Abstract
Aims:
Adult congenital heart disease(ACHD) includes multiple disease states that predispose to pulmonary hypertension(PH). Hemodynamically, PH depends on abnormalities in 3 components: pulmonary blood flow(Qp), pulmonary vascular resistance(PVR) and pulmonary venous pressure(PVP). We sought to evaluate the prevalence and prognostic impact of individual hemodynamic abnormalities in ACHD.
Methods and results:
Retrospective study of ACHD patients undergoing cardiac catheterization at Mayo Clinic between 1999-2022 were followed for the combined endpoint of death/heart transplantation. Among 1,005 patients, 37% had mean pulmonary artery pressure(mPA)≥25mmHg with more systemic ventricular disease, cyanotic disease and shunt lesions, highest NT-proBNP and worse right heart remodeling/dysfunction. Among those with biventricular circulation, elevated PVP, PVR and mPA were associated with prognosis, but not increased Qp>8 L/min. However, risk of death/transplant increased for PVR only at ≥3 Wood units[HR 3.00(95% CI [2.17-4.15),p<0.0001] and for mPA only at ≥25 mmHg[HR 3.15 (95% CI 2.17-4.58),p<0.0001], not at current recommended lower cutpoints. Combined abnormalities in PVP and PVR were associated with worst outcome[HR 5.20 (95% CI 3.55-7.63),p<0.0001] with intermediate risk with either abnormality[HR 2.11 (95% CI 1.46-3.04),p<0.0001]. Findings were consistent across type of biventricular ACHD. Only with the Fontan(univentricular) circulation was a lower mPA threshold(20mmHg) associated with adverse outcomes.
Conclusion:
Elevation of mPA≥25 mmHg in ACHD with a biventricular circulation is prognostically important regardless of disease phenotype, but milder PH of 21-25 mmHg is not associated with adverse outcome unless associated with Fontan circulation. Elevation in PVP>15 mmHg and PVR≥3 Wood units were each individually associated with mortality with combined abnormalities associated with greatest risk. Categorizing PH in ACHD by hemodynamic mechanism(PVR, PVP or Qp) allows meaningful prognostication, and may allow more unified study of targeted therapies across heterogeneous disease states in ACHD.
Keywords: Pulmonary Hypertension, Congenital heart disease, Hemodynamics, Right heart Catheterization
Introduction
The adult congenital heart disease (ACHD) population represent a heterogeneous collection of disease processes that begin from birth, leading to heart failure, pulmonary hypertension (PH) and premature mortality.1 PH in ACHD is pathophysiologically diverse, being related in varying parts to elevated pulmonary venous pressure (PVP), pulmonary vascular resistance (PVR), or pulmonary blood flow (Qp), with many patients having overlapping mechanisms. Current criteria for pulmonary arterial hypertension (PAH) in ACHD emphasize shunt lesions, with less clear applicability to other forms of ACHD.2 Guideline definitions of PH have evolved to define PH using lower mean PA (mPA) and PVR cutpoints,3,4 supported by the fact that adverse prognosis can be demonstrated in non-ACHD patients even at these lower cutpoints.5,6 These new PH criteria have been subsequently extrapolated to ACHD without validation. Classification of PH currently guides many critical treatment decisions in ACHD including pulmonary vasodilator therapy, shunt closure, medical therapy for ventricular dysfunction, or transplantation making comprehensive insight into prognostic implications paramount.
To address this knowledge gap, we retrospectively evaluated a large cohort of ACHD patients undergoing detailed measurement of intracardiac hemodynamics, pulmonary blood flow and shunt fraction to calculate PVR, and evaluated the prevalence and prognostic implications of pulmonary vascular disease and other forms of PH in contemporary ACHD practice. We also compared the prognostic utility of existing PH diagnostic criteria and the individual hemodynamic contributors to PH in ACHD (i.e. PVR, PVP and Qp), stratified by disease phenotype.
Methods
Study overview
The study sample included adult patients (≥18 years) with congenital heart disease who underwent resting right heart catheterization (RHC) data in the congenital catheterization laboratory at Mayo Clinic, Rochester, Minnesota between 1999 and 2022. Only patients with complete data necessary to calculate systemic and pulmonary blood flow and PVR were included. All heart catheterizations were performed by a cardiologist with training in ACHD and included additional transeptal or arterial access to determine shunt fraction and hemodynamics depending on the specific form of ACHD.
Right heart catheterization measures
Given anatomic heterogeneity in the systemic ventricle and the importance of atrial function beyond ventricular function to determine Pulmonary Venous Pressure (PVP) and cause of PH7,8, we utilized a hierarchical approach to determine postcapillary or PVP. PVP was defined preferentially as direct left atrial (LA) pressure when available through transeptal puncture. If LA pressure was not measured, pulmonary capillary wedge pressure (PCWP) was used to define PVP, and if neither LA pressure or PCWP were obtained, systemic ventricular end diastolic pressure (EDP) was used to define PVP. The hierarchy for assessing PVP was therefore LA pressure > PCWP > ventricular EDP, with direct LA pressure utilized preferentially when available.
