Pulmonary vein (PV) antrum isolation (PVAI) is effective in treating paroxysmal atrial fibrillation (AF) but is less so for persistent AF. A recent randomized study on the ablation strategies for persistent AF demonstrated that 2 common atrial substrate modifications, creation of linear lesions in the left atrium and ablation of complex fractionated electrogram sites, in addition to PVAI did not improve the outcome compared with stand-alone PVAI, suggesting the necessity of a more individualized, selective approach to persistent AF. There are emerging technologies, including high-resolution mapping with the use of multi-electrode catheter and auto mapping system and contact force (CF) guide ablation; the former allows rapid and accurate confirmation of the completeness of PVAI, and the latter enhances the achievement of durable ablation lesions more securely. Ablation for fibrotic area(s) has been proposed as a new approach for substrate modification, and high-resolution mapping is useful to define the area with low-voltage electrograms, a surrogate marker for atrial fibrosis. Ablation for non-PV triggers in addition to PVAI improves the outcome of persistent AF. Further, durable isolation of the left atrial posterior wall may reduce AF recurrence. These ablation strategies with concomitant use of the emerging technologies are strongly expected to enhance the effectiveness of catheter ablation for persistent AF.

It is thought that at least 6,500 low-molecular-weight metabolites exist in humans, and these metabolites have various important roles in biological systems in addition to proteins and genes. Comprehensive assessment of endogenous metabolites is called metabolomics, and recent advances in this field have enabled us to understand the critical role of previously unknown metabolites or metabolic pathways in the cardiovascular system. In this review, we will focus on heart failure and how metabolomic analysis has contributed to improving our understanding of the pathogenesis of this critical condition.

Background:A recent study suggested that midkine (MK), a heparin-binding growth factor, is associated with atherosclerosis progression in patients with artery disease. It has previously been reported that MK plays a critical role in neointima formation in a restenosis model, whereas the role of MK in the development of atherosclerosis has not been investigated. The present study assessed the effect of MK administration on the process of atherosclerotic plaque formation in apolipoprotein E-knockout (ApoE^−/−) mice.

Methods and Results:Using an osmotic pump, human recombinant MK protein was intraperitoneally administered for 12 weeks in C57BL/6 ApoE^−/−(ApoE^−/−-MK) and ApoE^+/+mice fed a high-fat diet. Saline was administered to the control groups of ApoE^−/−(ApoE^−/−-saline) and ApoE^+/+mice. The atherosclerotic lesion areas in longitudinal aortic sections were significantly larger in ApoE^−/−-MK mice than in ApoE^−/−-saline mice. The aortic mRNA levels of pro-inflammatory and angiogenic factors, and the percentage of macrophages in aortic root lesions, were significantly higher in ApoE^−/−-MK mice than in ApoE^−/−-saline mice, whereas the percentage of apoptotic cells was significantly lower in ApoE^−/−-MK mice than in ApoE^−/−-saline mice.

Conclusions:The systemic administration of MK in ApoE^−/−mice promoted atherosclerotic plaque formation through pro-inflammatory, angiogenic, and anti-apoptotic effects. MK may serve as a potential therapeutic target for the prevention of atherosclerosis under atherogenic conditions.

Background:Lipoprotein lipase (LPL) expressed in macrophages plays an important role in promoting the development of atherosclerosis or atherogenesis. MicroRNA-182 (miR-182) is involved in the regulation of lipid metabolism and inflammation. However, it remains unclear how miR-182 regulates LPL and atherogenesis.

Methods and Results:Using bioinformatics analyses and a dual-luciferase reporter assay, we identified histone deacetylase 9 (HDAC9) as a target gene of miR-182. Moreover, miR-182 upregulated LPL expression by directly targetingHDAC9in THP-1 macrophages. Hematoxylin-eosin (H&E), Oil Red O and Masson’s trichrome staining showed that apolipoprotein E (ApoE)-knockout (KO) mice treated with miR-182 exhibited more severe atherosclerotic plaques. Treatment with miR-182 increased CD68 and LPL expression in atherosclerotic lesions in ApoE-KO mice, as indicated by double immunofluorescence staining in the aortic sinus. Increased miR-182-induced increases in LPL expression in ApoE-KO mice was confirmed by real-time quantitative polymerase chain reaction and western blotting analyses. Treatment with miR-182 also increased plasma concentrations of proinflammatory cytokines and lipids in ApoE-KO mice.

