Pulmonary Hypertension, an Echo Assessment: Is it Arterial or Venous?

Abstract

Introduction:

Pulmonary hypertension (PH) is characterized by pulmonary vascular remodeling, right heart failure, and reduced survival. PH can be PH without left ventricular (LV) dysfunction – pulmonary arterial hypertension (PAH) - (Dana point Class I) and PH with LV dysfunction – pulmonary venous hypertension (PVH) - (Dana point Class II). Whatever the underlying cardiac disease, the presence of PH in patients with heart failure is associated with poor prognosis. Right ventricular dysfunction by ventricular interdependence can cause LV dysfunction.

Objective:

We aim to provide a distinction between PAH and PVH by echocardiography.

Methods:

Retrospective cross-sectional single-center data of 1075 subjects having PH as defined by echocardiography was collected. These were segregated into mild, moderate, and severe categories. The same cohort of PH subjects was also segregated by E/e’ derived pulmonary capillary wedge pressure (PCWP) values. Echocardiographic measurements and effort tolerance in Mets were analyzed. Data for 707 normal subjects were taken from an earlier published study on normative echocardiographic measurements of healthy Indians.

Results:

Our findings show that PAH and PVH can be distinguished using PCWP value >15 mmHg obtained by applying Nagueh’s formulaon E/e’.

Conclusion:

We recommend that PCWP derived from E/e’ should be reported with pulmonary artery systolic pressure measurement to distinguish between PAH and PVH.

Introduction

Pulmonary hypertension (PH) is characterized by pulmonary vascular remodeling, right heart failure, and reduced survival. PH can be PH without left ventricular (LV) dysfunction – pulmonary arterial hypertension (PAH) - (Dana point Class I) and PH with LV dysfunction – pulmonary venous hypertension (PVH) - (Dana point Class II). Whatever the underlying cardiac disease, the presence of PH in patients with heart failure is associated with poor prognosis. PH causes right ventricular (RV) dysfunction which by ventricular interdependence can cause LV dysfunction.

Noninvasive diagnosis of PH with Doppler echocardiography has a good sensitivity and specificity and overall accuracy.

Objective

We aim to provide a distinction between PAH and PVH by echocardiography.

Methods

Study design and population

This was a retrospective cross-sectional single-center study of 1075 PH subjects identified on echocardiography by having RV systolic pressure (RVSP) or pulmonary artery systolic pressure (PASP) being >35 mmHg determined by tricuspid regurgitant (TR) jet pressure + right atrial pressure (RAP). Data from comprehensive echocardiographic measurements including global longitudinal strain (GLS) and effort tolerance in Mets (where possible) were retrieved for analysis.

The study subjects were people who came for a cardiac medical check-up and consented. Five thousand and six hundred and eighty-seven echocardiography studies were done from April 2016 to June 2017 at our hospital. Subjects who had PASP >35 mmHg on echocardiography were selected. One thousand and two hundred and fifty-six studies were identified to have PH by PASP. Hundred and eighty-one studies (14%) were rejected due to suboptimal imaging (<15/17 LV segments clearly definable) or missing measurements.

Excluded patients in whom tricuspid regurgitation jets could not be analyzed, those with pulmonary valve stenosis (defined as peak systolic pressure gradient >5 mm Hg across the pulmonary valve), and those with hemodynamically significant left-sided valve stenosis. Data for 707 normal subjects were taken from a study on normative echocardiographic measurements of healthy Indians published earlier.[1]

One thousand and seventy-five subject’s studies were then segregated. First, on basis of RVSP (or PASP) as mild (RVSP 35–45 mmHg) 856 subjects, moderate (RVSP 45–60 mmHg) 292 subjects, and severe (RVSP >60 mmHg) 108 subjects. Second, they were segregated by estimated pulmonary capillary wedge pressure (PCWP) value using Nagueh’s formula[2] on E/e’ value. Among PCWP <15 mmHg with PH >35 mmHg, there were 147 subjects, and PCWP >15 mmHg with PH >35 mmHg, there were 662 subjects.

The study was approved by our institution’s ethical committee and conducted according to the Helsinki declaration. Written informed consent for the anonymous use of data for scientific academic purposes was taken from all subjects.

Examination

Echocardiography studies were performed by an experienced physician echocardiologist on a Philips Epiq 7C echocardiography system, Koninklijke Philips, Andover, MA, USA, using an X5-1 transducer. The studies were performed and measurements were taken as per the ASE guidelines.[3]

