Challenges and Strategies in Managing Pulmonary Arterial Hypertension Within the Indian Healthcare System: A Consensus Statement From the Pulmonary Vascular Research Institute India Taskforce

ABSTRACT

Pulmonary arterial hypertension (PAH) in India is a substantial yet under‐recognized contributor to cardiovascular morbidity and mortality. Its progressive course, nonspecific early manifestations, and heterogeneous aetiologies often lead to delayed diagnosis and fragmented care. The unique epidemiological profile of India, characterized by a higher prevalence of PAH due to factors such as uncorrected congenital heart disease, environmental exposure, and chronic infections, underscores the need for a management approach tailored to Indian settings. These realities intersect with systemic challenges, including late presentation, resource constraints, a lack of local guidelines, and the costs of diagnostic workups and therapies, which hinder the delivery of standardized care. Variabilty in clinical practice in PAH management underscores the need for guidelines that account for local context and resources. Despite robust international recommendations, including those from the European Society of Cardiology and the European Respiratory Society, implementation of standardized risk stratification and treatment algorithms remains inconsistent across Indian centers. This variability reflects disparities in infrastructure, expertise, and affordability rather than differences in disease biology. This consensus document reviews current guidelines and advances in the management of PAH, consolidating evidence with potential for adoption in India and other low‐ and middle‐income countries (LMICs). This document also highlights the need to establish centers of excellence, develop specialized care protocols, and increase awareness to improve patient outcomes.

1. Background

Pulmonary hypertension (PH) presents a unique and pressing challenge due to its progressive and life‐threatening nature. Characterized by increased pulmonary arterial pressure and significant alterations in the pulmonary circulation, the condition is complicated by its heterogeneous nature and nonspecific early symptoms, which lead to misdiagnosis or underdiagnosis [1, 2, 3]. The pathogenesis and progression of PH involve complex biological processes, including inflammation, metabolic changes, genetic factors, and right ventricular abnormalities [4]. Advanced stages of PH are characterized by endothelial dysfunction, vaso‐occlusive lesions, and vascular remodeling influenced by aberrations in signaling pathways, including mutations in the bone morphogenetic protein receptor‐II (BMPR2) gene [4].

Compared to the West, India's burden of PH is higher due to unoperated congenital heart disease (CHD) and rheumatic heart disease, alongside other predisposing factors like a higher incidence of diabetes mellitus, hypertension, smoking, exposure to air and household pollution, hemoglobinopathies, and infections [5, 6, 7, 8]. This consensus document addresses the evaluation and management of group 1 PH (pulmonary arterial hypertension, PAH).

PAH can be idiopathic, heritable, or associated with broader conditions such as connective tissue diseases (CTD), congenital heart defects (CHD), and exposure to certain drugs and toxins [9]. It requires distinct diagnostic criteria and targeted therapeutic approaches, different from those for other types of PH. Effective PAH‐directed therapy improves median survival, underscoring the importance of treatment in specialised centers with multiple resources to secure an accurate diagnosis and tailored treatment [2].

While international guidelines provide a robust, evidence‐based framework, their direct application in low‐ and middle‐income countries (LMICs) may not address the practical realities of such regions. The management of PAH in LMICs like India is fraught with numerous challenges, including late presentation, prevalent comorbidities, resource constraints, and high costs associated with necessary diagnostic workups and therapies [10]. The considerable variations and disparities in care delivery for PAH necessitate guidelines that account for local context and resources [5].

This consensus document consolidates current evidence on the diagnosis and management of PAH and reframes it within the operational realities of Indian practice. It aims to define core evaluation principles, promote systematic risk‐based management, and advocate for the development of specialized care models that deliver equitable and sustainable PAH care.

1.1. Scope and Limitations

This document presents an expert consensus on the evaluation and management of PAH in the Indian healthcare context. The recommendations are informed by available evidence, established international guidelines, and the collective clinical experience of the writing group.

Recognizing variations in healthcare infrastructure, access to therapies, and economic considerations, some recommendations may differ in emphasis from global guidelines to better reflect local contexts. These recommendations are primarily intended for Indian practice settings and similar healthcare environments. They are designed to support, not replace, individualized clinical judgment and patient‐centered decision‐making.

2. Methods

This Indian Consensus Statement on Pulmonary Arterial Hypertension (PAH) was developed by a multidisciplinary panel of experts from the PVRI India Task Force. The panel comprised cardiologists, pulmonologists, rheumatologists, cardiac surgeons, and cardiopulmonary rehabilitation specialists from leading tertiary care centers across India. Each member was assigned specific sections based on clinical expertise and research interests to ensure subject‐specific depth, balanced representation, and scientific rigor.

A structured review of contemporary literature was undertaken, including randomized controlled trials, meta‐analyses, registry data, and major international guidelines relevant to the diagnosis and management of PAH. Draft recommendations were prepared by designated section leads and circulated among the full panel for iterative review. Areas of divergence were addressed through structured deliberations and consensus building until broad agreement was achieved.

Recommendations were assigned a Class of Recommendation and Level of Evidence using standard guideline definitions [11]. Where high‐quality evidence was available, recommendations were aligned with international standards; in areas lacking India‐specific data, expert consensus was used to contextualize guidance according to local epidemiology, healthcare infrastructure, and resource availability.

2.1. Definition and Classification

The 2022 European Society of Cardiology/European Respiratory Society (ESC/ERS) guidelines provide a detailed definition and classification of PH [9]. PH is defined hemodynamically by a mean pulmonary artery pressure (mPAP) > 20 mmHg at rest on right heart catheterization (RHC). Pulmonary arterial hypertension (PAH) is characterized by pre‐capillary PH with pulmonary artery wedge pressure (PAWP) ≤ 15 mmHg and pulmonary vascular resistance (PVR) > 2 Wood units (WU), in the absence of other causes of pre‐capillary PH (Table 1). The inclusion of updated hemodynamic parameters and thresholds in the new PAH diagnosis criteria aims to broaden the patient spectrum to include early‐stage PAH [12].

Table 1.

Hemodynamic definitions of PH.

Definition	Hemodynamic characteristics
PH	mPAP > 20 mmHg
Pre‐capillary PH	mPAP > 20 mmHg; PAWP ≤ 15 mmHg; PVR > 2 WU
IpcPH	mPAP > 20 mmHg; PAWP > 15 mmHg; PVR ≤ 2 WU
CpcPH	mPAP > 20 mmHg; PAWP > 15 mmHg; PVR > 2 WU
Exercise PH	mPAP/CO slope between rest and exercise > 3 mmHg/L/min

Abbreviations: CO, cardiac output; CpcPH, combined post‐ and pre‐capillary pulmonary hypertension; IpcPH, isolated post‐capillary pulmonary hypertension; mPAP, mean pulmonary arterial pressure; PAWP, pulmonary arterial wedge pressure; PH, pulmonary hypertension; PVR, pulmonary vascular resistance; WU, Wood units.

Clinical classification should follow standard World Symposium groupings, as this guides diagnostic evaluation, therapeutic strategy, and prognosis (Table 2) [9].

Table 2.

Clinical classification of pulmonary hypertension.

Group		Description	mPAP	PAWP or LVEDP	PVR
Group 1	Pulmonary arterial hypertension (PAH)	▪ Idiopathic ◦ Non‐responders at vasoreactivity testing ◦ Acute responders at vasoreactivity testing ▪ Heritable ▪ Associated with drugs and toxins ▪ Associated with: ◦ Connective tissue disease ◦ HIV infection ◦ Portal hypertension ◦ Congenital heart disease ◦ Schistosomiasis ▪ PAH with features of venous/capillary (PVOD/PCH) involvement ▪ Persistent PH of the newborn	> 20 mmHg	≤ 15 mmHg	> 2 WU
Group 2	PH associated with left heart disease	▪ Heart failure: ◦ with preserved ejection fraction ◦ with reduced or mildly reduced ejection fractiona ▪ Valvular heart disease ▪ Congenital/acquired cardiovascular conditions leading to post‐capillary PH	> 20 mmHg	> 15 mmHg	Isolated Pre‐capillary: PVR ≤ 2 WU Combined pre and Post‐capillary: PVR > 2 WU
Group 3	PH associated with lung disease and/or hypoxia	▪ Obstructive lung disease or emphysema ▪ Restrictive lung disease ▪ Lung disease with mixed restrictive/obstructive pattern ▪ Hypoventilation syndromes ▪ Hypoxia without lung disease (e.g. high altitude) ▪ Developmental lung disorders	> 20 mmHg	Normal	Elevated depending on severity
Group 4	PH associated with pulmonary artery obstructions	▪ Chronic thrombo‐embolic PH ▪ Other pulmonary artery obstructionsb	> 20 mmHg	Normal	Typically elevated
Group 5	PH with unclear and/or multifactorial mechanisms	▪ Hematological disordersc ▪ Systemic disordersd ▪ Metabolic disorders ▪ Chronic renal failure with or without hemodialysis ▪ Pulmonary tumor thrombotic microangiopathy ▪ Fibrosing mediastinitis	> 20 mmHg	Variable	Variable

Abbreviations: HF, heart failure; HIV, human immunodeficiency virus; LVEDP, left ventricular end‐diastolic pressure; mPAP, mean pulmonary artery pressure; PAH, pulmonary arterial hypertension; PAWP, pulmonary arterial wedge pressure; PCH, pulmonary capillary hemangiomatosis; PH, pulmonary hypertension; PVOD, pulmonary veno‐occlusive disease; PVR, pulmonary vascular resistance.

^a Left ventricular ejection fraction for HF with reduced ejection fraction: ≤ 40%; for HF with mildly reduced ejection fraction: 41%–49%.

^b Other causes of pulmonary artery obstructions include: sarcomas (high‐ or intermediate‐grade or angiosarcoma), other malignant tumors (e.g. renal carcinoma, uterine carcinoma, germ‐cell tumors of the testis), non‐malignant tumors (e.g. uterine leiomyoma), arteritis without connective tissue disease, congenital pulmonary arterial stenoses, and hydatidosis.

^c Including inherited and acquired chronic hemolytic anemia and chronic myeloproliferative disorders.

^d Including sarcoidosis, pulmonary Langerhans's cell histiocytosis, and neurofibromatosis type 1.

2.2. Epidemiology of PAH

The Global Burden of Disease Study 2025 estimated approximately 192,000 prevalent PAH cases globally, with an age‐standardized prevalence of 2.28 per 100,000 population and about 43,000 incident cases annually. Idiopathic PAH (IPAH) accounts for 30%–50% of Group 1 PAH [13]. Contemporary single‐center and multicenter registries report that patients with IPAH are now diagnosed at older ages and have better survival than earlier NIH registry cohorts. There is a strong female predominance (70%–80%), which diminishes with advancing age [13]. Survival has improved substantially with PAH‐targeted therapies, with current registries showing 1‐year survival exceeding 85% and 3‐year survival of 68%–70% [14].

Epidemiological data from low‐ and middle‐income countries, including the Indian subcontinent, are limited and largely derived from single‐center registries [15, 16]. In the PROKERALA registry, the largest registry from South Asia, PAH constituted 21.2% of pulmonary hypertension cases, with IPAH being the most common subtype, followed by congenital heart disease and connective tissue disease‐associated PAH [17].

The evaluation of patients suspected of having PAH is also affected by the limited availability of echocardiography and right heart cardiac catheterization (RHC) with acute vaso‐reactivity testing (AVT). The treatment patterns reveal the inadequate use of PAH specific therapies as reported in the PROKERALA registry [6, 17].

