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Abstract

Objective

Pulmonary hypertension is a heterogeneous syndrome with diverse underlying etiologies. This study aimed to evaluate the association between preoperative hemodynamic parameters—assessed by right heart catheterization (RHC) and transthoracic echocardiography (TTE)—and histopathological findings in explanted lungs from transplant recipients residing at high altitude.

Methods

We conducted a retrospective analysis of lung transplant recipients with interstitial lung disease (ILD) who had available RHC and TTE data prior to transplantation. Clinical, functional, hemodynamic, and histopathological variables were collected to assess the presence and severity of pulmonary vasculopathy. Bivariate analyses, correlation tests, and internally validated predictive models were performed to explore these associations.

Results

A total of 38 patients were included (median age: 54 years). The median mean pulmonary artery pressure (mPAP) was 33 mmHg, and the pulmonary artery systolic pressure (PASP) was 42 mmHg. An inverse correlation was observed between vasculopathy grade and the ratio of tricuspid annular plane systolic excursion to PASP (TAPSE/PASP) (r = −0.49, p = 0.007). Trends toward significance were found for percent predicted forced vital capacity (FVC%) (r = −0.30, p = 0.074) and catheter-derived PASP (r = 0.30, p = 0.070). A moderate positive correlation was noted between vasculopathy grade and echocardiographic mPAP (r = 0.41, p = 0.003). Among all parameters evaluated, the product of TAPSE and FVC% demonstrated the highest discriminative ability for vasculopathy (area under the receiver operating characteristic curve [AUC] = 0.790), followed by FVC% (AUC = 0.689) and TAPSE (AUC = 0.678).

Conclusions

Noninvasive measures—particularly the TAPSE/PASP ratio and composite indices incorporating FVC%—demonstrate moderate correlation with histopathological evidence of pulmonary vasculopathy in ILD patients living at high altitude. These findings highlight the potential utility of noninvasive tools in the preoperative evaluation of pulmonary vascular disease in this population.

Keywords

Pulmonary hypertension lung transplantation interstitial lung disease pulmonary vasculopathy echocardiography heart catheterization

Introduction

Pulmonary hypertension (PH) encompasses a spectrum of conditions defined by a resting mean pulmonary artery pressure (mPAP) > 20 mmHg, as measured by right heart catheterization (RHC), leading to increased cardiac afterload and progressive right ventricular (RV) dysfunction.^1,2 However, mPAP alone is insufficient to characterize the underlying pathophysiology, as elevated values may arise from diverse etiologies with distinct therapeutic approaches and prognoses.³ Pulmonary vascular resistance (PVR), frequently evaluated alongside mPAP, serves as an additional key hemodynamic parameter⁴; a PVR ≥2 Wood units (WU) is commonly used to identify precapillary PH and has been associated with worse outcomes across various clinical scenarios.^5,6 Clinically, PH is categorized into five groups, all unified by elevated pulmonary arterial pressures.^1,2

Although RHC remains the diagnostic gold standard for PH, its use is limited by the absence of universal procedural standardization and the risk of technical inaccuracies stemming from suboptimal equipment calibration and maintenance.⁷ Furthermore, its invasive nature renders it unsuitable for widespread screening.⁷ As a noninvasive alternative, transthoracic echocardiography (TTE) is recommended in all patients with suspected PH to estimate pulmonary artery systolic pressure (PASP), typically derived from the tricuspid regurgitation velocity.^3,8,9 A recent Cochrane review encompassing 17 diagnostic cohort studies reported an overall sensitivity and specificity of 87% and 86%, respectively, for Doppler echocardiography in adults with suspected PH.⁸ Nevertheless, the review highlighted substantial heterogeneity and methodological limitations, precluding the determination of consistent diagnostic thresholds.⁸

