Idiopathic Pulmonary Arterial Hypertension (IPAH)

• Mean pulmonary arterial pressure (mPAP) >20 mmHg at rest.
• Pulmonary artery wedge pressure (PAWP) ≤15 mmHg.
• Pulmonary vascular resistance (PVR) >2 Wood units.

Classification

1. Idiopathic pulmonary arterial hypertension.
2. Heritable pulmonary arterial hypertension.
3. Drug- and toxin-induced pulmonary arterial hypertension.
4. PAH associated with conditions such as connective tissue disease, congenital heart defects, and HIV infection.
5. Persistent pulmonary hypertension of the newborn (PPHN)​

The World Health Organization (WHO) classifies patients with PH into five groups based upon aetiology 

• Group 1 – Pulmonary arterial hypertension (PAH)
• Group 2 – PH due to left heart disease
• Group 3 – PH due to chronic lung disease and/or hypoxemia
• Group 4 – PH due to pulmonary artery obstructions
• Group 5 – PH due to unclear multifactorial mechanisms

Genetic Factors

BMPR2 Mutations

• Most common genetic mutation associated with familial IPAH.
• Found in 11–40% of sporadic cases.
• Leads to impaired signaling in vascular cells, resulting in proliferative and anti-apoptotic changes.
• Incomplete penetrance: only 20% of mutation carriers develop the disease.

Other Genetic Mutations

• ACVRL1: Involved in TGF-beta signalling pathways; linked to vascular remodelling.
• ENG: Encodes endoglin, a protein involved in endothelial homeostasis.
• SMAD9: Facilitates intracellular TGF-beta signal transduction.
• CAV1: Encodes caveolin-1, impacting endothelial function.
• KCNK3: Encodes a potassium channel crucial for regulating pulmonary vascular tone.

Environmental and Associated Risk Factors

Drug-Induced Risk

• Anorexigens (e.g., appetite suppressants).
• Alpha-adrenergic stimulants (e.g., cocaine, amphetamines).

Associated Conditions

• Connective tissue diseases.
• Liver cirrhosis.
• HIV infection.

Inflammatory and Environmental Triggers

• Chronic inflammation may contribute to endothelial damage.
• Infections and inflammatory insults suspected but not well-defined.

Overview

• IPAH is a progressive disease of the pulmonary vasculature with unclear pathogenesis.
• The "multiple-hit theory" suggests that an environmental or hormonal insult in the setting of genetic predisposition triggers endothelial injury, initiating vascular remodeling.
• This process involves:
  • Endothelial dysfunction: Altered production of vasoactive mediators.
  • Vascular remodeling: Intimal and medial proliferation of smooth muscle cells.
  • Thrombosis: In situ thrombus formation in small pulmonary arteries.

Genetic Contributions

• BMPR2 Mutations:
  • Found in 15–20% of cases previously considered idiopathic.
  • Causes dysregulated TGF-beta signaling, resulting in cell proliferation and resistance to apoptosis.
  • Only 20–25% of mutation carriers develop IPAH, indicating incomplete penetrance and the role of additional factors.
• Other Genetic Mutations:
  • KCNK3: Encodes a potassium channel; mutations lead to impaired ion transport and increased vascular tone.
  • SMAD9, ACVRL1, ENG, and CAV1: Implicated in vascular remodeling and endothelial homeostasis.
  • These mutations highlight the role of genetic predisposition in modifying the pulmonary vasculature.

Key Vascular Changes

• Vasoconstriction:
  • Elevated levels of endothelin-1: A potent vasoconstrictor and mitogen.
  • Decreased levels of nitric oxide (NO) and prostacyclin: Impaired vasodilation and antiplatelet activity.
• Smooth Muscle Cell and Endothelial Proliferation:
  • Intimal and medial thickening driven by pro-inflammatory and mitogenic mediators.
• Thrombosis:
  • Procoagulant state characterised by elevated fibrinopeptide A, D-dimer, and von Willebrand factor.