2.3. Clinical Presentation

PAH presents a unique challenge due to the often‐delayed onset of symptoms and diagnosis. The gradual development of symptoms like shortness of breath and fatigue, coupled with their nonspecific nature, can lead to misdiagnosis and delay healthcare seeking. Signs and symptoms can vary based on the underlying cause and disease progression. (Figure 1) The presenting symptom of PAH is usually exertional dyspnea and fatigue [18]. Other possible symptoms include reduced exercise capacity, chest discomfort, palpitations, edema, chest pain and syncope. Additional manifestations may include cough, hoarseness, and bluish discoloration of the nail beds. Sometimes, the patient may present with features of right heart failure, like peripheral edema and ascites. General physical examination findings may reveal distended jugular veins, cyanosis, hepatosplenomegaly, and ascites, along with cardiovascular findings such as a loud second heart sound and a pansystolic murmur of tricuspid regurgitation or an early diastolic murmur of pulmonary regurgitation [19].

Figure 1.

Clinical manifestations of pulmonary arterial hypertension (PAH). The range of symptoms and signs in PAH includes early symptoms like exertional dyspnea, fatigue, palpitations, and syncope. As the disease progresses, patients may show abdominal distension, fluid retention, and hemoptysis. Examination may reveal an accentuated pulmonary component of the second heart sound (P2), murmurs of tricuspid regurgitation (TR) or pulmonary regurgitation (PR), cyanosis, and indications of right ventricular (RV) failure. Certain findings can point to underlying causes such as congenital heart disease (CHD), connective tissue disease (CTD), or chronic thromboembolic pulmonary hypertension (CTEPH).

Clinical features that may point to an etiology must be actively sought, for example, Raynaud's phenomenon, small‐joint pain, photosensitivity, and malar rash, which may suggest a connective tissue disorder; differential cyanosis, which could be secondary to PDA with Eisenmenger syndrome; or telangiectasia and nasal bleeding, which could point towards hereditary hemorrhagic telangiectasia.

2.4. Initial Assessment

A step‐wise algorithmic approach for initial assessment of patients with suspected PAH is shown in Figure 2 [20]. Classical features of PAH on chest X‐ray and ECG are depicted in Figure 3. If PAH is suspected based on these initial tests and clinical judgment, the primary physician refers the patient to a specialist in pulmonary hypertension who conducts a more detailed clinical evaluation, confirms symptoms, and delves deeper into the medical and family history to identify possible etiological factors. The diagnosis of PAH is confirmed through right heart catheterization (RHC). Further investigations are conducted to determine the cause of PAH and assess the presence of co‐morbidities. (Table 3)

Figure 2.

Stepwise diagnostic algorithm for suspected pulmonary PAH. Patients presenting with unexplained dyspnea, syncope, or edema should undergo a structured evaluation. This includes taking a clinical history, assessing WHO functional class (WHO‐FC), performing a physical examination, obtaining a chest X‐ray and ECG, and measuring B‐type natriuretic peptide (BNP) or N‐terminal pro‐BNP (NT‐proBNP). Further assessment involves detailed echocardiography, focusing on tricuspid regurgitation velocity (TRV) and right heart function, as well as pulmonary evaluations such as pulmonary function tests (PFT), diffusion capacity (DLCO), arterial blood gases (ABG), and high‐resolution computed tomography (HRCT) to estimate the likelihood of PAH. Patients with intermediate or high probability of PAH should then undergo right heart catheterization (RHC). If CTEPH is suspected, a ventilation–perfusion (V/Q) scan or computed tomography pulmonary angiography (CTPA) is recommended.

Figure 3.

Chest radiograph and electrocardiographic findings in PAH. Representative posteroanterior chest radiograph (A) shows cardiomegaly with right ventricular enlargement and prominent central pulmonary arteries, and lateral chest radiograph (B) shows reduction of the retrosternal air space, a sign of right ventricular enlargement. Electrocardiogram (ECG) (C) shows p pulmonale (p > 0.25 mV in lead II, blue arrow), right axis deviation (QRS axis > 90°), features of right ventricular hypertrophy (R/S > 1, with R > 0.5 mV in V1, R in V1 + S in V5 > 1 mV, green arrows), incomplete right bundle branch block (red arrow), RV strain pattern (ST depression and T wave in version in right precordial leads V1–V4 and II, III, aVF, yellow arrows) and prolonged QT interval corrected for heart rate. These findings support the clinical suspicion of PH but lack sufficient sensitivity and specificity for diagnosis. Imaging and ECG abnormalities should be interpreted alongside echocardiographic and hemodynamic assessment. Lung perfusion scintigraphy in a patient with PAH demonstrating relatively homogeneous bilateral tracer distribution with mild diffuse heterogeneity (green arrows), without segmental or wedge‐shaped perfusion defects across multiple projections. hypertension. (D) Lung perfusion scintigraphy in a patient with CTEPH demonstrating multiple bilateral segmental and wedge‐shaped perfusion defects (white arrows) with heterogeneous tracer distribution across multiple projections. The presence of segmental mismatched perfusion defects is characteristic of CTEPH (E).

Table 3.

Recommended baseline investigations for systematic evaluation of underlying etiologies and relevant comorbidities in pulmonary arterial hypertension (PAH) without an apparent cause identified. The listed investigations aim to identify associated conditions and contributory disorders, and to detect cardiopulmonary and metabolic comorbidities that may influence classification and management strategy. If hemoglobin levels are low, then consider doing serum iron studies and Hb electrophoresis.

Category	Investigations
Laboratory Tests	Complete blood count
	Renal function tests
	Liver function tests
	Thyroid function test
	ANA by immunofluorescence assay
	HIV serology
	Hepatitis B and C serology
	HbA1c
Imaging	CT pulmonary angiography with HRCT chest
	Ventilation–perfusion (V/Q) scan
	Abdominal ultrasound with portal venous Doppler
Pulmonary evaluation	Complete lung function test
	Diffusion capacity (DLCO)
	Arterial blood gas
	Polysomnography

Abbreviations: ANA, antinuclear antibody; DLCO, diffusion capacity for carbon monoxide; HIV, human immunodeficiency virus; HRCT, high‐resolution computed tomography; PAH, pulmonary arterial hypertension; V/Q, ventilation–perfusion.

Pulmonary function tests (PFTs), arterial blood gas (ABG) analysis, ventilation–perfusion (V/Q) scanning, and CT imaging are essential components of the diagnostic work‐up for patients with PH. In PAH, PFTs are typically normal or show mild abnormalities, whereas a markedly reduced diffusion capacity for carbon monoxide (DLCO < 45% predicted), particularly when spirometry is otherwise preserved, should raise suspicion for pulmonary veno‐occlusive disease (PVOD), interstitial lung disease, or other group 3 PH [21, 22, 23]. ABG commonly shows mild hypoxemia and low PaCO₂ due to hyperventilation; severe hypoxemia suggests a right‐to‐left shunt or parenchymal lung disease. A V/Q scan is recommended in all patients to screen for chronic thromboembolic PH (CTEPH); a normal perfusion scan effectively excludes CTEPH, whereas mismatched segmental defects suggest thromboembolic disease [24, 25]. CT imaging provides additional information on PH severity and etiology, including pulmonary artery enlargement, right heart dilatation, parenchymal lung disease, PVOD features and characteristic findings of CTEPH on CT pulmonary angiography [26, 27]. Digital subtraction angiography is reserved for confirming CTEPH and assessing operability or suitability for balloon pulmonary angioplasty [28]. Overnight oximetry or polysomnography should be considered when sleep‐disordered breathing or hypoventilation is suspected [29].

2.5. Echocardiogram for Screening, Diagnosis and Evaluation of PH

Owing to its minimally invasive nature and ready availability, echocardiography plays a vital role in the diagnostic algorithm for PAH. Moreover, many echocardiographic parameters are closely related to pulmonary hemodynamics [30]. The flowchart used to assess the probability of PAH from the tricuspid regurgitation (TR) jet is shown in Table 4 [31].

Table 4.

Echocardiographic signs used to help grade the probability of PH.

Tricuspid regurgitation velocity (m/sec)	A: The ventricles	B: Pulmonary artery	C: Inferior vena cava and right atrium
➣ > 3.4 m/sec or ➣ 2.9‐3.4 m/sec and ≥ 2 of A/B/C High Probability	Right ventricle/left ventricle basal diameter ratio > 1.0	Right ventricular outflow Doppler acceleration time < 105 ms and/or mid‐systolic notching	Inferior vena cava diameter > 21 mm with decreased inspiratory collapse ( < 50% with a sniff or < 20% with quiet respiration)
➣ 2.9 − 3.4 and any one of A/B/C or ➣ ≤ 2.8 and ≥ 2 of A/B/C Intermediate probability	Flattening of the interventricular septum (left ventricular eccentricity index > 1.1 in systole or both systole and diastole)	Early diastolic pulmonary regurgitation (PR) velocity > 2.2 m/s	Right atrial area (end systole) > 18 cm2
➣ ≤ 2.8 and < 2 of A/B/C Low probability		PA diameter > 25 mm

Note: Echocardiographic stratification of PH probability using peak tricuspid regurgitation velocity (TRV) combined with supportive signs from at least two anatomical categories (right ventricle, pulmonary artery, inferior vena cava/right atrium), as recommended by ESC/ERS. Probability is classified as low, intermediate, or high, guiding referral for RHC.

Abbreviations: IVC, inferior vena cava; PA, pulmonary artery; PH, pulmonary hypertension; RA, right atrium; RHC, right heart catheterization; RV, right ventricle; TRV, tricuspid regurgitation velocity. Adapted from ESC/ERS guidelines for management of PAH [9].

In addition to suspecting PAH, an echocardiogram can also rule out congenital heart disease and LV diastolic dysfunction, which could suggest heart failure with preserved ejection fraction (HFpEF).

Accurate differentiation between IPAH and HFpEF is essential, as management strategies effective for IPAH may be inappropriate or even harmful when applied to patients with HFpEF‐associated PH. Table 5 enlists the echocardiographic features that differentiate PAH from HFpEF.

Table 5.

Echocardiographic assessment of elevated left atrial pressure, which helps in differentiation between IPAH and HFpEF.

Step	Assessment	Criteria	Conclusion
Step 1	Mitral inflow (E/A ratio)	E/A ≤ 0.8 and E ≤ 50 cm/s	Normal LAP
		E/A ≥ 2	Increased LAP (Grade 3)
		E/A ≤ 0.8 with E > 50 cm/s or E/A 0.8–1.99	Proceed to Step 2
Step 2	Evaluate 3 key parameters	Average E/e’ ≥ 14 TR velocity ≥ 2.8 m/s LAVi > 34 mL/m²	Count abnormal parameters
		≥ 2 abnormal	Increased LAP (Grade 2)
		0–1 abnormal	Normal LAP (Grade 1 or normal LAP)
Supportive parameters (if indeterminate)	Additional markers	Reduced e’ (septal ≤ 6 cm/s, lateral ≤ 7 cm/s) LARS ≤ 18% Pulmonary vein S/D ≤ 0.67 IVRT ≤ 70 ms	Presence of at least one suggest elevated LAP

Note: Stepwise assessment of mitral inflow (E/A ratio), average E/e′ ratio, tricuspid regurgitation velocity, and left atrial volume index (LAVi) to estimate left ventricular filling pressure and classify normal versus increased left atrial pressure (LAP), consistent with ASE/EACVI recommendations.

Abbreviations: E/A, early‐to‐late mitral inflow ratio; e′, early diastolic annular velocity; IVRT, isovolumic relaxation time; LAVi, left atrial volume index; LAP, left atrial pressure; LARS, left atrial reservoir strain; TR, tricuspid regurgitation.

2.6. Key Points to Consider

• 1.Reliable variables for estimation of LV filling pressure in patients with PH include lateral E/e′, mitral E/A, left atrial volume indexed to body surface area (LAVi), and left atrial reservoir strain (LARS).
• 2.An E/A ratio ≤ 0.8 is usually observed in patients with noncardiac PH, whereas a ratio ≥ 2 is observed in patients with group II PH.
• 3.LAVi > 34 ml/m², lateral E/e′ > 13, and LARS < 18% favor the presence of group II PH.
• 4.The recommended algorithm for patients with PH begins with mitral E/A: a ratio ≤ 0.8 favors precapillary PH, and a ratio ≥ 2 favors post‐capillary PH. For E/A > 0.8 but < 2, lateral E/e′ > 13, LAVi > 34 mL/m², and LARS ≤ 18% favor the diagnosis of group II PH.

