Classification, Diagnosis, and Medical Treatment of Pulmonary Hypertension

Abstract

Pulmonary hypertension is a condition characterized by elevated blood pressure in pulmonary arteries due to increased muscle mass of vessel walls, leading to arterial constriction and reduced blood oxygenation. Commonly classified into five major groups, pulmonary hypertension is often viewed as quite rare when, in fact, it is far more common than traditionally advertised. It is also an extremely debilitating disease with far-reaching economic, societal, personal, and psychosocial impacts, especially in underserved populations. Though 10 FDA-approved medications—targeting four different biological pathways—have come to market over the last 20 years, more recent research has focused on complex signaling pathways regulating hypoxic and metabolic signaling, proliferation, apoptosis, senescence, and inflammation. In this chapter, we provide an overview of pulmonary hypertension’s prevalence and widespread impact, its underlying pathophysiology and clinical presentations, currently recognized treatment strategies, recommended regimens in special populations, and emerging therapeutic options and fields of research.

1. Introduction

Pulmonary hypertension (PH) is a pathological condition characterized by elevated blood pressure in the pulmonary arteries (i.e., mean pulmonary arterial pressure or mPAP >20 mmHg at rest) due to increased muscle mass of the vessel walls, leading to arterial constriction and reduced blood oxygenation [1, 2]. Definitions for PH are based on hemodynamic assessment by right heart catheterization (RHC). While hemodynamics is key in defining PH, the final diagnosis and classification must consider the entire clinical scenario, incorporating findings from all diagnostic evaluations [2].

This multifactorial disease is influenced by a variety of etiological factors, with left heart disease and chronic lung disease being the most common [1, 3]. It exhibits a higher prevalence among women, non-Hispanic Black populations, and the elderly [1]. Clinically, PH initially presents with nonspecific symptoms like dyspnea and fatigue, which can delay diagnosis, later progressing to more severe manifestations like syncope and chest pain [1]. While there is no cure for PH, treatment often focuses on symptom management and includes pharmacotherapy, diuretics, and oxygen therapy. Preventive strategies tend to emphasize lifestyle modifications and management of underlying conditions like systemic hypertension and coronary artery disease [1].

PH is often classified into five major groups based on similar pathophysiological mechanisms, clinical presentation, hemodynamic characteristics, and therapeutic management (Table 1) [2, 3]. Besides variations in hemodynamics, groups include a wide spectrum of underlying conditions, each with its own prevalence and distinctive treatment strategies [2, 3].

Group 1	Group 2	Group 3	Group 4	Group 5
PAH	PH caused by LHD	PH caused by lung diseases and/or hypoxia	PH caused by pulmonary artery obstructions	PH with unclear and/or multifactorial mechanisms
1.1 Idiopathic PAH; 1.2 Heritable PAH; 1.3 Drug- and toxin-induced PAH; 1.4 PAH associated with: 1.4.1 Connective tissue disease; 1.4.2 HIV infection; 1.4.3 Portal hypertension; 1.4.4 Congenital heart disease; 1.4.5 Schistosomiasis; 1.5 PAH long-term responders to calcium channel blockers; 1.6 PAH with overt features of venous/capillaries (PVOD/PCH) involvement; 1.7 Persistent PH of the newborn syndrome	2.1 PH caused by heart failure with preserved LVEF; 2.2 PH caused by heart failure with reduced LVEF; 2.3 Valvular heart disease; 2.4 Congenital/acquired cardiovascular conditions leading to postcapillary PH	3.1 Obstructive lung disease; 3.2 Restrictive lung disease; 3.3 Other lung disease with mixed restrictive/obstructive pattern; 3.4 Hypoxia without lung disease; 3.5 Developmental lung disorders	4.1 Chronic thromboembolic PH; 4.2 Other pulmonary artery obstructions	5.1 Hematological disorders: chronic hemolytic anemia, myeloproliferative disorders; 5.2 Systemic and metabolic disorders: sarcoidosis, pulmonary Langerhans cell histiocytosis, Gaucher disease, glycogen storage disease, neurofibromatosis; 5.3 Others: fibrosing mediastinitis, chronic renal failure (with or without dialysis); 5.4 Complex congenital heart disease

Table 1.

Clinical classification of pulmonary hypertension [2, 3].

Abbreviations: LVEF = left ventricular ejection fraction; PAH = pulmonary arterial hypertension; PCH = pulmonary capillary hemangiomatosis; PVOD = pulmonary veno-occlusive disease; LHD = left heart disease.

1.1 Prevalence of disease: United States and abroad

Unfortunately, the medical establishment has historically focused on rarer forms of PH—like PAH and chronic thromboembolic pulmonary hypertension—leading to the belief that PH, as a whole, is extremely rare [4]. However, as stated by Rich and colleagues, “Pulmonary hypertension should stop being treated as a rare disease of high-income countries and should be acknowledged as an important global disease, with a high prevalence that is largely neglected…The reality is that pulmonary hypertension has a spectrum from mild to severe and is associated with common disorders…Estimates suggest that pulmonary hypertension might be the fourth most prevalent cardiovascular disease in the world” [5]. With a prevalence of about 1% globally—and increasing up to 10% in patients greater than 65 years of age—as many as 20–70 million individuals could be afflicted with PH [4, 5]. Domestically, a population-based study from the United States found that 20% of older patients (i.e., 72–96 years old) showed echocardiographic evidence of PH, while a Canadian cohort study demonstrated a 28% increase in disease prevalence between 1993 and 2012 from 100 to 127 cases per 100,000 individuals [5, 6].

Approximately 80% of afflicted patients live in developing countries, where PH is frequently associated with congenital heart disease and infectious disorders like schistosomiasis, HIV, and rheumatic heart disease [4]. It is estimated that nearly 200 million individuals may be infected by Schistosoma species, nearly 85% of which live in Brazil and sub-Saharan Africa. Left-sided heart failure—particularly heart failure with preserved ejection fraction (HFpEF)—may be a leading cause of PH, affecting about 5–10% of individuals 65 years or older, or nearly 30 million patients worldwide [4]. Moreover, another 25 million individuals 40 years or older might be affected by PH due to COPD [4]. Chronic high-altitude exposure—impacting over 140 million people worldwide—is a known, yet sparsely researched, cause of PH. There is believed to be a strong association between a higher prevalence of PH and occupation at altitudes exceeding 4000 meters [4, 7]. Table 2 depicts crude estimates of the total number of patients worldwide afflicted with PH due to its frequent underlying disorders. It is self-evident that PH is far more common than traditionally advertised.

