Pulmonary hypertension

Last updated
Pulmonary hypertension
Other namesAyerza syndrome [1]
Pulmonary Hypertension.png
Pulmonary hypertension
Specialty Pulmonology, cardiology
Symptoms Chest pain, fatigue [2]
Usual onset20 to 60 years old [3]
DurationLong term [4]
CausesUnknown [4]
Risk factors Family history, pulmonary embolism, HIV/AIDS, sickle cell disease, cocaine use, COPD, sleep apnea, living at high altitudes [5] [3]
Diagnostic method Following ruling out other potential causes [4]
Treatment Supportive care, various medications, lung transplantation [4] [6]
Medication Epoprostenol, treprostinil, iloprost, bosentan, ambrisentan, macitentan, sildenafil [4]
Frequency1,000 new cases a year (US) [1]

Pulmonary hypertension (PH or PHTN) is a condition of increased blood pressure in the arteries of the lungs. [7] Symptoms include shortness of breath, fainting, tiredness, chest pain, swelling of the legs, and a fast heartbeat. [7] [1] The condition may make it difficult to exercise. [7] Onset is typically gradual. [8] 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.

Contents

The cause is often unknown. [4] Risk factors include a family history, prior pulmonary embolism (blood clots in the lungs), HIV/AIDS, sickle cell disease, cocaine use, chronic obstructive pulmonary disease, sleep apnea, living at high altitudes, and problems with the mitral valve. [5] [3] The underlying mechanism typically involves inflammation and subsequent remodeling of the arteries in the lungs. [5] Diagnosis involves first ruling out other potential causes. [4]

As of 2022 there was no cure for pulmonary hypertension, [6] although research to find a cure is ongoing. Treatment depends on the type of disease. [6] A number of supportive measures such as oxygen therapy, diuretics, and medications to inhibit blood clotting may be used. [4] Medications specifically used to treat pulmonary hypertension include epoprostenol, treprostinil, iloprost, bosentan, ambrisentan, macitentan, and sildenafil, tadalafil, selexipag, riociguat. [4] Lung transplantation may be an option in severe cases. [6]

The frequency of occurrence is estimated at 1,000 new cases per year in the United States. [3] [1] Females are more often affected than males. [1] Onset is typically between 20 and 60 years of age. [3] Pulmonary hypertension was identified by Ernst von Romberg in 1891. [9] [4]

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: [4] [11] [12]

WHO Group I – Pulmonary arterial hypertension (PAH)

WHO Group I' – Pulmonary veno-occlusive disease (PVOD), pulmonary capillary hemangiomatosis (PCH)

WHO Group I" – Persistent pulmonary hypertension of the newborn

WHO Group II – Pulmonary hypertension secondary to left heart disease

WHO Group III – Pulmonary hypertension due to lung disease, chronic hypoxia

WHO Group IV – Chronic arterial obstruction

WHO Group V – Pulmonary hypertension with unclear or multifactorial mechanisms

Signs and symptoms

The symptoms of pulmonary hypertension include the following: [2] [12] [15]

Less common signs/symptoms include non-productive cough and exercise-induced nausea and vomiting. [12] Coughing up of blood may occur in some patients, particularly those with specific subtypes of pulmonary hypertension such as heritable pulmonary arterial hypertension, Eisenmenger syndrome and chronic thromboembolic pulmonary hypertension. [16] Pulmonary venous hypertension typically presents with shortness of breath while lying flat or sleeping (orthopnea or paroxysmal nocturnal dyspnea), while pulmonary arterial hypertension (PAH) typically does not. [17]

Other typical signs of pulmonary hypertension include an accentuated pulmonary component of the second heart sound, a right ventricular third heart sound, and parasternal heave indicating a hypertrophied right ventricle. Signs of systemic congestion resulting from right-sided heart failure include jugular venous distension, ascites, and hepatojugular reflux. [12] [15] [18] Evidence of tricuspid insufficiency and pulmonic regurgitation is also sought and, if present, is consistent with the presence of pulmonary hypertension. [12] [15] [19]

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 2022, the WHO guidelines were updated by the European Society of Cardiology (ESC) and European Respiratory Society (ERS). [4] 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. [4]

