Pulmonary hypertension pathophysiology
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Assistant Editor(s)-in-Chief: Ralph Matar; Rim Halaby
Overview
Pulmonary hypertension (PH) is a pathological condition of the pulmonary vasculature present in several disease states and leading to hemodymical derangement. PH is defined as an elevated mean pulmonary artery pressure (PAP) as measured by right heart catheterization at rest.
The factors that are in involved in the pathophysiology of the increase in the mean pulmonary arterial pressure are: increase in pulmonary vascular resistance, increase in the right sided cardiac output and increase in the mean pulmonary venous pressure.
To note that “Pulmonary arterial hypertension” (PAH) refers to group 1 PAH in the updated WHO classification. “Pulmonary hypertension” (PH) refers to any of group 2 PH through group 5 PH. PH is also used when referring to all five groups collectively.
Pathophysiology
Increase in the Mean Pulmonary Arterial Pressure
PH is defined as an elevated mean pulmonary artery pressure (PAP) as measured by right heart catheterization at rest. PH can be hemodynamically classified into either pre-capillary PH or post-capillary PH. Shown below is a table summarizing the hemodynamic characteristics of PH.
Abbreviations: PAP: Pulmonary artery pressure; PWP: pulmonary wedge pressure
| Type of pulmonary hypertension | Possible clinical class | Mean PAP | PWP |
| Pre-capillary | Class I Class III Class IV Class V |
≥ 25 mmHg | ≤ 15 mmHg |
| Post-capillary | Class II | ≥ 25 mmHg | > 15 mmHg |
Increase in the Pulmonary Vascular Resistance
Occlusion of the small pulmonary arteries and arterioles [1]
- Idiopathic PAH
- Connective tissue disease
- HIV infection
- Congenital heart disease
Decrease in the area of the pulmonary vascular bed
Hypoxic vasoconstriction[3]
- Hypoventilation syndromes
- Parenchymal lung disease
Increase in The Right-sided Cardiac Output due to Left-to-Right Shunt
- Congenital heart diseases: atrial septal defects, ventricular septal defects, patent ductus arteriosus[4]
Increase in the Pulmonary Venous Pressure
- Mitral valve disease
- Left ventricular systolic or diastolic dysfunction
- Constrictive pericarditis
- Restrictivecardiomyopathy
- Pulmonary veno-occlusive disease
Sequence of Events in Pulmonary Hypertension
Pulmonary hypertension has several pathophysiologic mechanisms depending on the underlying etiology. Nevertheless, the following sequence of events is almost always present:
- An initiating factor leads to increased resistance in the pulmonary vasculature causing narrowing of the vessels and impaired blood flow, much as it is harder to make water flow through a narrow pipe as opposed to a wide one.
- As a consequence, the right ventricle adapts by increasing right ventricular systolic pressures to preserve the cardiac output from the right heart.
- Over time, increasing right ventricular systolic pressures will subsequently result in chronic changes in the pulmonary circulation and progressively the affected blood vessels become both stiffer and thicker, further increasing the blood pressure within the lungs and impairing blood flow.
- In addition, the increased workload of the heart causes thickening and enlargement of the right ventricle, making the heart less able to pump blood through the lungs, causing right heart failure.
- 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 physical activity.
Pulmonary Arterial Hypertension
PAH is a proliferative vasculopathy of the small muscular arteries and arterioles, involving vasoconstriction, endothelial and smooth cell proliferation, fibrosis, and thrombosis. Multiple pathologic patterns are found in PAH, including:
- Intimal hyperplasia.
- Medial hypertrophy.
- Adventitial proliferation.
- In-situ thrombosis.
- Inflammation
- Plexiform arteriopathy.
Medial hypertrophy is considered an early and reversible lesion in contrast to intimal fibrosis or plexogenic arteriopathy.
In fact, the vascular proliferative nature of PAH is probably the result of sequences of injury and repair of the pulmonary vasculature in the context of a combination of noxious stimuli affecting a predisposed vasculature. Some of the well-described predisposing factors are the mutations in the BMPR2 gene[5].
