Cyclophilin A (CyPA) is secreted from vascular smooth muscle cells, inflammatory cells, activated platelets, and cardiac fibroblasts in response to oxidative stress. Excessive and continuous activation of the RhoA/Rho-kinase system promotes the secretion of CyPA, resulting in the development of multiple cardiovascular diseases. Basigin (Bsg), a transmembrane glycoprotein that activates matrix metalloproteinases, is an extracellular receptor for CyPA that promotes cell proliferation and inflammation. Thus, the CyPA/Bsg system is potentially a novel therapeutic target for cardiovascular diseases. Importantly, plasma CyPA levels are increased in patients with coronary artery disease, abdominal aortic aneurysms, pulmonary hypertension, and heart failure. Moreover, plasma CyPA levels can predict all-cause death in patients with coronary artery disease and pulmonary hypertension. Additionally, plasma soluble Bsg levels are increased and predict all-cause death in patients with heart failure, suggesting that CyPA and Bsg are novel biomarkers for cardiovascular diseases. To discover further novel molecules targeting the CyPA/Bsg system, high-throughput screening of compounds found molecules that ameliorate the development of cardiovascular diseases. In addition to CyPA and Bsg, novel therapeutic targets and their inhibitors for patients with pulmonary arterial hypertension have been recently screened and identified. Ultimately, the final goal is to develop novel biomarkers and medications that will be useful for improving the prognosis and quality of life in patients with cardiovascular diseases.

Patients receiving vitamin K antagonists (VKAs) are at increased risk of bleeding. Intracranial hemorrhage (ICH) is a major cause of morbidity and mortality in this population, and is a particular concern among Japanese clinicians, given reports of an elevated risk of this bleeding type in patients of Asian ethnicity. Patients with VKA-associated ICH require rapid international normalized ratio (INR) reversal, and treatment guidelines suggest the use of prothrombin complex concentrates (PCCs) or plasma for this purpose. Although European and US guidelines recommend PCCs for the treatment of VKA-associated major bleeding, they do not make a specific recommendation in the setting of ICH, owing to the lack of comparative evidence. In contrast, Japanese guidelines recommend the use of PCCs rather than plasma for VKA reversal in patients with ICH; however, these agents are not currently licensed in Japan for this indication. Here we review the available evidence on the use of PCCs for the treatment of VKA-associated ICH, both globally and specifically in Japanese settings. Overall, the evidence reviewed here supports the use of PCC for rapid VKA reversal in these patients.

Background:An atrial fibrillation (AF) risk score for a non-Western general population has not been established.

Methods and Results:A total of 6,898 participants (30–79 years old) initially free of AF have been prospectively followed for incident AF since 1989. AF was diagnosed when AF or atrial flutter was present on ECG at a biannual health examination; was indicated as a current illness; or was in the medical records during follow-up. Cox proportional hazard ratios were analyzed after adjusting for cardiovascular risk factors at baseline. During the 95,180 person-years of follow-up, 311 incident AF events occurred. We developed a scoring system for each risk factor as follows: 0/−5, 3/0, 7/5, and 9/9 points for men/women in their 30 s–40 s, 50 s, 60 s, and 70 s, respectively; 2 points for systolic hypertension, overweight, excessive drinking, or coronary artery disease; 1 point for current smoking; −1 point for moderate non-high-density lipoprotein-cholesterol; 4 points for arrhythmia; and 8, 6, and 2 points for subjects with cardiac murmur in their 30 s–40 s, 50 s, and 60 s, respectively (C-statistic 0.749; 95% confidence interval, 0.724−0.774). Individuals with score ≤2, 10–11, or ≥16 points had, respectively, ≤1%, 9%, and 27% observed probability of developing AF in 10 years.

Conclusions:We developed a 10-year risk score for incident AF using traditional risk factors that are easily obtained in routine outpatient clinics/health examinations without ECG.