The echocardiography/Doppler examination was performed in parasternal long and short axis views and the three standard apical views. Three consecutive cardiac cycles were recorded during quiet respiration in each view in the left lateral decubitus at a frame rate of 50–70 fps. Separate grey-scale second harmonic mode (at mean frame rate 44 fps) and color tissue Doppler mode (at mean frame rate 100 fps) were recorded at the three apical planes. Doppler pulse repetition frequency was 1 kHz. Two-dimensional (2D) parasternal long-axis end-systolic left atrial (LA) diameter and end-diastolic mid RV diameter were measured as linear measurements. M-mode echocardiography in the left parasternal long axis view was used to measure LV end-diastolic diameter, LV end-systolic diameter, inter-ventricular septal thickness in diastole and LV posterior wall thickness in diastole. Apical 4 chamber M-mode echocardiography at lateral tricuspid annulus was used to measure tricuspid annular plane systolic excursion (TAPSE). Mitral E velocity, deceleration time, and E/A ratio were obtained using pulsed Doppler spectral recording at tips of the mitral valve in apical four-chamber view. S’, E’, and A’ velocities were measured at medial mitral annulus and S’ at lateral tricuspid annulus, using tissue Doppler imaging. LA end-systolic volume (LA Vol), LV end-diastolic volume (LVEDV), LV end-systolic volume (LVESV) and LV ejection fraction (EF) were measured using Simpson’s biplane (two- and four-chamber views) method of discs in end-diastolic and end-systolic frames. PASP (or RVSP) in the absence of any RV outflow obstruction was determined by TR jet pressure + RAP. RAP was determined by the respiratory variation of inferior vena cava diameter. PCWP was derived from E/e’ using Nagueh’s formula:[2] Mean PCWP = 1.91 + (1.24 × E/e’).

On-line 2D speckle tracking echocardiography (STE) was performed using electrocardiogram (ECG) gating on the three standard apical views (four-chamber, two-chamber, and three-chamber views) using automated cardiac motion quantification on Q-Lab software installed on the Epiq 7C system. The software automatically tracked the myocardial motion and operator manually adjusted the myocardial limits if automated tracking was incorrect. STE-generated regional longitudinal strain in ASE-defined 17 standard LV myocardial segments was recorded and averaged to generate GLS. Echocardiography studies’ data were stored digitally in a dicom server. Data generated from these studies were used for our analysis. Indexing to body surface area (BSA by Mosteller formula[4]) was done offline for LA vol (LAVI), LV Mass, LVEDV (LVEDVI), and LVESV (LVESVI).

Effort Tolerance was measured in metabolic equivalents (METS) which was obtained when subjects underwent an exercise tolerance test on Bruce Protocol on a Tread Mill system-GE Case premium T2100 V6.72, GE Medical Systems, 8200 West Tower Avenue, Milwaukee, WI, USA, by an experienced technician under the direct supervision of physician. The predetermined endpoints of exercise testing were a positive test or maximal exercise capacity. Heart rate was recorded from a continuous 12-lead ECG monitoring. The age-predicted maximal heart rate was calculated as 220-age. The target heart rate was defined as 85% of the age-predicted maximal heart rate. The exercise time was recorded. Maximal exercise capacity was defined by the achieved METs. Mets equal 3.5 ml of oxygen uptake per kilogram of body weight per minute and are estimated from exercise time as METs = 1.1 + (0.016 × exercise time in seconds).[5] Five Patients with good exercise capacity were defined as those who achieved ≥7 METs.

Statistics

Statistical analysis was done using Statistical Package for the Social Sciences (IBM SPSS Statistics 20.0 Chicago, IL, USA). Continuous variables were reported as mean and standard deviation Categorical variables were expressed in absolute numbers and percentages. Mann–Whitney U-test was used in certain cases as data were not normal. Continuous variables were checked for normality using Shapiro–Wilk’s test. Further one-way ANOVA was used to analyze the data and Tukey post hoc test was used to understand the differences between the groups. In case of categorical variables Chi-square test of independence was applied. The results were considered statistically significant when P < 0.05. Correlation values are reported wherever required.

Data reproducibility

Fifty echocardiography studies, 10 each from the RVSP and PCWP segregated groups, (from the 1075 studies) stored in our dicom digital server were retrieved. These were analyzed by a separate physician echocardiologist for inter-analyzer reproducibility and were re-analysed by the primary physician echocardioglogist for intra-analyzer reproducibility. Intra-class correlation coefficient (ICC)[6] was assessed on IBM SPSS Statistics 20.0 Chicago, IL, USA.

Results

Study population

One thousand and seventy-five Subjects’ data were analyzed for the study. The mild PH group had 856 subjects, moderate PH group had 292 subjects, and severe PH group had 108 subjects. These PH subjects were re-classified as PH >40 with PCWP <15 mmHg having 147 subjects and PH >40 with PCWP >15 mmHg having 662 subjects [Supplementary Table 1].

Supplementary Table 1.

