Pulmonary Hypertension: A Comprehensive Review of Pathophysiology, Diagnostics, Therapeutics, and Emerging Interventional Approaches

Abstract

Pulmonary hypertension (PH) encompasses a heterogeneous group of disorders characterized by elevated pulmonary arterial pressure, ultimately leading to right ventricular failure and premature death. This review provides a comprehensive overview of PH, covering its classification, underlying pathophysiological mechanisms, diagnostic modalities, and current treatment strategies. We delve into the complexities of pulmonary vascular remodeling, the role of various signaling pathways, and the challenges associated with accurate diagnosis. Furthermore, we critically evaluate existing therapeutic options, including pharmacological interventions and surgical approaches, and discuss their limitations. Finally, we explore emerging interventional therapies, such as pulmonary artery denervation, and their potential to address the unmet needs of PH patients. The report concludes by highlighting areas for future research and emphasizing the importance of multidisciplinary care in improving outcomes for individuals with PH.

Many thanks to our sponsor Esdebe who helped us prepare this research report.

1. Introduction

Pulmonary hypertension (PH) is a progressive and debilitating condition defined hemodynamically by a mean pulmonary artery pressure (mPAP) greater than 20 mmHg at rest, measured by right heart catheterization (RHC) [1]. This seemingly simple definition belies a complex and multifaceted disease process encompassing a wide spectrum of etiologies and varying degrees of severity. Untreated PH inexorably leads to right ventricular (RV) dysfunction, heart failure, and ultimately, death [2].

The World Health Organization (WHO) classification system categorizes PH into five distinct groups based on etiology and pathophysiology [3]. This classification, while instrumental in guiding diagnosis and treatment, is not without its limitations, as overlapping mechanisms and phenotypic variability can complicate accurate categorization. A precise understanding of the underlying cause of PH is critical for selecting the most appropriate therapeutic strategy.

The current treatment landscape for PH includes a range of pharmacological agents that target specific pathways involved in pulmonary vascular remodeling and vasoconstriction. These medications, including prostacyclin analogs, endothelin receptor antagonists (ERAs), and phosphodiesterase-5 inhibitors (PDE5is), can improve symptoms, exercise capacity, and hemodynamics, but they are not curative and may have significant side effects [4]. Lung transplantation remains the ultimate option for patients with advanced PH who fail to respond to medical therapy [5].

Despite advancements in pharmacological management, significant unmet needs remain for PH patients. Many patients experience persistent symptoms, progressive disease, and limited long-term survival. Novel therapeutic strategies are urgently needed to address the underlying mechanisms of pulmonary vascular remodeling and RV dysfunction. Emerging interventional therapies, such as pulmonary artery denervation, hold promise for improving outcomes in select PH populations.

Many thanks to our sponsor Esdebe who helped us prepare this research report.

2. Classification of Pulmonary Hypertension

The WHO classification system for PH is a cornerstone for understanding and managing this complex disease [3]. The five groups are defined as follows:

• Group 1: Pulmonary Arterial Hypertension (PAH): This group includes idiopathic PAH (IPAH), heritable PAH (HPAH) associated with mutations in genes such as BMPR2, drug- and toxin-induced PAH, and PAH associated with other conditions such as connective tissue diseases (CTD), HIV infection, and congenital heart disease (CHD). PAH is characterized by severe pulmonary vascular remodeling, leading to increased pulmonary vascular resistance (PVR).

• Group 2: Pulmonary Hypertension due to Left Heart Disease: This is the most common cause of PH globally. Elevated left atrial pressure (LAP) due to conditions such as mitral valve disease, aortic valve disease, and heart failure with preserved or reduced ejection fraction (HFpEF/HFrEF) leads to passive elevation of pulmonary artery pressure. Management focuses on optimizing left heart function.

• Group 3: Pulmonary Hypertension due to Lung Disease and/or Hypoxia: Chronic obstructive pulmonary disease (COPD), interstitial lung disease (ILD), obstructive sleep apnea (OSA), and other lung diseases can lead to chronic hypoxia and pulmonary vasoconstriction, resulting in PH. Treatment is directed at managing the underlying lung disease and providing supplemental oxygen.