In lung transplant candidates, both RHC and TTE are pivotal for perioperative planning and prognostic assessment.^8–10 The presence of PH may influence transplant eligibility in patients with end-stage lung disease,¹⁰ and as such, RHC and TTE are routinely employed in many transplant centers.¹⁰ However, relying solely on mPAP to assess pulmonary vascular disease may be inadequate, as structural vascular changes can precede hemodynamic manifestations detectable by RHC or TTE.¹¹ Given the limitations of both echocardiography and catheter-based measurements in detecting pulmonary vasculopathy and the risks associated with lung biopsy in patients with chronic pulmonary conditions,^11,12 this study aims to compare preoperative hemodynamic parameters obtained by RHC and TTE with histopathological findings of pulmonary vasculopathy in explanted lungs from transplant recipients residing at 2600 m above sea level.

Methods

Study design and eligibility criteria

A diagnostic test study was conducted at Fundación Neumológica Colombiana and Fundación Cardioinfantil in Bogotá, Colombia. This retrospective study utilized digitized data from RHC and TTE performed in patients with interstitial lung disease (ILD) who underwent lung transplantation up to the year 2020. Patients were selected consecutively based on the availability of both RHC and TTE results. Inclusion criteria comprised patients over 18 years of age who underwent lung transplantation and had both RHC and TTE data available. Exclusion criteria included the inability to retrieve data and pregnancy.

The study included patients with PH treated at the Fundación Neumológica Colombiana in Bogotá, Colombia (located at an altitude of 2625 m above sea level) between 2014 and 2020. The study was conducted in accordance with the principles of the current Helsinki Declaration of 1975, as revised in 2024, as well as local, regional, and international regulations pertaining to clinical research, including Colombian Law on Biomedical Research. Ethical approval was obtained from the Medical Ethics Committee of the Fundación Neumológica Colombiana Ethics Committee (code: 253_16_marzo_2020). All personal data of patients have been deleted. This was a retrospective study, and informed consent was not required. The reporting of this study conforms to STROBE guidelines.¹³

Variables

Clinical history data were collected, including factors potentially influencing the development and severity of pulmonary vascular disease, such as the severity and duration of the underlying lung disease, oxygen therapy, medication use, and duration of residence at high altitudes. Lung function tests included forced expiratory volume in one second (FEV₁) and forced vital capacity (FVC). Additionally, the six-minute walk test (6MWT) and diffusing capacity of the lungs for carbon monoxide (DLCO) were performed. PH was defined by pretransplant RHC values, following the most recent hemodynamic definition and updated clinical classification established by the 6th World Symposium on Pulmonary Hypertension Task Force: precapillary PH was defined by mPAP > 20 mmHg, PVR ≥ 3 WU, and pulmonary artery wedge pressure (PAWP) ≤ 15 mmHg³.

Right heart catheterization

Right heart catheterization was performed using a femoral or jugular venous approach. Cardiac output (CO) and cardiac index were calculated by the Fick method and thermodilution. Pulmonary artery pressures—including mPAP, PASP, and pulmonary artery (PA) diastolic pressure along with PAWP, and RV and right atrial pressures—were recorded during breath-hold at baseline over at least three cardiac cycles. PVR was calculated using the formula PVR = (mPAP − PAWP)/CO, and the transpulmonary pressure gradient (TPG) was calculated as TPG = mPAP − PAWP. The RHC-derived hemodynamic variables analyzed included mPAP, PVR, PAWP, and TPG.

Echocardiography

Echocardiographic studies were performed on commercially available ultrasound systems in accordance with American Society of Echocardiography guidelines. Imaging was obtained in the left lateral decubitus position for parasternal and apical views, and in the supine position for the subxiphoid view, using 1.5–4.0 MHz phased-array transducers. Comprehensive studies included standard 2D echocardiography for anatomic evaluation and Doppler imaging to assess flow velocities. Doppler measurements were taken over three cardiac cycles during passive expiration. All studies were stored digitally in a Picture Archiving and Communication System and were available for offline analysis.

