The prognostic relevance of exercise pulmonary hypertension in cardiac and pulmonary diseases.

PURPOSE OF REVIEW: In this review, we provide an overview of the prognostic implications of exPH in patients with various common cardiac and pulmonary diseases. RECENT FINDINGS: Exercise pulmonary hypertension (exPH) has been recently re-introduced in the current European Society of Cardiology/European Respiratory Society pulmonary hypertension guidelines. Accordingly, exPH is defined as a mean pulmonary arterial pressure (mPAP)/cardiac output (CO) slope greater than 3 mmHg/l/min. Key considerations for this re-introduction included increasing understanding on normal pulmonary hemodynamics during exercise and the broadly available evidence on the association of an abnormal mPAP/CO slope with poor survival in the general population and in different disease entities. SUMMARY: Exercise (patho-)physiology has opened a new field for clinical research facilitating recognition of cardiovascular and pulmonary vascular diseases in an early stage. Such early recognition with significant prognostic and possibly therapeutic relevance, but being undetectable at rest, makes exercise pulmonary hemodynamics particularly interesting for common diseases, such as valvular heart disease, left heart disease, and chronic pulmonary disease.

Elevated Pulmonary Arterial Compliance Is Associated with Survival in Pulmonary Hypertension: Results from a Novel Network Medicine Analysis.

Rationale: Predictors of adverse outcome in pulmonary hypertension (PH) are well established; however, data that inform survival are lacking. Objectives: We aim to identify clinical markers and therapeutic targets that inform the survival in PH. Methods: We included data from patients with elevated mean pulmonary artery pressure (mPAP) diagnosed by right heart catheterization in the U.S. Veterans Affairs system (October 1, 2006-September 30, 2018). Network medicine framework was used to subgroup patients when considering an N of 79 variables per patient. The results informed outcome analyses in the discovery cohort and a sex-balanced validation right heart catheterization cohort from Vanderbilt University (September 24, 1998-December 20, 2013). Measurements and Main Results: From an N of 4,737 complete case patients with mPAP of 19-24 mm Hg, there were 21 distinct subgroups (network modules) (all-cause mortality range = 15.9-61.2% per module). Pulmonary arterial compliance (PAC) drove patient assignment to modules characterized by increased survival. When modeled continuously in patients with mPAP ⩾19 mm Hg (N = 37,744; age, 67.2 yr [range = 61.7-73.8 yr]; 96.7% male; median follow-up time, 1,236 d [range = 570-1,971 d]), the adjusted all-cause mortality hazard ratio was <1.0 beginning at PAC ⩾3.0 ml/mm Hg and decreased progressively to ∼7 ml/mm Hg. A protective association between PAC ⩾3.0 ml/mm Hg and mortality was also observed in the validation cohort (N = 1,514; age, 60.2 yr [range = 49.2-69.1 yr]; 48.0% male; median follow-up time, 2,485 d [range = 671-3,580 d]). The association was strongest in patients with precapillary PH at the time of catheterization, in whom 41% (95% confidence interval, 0.55-0.62; P < 0.001) and 49% (95% confidence interval, 0.38-0.69; P < 0.001) improvements in survival were observed for PAC ⩾3.0 versus <3.0 ml/mm Hg in the discovery and validation cohorts, respectively. Conclusions: These data identify elevated PAC as an important parameter associated with survival in PH. Prospective studies are warranted that consider PAC ⩾3.0 ml/mm Hg as a therapeutic target to achieve through proven interventions.

[Pulmonary hypertension associated with lung disease]. / Pulmonale Hypertonie assoziiert mit Lungenerkrankungen.