	Heart failure	Moderate-to-severe COPD	HIV	Schistosomiasis	Rheumatic heart disease	Sickle cell disease
Worldwide estimates	61 million	250 million	30 million	200 million	15 million	20 million
Estimated PH-associated cases	30 million	25 million	150,000	Unclear	3.75 million	2 million

Table 2.

Estimated PH-associated cases due to underlying disorders.

1.2 Economic, societal, and personal impact of pulmonary hypertension

PH is a complex and often debilitating cardiovascular disorder characterized by high blood pressure in the pulmonary arteries, which can lead to right heart failure and a reduced quality of life. While PH affects individuals from various backgrounds, it disproportionately impacts underserved minority populations, exacerbating existing health disparities. This overview will discuss PH’s economic, societal, personal, and psychosocial impacts, with a special focus on its effects on underserved minorities.

PH imposes a substantial economic burden on individuals and healthcare systems. Ogbomo and colleagues detected significant direct and indirect healthcare costs associated with PH among commercially insured patients in the United States [8]. Their study found that the average annual healthcare cost per patient was approximately $105,943, including direct costs such as hospitalizations, specialized treatments, and medications. This financial burden can be particularly challenging for underserved minority populations, as they often face barriers to accessing healthcare services and insurance coverage [8].

The economic impact extends to Medicare and other healthcare programs. A 2017 United States Government Accountability Office (GAO) report discussed Medicare Part D and how it oversees prescription drug plan sponsors’ fraud and abuse programs. This work is relevant because it sheds light on how government healthcare programs address pharmaceutical costs associated with conditions like PH, which can have implications for underserved populations [9].

The societal impact of PH is profound since it can limit an individual’s ability to work and engage in daily activities. Patients often require frequent hospitalizations and specialized treatments, which can disrupt daily routines and reduce their capacity to participate in social events and contribute to society. A study by Badlam and company provided insights into the demographics of patients with PH in the United States, helping us understand populations affected by the disease [10]. Underserved minority communities may face additional challenges, such as limited access to healthcare facilities specializing in PH diagnosis and treatment, which can further exacerbate these disruptions [11].

Moreover, a study by Namuyonga and colleagues examined the impact of PH in underserved populations, specifically South African children. This case series highlighted the unique challenges and disparities in pediatric care, emphasizing the broader societal impact of the disease, especially in resource-limited settings [12].

Undoubtedly, PH takes a toll on mental health and well-being. Anxiety and depression are common comorbidities, and the afflicted may experience feelings of isolation and hopelessness. Underserved minority patients may face unique psychosocial challenges related to cultural stigma, mistrust of the healthcare system, and limited access to mental health resources, exacerbating their mental health burdens [11].

Underserved minority populations—including African Americans, Hispanics, and Native Americans—often face disparities in healthcare access and outcomes related to PH. African American and Hispanic patients with PH tend to have worse outcomes and higher mortality rates compared to their white counterparts, as reported in a 2021 study published in the European Respiratory Journal [13]. Such disparities can be attributed to socioeconomic factors, systemic racism, and cultural differences, often resulting in delayed diagnosis and inadequate care.

Addressing these disparities requires a comprehensive approach. Healthcare policies should focus on eliminating barriers to access, improving early diagnosis through community outreach and education programs, and providing culturally competent care. Research efforts should also prioritize understanding the determinants of PH in underserved minority populations to develop more personalized treatment approaches [11].

Ultimately, PH is a debilitating disease with far-reaching economic, societal, personal, and psychosocial impacts. Underserved minority populations bear a disproportionate burden of this disease, highlighting the need for targeted efforts to address healthcare disparities and improve outcomes for these individuals. By implementing comprehensive strategies that address both medical and social determinants of health, we can work toward reducing the disparities in PH management and enhancing the quality of life of all affected individuals.

2. Pathophysiology of pulmonary hypertension

The mechanisms behind PH include increased pulmonary vascular resistance, pulmonary venous pressure, and/or pulmonary venous flow due to congenital heart disease [14]. The progressive narrowing of blood vessels is caused by a combination of endothelial dysfunction and increased contractility of small pulmonary arteries, proliferation, and remodeling of endothelial and smooth muscle cells, and in situ thrombosis [15]. There is also increased activity of vasoconstrictors like thromboxane A2 and endothelin 1, along with reduced activity of vasodilators like prostacyclin and nitric oxide [14, 15].

Group 1 PAH is primarily caused by a loss and remodeling of the pulmonary vascular bed [16]. Thrombotic coagulopathy due to platelet dysfunction, increased activity of plasminogen activator inhibitor type 1 and fibrinopeptide A, and decreased tissue plasminogen activator activity may also contribute to an increase in pulmonary vascular resistance [14]. Group 4 PAH is generally caused by a pulmonary embolism or obstruction to pulmonary arteries, which thereby increases pulmonary vascular resistance [17].

Several mutations associated with idiopathic or hereditary PAH have been identified, including BMPR2, SMAD1, SMAD9, KCNK3, and CAV1 [18]. Most cases of hereditary and idiopathic PAH may be due to such mutations [14]. Of these, the most common include mutations in the BMPR2 gene, leading to disruptions in TGF-β/BMP endothelial cells and increased pulmonary vascular resistance [14, 15].

Increased pulmonary venous pressure, commonly seen in Group 2 PAH, is typically caused by disorders affecting the left side of the heart [16]. Persistently elevated pulmonary venous pressure can damage the alveolar-capillary wall and eventually lead to irreversible thickening of alveolar-capillary membrane walls and decreased lung function capacity [14]. Group 3 PAH is caused by chronic lung disease that elevates mean pulmonary arterial pressure and results in the loss of lung vasculature, vascular distensibility, and reduced vessel recruitment [16]. Lastly, increased pulmonary venous blood flow due to congenital heart disease may cause PH [14].

3. Clinical presentation of pulmonary hypertension

Signs and symptoms of PH differ depending on the stage of the disease. Initial signs and symptoms are general in nature and may include dyspnea, fatigue, and weakness. These early signs and symptoms are nonspecific in nature, making it difficult to diagnose PH in its early stages [19]. As the disease progresses, additional signs and symptoms may appear, including exertional chest pain, exertion intolerance, dyspnea at rest, worsening fatigue, bloating, distention of the abdomen (ascites), anorexia, lower extremity edema, and syncope [19].