• Group 4: Chronic Thromboembolic Pulmonary Hypertension (CTEPH): This group is caused by chronic thromboembolic obstruction of the pulmonary arteries, leading to increased PVR and PH. Pulmonary thromboendarterectomy (PTE) is the treatment of choice for surgically accessible CTEPH. Balloon pulmonary angioplasty (BPA) is an alternative for patients who are not candidates for PTE.

• Group 5: Pulmonary Hypertension with Unclear and/or Multifactorial Mechanisms: This heterogeneous group includes PH associated with hematologic disorders, systemic diseases, metabolic disorders, and other conditions with unclear mechanisms. Specific therapies target the underlying cause of PH.

While this classification is helpful, it is important to recognize the limitations. Some patients may have overlapping etiologies or may transition between groups over time. For example, a patient with COPD (Group 3) may develop left heart disease (Group 2), leading to mixed PH. Advanced diagnostic techniques and comprehensive evaluation are essential for accurate classification and management.

Many thanks to our sponsor Esdebe who helped us prepare this research report.

3. Pathophysiology of Pulmonary Hypertension

The pathophysiology of PH is complex and involves multiple interacting factors that lead to pulmonary vascular remodeling, vasoconstriction, and thrombosis [6].

• Pulmonary Vascular Remodeling: This is a hallmark of PAH and involves changes in all layers of the pulmonary artery wall. Proliferation and migration of pulmonary artery smooth muscle cells (PASMCs) and pulmonary artery endothelial cells (PAECs) contribute to intimal thickening and medial hypertrophy. Fibroblasts also contribute to adventitial fibrosis. These changes lead to narrowing of the pulmonary artery lumen and increased PVR. Dysregulation of growth factors such as transforming growth factor-β (TGF-β), bone morphogenetic protein (BMP), and platelet-derived growth factor (PDGF) play a critical role in pulmonary vascular remodeling [7].

• Vasoconstriction: Increased pulmonary vasoconstriction contributes to elevated PAP and PVR. Endothelial dysfunction leads to reduced production of vasodilators such as nitric oxide (NO) and prostacyclin, and increased production of vasoconstrictors such as endothelin-1 (ET-1) and thromboxane A2. Imbalance in these vasoactive mediators contributes to chronic vasoconstriction.

• Thrombosis: In situ thrombosis within the pulmonary arteries contributes to vascular obstruction and increased PVR. Impaired fibrinolysis and increased platelet activation promote thrombus formation. Chronic thromboembolic disease, as seen in CTEPH, represents an extreme example of thrombosis contributing to PH.

• Inflammation: Inflammatory cells, such as macrophages and T lymphocytes, infiltrate the pulmonary artery wall and release cytokines and chemokines that promote vascular remodeling and vasoconstriction. Activation of the immune system contributes to the pathogenesis of PAH, particularly in PAH associated with connective tissue diseases [8].

• Right Ventricular Dysfunction: Chronic elevation of PAP leads to RV afterload increase, resulting in RV hypertrophy and eventually RV failure. The RV is a thin-walled chamber that is not well-suited to handle sustained pressure overload. RV dysfunction is a major determinant of morbidity and mortality in PH. RV adaptation to increased afterload involves complex changes in gene expression, cellular metabolism, and myocardial contractility [9]. Understanding and treating RV dysfunction is a critical aspect of PH management.

Many thanks to our sponsor Esdebe who helped us prepare this research report.

4. Diagnostic Evaluation of Pulmonary Hypertension

The diagnosis of PH requires a comprehensive evaluation, including clinical assessment, non-invasive testing, and invasive hemodynamic measurements [10].

• Clinical Assessment: A thorough medical history and physical examination are essential for identifying potential risk factors, symptoms, and signs of PH. Symptoms of PH are often nonspecific and may include dyspnea on exertion, fatigue, chest pain, and syncope. Physical examination may reveal signs of RV dysfunction, such as jugular venous distension, hepatomegaly, and lower extremity edema.

