excursion systolique dans le plan annulaire tricuspide (TAPSE; tricuspid annular plane systolic excursion)-pression artérielle pulmonaire systolique (PAPs) était < 0,46 mm/mm Hg.

      Résultats

      Au total, 101 événements indésirables ont été recensés sur une période médiane de 340 jours chez les patients qui présentaient un découplage VD-AP. La dimension ventriculaire droite mesurée par échocardiographie était un facteur pronostique significativement important dans les analyses de régression de Cox à une et à plusieurs variables (rapport des risques instantanés [RRI] : 1,044; intervalle de confiance à 95 % : 1,014 à 1,074; p : 0,0042; et RRI : 1,036; intervalle de confiance à 95 % : 1,001 à 1,072; p : 0,0438; respectivement) avec prise en compte des covariables de l’âge, de la fibrillation auriculaire, de la fonction rénale, du fragment N-terminal du propeptide natriurétique de type B, et d’autres paramètres échocardiographiques. Nous avons ensuite réparti les patients en quatre groupes, d’abord en deux groupes, selon que leur rapport TAPSE-PAPs était ≥ ou < 0,46 mm/mm Hg, puis en quatre groupes selon des dimensions ventriculaires droites médianes de 31,9 et de 33,3 mm, respectivement. L’analyse de la courbe de Kaplan-Meier a révélé des résultats moins favorables chez les patients qui présentaient un faible rapport TAPSE-PAPs et une grande dimension ventriculaire droite (valeur de p < 0,0001 selon le test du log-rank).

      Conclusions

      Cette étude observationnelle multicentrique a mis en évidence l’importance d’une grande dimension ventriculaire droite dans l’établissement du pronostic chez les patients atteints d'ICFEP qui présentent un découplage VD-AP.

      Graphical abstract

      Figure thumbnail fx1
      Graphical AbstractLarger right ventricular dimension is significantly associated with a composite endpoint of cardiac mortality or heart failure re-admission among patients with heart failure with preserved ejection fraction and right ventricular to pulmonary arterial uncoupling.
      Heart failure (HF) with preserved ejection fraction (HFpEF) is a diverse syndrome,
      • Shah S.J.
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      • Borlaug B.A.
      • et al.
      Phenotype-specific treatment of heart failure with preserved ejection fraction: a multiorgan roadmap.
      and therapeutic strategies based on the clinical phenotypes have been proposed.
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      • Gavazzi A.
      • et al.
      New strategies for heart failure with preserved ejection fraction: the importance of targeted therapies for heart failure phenotypes.
      The pathophysiological importance of right ventricular (RV)-pulmonary artery (PA) uncoupling in HFpEF patients has received particular attention.
      • Guazzi M.
      • Dixon D.
      • Labate V.
      • et al.
      RV contractile function and its coupling to pulmonary circulation in heart failure with preserved ejection fraction: stratification of clinical phenotypes and outcomes.
      We have reported that a lowered tricuspid annular plane systolic excursion (TAPSE) to PA systolic pressure (PASP) ratio, which reflects RV-PA uncoupling on echocardiography, is an independent predictor of adverse outcomes in HFpEF.
      • Nakagawa A.
      • Yasumura Y.
      • Yoshida C.
      • et al.
      Prognostic importance of right ventricular-vascular uncoupling in acute decompensated heart failure with preserved ejection fraction.
      • Nakagawa A.
      • Yasumura Y.
      • Yoshida C.
      • et al.
      Prognostic importance of right ventricular-vascular uncoupling in acute decompensated heart failure with preserved ejection fraction.
      • Nakagawa A.
      • Yasumura Y.
      • Yoshida C.
      • et al.
      Distinctive prognostic factor of heart failure with preserved ejection fraction stratified with admission blood pressure.
      Although an established finding is that HFpEF patients with RV-PA uncoupling have a poor prognosis, intrinsic factors that lead to worse outcomes are still unknown. Accordingly, clarification of the key factors that impact outcomes in these patients will strengthen therapeutic management.
      RV dysfunction is common in HFpEF patients,
      • Melenovsky V.
      • Hwang S.J.
      • Lin G.
      • Redfield M.M.
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      Right heart dysfunction in heart failure with preserved ejection fraction.
      and RV remodeling, which is closely related to RV dysfunction, is also reported to be an important factor in patients with secondary tricuspid regurgitation (TR),
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      • Prihadi E.A.
      • van der Bijl P.
      • et al.
      Prognostic implications of right ventricular remodeling and function in patients with significant secondary tricuspid regurgitation.
      pulmonary hypertension,
      • Ryo K.
      • Goda A.
      • Onishi T.
      • et al.
      Characterization of right ventricular remodeling in pulmonary hypertension associated with patient outcomes by 3-dimensional wall motion tracking echocardiography.
      and left ventricular hypertrophy.
      • Tadic M.
      • Cuspidi C.
      • Vukomanovic V.
      • Kocijancic V.
      • Celic V.
      The impact of different left ventricular geometric patterns on right ventricular deformation and function in hypertensive patients.
      Even in HFpEF patients, RV dilatation is associated with cardiovascular adverse outcomes.
      • Burke M.A.
      • Katz D.H.
      • Beussink L.
      • et al.
      Prognostic importance of pathophysiologic markers in patients with heart failure and preserved ejection fraction.
      In this study, we aimed to identify clinically important prognostic factors in HFpEF patients involving RV-PA uncoupling, with particular regard to RV remodeling.