Pulmonary artery (PA) pressure was determined through direct pressure in the PA regardless of pulmonary valve prosthesis or right ventricular outflow tract pathology. Reported pressures reflect the average of pressure tracings over three spontaneous breaths. Pulmonary blood flow (Qp) was calculated using indirect Fick with estimated VO2 (standardized using the Dehmer equation as 125*body surface area), and A-V O2 difference across the pulmonary circulation in those without a right to left shunt was calculated as Hb*1.34 [arterial saturation – PA saturation]. Although the cutpoint for high cardiac output related PH is not well defined, pulmonary blood flow>8 L/min has been associated with high output heart failure and high Qp related PH9 and was considered an abnormally elevated Qp contributing to PH in this analysis. For patients who had systemic hypoxia from a right to left shunt we used pulmonary vein saturation when available instead of arterial saturation; and when pulmonary vein saturations were not available, we imputed 95% for pulmonary venous saturation to determine the A-V O2 difference across the pulmonary circulation and Qp. Systemic blood flow (Qs) was similarly calculated using the A-V O2 difference across the systemic circulation using Hb*1.34 [arterial saturation – PA saturation]. In the presence of a left to right shunt, the superior vena caval saturation was used instead of PA saturation to determine systemic A-V O2 difference and Qs. In the subset of left to right shunts due to an anomalous pulmonary vein/sinus venosus defect, the superior vena caval saturation to calculate Qs was obtained from the upper part of the superior vena cava above the level of possible shunt.
Pulmonary Hypertension classification
We classified patients by current hemodynamic classification as recommended by the most recent European Society of Cardiology/European Respiratory Society (ESC/ERS) 2022 guidelines, where mPAP of 20 mm Hg, PCWP of 15 mm Hg and PVR of 2 Wood units (WU) were used to define abnormalities in each component. This resulted in categorization as (i) Pre-capillary PH (PAH)[mPAP>20 mmHg, mean PCWP≤15 mmHg and PVR>2 WU], (ii) no pulmonary hypertension (no PH)[mPAP≤20 mmHg], (iii) isolated post-capillary PH (IpcPH) [mPAP>20 mmHg, PCWP> 15 mmHg, PVR≤2 WU] or (iv) combined pre and post-capillary PH (CpcPH) [mPAP>20 mmHg, PCWP> 15 mmHg, PVR>2 WU]. As per the new guidelines, unclassified PH was defined as mPA>20 mmHg, PVR ≤2 WU and PCWP ≤15 mmHg.3
To test the impact of progressive changes in PH classification schemes over time on ACHD associated PH, we also evaluated the diagnostic classification of the ESC/ERS 2015 guidelines which used the traditional definition of PAH with a PVR ≥3 WU and mPAP of ≥25 to definite abnormalities10, and the 2019 World Symposium on Pulmonary Hypertension that retained a PVR cutpoint of 3 WU but lowered the mPAP cutpoint to 20 mm Hg to define abnormalities.4 Categorization of PAH, IpcPH and CpcPH were as above at these different mPA and PVR cutpoints.
Right heart and pulmonary vascular indices
RV size and function were assessed qualitatively as mild, moderate or severe dysfunction using integrated clinical and visual assessment by a board certified congenital cardiologist. In a subset, RV global longitudinal strain, RV free wall longitudinal strain, right atrial and left atrial reservoir strain were available. Pulmonary vascular resistance (PVR) was calculated as (mPA - PVP)/Qp as a measure of steady state pulmonary vascular load. PVR calculation and its relative contribution to PH using this simplified hydraulic model only quantifies hemodynamic relationships at prevalent loading conditions while assuming independence between individual components. Pulsatile pulmonary vascular load was estimated by PA compliance [(PA stroke volume/PA pulse pressure] and PA elastance [PA systolic pressure/PA stroke volume] as previously described.11,12 R-C times reflecting the monoexponential time constant for PA diastolic pressure decay were calculated as the product of PVR and PA compliance. RV-PA coupling was calculated by dividing Tricuspid Annular Plane Systolic Excursion by catheterization measured PA systolic pressure.
Outcomes
Follow up for survival and/or heart transplantation (including either isolated heart transplantation or combined heart-lung transplantation) was performed from the time of catheterization until last known follow up. Outcomes were determined from manual review of electronic health records with mortality statistics (dead or alive) verified by using the Accurint system, an institution-approved mortality reporting system as previously described.13
Sub-Classification of ACHD
Given the anatomic and clinical heterogeneity across the spectrum of ACHD, particularly when associated with univentricular Fontan circulation, we also performed analyses stratified by subphenotype of ACHD. The primary analysis evaluated all biventricular circulation ACHD together, but we additionally performed subgroup analyses dividing these patients into 3 homogenous subphenotypes of biventricular circulation ACHD namely 1) systemic ventricular dysfunction (whether associated with RV or LV as the systemic ventricle) 2) shunt lesions and 3) right heart disease and cono-truncal lesions. Patients with Fontan circulation were separately evaluated in an independent analysis. Specific details of the individual ACHD disease phenotypes in each category are included in Table S1.
Statistical analysis
Data are reported as mean (SD), median (IQR) or number (%). Between-group differences across PH categories were compared by ANOVA, Kruskal Wallis or chi-square test with individual group differences compared by the Tukey test or Steel Dwass test as appropriate. Linear regression was used to evaluate the relationship between hemodynamic variables of interest. The primary outcome was risk of mortality and/or heart transplantation and was compared between PH groups using the log rank test with Cox models used for covariate adjustment in these comparisons. All tests were 2-sided, with a P value <0.05 considered significant. No correction for multiple hypothesis testing has been applied for reported p values. Analyses were performed with JMP, version 14.1.0 (JMP Statistical Discovery LLC).
Results
Baseline characteristics
A total of 1,005 patients with ACHD underwent RHC over the study period. Despite a young mean age (39 ± 15 years), PH was common ranging from 36% to 52% depending on whether a mPA of 25 or 20 mm Hg was used as definition. Overall, 48% (n=485) had no PH, 15% (n=149) had mild PH with mPA 20-25 (PH21-25), and 37% had more substantial PH with mPA ≥25 mm Hg (PH≥25). Compared to patients with no PH, those with PH≥25 were older, had more comorbidities including atrial fibrillation, obesity, sleep apnea, diabetes, hypertension, and coronary disease (Table 1). Renal function, anemia and N-terminal pro B type natriuretic peptide (NTproBNP) levels were most abnormal in patients with PH≥25 along with highest loop diuretic use, PAH vasodilator use and NYHA functional class.
