Amy L. Firth and Jason X.-J. Yuan
Establishing an accurate diagnosis of pulmonary hypertension (PH) is essential for proficient management of the disease. Indeed, several distinct cardiopulmonary diseases are encompassed by PH. Each requires an in-depth knowledge of the normal pulmonary vasculature and the pathophysiological progression of the disease.
The pulmonary vascular bed is normally a high-flow, low-resistance and low-pressure system that transports blood to the pulmonary capillaries; here, oxygen is taken up by the venous blood and excess carbon dioxide is unloaded through the blood–gas barrier. The complex branching structure of pulmonary vessels from the main pulmonary artery to small resistance vessels is described by three models: the Weibel model, the Strahler model, and the diameter-defined Strahler model. Regardless of the model used, the total resistance in the pulmonary vascular bed is dependent upon the intraluminal diameter, or cross-sectional area, of the pulmonary arteries. A reduction in this diameter can result from three fundamental pathologic processes: vasoconstriction, obstruction, and obliteration.
Pulmonary artery pressure (PAP) is calculated as a product of cardiac output (CO) and pulmonary vascular resistance (PVR), represented by the formula PAP = CO × PVR. While PAP is known to vary with age, the mean PAP is approximately 20 mmHg. It might be expected that during intense exercise there would be a large increase in PAP due to the increase in CO, but only a small increase is observed as the compliance of the pulmonary vascular wall compensates by increasing the cross-sectional area of the vessels through vasodilation and recruitment of previously unperfused vessels. The major cause of elevated PVR in PH patients is a decrease in pulmonary arterial wall compliance (e.g., an increase in vascular wall stiffness due to vascular remodeling is the major cause of elevated PVR in PH patients). In the early stages of PH, it is common for PAP and PVR to be normal under resting conditions; however, when blood flow increases, there is a notable increase in PAP. Resting PH ensues as the disease progresses. To sustain the increase in PAP, an increase in the musculature of the right ventricle is necessary. Right ventricular hypertrophy is thus an indicative feature of sustained PAP in PH. If the right ventricular afterload is high enough, right-sided heart failure develops, manifesting as resting dyspnea, jugular venous distension, hepatic congestion, ascites, and dependent edema.
It cannot be understated that PH, in whichever form it may present clinically, is a phenomenon comprising many unique but interrelated mechanisms at a cellular level. The arterial remodeling itself can encompass activation and proliferation of an array of cell types including endothelial cells, fibroblasts, myofibroblasts, and vascular smooth muscle cells (SMC). Pulmonary vasoconstriction, generally associated with chronic exposure to hypoxia, eventually leads to hypertrophy of the medial SMC layer of the artery, compromising the integrity of the vessel lumen. Consequences unfold and vascular wall tension will increase, leading to further proliferation and intimal scarring. Intimal lesions/fibrosis are common to most forms of PH. The pulmonary vascular bed integrity is maintained by a fine balance between apoptosis and proliferation; when either of these processes is compromised, arteriopathic changes occur in the pulmonary vasculature.
During the 4th World Symposium on PH held in 2008 in Dana Point, CA, experts in the field decided to modify the clinical classification of PH previously established in 2003 at the 3rd World Symposium held in Venice. The current classification is summarized in Table 73-1. Correctly distinguishing the pathogenesis of PH is of upmost importance when it comes to discerning the most effective treatment régime for the patient. The new classification system has been associated with notable improvements in the quality and efficacy of clinical care for PH patients. Class I, known as pulmonary arterial hypertension (PAH), encompasses idiopathic and hereditary PAH, among others. Patients with a mean PAP greater than 25 mmHg without evidence of increased wedge pressure, parenchymal lung disorders, or thromboembolic disease are considered to have PAH. Historically, idiopathic pulmonary arterial hypertension (IPAH, previously known as primary pulmonary hypertension) occurs without demonstrable etiology. Secondary PH, on the other hand, develops as a complication of other diseases. The hereditable nature of PAH is usually due to mutations in the bone morphogenetic protein receptor type 2 gene (BMPR2) or, less commonly, members of the transforming growth factor-β superfamily, namely activin-like kinase 1 (ALK1) and endoglin (ENG). The latter two are associated with hereditary hemorrhagic telangiectasia. While approximately 20% of patients with IPAH and 70% of those with hereditary PAH have heterozygous germline mutations in BMPR2, they a have variable lifetime penetrance of about 10% to 20% and, even if identified, there are no known preventative measures.
As mentioned previously, PAH is a common, often rare but life-threatening secondary complication of other conditions, most notably connective tissue diseases, HIV infection, portal hypertension (portopulmonary hypertension or PoPH), and congenital heart disease. PoPH has a prevalence of about 5% to 6% of patients with decompensated liver disease in which significant vascular remodeling increases PAP and PVR. A definitive diagnosis typically requires right heart catheterization. Furthermore, liver cirrhosis can also be complicated by hepatopulmonary syndrome (HPS) caused by intrapulmonary arteriovenous shunting with resultant hypoxemia. While HPS remains refractory to treatment, PoPH is responsive to vasodilators and improvement in pulmonary hemodynamics. Using PAH-specific therapies such as endothelin receptor antagonists may overcome the contraindication for liver transplantation. HIV-related PAH is of unknown etiology and can be associated with both early and late stages of immunodeficiency. Theories for pathogenesis currently focus on smooth muscle and endothelial cell injury postulated to be due to elevated levels of cytokines (e.g., ET-1, IL-6, and PDGF). The appetite suppressant fenfluramine was withdrawn from the market in 1997 due to its association with PAH. More recently (1998–2009), the fenfluramine derivative Benfluorex (on the market since 1976) has also been associated with PAH and valve disorders; these contraindications are currently being formally assessed.
Revised Nomenclature of Pulmonary Hypertension |
Class 1: Pulmonary Arterial Hypertension (PAH) | ||
1.1. | Idiopathic PAH | |
1.2. | Hereditable | |
| 1.2.1. | BMPR2 |
| 1.2.2. | ALK1, endoglin (with/without hereditary hemorrhagic telangiectasia) |
| 1.2.3. | Unknown |
1.3. |
||