When evaluating patients for PH, some objective signs include audible S₂ at the apex of the heart, mid-systolic ejection murmur, palpable left parasternal lift, right ventricular S₄ gallop, and a prominent “a” wave. These observed signs—along with the symptoms described above—are associated with right ventricular dysfunction, eventually leading to PH’s complication of right-sided heart failure [19].

However, as PH advances, signs and symptoms become more pronounced. More pronounced symptoms include further worsening of chest pain, dyspnea, and fatigue, as well as worsening signs like mid-systolic ejection murmur progressing to diastolic murmur of pulmonary regurgitation. Clinicians may also see a pansystolic murmur of tricuspid regurgitation, audible S₂ no longer at just the apex of the heart, an audible right ventricular S₃ gallop, distension of jugular veins, hepatojugular reflux, hypotension, and worsening of lower extremity edema accompanied by cool extremities suggestive of decreased cardiac output and increased vasoconstriction in the periphery [19].

Since signs and symptoms of PH are nonspecific, diagnosis is obtained via the exclusion of differential diagnoses. The first step involves determining the underlying cause of those signs and symptoms. Since fatigue and dyspnea are among the first, examination of physical indicators of PH like audible murmurs and distention—along with a good patient history—must be conducted [20]. This should be followed by imaging tests such as a chest X-ray or an echocardiogram to evaluate the presence of disease markers. If markers are present and support suspicions of PH, confirmation should be completed through right heart catheterization (RHC) [20].

RHC is ultimately used to confirm the presence of conditions like PAH [21]. It is an outpatient surgical procedure that measures pulmonary artery pressure in the lungs [21]. The measurements obtained are mean pulmonary artery pressure (mPAP), pulmonary capillary wedge pressure (PAWP), and pulmonary vascular resistance (PVR) [22]. Depending on the value of these measurements (e.g., mPAP > 20 mmHg, PAWP ≤ 15 mmHg, PVR > 2 WU), the presence of conditions like PAH may be confirmed [22]. In addition, performing an RHC provides insight into the severity of the disease, allows the assessment of congenital heart defects (including the exclusion of left-side heart disease), assesses patient response to vasodilator challenge, and helps guide clinical decision-making of pharmacotherapy [21, 23, 24].

RHC is not performed on all patients for a wide range of reasons. Reasons may include lack of knowledge or training to perform the procedure, overall cost, perception of elevated risk (due to its invasive nature), or presence of inadequately controlled pre-existing conditions [24, 25]. Since it is not performed on all patients, it is important to note that without an RHC, clinicians cannot—and typically should not—prescribe PH-specific therapies [21].

4. Medical treatment of pulmonary hypertension

The World Health Organization (WHO) has classified PH into five groups based on different underlying causes and pathophysiological mechanisms. The 2022 ESC/ERS guidelines recommend targeting treatment approaches based on the specific group. Below is an overview of the treatment strategies for each of the five groups:

4.1 Group 1: pulmonary arterial hypertension (PAH)

4.1.1 General measures

The comprehensive management of pulmonary arterial hypertension (PAH) involves a spectrum of general measures aimed at enhancing both the quality of life and overall well-being of affected individuals.

• Exercise training: With PAH patients on stable medical treatment, exercise training has positively influenced both exercise capacity and overall quality of life [26].

• Anticoagulation: PAH has been associated with a procoagulant state, but the use of anticoagulation therapy is tempered by elevated bleeding risk. Due to the absence of studies demonstrating clear clinical benefits, routine anticoagulation therapy is currently not recommended. Instead, decisions regarding the initiation of anticoagulation should be approached on an individualized basis, considering a careful assessment of the specific risks and potential benefits for each patient [24].

• Diuretics: In those experiencing right-sided heart failure with fluid retention, the use of loop diuretics, thiazides, and mineralocorticoid receptor antagonists can be considered either as standalone therapy or in combination, depending on the patient’s clinical condition and renal function [24].

• Oxygen: Due to the lack of robust data regarding oxygen therapy in PAH, current recommendations are based on data from COPD patients. If the PaO₂ is <8 kPa (60 mmHg; alternatively, SaO₂ < 92%) on at least two occasions, oxygen can be administered to achieve a PaO2 > 8 kPa [24].

• Iron: In PAH patients, iron deficiency can lead to impaired myocardial function and increased mortality risk. Therefore, routine monitoring of iron status and iron replacement is recommended. In patients with severe iron deficiency anemia (hemoglobin < 7–8 g/dL), IV iron supplementation is recommended [24].

• Vaccines: At a minimum, patients with PAH should receive vaccinations for influenza, Streptococcus pneumonia, and SARS-CoV-2 [24].

4.1.2 Treatment of vasoreactive patients with idiopathic, heritable, or drug-associated pulmonary arterial hypertension

Calcium channel blockers (CCB): For patients exhibiting positive responses to acute vasoreactivity testing, CCB therapy can be titrated to high doses. However, it is important to note that only 10% of individuals with idiopathic, hereditary, or drug- or toxin-induced PAH typically show positive results in vasoreactive tests. Additionally, a positive vasoreactive test does not reliably predict long-term response. Therefore, for such patients, the consideration of continuing CCB therapy is warranted in WHO-FC I or II with marked hemodynamic improvement. In cases where patients persist in World Health Organization Functional Class (WHO-FC) III or IV—or fail to show significant hemodynamic improvement despite high-dose CCB therapy—the introduction of additional PAH-specific therapies is recommended [24].

4.1.3 Recommendations for the treatment of non-vasoreactive patients with idiopathic, heritable, or drug-associated pulmonary arterial hypertension who present without cardiopulmonary comorbidities

For patients presenting at low-to-intermediate risk of death, initial combination therapy with an endothelin receptor antagonist (ERA) and a phosphodiesterase 5 inhibitor (PDE-5 inhibitor) is recommended (Class I recommendation). These patients can be considered for the addition of selexipag during follow-up to reduce the risk of clinical worsening. Alternatively, if receiving ERA/PDE-5 inhibitor therapy, the PDE-5 can be switched to riociguat if treatment-escalation is required [24].

Patients with a high risk of death should receive initial combination therapy with PDE-5 inhibitor, ERS, and IV/SC prostacyclin analogs (Class IIa Recommendation). If the addition of an intravenous (IV) or subcutaneous (SC) prostacyclin analog is not feasible, selexipag can be added, or the PDE-5 inhibitor can be switched to riociguat [24].