      Methods

      PURSUIT-HFpEF registry

      This study is a post hoc analysis of the prospective observational multicentre study known as the Prospective, Multicenter, Observational Study of Patients With Heart Failure With Preserved Ejection Fraction (PURSUIT-HFpEF) registry (UMIN000021831). The study has been described in detail elsewhere.
      • Suna S.
      • Hikoso S.
      • Yamada T.
      • et al.
      Study protocol for the PURSUIT-HFpEF study: a Prospective, Multicenter, Observational Study of Patients with Heart Failure with Preserved Ejection Fraction.
      Briefly, in collaboration with 31 hospitals in Japan (contributor list is provided in Supplemental Appendix S1), we enrolled consecutive acute decompensated HF patients who met the Framingham HF criteria.
      • Vasan R.S.
      • Levy D.
      Defining diastolic heart failure: a call for standardized diagnostic criteria.
      Inclusion criteria at the time of admission (during the initial 48 hours) also required the following: (i) left ventricular (LV) ejection fraction (LVEF) ≥ 50%, as measured using the Teichholz or biplane Simpson method; and (ii) N-terminal pro-B-type natriuretic peptide (NT-proBNP) ≥ 400 pg/mL or brain natriuretic peptide ≥ 100 pg/mL. Major exclusion criteria were age < 20 years, severe valvular disease or acute coronary syndrome on admission, life expectancy < 6 months due to prognosis for a noncardiac disease, and previous heart transplantation. The data were anonymized before being transferred to the data centre of Osaka University Hospital for analysis.
      • Matsumura Y.
      • Hattori A.
      • Manabe S.
      • et al.
      Case report form reporter: a key component for the integration of electronic medical records and the electronic data capture system.
      All clinical endpoints were investigator-reported. Postdischarge outpatient management was per the discretion of the attending physician at each facility. Outcomes after discharge were checked by confirming last visits to each facility, or via telephone contact or mail interview with the patients, their family members, or the most recent attending physician. Written informed consent was received from each participating patient. This study conformed to the principles of the Declaration of Helsinki and was approved by the institutional review board of each participating facility.

      Study population

      A total of 1095 hospitalized HFpEF patients were registered from June 2016 to January 2021 in the PURSUIT-HFpEF registry. We excluded 17 patients with in-hospital mortality, and 261 patients whose TAPSE and PASP were missing at discharge. We divided the remaining 817 patients with or without RV-PA uncoupling by the TAPSE/PASP ratio, as defined by a receiver operating curve analysis for a composite of cardiac death or HF readmission. We investigated the following: (i) prognostic factors for patients with RV-PA uncoupling; and (ii) whether RV dilatation, defined as an excess of median RV dimension (RVD), could be used to distinguish the phenotype of patients with RV-PA uncoupling. For this purpose, we further excluded 63 patients whose RVD was not obtained at discharge. We assigned the remaining 754 patients into 4 groups by TAPSE/PASP ratio and RVD (Fig. 1) and investigated the characteristics of those with both RV-PA uncoupling and RV dilatation.
      Figure thumbnail gr1
      Figure 1Overview of patients included in this study. Selection of the cohort is shown in a tree chart. Hatched boxes show populations subject to particular focus. The tricuspid annular plane systolic excursion /pulmonary artery systolic pressure (TAPSE/PASP) < 0.46 population is analyzed in , and patients in the boxes with multicolored edges are analyzed in , , and . HFpEF, heart failure with preserved ejection fraction; RVD, right ventricular dimension.

      Echocardiographic measurements

      Transthoracic echocardiography was performed at discharge and analyzed by an experienced sonographer in each institute according to the latest American Society of Echocardiography (ASE) and European Association of Cardiovascular Imaging recommendations.
      • Nagueh S.F.
      • Smiseth O.A.
      • Appleton C.P.
      • et al.
      Recommendations for the evaluation of left ventricular diastolic function by echocardiography: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging.
      • 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.
      • Rudski L.G.
      • Lai W.W.
      • Afilalo J.
      • et al.
      Guidelines for the echocardiographic assessment of the right heart in adults: a report from the American Society of Echocardiography endorsed by the European Association of Echocardiography, a registered branch of the European Society of Cardiology, and the Canadian Society of Echocardiography.
      LV end-diastolic volume, LV stroke volume, and LVEF were calculated using the biplane Simpson method. Details of the calculations of TAPSE and PASP have been described previously.
      • Nakagawa A.
      • Yasumura Y.
      • Yoshida C.
      • et al.
      Prognostic importance of right ventricular-vascular uncoupling in acute decompensated heart failure with preserved ejection fraction.
      RVD was measured at the mid-ventricle perpendicularly to the septum using an RV-focused apical 4-chamber view. In patients with atrial fibrillation (AF), recordings of 5 to 7 consecutive beats were recommended. Measurement of systolic or diastolic parameters for single beats occurring after 2 serial beats with an average RR interval, or a single beat with an average Doppler-wave contour with an average velocity were also permitted, in accordance with a previous study.
      • Abe Y.
      • Akamatsu K.
      • Ito K.
      • et al.
      Prevalence and prognostic significance of functional mitral and tricuspid regurgitation despite preserved left ventricular ejection fraction in atrial fibrillation patients.