Background:A global study designed to demonstrate the safety and efficacy of a transcatheter pacing system included 38 Japanese patients enrolled at 4 sites. Subgroup analysis to evaluate the performance of the leadless intracardiac transcatheter pacing system in Japanese patients was performed.

Methods and Results:Safety and efficacy outcomes, patient and implant procedure characteristics, and patient and physician acceptability from the Japanese population were compared with those from outside Japan. Differences in patient characteristics, implant procedure characteristics and patient acceptability were observed. There were no major complications in Japanese patients and pacing thresholds remained low and stable throughout follow-up. There were no observable differences between Japanese patients and patients from outside Japan in the freedom from major complication rate at 12-months post-implant (100.0% vs. 95.7%, P=0.211) or physician acceptability.

Conclusions:Although some differences in specific baseline characteristics, such as body size and pacing indication, and in implant procedure characteristics, including anticoagulation strategy and hospitalization period, were observed in the Japanese patients, transcatheter pacemaker performance was similar to that in the global trial. (Clinical Trial Registration: ClinicalTrials.gov ID NCT02004873.)

Background:Durable pulmonary vein isolation (PVI) is critical in reducing recurrence after radiofrequency catheter ablation for atrial fibrillation (AF). The VISITAG Module, an automatic annotation system that takes account of catheter stability and contact force (CF), might be useful in accomplishing this.

Methods and Results:In 49 patients undergoing VISITAG-guided AF ablation (group A), we set the following automatic annotation criteria: catheter stability range of motion ≤1.5 mm, duration ≥5 s, CF ≥5 g, time ≥25% and tag diameter at 6 mm. We used ablation >20 s and force-time integral >150 gs at each site, then moved to the next site where a new tag appeared that overlapped with the former tag. Results and outcome were retrospectively compared for 42 consecutive patients undergoing CF-guided AF ablation without this algorithm (group B). Successful PVI at completion of the initial anatomical line was more frequent in group A than B (66.3% vs. 36.9%, P=0.0006) while spontaneous PV reconnection was less frequent (14.2% vs. 30.9%, P=0.0014) and procedure time was shorter (138±35 min vs. 180±44 min, P<0.001). One-year success rate off anti-arrhythmic drugs was higher in group A (91.8% vs. 69.1%, log rank P=0.0058).

Conclusions:An automated annotation algorithm with an optimal setting reduced acute resumption of left atrium-PV conduction, shortened procedure time, and improved AF ablation outcome.

Background:Several reports have demonstrated the importance of severely low voltage areas as arrhythmogenic substrates of ventricular tachycardia (VT). However, a comparative study of dense scar-targeted and infarcted border zone-targeted strategies has not been reported.

Methods and Results:We divided 109 consecutive patients with VT post-infarction from 6 centers into 2 groups according to the ablation strategy used: dense scar-targeted ablation (DS ablation, 48%) or border zone-targeted ablation (BZ ablation, 52%). During DS ablation, we attempted to identify VT isthmuses in the dense scar areas (≤0.6 mV) using detailed pace mapping, and linear ablation lesions were applied mainly to those areas. During BZ ablation, linear ablation of standard low voltage areas (0.5–1.5 mV) was performed along with good pace map sites of the clinical VT. Acute success was defined as complete success (no VTs inducible) or partial success (clinical VT was noninducible). The acute complete success rate was significantly higher for DS ablation than for BZ ablation (62% vs. 42%, P=0.043). During a median follow-up of 37 months, the VT-free survival rate was significantly higher for DS ablation than for BZ ablation (80% vs. 58% at 48 months; log-rank P=0.038).

Conclusions:DS ablation may be a more effective therapy for post-infarction VT than BZ ablation in terms of the acute complete success rate and long-term follow-up.

Background:Diminishing yellow color is associated with plaque stabilization. We assessed the hypothesis that a combination of ezetimibe and statin provides more effective plaque stabilization and regression than statin alone as assessed by plaque color.

