Medical School · Year 1 · Respiratory · includes a quiz and discussion video

Lecture 10: Pulmonary Vascular Disease

Unit 1.8: Respiratory System

Learning Objectives

By the end of this lecture, students will be able to:

1. Describe the pathophysiology, diagnosis, and management of pulmonary embolism
2. Explain the classification and pathogenesis of pulmonary hypertension
3. Describe the clinical features and evaluation of pulmonary hypertension
4. Explain treatment strategies for pulmonary arterial hypertension
5. Describe the complications of pulmonary vascular disease including cor pulmonale
6. Apply risk stratification to patients with pulmonary embolism

Pulmonary Circulation Overview

The pulmonary circulation possesses unique characteristics that distinguish it from the systemic circulation and influence disease manifestations. Understanding these differences is essential for comprehending pulmonary vascular pathology.

Normal Pulmonary Circulation

The pulmonary circulation operates as a low-pressure, high-flow system. Normal mean pulmonary artery pressure ranges from 10-20 mmHg, approximately one-sixth of mean systemic arterial pressure. Despite receiving the entire cardiac output (approximately 5 L/min at rest), pulmonary vascular resistance remains only one-tenth of systemic vascular resistance. This low resistance results from the thin, compliant walls of pulmonary vessels, which lack the muscular media characteristic of systemic arteries.

A unique feature of the pulmonary circulation is its response to hypoxia. While systemic vessels dilate in response to low oxygen to increase tissue delivery, pulmonary vessels constrict. This hypoxic pulmonary vasoconstriction serves a physiological purpose: it diverts blood away from poorly ventilated lung regions toward better-ventilated areas, optimizing ventilation-perfusion matching. However, this protective mechanism becomes pathological when hypoxia is generalized, as in chronic lung disease, leading to diffuse vasoconstriction and elevated pulmonary pressures.

<image>Panel A: Pulmonary circulation showing the right ventricle pumping blood through thin-walled pulmonary arteries with minimal smooth muscle in cross-section, with pressure values labeled at mean PA 15 mmHg and PCWP 8 mmHg. Panel B: Systemic circulation showing the left ventricle pumping through thick-walled systemic arteries with prominent muscular media in cross-section, with mean arterial pressure 90 mmHg. Panel C: Hypoxic pulmonary vasoconstriction response showing pulmonary vessels constricting with narrowed lumen and inward-pointing arrows in response to low PO2. Panel D: Systemic vasodilation response showing systemic vessels dilating with widened lumen and outward-pointing arrows in response to low PO2, contrasting with the pulmonary response.</image>

Pulmonary Embolism Overview

Pulmonary embolism (PE) occurs when material—most commonly a blood clot—obstructs the pulmonary arteries, impairing blood flow and gas exchange. PE represents a potentially life-threatening emergency that requires rapid recognition and treatment.

Epidemiology

Pulmonary embolism affects approximately 1 per 1,000 individuals annually. Without treatment, mortality reaches 30%, but appropriate anticoagulation reduces this to 2-8%. The vast majority (over 90%) of pulmonary emboli originate from deep vein thrombosis (DVT) in the lower extremities or pelvis. Clots from the superficial veins, upper extremities, or right heart chambers account for a minority of cases.

Virchow's Triad

Rudolf Virchow identified three categories of factors predisposing to venous thrombosis, and this triad remains clinically relevant today. Venous stasis allows blood to pool and clotting factors to accumulate; risk factors include immobilization from surgery, prolonged travel, or illness, as well as conditions reducing venous return such as heart failure. Endothelial injury exposes prothrombotic subendothelial collagen; causes include recent surgery, trauma, and indwelling catheters. Hypercoagulability shifts the balance toward clot formation; this may be inherited (Factor V Leiden, prothrombin gene mutation) or acquired (malignancy, pregnancy, oral contraceptive use, antiphospholipid syndrome).