Pathologic Findings

• Histopathology reveals:
  • Medial hypertrophy, intimal hyperplasia, and adventitial fibrosis.
  • Plexiform lesions: Complex vascular remodeling involving obliteration of small pulmonary arteries.
• Progressive vascular occlusion leads to increased pulmonary vascular resistance (PVR), right ventricular strain, and eventual failure.

Molecular Mediators

• Endothelin-1:
  • Plasma levels correlate with disease severity.
  • Promotes vasoconstriction, inflammation, and proliferation.
• Nitric Oxide (NO):
  • Levels are reduced due to impaired synthesis or increased consumption.
  • Decreased NO exacerbates vasoconstriction and thrombosis.
• Prostacyclin:
  • Deficiency reduces vasodilation and promotes platelet aggregation.
• Other Factors:
  • Dysregulated serotonin, adrenomedullin, and vascular endothelial growth factor contribute to vascular remodeling.

Prevalence and Incidence

• Pulmonary arterial hypertension (PAH) is a rare disease with:
  • Prevalence: 48–55 cases per million adults globally.
  • Annual incidence: 2.4–6.0 cases per million people.
• Idiopathic PAH (IPAH) accounts for 30–50% of PAH cases.
• In the United States, IPAH incidence is approximately 2–6 cases per million population annually.
• Variability in prevalence exists worldwide. For instance:
  • The French registry reported a prevalence of 6 cases per million.
  • Registries from the UK and Ireland indicate an increasing prevalence over time, with an observed rise in diagnosis between 2001 and 2009.

Gender Distribution

• Female predilection is evident in IPAH:
  • Female-to-male ratio varies by region and study:
    • United States: 3.9:1 on average, with clinical trials reporting ratios as high as 4:1.
    • European data indicate ratios from 2.3:1 in younger patients to 1.2:1 in older individuals.
  • The reasons for the higher prevalence among females, particularly women of childbearing age, remain unclear.

Age at Diagnosis

• Mean age at diagnosis has increased over decades:
  • Early registries (1980s): Mean age was 36 years.
  • More recent registries (e.g., REVEAL and France): Mean age is now approximately 50 years.
  • A significant proportion of cases are diagnosed in individuals over 70 years, particularly in Europe.

Comorbidities

• Common comorbid conditions in patients with IPAH include:
  • Systemic hypertension.
  • Obesity.
  • Type 2 diabetes mellitus.
  • Ischemic heart disease.

Mortality

• IPAH contributes to approximately 125–150 deaths per year in the United States, reflecting its progressive and life-threatening nature.

Key Historical Features

Symptom Onset and Diagnosis Delay

• Average delay from symptom onset to diagnosis: ~2 years.
• Nonspecific symptoms in early stages often lead to misattribution to age, deconditioning, or other conditions.

Common Presenting Symptoms

• Dyspnea: Most common, affecting ~60% of patients; worsens with exertion.
• Fatigue and lethargy: Often associated with dyspnea.
• Syncope or near-syncope: Seen in ~13%, due to inadequate cardiac output or reflex bradycardia during activity.
• Exertional chest pain: Results from subendocardial hypoperfusion or compression of the left main coronary artery by an enlarged pulmonary artery.
• Peripheral oedema: Affects ~32%, related to right ventricular (RV) failure and fluid retention.
• Right upper quadrant pain or abdominal distension: Indicates hepatic congestion or ascites from advanced RV failure.

Uncommon Symptoms

• Cyanosis: Seen in ~20% of cases.
• Cough, hemoptysis, or hoarseness: Rare, with hoarseness linked to Ortner syndrome (compression of the left recurrent laryngeal nerve by a dilated pulmonary artery).
• Palpitations: Rare, associated with arrhythmias such as atrial fibrillation or flutter.

