ABSTRACT
The hemodynamic definitions of pulmonary hypertension consider resistive loading (pulmonary vascular resistance [PVR]), but there are increasing evidence that pulsatile loading (pulmonary artery compliance [PAC]) has functional and prognostic importance. The aims of the present study on patients with left heart disease, were to evaluate a novel echocardiographic right ventricular (RV) afterload score and to investigate its relation to risk of mortality or implantation of a left ventricular assist device. Patients (n = 220) with left ventricular ejection fraction < 50% consecutively referred for heart transplant or heart failure workup underwent echocardiography and right heart catheterization. Four metrics were included in the afterload score: the systolic pulmonary artery pressure (sPAPDoppler) and three variables related to pressure reflection in the pulmonary circulation. Two points were allocated for sPAPDoppler ≥ 60 mmHg and for each pressure reflection variable indicating PVR > 3 Wood units (WU). One point was allocated for sPAPDoppler 36–59 mmHg and for pressure reflection variables above the upper normal limit. Low afterload was defined as 0‐to‐1 points, intermediate as 2‐to‐4 points, and high as 5‐to‐8 points. There were in‐between the groups significant differences in PAC and PVR. A 5‐point RV dysfunction score showed with stepwise increased RV afterload more severe dysfunction. Unadjusted hazard ratio for endpoint was 3.34 (1.69–6.79) for intermediate score, and 5.11 (2.52–10.40) for patients with high score. In conclusion, in patients with severe heart failure, a novel echocardiographic RV afterload score is related to increased pulsatile and resistant load, more severe RV dysfunction, and increased risk of adverse outcome.
Keywords: echocardiography, left heart disease, right ventricular afterload, right ventricular dysfunction
Abbreviations
- AcT
acceleration time
- AP
augmented pressure
- CpcPH
combined pre‐and postcapillary pulmonary hypertension
- dPAP
diastolic pulmonary artery pressure
- Ea
pulmonary effective arterial elastance
- IpcPH
isolated postcapillary pulmonary hypertension
- IQR
inter‐quartile rang
- LHD
left heart disease
- mPAP
mean pulmonary artery pressure
- NoPH
no pulmonary hypertension
- PA
pulmonary artery
- PAC
pulmonary artery compliance
- PAP
pulmonary artery pressure
- PAWP
pulmonary artery wedge pressure
- PH
pulmonary hypertension
- PVR
pulmonary vascular resistance
- RV
right ventricle
- RVD
right ventricular dysfunction
- RVOT
right ventricular out‐flow tract
- sPAP
systolic pulmonary artery pressure
- tPV‐PP
the time interval from peak velocity in the RVOT to peak velocity (=peak pressure) in the tricuspid regurgitant jet
- WU
Wood units
1. Introduction
Right ventricular dysfunction (RVD) or failure is associated with poor clinical outcome in patients with left heart disease (LHD). In most cases, RVD occurs secondary to pulmonary hypertension (PH) and increased right ventricular (RV) afterload. The determinants of RV afterload consist of both pulsatile (pulmonary artery compliance [PAC]) and resistant components (pulmonary vascular resistance [PVR]), and each has been shown to predict RVD and mortality in LHD [1, 2, 3, 4, 5, 6]. However, in the current hemodynamic definition of PH only the static resistant load (PVR) is considered [7], and patients are divided into either having isolated post‐capillary PH (IpcPH) or combined pre‐ and post‐capillary PH (CpcPH). The presence of increased static load (PVR > 2WU) defines CpcPH. It can be argued that this division into pre‐ and post‐capillary, from what we know about the pulmonary circulation in patients with LHD, is a misnomer. Increased pulmonary artery wedge pressure (PAWP) will augment the RV pulsatile loading by amplifying the peripheral pulse reflection leading to a decline in PAC [8]. In the pulmonary circulation, contrary to the systemic circulation, there is an inverse and hyperbolic relation between PAC and PVR [9]. Patients with normal PAC will also have normal PVR and patients with increased PVR will have decreased PAC. In between there will be patients with reduced PAC but normal or mildly elevated PVR. As an alternative to the current definition of PH, we suggest classifying patients according to their RV afterload profile: either normal, dominated by reduced PAC, or by both increased PVR and reduced PAC.
Comprehensive phenotyping of PH and RV afterload in LHD patients typically requires right heart catheterization. However, right heart catheterization is restricted to a small part of patients with heart failure due to LHD, and therefore, it is of interest to explore to what extent echocardiography can be used to identify both increased pulsatile and resistive load. We recently showed how patients with increased resistive load (PVR > 3WU) can be identified using three easily obtainable echocardiographic variables related to pressure reflection in the pulmonary circulation. This has been shown in patient cohorts with a mixture of PH classes [10, 11] as well as in patients with LHD [12, 13]. To what extent the three echocardiographic pressure reflection variables are related to pulsatile load is unknown. In‐between the thresholds indicating increased resistive load and the upper normal limit for the pressure reflection variables, there is a gray zone that we in the present study hypothesized contains information related to increased pulsatile load. By combining the Doppler estimated pulmonary artery (PA) pressure with the three pressure reflection variables we established an echocardiographic score for grading the severity of RV afterload.
The study aims were twofold: first, to evaluate a novel echocardiographic RV afterload score, and second, to investigate the impact of increments of RV afterload score on prognostic stratification.
