10th March 2024

Pulmonary Hypertension

The cardinal manifestation of pulmonary hypertension is elevated pulmonary artery pressure (mean PAP >20mmHg). Classification of pulmonary hypertension is generally based on aetiology:

1. Group 1: idiopathic/pulmonary arterial hypertension (PAH)
2. Group 2: due to left heart disease
3. Group 3: due to chronic lung disease
4. Group 4: due to pulmonary vasculature obstructions
5. Group 5: due to unclear multifactorial mechanisms

Pathophysiology

Each group has its separate pathophysiology, clinical presentation, and management. Generally speaking, the pathophysiology of pulmonary hypertension can be easily understood by considering Ohm’s law that when adapted reads:

Pressure = Flow x Resistance

An increase in pulmonary vascular resistance is the most common cause of detectable pulmonary hypertension. In most situations, increased flow (i.e. right ventricle output) and increased pulmonary venous pressure alone are not sufficient to cause pulmonary hypertension due to available compensatory mechanisms, but they can prove to be significant in chronic conditions.

When applied to the pulmonary circulation, all the variables in Ohm’s law can be affected by different medical conditions:

• In Group 1, occlusive vasculopathy of the small pulmonary arteries and arterioles increases pulmonary vascular resistance
• In Group 2, congenital heart disease with left-to-right shunt may increase flow. Mitral valve disease, left ventricular systolic or diastolic dysfunction, or restrictive cardiomyopathy can increase pulmonary venous pressure.
• In Group 3, conditions that decrease the cross-sectional area of the pulmonary vascular bed (ILD) or induce hypoxic vasoconstriction (hypoventilation, parenchymal lung disease) cause an increase in pulmonary vascular resistance.
• In Group 4, multiple thrombotic events reduce the cross-sectional area of the pulmonary vascular bed, resulting in an increase in PVR.

As management and therapy vary depending on the specific type of pulmonary hypertension, these will be dealt with separately in this section.

Clinical manifestations 

Symptoms and signs of pulmonary hypertension are nonspecific but similar for all types of PH. Initial presenting complaints are usually exertional dyspnoea and fatigue that progress gradually over time with no obvious clinical signs and symptoms. Clinical signs and symptoms become apparent only when overt right ventricular failure develops due to severe pulmonary hypertension.

Classical signs and symptoms of cor pulmonale (i.e. right ventricular failure) include jugular venous distension, often with a prominent V wave and positive Kussmaul sign. Pitting lower limb oedema is usually present bilaterally, as well as ascites and hepatomegaly. On cardiac examination, it may be possible to find a RV heave, a loud P2, or a pansystolic murmur (due to tricuspid regurgitation).

In some cases, when there is an underlying cause for PH, the patient may have signs and symptoms of the disease, i.e. connective tissue disease, heart failure, and chronic lung diseases. PH is an under-recognised disorder that is frequently misdiagnosed until symptoms become severe.

Group 1: Pulmonary Arterial Hypertension

Pulmonary Arterial hypertension (PAH) is a rare disease which is idiopathic in about 50% of cases. It is typically a disorder of younger individuals, and females are affected more than males. Pathophysiologically, PAH is a proliferative vasculopathy characterised by extensive vasoconstriction, fibrosis, and micro-thrombosis. Some medications have been identified as definite risk factors for developing PAH (methamphetamines, rapeseed oil, benfluorex), while others represent possible risk factors (chronic use of cocaine, amphetamines, interferon therapy, and dasatinib). Other common conditions that can be associated with PAH include connective tissue diseases and HIV, and for this reason, all patients presenting with idiopathic PAH should be screened for these. A subset of patients also present with hereditary forms of PAH.

Diagnosis is confirmed by right heart catheterisation. Alternative tests need to be carried out at the same time to rule out other causes of pulmonary hypertension or concomitant pathology.

Treatment for this subgroup of pulmonary hypertension is different from the other ones in that there are evidence-based PH-targeted treatments available. Choosing what treatment regimen should be used is based on the patient’s WHO performance scale and whether their vasculature is vasoreactive on acute vasoreactivity testing. Some of the medications that are commonly used include:

• Calcium-channel blockers (long-acting nifedipine, diltiazem): these should be offered only to patients that have been positive on acute vasoreactivity testing. These are usually patients that have idiopathic PAH, hereditary PAH, or drug-related PAH. About half of the vasoreactive patients respond to CCB therapy, though the response is usually short-lived, and they may require the addition of another agent of a different class.
• Phosphodiesterase-5 inhibitors (sildenafil, tadalafil): agents in this class enhance the production or function of nitric oxide, a potent vasodilator.
• Endothelin receptor antagonist (ambrisentan, bosentan): endothelin-1 is a potent vasoconstrictor and smooth muscle mitogen. These medications target both endothelin receptors A and B, thus causing vasodilation. The main side effects are hepatotoxicity, peripheral oedema, and they are potent teratogens. 
• Parenteral prostanoids (epoprostenol): synthetic analogue prostacyclin
• Inhaled prostanoid (iloprost): prostacyclin analogue, it has the advantage that it specifically targets the lung vasculature and does not require intravenous administration. The main disadvantage is the need for frequent administration as it needs to be administered up to nine times per day.

