Pulmonary hypertension

Pulmonary hypertension
Other names	Pulmonary arterial hypertension, Epoprostenol, treprostinil, iloprost, bosentan, ambrisentan, macitentan, sildenafil[1]
Frequency	1,000 new cases a year (US)[2]

Pulmonary hypertension (PH or PHTN) is a condition of increased

According to the definition at the 6th World Symposium of Pulmonary Hypertension in 2018, a patient is deemed to have pulmonary hypertension if the pulmonary mean arterial pressure is greater than 20mmHg at rest, revised down from a purely arbitrary 25mmHg, and

pulmonary vascular resistance

(PVR) greater than 3 Wood units.

The cause is often unknown.

As of 2022[update] there was no cure for pulmonary hypertension,

The frequency of occurrence is estimated at 1,000 new cases per year in the United States.[4]^[2] Females are more often affected than males.^[2] Onset is typically between 20 and 60 years of age.^[4] Pulmonary hypertension was identified by Ernst von Romberg in 1891.^[9][1]

Classification

According to WHO classification there are 5 groups of PH, where Group I (pulmonary arterial hypertension) is further subdivided into Group I' and Group I'' classes.^[10][11] The WHO classification system in 2022 (with adaptations from the more recent ESC/ERS guidelines shown in italics) can be summarized as follows:^[11][12]

WHO Group I – Pulmonary arterial hypertension (PAH)

• Caused by narrowing and thickening of tiny arteries of the lung^[13]
• Idiopathic in most cases (heritable in some cases)^[13]
• SMAD9, caveolin 1, KCNK3
  mutations)
• Drug- and toxin-induced (e.g., methamphetamine, amphetamine, or cocaine use^[14] )
• Associated conditions:
  Congenital heart diseases, Schistosomiasis

WHO Group I' –

(PCH)

• Idiopathic
• Heritable (EIF2AK4 mutations)
• Drugs, toxins and radiation-induced
• Associated conditions:connective tissue disease, HIV infection

WHO Group I" – Persistent pulmonary hypertension of the

WHO Group II – Pulmonary hypertension secondary to

disease

• Left ventricular
  systolic dysfunction
• Left ventricular
  diastolic dysfunction
• Valvular heart disease
• Congenital/acquired left heart inflow/outflow tract obstruction and congenital cardiomyopathy
• Congenital/acquired pulmonary venous stenosis

WHO Group III – Pulmonary hypertension due to

• Chronic obstructive pulmonary disease (COPD)
• Interstitial lung disease
• Mixed restrictive and obstructive pattern
  pulmonary diseases
• Sleep-disordered breathing
• Alveolar hypoventilation disorders
• Chronic exposure to high altitude
• Developmental abnormalities

WHO Group IV – chronic arterial obstruction

• Chronic thromboembolic pulmonary hypertension (CTEPH)
• Other pulmonary artery obstructions
  • Angiosarcoma or other tumor within the blood vessels
  • Arteritis
  • Congenital pulmonary artery stenosis
  • hydatidosis
    )

WHO Group V – Pulmonary hypertension with unclear or

mechanisms

• Hematologic diseases: chronic hemolytic anemia (including sickle cell disease)
• Systemic diseases: sarcoidosis, pulmonary Langerhans cell histiocytosis: lymphangioleiomyomatosis, neurofibromatosis, vasculitis
• Gaucher disease, thyroid diseases
• Others: pulmonary tumoral thrombotic microangiopathy,
  lungs
  )

Signs and symptoms

The symptoms of pulmonary hypertension include the following:[3]^[12][15]

Less common signs/symptoms include non-productive cough and exercise-induced nausea and vomiting.