2. Methods
In this retrospective study, 275 patients with LHD who underwent both echocardiography and right heart catheterization at the Sahlgrenska University Hospital, Gothenburg, Sweden, between 2009 and 2019, were screened. All patients were considered to have LHD after a comprehensive diagnostic work‐up including right heart catheterization and often myocardial biopsy and coronary angiography. The main indications for catheterization were assessment of hemodynamic status as a part of a pre‐transplant work‐up, assessment of PH or restrictive cardiac physiology, and hemodynamic evaluation in connection with an endomyocardial biopsy. Patients with age < 18 years (n = 2), LV ejection fraction ≥ 50% (n = 26), patients without a tricuspid regurgitation (n = 16) that allowed Doppler estimation of systolic pulmonary artery pressure (sPAP) and patients with > 3 days between echocardiography and right heart catheterization (n = 11) were excluded. We also excluded five patients with massive or torrential tricuspid regurgitation with large defects of coaptation and Doppler gradients < 10 mmHg. The final study population then comprise 215 individuals. A retrospective chart review was performed to analyze the clinical characteristics of all the patients. Blood samples obtained were analyzed by the Central Laboratory of Sahlgrenska University Hospital (accredited according to the European Norm 45.001).
2.1. Clinical Outcomes
The study endpoint was a composite of all‐cause mortality and implantation of a left ventricular assist device. Patients were censored if they underwent heart transplantation or if they survived until the study census date (6 February 2024).
2.2. Pressure Recovery
In normal pulmonary circulation, in contrast to systemic circulation, the pressure and flow waves generated by the RV have a similar contour [14]. In the normal RV outflow tract (RVOT), there is no pressure gradient, and therefore, the contour of the RV pressure curve resembles the contour of the PA pressure curve. Changes in the pulmonary pre‐capillary properties, such as reduced compliance and increased resistance, result in the reflection of pressure and flow waves, with marked changes in wave contours [15]. Typically, in subjects with pressure reflection in the pulmonary circulation, the peak velocity in the RVOT will be earlier than in subjects without, and the pressure in the RV will, due to the reflected pressure wave, continue to increase following cessation of flow into the PA. Therefore, compared with subjects without pressure reflection, in those who have, the timing of the peak pressure in the RV (corresponding to continuous Doppler peak velocity in the tricuspid regurgitant jet) will be delayed relative to the peak RVOT velocity, and there will be augmentation of the RV pressure following the time point of peak RVOT velocity. From these flow and pressure characteristics of pressure reflection, three variables can be designed as illustrated in Figure 1: (1) acceleration time (AcT), the time interval from opening of the pulmonary valve to peak flow velocity in RVOT; (2) the time interval from peak velocity in the RVOT to peak velocity (= peak pressure) in the tricuspid regurgitant jet (tPV‐PP); and (3) augmented pressure (AP), the pressure increase (augmentation) in the RV following peak velocity in RVOT.
Figure 1.
Upper panel shows Pulsed Doppler in the right ventricular outflow tract (RVOT PWDoppler) and continuous‐wave Doppler of the tricuspid regurgitant jet (TR CWDoppler) in a patient (A) with low RV afterload score, a patient (B) with intermediate RV afterload score and (C) a patient with high RV afterload score. The time intervals from the QRS to the opening (a–b) of the pulmonary valve, peak velocity (a–d) in the outflow tract, and the peak right ventricular pressure (a–c) are determined. The AcT is then [(a‐d)‐(a‐b)], and tPV‐PP is [(a–c)–(a–d)]. The interval (a–d) is superimposed on the tricuspid velocity envelope to determine the right ventricular pressure corresponding to peak velocity in the right ventricular outflow tract. The lower panel shows the thresholds used for the four variables included, deciding the allocation of two, one, or zero points in the afterload score.
The assessment of the timing of peak velocity in the RVOT is crucial for the pressure reflection variables, and it is important at acquisition to acknowledge the spectral Doppler quality, especially concerning beat‐to‐beat variation (Figure 2). To improve quality and reduce the beat‐to‐beat variation, the sample volume should be repositioned, and often, the best Doppler tracing will be performed with the transducer in a more caudal position that shows the pulmonary trunk (Videos S1 and S3) and not in the standard short axis at the level of the aortic valve (Videos S2 and S4). The tPV‐PP interval and the AP are dependent on measurements from non‐simultaneous recordings in the RVOT and tricuspid regurgitation. To minimize the error due to differences in heart rate it is recommended to perform the pulsed Doppler recording in the RVOT immediately following the continuous Doppler recording of the tricuspid regurgitation.
Figure 2.
Measurements of the time from QRS to peak velocity in two patients. With the sample volume in the RVOT (A and C), as we see it at the level of the aortic valve in standard short axis (Videos S2 and S4) and after repositioning the transducer one intercostal space in the caudal direction and tilting the transducer to obtain a view of RVOT and the pulmonary trunk (Videos S1 and S3). As can be shown in B and D there is compared with A and C less beat‐to‐beat variability in the spectral Doppler contour as well as timing of the peak velocity.
