Abstract
Background:
Some symptomatic patients manifest pulmonary hypertension(PH) despite normal pulmonary vascular resistance(PVR) and pulmonary artery wedge pressure(PAWP) – a condition termed ‘unclassified’ PH. Although hypothesized to reflect increased flow as seen in congenital heart disease, broader clinical implications remain unknown.
Methods:
The current analysis included PVDOMICS participants with either no PH or unclassified PH who underwent dynamic right heart catheterization(RHC) and trans-pulmonary metabolomics. In a validation cohort, patients with no PH or unclassified PH underwent exercise RHC. In exploratory cohorts to understand the impact of increased flow, prevalence of unclassified PH was assessed in i) adult congenital heart disease and ii) high output heart failure.
Results:
The overall prevalence of unclassified PH in PVDOMICS(n=1046) and the validation cohort(n=1202) was 7.8%(175/2248), which was comparable to the 6.6%(66/1005) prevalence in adult congenital heart disease(n=1005), and lower than high output heart failure(n=159, prevalence 14.5%[23/159], p=0.006). Increased flow occurred in a minority of unclassified PH from both PVDOMICS(28%)(15/53) and the validation cohort(11%)(13/122). Unclassified PH(n=53) was associated with greater adiposity, higher HFpEF-ABA probability, and more left heart remodeling compared to those with no PH(n=216). Metabolomics revealed lower glycine metabolites in unclassified PH indicative of metabolic dysfunction. Left heart remodeling, quality of life, exercise capacity and glycine levels were all abnormal in unclassified PH relative to healthy controls(n=96). In the validation cohort, PAWP, PVR and PA compliance were subtly abnormal at rest in unclassified PH(n=122) compared to no PH(n=312). With exercise testing, 59%(72/122) with unclassified PH had exertional PAWP elevation consistent with undiagnosed HFpEF.
Conclusions:
The presence of PH without obvious cause most often reflects subclinical left heart and metabolic dysfunction consistent with unrecognized early-stage HFpEF. Dynamic provocation during RHC can unmask unrecognized HFpEF in over half of unclassified PH, which may help guide appropriate initiation of proven HFpEF therapies to improve symptoms and functional status.
Clinical Trial Identifier:
Keywords: Unclassified PH, hemodynamics, HFpEF
Introduction
During right heart catheterization (RHC), some patients with pulmonary hypertension (PH) have no obvious hemodynamic cause identified, with normal pulmonary artery wedge pressure (PAWP ≤15 mm Hg) and pulmonary vascular resistance (PVR ≤2 WU), despite having abnormal elevation in mean pulmonary artery pressure (mPAP>20 mm Hg).1,2 This condition has been labelled as ‘unclassified’ PH, and it has been speculated that it may represent an increased flow state such as those seen in shunting related to congenital heart disease.3 However, the clinical and therapeutic implications of unclassified PH in the much larger cohort of patients without congenital heart disease remain unknown.
With increasing adiposity and metabolic dysfunction, heart failure with preserved ejection fraction (HFpEF) has become the most common cause of PH.4–6 Pulmonary vascular dysfunction is common in HFpEF, even during early stages of disease,7–9 which led us to hypothesize that most patients with unclassified PH would not have increased flow, but would instead have evidence of HFpEF upon hemodynamic provocation. To test this hypothesis, we utilized the multicenter PVDOMICS cohort, where participants with unclassified PH and those without PH underwent dynamic RHC assessment and detailed phenotyping including metabolomics. We independently tested our hypothesis in a large single center cohort undergoing supine exercise RHC with unclassified PH or no PH at rest. To further understand the relative contribution of increased flow to unclassified PH, we evaluated the prevalence and pathophysiology of unclassified PH in two additional positive control cohorts with i) high output heart failure10, and ii) adult congenital heart disease3 undergoing RHC.
Methods
Primary cohort description
The PVDOMICS clinical research network is a National Heart, Lung, and Blood Institute–funded, prospective, longitudinal cohort study (NCT02980887) that enrolled participants from November 30, 2016, to October 18, 2019 at seven centers across the US as previously described.11 The protocol was approved at each institution by the local Institutional Review Board, and informed consent was obtained from all participants. The data that support the findings of this study are available from the corresponding author on reasonable request. Enrolling centers recruited subjects ≥18 years of age with known or suspected PH who were undergoing right heart catheterization (RHC) for clinical purposes and were able to complete diagnostic testing. Healthy controls were also recruited as part of PVDOMICS (largely from partners or accompanying friends of patients participating in the study), and were required to have normal cardiopulmonary screening by history and examination. Healthy controls underwent all non-invasive testing for reference values.
Hemodynamic group definitions
The current analysis included only participants who had either no PH (mPA≤20 mm Hg) or unclassified PH (mPAP>20 mm Hg, PAWP≤15 mm Hg, PVR≤2 Wood units) identified at RHC.12 Participants with PH associated with either resting PAWP elevation (>15 mm Hg) and/or resting PVR elevation (>2 Wood units) were excluded.
Clinical evaluation
Participants underwent detailed baseline evaluation including anthropometry, core-lab interpreted transthoracic echocardiography, and cardiac magnetic resonance imaging (CMR), as previously described.13 Cardiopulmonary exercise testing, 6-minute walk distance, and pulmonary function testing were also assessed.13 Quality of life was assessed using the Short Form-36 (SF-36) Physical Component Summary (lower scores worse) and the Minnesota Living with Heart Failure (MLHF) Questionnaire (higher scores worse). In this cohort without hemodynamic evidence of HFpEF at rest (by design), we also quantified pretest probability for unrecognized HFpEF upon provocation using the validated HFpEF-ABA algorithm based on age, BMI and atrial fibrillation.14
Metabolomics
Untargeted metabolomics were performed on venous blood samples obtained from participants in the postabsorptive state, with data preparation as previously described (additional details in online supplement).15 Targeted metabolomic analyses for amino acids were independently performed on blood sampled from peripheral venous, pulmonary artery and pulmonary wedge positions.
Right heart catheterization
Right heart catheterization was performed at rest in the supine position in all participants with manual re-adjudication of pressure measurements at end-expiration.16 Cardiac output (CO) was assessed by the thermodilution technique or direct Fick method where available. Following resting assessment and in the absence of contraindications, patients underwent repeat hemodynamic assessment during i) 100% oxygen challenge for 5 minutes and ii) inhaled nitric oxide (NO) challenge at 40 ppm for 5 minutes added to 100% oxygen, with assessment of PAWP, mPAP and CO by thermodilution in both phases. Pulmonary vascular resistance (PVR) and PA compliance were calculated as previously described.7 Hemodynamic provocation for left heart disease was performed based on center availability either through i) fluid challenge with 500 mL of room temperature 0.9% saline infused over a 10-minute period or ii) exercise hemodynamics to peak exhaustion.