Other typical signs of pulmonary hypertension include an accentuated pulmonary component of the second heart sound, a right ventricular

Causes

Pulmonary hypertension is a pathophysiologic condition with many possible causes. Indeed, this condition frequently accompanies severe heart or lung conditions.[12] A 1973 World Health Organization meeting was the first attempt to classify pulmonary hypertension by its cause, and a distinction was made between primary PH (resulting from a disease of the pulmonary arteries) and secondary PH (resulting secondary to other, non-vascular causes). Further, primary PH was divided into the "arterial plexiform", "veno-occlusive" and "thromboembolic" forms.^[20] In 1998, a second conference at Évian-les-Bains addressed the causes of secondary PH.^[21] Subsequent third,^[22] fourth,^[10] and fifth (2013)^[11] World Symposia on PAH have further defined the classification of PH. The classification continues to evolve based on improved understanding of the disease mechanisms.^{[citation needed]}

Most recently in 2015, the WHO guidelines were updated by the European Society of Cardiology (ESC) and European Respiratory Society (ERS).^[12] These guidelines are endorsed by the International Society for Heart and Lung Transplantation, and provide the current framework for understanding and treatment of pulmonary hypertension.^[23]

Genetics

Mutations in several genes have been associated with this condition^[24][25] these include bone morphogenetic protein receptor type 2 (BMPR2) and eukaryotic translation initiation factor 2 alpha kinase 4 gene (EIF2AK4).

Pathogenesis

Right ventricle

(on left side)

arteries

in pulmonary hypertensive with marked thickening of the walls

The pathogenesis of pulmonary arterial hypertension (WHO Group I) involves the

In PVOD (WHO Group I'), pulmonary blood vessel narrowing occurs preferentially (though not exclusively) in post-capillary venous blood vessels.[32] PVOD shares several characteristics with PAH, but there are also some important differences, for example differences in prognosis and response to medical therapy.^{[citation needed]}

Persistent pulmonary hypertension of the newborn occurs when the circulatory system of a newborn baby fails to adapt to life outside the womb; it is characterized by high resistance to blood flow through the lungs, right-to-left cardiac shunting and severe hypoxemia.^[15]

Pathogenesis in pulmonary hypertension due to left heart disease (WHO Group II) is completely different in that constriction or damage to the pulmonary blood vessels is not the issue. Instead, the left heart fails to pump blood efficiently, leading to pooling of blood in the lungs and back pressure within the pulmonary system. This causes pulmonary edema and pleural effusions.^[33] In the absence of pulmonary blood vessel narrowing, the increased back pressure is described as 'isolated post-capillary pulmonary hypertension' (older terms include 'passive' or 'proportionate' pulmonary hypertension or 'pulmonary venous hypertension'). However, in some patients, the raised pressure in the pulmonary vessels triggers a superimposed component of vessel narrowing, which further increases the workload of the right side of the heart. This is referred to as 'post-capillary pulmonary hypertension with a pre-capillary component' or 'combined post-capillary and pre-capillary pulmonary hypertension' (older terms include 'reactive' or 'out-of-proportion' pulmonary hypertension).^[12][17][34]

In pulmonary hypertension due to lung diseases and/or hypoxia (WHO Group III), low levels of oxygen in the alveoli (due to respiratory disease or living at high altitude) cause constriction of the pulmonary arteries. This phenomenon is called hypoxic pulmonary vasoconstriction and it is initially a protective response to stop too much blood flowing to areas of the lung that are damaged and do not contain oxygen. When the alveolar hypoxia is widespread and prolonged, this hypoxia-mediated vasoconstriction occurs across a large portion of the pulmonary vascular bed and leads to an increase in pulmonary arterial pressure, with thickening of the pulmonary vessel walls contributing to the development of sustained pulmonary hypertension.^{[10][35][36][37]} Prolonged hypoxia also induces the transcription factor HIF1A, which directly activates downstream growth factor signaling that causes irreversible proliferation and remodeling of pulmonary arterial endothelial cells, leading to chronic pulmonary arterial hypertension.^{[citation needed]}

