Sildenafil treatment in COPD does not affect stroke volume or exercise capacity

Rietema, Heleen; Holverda, Sebastiaan; Bogaard, Harm Jan; Marcus, J. Tim; Smit, Henk; Westerhof, Nico; Postmus, P.E.; Boonstra, Anco; Vonk‐Noordegraaf, Anton

doi:10.1183/09031936.00114207

Cited by 125 publications

(90 citation statements)

References 30 publications

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“…Currently, no effective treatments are available for PH in COPD (10,11), and clinical trials using presently approved therapies for pulmonary arterial hypertension (PAH) in patients with COPD and PH have proven disappointing (10,11,33,34). Thus, the need exists to elucidate the mechanisms that lead to PH in COPD, with the aim of developing specific treatments for this disorder.…”

Section: Discussionmentioning

confidence: 99%

Adenosine A2B Receptor and Hyaluronan Modulate Pulmonary Hypertension Associated with Chronic Obstructive Pulmonary Disease

Karmouty‐Quintana¹,

Weng

Garcia-Morales

et al. 2013

Am J Respir Cell Mol Biol

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Chronic obstructive pulmonary disease (COPD) is the fourth leading cause of death worldwide. The development of pulmonary hypertension (PH) in patients with COPD is strongly associated with increased mortality. Chronic inflammation and changes to the lung extracellular matrix (ECM) have been implicated in the pathogenesis of COPD, yet the mechanisms that lead to PH secondary to COPD remain unknown. Our experiments using human lung tissue show increased expression levels of the adenosine A 2B receptor (ADORA2B) and a heightened deposition of hyaluronan (HA; a component of the ECM) in remodeled vessels of patients with PH associated with COPD. We also demonstrate that the expression of HA synthase 2 correlates with mean pulmonary arterial pressures in patients with COPD, with and without a secondary diagnosis of PH. Using an animal model of airspace enlargement and PH, we show that the blockade of ADORA2B is able to attenuate the development of a PH phenotype that correlates with reduced levels of HA deposition in the vessels and the down-regulation of genes involved in the synthesis of HA.Keywords: adenosine; extracellular matrix; hyaluronic acid; remodeling; vascular Chronic obstructive pulmonary disease (COPD) is currently the fourth leading cause of death worldwide, and the World Health Organization predicts that it will become the third leading cause of death by 2030 (1). COPD is a heterogeneous disease characterized by airflow obstruction that is not fully reversible. Pathophysiological hallmarks of the disease include remodeling of the smallairway compartment, the loss of elastic recoil by emphysematous destruction of the parenchyma, inflammatory cell infiltration (2), and increased extracellular matrix (ECM) turnover (3). COPD is associated with a wide range of comorbidities, including ischemic heart disease, diabetes, skeletal muscle wasting, osteoporosis, and lung cancer (4). The development of pulmonary hypertension (PH) is a common and fatal complication in patients with COPD (5-7), and is strongly associated with decreased life expectancy (8).PH is a disorder of the pulmonary vasculature diagnosed by cardiac catheterization. PH is characterized by a mean pulmonary arterial pressure greater than or equal to 25 mm Hg that leads to right ventricular (RV) hypertrophy, followed by right-sided heart failure and death (9). Currently, treatment options are very limited for patients suffering from PH secondary to COPD (10, 11). Thus, to understand the mechanisms that lead to remodeling of the vasculature in COPD is important, with the hope of developing new treatment options for this fatal disorder.The pathogenesis of PH in COPD is a complex phenomenon characterized by extensive remodeling of the vasculature that results from an increased proliferation of pulmonary artery endothelial and smooth muscle cells, the muscularization of previously nonmuscular arteries, increased vascular tone, and the formation of complex vascular lesions (12). Factors involved in the development of PH in patients with COPD include ...

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Section: Discussionmentioning

confidence: 99%

Adenosine A2B Receptor and Hyaluronan Modulate Pulmonary Hypertension Associated with Chronic Obstructive Pulmonary Disease

Karmouty‐Quintana¹,

Weng

Garcia-Morales

et al. 2013

Am J Respir Cell Mol Biol

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“…Treatment with conventional vasodilators is not recommended because they may impair gas exchange due to the inhibition of hypoxic pulmonary vasoconstriction [241,242] and their lack of efficacy after long-term use [243,244]. Published experience with specific PAH drug therapy is scarce and consists of the assessment of acute effects [245,246] and uncontrolled studies in small series [247][248][249][250][251].…”

Section: Therapymentioning

confidence: 99%

Guidelines for the diagnosis and treatment of pulmonary hypertension

Hoeper¹,

Humbert²,

Torbicki³

et al. 2009

Eur Respir J

1,081

490

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“…3,4 Thus far, studies using selective and nonselective pulmonary vasodilators in COPD have not translated into improvements in meaningful clinical outcomes. [5][6][7][8][9][10][11] This has led to a renewed interest in the underlying pathogenesis of PH in COPD as a basis for determining the appropriateness of pursuing PH-specific therapies. 12 The pathogenesis of COPD-associated PH is complex.…”

Section: Introductionmentioning

confidence: 99%

Pulmonary Arterial Remodeling in Chronic Obstructive Pulmonary Disease is Lobe Dependent

et al. 2013

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Pulmonary arterial remodeling has been demonstrated in patients with severe chronic obstructive pulmonary disease (COPD), but it is not known whether lobar heterogeneity of remodeling occurs. Furthermore, the relationship between pulmonary hypertension (PH) and pulmonary arterial remodeling in COPD has not been established. Muscular pulmonary arterial remodeling in arteries 0.10-0.25 mm in diameter was assessed in COPD-explanted lungs and autopsy controls. Remodeling was quantified as the percentage wall thickness to vessel diameter (%WT) using digital image analysis. Repeat measures mixed-effects remodeling for %WT was performed according to lobar origin (upper and lower), muscular pulmonary arterial size (small, medium, and large), and echocardiography-based pulmonary arterial pressure (no PH, mild PH, and moderate-tosevere PH). Lobar perfusion and emphysema indices were determined from ventilationperfusion and computed tomography scans, respectively. Overall, %WT was greater in 42 subjects with COPD than in 5 control subjects (P < 0:0001 ). Within the COPD group, %WT was greater in the upper lobes (P < 0:0001 ) and in the small muscular pulmonary arteries (P < 0:0001 ). Lobar differences were most pronounced in medium and large arteries. Lobar emphysema index was not associated with arterial remodeling. However, there was a significant positive relationship between the lobar perfusion index and pulmonary arterial remodeling (P ¼ 0:024). The presence of PH on echocardiography showed only a trend to a small effect on lower lobe remodeling. The pattern of pulmonary arterial remodeling in COPD is complicated and lobe dependent. Differences in regional blood flow partially account for the lobar heterogeneity of pulmonary arterial remodeling in COPD.

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Sildenafil treatment in COPD does not affect stroke volume or exercise capacity

Cited by 125 publications

References 30 publications

Adenosine A2B Receptor and Hyaluronan Modulate Pulmonary Hypertension Associated with Chronic Obstructive Pulmonary Disease

Adenosine A2B Receptor and Hyaluronan Modulate Pulmonary Hypertension Associated with Chronic Obstructive Pulmonary Disease

Guidelines for the diagnosis and treatment of pulmonary hypertension

Pulmonary Arterial Remodeling in Chronic Obstructive Pulmonary Disease is Lobe Dependent

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