Noninvasive estimation of PASP was achieved by calculating RV systolic pressure and adding the estimated right atrial pressure. Right ventricular systolic pressure was derived using the peak tricuspid regurgitation velocity obtained by continuous wave Doppler and applying the modified Bernoulli equation: ΔP = 49Vmax². Right atrial pressure was estimated based on inferior vena cava diameter and its respiratory variability, as previously described.

Pulmonary artery systolic pressure was classified as normal (18–25 mmHg), mild (35–40 mmHg), moderate (40–60 mmHg), or severe (>60 mmHg). Additional echocardiographic variables included tricuspid annular plane systolic excursion (TAPSE), considered normal if ≥18 mm, and fractional area change, considered normal if ≥35%.⁹

Pathology

Two experienced pathologists in lung and pleural diseases reviewed the histopathological specimens. Tissue sections were assessed at 10× magnification. Pulmonary vasculature was graded according to the Heath and Edwards classification for hypertensive pulmonary vascular disease, which describes progressive structural changes^14,15 (Figure 1). All vessels present in each slide were examined; however, grading was applied only to pulmonary arterioles. Venules were assessed to exclude pulmonary veno-occlusive disease.

Figure 1.

Grades of vasculopathy in pulmonary arterial hypertension.

Histopathological evaluation of pulmonary vessels revealed a progressive spectrum of vascular remodeling consistent with the classification of pulmonary vascular disease. Grade 1 changes were characterized by medial hypertrophy, evidenced by thickening of the medial layer of the vessel walls (Masson's trichrome, 10×; Figure 1(a)). In Grade 2, intimal proliferation was observed, marked by increased cellularity within the intima of small muscular arteries (hematoxylin and eosin, 10×; Figure 1(b)). Grade 3 lesions demonstrated intimal fibrosis with concentric or eccentric deposition of fibrous tissue, associated with fibrous and fibroblastic reactions, ongoing cellular proliferation, and medial hypertrophy, sometimes with luminal dilation (hematoxylin and eosin, 10×; Figure 1(c)). Progressing to Grade 4, plexiform lesions were identified, featuring enlarged, irregular vascular channels and loss of elastic laminae, accompanied by widespread medial dilation (Masson's trichrome, 4×; Figure 1(d)). Grade 5 displayed angiomatoid lesions with pulmonary hemosiderosis and iron deposition, indicating advanced neovascularization, vascular architectural disruption, and microhemorrhages with iron accumulation in lung parenchyma (Masson's trichrome, 10×; Figure 1(e)). Finally, Grade 6 changes included all prior alterations along with necrotizing arteritis, represented by fibrinoid necrosis of the vascular wall, consistent with end-stage pulmonary vascular disease (hematoxylin and eosin, 10×; Figure 1(f)).

Statistical analysis

Data from the exercise tests and TTE were transcribed into an Excel spreadsheet and analyzed using SPSS version 25. Qualitative variables were summarized using frequencies and percentages. Quantitative variables were expressed as mean ± standard deviation (for normally distributed data) or median and interquartile range (for non-normally distributed data). Normality was assessed through distribution plots and the Shapiro–Wilk test; the central limit theorem was applied where appropriate.¹⁶

Bivariate analysis was conducted using the chi-square test for categorical variables and either Student's t-test or the Mann–Whitney U test for continuous variables, depending on data distribution. A p-value <0.05 was considered statistically significant.¹⁶

We evaluated the association between clinical, echocardiographic, functional, and hemodynamic parameters and the histopathological grade of pulmonary vasculopathy in patients undergoing lung transplantation. Given the non-normal distribution of vasculopathy grades, Spearman's rank correlation was applied for most variables, while Pearson's correlation was used when the assumption of normality was met.¹⁶ A Bland–Altman analysis was conducted to assess agreement between PASP measurements by TTE and RHC, including calculation of mean difference and 95% limits of agreement.¹⁶ To assess diagnostic accuracy in predicting histopathological vasculopathy, we performed receiver operating characteristic (ROC) curve analysis, dichotomizing vasculopathy grades based on clinically relevant cutoffs supported by existing literature.

