Continuing Education Activity

Pulmonary hypertension encompasses a heterogeneous group of disorders with the common feature of elevated pulmonary artery pressures. Patients often present with worsening dyspnea on exertion, with signs of right heart strain/failure. Diagnosis requires a high index of suspicion and extensive testing to confirm the condition as well as to determine the underlying etiology. Treatment is based on the management of the underlying etiology as well as medical therapy. Interventional and surgical options are available for chronic thromboembolic pulmonary hypertension. Lung transplantation can be considered for patients not responding to medical therapy. This activity reviews the evaluation and treatment of pulmonary hypertension and highlights the role of the interprofessional team in evaluating and treating patients with this condition.

Objectives:

• Identify the five groups of pulmonary hypertension.
• Review the typical presentation of a patient with pulmonary hypertension.
• Summarize diagnostic and management strategies according to the class of pulmonary hypertension.
• Describe how the coordination of the interprofessional team can lead to earlier diagnosis of pulmonary hypertension, allowing for treatment aimed at minimizing comorbidities, treating symptoms, and identifying and treating underlying etiologies, leading to better patient outcomes.

Introduction

Pulmonary hypertension (PH) encompasses a heterogeneous group of disorders with the common feature of elevated pulmonary artery pressure. It is divided into five clinical groups based on pathophysiology, hemodynamic characteristics, clinical features, and management.[1]

 TABLE 1: Clinical classification of PH

HIV: human immunodeficiency virus; LVEF: left ventricular ejection fraction; PAH: pulmonary arterial hypertension; PCH: pulmonary capillary hemangiomatosis; PVOD: pulmonary veno-occlusive disease.

Apart from the clinical classification, PH also has a hemodynamic classification that aids diagnosis. A mean pulmonary artery pressure (mPAP) >20 mmHg is considered above the upper limit of normal.[2][3][4][5] However, a mere elevation in mPAP is insufficient to define PH, as this could be due to an increase in cardiac output (CO) or pulmonary artery wedge pressure (PAWP). Hence the sixth World Symposium on Pulmonary Hypertension (WSPH) and the European Society of Cardiology (ESC)/European respiratory society (ERS) guidelines inculcated pulmonary vascular resistance (PVR) as well as PAWP to hemodynamically define PH as described in Table 2.[1][6]

TABLE 2: Hemodynamic classification of PH 

mPAP: mean pulmonary artery pressure; PAWP: pulmonary artery wedge pressure; PVR: pulmonary vascular resistance; WU: Wood units

These measurements are obtained during right heart catheterization (RHC) at rest in the supine position. The latest ESC/ERS guidelines inculcated the definition of exercise PH as a change in mPAP/CO slope between rest and exercise >3mmHg/L/min.[1] However, this definition cannot differentiate between pre-capillary and post-capillary PH. The change in PAWP/CO slope > 2 mmHg/L/min between rest and exercise might be able to differentiate between pre and post-capillary PH but measuring PAWP during exercise is challenging.[7][8]

As seen from the above table, all PH groups can have pre and post-capillary components contributing to their PH. These patients should be classified based on the presumed predominant underlying cause of the increased pulmonary artery pressures. Patients with PAH are typically characterized by pre-capillary PH in the absence of other conditions that can cause pre-capillary PH, such as those seen in group 3 and group 4 PH.

Etiology

The clinical groups defined in Table 1 describe the various etiologies of PH. This section will delve into more etiological details of the various subgroups.

Genetic mutations are associated with various types of PH, including idiopathic PAH (IPAH), heritable PAH (HPAH), and hereditary hemorrhagic telangiectasia (HHT) associated with PAH. The patients with HPAH have an inheritable genetic mutation, while patients with IPAH have a genetic predisposition and the mutations are sporadic, and these groups are clinically indistinguishable.[9] The various mutations associated with IPAH/HPAH are BMPR2 (most common), SMAD1, SMAD 9, KCNK3, CAV1, and SOX17, while those associated with HHT are ALK1, ENG, and SMAD4. 

The drugs/toxins that have been studied to definitely cause PAH to include aminorex, fenfluramine, dexfenfluramine, benfluorex, methamphetamines, dasatinib, and toxic rapeseed oil. Some drugs/toxins can possibly cause PAH, including cocaine, phenylpropanolamine, L-tryptophan, St. John's wort, amphetamines, interferon -α and -β, alkylating agents, bosutinib, direct-acting antivirals against hepatitis C, leflunomide, and indirubin.[6] Various connective tissue diseases (CTD) are known to cause PAH, including systemic sclerosis, systemic lupus erythematosus, rheumatoid arthritis, Raynaud's disease, and mixed connective tissue disease. Among these, systemic sclerosis is the most notorious for causing PAH. 

