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Am J Respir Crit Care Med
Am J Respir Crit Care Med
ajrccm
American Journal of Respiratory and Critical Care Medicine
1073-449X
1535-4970
American Thoracic Society

202401-0234LE
10.1164/rccm.202401-0234LE
Correspondence
Viscosity-Corrected Pulmonary Vascular Resistance Index in Pediatric Pulmonary Arterial Hypertension
Xu Zhuoyuan 1 3 4
Li Qiangqiang 2
Zhang Chen 2
Wang Qiang 2
Gu Hong 2
He Yihua 1 3 4
1 Maternal-Foetal Medicine Centre in Foetal Heart Disease and
2 Department of Paediatric Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing, China;
3 Beijing Key Laboratory of Maternal-Foetal Medicine in Foetal Heart Disease, Beijing, China; and
4 Beijing Laboratory for Cardiovascular Precision Medicine, Beijing, China
Correspondence and requests for reprints should be addressed to Yihua He, M.D., Ph.D., Maternal-Foetal Medicine Centre in Foetal Heart Disease, Beijing Anzhen Hospital, Capital Medical University, Beijing 100029, China. Email: heyihuaecho@hotmail.com.
12 6 2024
15 9 2024
12 6 2024
210 6 831834
Copyright © 2024 by the American Thoracic Society
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0. For commercial usage and reprints, please e-mail Diane Gern (dgern@thoracic.org).

Capital’s Funds for Health Improvement and Research, China2024-4-1055
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pmcTo the Editor:

Pulmonary arterial hypertension (PAH) is a progressive disorder that results in an elevated pulmonary vascular resistance index (PVRI) and increase of right ventricle (RV) afterload (1, 2). The PVRI assessed by invasive hemodynamics is essential for a diagnosis of PAH and for planning disease management (1, 3, 4). As hemoglobin (Hb) levels are commonly abnormal in patients with PAH, and blood viscosity may be abnormal and may affect the PVRI (4–6), we hypothesized that the PVRI corrected for blood viscosity would differ from raw measured PVRI in children with PAH and that the magnitude of the difference would be sufficiently large to affect treatment decisions. To test this hypothesis, we assessed PVRI corrected for blood viscosity (cPVRI) and evaluated how adjusting PVRI for blood viscosity would affect treatment decisions in a large group of patients with pediatric PAH undergoing protocolized right-heart catheterization at a large tertiary pulmonary hypertension and congenital heart disease (CHD) center according to guideline recommendations.

Methods

We included a total of 742 patients (ranging in age from 3 mo to 18 yr) who underwent standardized right-heart catheterization assessment at a large, single, tertiary referral center between 2003 and 2020. Blood viscosity was calculated according to the Hutton formula (7), and cPVRI was subsequently calculated for blood viscosity (4, 7, 8). For each patient, cPVRI was calculated by multiplying measured, raw PVRI by blood viscosity calculated for a Hb concentration of 14.0 g/dl and dividing by the patient’s blood viscosity. The study was approved by the ethics committee of Beijing Anzhen Hospital.

Results

Overall, 742 children were included, including 115 patients with idiopathic/heritable PAH. Of the patients with CHD, 82 patients had closed shunt defects, 413 patients had patent lesions with left-to-right shunt (without Eisenmenger syndrome), and 132 patients had patent shunts with Eisenmenger syndrome. Clinical and hemodynamic characteristics are shown in Table 1. Uncorrected median PVRI was 5.0 Wood units (WU) ⋅ m2 (interquartile range [IQR] = 1.5–16.8), and median cPVRI was 5.9 WU ⋅ m2 (IQR = 2.0–15.3).