Table 1:
Baseline Characteristics and Congenital Heart disease history across PH categories
| No PH ≤20 (n=485) |
PH 21-25 (n=149) |
PH≥25 (n=371) |
p value | |
|---|---|---|---|---|
| Age, years | 35.2 ± 14.2 | 38.3 ± 14.7 | 44.5 ± 15.9* | <0.0001 |
| Women, n (%) | 204 (42) | 77 (52) | 204 (55) | 0.0006 |
| Body mass index, kg/m2 | 25.1 ± 5.5* | 27.4 ± 5.8 | 27.9 ± 7.5 | <0.0001 |
| Obesity, n (%) | 54 (19) | 37 (28) | 124 (36) | <0.0001 |
| Obstructive Sleep Apnea, n (%) | 50 (10) | 36 (24) | 84 (23) | <0.0001 |
| Atrial Fibrillation, n (%) | 88 (18) | 33 (22) | 101 (27) | 0.007 |
| Hypertension, n (%) | 105 (22) | 39 (26) | 119 (32) | 0.003 |
| Diabetes, n (%) | 21 (4) | 17 (11) | 50 (14) | <0.0001 |
| Coronary Disease, n (%) | 17 (4) | 10 (7) | 32 (9) | 0.006 |
| NYHA Class III/IV, n (%) | 47 (17) | 19 (15) | 80 (24) | 0.03 |
|
| ||||
| Labs | ||||
| NTproBNP, pg/ml | 233 [84-565]* | 327 [135-868]* | 551 [215-2114]* | <0.0001 |
| Creatinine, mg/dl | 0.99 ± 0.44 | 1.10 ± 0.82 | 1.17 ± 0.88# | 0.0008 |
| Estimated GFR, ml/min/1.73m2 | 92 ± 27 | 87 ± 27 | 79 ± 31** | <0.0001 |
| Hemoglobin, g/dl | 14.2 ± 2.4 | 13.9 ± 2.1 | 13.4 ± 2.5# | <0.0001 |
|
| ||||
| Congenital heart history | ||||
| RHD/Cono-truncal lesions | 155 (32) | 73 (49) | 123 (33) | <0.0001 |
| Left Heart disease | 58 (12) | 24 (16) | 70 (19) | |
| Shunt Lesion | 59 (12) | 30 (20) | 92 (25) | |
| Cyanotic Heart disease | 0 (0 | 1 (1) | 44 (12) | |
| Systemic Right ventricle | 22 (5) | 8 (5) | 33 (9) | |
| Fontan | 191 (39) | 13 (9) | 9 (2) | |
| Prior Pulmonary valve replacement, n (%) | 64 (13) | 35 (23) | 61 (16) | 0.01 |
| Prior Mitral valve replacement, n (%) | 4 (1) | 5 (3) | 21 (6) | 0.0001 |
| Prior Aortic valve replacement, n (%) | 13 (3) | 7 (5) | 35 (9) | 0.0004 |
| Prior ASD closure (no/surgical/transcatheter), % | 92/3/5 | 89/8/3 | 89/7/4 | 0.004 |
| Prior VSD closure, n (%) | 13 (3) | 8 (5) | 21 (6) | 0.07 |
| Prior PDA ligation, n (%) | 1 (0.2) | 0 | 1 (0.3) | 0.71 |
| Prior PAPVR repair, n (%) | 17 (4) | 10 (7) | 26 (7) | 0.049 |
|
| ||||
| Medication at time of RHC | ||||
| Loop diuretics, n (%) | 149 (31) | 45 (30) | 159 (43) | 0.0005 |
| Endothelin Receptor Antagonist, n (%) | 0 (0) | 1 (1) | 12 (3) | <0.0001 |
| Phosphodiesterase inhibitor, n (%) | 24 (5) | 4 (3) | 22 (6) | 0.27 |
| Prostaglandin analogue, n (%) | 0 (0) | 0 (0) | 6 (2) | 0.003 |
Values represent mean (standard deviation) or median (25th, 75th),
p<0.05 vs all,
p<0.05 vs no PH,
Abbreviations: NTproBNP – N Terminal pro Brain Natriuretic Peptide; NYHA – New York Heart Association; GFR – Glomerular Filtration Rate; RHD- Right heart disease; ASD- Atrial septal defect; VSD- Ventricular Septal Defect; PDA – Patent Ductus Arteriosus; PAPVR – Partial Anomalous Pulmonary Venous Return;
Patients with PH≥25 were more likely to have had prior left sided valve replacement, ASD closure or partial anomalous pulmonary venous return repair. In terms of congenital heart disease (CHD) phenotype, cyanotic heart disease, congenital left heart disease, shunt lesions and systemic RV physiology were more common with PH≥25 , but patients with Fontan circulation rarely demonstrated a mPA≥25 mm Hg. Detailed breakdown of individual congenital diagnosis is provided in Table S1.
Patients with mild PH (PH21-25) demonstrated an intermediate group with generally more comorbidities compared to no PH with intermediate NTproBNP values. Cono-truncal and right heart disease congenital phenotypes were more common with mild PH with a higher prevalence of prior pulmonary valve replacement.