Basic characteristics and echocardiography measurements of the study subjects

	Normal 707			PH 35-45 856			PH 45-60 292			PH >60 108			PH >40 PCWP <15 147			PH >40 PCWP >15 662
	Max	Min	Mean±SD	Max	Min	Mean±SD	Max	Min	Mean±SD	Max	Min	Mean±SD	Max	Min	Mean±SD	Max	Min	Mean±SD
AgeYr	70	18	40.7±11.4	97	7	57.4±14.8	91	20	60.4±15	96	26	58.0±15	97	18	52.2±17	96	20	61.0±14
Sex
Ht	194	139	165.4±10.1	192	134	164.6±9.54	184	130	163.6±9.7	179	139	163.7±8.3	189	140	163.9±10	186	140	163.9±9.44
Wt	136	32	74.6±14.7	123	39	74.2±14.1	117	26	74.2±14	121	41	75.4±15	129	46	75.2±14	153	40	75.1±14.2
BMI	47	13	27.2±4.9	49	15	27.4±4.73	49	16	27.7±4.7	47	16	28.1±5.5	43	17	28.0±4.7	49.4	15	28.0±4.8
BSA	2.6	1.1	1.8±0.2	2.5	1.2	1.8±0.21	2.4	1	1.8±0.2	2.3	1.3	1.8±0.2	2.5	1.4	1.8±0.2	2.75	1.3	1.8±0.2
SBP	140	100	122.7±9.4	190	100	129.0±13.5	170	120	138.8±15	140	110	121.7±15	150	100	125.2±11	170	100	133.5±15.2
DBP	90	60	80.7±5.0	100	10	82.3±7.95	100	80	85.5±7.1	80	80	80.0±0	100	70	81.9±6.2	100	60	83.1±7.24
TMT METs	19	1.4	10.7±2.8	16	1	8.9±2.81	13	4.6	7.5±2.3	13	2.5	6.5±3.9	16	1.9	9.6±3.2	13.4	1	7.8±2.76
LA diamt – cm	4	1.7	3.2±0.4	5.5	1.9	3.5±0.49	7.2	2.3	3.9±0.7	6	2	3.9±0.9	5.2	1.9	3.3±0.5	7.2	2	3.8±0.65
RV – cm	3.6	1.6	2.7±0.3	5.1	1.9	2.9±0.39	4.6	1.9	3.0±0.4	4.7	1.9	3.2±0.5	5.1	2.1	3.0±0.5	4.71	1.9	3.0±0.43
IVS – mm	1.3	0.6	1.1±0.1	2.3	0.6	1.2±0.19	2.2	0.7	1.2±0.2	1.8	0.7	1.1±0.2	1.8	0.7	1.1±0.2	2.3	0.7	1.2±0.21
LVIDd – cm	5.7	3.2	4.6±0.4	8	2.9	4.9±0.64	7.6	3.3	5.1±0.7	7.9	3.1	5.0±1	6	3.2	4.6±0.5	7.99	3.1	5.1±0.78
PW – mm	1.3	0.7	1.1±0.1	1.8	0.6	1.2±0.14	1.9	0.7	1.2±0.2	1.5	0.7	1.1±0.2	1.7	0.8	1.1±0.1	1.88	0.7	1.2±0.16
LV mass Calc	275	75.1	176.8±37.7	567	41	217.5±63	525	73	237.2±75	481	63	223.1±90	405	95	194.2±51	567	63	235.6±75
RWT	0.7	0.3	0.47±0.1	0.8	0.3	0.5±0.08	1.1	0.3	0.5±0.1	0.7	0.2	0.5±0.1	0.8	0.3	0.5±0.1	0.89	0.2	0.5±0.1
LV mass index	181	46.5	96.9±22.2	298	24	119.6±36	278	44	130.6±42	325	36	122.3±51	192	51	106.1±27	308	38	128.8±41.6
RVSP - PASP – mmHg	37	13	22.9±4.9	70	14	38.2±4.46	72	18	51.5±5.6	151	38	76.6±17	121	28	46.8±14	151	18	49.9±13.1
TR - MPAP – mmHg	37	2	14.9±4.8	45	11	25.3±2.72	46	13	33.4±3.4	94	25	48.7±10	76	19	30.5±8.6	94.1	13	32.4±8
TAPSE – mm	46	17	23.9±3.2	282	10	23.4±9.61	40	6.5	21.4±5.1	34	7.3	19.1±5.6	35	10	23.7±4.4	40.4	6.5	21.6±4.74
RVEF % - TAPSE	77	18	52.1±6.8	78	22	50.6±8.23	89	14	47.0±11	75	16	41.7±12	77	23	51.7±10	88.5	14	47.4±10.4
E/A	3.3	0.9	1.4±0.3	7	0.4	1.2±0.52	4.2	0.5	1.4±0.7	3.9	0.5	1.6±0.8	2.1	0.5	1.1±0.4	4.2	0.4	1.4±0.68
MV Dt – msec	250	81	175.2±27.3	560	81	201.0±61.8	###	63	191.2±113	887	95	198.6±141	373	106	202.4±54	1187	63	193.8±103
MV’s – cm/s	14	4.6	8.3±1.3	14	2.6	7.4±1.69	15	0.7	6.5±2	11	1.5	6.0±1.8	15	4.8	8.5±1.5	14.4	0.7	6.5±1.83
E/e’	13	4.7	9.0±1.7	49	0.6	14.0±5.86	79	0.7	21.7±12	84	1.2	23.0±15	11	1.2	8.6±1.6	84	4.9	20.4±10.5
PCWP – mmHg	26	7.7	13.0±2.2	63	6.6	19.2±7.14	100	9.8	29.0±14	106	3.4	30.9±18	15	3.4	12.6±1.9	106	15	27.2±12.9
TV’s – cm/s	23	8.2	12.5±1.8	78	3.7	12.6±3.61	27	4.5	11.9±3.4	20	4.3	10.8±3.2	30	6.1	13.4±3.3	27.3	3.7	11.8±3.06
LA Vol - ml	60	7.7	33.2±7.9	138	20	46.3±18	379	21	64.4±37	249	20	69.8±38	83	16	39.9±14	379	20	60.0±31.6
LA Vol index	42	4.5	18.2±4.6	83	8.8	25.5±10.4	209	9.9	35.9±22	134	10	38.3±22	48	8.5	21.8±7.7	225	12	32.8±17.7
LVEDV – ml	155	18	88.0±20.7	368	32	101.8±36.2	447	42	120.7±51	269	32	118.0±56	165	32	88.8±25	447	32	117.1±49.1
LVEDV index	107	10.7	48.2±11.9	193	15	55.9±20.4	231	24	66.9±29	151	18	64.7±32	89	16	48.5±14	242	19	63.8±26.5
LVESV – ml	66	11	34.6±10.5	285	16	47.7±26.9	309	18	65.5±40	204	10	69.9±45	79	12	38.8±14	309	10	62.9±39.5
LVESV index	42	5.7	18.9±5.9	150	7.4	26.2±14.9	159	11	36.4±23	113	6.5	38.4±25	43	6	21.2±7.8	167	6.2	34.2±21.1
EF % - STE	85	48	61.2±5.1	73	18	54.9±9.18	72	21	48.4±12	69	19	44.8±12	74	34	56.7±7.7	74.9	18	49.3±12
GLS %	29	14	20.0±2.2	26	1	17.6±4.05	26	3.7	14.6±4.9	25	1.7	12.7±4.8	26	5	18.4±4	26	1.7	15.0±4.92
Strain ALB	30	6	19.6±3.6	34	1	17.1±5.06	29	2	14.4±5.5	28	2	12.3±4.9	32	1	17.9±5.1	31	2	14.6±5.47
Strain ALM	32	7	19.6±3.6	35	1	16.7±4.89	25	1	13.0±5.7	32	1	11.6±6	28	5	17.7±4.4	32	1	13.6±5.79
Strain LA	32	10	20.4±3.4	30	0	17.9±4.67	29	1	15.1±5.4	26	2	13.7±5.5	29	2	19.4±4.8	27	0	15.3±5.27
Strain ISB	26	7	16.2±3.2	25	1	13.7±3.96	23	0	11.0±4.3	24	0	9.7±4.2	24	4	14.9±4.2	23	0	11.3±4.16
Strain ISM	30	5	16.6±3.8	30	1	14.6±4.45	27	1	12.3±5.1	24	2	10.7±4.5	27	2	15.8±4.8	26	1	12.4±4.86
Strain SA	39	10	26.3±4.2	38	1	23.0±6.59	36	2	18.8±7.3	36	2	16.7±7.3	37	4	23.7±5.9	37	1	19.4±7.42
Strain AB	34	9	19.7±4.1	35	2	17.5±5.14	33	0	13.8±5.7	27	1	12.1±5.2	35	5	18.3±5.3	30	1	14.6±5.68
Strain AM	34	8	20.9±3.9	31	3	17.9±5.32	30	1	14.2±6.4	33	2	12.5±5.9	29	3	19.0±5.3	33	1	14.9±6.15
Strain AA	34	9	20.0±3.9	34	0	18.1±4.93	30	3	15.5±5.4	30	1	13.4±5.7	30	3	18.6±4.9	30	1	15.7±5.51
Strain IB	30	8	16.7±3.6	31	2	14.8±4.34	28	1	12.3±5.1	25	1	10.8±4.5	27	5	15.3±4.8	28	1	12.7±4.81
Strain IM	32	4	17.9±3.9	31	1	15.9±4.93	28	0	13.6±5.4	26	1	11.9±4.9	31	4	16.6±4.7	30	0	13.9±5.43
Strain IA	40	8	24.2±5.5	41	2	21.1±6.65	35	2	16.7±7.2	37	1	15.2±7.1	36	8	22.1±6.3	41	1	17.6±7.3
Strain ASB	34	1	18.0±4.2	30	1	16.6±4.48	27	4	13.7±4.9	22	0	11.7±4.7	26	4	17.1±4.5	27	0	14.3±4.96
Strain ASM	33	4	20.3±4.8	38	1	18.9±5.49	33	0	15.4±6.6	31	0	13.2±6.1	35	4	19.0±5.9	38	0	16.4±6.54
Strain ILB	31	1	17.0±4.6	38	1	16.3±5.13	28	1	14.0±5.1	25	0	12.3±5.3	38	3	16.4±5.4	32	0	14.5±5.35
Strain ILM	38	5	19.9±5.0	37	1	18.2±5.53	31	3	15.5±6.1	27	0	13.4±6.1	31	5	19.0±5.3	33	0	15.7±6.12
Strain Ap	34	14	22.3±2.9	30	1	19.6±4.85	30	4	16.3±5.6	29	2	14.5±5.8	30	6	20.5±4.5	30	1	16.7±5.68