Methods and Results:Stable coronary artery disease patients (n=131) who underwent elective percutaneous coronary intervention and had yellow plaques were randomized to combination therapy (atorvastatin 10–20 mg and ezetimibe 10 mg/day; Group C) or statin monotherapy (atorvastatin 10–20 mg; Group M). Changes in plaque color and plaque volume during 9 months were assessed by angioscopy and intravascular ultrasound. Low-density lipoprotein cholesterol (LDL-C) decreased from 103±28 to 63±18 mg/dL in Group C (P<0.001) and from 100±28 to 75±17 mg/dL in Group M (P<0.001). Yellow color grade decreased significantly in both Group M (2.1±1.1 vs. 1.7±1.0, P=0.005) and Group C (2.2±1.2 vs. 1.8±1.2, P=0.002), but did not differ between the groups. %plaque volume did not change in Group M (48.5±10.2% vs. 48.2±10.4%, P=0.4), but decreased significantly in Group C (50.0±9.8% vs. 49.3±9.8%, P=0.03).

Conclusions:Compared with statin monotherapy, combination therapy with ezetimibe further reduced LDL-C levels. Significant plaque volume reduction was achieved by the combination therapy, but not statin monotherapy; however, plaque stabilization was similarly achieved by both therapies. Furthermore, reduction in plaque volume was dependent on reduction in LDL-C, regardless of whether it was achieved by statin alone or statin plus ezetimibe.

Background:Coronary artery bypass grafting (CABG) reduces functional mitral regurgitation (MR) associated with ischemic heart disease, although the predictive factors or mechanisms of reversibility of functional MR after CABG are not fully understood.We investigated whether mitral valve structure is associated with the outcome of functional MR after CABG.

Methods and Results:From a consecutive series of 98 patients with mild-moderate functional MR preoperatively who underwent isolated CABG, we enrolled 66 patients who were followed up for >1 year postoperatively using echocardiography. The degree of MR was reduced in 34 patients (52%) postoperatively, in association with a lower rate of in-hospital treatment for cardiac failure in the long term, compared with the 32 patients (48%) with residual MR postoperatively. The patients with reduced MR postoperatively had longer estimated coaptation length and more anteriorly or centrally directed MR jets than those without reduced MR. On statistical analysis, the addition of estimated coaptation length and jet direction to the reported predictors (ejection fraction, left ventricular end-diastolic dimension, and tenting height) more accurately predicted changes in post-CABG MR than the reported 3 factors alone.

Conclusions:Residual MR was associated with the emergence of congestive heart failure in the long term after CABG. A specific mitral valve structure, such as large mitral leaflet size or predominant tethering of the posterior leaflet, was a predictive factor for the reversibility of post-CABG functional MR.

Background:The Alberta Stroke Program Early CT Score (ASPECTS) is used to assess early ischemic stroke damage. This study compared bilateral ASPECTS (ASPECTS-b) with the gray:white matter ratio (GWR) and quantitative regional abnormality (QRA) to evaluate the prognostic utility of early computed tomography (CT) findings in post-cardiac arrest patients.

Methods and Results:Out-of-hospital cardiac arrest patients with return of spontaneous circulation (ROSC) who underwent brain CT (<6 h after onset) and therapeutic hypothermia were recruited from a university hospital over a 2-year period. General demographics, ROSC characteristics, ASPECTS-b (total score=20 points), GWR, and QRA were assessed. Multivariate logistic regression analysis was used to predict neurologic outcome using cerebral performance category (CPC) at 1 month. The study population was divided into good (n=20; CPC 1–2) and poor (n=47; CPC 3–5) outcome groups. The good (vs. poor) outcome group was younger (mean [±SD] age 46.7±11.8 vs. 60.3±17.2 years; P=0.002) and had more initial shockable rhythms (40.0% vs. 8.5%; P=0.002). In addition, the good outcome group had a higher mean ASPECTS-b score (15.3±2.7 vs. 9.0±4.9; P<0.001), despite no differences in QRA and mean GWR. Age and ASPECTS-b were independent predictors of outcome after adjusting for potential confounders.