Cardiac structure and function
There was no difference in left ventricular size or ejection fraction across PH categories although E/e’ ratio was higher with more severe PH (Table 2). Right heart remodeling including qualitatively ≥moderate right atrial enlargement, RV enlargement and RV dysfunction was more common with PH≥25. Estimated right atrial pressure, RV systolic pressure, mitral and tricuspid regurgitation were also highest in those with PH≥25.. Among those with available quantitative metrics, LA volume index, right atrial volume index, LA reservoir strain, RA reservoir strain, RV free wall and global longitudinal strain were all most impaired in those with PH≥25. Notably, there were no group differences in any of these non-invasive metrics of cardiac structure/function between patients with no PH and mild PH (PH21-25).
Table 2:
Cardiac Structure and Function by echocardiography across PH categories
| No PH ≤20 (n=485) |
PH 21-25 (n=149) |
PH≥25 (n=371) |
p value | |
|---|---|---|---|---|
| Systemic ventricle indices | ||||
| LV End diastolic dimension, mm | 45 ± 15 | 46 ± 15 | 44 ± 17 | 0.36 |
| Ejection Fraction | 58 ± 9 | 57 ± 11 | 57 ± 10 | 0.79 |
| Medial E/e’ (n=521) | 9.4 ± 4.8 | 10.9 ± 6.2 | 11.8 ± 8.9* | 0.001 |
| ≥ moderate MR, n (%) | 5 (2) | 7 (6) | 30 (10) | 0.0003 |
| LA volume index, ml/m2 (n=644) | 25.5 ± 13.0 | 29.4 ± 15.5 | 33.1 ± 22.8# | <0.0001 |
| LA reservoir strain (n=350) | 29.4 ± 16.7 | 27.6 ± 15.1 | 21.1 ± 15.1* | <0.0001 |
|
| ||||
| Right heart indices | ||||
| ≥ Moderate RA enlargement, n (%) | 180 (38) | 57 (39) | 192 (52) | <0.0001 |
| ≥ Moderate RV enlargement, n (%) | 160 (37) | 46 (37) | 152 (53) | <0.0001 |
| ≥ Moderate RV dysfunction, n (%) | 30 (13) | 17 (16) | 82 (30) | <0.0001 |
| ≥ moderate TR | 44 (15) | 26 (20) | 103 (30) | <0.0001 |
| RA volume index, ml/m2 (n=321) | 37 ± 21 | 43 ± 29 | 48 ± 27# | 0.006 |
| RA reservoir strain (n=289) | 30.8 ± 15.6 | 27.6 ± 12.1 | 24.7 ± 13.0# | 0.005 |
| Estimated RA pressure | 7.6 ± 3.8 | 8.6 ± 4.4 | 9.8 ± 4.7* | <0.0001 |
| Estimated RV systolic pressure | 47 ± 23 | 51 ± 21 | 61 ± 25* | <0.0001 |
| TAPSE/cath PASP (n=358) | 0.71 ± 0.28* | 0.44 ± 0.16* | 0.32 ± 0.17* | <0.0001 |
| RV free wall strain (n=328) | 20.7 ± 9.4 | 21.3 ± 7.3 | 17.6 ± 9.6* | 0.005 |
| RV global longitudinal strain (n=323) | 19.5 ± 7.2 | 19.2 ± 5.6 | 17.2 ± 8.2# | 0.04 |
Values represent mean (standard deviation) or median (25th, 75th)
Abbreviations: LV – Left Ventricle; RA – Right Atrium; RV – Right Ventricle; MR – Mitral regurgitation; TR – Tricuspid Regurgitation; E/e’ – Mitral inflow E velocity/tissue doppler septal e’ velocity
p<0.05 vs all,
p<0.05 vs no PH
Hemodynamics and pulmonary vascular function
PVP was measured by the PCWP in 81%, direct left atrial pressure in 14% and by ventricular end diastolic pressure in 5%. As expected, mean PA pressure was highest in the PH≥25 group with the highest PA systolic and diastolic pressures (Table 3). There was progressive increase in PVP across the 3 groups with 64% of those with PH≥25 having an elevated PVP≥15 mmHg and 81% having a PVP≥12 mm Hg, suggestive of a high burden of systemic ventricular abnormalities with associated pulmonary venous hypertension contributing to PH in this ACHD cohort (Figure 1A).