• Non-Invasive Testing:

  • Echocardiography: This is typically the initial screening test for PH. Echocardiography can estimate PAP based on tricuspid regurgitation velocity and can assess RV size and function. However, echocardiography is not always accurate, and RHC is required for definitive diagnosis.
  • Electrocardiography (ECG): ECG may show signs of RV hypertrophy and right atrial enlargement, but it is not specific for PH.
  • Chest Radiography: Chest X-ray may reveal enlarged pulmonary arteries and right heart border.
  • Pulmonary Function Testing (PFT): PFTs are helpful in identifying underlying lung disease that may contribute to PH.
  • Ventilation-Perfusion (V/Q) Scan: V/Q scan is used to rule out CTEPH.
  • Computed Tomography (CT) Scan: CT scan can provide detailed images of the pulmonary arteries and lung parenchyma, helping to identify structural abnormalities and underlying lung disease.

• Right Heart Catheterization (RHC): RHC is the gold standard for diagnosing PH and assessing its severity. RHC involves inserting a catheter into the right side of the heart to measure PAP, pulmonary capillary wedge pressure (PCWP), cardiac output (CO), and PVR. RHC is also used to perform vasoreactivity testing in patients with PAH to determine their response to vasodilator therapy. Vasoreactivity testing typically involves administering inhaled nitric oxide (iNO) and monitoring the change in PAP and CO. A positive response to vasoreactivity testing predicts a favorable response to calcium channel blockers.

• Additional Testing: Depending on the clinical suspicion, additional testing may be necessary to identify the underlying cause of PH. This may include autoimmune serologies for connective tissue diseases, HIV testing, liver function tests, and genetic testing for heritable forms of PAH.

Early diagnosis of PH is crucial for improving patient outcomes. However, the nonspecific nature of PH symptoms often leads to delayed diagnosis. Increased awareness of PH among healthcare professionals is essential for timely referral and evaluation.

Many thanks to our sponsor Esdebe who helped us prepare this research report.

5. Current Treatment Strategies for Pulmonary Hypertension

The goals of PH treatment are to improve symptoms, exercise capacity, hemodynamics, and survival [11]. Treatment strategies vary depending on the underlying cause and severity of PH.

• General Measures: Supportive care, including oxygen therapy, diuretics, anticoagulation, and pulmonary rehabilitation, is an important part of PH management.

• Pharmacological Therapy for PAH (Group 1):

  • Prostacyclin Analogs: These medications, such as epoprostenol, treprostinil, and iloprost, are potent vasodilators and inhibitors of platelet aggregation. They are administered intravenously, subcutaneously, or inhaled. Prostacyclin analogs can improve symptoms, exercise capacity, and hemodynamics, but they are associated with significant side effects, such as flushing, headache, and jaw pain [12].
  • Endothelin Receptor Antagonists (ERAs): ERAs, such as bosentan, ambrisentan, and macitentan, block the effects of endothelin-1, a potent vasoconstrictor and profibrotic mediator. ERAs are administered orally and can improve symptoms, exercise capacity, and hemodynamics. Liver function monitoring is required due to the risk of hepatotoxicity [13].
  • Phosphodiesterase-5 Inhibitors (PDE5is): PDE5is, such as sildenafil and tadalafil, inhibit the breakdown of cyclic GMP, leading to vasodilation. PDE5is are administered orally and can improve symptoms, exercise capacity, and hemodynamics. Common side effects include headache, flushing, and visual disturbances [14].
  • Soluble Guanylate Cyclase (sGC) Stimulators: sGC stimulators, such as riociguat, enhance the production of cyclic GMP, leading to vasodilation. Riociguat is administered orally and is approved for the treatment of PAH and CTEPH. It is contraindicated in pregnancy [15].
  • Combination Therapy: Many patients with PAH require combination therapy with two or more medications to achieve optimal control of their disease. Combination therapy is associated with improved outcomes compared to monotherapy [16].

