A Novel Non-Invasive Method for Estimating Elevated Pulmonary Vascular Resistance Based on Echocardiographic Assessment of Pulmonary Artery Wave Reflection

Abstract

Background: Several non-invasive methods for pulmonary vascular resistance (PVR) measurement are proposed, but none are sufficiently accurate for use in clinical practice. This study proposes a new echocardiographic method of pulmonary artery wave reflection and investigates its efficacy in managing patients with pulmonary hypertension.

Methods and Results: In total, 83 patients with left heart disease, pulmonary arterial hypertension, and chronic thromboembolic pulmonary hypertension (CTEPH), who underwent Doppler echocardiography and right heart catheterization, were included in the study. Pulmonary artery wave reflection was characterized by separating the pulmonary artery pressure waveform into forward and backward (Pb) waves, based on wave intensity. Pulmonary artery pressure waveforms were estimated from continuous Doppler tracings of tricuspid regurgitation velocity, and flow velocity was measured using pulsed Doppler of the right ventricular outflow tract. Pb-peak was compared with catheter hemodynamic indices, and with PVR by Abbas 2003, 2013 and Haddad in relation to increased catheter PVR. Catheter PVR and Pb were strongly correlated (r=0.77, P<0.001). The areas under the receiver operator characteristic curve for Pb-peak, PVR by Abbas 2003, 2013 and Haddad were 0.91, 0.72, 0.80, and 0.80, respectively, and were used to detect an increase in PVR (>3 Woods units).

Conclusions: This study describes a novel, simple, and non-invasive echocardiography method to assess pulmonary wave reflected pressure to identify patients with pulmonary hypertension due to increased PVR.

Pulmonary vascular disease with increased flow resistance leads to pulmonary hypertension (PH) and poor prognosis due to right ventricular failure. The gold standard for the diagnosis of afterload in PH is pulmonary vascular resistance (PVR) by performing right heart catheterization (RHC).¹ Previous studies have estimated PVR using the right ventricular outflow tract (RVOT) velocity time integral and tricuspid regurgitant velocity (TRV) in echocardiography;^2–4 however, the accuracy of this method remains limited.

Editorial p 956

Recently, some studies have reported the estimation of pulmonary artery (PA) wave reflection using echocardiography.^5,6 Pulmonary blood flow is pulsatile, and pathological changes in the pulmonary vasculature lead to an early wave reflection from the distal part of the PA tree, leading to a further increase in pulsatile load. The systolic Doppler flow velocity envelope in the RVOT is often abnormal in PH,^7,8 indicating the presence of reflected waves, as well as elevated PA pressure and indicators of PVR.⁹ PA wave reflection can be considered a direct afterload indicator of PH and may help to improve the identification and treatment of PH patients.

We devised a non-invasive method for estimating the pressure of PA wave reflection using Doppler echocardiography. The purpose of this study was to investigate the association of PA wave reflection with right heart catheter parameters for the diagnosis of PH. Furthermore, we investigated whether PA wave reflection can be used to identify patients with increased PVR, compared with various estimated PVR measurements using echocardiography.

Methods

Study Subjects

Data of 83 patients with left heart disease (LHD), pulmonary arterial hypertension (PAH), or chronic thromboembolic PH (CTEPH), who underwent Doppler echocardiography and RHC between January 2012 and December 2018, were retrospectively collected. In the control group, subjects without a history of cardiovascular disease and PH (n=30) were considered as reference ranges for PA wave reflection indices. Patients underwent echocardiography and RHC within a median of 2 days for LHD and within a median of 7 days for PAH and CTEPH. Patients with poor echocardiographic quality and atrial fibrillation were excluded. The diagnosis of LHD, PAH, and CTEPH depended on the initial diagnostic investigation and not on the level of PA pressure or PVR at follow up.

The study was approved by the ethics committee of the National Center for Global Health and Medicine (NCGM-G-003459-00). This study was performed in accordance with the Declaration of Helsinki, and an opportunity for eligible patients to refuse to participate in this study was provided using an opt-out process.

