Right ventricular (RV)- pulmonary arterial (PA) uncoupling is an important predictor of outcomes in heart failure (HF), yet it may change substantially during hospitalization for acute HF. This study sought to investigate the dynamic changes in RV-PA uncoupling during acute HF hospitalization and their prognostic significance. Tricuspid annular plane systolic excursion to pulmonary artery systolic pressure (TAPSE/PASP) ratio was measured in consecutive hospitalized acute HF patients using echocardiography on admission and at discharge. TAPSE/PASP <0.36 mm/mmHg was considered as RV-PA uncoupling. Patients were divided into 3 groups; RV-PA coupling on admission and discharge, RV-PA uncoupling on admission that normalized to RV-PA coupling at discharge (normalized RV-PA uncoupling), and RV-PA uncoupling on admission that persisted at discharge (persistent RV-PA uncoupling). The primary endpoint was all-cause mortality and HF rehospitalization. Out of 490 patients (73.4 ± 11.9 years old), 216 (44.1%) had RV-PA coupling, 123 (25.1%) normalized RV-PA uncoupling, and 151 (30.8%) persistent RV-PA uncoupling. After a mean follow-up of 12.0 ± 2.6 months, 186 (38.0%) patients reached the primary endpoint. Significantly worse event-free survival rate was observed for the persistent RV-PA uncoupling patients (RV-PA coupling: 74.1%, normalized RV-PA uncoupling: 71.5%, persistent RV-PA uncoupling: 37.1%, Log-rank p < 0.001). Persistent RV-PA uncoupling status was independently associated with the primary endpoint (hazard ratio 2.78 [95% CI 1.73–4.44]; p < 0.001), and provided incremental prognostic information over a baseline model and RV-PA uncoupling on admission. In conclusion, in hospitalized acute HF patients, persistence of RV-PA uncoupling at discharge is associated with worse 1-year event-free survival. Clinical Trial Registration: https://www.clinicaltrials.gov/study/NCT05573997 .
Graphical Abstract
Abbreviations: HF = heart failure; PASP = pulmonary artery systolic pressure; RV-PA = right ventricular-pulmonary arterial; TAPSE = tricuspid annular plane systolic excursion
Right ventricular (RV) dysfunction is a widely recognized determinant of poor outcomes in patients with heart failure (HF), and its presence indicates an advanced stage of HF. , However, the RV dysfunction has to be normalized to its afterload, since it may be negligible when pulmonary arterial (PA) pressureis normal. , Hence, RV-PA coupling has emerged as a novel concept with powerful clinical implications, determining the prognosis in all HF patients. RV-PA coupling can be easily estimated using echocardiography, by the well-established ratio of tricuspid annular plane systolic excursion (TAPSE) over estimated pulmonary artery systolic pressure (PASP). ,,, As HF progresses and PA pressures raise, at some point the RV is unable to further compansate for the increasing afterload, signaling a turning point in the course of disease, that is termed RV-PA uncoupling, defined as TAPSE/PASP <0.36 mm/mmHg. However, RV-PA uncoupling may still be reversible for some patients, as acute HF treatment may drastically reduce RV afterload and improve global RV function through volume reduction, and inotropes. While there is a wealth of evidence regarding the prognostic value of assessing RV-PA coupling in HF, little is known about the dynamic changes of this measure during hospitalization for acute HF and its impact on outcome. Therefore, the present study aimed to scrutinize the dynamic trends of RV-PA coupling and their prognostic role during acute HF hospitalization, by examining the noninvasive echocardiographic ratio of TAPSE/PASP on the day of admission and at discharge.
Methods
All consecutive patients with acute HF who required hospitalization at the cardiology department of AHEPA University General Hospital in Thessaloniki, Greece from 04/2022 until 08/2024 were enrolled, if they fulfilled the prespecified inclusion criteria, that have been previously outlined (‘’Beyond-Myo HF Study’’- https://www.clinicaltrials.gov/study/NCT05573997 ). In brief, all ≥18 years old patients with (1) symptoms and/or signs of HF, (2) abnormal N-terminal pro B-type natriuretic peptide (NT-pro-BNP) levels as defined by the European Society of Cardiology, and (3) echocardiographic evidence of cardiac structural and/or functional abnormalities evaluated within 24 hours from admission were included.