AgeYr: Age in years; Ht: Height; Wt: Weight; BMI: Body mass index; BSA: Body surface area; SBP: Systolic blood pressure; DBP: Diastolic blood pressure; METs: Metabolic equivalents; RV: Right ventricular; TAPSE: Tricuspid annular plane systolic excursion; LA: Left atrial; MV’s: Mitral valve’s; IVS: Interventricular septal; LVIDd: Left ventricular internal diameter in diastole; LV: Left ventricle; RWT: Relative wall thickness; LVEDV: Left ventricular end diastolic volume; LVESV: Left ventricular end systolic volume; EF: Ejection fraction; GLS: Global longitudinal strain; RVSP: Right ventricular systolic pressure; PASP: Pulmonary artery systolic pressure; AB: Anterior-Basal; ASB: Antero-Septal Basal; ISB: Inferior-Septal Basal; IB: Inferior Basal; ILB: Inferior-Lateral Basal; ALB: Anterior-lateral basal; AM: Anterior Mid; ASM: Anterior-Septal Mid; ISM: Inferior-Septal Mid; IM: Inferior Mid; ILM: Inferior-Lateral Mid; ALM: Anterior-Lateral Mid; AA: Anterior Apical; SA: Septal Apical; IA: Inferior Apical; LA: Lateral apical; AP: Apex; PH: Pulmonary hypertension; PCWP: Pulmonary capillary wedge pressure; SD: Standard deviation; Min: Minimum value; Max: Maximum value; TVs: Tricuspid valves; PW: Posterior wall; TR-MPAP: Mean pulmonary artery pressure by tricuspid regurgitation; STE: Speckle tracking echocardiography