Validation cohort
The validation cohort included a single center cohort of consecutive patients undergoing supine exercise RHC with high fidelity micromanometers and simultaneous gas exchange measurement at the Mayo Clinic between 2006 and 2024 as previously described.17,18 All tracings were digitized and stored for offline analysis and were manually remeasured at end-expiration from micromanometer tracings by a single cardiologist with experience in hemodynamic interpretation (YNR) while blinded to clinical information. The PAWP was measured at end-expiration at mid a wave for the primary analysis, with the peak height of the V wave independently measured at end-expiration as an independent marker of left atrial non-compliance.19 The right atrial pressure was similarly measured at end-expiration at mid a wave. Pulmonary artery systolic and diastolic pressures were manually measured at end-expiration with the mean pulmonary artery pressure estimated at end-expiration using the Chemla equation as (0.61*PA systolic pressure) + 2.20 Like the PVDOMICS cohort, the current analysis only included the subset with resting evidence of either unclassified PH (mPAP>20 mm Hg, PAWP≤15 mm Hg and PVR≤2 Wood units) or no PH (mPAP≤20 mm Hg).
In a sensitivity analysis, we also report the other commonly used approach of averaging recorded pressure tracings over free breathing during the respiratory cycle for mPAP, PAWP and RAP. Respiratory averaged pressures were obtained time-synchronized over the same waveforms from which end-expiratory pressure measurements were made. Although the respiratory averaged PAWP allows incorporation of the V wave information into the PAWP assessment, the respiratory averaged PAWP tends to be lower than end-expiratory measurements due to inspiratory pleural pressure reduction.21 It has also recently been proposed that the upper limit of normal for resting PAWP might be 12 mm Hg instead of the current guideline recommended threshold of 15 mm Hg.21,22 We therefore also tested the impact of this lower PAWP threshold to define unclassified PH.
Exploratory cohorts
Given the hypothesized potential for increased flow and congenital shunt lesions to contribute to unclassified PH1, we independently evaluated the prevalence and pathophysiology of unclassified PH in i) a cohort of patients with adult congenital heart disease3 undergoing resting RHC at the Mayo Clinic between 1999 and 2022 and ii) a cohort of patients with high output heart failure (defined as cardiac output >8 L/min or cardiac index>4 L/min/m2 with clinical heart failure) undergoing resting RHC at the Mayo Clinic between 2000 and 2014.10
Statistical analysis
Differences between the unclassified PH and no PH groups were compared using T tests (assuming equal variance), Kruskal Wallis test and chi square test as appropriate. Our primary hypothesis that HFpEF upon provocation would be more common in unclassified PH compared to no PH was evaluated by chi square test. Given the central importance of PAWP response to provocation to unmask a latent diagnosis of HFpEF that is not present at rest in unclassified PH, we utilized a mixed model approach to model repeated PAWP measurements across various provocation phases in both PVDOMICS and the Mayo cohort, using a compound symmetry covariance structure with participant ID as a random effect and with group, phase and their interaction as fixed effects. In comparison of healthy controls with unclassified PH, linear regression was used to adjust for baseline imbalances in age, BMI and hypertension. Metabolomic data preparation and analyses are detailed in the online supplement. Briefly, the Benjamini-Hochberg approach was used to correct for false discovery in testing of the 954 untargeted metabolites by T test comparison between the two groups, and separately for the 27 targeted amino acid metabolites. To evaluate transpulmonary release for key metabolites that differed between unclassified PH and no PH after correcting for false discovery, mixed models were used as above but with sampling site and group*site interaction added as fixed effects.
Results
Baseline characteristics of Unclassified PH from PVDOMICS
Out of 1046 patients with suspected PH undergoing RHC in PVDOMICS, 53 (5.1%) had unclassified PH and 216 (20.7%) had no PH. Patients with unclassified PH had similar age and atrial fibrillation prevalence as those with no PH, but had greater adiposity as reflected by higher body mass index, waist circumference, waist to height ratio, and bioimpedance measured fat mass (Table 1). Inflammation (c-reactive protein) and insulin resistance (homeostasis model of insulin resistance) were higher in unclassified PH, along with more diabetes, sleep apnea, chronic obstructive lung disease and diuretic use. The estimated pretest probability for HFpEF was higher in unclassified PH compared to no PH (Table 1).
Table 1:
Baseline Characteristics of unclassified versus no PH in PVDOMICS
| Unclassified PH (n=53) |
p value | |
|---|---|---|
| Age, years (n=269) | 60.8 ± 12.5 | 0.32 |
| Body mass index, kg/m2(n=269) | 35.4 ± 8.8 | <0.0001 |
| Obesity (BMI ≥ 30 kg/m2), % | 72 | <0.0001 |
| Atrial fibrillation, % | 8 | 0.13 |
| Female, % | 43 | 0.003 |
| Waist circumference, cm (n=238) | 115.2 ± 18.8 | <0.0001 |
| Waist/height ratio (n=238) | 0.67 ± 0.11 | <0.0001 |
| Waist/height ≥0.5 | 95 | 0.004 |
| Body fat, % (n=201) | 37.4 ± 11.5 | 0.008 |
| Fat mass, kg (n=201) | 41.3 ± 21.4 | <0.0001 |
| Hypertension, % | 60 | 0.03 |
| Diabetes, % | 28 | 0.03 |
| HFpEF-ABA probability | 71.3 [49.2–86.6] | <0.0001 |
| Obstructive sleep apnea, % | 53 | 0.0003 |
| COPD, % | 28 | 0.001 |
| Interstitial lung disease, % | 11 | 0.45 |
| Arterial saturation (n=243), % | 95.4 ± 3.0 | <0.0001 |
| Functional status | ||
| SF-36 Physical component summary | 35.7 ± 9.9 | 0.61 |
| Minnesota Living with Heart Failure Questionnaire | 43.1 ± 27.0 | 0.26 |
| 6-minute walk distance, m (n=233) | 320 [270–415] | 0.008 |
| Peak VO2, ml/kg/min (n=218) | 13.3 ± 5.0 | 0.039 |
| Lab testing | ||
| Hemoglobin, g/dl (n=264) | 13.7 ± 2.0 | 0.12 |
| GFR, ml/min/1.73m2(n=254) | 76.5 ± 23.5 | 0.60 |
| Homeostasis Assay- Insulin Resistance (n=265) | 4.3 [2.6–8.2] | <0.0001 |
| C-Reactive Protein, mg/L (n=265) | 3.8 [1.6–6.1] | 0.03 |
| N-Terminal proBNP, pg/ml (n=260) | 119 [65–222] | 0.42 |
| Baseline Medications/PH risk | ||
| Diuretics, % | 55 | 0.008 |
| ACEi/ARB, % | 34 | 0.25 |
| Beta blockers, % | 34 | 0.17 |
Values represent mean (standard deviation) or median [interquartile range]. Abbreviations. PH, pulmonary hypertension; BMI, body mass index; HFpEF-ABA, heart failure with preserved ejection fraction age, body mass index, atrial fibrillation score; COPD, chronic obstructive pulmonary disease; SF-36, short form 36; VO2, oxygen consumption; GFR, glomerular filtration rate, BNP, brain natriuretic peptide; ACEi, angiotensin converting enzyme inhibitor; ARB, angiotensin receptor blocker
Cardiac Structure and Function in Unclassified PH from PVDOMICS
Unclassified PH was associated with greater LV enlargement, LV hypertrophy and LA enlargement compared to those with no PH, and this persisted even after indexing to height to account for differences in body size (Table 2). LA volume was greater in unclassified PH than no PH, but not after indexing to height. Cardiac output was modestly higher with unclassified PH which was related to differences in body size, with no differences after indexing to body surface area (cardiac index) between groups. Unclassified PH was associated with RV enlargement, RV hypertrophy and worse RV-PA coupling.