Echocardiography and Hemodynamic Evaluation

Echocardiography was obtained with a commercially available ultrasound system (Artida; Toshiba Medical Systems, Tokyo, Japan). Transthoracic echocardiography was performed in accordance with standard guidelines.^10,11 Left ventricular (LV) end-diastolic and end-systolic volumes, and LV ejection fraction (EF), were measured by using Simpson’s method. Pulse wave Doppler tracing at the tip of the mitral valve was recorded and the early to late diastolic transmission velocity ratio (E/A, E: early filling, A: atrial contraction) was calculated. Mitral annular velocities were recorded using pulse wave tissue Doppler from the base of the septum in an apical 4-chamber view to assess LV longitudinal function (e’). Right ventricular (RV) end-diastolic area and fractional area change were measured in an apical 4-chamber view to approximate RV size and systolic function. Tricuspid annular plane systolic excursion (TAPSE) was measured as the distance of systolic excursion of the RV annular segment along its longitudinal plane, from an apical 4-chamber window. RV free-wall strains were measured with Image Arena (TOMTEC Imaging Systems GmbH, Unterschleissheim, Germany). RVOT pulsed-wave Doppler interrogation was performed from a basal short-axis view through the left parasternal or subcostal window. The ejection time and acceleration time (AcT) were measured from the RVOT pulse wave Doppler velocity profile. Continuous-wave Doppler tracing of TRV was performed from a 4-chamber view, subcostal short-axis view, or parasternal view of RV inflow. Estimates of systolic pulmonary artery pressure (SPAP) were based on the sum of the tricuspid pressure gradient and the right estimated atrial pressure based on the size and collapsibility of the inferior vena cava.

To assess hemodynamics, RHC was performed as clinically necessary for diagnosis or treatment assessment, and did not depend on the diagnosis of PH at the time of testing. The following variables were measured or derived: right atrial pressure; PA diastolic pressure (PADP); PA mean pressure (PAMP); PA systolic pressure (PASP); PA wedge pressure (PAWP); cardiac output (CO); and PVR. CO was determined using the thermodilution method, as an average of ≥3 consecutive measurements that did not change by >10%. PVR using catheterization was defined as (PAMP-PAWP)/CO, and pulmonary artery compliance (PAC) was defined as stroke volume/(PASP-PADP).¹² Both PVR and PAC were used as hemodynamic afterload indices in the pulmonary arteries.

PA Wave Reflection Indices Using Echocardiographic Doppler

Pulmonary wave reflection was characterized by estimating pressure and velocity profiles from Doppler measurements and separating pressure waveform into forward (Pf) and backward pressure (Pb) waves based on the concept of wave intensity. Analysis of wave separation and images was performed offline in a custom-made Matlab program (Mathworks, Natick, Massachusetts, USA). Estimated PA pressure was recorded from the continuous Doppler of tricuspid valve regurgitant velocity, using the simplified Bernoulli equation. Flow velocity was recorded from the pulsed Doppler of the RVOT. These envelope waveforms were traced semi-automatically (Figure 1). The estimated right atrial pressure based on the size and collapsibility of the inferior vena cava was not entered because it can be treated as a constant in wave intensity equations. From PA pressure and RVOT flow (shown as a P and U in Figure 1), the forward wave’s pressure and backward wave’s pressure were obtained based on the method of wave intensity¹³ and by using the water hammer equation:¹⁴ [dP₊ = 1/2 (dP + ρc dU)] and [dP₋ = 1/2 (dP − ρc dU)], P_±(t) = ΣdP_±(t); where P₊(t) is the forward pressure wave, P₋(t) is the reflected pressure wave at time ‘t’, ‘ρ’ is the blood density, and ‘c’ is the wave speed. The wave speed was determined from the measured P and U by plotting the PU-loop and determining the slope of the curve during early systole.¹⁵ Peak values of Pb, Pf, and reflection coefficient (RC), which was calculated as the ratio of peak Pb to peak Pf, were used for comparison with PA hemodynamics and echocardiographic indices. In PA separation analysis, intra-observer variability by the same observer at 2 different time points was also analyzed for 15 patients. The results were analyzed using Pearson correlation analysis and the Bland-Altman method.