2.3. Right Ventricular Afterload Score
In the present study, we assessed the RV afterload using the estimated sPAP by Doppler and the three echocardiographic variables related to pressure reflection described above. With the RV afterload score, three severity levels were defined, denoted low, intermediate, and high. For each of the four variables, 2 points were allocated if they indicated high afterload with PVR > 3 WU and 0 points if the variable indicated low (normal) afterload, and 1 point if the variable was outside the normal range but less than indicating PVR > 3 WU (Figure 1). The total points then can be 8. The thresholds for Doppler sPAP indicating low and high RV afterload were based on a previous study on phenotyping of PH with echocardiography where ≤ 36 mmHg indicated low likelihood of pulmonary hypertension and ≥ 60 mmHg indicated PVR > 3 WU [13]. The upper normal limits for the pressure reflection variables originate from a control group previously investigated [11], and the thresholds indicating high RV afterload are those previously defined, indicating increased likelihood of PVR > 3 WU [10]. We hypothesized that incremental increase in RV afterload score would also imply incremental increase in RV dysfunction (RVD) and indicate more severe prognosis. Low RV afterload was defined as 0‐to‐1 points, intermediate RV afterload as 2‐to‐4 points, and high RV afterload as 5‐to‐8 points.
2.4. Assessment of Right Ventricular Function
The echocardiographic assessment of RV function included solitary measurements describing RV dilatation (RV inflow diameter, indexed RV diastolic area), reduced longitudinal function (tricuspid annular plane systolic excursion (TAPSE), the velocity of the annular plane and the deformation of the RV free wall using speckle tracking imaging) and reduced radial and longitudinal function (RV fractional area change [FAC]). Speckle tracking was performed on the RV‐free wall by manual tracing. Finally, we used a recently described multiparameter RVD score that is empirical but based on the pathophysiology of RV decompensation [16, 17]. The echocardiographic parameters included in the RVD score were selected to represent either the common cause of RVD (PH), acknowledged sign of RVD (reduced longitudinal function), or findings indicating RV‐PA uncoupling (RV enlargement, increased central venous pressure, and moderate or severe tricuspid regurgitation) [9, 18, 19]. Each of the selected variables contributes with one point in the 5‐point RVD score.
2.5. Hemodynamic Measurements
The period of fasting before the investigation was at least 4 h and liquids stopped at least 2 h before the procedure. We aimed to minimize the effect of fasting by keeping this period as short as possible without compromising the safety aspects. A PA catheter (7F, Baxter Healthcare, Edwards Critical Care Division, Deerfield, Illinois, USA) was introduced using the Seldinger technique.
The following variables were measured or derived: heart rate, right atrial pressure, RV end diastolic pressure, systolic PAP (sPAP), diastolic PAP (dPAP), mPAP, PAWP, cardiac output, and PVR. PAWP was measured as the mean pressure during quiet breathing. Cardiac output was determined by the thermodilution method as the mean of three to five consecutive measurements not varying by more than 10%. Stroke volume and cardiac output were indexed to body surface area yielding stroke volume index and cardiac index. PVR was calculated as the difference between mPAP and PAWP divided by cardiac output and expressed in WU. The transpulmonary pressure gradient was calculated as the difference between the mPAP and PAWP. PAC and Ea were defined as stroke volume divided by pulmonary pulse pressure (sPAP − dPAP) and sPAP/stroke volume, respectively. The RV stroke work index was defined as: stroke volume index × (mPAP − right atrial pressure) × 0.0136 [20]. From the invasive assessment of RV afterload the patients were divided into three groups: Normal afterload defined as PAC > 3.8 mL/mmHg [21] and PVR ≤ 2 WU, predominantly increased pulsatile load defined as PAC < 3.8 ml/mmHg and PVR < 3 WU, and predominantly resistant load defined as PVR > 3 WU. The patients were divided according to hemodynamic PH‐phenotype into three groups: Patients without PH (NoPH, mPAP≤ 20 mmHg), patients with IpcPH (mPAP> 20 mmHg, PAWP > 15 mmHg and PVR ≤ 2 WU) and patients with CpcPH (mPAP> 20 mmHg, PAWP > 15 mmHg and PVR > 2 WU) [7].
2.6. Statistical Analysis
Continuous variables are expressed as the mean ± SD, medians with interquartile ranges or as numbers with percentages. The degree of the linear relationship between variables was assessed by Pearson's correlation coefficient (R). To compare multiple groups, one‐way ANOVA test was used when the distribution was normal or the Kruskal–Wallis test in case of non‐normal distribution. In cases where the null‐hypothesis was rejected (p value < 0.05 considered statistically significant), a post‐hoc analysis of intergroup comparisons using the independent‐sample t‐test, or Mann–Whitney test when appropriate, was applied. Using the Bonferroni correction for multiple testing, the null hypothesis was rejected if the p value was < 0.016. The association between the afterload score and end‐point (all‐cause mortality and implantation of a left ventricular assist device) was analyzed using Cox proportional hazard regression. In the case of missing values for NT‐proBNP (n = 18), the median value (3130 ng/L) was imputed. Hazard ratios are presented with 95% confidence intervals, unadjusted and adjusted for potential confounders. Relevant variables were designated as confounders if they, based on subject knowledge, were (1) associated with the outcome, (2) associated with or unevenly distributed among different groups of afterload score, and (3) not an effect of high afterload, that is, not on the causal pathway. Based on this, age, sex, LVEF, LAVI, presence of moderate/severe mitral regurgitation, and heart failure etiology were included in the multivariable analysis. By not fulfilling the third criterion, NYHA class, NT‐proBNP, and measures of RV function were not included in the multivariable analysis. The incremental prognostic value of afterload score to conventional risk markers used in clinical practice (LVEF, NT‐proBNP, and NYHA class) was analyzed separately and determined using the likelihood ratio test. The assumption of proportional hazards was confirmed using Schoenfeld's residuals.
To evaluate the interindividual variability the measurements included in the RV afterload score were repeated by two investigators on the same investigation (n = 30). The results are reported as linear relation and using κ statistics to evaluate the agreement regarding individual score and the final RV afterload classification (low, intermediate, high).