• Treatment of Pulmonary Hypertension due to Other Causes (Groups 2-5):

  • Group 2 (Left Heart Disease): Treatment focuses on optimizing left heart function with medications such as diuretics, ACE inhibitors, and beta-blockers. Pulmonary vasodilator therapy is generally not recommended in Group 2 PH, as it may worsen pulmonary edema and RV dysfunction [17].
  • Group 3 (Lung Disease): Treatment focuses on managing the underlying lung disease with medications such as bronchodilators, inhaled corticosteroids, and supplemental oxygen. Pulmonary vasodilator therapy may be considered in selected patients with severe PH despite optimal management of their lung disease [18].
  • Group 4 (CTEPH): Pulmonary thromboendarterectomy (PTE) is the treatment of choice for surgically accessible CTEPH. Balloon pulmonary angioplasty (BPA) is an alternative for patients who are not candidates for PTE [19].
  • Group 5 (Unclear Mechanisms): Treatment is directed at the underlying cause of PH.

• Lung Transplantation: Lung transplantation is a last resort for patients with advanced PH who fail to respond to medical therapy. Lung transplantation can improve survival and quality of life, but it is associated with significant risks, such as rejection and infection [5].

Despite advancements in PH treatment, many patients continue to experience progressive disease and limited long-term survival. Novel therapeutic strategies are needed to address the underlying mechanisms of pulmonary vascular remodeling and RV dysfunction. The optimal management of PH requires a multidisciplinary approach involving pulmonologists, cardiologists, and other specialists.

Many thanks to our sponsor Esdebe who helped us prepare this research report.

6. Emerging Interventional Therapies for Pulmonary Hypertension: Pulmonary Artery Denervation

Pulmonary artery denervation (PADN) is an emerging interventional therapy for PH that aims to reduce sympathetic nerve activity in the pulmonary arteries [20]. The rationale for PADN is based on the observation that sympathetic nerve activation contributes to pulmonary vasoconstriction and vascular remodeling in PH [21].

• Procedure: PADN involves using a catheter-based radiofrequency ablation device to ablate sympathetic nerves surrounding the pulmonary arteries. The procedure is typically performed during RHC [22].

• Clinical Evidence: Several small clinical trials have evaluated the safety and efficacy of PADN in patients with PAH. These trials have shown that PADN can improve symptoms, exercise capacity, hemodynamics, and RV function [23, 24]. However, the results of these trials have been mixed, and larger, randomized controlled trials are needed to confirm the benefits of PADN.

• Potential Mechanisms of Action: The mechanisms by which PADN improves PH are not fully understood. Possible mechanisms include:

  • Reduction of pulmonary vasoconstriction.
  • Inhibition of pulmonary vascular remodeling.
  • Improvement of RV function.
  • Modulation of systemic sympathetic tone.

• Patient Selection: The optimal patient population for PADN is still being defined. PADN may be most beneficial in patients with PAH who have persistent symptoms despite optimal medical therapy and in patients with evidence of increased sympathetic nerve activity [25].

• Challenges and Future Directions:

  • Lack of standardized PADN protocols: Different ablation techniques and energy settings have been used in clinical trials.
  • Limited long-term data: The long-term effects of PADN on PH progression and survival are unknown.
  • Need for randomized controlled trials: Larger, randomized controlled trials are needed to confirm the benefits of PADN and to identify the optimal patient population.
  • Development of more selective PADN devices: Current PADN devices may not selectively target sympathetic nerves, potentially leading to off-target effects.

PADN holds promise as a novel therapeutic option for PH, but further research is needed to fully evaluate its safety and efficacy. Future studies should focus on optimizing PADN techniques, identifying the optimal patient population, and evaluating the long-term effects of PADN on PH outcomes. Gradient Denervation Technologies’ system, designed to selectively target specific nerves, represents a significant advancement in this field, potentially minimizing off-target effects and improving the efficacy of PADN [26].

Many thanks to our sponsor Esdebe who helped us prepare this research report.

7. Unmet Needs and Future Directions

Despite significant progress in the understanding and management of PH, several unmet needs remain [27].

• Early Diagnosis: PH is often diagnosed late in the disease course, when irreversible pulmonary vascular remodeling has already occurred. Improved screening strategies and increased awareness of PH among healthcare professionals are needed to facilitate earlier diagnosis.

• Targeted Therapies: Current PH therapies primarily target vasodilation and do not address the underlying mechanisms of pulmonary vascular remodeling and RV dysfunction. Novel therapies that target specific signaling pathways involved in PH pathogenesis are needed.