PAH is a progressive disease, and in some cases, patients may progress to a point where they are refractory to PAH-specific therapy. One temporising measure is the creation of a right-to-left shunt. Lung transplantation is a definitive form of therapy and should be offered if the patient meets the following criteria:

• WHO functional class III or IV during escalating therapy
• Rapidly progressive disease
• Use of parenteral prostanoid therapy (independent of WHO classification)

Bilateral lung or heart-lung transplantation is the procedure of choice.

Group 2: Left heart disease

Left-sided heart failure is the most common cause of pulmonary hypertension, and this can happen in patients with both HF-pEF and HF-rEF. Recognising that pulmonary hypertension is present in these patients is essential as it carries an increased morbidity and mortality, though there are no specifically targeted therapies.

When considering pathophysiology, the first hemodynamic insult in this group of patients is an increase in left atrial or ventricular filling pressures. This, in turn, can reduce pulmonary arterial compliance, causing the pulmonary vasculature to become stiffer and increasing the pressure against which the RV needs to contract. Patients with left heart disease with both post- and pre-capillary pulmonary hypertension can develop pulmonary hypertension due to ongoing vasoconstriction and chronic remodelling of the pulmonary vascular beds. The increase in pulmonary pressures will cause an increased resistive afterload and, ultimately, dilatation, hypertrophy, and failure of the right ventricle (cor pulmonale).

Signs that raise the suspicion of pulmonary hypertension in these patients are: clinical signs (loud P2, RV heave), PASP>35mmHg on TTE, or right ventricular structural abnormalities or tricuspid regurgitation on cardiac imaging.

The initial diagnostic evaluation includes a TTE, which is the cornerstone to determine type and severity of heart failure, additional valvular abnormalities, and PASP. Right heart catheterisation is considered if PASP>35mmHg, and there is evidence of RV dysfunction, the cause of PH is unclear, and/or advanced therapies for heart failure are being considered. Right heart catheterisation is the gold standard for confirming the diagnosis and further categorising pulmonary hypertension.

The cornerstone of treatment is management of the underlying left heart disease with all evidence-based medical and surgical therapies available. Treatment for left heart disease aims to reduce left-sided filling pressures, which should consequently lead to an improvement in pulmonary pressures. Adequate decongestion with diuretics is essential to reduce left-sided pressures and improve pulmonary vascular function.

Systemic vasodilator challenge is only indicated for some candidates for heart transplantation to assess the reversibility of pulmonary hypertension. PH- targeted therapy is not indicated for routine use in group 2 PH as there is not sufficient evidence, and it may occasionally worsen pulmonary oedema.

Group 3: Chronic lung disease

The strongest mechanism that drives the development of pulmonary hypertension in this group is hypoxic pulmonary vasoconstriction, a normal regulatory mechanism that has the aim of limiting blood flow to hypoxic alveoli to preserve ventilation-perfusion matching. The effects of this mechanism on pulmonary vascular pressure is dependent on the duration of the hypoxia. Chronic hypoxia causes pulmonary vasoconstriction by a variety of mechanisms (decrease in nitric oxide, increase in endothelin -1) and is often only partially reversible. Vascular remodelling (obliterative in nature) occurs over time and leads to a reduction in peripheral blood vessels and, consequently, increased peripheral vascular resistance. Additional mechanisms come into play in the setting of ILD-associated PH due to the additional element of vascular destruction caused by progressive parenchymal fibrosis, thrombotic angiopathy, and endothelial dysfunction. The mechanism of pulmonary hypertension in patients with sleep-related breathing disorders (e.g. OSAS) is thought to be related to hypoxic pulmonary vasoconstriction during nocturnal events. Daytime hypoxemia from coexistent chronic lung disease or diastolic heart failure may further contribute.

Diagnosis is only made if there is a high degree of suspicion, given the symptom overlap between pulmonary hypertension and lung disease. Of note, evaluation should always occur when patients are stable, rather than during an exacerbation of their primary lung pathology, as this can temporarily increase pulmonary pressures due to hypoxic vasoconstriction. Specific findings that should prompt consideration of PH in patients with lung disease are:

• Exertional dyspnoea/hypoxaemia not fully accounted for by extent of parenchymal disease or sleep disorder.
• Rapid decline of arterial oxygenation on exercising
• Clinical features of right-sided heart failure
• Imaging (especially HRCT) that shows enlarged pulmonary arteries, attenuation of peripheral pulmonary vasculature, or RV enlargement
• PFT showing severe reductions in DLCO, especially when out of proportion to the severity of the lung defect

The first diagnostic investigation to identify pulmonary hypertension is a TTE to detect elevated PASP as well as alterations in RV structure or function and lack of left-sided heart disease. If, on echocardiography, pulmonary hypertension is moderate or severe, the next step is referral to a centre with expertise in PH to proceed with right heart catheterisation. Several additional diagnostic tests may be performed to evaluate patients with suspected PH to identify specific pulmonary aetiologies and to exclude other aetiologies of PH. These may include overnight oximetry, polysomnography, V/Q scanning, CT pulmonary angiography, the six-minute walk test, and laboratory studies.