An exploratory predictive model for histopathologically confirmed pulmonary vasculopathy was developed using binary logistic regression.¹⁶ The model incorporated both echocardiographic and catheterization variables that discriminated the presence or absence of vasculopathy. The model results were used to estimate the sample size required for future validation. Model fit was assessed using the Hosmer–Lemeshow test and the area under the ROC curve.¹⁶ Internal validation was performed using the bootstrap method.

Results

Thirty-eight patients and surgical specimens were analyzed. The median age was 54 years (IQR: 39–57) with a male-to-female ratio of 1:1 and a median body mass index of 23.5 (IQR: 21–26). The most frequent morbidities were hypothyroidism (16%; 6/38), systemic arterial hypertension (13%; 5/38), and gastroesophageal reflux (13%; 5/38). The main etiology of lung transplantation was ILD (55%; 21/38). The general characteristics of the population are described in Table 1.

Table 1.

General characteristics.

Number patients, n (%)	38 (100)
Age, years, m (IQR)	54 (39–57)
Female, n (%)	19 (50)
BMI kg/m², m (IQR)	23.5 (21–26)
Comorbidities, n (%)
Hypothyroidism	6 (16)
Type 2 diabetes	3 (8)
Arterial hypertension	5 (13)
Autoimmune diseases	4 (11)
Gastroesophageal reflux	5 (13)
Charlson Comorbidity Index, m (IQR)	1 (1–2)
mMRC dyspnea scale, m (IQR)	4 (3–4)
Transplant etiology, n (%)
interstitial lung disease	21 (55)
COPD	4 (10)
Lymphangioleiomyomatosis	4 (10)
Cystic fibrosis	3 (8)
Constrictive bronchiolitis	3 (8)
Sarcoidosis	1 (3)
Alveolar proteinosis	1 (3)
Silicosis	1 (3)

m: median; IQR: interquartile range; n: number; BMI: body mass index; mMRC: modified medical research council; COPD: chronic obstructive pulmonary disease.

Cardiac catheterization variables showed a median mPAP of 33 mmHg (IQR: 26–36) Table 2. Echocardiographic variables of the patients before transplantation showed a median PASP of 42 mmHg (IQR: 33–60) and a median TAPSE of 17.5 mm (IQR: 16–23). The median 6MWT was 442 m (IQR: 192–681). Lung function is described in Table 3. Vasculopathy of grades 1 (50%; 19/38) and 2 (47%; 18/38) was most common (Figure 2).

Figure 2.

Distribution of patients based on the grades of vasculopathy.

Table 2.

Right heart catheterization and echocardiogram variables.

Right heart catheterization variables
Pulmonary artery systolic pressure mmHg, m (IQR)	74 (34–108)
Mean pulmonary artery pressure mmHg, m (IQR)	33 (26–36)
Right ventricular cardiac output mmHg, m (IQR)	5.4 (4–6)
Right atrial pressure mmHg, m (IQR)	10 (7–13)
Pulmonary vascular resistance dynes/sec/cm⁵, m (IQR)	248.9 (205–353)
Pulmonary wedge pressure mmHg, m (IQR)	12.5 (9–17)
Echocardiogram variables
Left ventricular ejection fraction, m (IQR)	55 (54.25–60)
Pulmonary artery systolic pressure mmHg, m (IQR)	42 (33–60)
TAPSE mm, m (IQR)	17.5 (16–23)

m: median; IQR: interquartile range; mmHg: millimeters of mercury; TAPSE: tricuspid annular plane systolic excursion.

Table 3.

Lung function and physical activity.