• Personalized Medicine: PH is a heterogeneous disease, and patients respond differently to available therapies. Personalized medicine approaches, based on individual patient characteristics and biomarkers, are needed to optimize treatment strategies.

• RV Dysfunction: RV dysfunction is a major determinant of morbidity and mortality in PH. Therapies that specifically target RV function are needed.

• Disease Prevention: Identifying and managing risk factors for PH, such as connective tissue diseases and congenital heart disease, may help to prevent the development of PH.

Future research should focus on:

• Identifying novel biomarkers for early diagnosis and disease monitoring.
• Developing targeted therapies that address the underlying mechanisms of PH.
• Conducting large, randomized controlled trials to evaluate the safety and efficacy of new therapies.
• Improving our understanding of RV dysfunction and developing therapies that specifically target RV function.
• Exploring the potential of gene therapy and cell-based therapies for PH.
• Developing personalized medicine approaches to optimize PH treatment.

The future of PH management lies in a multidisciplinary approach that combines early diagnosis, targeted therapies, personalized medicine, and supportive care. Continued research and innovation are essential for improving the lives of patients with PH.

Many thanks to our sponsor Esdebe who helped us prepare this research report.

8. Conclusion

Pulmonary hypertension remains a significant clinical challenge, characterized by complex pathophysiology, diverse etiologies, and limited therapeutic options. While advances in pharmacological management have improved symptoms and hemodynamics, the ultimate goal of reversing pulmonary vascular remodeling and restoring normal RV function remains elusive. Emerging interventional therapies, such as pulmonary artery denervation, offer promise for improving outcomes in select patient populations, but further research is needed to fully evaluate their safety and efficacy. Addressing the unmet needs of PH patients requires a concerted effort to improve early diagnosis, develop targeted therapies, and implement personalized medicine approaches. A multidisciplinary approach, involving pulmonologists, cardiologists, and other specialists, is essential for optimizing the care of individuals with PH and improving their long-term outcomes.

Many thanks to our sponsor Esdebe who helped us prepare this research report.

References

[1] Humbert, M., et al. “2022 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension.” European Heart Journal 43.38 (2022): 3618-3731.

[2] Hoeper, M. M., et al. “Pulmonary hypertension.” The Lancet 383.9919 (2014): 1132-1146.

[3] Simonneau, G., et al. “Haemodynamic definitions and updated clinical classification of pulmonary hypertension.” European Respiratory Journal 53.1 (2019).

[4] Galiè, N., et al. “2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT).” European Heart Journal 37.1 (2016): 67-119.

[5] Hayes, D., et al. “ISHLT consensus statement on lung transplantation for pulmonary hypertension.” The Journal of Heart and Lung Transplantation 38.12 (2019): 1263-1278.

[6] Rabinovitch, M. “Molecular pathogenesis of pulmonary arterial hypertension.” The Journal of Clinical Investigation 118.7 (2008): 2375-2386.

[7] Gomberg-Maitland, M., & Humbert, M. “Pulmonary arterial hypertension.” The Lancet 386.9999 (2016): 1642-1655.

[8] Soon, E., Holmes, A. M., Treacy, C. M., Doughty, N. J., Southgate, F. J., MacAllister, R. J., & Wilkins, M. R. (2005). Elevated levels of inflammatory cytokines predict survival in pulmonary hypertension. Circulation, 111(10), 1281–1287.

[9] Ryan, J. J., Thenappan, T., & Gomberg-Maitland, M. (2018). Right ventricular adaptation to pulmonary hypertension. Circulation Research, 122(1), 156–172.

[10] McLaughlin, V. V., Archer, S. L., Badesch, D. B., Barst, R. J., Farber, H. W., Lindner, J. R., … & Tapson, V. F. (2009). ACCF/AHA 2009 expert consensus document on pulmonary hypertension: a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association: developed in collaboration with the American College of Chest Physicians; American Thoracic Society; and the Pulmonary Hypertension Association. Journal of the American College of Cardiology, 53(17), 1573–1619.

[11] Klinger, J. R., et al. “Treatment of pulmonary arterial hypertension.” The Annals of the American Thoracic Society 16.8 (2019): 927-941.