Lung diseases and hypoventilation syndromes are often associated with pulmonary hypertension (PH). In most cases, PH is not severe. This is defined hemodynamically by a mean pulmonary arterial pressure (PAPm) > 20 mmHg, a pulmonary arterial wedge pressure (PAWP) ≤ 15 mmHg and a pulmonary vascular resistance of ≤ 5 Wood units (WU). Both the non-severe (PVR ≤ 5 WU) and much more the severe PH (PVR > 5 WU) have an unfavorable prognosis.If PH is suspected, it is recommended to primarily check whether risk factors for pulmonary arterial hypertension (PAH, group 1 PH) or chronic thromboembolic pulmonary hypertension (CTEPH, group 4 PH) are present. If risk factors are present or there is a suspicion of severe PH in lung patients, it is recommended that the patient should be presented to a PH outpatient clinic promptly.For patients with severe PH associated with lung diseases, personalized, individual therapy is recommended - if possible within the framework of therapy studies. Currently, a therapy attempt with PH specific drugs should only be considered in COPD patients if the associated PH is severe and a "pulmonary vascular" phenotype (severe precapillary PH, but typically only mild to moderate airway obstruction, no or mild hypercapnia and DLCO < 45 % of predicted value) is present. In patients with severe PH associated with interstitial lung disease phosphodiesterase-5-inhibitors may be considered in individual cases. Inhaled treprostinil may be considered also in non-severe PH in this patient population.

Diagnostic, prognostic and differential-diagnostic relevance of pulmonary haemodynamic parameters during exercise: a systematic review.

BACKGROUND: The cardiopulmonary haemodynamic profile observed during exercise may identify patients with early-stage pulmonary vascular and primary cardiac diseases, and is used clinically to inform prognosis. However, a standardised approach to interpreting haemodynamic parameters is lacking. METHODS: We performed a systematic literature search according to PRISMA guidelines to identify parameters that may be diagnostic for an abnormal haemodynamic response to exercise and offer optimal prognostic and differential-diagnostic value. We performed random-effects meta-analyses of the normal values and report effect sizes as weighted mean±sd. Results of diagnostic and prognostic studies are reported descriptively. RESULTS: We identified 45 eligible studies with a total of 5598 subjects. The mean pulmonary arterial pressure (mPAP)/cardiac output (CO) slope, pulmonary arterial wedge pressure (PAWP)/CO slope and peak cardiac index (or CO) provided the most consistent prognostic haemodynamic parameters during exercise. The best cut-offs for survival and cardiovascular events were a mPAP/CO slope >3 Wood units (WU) and PAWP/CO slope >2 WU. A PAWP/CO slope cut-off >2 WU best differentiated pre- from post-capillary causes of PAP elevation during exercise. Upper limits of normal (defined as mean+2sd) for the mPAP/CO and PAWP/CO slopes were strongly age-dependent and ranged in 30-70-year-old healthy subjects from 1.6 to 3.3 WU and 0.6 to 1.8 WU, respectively. CONCLUSION: An increased mPAP/CO slope during exercise is associated with impaired survival and an independent, prognostically relevant cut-off >3 WU has been validated. A PAWP/CO slope >2 WU may be suitable for the differentiation between pre- and post-capillary causes of PAP increase during exercise.

Abnormal pulmonary hemodynamics during exercise is associated with exercise capacity in COPD.