Table 3:
Hemodynamics across PH categories
| No PH ≤20 (n=485) | PH 21-25 (n=149) | PH≥25 (n=371) | P value | |
|---|---|---|---|---|
| Pressure | ||||
| mPA, mm Hg | 15.4 ± 3.1 | 22.6 ± 1.1 | 39.4 ± 14.9 | - |
| PA systolic pressure, mm Hg | 26.7 ± 6.3* | 37.0 ± 6.4* | 62.4 ± 22.0* | <0.0001 |
| PA diastolic pressure, mm Hg | 8.9 ± 3.2* | 12.0 ± 3.4* | 24.4 ± 13.3* | <0.0001 |
| PVP, mm Hg | 9.6 ± 3.1* | 13.6 ± 3.5* | 17.6 ± 7.3* | <0.0001 |
| Transpulmonary gradient, mm Hg | 5.8 ± 2.8* | 9.0 ± 3.6* | 21.8 ± 15.6* | <0.0001 |
| Right atrial pressure, mm Hg | 10.3 ± 5 | 10.9 ± 5.7 | 13.3 ± 6.6* | <0.0001 |
| RA/PVP | 1.12 ± 0.57* | 0.80 ± 0.32 | 0.80 ± 0.33 | <0.0001 |
| PVP<12, n (%) | 364 (76) | 102 (41) | 19 (7) | <0.0001 |
| PVP 12-15, n (%) | 43 (9) | 61 (25) | 45 (16) | |
| PVP>15, n (%) | 70 (15) | 84 (34) | 217 (77) | |
|
| ||||
| Resistance | ||||
| PVR WU, median [IQR] | 1.1 [0.7-1.5]* | 1.6 [1.1-2.2]* | 3.4 [2.0-5.5]* | <0.0001 |
| PVR < 2 WU, n (%) | 433 (89) | 102 (69) | 93 (25) | <0.0001 |
| PVR 2-3 WU, n (%) | 45 (9) | 36 (24) | 71 (19) | |
| PVR ≥ 3 WU, n (%) | 7 (1) | 11 (7) | 207 (56) | |
| PVR ≥ 5 WU, n (%) | 0 (0) | 1 (1) | 113 (31) | <0.0001 |
| PA compliance | 5.9 ± 4.2* | 3.9 ± 2.5* | 2.5 ± 2.1* | <0.0001 |
| PA elastance | 0.3 ± 0.2* | 0.5 ± 0.3* | 1.0 ± 0.8* | <0.0001 |
| RC time, seconds | 0.37 ± 0.26 | 0.35 ± 0.17 | 0.50 ± 0.35* | <0.0001 |
|
| ||||
| Flow | ||||
| Qp, L/min | 5.6 ± 3.0 | 6.0 ± 3.3 | 5.7 ± 3.5 | 0.30 |
| Qs, L/min | 5.3 ± 3.0 | 5.2 ± 6.1 | 5.5 ± 6.3 | 0.75 |
| Qp/Qs>1.5, n (%) | 40 (8) | 17 (11) | 54 (15) | 0.01 |
| R to L shunt, n (%) | 60 (12) | 13 (9) | 55 (15) | 0.15 |
| Arterial saturation, median [IQR] | 95 [93-98] | 96 [93-98] | 94 [91-97]* | <0.0001 |
| Arterial saturation<90%, n (%) | 63 (13) | 14 (9) | 77 (21) | 0.0007 |
Abbreviations as above,
p<0.05 vs all
Figure 1: Hemodynamic abnormalities in patients with Adult Congenital Heart Disease undergoing Right heart catheterization.
Patients with PH≥25 were more likely to have abnormalities in multiple individual hemodynamic determinants of PA pressure compared to patients with borderline PH with mPA of 21-25 (A). Progressive abnormalities in pulmonary venous pressure (PVP) and pulmonary vascular resistance (PVR) were greater with increasing severity of pulmonary hypertension (B,C). Across the study population, PVR demonstrated a non-normal distribution with 78% having a PVR less than 3, and for the 22% with PVR>3 there was skewed distribution with many having marked PVR elevation (D).
There was also evidence of pulmonary vascular dysfunction which was greatest in the group with PH≥25, although patients with mild PH also had demonstrable group differences in pulmonary vascular load compared to those with no PH. Graded worsening of both steady state (PVR) and pulsatile vascular load (PA compliance and elastance) was seen across PH categories along with the highest transpulmonary gradient. Patients with PH≥25 were more likely to have 2 independent hemodynamic abnormalities contributing to their PH compared to those with PH20-25.(Figure 1B, 1C). A PVR over 3 or 5 WUs was much more common among those with PH≥25 and the distribution of PVR was skewed rightward with a notable minority having substantially elevated PVR beyond 3 WUs (Figure 1D). RV-PA coupling worsened progressively as PH severity worsened (Table 2).
There was overall no group difference in Qp or Qs across PH categories although the presence of a significant relative left to right shunt (Qp/Qs>1.5) was more common with PH≥25. There was no difference in right to left shunting across groups, but hypoxia was more common with PH≥25.
Impact of PH criteria on pulmonary hypertension phenotype
Using current PH classification criteria, patients with mild PH had roughly equal distributions of PAH and IpcPH, with nearly a third having unclassified PH (Figure 2A) (Table 4). Unclassified PH was most commonly associated with shunt lesions followed by right heart/cono-truncal abnormalities and generally reflected mild PH frequently associated with high Qp (Table S2). In contrast, the presence of CpcPH was highest (44%) among those with PH≥25 with 31% having PAH and 20% having IpcPH and only 5% having unclassified PH. Overall, the higher the mPA, the lower the relative contribution of PVP alone was to the measured mPA (Figure 2B), an effect that was most prominent in those with mPA≥25 mm Hg (Figure 2C).
Figure 2: PH classification stratified by mean PA pressure.
Using current adult PH guidelines, ACHD patients with mPA between 21-25 had a high rate of unclassified PH with a quarter receiving a diagnosis of PAH (A). Among those with mPA ≥25 mm Hg, there was less unclassified PH and more Cpc PH. With increasing PA pressures, there was a decrease in the relative contribution of Pulmonary venous pressure (PVP) to the absolute PA pressure (B), an effect most prominent in those with mPA≥25 mm Hg (C). Use of prior PH guidelines demonstrated a roughly equal split between PAH, IpcPH and CpcPH in those with mPA≥25 mm Hg (D).