The statistical analysis was performed using SPSS for Macintosh, version 28, and R version 4.3.1.
3. Results
The mean ± SD age in the study was 54 ± 13 years and 77% were males. One‐hundred seventy‐nine patients (83%) were referred for heart transplant work‐up. Echocardiography and right heart catheterization were performed on the same day in 45 patients (21%). Echocardiography was performed the day before catheterization in 95 patients (44%) and the day after in 24 patients (11%). Ninety‐two percent received a beta‐blocker, 80% loop‐diuretics, 60% an aldosterone inhibitor, 47% an angiotensin‐converting‐enzyme inhibitor, and 28% an angiotensin 2 inhibitor.
3.1. Clinical Characteristics and LV/RV Function
Patients with intermediate afterload score had compared to those with a low score higher NT‐proBNP, lower peak VO2, more severe LV dysfunction with lower LV ejection fraction, reduced LV global strain, more enlarged left atrium, more often ≥ moderate mitral regurgitation, higher PAWP and lower cardiac index (Table 1). Measures of LV function by right heart catheterization or echocardiography did not significantly differ between patients with high or intermediate score. Patients with intermediate or high RV afterload score had compared with low score signs of more pronounced RV dysfunction at right heart catheterization with increased right atrial pressure and RV end diastolic pressure (Table 1). Patients with high RV afterload score had increased RV stroke work index compared with patients with intermediate RV afterload score (Table 1). Concerning RV function there was no difference between intermediate and high RV afterload score regarding findings at right heart catheterization (right atrial pressure, RV end diastolic pressure) or using single echocardiographic variables describing RV longitudinal (TAPSE, RV free‐wall strain, Figure 3A,B) or global (RV fractional area change, Figure 3C) function. The multiparameter RVD score showed significant differences between the three RV afterload subtypes (Figure 3D).
Table 1.
Clinical characteristics and LV/RV function in different RV afterload subtypes.
| RV afterload score | Post hoc analysisa | ||||||
|---|---|---|---|---|---|---|---|
| Low0–1 (n = 77) | Intermediate2–4 (n = 79) | High5–8 (n = 59) | Overall p Value | Low vs. Intermediate | Low vs. high | Intermediate vs. high | |
| Clinical | |||||||
| Age (years) | 51 ± 13 | 52 ± 14 | 59 ± 11 | 0.002 | 1.0 | < 0.001 | 0.009 |
| Female gender (%) | 35 | 19 | 15 | 0.03 | 0.09 | 0.03 | 1.0 |
| Etiology (%) | |||||||
| Dilated CM | 57 | 78 | 51 | 0.5 | — | — | — |
| Ischemic CM | 19 | 18 | 36 | 0.07 | — | — | — |
| Other | 24 | 16 | 10 | 0.17 | — | — | — |
| Time to event or censored (months) | 43 (6; 86) | 9 (3; 72) | 7 (2; 35) | 0.003 | 0.04 | 0.003 | 0.9 |
| Proportion Htx (%) | 39 | 47 | 49 | 0.69 | — | — | — |
| Mortality (%) | 14 | 27 | 36 | 0.04 | 0.2 | 0.01 | 0.8 |
| Laboratory | |||||||
| Creatinine | 98 (83; 136) | 100 (86; 128) | 112 (91; 150) | 0.10 | — | — | — |
| NT‐proBNP | 1800 (1024; 3435) | 3465 (1647; 6100) | 3630 (2020; 5900) | < 0.001 | 0.002 | 0.001 | 1.0 |
| Functional capacity | |||||||
| NYHA class 3–4 (%) | 67 | 85 | 91 | 0.30 | — | — | — |
| Peak Workload (watt) | 85 (71; 110) | 76 (54; 100) | 70 (54; 90) | 0.02 | 0.11 | 0.02 | 1.0 |
| Peak VO2 (mL/kg/min) | 15.5 ± 5.2 | 12.3 ± 3.6 | 11.8 ± 2.5 | < 0.001 | 0.002 | 0.005 | 1.0 |
| LV/LA dimension and function | |||||||
| LVEF (%) | 30 ± 10 | 23 ± 8 | 23 ± 8 | < 0.001 | < 0.001 | 0.001 | 1.0 |
| LVEDvol (mL) | 185 (130; 245) | 233 (176; 286) | 203 (166; 257) | 0.005 | 0.008 | 0.55 | 0.42 |
| LV GLS (%) | ‐8 (‐10; ‐6) | ‐6 (‐8; ‐4) | ‐6 (‐7; ‐4) | < 0.001 | < 0.001 | 0.001 | 1.0 |
| LAVI (mL/m2) | 47 ± 15 | 58 ± 20 | 65 ± 27 | < 0.001 | 0.001 | < 0.001 | 0.3 |
| E/e' | 14 (9; 16) | 15 (12; 20) | 18 (11; 23) | 0.005 | 0.048 | 0.007 | 1.0 |
| MR≥ grade 2 (%) | 19 | 39 | 41 | 0.04 | 0.02 | 0.02 | 1.0 |
| Heart beats (beats/min) | 68 ± 12 | 76 ± 16 | 72 ± 14 | 0.004 | 0.004 | 0.3 | 0.48 |
| MAP (mmHg) | 74 ± 13 | 72 ± 10 | 75 ± 12 | 0.39 | — | — | — |
| PAWP (mmHg) | 10 (5; 16) | 20 (16; 25) | 22 (17; 26) | < 0.001 | < 0.001 | < 0.001 | 1.0 |
| PAWP > 15 mmHg | 32 | 76 | 81 | < 0.001 | < 0.001 | < 0.001 | 1.0 |
| Cardiac index (L/min/m2) | 2.4 ± 0.6 | 2.1 ± 0.6 | 2.0 ± 0.5 | < 0.001 | < 0.001 | < 0.001 | 1.0 |
| SvO2 (%) | 67 ± 7 | 57 ± 9 | 57 ± 11 | < 0.001 | < 0.001 | < 0.001 | 1.0 |
