Topiroxostat versus allopurinol in patients with chronic heart failure complicated by hyperuricemia: A prospective, randomized, open-label, blinded-end-point clinical trial.

BACKGROUND: The benefits of xanthine oxidase inhibitors to chronic heart failure (CHF) patients is controversial. We investigated the beneficial effects of a novel xanthine oxidoreductase inhibitor, topiroxostat, in patients with CHF and hyperuricemia (HU), in comparison to allopurinol. METHODS AND RESULTS: The prospective, randomized open-label, blinded-end-point study was performed in 141 patients with CHF and HU at 4 centers. Patients were randomly assigned to either topiroxostat or allopurinol group to achieve target uric acid level ≤6.0 mg/dL. According to the protocol, 140 patients were followed up for 24 weeks. Percent change in ln (N-terminal-proB-type natriuretic peptide) at week 24 (primary endpoint) was comparable between topiroxostat and allopurinol groups (1.6±8.2 versus -0.4±8.0%; P = 0.17). In the limited number of patients with heart failure with reduced ejection fraction (HFrEF) (left ventricle ejection fraction <45%), ratio of peak early diastolic flow velocity at mitral valve leaflet to early diastolic mitral annular motion velocity (E/e') decreased in topiroxostat group, but not in allopurinol group. Urinary 8-hydroxy-2'-deoxyguanosine and L-type fatty acid-binding protein levels increased and osmolality decreased significantly in allopurinol group, while these changes were less or absent in topiroxostat group. In allopurinol group HFrEF patients, additional to the increases in these urinary marker levels, urinary creatinine levels decreased, with no change in clearance, but not in topiroxostat group. CONCLUSIONS: Compared with allopurinol, topiroxostat did not show great benefits in patients with CHF and HU. However, topiroxostat might have potential advantages of reducing left ventricular end-diastolic pressure, not worsening oxidative stress in proximal renal tubule, and renoprotection over allopurinol in HFrEF patients.

Reduction of door-to-balloon time in patients with ST-elevation myocardial infarction by single-catheter primary percutaneous coronary intervention method.

OBJECTIVES: The objectives of this study is to confirm reduction of door-to-balloon (D2B) time with single-catheter percutaneous coronary intervention (SC-PCI) method. BACKGROUND: Reduction of total ischemic time is important in the emergency treatment of ST-elevation myocardial infarction (STEMI). There have been no established methods in primary percutaneous coronary intervention (PCI) to shorten ischemic time via radial access. Ikari left curve was reported as a universal guiding catheter for left and right coronary arteries. Several procedure steps can be skipped by SC-PCI method as the advantage of a universal catheter. METHODS: This study is a retrospective analysis of a total of 1,275 consecutive STEMI cases treated with primary PCI in 14 hospitals. Patients were divided into two groups, SC-PCI method (n = 298) and conventional PCI method (n = 977). Primary endpoints were door-to-balloon (D2B) time and radiation exposure dose. RESULTS: The mean age was 68 ± 13 years old. Radial access was used in 85% of participants. PCI success was achieved in 99.5% of participants and the SC-PCI method was successfully performed in 92.6%. The D2B time was shorter (68 ± 46 vs. 74 ± 50 min, respectively; p = .02), and the radiation exposure dose was lower (1,664 ± 970 vs. 2008 ± 1,605 mGy, respectively; p < .0001) in the SC-PCI group than in the conventional group. CONCLUSION: Primary PCI with SC-PCI method for patients with STEMI demonstrated shorter D2B time and lower radiation exposure dose.

Usefulness of dual-axis rotational coronary angiography in primary percutaneous coronary intervention for patients with ST-elevation myocardial infarction.

Several studies have shown that dual-axis rotational coronary angiography (DARCA) reduces contrast medium volume and radiation exposure compared to conventional coronary angiography (CCA). However, there are no studies comparing the safety and usefulness of DARCA in primary percutaneous coronary intervention (PCI) for patients with ST-elevation myocardial infarction (STEMI). The aim of this study was to investigate the effects of DARCA on contrast medium volume, radiation exposure, time course of treatment, and adverse events in primary PCI for patients with STEMI. A total of 82 patients undergoing primary PCI were included in this study. Subjects were propensity matched to 41 patients in the CCA group and 41 in the DARCA group. Data were retrospectively collected from in-patient medical records and the contrast medium volume and radiation exposure (dose-area product, DAP) during the PCI procedure was compared between the two groups. Contrast medium volume [100.0 (82.5-115.0) vs 110 (102.5-127.5) ml, p = 0.018, r = 0.26] and DAP [113.4 (74.3-141.1) vs 138.1 (100.5-194.7) Gy cm2, p = 0.014, r = 0.27] were significantly lower in the DARCA group, compared with the CCA group. Door to device time (68.7 ± 26.1 vs 76.5 ± 44.2 min, p = 0.33) were comparable between the two groups. There were no adverse events requiring treatment reported in either groups. DARCA may reduce contrast medium volume and radiation exposure in primary PCI for patients with STEMI, and can be used safely, without delaying reperfusion of the infarct-related coronary artery.

