Sandra Pizarro

Hemodynamic and gas exchange effects of sildenafil in patients with chronic obstructive pulmonary disease and pulmonary hypertension.

RATIONALE Sildenafil, a phosphodiesterase-5 inhibitor, could be useful for treating pulmonary hypertension (PH) in chronic obstructive pulmonary disease (COPD). However, vasodilators may inhibit hypoxic pulmonary vasoconstriction and impair gas exchange in this condition. OBJECTIVES To assess the acute hemodynamic and gas exchange effects of sildenafil in patients with COPD-associated PH. METHODS We conducted a randomized, dose comparison trial in 20 patients with COPD-associated PH. Eleven patients were assigned to 20 mg, and 9 patients to 40 mg, of sildenafil. Pulmonary hemodynamics and gas exchange, including ventilation-perfusion (V(A)/Q) relationships, were assessed at rest and during constant-work rate exercise, before and 1 hour after sildenafil administration. MEASUREMENTS AND MAIN RESULTS Both sildenafil doses reduced the mean pulmonary arterial pressure (PAP) at rest and during exercise, without differences between them. Overall, PAP decreased -6 mm Hg (95% confidence interval [95% CI], -7 to -4) at rest and -11 mm Hg (95% CI, -14 to -8) during exercise. After sildenafil, Pa(O(2)) decreased -6 mm Hg (95% CI, -8 to -4) at rest because of increased perfusion in units with low V(A)/Q ratio, without differences between doses. No change in Pa(O(2)) (95% CI, -3 to 0.2 mm Hg) or V(A)/Q relationships occurred during exercise after sildenafil. Changes induced by sildenafil in Pa(O(2)) and V(A)/Q distributions at rest correlated with their respective values at baseline. CONCLUSIONS In patients with COPD-associated PH, sildenafil improves pulmonary hemodynamics at rest and during exercise. This effect is accompanied by the inhibition of hypoxic vasoconstriction, which impairs arterial oxygenation at rest. The use of sildenafil in COPD should be done cautiously and under close monitoring of blood gases. Clinical trial registered with www.clinicaltrials.gov (NCT00491803).

Pulmonary Vascular Involvement in COPD

Alterations in pulmonary vessel structure and function are highly prevalent in patients with COPD. Vascular abnormalities impair gas exchange and may result in pulmonary hypertension, which is one of the principal factors associated with reduced survival in COPD patients. Changes in pulmonary circulation have been identified at initial disease stages, providing new insight into their pathogenesis. Endothelial cell damage and dysfunction produced by the effects of cigarette smoke products or inflammatory elements is now considered to be the primary alteration that initiates the sequence of events resulting in pulmonary hypertension. Cellular and molecular mechanisms involved in this process are being extensively investigated. Progress in the understanding of the pathobiology of pulmonary hypertension associated with COPD may provide the basis for a new therapeutic approach addressed to correct the imbalance between endothelium-derived vasoactive agents. The safety and efficacy of endothelium-targeted therapy in COPD-associated pulmonary hypertension warrants further investigation in randomized clinical trials.

Similar gene expression profiles in smokers and patients with moderate COPD.

Chronic obstructive pulmonary disease (COPD) is characterized by multiple cellular and structural changes affecting the airways, lung parenchyma and vasculature, some of which are also identified in smokers without COPD. The molecular mechanisms underlying these changes remain poorly understood. With the aim of identifying mediators potentially implicated in the pathogenic processes that occur in COPD and their potential relationship with cigarette smoking, we evaluated the mRNA expression of genes involved in inflammation, tissue remodeling and vessel maintenance. Lung tissue samples were obtained from 60 patients who underwent lung resection (nonsmokers, n=12; smokers, n=12; and moderate COPD, n=21) or lung transplant (severe-to-very severe COPD, n=15). PCR arrays containing 42 genes coding for growth factors/receptors, cytokines, metalloproteinases, adhesion molecules, and vessel maintenance mediators were used. Smoking-induced changes include the up-regulation of inflammatory genes (IL-1β, IL-6, IL-8, CCL2, and CCL8) and the decreased expression of growth factor/receptor genes (BMPR2, CTGF, FGF1, KDR and TEK) and genes coding for vessel maintenance factors (EDNRB). All these genes exhibited a similar profile in moderate COPD patients. The up-regulation of MMP1 and MMP9 was the main change associated with COPD. Inflammatory genes as well as the endothelial selectin gene (SELE) were down-regulated in patients with more severe COPD. Clustering analysis revealed a closer relationship between moderate COPD and smokers than between both subsets of COPD patients for this selected set of genes. The study reveals striking similarities between smokers and COPD patients with moderate disease emphasizing the crucial role of cigarette smoking in the genesis of these changes, and provides additional evidence of the involvement of the matrix metalloproteinases in the remodeling process of the lung in COPD.