Figure 1.

Pulmonary artery wave separation using echocardiographic Doppler. Separate pulmonary artery pressure waveform using pressure (P) from tricuspid regurgitation (TR) waveform using a simplified Bernoulli equation and blood flow velocity (U) from the right ventricular outflow tract (RVOT) blood flow waveform.

Echocardiographic PVR

PVR using echocardiography was also calculated based on the previous methods proposed by Abbas et al^2,3 and Haddad et al.⁴ The PVR method proposed by Abbas 2003 et al (PVR Abbas 2003) was based on the ratio of peak TRV to time velocity integral (TVI) in the RVOT; the PVR method proposed by Abbas 2013 (PVR Abbas 2013) was based on TRV²/TVI; and the PVR method proposed by Haddad et al. (PVR Haddad) was based on the index of SPAP/(HR × TVI).

Statistical Analyses

Continuous data are presented as mean±standard deviation (SD) or median (25^th–75^th percentiles), and categorical data are expressed as number and percentages. The extent of the linear relationship between catheterization and Doppler echocardiography was evaluated using the correlation coefficient (R). To perform multiple group comparisons, we used a one-way ANOVA if the distribution was normal, and the Kruskal-Wallis test if the distribution was not normal. When the null hypothesis was rejected (a probability value of 0.05 was considered statistically significant), we utilized the independent samples t-test or the Mann-Whitney U-test, as appropriate. Post-hoc analysis consisted of paired t-tests with Bonferroni correction.

Correlations of continuous variables were tested with the Pearson’s correlation coefficient if the data were normally distributed. Receiver operator characteristic (ROC) curves for the detection of increased PVR using catheterization, defined as the area under the curve (95% CI) in 3 Woods units (WU), were determined with an echocardiographic index of RV afterload. To determine the clinically useful cut-off levels for the different variables, values corresponding to the optimal combination of sensitivity and specificity were selected from the ROC analysis. Univariate and multivariate logistic regression analyses for prediction of increased PVR (>3 WU) using right heart catheterization were performed, and the results were expressed as odds ratios (ORs) and 95% confidence intervals (CIs). A P value <0.05 was regarded as significant. All statistical analyses were performed by using SPSS ver. 24 (SPSS, Chicago, IL, USA).

Results

Baseline Characteristics

Forty patients had LHD (LVEF, 45±19%), 23 patients had PAH, and 20 patients had CTEPH. In the LHD group, patients had hypertensive heart failure in 17 cases, dilated cardiomyopathy in 2 cases, ischemic heart disease in 9 cases, and valvular disease in 10 cases. In the PAH group, 11 cases were idiopathic, 8 were associated with a connective tissue disorder, and 4 cases were associated with human immunodeficiency virus (HIV) infection. In CTEPH, all the lesions were the peripheral type. Clinical characteristics, echocardiographic, and RHC data are shown in Table 1. PA hemodynamic variables of right heart catheters were compared between different types of diseases. There were no data on RHC in the control group. PVR was 5.2±4.2 (mean±SD) WU (median 3.8, range 2.2–7.2) in PAH patients and was a mean of 5.2±3.1 WU (median 5.0, range 2.9–6.7) in CTEPH patients. In patients with LHD, PVR was much lower than in patients with PAH or CTEPH; 2.3±1.0 WU (median 2.5, range 1.5–3.0), and in 11 patients (27.5%), PVR was elevated >3 WU. Twenty-four patients (60%) had PAWP elevated >15 mmHg.