Conclusions:These findings suggest that an initial CT score (ASPECTS-b) could help estimate early neurologic outcomes in post-cardiac arrest patients treated with therapeutic hypothermia.

Background:This study determined the current status of the incidence, management, and prognosis of stroke in Japan using a population-based stroke registry.

Methods and Results:Shiga Stroke Registry is an ongoing population-based registry that covers approximately 1.4 million residents of Shiga Prefecture. Cases of acute stroke were identified using standard definitions through surveillance of both all acute-care hospitals with neurology/neurosurgery facilities and death certificates in 2011. A total of 2,956 stroke cases and 2,176 first-ever stroke cases were identified. The age- and sex-adjusted incidence rate for first-ever stroke using the 2013 European Standard Population as standard was per 100,000 person-years: 91.3 for ischemic stroke, 36.4 for intracerebral hemorrhage, and 13.7 for subarachnoid hemorrhage. It was estimated that approximately 220,000 new strokes occurred in 2011 in Japan. Among the 2,956 cases, most stroke patients underwent neuroimaging, 268 received surgical or endovascular treatment, and 2,158 had rehabilitation therapy; 78 patients received intravenous thrombolysis. A total of 1,846 stroke patients had died or were dependent at hospital discharge, and 390 died within 28 days of onset.

Conclusions:Incidence rates of stroke by subtypes were clarified and the total number of new strokes in Japan was estimated. More than half of stroke patients die or become dependent after a stroke. This study re-emphasized the importance of public health measures in reducing the burden of stroke in Japan.

Background:The association of morning and evening home blood pressures (HBPs) with carotid atherosclerosis has been uncertain in general populations, so we aimed to investigate it in a general Japanese population.

Methods and Results:We performed a cross-sectional survey of 2,856 community-dwelling individuals aged ≥40 years to examine the association of morning and evening HBPs with carotid mean intima-media thickness (IMT). The age- and sex-adjusted geometric averages of carotid mean IMT increased significantly with increasing morning HBP (optimal: 0.67 mm; normal: 0.69 mm; high normal: 0.72 mm; grade 1 hypertension: 0.74 mm; and grade 2+3 hypertension: 0.76 mm) and with increasing evening HBP (0.68 mm, 0.71 mm, 0.73 mm, 0.76 mm, and 0.78 mm, respectively) (both P for trend <0.001). These associations remained significant even after adjusting for potential confounding factors. Likewise, both isolated morning hypertension (morning HBP ≥135/85 mmHg and evening HBP <135/85 mmHg) and isolated evening hypertension (evening HBP ≥135/85 mmHg and morning HBP <135/85 mmHg) as well as sustained hypertension (both morning and evening HBP ≥135/85 mmHg) were significantly associated with thicker mean IMT.

Conclusions:Our findings suggested that both morning and evening HBPs were significantly associated with carotid atherosclerosis in this general Japanese population.

Background:Concentrations of the anti-angiogenic factor soluble fms-like tyrosine kinase-1 (sFlt-1) are altered in peripartum cardiomyopathy (PPCM). In this study we investigated changes in the angiogenesis balance in PPCM.

Methods and Results:Plasma concentrations of sFlt-1 and the pro-angiogenic placenta growth factor (PlGF) were determined in patients with PPCM during the post-partum phase (n=83), in healthy women at delivery (n=30), and in patients with acute heart failure (AHF; n=65). Women with cardiac failure prepartum or associated with any form of hypertension, including pre-eclampsia, were excluded. Compared with non-pregnant women, in women with AHF and PPCM, median PlGF concentrations were greater (19 [IQR 16–22] and 98 [IQR 78–126] ng/mL, respectively; P<0.001) and the sFlt-1/PlGF ratio was lower (9.8 [6.6–11.3] and 1.2 [0.9–2.8], respectively; P<0.001). The sFlt-1/PlGF ratio was lower in PPCM than in normal deliveries (1.2 [0.9–2.8] vs. 94.8 [68.8–194.1], respectively; P<0.0001). The area under the curve for PlGF (cut-off value: 50ng/mL) and/or the sFlt-1/PlGF ratio (cut-off value: 4) to distinguish PPCM from either normal delivery or AHF was >0.94. Median plasma concentrations of the anti-angiogenic factor relaxin-2 were lower in PPCM and AHF (0.3 [IQR 0.3–1.7] and 0.3 [IQR 0.3–1] ng/mL, respectively) compared with normal deliveries (1,807 [IQR 1,101–4,050] ng/mL; P<0.001).