      Statistical analysis

      Most data are presented as a median and interquartile range of 25%-75%, for continuous variables, and as frequency and percentage for categorical variables. Continuous variables were compared using the Kruskal-Wallis test (with the Steel-Dwass test between groups), and categorical variables were compared using Fisher’s exact test (with Bonferroni adjustment between groups). The primary endpoint was defined as a composite of cardiac death or HF readmission; this was assessed with the Kaplan-Meier method and compared with the log-rank test. The duration of the follow-up period was calculated from the day of discharge until an endpoint, or at the time of last patient contact. Cox proportional hazards regression models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for associations between clinical factors and the endpoint. We used multivariable Cox proportional hazards regression analysis with statistical interactions to test effect modification (described as P for interaction) in each TAPSE/PASP-categorized group. We then provided stratified analysis to explore associations within each group. Based on our clinical experience and previous literature, multivariable Cox regression for the endpoint of the patients with RV-PA uncoupling was performed using the following covariates: age, sex, AF, estimated glomerular filtration rates (eGFRs), log-transformed NT-proBNP, left atrial volume index, mean of septal and lateral walls of E/e', RVD, TAPSE, PASP, and the presence of significant (moderate or severe) TR. All statistical tests were 2-sided, and results for which P < 0.05 were regarded as statistically significant. Statistical analysis was performed using JMP Pro 13.2.1, (SAS Institute, Chicago, IL) or EZR version 1.51 (Saitama Medical Centre, Jichi Medical University, Saitama, Japan).

      Results

      Prognostic factors for HFpEF patients with RV-PA uncoupling

      Median age (interquartile range [IQR] of 25%, 75%) of the 288 RV-PA uncoupled patients whose TAPSE/PASP ratio was under 0.46 mm/mm Hg was 84 years (IQR 79, 88), and 176 (relative frequency of 61%) were female. The ideal cutoff of the TAPSE/PASP ratio for predicting the primary endpoint was 0.46 mm/mm Hg (area under the curve, 0.60; sensitivity, 0.46; specificity, 0.69; P < 0.0001; Supplemental Fig. S1, A and B). Among those 288 RV-PA uncoupled patients, 101 patients (35%) reached the primary endpoint of cardiac death or HF readmission with a median follow-up of 340 days (IQR 90, 620), consisting of 37 (13%) cardiac deaths and 89 (31%) HF readmissions. Among them, univariable Cox regression models showed that age (hazard ratio [HR] 1.194, 95% confidence interval [CI] 1.032-1.387, P = 0.0169), NT-proBNP (HR 1.752, 95% CI 1.437-2.142, P < 0.0001), RVD (HR 1.044, 95% CI 1.014-1.074, P = 0.0042), PASP (HR 1.025, 95% CI 1.008-1.041, P = 0.0036), and the presence of significant TR (HR 1.731, 95% CI 1.170-2.566, P = 0.0061) were significantly associated with a poor outcome (Table 1, centre column). The multivariable Cox regression model revealed that NT-proBNP (HR 1.695, 95% CI 1.299-2.210, P = 0.0001) and RVD (HR 1.036, 95% CI 1.001-1.072, P = 0.0438) were significantly and independently associated with these outcomes (Table 1, right column). RVD was significantly larger in patients with TAPSE/PASP < 0.46 mm/mm Hg than in those with TAPSE/PASP ≥ 0.46 mm/mm Hg (medians of 33.3 vs 31.9 mm, P < 0.0001; Fig. 2).
      Table 1Cox regression hazard models for the composite endpoint of cardiac death or heart failure readmission in patients with right ventricular-pulmonary artery uncoupled heart failure with preserved ejection fraction
      P for interactionUnadjusted HR [95% CI]PAdjusted HR [95% CI]P
      Age (5 y)0.65341.194 [1.032–1.387]0.01691.192 [0.978–1.453]0.0827
      Sex, female0.43990.972 [0.653–1.466]0.88981.099 [0.631–1.950]0.7430
      Systolic blood pressure (5 mm Hg)0.02890.955 [0.897–1.015]0.1398
      Heart rate (5 bpm)0.84981.063 [0.983–1.145]0.1243
      Atrial fibrillation0.16161.151 [0.775–1.727]0.48790.972 [0.578–1.653]0.9167
      eGFR (10 mL/min per 1.73 m2)0.01330.888 [0.776–1.012]0.07460.993 [0.823–1.199]0.9438
      Log NT-proBNP (1 unit of ln pg/mL)0.97191.752 [1.437–2.142]< 0.00011.695 [1.299–2.210]0.0001
      LVDd (1 mm)0.04350.994 [0.961–1.028]0.7369
      LVEF (5%)0.97780.949 [0.844–1.071]0.3917
      LAVI (10 mL/m2)0.91991.026 [0.982–1.059]0.21571.019 [0.997–1.075]0.4801
      E/e' (1 unit)0.27311.001 [0.972–1.027]0.95021.001 [0.963–1.039]0.9721
      RVD (1 mm)0.01821.044 [1.014–1.074]0.00421.036 [1.001–1.072]0.0438
      TAPSE (1 mm)0.49261.005 [0.949–1.062]0.87330.979 [0.907–1.058]0.5963
      PASP (5 mm Hg)0.11211.133 [1.043–1.224]0.00361.070 [0.952–1.203]0.2554
      TAPSE/PASP (0.1 mm Hg/mm)0.68590.719 [0.570–0.912]0.0070
      Presence of moderate or severe TR0.90141.731 [1.170–2.566]0.00611.395 [0.837–2.330]0.2005
      P values of the interaction between presence/absence of TAPSE/PASP < 0.46 mm/mm Hg and each parameter (P for interaction) were assessed for the endpoint. Units in parentheses indicate increments.
      bpm, beats per minute; CI, confidence interval; eGFR, estimated glomerular filtration rate; HR, hazard ratio; LAVI, left atrium volume index; LVDd, left ventricular diastolic dimension; LVEF, left ventricular ejection fraction; LVMI, left ventricular mass index; NT-proBNP, N-terminal pro-B-type natriuretic peptide; PASP, pulmonary artery systolic pressure ratio; RVD, right ventricular dimension; TAPSE, tricuspid annular plane systolic excursion; TR, tricuspid regurgitation.
      Figure thumbnail gr2
      Figure 2Difference in right ventricular dimension between patients with tricuspid annular plane systolic excursion /pulmonary artery systolic pressure (TAPSE/PASP) ≥ 0.46 and TAPSE/PASP < 0.46 mm/mm Hg. Statistical comparison was performed using the Kruskal–Wallis test.
      The median age of the 529 RV-PA coupled patients whose TAPSE/PASP ratios were ≥ 0.46 mm/mm Hg was 83 years (IQR 77, 87), and 285 (54%) were female. Among them, 121 patients (23%) reached the primary endpoint with a median follow-up of 367 days (IQR 88, 742). Among these patients, RVD was not significantly associated with outcome in the univariable Cox regression model (HR 0.996, 95% CI 0.964-1.046, P = 0.8242; Supplemental Table S1, left column), whereas eGFR was significantly associated in both the univariable and multivariable Cox regression models (HR 0.812, 95% CI 0.736-0.895, P < 0.0001 and HR 0.846, 95% CI 0.731-0.971, P = 0.0165, respectively; Supplemental Table S1).