Table 2:
Cardiac Structure and function of unclassified versus no PH in PVDOMICS
| Unclassified PH (n=53) |
p value | |
|---|---|---|
| Echocardiography | ||
| Left heart remodeling/function | ||
| LV end diastolic volume, ml (n=209) | 109.7 ± 33.6 | <0.0001 |
| LV end diastolic volume/height2.7, ml/m2.7 (n=209) | 25.3 ± 8.2 | 0.0002 |
| LV mass, g (n=229) | 180.1 ± 46.6 | <0.0001 |
| LV mass/height2.7, ml/m2.7 (n=229) | 41.5 ± 10.8 | <0.0001 |
| LA volume, ml (n=232) | 56.1 ± 20.4 | 0.0005 |
| LA volume/height2.7, ml/m2.7 (n=232) | 12.8 ± 4.3 | 0.009 |
| LV ejection fraction, % (n=236) | 58.0 ± 8.5 | 0.24 |
| LV global longitudinal strain, % (n=177) | 17.7 ± 3.4 | 0.80 |
| Lateral e’, cm/s (n=227) | 9.5 ± 3.0 | 0.63 |
| Lateral E/e’, (n=223) | 8.8 ± 4.1 | 0.76 |
| LV cardiac output, L/min (n=214) | 4.2 ± 1.1 | 0.008 |
| LV cardiac index, L/min/m2 (n=214) | 2.0 ± 0.5 | 0.45 |
| Right heart remodeling/function | ||
| RV end diastolic area, cm2(n=193) | 24.6 ± 7.1 | <0.0001 |
| TAPSE, mm (n=174) | 20.8 ± 4.7 | 0.82 |
| TAPSE/PASP, %/mm (n=136) | 0.52 ± 0.19 | 0.002 |
| Magnetic Resonance Imaging | ||
| LV end diastolic volume, ml (n=159) | 146.1 [123.8–170.7] | 0.04 |
| LV EF, (n=159) | 56.5 ± 6.0 | 0.79 |
| LV global longitudinal strain, % (n=118) | 11.2 ± 2.5 | 0.045 |
| LV mass, g | 96.7 ± 24.0 | 0.03 |
| RV Ejection Fraction, % (n=160) | 50.9 ± 8.0 | 0.57 |
| RV GLS, % | 19.2 ± 4.7 | 0.43 |
| RV mass, g (n=159) | 29.2 [24.6–39.1] | 0.007 |
Values represent mean (standard deviation) or median [interquartile range]. Abbreviations LV, left ventricular; LA, left atrial; RV, right ventricular; TAPSE, tricuspid annular plane systolic excursion; PASP- Pulmonary Artery Systolic Pressure, EF, ejection fraction; GLS, global longitudinal strain
A total of 96 healthy controls were recruited to PVDOMICS and were younger, less obese and with less hypertension compared to unclassified PH (Table S1). When contextualizing cardiac remodeling in unclassified PH to values observed in healthy controls, LV size, LV mass, RV size and RV-PA uncoupling remained higher in unclassified PH compared to healthy controls, even after adjustment for age, body mass index and hypertension. (Table S1)
Functional status in Unclassified PH from PVDOMICS
Patients with unclassified PH had marked impairment in aerobic capacity, 6-minute walk distance, and quality of life compared to healthy controls (Figure S1). Peak exercise capacity and 6-minute walk distance were also lower in unclassified PH compared to patients with no PH, but quality of life was similarly impaired in unclassified PH compared with no PH (Table 3).
Table 3:
Rest and Fluid challenge Hemodynamics of Unclassified versus no PH in PVDOMICS
| Rest | Fluid challenge | Delta (Fluid challenge- Rest) | |||||||
|---|---|---|---|---|---|---|---|---|---|
| Unclassified PH (n=53) |
p value | No PH (n=85) |
Unclassified PH (n=20) |
p value | No PH (n=85) |
Unclassified PH (n=20) |
|||
| Heart rate, bpm | 71.1 ± 12.1 | 0.81 | 69.5 ± 10.9 | 68.4 ± 10.8 | 0.66 | −0.3 ± 7.4 | +0.5 ± 10.5 | 0.71 | |
| RAP mean, mm Hg | 8.3 ± 3.2 | <0.0001 | 7.7 ± 3.2 | 10.1 ± 3.9 | 0.005 | 3.9 ± 2.6 | 2.7 ± 2.3 | 0.08 | |
| PAWP mean, mm Hg | 12.8 ± 2.3 | <0.0001 | 13.1 ± 3.7 | 17.7 ± 6.0 | <0.0001 | 5.3 ± 3.6 | 5.9 ± 4.4 | 0.50 | |
| PAWP v wave mm Hg | 16.0 ± 3.6 | <0.0001 | 17.8 ± 5.6 | 22.2 ± 7.8 | 0.005 | 7.4 ± 4.8 | 7.7 ± 7.9 | 0.88 | |
| Rest PAWP≤12 mm Hg, n (%) | 22 (41.5) | <0.0001 | - | - | - | - | - | - | |
| Fluid PAWP>18 mm Hg, n (%) | - | - | 5 (6) | 8 (40) | 0.0002 | - | - | - | |
| PA mean, mm Hg | 24.2 ± 3.3 | <0.0001 | 22.7 ± 5.1 | 31.7 ± 4.4 | <0.0001 | 6.6 ± 4.0 | 6.9 ± 3.4 | 0.74 | |
| PA diastolic pressure, mm Hg | 16.9 ± 3.5 | <0.0001 | 14.6 ± 3.6 | 21.7 ± 3.8 | <0.0001 | 4.6 ± 3.3 | 5.1 ± 2.6 | 0.55 | |
| PVR, Wood units | 1.7 [1.4–1.9] | 0.26 | 1.6 [1.1–2.5] | 1.9 [1.2–2.1] | 0.92 | 0.1 ± 0.8 | 0.1 ± 0.6 | 0.87 | |
| Cardiac output, L/min | 7.2 ± 2.1 | <0.0001 | 5.7 ± 1.8 | 8.7 ± 2.6 | <0.0001 | 0.5 ± 0.7 | 0.8 ± 1.3 | 0.21 | |
| Cardiac Index, L/min/m2 | 3.0 [2.6–3.6] | 0.0002 | 2.9 [2.4–3.3] | 3.6 [3.3–4.6] | 0.0004 | 0.3 ± 0.4 | 0.3 ± 0.6 | 0.47 | |
| Cardiac output>8 L/min, n (%) | 15 (28) | <0.0001 | - | - | - | - | - | - | |
| Cardiac index>4 L/min/m2, n (%) | 6 (11) | 0.26 | - | - | - | - | - | - | |
Values represent mean (standard deviation) or median [interquartile range]. Abbreviations PH, pulmonary hypertension; RAP, right atrial pressure; PAWP, pulmonary artery wedge pressure; PA, pulmonary artery; PVR, pulmonary vascular resistance
Hemodynamics of Unclassified PH from PVDOMICS
Despite having a resting PAWP less than the conventional threshold for abnormal of 15 mm Hg (by definition), patients with unclassified PH had higher resting PAWP compared to those with no PH, which persisted across all phases of passive provocation with oxygen, nitric oxide and fluid challenge (p<0.0001) (Figure 1) (Table 3) (Table S2). The PAWP v wave and right atrial pressure were also elevated across all phases in unclassified PH compared to no PH. The cardiac output was on average higher in unclassified PH compared to no PH, but only 28% had a high cardiac output >8 L/min at rest.