4.1.4 Recommendations for the treatment of non-vasoreactive patients with idiopathic, heritable, or drug-associated pulmonary arterial hypertension who present with cardiopulmonary comorbidities

There is a lack of conclusive evidence regarding the optimal treatment for elderly patients with PAH and cardiopulmonary comorbidities. As a result, the current recommendation suggests initiating monotherapy with a PDE-5 inhibitor with an ERA. Nevertheless, individualized consideration for additional therapy is advisable, particularly for those at intermediate or high risk of mortality while on monotherapy [24].

4.1.5 Interventional therapies

Balloon atrial septostomy and the Potts shunt are surgical procedures that decompress the right heart and increase systemic blood flow. However, these procedures are rarely performed due to the substantial risk of procedure-related mortality. Pulmonary artery denervation (PADN) applies radiofrequency to the pulmonary arterial baroreceptors to decrease sympathetic activation in PAH. While PADN showed positive benefits for a 6-minute walk distance in a small study, this therapy is considered experimental [24].

4.1.6 Lung and heart-lung transplantation

If patients remain refractory to optimized medical therapy, lung transplant is an important treatment option, and referral to a transplant center should be considered early. Most patients receive bilateral lung transplants, while heart-lung transplants can be considered in patients with non-correctable cardiac conditions [24].

4.2 Group 2: pulmonary hypertension due to left heart disease (LHD)

For individuals with PH due to left heart disease (PH-LHD), the primary focus of therapy should revolve around optimizing the management of the underlying cardiac condition. In cases where fluid retention is a concern in PH-LHD, diuretics serve as a cornerstone of treatment. Notably, drugs approved for PAH are generally not advisable for PH-LHD, since available data suggests inefficacy and heightened risk of adverse effects, including fluid retention [24].

While no specific recommendation is provided for the use of PDE-5 inhibitors in the context of heart failure with preserved ejection fraction (HFpEF) and combined post and precapillary pulmonary hypertension (CpcPH), it is worth noting that PDE-5 inhibitors may be safely considered for administration in this population [24].

4.3 Group 3: pulmonary hypertension due to lung diseases and/or hypoxia

For an individual’s lung disease and PH, it is recommended to optimize the treatment of the underlying lung disease. Overall, the use of PAH medications is not recommended in patients with lung disease and nonsevere PH. In severe PH, referral to a PH center is recommended for individualized treatment decisions and consideration for lung transplantation. PH centers may consider PDE-5 inhibitors in severe PH associated with ILD [24].

4.4 Group 4: chronic thromboembolic pulmonary hypertension (CTEPH)

In patients with confirmed CTEPH, lifelong anticoagulation is recommended due to the risk of recurrent pulmonary thromboembolism. If the condition is operable, pulmonary endarterectomy (PEA) is the treatment of choice. If symptoms are persistent or recurrent, medical therapy followed by possible balloon pulmonary angioplasty (BPA) is recommended. PEA will treat proximal PA fibrotic obstructions, BPA will treat distal PA fibrotic obstructions, and medical therapy will treat microvasculopathy [24].

Riociguat and SC treprostinil are indicated in patients with inoperable CTEPH or persistent/recurrent PH after PEA. Other medical therapies are primarily used off-label in symptomatic patients with inoperable CTEPH. For example, PDE-5 inhibitors and ERAs are common treatments in CTEPH with severe hemodynamic compromise despite the lack of data from recent trials. General measures recommended in PAH are recommended in CTEPH, including exercise training, which has been shown to be safe and effective in cases of operable and inoperable CTEPH [24].

4.5 Group 5: pulmonary hypertension with unclear and/or multifactorial mechanisms

For patients in Group 5, the therapeutic approach is directed toward identifying and managing underlying conditions contributing to PH [4]. In cases such as sickle-cell disease (SCD), the limited available data suggests a cautious stance regarding the use of PAH drugs in SCD-associated PH. Optimal management for these patients necessitates the expertise of multidisciplinary teams capable of tailoring treatment strategies to address underlying conditions effectively. On the other hand, preliminary data supports the use of PAH drugs in specific populations—such as potential improvement in a 6-minute walk distance in sarcoidosis with PH—these findings warrant validation through larger-scale studies to conclusively establish their therapeutic benefits (Table 3) [24, 27].

Group 1: Pulmonary arterial hypertension (PAH)	Vasodilator therapy: Medications such as prostacyclin analogs, endothelin receptor antagonists, and phosphodiesterase-5 inhibitors are commonly used. The number of agents will depend on whether patients are at low- intermediate- or high risk of death.; Supportive therapies: Diuretics, anticoagulants, and oxygen therapy may be used to manage symptoms and improve exercise tolerance. Iron therapy should be administered in patients with iron deficiency.; Vaccines: influenza, Streptococcus pneumoniae, SARS-CoV-2; If acute vasoreactivity test is positive, titrate calcium channel blockers to high doses; however, many patients will not have sustained long-term response.
Group 2: Pulmonary hypertension due to left heart disease	Treatment of underlying cause: Management focuses on addressing the underlying heart condition and optimization of fluid status. Diuretics may be prescribed to manage fluid overload.
Group 3: Pulmonary hypertension due to lung diseases and/or hypoxia	Treatment of underlying lung disease: Managing conditions such as chronic obstructive pulmonary disease (COPD) or interstitial lung disease is essential. Refer to a PH center for individualized decision-making. Oxygen therapy may be needed.; Pulmonary rehabilitation: Exercise and pulmonary rehabilitation therapy may be beneficial.
Group 4: Chronic thromboembolic pulmonary hypertension (CTEPH)	Anticoagulation: Long-term anticoagulation therapy is often prescribed to prevent further clot formation.; Pulmonary endarterectomy (PEA): Surgical removal of chronic blood clots from the pulmonary arteries is the preferred treatment when feasible.; Balloon pulmonary angioplasty (BPA): In cases where PEA is not possible, BPA may be considered as an alternative.; Medical therapy is indicated in patients within operable CTEPH or persistent/recurrent PH after PEA.
Group 5: Pulmonary hypertension with unclear or multifactorial mechanisms	Treatment of underlying causes: Identify and manage any underlying conditions contributing to pulmonary hypertension.

Table 3.

Treatment strategies for pulmonary hypertension by group.