Conclusions:Plasma of PPCM patients shows imbalanced angiogenesis. High PlGF and/or low sFlt-1/PlGF may be used to diagnose PPCM.

Background:Although experimental animal studies report many pleiotropic effects of dipeptidyl peptidase-4 inhibitors (DPP-4i), their prognostic value has not been demonstrated in clinical trials.

Methods and Results:Among 838 prospectively enrolled heart failure (HF) patients hospitalized for acute decompensated HF, 79 treated with DPP-4i were compared with 79 propensity score-matched non-DPP-4i diabetes mellitus (DM) patients. The primary endpoint was all-cause mortality; the secondary endpoint was a composite of cardiovascular death and hospitalization. During follow-up (423±260 days), 8 patients (10.1%) in the DPP-4i group and 13 (16.5%) in the non-DPP-4i group died (log-rank, P=0.283). The DPP-4i group did not have a significantly higher rate of all-cause mortality (log-rank, P=0.283), or cardiovascular death or hospitalization (log-rank, P=0.425). In a subgroup analysis of HF with preserved ejection fraction (HFpEF; n=75), the DPP-4i group had a significantly better prognosis than the non-DPP-4i group regarding the primary endpoint (log-rank, P=0.021) and a tendency to have better prognosis regarding the secondary endpoint (log-rank, P=0.119). In patients with HF with reduced EF (n=83), DPP-4i did not result in better prognosis.

Conclusions:DPP-4i did not increase the risk of adverse clinical outcomes in patients with DM and HF. DPP-4i may be beneficial in HFpEF.

Background:We investigated the effect of anemia on cardiovascular hemodynamics, therapeutic strategies and clinical outcomes in heart failure (HF) patients.

Methods and Results:We divided 198 consecutive HF patients who underwent right heart catheterization before in-hospital HF treatment into 2 groups according to the presence or absence of hemodynamic congestion (HC: mean pulmonary capillary wedge pressure ≥15 mmHg and/or mean right atrial pressure ≥10 mmHg). The hemoglobin level correlated with the cardiac index (CI) and systemic vascular resistance index (SVRI) (r=−0.34 and 0.42, P<0.05, respectively), and was the strongest contributor of SVRI only in the HC group. Anemic patients more frequently required intravenous inotropic support despite having higher CI and lower SVRI than non-anemic patients in the HC group. The novel hemodynamic subsets based on mean right atrial pressure and estimated left ventricular stroke work index but not Forrester subsets appropriately predicted the need for intravenous inotropic support. The probability of hospitalization for worsening HF during 2-year follow-up period was significantly higher in anemic patients than in non-anemic patients in the HC group.

Conclusions:Anemia had a direct effect on cardiovascular hemodynamics and thus can confound therapeutic planning in HF patients with HC. The novel hemodynamic subsets can be applied in daily clinical practice regardless of the presence or absence of anemia.

Background:Revascularization therapy relieves myocardial ischemia, but can also result in ischemia-reperfusion injury caused by oxidative stress. However, the biokinetics of oxidative stress after myocardial ischemia-reperfusion are uncertain. This study aimed to evaluate the dynamics of oxidative stress after off-pump coronary artery bypass grafting (OPCAB) by measuring urinary biopyrrin levels. Biopyrrin is an oxidative metabolite of bilirubin thought to reflect oxidative stress, along with reactive nitrogen species (RNS).