FVC L, m (IQR)	2,17 (1–2.66)
FVC %, m (IQR)	56 (50–68)
FEV₁ L, m (IQR)	1.31 (0.9–1.89)
FEV₁%, m (IQR)	42 (27–56)
6MWT meters, m (IQR)	442 (391–519)
DLCO %, m (IQR)	12.7 (3–38)

m: median; IQR: interquartile range; FVC: forced vital capacity; VEF1: maximum expiratory volume in one second; 6MWT: 6-min walk test; DLCO: diffusing capacity of the lungs for carbon monoxide.

A Bland–Altman analysis was performed to assess the agreement between PASP measurements obtained by TTE and RHC (Figure 3). The mean difference between PASP measured by echocardiography and catheterization was 16.5 mmHg. The 95% limits of agreement ranged from −21.4 mmHg to 54.4 mmHg. The plot visually demonstrates a trend where the difference between measurements increases as the mean PASP increases.

Figure 3.

Bland–Altman plot of pulmonary artery systolic pressure agreement between echocardiography and catheterization.

Among the variables analyzed, a significant inverse correlation was observed between the histopathological grade of pulmonary vasculopathy and the TAPSE/PASP ratio measured by RHC (r = −0.49, 95% CI: −0.82 to −0.09, p = 0.007) (Table 4). Additionally, trends toward statistical significance were noted for FVC % predicted (r = −0.30, 95% CI: −0.61 to 0.01, p = 0.074) and PASP measured by RHC (r = 0.30, 95% CI: −0.08 to 0.56, p = 0.070). A moderate positive correlation was also found between vasculopathy grade and mPAP assessed by echocardiography (r = 0.41, 95% CI: 0.14 to 0.79, p = 0.003).

Table 4.

Correlation between vasculopathy grade and cardiopulmonary parameters.

	Spearman's rank correlation	95% CI (Lower–Upper)	p value
TAPSE/PASP ratio by RHC	−0.49	−0.82 to −0.09	0.007
TAPSE/PASP ratio by echocardiography	−0.42	−0.68 to 0.14	0.136
FVC, % predicted	−0.30	−0.61 to 0.01	0.074
DLCO, % predicted	−0.08	−0.34 to 0.27	0.618
PASP by RHC	0.30	−0.08 to 0.56	0.070
mPAP by RHC	0.25	−0.01 to 0.47	0.132
PASP by echocardiography	−0.07	−0.43 to 0.33	0.788
mPAP by echocardiography	0.41	0.14 to 0.79	0.003

TAPSE: tricuspid annular plane systolic excursion; PASP: pulmonary artery systolic pressure; FVC: forced vital capacity; DLCO: diffusing capacity of the lung for carbon monoxide; RHC: right heart catheterization; mPAP: mean pulmonary artery pressure.

Receiver operating characteristic curve for predicting histopathological vasculopathy was 0.678 (95% CI: 0.476–0.841; p = 0.125) for TAPSE, 0.790 (95% CI: 0.591–0.922; p = 0.002) for TAPSE × FVC%, 0.689 (95% CI: 0.516–0.830; p = 0.043) for FVC% and 0.525 (95% CI: 0.353–0.694; p = 0.808) for 6MWD (Figure 4).

Figure 4.

Receiver operating characteristic curves for predicting histopathological vasculopathy.

Discussion

This study examined the relationship between noninvasive clinical variables and histopathological evidence of pulmonary arterial vasculopathy in patients with end-stage lung disease undergoing lung transplantation. The analysis of correlation coefficients and p-values provided a clear summary of the data, highlighting TAPSE-based indices, FVC%, and PASP as the most promising noninvasive predictors of pulmonary vasculopathy. Our findings suggest that specific echocardiographic and functional parameters may serve as valuable indicators of underlying pulmonary vascular remodeling, offering potential utility for early risk stratification and timely referral for RHC or transplant evaluation.