      Importance of RV dimension in HFpEF patients with RV-PA uncoupling

      We identified not only NT-proBNP but also RVD as being clinically important for HFpEF patients with RV-PA uncoupling. Characteristics of the 754 patients whose investigation focused on RV-PA coupling and RVD are shown in Table 2. The median age was 83 years (IQR78, 88), and 428 (57%) were female. Among the RV-PA-uncoupled population (group 3 and group 4, Fig. 1), larger RVD patients (group 4) in particular presented with the following: increased left atrial volume (median left atrial volume index of group 3 vs group 4: 54 mL/m2 [IQR 41, 74] vs 63 mL/m2 [IQR 47, 93], P = 0.0177); dilated inferior vena cava (15 mm [IQR 12, 19] vs 18 mm [IQR 14, 21] at expiration, P = 0.0006); elevated PASP (37 mm Hg [IQR 31, 44] vs 43 mm Hg [IQR 36, 53], P < 0.0001); lowered TAPSE/PASP ratio (0.37 mm/mm Hg [IQR 0.32, 0.43] vs 0.34 mm/mm Hg [IQR 0.29, 0.40] ; P = 0.0266); and higher grade of TR (27% of moderate and 3% of severe vs 42% of moderate and 9% of severe, P = 0.0077; Table 2). Regarding medications at discharge, although diuretics were commonly used among the RV-PA-uncoupled population, no particular differences were seen between patients with larger vs smaller RVD (use of loop diuretics, 88% in group 3 and 90% in group 4; Supplemental Table S2). Of the total of 754 patients (groups 1 through 4), 196 (26%) reached the primary endpoint with a median follow-up of 362 days (IQR 92, 720), which consisted of 55 (7%) cardiac deaths and 185 (25%) HF readmissions. Kaplan-Meier curve analysis and Cox regression models clarified that group 4 had the highest risk of adverse outcomes among the 4 groups (Fig. 3; Table 3). This result was also seen on analysis of both men and women separately (Supplemental Fig. S2).
      Table 2Patient background of each group
      CharacteristicTotalMissingGroup 1Group 2Group 3Group 4P
      N754N/A245245132132
      Age, y83 [78–88]083 [77–87]82 [77–86] ‡§85 [79–89] 84 [79–88] 0.0026
      Sex, female428 (57)0157 (64)105 (43) 93 (70) 73 (55)< 0.0001
      Heart failure history173 (23)1336 (15) ‡§49 (20) §39 (30)49 (37)∗< 0.0001
      Comorbidities
       Hypertension639 (85)2206 (84)215 (88)112 (86)106 (80)0.2810
       Diabetes245 (33)576 (31)85 (35)44 (34)40 (30)0.7646
       Chronic kidney disease283 (38)483 (34)94 (39)48 (36)58 (45)0.2381
       COPD53 (7)3116 (7)15 (6)9 (7)13 (11)0.5042
      Status at discharge
       NYHA functional class5§0.0099
       I272 (36)97 (40)98 (40)40 (30)37 (28)
       II437 (58)132 (54)137 (56)88 (67)80 (61)
       III39 (5)14 (6)7 (3)4 (3)14 (11)
       IV1 (0.1)0 (0)1 (0.4)0 (0)0 (0)
       Body mass index, kg/m221.2 [18.8–24.0]420.3 [18.1–22.9] 22.3 [19.3–24.9] ∗21.1 [18.8–23.3] 21.2 [19.3–23.8]< 0.0001
       Systolic BP, mm Hg119 [106–130]0119 [106–131]120 [107–132]116 [104–128]120 [107–130]0.1716
       Heart rate70 [61–78]070 [62–80]67 [60–77] 72 [64–80] 69 [60–78]0.0029
       Atrial fibrillation292 (39)162 (25) ‡§81 (33) ‡§70 (53) ∗79 (60) ∗< 0.0001
       6-minute walk distance, m250 [155–330]314250 [161–330]275 [180–360]218 [153–315]232 [136–304]0.0464
       Hemoglobin, g/dL11.4 [10.1–12.8]011.6 [10.3–13.0]11.2 [10.2–12.5]11.7 [10.2–13.1]11.0 [9.6–12.6]0.1461
       Hematocrit, %35 [31–39]035 [32–39]34 [31–38]35 [31–40]34 [27–39]0.1206
       eGFR, mL/min per 1.73 m243 [31–55]1345 [34–59] §44 [29–56]43 [29–52]40 [32–51] ∗0.0145
       Albumin, g/dL3.4 [3.1–3.7]103.4 [3.1–3.7]3.5 [3.2–3.7]3.4 [3.1–3.7]3.3 [3.0–3.7]0.3132
       Total bilirubin, mg/dL0.6 [0.4–0.8]40.5 [0.4–0.7] ‡§0.6 [0.4–0.8] §0.6 [0.5–0.8] ∗0.7 [0.5–0.9] ∗< 0.0001
       NT-proBNP, pg/mL1056 [470–2374]72866 [382–1835] ‡§791 [370–2041] ‡§1660 [653–2920] ∗1345 [748–2953] ∗< 0.0001
      Echocardiography at discharge
       LVDd, mm45 [41–50]044 [40–48] 48 [43–52] ∗‡§44 [40–48] 46 [41–50] < 0.0001
       LVEDV, mL77 [57–101]4469 [54–91] †§89 [66–113] ∗72 [53–92] †§83 [59–108] ∗< 0.0001
       LVMI, g/m2102 [85–123]5101 [83–121]105 [87–125]103 [87–123]99 [81–119]0.2193
       LVEF, %61 [56–66]3362 [57–66]61 [56–65]60 [55–66]59 [53–66]0.1856
       Stroke volume, mL46 [35–61]4442 [32–55] †§53 [40–66] ∗43 [31–54] †§49 [36–64] ∗< 0.0001
       LAVI, mL/m251 [37–66]6243 [32–56] †‡§51 [38–66] ∗§54 [41–74] ∗§63 [47–93] ∗†‡< 0.0001