| SvO2 < 60% (%) | 12 | 61 | 61 | < 0.001 | < 0.001 | < 0.001 | 1.0 |
| RV dimension and function | |||||||
| RVD1 (mm) | 43 ± 8 | 48 ± 7 | 50 ± 8 | < 0.001 | 0.001 | < 0.001 | 0.4 |
| RVDAi (cm2/m2) | 10.3 ± 2.8 | 11.8 ± 2.7 | 13.3 ± 2.6 | < 0.001 | 0.006 | < 0.001 | 0.015 |
| RAAi (cm2/m2) | 10.4 ± 3.1 | 12.0 ± 3.6 | 13.2 ± 4.1 | < 0.001 | 0.01 | < 0.001 | 0.18 |
| TAPSE (mm) | 16 ± 5 | 14 ± 5 | 13 ± 4 | < 0.001 | 0.12 | < 0.001 | 0.15 |
| FAC (%) | 36 ± 12 | 26 ± 10 | 22 ± 9 | < 0.001 | < 0.001 | < 0.001 | 0.90 |
| S velocity (cm/s) | 9 ± 3 | 8 ± 2 | 8 ± 2 | 0.007 | 0.09 | 0.002 | 0.69 |
| RV free‐wall strain (%) | ‐19 ± 6 | ‐15 ± 5 | ‐15 ± 5 | < 0.001 | < 0.001 | < 0.001 | 1.0 |
| RVD score | 1 (0; 2) | 2 (1; 3) | 3 (3; 4) | < 0.001 | < 0.001 | < 0.001 | < 0.001 |
| TR≥ grade 2 (%) | 13 | 29 | 36 | 0.02 | 0.054 | 0.01 | 1.0 |
| IVC collapsibility (%) | 68 (53; 100) | 39 (24; 67) | 31 (18; 50) | < 0.001 | < 0.001 | < 0.001 | 0.14 |
| RAP (mmHg) | 3 (1; 6) | 8 (4; 14) | 9 (5; 13) | < 0.001 | < 0.001 | < 0.001 | 1.0 |
| RVEDP (mmHg) | 5 (2; 7) | 10 (6; 14) | 11 (6; 15) | < 0.001 | < 0.001 | < 0.001 | 1.0 |
| RVSWI (g/m/beat/m2) | 5.9 (4.7; 8.3) | 7.0 (5.1; 9.1) | 9.3 (7.3; 12.2) | < 0.001 | 0.75 | < 0.001 | < 0.001 |
Note: Values are mean ± SD, median and interquartile range (25%; 75%) or percentage.
Abbreviations: CM, cardiomyopathy; E/e’, ratio between early diastolic mitral blood flow velocity and the early tissue Doppler mitral annular velocity; FAC, fractional area change; Htx, heart transplant; IVC, internal vena cava; LA, left atrium; LAVI, left atrial volume indexed to body surface area; LV, left ventricle; LVEDIvol, left ventricular end‐diastolic volume; LVEF, left ventricular ejection fraction; LV GLS, left ventricular global longitudinal strain; MAP, mean systemic arterial blood pressure; MR, mitral regurgitation; NYHA, New York Heart Association; NT‐proBNP, N‐terminal prohormone of brain natriuretic peptide; PAWP, pulmonary artery wedge pressure; RAAi, right atrial area indexed to body surface area; RAP, right atrial pressure; RV, right ventricle; RVD, right ventricular dysfunction; RVD1, the diastolic diameter of the right ventricular inflow; RVDAi, right ventricular diastolic area indexed to body surface area; RVEDP, right ventricular end diastolic pressure; RVSWI, right ventricular stroke work index; S velocity, tissue Doppler systolic velocity; TAPSE, tricuspid annular plane systolic excursion; TR, tricuspid regurgitation; VO2, maximum rate of oxygene consumption.
Post‐hoc analysis significance values have been adjusted by the Bonferroni correction for multiple tests.
Figure 3.
Boxplots showing the relation between increments of RV afterload score and RV function: (A) TAPSE, (B) RV free‐wall strain, (C) RV fractional area change, and (D) RVD score. Post‐hoc analysis significance values have been adjusted by the Bonferroni correction for multiple tests.
3.2. Relation Between Echocardiographic Afterload Variables and RV Load
The linear relationship between Doppler sPAP and pulsatile (PAC, Ea) and resistant afterload (PVR) was moderate, with correlation coefficients ranging from 0.54 to 0.60 (Supporting Information S1: Table 1). The corresponding relationship for the pressure reflection variables was moderate or weak, with a correlation coefficient range 0.29 to 0.59 (Supporting Information S1: Table 1). The relationship between pulsatile/resistive load and the RV afterload score was moderate, with a correlation coefficient range of 0.57 to 0.64. Transpulmonary gradient, mPAP (Table 2), pulsatile (PAC, Ea, Figure 4A,B), and resistive (PVR, Figure 4C) load significantly increased with increasing RV afterload scores. The proportion with predominantly increased resistant load was significantly higher in patients with high compared with intermediate RV afterload score (Table 2, Figure 4D). In patients with intermediate RV afterload score, reduced PAC was more common than PVR ≥ 3WU, while in patients with high RV afterload score both reduced PAC and PVR > 3 WU were common. The PAC‐PVR relation showed a hyperbolic pattern (Figure 4E). There was a large overlap between patients with low and intermediate RV afterload score, whereas patients with high RV afterload score were mainly dispersed along the horizontal part of the curve with both reduced PAC and high PVR. At comparable levels of PVR, patients with increased PAWP showed signs of more reduced compliance (Figure 4F).