Figure 1: Pulmonary artery wedge pressure (PAWP) with provocation in PVDOMICS and Mayo validation cohort.
PAWP was higher at rest in unclassified PH compared to no PH, and with passive provocation with oxygen (O2), nitric oxide (NO) and fluid challenge in PVDOMICS (A). In the Mayo validation cohort (B), PAWP was higher at rest, feet up and exercise phases with greater rise during exercise in unclassified compared to no PH.
Mayo Validation cohort
Among 1202 patients undergoing exercise RHC in the validation cohort, 312 (26.0%) had no PH and 122 (10.1%) had unclassified PH. Patients with unclassified PH were more obese with greater LV hypertrophy, LA enlargement and slightly worse LV diastolic function indices compared to those with no PH, largely mirroring the findings in PVDOMICS. (Table S3) However, in contrast to PVDOMICS, patients with unclassified PH in the Mayo cohort were older than those with no PH. Despite having a PAWP<15 mm Hg by definition, those with unclassified PH again had higher PAWP and PAWP v waves compared to those with no PH not only at rest, but also with greater rise with feet up and exercise (p<0.0001, interaction p=0.048). (Table 4) (Table S4) (Figure 1) Similarly, despite having a PVR<2 Wood units at rest (by definition), unclassified PH was associated with a higher PVR and lower PA compliance during both rest and exercise, coupled with worse exercise PH. (Figure 2). Cardiac output was again slightly higher at rest in unclassified PH, but only 11% had a high cardiac output >8 L/min at rest. There was no meaningful correlation between resting cardiac index with mPAP, PAWP or transpulmonary gradients further suggesting that increased flow was not the predominant driver of unclassified PH. (Figure S2) Peak exercise cardiac output was comparable between groups, but the increases in cardiac output relative to workload and peak oxygen consumption were lower in unclassified PH.
Table 4:
Rest and Exercise Hemodynamics of unclassified versus no PH in Mayo cohort
| Rest | Exercise | Delta (Exercise- Rest) | |||||||
|---|---|---|---|---|---|---|---|---|---|
| Unclassified PH (n=122) |
p value | No PH (n=312) |
Unclassified PH (n=122) |
p value | No PH (n=312) |
Unclassified PH (n=122) |
p value | ||
| RAP mean, mm Hg | 8.7 ± 2.3 | <0.0001 | 13.6 ± 6.0 | 16.4 ± 5.2 | 0.0001 | 6.5 ± 4.9 | 7.8 ± 4.4 | 0.04 | |
| PAWP mean, mm Hg | 13.3 ± 1.7 | <0.0001 | 22.1 ± 8.4 | 26.5 ± 7.6 | <0.0001 | 11.6 ± 7.3 | 13.2 ± 7.5 | 0.04 | |
| PAWP v wave mm Hg | 15.9 ± 3.7 | <0.0001 | 28.7 ± 13.5 | 35.4 ± 14.5 | <0.0001 | 16.4 ± 12.6 | 19.5 ± 14.0 | 0.03 | |
| Rest PAWP≤12 mm Hg, n (%) | 40 (32.8) | <0.0001 | - | - | - | - | - | - | |
| Exercise PAWP≥25 mmHg, n (%) | - | - | 116 (37.2) | 72 (59.0) | <0.0001 | - | - | - | |
| PAWP/CO slope, mm Hg/L/min | - | - | 2.1 [1.1–4.0] | 3.2 [1.7–5.3] | 0.001 | - | - | - | |
| PAWP/CO slope>2, n (%) | - | - | 153 (51) | 76 (68) | 0.002 | - | - | - | |
| PA mean, mm Hg | 22.1 ± 1.6 | <0.0001 | 30.5 ± 8.2 | 37.1 ± 7.6 | <0.0001 | 13.8 ± 7.5 | 15.0 ± 7.4 | 0.14 | |
| PA diastolic pressure, mm Hg | 16.3 ± 2.7 | <0.0001 | 26.2 ± 8.3 | 31.2 ± 8.3 | <0.0001 | 14.0 ± 7.1 | 14.9 ± 7.9 | 0.26 | |
| PVR, Wood units | 1.5 ± 0.3 | <0.0001 | 0.9 ± 0.6 | 1.1 ± 0.7 | 0.0005 | −0.3 ± 0.7 | −0.4 ± 0.7 | 0.57 | |
| PA compliance, ml/mm Hg | 5.4 ± 1.8 | <0.0001 | 5.1 ± 2.4 | 4.1 ± 2.0 | 0.0002 | −1.7 ± 2.7 | −1.2 ± 2.0 | 0.07 | |
| Cardiac output, L/min | 6.1 ± 1.6 | 0.0001 | 10.6 ± 3.0 | 10.6 ± 3.3 | 0.94 | 5.2 ± 2.7 | 4.6 ± 2.8 | 0.07 | |
| Cardiac Index, L/min/m2 | 2.9 ± 0.8 | 0.06 | 5.4 ± 1.5 | 5.1 ± 1.5 | 0.10 | 2.6 ± 1.4 | 2.2 ± 1.3 | 0.004 | |
| Cardiac output>8 L/min, % | 13 (10.7) | 0.09 | - | - | - | - | - | - | |
| Cardiac index>4 L/min/m2, % | 10 (8.2) | 0.95 | - | - | - | - | - | - | |
| Peak VO2, ml/kg/min | - | - | 12.7 ± 4.6 | 11.6 ± 4.7 | 0.04 | - | - | - | |
| Delta CO/delta VO2 | - | - | 6.2 [4.9–7.7] | 5.7 [4.5–7.2] | 0.04 | - | - | - | |
Values represent mean (standard deviation) or median [interquartile range]. Abbreviations PH, pulmonary hypertension; RAP, right atrial pressure; PAWP, pulmonary artery wedge pressure; PA, pulmonary artery; PVR, pulmonary vascular resistance; VO2, oxygen consumption; CO, cardiac output
Figure 2: Pulmonary vascular dysfunction in unclassified PH compared to no PH in Mayo validation cohort.
By definition, mean PA pressure was above 20 mm Hg in unclassified PH compared to no PH. With exercise, mean PA pressure was higher on average in unclassified PH but there was substantial overlap with no PH. Despite having ‘normal’ pulmonary vascular resistance <2 Wood units by design in unclassified PH, the mean PVR and PA compliance was abnormal compared to no PH, both at rest and with exercise indicative of subtle pulmonary vascular dysfunction.