       E/e' (mean)12.6 [9.7–16.7]3112.5 [9.8–16.3]11.3 [9.0–15.5] 13.7 [10.5–18.6] 13.4 [9.9–18.2]0.0005
       RVD, mm32 [28–37]027 [25–30] †‡§36 [33–39] ∗‡§29 [27–32] ∗†§38 [36–43] ∗†‡< 0.0001
       TAPSE, mm17.3 [14.5–20.3]018.2 [16.5–21.0] †‡§19.4 [17.0–22.4] ∗‡§13.4 [11.9–16.0] ∗14.8 [11.4–17.1] ∗< 0.0001
       IVC max, mm14 [11–17]012 [10–15] †‡§14 [11–16] ∗‡§15 [12–19] ∗†§18 [14–21] ∗†‡< 0.0001
       IVC min, mm6 [4–8]05 [4–6] ‡§5 [4–7] ‡§7 [5–11] ∗†§9 [6–13] ∗†‡< 0.0001
       IVC collapsibility, %55 [44–64]057 [50–63] §56 [50–67] ‡§54 [38–65] 47 [34–58] ∗< 0.0001
       RAP (median), mm Hg3 [3–8]03 [3–8]3 [3–8]3 [3–8]3 [3–8]
       RAP (mean), mm Hg5.1 ± 3.304.3 ± 2.3 ‡§4.4 ± 2.6 ‡§5.8 ± 3.5 ∗†§7.3 ± 4.3 ∗†‡< 0.0001
       TRPG, mm Hg27 [22–33]023 [19–27] †‡§25 [21–30] ∗‡§31 [26–38] ∗†§36 [29–45] ∗†‡< 0.0001
       PASP, mm Hg31 [26–38]027 [23–31] †‡§29 [25–35] ∗‡§37 [31–44] ∗†§43 [36–53] ∗†‡< 0.0001
       TAPSE/PASP, mm/mm Hg0.54 [0.41–0.72]00.68 [0.57–0.78] ‡§0.64 [0.54–0.79] ‡§0.37 [0.32–0.43] ∗†§0.34 [0.29–0.40] ∗†‡< 0.0001
      Mitral regurgitation0त< 0.0001
       None31 (4)10 (4)14 (6)2 (1.5)5 (4)
       Trace248 (33)109 (44)81 (33)35 (27)23 (17)
       Mild340 (45)98 (40)112 (46)63 (48)67 (51)
       Moderate131 (17)28 (11)37 (15)32 (24)34 (26)
       Severe4 (0.5)0 (0)1 (0.4)0 (0)3 (2)
      Tricuspid regurgitation0‡§‡§†§†‡< 0.0001
       None10 (1.3)3 (1.2)2 (0.8)1 (0.8)4 (3)
       Trace243 (32)111 (45)96 (39)24 (18)12 (9)
       Mild323 (43)101 (41)107 (44)67 (51)48 (36)
       Moderate155 (21)27 (11)36 (27)36 (27)56 (42)
       Severe23 (3)3 (1.2)4 (1.6)4 (3)12 (9)
      Values are given as median [interquartile range] or n (%). RAP is also given as mean ± standard error. Statistical comparisons were performed using the Kruskal Wallis test or Fisher’s exact test. Statistical significance of difference between groups (P < 0.05) using the Steel-Dwass test for continuous variables and Fisher’s exact test with Bonferroni adjustment for categorical variables are shown as follows: significance vs group 1∗, group 2, group 3, and group 4.§
      BP, blood pressure; COPD, chronic obstructive pulmonary diseaseeGFR, estimated glomerular filtration rate; IVC, inferior vena cava; LAVI, left atrium volume index; LVDd, left ventricular diastolic dimension; LVEDV, left ventricular end-diastolic volume; LVEF, left ventricular ejection fraction; LVMI, left ventricular mass index; N/A, not available; NT-proBNP, N-terminal pro-B-type natriuretic peptide; NYHA, New York Heart Association; PASP, pulmonary artery systolic pressure; RAP, right atrial pressure; RVD, right ventricular dimension; TAPSE, tricuspid annular plane systolic excursion; TRPG, tricuspid regurgitation pressure gradient.
      Figure thumbnail gr3
      Figure 3Kaplan-Meier curves for composite endpoint, stratified by tricuspid annular plane systolic excursion/pulmonary artery systolic pressure (TAPSE/PASP) ratio and right ventricular dimension (RVD). Group 4 represents the worst event rate. Group 1, TAPSE/PASP ≥ 0.46 mm/mm Hg and RVD < 31.9 mm; group 2, TAPSE/PASP ≥ 0.46 mm/mm Hg, and RVD ≥ 31.9 mm; group 3, TAPSE/PASP < 0.46 mm/mm Hg, and RVD < 33.3 mm; and group 4, TAPSE/PASP < 0.46 mm/mm Hg, and RVD ≥ 33.3 mm.
      Table 3Association of classification (group 1 to group 4) with adverse outcomes on Cox proportional hazards analysis
      Group 1 (n = 245)Group 2 (n = 245)Group 3 (n = 132)Group 4 (n = 132)P
      Outcome
       Cardiac mortality12 (5) §11 (4) §13 (10)19 (14)∗0.0019
       Heart failure readmission55 (22)51(21)35 (27)44 (33)0.0462
       Composite endpoint58 (24) §49 (20) §35 (27)54 (41) ∗0.0002
      Unadjusted hazard ratio
       Cardiac mortality0.29 [0.14-0.59] 0.29 [0.14-0.61] 0.77 [0.37-1.55]1.0 (referent)0.0006
       Heart failure readmission0.57 [0.38-0.85] 0.57 [0.38-0.85] 0.77 [0.49-1.20]1.00.0197
       Composite endpoint0.49 [0.34-0.71] 0.45 [0.30-0.66] 0.63 [0.41-0.96] ||1.00.0003
      Values are n (%) or hazard ratio [95% confidence interval]. Statistical comparisons for event numbers were performed using the Kruskal Wallis test or Fisher’s exact test between groups with Bonferroni adjustment. Significant differences between groups (P < 0.05) are shown as follows: vs group 1∗, group 2, group 3, and group 4§. Significant differences in Cox regression models are shown as follows: ||P < 0.05 and P < 0.01.