BACKGROUND: Pulmonary hypertension (PH) is a frequent complication in COPD and it is associated with decreased exercise capacity and poor prognosis. We hypothesized that even in COPD patients without significant PH at rest, abnormal pulmonary hemodynamics during exercise affect exercise capacity. METHODS: Consecutive COPD patients with clinically indicated right heart catheterization and resting mean pulmonary arterial pressure (mPAP) < 25 mmHg and age- and sex-matched controls with the same limits of pulmonary hemodynamics but no chronic lung disease who underwent clinical work-up including invasive hemodynamic assessment during exercise, were retrospectively analyzed. Chi-square tests were used to evaluate differences between groups for categorical data and Fisher's exact test or Mann-Whitney-U-tests for continuous variables. Associations were analyzed with Spearman rank correlation tests. RESULTS: We included n = 26 COPD patients (female/male: 16/10, 66 ± 11 yr, FEV1: 56 ± 25%predicted) and n = 26 matched controls (FEV1: 96 ± 22%predicted). At rest, COPD patients presented with slightly increased mPAP (21 (18-23) vs. 17 (14-20) mmHg, p = 0.022), and pulmonary vascular resistance (PVR) [2.5 (1.9-3.0) vs. 1.9 (1.5-2.4) WU, p = 0.020] as compared to controls. During exercise, COPD patients reached significantly higher mPAP [47 (40-52) vs. 38 (32-44) mmHg, p = 0.015] and PVR [3.1 (2.2-3.7) vs. 1.7 (1.1-2.9) WU, p = 0.028] values despite lower peak exercise level [50 (50-75) vs. 100 (75-125) Watt, p = 0.002]. The mPAP/cardiac output slope was increased in COPD vs. controls [6.9 (5.5-10.9) vs. 3.7 (2.4-7.4) mmHg/L/min, p = 0.007] and negatively correlated with both peak oxygen uptake (r = - 0.46, p = 0.007) and 6-min walk distance (r = - 0.46, p = 0.001). CONCLUSION: Even in the absence of significant PH at rest, COPD patients reveal characteristic abnormalities in pulmonary hemodynamics during exercise, which may represent an important exercise-limiting factor.

Volatile Organic Compounds, Bacterial Airway Microbiome, Spirometry and Exercise Performance of Patients after Surgical Repair of Congenital Diaphragmatic Hernia.

The aim of this study was to analyze the exhaled volatile organic compounds (VOCs) profile, airway microbiome, lung function and exercise performance in congenital diaphragmatic hernia (CDH) patients compared to healthy age and sex-matched controls. A total of nine patients (median age 9 years, range 6-13 years) treated for CDH were included. Exhaled VOCs were measured by GC-MS. Airway microbiome was determined from deep induced sputum by 16S rRNA gene sequencing. Patients underwent conventional spirometry and exhausting bicycle spiroergometry. The exhaled VOC profile showed significantly higher levels of cyclohexane and significantly lower levels of acetone and 2-methylbutane in CDH patients. Microbiome analysis revealed no significant differences for alpha-diversity, beta-diversity and LefSe analysis. CDH patients had significantly lower relative abundances of Pasteurellales and Pasteurellaceae. CDH patients exhibited a significantly reduced Tiffeneau Index. Spiroergometry showed no significant differences. This is the first study to report the VOCs profile and airway microbiome in patients with CDH. Elevations of cyclohexane observed in the CDH group have also been reported in cases of lung cancer and pneumonia. CDH patients had no signs of impaired physical performance capacity, fueling controversial reports in the literature.

The Management of Mild Pulmonary Hypertension in Clinical Practice.

The definition of pulmonary hypertension (PH) has been revised recently by lowering the mean pulmonary artery pressure (mPAP) threshold from ≥25 mmHg to >20mmHg, assessed by right heart catheterization (RHC). This change reflects the mPAP upper limit of normal and lower limit that is independently associated with adverse outcome. To improve the specificity of diagnosing pathogenic elevation in mPAP, however, classifying patients with precapillary PH now also includes pulmonary vascular resistance (PVR) >2.0WU (from >3.0WU). These changes are positioned to capture ~55% more patients with PH. Since all clinical trials showing benefit of pulmonary vasodilator therapy in precapillary PH used the classical hemodynamic definition, the approach to diagnosis and management of patients with mild PH (i.e., mPAP 21-24mmHg and PVR 2-3WU) requires particular consideration. Here, we use a question- answer format to discuss key areas in the management of mild PH, including practical information catered to clinicians without training in PH.

Pulmonary hypertension and chronic kidney disease: prevalence, pathophysiology and outcomes.