Global longitudinal strain across different grades of pulmonary hypertension

The results highlight that there is a significant difference in GLS in these four different PH grades, i.e., normal, mild, moderate, and severe as the value of F (250.633) and is significant at 1%level of significance [Supplementary Table 2]. To further explore the significant difference between the groups Tukey’s Post hoc test was applied and it has been found that GLS is progressively decreasing across all grades of PH [Supplementary Table 3].

Supplementary Table 2.

Descriptive of global longitudinal strain across different pulmonary hypertension grades

PH grades	n	Mean±SD
Normal	707	20.0042±2.22473
Mild	661	14.9419±5.02545
Moderate	299	14.4925±5.09484
Severe	115	12.6054±5.25687

PH: Pulmonary hypertension; SD: Standard deviation

Supplementary Table 3.

Tukey’s post hoc test across all grades of pulmonary hypertension

PH	Significant
Mild
Moderate	0.412
Severe	0.000
Normal	0.000
Moderate
Mild	0.412
Severe	0.000
Normal	0.000
Severe
Mild	0.000
Moderate	0.000
Normal	0.000
Normal
Mild	0.000
Moderate	0.000
Severe	0.000

PH: Pulmonary hypertension

Effort Tolerance in Mets across different grades of pulmonary hypertension

Treadmill Test (TMT) Mets value mean is decreasing with increase in PH grade severity of a patient. It can be noted that the mean value of TMT Mets in a normal person is 10.1, in mild it is 8.9, and in moderate it is 7.5 as can also be seen from the Mean Plot of TMT Mets [Figure 1]. In severe PH grades, due to very sick patients, exercise effort tolerance was not feasible. However, to find whether this mean value is significantly different from each other one-way ANOVA is applied. It can be seen that the value of ANOVA is 64.143 and is significant at 1% level of significance. Further to explore that in which group it is statistically significant, Tukey’s HSD test was applied and it has been found that Normal is significantly different from mild and Moderate. Mild is significantly different from Moderate at 1 percent level of significance [Supplementary Table 4].

Figure 1.

Showing mean plots of TMT Mets, TAPSE (in mm), MVs’ (in cm/sec), E/e’, TVs’ (in cm/sec), EF (%) and GLS (%) across different grades of PH (normal, mild, moderate and severe). TAPSE: Tricuspid annular plane systolic excursion, PH: Pulmonary hypertension, GLS: Global longitudinal strain, EF: Ejection fraction, TMT: Treadmill Test

Supplementary Table 4.

ANOVA of treadmill test metabolic equivalents across different pulmonary hypertension grades

TMT METs	TMT METs	Significant
Normal	Mild	0.000
	Moderate	0.000
Mild	Normal	0.000
	Moderate	0.023
Moderate	Normal	0.000
	Mild	0.023

METs: Metabolic equivalent; TMT: Treadmill test

MVs’, E/e’, tricuspid annular plane systolic excursion, TVs’ across different grades of pulmonary hypertension

The result indicates that TAPSE, MV s’, E/e’, and TV s’ are all significantly different from each other at 1% level of significance and that is there is difference between mild, moderate, severe, and normal. Further, it has been also revealed that in case of TAPSE mild is significantly different from moderate and severe but not from normal. Moderate is significantly different from mild, severe, and normal. Severe is significantly different from all the categories. Normal is significantly different from moderate and severe. Similarly, it can be seen that across different PH grades, MV’s and E/e’ values are significantly different [Figure 1 and Supplementary Table 5].