      Discussion

      Although RV function has long been forgotten as attention has been focused on left-sided HF, now evident is the finding that RV dysfunction is highly prevalent and contributes to poor prognosis in HFpEF.
      • Melenovsky V.
      • Hwang S.J.
      • Lin G.
      • Redfield M.M.
      • Borlaug B.A.
      Right heart dysfunction in heart failure with preserved ejection fraction.
      ,
      • Berglund F.
      • Piña P.
      • Herrera C.J.
      Right ventricle in heart failure with preserved ejection fraction.
      RV-PA uncoupling also is known to be a sensitive prognostic marker.
      • Guazzi M.
      • Dixon D.
      • Labate V.
      • et al.
      RV contractile function and its coupling to pulmonary circulation in heart failure with preserved ejection fraction: stratification of clinical phenotypes and outcomes.
      ,
      • Nakagawa A.
      • Yasumura Y.
      • Yoshida C.
      • et al.
      Prognostic importance of right ventricular-vascular uncoupling in acute decompensated heart failure with preserved ejection fraction.
      ,
      • Singh I.
      • Rahaghi F.N.
      • Naeije R.
      • et al.
      Right ventricular-arterial uncoupling during exercise in heart failure with preserved ejection fraction: role of pulmonary vascular dysfunction.
      Our results provide valuable insights into the importance of RV dilatation as a factor in the poor prognosis of HFpEF patients with RV-PA uncoupling.
      In a community-based study of HFpEF, Mohammed et al. described that RV enlargement and a higher grade of TR were prominent.
      • Mohammed S.F.
      • Hussain I.
      • AbouEzzeddine O.F.
      • et al.
      Right ventricular function in heart failure with preserved ejection fraction: a community-based study.
      Parrinello et al. also showed in an observational study of a small number of patients (n = 135) that RVD could be a distinctive prognostic factor for patients with HFpEF but not for those with HF with reduced ejection fraction (HFrEF).
      • Parrinello G.
      • Torres D.
      • Buscemi S.
      • et al.
      Right ventricular diameter predicts all-cause mortality in heart failure with preserved ejection fraction.
      Obokata et al. reported that RV structure and function deteriorate over time in HFpEF patients, compared with changes seen in the left ventricle among them.
      • Obokata M.
      • Reddy Y.N.V.
      • Melenovsky V.
      • Pislaru S.
      • Borlaug B.A.
      Deterioration in right ventricular structure and function over time in patients with heart failure and preserved ejection fraction.
      Regarding the pathogenic processes underlying RV dysfunction in HFpEF, RV dilatation and contractile impairment occur secondary to the failure to compensate for the pressure overload caused by the decline in pulmonary arterial compliance and the increase in vascular resistance.
      • Kammerlander A.A.
      • Marzluf B.A.
      • Graf A.
      • et al.
      Right ventricular dysfunction, but not tricuspid regurgitation, is associated with outcome late after left heart valve procedure.
      • Aschauer S.
      • Kammerlander A.A.
      • Zotter-Tufaro C.
      • et al.
      The right heart in heart failure with preserved ejection fraction: insights from cardiac magnetic resonance imaging and invasive haemodynamics.
      • Vonk Noordegraaf A.
      • Westerhof B.E.
      • Westerhof N.
      The relationship between the right ventricle and its load in pulmonary hypertension.
      RV enlargement and remodeling are observed in an advanced stage of RV dysfunction even in HFpEF. Additional deterioration could promote further pulmonary remodeling and create a vicious cycle that leads to a worse prognosis.
      • Gorter T.M.
      • van Veldhuisen D.J.
      • Voors A.A.
      Rapid right-sided deterioration in heart failure with preserved ejection fraction.
      In the current investigation, this finding explains why RV dilatation could be used to independently stratify prognosis in the subgroup of patients with HFpEF with RV-PA uncoupling.
      The impact on prognostic prediction of larger RV dimension among RV-PA-coupled patients (Supplemental Table S1) differed from that among RV-PA-uncoupled patients (Table 1). This difference means that RV dilatation has a different prognostic meaning in these 2 populations. Melenovsky et al. reported that HFpEF with RV dysfunction (determined by RV fractional area change ≤ 35%) represented a larger mid-ventricular RV diameter (35 vs 29 mm, P = 0.0005) and diastolic area (25 vs 19 cm2, P < 0.0001), compared with HFpEF without RV dysfunction.
      • Melenovsky V.
      • Hwang S.J.
      • Lin G.
      • Redfield M.M.
      • Borlaug B.A.
      Right heart dysfunction in heart failure with preserved ejection fraction.
      These authors indicated that not only RV fractional area change but also diastolic area were independent and significant predictors of mortality even after adjustment by PASP in a Cox proportional hazards model among all the uncategorized HFpEF patients. This finding appears consistent with our present results: PASP (56 ± 18 mm Hg) in their HFpEF patients was higher than it was in our cohort (31 mm Hg [IQR 26-38]), indicating that their major targets were selected patients with pulmonary hypertension, similar to our RV-PA uncoupling patients. In a study that focused on patients with significant secondary TR, Dietz et al. reported that patients with RV systolic dysfunction (TAPSE < 17 mm) had worse outcomes, regardless of the presence of RV dilatation (RVD ≥ 40 mm).
      • Dietz M.F.
      • Prihadi E.A.
      • van der Bijl P.
      • et al.
      Prognostic implications of right ventricular remodeling and function in patients with significant secondary tricuspid regurgitation.
      In contrast to our study, their patients included those with not only HFpEF (490 patients, 39%) but also HFrEF (490 patients, 38%) and HF with mildly reduced LVEF (298 patients, 23%). In our present study, which focused on HFpEF patients, multivariable Cox regression analysis showed that RV dilatation was closely associated with outcomes, even after adjusting for TAPSE and the presence of significant TR among HFpEF patients with RV-PA uncoupling. The univariable Cox regression analysis among RV-PA-coupled HFpEF patients showed that RVD was not significantly associated with outcomes, which indicates that RVD is fundamentally less responsible for the outcomes. Among those patients, RVD had less prognostic meaning than it did among RV-PA-uncoupled patients, but in contrast, renal dysfunction was important, as shown by statistically significant results in both the univariable and multivariable Cox regression analyses (Supplemental Table S1).