Demographics and Risk Factors

Age Distribution

• Historical US registries (1980s): Mean age at diagnosis was 36 years.
• Contemporary data:
  • Mean age increased to ~50 years.
  • 9% of patients in the French registry were over 70 years old at diagnosis.
  • European registries report a median diagnosis age of 71 years.

Gender

• Female-to-male ratio varies:
  • Early registries: ~1.7:1.
  • More recent US data: ~3.9:1.
  • In younger patients (<50 years), ratio is ~2.3:1; older patients (~70 years) have a nearly even ratio (~1.2:1).

Family History

• Familial IPAH seen in ~6% of cases.
• Genetic anticipation and autosomal dominant inheritance with incomplete penetrance.

Drug Use

• History of stimulant use (e.g., methamphetamines) reported in ~28.9%.
• Appetite suppressants (e.g., aminorex, fenfluramine) are definitive risk factors.

Historical Findings Related to Disease Progression

Initial Symptoms

• Often exertional and nonspecific, leading to delayed recognition.
• May include fatigue, dyspnea, and lethargy due to inadequate cardiac output during exercise.

Symptoms of Right Ventricular Failure

• Weight gain from fluid retention.
• Abdominal swelling or anorexia from hepatic congestion.
• Progressive dyspnea or signs of systemic venous congestion.

Advanced Symptoms

• Syncope with activity due to fixed cardiac output.
• Signs of advanced RV failure, including peripheral edema and jugular venous distension.

Cardiac Auscultation

 Increased intensity of the pulmonic component (P2) of the second heart sound

• Common initial finding due to elevated pulmonary pressures.
• May demonstrate fixed or paradoxical splitting with severe right ventricular (RV) dysfunction.

Tricuspid regurgitation murmur

• High-pitched, holosystolic, best heard at the left sternal border.

Pulmonic regurgitation murmur (Graham Steell murmur)

• Early diastolic, high-pitched murmur heard in the pulmonary area.

Right Ventricular Findings

 RV heave/lift

• A left parasternal heave or downward subxiphoid thrust, indicative of RV hypertrophy.

Right-sided S3 or S4 gallop

• Suggests RV failure or reduced compliance.

Jugular Venous Pressure (JVP)

 Elevated JVP, with

• Prominent "a" waves: Poor RV compliance.
• Prominent "v" waves: Severe tricuspid regurgitation.
• Hepatojugular reflux may also be present.

Signs of Right Heart Failure

 Hepatomegaly

• Palpable, pulsatile liver due to RV volume overload.

Peripheral oedema

• Pitting oedema, often progressing to ascites in advanced cases.

Ascites

• Indicates decompensated right heart failure.

Pleural effusion

• Often associated with severe decompensation.

Lung Examination

• Typically normal, as the primary pathology involves the pulmonary vasculature.

Extremities

 Peripheral oedema

• Most often in dependent areas, including sacral oedema in bedridden patients.

Cyanosis

• Present in advanced disease.

First-Line Investigations

 Chest X-ray

• Findings: Enlarged main pulmonary artery (90%), enlarged hilar vessels (80%), and pruning of peripheral vasculature (51%).
• Sensitivity: Not specific or sensitive enough to confirm diagnosis. Normal in ~6% of patients.

Electrocardiogram (ECG)

• Findings:
  • Right ventricular hypertrophy (RVH): Tall R wave in V1, qR complex in V1, S1S2S3 pattern.
  • Right axis deviation (QRS axis >100 degrees).
  • Right atrial enlargement (P wave ≥2.5 mm in leads II, III, aVF).
• Sensitivity/Specificity:
  • Sensitivity: ~73% for right axis deviation and 55% for RVH.
  • Specificity: ~70% for both

Transthoracic Doppler Echocardiography

• Purpose: Screening tool; evaluates pulmonary artery systolic pressure (sPAP), tricuspid regurgitation velocity (TRV), and RV function.
• Findings:
  • TRV >2.8 m/s suggests pulmonary hypertension.
  • Additional measures: RV size, TAPSE <18 mm, RV fractional area change, and RV ejection fraction.
• Sensitivity: ~79–100%; specificity: ~60–98%.
• Limitation: Confirmation with right heart catheterisation (RHC) is required.