Table 4:
Prevalence of PH categories across guideline changes
| PH 21-25 (n=149) |
PH≥25 (n=371) |
P value | |
|---|---|---|---|
| 2022 PH criteria (mPA>20, PVR≥2 WU) | |||
| Unclassified PH, n (%) | 47 (32) | 19 (5) | <0.0001 |
| PAH, n (%) | 39 (26) | 116 (31) | |
| Ipc PH, n (%) | 55 (37) | 74 (20) | |
| Cpc PH, n (%) | 8 (5) | 162 (44) | |
|
| |||
| 2019 PH criteria (mPA>20, PVR≥3WU) | |||
| PAH, n (%) | 11 (7) | 105 (28) | <0.0001 |
| Ipc PH, n (%) | 45 (30) | 115 (31) | |
| Cpc PH, n (%) | 0 (0) | 102 (28) | |
|
| |||
| 2015 PH criteria (mPA≥25, PVR≥3WU) | |||
| PAH, n (%) | 0 (0) | 105 (28) | <0.0001 |
| Ipc PH, n (%) | 0 (0) | 115 (31) | |
| Cpc PH, n (%) | 0 (0) | 102 (28) | |
|
| |||
| Total hemodynamic abnormalities (PVP≥15, PVR≥3, Qp>8) 0/1/2/3, % |
38/58/4/0 | 7/54/38/1 | <0.0001 |
With the 2015 PH guidelines (mPA≥25 mm Hg and PVR≥3 WU abnormal), there was a roughly equal split between PAH, IpcPH and CpcPH among those with PH≥25 (Figure 2D). The 2019 PH guidelines (mPA>20 mm Hg and PVR≥3 WU abnormal) resulted in 7% of patients with PH20-25 being diagnosed with PAH in contrast to 26% with the new PH guidelines. (Table 4)
Prognosis in relation to PH categorization with biventricular circulation
Given the known differences in prognostic thresholds for hemodynamic measures with a single ventricular Fontan circulation14, we first evaluated prognostic impact of various PH indices in the biventricular circulation participants (n=792) excluding those with Fontan circulation. Over a median follow up of 6 years [1-13 IQR] there were a total of 183 primary endpoints events of death/heart transplantation. On a continual scale, mean PA pressure, PVP and PVR were predictive of death or heart transplantation (Table 5). A higher Qp and Qp/Qs ratio was associated with better prognosis. Qs was not associated with outcomes.
Table 5:
Outcomes in biventricular circulation ACHD
| HR [95% CI] | P value | Adjusted* HR | P value | |
|---|---|---|---|---|
| Mean PA, mm Hg | 1.03 [1.02-1.04] | <0.0001 | 1.03 [1.02-1.04] | <0.0001 |
| PVR, WU | 1.04 [1.02-1.05] | 0.0001 | 1.05 [1.03-1.07] | <0.0001 |
| PVP, mm Hg | 1.09 [1.06-1.11] | <0.0001 | 1.07 [1.05-1.10] | <0.0001 |
| Qp, L/min | 0.94 [0.88-0.99] | 0.04 | 0.90 [0.84-0.97] | 0.002 |
| Qs, L/min | 1.02 [0.99-1.03] | 0.15 | 1.01 [0.99-1.04] | 0.14 |
| Qp/Qs | 0.77 [0.51-1.08] | 0.14 | 0.68 [0.45-0.97] | 0.03 |
| Qp>8, L/min | 0.65 [0.37-1.14] | 0.11 | 0.58 [0.33-1.04] | 0.07 |
| Hemodynamic cutpoints | ||||
| mPA ≤20 mm Hg | Reference | - | Reference | - |
| mPA 21-25 mm Hg | 0.93 [0.52-1.66] | 0.80 | 0.83 [0.45-1.53] | 0.54 |
| mPA≥25 mm Hg | 3.15 [2.17-4.58] | <0.0001 | 2.91 [1.95-4.33] | <0.0001 |
| 3.40 [2.05-5.64] for mPA≥25 vs 20-25 |
<0.0001 | 3.52 [2.04-6.06] for mPA≥25 vs 20-25 |
<0.0001 | |
| PVR<2 WU | Reference | Reference | ||
| PVR 2-3 WU | 1.48 [0.96-2.28] | 0.08 | 1.52 [0.97-2.38] | 0.07 |
| PVR≥3 WU | 3.00 [2.17-4.15] | <0.0001 | 3.08 [2.16-4.39] | <0.0001 |
| 2.03 [1.35-3.06] for PVR≥3 vs 2-3 |
0.0007 | 2.03 [1.33-3.10] for PVR≥3 vs 2-3 |
0.001 | |
| PVP<12 mm Hg | Reference | Reference | ||
| PVP 12-15 mm Hg | 1.35 [0.89-2.06] | 0.16 | 1.34 [0.86-2.09] | 0.20 |
| PVP >15 mm Hg | 2.76 [1.95-3.92] | <0.0001 | 2.33 [1.60-3.39] | <0.0001 |
| 2.05 [1.41-2.96] for PVP>15 vs 12-15 |
0.0002 | 1.74 [1.18-2.58] for PVP>15 vs 12-15 |
0.005 | |
| 0 abnormal (PVP<15 mm Hg and PVR<3 WU) |
Reference | - | Reference | - |
| 1 abnormality | 2.11 [1.46-3.04] | <0.0001 | 2.03 [1.38-2.98] | 0.0003 |
| 2 abnormalities | 5.20 [3.55-7.63] | <0.0001 | 4.4 [2.88-6.54] | <0.0001 |
| 2.47 [1.76-3.46] for 2 vs 1 abnormalities |
<0.0001 | 2.14 [1.49-3.06] for 2 vs 1 abnormalities |
<0.0001 | |
| 2022 PH criteria (mPA>20 mm Hg, PVR≥ 2 WU) | ||||
| No PH | Reference | Reference | ||
| PAH | 1.71 [1.07-2.73] | 0.02 | 1.83 [1.12-2.99] | 0.02 |
| Cpc PH | 4.33 [2.90-6.46] | <0.0001 | 3.70 [2.41-5.70] | <0.0001 |
| Ipc PH | 2.00 [1.22-3.27] | 0.006 | 1.70 [1.02-2.85] | 0.04 |
| Unclassified PH | 1.01 [0.45-2.28] | 0.97 | 0.88 [0.37-2.10] | 0.77 |
| 2019 PH criteria (mPA>20 mm Hg, PVR≥3WU) | ||||
| No PH | Reference | Reference | ||
| PAH | 2.38 [1.55-3.65] | <0.0001 | 2.55 [1.60-4.05] | <0.0001 |
| Cpc PH | 4.75 [3.26-6.91] | <0.0001 | 3.86 [2.58-5.77] | <0.0001 |
| Ipc PH | 2.20 [1.46-3.30] | 0.0002 | 1.86 [1.22-2.85] | 0.004 |
| 2015 PH criteria (mPA≥25 mm Hg, PVR≥3WU) | ||||
| No PH | Reference | Reference | ||
| PAH | 2.39 [1.56-3.67] | <0.0001 | 2.62 [1.64-4.19] | <0.001 |
| Cpc PH | 4.66 [3.23-6.71] | <0.0001 | 3.96 [2.67-5.87] | <0.0001 |
| Ipc PH | 2.53 [1.67-3.83] | <0.0001 | 2.31 [1.50-3.54] | 0.0001 |
Adjusted for age, BMI, creatinine and hemoglobin.