Methods and Results:The study included 18 patients who underwent OPCAB; patients were divided into effort angina pectoris (EAP; n=11) and unstable angina pectoris (UAP; n=7). Urinary biopyrrin and RNS levels were measured during the perioperative period (≤48 h after surgery). Biopyrrin levels transiently increased 4–12 h post-surgery (early phase), followed by a prolonged increase approximately 24–32 h post-surgery (late phase). The delayed increase in biopyrrin tended to be higher in patients with UAP, with a simultaneous increase in RNS. The patients in the UAP group had generally high pulmonary capillary wedge pressure (PCWP), although the cardiac index was within a normal range during the delay phase.

Conclusions:The dynamics of biopyrrin levels revealed a biphasic pattern of oxidative stress after OPCAB. Delayed production of oxidative stress may be influenced by preoperative severity of myocardial ischemia and delayed RNS production.

Background:Inhibition of cholesteryl ester transfer protein with evacetrapib may provide an additional treatment option for patients who do not reach their low-density lipoprotein cholesterol (LDL-C) goal with statins or patients who cannot tolerate statins.

Methods and Results:This multicenter, randomized, 12-week, double-blind, parallel group, placebo-controlled, outpatient, phase 3 study evaluated the efficacy of evacetrapib in reducing LDL-C in 54 Japanese patients (27 evacetrapib, 27 placebo) with primary hypercholesterolemia. Primary efficacy measure was the percent change from baseline to week 12 in LDL-C (β quantification). Treatment with evacetrapib 130 mg once daily for 12 weeks resulted in statistically significant (P<0.001) change in LDL-C (β quantification) compared with placebo. Least-squares mean percentage changes from baseline were −34.3% in the evacetrapib group vs. 0.0% in the placebo group. Treatment with evacetrapib 130 mg also resulted in a statistically significant (P<0.001) increase in high-density lipoprotein cholesterol compared with placebo in mean percent change from baseline, with a least-squares mean difference of 124.0% (95% confidence interval: 104.6–143.5). No deaths, serious adverse events, or discontinuations because of adverse events were reported; 5 patients (18.5%) in the evacetrapib group and 7 patients (26.9%) in the placebo group experienced treatment-emergent adverse events.

Conclusions:Once-daily evacetrapib 130 mg monotherapy was superior to placebo in lowering LDL-C after 12 weeks. No new safety risks were identified.

Background:Patients with ST-elevation myocardial infarction (STEMI) who arrive at a hospital via self-transport reportedly have a delayed door-to-balloon time (DBT). However, the clinical impacts of delayed DBT on in-hospital mortality among such patients are not well known.

Methods and Results:In total, 1,172 STEMI patients who underwent primary percutaneous coronary intervention between January 2009 and December 2013 from the Acute Myocardial Infarction (AMI) Kyoto Registry were analyzed. Compared with the emergency medical service (EMS) group (n=804), the self-transport group (n=368) was younger and had a significantly longer DBT (115 min vs. 90 min, P<0.01), with fewer patients having a Killip classification of 2 or higher. The in-hospital mortality rate was lower in the self-transport group than in the EMS group (3.3% vs. 7.1%, P<0.01). A DBT >90 min was an independent predictor of in-hospital mortality in EMS patients (odds ratio (OR)=2.43, P=0.01) but not in self-transport patients (OR=0.89, P=0.87).

Conclusions:The present study demonstrated that there was no relationship between in-hospital prognosis and DBT ≤90 min in STEMI patients using self-transport. The prognosis of these patients cannot be improved by focusing only on DBT. Treatment strategies based on means of transport should also be considered.

Background:The temporal sequence of right ventricular (RV) deformation is related to RV dysfunction. The sequence of RV free wall contraction was investigated.