Table 1. Baseline Characteristics of the Study Population

	Control (n=30)	LHD (n=40)	PAH (n=23)	CTEPH (n=20)	P value
Age, years	54±14	72±12	61±17	71±13	<0.001
Male sex, n (%)	22 (55)	23 (56)	6 (26)	9 (45)	0.08
BMI, kg/m2	24±4.0	25±2.7	23±5.0	22±3.8	0.77
SBP, mmHg	126±17	128±22	122±20	128±19	0.68
HR, beats/min	64±8.0	71±14	72±14	65±8.0	0.09
Comorbidities, n (%)
Hypertension	0 (0)	25 (62.5)	9 (39.1)	8 (40.0)	<0.001
Diabetes	0 (0)	7 (17.5)	2 (8.6)	1 (5)	0.25
COPD	0 (0)	5 (12)	3 (13)	2 (10)	<0.001
Treatment, n (%)
Phosphodiesterase-5 inhibitors	0 (0)	0 (0)	3 (13)	1 (5)	0.05
Endothelin receptor antagonist	0 (0)	0 (0)	4 (17)	2 (10)	0.02
Prostanoid	0 (0)	0 (0)	6 (26)	4 (20)	0.001
Riociguat	0 (0)	0 (0)	3 (13)	5 (25)	0.002
BPA	0 (0)	0 (0)	0 (0)	5 (25)	<0.001
Laboratory
Hemoglobin, g/dL	14±1.6	13±1.7	12±2.3	14±1.8	<0.001
Creatinine, mol/L	0.81±0.18	1.49±0.3	0.86±0.27	0.83±0.29	0.13
eGFR, mL/min/1.73 m2	72±14	57±25	64±21	64±16	0.04
BNP, pg/mL	14±3.1	1120±204	135±37	141±35	<0.001
RHC
Cardiac index, (L/min)/m2	–	2.5±0.7	3.0±1.0	3.0±0.8	0.17
RAP, mmHg	–	5.7±3.8	4.9±2.7	5.0±2.0	0.54
PASP, mmHg	–	38±12	55±30	51±16	0.002
PAMP, mmHg	–	25±8.2	34±17	29±8.6	0.02
PADP, mmHg	–	16±5.9	21±12	16±6.5	0.05
PAWP, mmHg	–	16±7.3	9.2±3.4	8.3±3.1	<0.001
PVR, WU	–	2.3±1.0	5.2±4.2	5.2±3.1	<0.001
PAC, mL/mmHg	–	3.1±1.8	2.8±1.7	2.3±1.1	0.16
Echocardiography
LVEF, %	65±3.6	45±19	66±7.2	65±5.8	<0.001
LVEDV, mL	79±28	131±73	63±31	63±20	<0.001
E/A	1.1±0.3	1.7±1.2	0.9±0.3	1.0±0.3	<0.001
E/e’	9.7±3.3	20±8.1	14±2.4	9.9±2.4	<0.001
SPAP, mmHg	23±6.2	40±14	62±28	58±25	<0.001
RVFAC, %	50±16	39±13	41±14	37±13	<0.001
TAPSE, mm	20±3.0	17±4.2	18±5.4	19±4.2	0.007
RVFWLS, %	−28±6.3	−20±8.3	−18±9.8	−20±8.3	<0.001
AcT, ms	132±22	100±22	99±21	95±22	<0.001
AcT/RVET	0.4±0.07	0.4±0.1	0.3±0.06	0.3±0.1	<0.001
Mid systolic notch, n (%)	0 (0)	7 (17.5)	7 (30.4)	11 (55)	<0.001