Right Heart Catheterization (RHC)

• Gold standard diagnostic test for confirming IPAH.
• Criteria:
  • Mean pulmonary arterial pressure (mPAP) >20 mmHg.
  • Pulmonary arterial wedge pressure (PAWP) ≤15 mmHg.
  • Pulmonary vascular resistance (PVR) >2 Wood units.

Laboratory Investigations

 Antinuclear Antibodies (ANA)

• Purpose: Screens for secondary causes (e.g., connective tissue disease).
• Result: Negative or low-titer positive (≤1:80).

Pulmonary Function Tests (PFTs)

• Findings:
  • Mild restrictive lung defects (20–50%).
  • Mild diffusion capacity reduction in most patients.

Arterial Blood Gas (ABG)

• Findings:
  • Normal or reduced PaO₂.
  • Reduced PaCO₂, indicating hyperventilation.

Brain Natriuretic Peptide (BNP) or N-terminal ProBNP (NT-proBNP)

• Elevated in right ventricular overload.
• Threshold:
  • NT-proBNP >300 ng/L or BNP >50 ng/L correlates with severity and mortality risk.

HIV Serology

• Purpose: Rule out HIV-associated pulmonary hypertension.

Liver and Thyroid Function Tests (LFTs/TFTs)

• Purpose: Exclude liver disease or thyroid dysfunction as secondary causes.

Specialised and Additional Tests

 High-Resolution CT (HRCT) and CT Pulmonary Angiography (CTPA)

• Purpose: Assess interstitial lung disease, emphysema, or chronic thromboembolic disease.
• Findings: Pulmonary artery dilation, narrowed peripheral vessels, right heart enlargement.

Ventilation-Perfusion (V/Q) Scintigraphy

• Use: Differentiate chronic thromboembolic pulmonary hypertension from IPAH.
• Findings: Normal or low probability of thromboembolism.

Cardiac MRI

• Findings:
  • Assesses RV/LV size and function, myocardial strain, stroke volume.
  • Provides detailed prognosis and monitoring.

6-Minute Walk Test (6MWT)

• Purpose: Evaluate exercise capacity and disease severity.
• Parameters: Distance walked, oxygen saturation, and Borg dyspnea scale.

Vasodilator Testing

• Agents: Inhaled nitric oxide, iloprost, or IV epoprostenol.
• Purpose: Identify acute responders suitable for calcium channel blocker therapy.
• Criteria: Fall in mPAP ≥10 mmHg to ≤40 mmHg with unchanged or increased cardiac output.

Pulmonary Arterial Hypertension (PAH) Associated with Secondary Conditions

 PAH with Left-sided Heart Disease

• Signs/Symptoms:
  • Older age, male preponderance.
  • Typical cardiovascular risk factors (hypertension, diabetes, smoking).
  • Features of left-sided heart failure: gallops, mitral valve murmurs.
• Investigations:
  • Echocardiography: Left atrial enlargement, systolic/diastolic dysfunction, mitral valve disease.
  • RHC: Elevated pulmonary arterial wedge pressure (PAWP) >15 mmHg.

PAH with Respiratory Diseases and Hypoxia

• Associated Conditions:
  • Chronic obstructive pulmonary disease (COPD): Smoking history, chronic cough, wheezing.
  • Interstitial lung disease: Inspiratory crackles, clubbing.
  • Sleep-disordered breathing (e.g., obstructive sleep apnea): Snoring, daytime sleepiness.
• Investigations:
  • PFTs: Obstructive or restrictive pattern.
  • ABG: Hypoxemia, hypercapnia.
  • HRCT: Emphysema, interstitial fibrosis.