Genetics

Mutations in several genes have been associated with this condition [23] [24] these include bone morphogenetic protein receptor type 2 (BMPR2) and eukaryotic translation initiation factor 2 alpha kinase 4 gene (EIF2AK4). 80% of familial pulmonary arterial hypertension and 20% of sporadic variants have mutations in BMPR2. [25] BMPR2 is involved in endothelial proliferation and remodeling. Other mutations associated with PAH include ACVRL1 (which encodes activin receptor–like kinase 1) and ENG encoding endoglin, two proteins which also participate in BMPR2 signaling. [25] The SMAD transcription factor family, including SMAD1, SMAD4, and SMAD9 are involved in signaling pathways downstream from BMPR2 and are also implicated in the development of pulmonary arterial hypertension. [25]

Pathogenesis

Right ventricle (on left side) CG Heart.gif
Right ventricle (on left side)
Micrograph showing arteries in pulmonary hypertensive with marked thickening of the walls Pulmonary hypertensive arteriopathy (4348170715).jpg
Micrograph showing arteries in pulmonary hypertensive with marked thickening of the walls

The pathogenesis of pulmonary arterial hypertension (WHO Group I) involves the narrowing of blood vessels connected to and within the lungs. This makes it harder for the heart to pump blood through the lungs, as it is much harder to make water flow through a narrow pipe as opposed to a wide one. Over time, the affected blood vessels become stiffer and thicker, in a process known as fibrosis. The mechanisms involved in this narrowing process include vasoconstriction, thrombosis, and vascular remodeling (excessive cellular proliferation, fibrosis, and reduced apoptosis/programmed cell death in the vessel walls, caused by inflammation, disordered metabolism and dysregulation of certain growth factors). [26] [27] This further increases the blood pressure within the lungs and impairs their blood flow. In common with other types of pulmonary hypertension, these changes result in an increased workload for the right side of the heart. [15] [28] The right ventricle is normally part of a low pressure system, with systolic ventricular pressures that are lower than those that the left ventricle normally encounters. As such, the right ventricle cannot cope as well with higher pressures, and although right ventricular adaptations (hypertrophy and increased contractility of the heart muscle) initially help to preserve stroke volume, ultimately these compensatory mechanisms are insufficient; the right ventricular muscle cannot get enough oxygen to meet its needs and right heart failure follows. [15] [27] [28] As the blood flowing through the lungs decreases, the left side of the heart receives less blood. This blood may also carry less oxygen than normal. Therefore, it becomes harder and harder for the left side of the heart to supply sufficient oxygen to the rest of the body, especially during physical activity. [29] [30] [10] During the end-systolic volume phase of the cardiac cycle, the Gaussian curvature and the mean curvature of right ventricular endocardial wall of PH patients was found to be significantly different as compared to controls. [31]

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. [33]

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. [34] 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] [35]

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] [36] [37] [38] 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. [39] [40]

Molecular pathology

Three major signaling pathways involved in the pathogenesis of pulmonary arterial hypertension Molecular Pathology.png
Three major signaling pathways involved in the pathogenesis of pulmonary arterial hypertension

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 and prostacyclin. [41] Moreover, there is a stimulation of the synthesis of vasoconstrictors such as thromboxane and vascular endothelial growth factor (VEGF). These result in a severe vasoconstriction and vascular smooth muscle and adventitial hypertrophy characteristic of patients with PAH. [41]

Nitric oxide-soluble guanylate cyclase pathway

In normal conditions, the vascular endothelial nitric oxide synthase produces nitric oxide from L-arginine in the presence of oxygen. [42]

This nitric oxide diffuses into neighboring cells (including vascular smooth muscle cells and platelets), where it increases the activity of the enzyme soluble guanylate cyclase, leading to increased formation of cyclic guanosine monophosphate (cGMP) from guanosine triphosphate (GTP). [43] The cGMP then activates cGMP-dependent kinase or PKG (protein kinase G). Activated PKG promotes vasorelaxation (via a reduction of intracellular calcium levels), alters the expression of genes involved in smooth muscle cell contraction, migration and differentiation, and inhibits platelet activation. [44] Nitric oxide–soluble guanylate cyclase signaling also leads to anti-inflammatory effects. [45]

Phosphodiesterase type 5 (PDE5), which is abundant in the pulmonary tissue, hydrolyzes the cyclic bond of cGMP. Consequently, the concentration of cGMP (and thus PKG activity) decreases. [46] [44]