Prevalence of unrecognized HFpEF in Unclassified PH
In PVDOMICS, passive volume loading caused the PAWP to rise to the abnormal threshold of >18 mm Hg23 in 40% of unclassified PH, compared to 6% with no PH (p=0.0002). In the subset of PVDOMICS with exercise testing, an abnormal absolute PAWP (≥20 mm Hg with upright exercise or ≥25 mm Hg with supine exercise) was observed in 43% of unclassified PH compared to 15% with no PH (p=0.002).
In the Mayo validation cohort where all patients underwent passive volume loading with passive leg raise, followed by supine exercise to exhaustion, 55% with unclassified PH had an abnormal PAWP>18 mm Hg with leg raise, compared to 21% in the no PH group (p<0.0001). With exercise, 59% of unclassified PH had abnormal exercise PAWP response (≥25 mm Hg) compared to 37% with no PH (p<0.0001) (Figure 3). Overall, performance of exercise RHC resulted in participants with unclassified or no PH being reclassified to the diagnosis of HFpEF in 43% and non-cardiac dyspnea in 57% (Figure 4). The PAWP/CO slope was also higher in unclassified PH being abnormal (>2 mm Hg/L/min) in 68%. (Figure S3)
Figure 3: Prevalence of unclassified PH and heart failure with preserved ejection fraction during feet up and exercise phases.
In the Mayo validation cohort (A), 55% with unclassified PH had an abnormal PAWP>18 mm Hg during the feet up phase compared to 21% in the no PH group (p<0.0001). With exercise, 59% of unclassified PH had abnormal exercise PAWP response≥25 mm Hg compared to 37% with no PH (p<0.0001). Unclassified PH was only slightly more common in high output heart failure compared to patients with adult congenital heart disease or a broader cohort from PVDOMICS and the cohort (B).
Figure 4: Reclassification from rest to exercise RHC among patients with either unclassified or no PH at rest.
Compared to a diagnosis of either no PH or unclassified PH at rest, exercise RHC resulted in diagnosis of HFpEF in 43% and non-cardiac dyspnea in 57%
Sensitivity analyses in Mayo cohort
When using respiratory averaged pressures, there was comparable prevalence of unclassified PH (n=116, 9.7%) compared to use of end-expiratory pressure measurements (n=122, 10.1%) with persistently greater PAWP at rest, feet-up and exercise phases. Similar to end-expiratory assessments, more patients with unclassified PH using respiratory averaged pressures had abnormal PAWP response during feet up (54%) or exercise (74%) (Table S5). When comparing unclassified PH using a PAWP threshold of ≤12 to define normal, there was comparably high peak exercise PAWP in both the PAWP ≤12 and 12–15 groups with unclassified PH (Table S6). When evaluating unclassified PH with and without obesity, patients with obesity had comparable resting PAWP abnormalities but higher exercise PAWP both using end-expiratory and respiratory averaged measurements compared to those with unclassified PH and no obesity (Table S7).
Metabolomics of unclassified PH
After correction for false discovery, untargeted metabolomics demonstrated 5 metabolites were lower in unclassified PH compared to no PH (glycine, gamma-glutamylglycine, propionylglycine, gamma-glutamylcitrulline and 3-beta-hydroxy-5-cholestenoate) (Figure S2, full metabolomic results are provided in online supplement). Targeted amino acid metabolomics confirmed glycine was lower in unclassified PH compared to no PH, which persisted even after adjustment for BMI and insulin resistance (HOMA-IR) (Table S8). This finding was replicated in triplicate samples across the pulmonary circulation (vein, pulmonary artery and wedge samples), without differential transpulmonary gradients, suggesting non-pulmonary origin. Glycine was also abnormally low in unclassified PH when compared to healthy controls consistent with greater metabolic dysfunction. (Figure S4)
Exploratory cohorts with adult congenital heart disease and high output heart failure
Among 1005 patients with adult congenital heart disease undergoing RHC, only 66 (6.6%) had unclassified PH, of whom only 37 (56%) had increased pulmonary blood flow, with 24 (36%) having an active shunt with Qp/Qs>1.5. Among the overall cohort, 111 patients had an active shunt (Qp/Qs>1.5) of whom only 24 (22%) had unclassified PH (Table S9). In a cohort of 159 patients who all had invasively confirmed high cardiac output and clinical heart failure, only 23 (14.5%) had unclassified PH (Table S10). Prevalence of unclassified PH in high output failure (14.5%) exceeded that observed in the pooled PVDOMICS and Mayo cohorts (7.8%) and the adult congenital cohort (6.6%) (chi square p=0.006) (Figure 4).
Discussion
In this study, we provide the first comprehensive phenotypic characterization of unclassified PH, showing that this is not a benign condition, but one that is characterized by exercise intolerance, impaired quality of life and invasively confirmed evidence of pulmonary hypertension, even as there is not an actionable hemodynamic diagnosis based upon resting assessment alone. However, with dynamic provocation, we identify subclinical left heart and pulmonary vascular dysfunction in unclassified PH that was not apparent at rest, with an underlying diagnosis of HFpEF that could be unmasked with hemodynamic stress testing. Although the hemodynamic classification of unclassified PH was modestly sensitive to PAWP measurement technique, the prevalence of HFpEF was generally high regardless of approach, and a number of non-hemodynamic findings corroborated greater burden of metabolic dysfunction and risk of cardiometabolic HFpEF including greater non-invasive pre-test probability for HFpEF, greater adiposity, and unbiased metabolomic evidence of glycine deficiency (which has been associated with higher HFpEF likelihood15 and metabolic dysfunction).24–26 Increased flow states were distinctly uncommon in unclassified PH, and even patients with adult congenital heart disease with shunts or overt high output heart failure uncommonly manifested the hemodynamic profile of unclassified PH. Collectively, these data support consideration of routine hemodynamic stress testing when unclassified PH is identified at rest, to help guide more accurate upfront diagnosis and guide initiation of proven HFpEF therapies to improve functional status and quality of life.
Relationship to prior literature
Multiple studies have demonstrated that a mean PA pressure >20 mm Hg is associated with increased mortality, even among those with mild PH and a mean PA pressure between 20–25 mm Hg.2,27–29 This has prompted guideline revisions, with lowering of the threshold for diagnosing PH from 25 to 20 mm Hg, while acknowledging a new category of uncertainty referred to as unclassified PH, where there is PH, without PAWP or PVR abnormalities by currently used thresholds.1 Little is known about this condition apart from an approximately 5–10% prevalence across multiple disease states including aortic stenosis, lung disease, systemic sclerosis and valvular heart disease.2,30,31 Some have speculated that this unique profile may result from increased flow increasing PA pressure despite ‘normal’ PAWP and PVR, and potentially being overrepresented in adult congenital heart disease with related shunts.