      Recently, Patel et al. reported the detection of diffuse RV fibrosis by cardiovascular magnetic resonance-derived extracellular volume particularly in HFpEF with pulmonary hypertension.
      • Patel R.B.
      • Li E.
      • Benefield B.C.
      • et al.
      Diffuse right ventricular fibrosis in heart failure with preserved ejection fraction and pulmonary hypertension.
      Although RV adapts to the afterload increase by increasing muscle contractility and wall thickness in the RV-PA coupling phase to maintain cardiac output,
      • Vonk Noordegraaf A.
      • Westerhof B.E.
      • Westerhof N.
      The relationship between the right ventricle and its load in pulmonary hypertension.
      RV-PA uncoupling appears over time and might cause irreversible and critical fibrotic alterations in the RV wall. Among our patients with RV-PA uncoupling, those with RV dilatation (group 4) showed changes resulting from RV-PA uncoupling, namely a more dilated vena cava and a higher grade of TR than those without RV dilatation (group 3).
      AF has shown a strong association with reduced RV and right atrial function in HFpEF patients, independent of pulmonary pressures.
      • Gorter T.M.
      • van Melle J.P.
      • Rienstra M.
      • et al.
      Right heart dysfunction in heart failure with preserved ejection fraction: the impact of atrial fibrillation.
      Further, the comorbidity of AF was particularly increased in our lower TAPSE/PASP groups (Table 2). Whereas AF itself was not a significant prognostic predictor for HFpEF patients with RV-PA uncoupling, RVD was shown to be a significant predictor independent of AF (Table 1).
      Because the complicated pathophysiology of HFpEF makes it difficult to establish a prognosis in these patients, and therapeutic options to improve prognosis are limited, phenotype-specific treatment strategies are needed.
      • Shah S.J.
      • Kitzman D.W.
      • Borlaug B.A.
      • et al.
      Phenotype-specific treatment of heart failure with preserved ejection fraction: a multiorgan roadmap.
      Although a now clear finding is that RV-PA uncoupling determined by the TAPSE/PASP ratio is a useful prognostic marker for HFpEF patients,
      • Guazzi M.
      • Dixon D.
      • Labate V.
      • et al.
      RV contractile function and its coupling to pulmonary circulation in heart failure with preserved ejection fraction: stratification of clinical phenotypes and outcomes.
      ,
      • Nakagawa A.
      • Yasumura Y.
      • Yoshida C.
      • et al.
      Prognostic importance of right ventricular-vascular uncoupling in acute decompensated heart failure with preserved ejection fraction.
      ,
      • Gorter T.M.
      • van Veldhuisen D.J.
      • Voors A.A.
      • et al.
      Right ventricular-vascular coupling in heart failure with preserved ejection fraction and pre- vs. post-capillary pulmonary hypertension.
      subsequent efforts should focus on what is next most important in appropriately stratified patients. We elucidated that RVD has an important prognostic meaning among RV-PA-uncoupled HFpEF patients, who have a poor prognosis. Thus, RVD may help us identify patients who would benefit from advanced therapy, including emerging treatment candidates.
      Several limitations of this study should be noted. First, we excluded 261 of 1078 discharged alive patients (24%) whose TAPSE and PASP at discharge were not obtained, and 63 of 817 patients (8%) whose RVD was not obtained. Although these exclusions were unavoidable given the study’s design as a post hoc analysis of an observational study, they must have caused some degree of selection bias. Second, the patients were all Asians who were characterized by advanced age (median of 83 years), frequent comorbidity of AF (39%), a high ratio of moderate to severe TR (24%), and an elevated NT-proBNP level (median of 1056 pg/mL), and care is accordingly required in any generalization of the results. Third, although we stratified the RV-PA uncoupled population using receiver operating characteristic curve analysis following our previous report,
      • Nakagawa A.
      • Yasumura Y.
      • Yoshida C.
      • et al.
      Prognostic importance of right ventricular-vascular uncoupling in acute decompensated heart failure with preserved ejection fraction.
      the method used to determine a cutoff was not ideal given time-to-event considerations. We included some covariates that had some interaction with TAPSE/PASP in the multivariable analysis among the subgroups categorized by TAPSE/PASP ratio. The unavoidable possibility of overfitting in the multivariable analyses should be noted. Fourth, the present study was performed using mainly echocardiography, whereas cardiac magnetic resonance imaging is considered the gold standard for RV functional assessment. Although PASP is usually evaluated with right heart catheterization, echocardiographic estimation of PASP is reported to be a reliable substitute.
      • Greiner S.
      • Jud A.
      • Aurich M.
      • et al.
      Reliability of noninvasive assessment of systolic pulmonary artery pressure by Doppler echocardiography compared to right heart catheterization: analysis in a large patient population.
      RV function was assessed by only TAPSE and RVD, whereas other parameters were not assessed, such as 3-dimensional measurement, fractional area change, RV S', RV global/free wall systolic strain
      • Morris D.A.
      • Krisper M.
      • Nakatani S.
      • et al.
      Normal range and usefulness of right ventricular systolic strain to detect subtle right ventricular systolic abnormalities in patients with heart failure: a multicentre study.
      pulmonary vasculature, and atrial function. In particular, although the main findings were in relation to RVD, 2-dimensional RV dimension is a relatively imprecise measure of RV volume. Fifth, cardiac sonographers were not blinded to clinical information, which may have caused measurement bias. Moreover, measurements were done by sonographers and were not evaluated by an imaging core lab. Further investigations are required to confirm the results of this study and to support a deeper understanding of the meaning of RVD in HFpEF patients with RV-PA uncoupling.