Chronic Thromboembolic Pulmonary Hypertension (CTEPH)

• Signs/Symptoms:
  • History of pulmonary embolism.
  • Bruits over lung fields (pulmonary flow murmurs).
• Investigations:
  • V/Q scan: Segmental or larger unmatched perfusion defects.
  • Pulmonary angiography: Intimal irregularities, abrupt narrowing, vascular webs.

PAH Associated with Systemic and Connective Tissue Disorders

 Connective Tissue Disease-Associated PAH

• Signs/Symptoms:
  • Multi-system involvement: Arthralgias, skin changes, Raynaud's phenomenon.
  • Scleroderma (especially CREST syndrome) is a significant risk factor.
• Investigations:
  • ANA, anti-centromere antibodies (scleroderma).
  • Anti-U3 RNP and anticardiolipin antibodies (lupus, mixed connective tissue disease).

Congenital Heart Diseases

• Simple Shunts:
  • Ventricular septal defect (VSD), atrial septal defect (ASD), or patent ductus arteriosus.
• Complex Shunts:
  • Eisenmenger syndrome (reversal of shunt flow).
• Investigations:
  • Contrast echocardiography with agitated saline.
  • RHC for oxygen saturation measurements.

Miscellaneous Causes of PAH

 Portopulmonary Hypertension (PAH with Portal Hypertension)

• Signs/Symptoms:
  • Liver disease (jaundice, ascites, spider telangiectasia).
• Investigations:
  • Abnormal liver function tests.
  • Doppler ultrasound of the liver.

HIV-associated PAH

• Signs/Symptoms:
  • Risk factors for HIV infection.
• Investigations:
  • HIV serology.

PAH with Drug and Toxin Exposure

• Associated Substances:
  • Appetite suppressants (e.g., aminorex, fenfluramine derivatives).
  • Methamphetamine use.
• Investigations:
  • Toxicology screening.

Pulmonary Veno-occlusive Disease (PVOD)

• Signs/Symptoms:
  • Severe hypoxemia, ground-glass opacities on imaging.
• Investigations:
  • HRCT: Ground-glass opacities, septal lines.
  • Bronchoalveolar lavage: Hemosiderin-laden macrophages.

Common Non-PAH Causes of Dyspnea Mimicking IPAH

Chronic Obstructive Pulmonary Disease (COPD)

• Chronic cough, sputum production, and history of smoking.

Heart Failure (HF)

• Reduced or preserved ejection fraction causing similar symptoms.

Anaemia

• Fatigue and dyspnea due to low oxygen-carrying capacity.

Obstructive Sleep Apnea (OSA)

• Snoring, daytime fatigue, and mild pulmonary hypertension secondary to hypoxia.

General Goals of Management

• Improve functional status to WHO Functional Class I or II.
• Achieve a 6-minute walk distance (6MWD) of 380–440 meters.
• Normalise right ventricular (RV) function (RV size, pressure, and cardiac index).
• Reduce biomarkers such as B-type natriuretic peptide (BNP).
• Optimise hemodynamics (e.g., right atrial pressure <8 mmHg, cardiac index >2.5 L/min/m²).

Supportive Therapy

Exercise Training

• Supervised programs recommended for stable patients.
• Avoid heavy physical exertion or isometric exercises.

Vaccination

• Annual influenza, pneumococcal, and COVID-19 vaccines.

Psychosocial Support

• Advanced care planning and palliative care referrals as needed.

Diuretics

• To manage fluid retention and right ventricular failure.

Oxygen Therapy

• Administered for patients with hypoxemia.

Iron Supplementation

• For iron deficiency, particularly in cases of associated anemia.

Anticoagulation

• Case-by-case use; not routinely recommended.

Pregnancy Avoidance

• IPAH poses significant risks during pregnancy; patients should be counseled on contraception and risks.