Mild PH with a mPA of 21-25 mm Hg was not associated with worse prognosis in contrast to PH with mPA≥25 mm Hg (Figure 4A). Similarly mild elevation in PVR of 2-3 was not associated with worse prognosis compared to a PVR<2 (Figure 4B). In contrast, a PVR≥3 WU was significantly associated with adverse prognosis. A PVP>15 was associated with mortality, but not milder PVP elevation of 12-15 mm Hg. (Figure 4C).
Figure 4: Risk of death or transplantation by PH classification.
Using current and particularly prior adult PH guidelines, ACHD patients with Cpc PH with combined abnormalities in PVR and PVP had the worst overall prognosis (A,B). Presence of either isolated systemic ventricular filling pressure elevation (IpC PH) or pulmonary vascular dysfunction (PAH) was also associated with worse prognosis.
The presence of either elevated PVP, PVR or both was associated with incremental worsening gradient of mortality risk(Figure 4D). Regardless of PH criteria used, the diagnosis of CpcPH was associated with greatest risk of death (Figure 5). The diagnosis of PAH or Ipc PH with isolated PVR or PVP abnormalities was associated with intermediate mortality risk (Figure 5). Patients with unclassified PH with normal PVR or PVP had outcome comparable to those with no PH. Although the overall diagnosis of PAH by the new PAH criteria (mPA >20, PVR>2) was associated with mortality, this was primarily driven by individuals with mPA >25 where mortality was higher compared to those with mPA 20-25 [HR 4.62 (95% CI 1.41-15.09), p=0.002].
The distribution and prognostic value of individual hemodynamic abnormalities were generally consistent across evaluated biventricular ACHD subgroups including those with systemic ventricular dysfunction, shunt lesions and right heart disease/cono-truncal lesions (Table S2–S7). In the subset of shunt patients with an active left to right shunt (Qp/Qs>1.5), there was no clear association between hemodynamics and outcome, whereas a stronger association between hemodynamics and outcome was seen in patients with no hemodynamically significant left to right shunt at RHC (including prior shunt closure or a small residual shunt with Qp/Qs<1.5) (Table S8). When stratifying patients by presence or absence of pulmonary venous hypertension (PVP≥15 mm Hg). the magnitude of PVP elevation was only prognostic in those with baseline PVP≥15 while PVR elevation and mPA elevation were prognostic in either group (Table S9).
Prognosis related to PH in Fontan circulation
In contrast to those with a biventricular circulation, patients with Fontan circulation most often had a mPA≤20 (Table S10), with a lower mPA of 21-25 and lower PVP of 12-15 mm Hg being associated with worse outcomes (Table S11). Notably, the magnitude of PVP elevation was prognostic regardless of the presence or absence of PVP≥15 mm Hg supporting the importance of even lower grade PVP elevation with the Fontan circulation (Table S12).
Discussion
In this study, we evaluated a large cohort of ACHD patients undergoing invasive evaluation for PH and observed a high prevalence of pulmonary venous hypertension and pulmonary vascular disease associated PH. However, currently recommended cutpoints to define abnormalities at a PVR of 2 WU and mPA of 20 mm Hgs3–6, were not associated with adverse prognosis in ACHD regardless of disease phenotype. Only patients with single ventricular Fontan circulation demonstrated increased mortality with milder PH at mPA of 21-25 mm Hg. In contrast, historically applied higher cutpoints with a PVR of 3 WU and mPA of 25 mm Hg appeared to consistently identify prognostically relevant thresholds in biventricular circulation ACHD where long term mortality was increased regardless of ACHD disease phenotype. Systemic ventricular disease with associated pulmonary venous hypertension despite a generally preserved ejection fraction was common and represented the most common cause of PH in ACHD with PVP elevation being universally associated with poor prognosis regardless of ACHD etiology. Pulmonary vascular dysfunction was also common, with combined abnormalities in PVP and PVR (i.e. Cpc PH) associated with the worst overall prognosis in this cohort. An elevated Qp with PH was paradoxically associated with better prognosis and high incidience of unclassified PH likely related to the general presence of a treatable cause of PH from a shunt or reversible defect causing high flow related PH.
