Takayuki Sugai

Association of plasma xanthine oxidoreductase activity with severity and clinical outcome in patients with chronic heart failure

BACKGROUND Oxidative stress due to purine degradation is associated with the development of chronic heart failure (CHF). Xanthine oxidoreductase (XOR) is a rate-limiting enzyme of purine degradation that plays a key role in uric acid (UA) production with a resultant increase in reactive oxygen species. However, the relationship between plasma XOR activity and CHF severity and clinical outcome remains unclear. METHODS AND RESULTS We measured XOR activity in 440 patients with CHF and 44 control subjects. Abnormally high and low XOR activities were identified based on the results for 95% of the control subjects (high and low XOR activities ≥120 and <33pmol/100μL/h, respectively). The prevalence rates of high and low XOR activities increased with advancing New York Heart Association functional class. There were 158 cardiac events during a median follow-up period of 1034days. Multivariate Cox proportional hazard regression analysis showed that both high and low XOR activities were significantly associated with cardiac events in patients with CHF after adjustment for confounding risk factors including serum UA and loop diuretic use. Kaplan-Meier analysis revealed that the cardiac event rate was significantly higher in patients with either high or low XOR activity. The net reclassification index was significantly improved by adding XOR activity to the basic risk factors. CONCLUSIONS We provide the first evidence of an association of plasma XOR activity with CHF severity and clinical outcome. Plasma XOR activity could be used to identify high-risk CHF patients and could be a therapeutic target for XOR inhibitors.

Impact of Objective Malnutrition Status on the Clinical Outcomes in Patients With Peripheral Artery Disease Following Endovascular Therapy

BACKGROUND Peripheral artery disease (PAD) is an athero-occlusive disease and a known risk factor for cardiovascular events. The controlling nutritional status (CONUT) score and geriatric nutritional risk index (GNRI) are objective tools for evaluating malnutrition and are reportedly associated with poor clinical outcomes in patients with fatal diseases. However, the effect of malnutrition on the clinical outcomes in patients with PAD remains unclear.Methods and Results:We enrolled 357 patients with PAD who underwent endovascular therapy. Malnutrition was diagnosed by CONUT score and GNRI as in previous reports. During a median follow-up period of 1,071 days, there were 67 major adverse cardiovascular and leg events (MACLEs). The CONUT score- and GNRI-based malnutrition statuses were identified in 56% and 46% of the patients, respectively. Proportion of malnutrition increased with advancing Fontaine class. The multivariate Cox proportional hazard regression analysis demonstrated that both the CONUT score- and GNRI-based malnutrition status was an independent predictor of MACLEs. The Kaplan-Meier analysis demonstrated that the MACLE ratio increased with deteriorating malnutrition. Finally, the addition of the CONUT score or GNRI to the known risk factors significantly improved the net reclassification index and integrated discrimination index. CONCLUSIONS Malnutrition was common and closely associated with the clinical outcomes in patients with PAD, indicating that it is a novel therapeutic target in the management of these patients.

Deficiency of Senescence Marker Protein 30 Exacerbates Cardiac Injury after Ischemia/Reperfusion

Early myocardial reperfusion is an effective therapy but ischemia/reperfusion (I/R) causes lethal myocardial injury. The aging heart was reported to show greater cardiac damage after I/R injury than that observed in young hearts. Senescence marker protein 30 (SMP30), whose expression decreases with age, plays a role in reducing oxidative stress and apoptosis. However, the impact of SMP30 on myocardial I/R injury remains to be determined. In this study, the left anterior descending coronary artery was occluded for 30 min, followed by reperfusion in wild-type (WT) and SMP30 knockout (KO) mice. After I/R, cardiomyocyte apoptosis and the ratio of infarct area/area at risk were higher, left ventricular fractional shortening was lower, and reactive oxygen species (ROS) generation was enhanced in SMP30 KO mice. Moreover, the previously increased phosphorylation of GSK-3β and Akt was lower in SMP30 KO mice than in WT mice. In cardiomyocytes, silencing of SMP30 expression attenuated Akt and GSK-3β phosphorylation, and increased Bax to Bcl-2 ratio and cardiomyocyte apoptosis induced by hydrogen peroxide. These results suggested that SMP30 deficiency augments myocardial I/R injury through ROS generation and attenuation of Akt activation.

Ventricular wall stress and silent myocardial damage are associated with pulse pressure in the general population

Pulse pressure (PP) is a risk factor for cardiovascular diseases and is associated with increased afterload and myocardial oxygen demand. Brain natriuretic peptide (BNP) and heart‐type fatty acid–binding protein (H‐FABP) are known as biomarkers indicating ventricular wall stress and silent myocardial damage. However, the association between PP and ventricular wall stress and silent myocardial damage in the general population is unclear. The authors enrolled 3504 patients who participated in a community‐based annual health check. Serum levels of BNP and H‐FABP were measured as markers of ventricular wall stress and silent myocardial damage. Patients were divided into four groups according to the quartiles of PP. Patients in the highest PP group showed higher serum BNP and H‐FABP levels than that of the other groups. Multivariate logistic analysis showed that high PP was independently associated with ventricular wall stress and silent myocardial damage on the basis of BNP and H‐FABP levels. Compared with systolic blood pressure, diastolic blood pressure, and mean blood pressure, PP was superior in predicting ventricular wall stress and silent myocardial damage evaluated according to BNP and H‐FABP levels, which was reflected by the receiver operating characteristic analysis. Screening of healthy patients revealed that high PP was related to high BNP and H‐FABP levels, suggesting that an asymptomatic general population with high PP may be exposed to ventricular wall stress and myocardial damage and might be susceptible to silent heart failure.

Increased plasma xanthine oxidoreductase activity deteriorates coronary artery spasm

Increased reactive oxygen species (ROS) contributes to the development of endothelial dysfunction, which is involved in coronary artery spasm (CAS). Xanthine oxidoreductase (XOR) plays a pivotal role in producing both uric acid and ROS. However, the association between plasma XOR activity and CAS has not been elucidated. The aim of this study was to investigate whether plasma XOR activity is associated with CAS. We measured XOR activity in 104 patients suspected for CAS, who presented without significant coronary artery stenosis and underwent intracoronary acetylcholine provocation tests. CAS was provoked in 44 patients and they had significantly higher XOR activity as compared with those without CAS. The patients were divided into three groups based on the XOR activity. The prevalence rate of CAS was increased with increasing XOR activity. A multivariate logistic regression analysis showed that the 3rd tertile group exhibited a higher incidence of CAS as compared with the 1st tertile group [odds ratio (OR) 6.9, P = 0.001) and the 2nd tertile group (OR 3.2, P = 0.033) after adjustment for conventional CAS risk factors, respectively. The C index was significantly improved by the addition of XOR activity to the baseline model based on CAS risk factors. Furthermore, the 3rd tertile group had the highest incidence of severe spasm defined as total obstruction, flow-limiting stenosis, diffuse spasm, multivessel spasm, and/or lethal arrhythmia. This is a first report to elucidate the association of plasma XOR activity with CAS. Increased plasma XOR activity is significantly associated with CAS.