Types of Emboli

While thromboembolism is by far the most common type of PE, other materials may embolize to the pulmonary circulation. Fat embolism occurs after long bone fractures, particularly femur fractures, and presents with the triad of respiratory distress, neurological changes, and petechial rash. Air embolism may complicate central venous catheter placement or removal, surgery, or trauma. Amniotic fluid embolism is a rare but catastrophic complication of labor and delivery. Tumor embolism occurs most commonly with renal cell carcinoma extending into the inferior vena cava. Septic emboli arise from right-sided endocarditis, typically in intravenous drug users.

<image>Panel A: Virchow's triad triangle with three vertices labeled Stasis, Endothelial Injury, and Hypercoagulability, each surrounded by relevant risk factor icons including hospital bed, surgical scalpel, cancer cells, oral contraceptives, and DNA helix. Panel B: Pathway of thromboembolism showing DVT in the deep femoral vein traveling through the inferior vena cava, right atrium, and right ventricle to lodge in the pulmonary artery. Panel C: Other emboli types shown in inset panels: fat globules associated with long bone fracture, air bubbles from central venous catheter, and septic vegetations from the tricuspid valve. Panel D: Risk factor details for each triad component: immobilization and travel for stasis, trauma and catheter for endothelial injury, and genetic factors and pregnancy for hypercoagulability.</image>

Pulmonary Embolism Pathophysiology

Hemodynamic Consequences

When emboli obstruct the pulmonary arteries, pulmonary vascular resistance increases acutely. The right ventricle, which normally operates against low afterload, must generate higher pressures to maintain cardiac output. This pressure overload causes right ventricular dilation. As the RV dilates, the interventricular septum shifts leftward, compromising left ventricular filling—a phenomenon termed ventricular interdependence. Reduced LV preload leads to decreased cardiac output and hypotension. In severe cases, this cascade produces obstructive shock.

Gas Exchange Abnormalities

PE disrupts ventilation-perfusion relationships. Regions supplied by obstructed vessels receive ventilation but no perfusion, creating dead space. Other regions may develop low V/Q ratios as blood is redistributed. The result is hypoxemia, typically mild to moderate unless embolism is massive. Patients hyperventilate in response, producing hypocapnia (low PaCO2) and respiratory alkalosis. The alveolar-arterial oxygen gradient is elevated, reflecting V/Q mismatch.

Severity Spectrum

Pulmonary embolism ranges from incidental findings to immediately life-threatening events. Small emboli may produce minimal symptoms or go undetected. Moderate PE causes hypoxemia and right ventricular strain visible on echocardiography. Massive PE, defined by systemic hypotension (systolic blood pressure below 90 mmHg), indicates hemodynamic compromise requiring aggressive intervention. A saddle embolus lodging at the bifurcation of the main pulmonary artery is often massive by definition.

<image>Panel A: Heart cross-section during massive PE showing dilated right ventricle with pressure overload, interventricular septum bowing into the left ventricle, and compressed left ventricular chamber with reduced cardiac output from the aorta. Panel B: Pressure values labeled in each cardiac chamber demonstrating the hemodynamic consequences of acute pulmonary vascular obstruction. Panel C: Alveolar gas exchange comparison showing a normal alveolus with matched ventilation and perfusion, a dead space unit with ventilated alveolus but blocked capillary containing embolus, and redistributed blood flow creating low V/Q in adjacent alveoli. Panel D: Arterial blood gas values displaying decreased PaO2, decreased PaCO2 from hyperventilation, elevated pH indicating respiratory alkalosis, and widened alveolar-arterial oxygen gradient.</image>

Pulmonary Embolism Clinical Features

Symptoms

The clinical presentation of PE is notoriously variable, earning it the moniker "the great masquerader." Dyspnea is the most common symptom, present in approximately 80% of cases and often of sudden onset. Pleuritic chest pain—sharp and worsening with inspiration—occurs in about half of patients, particularly with peripheral emboli that irritate the pleura. Cough is present in 20% and may be dry or produce blood-tinged sputum. Frank hemoptysis, though classic, occurs in only 10%. Syncope suggests massive PE with transient cerebral hypoperfusion and carries prognostic significance.