Non-drug treatments are part of a comprehensive approach to managing PH, which focuses on reducing symptoms, preventing complications, and improving patient quality of life. PH sufferers may want to avoid certain medications or drug classes. For example, cardiovascular drugs used in systemic hypertension or left-sided heart failure—such as angiotensin-converting enzyme inhibitors (ACEs), angiotensin receptor blockers (ARBs), angiotensin receptor-neprilysin inhibitors (ARNIs), sodium-glucose cotransporter-2 inhibitors (SGLT-2is), beta-blockers, and ivabradine—may cause potentially dangerous drops in blood pressure and heart rate in PH patients. Thus, their use is generally not recommended unless necessary for comorbid conditions [24].

While guidelines do not explicitly mention limiting sodium intake, this is a common recommendation in managing heart failure and conditions like PAH since it helps to reduce fluid retention and pressure on the heart. Immunization against SARS-CoV-2, influenza, and Streptococcus pneumoniae is recommended for patients with PH. This is also important for preventing infections that may exacerbate PH [24]. Long-term oxygen therapy is recommended for those with an arterial blood oxygen pressure below 8 kPa (60 mmHg). Evaluation for obstructive sleep apnea and nocturnal oxygen therapy should be considered in the case of sleep-related desaturation [24].

Surgical interventions are typically reserved for advanced or complex cases of PH where other medical treatments have failed to provide adequate symptom relief or slow disease progression. The choice of intervention depends on the specific type of PH, the patient’s overall health, and the availability of surgical expertise and resources.

1. Lung transplantation is for patients with certain types of PH refractory to optimized medical therapy. Early referral to a lung transplantation center is advised for those eligible for transplantation, especially in cases of treatment failure, progressive disease, recent hospitalization for worsening disease, need for IV or SC prostacyclin therapy, and presence of high-risk variants such as pulmonary veno-occlusive disease (PVOD) or pulmonary capillary hemangiomatosis (PCH), systemic sclerosis, large and progressive pulmonary artery aneurysms, or secondary liver or kidney dysfunction due to PH [24].

2. Heart-lung transplantation is considered for rarer cases unresponsive to medical treatment, with limited availability due to organ availability and lesion complexity. Unfortunately, this treatment option is associated with high mortality during the first year after surgery [24].

PEA for CTEPH is recommended when the risk of pulmonary embolism recurrence is intermediate or high. Surgical PEA is the treatment of choice for those with accessible pulmonary artery lesions. Operability decisions are based on team experience, accessibility of lesions, the correlation between PH severity and degree of artery obstructions, and comorbidities [24]. Balloon atrial septostomy and Potts shunts are considered interventional therapies in the management of PH, especially in advanced cases where other treatments might not be sufficient or applicable [24].

Responders to calcium CCB therapy demonstrate a reduction in PAP and PVR, with an increase in cardiac output during the test. Long-term treatment may include high doses of CCBs like nifedipine, diltiazem, or amlodipine. Regular follow-up and monitoring are recommended to ensure continued responsiveness and management of potential side effects from high-dose therapy. Conversely, some “non-responders” may not show significant improvement during a vasoreactivity test; CCB therapy is generally not effective and may even be harmful in such patients. Treatment typically involves alternative PAH-specific therapies, such as ERAs, PDE-5 inhibitors, or prostacyclin analogs. Management is focused on the underlying pathophysiological mechanisms. Only a small percentage of patients with PH are actual “responders” to CCBs. Therefore, careful assessment and close monitoring are essential to determine the appropriate therapy for each individual [24].

5. Pharmacologic treatment of pulmonary hypertension

5.1 Endothelin receptor antagonists (ERAs)

Bosentan: Endothelins (ETs) are made of 21 amino acid peptides and three different isoforms: ET-1, ET-2, and ET-3. The most common isoform, ET-1, is seen in airway epithelial lining, lung parenchymal cells, pulmonary tumors, pulmonary vessels, kidneys, small intestine, and cardiac myocytes [28]. Once endothelins are produced and secreted, they bind to endothelin G protein-coupled receptors, known as endothelin A and endothelin B (ETA, ETB). More specifically, bosentan is a nonselective ET-1 receptor antagonist.

Pulmonary vasculature and airway smooth muscles are populated with ETA receptors, though ETB receptors are mainly found in the endothelium [29]. The binding of endothelin to ETA receptors causes vasoconstriction while binding to ETB receptors causes bronchoconstriction. Because of the functions and locations of endothelin, they are associated with many respiratory diseases, including asthma, pulmonary hypertension, COPD, connective tissue disorders, bronchiolitis obliterans, and lung transplant rejections. Bosentan antagonizes receptors in lung tissue, causing smooth muscle relaxation along the pulmonary vasculature and decreasing pulmonary pressure and resistance [28]. Adverse effects of bosentan include nasopharyngitis, headache, chest pain, syncope, flushing, hypotension, sinusitis, arthralgia, abnormal liver enzymes, peripheral edema, palpitation, and decreased hemoglobin. Bosentan’s target dose is 125 mg by mouth twice daily—with monthly liver function testing—since dose-dependent increases in liver transaminases (though reversible) may occur in approximately 10% of patients.

Macitentan: As a dual ERA, it demonstrates superior receptor-binding properties, with improved tissue penetration and a longer duration of action, which allows for daily dosing. The recommended dose for oral macitentan is 10 mg by mouth once daily.

This drug has a favorable side effect profile with little evidence of increased risk of hepatotoxicity or peripheral edema, though concentrations may be reduced by significant anemia [30]. Notable side effects include reduced sperm counts during spermatogenesis, leading to oligospermia and infertility. It is, therefore, contraindicated in pregnancy due to the risk of fetal harm. Though it may elevate hepatic enzymes, little evidence exists for hepatotoxicity. It may also cause anemia, peripheral edema, nasopharyngitis, and hypersensitivity reactions.

Ambrisentan: It works as a selective ERA for treating idiopathic, heritable, and connective tissue disease-associated PAH [31]. Ambrisentan enhances exercise capacity and hemodynamics by inhibiting endothelin, reducing lung pressures, and reducing right heart stress. Side effects include peripheral edema, elevated liver enzymes, and respiratory-related side effects (i.e., nasal congestion, sinusitis, and cough). Recommended oral dosages are 5 and 10 mg by mouth once daily.

5.2 Phosphodiesterase-5 inhibitors (PDE-5)

This class works by inhibiting the phosphodiesterase type 5 enzyme, which is abundant in pulmonary vasculature. This inhibition leads to increased levels of cyclic guanosine monophosphate (cGMP), causing relaxation of pulmonary arterial smooth muscle cells and vasodilation [24].