Pulmonary hypertension (PH) is common in patients with chronic kidney disease (CKD) or kidney failure, with an estimated prevalence of up to 78% in those referred for right-heart catheterization. PH is independently associated with adverse outcomes in CKD, raising the possibility that early detection and appropriate management of PH might improve outcomes in at-risk patients. Among patients with PH, the prevalence of CKD stages 3 and 4 is estimated to be as high as 36%, and CKD is also independently associated with adverse outcomes. However, the complex, heterogenous pathophysiology and clinical profile of CKD-PH requires further characterization. CKD is often associated with elevated left ventricular filling pressure and volume overload, which presumably leads to pulmonary vascular stiffening and post-capillary PH. By contrast, a distinct subgroup of patients at high risk is characterized by elevated pulmonary vascular resistance and right ventricular dysfunction in the absence of pulmonary venous hypertension, which may represent a right-sided cardiorenal syndrome defined in principle by hypervolaemia, salt avidity, low cardiac output and normal left ventricular function. Current understanding of CKD-PH is limited, despite its potentially important ramifications for clinical decision making. In particular, whether PH should be considered when determining the suitability and timing of kidney replacement therapy or kidney transplantation is unclear. More research is urgently needed to address these knowledge gaps and improve the outcomes of patients with or at risk of CKD-PH.

Association of Cardiopulmonary Hemodynamics and Mortality in Veterans With Liver Cirrhosis: A Retrospective Cohort Study.

BACKGROUND: Portopulmonary hypertension (PoPH), associated with increased mortality, can limit treatment options for liver diseases. Data on the continuum of clinical risk related to cardiopulmonary hemodynamics in PoPH are lacking. METHODS AND RESULTS: As part of the United States national Veterans Affairs Clinical Assessment, Reporting, and Tracking database, we performed a retrospective cohort study of adults with cirrhosis undergoing right heart catheterization between October 1, 2017, and September 30, 2022. Pulmonary hypertension (mean pulmonary arterial pressure [mPAP] >20 mm Hg without PoPH) and PoPH (mPAP >20 mm Hg+pulmonary artery wedge pressure ≤15 mm Hg+pulmonary vascular resistance ≥3 WU) were defined by right heart catheterization hemodynamics. Multivariable Cox proportional hazards using natural splines for hemodynamic variables were used to evaluate the association between cardiopulmonary hemodynamics and mortality following right heart catheterization. A total of 4409 patients were included in the final analysis, predominantly men (96.3%), with a mean age of 68.5 years. Pulmonary hypertension and PoPH were observed in 71.6% and 10.2% of the cohort, respectively. Compared with a reference cardiac index of 2.5 L/min per m2, the hazard for mortality increased progressively with decreasing cardiac index, even after adjustment for mPAP and pulmonary vascular resistance. The minority of patients with PoPH (N=65, 14.5%) were prescribed pulmonary vasodilator therapy. CONCLUSIONS: These data suggest that pulmonary hypertension and PoPH are prevalent in veterans with chronic liver disease, but low use of targeted PoPH therapy persists. Cardiac function discriminated mortality risk across a wide range of mPAP and pulmonary vascular resistance values and may diagnose and clarify prognosis in this patient population.

Cluster analysis identifies novel real-world lung disease-pulmonary hypertension subphenotypes: implications for treatment response.

Background: Clinical trials repurposing pulmonary arterial hypertension (PAH) therapies to patients with lung disease- or hypoxia-pulmonary hypertension (PH) (classified as World Health Organization Group 3 PH) have failed to show a consistent benefit. However, Group 3 PH clinical heterogeneity suggests robust phenotyping may inform detection of treatment-responsive subgroups. We hypothesised that cluster analysis would identify subphenotypes with differential responses to oral PAH therapy. Methods: Two k-means analyses were performed on a national cohort of US veterans with Group 3 PH; an inclusive model (I) of all treated patients (n=196) and a haemodynamic model (H) limited to patients with right heart catheterisations (n=112). The primary outcome was organ failure or all-cause mortality by cluster. An exploratory analysis evaluated within-cluster treatment effects. Results: Three distinct clusters of Group 3 PH patients were identified. In the inclusive model (C1I n=43, 21.9%; C2I n=102, 52.0%; C3I n=51, 26.0%), lung disease and spirometry drove cluster assignment. By contrast, in the haemodynamic model (C1H n=44, 39.3%; C2H n=43, 38.4%; C3H n=25, 22.3%), right heart catheterisation data surpassed the importance of lung disease and spirometry. In the haemodynamic model, compared to C3H, C1H experienced the greatest hazard for respiratory failure or death (HR 6.1, 95% CI 3.2-11.8). In an exploratory analysis, cluster determined treatment response (p=0.006). Conclusions regarding within-cluster treatment responses were limited by significant differences between select variables in the treated and untreated groups. Conclusions: Cluster analysis identifies novel real-world subphenotypes of Group 3 PH patients with distinct clinical trajectories. Future studies may consider this methodological approach to identify subgroups of heterogeneous patients that may be responsive to existing pulmonary vasodilatory therapies.