Endothelin

Endothelin-1 is a peptide (comprising 21 amino acids) that is produced in endothelial cells. It acts on the endothelin receptors ETA and ETB in various cell types including vascular smooth muscle cells and fibroblasts, leading to vasoconstriction, hypertrophy, proliferation, inflammation, and fibrosis. It also acts on ETB receptors in endothelial cells; this leads to the release of both vasoconstrictors and vasodilators from those cells, and clears endothelin-1 from the system. [47] [48]

Prostacyclin and thromboxane

Prostacyclin is synthesized from arachidonic acid in endothelial cells. In vascular smooth muscle cells, prostacyclin binds mainly to the prostaglandin I receptor. This sends a signal to increase adenylate cyclase activity, which leads to increased synthesis of cyclic adenosine monophosphate (cAMP). This in turn leads to increased cAMP-dependent protein kinase or PKA (protein kinase A) activity, ultimately promoting vasodilation and inhibiting cell proliferation. Prostacyclin signaling also leads to anti-thrombotic, anti-fibrotic, and anti-inflammatory effects. Levels of cAMP (which mediates most of the biological effects of prostacyclin) are reduced by phosphodiesterases 3 and 4. [49] [50] The vasoconstrictor thromboxane is also synthesized from arachidonic acid. In PAH, the balance is shifted away from synthesis of prostacyclin toward synthesis of thromboxane. [49]

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 mitochondrial enzyme pyruvate dehydrogenase kinase (PDK) is pathologically activated in PAH, causing a metabolic shift from oxidative phosphorylation to glycolysis and leading to increased cell proliferation and impaired apoptosis. [49] [51] Expression of vasoactive intestinal peptide, a potent vasodilator with anti-inflammatory and immune-modulatory roles, is reduced in PAH, while expression of its receptor is increased. [49] [51] 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] [49] 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. [49] Other factors underlying the proliferative state of pulmonary vascular smooth muscle cells include OPG [52] and TRAIL. [53] 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. [54] 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. [54] 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. [54]

Diagnosis

Phonocardiogram and jugular venous pulse tracing from a middle-aged man with pulmonary hypertension caused by cardiomyopathy. The jugular venous pulse tracing demonstrates a prominent a wave without a c or v wave being observed. The phonocardiograms (fourth left interspace and cardiac apex) show a murmur of tricuspid insufficiency and ventricular and atrial gallops. Phonocardiogram.jpg
Phonocardiogram and jugular venous pulse tracing from a middle-aged man with pulmonary hypertension caused by cardiomyopathy. The jugular venous pulse tracing demonstrates a prominent a wave without a c or v wave being observed. The phonocardiograms (fourth left interspace and cardiac apex) show a murmur of tricuspid insufficiency and ventricular and atrial gallops.
Pulmonary artery catheter Pulmonary artery catheter english.JPG
Pulmonary artery catheter
Severe tricuspid regurgitation Severe tricuspid regurgitation E00572 (CardioNetworks ECHOpedia).jpg
Severe tricuspid regurgitation

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 physical examination is performed to look for typical signs of pulmonary hypertension (described above), [55] and a detailed family history is established to determine whether the disease might be heritable. [56] [57] [58] A history of exposure to drugs such as benfluorex (a fenfluramine derivative), dasatinib, cocaine, methamphetamine, ethanol leading to cirrhosis, and tobacco leading to emphysema is considered significant. [15] [59] [11] Use of selective serotonin reuptake inhibitors during pregnancy (particularly late pregnancy) is associated with an increased risk of the baby developing persistent pulmonary hypertension of the newborn. [11]

Echocardiography

If pulmonary hypertension is suspected based on the above assessments, echocardiography is performed as the next step. [12] [15] [58] A meta-analysis of Doppler echocardiography for predicting the results of right heart catheterization reported a sensitivity and specificity of 88% and 56%, respectively. [60] 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 electrocardiography (ECG), pulmonary function tests including lung diffusion capacity for carbon monoxide and arterial blood gas measurements, X-rays of the chest and high-resolution computed tomography (CT) scanning. [12] [15] [58] [61]

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] [58]

CT scan

Pulmonary artery hypertension and emphysema as seen on a CT scan with contrast PulArtHyperandEmphysemaMark.png
Pulmonary artery hypertension and emphysema as seen on a CT scan with contrast

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

  • A ratio of 1.0 is suggested as a cutoff in adults. [62]
  • Cutoff ~1.09 in children. [62]