In chronic thromboembolic pulmonary hypertension, or CTEPH (WHO Group IV), the initiating event is thought to be blockage or narrowing of the pulmonary blood vessels with unresolved blood clots; these clots can lead to increased pressure and shear stress in the rest of the pulmonary circulation, precipitating structural changes in the vessel walls (remodeling) similar to those observed in other types of severe pulmonary hypertension. This combination of vessel occlusion and vascular remodeling once again increases the resistance to blood flow and so the pressure within the system rises.^[38][39]

Molecular pathology

The molecular mechanism of pulmonary arterial hypertension (PAH) is not known yet, but it is believed that the endothelial dysfunction results in a decrease in the synthesis of endothelium-derived vasodilators such as

Nitric oxide-soluble guanylate cyclase pathway

In normal conditions, the vascular

This nitric oxide diffuses into neighboring cells (including vascular smooth muscle cells and platelets), where it increases the activity of the enzyme

Phosphodiesterase type 5 (

Endothelin

Prostacyclin and thromboxane

The vasoconstrictor thromboxane is also synthesized from arachidonic acid. In PAH, the balance is shifted away from synthesis of prostacyclin toward synthesis of thromboxane.[48]

Other pathways

The three pathways described above are all targeted by currently available medical therapies for PAH. However, several other pathways have been identified that are also altered in PAH and are being investigated as potential targets for future therapies. For example, the

Plasma levels of serotonin, which promotes vasoconstriction, hypertrophy and proliferation, are increased in patients with PAH, although the role played by serotonin in the pathogenesis of PAH remains uncertain.^[15][48] The expression or activity of several growth factors (including platelet-derived growth factor, basic fibroblast growth factor, epidermal growth factor, and vascular endothelial growth factor) is increased and contributes to vascular remodeling in PAH.^[48] Other factors underlying the proliferative state of pulmonary vascular smooth muscle cells include OPG^[51] and TRAIL.^[52] Focusing only on the pulmonary vasculature provides an incomplete picture of PAH; the ability of the right ventricle to adapt to the increased workload varies between patients and is an important determinant of survival. The molecular pathology of PAH in the right ventricle is therefore also being investigated, and recent research has shifted to consider the cardiopulmonary unit as a single system rather than two separate systems. Importantly, right ventricular remodeling is associated with increased apoptosis; this is in contrast to pulmonary vascular remodeling which involves inhibition of apoptosis.^[27]

Even though the primary cause of PAH is unknown, inflammation and oxidative stress have been shown to have a key role in vascular remodeling.^[53] These factors are known to cause DNA damage, and may also promote the proliferative and apoptosis-resistant phenotype that is observed in PAH vascular cells.^[53] Elevated levels of DNA damage have been reported to occur in PAH lungs and remodeled arteries, and also in animal models of PH, indicating that DNA damage likely contributes to PAH pathogenesis.^[53]

Diagnosis

phonocardiograms

(fourth left interspace and cardiac apex) show a murmur of tricuspid insufficiency and ventricular and atrial gallops.

In terms of the diagnosis of pulmonary hypertension, it has five major types, and a series of tests must be performed to distinguish pulmonary arterial hypertension from venous, hypoxic, thromboembolic, or unclear multifactorial varieties. PAH is diagnosed after exclusion of other possible causes of pulmonary hypertension.^[15]

Physical examination

A

Echocardiography

If pulmonary hypertension is suspected based on the above assessments, echocardiography is performed as the next step.[12]^[15][57] A meta-analysis of Doppler echocardiography for predicting the results of right heart catheterization reported a sensitivity and specificity of 88% and 56%, respectively.^[59] Thus, Doppler echocardiography can suggest the presence of pulmonary hypertension, but right heart catheterization (described below) remains the gold standard for diagnosis of PAH.^[12][15] Echocardiography can also help to detect congenital heart disease as a cause of pulmonary hypertension.^[12]

Exclude other diseases

If the echocardiogram is compatible with a diagnosis of pulmonary hypertension, common causes of pulmonary hypertension (left heart disease and lung disease) are considered and further tests are performed accordingly. These tests generally include