Here we demonstrate across multiple cohorts that increased flow is an uncommon cause of unclassified PH, further supported by the fact that only a minority of patients with high output heart failure or congenital heart disease manifested this hemodynamic profile. However, in the majority of other unclassified PH without increased flow, there were subtle PAWP abnormalities even at rest that became frankly abnormal during exertion emphasizing the continuum of pathological resting PAWP abnormalities that may be present even below the current guideline threshold of 15 mmHg.32,33 Excess adiposity does lead to a high output state in some due to volume expansion, and while this may contribute10, the other cardiometabolic mediated abnormalities identified appear to be more physiologically important likely through the well-described associations between adiposity, diastolic dysfunction and pericardial constraint.34–36
Provocative Testing to Reveal the Etiology of Unclassified PH
The most clinically relevant finding of this analysis is the very high prevalence of unrecognized HFpEF upon hemodynamic provocation of patients with unclassified PH. While there is no clear cause of symptoms or PH in unclassified PH, hemodynamic stress testing unmasked a true diagnosis of HFpEF in over half of cases, regardless of measurement approach. Given the substantial impairment in quality of life and functional status in unclassified PH, along with high prevalence of adiposity and metabolic dysfunction, appropriate recognition of underlying HFpEF can guide initiation of proven therapies that improve quality of life and exercise function while reducing risk for HF hospitalizations in HFpEF, including sodium glucose co-transporter 2 (SGLT2) inhibitors, mineralocorticoid receptor antagonists, and incretins.37–42 Notably, SGLT2 inhibitors have also been shown to lower PA and PAWP pressures at rest and exercise, which would be beneficial for patients with unclassified PH at rest but HFpEF apparent upon exertion.43,44 It is also notable that cardiac output was higher at rest in unclassified PH in the context of greater obesity, and weight loss has been associated with decreased metabolic demand and lowering of cardiac output with improved hemodynamics,45 related in part to decreases in volume expansion.46 Collectively, these data would support routine use of dynamic hemodynamic testing in unclassified PH, where a more precise diagnosis of HFpEF can be obtained in a large proportion to guide treatment, as opposed to the nonactionable label of ‘unclassified PH’.
Strengths and Limitations
The present analysis has multiple strengths including its multicenter representation, prospective data collection using consistent protocols, core-lab adjudication of hemodynamics at end-expiration, and validation in independent cohorts. However, PVDOMICS centers performed either fluid or exercise testing depending on site availability and therefore not all patients underwent the most sensitive test of exercise hemodynamics to identify unrecognized HFpEF.47 Therefore it is possible that the prevalence of unrecognized HFpEF in unclassified PH from PVDOMICS may be even higher than reported, as suggested by the higher prevalence in the validation cohort where all patients underwent exercise testing. Although there were age differences between included cohorts of unclassified PH, the prevalence of HFpEF upon provocation was largely comparable, supporting potential generalizability of our findings across the spectrum of age in unclassified PH. The hemodynamic thresholds to define HFpEF upon provocation and measurement techniques for PAWP are not standardized in the literature, and the current study demonstrates potentially meaningful reclassification impact depending on approach applied. These data call for the need to standardize reporting and measurement approaches for PAWP and pulmonary vascular pressures in clinical practice, which is of particular relevance when interpreting low magnitude hemodynamic abnormalities such as those seen in unclassified PH.
Conclusion
Although a resting PAWP >15 mm Hg is commonly used to diagnose HFpEF as the cause of pulmonary hypertension, the identification of pulmonary hypertension with no obvious hemodynamic cause most often reflects subclinical left heart and metabolic dysfunction consistent with early unrecognized HFpEF. Dynamic provocation during RHC can unmask unrecognized HFpEF in over half of unclassified PH, which may help guide appropriate initiation of proven HFpEF therapies to improve exercise tolerance and quality of life.
Supplementary Material
What is new?
The presence of unclassified pulmonary hypertension with no obvious cause at rest occurs in approximately 1 in 12 patients undergoing right heart catheterization
Increase flow was not a common cause of unclassified pulmonary hypertension which was most often related to unrecognized heart failure with preserved ejection fraction, as supported by multiple non-hemodynamic abnormalities in left heart remodeling, metabolomic dysfunction and functional status.
Dynamic hemodynamic provocation could unmask a true diagnosis of heart failure with preserved ejection fraction in over half of patients with unclassified pulmonary hypertension, even as no actionable diagnosis was present at rest.
What are the clinical implications
The identification of pulmonary hypertension without abnormalities in resting pulmonary artery wedge pressure or pulmonary vascular resistance by current criteria most often reflects subtle abnormalities reflective of unrecognized heart failure with preserved ejection fraction
The use of dynamic provocation during right heart catheterization in patients with such ‘unclassified’ pulmonary hypertension will unmask a true diagnosis of heart failure with preserved ejection fraction in over half of patients, which may be useful to guide therapy.
Acknowledgments
The authors thank the patients participating in the PVDOMICS network who agreed to participate in research, allowing for this study to be completed.
Support
The study was supported by grants from the NIH/NHLBI: U01 HL125218 (PI: E.B. Rosenzweig), U01 HL125205 (PI: R.P. Frantz), U01 HL125212 (PI: A.R. Hemnes), U01 HL125208 (PI: F.P. Rischard), U01 HL125175 (PI: P.M. Hassoun), U01 HL125215 (PI: J.A. Leopold), and U01 HL125177 (PI: G.J. Beck), and by the Pulmonary Hypertension Association. Dr Reddy is supported by NIH grant K23HL164901. Dr. Borlaug is supported by R01 HL128526, R01 HL162828, and U01 HL160226, from the NIH/NHLBI, and W81XWH2210245 from the US Department of Defense.
Disclosures
Dr. Reddy receives research grants from the National Institutes of Health (NIH), Sleep Number, Bayer Accelerated Pulmonary Hypertension Award, United Jenesis Award, Merck, and the Earl Wood Career development award from Mayo Clinic. Dr. Borlaug receives research support from the National Institutes of Health (NIH) and the United States Department of Defense, as well as research grant funding from AstraZeneca, Axon, GlaxoSmithKline, Medtronic, Mesoblast, Novo Nordisk, and Tenax Therapeutics. Dr. Borlaug has served as a consultant for Actelion, Amgen, Aria, Axon Therapies, BD, Boehringer Ingelheim, Cytokinetics, Edwards Lifesciences, Eli Lilly, Imbria, Janssen, Merck, Novo Nordisk, NGM, NXT, and VADovations, and is named inventor (US Patent no. 10,307,179) for the tools and approach for a minimally invasive pericardial modification procedure to treat heart failure.