Right heart catheterization

Although pulmonary arterial pressure (PAP) can be estimated on the basis of echocardiography, [63] 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). [58] 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] [64] 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. [65] Due to the invasive nature of this procedure, the use of computational fluid dynamics based hemodynamic indices have been postulated. [66] [67]

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, serological tests to detect underlying connective tissue disease, HIV infection or hepatitis, ultrasonography to confirm the presence of portal hypertension, echocardiography/cardiac magnetic resonance imaging for congenital heart disease, laboratory tests for schistosomiasis, and high-resolution CT for PVOD and pulmonary capillary hemangiomatosis). Routine lung biopsy is discouraged in patients with PAH, because of the risk to the patient and because the findings are unlikely to alter the diagnosis and treatment. [12] [28] [58]

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. [68] 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. [69] 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. [69] Using treatments for other kinds of pulmonary hypertension in patients with these conditions can harm the patient and wastes substantial medical resources. [69]

High-dose calcium channel blockers are useful in only 5% of IPAH patients who are vasoreactive by Swan-Ganz catheter. Calcium channel blockers have been largely misused, being prescribed to many patients with non-vasoreactive PAH, leading to excess morbidity and mortality. [19] The criteria for vasoreactivity have changed. Only those patients whose mean pulmonary artery pressure falls by more than 10 mm Hg to less than 40 mm Hg with an unchanged or increased cardiac output when challenged with adenosine, epoprostenol, or nitric oxide are considered vasoreactive. [70] Of these, only half of the patients are responsive to calcium channel blockers in the long term. [71]

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. [72]

Sotatercept (Winrevair) was approved for medical use in the United States in March 2024. [73]

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 health related quality of life, without significantly increasing adverse events. [74]

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. [75]

Prostaglandins

Prostacyclin (prostaglandin I2) is commonly considered the most effective treatment for PAH. Epoprostenol (synthetic prostacyclin) is given via continuous infusion that requires a semi-permanent central venous catheter. This delivery system can cause sepsis and thrombosis. Prostacyclin is unstable, and therefore has to be kept on ice during administration. Since it has a half-life of 3 to 5 minutes, the infusion has to be continuous, and interruption can be fatal. [76] Other prostanoids have therefore been developed. Treprostinil can be given intravenously or subcutaneously, but the subcutaneous form can be very painful. An increased risk of sepsis with intravenous Remodulin has been reported by the CDC. Iloprost is also used in Europe intravenously and has a longer half life. Iloprost was the only inhaled form of prostacyclin approved for use in the US and Europe, until the inhaled form of treprostinil was approved by the FDA in July 2009. [77]

Endothelin receptor antagonists

Moderate quality evidence suggests that endothelin receptor antagonists improve exercise capacity and decrease symptoms severity. [78] The dual (ETA and ETB) endothelin receptor antagonist bosentan was approved in 2001. Macitentan is another ETA and ETB dual endothelin receptor blocker that is used. [25] Sitaxentan (Thelin) was approved for use in Canada, Australia, and the European Union, [79] but not in the United States. In 2010, Pfizer withdrew sitaxentan worldwide because of fatal liver complications. [80] A similar drug, ambrisentan (which is a ETA endothelin receptor blocker) is sold under the brand name Letairis in the US by Gilead Sciences. [81]

Phosphodiesterase type 5 inhibitors

The US FDA approved sildenafil, a selective inhibitor of cGMP specific phosphodiesterase type 5 (PDE5), for the treatment of PAH in 2005. It is marketed for PAH as Revatio. In 2009, they also approved tadalafil, another PDE5 inhibitor, marketed under the name Adcirca. [82] PDE5 inhibitors are believed to increase pulmonary artery vasodilation, and inhibit vascular remodeling, thus lowering pulmonary arterial pressure and pulmonary vascular resistance. [83]

Tadalafil is taken orally, as well as sildenafil, and it is rapidly absorbed (serum levels are detectable at 20 minutes). The T1/2 (biological half-life) hovers around 17.5 hours in healthy subjects. [84] Moreover, if we consider pharmacoeconomic implications, patients that take tadalafil would pay two-thirds of the cost of sildenafil therapy. [85] However, there are some adverse effects of this drug such as headache, diarrhea, nausea, back pain, dyspepsia, flushing and myalgia. [86]

The combination medication macitentan/tadalafil (Opsynvi) was approved for medical use in Canada in October 2021, [87] and in the United States in March 2024. [88] [89]