Sildenafil: It is an orally active, potent, and selective inhibitor of PDE-5, which is often found in high concentrations in pulmonary arteries and the corpora cavernosum [32]. It has been shown to improve exercise capacity, symptoms, and hemodynamics. The recommended dose is 20 mg by mouth three times daily. Adverse effects include headache, flushing, and dizziness. Priapism has also been reported in post-marketing surveillance [33].

Tadalafil: It is a once-daily PDE-5 inhibitor shown to have positive outcomes on exercise capacity, symptoms, hemodynamics, and time to clinical worsening in PAH patients [24]. Recommended doses are up to 40 mg once daily. Side effects are usually mild to moderate and are mainly related to vasodilation, including headache, flushing, heart palpitations, syncope, and epistaxis [34].

General: PDE-5 inhibitors should not be combined with soluble guanylate cyclase stimulators or nitrates, as this may lead to systemic hypotension. Interactions between PDE-5 inhibitors and protease inhibitors have been reported, resulting in major increases in PDE-5 drug concentrations. Caution is advised when combining these drugs; lower dosages and close monitoring of potential side effects like hypotension are recommended [24]. Regular follow-ups to monitor hemodynamics, exercise capacity, and clinical symptoms are crucial. Patients should be educated about potential side effects and when to seek medical attention.

5.3 Soluble guanylate cyclase stimulators

Riociguat: It is a soluble guanylate cyclase (sGC) stimulator with a dual mode of action. It acts in collaboration with endogenous nitric oxide and directly stimulates sGC, independent of nitric oxide availability. This action ultimately increases cyclic guanosine monophosphate (cGMP) production, causing vasorelaxation, antiproliferative, and anti-fibrotic effects. Side effects include hypotension, bleeding, vomiting, diarrhea, and GERD [35].

5.4 Prostacyclin pathway or prostanoids

Prostanoids include epoprostenol (IV), treprostinil (IV, SC, inhaled), iloprost (inhaled), and selexipag (oral) [36]. This class binds to prostacyclin receptors, thereby increasing cyclic adenosine monophosphate (cAMP) and leading to vasodilation, antiproliferative and antithrombotic effects. Common side effects include flushing, jaw pain, headache, diarrhea, nausea, rash, and muscle aches (particularly in legs and feet). Side effects can be dependent on the dosage and can be eliminated with dose reductions [37].

5.5 Calcium channel blockers (CCBs)

CCBs inhibit the flow of extracellular calcium through ion-specific channels that spread through the cell wall. When its inward flow is prevented, vascular smooth muscle cells relax, leading to vasodilation and a decrease in blood pressure. In heart muscles, contractility is decreased, and the sinus pacemaker and atrioventricular conduction velocities are slowed [38, 39].

Nifedipine: It blocks the entry of calcium ions by inhibiting voltage-dependent L-type channels in smooth muscles of vessels and myocardial cells. During the depolarization phase in smooth muscle cells, there is usually an influx of calcium ions through voltage-gated channels. Since intracellular calcium is reduced by nifedipine, there is decrease PVR and dilatation of coronary arteries, leading to a reduction in systemic blood pressure and increased myocardial oxygen delivery. Thus, nifedipine has both hypotensive and antianginal properties. Its immediate-release formulations are available in 10–20 mg capsules, while extended-release formulations are available in 30, 60, and 90 mg tablets [39].

The recommended dose for PH is 20 mg by mouth daily [40]. Key side effects include peripheral edema, dizziness, headache, and flushing. Hypersensitivity reactions like pruritus, urticaria, and bronchospasms tend to be rare. Discontinuation after long-term use can lead to hypertension or angina. Nifedipine is absolutely contraindicated in hypersensitivity and ST-elevated myocardial infarction, while relative contraindications include severe aortic stenosis, unstable angina, hypotension, heart failure, and moderate-to-severe hepatic impairment. Patients should be monitored for peripheral edema, dizziness, and flushing; regular blood pressure checks are recommended [39].

Amlodipine: It is a long-acting, lipophilic, third-generation dihydropyridine (DHP) CCB that prevents the influx of calcium ions into smooth muscles of vessels and myocardial cells, leading to decreased PVR. Due to its long half-life, it is typically dosed once daily, which is favorable for patient compliance. The recommended starting dose is 5 mg by mouth once daily, with a maximum dose of 10 mg. The 2.5 mg dose is usually reserved for elderly patients and those with hepatic failure.

Side effects may include peripheral edema, dizziness, fatigue, headache, palpitations, and nausea. Amlodipine is contraindicated in cases of breastfeeding, cardiogenic shock, and unstable angina. Its vasodilatory effect can lead to reduced cardiac output in aortic stenosis [41]. Moreover, it should be used cautiously in those with hepatic diseases and titrated in small doses. Using amlodipine together with dihydrocodeine may increase plasma concentrations of dihydrocodeine, increasing the likelihood of opioid adverse reactions like hypotension, respiratory depression, sedation, coma, or death.

Diltiazem: It is used in treating stable and unstable angina and systemic hypertension (mild-to-moderate) but has also proven effective at terminating supraventricular tachycardia and controlling ventricular feedback in atrial fibrillation/flutter. Diltiazem has complex cardioprotective effects, which have been beneficial after intracoronary administration to patients undergoing coronary angiography and bypass procedures [42]. The dosages of 120–360 mg by mouth once daily are used for systemic hypertension and angina pectoris, while those in the 480–720 mg per day range are used for pulmonary hypertension [43]. Side effects include edema, nausea, headache, dizziness, asthenia, and rash [42]. It is contraindicated in acute myocardial infarction, pulmonary congestion, sick sinus syndrome, and severe ventricular arrhythmia. Coadministration with acalabrutinib may cause infection, bleeding, and atrial arrhythmias. Monitoring parameters include blood pressure, EKG, heart rate, liver function tests, and serum creatinine.

General: Current PAH guidelines suggest that the effectiveness of this class is limited to a small percentage of patients with significant acute responses to CCBs (i.e., “responders”). According to recent guidelines, specific advanced agents are recommended for treating patients with PAH [44].

5.6 Combination therapies

Combination therapies involve drugs with different mechanisms of action to achieve a more effective management of PH. Unfortunately, a significant number of patients with PH require two- or three-drug regimens due to the complexity and severity of the disease. This approach may be based on various factors, including:

1. Disease progression and severity: PH is a progressive disease, and many patients may not respond adequately to monotherapy. As the disease advances, it often becomes necessary to add additional medications to achieve better control of symptoms and to slow disease progression [24]. Recent guidelines suggest starting dual-combination therapy if the patient can tolerate it.