Table 2.
Relation between echocardiographic RV afterload subtype and RV load.
| RV afterload score | Post hoc analysisa | ||||||
|---|---|---|---|---|---|---|---|
| Low0–1 (n = 77) | Intermediate2–4 (n = 79) | High5‐8 (n = 59) | Overall p value | Low vs. Intermediate | Low vs. high | Intermediate vs. high | |
| sPAP (mmHg) | 29 ± 10 | 43 ± 9 | 56 ± 14 | < 0.001 | < 0.001 | < 0.001 | < 0.001 |
| mPAP (mmHg) | 19 ± 7 | 29 ± 7 | 36 ± 9 | < 0.001 | < 0.001 | < 0.001 | < 0.001 |
| mPAP‐PAWP (mmHg) | 8 ± 3 | 9 ± 4 | 15 ± 6 | < 0.001 | 0.02 | < 0.001 | < 0.001 |
| sPAP‐dPAP (mmHg) | 18 ± 5 | 23 ± 7 | 33 ± 11 | < 0.001 | < 0.001 | < 0.001 | < 0.001 |
| PAC (mL/mmHg) | 3.6 (3.0; 4.5) | 2.4 (1.8; 3.1) | 1.6 (1.2; 2.2) | < 0.001 | < 0.001 | < 0.001 | < 0.001 |
| Ea (mmHg/mL) | 0.40 (0.31; 0.60) | 0.80 (0.63; 1.0) | 1.1 (0.74; 1.43) | < 0.001 | < 0.001 | < 0.001 | < 0.001 |
| PVR (Wood units) | 1.7 (1.3; 2.3) | 2.2 (1.6; 2.9) | 3.7 (2.6; 5.2) | < 0.001 | 0.004 | < 0.001 | < 0.001 |
| Afterload subtype (%) | |||||||
| Normal afterload | 41 | 9 | 2 | < 0.001 | < 0.001 | < 0.001 | 0.42 |
| Pulsatile load | 55 | 68 | 30 | < 0.001 | 1.0 | 0.03 | < 0.001 |
| Resistant load | 4 | 23 | 68 | < 0.001 | 0.004 | < 0.001 | < 0.001 |
| PH phenotype (%) | |||||||
| No PH | 60 | 11 | 5 | < 0.001 | < 0.001 | < 0.001 | 0.69 |
| IpcPH | 18 | 33 | 12 | 0.02 | 0.12 | 1.0 | 0.01 |
| CpcPH | 22 | 56 | 83 | < 0.001 | < 0.001 | < 0.001 | 0.005 |
Note: Values are mean ± SD, median and interquartile range (25%; 75%) or percentage.
Abbreviations: CpcPH, combined pre‐ and post‐capillary pulmonary hypertension; Ea, pulmonary artery elastance; IpcPH, isolated post‐capillary pulmonary hypertension; mPAP, mean pulmonary artery pressure; PAC, pulmonary artery compliance; PAWP, pulmonary artery wedge pressure; PH, pulmonary hypertension; PVR, pulmonary vascular resistance; RV, right ventricle; sPAP, systolic pulmonary artery pressure.
Post‐hoc analysis significance values have been adjusted by the Bonferroni correction for multiple tests.
Figure 4.
Boxplots (A–C) showing the relation between increments of RV afterload score and PAC (A), Ea (B) and PVR (C). The distribution within each RV afterload subtype of patients with reduced normal RV afterload, increased pulsatile and resistant load are shown in (D). The distribution in the PAC‐PVR relation of increments of RV afterload score and increased versus normal PAWP are shown in (E) and (F), respectively.
3.3. Clinical Outcomes and Prognostic Value
During a median follow‐up time of 13.5 months (IQR 3.0 to 67.1) 45 patients (21%) died, 23 patients (11%) received a left ventricular assist device, and 96 patients (45%) underwent heart transplantation. Figure 5 shows the Kaplan‐Meier curves for survival free of endpoint in patients according to echocardiographic RV afterload score. Event rates at 1 year for patients with high afterload score were 30%, 27% for patients with intermediate scores, and 5% for those with a low score. At 3 years, the corresponding numbers were 49%, 40%, and 11%. The 3‐grade afterload score was associated with death or left ventricular assist device implantation both in the univariable analysis and after adjustment for confounders (Table 3). In the univariable analysis, increasing afterload score was associated with incrementally higher risk.
Figure 5.
Kaplan–Meier curves for the endpoint of all‐cause mortality and implantation of a left ventricular assist device in patients with low, intermediate and high RV afterload scor.
Table 3.