Activators of soluble guanylate cyclase

Soluble guanylate cyclase (sGC) is the intracellular receptor for NO. As of April 2009, the sGC activators cinaciguat and riociguat were undergoing clinical trials for the treatment of PAH. [90]

Surgical

Atrial septostomy is a surgical procedure that creates a communication between the right and left atria. It relieves pressure on the right side of the heart, but at the cost of lower oxygen levels in blood (hypoxemia). Lung transplantation replaces a chronic condition with the ongoing need for treatment. [91] There is a post-surgical median survival of just over five years. [92]

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. [93]

Monitoring

Established clinical practice guidelines dictate the frequency of pulmonary nodule evaluation and surveillance, [69] [94] patients are normally monitored through commonly available tests such as:[ citation needed ]

Prognosis

Cor pulmonale Heart - cor pulmonale- right ventricular hypertrophy (4351912426).jpg
Cor pulmonale

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 (cor pulmonale). [96] The survival time is variable and depends on many factors. [97] A recent outcome study of those patients who had started treatment with bosentan (Tracleer) showed that 89% of patients were alive at 2 years. [98] With new therapies, survival rates are increasing. For 2,635 patients enrolled in The Registry to Evaluate Early and Long-term Pulmonary Arterial Hypertension Disease Management (REVEAL Registry) from March 2006 to December 2009, 1-, 3-, 5-, and 7-year survival rates were 85%, 68%, 57%, and 49%, respectively. For patients with idiopathic/familial PAH, survival rates were 91%, 74%, 65%, and 59%. [99] Levels of mortality are very high in pregnant women with severe pulmonary arterial hypertension (WHO Group I). Pregnancy is sometimes described as contraindicated in these women. [100] [101] [102]

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). [103] Other forms of PH are far more common. In systemic scleroderma, the incidence has been estimated to be 8 to 12% of all patients; [104] in rheumatoid arthritis it is rare. [105] However, in systemic lupus erythematosus it is 4 to 14%, [106] and in sickle cell disease, it ranges from 20 to 40%. [107] Up to 4% of people who develop a pulmonary embolism go on to develop chronic thromboembolic disease including pulmonary hypertension. [40] A small percentage of patients with COPD develop pulmonary hypertension with no other disease to explain the high pressure. [108] On the other hand, obesity-hypoventilation syndrome is very commonly associated with right heart failure due to pulmonary hypertension. [109]

Research

For people that inherited the disease, gene therapy is being studied. [110]

Culture and society

Notable cases

See also

Related Research Articles

<span class="mw-page-title-main">Cardiology</span> Branch of medicine dealing with the heart

Cardiology is the study of the heart. Cardiology is a branch of medicine that deals with disorders of the heart and the cardiovascular system. The field includes medical diagnosis and treatment of congenital heart defects, coronary artery disease, heart failure, valvular heart disease, and electrophysiology. Physicians who specialize in this field of medicine are called cardiologists, a sub-specialty of internal medicine. Pediatric cardiologists are pediatricians who specialize in cardiology. Physicians who specialize in cardiac surgery are called cardiothoracic surgeons or cardiac surgeons, a specialty of general surgery.

<span class="mw-page-title-main">Pulmonary edema</span> Fluid accumulation in the tissue and air spaces of the lungs

Pulmonary edema, also known as pulmonary congestion, is excessive fluid accumulation in the tissue or air spaces of the lungs. This leads to impaired gas exchange, most often leading to shortness of breath (dyspnea) which can progress to hypoxemia and respiratory failure. Pulmonary edema has multiple causes and is traditionally classified as cardiogenic or noncardiogenic.

<span class="mw-page-title-main">Prostacyclin</span> Chemical compound

Prostacyclin (also called prostaglandin I2 or PGI2) is a prostaglandin member of the eicosanoid family of lipid molecules. It inhibits platelet activation and is also an effective vasodilator.

<span class="mw-page-title-main">Haemodynamic response</span>

In haemodynamics, the body must respond to physical activities, external temperature, and other factors by homeostatically adjusting its blood flow to deliver nutrients such as oxygen and glucose to stressed tissues and allow them to function. Haemodynamic response (HR) allows the rapid delivery of blood to active neuronal tissues. The brain consumes large amounts of energy but does not have a reservoir of stored energy substrates. Since higher processes in the brain occur almost constantly, cerebral blood flow is essential for the maintenance of neurons, astrocytes, and other cells of the brain. This coupling between neuronal activity and blood flow is also referred to as neurovascular coupling.

