**1. Introduction**

[54] Barst RJ, Langleben D, Frost A, Horn EM, Oudiz R, Shapiro S, et al. Sitaxesentan therapy for pulmonary arterial hypertension. Am J Respir Crit Care Med 2004;169

[55] McLaughlin VV, McGoon MD. Pulmonary Arterial Hypertension. Circulation. 2006;

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(4):441-7.

20 Pulmonary Hypertension

114:1417-1431.

2012; 141:354.

Pulmonary hypertension is a common complication in lung disease. In the most recent revised classification of pulmonary hypertension (PH), chronic lung diseases or conditions with alveolar hypoxia are included in WHO Group III of PH-related diseases (Table 1) [1,2]. In this classification the structure of this group was for the most part unchanged. The heading has been recently modified to denote cause and effect on PH development. The primary modifi‐ cation was to add a new category of chronic lung disease of a mixed obstructive and restrictive pattern, which includes chronic bronchiectasis, cystic fibrosis and a syndrome characterized by the combination of pulmonary fibrosis (mainly of the lower zones of the lung) and emphy‐ sema (mainly of the upper zones of the lung), in which the prevalence of PH is almost 50%.

Alveolar hypoxia and thereby PH may occur in distinct conditions including: parenchymal lung disease, chronic airway diseases, ventilatory control abnormalities, residence at high altitude, progressive neuromuscular diseases and mixed obstructive and restrictive lung diseases [1,3,4]. As both the primary respiratory condition and PH may be associated with dyspnoea, the latter often goes unrecognised. Therefore, data on PH prevalence in each of these conditions is limited [5].

Prevalence of COPD-related PH is influenced by COPD progression, its heterogeneity, comorbidities and methods of measurement. In a retrospective cohort study of over 4000 patients with advanced COPD awaiting lung transplant, a 30.4% prevalence of PH has been reported [6]. Elevated pulmonary artery pressure (PAP) is common in severe emphysema, although it may be independent of hypoxia [7]. However, the gold standard of measuring PAP by right heart catheterization to define PH has not been applied in the majority of prevalence studies.

© 2013 Sajkov et al.; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2013 Sajkov et al.; licensee InTech. This is a paper distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

In end-stage cystic fibrosis, PH prevalence, defined as mean PAP ≥25 mmHg, has been reported as high as 63% [8].

In high altitude residents, PH prevalence is between 8-18% [9,10]. A geographical variation in altitude-related PH prevalence may suggest differences in genetic susceptibility to develop‐ ment of PH in people living above 2000 m [11,12]. Variations have been observed in PAP changes among individuals living in the same regions, with some familial clustering and ethnic differences, although no definite gene polymorphism affecting PAP has been isolated [13].

Pulmonary Hypertension in Chronic Lung Diseases and/or Hypoxia

http://dx.doi.org/10.5772/55681

23

Until recently there was disagreement whether intermittent hypoxia, such as occurs in obstructive sleep apnoea (OSA), without primary lung or cardiovascular disease can cause sustained PH. Recent studies have resolved this controversy by demonstrating that OSA is associated with PH, with co-prevalence rates varying between 20-40% [14-16]. However, no large population-based studies of PH prevalence in OSA have been reported and management of PH in patients with OSA has been mainly directed to managing the primary condition.

Alveolar hypoxia is a potent stimulus for pulmonary vasoconstriction. It operates at the endothelial level and is one of the most important pathways leading to PH development in chronic lung diseases. Alveolar hypoventilation precipitates acute pulmonary vasoconstric‐ tion in some regions of the lungs, and vasodilation in others, causing physiological shunt. Hypoxia causes pulmonary vasoconstriction leading to an increase in pulmonary vascular resistance. Two mechanisms are postulated to underpin this phenomenon. Vasoconstriction is achieved either through activation of a vasoconstrictor pathway or inactivation of a vaso‐ dilator pathway, or alternatively via the effects of hypoxia on the vascular smooth muscle [17]. Studies in rats exposed to hypoxia suggest that hypoxia-exposed arterioles develop smooth muscle in the walls of non-muscular pre-capillary blood vessels, which persists after removal

Hypoxic insults can be sustained or intermittent. In sleep-disordered breathing, the presence of intermittent hypoxia has been linked to the development of systemic hypertension with changes in the vasculature similar to the changes in PH. It remains undetermined whether sustained or intermittent hypoxia elicits these changes through similar mechanisms [18]. Studies in mice and rats exposed to intermittent hypoxia, mimicking sleep disordered breathing, showed development of sustained PH and right ventricular hypertrophy [17]. Treatment with CPAP in sleep-disordered breathing results in the reversal of PH, supporting a role for acute hypoxic pulmonary vasoconstriction and endothelial dysfunction in these

Studies in mouse models of emphysema have suggested alternative mechanisms to the vascular changes associated with PH in COPD patients, as the mice developed pulmonary vascular changes independent of hypoxia indicative of a much more complex mechanism than

The development of PH as a result of hypoxic insults, both intermittent and chronic, is subject to ongoing investigations, with several pathways implicated in hypoxic pulmonary vasocon‐

**2. Pathophysiology**

patients [17,19].

hypoxia alone [5,20].

of the stimulus and contributes to ongoing PH [9].


5.4 Others: tumoural obstruction, fibrosing mediastinitis, chronic renal failure on dialysis

BMPR2: bone morphogenetic protein receptor, type 2; ALK-1: activin receptor-like kinase 1 gene; APAH: associated pulmonary arterial hypertension; PAH: pulmonary arterial hypertension. From : Simonneau G et al, JACC 2009 [1].

In high altitude residents, PH prevalence is between 8-18% [9,10]. A geographical variation in altitude-related PH prevalence may suggest differences in genetic susceptibility to develop‐ ment of PH in people living above 2000 m [11,12]. Variations have been observed in PAP changes among individuals living in the same regions, with some familial clustering and ethnic differences, although no definite gene polymorphism affecting PAP has been isolated [13].

Until recently there was disagreement whether intermittent hypoxia, such as occurs in obstructive sleep apnoea (OSA), without primary lung or cardiovascular disease can cause sustained PH. Recent studies have resolved this controversy by demonstrating that OSA is associated with PH, with co-prevalence rates varying between 20-40% [14-16]. However, no large population-based studies of PH prevalence in OSA have been reported and management of PH in patients with OSA has been mainly directed to managing the primary condition.