In the current analysis, only the patients with obtainable TAPSE and PASP by echocardiography on admision and at discharge were included. RV-PA coupling was assessed noninvasively on admission and at discharge by the ratio of 2 standard echocardiographic measurements: TAPSE over PASP. The cut-off value of 0.36 mm/mmHg proposed by Guazzi et al. and subsequently externally validated in different HF cohorts ,, was used to characterize RV-PA coupling and RV-PA uncoupling. In particular, TAPSE/PASP ≥0.36 mm/mmHg was considered as RV-PA coupling and TAPSE/PASP <0.36 mm/mmHg as RV-PA uncoupling. The sample size was divided into 3 groups based on the changes of the ratio during hospitalization: Patients with TAPSE/PASP ≥0.36 mm/mmHg on admission and discharge were considered the RV-PA coupling group. Patients with TAPSE/PASP <0.36 mm/mmHg on admission that improved to TAPSE/PASP ≥0.36 mm/mmHg at discharge were characterized normalized RV-PA uncoupling. Patients with TAPSE/PASP <0.36 mm/mmHg on admission that remained <0.36 mm/mmHg at discharge were characterized persistent RV-PA uncoupling ( Figure 1 ).
Flow chart. Abbreviations: HF = heart failure; PASP = pulmonary artery systolic pressure; RV-PA = right ventricular-pulmonary arterial; TAPSE = tricuspid annular plane systolic excursion.
The present study adhered to the principles of the Declaration of Helsinki (2013 Amendment). The conduction of this study was formally assessed and authorized by the Ethics Committee of the School of Medicine of Aristotle University of Thessaloniki (Approval number: 19/2022). All patients gave informed consent to take part in this study.
Clinical characteristics, laboratory indices, and the therapeutic management of the patients during hospitalization were recorded.
All patients underwent a comprehensive echocardiographic assessment within 24 hours from hospitalization. In addition, all participants had another echocardiographic assessment within 24 hours before discharge, when the patients were judged to be clinically stable, euvolemic, and fit for discharge. Assessment of stability and euvolemia was performed on a clinical basis using a multiparametric approach based on specific objective criteria, but ultimately it was left at the discretion of each treating physician to discharge the patient. None of the patients required intravenous inotropic support at discharge. All echocardiographic studies were performed using Vivid E95 or Vivid S70 ultrasound systems (GE Healthcare, Chicago, IL, USA). The echocardiographic data were analyzed offline on an EchoPac 112.0.1 workstation (GE Medical Systems, Horten, Norway).
All left-heart echocardiographic parameters including dimensions, and Doppler indices were acquired and analyzed as suggested by the current recommendations. ,, If the patient had atrial fibrillation during image acquisition, 3 beats were acquired and averaged. Left ventricular ejection fraction was measured using the Simpson’s biplane method. Left atrial maximum volume was measured at an end-systolic frame of the apical 4- and 2-chamber views using the biplane method. Diastolic function parameters including annular velocities and mitral inflow were also assessed. Severe left-sided valvular heart disease was defined as at least one of the following: severe aortic stenosis, severe aortic regurgitation, severe mitral stenosis, severe mitral regurgitation, and was evaluated using all available qualitative, quantitative, and semiquantitative methods in line with the respective guidelines.
Metrics of RV size and function were evaluated from an apical RV-focused view. Indices of RV function including TAPSE by M-mode, fractional area change, and systolic movement of the RV free wall by tissue Doppler imaging S’ wave, were calculated and reported. For RV fractional area change, RV end-diastolic and end-systolic frames were used to trace areas. RV was sized from 3 levels using linear dimensions at an end-diastole frame; namely tricuspid annulus, RV base, RV mid-diameter. A pulmonary artery-focused short-axis view was used to assess pulmonary valve acceleration time, which was measured by sampling pulse-wave Doppler at the tips of the pulmonary valve. Right atrial volume was evaluated by tracing at an end-systolic frame. PASP was derived from the tricuspid regurgitant jet peak velocity using the simplified Bernoulli equation, while end-expiratory diameter and inspiratory variations of the inferior vena cava were evaluated to estimate right atrial pressure. Special attention was employed to sample correctly tricuspid regurgitation velocity which was assessed from multiple acoustic windows to accurately identify the peak velocity. Severity of tricuspid regurgitation grade was assessed using a multiparametric approach including all available information as recommended. ,
Strain was evaluated using speckle tracking echocardiography by averaging measurements of 3 cardiac cycles and using the onset of the QRS as the reference point. Care was taken to acquire images at frame rates of 50-80 Hz. Left ventricular and RV longitudinal strain are reported in absolute numbers (i.e., positive).