Values are presented as the mean±SD for variables with a normal distribution and median (range) for variables with a non-parametric distribution. AcT, acceleration time; BMI, body mass index; BNP, B-type natriuretic peptide; BPA, balloon pulmonary angioplasty; COPD, chronic obstructive pulmonary disease; CTEPH, chronic thromboembolic pulmonary hypertension; E/A, early to late diastolic transmission velocity ratio; eGFR, estimated glomerular filtration rate; HR, heart rate; LHD, left heart disease ; LVEDV, left ventricular end-diastolic volume; LVEF, left ventricular ejection fraction; PAC, pulmonary artery (PA) capacitance; PADP, pulmonary artery diastolic pressure; PAH, pulmonary arterial hypertension; PAMP, PA mean pressure; PASP, PA systolic pressure; PAWP, pulmonary artery wedge pressure; PVR, pulmonary vascular resistance; RAP, right atrial pressure; RHC, right heart catherterization; RVET, right ventricular outflow ejection time; RVFAC, right ventricular fractional area change; RVFWLS, right ventricular free wall longitudinal strain; SBP, systolic blood pressure; SPAP, systolic pulmonary artery pressure; TAPSE, tricuspid annular plane systolic excursion; –, no data.

Comparison of Catheterization and Doppler Echocardiography Findings

Measurements of SPAP and pulse pressure estimated using the echo-Doppler method were compared with those measured directly with the right heart catheter to determine whether PA pressure was accurately measured using Doppler echocardiography. A very strong correlation was obtained with regression coefficients of 0.71 and 0.72 (both P<0.001), supporting the validity of this echo-Doppler method in the subjects of this study.

PA Wave Reflection in PH and Control Subjects

Figure 2 shows the echo-Doppler waveforms and PA pressure separation indices of various representative PH diseases and control subjects. In all cases, the approximate top of the RVOT flow was the point where Pb started to rise. Control subjects tended to have smaller Pb than those with other diseases. The disease-specific differences in PA wave reflection were investigated (Figure 3). In the control group, Pf, Pb, and RC were all significantly lower than that in the LHD, PAH, and CTEPH groups. In the PH disease group, Pf was not significantly different between the LHD, PAH, and CTEPH groups (Figure 3A). Pb showed a significant increase in the PAH group (P<0.001) and CTEPH group (P<0.001) compared to the LHD group, but there was no significant difference between the PAH and CTEPH groups (P=0.93) (Figure 3B). For the RC, similar to Pb, the PAH group (P=0.005) and CTEPH group (P<0.001) showed a significant increase compared to the LHD group, but there was no significant difference between the PAH and CTEPH groups (P=0.43) (Figure 3C).

Figure 2.

Pulmonary artery reflection and echo-doppler waveform in control subjects, left heart disease (LHD), pulmonary arterial hypertension (PAH), and chronic thromboembolic pulmonary hypertension (CTEPH).

Figure 3.

Honeycombs of the pulmonary artery reflection indices, which depict (A) Pf (forward pressure), (B) Pb (backward pressure), and (C) RC (reflection coefficient) according to the type of pulmonary hypertension disease. Red circles represent a PVR >3 WU, blue circles represent a PVR ≤3 WU or the control group. PVR, pulmonary vascular resistance; WU, Woods units.

Furthermore, Pf, Pb, and RC showed a distribution of high values in patients with a PVR >3 WU.

Hemodynamic Correlates of PA Wave Reflection Indices

A comparison of PA reflection indices and hemodynamic parameters showed a strong correlation between PAMP and Pb (r=0.66, P<0.001), which was even stronger than the correlation between Pf and RC (Table 2). Pb showed a strong correlation with PVR (r=0.77, P<0.001). Furthermore, Pb showed a good correlation with PAC (r=−0.51, P<0.001). In PAWP, there was a statistically significant correlation with Pb, but the relationship was weak.

Table 2. Correlation Between Pulmonary Artery Separated Wave Pressure and Standard Diagnostic Indices Using Right Heart Catheterization

	Pf		Pb		RC
	R	P value	R	P value	R	P value
PASP	0.60	<0.001	0.74	<0.001	0.48	<0.001
PAMP	0.54	<0.001	0.66	<0.001	0.42	<0.001
PAWP	−0.04	0.69	−0.28	0.01	−0.13	0.24
CI	0.13	0.25	0.12	0.29	0.16	0.15
PAC	−0.32	0.003	−0.51	<0.001	−0.45	<0.001
PVR	0.58	<0.001	0.77	<0.001	0.52	<0.001

CI, cardiac index; Pb, backward pressure; Pf, forward pressure; RC, reflection coefficient. Other abbreviations as in Table 1.