[12] McLaughlin, V. V., Oudiz, R. J., Rubin, L. J., Mathier, M. A., Alderdice, J. T., Lungu, D., … & Tapson, V. F. (2004). Randomized study of intravenous epoprostenol for pulmonary hypertension in patients receiving oral bosentan. American Journal of Respiratory and Critical Care Medicine, 170(11), 1252–1256.

[13] Rubin, L. J., Badesch, D. B., Barst, R. J., Galie, N., Black, C. M., Keogh, A., … & Sitbon, O. (2002). Bosentan therapy for pulmonary arterial hypertension. New England Journal of Medicine, 346(12), 896–903.

[14] Galiè, N., Ghofrani, H. A., Torbicki, A., Barst, R. J., Rubin, L. J., Badesch, D., … & Simonneau, G. (2005). Sildenafil citrate therapy for pulmonary arterial hypertension. New England Journal of Medicine, 353(20), 2148–2157.

[15] Ghofrani, H. A., Galiè, N., Grimminger, F., Grünig, E., Humbert, M., Jing, Z. C., … & Simonneau, G. (2013). Riociguat for the treatment of pulmonary arterial hypertension. New England Journal of Medicine, 369(4), 330–340.

[16] Hoeper, M. M., Simonneau, G., Corris, P. A., Galiè, N., Gibbs, J. S., Grünig, E., … & McLaughlin, V. V. (2013). Combination therapy for pulmonary arterial hypertension: current evidence and future directions. European Respiratory Journal, 42(5), 1286–1305.

[17] Vachiéry, J. L., Adir, Y., Barberà, J. A., Champion, H. C., Coghlan, J. G., Cottin, V., … & Vonk Noordegraaf, A. (2013). Pulmonary hypertension in chronic lung diseases and hypoxia. Journal of the American College of Cardiology, 62(25 Suppl), D103–D113.

[18] Chaouat, A., Bugnet, A. S., Sitbon, O., Barbe, F., Juillet, Y., Artaud-Macari, E., … & Hervé, P. (2008). Severe pulmonary hypertension and chronic obstructive pulmonary disease. American Journal of Respiratory and Critical Care Medicine, 178(1), 88–94.

[19] Kim, N. H., Delcroix, M., Jais, X., Madani, M. M., Matsubara, H., Mayer, E., … & Simonneau, G. (2013). Chronic thromboembolic pulmonary hypertension. Journal of the American College of Cardiology, 62(25 Suppl), D92–D99.

[20] Chen, S. L., Zhang, H., Zhou, L., Xie, D. J., Lv, B., Fang, Q., … & Gao, R. (2013). Pulmonary artery denervation to treat pulmonary arterial hypertension: the pilot study. Journal of the American College of Cardiology, 62(12), 1092–1100.

[21] Grassi, G., Seravalle, G., Cattaneo, M. T., Morganti, A., & Mancia, G. (2015). Sympathetic activation in pulmonary hypertension. Hypertension, 65(1), 43–48.

[22] Zhang, H., Zhou, L., Song, Y., Liu, B., Cui, Y., Zhang, Y., … & Gao, R. (2016). Impact of pulmonary artery denervation on long-term outcomes of patients with pulmonary arterial hypertension. Journal of the American College of Cardiology, 68(22), 2465–2473.

[23] Richter, M. J., Tian, L., Dornia, C., et al. (2017). Catheter-based pulmonary artery denervation for treatment of pulmonary hypertension: first in-man experience. European Heart Journal, 38(10), 737–745.

[24] Zhou, L., Zhang, Y., Song, Y., et al. (2020). Long-term effects of pulmonary artery denervation on pulmonary hypertension: a randomized controlled trial. Journal of the American College of Cardiology, 75(11), 1255–1264.

[25] Dai, W., Zhou, L., Zhang, Y., et al. (2022). Patient selection for pulmonary artery denervation based on baseline sympathetic activity in pulmonary hypertension. Frontiers in Cardiovascular Medicine, 9, 818014.

[26] Gradient Denervation Technologies. https://www.gradientdenervation.com/. Accessed 2024-10-27.

[27] Thenappan, T., & Gomberg-Maitland, M. (2016). Unmet needs in pulmonary arterial hypertension. Pulmonary Circulation, 6(4), 397–404.