Table 1. Clinical Characteristics and Hemodynamics of Patients with CHD and PAH

Characteristic	All Patients (n = 742)	Open Shunt Lesions (n = 545)	Closed/Nonshunt Lesions (n = 197)	
L-R Shunts without PAH (n = 211)	L-R Shunts with PAH (n = 202)	Eisenmenger Syndrome (n = 132)	Postoperative PAH (n = 82)	I/HPAH (n = 115)	
Age at catheterization, yr	6.2 (3.0, 12.1)	4.2 (3.0, 6.7)	3.8 (2.8, 9.7)	10.5 (4.9, 14.0)	12.0 (7.9, 15.3)	8.5 (4.5, 13.0)	
Female, n (%)	472 (63.6)	144 (66.7)	130 (64.4)	88 (66.7)	59 (72.0)	57 (49.6)	
Haemoglobin, g/dl, mean ± SE	13.6 ± 2.1	12.6 ± 1.1	12.6 ± 1.9	15.4 ± 2.4	14.0 ± 1.7	13.7 ± 1.5	
SaO2, %, mean ± SE	93.1 ± 4.9	96.0 ± 3.0	93.9 ± 3.8	88.9 ± 6.4	94.2 ± 4.1	95.3 ± 3.5	
MCH, %, mean ± SE	28.3 ± 2.5	28.1 ± 1.7	27.4 ± 3.0	28.9 ± 3.0	29.0 ± 2.3	28.6 ± 2.3	
Viscosity, mean ± SE	12.0 ± 4.3	9.9 ± 1.6	10.3 ± 2.9	15.9 ± 6.8	12.3 ± 3.0	11.8 ± 2.8	
Viscosity at Hb of 14 g/dl, mean ± SE	12.3 ± 0.9	12.3 ± 0.5	12.6 ± 1.1	12.2 ± 1.2	12.1 ± 0.6	12.2 ± 0.7	
mPAP, mm Hg, mean ± SE	49.8 ± 27.9	18.6 ± 3.8	48.2 ± 19.9	78.6 ± 12.8	63.1 ± 23.5	64.6 ± 22.2	
MPAP, mmHg, median (IQR)	48.0 (22.0, 75.3)	21.0 (19.0, 24.0)	41.5 (30.0, 63.3)	79.0 (71.5, 88.0)	67.0 (47.0, 81.5)	64.5 (49.0, 80.0)	
RAP, mm Hg, mean ± SE	7.7 ± 4.0	6.3 ± 2.1	7.6 ± 2.8	7.9 ±  3.0	8.7 ± 3.7	8.5 ± 3.8	
PAWP, mm Hg, mean ± SE	10.5 ± 4.3	9.2 ± 3.3	10.7 ± 4.5	10.4 ±   3.7	11.2 ± 4.2	11.2 ± 4.1	
PVR, WU, median (IQR)	6.6 (2.3, 15.6)	1.5 (0.9, 2.2)	5.3 (2.8, 9.7)	19.6 (16.0, 24.7)	12.2 (5.2, 18.8)	15.2 (9.0, 24.0)	
PVRI, WU ⋅ m2, median (IQR)	5.0 (1.5, 16.9)	1.2 (0.8, 1.6)	3.4 (1.8, 7.1)	20.9 (15.0, 28.6)	12.4 (6.3, 22.5)	16.7 (10.0, 22.6)	
cPVR, WU, median (IQR)	7.3 (2.5, 14.9)	1.8 (1.1, 2.9)	7.1 (3.6, 10.7)	16.2 (12.4, 21.6)	12.5 (5.8, 16.6)	14.8 (8.9, 28.0)	
ABS delta PVR, WU, median (IQR)	1.1 (0.4, 3.6)	0.3 (0.1, 0.7)	1.5 (0.6, 3,1)	5.3 (2.5, 8.5)	1.7 (0.7, 3.7)	1.8 (0.8, 4.4)	
Qp, L/min, median (IQR)	4.8 (3.3, 6.7)	5.6 (4.2, 7.0)	6.1 (4.4, 8.3)	3.3 (2.5, 4.3)	4.1 (3.3, 5.9)	3.3 (2.6, 4.4)	
Qs, L/min, median (IQR)	3.6 (2.8, 4.6)	3.9 (3.1, 4.9)	3.4 (2.5, 4.1)	3.4 (2.8, 4.4)	4.0 (3.2, 5.8)	3.4 (2.6, 4.4)	
SvO2, %, mean ± SE	69.7 ± 11.0	72.3 ± 11.3	70.1 ± 10.3	63.4 ± 9.6	70.3 ± 9.1	67.9 ± 12.4	
Cardiac index, L/min/m2, median (IQR)	4.2 (3.2, 5.1)	4.9 (4.2, 5.5)	4.6 (3.6, 5.7)	3.4 (2.8, 4.7)	3.4 (2.7, 4.4)	3.4 (2.7, 4.2)	
Definition of abbreviations: ABS = absolute value; CHD = congenital heart disease; cPVR = corrected pulmonary vascular resistance; Hb = hemoglobin; I/HPAH = idiopathic pulmonary arterial hypertension/heritable pulmonary arterial hypertension; L-R = left-to-right; MCH = mean corpuscular hemoglobin; mPAP = mean pulmonary arterial pressure; PAH = pulmonary arterial hypertension; PAWP = pulmonary artery wedge pressure; PVR = pulmonary vascular resistance; PVRI = pulmonary vascular resistance index; Qp = pulmonary flow; Qs = systemic flow; RAP = right atrial pressure; SaO2 = arterial oxygen saturation; SvO2 = mixed venous oxygen saturation; WU = Wood units.

