Cristine E. Berry

Xanthine oxidoreductase and cardiovascular disease: molecular mechanisms and pathophysiological implications

There is substantial evidence that oxidative stress participates in the pathophysiology of cardiovascular disease. Biochemical, molecular and pharmacological studies further implicate xanthine oxidoreductase (XOR) as a source of reactive oxygen species in the cardiovascular system. XOR is a member of the molybdoenzyme family and is best known for its catalytic role in purine degradation, metabolizing hypoxanthine and xanthine to uric acid with concomitant generation of superoxide. Gene expression of XOR is regulated by oxygen tension, cytokines and glucocorticoids. XOR requires molybdopterin, iron–sulphur centres, and FAD as cofactors and has two interconvertible forms, xanthine oxidase and xanthine dehydrogenase, which transfer electrons from xanthine to oxygen and NAD+, respectively, yielding superoxide, hydrogen peroxide and NADH. Additionally, XOR can generate superoxide via NADH oxidase activity and can produce nitric oxide via nitrate and nitrite reductase activities. While a role for XOR beyond purine metabolism was first suggested in ischaemia–reperfusion injury, there is growing awareness that it also participates in endothelial dysfunction, hypertension and heart failure. Importantly, the XOR inhibitors allopurinol and oxypurinol attenuate dysfunction caused by XOR in these disease states. Attention to the broader range of XOR bioactivity in the cardiovascular system has prompted initiation of several randomised clinical outcome trials, particularly for congestive heart failure. Here we review XOR gene structure and regulation, protein structure, enzymology, tissue distribution and pathophysiological role in cardiovascular disease with an emphasis on heart failure.

Xanthine Oxidoreductase Inhibition Causes Reverse Remodeling in Rats With Dilated Cardiomyopathy

Increased reactive oxygen species (ROS) generation is implicated in cardiac remodeling in heart failure (HF). As xanthine oxidoreductase (XOR) is 1 of the major sources of ROS, we tested whether XOR inhibition could improve cardiac performance and induce reverse remodeling in a model of established HF, the spontaneously hypertensive/HF (SHHF) rat. We randomized Wistar Kyoto (WKY, controls, 18 to 21 months) and SHHF (19 to 21 months) rats to oxypurinol (1 mmol/L; n=4 and n=15, respectively) or placebo (n=3 and n=10, respectively) orally for 4 weeks. At baseline, SHHF rats had decreased fractional shortening (FS) (31±3% versus 67±3% in WKY, P<0.0001) and increased left-ventricular (LV) end-diastolic dimension (9.7±0.2 mm versus 7.0±0.4 mm in WKY, P<0.0001). Whereas placebo and oxypurinol did not change cardiac architecture in WKY, oxypurinol attenuated decreased FS and elevated LV end-diastolic dimension, LV end-systolic dimension, and LV mass in SHHF. Increased myocyte width in SHHF was reduced by oxypurinol. Additionally, fetal gene activation, altered calcium cycling proteins, and upregulated phospho–extracellular signal–regulated kinase were restored toward normal by oxypurinol (P<0.05 versus placebo-SHHF). Importantly, SHHF rats exhibited increased XOR mRNA expression and activity, and oxypurinol treatment reduced XOR activity and superoxide production toward normal, but not expression. On the other hand, NADPH oxidase activity remained unchanged, despite elevated subunit protein abundance in treated and untreated SHHF rats. Together these data demonstrate that chronic XOR inhibition restores cardiac structure and function and offsets alterations in fetal gene expression/Ca2+ handling pathways, supporting the idea that inhibiting XOR-derived oxidative stress substantially improves the HF phenotype.

Mortality in COPD: Causes, Risk Factors, and Prevention

ABSTRACT Chronic obstructive pulmonary disease (COPD) is a leading and increasing cause of death, the extent of which is underestimated as a consequence of underdiagnosis and underreporting on death certificates. Data from large trials, such as the Lung Health Study, Towards a Revolution in COPD Health (TORCH), Understanding Potential Long-term Impacts on Function with Tiotropium (UPLIFT), European Respiratory Society Study on Chronic Obstructive Pulmonary Disease (EUROSCOP), and Inhaled Steroids in Obstructive Lung Disease (ISOLDE), have shown that the causes of death in patients with mild COPD are predominantly cancer and cardiovascular disease, but as COPD severity increases, deaths due to non-malignant respiratory disease are increasingly common. In practice, mortality of patients with COPD can be predicted by a variety of measures including: forced expiratory volume in one second (FEV1), the ratio of inspiratory and total lung capacities, exercise capacity, dyspnea scores, and composite indices such as the body-mass index (B), degree of airflow obstruction (O), degree of functional dyspnea (D), and exercise capacity (E) (BODE) index. Smoking cessation improves survival in COPD patients, and in select patients with advanced disease, oxygen therapy, lung volume reduction surgery, or lung transplantation may also improve survival.

Relationship Between Lung Function Impairment and Health-Related Quality of Life in COPD and Interstitial Lung Disease

BACKGROUND Health-related quality-of-life (HRQL) measures have been correlated with lung function in patients with COPD and interstitial lung disease (ILD). However, different pathophysiologic mechanisms may influence how these distinct diseases affect HRQL, resulting in differing HRQL by pulmonary diagnosis among patients with similar severity of ventilatory impairment. METHODS The National Heart, Lung, and Blood Institute Lung Tissue Research Consortium provided data on well-characterized participants with COPD (n = 576) and ILD (n = 405) at four clinical sites. Using multiple linear regression, we examined the effects of FEV₁ (% predicted) and diagnosis (ILD vs COPD) on HRQL scores, including total St. George Respiratory Questionnaire (SGRQ) scores and Short Form-12 (SF-12) physical component summary (PCS) and mental component summary (MCS) scores. RESULTS Participants with ILD had, on average, higher SGRQ scores (15.33 points; 95% CI, 12.46-18.19; P <.001) and lower SF-12 PCS scores (-4.73 points; 95% CI, -6.31 to -3.14; P <.001) compared with patients with COPD with similar FEV₁ % predicted values, indicating worse HRQL. The specific diagnosis also modified the effect of FEV₁ on the total SGRQ score (P = .003) and the SF-12 PCS score (P = .03). There was no relationship between lung function and SF-12 MCS scores. CONCLUSIONS HRQL scores were worse for patients with ILD compared with patients with COPD with similar degrees of ventilatory impairment. Differences in dyspnea mechanism or in the rate of disease progression may account for these differences in HRQL.

Interpretation of Pulmonary Function Test: Issues and Controversies

Pulmonary function testing (PFT) serves many purposes in clinical practice, and in contrast to other laboratory measures, PFT results are often provided with a clinical interpretation. PFT interpretation depends on the clinical context, and multiple challenges influence PFT interpretation. Overall, the goal of PFT interpretation is to distinguish normal from abnormal, and this is affected by the selection of reference standards, as well as the arbitrary albeit not necessarily irrational choice of cut-off values. Controversies regarding PFT analysis may lead to important differences in interpretation. In this article, issues associated with the selection of reference standards are discussed, followed by a review of the controversies related to PFT interpretation in the diagnosis of obstructive ventilatory defect, restrictive ventilatory defect, gas transfer defect, and flow-volume loop abnormalities. Given the challenges facing PFT interpretation, no single interpretative algorithm is sufficient; rather, PFT interpretation requires a comprehensive approach including consideration of the clinical context, laboratory methodology, and reference standards and an understanding of the consequences of a normal or abnormal designation.