Physical Examination

Tachypnea (respiratory rate over 20) is the most common sign. Tachycardia is frequent. Hypoxemia may be evident on pulse oximetry, though oxygen saturation may be normal in small PE. Hypotension indicates massive PE with hemodynamic compromise. Signs of right heart strain include elevated jugular venous pressure, a loud pulmonic component of the second heart sound (P2) from pulmonary hypertension, and a right ventricular heave palpable at the left sternal border. These findings reflect acute right ventricular pressure overload.

DVT Signs

Since most pulmonary emboli originate from lower extremity DVT, examining the legs is essential. Findings include unilateral leg swelling, warmth, and erythema; calf tenderness to palpation, particularly along the course of the deep veins; and occasionally a palpable cord representing the thrombosed vein. Homan's sign—calf pain with passive dorsiflexion of the foot—is neither sensitive nor specific and should not drive clinical decision-making. Importantly, the absence of DVT signs does not exclude PE, as the clot may have embolized completely.

<image>Panel A: Anterior view of a patient with labeled PE symptoms including dyspnea with rapid breathing pattern, chest pain shown as lightning bolt over lateral chest, and syncope with dizziness stars, alongside vital sign monitor showing tachycardia, tachypnea, and borderline SpO2. Panel B: Expanded neck view showing jugular venous distension with visible pulsation and stethoscope placement over the pulmonic area indicating the location of loud P2. Panel C: Bilateral leg comparison with the right leg demonstrating DVT signs including increased calf circumference on measurement tape, redness, and warmth indicated by heat icon, versus normal left leg. Panel D: Blood pressure display and hemodynamic assessment showing the spectrum from stable vitals to hypotension indicating massive PE with hemodynamic compromise.</image>

Pulmonary Embolism Diagnosis

Clinical Probability Assessment

Before ordering tests, clinicians should estimate the pretest probability of PE using validated scoring systems. The Wells Score for PE assigns points based on clinical findings: 3 points each for clinical signs of DVT and for PE being more likely than alternative diagnoses; 1.5 points each for heart rate over 100, immobilization or recent surgery, and previous DVT/PE history; 1 point each for hemoptysis and active malignancy. A score of 4 or less indicates PE is unlikely, while greater than 4 suggests PE is likely. This stratification determines the appropriate diagnostic pathway.

D-Dimer Testing

D-dimer is a fibrin degradation product elevated in the presence of thrombus. Its primary value lies in its high negative predictive value in low-probability patients: a normal D-dimer effectively excludes PE when clinical probability is low. However, D-dimer is elevated in many conditions including advanced age, pregnancy, inflammation, infection, malignancy, and recent surgery, limiting its specificity. It should not be used as a screening test in patients with high clinical probability.

Imaging

CT pulmonary angiography (CTPA) is the gold standard diagnostic test for PE. It directly visualizes intraluminal filling defects in the pulmonary arteries. CTPA also provides information about right ventricular size, alternative diagnoses, and the extent of embolic burden. Ventilation-perfusion (V/Q) scanning is an alternative when CTPA is contraindicated (renal insufficiency, contrast allergy) or unavailable. A segmental perfusion defect with preserved ventilation (mismatch) is characteristic of PE. Lower extremity Doppler ultrasound may detect DVT, and in patients with high clinical suspicion, documented DVT warrants anticoagulation regardless of direct PE imaging.

Echocardiography and ECG

Echocardiography cannot directly visualize most pulmonary emboli but can demonstrate RV strain: dilation, hypokinesis, and the McConnell sign (RV free wall hypokinesis with apical sparing). These findings have prognostic significance. ECG findings in PE are neither sensitive nor specific. Sinus tachycardia is most common. The classic S1Q3T3 pattern (deep S wave in lead I, Q wave and inverted T in lead III) is uncommon but suggestive. New right bundle branch block and T-wave inversions in V1-V4 indicate RV strain.