Eisenmenger syndrome was defined as PVR more than 10 WU and SaO2 <90% at rest.

When adjusting for Hb, cPVRI changed by ⩾2 WU compared with raw measured PVRI in 253 (34.1%) patients. In patients with CHD and PAH who required decisions on shunt closure, 9.2% moved above or below the threshold of 4 WU ⋅ m2, and 6.1% crossed the threshold of 8 WU ⋅ m2 after correcting for blood viscosiy. Although, overall, no major systematic difference between the cPVRI and raw PVRI was evident, separate analyses by underlying type of PAH and Hb level revealed significant systematic differences between the groups. Figure 1A shows that the raw PVRI systematically underestimates the cPVRI by, on average, 45% (i.e., slope of −0.45) in patients with low Hb, whereas it overestimates the cPVRI by an average of 49% (i.e., slope of +0.49) in erythrocytotic patients. Assessing patients with anemia or erythrocytosis, respectively, revealed that, in up to 13.9% of patients with anemia who had an uncorrected PVRI <4 WU ⋅ m2, the cPVRI rose to 4–8 WU ⋅ m2, whereas 9.5% of patients with an uncorrected PVRI between 4 and 8 WU ⋅ m2 had a cPVRI >8 WU ⋅ m2. In the erythrocytosis group of patients with uncorrected PVRIs between 4 and 8 WU ⋅ m2, 2.2% had a cPVRI <4 WU ⋅ m2, and 5.6% of patients whose PVRI was >8 WU ⋅ m2 had a cPVRI between 4 and 8 WU ⋅ m2 after adjusting for viscosity (Figure 1B).

Figure 1. (A) Scatterplots with the regression line of the linear correlation for patients with hemoglobin (Hb) levels below 12 g/dl (left) and patients with Hb levels above 16 g/dl (right). The correlation between the mean of raw and viscosity-corrected (corr.) pulmonary vascular resistance indexes (PVRIs) (x-axis) versus the difference between raw and viscosity-corrected PVRIs (y-axis) is illustrated. (B) Alluvial plot analysis of the changes in PVRI in patients with HB levels below 12 g/dl (left) and patients with Hb levels above 16 g/dl (right). A considerable proportion of patients “change” PVRI categories if the PVRI is corrected by blood viscosity values. (C) Two example cases from the dataset illustrating the impact of viscosity correction on therapeutic decisions. Depending on the underlying Hb concentration, including the viscosity-corrected PVRI in the decision-making process may significantly alter the treatment process. MCH = mean corpuscular hemoglobin; mPAP = mean pulmonary arterial pressure; PCWp = pulmonary capillary wedge pressure; PDA = patent ductus arteriosus; Qp = pulmonary flow; Tx = treatment; VSD = ventricular septal defect; WU = Wood units.

Over a median follow-up period of 9.85 years, 118 patients died. In the overall cohort, both uncorrected PVRI (hazard ratio [HR], 1.069; 95% confidence interval [CI] = 1.056–1.081; P < 0.001; c-index = 0.79) and cPVRI (HR, 1.075; 95% CI = 1.062–1.088; P < 0.001; c-index = 0.80) were significantly associated with worse prognosis.

Stratifying patients by level of erythrocytosis showed that, in patients with an Hb value >16 g/dl, uncorrected PVRI was not significantly related to prognosis (HR, 1.027; 95% CI = 0.998–1.057; P = 0.07), whereas viscosity cPVRI (HR, 1.060; 95% CI = 1.011–1.110; P = 0.02) remained associated with poor prognosis, even in erythrocytotic patients.

