Right ventricle (on left side) 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). This further increases the blood pressure within the lungs and impairs their blood flow. In common with other types of<unk> , these changes result in an increased 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 pump to supply sufficient oxygen to the rest of the body, especially during<unk> ysical activity. During the end-systolic volume<unk> ase of the cardiac cycle, the Gaussian curvature and the mean curvature of right ventricular endocardial wall of<unk>  patients was 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<unk>  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<unk>  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<unk> ' (older terms include 'passive' or 'proportionate'<unk>  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<unk>  with a pre-capillary component' or 'combined post-capillary and pre-capillary<unk> ' (older terms include 'reactive' or 'out-of-proportion'<unk> . In<unk>  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<unk> enomenon is called hypoxic pulmonary vasoconstriction and it is initially a protective response designed 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<unk> . 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. In 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<unk> . This combination of vessel occlusion and vascular remodeling once again increases the resistance to blood flow and so the pressure within the system rises. Molecular pathology 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. 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. 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. 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). 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. Nitric oxide–soluble guanylate cyclase signaling also leads to anti-inflammatory effects.<unk> osphodiesterase 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. 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. 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<unk> osphodiesterases 3 and 4. The vasoconstrictor thromboxane is also synthesized from arachidonic acid. In PAH, the balance is shifted away from synthesis of prostacyclin towards synthesis of thromboxane. 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<unk> osphorylation to glycolysis and leading to increased cell proliferation and impaired apoptosis. 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. 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. 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. Other factors underlying the proliferative state of pulmonary vascular smooth muscle cells include OPG and TRAIL. 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.
Pulmonary hypertension
Portopulmonary hypertension
Chronic thromboembolic pulmonary hypertension
Asthma
Chronic obstructive pulmonary disease
Emphysema
Hypertensive heart disease
Reactive airway disease