<span class="mw-page-title-main">Eisenmenger syndrome</span> Medical condition

Eisenmenger syndrome or Eisenmenger's syndrome is defined as the process in which a long-standing left-to-right cardiac shunt caused by a congenital heart defect causes pulmonary hypertension and eventual reversal of the shunt into a cyanotic right-to-left shunt. Because of the advent of fetal screening with echocardiography early in life, the incidence of heart defects progressing to Eisenmenger syndrome has decreased.

<span class="mw-page-title-main">PDE5 inhibitor</span> Vasodilating drug

A phosphodiesterase type 5 inhibitor is a vasodilating drug that works by blocking the degradative action of cGMP-specific phosphodiesterase type 5 (PDE5) on cyclic GMP in the smooth muscle cells lining the blood vessels supplying various tissues. These drugs dilate the corpora cavernosa of the penis, facilitating erection with sexual stimulation, and are used in the treatment of erectile dysfunction (ED). Sildenafil was the first effective oral treatment available for ED. Because PDE5 is also present in the smooth muscle of the walls of the arterioles within the lungs, two PDE5 inhibitors, sildenafil and tadalafil, are FDA-approved for the treatment of pulmonary hypertension. As of 2019, the wider cardiovascular benefits of PDE5 inhibitors are being appreciated.

<span class="mw-page-title-main">Hypoplastic left heart syndrome</span> Type of congenital heart defect

Hypoplastic left heart syndrome (HLHS) is a rare congenital heart defect in which the left side of the heart is severely underdeveloped and incapable of supporting the systemic circulation. It is estimated to account for 2-3% of all congenital heart disease. Early signs and symptoms include poor feeding, cyanosis, and diminished pulse in the extremities. The etiology is believed to be multifactorial resulting from a combination of genetic mutations and defects resulting in altered blood flow in the heart. Several structures can be affected including the left ventricle, aorta, aortic valve, or mitral valve all resulting in decreased systemic blood flow.

Portopulmonary hypertension (PPH) is defined by the coexistence of portal and pulmonary hypertension. PPH is a serious complication of liver disease, present in 0.25 to 4% of all patients with cirrhosis. Once an absolute contraindication to liver transplantation, it is no longer, thanks to rapid advances in the treatment of this condition. Today, PPH is comorbid in 4-6% of those referred for a liver transplant.

<span class="mw-page-title-main">Vascular disease</span> Medical condition

Vascular disease is a class of diseases of the vessels of the circulatory system in the body, including blood vessels – the arteries and veins, and the lymphatic vessels. Vascular disease is a subgroup of cardiovascular disease. Disorders in this vast network of blood and lymph vessels can cause a range of health problems that can sometimes become severe, and fatal. Coronary heart disease for example, is the leading cause of death for men and women in the United States.

<span class="mw-page-title-main">Right ventricular hypertrophy</span> Medical condition

Right ventricular hypertrophy (RVH) is a condition defined by an abnormal enlargement of the cardiac muscle surrounding the right ventricle. The right ventricle is one of the four chambers of the heart. It is located towards the right lower chamber of the heart and it receives Deoxygenated blood from the right upper chamber and pumps blood into the lungs.

In medicine, hepatopulmonary syndrome is a syndrome of shortness of breath and hypoxemia caused by vasodilation in the lungs of patients with liver disease. Dyspnea and hypoxemia are worse in the upright position.

<span class="mw-page-title-main">Ambrisentan</span> Chemical compound

Ambrisentan, sold under the brand name Letairis among others, is a drug used for the treatment of pulmonary hypertension. It is an endothelin receptor antagonist.

<span class="mw-page-title-main">Prostacyclin receptor</span> Mammalian protein found in Homo sapiens

The prostacyclin receptor, also termed the prostaglandin I2 receptor or just IP, is a receptor belonging to the prostaglandin (PG) group of receptors. IP binds to and mediates the biological actions of prostacyclin (also termed prostaglandin I2, PGI2, or when used as a drug, epoprostenol). IP is encoded in humans by the PTGIR gene. While possessing many functions as defined in animal model studies, the major clinical relevancy of IP is as a powerful vasodilator: stimulators of IP are used to treat severe and even life-threatening diseases involving pathological vasoconstriction.