Acute Vasoreactivity Testing

Positive Response

• Fall in mean pulmonary arterial pressure (mPAP) by ≥10 mmHg to ≤40 mmHg with unchanged/increased cardiac output.
• Approximately 12% of IPAH patients are responsive.

Management

• Initiate CCBs (e.g., nifedipine, diltiazem, amlodipine) and reassess in 3–6 months.
• Non-responders or those with unsustained responses transition to other PAH-specific therapies.

Targeted PAH Therapies

Prostanoids

Epoprostenol (intravenous)

• Improves exercise capacity, hemodynamics, and survival in severe IPAH.

Treprostinil (subcutaneous/intravenous)

• Reduces clinical worsening and improves exercise capacity.

Iloprost (inhaled)

• Offers symptom relief with fewer systemic side effects.

Endothelin Receptor Antagonists (ERAs)

Bosentan (dual receptor antagonist)

• Improves functional class, exercise capacity, and hemodynamics.
• Requires liver function monitoring.

Ambrisentan (selective receptor antagonist)

• Associated with fewer hepatic side effects.

Macitentan

• Reduces morbidity and mortality, with long-term efficacy.

Phosphodiesterase-5 (PDE5) Inhibitors

Sildenafil and Tadalafil

• Enhance the nitric oxide (NO) pathway, improving exercise capacity and functional class.

Soluble Guanylate Cyclase Stimulators

Riociguat

• Enhances NO-cGMP signalling to reduce pulmonary vascular resistance.

Selective Prostacyclin Receptor Agonists

Selexipag

• Reduces hospitalisations and disease progression.

Activin Signalling Inhibitors

Sotatercept

• Targets the bone morphogenetic protein (BMP) pathway to reverse vascular remodelling.
• Demonstrated efficacy in reducing pulmonary vascular resistance and improving exercise capacity.

Combination Therapy

Upfront Triple Therapy

• For high-risk patients (e.g., ERA + PDE5 inhibitor + intravenous prostanoid).

Sequential Therapy

• For patients who fail monotherapy or dual therapy.

Advanced Interventions

Lung Transplantation

• Double-lung or heart-lung transplantation is an option for refractory IPAH.
• Indicated in patients unresponsive to combination therapy and at high risk.

Balloon Atrial Septostomy

• Palliative measure or bridge to transplantation, decompressing the RV and improving systemic perfusion.

Risk Stratification and Follow-up

Goals of therapy

• Achieve and maintain a low-risk profile.
• Monitor patients every 3–6 months with:
  • WHO functional class.
  • 6MWD.
  • Biomarkers (BNP/NT-proBNP).
  • Hemodynamic parameters.
• Adjust therapy based on changes in risk stratification.

Survival Rates

Without Treatment median survival is 2.8 years, with survival rates of:

• 1 year: 68%
• 3 years: 48%
• 5 years: 34%

With Treatment

• Epoprostenol Therapy:
  • 1-year: 88%
  • 3-year: 63%
  • 5-year: 47%
• Registry data report improvements in survival with modern therapies:
  • 1-year: 91%
  • 3-year: 74%
  • 5-year: 65%
• Meta-analyses suggest that targeted PAH therapies reduce all-cause mortality.

Poor Prognostic Factors

Demographics

• Male sex
• Older age

Clinical Features

• Syncope
• NYHA Functional Class IV
• 6-minute walk distance (6MWD) <300–440 meters

Echocardiography

• Presence of pericardial effusion
• Tricuspid annular plane systolic excursion (TAPSE) <1.5 cm

Biomarkers

• Elevated B-type natriuretic peptide (BNP) >180 ng/L

Hemodynamics

• Right atrial pressure >15 mmHg
• Cardiac index ≤2 L/min/m²

Adverse Prognostic Factors After Therapy

 Factors associated with poor outcomes post-therapy

• NYHA Functional Class III or IV after therapy
• Persistent 6MWD <380 meters
• Elevated BNP or NT-proBNP
• Low cardiac index and high right atrial pressure

Predictors of improved survival after therapy

• Achieving NYHA Functional Class I or II
• Cardiac index ≥2.5 L/min/m²
• Mixed venous oxygen saturation ≥65%

Emerging Evidence

• Changes in functional status and biomarkers (e.g., NYHA class, NT-proBNP) are better predictors of survival than changes in 6MWD.