The increase in pulmonary vascular resistance results from vascular changes that are the consequences of:
1- Release of cytokines and chemokines and influx of inflammatory cells and mediators [6]
2- An imbalance between
- Locally produced vasodilators (nitric oxide and prostacyclin) [7]
- Vasoconstrictors (endothelin and thromboxane)[8]
- Apoptotic and mitogenic factors[9]
- Prothrombotic and antithrombotic factors [10]
3- Vascular wall remodeling
- Endothelial and smooth muscle cells proliferation in addition to changes in the extracellular matrix[11]
The Role of Endothelial Cells Injury
All classes of pulmonary hypertension are associated with narrowing and obliteration of the pulmonary arterioles due to thickening of the intima by fibromuscular dysplasia. This constant finding has increased the interest in the role of endothelial injury and the release of vasoactive mediators in the pathogenesis of pulmonary hypertension. These mediators include both vasoconstrictors and vasodilators. Whereas the main vasoconstrictor is Endothelin, Nitric Oxide (NO), PGI2 and endothelium derived hyperpolarizing factor (EDHF) are vasodilators, of which NO is the most potent in reversing the effects of Endothelin.[12]
Factors Determining the Ability of the RV to Adapt to Increased PVR
- Age of the patient at onset.
- Rapidity of onset of pulmonary hypertension.
- Coexisting hypoxemia.
Molecular Abnormalities
- Pulmonary arterial hypertension is characterized by endothelial dysfunction such that there is an imbalance between apoptosis and pulmonary artery smooth muscle proliferation favoring the proliferation. There is also thickened and disordered adventitia due to excessive amounts of adventitial metalloproteinases.
- Mutations of two genes in the TGF-beta receptor pathway have been identified in familial pulmonary arterial hypertension:
- BMPR2: BMPR2 gene encodes a serine/threonine kinase that functions as a receptor for bone morphogenetic proteins which forms a heterodimer cytoplasmic complex of two type II and two type I receptors. The downstream signaling involves activation of SMAD transcription factor which mediates anti-proliferation in smooth muscle cells.
- Activin-like kinase 1: detected in patients with hereditary hemorrhagic telangiectasia and pulmonary arterial hypertension. Mutation would cause growth-promoting alterations.
Both genes are involved SMAD-dependent signaling pathways.
Molecular Pathogenesis
Several pathways are implicated in development of vascular remodeling, which is the hallmark of pathologic changes in pulmonary hypertension:
1. Thrombosis-mediated remodeling
Thrombin plays a key role in mediating vascular remodeling by activating platelet, upregulating angiogenesis-related genes (including tissue factor [TF], basic fibroblast growth factor [bFGF], and matrix metalloproteinase-2), and transactivating vascular endothelial growth factor (VEGF) by inducing the production of reactive oxygen species (ROS) and the expression of the hypoxia inducible factor-1 alpha. Upregulation of TF in the vasculature leads to initiation of coagulation cascade and migration and proliferation of smooth muscle cells upon vascular injury. In addition, platelet activation by thrombin results in the release of granules containing substances that promote mitogenesis and vasoconstriction including VEGF, bFGF, platelet-derived growth factor, and serotonin, which also contribute to increased endothelial cell migration and proliferation.
2. Vasoconstriction-mediated remodeling
Imbalance of vasoactive signals is suggested in the pathogensis of remodeling. Reduced levels of vasodilatory mediators, in particular prostaglandin I2, nitric oxide, and cyclic guanine monophosphate, and elevated levels of vasocontricting molecules such as endothelin 1, thromboxane, and 5-hydroxytryptamine contribute to alterations in the vascular tone. Downregulation of the voltage-gated potassium channels has also been linked with altered pulmonary vascular tone, dysregulation of cellular homeostasis, and induction of proliferative sequelae in vascular smooth muscle cells.
3. Proliferation-mediated remodeling
Serotonin exerts both vasoconstrictive and mitogenic effects on smooth muscle cells (SMC). Serotonin may bind to 5-hydroxytryptamine 1A and 2B receptors or may enter SMC via serotonin transporter which induces generation of ROS, rho kinase, and mitogen-activated protein kinases. This in turn leads to the expression of growth factors and proliferation. Bone morphogenetic protein (BMP) is also involved in the SMC proliferation. Upon binding of BMP to its heterodimerized receptors, a group of cytoplasmic proteins known as receptor-mediated Smads are phosphorylated and translocated to the nucleus where they upregulate genes related to anti-proliferation. Serotonin is shown to antagonize the BMP/Smad pathway thus facilitating the proliferation of smooth muscle cells.