Pulmonary hypertension associated with congenital heart disease (PH-CHD) is classified into CHD that causes Eisenmenger syndrome, PAH associated with prevalent systemic-to-pulmonary shunts, PAH with small/coincidental defects, and PAH after defect correction.[10] While PH-CHD is predominantly classified under Group 1 PAH, there are some defects causing mitral valve disease, left ventricular inflow/outflow obstruction, or left ventricular systolic/diastolic dysfunction that may result in post-capillary PH as well and hence classified under Group 2. 

Hypoventilation syndromes in group 3 comprise conditions causing sleep-disordered breathing, while hypoxia without hypoventilation is seen at high altitudes. In patients with Group 4, apart from chronic thromboembolic disease, the other causes include sarcoma, other malignant tumors such as renal carcinoma, uterine carcinoma, testicular germ cell tumors, as well as nonmalignant tumors such as leiomyoma, arteritis without connective tissue disease, congenital pulmonary artery stenoses and hydatidosis that can cause obstructions in the pulmonary artery leading to PH. 

In group 5, the hematological disorders causing PH include chronic hemolytic anemia and myeloproliferative disorders. The systemic diseases that can cause PH include pulmonary Langerhans cell histiocytosis, neurofibromatosis type 1, and sarcoidosis. Glycogen storage diseases and Gaucher disease are metabolic disorders that can cause PH. 

Epidemiology

All age groups can be affected by PH, and present estimates suggest a prevalence of approximately 1% in the global population, with left heart disease (LHD) being the leading cause, followed by lung disease especially chronic obstructive pulmonary disease (COPD).[11] In developing countries, congenital heart disease, infectious diseases (schistosomiasis, human immunodeficiency virus), and high altitude are important causes of PH. The incidence of PAH is ~ 6 cases per million adults, and the prevalence is about 49-55 cases per million adults. It was initially thought to affect young females, but recent data shows it is being diagnosed with patients ≥65 years who often have cardiovascular comorbidities, which makes the sex distribution more equal.[12][13][14]

At least 50% of patients with heart failure with preserved ejection fraction either have IpcPH or CpcPH.[15][16] The prevalence of PH increases with disease severity in these patients, with 60 to 70% of patients with severe and symptomatic mitral valve disease and 50% with symptomatic aortic stenosis affected by PH.[17][18] Mild PH is common in patients with advanced COPD and interstitial lung disease (ILD). Only 1-5% of patients with advanced COPD were found to have severe PH. In patients with idiopathic pulmonary fibrosis, the prevalence increases with increasing severity and is as high as 60% in patients with end-stage disease.[19][20] 

Data from registries indicate the incidence and prevalence of chronic thromboembolic pulmonary hypertension (CTEPH) to be 2-6 and 26-39 cases per million adults, respectively.[12][21][22] In patients with sarcoidosis, PH can be common and is associated with increased mortality and morbidity.[23][24]

History and Physical

History: The hallmark presenting symptom of PH is shortness of breath on exertion; other nonspecific symptoms can include hemoptysis, fatigue, early exhaustion, palpitations, and syncope. As the disease progresses, symptoms of right-sided heart failure manifest, such as weight gain, edema, abdominal distention, and ascites.[25]

Rare symptoms due to enlargement of the pulmonary artery (PA) can include chest pain on exertion (due to compression of the left main coronary artery), hoarseness of voice (caused by compression of left recurrent laryngeal nerve - Ortner Syndrome), wheezing, cough, lower respiratory tract infections, atelectasis (due to compression of bronchi).

Patients may have symptoms related to their underlying diseases, such as joint pains, skin rashes, cough, daytime somnolence, and a history of blood clots. A family history, sexual history, and travel history are extremely important when evaluating a patient with suspected PH.

Physical: An increased P2 (pulmonic) component of the second heart sound is usually the initial physical finding. As the disease progresses and right ventricular dysfunction ensues, jugular venous distention with a prominent "a" wave is seen with an eventual prominent "v" wave signifying tricuspid regurgitation. Murmurs of tricuspid and pulmonic regurgitation, as well as right-sided S3 or S4, may be heard. These are caused by elevated pulmonary pressures and eventually right ventricular (RV) failure. Ascites, abdominal distention, hepatomegaly and/or splenomegaly, and dependent edema may be present. As RV failure progresses, dizziness, pallor, delayed capillary refill, and peripheral cyanosis may be seen, signifying a low cardiac output state. 

Various other physical exam findings may be present in patients with CTD or chronic lung diseases, such as digital clubbing, telangiectasias, Raynaud's phenomenon, digital ulceration, symptoms related to gastroesophageal reflux, crackles/wheezing on lung auscultation, joint swelling/erythema. 