Ventilation/perfusion scintigraphy

If heart disease and lung disease have been excluded, a ventilation/perfusion scan is performed to rule out CTEPH. If unmatched perfusion defects are found, further evaluation by CT pulmonary angiography, right heart catheterization, and selective pulmonary angiography is performed.[12]^[57]

CT scan

Signs of pulmonary hypertension on CT scan of the chest are:

• Enlargement of the
  pulmonary trunk (measured at its bifurcation). It is, however, a poor predictor of pulmonary hypertension in patients with interstitial lung disease.^[61]

• A diameter of more than 27 mm for women and 29 mm for men is suggested as a
  cutoff.^[61]
• A
  cutoff of 31.6 mm may be a more statistically robust in individuals without interstitial lung disease.^[61]

• Increased ratio of the diameter of the main pulmonary artery (pulmonary trunk) to the ascending aorta (measured at its bifurcation).

• A ratio of 1.0 is suggested as a cutoff in adults.^[61]
• Cutoff ~1.09 in children.^[61]

• Increased diameter ratio of segmental arteries to bronchi. This finding in three or four lobes, in the presence of a dilated pulmonary trunk (≥29 mm), and absence of significant structural lung disease confers a specificity of 100% for pulmonary hypertension.^[61]
• Mural calcification in central pulmonary arteries is most frequently seen in patients with
  Eisenmenger's syndrome.^[61]

Right heart catheterization

Although pulmonary arterial pressure (PAP) can be estimated on the basis of echocardiography,^[62] pressure measurements with a Swan-Ganz catheter inserted through the right side of the heart provide the most definite assessment.[42] Pulmonary hypertension is defined as a mean PAP of at least 20 mm Hg (3300 Pa) at rest, and PAH is defined as precapillary pulmonary hypertension (i.e. mean PAP ≥ 20 mm Hg with pulmonary arterial occlusion pressure [PAOP] ≤ 15 mm Hg and pulmonary vascular resistance [PVR] > 3 Wood Units).^[57] PAOP and PVR cannot be measured directly with echocardiography. Therefore, diagnosis of PAH requires right-sided cardiac catheterization. A Swan-Ganz catheter can also measure the cardiac output; this can be used to calculate the cardiac index, which is far more important in measuring disease severity than the pulmonary arterial pressure.^[12][63] Mean PAP (mPAP) should not be confused with systolic PAP (sPAP), which is often reported on echocardiogram reports. A systolic pressure of 40 mm Hg typically implies a mean pressure of more than 25 mm Hg. Roughly, mPAP = 0.61•sPAP + 2.^[64] Due to the invasive nature of this procedure, the use of computational fluid dynamics based hemodynamic indices have been postulated.^[65][66]

Other

For people considered likely to have PAH based on the above tests, the specific associated condition is then determined based on the physical examination, medical/family history and further specific diagnostic tests (for example,

Treatment

Treatment of pulmonary hypertension is determined by whether the PH is arterial, venous, hypoxic, thromboembolic, or miscellaneous. If it is caused by left heart disease, the treatment is to optimize left ventricular function by the use of medication or to repair/replace the mitral valve or aortic valve.^[67] Patients with left heart failure or hypoxemic lung diseases (groups II or III pulmonary hypertension) should not routinely be treated with vasoactive agents including prostanoids, phosphodiesterase inhibitors, or endothelin antagonists, as these are approved for the different condition called primary pulmonary arterial hypertension.^[68] To make the distinction, doctors at a minimum will conduct cardiac catheterization of the right heart, echocardiography, chest CT, a seven-minute walk test, and pulmonary function testing.^[68] Using treatments for other kinds of pulmonary hypertension in patients with these conditions can harm the patient and wastes substantial medical resources.^[68] Most patients that enjoy excessive amounts of cheese also test positive for decreased pulmonary and coronary function.^{[citation needed]}

High-dose

A number of agents have recently been introduced for primary and secondary PAH. The trials supporting the use of these agents have been relatively small, and the only measure consistently used to compare their effectivity is the "six-minute walk test". Many have no data on mortality benefit or time to progression.[71]