4. Inflammation-mediated remodeling
Influx of inflammatory effector cells is stimulated by the release of chemokines such as CCL5 and CX3CL1. On the other hand, endothelial cell and smooth muscle cell dysfunction contributes to the release of vasomotor and growth factors, activation of transcription factors, influx of calcium, and dysfunction of mitochondria. The net effect is a shift of balance in favor of proliferation and suppressed apoptosis, leading to remodeling of the pulmonary vasculature.
Histopathology
PH is a pathological condition present in different disease states that share similar clinical manifestation and some common histopathological features. Shown below is a table that summarizes the classification of PH based on histopathology findings.[13]
| Class | Histopathological findings[13] |
| Pulmonary arteriopathy | Constrictive lesions in pulmonary arteries
Complex lesions in pulmonary arteries
|
| Pulmonary arteriopathy with venous-venular changes | Changes similar to pulmonary arteriopathy PLUS Changes in venules and veins |
| Pulmonary occlusive venopathy | Changes in venules and veins Diffuse fibrotic occlusion Intimal thickening Medial thickening Adventitial thickening |
| Pulmonary microvasculopathy | Localized capillary proliferation |
| Unclassified | Non specific |
References
- ↑ Vallerie V.; McLaughlin; Michael D. McGoon. Pulmonary Arterial Hypertension. Circulation. 2006; 114: 1417-1431
- ↑ Behr J, Ryu JH (2008). "Pulmonary hypertension in interstitial lung disease". Eur Respir J. 31 (6): 1357–67. doi:10.1183/09031936.00171307. PMID 18515559.
- ↑ Sommer N, Dietrich A, Schermuly RT, Ghofrani HA, Gudermann T, Schulz R; et al. (2008). "Regulation of hypoxic pulmonary vasoconstriction: basic mechanisms". Eur Respir J. 32 (6): 1639–51. doi:10.1183/09031936.00013908. PMID 19043010.
- ↑ Schulze-Neick I, Kaemmerer H (2009). "[Pulmonary hypertension and pulmonary circulation in congenital heart disease]". Dtsch Med Wochenschr. 134 Suppl 5: S170–2. doi:10.1055/s-0029-1225317. PMID 19718608.
- ↑ Yuan JX, Rubin LJ (2005). "Pathogenesis of pulmonary arterial hypertension: the need for multiple hits". Circulation. 111 (5): 534–8. doi:10.1161/01.CIR.0000156326.48823.55. PMID 15699271.
- ↑ Vallerie V.; McLaughlin; Michael D. McGoon. Pulmonary Arterial Hypertension. Circulation. 2006; 114: 1417-1431
- ↑ Giaid A, Saleh D (1995). "Reduced expression of endothelial nitric oxide synthase in the lungs of patients with pulmonary hypertension". N Engl J Med. 333 (4): 214–21. doi:10.1056/NEJM199507273330403. PMID 7540722.
- ↑ Christman BW, McPherson CD, Newman JH, King GA, Bernard GR, Groves BM; et al. (1992). "An imbalance between the excretion of thromboxane and prostacyclin metabolites in pulmonary hypertension". N Engl J Med. 327 (2): 70–5. doi:10.1056/NEJM199207093270202. PMID 1603138.
- ↑ Harrison W. Pulmonary Arterial Hypertension, N Engl J Med 2004;351:1655-65
- ↑ Harrison W. Pulmonary Arterial Hypertension, N Engl J Med 2004;351:1655-65
- ↑ International PPH Consortium. Lane KB, Machado RD, Pauciulo MW, Thomson JR, Phillips JA; et al. (2000). "Heterozygous germline mutations in BMPR2, encoding a TGF-beta receptor, cause familial primary pulmonary hypertension". Nat Genet. 26 (1): 81–4. doi:10.1038/79226. PMID 10973254.
- ↑ Higenbottam Tim(1994) "Pathophysiology of Pulmonary Hypertension, A role for endothelial dysfunction" Chest journal"
- ↑ 13.0 13.1 Pietra GG, Capron F, Stewart S, Leone O, Humbert M, Robbins IM; et al. (2004). "Pathologic assessment of vasculopathies in pulmonary hypertension". J Am Coll Cardiol. 43 (12 Suppl S): 25S–32S. doi:10.1016/j.jacc.2004.02.033. PMID 15194175.