Methods and Results:In this prospective study, strain profiles using speckle-tracking echocardiography and tissue Doppler-derived pulmonary and tricuspid annular motion were assessed in 60 normal children. Circumferential RV free wall strain of 3 individual segments (anterior, lateral, and inferior) was evaluated. Longitudinal strain was assessed in 3 individual segments (RV outflow tract [RVOT], apical, and RV inflow tract [RVIT]). The isovolumetric contraction time (ICT) and the time interval between the onset of the QRS wave to the peak s’ wave were measured for pulmonary and tricuspid annular motion velocities. The time to peak circumferential strain was significantly lower in the anterior than in the lateral and inferior segments (339.1±19.5, 358.3±21.8, and 366.6±22.4 ms, respectively; P<0.0001). Longitudinal deformation of the RVOT segment occurred before the apical and RVIT segments (351.8±23.1, 366.3±20.1, and 369.2±21.3 ms, respectively; P<0.0001). The ICT and the time to peak s’ were significantly shorter in pulmonary than in tricuspid annular motion (49.4±10.1 vs 58.0±13.2 ms; and 104.7±12.2 vs. 160.5±27.1 ms; P<0.0001 for each).

Conclusions:Longitudinal deformation of RVOT precedes RVIT. Circumferential deformation occurs in the anterior segment before the lateral and posterior segments. The presence of mechanical time heterogeneity appears important for RV performance.

Background:We previously reported that febuxostat was more effective for hyperuricemia than allopurinol. The efficacy, however, of topiroxostat (a novel xanthine oxidase reductase inhibitor similar to febuxostat), for hyperuricemia is unknown.

Methods and Results:Patients with cardiovascular disease and hyperuricemia, in whom serum uric acid (s-UA) was controlled at ≤6 mg/dL, were eligible for enrollment. Fifty-five patients were randomized to receive either febuxostat or topiroxostat for 6 months and were switched to the other drug for the following 6 months. The primary endpoint was s-UA. Secondary endpoints included serum creatinine, estimated glomerular filtration rate, urinary albumin, cystatin-C, oxidized low-density lipoprotein, eicosapentaenoic acid/arachidonic acid ratio, lipid biomarkers, high-sensitivity C-reactive protein and B-type natriuretic protein. Although s-UA level was similar for both drugs, significantly more patients required dose escalation during treatment with topiroxostat. There were no differences in renal function, inflammatory and lipid markers between the 2 drugs. A biomarker of oxidative stress was significantly lower after 3 months of febuxostat compared with topiroxostat.

Conclusions:Febuxostat causes more marked and more rapid reduction of s-UA than topiroxostat. With regard to the antioxidant effect, febuxostat was superior to topiroxostat after 3 months. The renal protective and anti-inflammatory effects of both drugs were also similar after 6 months of treatment. Thus, both of these agents were similarly effective for hyperuricemia in patients with cardiovascular disease.

Background:Cell therapy is a therapeutic option for patients presenting with nonrevascularizable critical limb ischemia (CLI). However there is a lack of firm evidence on its efficacy because of the paucity of randomized controlled trials.

Methods and Results:The BALI trial was a multicenter, randomized, controlled, double-blind clinical trial that included 38 patients. For all of them, 500 mL of bone marrow were collected for preparation of a BM-MNC product that was implanted in patients assigned to active treatment. For the placebo group, a placebo cell-free product was implanted. Within 6 months after inclusion, major amputations had to be performed in 5 of the 19 placebo-treated patients and in 3 of the 17 BM-MNC-treated patients. According to a classical logistic regression analysis there was no significant difference. However, when using the jackknife analysis, 6 months after inclusion BM-MNC implantation was associated with a lower risk of major amputation (odds ratio (OR): 0.55; 95% confidence interval (CI): 0.52–0.58; P<0.0001) and of occurrence of any event (major or minor amputation, or revascularization) (OR: 0.30; 95% CI: 0.29–0.31; P<0.0001). The secondary endpoints (i.e., pain, ulcers, TcPO₂, and ankle-brachial index value) were not statistically different between groups.

Conclusions:Our results suggested that cell therapy reduced the risk of major amputation in patients presenting with nonrevascularizable CLI.