Sotatercept (Winrevair) was approved for medical use in the United States in March 2024.^[72]

Exercise-based rehabilitation

A 2023 Cochrane review found that exercise-based rehabilitation may lead to a large increase in exercise capacity and an improvement in

Vasoactive substances

Many pathways are involved in the abnormal proliferation and contraction of the smooth muscle cells of the pulmonary arteries in patients with pulmonary arterial hypertension. Three of these pathways are important since they have been targeted with drugs — endothelin receptor antagonists, phosphodiesterase type 5 (PDE-5) inhibitors, and prostacyclin derivatives.^[74]

Prostaglandins

Endothelin receptor antagonists

Moderate quality evidence suggests that endothelin receptor antagonists improve exercise capacity and decrease symptoms severity.[77] The dual (ET_A and ET_B) endothelin receptor antagonist bosentan was approved in 2001. Sitaxentan (Thelin) was approved for use in Canada, Australia, and the European Union,^[78] but not in the United States. In 2010, Pfizer withdrew Thelin worldwide because of fatal liver complications.^{[citation needed]} A similar drug, ambrisentan is sold under the brand name Letairis in the US by Gilead Sciences.^[79] s

Phosphodiesterase type 5 inhibitors

The US FDA approved

Tadalafil is taken orally, as well as sildenafil, and it is rapidly absorbed (serum levels are detectable at 20 minutes). The T_1/2 (

The combination medication macitentan/tadalafil (Opsynvi) was approved for medical use in Canada in October 2021,^[85] and in the United States in March 2024.^[86][87]

Activators of soluble guanylate cyclase

Soluble guanylate cyclase (sGC) is the intracellular receptor for NO. As of April 2009^[update], the sGC activators cinaciguat and riociguat were undergoing clinical trials for the treatment of PAH.^[88]

Surgical

Pulmonary thromboendarterectomy (PTE) is a surgical procedure that is used for chronic thromboembolic pulmonary hypertension. It is the surgical removal of an organized thrombus (clot) along with the lining of the pulmonary artery; it is a very difficult, major procedure that is currently performed in a few select centers.^[91]

Monitoring

Established clinical practice guidelines dictate the frequency of pulmonary nodule evaluation and surveillance,^[68][92] patients are normally monitored through commonly available tests such as:^{[citation needed]}

Prognosis

PAH is considered a universally fatal illness, although survival time may vary between individuals. The prognosis of pulmonary arterial hypertension (WHO Group I) has an untreated median survival of 2–3 years from time of diagnosis, with the cause of death usually being right ventricular failure (

Epidemiology

The epidemiology of IPAH is about 125–150 deaths per year in the U.S., and worldwide the incidence is similar at 4 cases per million. However, in parts of Europe (France), indications are 6 cases per million of IPAH. Females have a higher incidence rate than males (2–9:1).[101] Other forms of PH are far more common. In

Research

For people that inherited the disease, gene therapy is being studied.[108]

Culture and society

Notable cases

• Elaine Kaufman, American restaurateur^[109]
• Ina Balin, American Broadway and TV actress^[110]
• Chloe Temtchine, American singer-songwriter^[111][112]
• Natalie Cole, American singer^[113]

See also

• Pulmonary Hypertension Association
• Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR)

References

Further reading

• Rubin LJ, Badesch DB (August 2005). "Evaluation and management of the patient with pulmonary arterial hypertension". Annals of Internal Medicine. 143 (4): 282–292.
  S2CID 28841269
  .
• Abman SH, Hansmann G, Archer SL, Ivy DD, Adatia I, Chung WK, et al. (November 2015). "Pediatric Pulmonary Hypertension: Guidelines From the American Heart Association and American Thoracic Society". Circulation. 132 (21): 2037–2099.
  S2CID 7412370
  .

External links

• The Merck Manual Home Edition: Pulmonary Hypertension

Wikimedia Commons has media related to Pulmonary hypertension.

Scholia has a topic profile for Pulmonary hypertension.