Supplementary Table 5.

Result of ANOVA for tricuspid annular plane systolic excursion, mitral valves, E/e’, tricuspid valves’ across different grades of pulmonary hypertension

Dependent variable	Significant
TAPSE
Mild
Moderate	0.000
Severe	0.000
PH >40 PCWP <15	0.996
Normal	0.746
PH >40 PPCWP >15	0.000
Moderate
Mild	0.000
Severe	0.013
PH >40 PCWP <15	0.007
Normal	0.000
PH >40 PPCWP >15	0.998
Severe
Mild	0.000
Moderate	0.013
PH >40 PCWP <15	0.000
Normal	0.000
PH >40 PPCWP >15	0.002
PH >40 PCWP <15
Mild	0.996
Moderate	0.007
Severe	0.000
Normal	10.000
PH >40 PPCWP >15	0.005
Normal
Mild	0.746
Moderate	0.000
Severe	0.000
PH >40 PCWP <15	10.000
PH >40 PPCWP >15	0.000
PH >40 PPCWP >15
Mild	0.000
Moderate	0.998
Severe	0.002
PH >40 PCWP <15	0.005
Normal	0.000
MVscm
Mild
Moderate	0.000
Severe	0.000
PH >40 PCWP <15	0.000
Normal	0.000
PH >40 PPCWP >15	0.000
Moderate
Mild	0.000
Severe	0.098
PH >40 PCWP <15	0.000
Normal	0.000
PH >40 PPCWP >15	10.000
Severe
Mild	0.000
Moderate	0.098
PH >40 PCWP <15	0.000
Normal	0.000
PH >40 PPCWP >15	0.068
PH >40 PCWP <15
Mild	0.000
Moderate	0.000
Severe	0.000
Normal	0.844
PH >40 PPCWP >15	0.000
Normal
Mild	0.000
Moderate	0.000
Severe	0.000
PH >40 PCWP <15	0.844
PH >40 PPCWP >15	0.000
PH >40 PPCWP >15
Mild	0.000
Moderate	10.000
Severe	0.068
PH >40 PCWP <15	0.000
Normal	0.000
Ees
Mild
Moderate	0.000
Severe	0.000
PH >40 PCWP <15	0.000
Normal	0.000
PH >40 PPCWP >15	0.000
Moderate
Mild	0.000
Severe	0.693
PH >40 PCWP <15	0.000
Normal	0.000
PH >40 PPCWP >15	0.099
Severe
Mild	0.000
Moderate	0.693
PH >40 PCWP <15	0.000
Normal	0.000
PH >40 PPCWP >15	0.012
PH >40 PCWP <15
Mild	0.000
Moderate	0.000
Severe	0.000
Normal	0.997
PH >40 PPCWP >15	0.000
Normal
Mild	0.000
Moderate	0.000
Severe	0.000
PH >40 PCWP <15	0.997
PH >40 PCWP >15	0.000
PH >40 PCWP >15
Mild	0.000
Moderate	0.099
Severe	0.012
PH >40 PCWP <15	0.000
Normal	0.000
TVs
Mild
Moderate	0.011
Severe	0.000
PH >40 PCWP <15	0.038
Normal	0.963
PH >40 PCWP >15	0.000
Moderate
Mild	0.011
Severe	0.020
PH >40 PCWP <15	0.000
Normal	0.086
PH >40 PCWP >15	10.000
Severe
Mild	0.000
Moderate	0.020
PH >40 PCWP <15	0.000
Normal	0.000
PH >40 PCWP >15	0.016
PH >40 PCWP <15
Mild	0.038
Moderate	0.000
Severe	0.000
Normal	0.010
PH >40 PCWP >15	0.000
Normal
Mild	0.963
Moderate	0.086
Severe	0.000
PH >40 PCWP <15	0.010
PH >40 PCWP >15	0.002
PH >40 PCWP >15
Mild	0.000
Moderate	10.000
Severe	0.016
PH >40 PCWP <15	0.000
Normal	0.002

PH: Pulmonary hypertension; PCWP: Pulmonary capillary wedge pressure

Pulmonary capillary wedge pressure <15 and >15 reflected upon pulmonary hypertension, global longitudinal strain, ejection fraction, left atrial end systolic volume, right ventricular diamt, tricuspid annular plane systolic excursion, TVs’

The Shapiro–Wilk test was applied to check and it was found that GLS, EF, RV diameter, TAPSE, TV s’, and LA vol (index) are not normal and therefore Wilcoxon Mann–Whitney test is used and it has been found that in all these parameters the values in the groups PH >40 PCWP <15 and PH >40 PCWP >15 are significantly different at 1% level of significance [Figure 2].

Figure 2.