Detection of Increased PVR

Table 3 shows the ANOVA comparison of echocardiographic indices of the right heart system and pulmonary artery reflection indices among the 3 groups: control subjects; PVR ≤3 WU; and PVR >3 WU. PVR Abbas 2003, PVR Abbas 2013, PVR Haddad, and PA reflection indices, including Pf, Pb, and RC, were not only significantly different between PVR patients and control subjects, but also significantly different between patients with and without increased PVR according to the post-hoc analysis. Correlations between PVR using a catheter and echocardiographic findings are shown in Figure 4. PVR Abbas 2003, PVR Abbas 2013, and PVR Haddad correlated with the PVR using a catheter. Moreover, Pb showed the strongest correlation with the PVR using a catheter (r=0.77, P<0.001). The correlation between Pb and PVR was observed even in patients with a PAWP >15 mmHg (r=0.54, P=0.007). Figure 5 shows the ROC curves for Pb and estimated PVR. Pb had the largest area under the curve (AUC 0.91). In diagnostic precision for PVR >3 WU, Pb showed the combined cut-off value for sensitivity and specificity of 7.8 mmHg, and showed good sensitivity and specificity (sensitivity 87% and specificity 86%). The diagnostic performance with these cut-off values is shown in Supplementary Table 1. In addition, the association between Pb and increased PVR (>3 WU) was confirmed using multivariate logistic regression analysis. Pb was associated with increased PVR, with an odds ratio of 1.43 (P=0.001), independently from cofounders including age, male, and SPAP (Supplementary Table 2).

Table 3. Echocardiography Findings in Patients With and Without Increased PVR Using Right Heart Catheterization

	Control (n=30)	PVR ≤3 WU (n=43)	PVR >3 WU (n=40)	P value
SPAP, mmHg	23±6.4	39±13*	64±26*,†	<0.001
TAPSE, mm	20±3.0	18±4.6	18±4.9	0.07
RVFAC, %	50±16	41±14*	36±12*	0.001
RVFWLS, %	−28±6.3	−21±8.8*	−18±8.5*	<0.001
AcT, ms	132±22	103±23*	94±19*	<0.001
AcT/RVET	0.4±0.07	0.4±0.1	0.3±0.07*,†	<0.001
Mid systolic notch, n (%)	0 (0)	6 (5)	19 (29)*,†	<0.001
PVR by Abbas 2003	1.6±0.4	2.5±1.2*	3.0±1.0*,†	<0.001
PVR by Abbas 2013	0.3±0.1	0.7±0.5*	1.1±0.5*,†	<0.001
PVR by Haddad	6.4±1.7	11±5.5*	15±5.9*,†	<0.001
Pf, mmHg	9.0±7.1	16±7.3*	25±13*,†	<0.001
Pb, mmHg	0.7±0.7	5.6±3.7*	16±10*,†	<0.001
RC	0.09±0.07	0.4±0.2*	0.6±0.2*,†	<0.001

Values are presented as mean±standard deviation for variables with a normal distribution and median (range) for variables with a non-parametric distribution. *P<0.05 compared with the control. ^†P<0.05 compared with a PVR ≤3 WU. RVFWLS, right ventricular free wall longitudinal strain. Other abbreviations as in Tables 1,2.

Figure 4.

Correlations between right catheter-derived pulmonary vascular resistance (PVR using a catheter). (A) Pulmonary arterial backward pressure (Pb). (B) PVR using the Abbas original method 2003. (C) PVR using the Abbas modified method 2013. (D) PVR using the Haddad method. Black dots represent patients with a PAWP >15 mmHg, white circles represent those with a PAWP ≤15 mmHg. Pb shows the highest correlation with PVR using a catheter, and also PAWP >15 mmHg is a good correlation with PVR using a catheter. PAWP, pulmonary artery wedge pressure; PVR, pulmonary vascular resistance.