Evaluation

Despite advances in technology, the time from symptom onset to diagnosis of pulmonary hypertension remains at more than two years; hence a high index of suspicion is required.[26][27] Patients with unexplained shortness of breath or symptoms/signs concerning for pulmonary hypertension should be thoroughly evaluated with a comprehensive medical and family history, physical examination, monitoring of blood pressure, heart rate, oxygen saturation, and blood tests, including brain natriuretic peptide (BNP)/ N-terminal pro-BNP (NT-proBNP) with a resting electrocardiogram. This first step helps in raising suspicion of a cardiopulmonary cause. The second step involves assessment of the heart with echocardiography and the lungs (if history is suggestive) using pulmonary function tests, chest imaging including X-ray and/or computed tomography, and in certain cases, cardiopulmonary exercise testing. 

The echocardiogram can help grade the probability of PH into low/intermediate/high categories, which are explained in detail below. Patients with intermediate/high probability of PH on echocardiogram and those with risk factors of PAH/CTEPH but with low probability and no other causes other than PH identified should be referred to a PH center for further comprehensive testing and confirmation of PH. The tests commonly used are mentioned below. 

Risk factors for PAH include CTD, human immunodeficiency virus (HIV), family history of PAH, portal hypertension, and risk factors for CTEPH include a history of pulmonary embolism, permanent intravascular devices, malignancy, inflammatory bowel diseases, essential thrombocythemia, and high dose thyroid replacement. 

During any time, if there are warning signs, including rapidly evolving clinical symptoms of RV failure, syncope, signs of low CO, decompensating hemodynamic status, or poorly tolerated arrhythmias, a fast-track referral should be made to a PH center. 

1. Laboratory testing: In all patients with PH, routine hematology studies, renal function tests, hepatic function tests, iron profiles, as well as thyroid studies should be performed. Thyroid dysfunction should always be suspected in cases with abrupt deterioration, as it is common in PAH and can occur during the course of the disease. Patients may also have abnormalities with liver function tests either due to congestive hepatopathy from right failure, liver disease, and/or endothelin receptor antagonist (ERA) therapy; such cases should be evaluated with hepatitis serologies. 

In addition, routine screening for HIV, serologies for hepatitis viruses, and CTD should be done. Patients with scleroderma have a high prevalence of PAH and should be routinely screened with ANA immunofluorescence. If the clinical index of suspicion is high, anticentromere, antitopoisomerase, anti-RNA polymerase III, double-stranded DNA, anti-Ro, anti-La, and U1-RNP antibodies should be obtained. Patients with CTEPH and those with CTD associated with thrombophilic states should be screened for coagulopathies, and thrombophilias, including lupus anticoagulant, anticardiolipin antibodies, and anti-β2-glycoprotein antibodies. 

Levels of BNP and NT-proBNP are independent predictors of outcomes and should be obtained in these patients. 

2. Electrocardiogram (ECG): A normal ECG does not exclude the diagnosis of PH, while an abnormal ECG may point towards severe disease, especially prolongation of the QRS complex and the QTc.[28][29][30][31] ECG abnormalities may include signs of right-sided heart strain and chamber enlargement, including P pulmonale, right axis deviation, RV strain, RV hypertrophy, right bundle branch block, and prolongation of the QTc. In advanced disease, supraventricular tachycardias, including atrial flutter and atrial fibrillation, can occur, while ventricular arrhythmias are rare.[32]

3. Chest radiography: Chest radiography may hold clues to underlying pulmonary hypertension, such as right heart enlargement, PA enlargement, pruning of peripheral vessels, and water bottle-shaped cardiac silhouette. Additionally, there may be signs of left heart disease such as Kerley B lines, pleural effusions, enlargement of the left heart, and signs of lung disease such as flattening of the diaphragm (COPD), hyperlucency (COPD), volume loss, and reticular opacifications (fibrotic lung disease). A normal chest X-ray does not rule out PH.[33][34][35]

4. Pulmonary Function Testing (PFT) and arterial blood gases: A complete set of PFTs can give diagnostic and prognostic information. Most patients with PAH have decreased diffusion capacity for carbon monoxide (DLCO), and a low DLCO of < 45% is associated with poor outcomes.[36][37] Spirometry can help detect obstructive airway disorders. A decrease in lung volumes and a decrease in DLCO may indicate interstitial lung disease. 

Patients with PAH usually have low normal or slightly low partial pressure of oxygen (PaO2). A severely reduced PaO2 should raise suspicion for shunting, such as in patent foramen ovale and hepatic disease. These patients also have alveolar hyperventilation, and as a result, the partial pressure of carbon dioxide (PaCO2) is low to low normal.[38] Unfavorable outcomes have been reported in patients with low PaCO2 at diagnosis and follow-up.[39] An elevated PaCO2 is unusual and should raise suspicion of sleep-disordered breathing or hypoventilation.[40]

5. Chest computed tomography (CT) and digital subtraction angiography (DSA): Chest CT is an important tool to identify interstitial lung diseases and thus helps in discriminating between various groups of PH. It also provides additional information which raises suspicion of PH, such as enlarged PA diameter, main PA/ascending aorta diameter ratio >0.9, and enlarged right heart chambers. A PA diameter ≥ 30 mm, right ventricular outflow tract (RVOT) thickness ≥ 6 mm, and septal deviation greater than 140 degrees (or right ventricle/left ventricle ratio ≥ 1) is highly predictive of PH.[41]

Contrast CT pulmonary angiography can demonstrate signs of CTEPH such as webs, bands, filling defects, enlarged bronchial arteries, and mosaic perfusion. When high-quality multi-detector CT scanners are coupled with experienced readers, CT pulmonary angiography can have high diagnostic accuracy for CTEPH.[42][43] Digital subtraction angiography (DSA) with conventional two or three-planar imaging is used in most centers to confirm CTEPH diagnosis and assess operability for endarterectomy or balloon pulmonary angioplasty.