2.7. Right Heart Catheterization (RHC)

RHC remains the gold standard for the diagnosis and hemodynamic classification and risk assessment of PAH [9]. It provides essential hemodynamic information, including right atrial pressure, cardiac output, pulmonary artery pressure, pulmonary artery wedge pressure, pulmonary vascular resistance and response to acute vasodilator testing (AVT). Given the resource constraints in India, RHC should be performed in experienced centers to minimize complications and diagnostic errors [32, 33, 34]. The indications for RHC are provided in Table 6. In carefully selected patients with unequivocal echocardiographic evidence of PAH and no evidence of left heart disease, temporary deferral of RHC may be considered. (Table 7) This approach must not be considered a substitute for invasive hemodynamic confirmation and RHC should be performed at the earliest feasible opportunity post initiation of medications. Invasive hemodynamic confirmation is necessary before major therapeutic escalation or when clinical uncertainty exists.

Table 6.

Indications, contraindications, and barriers in right heart catheterization.

Indications

Confirmation of PAH diagnosis Classification into pre and post‐capillary PH Assessing hemodynamics and calculation of parameters Identification of acute responders

RHC is mandatory

Diagnostic Doubt: ◦ Presence or absence of PH ◦ Reasonable doubt regarding group of PH (Group 1 vs Group 2) Before initiation of advanced therapy: Patients with inadequate response to upfront dual combination therapy, before initiating advanced pulmonary vasodilator therapy especially parenteral or inhaled prostacyclin analogs or sotatercept) Pre‐intervention: Atrial septostomy, Potts shunt Pre‐transplant: As part of workup for lung/heart and lung transplant Assess operability: To test for reversibility of pulmonary vascular disease in Congenital Heart Disease

Note: Indications for RHC include confirming the PH diagnosis, hemodynamic classification, assessing severity, performing vasoreactivity testing in selected patients with PAH, and pre‐intervention evaluation. Contraindications and systemic barriers in resource‐limited settings are summarized

Abbreviations: PAH, pulmonary arterial hypertension; PH, pulmonary hypertension; RA, right atrium; RHC, right heart catheterization; RV, right ventricle.

Table 7.

Echocardiographic Criteria in whom right heart catheterization may be deferred before initiation of pulmonary vasodilators.

High probability of PH * (Mandatory)

Absence of left heart disease (Mandatory) ◦ LVEF ≥ 55% ◦ No more than mild mitral or aortic valvular disease ◦ No evidence of elevated left atrial pressure**

Right‐sided pressure overload in absence of right ventricular outflow tract obstruction (At least 2) ◦ Moderate–severe RV dilatation: 1. RV basal diameter > 44 mm ( > 26 mm/m2) or 2. RV end diastolic area > 28 cm2 (> 15 cm2/m2) ◦ RV/LV basal diameter ratio > 1.0 ◦ Left ventricular eccentricity index > 1.1 in systole)

Objective RV dysfunction consistent with pressure overload (At least 2) ◦ TAPSE ≤ 17 mm or RV fractional area change ≤ 35% ◦ TAPSE/sPAp < 0.32 mm/mmHg ◦ IVC is dilated ( > 20 mm) and < 50% collapse with sniff

Note: This table summarizes the stringent echocardiographic criteria required before considering exceptional and temporary deferral of right heart catheterization (RHC) prior to initiation of oral pulmonary arterial hypertension (PAH)–specific therapy. In patients with a high probability of PH on echocardiography and without left heart disease, the specified number of supportive criteria in each category must be met. RHC remains the gold standard and should be performed at the earliest feasible opportunity.

Abbreviations: IVC, inferior vena cava; LV, left ventricle; LVEF, left ventricular ejection fraction; PH, pulmonary hypertension; RHC, right heart catheterization; RV, right ventricle; sPAP, systolic pulmonary artery pressure; TAPSE, tricuspid annular plane systolic excursion.

^*Criteria mentioned in Table 4.

^**Criteria as mentioned in Table 5.

Acute vasodilator testing (AVT) is a vital component of RHC, used to identify acute responders for initiation of calcium channel blockers (CCB). However, caution should be exercised in patients with suspicion of pulmonary veno‐occlusive disease (PVOD)/pulmonary capillary hemangiomatosis (PCH) or left heart disease, as AVT may induce flash pulmonary edema [35]. An acute responder is identified by a drop in mean PA pressure of ≥ 10 mmHg from baseline and an absolute mean PA pressure of less than 40 mmHg with an increase or no change to cardiac output (according to Sitbon's criterion) [36].

An ideal pulmonary vasodilator for AVT should be short‐acting, have minimal effect on the systemic circulation, and have maximal effect on the pulmonary circulation. The ideal agent for AVT is inhaled nitric oxide (iNO) at 10–20 ppm for 5–10 min [9]. Alternative agents, such as inhaled iloprost and epoprostenol, are not readily available in India. Oxygen is not recommended for AVT due to inherent fallacies and uncertainty regarding oxygen consumption [37]. Adenosine was previously recommended for AVT; however, due to a higher incidence of hypotension, the recent ESC/ERS guidelines no longer recommend its use [9]. Recently, intravenous sildenafil has been suggested as an alternative to iNO for AVT in resource‐limited settings where iNO is unavailable; however, additional data is needed before it can be routinely used for AVT [38].

2.8. Genetic Evaluation in PAH

Genetic testing helps to identify the specific gene mutations causing PAH, assess the prognosis and guide clinical decisions in patients with heritable PAH. It also aids in the risk stratification of family members. About 70%–80% of familial PAH and 10%–20% of idiopathic PAH are believed to result from BMPR2 mutations. In addition to BMPR2, around 20 other genes have been identified over the past two decades that are associated with an increased risk of PAH [39]. Genetic testing is recommended for patients with PAH without an identifiable cause, PAH that is out of proportion to CHD, or in patients with suspected PVOD/PCH. However, its routine implementation remains constrained by limited availability and high associated costs, particularly in resource‐limited settings. Table 8 outlines the target population for whom genetic testing is clinically indicated.

Table 8.

Target population for genetic testing.

A documented family history of PAH or unexplained premature cardiopulmonary death suggestive of heritable disease. Pre‐conception counseling in individuals with PAH, or in families in which one first‐degree relative has confirmed PAH, to enable informed reproductive decision‐making. Clinical or radiological suspicion of PVOD or PCH where genetic testing may assist in diagnostic confirmation. PAH that appears disproportionate to the underlying congenital heart disease, raising concern for superimposed pulmonary vascular disease or a genetic susceptibility.

Note: Clinical scenarios warranting genetic evaluation include family history of PAH, suspected heritable PAH, pulmonary veno‐occlusive disease/pulmonary capillary hemangiomatosis, inadequate response to therapy, and reproductive counseling.

Abbreviations: PAH, pulmonary arterial hypertension; PVOD, pulmonary veno‐occlusive disease; PCH, pulmonary capillary hemangiomatosis.

The genes associated with PAH include BMPR2, EIF2AK4, TBX4, ATP13A3, GDF2, SOX17, AQP1, ACVRL1, SMAD9, ENG, KCNK3, CAV1, and others [40]. While most PAH‐associated mutations are autosomal dominant, de novo mutations account for 19% of cases. Female sex is the most important factor determining the penetrance of the mutation, though other epigenetic and environmental factors may also influence it [41]. BMPR2 and ACVRL1 mutations often portend worse survival outcomes with a low probability of acute vasoreactivity. In patients with pulmonary veno‐occlusive disease (PVOD) or pulmonary capillary hemangiomatosis (PCH) identification of biallelic EIF2AK4 mutations confirms the diagnosis expediting the listing for lung transplant [42].

2.9. PAH in Special Situations (Other Than IPAH or HPAH)

• A. Connective tissue disorder associated PAH (CTD‐PAH)

  PAH is a recognized complication of connective tissue diseases, most commonly systemic sclerosis (SSc), systemic lupus erythematosus (SLE), and mixed CTD [43, 44]. In Western cohorts, SSc predominates, whereas SLE‐associated PAH may be more frequent in Asian populations [43, 44]. The prevalence of PAH in SSc ranges from 5% to 19%. Compared with idiopathic PAH (IPAH), CTD‐PAH patients are typically older, predominantly female ( ≈ 4:1), and often have coexisting interstitial lung disease, left heart involvement, or pulmonary venous/capillary pathology, which contribute to worse outcomes [43, 44]. Survival remains inferior to IPAH despite similar treatment algorithms [45]. Annual echocardiographic screening is recommended for asymptomatic SSc patients; other CTDs should be evaluated when symptomatic. Right heart catheterization (RHC) is recommended to confirm the diagnosis and exclude post‐capillary PH [9]. Management of CTD PAH generally follows IPAH pathways [9]. Immunosuppressive therapy may benefit selected patients with SLE‐ or mixed CTD‐associated PAH but has a limited role in SSc‐PAH [44]. Lung transplantation should not be withheld solely due to CTD, provided systemic involvement is carefully assessed [46].

• B. Drug/toxin‐induced PAH (DPAH)

  Exposure to anorexigens (e.g., fenfluramine), methamphetamine, cocaine, dasatinib, interferons (Type 1 interferons, specifically IFN α and IFN β), chemotherapeutic agents, and certain toxins is associated with PAH or, occasionally, PVOD/PCH [47, 48, 49]. Unlike IPAH, DPAH is characterized by a clear exposure history and potential reversibility, particularly with agents such as dasatinib and interferons [48].

  Once established, hemodynamics resemble IPAH. Immediate discontinuation of the offending agent is essential. In low‐risk patients, observation for 3–4 months after drug withdrawal may be reasonable before initiating PAH‐specific therapy [9]. Patients with persistent hemodynamic abnormalities or advanced presentation should receive standard PAH therapy [9]. Unlike IPAH, treatment de‐escalation may be possible in selected cases after recovery [49].

• C. Portopulmonary hypertension (PoPH) and portocaval malformations

  Portopulmonary hypertension occurs in 2–6% of patients with portal hypertension, with or without advanced liver disease [50, 51]. It must be distinguished from hepatopulmonary syndrome (HPS), which results from pulmonary arteriovenous dilatations. However, both conditions may coexist. Excess circulating vasoactive mediators from portosystemic shunting contribute to pulmonary vascular remodeling. Congenital or acquired portocaval malformations (e.g., Abernethy malformation) are a related entity in which direct portal‐systemic shunting can cause PAH even in the absence of cirrhosis [52, 53]. Compared with IPAH, these patients may present with high cardiac output, thrombocytopenia, liver dysfunction, or abnormal hepatic imaging. Echocardiography may overestimate severity due to a hyperdynamic circulation; RHC is mandatory for diagnosis [9]. In selected patients with portocaval malformations, shunt correction may improve hemodynamics [52]. PAH therapy follows standard algorithms but requires careful attention to hepatic function and gas exchange [9]. Although PoPH is not a contraindication for liver transplantation, severe PAH increases liver transplant risk; mean PAP > 45 mmHg is generally considered a contraindication, and hemodynamic optimization (mPAP < 35 mmHg with acceptable PVR) is recommended before listing [54].