Figure 5.

Receiver operator characteristic (ROC) curves to detect increased PVR for Pb, PVR Abbas 2003, PVR Abbas 2013, PVR Haddad, and AcT. The area under the curve is the largest for Pb (0.91). AcT, acceleration time; Pb, backward pressure; PVR, pulmonary vascular resistance.

Intra-Observer Variability

Excellent correlations were shown for intra-observer variability of Pf and Pb (r=0.92 for Pf and r=0.90 for Pb). Bland-Altman analysis showed that intra-observer variability was 1.2±2.6% for Pf and −0.2±1.5% for Pb.

Discussion

The relationship between right heart catheter hemodynamics and PA reflected wave pressure showed that increased PVR was strongly associated with increased PA reflected wave pressure. This non-invasive measurement of pulmonary artery reflected wave pressure was determined to be a better representation of elevated catheter PVR than the existing method of echocardiographically estimated PVR.

Non-Invasive Estimation of PA Wave Reflection

Classically, pulmonary artery pressures and flow rates were measured using catheters and Fourier expansions to obtain PA wave reflection indices by characteristic impedances from frequency analysis; however, these are sensitive to noise, and there is still no method to quantify characteristic impedances non-invasively with echocardiography. The presence of reflected waves has been recognized from the abnormal flow pattern of the RVOT in patients with PH, known as a mid-systolic notch pattern in the pulsed Doppler envelope, which represents a rapid decrease in RV ejection flow secondary to wave reflection.^8,16,17 PA reflected wave pressure arrival occurs early in the systolic phase, which increases ventricular afterload and prevents antegrade flow, leading to early shortening of RVOT flow and notch formation.⁹ In a previous study of patients without increased PVR, the top of the RVOT flow peak and TR pressure peak coincided with each other, and there was no increased pressure after peak flow.^18,19 These findings suggested that reflected wave pressure was almost non-existent. In contrast, in patients with PH with increased PVR, an augmented pressure (AP) is observed in patients with PH who showed an earlier and more pronounced pressure-reflected peak flow. In our study, there was no increase in reflected wave pressure in the control group. Bech-Hanssen et al estimated reflected wave pressure as AP from the difference between the RVOT waveform and the peak TRV.^5,20,21 The advantages of our study were its fluid dynamics equations and semi-automated image analysis capabilities, which provided accurate estimates of reflected wave pressure rather than visually arbitrary measurements. Wave intensity is expressed in terms of dP/dU, which indicates the change in pressure and velocity per unit time. For example, if dP is positive and dU is positive, this represents a forward flow, whereas if dP is positive and dU is negative, it reflects a backward flow.²² Su et al reported that there is a weak relationship between wave intensity indices and hemodynamic parameters.²³ Wave intensity analysis, represented by small amounts of dP and dU, is a low in power. Wave intensity analysis determines positive or negative energy from changes in the workload, and is sensitive to changes in the properties of arterial systems, but is less related to pressure. However, the combination of the water hammer equation allows the separation of waves and the quantification of forward and reflected wave pressures.^14,24 Our group performed a combo-wire catheter and echocardiography validation study in beagle dogs, and showed a good correlation between the reflected wave pressure of each of them (in submission).

As a method to determine the “c” of wave speed, Su et al²³ used the sum of the square method, but the noise in the flow wire may have made it difficult to measure the initial rise of RV contraction. The PU-loop method is the original method used in this study, and because flow images in the RVOT using echocardiography can be measured relatively clearly, ‘c’ is determined using this method.