<image>Panel A: Diagnostic flowchart beginning with suspected PE and branching by Wells Score into PE Unlikely (4 or fewer points) leading to D-dimer testing, and PE Likely (greater than 4 points) proceeding directly to CTPA, with negative D-dimer excluding PE. Panel B: CTPA image showing a saddle embolus at the main pulmonary artery bifurcation with filling defects labeled in both branches, and alternative V/Q scan pathway showing matched versus mismatched perfusion patterns. Panel C: ECG strips displaying sinus tachycardia and the classic S1Q3T3 pattern with labeled leads indicating right ventricular strain. Panel D: Echocardiogram short-axis view showing right ventricular dilation with septal flattening producing a D-shaped left ventricle, demonstrating the McConnell sign of RV strain.</image>

Pulmonary Embolism Risk Stratification and Management

Risk Stratification

Risk stratification guides treatment intensity and disposition. Massive PE is defined by hemodynamic instability (sustained hypotension with systolic BP below 90 mmHg, shock, or cardiac arrest) and carries mortality exceeding 15%, necessitating consideration of aggressive reperfusion therapy. Submassive PE (intermediate risk) features hemodynamic stability but evidence of RV dysfunction (on echocardiography or CT) and/or elevated cardiac biomarkers (troponin, BNP); mortality ranges from 3-15%. Low-risk PE has no hemodynamic compromise or RV strain and carries less than 1% short-term mortality; selected patients may be managed as outpatients.

Anticoagulation

Anticoagulation is the cornerstone of PE treatment. If clinical suspicion is high, anticoagulation should begin before imaging confirmation. Options for initial therapy include low-molecular-weight heparin (enoxaparin), which offers predictable dosing without monitoring; unfractionated heparin infusion, preferred in massive PE (allowing rapid reversal if intervention needed) and renal failure; and direct oral anticoagulants (DOACs) such as rivaroxaban or apixaban, which can be initiated without parenteral bridging in stable patients and have become first-line for many patients due to convenience and efficacy.

Warfarin remains an option but requires parenteral anticoagulation bridging until INR is therapeutic (2-3). Duration of anticoagulation depends on the clinical scenario: 3 months for provoked PE with transient risk factor (surgery, immobilization), at least 3 months with consideration of indefinite therapy for unprovoked PE (as recurrence risk is higher), and indefinite anticoagulation for recurrent VTE or persistent risk factors (active cancer, thrombophilia).

Advanced Therapies

Systemic thrombolysis with alteplase accelerates clot dissolution and is indicated for massive PE with hemodynamic collapse. The major risk is bleeding, including intracranial hemorrhage. Catheter-directed therapy (local thrombolysis or mechanical thrombectomy) may reduce bleeding risk while achieving reperfusion and is increasingly used for submassive PE with impending deterioration. Surgical embolectomy is reserved for patients with massive PE who have contraindications to thrombolysis or who fail pharmacological therapy. Inferior vena cava (IVC) filters provide a mechanical barrier against additional emboli and are indicated when anticoagulation is absolutely contraindicated or when PE recurs despite adequate anticoagulation.

<image>Panel A: Risk stratification showing three patient silhouettes: massive PE in red with hypotension and flat blood pressure tracing, submassive PE in yellow with echocardiographic RV strain and elevated troponin, and low-risk PE in green with stable vital signs. Panel B: Anticoagulation options including LMWH syringe, DOAC pills, heparin drip, and warfarin tablets with INR monitor, with duration timeline showing 3 months for provoked and extended or indefinite for unprovoked PE. Panel C: Advanced reperfusion therapies showing systemic thrombolysis with alteplase bottle and brain bleeding risk icon, catheter-directed intervention with clot fragmentation in the pulmonary artery, and surgical embolectomy operative field. Panel D: IVC filter showing conical device deployed in the inferior vena cava for patients with contraindications to anticoagulation or recurrent PE despite therapy.</image>

Pulmonary Hypertension Overview

Definition

Pulmonary hypertension is defined hemodynamically as a mean pulmonary artery pressure of 20 mmHg or greater at rest, measured by right heart catheterization. This threshold was revised in 2018 from the previous 25 mmHg, as evidence demonstrated that patients with mPAP 21-24 mmHg have increased mortality.