6. Echocardiogram: Transthoracic echocardiography remains the single most important noninvasive assessment tool for PH. However, echocardiographic assessment should only be used to estimate the probability of PH, and an RHC is needed for confirmation of diagnosis as well as to guide therapy. Based on the data obtained from normal adults, the ESC/ERS guidelines came up with the following criteria that can be used to assign a low, intermediate, or high probability of PH. Tables 3 and 4 provide information about echocardiographic probability and signs suggestive of PH, respectively.[44][45][46][47]

Table 3: Echocardiographic probability of PH

Table 4: Signs on echocardiography suggestive of PH 

AR: aortic root; IVC: inferior vena cava; LV: left ventricle; LVEI: left ventricular eccentricity index; PA: pulmonary artery; RV: right ventricle; RVOT AT: right ventricular outflow tract acceleration time; sPAP: systolic pulmonary artery pressure; TAPSE: tricuspid annular plane systolic excursion; TRV: tricuspid regurgitation velocity

In patients with a high probability of PH on echocardiography with or without risk factors for PAH or CTEPH, an RHC should be done. In patients with risk factors for PAH/CTEPH and a low probability of PH on echocardiography, follow-up imaging should be considered. In similar patients with a medium probability of pulmonary hypertension, an RHC should be considered. In patients without risk factors for PAH or CTEPH and a low probability of PH on echocardiography, an alternative diagnosis should be considered, while in those with medium probability, an alternative diagnosis or further investigations can be considered.

Apart from assessing the probability of PH, echocardiography can also help detect the cause of PH, including congenital heart disease, valvular heart disease, as well as left-sided heart dysfunction. 

7. Cardiopulmonary exercise testing (CPET): In patients with symptoms induced by exercise, CPET is an important tool to assess the underlying cause. In patients with PAH, a low end-tidal partial pressure of carbon dioxide (PETCO2), high ventilatory equivalent for carbon dioxide (VE/VECO2), low oxygen pulse (VO2/HR), and low peak oxygen uptake (VO2) is typically seen.[48] In patients with systemic sclerosis, a normal peak VO2 can exclude the diagnosis of PAH.[49]

 8. Ventilation/perfusion scanning (V/Q): In patients with PH, a V/Q scan should be performed to rule out CTEPH, and it remains the preferred modality since a normal scan can exclude CTEPH with a sensitivity of 90-100% and a specificity of 94-100%.[50][51] With recent advances in computed tomography (CT), magnetic resonance imaging (MRI), and single photon emission CT (SPECT), the gap is narrowing between V/Q scans and these other modalities. The V/Q SPECT is superior to planar V/Q scan and should be the preferred modality if available.[33] Some of these imaging modalities and the expertise to interpret them may not be widely available, and further studies are needed to establish their clinical utility.[52][53][54]

9. Cardiac magnetic resonance imaging (cMRI): This is an incredibly powerful tool that accurately assesses the function of the atria and ventricles as well as their morphology. It can also measure blood flow through the vena cava, PA, and aorta, allowing for the quantification of stroke volume. However, there is no reliable method to estimate pulmonary artery pressures. The cost and availability are huge barriers to using cMRI, which is sensitive in detecting early PH.[55]

10. Abdominal ultrasound: The major reason to obtain an abdominal ultrasound is to detect liver abnormalities and/or portal hypertension. As pulmonary hypertension progresses, secondary damage to the liver and kidneys may occur, and this imaging modality will help in assessing the extent of the damage.[56]

11. Genetic testing and counseling: A trained PAH provider or geneticist should counsel patients with familial PAH, IPAH, HPAH, anorexigenic-associated PAH, pulmonary veno-occlusive disease, and pulmonary capillary hemangiomatosis that the family members could carry a mutation that increases their risk of PAH.[57] Whether testing is performed or not, this can inform the patient and family members to screen for early symptoms and signs to ensure a timely diagnosis. Advances in genetic sequencing technology have led to the development of gene panels that can simultaneously test for several gene mutations.[58] It is essential that a trained geneticist provides counseling and also help with the interpretation of the tests. 