The effects of xanthine oxidase inhibitor in patients with chronic heart failure complicated with hyperuricemia: a prospective randomized controlled clinical trial of topiroxostat vs allopurinol-study protocol.

BACKGROUND: Hyperuricemia has a close relationship with cardiovascular diseases including heart failure. However, it is controversial whether xanthine oxidase inhibition has benefits for patients with chronic heart failure. We designed the Effect of Xanthine Oxidase Inhibitor in Chronic Heart Failure Patients Complicated with Hyperuricemia study (Excited-UA study) to compare the beneficial effects between a novel xanthine oxidoreductase inhibitor, topiroxostat, and a conventional agent, allopurinol, in patients with chronic heart failure and hyperuricemia. We focus on serum N-terminal pro-brain natriuretic peptide (NT-proBNP) level, echocardiography-based cardiac function, vascular endothelial function, renal function, inflammation, and oxidative stress. METHODS: The excited-UA is a prospective, randomized, open-label, blinded-endpoint clinical trial designed to prove our hypothesis that topiroxostat is more effective than allopurinol in patients with chronic heart failure and hyperuricemia. A total of 140 patients with chronic heart failure and hyperuricemia (plasma brain natriuretic peptide level ≥ 40 pg/mL and serum uric acid level ≥ 7.0 mg/dL) are randomly assigned (ratio 1:1) into either the topiroxostat group (40-160 mg/day) or allopurinol group (100-300 mg/day), to achieve the target uric acid level of 6.0 mg/dL. According to the protocol, all patients are followed up annually for 24 weeks. The primary endpoint is percent change in serum NT-proBNP level at 24 weeks from baseline. CONCLUSIONS: The Excited-UA study would provide novel evidence for the clinical relevancy of xanthine oxidoreductase inhibitor treatment in patients with chronic heart failure and hyperuricemia.

Rationale and Design of Low-dose Administration of Carperitide for Acute Heart Failure (LASCAR-AHF).

BACKGROUNDS: Despite current therapies, acute heart failure (AHF) remains a major public health burden with high rates of in-hospital and post-discharge morbidity and mortality. Carperitide is a recombinantly produced intravenous formulation of human atrial natriuretic peptide that promotes vasodilation with increased salt and water excretion, which leads to reduction of cardiac filling pressures. A previous open-label randomized controlled study showed that carperitide improved long-term cardiovascular mortality and heart failure (HF) hospitalization for patients with AHF, when adding to standard therapy. However, the study was underpowered to detect a difference in mortality because of the small sample size. METHODS: Low-dose Administration of Carperitide for Acute Heart Failure (LASCAR-AHF) is a multicenter, randomized, open-label, controlled study designed to evaluate the efficacy of intravenous carperitide in hospitalized patients with AHF. Patients hospitalized for AHF will be randomly assigned to receive either intravenous carperitide (0.02 µg/kg/min) in addition to standard treatment or matching standard treatment for 72 h. The primary end point is death or rehospitalization for HF within 2 years. A total of 260 patients will be enrolled between 2013 and 2018. CONCLUSION: The design of LASCAR-AHF will provide data of whether carperitide reduces the risk of mortality and rehospitalization for HF in selected patients with AHF.

Varenicline-assisted smoking cessation decreases oxidative stress and restores endothelial function.

Smoking cessation decreases oxidative stress and restores vascular endothelial function. However, a recent meta-analysis suggests that the use of varenicline, a α4ß2 nicotinic acetylcholine receptor partial agonist, increases the risk of cardiovascular events. This study was designed to determine the effect of varenicline-assisted smoking cessation on vascular endothelial function. Study subjects were 11 healthy Japanese males (mean age, 54.4 years) without evidence of cardiovascular disease who were eager to quit smoking. Each subject was treated with varenicline titrated up to 1.0 mg twice daily. We evaluated serum derivatives of reactive oxygen metabolites (d-ROMs) as a marker of oxidative stress, and flow-mediated dilation (FMD) of the brachial artery as a marker of vascular endothelial function. Both measurements were performed before and 3 months after completing smoking cessation. All subjects gained weight (average, 1.7 kg) after smoking cessation. However, there were no significant differences in the following parameters before and after smoking cessation: systolic blood pressure, diastolic blood pressure, heart rate, triglycerides, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, glucose and hemoglobin A1c. Serum d-ROM levels significantly decreased from 340.7±70.4 to 300.0±43.2 U.CARR (P=0.012), and FMD significantly increased from 3.36±1.26 to 5.25±1.33% (P=0.00067) after smoking cessation. There was an inverse correlation between FMD and serum d-ROM levels (R=-0.377; P=0.043). Our observations suggest that varenicline-assisted smoking cessation restores vascular endothelial function, and this is associated with decreased oxidative stress, despite an increase in body weight. As varenicline-assisted smoking cessation possibly has beneficial effects on vascular endothelial function, it might also reduce cardiovascular risk.