WHO Classification

The World Health Organization classification organizes pulmonary hypertension into five groups based on underlying mechanism and treatment approach. Group 1, pulmonary arterial hypertension (PAH), encompasses conditions causing intrinsic pulmonary vascular disease: idiopathic PAH, heritable forms, drug-induced (anorexigens, methamphetamine), and PAH associated with connective tissue disease, HIV, portal hypertension, and congenital heart disease. Group 2 is pulmonary hypertension due to left heart disease, including heart failure with reduced or preserved ejection fraction and valvular disease; this is the most common cause of pulmonary hypertension overall. Group 3 is pulmonary hypertension due to lung disease or hypoxia, including COPD, interstitial lung disease, and sleep-disordered breathing. Group 4 is chronic thromboembolic pulmonary hypertension (CTEPH), caused by organized thrombi that fail to resolve after acute PE. Group 5 encompasses miscellaneous and multifactorial causes including sarcoidosis and hematologic disorders.

This classification matters because treatments differ substantially across groups. PAH-specific vasodilator therapies are effective for Group 1 but may be harmful in Groups 2 and 3 where the underlying disease must be addressed.

<image>Panel A: Central heart and lung diagram with pulmonary arteries highlighted, surrounded by five radiating WHO classification sections, with Group 1 in purple showing intrinsic vascular changes with narrowed arterioles and icons for connective tissue disease, HIV, portal hypertension, and drugs. Panel B: Group 2 in blue as the most prominent section showing left heart disease with dilated chambers and mitral valve labeled as the most common cause of pulmonary hypertension. Panel C: Group 3 in green showing emphysematous and fibrotic lung patterns with oxygen tubing, and Group 4 in orange showing organized thrombi within pulmonary arteries with V/Q scan mismatched defects. Panel D: Group 5 in gray showing granulomas and blood cells representing sarcoidosis and hematologic causes, with relative prevalence of all groups indicated by section size.</image>

Pulmonary Arterial Hypertension (Group 1)

Pathophysiology

Pulmonary arterial hypertension results from progressive narrowing of small pulmonary arteries due to vasoconstriction and structural remodeling. At the cellular level, endothelial dysfunction creates an imbalance between vasoactive mediators: excess endothelin (a potent vasoconstrictor and promoter of smooth muscle proliferation), deficiency of nitric oxide (a vasodilator), and deficiency of prostacyclin (a vasodilator with antiproliferative effects). This milieu promotes sustained vasoconstriction, smooth muscle hypertrophy, intimal hyperplasia, and in situ thrombosis.

As disease progresses, characteristic histological changes develop. Medial hypertrophy thickens the vessel wall from smooth muscle proliferation. Intimal fibrosis narrows the lumen. In advanced disease, plexiform lesions develop—disorganized networks of vascular channels that are pathognomonic of PAH.

Genetic Associations

Heritable PAH accounts for approximately 6% of cases and most commonly results from mutations in BMPR2 (bone morphogenetic protein receptor type 2), a member of the TGF-β superfamily. About 70% of familial cases have identifiable BMPR2 mutations, though penetrance is incomplete. Mutations in ALK1 are associated with hereditary hemorrhagic telangiectasia-related PAH.

Associated Conditions

PAH develops in association with several systemic diseases. Connective tissue diseases, particularly systemic sclerosis (scleroderma), are the most common; up to 15% of scleroderma patients develop PAH. HIV infection causes PAH through incompletely understood mechanisms. Portal hypertension leads to portopulmonary hypertension through shunting of vasoactive substances and increased cardiac output. Congenital heart disease with left-to-right shunts produces PAH through chronic volume and pressure overload; severe cases develop Eisenmenger syndrome with shunt reversal.