• D. Human Immunodeficiency Virus associated PAH (HIV‐PAH)

  The prevalence of PAH among people living with HIV is approximately 0.4–0.5% [55]. HIV proteins like Tat and Nef may play a role in the pathogenesis of HIV‐PAH. Routine screening of asymptomatic individuals is not recommended; echocardiography should be performed in those with unexplained dyspnea and should be confirmed on RHC [55]. Clinical and histopathological features resemble IPAH, but there is no consistent correlation with viral load, CD4 count, or HIV stage [56]. Highly active antiretroviral therapy (HAART) is recommended for all patients, irrespective of immune status, and improves functional outcomes [57]. Endothelin receptor antagonists, PDE5 inhibitors, and prostacyclin analogs may be used; however, drug–drug interactions, particularly between PDE5 inhibitors and protease inhibitors, require careful dose adjustment [58]. Unlike IPAH, upfront combination therapy is not well established, and many patients may begin with monotherapy followed by individualized escalation [9]. Prognosis has improved substantially in the HAART era, with outcomes matching those of IPAH [57].

• E. PAH with venous or capillary involvement: Pulmonary veno‐occlusive disease (PVOD) and pulmonary capillary hemangiomatosis (PCH)

  PVOD and PCH are rare causes of pre‐capillary PH, accounting for up to 5%–10% of cases initially labeled as IPAH with an estimated prevalence of < 1/million [59]. Compared with IPAH, PVOD/PCH often presents with more severe exercise hypoxemia, markedly reduced DLCO ( < 50% predicted), and characteristic high‐resolution computerized tomography (HRCT) findings, including smooth septal thickening, centrilobular ground‐glass opacities, and mediastinal lymphadenopathy [59]. Hemodynamics are consistent with IPAH, but pathology predominantly involves the small pulmonary veins and capillaries. EIF2AK4 mutations confirm heritable forms [35]. Lung biopsy is contraindicated due to high procedural risk [9]. Unlike IPAH, vasodilator therapy may precipitate pulmonary edema and should be initiated cautiously in expert centers [59]. Imatinib, a tyrosine kinase inhibitor with antiproliferative properties, has been explored in PVOD. Small observational studies report improvements in functional class, hemodynamics, oxygenation, and survival [60, 61]. However, evidence remains limited, and larger prospective studies are needed to establish safety and efficacy. Lung transplantation is the only definitive treatment, and early referral is strongly recommended [9].

• F. Pulmonary arterial hypertension associated with congenital heart disease (PAH‐CHD)

  PAH‐CHD represents a heterogeneous subgroup within Group 1 PH and occurs in approximately 3%–7% of adults with CHD, with higher risk in females and in unrepaired or late‐repaired lesions [62]. Clinical phenotypes include Eisenmenger syndrome, PAH with prevalent systemic‐to‐pulmonary shunts (correctable or non‐correctable), PAH with small/coincidental defects, and PAH that persists or recurs after defect closure [9]. Compared with IPAH, patients with Eisenmenger syndrome (ES) may have relatively preserved right ventricular function with maintained cardiac output due to right‐to‐left shunting, resulting in a relatively stable long‐term course [63]. However, cyanosis secondary to the right‐to‐left shunt results in multisystem complications [63]. Diagnosis requires comprehensive imaging. Although RHC with oximetry is the gold standard, it may not be mandatory if all the clinical, radiologic and echocardiographic criteria for ES are met. Shunt closure is contraindicated in patients with ES, as well as in those with a coincidental shunt [9]. Targeted PAH therapy with sequential up titration improves functional capacity and hemodynamics, particularly in patients with ES [9]. Management should include careful attention to arrhythmia management, iron deficiency, anticoagulation decisions, and pregnancy counseling [64].

In patients with a prevalent systemic‐to‐pulmonary shunt, shunt closure (partial or complete) should be performed only after careful multiparametric assessment, including RHC [9]. However, it should be noted that there is a lack of prospective data to suggest the usefulness of vasoreactive testing, balloon occlusion or lung biopsy to predict normalization of PVR post shunt closure [65]. With an estimated prevalence of 3%, patients with persistent or recurrent PAH after shunt closure have a worse prognosis than those with ES and behave more like IPAH [66]. Management guidelines for these patients should follow those for IPAH [9].

2.10. Management of Pulmonary Arterial Hypertension

• I. Risk stratification

  The first step in managing PAH is risk stratification. The 2015 ESC/ERS guidelines introduced a risk stratification model categorizing patients with PAH into three risk groups based on estimated 1‐year mortality: low ( < 5%), intermediate (5%–10%), and high ( > 10%) [67]. Subsequent analyses of large registries showed that observed mortality often exceeded the initial estimates, prompting refinement of risk categorization [9]. Over time, the development of simplified risk stratification tools has substantially improved the clinical applicability of these frameworks. Among these, the REVEAL 2.0 score and its simplified version, REVEAL Lite 2, derived from the US‐based REVEAL registry, have highlighted the prognostic importance of readily measurable variables such as WHO functional class, 6‐min walk distance (6MWD), and BNP/NT‐proBNP levels [68, 69].

  In 2022, the ESC/ERS guidelines further updated the risk assessment strategy, recommending a three‐strata model at baseline and a simplified three‐parameter, four‐strata model during follow‐up [9, 70]. (Table 9 and 10) Risk stratification should be performed at baseline and at each follow‐up (3−6 months, depending on the patient's clinical condition).

  The nature of these models, including reliance on invasive hemodynamic and advanced investigations especially at baseline assessment, may limit consistent implementation in resource‐limited settings such as India, and there is a pressing need to develop and validate such algorithms in the Indian clinical setting.

  Alongside traditional risk stratification models, echocardiography is an important tool for assessing disease severity and response to therapy. A common misconception is to interpret changes in right ventricular systolic pressure (RVSP), as estimated by echocardiography, as a direct indicator of clinical improvement or deterioration. In reality, RVSP alone may not reliably reflect hemodynamic status or treatment response [9]. Greater prognostic value lies in assessing RV function and RV‐to‐PA coupling. Parameters reflecting RV adaptation to increased afterload provide more meaningful insights into disease trajectory and outcomes [11]. The key echocardiographic parameters to be measured at baseline and follow‐up are listed in Table 11.

• II. General measures

Table 9.

ESC/ERS risk stratification for PAH at baseline assessment.

Determinants of prognosis (estimated 1‐year mortality)	Low risk (< 5%)	Intermediate risk (5%–10%)	High Risk (> 20%)
Clinical observations and modifiable variables
Signs of right heart failure	absent	absent	present
Progression of symptoms and clinical manifestations	No	Slow	Rapid
Syncope	No	Occasional	Repeated Syncope
WHO‐FC	I, II	III	IV
6MWD	> 440 m	165–440 m	< 165 m
CPET	Peak VO2 > 15 mL/min/Kg( > 65% pred.) VE/VCO2 slope < 36	Peak VO2 11–15 mL/min/Kg(35%–65% pred.) VE/VCO2 36–44	Peak VO2 < 11 ml/min/Kg(< 35% pred.) VE/VCO2 slope > 44
Biomarkers: BNP or NT‐proBNP	BNP < 50 ng/L NT‐proBNP < 300 ng/L	BNP 50–800 ng/L NT‐proBNP 300–1100 ng/L	BNP > 800 ng/L NT‐proBNP > 1100 ng/L
Echocardiography	RA area < 18 cm2 TAPSE/sPAP > 0.32 mm/mmHg No pericardial effusion	RA area 18–26 cm2 TAPSE/sPAP 0.19–0.32 mm/mmHg Minimal pericardial effusion	RA area > 26 cm2 TAPSE/sPAP < 0.19 mm/mmHg Moderate or large pericardial effusion
cMRI	RVEF > 54% SVI > 40 mL/m2 RVESVI < 42 mL/m2	RVEF 37‐54% SVI 26–40 mL/m2 RVESVI 42–54 mL/m2	RVEF < 37% SVI < 26 mL/m2 RVESVI > 54 mL/m2
Hemodynamics	RAP < 8 mmHg CI ≥ 2.5 L/min/m2 SVI > 38 ml/m2 SvO2 > 65%	RAP 8–14 mmHg CI 2.0–2.4 L/min/m2 SVI 31–38 ml/m2 SvO2 60%–65%	RAP > 14 mmHg CI < 2.0 L/min/m2 SVI < 31 mL/m2 SvO2 < 60%

Note: The ESC/ERS risk model is a three‐tier classification at diagnosis, reproduced with permission [9]. It integrates clinical status, biomarkers, echocardiographic parameters, and 6‐min walk distance to categorize patients into low, intermediate, or high risk. The risk assessment algorithm assigns a value to each variable—1 point for low risk ( < 5% 1‐year mortality), 2 points for intermediate risk (5%–20%), and 3 points for high risk ( > 20%), thus quantifying the severity of RV dysfunction and functional limitation. A valid baseline stratification requires integration of at least 3 disparate parameters out of 10 (e.g., WHO‐FC, 6MWD, NT‐pro‐BNP, or Echo indices) to compute a composite score that reflects the patient's state. The sum of all variable scores is divided by the number of variables entered and then categorized as low risk (1–1.5), intermediate risk (1.5–2.5), and high risk ( > 2.5).

Abbreviations: 6MWD, 6‐min walk distance; BNP, B‐type natriuretic peptide; CI, Cardiac Index; cMRI, cardiac magnetic resonance imaging; CPET, cardiopulmonary exercise testing; NT‐pro BNP, N‐terminal pro–B‐type natriuretic peptide; PAH, pulmonary arterial hypertension; Peak VO₂, peak oxygen consumption; RA, right atrial; RAP, right atrial pressure; RVEF, right ventricular ejection fraction; RVESVI, Right Ventricular End‐Systolic Volume Index; sPAP, systolic pulmonary arterial pressure; SVI, Stroke Volume Index; SvO_2, mixed venous oxygen saturation; TAPSE, tricuspid annular plane systolic excursion; VCO₂, carbon dioxide production; VE, minute ventilation; WHO‐FC, World Health Organization functional class.

Table 10.

ESC/ERS three‐parameter strata risk stratification at follow‐up.

Determinants of prognosis	Low risk	Intermediate‐low risk	Intermediate‐high risk	High risk
Points assigned	1	2	3	4
WHO‐FC	I or II	—	III	IV
6MWD, m	> 440	320–440	165–319	< 165
BNP or NT‐proBNP, ng/L	< 50 < 300	50–199 300–649	200–800 650–1100	> 800 > 1100

Note: This table summarizes the three‐parameter, four‐strata risk assessment model for pulmonary arterial hypertension (PAH) at four‐year follow‐up as proposed in the European Society of Cardiology/European Respiratory Society (ESC/ERS) guidelines, and is reproduced with permission [9]. Patients are categorized into low, intermediate‐low, intermediate‐high, and high‐risk groups based on integrated assessment of functional status, exercise capacity, and biomarkers. Points (1–4) correspond to increasing risk severity. Risk stratification should be based on a comprehensive evaluation rather than a single parameter. Risk is calculated by dividing the sum of all grades by the number of variables and rounding to the next integer. WHO‐FC I & II are assigned 1 point as both are associated with good long‐term survival.

Abbreviations: 6MWD, 6‐min walk distance; BNP, B‐type natriuretic peptide; NT‐proBNP, N‐terminal pro–B‐type natriuretic peptide; WHO‐FC, World Health Organization functional class.

Table 11.

Echocardiographic parameters that should be recorded at baseline as well as on follow‐up in patients with PAH.