All patients in this cohort had PH classified as Group 3, which is primarily driven by chronic hypoxic vasoconstriction and structural changes in the pulmonary vasculature—most notably medial hypertrophy and intimal proliferation. These changes lead to increased PVR and loss of functional vascular bed. This pathophysiological mechanism distinguishes Group 3 PH from Group 1 PH, which typically presents with plexiform lesions and angioproliferative remodeling.¹⁰ Notably, none of the patients in our study exhibited plexiform lesions.

It is important to note that the histopathological grading used in our study does not aim to provide a direct quantification of PVR, but rather serves as a semiquantitative descriptor of the structural changes observed in the pulmonary vasculature of explanted lungs.^17–19 In contrast to congenital heart disease–associated PH, where histopathology has been used to assess the progression and potential reversibility of vascular lesions, the pathophysiology in ILD is more complex and multifactorial.^18,19 In ILD, PVR elevation may result from several interrelated mechanisms, including interstitial fibrosis compressing the vasculature, obliteration of the capillary bed, hypoxic vasoconstriction, and advanced remodeling of all layers of the vascular wall.^17,20 Our findings suggest that histological features such as intimal thickening and medial hypertrophy should be interpreted in this broader context, and not as isolated determinants of hemodynamic severity. We acknowledge these limitations and have adjusted our interpretation accordingly.

The interpretation of PVR in ILD must consider the impact of reduced lung volumes on pulmonary hemodynamics. In restrictive lung diseases, decreased lung volumes can elevate PVR due to mechanical distortion and compression of the pulmonary vasculature, loss of vascular bed, and altered pulmonary mechanics.^{18,19,21–23} Several studies have demonstrated that PVR is influenced not only by intrinsic vascular remodeling but also by extrinsic factors such as lung inflation and parenchymal architecture.^18,21–23 In our cohort, despite preserved cardiac output, reduced lung volumes likely contributed to increased PVR, reinforcing the multifactorial nature of PH in ILD.^18,19,23 These factors highlight the importance of interpreting PVR values within the broader physiological and structural context of lung restriction.

Tricuspid annular plane systolic excursion is widely accepted as a marker of RV ejection performance and has been associated with clinical outcomes in various settings.^24–28 A key finding was the moderate, statistically significant inverse correlation between the TAPSE/PASP ratio measured by RHC and histopathologic vasculopathy grade (r = −0.49, p = 0.007), reinforcing its role as a marker of RV–PA coupling and disease severity. This is consistent with prior studies demonstrating the prognostic utility of this ratio in PH and fibrotic lung disease, where it reflects the progressive uncoupling of RV function from vascular load as remodeling advances.^24–30 This underscores the importance of derived indices such as TAPSE/PASP, which offer a more integrated assessment of right heart function under vascular load.^26–30

The TAPSE/PASP ratio demonstrated a significant inverse correlation with the degree of pulmonary vascular disease; this finding may be explained by the fact that the ratio incorporates both RV systolic function and pulmonary arterial afterload, thereby serving as a surrogate marker of ventriculo-arterial coupling.^24–30 A lower TAPSE/PASP ratio indicates impaired coupling, which aligns with more advanced stages of vascular pathology.^24–30 In contrast, TAPSE alone may not fully capture the interplay between RV contractility and elevated PVR, particularly in the early or moderate phases of disease progression.^24–30

The Bland–Altman analysis revealed a systematic overestimation of PASP by TTE compared to RHC, with a mean difference of 16.5 mmHg. The wide 95% limits of agreement (−21.4 to 54.4 mmHg), coupled with this positive bias, suggest considerable variability and a lack of strong agreement between the two methods for individual PASP measurements in this cohort. Furthermore, the observed trend where the difference between measurements increases with higher mean PASP indicates that the agreement between TTE and RHC diminishes at higher pressure values, limiting the interchangeability of these measurements, particularly in patients with more elevated pulmonary pressures.³¹

Regarding pulmonary function, FVC% was inversely associated with echocardiographic PASP (r = −0.58, p = 0.0175), supporting the notion that reduced lung volumes—reflective of fibrotic burden—are paralleled by elevations in PVR.^17–22 Moreover, both FVC% and invasively measured PASP showed trends toward significance with vasculopathy grade, suggesting a pathophysiologic continuum wherein parenchymal and vascular remodeling cooccur.