<image>Panel A: Cross-sections of a small pulmonary arteriole showing progressive changes from normal vessel with thin wall and open lumen, to medial hypertrophy with thickened smooth muscle, to intimal fibrosis with narrowed lumen, to plexiform lesion with chaotic tangle of small channels. Panel B: Molecular pathway imbalance depicted as three balance scales: endothelin elevated with scale tilted up promoting vasoconstriction and proliferation, nitric oxide decreased with scale tilted down, and prostacyclin decreased with scale tilted down. Panel C: Associated conditions including scleroderma with thickened skin over hands, HIV virus particle, and liver with portal varices. Panel D: Heart with ventricular septal defect and bidirectional arrow representing Eisenmenger syndrome, illustrating congenital heart disease progression from left-to-right shunt to shunt reversal with pulmonary hypertension.</image>

Pulmonary Hypertension Clinical Features and Diagnosis

Symptoms

Symptoms of pulmonary hypertension are often nonspecific and insidious, leading to delayed diagnosis. Exertional dyspnea is typically the earliest and most common symptom, resulting from the inability to augment cardiac output with exercise as pulmonary vascular resistance is fixed. Fatigue reflects chronic low cardiac output. Chest pain with anginal quality occurs from right ventricular ischemia—the hypertrophied RV has increased oxygen demand but reduced coronary perfusion, particularly during exertion. Exertional syncope is ominous, indicating inability to maintain cerebral perfusion during activity; it predicts poor prognosis. As right heart failure develops, patients notice lower extremity edema and abdominal distension from ascites.

Physical Examination

Physical findings reflect elevated pulmonary pressures and right heart strain. Cardiac examination reveals a loud pulmonic component of the second heart sound (P2), heard best at the upper left sternal border, due to forceful pulmonic valve closure against elevated pressures. A right ventricular heave may be palpable at the left sternal border. The murmur of tricuspid regurgitation—holosystolic at the lower left sternal border, increasing with inspiration—develops as the right ventricle dilates and the tricuspid annulus stretches. Signs of right heart failure include elevated jugular venous pressure with prominent A waves (from RV noncompliance) or V waves (from TR), hepatomegaly with pulsatile liver, ascites, and peripheral edema. Central cyanosis indicates severe disease with right-to-left shunting.

Diagnostic Evaluation

Echocardiography is the initial screening test, providing estimated right ventricular systolic pressure (derived from tricuspid regurgitation velocity), assessment of RV size and function, and exclusion of left heart disease. Right heart catheterization remains the gold standard for diagnosis and classification. Criteria for PAH specifically require mPAP of 20 mmHg or greater, pulmonary capillary wedge pressure of 15 mmHg or less (excluding left heart disease), and pulmonary vascular resistance greater than 3 Wood units.

Additional workup identifies the underlying cause and WHO group. Pulmonary function tests exclude lung disease (Group 3). V/Q scan is essential to exclude CTEPH (Group 4), as it has higher sensitivity than CTPA for chronic organized thrombi. CT chest evaluates parenchymal lung disease. Laboratory testing includes BNP (prognosis), autoantibodies for connective tissue disease, and HIV serology. The 6-minute walk test quantifies functional capacity and guides treatment response.

<image>Panel A: Initial echocardiogram screening showing RV dilation, D-shaped septum in short axis view, tricuspid regurgitation jet measurement with velocity, and calculated right ventricular systolic pressure for suspected pulmonary hypertension. Panel B: Right heart catheterization with catheter diagram in the heart and pressure tracings displaying mean pulmonary artery pressure, pulmonary capillary wedge pressure, and pulmonary vascular resistance to differentiate pre- from post-capillary PH. Panel C: Etiologic workup icons including pulmonary function tests with spirometry tracing, V/Q scan showing mismatched defects for CTEPH, CT chest with fibrotic lung pattern, and laboratory tubes for BNP, ANA, and HIV testing. Panel D: Functional assessment with 6-minute walk test showing a figure walking with distance measured, and final diagnostic branching into WHO Groups 1 through 5 based on combined findings.</image>