Parameter	Purpose/Clinical relevance	Baseline assessment	Follow‐Up assessment	Notes (Indian Context/Practical Cut‐offs)
RV size (basal diameter/area)	Detect RV dilation, monitor remodeling	☑	☑	RV basal diameter ≥ 42 mm abnormal; RA/RV area ratio can supplement
RV systolic function (TAPSE)	Assess RV contractility	☑	☑	TAPSE ≥ 17 mm normal; easy and widely available
TAPSE/sPAP ratio	Surrogate of RV–PA coupling; prognostic	☑	☑	TAPSE/sPAP < 0.31 mm/mmHg indicates worse prognosis; feasible in echo labs with Doppler
RV fractional area change (FAC)	Complement TAPSE for RV function	☑	☑	Optional if reproducible
Tricuspid regurgitation (TR) velocity/gradient	Estimate PASP and RV pressure	☑	☑	Easy Doppler‐based estimate of RVSP
RA size/RA area	Assess right atrial enlargement	☑	☑	RA area > 18 cm² abnormal; monitor for progression
Pericardial effusion	Prognostic marker	☑	☑	Small/moderate/large; included in risk scoring
IVC diameter & collapsibility	Estimate RA pressure, assess volume status	☑	☑	IVC diameter ≤ 21 mm with > 50% collapsibility = normal RA pressure
RVGLS and RVFWS	Assess RV function	☑	☑	Optional parameters to assess RV function

Note: Key structural and functional parameters to be recorded at diagnosis and during follow‐up in PAH, including right ventricular size and function (TAPSE, fractional area change), TAPSE/systolic pulmonary arterial pressure ratio, right atrial area, tricuspid regurgitation velocity, inferior vena cava dimensions, and pericardial effusion.

Abbreviations: PAH, pulmonary arterial hypertension; TAPSE, tricuspid annular plane systolic excursion; FAC, fractional area change; sPAP, systolic pulmonary arterial pressure; RA, right atrium; IVC, inferior vena cava; TEE, transesophageal echocardiography; RVGLS, Right Ventricle Global Longitudinal Strain; RVFWS, Right Ventricle Free Wall Strain.

Supportive therapies play an essential role in optimizing the management of patients with PAH alongside disease‐specific pharmacologic and interventional treatments. These measures aim to relieve symptoms, prevent complications, and enhance quality of life.

• A. Diuretics

  Diuretics are frequently used to control volume overload and peripheral edema secondary to right heart failure. Increased right‐sided filling pressures are transmitted to the renal veins, thereby increasing tubular and hydrostatic pressures and decreasing glomerular filtration rate, worsening renal function. Fluid restriction and diuretic therapy, including loop diuretics, thiazide diuretics and mineralocorticoid receptor antagonists, could be used in isolation or combination, depending on the patient's general condition. Care should, however, be taken to avoid intravascular volume depletion, which may lead to further decrease in cardiac output and systemic blood pressure [71].

• B. Oxygen

  While oxygen is recognized for its positive impact on pulmonary hemodynamics, there is limited data on the advantages of long‐term oxygen therapy for patients with PAH. It may be recommended for patients with SpO2 less than 92% on room air at sea level. Ambulatory oxygen may be recommended if there is symptomatic benefit and correctable desaturation during exercise [72].

• C. Treatment of anemia and iron deficiency

  In a patient with PH and anemia, it is imperative to identify the cause of anemia and offer appropriate treatment. Hb electrophoresis should be performed to rule out hemoglobinopathies, as they are an important causes of PH.

  Iron deficiency, defined as serum ferritin < 100 mcg/L or serum ferritin 100‐299 mcg/L and transferrin saturation < 20%, is common in patients with PAH. It is associated with impaired myocardial function, decreased exercise capacity and increased mortality. Parenteral iron supplementation is recommended in the presence of severe anemia (Hb < 7‐8 g/dl) [9].

• D. Anticoagulation

  Patients with PAH may have a prothrombotic state due to abnormalities in coagulation and fibrinolytic pathways. However, there is a lack of robust data demonstrating the benefit of anticoagulation in PAH. Moreover, anticoagulation is associated with an increased risk of bleeding, thus warranting an individualized approach to initiation and long‐term continuation of anticoagulants [9]. In patients with IPAH/HPAH, anticoagulation may be considered for those with evidence of in situ thrombosis [9]. Anticoagulation remains appropriate in PAH patients with established cardiovascular indications such as atrial fibrillation or documented venous thromboembolism. In contrast, it is generally not recommended in connective tissue disease–associated PAH, portopulmonary hypertension, congenital heart disease–associated PAH or suspected pulmonary veno‐occlusive disease, where bleeding risk may outweigh potential benefit [9].

• E. Vaccination

  In addition to routine vaccination, it is recommended that all patients with PAH should be vaccinated against influenza and Streptococcus pneumoniae [9].

• F. Exercise and yoga‐based rehabilitation

  Exercise‐based rehabilitation for PAH is a topic of growing interest due to its potential to improve patient outcomes through physiological pathways. These programs can improve functional capacity, quality of life, and long‐term survival in patients with PAH [73, 74]. They follow general guidelines: a warm‐up, aerobic and strength‐training components, and a cool‐down. Training components may vary slightly based on the etiology of PAH [73]. The programs are usually offered supervised or unsupervised, with sessions being delivered two to three times per week for a minimum of 4 weeks [75]. Flexibility in delivery, based on technology availability, could facilitate participation in home‐based programs that have been implemented safely and effectively in the Indian setting [75, 76]. The functional benefits also translate to cost‐effectiveness and survival benefits of 97%–100% at 1 year, 94%–100% at 2 years, and 80%–86% at 3 years, as shown from non‐randomized trials [77, 78, 79, 80, 81]. Table 12 enlists the referral criteria, exercise prescription parameters, monitoring requirements, and termination criteria for structured exercise training in patients with PAH [74, 76].

  Recently, integration of yoga‐based approaches in cardiopulmonary rehabilitation have been gaining prominence. Yoga‐based exercises could improve the quality of life in the short term and be safe in those with PAH [82, 83]. While the optimal training dose, supervision characteristics, mechanisms of adaptation, and long‐term impact on survival in PAH remain uncertain, there appears to be potential for yoga‐based interventions.

• G. Support groups

  In addition to medical and supportive therapies, patient support groups have emerged as an important adjunct in the comprehensive management of PAH. These groups provide an essential platform for patients and caregivers to share experiences, foster peer support, and deepen understanding of the disease and its treatment. Globally, the Pulmonary Hypertension Association (PHA) has played a vital role. In India, the Pulmonary Hypertension India (PHI) (https://pulmonaryhypertensionindia.org/) group has played a pivotal role in patient education, advocacy, and community building.

Table 12.

Recommendations for referral to exercise‐based cardiopulmonary rehabilitation, prescription, monitoring and termination of exercise.

Referral

Any etiology of PAH and PH WHO functional class I–III Stable on medical therapy for 3 months

Prescription (Aerobic Exercise)

Frequency: 3–5 days/week Intensity: Moderate intensity (Borg's rating of perceived exertion; RPE: 11–13/20) Type: Walking, cycling, stepping, stair climbing Time: 10–15 min Progression: Every two weeks

Prescription (Resistance exercise)

Frequency: 2–3 days/week Intensity: Moderate intensity (Borg's rating of perceived exertion; RPE: 11–13/20) Type: Body weight supported for upper and lower limb, low resistance with free weights Time: 10–15 repetitions Progression: Every two weeks

Mode of delivery

Home, supervised, or hybrid

Type of exercise intervention

Aerobic and resistance ± inspiratory muscle training

Monitoring

Symptoms (dizziness, syncope, palpitation, breathlessness) Borgs Rating of perceived exertion Oxygen saturation Heart rate (if telemetry available) New onset arrhythmias (if telemetry available) Blood pressure

Termination of exercise

Worsening symptoms or symptoms out of proportion to usual High levels of exertion (RPE > 14/20) Drop in oxygen saturation ( < 85%) Heart rate > 120 bpm (if telemetry available) New onset arrhythmias (if telemetry available) > 20 mmHg drop in systolic blood pressure or > 220 mmHg systolic blood pressure or diastolic blood pressure > 110 mmHg

Note: This table summarizes referral criteria, exercise prescription parameters, monitoring recommendations, and termination criteria for structured aerobic and resistance training in clinically stable patients with PAH and PH. Exercise should be individualized and delivered through supervised, home‐based, or hybrid rehabilitation programs with appropriate safety

monitoring. Adapted from: Poojary G et al. Pulse (Basel). 2024;12:66–75 [63]; and Babu AS et al. Indian Heart J. 2019;71:161–165 [65].

Abbreviations: PAH, pulmonary arterial hypertension; PH, pulmonary hypertension; RPE, rating of perceived exertion; WHO‐FC, World Health Organization functional class.

• III. Special issues of concern in PAH

• A. Travel and altitude

  In patients with PAH, hypobaric hypoxia can cause arterial hypoxemia, leading to pulmonary vasoconstriction and increased right ventricular (RV) afterload. However, short‐term hypoxia (less than 1 day) is generally well tolerated in these patients. For those with SpO2 below 92% on room air at sea level, in‐flight oxygen supplementation is advised. Since the impacts of moderate to long‐term hypoxia in PAH patients are not fully understood, supplemental oxygen is recommended, particularly at altitudes exceeding 1500 meters [9].

• B. Pregnancy and contraception

  Peripartum maternal and neonatal mortality in PAH remains high despite advances in therapy. Most improvements in outcomes in high‐income countries are driven by access to parenteral and inhaled prostacyclin analogs, which are considered relatively safe in pregnancy but remain limited in availability in India [84]. In contrast, endothelin receptor antagonists and riociguat are contraindicated due to proven teratogenicity in animal studies at doses higher than those used in humans [84]. Given these constraints, pregnancy avoidance should be strongly recommended for women with PAH in India, particularly those in the intermediate or high risk category [9, 84]. Medical termination of pregnancy should be advised for patients who become pregnant inadvertly [84]. The same should ideally be performed under the supervision of a multidisciplinary team at a PAH care center. Similarly, if a patient wishes to become pregnant or continue the pregnancy, it should be managed at a PAH care center throughout pregnancy and the post‐partum period [9, 84].

  Women of childbearing potential with pulmonary hypertension should receive early and repeated counseling regarding effective contraception, given the high maternal and fetal risk associated with pregnancy [84]. Contraceptive choice should be individualized, considering availability, affordability, and drug interactions. Abstinence and barrier methods of contraception have high failure rates and should not be used as primary method for contraception, Methods with low failure rates ( < 1%), such as intrauterine devices, implants, and male/female sterilization, are the most preferred options [9, 84]. For tubal ligation, an open mini‐laparotomy might be favored over laparoscopic procedures in women with PAH [84]. Estrogen‐based contraceptive methods are not recommended in PAH due to prothrombotic properties and adverse effects on pulmonary vasculature [84]. Progesterone‐only contraceptive methods, including implants, depot medroxyprogesterone acetate injections, and progesterone‐only pills, are acceptable methods for contraception in PAH [84]. However, dual contraception is preferred in patients using progesterone‐only pills due to higher failure rates [84]. Long‐acting progesterone‐only intrauterine devices (IUDs) are preferred over copper IUDs due to a lower risk of menorrhagia [84]. In patients receiving bosentan, reduced efficacy of hormonal contraceptives should be anticipated. Emergency post‐coital contraception, especially levonorgestrel‐based contraception, is safe in PAH [9].

• C. Non‐cardiac surgery

  Surgical procedures in patients with pulmonary hypertension carry a high risk of right heart failure and perioperative mortality, particularly in emergency settings and advanced disease. Outcomes are strongly influenced by PAH severity, surgical urgency, and availability of perioperative expertise. Surgical decisions should be individualized and made by a multidisciplinary team comprising a PH specialist, anaesthesiologist, and surgeon. Careful risk–benefit assessment is essential, taking into account surgical urgency, PAH severity, and patient preference. Pre‐operative optimization of PAH therapy should be attempted whenever feasible. No uniform recommendation can be made regarding anesthetic technique; procedures should be performed at experienced centers whenever possible [85].

• IV. Pharmacological management of PAH

  Several targeted therapies are now approved for the treatment of PAH, supported by robust randomized clinical trial data demonstrating improvements in symptoms, exercise capacity, hemodynamics, and clinical outcomes.