Dotan et al. in patients with end-stage ILD undergoing lung transplantation found significant pulmonary vasculopathy that did not correlate with clinical severity or catheterization-based PH measurements.¹¹ While echocardiographic data were not included, that study similarly highlighted a lack of correlation between hemodynamic and histologic findings, as well as between vasculopathy and lung function.^11,17

Diffusing capacity of the lungs for carbon monoxide (% predicted) did not correlate significantly with vasculopathy grade in our cohort, likely reflecting its lower specificity in the setting of coexisting fibrosis and its susceptibility to confounding factors such as anemia and emphysema.^27–29 Although DLCO is a recognized diagnostic and prognostic marker in PH, its reductions are nonspecific. Still, DLCO values below 40% have been strongly associated with PH, demonstrating high sensitivity and specificity.²⁷

From a diagnostic standpoint, the composite variable TAPSE × FVC% showed the highest accuracy for identifying moderate-to-severe vasculopathy (AUC 0.790, p = 0.002), outperforming individual parameters such as TAPSE (AUC 0.678) and FVC% (AUC 0.689). A threshold of ≤918 for TAPSE × FVC% yielded high specificity (88.9%) but moderate sensitivity (50%), indicating potential value as a screening tool in identifying advanced disease. These findings support the growing emphasis on integrated, multivariable approaches to risk assessment in PH associated with ILD, rather than relying on isolated metrics.^17–23

This perspective aligns with recent studies advocating for combined physiologic markers. Xiong et al. demonstrated that the FVC/DLCO ratio, DLCO, and FEV1/FVC were predictive of disease progression in Group 1 PH associated with connective tissue disease.³² Similarly, Donato et al. found that an elevated FVC/DLCO ratio predicted worse outcomes and correlated with mPAP in systemic sclerosis–associated PH.³⁰ The Ford model by Natan et al. combined four variables—including FVC%/DLCO%, oxygen desaturation during 6MWT, race, and walking distance—yielding strong predictive accuracy and practical clinical application.²⁹

An important contextual factor in our study is the high-altitude setting (2640 m above sea level), which may significantly affect pulmonary vascular physiology. Chronic exposure to hypobaric hypoxia can cause persistent pulmonary vasoconstriction, elevated pulmonary pressures, and vascular remodeling—even in the absence of lung disease.^33–36 In patients with ILD, this environmental stressor may exacerbate or accelerate PH progression. The moderate vasculopathy observed in our cohort could reflect both fibrotic disease and altitude-related hypoxia.^17,18,35,36 Furthermore, the interpretation of TAPSE, PASP, and related indices at high altitude may require altitude-specific reference values. These findings underscore the importance of considering geographic and environmental context when evaluating PH risk and designing risk prediction models for high-altitude populations.

An intriguing finding in our study is that, despite chronic hypoxic exposure at high altitude, the severity of PH in our ILD cohort was generally mild to moderate.^35,36 This observation suggests that hypoxia alone may not be the primary driver of pulmonary vascular disease in this population. Several hypotheses may explain this phenomenon. First, individuals residing at high altitude may undergo long-term vascular and hematologic adaptation, which could mitigate the vasoconstrictive response to hypoxia.^35,36 Second, structural parenchymal changes and vascular remodeling inherent to ILD may play a more prominent role in elevating PVR than environmental hypoxia.^{17–19,35,36} Recent studies have also shown that the prevalence and severity of PH at altitude can vary depending on the underlying disease mechanism, further supporting a multifactorial etiology.³⁶ These findings highlight the complexity of PH pathophysiology in ILD and underscore the need for further investigation into how chronic hypoxia interacts with fibrotic and vascular processes in this setting.^33–36

Limitations

This study is limited by its retrospective design and relatively small sample size, particularly in subanalyses involving echocardiographic or invasive hemodynamic data. Although histopathologic grading was performed using a consensus-based classification, interobserver variability remains a potential limitation. To mitigate this, pathology review was conducted independently and in a blinded fashion. Additionally, while the cohort is representative of real-world transplant candidates, the generalizability to earlier disease stages is limited.