12. Right heart catheterization (RHC): To confirm the diagnosis of PH, an RHC is mandatory. This should ideally be done at an expert center which tends to have low morbidity/mortality rates as well as the technical expertise to obtain high-quality data.[59] The procedure can yield enormous data, including right and left-sided filling pressures, PA pressure, PAWP, PVR, and CO. A few nuances regarding RHC measurements

• External pressure transducers must be zeroed at the level of the left atrium.

• PAWP should be measured at the end of normal expiration.[60]

• Cardiac output should be measured using the thermodilution method in triplicate. Thermodilution may be inaccurate in patients with intracardiac shunts, and direct Fick estimation may be needed.[61] This data should, however, be interpreted in context with the clinical picture and imaging findings, especially the echocardiography. 

Another component of RHC is vasoreactivity testing which should only be done in patients with IPAH, HPAP, and drug-induced IPAH. Inhaled nitric oxide at 10-20 parts per million is usually preferred, but intravenous epoprostenol, intravenous adenosine, or inhaled iloprost can also be used. If there is a reduction in mPAP ≥10 mmHg to the point where the absolute mPAP ≤40 mmHg with either unchanged or increased CO, it is considered a positive test. Patients who test positive are suitable for high-dose calcium channel blocker treatments. 

Other maneuvers, such as fluid challenge, can be used to discriminate IPAH from left ventricular diastolic dysfunction, but this needs to be further studied before it becomes the standard of care.[62][63] In patients with clinical risk factors for coronary artery disease or echocardiographic signs of left heart systolic/diastolic dysfunction, a left heart catheterization should also be performed. 

Contraindications to RHC include a recently implanted pacemaker (<1 month), known right atrial/ventricular thrombus, mechanical right heart valve, tricuspid valve clip, and acute infection. The most feared complication of the procedure is the rupture of the PA. 

Treatment / Management

The current treatment approach for a patient with PAH is based on a risk stratification approach that considers clinical, functional, exercise, hemodynamic, and right ventricular function parameters. Multiple studies have shown this approach of treatment based on methodical risk assessment at baseline and follow-up to predict survival or event-free survival.[64][65][66][67]

Every patient should be assessed at every visit using a multidimensional approach. To tackle this, there are various risk scores, but the three major ones that are used in the risk stratification are the US Registry to Evaluate Early and Long-term PAH Disease Management (REVEAL) equation and risk score, the 2022 European Society of Cardiology/European Respiratory Society (ESC/ERS) guidelines risk table which divides patients into low (<5%), intermediate (5 to 20%) or high (>20%) risk based on estimated one-year mortality and the French Pulmonary Hypertension Network (FPHN) Registry risk equation. The REVEAL 2.0 risk score calculator updates the original risk score calculator.[44][68][69][70][71][72][73][74] Across all the risk scores, studies have shown World Health Organization-functional class (WHO-FC), 6-minute walk distance, and BNP/NT-proBNP to be the strongest predictors of survival.[65][66][75]

There is some concordance between the ESC/ERS risk stratification and the REVEAL 2.0 score as follows: low risk = REVEAL score ≤6, intermediate risk=REVEAL score 7 and 8, and high risk=REVEAL score ≥9.[66] The REVEAL score has a large number of variables and a relatively short prediction period (1 year), while the ESC/ERS scoring system might have prognostic parameters belonging to more than one risk designation in the same patient. In general, there are limitations to all these stratification systems. Hence, a comprehensive risk assessment strategy that includes clinical judgment should be done for each patient while using these various scores as tools.[76] The overall goal of treatment is to achieve low-risk status. 

General and Supportive Measures

• For patients with PAH under medical therapy, a supervised exercise training program is recommended along with psychosocial support, while excessive physical activity causing distressing symptoms should be avoided.
• Patients with PAH should obtain vaccination against influenza, SARS-CoV-2, and Streptococcus pneumonia. 
• In patients with PAH with the arterial partial pressure of oxygen <60mmHg, long-term oxygen therapy, including in-flight oxygen, is recommended. 
• Optimization of anemia/iron status is recommended in patients with PAH. 
• Anticoagulation is not generally recommended in PAH but can be considered on an individual basis.
• For procedures requiring anesthesia, a multidisciplinary consultation at a PH center should be considered to assess the risks and benefits.
• Women of childbearing potential with PAH should be counseled against pregnancy and provided with clear contraceptive advice and psychosocial support.
• If women of childbearing potential desire to become pregnant or who become pregnant, counseling at an expert PH center, including genetic counseling, should be done. Adoption and surrogacy with pre-conception genetic counseling may be considered.
• Termination of pregnancy in women with PAH should be done at expert centers. Endothelin receptor antagonists and riociguat are teratogenic and should not be used during pregnancy. 
• Patients with PAH with signs of fluid retention and right ventricular failure should be treated with diuretic therapy. 
• The use of angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, beta-blockers, angiotensin receptor-neprilysin inhibitors, or ivabradine is not recommended in PAH unless other indications exist, such as hypertension, left heart failure, coronary artery disease or arrhythmias. 