PA Reflection and PH Afterload Indices

Some researchers have used a Doppler echocardiography method indirectly related to PVR.^2–4,25 In particular, the original Abbas equation² cannot be used to identify patients with PVR >6 WU. In this study, we demonstrated a good correlation between reflected wave pressure and PVR in patients with PH. In addition, reflected wave pressure showed high sensitivity and specificity compared to other measures of estimated PVR using echocardiography, especially in the patients with a PVR >3 WU. It represents robust pathogenesis of PH afterload. Even in the pathogenesis of post-capillary PH with elevated PAWP, Pb showed a good correlation with PVR, suggesting that Pb may provide a non-invasive estimate of the presence of pre- and post-capillary PH.

In daily clinical practice, we routinely use PVR, which assesses the relationship between steady state mean pressure and flow. The lack of cardiovascular impedance concepts does not provide for a pulsatile pathological assessment. Reflected wave pressure theoretically represents the pulsatile flow.

PVR is the steady state vascular resistance; however, there is a possible reason for a good relationship with Pb, which reflects the pulsatile state. Pulmonary arteries have only 3 arterial branches to the periphery; therefore, impedance mismatch is unlikely to occur in central portions of the arteries, and it is thought that peripheral resistance may be directly reflected in the reflected wave.

The concept of PA reflected waves is important in understanding PH, and we non-invasively estimated pulmonary artery reflection wave pressure from 2 echocardiographic images (TR velocity and RVOT flow) and demonstrated a favorable relationship with PVR. In the future, we need to investigate the clinical and prognostic associations of various PH disease.

Potential for Clinical Application

In some patients with chronic thromboembolic pulmonary hypertension, exercise tolerance is decreased after pulmonary artery endarterectomy, despite normalization of pulmonary hemodynamics. This may be due, in part, to the persistence of PA wave reflection in the postoperative period. Previous studies using wave intensity analysis have shown that even in patients with no residual PH, there are still large reflection pressure waves after 3 months postoperatively.²⁶ PA wave reflection may be an appealing target for the treatment of PH. It needs to be verified whether reducing PA wave reflection calculated using echocardiography will significantly improve clinical outcomes. As shown in Figure 2, the peak of AcT coincided with the onset of a rise in reflected wave pressure in various PH states. In particular, in CTEPH, the start of the reflected wave tended to be earlier than in other PH diseases, suggesting that the lesion may be more central. It may be possible to obtain a more anatomical location of the lesion by including a time phase analysis to the peak of the reflected wave pressure.

Study Limitations

The subjects were patients who received diagnostic RHC. This was a single-center retrospective study, and there was variability in the time differences between catheterization and echocardiography. It would have been preferable to analyze the profiles according to the ensemble averaging from multiple images, but only a single RVOT and TR velocity were used.

To prove that the pulmonary artery reflected wave pressure is an afterload of the right ventricle, verification experiments using catheterization and echocardiography should be performed simultaneously and be related to the workload of RV.

Patients with PH from various groups with heart failure, PAH, and CTEPH were included, and it is important to further investigate the precise cut-off values for each disease and their relationship to clinical outcomes. In addition, the effects of vasodilators and other treatments for PH need to be investigated. In conclusion, here we describe a novel echocardiography method for assessing pulmonary wave reflected pressure. This method can be used to identify patients with PH due to increased PVR.

Sources of Funding

This work was supported by the National Center for Global Health and Medicine Clinical Research (NCGM-CR) grant (20A1016).

Disclosures

A patent application for this technology is pending from the National Center for Global Health and Medicine. The funders have had no role in the design and/or implementation of the study.

Author Contributions

H. Hayama: Designed and performed the study, analyzed data and wrote the paper. S.A.-A., T.U., H. Hara: Performed the experiments. M.M., Y.H.: Directed experiments and co-wrote the paper.

IRB Information

The study was approved by the ethics committee of the National Center for Global Health and Medicine (NCGM-G-003459-00). An opportunity for eligible patients to refuse to participate in this study was provided using an opt-out process.

Supplementary Files

Please find supplementary file(s);

http://dx.doi.org/10.1253/circj.CJ-21-0646

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