Treatment of the underlying condition is indicated in all groups with group 3 pulmonary hypertension. Disease-specific therapies are assumed to improve alveolar hypoxia, thus limiting the progression of pulmonary hypertension. Patients should be advised to exercise, receive routine vaccinations, be encouraged to stop smoking, and be treated with supportive measures such as oxygen and diuretics as needed. Supplemental oxygen has only been documented to improve survival and pulmonary vascular resistance in patients with COPD-associated pulmonary hypertension with hypoxemia.

Use of pharmacologic agents for PAH-directed therapy (iloprost, sildenafil, bosentan, etc.) have a limited efficacy in group 3 PH and may also be harmful in some cases. The poor performance of PAH-directed therapy in this population may be partially explained by vasodilatory effects that may exacerbate ventilation-perfusion abnormalities and worsen gas exchange.

Group 4: Pulmonary vasculature obstruction

This type of pulmonary hypertension is most commonly caused by chronic thromboembolism and is also called chronic thromboembolic pulmonary hypertension (CTEPH). It occurs because of pulmonary artery obstruction and unresolved thromboembolic disease. It is paramount to distinguish this type of pulmonary hypertension from the other groups as it has a different therapeutic management.

This condition may represent the final manifestation of unresolved pulmonary embolism, but it is unclear why some patients with acute PE develop CTEPH, and others do not. Some studies suggest that an underlying hypercoagulable state may be the cause of CTEPH, but not all hypercoagulable abnormalities have been associated with the condition. There are a number of varying theories accounting for the possible pathogenesis of the disease, including one that suggests that pulmonary arteriopathy or in situ thrombosis may be the culprit. This theory is based on the fact that a substantial number of patients do not have a prior history of VTE and that most hypercoagulable states do not confer an increased risk for CTEPH.

The diagnosis of CTEPH is usually delayed due to its nonspecific clinical presentation and the low rate of CTEPH as a complication of VTE. The diagnosis is dependent upon imaging that uses contrast enhancement to identify chronic thromboembolism in the proximal or distal vasculature. Similarly to other groups of pulmonary hypertension, testing includes echocardiography, pulmonary function testing, V/Q scanning, CT pulmonary angiogram, and right heart catheterisation. The initial test of choice in this setting is a V/Q lung scan, as a normal test accurately excludes chronic thromboembolic disease with a sensitivity of 97%. Furthermore, V/Q scanning is useful in differentiating proximal large vessel obstruction from distal small vessel obstruction, as can be seen in group 1 PAH. As V/Q scan is sensitive but not specific (e.g. pulmonary artery stenosis, tumours, fibrosing mediastinitis), most patients will need a CTPA as a complementary study. CT pulmonary angiography is not performed on its own, as a negative CT scan cannot exclude the possibility of CTEPH.

Pulmonary thromboendarterectomy is the only definitive therapy for patients with CTEPH.

Group 5: Multifactorial

This group includes patients with pulmonary hypertension who do not fit into any of the other categories. They can be further subclassified into:

• Haematological diseases 
  • Chronic haemolytic anaemias (sickle cell disease, beta-thalassemia, spherocytosis)
  • Myeloproliferative disorders
• Systemic or metabolic disorders
  • Sarcoidosis
  • Pulmonary Langerhans’ histiocytosis X
  • Neurofibromatosis
  • Glycogen      storage disease
• Complex congenital heart disease except those with PH due to corrected or uncorrected      left to right shunts
• Other (CKD, fibrosing mediastinitis)

References

• Uptodate. Treatment of pulmonary arterial hypertension (group 1) in adults: Pulmonary hypertension-specific therapy. Available at: https://www.uptodate.com/contents/treatment-of-pulmonary-arterial-hypertension-group-1-in-adults-pulmonary-hypertension-specific-therapy
• Uptodate. Pulmonary hypertension due to left heart disease (group 2 pulmonary hypertension) in adults. Available at: https://www.uptodate.com/contents/clinical-features-and-diagnosis-of-pulmonary-hypertension-of-unclear-etiology-in-adults
• Uptodate. Pulmonary hypertension due to lung disease and/or hypoxemia (group 3 pulmonary hypertension): Treatment and prognosis. 
• ESC guidelines on Pulmonary Hypertension. European Heart Journal 2016:37;67–119 -doi:10.1093/eurheartj/ehv317