Medical Management for IPAH

• Drug classes
  • Calcium channel blockers (CCBs): In patients with IPAH, HPAH, and drug-induced PAH that test positive during vasoreactivity testing, high-dose CCBs can be used as the first-line therapy. Amlodipine or nifedipine is preferred in patients who are relatively bradycardic at baseline.[77][78] Diltiazem is preferred in patients who are relatively tachycardic at baseline. Follow-up should be done 3 to 4 months after initiation of therapy. If the patient does not meet treatment goals, i.e., low-risk status defined as being WHO-FC I-II with marked hemodynamic improvement, additional PAH therapy should be initiated. The common side effects include hypotension and edema. 
  • Endothelin receptor antagonists (ERAs): Endothelin -1 causes vasoconstriction and mitogenic effects via the endothelin receptors type A. Endothelin B receptors promote vasodilation through clearance of endothelin-1 and accelerated production of prostacyclin and nitric oxide. However, non-selective blocking of endothelin receptors or selective blocking of endothelin A receptors has similar effectiveness in PAH.[79] Ambrisentan is an endothelin receptor type A antagonist, while bosentan and macitentan are dual type A and type B ERAs. Peripheral edema is seen with ambrisentan use; liver function test abnormalities can be seen with both ambrisentan and bosentan. Bosentan can reduce warfarin, sildenafil, and tadalafil levels and negate hormonal contraceptives' effects. Macitentan can cause a reduction in hemoglobin levels. These should not be used during pregnancy due to their teratogenic potential. 
  • Phosphodiesterase type 5 inhibitors (PDE-5i) and soluble Guanylate cyclase stimulators (sGCS): These medications predominantly act on the nitric oxide (NO) pathway. PDE-5 inhibitors prevent the degradation of cyclic guanosine monophosphate (cGMP), thus causing increased NO levels leading to vasodilation; they also have antiproliferative effects.[80][81][82] Sildenafil, tadalafil, and vardenafil are the PDE-5 inhibitors studied in PAH and cause side effects related to vasodilation, including flushing, headache, and epistaxis. Riociguat is a soluble guanylate cyclase stimulator enhancing cGMP production leading to vasodilation, with animal models even exhibiting antiproliferative and anti-remodeling properties.[83] It is currently approved for patients with CTEPH, and the most common serious adverse effect is syncope. It should not be combined with PDE-5 inhibitors as it can precipitate hypotension.
  • Prostacyclin analogs (PCA) and prostacyclin receptor agonists (PRA): Prostacyclins are potent vasodilators and endogenous inhibitors of platelet aggregation with cytoprotective and antiproliferative properties.[84] In patients with PAH, there is dysregulation of the prostacyclin pathway; hence, drugs targeting this pathway have been studied in PAH. Epoprostenol is a synthetic prostacyclin analog with a short half-life of 3 to 5 minutes and is administered via the intravenous route. Serious adverse events can occur due to pump malfunction, local site infection, catheter obstruction, and sepsis.[85] It is usually started at a dose of 2 to 4 ng/kg/min and up-titrated based on tolerance of side effects, including flushing, headache, leg pain, and diarrhea. Treprostinil can be administered via intravenous and subcutaneous routes predominantly. Oral and inhaled treprostinil formulations are also available. The drug can be administered via an infusion pump and subcutaneous catheter; the intravenous route is used only for those who cannot tolerate the subcutaneous infusion. Infusion site pain is the most common side effect.[86] Subcutaneous treprostinil is started at a dose of 1 to 2 ng/kg/min, and doses are escalated based on tolerance of side effects, including local site pain, flushing, and headache. Iloprost is another analog with intravenous formulations available. Selexipag is a prostacyclin receptor agonist and is administered orally. 

• Treatment approach: The drugs mentioned above target three separate pathways which lead to improvement in the disease - the endothelin system (antagonism), the prostacyclin pathway (agonism) as well as the nitric oxide pathway (agonism). The hemodynamic definitions of PH have changed recently, where the cutoff for abnormal mPAP was changed from ≥25 mmHg to >20 mmHg, and the cutoff for abnormal PVR from >3 WU to >2 WU. All the above-mentioned drugs have been studied in patients with mPAP >25mmHg and PVR>3 WU, and the efficacy of these drugs in patients with mPAP between 21 to 24mmHg and PVR 2-3 WU has not been established. Based on global experience and randomized controlled trials, the following treatment strategies have been recommended by the latest ESC/ERS guidelines.[1] These include:
  • General and supportive measures should be provided to all patients.
  • The new ESC/ERS guidelines recommend using the three strata risk stratification at initial evaluation (low risk, intermediate risk, and high risk) and four strata risk stratification at subsequent visits (low risk, intermediate-low risk, intermediate-high risk, and high risk). 
  • In patients without cardiopulmonary comorbidities who are classified as high risk, initial triple therapy with ERA, PDE-5i, and intravenous/subcutaneous PCA should be started. If the patient remains at high risk on follow-up, lung transplant evaluation should be initiated.
  • In patients without cardiopulmonary comorbidities who are low to intermediate risk, initial therapy should consist of ERA and PDE5i. If they remain in the intermediate-low risk status, PRA can be added, or the PDE5i can be switched to sGCS. If the patient goes into high-risk status, intravenous/subcutaneous PCA should be added. 
  • In patients with cardiopulmonary comorbidities, initial therapy should consist of either PDE5i or ERA. Thereafter, these patients should receive regular follow-up and individualized therapy. 
  • Cardiac comorbidities are defined as conditions associated with an increased risk of left ventricular diastolic dysfunction, including obesity, hypertension, diabetes mellitus, and coronary heart disease. Pulmonary comorbidities include parenchymal lung diseases and are often associated with low DLCO (<45% predicted value)