Background:Surgical treatment for endocarditis patients with a perivalvular abscess is still challenging.

Methods and Results:From 2009 to 2016, 470 patients underwent surgery for active endocarditis at 11 hospitals. Of these, 226 patients underwent aortic valve surgery. We compared the clinical results of 162 patients without a perivalvular abscess, 37 patients who required patch reconstruction of the aortic annulus (PR group) and 27 who underwent aortic root replacement (ARR group). Patients with a perivalvular abscess had a greater number ofStaphylococcusspecies and prosthetic valve endocarditis, a greater level of inflammation at diagnosis and symptomatic heart failure before surgery, especially in the ARR group. Nevertheless, the duration between diagnosis and surgery was similar, because of a high prevalence of intracranial hemorrhage in the ARR group. Hospital death occurred in 13 (9%) patients without a perivalvular abscess, in 4 (12%) in the PR and in 7 (32%) in the ARR group. Postoperative inflammation and end-organ function were similar between the groups. Overall survival of patients without a perivalvular abscess and that of the PR group was similar, but was significantly worse in the ARR group (P=0.050, 0.026). Freedom from endocarditis recurrence was similar among all patients.

Conclusions:Patients treated with patch reconstruction showed favorable clinical results. Early surgical intervention is necessary when a refractory invasive infection is suspected.

Background:As mitral valve (MV) repair for Barlow’s disease remains surgically challenging, it is important to distinguish Barlow’s disease from fibroelastic deficiency (FED) preoperatively. We hypothesized that the prolapse volume to prolapse height ratio (PV-PH ratio) may be useful to differentiate Barlow’s disease and FED.

Methods and Results:In 76 patients with MV prolapse who underwent presurgical transesophageal echocardiography, the 3D MV morphology was quantified: 19 patients were diagnosed with Barlow’s disease and 57 with FED. The patients with Barlow’s disease had greater prolapse volume and height than the patients with FED, as well as greater PV-PH ratio (0.61±0.35 vs. 0.17±0.10, P<0.001). Receiver-operating characteristic analysis revealed that with a cutoff value of 0.27, the PV-PH ratio differentiated Barlow’s disease from FED with 84.2% sensitivity and 84.2% specificity. Net reclassification improvement showed that the differentiating ability of the PV-PH ratio was significantly superior to prolapse volume (1.30, P<0.001). After being adjusted by each of prolapse volume and height, annular area and shape, and the number of prolapsed segments, the PV-PH ratio had an independent association with Barlow’s disease.

Conclusions:The PV-PH ratio was able to differentiate Barlow’s disease from FED with high accuracy. 3D quantification including this value should be performed before MV repair.

Background:We assessed the long-term safety and efficacy of tolvaptan in 102 patients with heart failure (HF) and chronic kidney disease (CKD). Median follow-up duration was 1.6 years (1.0–4.4 years).

Methods and Results:One patient discontinued tolvaptan because of hypernatremia. There were no changes in renal function or electrolytes during the 1-year follow-up. The cardiac-related death-free or HF-related hospitalization-free survival rate was significantly higher in patients receiving tolvaptan than in propensity score-matched patients who did not receive tolvaptan.

Conclusions:In patients with HF and CKD, long-term administration of tolvaptan was well-tolerated, relatively safe and effective, suggesting its utility for long-term management of these conditions.

Background:Cardiac sarcoidosis (CS) is a life-threatening disease that is frequently under-diagnosed.

Methods and Results:We used a nationwide inpatient sample to identify CS patients from 2005 to 2011 in the USA. The annual admissions of CS increased from 1,108 in 2005 to 2,182 in 2011, representing a 2-fold rise over a short time. The proportions of CS patients with severe comorbidities, ventricular tachycardia, ventricular fibrillation and heart failure all increased from 2005 to 2011. However, the in-hospital mortality rate declined.

Conclusions:An increasing trend of CS was observed. Cardiologists should notice that CS is not as rare as thought.