Assessment of acute pulmonary vascular reactivity in portopulmonary hypertension

The role of acute pulmonary vasodilator testing in portopulmonary hypertension (PoPH), a current contraindication for orthotopic liver transplantation (OLT), has not been thoroughly elucidated. The purpose of this work was to analyze the results of acute vasodilator testing with inhaled nitric oxide (NO), to compare them with intravenous epoprostenol (PGI2), and to investigate the acute effects of the oral vasodilator isosorbide‐5‐mononitrate (Is‐5‐MN), in patients with PoPH. A total of 19 patients with PoPH (male/female = 9/10) were studied. Pulmonary hemodynamic measurements were performed at baseline and during NO inhalation (40 ppm); additionally, 15 patients were tested with PGI2 (2–12 μg/kg/minute) and 8 were tested with Is‐5‐MN (20–40 mg). Inhaled NO reduced pulmonary artery pressure (PAP) and pulmonary vascular resistance (PVR) by 5.7% and 11.0%, respectively. PGI2 elicited greater reductions in PAP (11.8%) and PVR (−24.0%), and produced a 28% drop in systemic vascular resistance (SVR) and a 17% increase in the cardiac index (CI). Is‐5‐MN reduced PAP by 25.6% and PVR by 21.5%, without systemic changes. There was good agreement between the response to PGI2 and Is‐5‐MN: 6 patients of the whole series (32%) decreased PAP >20% from baseline, reaching a final value ≤35 mmHg, the current limit for OLT. In conclusion, acute vasodilator testing has a relevant role in PoPH, as it identifies one‐third of patients able to reach a more favorable hemodynamic situation, which can be determinant for their management. For vasodilator testing, PGI2 is more suitable than NO in PoPH. Is‐5‐MN exerts a selective effect on pulmonary circulation in patients who had already responded to PGI2. Liver Transpl 13:1506–1514, 2007.

Circulating Progenitor Cells and Vascular Dysfunction in Chronic Obstructive Pulmonary Disease

Background In chronic obstructive pulmonary disease (COPD), decreased progenitor cells and impairment of systemic vascular function have been suggested to confer higher cardiovascular risk. The origin of these changes and their relationship with alterations in the pulmonary circulation are unknown. Objectives To investigate whether changes in the number of circulating hematopoietic progenitor cells are associated with pulmonary hypertension or changes in endothelial function. Methods 62 COPD patients and 35 controls (18 non-smokers and 17 smokers) without cardiovascular risk factors other than cigarette smoking were studied. The number of circulating progenitors was measured as CD45+CD34+CD133+ labeled cells by flow cytometry. Endothelial function was assessed by flow-mediated dilation. Markers of inflammation and angiogenesis were also measured in all subjects. Results Compared with controls, the number of circulating progenitor cells was reduced in COPD patients. Progenitor cells did not differ between control smokers and non-smokers. COPD patients with pulmonary hypertension showed greater number of progenitor cells than those without pulmonary hypertension. Systemic endothelial function was worse in both control smokers and COPD patients. Interleukin-6, fibrinogen, high sensitivity C-reactive protein, vascular endothelial growth factor and tumor necrosis factor were increased in COPD. In COPD patients, the number of circulating progenitor cells was inversely related to the flow-mediated dilation of systemic arteries. Conclusions Pulmonary and systemic vascular impairment in COPD is associated with cigarette smoking but not with the reduced number of circulating hematopoietic progenitors. The latter appears to be a consequence of the disease itself not related to smoking habit.

Effect of targeted therapy on circulating progenitor cells in precapillary pulmonary hypertension

BACKGROUND Endothelial dysfunction is key in the development of pulmonary hypertension (PH) and is associated with reduced number of circulating progenitor cells. Studies to date evaluating levels of circulating progenitor cells in PH have provided conflicting results. Current treatment of pulmonary arterial hypertension (PAH) and medical treatment of chronic thromboembolic pulmonary hypertension (CTEPH) targets endothelium dependent signalling pathways. The effect of PAH-targeted therapy on circulating progenitor cells has not been clearly established. OBJECTIVES To investigate whether levels of circulating progenitor cells in treatment-naïve patients with PAH or CTEPH differ from healthy subjects and to assess the effect of PAH-targeted therapy on the circulating levels of these progenitors. METHODS Thirty controls, 33 PAH and 11 CTEPH treatment-naïve patients were studied. Eighteen patients with PAH and 9 with CTEPH were re-evaluated 6-12months after starting PAH-targeted therapy. Levels of progenitors were measured by flow cytometry as CD45+CD34+ and CD45+CD34+CD133+ cells. RESULTS Compared with controls, the number of circulating progenitor cells was reduced in PAH but not in CTEPH. After 6-12months of treatment, levels of circulating progenitors increased in PAH and remained unchanged in CTEPH. Patients with lower exercise tolerance presented lower levels of circulating progenitors. No other relation was found between levels of progenitors and clinical or hemodynamic parameters. CONCLUSIONS Patients with PAH, but not those with CTEPH, present reduced levels of circulating progenitor cells. PAH-targeted therapy increases levels of progenitors in PAH but not in CTEPH, suggesting different involvement of progenitor cells in the pathobiology of these pulmonary hypertensive disorders.