      Conclusion

      We showed in a multicentred observational cohort that RVD is an important prognostic indicator in HFpEF patients with RV-PA uncoupling. The appearance of RV remodeling should be considered a distinctive indicator of the eventual prognosis of HFpEF patients in the advanced phase.

      Funding Sources

      This work was funded by Roche Diagnostics K.K. and Fuji Film Toyama Chemical Co. Ltd.

      Disclosures

      D.N. has received honoraria from Roche Diagnostics . S.H. has received personal fees from Daiichi Sankyo Company, Bayer, Astellas Pharma, Pfizer Pharmaceuticals and Boehringer Ingelheim Japan, and grants from Roche Diagnostics , FUJIFILM Toyama Chemical, and Actelion Pharmaceuticals . Y.S. has received personal fees from Otsuka Pharmaceutical, Ono Pharmaceutical, Daiichi Sankyo Company, Mitsubishi Tanabe Pharma Corporation, and Actelion Pharmaceuticals, and grants from Roche Diagnostic, FUJIFILM Toyama Chemical, Abbott Japan LLC, Otsuka Pharmaceutical , Daiichi Sankyo Company , Mitsubishi Tanabe Pharma Corporation , and Biotronik . The other authors have no conflicts of interest to disclose.

      Acknowledgements

      The authors thank all the investigators, clinical research coordinators, and data managers involved in the PURSUIT-HFpEF registry for their dedicated contributions. In particular, the authors thank Nagisa Yoshioka, Kyoko Tatsumi, Satomi Kishimoto, Noriko Murakami, and Sugako Mitsuoka for their excellent assistance with data collection.

      Supplementary Material

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