Two-week administration of rivaroxaban resolved left atrial thrombus.

An 89-year-old man visited our hospital complaining of palpitation. Electrocardiography showed atrial fibrillation, and transthoracic echocardiography demonstrated a mobile thrombus of 28.6 mm × 20.8 mm in the left atrium. Administration of a direct factor Xa inhibitor rivaroxaban (10 mg/day) was started. The thrombus reduced its size and disappeared completely 2 weeks after the commencement of rivaroxaban treatment. To our knowledge, this is the first case report that rivaroxaban successfully dissolved left atrial thrombus during a short period. Rivaroxaban might have a potential, not only to prevent de novo thrombus formation, but also to dissolve established thrombi by direct inhibition of free and thrombus-associated factor Xa. .

Torsade de pointes associated with the combination of solifenacin and clenbuterol for urinary incontinence.

A 79-year-old woman undergoing medical treatment with solifenacin and clenbuterol for urinary incontinence was admitted to our hospital because of recurrent syncope. Her syncope appeared one month after the doses of clenbuterol were increased. Torsade de pointes (TdP) was evident on her Holter electrocardiogram at the time when she developed syncope. Ultimately, a cardioverter-defibrillator with dual chamber pacing capability was implanted. To our knowledge, this is the first report of TdP associated with the combination of solifenacin and clenbuterol for urinary incontinence. .

The Japanese experience with sirolimus-eluting stent implantation in the infarct-related artery: five years of observation from the J-PMS study.

BACKGROUND: Long-term outcome and safety concerns regarding drug-eluting stents (DES) for acute myocardial infarction (AMI) treatment is still debated. METHODS AND RESULTS: We analyzed data from 1937 patients with complete 5-year follow-up (94.5%) from a multicenter registry of sirolimus-eluting stents (J-PMS). The patients were divided into 2 groups: AMI (n=133) and non-AMI (n=1804) by clinical presentation of index procedure, and compared the outcomes. At 5-year follow-up, there were no significant differences in major adverse cardiac events (MACE), death, MI, or stent thrombosis between the groups. However, target vessel related events (TVF; revascularization, cardiac death, MI, thrombosis) were higher in the non-AMI group (p=0.03). In the early phase (0-6 months), MACE and death/MI were higher in the AMI group (6.0% vs. 3.0%; p=0.02 and 6.8% vs. 2.1%; p<0.001). However, in the late phase (6-60 months), there was a difference in TVF between the 2 groups, with a steady increase in the non-AMI group (p=0.03). Over 60% of patients with AMIs were started on dual antiplatelet therapy after stent implantation or on the same day. However, dual anti-platelet therapy duration was similar (867 ± 18 days in the AMI and 727 ± 57 days in the non-AMI group, p=0.5). Frequency of bleeding was similar. CONCLUSION: Five-year observation of AMI treatment using drug-eluting stent compared with non-AMI has no clinical disadvantage.

A rare connection by newly formed conduit vessels between the left internal mammalian artery and radial artery bypass grafts after failure of grafts.

Neovascularization such as formation of collateral vessels following total occlusion of native coronary artery is common in coronary artery disease. This is a case report of a very rare connection by newly formed conduit vessels between the left internal mammalian artery and the radial artery establishing bypass, which occurred after failure of bypass grafts.

Plasma microRNA 499 as a biomarker of acute myocardial infarction.

BACKGROUND: MicroRNAs (miRNAs) are endogenous small RNAs 21-25 nucleotides in length. Recently, we reported that miRNA 208 (miR-208) is produced exclusively in the rat myocardium and that plasma miR-208 is a biomarker of myocardial injury in rats. In the present study, we assessed the hypothesis that plasma concentrations of myocardial-specific miRNAs can be used to diagnose myocardial injury in humans. METHODS: We used array analysis of miRNA production in various human tissues to identify heart-specific miRNAs. We assessed the plasma concentrations of miR-499 in 14 individuals with acute coronary syndromes, 15 individuals with congestive heart failure, and 10 individuals without cardiovascular diseases. Plasma miR-499 concentrations were measured with a real-time reverse-transcription PCR method that used an artificial small RNA as an internal calibrator. RESULTS: The miRNA array analysis of various human tissues indicated that miR-499 was produced almost exclusively in the heart. Plasma miR-499 concentrations were measurably increased in all individuals with acute myocardial infarction but were below the limit of detection for all individuals in the other patient groups. CONCLUSIONS: The plasma concentration of miR-499 may be a useful biomarker of myocardial infarction in humans.