Pulmonary hypertension (PH or PHTN) is a condition of increased blood pressure in the arteries of the lungs. Symptoms include shortness of breath, fainting, tiredness, chest pain, swelling of the legs, and a fast heartbeat. The condition may make it difficult to exercise. Onset is typically gradual.
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. 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. The underlying mechanism typically involves inflammation and subsequent remodeling of the arteries in the lungs. Diagnosis involves first ruling out other potential causes. High cardiac output states, such as advanced liver disease or the presence of large arteriovenous fistulas, may lead to an elevated mean pulmonary artery pressure (mPAP) greater than 20 mm Hg despite a pulmonary vascular resistance (PVR) less than 2 Wood units, which does not necessarily indicate pulmonary vascular disease.
there was no cure for pulmonary hypertension, although research to find a cure is ongoing. Treatment depends on the type of disease. A number of supportive measures such as oxygen therapy, diuretics, and medications to inhibit blood clotting may be used. Medications specifically used to treat pulmonary hypertension include epoprostenol, treprostinil, iloprost, bosentan, ambrisentan, macitentan, and sildenafil, tadalafil, selexipag, riociguat. Lung transplantation may be an option in severe cases.
The frequency of occurrence is estimated at 1,000 new cases per year in the United States. Females are more often affected than males. Onset is typically between 20 and 60 years of age. Pulmonary hypertension was identified by Ernst von Romberg in 1891.
Classification According to the WHO classification, there are 5 groups of PH. Group I (pulmonary arterial hypertension) is further subdivided into Group I' and Group I'' classes. The WHO classification system in 2022 (with adaptations from the more recent ESC/ERS guidelines shown in italics) can be summarized as follows:
WHO Group I – Pulmonary arterial hypertension (PAH) Caused by narrowing and thickening of tiny arteries of the lung Idiopathic in most cases (heritable in some cases) Heritable (BMPR2, ALK1, SMAD9, caveolin 1, KCNK3 mutations) Drug- and toxin-induced (e.g., methamphetamine, amphetamine, or cocaine use ) Associated conditions:Connective tissue disease, HIV infection, Portal hypertension, Congenital heart diseases, Schistosomiasis WHO Group I' – Pulmonary veno-occlusive disease (PVOD), pulmonary capillary hemangiomatosis (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 newborn
WHO Group II – Pulmonary hypertension secondary to left heart 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 lung disease, chronic hypoxia 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 Parasitic infection (hydatidosis) WHO Group V – Pulmonary hypertension with unclear or multifactorial mechanisms Hematologic diseases: chronic hemolytic anemia (including sickle cell disease) Systemic diseases: sarcoidosis, pulmonary Langerhans cell histiocytosis: lymphangioleiomyomatosis, neurofibromatosis, vasculitis Metabolic disorders: glycogen storage disease, Gaucher disease, thyroid diseases Others: pulmonary tumoral thrombotic microangiopathy, fibrosing mediastinitis, chronic kidney failure, segmental pulmonary hypertension (pulmonary hypertension restricted to one or more lobes of the lungs)
Signs and symptoms The symptoms of pulmonary hypertension include the following:
Less common signs/symptoms include a non-productive cough and exercise-induced nausea and vomiting. 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. 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.
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. Evidence of tricuspid insufficiency and pulmonic regurgitation is also sought and, if present, is consistent with the presence of pulmonary hypertension.
Causes Pulmonary hypertension is a pathophysiologic condition with many possible causes. Indeed, this condition frequently accompanies severe heart or lung conditions. 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). In 1998, a second conference at Évian-les-Bains addressed the causes of secondary PH. Subsequent third, fourth, and fifth (2013) World Symposia on PAH have further defined the classification of PH. The classification continues to evolve based on improved understanding of disease mechanisms.
Most recently in 2022, the WHO guidelines were updated by the European Society of Cardiology (ESC) and European Respiratory Society (ERS). 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.
Genetics
Mutations in several genes have been associated with this condition 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. 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. 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.
Pathogenesis
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 rather than 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). This further increases the blood pressure within the lungs and impairs their blood flow. Along with other forms of pulmonary hypertension, these changes increase workload for the right side of the heart. 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. 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. During the end-systolic volume phase of the cardiac cycle, the Gaussian curvature and the mean curvature of the right ventricular endocardial wall of PH patients were found to be significantly different as compared to controls.
In PVOD (WHO Group I'), pulmonary blood vessel narrowing occurs preferentially (though not exclusively) in post-capillary venous blood vessels. PVOD shares several characteristics with PAH, but there are also some important differences, for example differences in prognosis and response to medical therapy.
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.
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. 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).