Compartment-specific remodeling patterns in end-stage chronic obstructive pulmonary disease with and without severe pulmonary hypertension.

BACKGROUND: In patients with end-stage chronic obstructive pulmonary disease (COPD), severe pulmonary hypertension (PH) is frequently associated with less severe airway obstruction as compared to mild or no PH. However, the histologic correlate of this finding is not clear. We aimed to quantify remodeling of pulmonary arteries, airways, and parenchyma in random samples of explanted end-stage COPD lungs. METHODS: We quantified remodeling of small pulmonary arteries, small airways, and the degree of emphysema (mean interseptal distance [MID]) with dedicated software. As primary objective, we compared COPD patients with severe PH (SevPH-COPD) with age- and sex-matched MildPH-COPD. For comparison, we also investigated COPD lungs with no PH (NoPH-COPD), idiopathic PAH (IPAH), and healthy donors. RESULTS: We included n = 17 SevPH-COPD (mPAP = 43 [39-45]mm Hg), n = 17 MildPH-COPD (mPAP = 28 [24-31]mm Hg), n = 5 NoPH-COPD (mPAP = 18 [16-19]mm Hg), n = 10 IPAH (mPAP = 72 [65-91]mm Hg), and n = 10 healthy donor lungs. SevPH-COPD versus MildPH-COPD was characterized by better preserved forced vital capacity (51% vs 40% predicted, p < 0.05), less emphysema (MID 169 µm vs 279 µm, p < 0.001), and less PAS-positive and CD45-positive mucosa cells (15% vs 22%, p = 0.063% and 5% vs 7%, p = 0.058) suggesting less airway inflammation. In COPD patients, intimal and medial thickening were strongly correlated with mPAP (r = 0.676, p < 0.001 and r = 0.595, p < 0.001). MID was negatively correlated with mPAP (r = -0.556, p < 0.001) and was highest in NoPH-COPD (mean 281 µm), suggesting that emphysema per se is not associated with PH. CONCLUSIONS: End-stage COPD with severe PH is characterized by pronounced pulmonary vascular remodeling, less inflammation of small airways, and less emphysema as compared to COPD with mild PH or no PH, suggesting that COPD with severe PH may represent a unique phenotype of COPD.

Pulmonary vascular fibrosis in pulmonary hypertension - The role of the extracellular matrix as a therapeutic target.

Pulmonary hypertension (PH) is a condition characterized by changes in extracellular matrix (ECM) deposition and vascular remodeling of distal pulmonary arteries. These changes result in increased vessel wall thickness and lumen occlusion, leading to a loss of elasticity and vessel stiffening. Clinically, the mechanobiology of the pulmonary vasculature is becoming increasingly recognized for its prognostic and diagnostic value in PH. Specifically, increased vascular fibrosis and stiffening resulting from ECM accumulation and crosslinking may be a promising target for the development of anti- or reverse-remodeling therapies. Indeed, there is a huge potential in therapeutic interference with mechano-associated pathways in vascular fibrosis and stiffening. The most direct approach is aiming to restore extracellular matrix homeostasis, by interference with its production, deposition, modification and turnover. Besides structural cells, immune cells contribute to the level of ECM maturation and degradation by direct cell-cell contact or the release of mediators and proteases, thereby opening a huge avenue to target vascular fibrosis via immunomodulation approaches. Indirectly, intracellular pathways associated with altered mechanobiology, ECM production, and fibrosis, offer a third option for therapeutic intervention. In PH, a vicious cycle of persistent activation of mechanosensing pathways such as YAP/TAZ initiates and perpetuates vascular stiffening, and is linked to key pathways disturbed in PH, such as TGF-ß/BMPR2/STAT. Together, this complexity of the regulation of vascular fibrosis and stiffening in PH allows the exploration of numerous potential therapeutic interventions. This review discusses connections and turning points of several of these interventions in detail.