Pulmonary Hypertension Management

General Measures

All patients with pulmonary hypertension benefit from general supportive measures. Supplemental oxygen maintains saturations above 90% to prevent hypoxic vasoconstriction. Diuretics manage right heart failure symptoms—judicious dosing is important as excessive preload reduction compromises RV output. Supervised exercise rehabilitation improves functional capacity and quality of life. Vaccinations (influenza, pneumococcal) prevent respiratory infections that can precipitate decompensation. Contraception counseling is essential for women with PAH, as pregnancy carries prohibitive mortality (30-50%).

PAH-Specific Therapies

Treatment of Group 1 PAH targets the three pathobiological pathways identified in the disease. Prostacyclin pathway agents compensate for deficient endogenous prostacyclin: epoprostenol (continuous IV infusion, most potent), treprostinil (subcutaneous, IV, inhaled, or oral), iloprost (inhaled), and selexipag (oral prostacyclin receptor agonist). Endothelin receptor antagonists (ERAs) block the effects of excess endothelin: bosentan, ambrisentan, and macitentan. Nitric oxide pathway therapies enhance vasodilation: phosphodiesterase-5 inhibitors (sildenafil, tadalafil) prevent cGMP breakdown, while soluble guanylate cyclase stimulators (riociguat) directly stimulate cGMP production.

Treatment intensity is based on risk stratification. Low to intermediate risk patients typically begin with oral combination therapy (ERA plus PDE-5 inhibitor). High-risk patients should receive a prostacyclin analog as part of their initial regimen. Refractory disease may require triple combination therapy including intravenous prostacyclin.

Group-Specific Treatments

Treatment of pulmonary hypertension due to left heart disease (Group 2) focuses on optimizing the underlying cardiac condition; PAH-specific vasodilators may worsen outcomes by increasing left heart filling pressures. Similarly, Group 3 PH from lung disease is managed by treating the underlying condition and providing supplemental oxygen; vasodilators may worsen V/Q matching.

Group 4 CTEPH has a unique treatment pathway. Pulmonary endarterectomy (surgical removal of organized thrombus) is potentially curative for accessible disease and should be considered in all patients. Riociguat is approved for inoperable CTEPH or persistent PH after surgery. Balloon pulmonary angioplasty is emerging as an option for distal disease.

Advanced therapies for end-stage PAH include atrial septostomy, which creates a right-to-left shunt to decompress the right ventricle at the cost of hypoxemia, serving as a bridge to transplantation. Lung or heart-lung transplantation is the definitive treatment for refractory disease.

<image>Panel A: Three molecular pathways with therapeutic targets: prostacyclin pathway with receptor leading to vasodilation and drugs epoprostenol, treprostinil, and iloprost; endothelin pathway with ERA drugs bosentan, ambrisentan, and macitentan blocking vasoconstriction; and nitric oxide pathway with PDE-5 inhibitors sildenafil and tadalafil and sGC stimulator riociguat. Panel B: Treatment escalation based on risk stratification: low risk with oral monotherapy or dual therapy, intermediate with oral combination, high risk adding prostacyclin continuous infusion pump, and refractory with advanced options including heart-lung transplant. Panel C: Group-specific approaches showing Group 2 managed with diuretics and cardiac optimization, and Group 3 managed with supplemental oxygen and treatment of underlying lung disease. Panel D: Group 4 CTEPH treatment showing pulmonary endarterectomy specimen with organized thrombus, riociguat for inoperable disease, and balloon pulmonary angioplasty for distal disease.</image>

Cor Pulmonale

Definition

Cor pulmonale refers to right ventricular dysfunction resulting from pulmonary disease, specifically excluding right heart failure caused by left heart disease or congenital heart disease. It represents the cardiac consequence of chronic pulmonary pathology.