Interventional Therapy for IPAH

Balloon atrial septostomy and Potts shunt (shunt between left PA and descending aorta) can decompress the right heart, improving systemic blood flow and oxygen transportation despite causing desaturation. The procedures are rarely performed, are complex, and have substantial procedure-related mortality. They can only be considered in centers with expertise in the procedure.[87][88] Pulmonary artery denervation using intravascular ultrasound catheters and radiofrequency ablation is still in the experimental stages.[89][90] The technique aims to reduce sympathetic overdrive associated with vasoconstriction and vascular remodeling mediated through baroreceptors at the bifurcation of the PA.[91][92][93][94]

Lung and Heart-lung Transplantation

Referral to a transplant center should be made in patients with PAH who have an inadequate response to combination therapy, remain at intermediate-high or high risk of death, or have diseases such as pulmonary veno-occlusive disease or pulmonary capillary hemangiomatosis which respond poorly to medical treatment. 

A majority of patients receive a bilateral lung transplant with heart-lung transplant only reserved for patients with non-correctable cardiac conditions.[95] Patients who survive the early post-transplant period have good long-term outcomes, with one study demonstrating median survival of 10 years in patients who survived the first year post-transplant.[96]

Treatment of Group 1 Other Than IPAH/HPAH

• Drug-induced PAH should be diagnosed after eliciting relevant exposure and after other causes have been ruled out. The causative agent should be discontinued immediately if possible, and immediate PAH therapy should be considered in intermediate/high-risk patients. Patients who are low risk should be reassessed in 3 to 4 months, and PAH therapy can be considered if the hemodynamics are still abnormal.
• In patients with connective tissue disease-associated PAH, the underlying conditions should be treated, and the same approach as mentioned above for IPAH can be followed. 
• In HIV-associated PAH, antiretroviral treatment should be started. Initial monotherapy for PAH can be considered with a sequential combination if necessary. 
• In patients suspected to have Porto-pulmonary hypertension, a screening echocardiogram should be done, and they should be referred to expert centers. Initial monotherapy for PAH can be considered with a sequential combination if necessary. Liver transplantation can be considered on an individual basis as long as PVR is normal or near normal with PAH therapy.
• In patients with PAH due to congenital heart disease, closure of atrial septal defect (ASD), ventricular septal defect (VSD), or patent ductus arteriosus (PDA) is recommended if PVR <3 WU. For those with PVR between 3 and 5 WU, and PVR >5 WU initially that declines to < 5 WU after therapy, shunt closure can be considered. In patients with PVR >5 WU despite treatment, shunt closure should not be done. 
• In patients with congenital heart disease with defect closure/repair, risk assessment is recommended, and a treatment approach with initial combination therapy and subsequent sequential therapy based on risk assessment should be considered similar to patients with IPAH.
• In patients with Eisenmenger's syndrome, a risk assessment should be considered. In symptomatic patients, bosentan is recommended with consideration of adding other medications sequentially if treatment goals are not met. 

Management of PH-LHD

• Patients with suspected PH-LHD should be phenotyped into the probability of likeliness of LHD causing their PH, which is based on age, risk factors for LHD (obesity, hypertension, dyslipidemia, and diabetes), presence of known LHD, previous cardiac intervention, atrial fibrillation, structural LHD, ECG, echocardiogram, CPET, and cMRI. This will help in the decision to pursue further invasive assessment.
• An RHC should only be pursued if it will aid treatment decisions. If a severe pre-capillary component is suspected, a referral should be made to an expert center for further evaluation. 
• The cornerstone of therapy is optimizing underlying cardiac disease. 
• In patients with CpcPH, an individualized approach to treatment can be considered at an expert center, and current guidelines do not recommend for or against the use of PDE5i. However, these medications should definitely not be used in patients with IpcPH. 