One of the key limitations of our analysis is the interpretation of RV–PA coupling as a surrogate for pulmonary vascular obstruction.^17,22,36 While RV–PA coupling provides valuable insight into RV function and adaptation to increased afterload, it cannot reliably quantify the extent of pulmonary vascular disease.^17,22,36 This is due to the inherently variable response of the right ventricle to elevated PVR, which is influenced by myocardial reserve, comorbidities, and disease duration. Therefore, although TAPSE/PASP and other coupling indices may reflect the likelihood of PH and RV strain, they should not be interpreted as direct markers of vascular obstruction.^17,22,36 Our findings must be viewed within this physiological context, and we emphasize the need for caution when extrapolating RV–PA coupling measurements as indicators of disease severity in ILD.^20–23

Despite these limitations, the study has several strengths. It is only the second to evaluate the relationship between histopathologic vasculopathy and clinical parameters in lung transplant recipients, and the first to do so in a high-altitude population. Notably, this is the first study to assess the predictive value of echocardiographic and spirometric parameters—specifically TAPSE, TAPSE/PASP, and TAPSE × FVC%—as noninvasive markers of pulmonary vascular disease in this context.

Conclusions

Noninvasive parameters—particularly the TAPSE/PASP ratio and composite indices incorporating FVC%—demonstrate moderate correlations with histopathologic pulmonary vasculopathy in patients with ILD. These markers may support early identification of high-risk individuals, enabling timely referral and intervention. Further prospective studies are warranted to validate these tools and integrate them into clinical risk stratification frameworks for PH associated with ILD.

Footnotes

Acknowledgments

The authors are most thankful for the Universidad de La Sabana and Fundación Neumológica Colombiana.

ORCID iDs

Rafael Conde-Camacho

Eduardo Tuta-Quintero

Fabio Varón-Vega

Jacqueline Mugnier

Libardo Marmolejo

Diego Severiche

Luis F Giraldo-Cadavid

Ethics approval statement

The study was conducted in accordance with the principles of the current Helsinki Declaration of 1975, as revised in 2024, as well as local, regional, and international regulations pertaining to clinical research, including Colombian Law on Biomedical Research. Ethical approval was obtained from the Medical Ethics Committee of the Fundación Neumológica Colombiana Ethics Committee (code: 253_16_marzo_2020). All personal data of patients have been deleted. This was a retrospective study, and informed consent was not required.

Author contributions

RCC, ETQ, FVV, JM, LM, DS, and LFGC contributed to the conception and design. They also supervised the whole process, data collection, analysis, and interpretation of the patient data. ETQ and LFGC wrote major parts of the manuscript, and RCC revised it. All authors read and approved of the final manuscript.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by Fundación Cardioinfantil – Instituto de Cardiología, Fundación Neumológica Colombiana, and Universidad de La Sabana (Grant: MEDPHD-30-2024).

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Authors’ note

Data availability statement: The data that support the findings of this study are available from the corresponding author upon reasonable request. AI tools: No AI tools were used.

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Association of hemodynamic and functional variables with pulmonary vasculopathy in lung transplant recipients living at high altitude: A retrospective study

Abstract

Objective

Methods

Results

Conclusions

Keywords

Introduction

Methods

Study design and eligibility criteria

Variables

Right heart catheterization

Echocardiography

Pathology

Statistical analysis

Results

Discussion

Limitations

Conclusions

Footnotes

Acknowledgments

ORCID iDs

Ethics approval statement

Author contributions

Funding

Declaration of conflicting interests

Authors’ note

References