Discussion

PVR and the PVRI are central to diagnosis and decision-making in patients with pulmonary hypertension (3). Several decades ago, Tyson and colleagues already indicated that changes in blood viscosity exert a direct influence on PVR and PVRI (9). However, this important concept has only recently received attention in pulmonary vascular diseases, especially in patients with CHD and PAH, where a significant difference between the measured PVRI and cPVRI has been reported in adult patients (4, 8). The present study emphasizes the importance of this concept by illustrating that the PVRI is heavily affected by patients’ blood viscosity and that adjusting for blood viscosity significantly alters cPVRI (5, 6). This has clinical consequences, by potentially placing children with PAH in a different treatment trajectory depending on PVRI (10). As blood viscosity is directly related to Hb levels (5), two groups of patients are particularly affected. In children with anemia, raw PVRI is significantly lower than cPVRI, whereas in patients with raised Hb (erythrocytosis), raw PVRI is higher than cPVRI. Our study shows that depending on underlying Hb concentration, including cPVRI in the decision-making process, may significantly alter the treatment process (Figure 1C). To allow readers to easily assess the potential impact of Hb concentration of PVR/PVRI, we provide an online tool to calculate cPVR for patients (https://pvrcalc.shinyapps.io/cPVR/).

The clinical value of cPVRI is underlined by the fact that, in our survival analysis, the association between raw PVRI and survival was modulated by viscosity. When we specifically investigated the prognostic value of PVRI and cPVR in patients with erythrocytosis with a PVRI >16, we found that the raw PVRI was not significantly related to survival, whereas the cPVRI maintained its prognostic value. We contend that this fact supports the use of the cPVRI, especially in subjects with very abnormal Hb and, thus, viscosity values.

Conclusion

Patients with pediatric PAH commonly have abnormal blood viscosity, and this affects PVRI. Correcting the PVRI for viscosity is prognostically beneficial in patients with erythrocytosis, potentially alters therapeutic decisions, and should be included in the routine decision-making process, especially for patients with abnormal Hb.

Supported by the Capital’s Funds for Health Improvement and Research, China (2024-4-1055); the Beijing Key Laboratory of Maternal-Foetal Medicine in Foetal Heart Disease (BZ0308); and the Beijing Laboratory for Cardiovascular Precision Medicine (PXM2018_014226_000013).

Author Contributions: Z.X. contributed to conceptualization, formal analysis, project administration, access and verification of data, writing the original draft, production of figures, and reviewing and editing of the manuscript. Y.H. contributed to conceptualization, methodology, access and verification of data, supervision, interpretation, writing the original draft, and review and editing of the manuscript. Q.L., C.Z., Q.W. and H.G. contributed to the conceptualization, interpretation, and reviewing and editing of the manuscript. All authors have significantly critical review of the manuscript and have approved the final version of the paper.

Originally Published in Press as DOI: 10.1164/rccm.202401-0234LE on June 12, 2024

Author disclosures are available with the text of this letter at www.atsjournals.org.
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References

1. Rosenzweig EB Abman SH Adatia I Beghetti M Bonnet D Haworth S et al. Paediatric pulmonary arterial hypertension: updates on definition, classification, diagnostics and management Eur Respir J 2019 53 1801916 30545978
2. Humbert M Kovacs G Hoeper MM Badagliacca R Berger RMF Brida M et al. ESC/ERS Scientific Document Group 2022 ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension Eur Heart J 2022 43 3618 3731 36017548
3. Constantine A Dimopoulos K Haworth SG Muthurangu V Moledina S Twenty-year experience and outcomes in a national pediatric pulmonary hypertension service Am J Respir Crit Care Med 2022 206 758 766 35579610
4. Hoffman JI Pulmonary vascular resistance and viscosity: the forgotten factor Pediatr Cardiol 2011 32 557 561 21432030
5. Vanderpool RR Naeije R Hematocrit-corrected pulmonary vascular resistance Am J Respir Crit Care Med 2018 198 305 309 29537290
6. Naeije R Richter MJ Rubin LJ The physiological basis of pulmonary arterial hypertension Eur Respir J 2022 59 2102334 34737219
7. Hutton RD The effect of iron deficiency on whole blood viscosity in polycythaemic patients Br J Haematol 1979 43 191 199 508628
8. Kempny A Dimopoulos K Fraisse A Diller GP Price LC Rafiq I et al. Blood viscosity and its relevance to the diagnosis and management of pulmonary hypertension J Am Coll Cardiol 2019 73 2640 2642 31118156
9. Tyson KR Sciarrotta N Fender HR McNeel LA Effect of blood viscosity on pulmonary vascular resistance J Pediatr Surg 1971 6 559 564 5126275
10. Dimopoulos K Wort SJ Gatzoulis MA Pulmonary hypertension related to congenital heart disease: a call for action Eur Heart J 2014 35 691 700 24168793