 Management of Group 3 PH

PH in patients with lung disease is classified into severe PH (PVR >5 WU) or nonsevere (PVR < 5 WU).[97][98] However, it can sometimes be challenging to differentiate between group 1 and group 3 PH. An RHC should be done in patients suspected to have PAH or CTEPH as it may help with disease phenotyping; it should also be done in patients who are being considered for lung surgery, including lung transplant or lung volume reduction. Therapy should be focused on the treatment of the underlying disease. These patients should ideally be referred to expert centers for individualized treatment and consideration of transplant. Inhaled treprostinil has been approved in the United States for use in patients with PH associated with lung disease.

Management of Group 4 PH

Patients with suspected CTEPH should be referred to an expert center where confirmation of diagnosis should be done with computed tomography with contrast and/or digital subtraction angiography along with an RHC. Once the diagnosis is confirmed, the patients should be started on lifelong anticoagulation. Such patients should be discussed with a multidisciplinary team and, if deemed operable, should undergo pulmonary endarterectomy. Patients who are inoperable can be treated with balloon pulmonary angioplasty and/or riociguat. Sometimes patients with a pulmonary endarterectomy may have residual disease, and such patients can be treated with balloon pulmonary angioplasty and/or riociguat. 

Management of Group 5 PH

The mainstay of treatment is the management of the underlying condition. 

Differential Diagnosis

Diagnosis of PH is commonly delayed as the presenting symptoms overlap with other disease processes. Other conditions to be considered in the differential diagnosis include, but are not limited to, congestive heart failure, coronary artery disease, pulmonary fibrosis, chronic obstructive pulmonary disease, valvular heart disease, congenital heart disease, and pulmonary embolism.

Prognosis

If treatment is not initiated, progressive right heart failure and death occur in patients with PAH. Recent data from the United States suggests 1-year mortality as high as 8% for intermediate risk and 19% for high-risk patients, with 3-year mortality rates being 20% and 55% for those groups, respectively.[99] This emphasizes the importance of early diagnosis and aggressive therapy. Prognosis varies among different subgroups of PAH based on underlying etiology. Among patients with LHD, the presence of PH and right ventricular dysfunction is associated with high mortality.[15] In patients with lung disease, even nonsevere PH negatively impacts survival and is associated with increased hospitalization; those with severe PH have worse outcomes than those with nonsevere PH.[97][98][100] CTEPH has an excellent long-term prognosis if the disease is operable. 

Complications

• Right ventricular dysfunction/right heart failure
• Tachyarrythmias, including atrial fibrillation and atrial flutter; ventricular arrhythmias are less common
• Hemoptysis
• Mechanical complications include PA aneurysm/dissection/rupture, compression of the left main coronary artery, pulmonary veins, main bronchi, and recurrent laryngeal nerves
• Congestive hepatopathy/cirrhosis

Deterrence and Patient Education

Pulmonary hypertension has a diagnosis delay of more than two years from symptom onset, and clinicians should have a high index of suspicion. A stepwise evaluation and referral to expert centers should be done in a timely manner for prompt diagnosis of PH, its underlying cause, and aggressive therapy, as the disease can confer high morbidity and mortality. 

Patients should be aware of typical symptoms of the disease, such as shortness of breath on exertion, weight gain, and even subtle symptoms, such as fatigue, loss of appetite, chest pain, belly pain, and tiredness. They should be vigilant of such symptoms, especially if they have a family history of PH. There can be a delay in diagnosis, and patients may have to visit multiple doctors across various institutions before finally arriving at the diagnosis. This can lead to anxiety and frustration. Patients may have to undergo extensive testing, including blood tests, lung function tests, sleep studies, echocardiogram, and even a right heart catheterization. Management involves adhering to a low-salt diet, exercise, oxygen therapy, and medications such as diuretics and/or anticoagulants. Patients with PAH may require subcutaneous or intravenous drug therapy and need specialized education to manage those medications. 

Enhancing Healthcare Team Outcomes

Pulmonary hypertension can occur due to a variety of causes, as described above, but conditions such as PAH and CTEPH require highly specialized multidisciplinary care. An expert center is designated based on the availability of an interprofessional team, including a cardiologist, pulmonologist, rheumatologist, cardiothoracic surgery, interventional radiology, nurse specialist, pharmacists, social workers, and on-call experts. Such centers usually get referrals and therefore have large volumes, which tends to provide the best standard of care with better clinical outcomes.[101] [Level 2]

 Interprofessional care involves coordinated activity and open communication between all care team members, with each contributing from their areas of expertise. Clinicians will focus on their particular practice expertise, coordinating their actions with other disciplines. Nurses provide invaluable input, assisting in patient evaluation, helping with surgical procedures when necessary, counseling patients, and coordinating activities between the team members. Pharmacists will coordinate medication regimens, perform medication reconciliation, counsel patients on their drugs, and answer clinician questions regarding medications. Other areas, such as psychological professionals, will likewise coordinate their activities within the context of the rest of the care team. Interprofessional care teams provide the optimal approach for patients with pulmonary hypertension, leading to improved patient outcomes. [Level 5]