A focused left ventricular apical 4-, 3-, and 2-chamber view was acquired to estimate left ventricular global longitudinal strain. The region of interest was identified by the software and the entire myocardial wall was included after manual adjustments. The software divided left ventricular myocardium into 16 segments and global longitudinal strain was automatically obtained by averaging the peak negative values of all segments.
For the RV strain, an apical RV-focused view was aquired. The basal, mid, and apical segments of the RV free wall and the septum were traced in a 6-segment model in order to obtain RV global longitudinal strain. For calculation of the RV free wall longitudinal strain only the basal, mid, and apical segments of the RV free wall were included and averaged in a 3-segment model. RV myocardium was automatically traced and then the myocardial thickness was adjusted manually.
Apical 4-chamber and 2-chamber views were used for left atrial strain analysis. The software automatically generated a 6-segment left atrial model and the peak strain values of each segment were averaged. The same software and process was followed for the right atrial strain, and the right atrial wall was traced from the lateral to the septal aspect of the tricuspid annulus in an right atrial-focused apical 4-chamber view, to avoid foreshortening. Gain and depth were optimized during image acquisition. Reservoir strain values for the left and the right atrium were reported, considering the high prevalence of atrial fibrillation of the cohort.
After discharge, all participants were followed-up at the HF outpatient clinic in person or via telephone. The primary endpoint was the composite outcome of all-cause mortality and HF rehospitalization. The medical records and the national electronic prescription system were reviewed to confirm all events. Complete follow-up data were available for all study participants.
Categorical variables are reported as frequencies (percentages) and were compared with the chi-square test. Continuous variables are presented as mean ± standard deviation when they follow normal distribution and as median (interquartile range) when they follow a non-normal distribution. The baseline clinical and echocardiographic characteristics on admission between the 3 groups were compared with the 1-way ANOVA test using the Bonferroni’s correction for normally distributed continuous variables and with the Kruskal– Wallis test for non-normally distributed continuous variables.
Relevant clinical, laboratory, and echocardiographic variables on admission were tested using univariable logistic regression analysis to identify those associated with Persistent RV-PA uncoupling. Subsequently, the variables that demonstrated univariably statistical significance were entered in a multivariable model to identify independent associations with the persistent RV-PA uncoupling. The odds ratio, 95% Confidence interval (CI), and P -value were calculated and reported.
A time-to-first-event outcome analysis was performed with censoring on the first event: all-cause mortality or HF rehospitalization. To compare the percentage of event-free survival rates among the 3 groups Kaplan-Meier analysis was performed. The association of clinical, biochemical, and echocardiographic variables with the primary endpoint, i.e., all-cause mortality and HF rehospitalization, was tested using Cox proportional hazard regression analysis. Potential confounders with statistical significance in the univariable analysis were included in the multivariable Cox regression analysis. The hazard ratio and 95% CIs were estimated and presented. All parameters with statistical significance in univariable Cox proportional hazard regression analysis were included to construct a robust baseline model. The RV-PA uncoupling on admission and the persistent RV-PA uncoupling were added to the baseline model on a stepwise approach and the model comparison was performed with the chi-square test.
All tests were 2-sided and p < 0.05 was considered statistically significant. Statistical analysis was conducted using the SPSS software, version 25.0 (IBM SPSS Statistics, for Windows, Armonk, NY) and R version 3.4.4 (R Foundation for Statistical Computing, Vienna, Austria).
Results
Out of 592 patients hospitalized for acute HF, 490 (age 73.4 ± 11.9 years, male 59.4%) were included in the final cohort ( Figure 1 ). These patients were divided into 3 groups based on their RV-PA coupling status; RV-PA coupling (n = 216, 44.1%), normalized RV-PA uncoupling (n = 123, 25.1%), persistent RV-PA uncoupling (n = 151, 30.8%). The baseline clinical characteristics of the 3 groups are presented in Table 1 . Among others, patients with normalized RV-PA uncoupling and persistent RV-PA uncoupling were older and had lower systolic blood pressure on admission compared to the RV-PA coupling group. Persistent RV-PA uncoupling patients had a higher prevalence of chronic HF, chronic atrial fibrillation, and chronic kidney disease. They also were more likely to require inotropes, and were prescribed higher doses on intravenous furosemide during hospitalization. In terms of their biochemical profile, they had worse NT-pro-BNP levels on admission.