  High dose calcium channel blockers (CCB) were one of the first medications used in management of PAH [86]. However, CCB should only be prescribed to patients who show positive vasodilator response during RHC. Empirical use of CCBs in the absence of documented vasoreactivity is not recommended [9]. It should also be recognized that the initial vasodilator response may not be durable in all patients, and loss of response can occur over time [36]. Therefore, careful clinical follow‐up with periodic reassessment—including hemodynamic evaluation when indicated—is essential to ensure continued low‐risk status and therapeutic appropriateness. Patients who fail to maintain clinical and hemodynamic response should be transitioned promptly to guideline‐directed PAH‐specific therapy [11].

  In addition to high dose CCB; current PAH pharmacotherapy targets four principal pathobiological pathways: the endothelin pathway, nitric oxide pathway, prostacyclin pathway, and the activin signaling pathway [36, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99]. (Table 13)

  Endothelin receptor antagonists (bosentan, ambrisentan, and macitentan) mitigate endothelin‐mediated vasoconstriction and vascular remodeling. Agents targeting the nitric oxide pathway include phosphodiesterase‐5 inhibitors (sildenafil and tadalafil) and the soluble guanylate cyclase stimulator riociguat. Prostacyclin pathway therapies comprise parenteral agents (epoprostenol, treprostinil), inhaled formulations, and oral agents such as selexipag.

  Adding to the expanding armamentarium in PAH management, sotatercept represents a novel class of disease‐modifying therapy that acts through restoration of the BMPR‐II signaling pathway. By trapping activins and growth differentiation factors, it mitigates vascular remodeling, thereby targeting the underlying pathobiology of PAH rather than providing purely vasodilatory effects [100]. Both the STELLAR and PULSAR trials demonstrated significant improvements in 6‐min walk distance, pulmonary vascular resistance, and time to clinical worsening when sotatercept was added to background therapy, marking an important advance in the management of PAH [100, 101]. Similarly, ZENITH and HYPERION trials demonstrated a reduction in the risk of all‐cause mortality, lung transplantation, or hospitalization in high‐risk PAH patients, as well as newly diagnosed PAH patients respectively [102, 103]. The SOTERIA trial demonstrated the sustained benefit of sotatracept over a median duration of 1 year after initiation [104].

  Alongside sotatercept, several other investigational therapies are being explored in PAH [105]. These include novel agents that target specific molecular pathways implicated in pulmonary vascular remodeling, inflammation, and endothelial dysfunction [106]. These diverse approaches have the potential to advance the field of PAH therapeutics and improve patient outcomes. In India, clinicians should proactively collaborate with the basic science laboratories and the pharma industry and try to understand the molecular pathways better and facilitate the development of indigenous therapeutic agents.

Table 13.

Pharmacological therapies approved for pulmonary arterial hypertension (PAH).

Pathway/Class	Mechanism of Action	Drug	Route	Recommended Adult Dose	Key Points
Endothelin Receptor Antagonists (ERAs)	Block endothelin (ETA/ETB) receptors → ↓ vasoconstriction & smooth muscle proliferation	Bosentan [78]	Oral	62.5 mg BD × 4 weeks → 125 mg BD	Dual ETA/ETB blocker; monitor LFTs
		Ambrisentan [79]	Oral	5 mg OD → 10 mg OD	Selective ETA antagonist; fewer hepatic effects
		Macitentan [80]	Oral	10 mg OD	Dual blocker; once daily; good tolerability
PDE5 Inhibitors/sGC Stimulator	Enhance cGMP signaling → vasodilation & antiproliferation	Sildenafil [74, 75]	Oral/IV	20 mg TID	Short‐acting; avoid with nitrates/riociguat
		Tadalafil [76]	Oral	40 mg OD	Once daily; longer‐acting
		Riociguat [77]	Oral	Start 0.5 mg TID → titrate by 0.5 mg to 2.5 mg TID or maximum tolerated dose	Stimulates sGC directly; avoid with PDE5i; for PAH & CTEPH
Prostacyclin (Prostanoid) Pathway Agents	Stimulate IP receptor → ↑ cAMP → vasodilation, antiproliferation, platelet inhibition	Epoprostenol [81]	IV continuous	Start 2 ng/kg/min → titrate (25–40 ng/kg/min typical)	Gold standard for severe PAH; needs central line
		Treprostinil [82]	IV/SC/Inhaled/Oral	IV/SC: 1.25 ng/kg/min → titrate; Inhaled: 18 µg QID → 54 µg QID; Oral: 0.25–0.5 mg BID → 8–12 mg BID	Multiple routes; SC pain common
		Iloprost [83, 84, 99]	Inhaled/IVa	2.5–5 µg/inhalation, 6–9×/day	Short‐acting; frequent dosing
		Selexipag [85]	Oral	Start 200 µg BID → increase weekly by 200 µg up to 1600 µg BID or maximum tolerated dose	Oral IP receptor agonist; titrate slowly
Calcium Channel Blockers (Vasoreactive PAH)	Block l‐type Ca²⁺ channels → vasodilation (only effective in responders)	Amlodipine [25]	Oral	20–30 mg OD	For vasoreactive patients; may cause edema
		Nifedipine [25]	Oral	120–240 mg/day (divided)	Hypotension risk; avoid in RV failure
		Diltiazem [25]	Oral	240–720 mg/day	Use if tachycardic; avoid in LV dysfunction
BMPR‐II/Activin Signaling Modulator	Restores BMPR‐II signaling by trapping activins/GDFs → reverses vascular remodeling	Sotatercept [86, 87, 88, 89, 90]	Subcutaneous	Start 0.3 mg/kg q3wk → Maintenance 0.7 mg/kg q3wk	First disease‐modifying agent; monitor Hb & BP; add‐on to background therapy

Note: Summary of drug classes targeting the endothelin, nitric oxide, and prostacyclin pathways, including endothelin receptor antagonists, phosphodiesterase‐5 inhibitors, soluble guanylate cyclase stimulators, prostacyclin analogs, and sotatercept. Mechanisms, routes, and key considerations are outlined. ^aIntravenous iloprost has been used in PAH where other parenteral prostacyclin analogs are unavailable, with a good initial hemodynamic response but limited long‐term survival benefit [99].

Abbreviations: CTEPH, chronic thromboembolic pulmonary hypertension; ERA, endothelin receptor antagonist; IV, intravenous; PAH, pulmonary arterial hypertension; PDE5i, phosphodiesterase‐5 inhibitor; SC, subcutaneous; sGC, soluble guanylate cyclase.

2.11. Treatment Strategies for Idiopathic, Hereditary, Drug‐Associated, or Connective Tissue Disorder Associated PAH

The pharmacological management of patients with PAH should be guided by the risk assessment by ESC/ERS risk stratification at presentation as well as at each follow up. Since parental prostacyclin analogues which form an integral part of treatment especially in high risk patients are not easily available in India; we propose an India‐specific treatment algorithm (Figure 4).

Figure 4.

Risk‐stratification guided treatment algorithm for PAH in India. Management pathway for confirmed PAH based on an initial three‐strata risk assessment. Low‐ or intermediate‐risk patients receive upfront dual oral therapy with a phosphodiesterase‐5 inhibitor (PDE5i) and an endothelin receptor antagonist (ERA). High‐risk patients are considered for initial triple therapy that includes a prostacyclin pathway agent. In conditions where parenteral or inhaled prostacyclin analogues are not available, triple combination therapy including Selexipag or sotatercept could be considered. Follow‐up assessment using a four‐strata model guides escalation. Patients who do not achieve low‐risk status may require the addition of prostacyclin pathway agents or sotatercept. Refractory cases should be evaluated for lung transplantation, heart–lung transplantation, atrial septostomy, or Potts shunt.

2.12. Low/Intermediate Risk at Presentation

Upfront combination therapy—most commonly an endothelin receptor antagonist (ERA) plus a phosphodiesterase‐5 inhibitor (PDE5i)—has become the recommended initial strategy for treatment‐naïve patients presenting in low or intermediate risk [9]. It produces earlier and larger hemodynamic and clinical benefits than monotherapy and reduces the risk of clinical failure. The AMBITION trial (ambrisentan + tadalafil) showed a large reduction in clinical‐failure events versus monotherapy and is the clearest randomized evidence supporting initial dual therapy [107]. Similarly an initial combination therapy using macitentan and tadalfil has shown to be beneficial in PAH patients with or without co‐morbidities [108].

The randomized TRITON trial did not meet its primary endpoint of superior short‐term hemodynamic improvement with initial triple oral therapy (macitentan + tadalafil + selexipag) versus initial double oral therapy, so routine use of upfront triple oral therapy with selexipag cannot be broadly recommended especially in patients at low or intermediate risk at presentation [109].

2.13. High Risk at Presentation

Patients presenting with high‐risk features should receive upfront triple combination therapy that includes inhaled or parenteral prostacyclin analogs (PPA) preferably at PAH care centers [9]. However, availability, procurement time, and cost limit the use of these drugs, which are a mainstay of PAH treatment in many countries including India [97]. The average delay from prescription to drug acquisition has been reported to be around 15 days making it challenging to use them as rescue therapy in high risk patients [97]. Hence triple combination therapy with ERA, PDE5i and selexipag or sotatercept should be considered in these patients.

2.14. Inadequate Response to Initial Therapy

In patients who remain at intermediate‐low, intermediate‐high, or high risk according to the ESC/ERS four‐strata risk stratification or REVEAL 2 lite model, treatment escalation is recommended [9]. This includes the addition of oral, inhaled, or parenteral prostacyclin pathway therapies, tailored to disease severity and clinical status. Riociguat may be considered as an alternative to phosphodiesterase‐5 inhibitors; however, concomitant use is contraindicated [110]. Addition of sotatercept should also be considered if it has not been incorporated earlier in the treatment strategy.

2.15. Other Heart Failure Medications in PAH

The routine use of angiotensin‐converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), angiotensin receptor–neprilysin inhibitors (ARNIs), beta‐blockers, or ivabradine is not recommended in patients with PAH. These agents should be prescribed only when indicated for coexisting conditions such as systemic hypertension, coronary artery disease, left heart failure, or clinically significant arrhythmias [9].

2.16. Patients with Group 2/Group 3 PH

PAH‐specific therapies are not recommended for patients with pulmonary hypertension due to left heart disease or lung disease [9].

2.17. Interventional and Surgical Management

Interventional procedures in PAH are palliative strategies aimed at right ventricular decompression in carefully selected patients and should be undertaken in experienced centers [111]. In India, where access to expensive PAH‐specific medications is limited, cost‐effective alternatives, such as the Potts shunt, have been explored with favorable outcomes, making these interventions a valuable addition to the therapeutic arsenal [112, 113].

• Creation of Interatrial communication:

  Creation of an interatrial communication is a palliative intervention designed to decompress the right atrium and ventricle by creating a controlled right‐to‐left shunt, thereby improving cardiac output and systemic perfusion in advanced or refractory pulmonary arterial hypertension (PAH) [114]. Early work by Sandoval et al. demonstrated that balloon atrial septostomy can provide symptomatic and hemodynamic improvement in selected patients with severe PAH [115]. However, the created interatrial communication tends to decrease in size over time limitation which could be mitigated by using newer devices like the atrial flow regulator (AFR) [113, 114]. However, the procedure carries inherent risks of hypoxemia and paradoxical embolism. It should be avoided in patients with severe right ventricular systolic dysfunction, mean right atrial pressure > 20 mmHg, resting oxygen saturation < 90%, or baseline left ventricular end‐diastolic pressure > 18 mmHg [116].