<span class="mw-page-title-main">Riociguat</span> Chemical compound

Riociguat, sold under the brand name Adempas, is a medication by Bayer that is a stimulator of soluble guanylate cyclase (sGC). It is used to treat two forms of pulmonary hypertension (PH): chronic thromboembolic pulmonary hypertension (CTEPH) and pulmonary arterial hypertension (PAH). Riociguat constitutes the first drug of the class of sGC stimulators. The drug has a half-life of 12 hours and will decrease dyspnea associated with pulmonary arterial hypertension.

<span class="mw-page-title-main">Heart failure with preserved ejection fraction</span> Medical condition

Heart failure with preserved ejection fraction (HFpEF) is a form of heart failure in which the ejection fraction – the percentage of the volume of blood ejected from the left ventricle with each heartbeat divided by the volume of blood when the left ventricle is maximally filled – is normal, defined as greater than 50%; this may be measured by echocardiography or cardiac catheterization. Approximately half of people with heart failure have preserved ejection fraction, while the other half have a reduction in ejection fraction, called heart failure with reduced ejection fraction (HFrEF).

<span class="mw-page-title-main">Macitentan</span> Chemical compound

Macitentan, sold under the brand name Opsumit, is an endothelin receptor antagonist developed by Actelion and approved for the treatment of pulmonary arterial hypertension (PAH). Macitentan is a dual endothelin receptor antagonist, meaning that it acts as an antagonist of two endothelin (ET) receptor subtypes, ETA and ETB. However, macitentan has a 50-fold increased selectivity for the ETA subtype compared to the ETB subtype.

Chronic thromboembolic pulmonary hypertension (CTEPH) is a long-term disease caused by a blockage in the blood vessels that deliver blood from the heart to the lungs. These blockages cause increased resistance to flow in the pulmonary arterial tree which in turn leads to rise in pressure in these arteries. The blockages either result from organised blood clots that usually originate from the deep veins of the lower limbs of the body (thromboembolism) and lodge in the pulmonary arterial tree after passing through the right side of the heart. The blockages may also result from scar tissue that forms at the site where the clot has damaged the endothelial lining of the pulmonary arteries, causing permanent fibrous obstruction. Most patients have a combination of microvascular and macrovascular obstruction. Some patients may present with normal or near-normal pulmonary pressures at rest despite symptomatic disease. These patients are labelled as having chronic thromboembolic disease (CTED).

<span class="mw-page-title-main">Balloon pulmonary angioplasty</span> Medical procedure

Balloon pulmonary angioplasty (BPA) is an emerging minimally invasive procedure to treat chronic thromboembolic pulmonary hypertension (CTEPH) in people who are not suitable for pulmonary thromboendarterectomy (PTE) or still have residual pulmonary hypertension and areas of narrowing in the pulmonary arterial tree following previous PTE.

<span class="mw-page-title-main">Pulmonary artery agenesis</span>

Pulmonary artery agenesis refers to a rare congenital absence of pulmonary artery due to a malformation in the sixth aortic arch. It can occur bilaterally, with both left and right pulmonary arteries being absent, or unilaterally, the absence of either left or right pulmonary artery (UAPA). About 67% of UAPA occurs isolated in the right lung. The absence of pulmonary artery can be an isolated disorder, or accompanied by other related lesions, most commonly Tetralogy of Fallot.

<span class="mw-page-title-main">Pulmonary arterial hypertension</span> Elevated pressure in the pulmonary circulation limited to the pre-capillary blood vessels

Pulmonary Arterial Hypertension (PAH) is a syndrome in which the blood pressure in the pulmonary arteries and pulmonary arterioles is elevated. This pre-capillary pulmonary artery pressure being elevated is essential, and by definition a mean pulmonary artery pressure greater than 20 mmHg as measured by a right heart catheterization is required for the diagnosis. This pre-capillary pulmonary hypertension is confirmed with measuring pulmonary vascular resistance being greater than 3 Woods Units. A pulmonary artery wedge pressure being less than 15 mmHg excludes post-capillary bed pulmonary hypertension. Pulmonary arterial hypertension is a subgroup of pulmonary hypertension and is categorized as World Health Organization as group 1. PAH is further subdivided into various categories based on the cause, including idiopathic, heritable, drug and toxin induced, PAH associated with specific diseases, PAH that is responsive to vasodilators, PAH with venous or capillary involvement, and persistent PAH in the newborn period.

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