These data emphasize the limitations of extrapolating adult hemodynamic criteria to patients with unique and complex physiology in ACHD, and suggest that current sensitive criteria for diagnosis of mild PH is of limited prognostic value in ACHD. This also questions whether the newer criteria are optimal to guide PAH vasodilator therapies in this hemodynamically complex population at high risk for pulmonary venous hypertension, though this requires prospective testing. Use of traditional more specific hemodynamic criteria with a mPA≥25 and PVR≥3 Wood units may be preferrable in biventricular circulation ACHD given the observed prognostic value of these cutpoints, that have been validated by randomized trials.15–17 A pragmatic hemodynamic approach determining individual hemodynamic derangements in PVP, PVR or Qp identifies ACHD groups with distinct prognostic trajectories. and may help guide targeted hemodynamic therapies regardless of underlying ACHD phenotype.
Hemodynamic identification of the cause of PH in ACHD
Patients with ACHD represent a diverse collection of pathological insults that predispose to heart failure and PH. An elevated mPA is ultimately a sign of disease that requires careful consideration of the underlying cause to guide treatment. In contrast to patients without ACHD, there is a higher prevalence of left to right shunts increasing Qp that requires hemodynamic consideration given their potential reversibility with shunt closure, and this reversible nature likely explains the improved prognosis in the presence of higher Qp and shunt fraction, a relationship not observed with Qs.
Additionally, across disease states in ACHD, systemic ventricular systolic and diastolic dysfunction with pulmonary venous hypertension represent a common hemodynamic endpoint with progressive adverse myocardial remodeling leading to PH. Pulmonary venous hypertension with or without superimposed pulmonary vascular disease was indeed the most common cause of PH in ACHD across congenital disease states. In fact, the occurrence of PH in the absence of pulmonary venous hypertension or pulmonary vascular dysfunction (unclassified PH) was often associated with isolated high flow related PH and demonstrated favorable outcome comparable to those with no PH. Secondary pulmonary vascular dysfunction with Cpc PH is not only common in ACHD but important to recognize since accurate differentiation of this condition from PAH is critical to guide therapy. Pulmonary vasodilators are the mainstay of treatment in PAH from ACHD15–17 whereas these drugs may be harmful in Cpc PH18,19, where sustained reduction in pulmonary venous pressure remains the mainstay of therapy as in traditional forms of left heart failure with Cpc PH.20 Accurate quantification of pulmonary vascular disease in ACHD is also an important consideration for isolated heart transplantation21 which represents the final treatment option for many cases of ACHD.
Diagnosing Precapillary PAH in ACHD
The present study suggests that hemodynamic identification of PAH may be optimized in ACHD by utilizing more specific criteria with a mPA of ≥25 mm Hg and PVR of at least ≥3 WU, with PVP<15 mm Hg used to exclude systemic ventricular dysfunction. PVP in patients with true pediatric precapillary PAH are generally well below 15 mm Hg with a large multicenter registry of PAH related to CHD demonstrating a mean PCWP of 9 mm Hg with a narrow 95% of 8-9 mm Hg.22 Utilization of more strict criteria to diagnose PAH in ACHD is also supported by existing PAH treatment trials in ACHD all of which required at least a PVR>3 Wood units (with most trials of Eisenmenger syndrome having mean PVR>20 Wood units), and PAH trials that included ACHD associated PAH (such as the GRIPHON trial testing selexipag) required a PVR>5 Wood units.15–17 Although patients with milder PH of 21-25 have worse outcomes in non-ACHD populations3–6, this does not appear to be the case in ACHD unless associated with the unique single ventricular physiology of the Fontan circulation. Whether longitudinal hemodynamic follow-up or exercise hemodynamic evaluation of ACHD patients with milder PH can further refine risk requires further study..
Limitations
The study sample is restricted to those referred for cardiac catheterization leading to referral bias, and the reason for referral for catheterization was not routinely captured. Across this heterogeneous population, some patients underwent targeted therapy towards their underlying congenital disease process which may impact associations between baseline hemodynamics and outcome. Further study of the impact of targeted interventions in specific forms of ACHD are needed to address their impact on mortality. The use of measured VO2 with the direct Fick method is the gold-standard method to measure cardiac output but was not routinely performed for congenital RHCs over most of the study period, and this may have affected our ability to assess the prognostic impact of Qs in ACHD requiring further study. However, error in cardiac output assessment would only be expected to bias flow dependent results (such as PVR) to the null. Despite this, we still observed highly significant associations between PVR and survival suggesting that this did not meaningfully impact our results.
Conclusion
Among a broad spectrum of CHD diagnoses, PH is common and most often related to pulmonary venous hypertension with frequent superimposed pulmonary vascular disease. Elevation of mPA pressures≥25 mm Hg in ACHD with a biventricular circulation is prognostically important regardless of disease phenotype, but milder PH of 21-25 mm Hg is not associated with adverse outcome unless associated with Fontan circulation. Elevation in PVP>15 mm Hg and PVR≥3 Wood units were each individually associated with mortality with combined abnormalities associated with greatest risk. Categorizing PH in ACHD by hemodynamic mechanism(PVR, PVP or Qp) allows meaningful prognostication, and may allow more unified study of targeted therapies in those with common pathophysiological mechanisms regardless of underlying primary disease.
Supplementary Material
Figure 3: Risk of death or transplantation by hemodynamic abnormalities.
ACHD patients had increased risk of death with increase in mPA ≥25, PVP>15 and PVR≥3 Wood units but not with mPA between 21-25 or PVR between 2-3 Wood units (A,B,C). The presence of neither, one, or both abnormalities in PVP or PVR was associated with progressive increase in risk of death (D).
Disclosures
Dr Reddy is supported by NIH grant K23HL164901. Dr. Borlaug receives research support from the National Institutes of Health (NIH) and the United States Department of Defense. Dr. Egbe is supported by National Heart, Lung, and Blood Institute (NHLBI) grants (R01 HL158517, R01 HL160761, and R01 HL162830).
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