The association between the 3‐grade RV afterload score and all‐cause mortality or implantation of a left ventricular assist device presented as hazard ratios (HR) with 95% confidence intervals.
| Univariable analysis | Multivariable analysisa | ||
|---|---|---|---|
| Afterload score | HR (95% CI) | C statistic | HR (95% CI) |
| Intermediate | 3.34 (1.69–6.79) | 0.67 (0.62–0.72) | 2.48 (1.18–5.21) |
| High | 5.11 (2.52–10.40) | 2.60 (1.19–5.70) | |
Adjusted for age, sex, left ventricular ejection fraction, left atrial volume indexed to body‐surface area, moderate/severe mitral regurgitation, and heart failure etiology.
Afterload score provided incremental predictive information to clinically applied risk markers (NT‐proBNP, NYHA class, and LVEF), p = 0.007.
3.4. Interobserver Variability
The correlation between the RR interval during RVOT pulsed wave Doppler recording and the RR interval during continuous Doppler tricuspid regurgitant recording was strong (R 2 = 0.92), and the mean difference ± SD between the two RR intervals was 4 ± 45 ms with a mean RR length of 845 ms. The results of assessment of interobserver variability are described in detail in Supporting Information S1: Table 1 and Figure 1. The linear relation was strongest for the assessment of Doppler sPAP (R 2 = 0.93) and weakest for tPV‐PP (R 2 = 0.77). The agreement in points allocated (0, 1, 2) for the four individual parameters in the RV afterload score was almost perfect for sPAP (κ 0.87), substantial for AP (κ 0.67) and AcT (κ 0.64), and fair for tPV‐PP (κ 0.38). The agreement in the final assessment of RV afterload severity subtype (low, intermediate, high) was substantial (κ 0.75).
4. Discussion
The main findings in the present study of patients with LHD and reduced LV ejection fraction were that (1) a novel echocardiographic RV afterload score that is based on the assessment of sPAP by Doppler and pressure reflection variables, is related to both the pulsatile (PAC, Ea) and flow resistive (PVR) components of RV afterload, (2) increments of RV afterload score is associated with more severe RVD and (3) the RV afterload score is associated with mortality and morbidity.
Pulmonary hypertension is a common finding in patients with LHD, but only a small proportion will be subjected to right heart catheterization. Therefore, it is important if we can grade the RV afterload burden using easily obtainable variables from standard echocardiography. Originally, we described how pressure reflection variables could be used to detect patients with increased PVR ( > 3WU) [10, 11, 12]. Between the thresholds indicating PVR > 3 WU and what we found as the upper normal limit, there was a rather wide gray zone. In the present study, we reveal that these gray zone findings contain information about the pulsatile RV load. This is not unexpected since lowered compliance is known to cause pressure reflection that will occur in patients with normal PVR [22]. Numerous noninvasive metrics of RV‐PA uncoupling have been proposed, but they are indirect measures of RVD and, therefore, they are related to myocardial function as well as pulsatile and resistant loading conditions [23, 24]. To the best of our knowledge, there are no other echocardiographic variables directly related to pulsatile and resistant RV afterload.
The clinical importance of recognizing early increased pulsatile RV load is that it should raise the question of whether the heart failure treatment can be optimized. The decrease in PAC is driven by the increased PAWP [8] and it has been shown that by lowering the PAWP, pulsatile vascular loading will be reduced [1]. The increase in PVR seen in patients with LHD is considered due to increased vascular tonus [25] but also to structural changes in arteries as well as veins with thickening of the arterial media and arterialization of the veins [26]. These different mechanisms constitute different therapy targets [27]. Regarding increased vascular tone, drugs approved for the treatment of PAH, such as endothelin receptor antagonist or phosphodiesterase 5 inhibitors, have been assessed but with conflicting results, and today, these drugs are not recommended for patients with PH due to LHD [7]. Likewise, in trials with drugs as prostacyclin analogs targeting vessel remodeling and approved in PAH, the results have been conflicting and shown potentially harmful effects [7, 27].
The hyperbolic PAC‐PVR relationship as shown in Figure 4E,F, has the implication that in patients with more severely increased PVR and high afterload score, pulsatile RV load will remain increased even following a reduction in PVR [3, 28]. The disappointing results in different trials with PAH drugs on patients with LHD have partly been explained, resulting from suboptimal patient selection. In this context, it could be of interest that echocardiography can be used to identify patients with mainly increased pulsatile load from patients with increased both pulsatile and resistant RV load. There were no other laboratory (NT‐prBNP), clinical (NYHA class), or echocardiographic (LVEF, E/e’, TAPSE) findings that could differentiate patients with mainly increased pulsatile load from those with both increased pulsatile and resistive load. Patients with high RV afterload score had CpcPH to a larger extent than patients with intermediate RV afterload score. Therefore, we can speculate that patients with high RV afterload score are less amenable to heart failure therapies that lower the left atrial pressure while in contrast, patients with intermediate RV afterload score should be more responsive to these therapies. Further, longitudinal studies with repeat clinical and echocardiographic assessments following the optimization of heart failure therapies are needed to investigate the accuracy of this hypothesis. Importantly, echocardiographic assessment of RV afterload profile cannot replace right heart catheterization when considered important in the context of pre‐transplant work‐up or assessment of PH or restrictive physiology.
