**2. Pathophysiology**

In end-stage cystic fibrosis, PH prevalence, defined as mean PAP ≥25 mmHg, has been reported

1.2.2 ALK-1, endoglin (with or without hereditary haemorrhagic telangiectasia)

as high as 63% [8].

22 Pulmonary Hypertension

1.2 Heritable

1.1 Idiopathic PAH (IPAH)

1.2.1 BMPR2

1.2.3 Unknown 1.3 Drugs and toxins induced 1.4 Associated with (APAH)

> 1.4.2 HIV infection 1.4.3 Portal hypertension 1.4.4 Congenital heart disease 1.4.5 Schistosomiasis

1.4.1 Connective tissue diseases

1.4.6 Chronic haemolytic anaemia 1.5 Persistent pulmonary hypertension of the newborn

**2. Pulmonary hypertension due to left heart disease**

3.1 Chronic obstructive pulmonary disease

**4. Chronic thromboembolic pulmonary hypertension 5. PH with unclear and/or multifactorial mechanisms**

hypertension; PAH: pulmonary arterial hypertension. From : Simonneau G et al, JACC 2009 [1].

**Table 1.** Classification of Pulmonary Hypertension

**3. Pulmonary hypertension due to lung diseases and/or hypoxia**

2.1 Systolic dysfunction 2.2 Diastolic dysfunction 2.3 Valvular disease

3.2 Interstitial lung disease

vasculitis

3.4 Sleep-disordered breathing 3.5 Alveolar hypoventilation disorders 3.6 Chronic exposure to high altitude 3.7 Developmental abnormalities

**1' Pulmonary veno-occlusive disease and/or pulmonary capillary haemangiomatosis**

3.3 Other pulmonary diseases with mixed restrictive and obstructive pattern

5.1 Haematological disorders: myeloproliferative disorders, splenectomy

5.3 Metabolic disorders: glycogen storage disease, Gaucher disease, thyroid disorders 5.4 Others: tumoural obstruction, fibrosing mediastinitis, chronic renal failure on dialysis

5.2 Systemic disorders: sarcoidosis, pulmonary Langerhans cell histiocytosis, lymphangioleiomyomatosis, neurofibromatosis,

BMPR2: bone morphogenetic protein receptor, type 2; ALK-1: activin receptor-like kinase 1 gene; APAH: associated pulmonary arterial

**1. PAH**

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

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 patients [17,19].

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 hypoxia alone [5,20].

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‐ striction (HPV). However, neither the oxygen sensing process nor the exact HPV pathways are fully understood [21]. The effector pathway is suggested to include L-type calcium channels, non-specific cation channels and voltage-dependent potassium channels, whereas mitochondria and nicotinamide adenine dinucleotide phosphate oxidases have been described as oxygen sensors (Figure 1). Reactive oxygen species (ROS), redox couples and adenosine monophosphate-activated kinases are also under investigation as mediators of HPV. More‐ over, the role of calcium sensitisation, intracellular calcium stores and direction of change of reactive oxygen species is still under debate. Other pathways, such as the endothelin-1 pathway, nitric oxide pathway and ROS may also explain development of sustained PH. Endothelin-1 is an important mediator of systemic hypertension in intermittent hypoxic states [18,22] and ongoing studies suggest a role for endothelin in acute HPV. ROS are highly reactive and unstable free radicals. Intermittent hypoxia stimulates the synthesis and release of ROS through the tyrosine hydroxylase system, leading to the development of systemic hyperten‐ sion. ROS have also been implicated in the induction of endothelin-1 and in angiotensinogen synthesis with all these agents believed to contribute to the development of PH induced by intermittent hypoxia [18,21,23].

**3. Pulmonary vascular remodelling**

indicating reduction in proliferation [24,28].

**4. Role of systemic inflammation**

systemic inflammation was not observed [32].

outcomes have not been defined [33].

**5. COPD and PH**

Studies of the vasculature in hypoxic PH have demonstrated changes including intimal thickening, medial hypertrophy and muscularization of the small arterioles [5]. When the balance between apoptosis and proliferation of endothelial cells in the pre-capillary pulmonary blood vessels, in particular, is altered in favour of proliferation, the overall resistance pattern is increased [24]. As shown in neonatal calves and rodent models, chronic hypoxia triggers endothelial cell proliferation [24,25]. Acute hypoxia triggers adventitial fibroblast proliferation within hours of exposure while medial hypertrophy and hyperplasia takes longer to develop [24,26,27]. Fibroblasts stimulated by chronic hypoxia can transform into smooth muscle cells. Hyperplasia is more prevalent in the less muscular arterioles, while hypertrophy is more common in the muscular arterioles. Chronic hypoxia in rat models results in a doubling of muscular arteries with proliferation into non-muscularized vessels [24]. The response of pulmonary vascular smooth muscle cells to acute hypoxia is still debatable with some studies

Pulmonary Hypertension in Chronic Lung Diseases and/or Hypoxia

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

25

Inflammation associated with underlying lung disease may be partly responsible for the development of PH in hypoxic states. Inflammatory cells have been detected in local vascular structures in COPD patients, in addition to the evidence of systemic inflammation with raised inflammatory markers, such as CRP and TNF–α [29,30]. In rats exposed to hypoxia, alveolar macrophages play a critical role in the inflammatory process, with inflammation occurring in the presence of reduced alveolar PaO2 [31]. In alveolar macrophage-depleted conditions,

There is a growing body of evidence supporting different phenotypes among patients with COPD. These COPD phenotypes may be useful in defining patients who may benefit from particular therapies or interventions more than others. Potential phenotypes may be defined by symptoms, physiology, radiology and exacerbation history, although the relevant clinical

A PH phenotype in COPD is potentially defined by perceivable effects on functional perform‐ ance status and mortality [5]. PH is an independent prognostic factor in COPD [34-36]. The current accepted definition of PH in COPD is a mean PAP ≥ 25mmHg with underlying hypoxia. PH ideally should be measured by right heart catheterization, which may not be feasible in many cases. As an alternative, Doppler echocardiographic measurements have been used in a number of studies, although Doppler can be technically challenging due to body habitus and poor acoustic windows, precluding detection of a significant left heart pathology, which may

**Figure 1.** Pathways involved in hypoxic pulmonary vasoconstriction. Acute hypoxia results in an increase of intracellu‐ lar calcium in pulmonary arterial smooth muscle cells and thus contraction. This increase in calcium is achieved by in‐ flow of extracellular calcium through plasmalemnal calcium channels and release of intracellularly stored calcium. Hypoxic effects could be mediated or modulated by a decrease (left side) or increase (right side) of reactive oxygen species (ROS). NADPH: reduced nicotinamide adenine dinucleotide phosphate; NSCC: nonspecific cation channels; TRP: transient receptor potential; NADH: reduced nicotinamide adenine dinucleotide; NAD: nicotinamide adenine di‐ nulceotide; NADP: nicotinamide adenine dinucleotide phosphate; CCE: capacitative calcium entry; ATP: adenosine tri‐ phosphate; IP3: inositol triphosphate; cADPR: cyclic ADP-ribose; SR: sarcoplasmatic reticulum; *Sommer N et al. Eur Respir J 2008 [21], Reproduced with permission of the European Respiratory Society*