• Reversed Potts Shunt (Left Pulmonary Artery–Descending Aorta Anastomosis):

  Reversed Potts shunt is a palliative surgical or transcatheter intervention that creates a right‐to‐left shunt at the arterial level, effectively offloading the right ventricle by decompressing suprasystemic pulmonary arterial pressures into the systemic circulation. This procedure mimics the physiology observed in patent ductus arteriosus with Eisenmenger syndrome resulting in improvements in survival, functional class, and hemodynamics [112, 117]. Although associated with procedural risks such as bleeding, left‐to‐right shunting, or spinal ischemia, the Potts shunt provides meaningful palliation and serves as a bridge to lung transplantation. It should be avoided in patients who are critically ill (no improvement even after ICU admission, dependent on ionotropic support or require ECMO) and with severe RV systolic dysfunction (RVFAC < 20%, RVEF < 25%) [112]. Unidirectional reversed Potts shunt may be considered for patients who have sub‐systemic PA pressures at rest but have a history of syncope on exertion [118].

• Pulmonary artery denervation (PADN):

  Pulmonary artery denervation is an emerging interventional approach that targets the sympathetic nerve fibers surrounding the main pulmonary artery to attenuate excessive sympathetic activity [119]. However, the current evidence base remains limited, and insufficient high‐quality randomized data preclude its recommendation for routine clinical practice.

• Lung and Heart ‐ Lung transplantation

Lung Transplantation remains the definitive surgical treatment option for patients with PAH who are refractory to maximal medical and interventional therapies. Heart–lung transplantation is reserved for patients with complex congenital heart disease, Eisenmenger physiology, or severe, irreversible right ventricular dysfunction not amenable to isolated lung transplant. Table 14 enlists the criteria for referring and listing a patient with PAH for Lung transplant [120].

Table 14.

Indications for referral and listing for lung transplant.

Indication for referral for lung transplant	Indication for listing for lung transplant
Despite appropriate therapy
ESC/ERS 3‐strata high risk REVEAL2.0 intermediate‐high risk ESC/ERS 4‐strata intermediate‐high risk RV dysfunction Progression of disease PAH hospitalization Hemoptysis WHO FC‐III‐IV More than trace pericardial effusion Cardiac index < 2 l/min/m2 Renal dysfunction Hepatic dysfunction	WHO FC IV REVEAL LITE 2‐ high risk disease ESC/ERS high risk disease
At any time Require parenteral therapy Suspected PVOD/PCH Heritable PAH Large/progressive PA aneurysm Concomitant significant left heart disease Atrial septostomy Coronary compressiona

Note: Referral and listing criteria based on ESC/ERS risk stratification, REVEAL score, progressive right ventricular failure, recurrent hospitalization, hemoptysis, and need for parenteral prostacyclin therapy. ^aCoronary compression of the left main coronary artery is sometimes seen due to enlarged pulmonary arteries; in some cases, this may be amenable to stenting.

Abbreviations: ESC/ERS, European Society of Cardiology/European Respiratory Society; PA, Pulmonary artery; PAH, pulmonary arterial hypertension; PCH, Pulmonary Capillary Hemangiomatosis; PVOD, Pulmonary Veno‐Occlusive Disease; REVEAL, Registry to Evaluate Early and Long‐Term PAH Disease Management; RV, right ventricle; WHO‐FC, World Health Organization functional class.

Worldwide, significant improvement in long‐term survival after lung transplantation for PAH has recently been reported, with median survival approaching 7 years and 5‐year survival rates around 60% [121]. In India, lung transplantation has increasingly emerged as a viable therapeutic option, with several major centers now performing both bilateral lung and combined heart–lung transplants for advanced PAH. Approximately 100–120 lung transplants for all casues of end stage lung disease are performed annually across the country [122]. Of these 10% are for IPAH, with survival rates of about 80–85% at 1 year, and ~50% at 5 years [123, 124].

2.18. Quality of Life Adherence and Counseling

Structured counseling at initiation and during follow‐up is essential. Patients and caregivers should be educated regarding expected benefits, potential side effects, early warning signs, and the importance of uninterrupted therapy. Practical strategies to improve adherence, including simplified regimens where possible, proactive management of adverse effects, and addressing socioeconomic barriers, should be part of routine practice. Shared decision‐making and regular reassessment of tolerability can enhance long‐term treatment success and overall quality of life.

Quality of life (QoL) assessment is a key therapeutic goal in PAH, beyond survival and hemodynamic improvement. Disease specific, validated tools such as PAH‐SYMPACT and EmPHasis‐10 should be routinely used in clinical practice [125, 126]. They quantify symptom burden, psychosocial impact, and activity limitation, may detect early deterioration, and help assess treatment response and adherence. Routine use supports shared decision‐making and enables structured longitudinal follow‐up in long‐term PAH care.

2.19. Barriers and Proposed Solutions in the Indian Context

Several barriers and challenges have been identified in the management of PH in India. These include limited resources and expertise; late presentation; comorbidities that complicate management; cost constraints; limited access to essential medications and RHC; the absence of dedicated PAH programs, leading to variability in clinical practice; and a lack of specialized training and guidelines for physicians. Specific challenges in care delivery identified through interviews with physicians across eight healthcare systems in India, using semi‐structured inquiries, are outlined in Table 15 [5].

Table 15.

Commonly perceived barriers in pulmonary hypertension care delivery in India.

A	Diagnostic workup of pulmonary hypertension
	1. Implementing low‐yield tests (for treatable causes making them irreversible), due to lack of physician awareness 2. Lack of agreed protocol 3. Hesitancy toward invasive procedures among patients and physicians 4. Underutilization of ventilation/perfusion scan and sleep studies, due to unavailability 5. Lack of dedicated pulmonary hypertension centers of excellence
B	Lifestyle and exercise based cardiopulmonary rehabilitation
	1. Limited availability and accessibility of centers and professional delivering exercise‐based cardiopulmonary rehabilitation for pulmonary hypertension 2. Perception amongst physicians that it is not worthwhile 3. Lack of awareness amongst patients about the benefits of exercise‐based cardiopulmonary rehabilitation
C	Pulmonary vasodilator medical therapy
	1. Paucity of agreed guidelines for risk stratification among physicians, due to lack of physician awareness 2. Unavailability of prostacyclin 3. Cost of medications 4. Improper dosage of drugs
D	Surgical and interventional therapies
	1. Limited surgeons with technical expertise and experience 2. Lack of motivation given the perception of the time‐consuming and high‐risk nature of the procedure 3. Limited to very few centers 4. Social stigma about organ donation in Indian culture 5. misconceptions about indications and contra‐indications for surgery of shunt lesions.
E	Palliative care
	1. Patients perceive that these invasive and expensive procedures are not worth it in late stages of pulmonary hypertension 2. Reluctance amongst the surgeons as they perceive that these procedures are cumbersome and nonrewarding

Note: Patient‐, physician‐, and system‐level barriers affecting timely diagnosis, risk stratification, pharmacotherapy, advanced interventions, and palliative care in PH.

Abbreviations: PH, pulmonary hypertension; PAH, pulmonary arterial hypertension.

To address these challenges, potential solutions have been proposed.

Some of the critical insights in this context include:

• 1. Enhance Awareness and Education

  Promote nationwide educational initiatives to increase awareness about PAH among healthcare professionals, ensuring early recognition and timely referral.

• 2. Standardize Care through Guidelines

  Develop and implement India‐specific consensus guidelines that reflect local epidemiology, healthcare resources, and treatment access.

• 3. Strengthen Training and Capacity Building

  Create structured training programs in PH diagnosis, risk stratification, and management for physicians, healthcare professionals and nurses.

• 4. Establish PAH care centers

  Create dedicated, high quality, multidisciplinary care centers with standardized protocols to deliver comprehensive, interdisciplinary treatment including advanced therapies. (Table 16)

• 5. Develop a Collaborative Care Framework

  Implement a patient‐centered, personalised approach through coordinated care among cardiologists, pulmonologists, rheumatologists, and other specialists. Involvement of other healthcare professionals (i.e., psychologists, physiotherapists, exercise specialists, rehabilitation experts), social workers and nurses are vital to the success of collaborative care.

• 6. Adopt a Hub and spoke Referral Model

  Build partnerships between expert centers and regional hospitals to facilitate timely referrals and reduce diagnostic delays.

• 7. Create a National PAH Registry

  Establish a centralized database to collect epidemiological data, monitor outcomes, and evaluate quality indicators of care.

• 8. Address Financial and Access Barriers

  Collaboration among policymakers, insurers, and patient advocacy groups is essential to improve affordability and equitable access to diagnostic services and advanced therapies for PAH in India. Policy efforts should focus on recognising PAH as a rare cardiovascular disorder, expanding insurance coverage (including Ayushman Bharat), improving drug affordability through tax rationalization, and strengthening referral networks to specialized centers.

• 9. Encourage Local Research and Clinical Trials

  Conduct India‐specific high quality clinical and implementation trials to evaluate efficacy, safety, and feasibility of PAH therapies in resource‐limited settings.

• 10. Focus on Implementation of Science

Table 16.

Core infrastructure and service requirements for a basic pulmonary arterial hypertension (PAH) care center in India.

Domain	Minimum requirements
Clinical services	Dedicated PH‐trained cardiologist/pulmonologist; structured outpatient clinic; monitored inpatient beds with ICU access
Core diagnostics	Echocardiography with RV assessment; right heart catheterization with vasoreactivity testing; CT pulmonary angiography/HRCT; V/Q scan access; pulmonary function testing with DLCO; NT‐proBNP and autoimmune serology
Multidisciplinary access	Cardiology, rheumatology, pulmonology, radiology, hepatology; cardiac anesthesia support
Therapeutic capability	Availability of PAH‐specific oral therapies and newer medications and monitoring the side effects
Monitoring and systems	6‐min walk test; structured risk assessment protocol; patient registry/database; defined referral pathway to advanced center

Note: The framework emphasizes essential diagnostics, multidisciplinary collaboration, therapeutic availability, and systematic risk assessment, all necessary for comprehensive PAH management.

Abbreviations: PH, pulmonary hypertension; PAH, pulmonary arterial hypertension; RV, Right Ventricle; HRCT, High‐Resolution Computed Tomography; V/Q, Ventilation/Perfusion; DLCO, Diffusing Capacity of the Lungs for Carbon Monoxide; NT‐proBNP, N‐terminal pro‐B‐type natriuretic peptide.

Develop hybrid‐implementation models to assess real‐world adoption of guidelines, identify barriers, and optimize integration into health systems.

By implementing these solutions, the management of PAH in India can be optimized to provide standardized, evidence‐based care for patients with this complex condition, ultimately improving outcomes and quality of life.

2.20. Key Pragmatic Modifications in the Indian Consensus Statement on PAH

The Indian consensus statement on pulmonary arterial hypertension introduces several pragmatic modifications tailored to the realities of low‐ and middle‐income settings (Table 17). While right heart catheterization remains the gold standard for diagnosis, temporary deferral may be considered in selected patients with a high echocardiographic probability of PAH and no evidence of left heart disease, allowing initiation of therapy with planned referral for invasive confirmation. For high‐risk patients, the algorithm acknowledges the limited availability of parenteral prostacyclins and permits consideration of triple oral combination therapy, including prostacyclin pathway agents and, in selected cases, add‐on sotatercept. The document also defines minimum requirements for a PAH care center to standardize care delivery. Additionally, it recognizes the limited epidemiological data and endorses structured, exercise‐based cardiopulmonary rehabilitation along with culturally relevant adjuncts (such as yoga‐based interventions) into conventional supervised exercise programs, thereby reflecting a holistic and pragmatic adaptation to the Indian healthcare context.

Table 17.

Pragmatic Adaptations in the Indian Consensus Statement for PAH Management in LMIC Settings.