Table 1
Baseline clinical characteristics on admission
| Variable |
All
(n = 490) |
RV-PA coupling
(n = 216) |
Normalized RV-PA uncoupling (n = 123) | Persistent RV-PA uncoupling (n = 151) | p-value |
|---|---|---|---|---|---|
| Clinical characteristics | |||||
| Age, years | 73.4 ± 11.9 | 70.8 ± 12.4 , | 75.5 ± 10.9^ | 75.2 ± 11.4 | < 0.001 |
| Male gender, n (%) | 291 (59.4) | 131 (60.6) | 65 (52.8) | 95 (62.9) | 0.35 |
| Body surface area, m 2 | 1.92 ± 0.24 | 1.95 ± 0.24 | 1.91 ± 0.25 | 1.89 ± 0.21 | 0.020 |
| Systolic blood pressure, mmHg | 124.7 ± 19.0 | 127.1 ± 18.8 | 124.0 ± 21.6 | 121.8 ± 16.7 | 0.031 |
| Diastolic blood pressure, mmHg | 74.2 ± 15.0 | 75.6 ± 15.8 | 73.1 ± 16.6 | 73.0 ± 12.1 | 0.16 |
| Heart rate, bpm | 82.8 ± 17.3 | 81.8 ± 17.5 | 85.3 ± 17.4 | 82.2 ± 16.9 | 0.17 |
| Medical history | |||||
| Chronic heart failure, n (%) | 271 (44.3) | 87 (40.3) | 67 (54.5) | 117 (77.5) | < 0.001 |
| Ischemic heart disease, n (%) | 182 (37.1) | 82 (38.0) | 39 (31.7) | 61 (40.4) | 0.31 |
| Dilated cardiomyopathy, n (%) | 58 (11.8) | 29 (13.4) | 15 (12.2) | 14 (9.3) | 0.48 |
| Chronic atrial fibrillation, n (%) | 156 (31.8) | 34 (15.7) | 46 (37.4) | 76 (50.3) | < 0.001 |
| Hypertension, n (%) | 246 (50.2) | 116 (53.7) | 63 (51.2) | 67 (44.4) | 0.18 |
| Type 2 diabetes mellitus, n (%) | 181 (36.9) | 72 (33.3) | 47 (38.2) | 62 (41.1) | 0.30 |
| Chronic kidney disease, n (%) | 83 (16.9) | 24 (11.1) | 24 (19.5) | 35 (23.2) | 0.007 |
| COPD, n (%) | 70 (14.3) | 23 (10.6) | 19 (15.4) | 28 (18.5) | 0.10 |
| In-hospital medical therapy | |||||
| Inotropes iv, n (%) | 64 (13.1) | 19 (8.8) | 18 (14.6) | 27 (17.9) | 0.033 |
| Furosemide iv dose, mg/day | 158.7 ± 117.7 | 135.6 ± 108.7 | 152.7 ± 109.9 | 197.7 ± 127.2 , | < 0.001 |
| Biochemical indices | |||||
| NT-pro-BNP, pg/mL (range) | 4,475 (2,038–10,687) | 3,128 (1,465–7,620) , | 4,820 (2,422–17,282)^ | 6,987 (2,900–16,615) | < 0.001 |
|
Troponin I, ng/L (range)
AST, U/L (range) |
40 (25–80)
25 (18–37) |
40 (24–114)
25 (18–41) |
37 (24–62)
25 (19–37) |
47 (30–76)
23 (17–33) |
0.14
0.08 |
| ALT, U/L (range) | 19 (12–35) | 21 (14–40) | 20 (12–35) | 16 (11–26) | 0.003 |
| Creatitine, mg/dL | 1.33 ± 0.54 | 1.26 ± 0.52 , | 1.30 ± 0.49 | 1.47 ± 0.57 , | 0.001 |
| BUN, mg/dL (range) | 54 (40–77) | 49 (36–65) | 55 (41–74) | 64 (47–101) , | < 0.001 |
|
Sodium, mEq/L
Potassium, mEq/L |
138.2 ± 9.8
4.2 ± 0.6 |