Shows GLS (%), EF (%), RV diameter (cm), LA volume (ml), TAPSE (mm), MVs’ (cm/s), E/e’ and TVs’ (cm/s) across two groups PH >40 mmHg with PCWP <15 mmHg and PH >40 mmHg with PCWP >15 mmHg. GLS: Global longitudinal strain, PH: Pulmonary hypertension, TAPSE: Tricuspid annular plane systolic excursion, PCWP: Pulmonary capillary wedge pressure. LA: Left atrial, RV: Right ventricular, EF: Ejection fraction

ICC values for intra-analyzer assessment ranged from 0.814 to 0.998 showing good to excellent reliability. For inter-analyzer assessment ICC values were 0.696–0.989 showing moderate to excellent reliability.

[Note: For ICC values, see Supplementary Table 6].

Supplementary Table 6.

Reproducibility - intraclass correlation coefficient - Intra and Inter AnalyZer

Variable	Intra-Obv 1stRead 50 Subjects, mean±SD	Intra-Obv 2nd Read 50 Subjects, mean±SD	Intraanalyser ICC	Inter-Obv 50 subjects, mean±SD	Interanalyser ICC
LA Diamt – cm	3.53±0.55	3.53±0.57	0.97	3.51±0.70	0.96
RV – cm	2.80±0.41	2.77±0.41	0.98	2.77±0.42	0.95
IVS – mm	1.17±0.23	1.13±0.23	0.96	1.13±0.23	0.96
LVIDd – cm	4.81±0.59	4.78±0.59	0.99	4.76±0.69	0.95
PW – mm	1.17±0.16	1.13±0.13	0.95	1.13±0.14	0.94
LV mass – g	205.42±68.84	205.57±68.84	0.99	205.45±68.90	0.97
RWT	0.48±0.07	0.48±0.07	0.98	0.47±0.22	0.94
LV Mass Index	120.31±46.00	120.57±46.34	0.96	120.45±46.36	0.94
TAPSE – mm	22.27±4.98	22.03±4.99	0.94	22.38±5.00	0.92
E/A	1.33±0.64	1.39±0.64	0.98	1.30±0.65	0.96
MV Dt – msec	209.42±87.11	212.71±82.87	0.99	213.72±82.67	0.97
MV s’ – cm/s	6.98±2.07	7.70±2.01	0.98	8.13±2.09	0.91
E/e’	18.17±12.07	19.03±11.88	0.99	19.81±11.94	0.98
Nagueh PCWP – mmHg	23.77±15.02	23.69±15.24	0.98	23.65±15.45	0.96
TV s’ – cm/s	12.42±3.79	13.21±3.80	0.98	13.93±3.81	0.94
LA Vol – ml	53.20±35.46	49.59±19.28	0.99	50.22±19.33	0.96
LA Vol Index	31.20±21.97	29.43±12.33	0.97	29.99±12.33	0.96
LVEDV – ml	95.27±33.71	96.24±33.78	0.99	97.05±33.82	0.96
LVEDV Index	55.63±21.36	56.32±21.43	0.98	56.92±21.36	0.97
LVESV – ml	45.77±26.67	46.57±26.68	0.98	47.12±26.62	0.94
LVESV Index	26.75±16.29	26.36±16.12	0.96	25.91±16.00	0.96
EF % – STE	53.75±12.07	53.67±12.24	0.98	53.51±12.82	0.94
GLS %	17.70±5.62	17.42±5.46	0.98	17.38±5.85	0.94

Interpretation of ICC is as follows: ICC values <0.5 indicate poor reliability, values between 0.5 and 0.75 indicate moderate reliability, values between 0.75 and 0.9 indicate good reliability, and values <0.90 are indicative of excellent reliability. Koo TK, Li MY. Guideline of selecting and reporting intraclass correlation coefficients for reliability research. J Chiropr Med 2016;15:155-63.[6]. ICC: Intra-class correlation coefficient; SD: Standard deviation; LA: Left atrial; RV: Right ventricular; IVS: Interventricular septal; LVIDd: Left ventricular internal diameter in diastole; LV: Left ventricle; RWT: Relative wall thickness; TAPSE: Tricuspid annular plane systolic excursion; MV: Mitral valve; PCWP: Pulmonary capillary wedge pressure; TV: Tricuspid valve; LVEDV: Left ventricular end-diastolic volume; LVESV: Left ventricular end-systolic volume; EF: Ejection fraction; GLS: Global longitudinal strain; PW: Posterior wall; STE: Speckle-tracking echocardiography

Discussion

PH is characterized by pulmonary vascular remodeling, right heart failure, and reduced survival.[7] Noninvasive diagnosis of PH with Doppler echocardiography had a good sensitivity (87%) and specificity (79%), positive and negative predictive values (91% and 70%), as well as accuracy (85%) for a PASP cutoff value of 36 mm Hg.[8]

We observed that increase in PH causes a progressive reduction in effort tolerance in TMT Mets.