Abbreviations
- RHC
Right heart catheterization
- PAWP
Pulmonary artery wedge pressure
- PH
Pulmonary hypertension
- PVR
Pulmonary vascular resistance
- HFpEF
Heart failure with preserved ejection fraction
References
- 1.Humbert M, Kovacs G, Hoeper MM, Badagliacca R, Berger RMF, Brida M, Carlsen J, Coats AJS, Escribano-Subias P, Ferrari P, et al. 2022 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Heart J. 2022;43:3618–3731. [DOI] [PubMed] [Google Scholar]
- 2.Karia N, Howard L, Johnson M, Kiely DG, Lordan J, McCabe C, Pepke-Zaba J, Ong R, Preiss M, Knight D, et al. Predictors of outcomes in mild pulmonary hypertension according to 2022 ESC/ERS Guidelines: the EVIDENCE-PAH UK study. Eur Heart J. 2023;44:4678–4691. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Reddy YNV, Miranda WR, Jain CC, Borlaug BA, Egbe AC. Haemodynamic contributors to pulmonary hypertension across the spectrum of adult congenital heart disease. Eur J Heart Fail. 2024;26:2356–2366. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Vanderpool RR, Saul M, Nouraie M, Gladwin MT, Simon MA. Association Between Hemodynamic Markers of Pulmonary Hypertension and Outcomes in Heart Failure With Preserved Ejection Fraction. JAMA Cardiol. 2018;3:298–306. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Reddy YNV, Borlaug BA. Pulmonary Hypertension in Left Heart Disease. Clin Chest Med. 2021;42:39–58. [DOI] [PubMed] [Google Scholar]
- 6.Vasan RS, Enserro DM, Beiser AS, Xanthakis V. Lifetime Risk of Heart Failure Among Participants in the Framingham Study. J Am Coll Cardiol. 2022;79:250–263. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Reddy YNV, Obokata M, Koepp KE, Egbe AC, Wiley B, Borlaug BA. The β-Adrenergic Agonist Albuterol Improves Pulmonary Vascular Reserve in Heart Failure With Preserved Ejection Fraction. Circ Res. 2019;124:306–314. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Andersen MJ, Hwang S-J, Kane GC, Melenovsky V, Olson TP, Fetterly K, Borlaug BA. Enhanced pulmonary vasodilator reserve and abnormal right ventricular: pulmonary artery coupling in heart failure with preserved ejection fraction. Circ Heart Fail. 2015;8:542–550. [DOI] [PubMed] [Google Scholar]
- 9.Borlaug BA, Kane GC, Melenovsky V, Olson TP. Abnormal right ventricular-pulmonary artery coupling with exercise in heart failure with preserved ejection fraction. Eur Heart J. 2016;37:3293–3302. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Reddy YNV, Melenovsky V, Redfield MM, Nishimura RA, Borlaug BA. High-Output Heart Failure: A 15-Year Experience. J Am Coll Cardiol. 2016;68:473–482. [DOI] [PubMed] [Google Scholar]
- 11.Hemnes AR, Leopold JA, Radeva MK, Beck GJ, Abidov A, Aldred MA, Barnard J, Rosenzweig EB, Borlaug BA, Chung WK, et al. Clinical Characteristics and Transplant-Free Survival Across the Spectrum of Pulmonary Vascular Disease. J Am Coll Cardiol. 2022;80:697–718. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Kovacs G, Bartolome S, Denton CP, Gatzoulis MA, Gu S, Khanna D, Badesch D, Montani D. Definition, classification and diagnosis of pulmonary hypertension. Eur Respir J. 2024;64:2401324. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Hemnes AR, Beck GJ, Newman JH, Abidov A, Aldred MA, Barnard J, Berman Rosenzweig E, Borlaug BA, Chung WK, Comhair SAA, et al. PVDOMICS: A Multi-Center Study to Improve Understanding of Pulmonary Vascular Disease Through Phenomics. Circ Res. 2017;121:1136–1139. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Reddy YNV, Carter RE, Sundaram V, Kaye DM, Handoko ML, Tedford RJ, Andersen MJ, Sharma K, Obokata M, Verbrugge FH, et al. An evidence-based screening tool for heart failure with preserved ejection fraction: the HFpEF-ABA score. Nat Med. 2024;30:2258–2264. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Reddy YNV, Asokan AK, Frantz RP, Hemnes A, Hassoun PM, Barnard J, Horn E, Leopold JA, Rischard F, Rosenzweig EB, et al. Metabolomic Evidence of Biological Overlap with Heart Failure with Preserved Ejection Fraction in a Subset of Pulmonary Arterial Hypertension. Am J Respir Crit Care Med. 2025;211:1701–1713. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Tang WHW, Wilcox JD, Jacob MS, Rosenzweig EB, Borlaug BA, Frantz RP, Hassoun PM, Hemnes AR, Hill NS, Horn EM, et al. Comprehensive Diagnostic Evaluation of Cardiovascular Physiology in Patients With Pulmonary Vascular Disease: Insights From the PVDOMICS Program. Circ Heart Fail. 2020;13:e006363. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Reddy YNV, Carter RE, Sorimachi H, Omar M, Popovic D, Alogna A, Jensen MD, Borlaug BA. Dapagliflozin and Right Ventricular-Pulmonary Vascular Interaction in Heart Failure With Preserved Ejection Fraction: A Secondary Analysis of a Randomized Clinical Trial. JAMA Cardiol. 2024;9:843–851. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Reddy YNV, Carter RE, Obokata M, Redfield MM, Borlaug BA. A Simple, Evidence-Based Approach to Help Guide Diagnosis of Heart Failure With Preserved Ejection Fraction. Circulation. 2018;138:861–870. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Reddy YNV, Obokata M, Verbrugge FH, Lin G, Borlaug BA. Atrial Dysfunction in Patients With Heart Failure With Preserved Ejection Fraction and Atrial Fibrillation. J Am Coll Cardiol. 2020;76:1051–1064. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Chemla D, Castelain V, Humbert M, Hébert J-L, Simonneau G, Lecarpentier Y, Hervé P. New formula for predicting mean pulmonary artery pressure using systolic pulmonary artery pressure. Chest. 2004;126:1313–1317. [DOI] [PubMed] [Google Scholar]
- 21.Naeije R, Chin K. Differentiating Precapillary From Postcapillary Pulmonary Hypertension. Circulation. 2019;140:712–714. [DOI] [PubMed] [Google Scholar]
- 22.Zeder K, Avian A, Mak S, Giannakoulas G, Kawut SM, Maron BA, Humbert M, Olschewski H, Kovacs G. Pulmonary arterial wedge pressure in healthy subjects: a meta-analysis. Eur Respir J. 2024;64:2400967. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.van de Bovenkamp AA, Wijkstra N, Oosterveer FPT, Vonk Noordegraaf A, Bogaard HJ, van Rossum AC, de Man FS, Borlaug BA, Handoko ML. The Value of Passive Leg Raise During Right Heart Catheterization in Diagnosing Heart Failure With Preserved Ejection Fraction. Circ Heart Fail. 2022;15:e008935. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.El Hafidi M, Pérez I, Zamora J, Soto V, Carvajal-Sandoval G, Baños G. Glycine intake decreases plasma free fatty acids, adipose cell size, and blood pressure in sucrose-fed rats. Am J Physiol Regul Integr Comp Physiol. 2004;287:R1387–1393. [DOI] [PubMed] [Google Scholar]