138.3 ± 10.2
4.3 ± 0.6 |
137.7 ± 13.2
4.3 ± 0.6 |
138.5 ± 4.7
4.1 ± 0.5 |
0.82
0.06 |
| Hemoglobin, g/dL | 12.2 ± 2.2 | 12.8 ± 2.1 | 12.1 ± 2.0 | 11.6 ± 2.3 | < 0.001 |
| Platelets, K/dL (range) | 222 (175–284) | 226 (183–288) | 224 (175–284) | 213 (159–263) | 0.038 |
The baseline echocardiographic characteristics of the 3 groups on admission are presented in Table 2 . Patients with normalized RV-PA uncoupling and persistent RV-PA uncoupling had worse indices of left ventricular diastolic function, and higher noninvasive left ventricular filling pressures compared to patients with RV-PA coupling; however no significant differences in left-ventricular systolic function indices were observed among the 3 groups. All metrics of RV size and function were significantly worse for patients with persistent RV-PA uncoupling compared to the other 2 groups. Persistent RV-PA uncoupling patients had larger left and right atrial volume and more impaired reservoir strain. Severe left-sided valvular heart disease and severe tricuspid regurgitation were more prevalent in the persistent RV-PA uncoupling group, who also had larger inferior vena cava size.
Table 2
Baseline echocardiographic characteristics on admission
| Variable |
All
(n = 490) |
RV-PA coupling
(n = 216) |
Normalized RV-PA uncoupling (n = 123) | Persistent RV-PA uncoupling (n = 151) | p-value |
|---|---|---|---|---|---|
| Left ventricle | |||||
| LV end-diastolic diameter, mm | 55.4 ± 10.6 | 55.3 ± 10.8 | 54.7 ± 9.6 | 56.2 ± 11.1 | 0.53 |
| LV end-systolic diameter, mm | 44.8 ± 11.9 | 44.3 ± 11.7 | 44.3 ± 11.2 | 46.1 ± 12.9 | 0.31 |
| LV end-diastolic volume indexed, ml/m 2 | 86.2 ± 36.6 | 87.6 ± 36.4 | 81.3 ± 33.0 | 88.2 ± 39.4 | 0.22 |
| LV end-systolic volume indexed, ml/m 2 | 55.8 ± 33.8 | 55.5 ± 33.4 | 52.4 ± 30.2 | 59.1 ± 36.8 | 0.25 |
| LV ejection fraction, % | 39.5 ± 14.5 | 40.8 ± 14.0 | 39.6 ± 14.5 | 37.6 ± 15.0 | 0.12 |
| LV ejection fraction < 40%, % | 254 (51.8) | 111 (51.4) | 61 (49.6) | 82 (54.3) | 0.73 |
| LV global longitudinal strain, % | 10.3 ± 5.1 | 10.6 ± 5.1 | 10.6 ± 4.9 | 9.6 ± 5.1 | 0.15 |
| Transmitral E wave, cm/s | 103.5 ± 26.9 | 96.9 ± 26.3 ^ , ˅ | 107.3 ± 27.0 ^ | 110.1 ± 25.6 ˅ | < 0.001 |
| Transmitral A wave, cm/s | 59.2 ± 27.9 | 63.4 ± 28.8 ˅ | 55.4 ± 23.8 | 51.4 ± 28.0 ˅ | 0.015 |
| E/A ratio | 2.03±1.12 | 1.81±1.06 ^ , ˅ | 2.29±1.22 ^ | 2.37±1.05 ˅ | 0.001 |