2. Targeting multiple pathways: PH may involve the endothelin, nitric oxide, and prostacyclin pathways. Using drugs that target different pathways can provide a more comprehensive treatment approach. For instance, an ERA can be combined with a PDE-5 inhibitor and/or a prostacyclin analog to cover multiple aspects of the disease process [24].

3. Clinical evidence: Recent research has demonstrated the benefits of combination therapy in PH. For instance, the TRITON study, which investigated treatment-naïve patients with PAH, demonstrated the superior efficacy of initial dual-combination therapy with macitentan and tadalafil or triple-combination therapy with macitentan, tadalafil, and selexipag. Though combination therapies have been associated with a significant reduction in the risk of clinical worsening in PAH patients, their impact on all-cause mortality is less clear [24].

4. Individualized treatment plans: The decision to use two- or three-drug regimens is based on individual patient factors, including response to initial therapy, side effect profiles, and presence of comorbid conditions. This personalized approach helps to optimize treatment effectiveness and manage risks associated with advanced PH.

5. Initial combination therapy: In the TRITON study mentioned above, treatment-naïve PAH patients were assigned to initial dual-combination therapy with macitentan and tadalafil or initial triple-combination therapy with macitentan, tadalafil, and selexipag. For those presenting at low or intermediate risk, initial combination therapy with an ERA and PDE-5 inhibitor is recommended. Initial combination therapy with ambrisentan and tadalafil, as well as macitentan and tadalafil, is recommended. However, initial combination therapy with macitentan, tadalafil, and selexipag is not recommended [24].

6. Sequential drug combination therapy: For those with idiopathic, heritable, or drug-associated PAH, the addition of macitentan to PDE-5 inhibitors or oral/inhaled prostacyclin analogs is recommended to reduce the risk of morbidity/mortality events. In patients receiving ERA/PDE-5 inhibitor combination therapy, the addition of selexipag was shown to reduce the risk of clinical worsening events compared to placebo [24]. Combination therapy has been associated with significant risk reduction for clinical worsening; however, its impact on all-cause mortality remains unclear. A substantial proportion of patients may still experience clinical worsening or death despite combination therapy [24].

6. Special populations

6.1 Treating pulmonary hypertension in pregnancy

In cases of PH, including idiopathic PAH responsive to CCB therapy, there have been instances of successful pregnancy outcomes [24]. However, pregnancy in women with PH is still fraught with unpredictable risks and can potentially worsen disease progression [24]. At any point during or after pregnancy, women are vulnerable to health deterioration [24]. It is essential for healthcare providers to thoroughly discuss the potential risks associated with pregnancy with patients, enabling women and their families to make well-informed decisions [24].

For women with PH who conceive or are diagnosed with PAH during pregnancy, treatment in specialized centers with expertise in managing PH in pregnant patients is recommended. Ongoing pregnancy may necessitate adjustments in disease treatment protocols [24]. Drugs such as ERAs, riociguat, and selexipag are typically discontinued due to their potential or unknown risks to fetal development [24, 45]. Conversely, treatments like CCBs, PDE-5 inhibitors, and prostacyclin analogs administered via inhalation, IV, or SC routes are generally deemed safe during pregnancy [24, 45].

To manage right heart failure decompensation symptoms, diuretics such as torsemide or furosemide may be utilized [24, 45]. However, the use of spironolactone is not recommended during the first trimester due to its antiandrogenic properties [24, 45]. When administering diuretics, it is crucial to regularly monitor renal function and serum electrolytes to prevent complications like volume depletion, which could further reduce cardiac output and systemic blood pressure [45].

During pregnancy, women are often hypercoagulable, elevating the risk of thrombosis. Heparins are the first-line anticoagulants recommended—particularly low molecular weight heparin (LMWH)—due to their reduced fetal impact and osteoporosis risk. They are recommended for those with cardiopulmonary dysfunction and PH to mitigate thrombosis risks [45]. However, the effectiveness of LMWH in preventing valve thrombosis is limited. Warfarin, though used in specific dosages during the second and third trimesters, poses teratogenic risks and its use remains controversial during pregnancy [45]. Novel oral anticoagulants like dabigatran and rivaroxaban lack robust evidence for safety and efficacy in pregnant women and are associated with higher risks of miscarriage and birth defects; as a result, their use is generally not recommended [45].

6.2 Treating portopulmonary hypertension and pulmonary arterial hypertension associated with congenital heart disease

Management of portopulmonary hypertension (PoPH) and PAH associated with congenital heart disease (PAH-CHD) requires a multidisciplinary management approach [46]. Larger clinical trials have either underrepresented or excluded patients with these conditions, leading to treatment strategies often based on the experience of clinical experts or findings from retrospective studies [47].

Supportive therapy, such as the administration of diuretics and oxygen, along with supervised exercise rehabilitation, plays an important role in the management of both PoPH and PAH-CHD [46]. The use of beta-blockers, anticoagulants, and CCBs is not recommended in this patient population [46, 48].

Medications that target three different pathways—nitric oxide, endothelins, and prostanoids—have shown increasing evidence of efficacy in those with PAH-CHD [49]. PDE-5 inhibitors like sildenafil and tadalafil are cheaper options and work by increasing intracellular cGMP levels [48]. These agents have been shown to improve hemodynamics and exercise capacity [47]. Agents exerting their action through the endothelin pathway include bosentan, macitentan, and ambrisentan; they have achieved favorable results in patients with PAH-CHD. Endothelin-1 has been shown to be a potent mediator of vascular constriction [47].

Bosentan, a dual-receptor endothelin antagonist, is increasingly used in symptomatic patients with PAH-CHD. There is ongoing debate about whether ambrisentan or macitentan is preferred. Ambrisentan is relatively ETA selective with fewer drug-drug interactions. On the other hand, macitentan has slow dissociation kinetics, high receptor occupancy half-life, and provides noncompetitive antagonism at the endothelin receptor [48]. Single-center clinical trials of bosentan and ambrisentan—but not macitentan—have proven effective in improving hemodynamics in this PAH subpopulation [47]. Targeting the prostanoid pathway involves prostaglandin analogs like epoprostenol and iloprost. Oral or inhaled therapies are preferred in CHD patients as opposed to IV therapies since use of central lines may lead to sepsis or paradoxical emboli in those with unrepaired defects. Lastly, surgical options such as ductal stenting, Potts shunts, atrial septostomy, and lung transplantation remain as non-pharmacologic treatment options for patients [47, 48, 49].