Domain	Indian Consensus Adaptation	Rationale for LMIC Settings
Hemodynamic definition	Retains standard hemodynamic definition of PAH	Maintains alignment with international classification
Diagnostic strategy	Temporary deferral of right heart catheterization in selected patients with high echocardiographic probability and no left heart disease	Limited access to invasive testing and delayed referrals
Initiation of therapy	PAH‐specific therapy may be started before invasive confirmation in carefully selected patients	Avoids treatment delay in resource‐limited regions
High‐risk treatment approach	Triple oral combination therapy may be considered when parenteral prostacyclins are unavailable, including prostacyclin pathway agents such as selexipag and add‐on therapy with sotatercept in selected patients	High cost and limited availability of parenteral prostacyclins; need for feasible escalation strategies
PAH care center requirements	Defines minimum standards for basic PAH care centers	Promotes equitable and structured care delivery
Epidemiological data	Acknowledges reliance on single‐center registries and limited LMIC data	Highlights need for regional data generation
Rehabilitation strategy	Incorporates structured exercise and yoga‐based rehabilitation	Culturally relevant, low‐cost adjunct to supervised programs
Pragmatic adaptations in the Indian consensus statement on pulmonary arterial hypertension (PAH) tailored to low‐ and middle‐income countries (LMICs). The table summarizes context‐specific modifications to diagnostic pathways, treatment escalation—including consideration of oral combination therapy with prostacyclin pathway agents and add‐on sotatercept when parenteral prostacyclins are not feasible—minimum requirements for PAH care centers, and the incorporation of culturally relevant rehabilitation strategies to improve access and standardize care.
Recommendation Table 1: Assessment and follow‐up of PAH patients in India.

Clinical Scenario/Assessment	Recommendation	CoR	LoE
Initial evaluation
Echocardiography	Echocardiography is recommended as first line, non‐invasive tool for screening, diagnosis and follow up.	I	B
CT pulmonary angiography with HRCT chest	Is recommended to be performed to rule out CTEPH and lung disease in patients with intermediate or high probability of PH on echocardiography	I	C
Pulmonary function test	Pulmonary function test with DLCO is recommended in all patients with high probability of PH to rule out lung disease	I	C
Baseline laboratory tests	Hemoglobin, renal function, liver function, and BNP or NT‐proBNP should be measured at baseline in all patients with PAH.	I	C
Screening for associated conditions/etiology	Evaluation for CHD, obstructive sleep apnea, connective tissue disease, HIV, hepatitis B and C, portal hypertension, thyroid dysfunction and tuberculosis is recommended in all patients with PAH	I	C
Lung perfusion scan (VQ scan)	A lung perfusion scan is recommended in the diagnostic work‐up of suspected PAH to exclude CTEPH	I	B
Hemoglobin electrophoresis	Hemoglobin electrophoresis should be considered in the evaluation of PAH, particularly in regions with a high prevalence of hemoglobinopathies	IIa	C
Right heart catheterization (RHC)	RHC should be performed to confirm PAH unless contraindicated	I	C
Deferred RHC	In selected patients with strong clinical and echocardiographic probability, treatment initiation before RHC may be considered.	IIb	C
Acute vasoreactivity testing	Vasoreactivity testing may be considered in suspected IPAH or HPAH or drug induced PAH at experienced centers.	IIa	C
Exercise capacity assessment	6‐min walk distance is recommended for baseline and follow‐up assessment	I	B
CPET	CPET may be considered where available Esp if the six min walk test distance is more than 400 meters	IIb	C
Baseline risk stratification	Simplified three strata risk assessment using ESC/ERS model or REVEAL 2 score is recommended	I	B
Follow up evaluation
Frequency of follow‐up	Follow‐up every 3 months is recommended for high‐risk patients, Longer intervals may be considered for low/intermediate‐low risk patients	I	C
Follow‐up investigations	WHO FC, anemia assessment, 6MWD, BNP/NT‐pro BNP, and echocardiography should be repeated during follow‐up	I	B
Risk reassessment at follow‐up	Four strata Risk stratification using ESC/ERS model or REVEAL 2 lite score should be reassessed at each visit.	I	B
Repeat RHC	Repeat RHC may be considered in case of clinical worsening or prior to initiation of parenteral medications or performing intervention or referring/listing for lung transplant	IIa	C
Referral to expert center	Early referral is recommended for high‐risk patients or those with inadequate treatment response	I	C
This table summarizes recommendations for the initial evaluation and follow‐up of PAH in the Indian setting, graded by CoR and LoE. A pragmatic, stepwise approach emphasizing clinical assessment, exercise capacity, biomarkers, echocardiography, and risk stratification is recommended. RHC remains the diagnostic standard, though treatment may be initiated before catheterization in selected high‐probability cases.
Where recommended investigations are unavailable, treatment decisions should be guided by the best available clinical, echocardiographic, and biochemical data, with referral to expert centers whenever feasible.
PAH: pulmonary arterial hypertension; CoR: class of recommendation; LoE: level of evidence; RHC: right heart catheterization; WHO FC: World Health Organization functional class; 6MWD: 6‐min walk distance; BNP: B‐type natriuretic peptide; Nt‐proBNP: N terminal Pro Brain natriuretic peptide; CMR: cardiac magnetic resonance; CPET: cardiopulmonary exercise testing; HRCT: High resolution computerized tomogram; V/Q scan: Ventilation–perfusion scan; CHD: congenital heart disease; CTEPH: chronic thromboembolic pulmonary hypertension.
Recommendation Table 2: Non‐pharmacological and pharmacological therapy in idiopathic or heritable Pulmonary Arterial Hypertension.

Clinical Scenario/Intervention	Recommendation	CoR	LoE
General measures
Diuretics	Diuretics are recommended for patients with PAH with fluid retention and signs of right ventricular failure	I	C
Oxygen	Long term oxygen therapy is recommended in patients with PAH with PaO2 < 60 mmHg (Spo2 < 92%)	I	C
Cardio‐pulmonary rehabilitation	Supervised exercise training is recommend in patients with PAH who are stable on medical therapy	I	A
Iron deficiency	Correction of iron status is recommended for patients with PAH and iron deficiency anemia	I	C
Anticoagulation	Not generally recommended but may be considered on individual basis	IIb	C
Anesthesia	Interventions requiring anaesthesia should be vetted by a multi‐disciplinary team at PH care center to assess the risk and benefit.	IIa	C
Pregnancy and contraception	Clear contraceptive advice is to be provided to all women of child bearing age with PAH	I	C
	ERA and riociguat have been reported to have teratogenic potential and are not recommended during pregnancy	III	B
Travel and altitude	Inflight oxygen is recommended for patients with PAH and Spo2 < 92% at sea‐level	I	C
Specific pulmonary vasodilators
Low‐risk PAH at diagnosis	Initial oral combination therapy with a PDE5 inhibitor and an endothelin receptor antagonist (ERA) should be considered	I	B
Intermediate‐risk PAH at diagnosis	Initial combination therapy with a PDE5i and an ERA is recommended	I	B
High‐risk PAH at diagnosis	Initial combination therapy including inhaled, intravenous or parenteral prostacyclin analogs is recommended	I	B
	Initial combination therapy with selexipag or sotatercept may be considered when parenteral or inhaled prostacyclin analogs are not easily available	IIa	C
Positive acute vasoreactivity test	High‐dose calcium channel blockers may be considered in patients with sustained response	I	C
Treatment at follow up: Inadequate clinical response in patients low or intermediate risk at baseline
Inadequate clinical response to initial therapy	Triple oral combination therapy including selexipag should be considered	IIb	B
PDE5i → sGC stimulator	Switching PDE5i with riociguat may be considered	IIb	B
Sotatercept	Addition of sotatercept is recommended in patients who continue to be in intermediate low, intermediate high or high risk category despite dual or triple background therapy.	IIa	C
Persistent intermediate–high or high risk despite triple oral combination therapy
	Substitution of selexipag with inhaled or parenteral prostacyclin therapy should be considered	IIa	B
	Sotatercept may be considered as add‐on therapy	IIa	B
Combination of PDE5 inhibitor and riociguat	Concomitant use is contraindicated	III	B
PAH‐specific therapy in PH due to left heart or lung disease	PAH‐targeted drugs are not recommended	III	C
Other Heart failure drugs	Heart Failure medications like ACEi, Beta blockers, ARNIs, ARBs, Ivabradine are contraindicated in PAH unless being used for associated co‐morbidities like hypertension, coronary artery disease, left HF or arrythmias	III	C
Interventions
Creation of interatrial communication	Severe PAH with recurrent syncope or right heart failure despite optimal medical therapy, with RA pressure (RAP) ≤ 20 mmHg and acceptable systemic oxygen saturation ( ≥ 90%)	IIa	C
	Procedure is contraindicated in patients with RAP > 20 mmHg or Sp2o < 90% or LVED > 18 mmHg	III	C
Reversed Potts shunt	Surgical or transcatheter reversed Potts shunt may be considered in children and young adults with supra‐systemic PA pressures inspite of maximal medical therapy	IIa	C
Transplant	Bilateral lung or heart and lung transplant is recommended in patients in high risk profile inspite of maximal medical therapy	I	B

Note: This table presents risk‐based recommendations for pharmacological management of PAH at diagnosis and during follow‐up, graded by Class of Recommendation (CoR) and Level of Evidence (LoE). Treatment selection and escalation are guided by baseline and follow‐up risk stratification, with combination therapy prioritized and contraindicated drug combinations clearly identified. Choice of therapy should consider drug availability, affordability, and patient adherence, particularly in resource‐limited settings. Oral combination therapy may be initiated sequentially when upfront dual therapy is not feasible. Inhaled or Parenteral prostacyclin therapy should be administered at expert PAH centers with appropriate infrastructure. Regular reassessment (every 3–6 months) is mandatory to determine treatment escalation.

Abbreviations: ACEi, angiotensin converting enzyme inhibitor; ARB, angiotensin receptor blockers; ARNI, angiotensin receptor–neprilysin inhibitors; CoR, class of recommendation; ERA, endothelin receptor antagonist; LoE, level of evidence; PAH, pulmonary arterial hypertension; PDE5i, phosphodiesterase type‐5 inhibitor; PH, pulmonary hypertension; sGC, soluble guanylate cyclase.

3. Conclusion

In this consensus paper, the expert panel emphasizes that managing PAH in India requires a coordinated, multifaceted strategy to address the unique challenges of a resource‐limited healthcare environment. Although RHC, oral pulmonary vasodilators, and advanced therapies are available, their use remains inconsistent due to financial constraints, the absence of standardised treatment protocols, and variability in clinical practice. Surgical and interventional therapies, while effective in selected patients, are often constrained by limited specialized expertise and advanced critical care facilities. The emergence of novel agents such as sotatercept and evolving interventional strategies marks a promising new era in PAH care, underscoring the need for equitable access and India‐specific treatment frameworks. The group unanimously recognises the importance of establishing dedicated PAH care centers, fostering multidisciplinary collaboration, and developing national guidelines to standardize diagnosis and management. Strengthening education, research, and advocacy efforts, and integrating patient‐centered and affordable care pathways, will be key to improving outcomes and shaping the future of PAH management in India.

Author Contributions

Prashant Bobhate conceptualized the consensus statement, coordinated the expert panel discussions, synthesized the recommendations, drafted the initial manuscript, and revised subsequent versions. Prashant Bobhate serves as the guarantor of the work and takes full responsibility for the integrity of the manuscript and the decision to submit for publication. Neeraj Awasthy, Abraham Samuel Babu, Shatabdi Giri, Arun Gopalakrishnan, Sivadasanpillai Harikrishnan, Niharikar Karandikar N., Basha J. Khan, Snehal Kulkarni, Shine Kumar, Rahul Mehrotra, Smrutiranjan Mohanty, S. Ramakrishnan, Anita Saxena, Padmanabha Shenoy P., Basha J. Khan, and T. Sunder contributed to the development of the consensus recommendations, provided critical intellectual input, reviewed and revised the manuscript for important academic content, and approved the final version prior to submission.

Funding

The authors have nothing to report.

Ethics Statement

NA. This is a consensus statement and does not involve primary patient data, human subjects research, or animal experimentation.

Conflicts of Interest

The authors declare no conflicts of interest.

Data Availability Statement

Data sharing not applicable to this article as no datasets were generated or analysed during the current study.