| Mean E/e’ ratio | 18.3 ± 6.0 | 17.4 ± 5.5 ^ , ˅ | 19.2 ± 5.9 ^ | 19.1 ± 6.7 ˅ | 0.07 |
| Right ventricle | |||||
| RV end-diastolic area, cm 2 | 22.1 ± 6.9 | 20.7 ± 6.8 ˅ | 21.5 ± 5.9 * | 24.8 ± 7.2 ˅ , * | < 0.001 |
| RV end-systolic area, cm 2 | 14.9 ± 5.9 | 12.9 ± 5.2 ^ , ˅ | 14.8 ± 5.0 ^ , * | 17.8 ± 6.4. ˅ , * | < 0.001 |
| Tricuspid annular diameter, mm | 35.7 ± 7.2 | 33.2 ± 7.4 ^ , ˅ | 36.3 ± 6.1 ^ . * | 38.6 ± 6.5 ˅ , * | < 0.001 |
| Basal RV diameter, mm | 46.1 ± 7.9 | 44.2 ± 8.2 ˅ | 45.6 ± 7.1 * | 49.3 ± 7.3 ˅ , * | < 0.001 |
| Mid RV diameter, mm | 34.6 ± 7.9 | 32.9 ± 8.0 ˅ | 33.8 ± 6.5 * | 37.8 ± 7.8 ˅ , * | < 0.001 |
| Apex-to-base RV, mm | 75.7 ± 13.2 | 76.3 ± 12.8 | 74.7 ± 11.6 | 75.8 ± 15.0 | 0.56 |
| Fractional area change, % | 33.7 ± 9.7 | 38.2 ± 8.6 ^ , ˅ | 31.7 ± 9.0 ^ | 29.1 ± 8.9 ˅ | < 0.001 |
| S’TDI tricuspid, cm/s | 9.5 ± 2.9 | 11.1 ± 2.7 ^ , ˅ | 9.1 ± 2.5 ^ , * | 7.5 ± 2.3 ˅ * | < 0.001 |
| TAPSE, mm | 16.3 ± 4.0 | 19.0 ± 3.3 ^ , ˅ | 15.4 ± 3.2 ^ , * | 13.2 ± 2.9 ˅ , * | < 0.001 |
| TAPSE/PASP, mm/mmHg | 0.36±0.15 | 0.49±0.13 ^ , ˅ | 0.29±0.05 ^ , * | 0.23±0.06 ˅ , * | < 0.001 |
| PV acceleration time, ms | 83.1 ± 23.5 | 89.6 ± 21.8 ^ , ˅ | 79.3 ± 21.9 ^ | 76.9 ± 24.8 ˅ | < 0.001 |
| RV free wall longitudinal strain, % | 19.0 ± 6.7 | 22.0 ± 6.4 ^ , ˅ | 18.2 ± 5.8 ^ , * | 15.3 ± 5.5 ˅ , * | < 0.001 |
| RV global longitudinal strain, % | 15.0 ± 5.3 | 17.0 ± 5.1 ^ , ˅ | 14.4 ± 4.7 ^ , * | 12.5 ± 4.8 ˅ , * | < 0.001 |
| Atria | |||||
| Left atrial volume indexed, ml/m 2 | 60.0 ± 28.2 | 54.3 ± 26.4 ^ | 60.0 ± 18.4 ^ , * | 68.2 ± 34.5 * | < 0.001 |
| Left reservoir strain atrial, % | 8.6 ± 4.6 | 10.3 ± 5.0 ^ , ˅ | 7.7 ± 3.9 ^ | 6.9 ± 3.5 ˅ | < 0.001 |
| Right atrial volume, ml | 85.3 ± 47.4 | 72.6 ± 46.8 ^ , ˅ | 86.9 ± 39.8 ^ , * | 102.1 ± 48.9 ˅ * | < 0.001 |
| Right atrial reservoir strain, % | 14.0 ± 10.4 | 20.0 ± 10.9 ^ , ˅ | 11.6 ± 7.8 ^ , * | 7.3 ± 5.7 ˅ * | < 0.001 |
| Others | |||||
| Severe left-sided valvular heart disease, % | 97 (19.8) | 21 (9.7) | 29 (23.6) | 47 (31.1) | < 0.001 |
| Severe tricuspid regurgitation | 184 (37.6) | 42 (19.4) | 48 (39.0) | 94 (62.3) | < 0.001 |
| PASP, mmHg | 49.5 ± 13.2 | 40.6 ± 9.4 ^ , ˅ | 54.0 ± 9.0 ^ , * | 58.6 ± 12.6 ˅ * | < 0.001 |
| Inferior vena cava diameter, mm | 23.1 ± 5.5 | 21.3 ± 6.0 ^ , ˅ | 23.6 ± 3.9 ^ , * | 25.2 ± 4.8 ˅ * | < 0.001 |
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