We also observed that increase in PH causes a progressive reduction in GLS. As PH severity progressively increases, MVs’, TAPSE, and TVs’ reduce progressively but E/e’ increases. These changes suggest that a progressive increase in PH is associated with a reduction in RV and LV systolic function. These changes also suggest a deterioration of diastolic relaxation reflected by increase in PCWP or LA pressure as seen by increase in E/e’.

This underlies the important and clinically relevant concept of ventricular interdependence in PAH. RV and LV do not function in isolation, there is ventricular interdependence as they share a common pericardial sac and inter-ventricular septum.[9] Increased RV pressure and RV dilatation result in higher trans-septal pressures, which as a result of the shared space within the pericardial sac, cause a bowing of the inter-ventricular septum into the LV with resultant distortion of LV geometry and function.[10-12]

PVH or PH-LHD is distinguished from PAH by the presence of a PCWP >15 mmHg.[13]

PCWP of 15 mmHg has been used to discriminate between pre-and post-capillary pulmonary pressure elevation which mostly occurs as a consequence of left-sided heart disease.[14] Precapillary PH was diagnosed if mean pulmonary arterial pressure exceeded 25 mmHg at rest, and PCWP was <15 mmHg.[15]

The accuracy of echocardiography for the diagnosis of elevated PCWP was 87%, with a positive predictive value of 91% (the likelihood that PCWP was in fact elevated if echocardiography predicted so) and a negative predictive value of 87% (the likelihood that PCWP was, in fact, normal if echocardiography predicted so).[16] E/e’ ratio >10 detected a mean PCWP >15 mm Hg, with a sensitivity of 97% and a specificity of 78%. Mean PCWP = 1.91 + (1.24 × E/e’).[2]

A single study of advanced heart failure subjects showed a less robust association of E/e’ with PCWP.[17] This study, however, also showed a better correlation of E/e’ with PCWP in advanced heart failure subjects without cardiac resynchronization device as compared to those with it.

Classifying all PH subjects on the basis of PCWP being <15 mmHg or >15 mmHg, we created two groups. In our sample, the PVH group was larger as it is the more commonly seen cause for PH. We then assessed the effects on LV function, RV function, GLS, and effort tolerance in Mets. For a comparable level of PASP, 46.8 ± 14 mmHg in PCWP <15 mmHg and 49.9 ± 13.1 mmHg in PCWP >15 mmHg, there were significant differences in both groups. The PCWP >15 mmHg group showed a lower effort tolerance (7.8 vs. 9.6 Mets), EF (49.3 vs. 56.7%), GLS (−15.0 vs. −18.4%), TAPSE (21.6 vs. 23.7 mm), TVs’ (11.8 vs. 13.4 cm/s) and higher E/e’(20.4 vs. 8.6), LV mass (128.8 vs. 106.1 gm), LA volume (32.8 vs. 21.8 ml), LVESV (34.2 vs. 21.2 ml), LVEDV (63.8 vs. 48.5 ml) in comparison to the PCWP <15 mmHg group.

These observations suggest that (1) PCWP by E/e’ estimation is an ideal marker to discriminate between PVH and PAH. (2) Validates the PCWP cutoff value of 15 mmHg to discriminate PVH and PAH. (3) PASP or RVSP when reported by Echo in a PH patient must be accompanied by PCWP value derived from E/e’ for the clinician to have a better understanding.

Limitations

This is a single-center retrospective data study where all echocardiography examinations were performed by a single physician. The study was done on single-vendor equipment. This situation cannot exclude selection or procedure bias. This work is also limited by not taking into consideration medicines being taken by subjects when their echocardiogram was performed. Further, being retrospective in nature and with a large sample size, later inclusion of medication status was not possible. The assessment of effort tolerance was limited only up to moderate PH. Severe PH subjects were not assessed for effort tolerance due to their clinical condition. Our study lacks direct hemodynamic data validation by right heart catheterization. It also lacks biochemical markers like β natriuretic peptide and N-terminal pro-brain natriuretic peptide for diagnosing heart failure.

Conclusion

PH can be PAH or PVH. The most important discriminating factor is the measurement of PCWP. A high PCWP >15 mmHg favors PVH by definition. PCWP measurement is invasive. Echocardiography can help in measuring PCWP noninvasively using Nagueh’s formula to calculate PCWP from E/e’. This is a simple and effective way to distinguish PAH from PVH. We recommend that in patients diagnosed with PH on echocardiography, along with routinely reported PASP value, PCWP value derived from E/e’ must be mentioned. This will help the clinician better understanding the physiological status of the concerned PH patient.

PH leads to RV dysfunction, congestive cardiac failure, and associated morbidity and mortality. PH also causes LV dysfunction as evidenced by deterioration in GLS values. This happens both in PAH and PVH. LV dysfunction due to PH is a result of ventricular interdependence. We recommend that in PH patients, echocardiographic assessment of LV function should always include LV GLS assessment to rule out subtle LV dysfunction with preserved EF.

Ethical statement

The study was approved by the institutional Ethics committee of Bombay Hospital Indore, Approval No – BHI:DDMS:EC:2020-01:0005.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.