Updated definition of exercise pulmonary hypertension.

In the recently published European Society of Cardiology/European Respiratory Society guidelines on the diagnosis and treatment of pulmonary hypertension (PH) the haemodynamic definitions of PH were updated and a new definition for exercise PH was introduced. Accordingly, exercise PH is characterised by a mean pulmonary arterial pressure/cardiac output (CO) slope >3 Wood units (WU) from rest to exercise. This threshold is supported by several studies demonstrating prognostic and diagnostic relevance of exercise haemodynamics in various patient cohorts. From a differential diagnostic point of view, an elevated pulmonary arterial wedge pressure/CO slope >2 WU may be suitable to identify post-capillary causes of exercise PH. Right heart catheterisation remains the gold standard to assess pulmonary haemodynamics both at rest and exercise. In this review, we discuss the evidence that led to the reintroduction of exercise PH in the PH definitions.

Severe Pulmonary Hypertension in COPD: Impact on Survival and Diagnostic Approach.

BACKGROUND: Severe pulmonary hypertension (PH) is prognostically highly relevant in patients with COPD. The criteria for severe PH have been defined based on hemodynamic thresholds in right heart catheterization. RESEARCH QUESTION: Can noninvasive clinical tools predict severe PH in patients with COPD? How does the mortality risk change with increasing severity of airflow limitation and pulmonary vascular disease? STUDY DESIGN AND METHODS: We retrospectively analyzed all consecutive patients with COPD with suspected PH undergoing in-depth clinical evaluation, including right heart catheterization, in our PH clinic between 2005 and 2018. Clinical variables potentially indicative of severe PH or death were analyzed using univariate and stepwise multivariate logistic regression and Cox regression analysis adjusted for age and sex. RESULTS: We included 142 patients with median FEV1 of 55.0% predicted (interquartile range [IQR], 42.4%-69.4% predicted) and mean pulmonary arterial pressure of 35 mm Hg (IQR, 27-43 mm Hg). A multivariate model combining echocardiographic systolic pulmonary arterial pressure of ≥ 56 mm Hg, N-terminal pro-brain natriuretic peptide (NT-proBNP) plasma levels of ≥ 650 pg/mL, and pulmonary artery (PA) to ascending aorta (Ao) diameter ratio on chest CT scan of ≥ 0.93 predicted severe PH with high positive and negative predictive values (both 94%). After correction for age and sex, both airflow limitation (P = .002; Global Initiative for Chronic Obstructive Lung Disease [GOLD] stages 1-2 vs stage 3: hazard ratio [HR], 1.56 [95% CI, 0.90-2.71]; GOLD stages 1-2 vs stage 4: HR, 3.45 [95% CI, 1.75-6.79]) and PH severity (P = .012; HR, 1.85 [95% CI, 1.15-2.99]) remained associated independently with survival. The combination of GOLD stages 3 and 4 airflow limitation and severe PH showed the poorest survival (HR for death, 3.26 [95% CI, 1.62-6.57; P = .001] vs GOLD stages 1-2 combined with nonsevere PH). INTERPRETATION: In patients with COPD, the combination of echocardiography, NT-proBNP level, and PA to Ao diameter ratio predicts severe PH with high sensitivity and specificity. The contribution of severe PH and severe airflow limitation to impaired survival is comparable.