6.3 Treating pulmonary hypertension in patients with connective tissues disease

PAH is a severe complication of connective tissue disorders, and connective tissue disease-PAH (CTD-PAH) is the second recognized cause of PAH after the idiopathic type [50]. As previously discussed, PH is classified into five groups. Those with PH hypertension in association with connective tissue disorders can be found in Groups 1, 2, 3, and 4 [51].

PH has a severe impact on daily living. Since it is life-threatening, sufferers should receive psychological, social, and emotional support, which specialized nurses can provide [52]. Physical activity within limits is also advised. Patients with CTEPH require anticoagulants, diuretics, and digoxin for heart failure, and long-term oxygen may be necessary. Vaccinations against influenza and pneumococcal pneumonia and iron supplementation may also be indicated.

PAH treatment in those with connective tissue disorders is a complex strategy based on preliminary evaluation of severity and prognostic risk, as well as subsequent response to treatment. Patients with PH should be referred to expert centers and treated by multidisciplinary teams of rheumatologists, cardiologists, chest physicians, and specialized nurses [36].

7. Current clinical investigations and future therapeutic options

Over the last 20 years, 10 FDA-approved medications—targeting four different pathways—have come to market, but, as many experts lament, the medical establishment is still far away from developing a cure for PH [53]. Encouragingly, there is no shortage of novel drug targets or medications on the horizon [54].

The first medication to show recent promise is sotatercept, a first-in-class fusion protein containing a domain of human activin receptor type IIA paired with the Fc domain of human IgG1. Blocking proliferative pathways in pulmonary vessels incites death in excess cells, helping to reopen those vessels. In the STELLAR (Study of Sotatercept for the Treatment of Pulmonary Arterial Hypertension) trial, the drug dramatically improved the 6-minute walking distance in the treatment group compared to those given placebo. It also produced an 84% reduction in the risk of death or clinical worsening.

Two tyrosine kinase inhibitors, imatinib, and sorafenib have received significant attention as adjunct therapy in patients resistant to more traditional drug combinations targeting the nitric oxide, endothelin, and prostacyclin pathways. The IMPRES (Imatinib in Pulmonary Arterial Hypertension, a Randomized, Efficacy Study) trial demonstrated significant improvement in 6-minute walking distance and PVR in patients receiving two or traditional PAH therapies [55]. Meanwhile, sorafenib has been connected to improvements in functional class and mPAP and is being further investigated for refractory PAH [55].

Other novel drugs or delivery systems include inhaled vardenafil, which can be used as needed for PAH symptom exacerbations. Rodatristat ethyl, which inhibits tryptophan hydroxylase and blocks the synthesis of serotonin from tryptophan, is also under investigation. It is believed that excessive serotonin could contribute to vasoconstriction and vascular remodeling seen in PAH [55]. As the first dedicated hemodynamic study comparing two drugs versus one alone, the A DUE trial (Macitentan/Tadalafil Fixed-Dose Combination in Pulmonary Arterial Hypertension) showed that use of a combination pill containing fixed doses of macitentan and tadalafil led to a two-fold greater reduction in PVR compared to either drug alone. The distinct advantage of a single, once-daily combination pill lies in its potential to dramatically increase patient adherence [53].

As stated by George and colleagues, “New therapies have emerged that move us beyond vasodilation, vasoconstriction, and endothelial dysfunction, toward more complex signaling pathways that regulate hypoxic and metabolic signaling, proliferation, apoptosis, senescence, and inflammation” [56]. The first such signaling pathway involves growth suppressor TSC2, which is lacking in small pulmonary arteries of PAH sufferers. Biologically, SC2 controls cell growth; if present in larger quantities, it could block the stiffening and remodeling of pulmonary arteries seen in the disease [56]. Since TSC2 is regulated by the protein SIRT1, researchers have tested the effect of the SIRT1 activator molecule SRT2104, which caused improved lung function and reduced PH in rodent models. SRT2014 is now undergoing further clinical study [57].

Other novel signaling pathways tied to PH pathogenesis—and serving as the basis for future clinical investigations—include the following: (a) inhibition of propyl hydroxylase domain-containing protein 2 (PHD2); (b) inhibition of mammalian target of rapamycin complex (MTORC); (c) inhibition of hypoxia-inducible factor-1 (HIF-1α); (d) activation of Forkhead box protein O1 (FOXO1); (e) activation of AMP-activated protein kinase (AMPK); (f) inhibition of pyruvate dehydrogenase kinase (PDK); (g) inhibition of carnitine palmitoyltransferase (CPT1A); (h) inhibition of phosphatidylinositol-glycan biosynthesis class F protein (PIGF); and (i) improvement of insulin sensitivity or activation of ketogenesis using drugs like metformin, pioglitazone, or SGLT-2 inhibitors [56].

Finally, recent research has targeted the following pathophysiological mechanisms: (a) fatty acid oxidation using ranolazine and trimetazidine; (b) glycolysis using dichloroacetate; (c) modulation of Nrf2 and NF-κB pathways using bardoxolone methyl; (d) metabolic syndrome and AMPK signaling using metformin; (e) modulation of cytokine pathways using anakinra and tocilizumab; (f) inflammation using ubenimex; (g) modulation of estrogen pathways using anastrozole and fulvestrant; and (h) improvement in oxygenation using acetazolamide [54].

Though there has been incredible progress over the last two or three decades in the treatment of PH, researchers hope that the therapies outlined above will help to move the field toward truly effective and targeted therapies capable of reversing the underlying pathology in disease sufferers, dramatically increasing quality of life and overall mortality rates [54, 55, 56].

8. Conclusion

Recent research suggests that PH is more commonplace and widespread than traditionally advertised, particularly in developing countries. It also has far-reaching economic, societal, personal, and psychosocial impacts, particularly in underserved minority populations. Though current therapies tend to focus on the use of ERAs, PDE-5 inhibitors, CCBs, prostanoids, and soluble guanylate cyclase stimulators, recent clinical investigations have focused on underlying signaling pathways and pathophysiological mechanisms, with the promise of significantly improved outcomes and, perhaps, a cure 1 day. The diagnosis and treatment of PH have undergone substantial changes in recent decades, and it will continue to evolve even more significantly in the coming years.