Causes

COPD is the most common cause of cor pulmonale, accounting for over 50% of cases. Chronic hypoxemia from emphysema and chronic bronchitis triggers sustained hypoxic pulmonary vasoconstriction. Other pulmonary parenchymal diseases including interstitial lung disease similarly cause hypoxemic vasoconstriction and vascular destruction. Pulmonary vascular diseases (PAH, CTEPH, vasculitis) directly elevate pulmonary vascular resistance. Chest wall abnormalities such as severe kyphoscoliosis restrict ventilation and cause hypoxemia. Neuromuscular diseases (muscular dystrophy, ALS) lead to hypoventilation. Obesity hypoventilation syndrome and severe obstructive sleep apnea cause nocturnal and sometimes daytime hypoxemia and hypercapnia.

Pathophysiology

The sequence begins with chronic hypoxia, which triggers hypoxic pulmonary vasoconstriction as an initially protective mechanism. With sustained hypoxia, vascular smooth muscle hypertrophy develops, and structural remodeling of pulmonary arterioles produces fixed elevation of pulmonary vascular resistance. Pulmonary hypertension increases right ventricular afterload. The RV initially compensates through hypertrophy, maintaining cardiac output against elevated pressures. Eventually, the RV decompensates, dilating and failing, with tricuspid regurgitation developing as the annulus stretches.

Clinical Features and Management

Patients present with symptoms of the underlying lung disease plus manifestations of right heart failure: peripheral edema, often severe; elevated jugular venous pressure; hepatomegaly with hepatojugular reflux; and ascites in advanced cases. Tricuspid regurgitation produces a holosystolic murmur that increases with inspiration.

Management focuses on treating the underlying pulmonary disease. Long-term oxygen therapy in hypoxemic patients is the most effective intervention, reducing hypoxic vasoconstriction and slowing disease progression. Diuretics alleviate fluid overload but must be used cautiously—the failing RV is preload-dependent, and excessive diuresis compromises cardiac output. Avoiding medications that decrease preload (nitrates) or increase pulmonary vascular resistance is important.

<image>Panel A: Causes of cor pulmonale shown as initiating conditions: COPD with emphysematous lung, kyphoscoliotic spine, obesity hypoventilation with large abdomen, and sleep apnea with upper airway obstruction diagram, all leading to chronic hypoxia. Panel B: Pathophysiology progression from hypoxic pulmonary vasoconstriction with narrowed arteriolar lumen, to vascular remodeling with thickened arteriole wall, to pulmonary hypertension, to RV hypertrophy, and finally to RV failure with dilated thin RV and tricuspid regurgitation jet. Panel C: Clinical manifestations shown on a patient figure including elevated jugular venous pressure, tender hepatomegaly with hepatojugular reflux, and pitting edema in the lower extremities. Panel D: Treatment icons including supplemental oxygen tank as the primary intervention, diuretic pills for fluid management, and underlying disease management with inhaler and CPAP machine.</image>

Summary

Pulmonary embolism usually arises from DVT, with Virchow's triad (stasis, endothelial injury, hypercoagulability) predisposing to thrombosis. It presents with dyspnea and pleuritic chest pain, and CT pulmonary angiography is the diagnostic gold standard.

PE risk stratification distinguishes massive (hypotension requiring reperfusion), submassive (RV dysfunction), and low-risk (stable, suitable for outpatient therapy) categories.

All PE patients require anticoagulation; systemic thrombolysis is reserved for massive PE with hemodynamic compromise.

Pulmonary hypertension is defined as mean PA pressure of 20 mmHg or greater and is classified into five WHO groups with distinct etiologies and treatments.

Pulmonary arterial hypertension (Group 1) results from endothelial dysfunction and vascular remodeling; treatment targets prostacyclin, endothelin, and nitric oxide pathways.

Group 2 (left heart disease) is the most common cause of PH overall and is managed by treating the underlying cardiac condition.

CTEPH (Group 4) is potentially curable with pulmonary endarterectomy.

Cor pulmonale is right ventricular failure from pulmonary disease; treating the underlying cause and providing supplemental oxygen are the cornerstones of management.

Key Terms

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