- 25.Cruz M, Maldonado-Bernal C, Mondragón-Gonzalez R, Sanchez-Barrera R, Wacher NH, Carvajal-Sandoval G, Kumate J. Glycine treatment decreases proinflammatory cytokines and increases interferon-gamma in patients with type 2 diabetes. J Endocrinol Invest. 2008;31:694–699. [DOI] [PubMed] [Google Scholar]
- 26.Caldow MK, Ham DJ, Godeassi DP, Chee A, Lynch GS, Koopman R. Glycine supplementation during calorie restriction accelerates fat loss and protects against further muscle loss in obese mice. Clin Nutr. 2016;35:1118–1126. [DOI] [PubMed] [Google Scholar]
- 27.Maron BA, Brittain EL, Hess E, Waldo SW, Barón AE, Huang S, Goldstein RH, Assad T, Wertheim BM, Alba GA, et al. Pulmonary vascular resistance and clinical outcomes in patients with pulmonary hypertension: a retrospective cohort study. Lancet Respir Med. 2020;8:873–884. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28.Kolte D, Lakshmanan S, Jankowich MD, Brittain EL, Maron BA, Choudhary G. Mild Pulmonary Hypertension Is Associated With Increased Mortality: A Systematic Review and Meta-Analysis. J Am Heart Assoc. 2018;7:e009729. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29.Strange G, Stewart S, Celermajer DS, Prior D, Scalia GM, Marwick TH, Gabbay E, Ilton M, Joseph M, Codde J, et al. Threshold of Pulmonary Hypertension Associated With Increased Mortality. J Am Coll Cardiol. 2019;73:2660–2672. [DOI] [PubMed] [Google Scholar]
- 30.Maeder MT, Weber L, Pohle S, Chronis J, Baty F, Rigger J, Brutsche M, Haager P, Rickli H, Brenner R. Impact of the 2022 pulmonary hypertension definition on haemodynamic classification and mortality in patients with aortic stenosis undergoing valve replacement. Eur Heart J Open. 2024;4:oeae037. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31.Smith H, Thompson AAR, Akil M, Alabed S, Charalampopoulos A, Dwivedi K, Elliot CA, Hameed A, Haque A, Hamilton N, et al. The spectrum of systemic sclerosis-associated pulmonary hypertension: Insights from the ASPIRE registry. J Heart Lung Transplant. 2024;43:1629–1639. [DOI] [PubMed] [Google Scholar]
- 32.Ibe T, Reddy YNV, Harada T, Doi S, Tada A, Naser JA, Demmer RT, Borlaug BA. Utility of HFpEF Diagnostic Scores to Stratify Cardiac Reserve Among Patients With Dyspnea. JACC Heart Fail. 2025;13:102526. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 33.Koepp KE, Reddy YNV, Obokata M, Sorimachi H, Verbrugge FH, Jain CC, Egbe AC, Redfield MM, Olson TP, Borlaug BA. Identification of Patients with Preclinical Heart Failure with preserved Ejection Fraction Using the H2FPEF Score. Nat Cardiovasc Res. 2022;1:59–66. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 34.Obokata M, Reddy YNV, Pislaru SV, Melenovsky V, Borlaug BA. Evidence Supporting the Existence of a Distinct Obese Phenotype of Heart Failure With Preserved Ejection Fraction. Circulation. 2017;136:6–19. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 35.Sorimachi H, Burkhoff D, Verbrugge FH, Omote K, Obokata M, Reddy YNV, Takahashi N, Sunagawa K, Borlaug BA. Obesity, venous capacitance, and venous compliance in heart failure with preserved ejection fraction. Eur J Heart Fail. 2021;23:1648–1658. [DOI] [PubMed] [Google Scholar]
- 36.Borlaug BA, Jensen MD, Kitzman DW, Lam CSP, Obokata M, Rider OJ. Obesity and heart failure with preserved ejection fraction: new insights and pathophysiological targets. Cardiovasc Res. 2023;118:3434–3450. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 37.Packer M, Zile MR, Kramer CM, Baum SJ, Litwin SE, Menon V, Ge J, Weerakkody GJ, Ou Y, Bunck MC, et al. Tirzepatide for Heart Failure with Preserved Ejection Fraction and Obesity. N Engl J Med. 2025;392:427–437. [DOI] [PubMed] [Google Scholar]
- 38.Butler J, Shah SJ, Petrie MC, Borlaug BA, Abildstrøm SZ, Davies MJ, Hovingh GK, Kitzman DW, Møller DV, Verma S, et al. Semaglutide versus placebo in people with obesity-related heart failure with preserved ejection fraction: a pooled analysis of the STEP-HFpEF and STEP-HFpEF DM randomised trials. Lancet. 2024;403:1635–1648. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 39.Nassif ME, Windsor SL, Borlaug BA, Kitzman DW, Shah SJ, Tang F, Khariton Y, Malik AO, Khumri T, Umpierrez G, et al. The SGLT2 inhibitor dapagliflozin in heart failure with preserved ejection fraction: a multicenter randomized trial. Nat Med. 2021;27:1954–1960. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 40.Solomon SD, McMurray JJV, Vaduganathan M, Claggett B, Jhund PS, Desai AS, Henderson AD, Lam CSP, Pitt B, Senni M, et al. Finerenone in Heart Failure with Mildly Reduced or Preserved Ejection Fraction. N Engl J Med. 2024;391:1475–1485. [DOI] [PubMed] [Google Scholar]
- 41.Anker SD, Butler J, Filippatos G, Ferreira JP, Bocchi E, Böhm M, Brunner-La Rocca H-P, Choi D-J, Chopra V, Chuquiure-Valenzuela E, et al. Empagliflozin in Heart Failure with a Preserved Ejection Fraction. N Engl J Med. 2021;385:1451–1461. [DOI] [PubMed] [Google Scholar]
- 42.Solomon SD, McMurray JJV, Claggett B, de Boer RA, DeMets D, Hernandez AF, Inzucchi SE, Kosiborod MN, Lam CSP, Martinez F, et al. Dapagliflozin in Heart Failure with Mildly Reduced or Preserved Ejection Fraction. N Engl J Med. 2022;387:1089–1098. [DOI] [PubMed] [Google Scholar]
- 43.Borlaug BA, Reddy YNV, Braun A, Sorimachi H, Omar M, Popovic D, Alogna A, Jensen MD, Carter R. Cardiac and Metabolic Effects of Dapagliflozin in Heart Failure With Preserved Ejection Fraction: The CAMEO-DAPA Trial. Circulation. 2023;148:834–844. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 44.Nassif ME, Qintar M, Windsor SL, Jermyn R, Shavelle DM, Tang F, Lamba S, Bhatt K, Brush J, Civitello A, et al. Empagliflozin Effects on Pulmonary Artery Pressure in Patients With Heart Failure: Results From the EMBRACE-HF Trial. Circulation. 2021;143:1673–1686. [DOI] [PubMed] [Google Scholar]
- 45.Reddy YNV, Anantha-Narayanan M, Obokata M, Koepp KE, Erwin P, Carter RE, Borlaug BA. Hemodynamic Effects of Weight Loss in Obesity: A Systematic Review and Meta-Analysis. JACC Heart Fail. 2019;7:678–687. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 46.Borlaug BA, Zile MR, Kramer CM, Baum SJ, Hurt K, Litwin SE, Murakami M, Ou Y, Upadhyay N, Packer M. Effects of tirzepatide on circulatory overload and end-organ damage in heart failure with preserved ejection fraction and obesity: a secondary analysis of the SUMMIT trial. Nat Med. 2025;31:544–551. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 47.Wernhart S, Goertz A, Hedderich J, Papathanasiou M, Hoffmann J, Rassaf T, Luedike P. Diastolic exercise stress testing in heart failure with preserved ejection fraction: The DEST-HF study. Eur J Heart Fail. 2023;25:1768–1780. [DOI] [PubMed] [Google Scholar]
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