During the last two decades, RVD has been recognized as a predictor of adverse events in patients with chronic heart failure. The functional echocardiographic parameters used have been related to the longitudinal contraction of the RV‐free wall, and their prognostic impact has been documented [29, 30, 31, 32]. Still, grading severity of RVD (mild, moderate, severe) has not gained much attention. Typically, in studies on how PH phenotype (CpcPH vs. IpcPH) or afterload (pulsatile vs. resistant) affect the RV function, grading severity is performed by eyeballing and often described in a way that does not allow replication [1, 2, 3, 6]. In the present study, we hypothesized that incremental increase in RV afterload score would also imply incremental increase in RVD. For the assessment of RV function, we used single parameters related to RV filling pressure (right atrial mean pressure), longitudinal (TAPSE, S'‐velocity, RV free‐wall strain) or global function (FAC) but also a novel multiparameter RVD score [16, 17]. Only the multiparameter RVD score could describe a difference in RV function between patients with intermediate and high RV afterload score. This illustrates the strength of a composite measure of RV function that contains a combination of parameters related to different characteristics of RV function as it changes from the compensated to un‐compensated or RV‐PA uncoupled state. The longitudinal function (TAPSE) related to myocardial contractility, RV enlargement, and tricuspid regurgitation as a sign of RV‐PA uncoupling and reduced inferior cava collapsibility related to RV backward failure.
The increased RV pulsatile loading in patients with LHD has been shown to negatively affect RV function and survival [1, 2, 3]. RV pulsatile loading emerges as a more consistent predictor of mortality than PVR in patients with various degrees of LHD, irrespective of LV ejection fraction [2]. As the PAC‐PVR relation clearly demonstrates, patients with increased PVR will also have reduced PAC and, therefore, comparing the prognostic impact of reduced pulsatile loading with that of increased PVR might be less relevant. Therefore, the superiority of pulsatile parameters compared with PVR in predicting mortality can likely be explained by patient selection and statistical methods [1, 2, 3], and should be interpreted with caution. Our results support the importance of pulsatile loading regarding both RVD and event rate in the unadjusted model. However, we also demonstrate how the combination of increased pulsatile loading and increased PVR as seen in the high RV afterload score, has the worst effect on RV function and prognostic importance in a multivariable analysis.
4.1. Study Limitations
Several limitations should be discussed. The present study is retrospective and single center with most of the patients undergoing heart transplant work‐up, that indicates advanced heart failure. For the study object that was to evaluate the novel RV afterload score, we needed right heart catheterization data as a reference, and as an inevitable consequence, the study population will not be representative for the overall heart failure population. We can only speculate how this might influence our results. It is less likely that the observed relationship between the RV afterload score and pulsatile and resistant load should be biased. In patients with long‐standing LHD and severe symptoms, the RVD and mortality observed might be due to RV myocardial dysfunction, severe LV dysfunction, and not necessarily due to increased RV afterload. Further studies are needed, including patients with clinically stable LHD, to investigate the prognostic importance of increments of RV afterload score. For the assessment of cardiac output, we used thermodilution. We excluded five patients with torrential tricuspid regurgitation, but in the remaining nine study patients (4%) with severe tricuspid regurgitation, this might have introduced an underestimation of cardiac output and consequently an overestimation of resistant load. Of these nine, two patients had PVR > 3 WU and we can argue that using thermodilution has not importantly biased our results. The pressure reflection variables are dependent on measurements of time intervals, and for tPV‐PP and AP, two non‐simultaneous measurements are combined. This can be challenging and errors in measurements might lead to both under‐ and overestimation of RV afterload. At our institution, the scientific interest for more than 10 years in echocardiography and pressure reflection has led to high‐quality RVOT Doppler recordings in the daily routine. In the present study, we report substantial interobserver agreement in RV afterload grading, but ideally, the variability should have been assessed with a test‐retest approach. In addition, the Kaplan Meier graph showed an increasing risk of the endpoint with an increasing grade of RV afterload score. At the unadjusted Cox proportional hazard regression, numerically, there was a difference, but the confidence intervals were wide and overlapping. It is conceivable that having both increased pulsatile and resistant load will increase the risk of adverse outcomes, but further studies with larger sample sizes are needed to establish any incremental risk increase with higher scores. Also, there are possibly other relevant confounders that could have been included in a larger sample size. The confounders included in this analysis are considered to include both general confounders such as age and gender, but also confounders based on left ventricular function (left ventricular ejection fraction) and left atrial pressure (left atrial size, mitral regurgitation) that are likely to contribute to increased RV afterload.
5. Conclusions
In conclusion, in the present study, we show that by using standard echocardiographic assessment of sPAP and three variables related to pressure reflection, we can define three subtypes indicating low, intermediate, and high RV afterload. Patients with intermediate RV afterload have increased pulsatile load, while patients with high afterload score have both increased pulsatile and resistant RV load. The differences in afterload profile translate into stepwise differences in RV function and event risk.
Author Contributions
study conception and design: Odd Bech‐Hanssen, Thomas Lindow, Marco Astengo, Entela Bollano, Sven‐Erik Ricksten. Data collection: Odd Bech‐Hanssen, Marco Astengo. Analysis and interpretation of results: Odd Bech‐Hanssen, Thomas Lindow, Marco Astengo, Entela Bollano, Sven‐Erik Ricksten. draft manuscript preparation: Odd Bech‐Hanssen. All authors reviewed the results and approved the final version of the manuscript.
Ethics Statement
The study protocol was approved by the Regional Ethical Review Board in Gothenburg, Sweden (Dnr. 286‐18).
Conflicts of Interest
The authors declare no conflicts of interest.
Supporting information
Supporting information.
Supporting information.
Supporting information.
Supporting information.
Supporting information.
Acknowledgments
We would like to thank technician Eric Täll for participating in the interobserver variability assessment.
Data Availability Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Supporting information.
Supporting information.
Supporting information.
Supporting information.
Supporting information.
Data Availability Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.