Impact of Targeted Therapies

• Advances in treatments, including prostacyclin analogs, endothelin receptor antagonists, and phosphodiesterase-5 inhibitors, have significantly improved outcomes.
• Long-term studies show improved survival with combination therapies.

Complications

Cardiac

• Right-sided heart failure
• Hepatic congestion

Fluid Overload

• Pedal oedema
• Pleural effusions
• Ascites

Respiratory

• Worsening dyspnea on exertion

REVEAL Registry

• The largest PAH registry to date identified:
• 19 independent prognostic factors, allowing for risk stratification and survival prediction
• Patients with higher pulmonary capillary wedge pressure (PCWP 16–18 mmHg) had worse survival, often linked to left ventricular diastolic dysfunction

Cardiovascular Complications

 Right Ventricular (RV) Failure

• Timeframe: Long term.
• Likelihood: High.
• Pathophysiology: Progressive pulmonary vascular narrowing increases pulmonary vascular resistance, leading to RV overload, hypertrophy, and eventual failure.
• Symptoms: Dyspnea, peripheral oedema, ascites, hepatomegaly, and fatigue.
• Management:
  • Diuretics to manage fluid retention.
  • Digoxin for symptomatic relief.
  • Oxygen supplementation.
  • Pulmonary vasodilator therapy (oral or parenteral).

Supraventricular Tachyarrhythmias

• Timeframe: Long term.
• Likelihood: Medium (occurs in 11% of severe cases).
• Mechanism: Chronic pressure overload leads to structural changes, including enlargement of the right atrium and right ventricle.
• Common Arrhythmias: Paroxysmal atrial tachycardia.
• Management:
  • Digoxin to control ventricular rate.
  • Electrical cardioversion for unstable patients.
  • Overdrive pacing and radiofrequency ablation for recurrent episodes.

Respiratory and Hemodynamic Complications

 Pleural Effusions

• Result from increased venous pressure and systemic congestion.
• Symptoms include dyspnea and pleuritic chest pain.
• Management includes thoracentesis and optimising RV function.

Dyspnea at Rest

• Indicates advanced disease with significant hemodynamic compromise.
• Treated with oxygen supplementation, diuretics, and vasodilator therapy.

Abdominal and Systemic Complications

 Ascites

• Mechanism: Hepatic congestion due to elevated venous pressures.
• Symptoms: Abdominal distension, early satiety, and discomfort.
• Management: Diuretics and sodium restriction.

Death

• Primarily due to RV failure or sudden cardiac events in advanced disease.

Treatment-Related Complications

 Headache

• Timeframe: Variable.
• Likelihood: High.
• Causes:
  • Adverse effect of prostanoids, endothelin receptor antagonists, and phosphodiesterase-5 inhibitors.
• Management: Symptomatic treatment with analgesics or dose adjustments.

Central Venous Catheter-Related Infections

• Timeframe: Variable.
• Likelihood: High in patients receiving prostanoids via central venous catheters.
• Management:
  • Prompt recognition and treatment of bloodstream infections.
  • Preventive strategies include strict aseptic techniques and adherence to catheter care guidelines.

Rare Complications

 Paradoxical Embolism

• May occur in patients with an undiagnosed atrial septal defect or patent foramen ovale.
• Can result in stroke or systemic embolism.

Hemoptysis

• Results from rupture of hypertensive pulmonary arteries.
• Requires urgent intervention, including embolisation or surgery.

Pulmonary Arterial Aneurysm

• Rare but associated with a high risk of rupture and mortality.

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