Conclusions:The results of the present study suggest that miR-182 upregulates LPL expression, promotes lipid accumulation in atherosclerotic lesions, and increases proinflammatory cytokine secretion, likely through targetingHDAC9, leading to an acceleration of atherogenesis in ApoE-KO mice.

Background:Variability in the international normalized ratio (INR) of prothrombin time has been suggested to be related to outcome in patients with atrial fibrillation (AF) under warfarin therapy, but its determinants remain unclear.

Methods and Results:The study population consisted of 626 AF patients under warfarin therapy in the Shinken Database (n=22,230). INR variability was calculated by Fihn’s method. Determinants of high log INR variability (defined as over mean+standard deviation) were determined by logistic regression analyses. Symptomatic heart failure (odds ratio [OR] 3.974, 95% confidence interval [CI] 2.510–6.292), older age (≥75 years old; OR 2.984, 95% CI 1.844–4.826) and severe renal dysfunction (eGFR <30 mL/min/1.73 m²; OR 3.918, 95% CI 1.742–8.813) were identified as independent predictors of high INR variability on multivariate logistic regression analysis.

Conclusions:The determinants of INR variability in AF patients under warfarin therapy could assist Japanese clinicians in identifying patients likely to show unstable warfarin control irrespective of the definition of the target INR range.

Background:Intracardiac echocardiography (ICE) and cardiac computed tomography (CCT), in addition to standard transesophageal echocardiography (TEE), have been used to identify left atrial (LA) thrombi prior to ablation for atrial fibrillation (AF). The clinical advantages of this, however, remain unclear. This study therefore investigated the advantages of additional pre-procedural LA appendage (LAA) thrombus evaluation using ICE and the clinical value of CCT in persistent and long-standing persistent AF.

Methods and Results:We analyzed data from 108 consecutive patients with persistent and long-standing persistent AF who were scheduled to undergo AF ablation. TEE was performed within 24 h prior to ablation. ICE was performed for 97 patients in whom a thrombus was not detected on TEE. CCT was performed in 95 patients. Thrombus or sludge was detected on TEE in 11 patients (10.3%), for whom ablation was cancelled. Four additional patients were diagnosed with LAA thrombus on ICE. When TEE and ICE were used as the reference for thrombus detection, the sensitivity, specificity, positive predictive value, and negative predictive value of CCT for identifying contrast defects in the LAA were 100%, 81.0%, 40.7%, and 100%, respectively.

Conclusions:ICE combined with TEE increased the detection rate of LAA thrombi in patients with persistent and long-standing persistent AF. Moreover, CCT had high sensitivity and negative predictive value for LAA thrombus detection.

Background:Patients with Brugada syndrome (BrS) and a history of syncope or sustained ventricular arrhythmia have longer right ventricular ejection delays (RVEDs) than asymptomatic BrS patients. Different types ofSCN5Avariants leading to different reductions in sodium current (I_Na) may have different effects on conduction delay, and consequently on electromechanical coupling (i.e., RVED). Thus, we investigated the genotype-phenotype relationship by measuring RVED to establish whether BrS patients carrying more severeSCN5Avariants leading to premature protein truncation (T) and presumably 100%I_Nareduction have a longer RVED than patients carrying missense variants (M) with different degrees ofI_Nareduction.

Methods and Results:There were 34 BrS patients (mean [±SD] age 43.3±12.9 years; 52.9% male) carrying anSCN5Avariant and 66 non-carriers in this cross-sectional study. Patients carrying aSCN5Avariant were divided into T-carriers (n=13) and M-carriers (n=21). Using tissue velocity imaging, RVED and left ventricular ejection delay (LVED) were measured as the time from QRS onset to the onset of the systolic ejection wave at the end of the isovolumetric contraction. T-carriers had longer RVEDs than M-carriers (139.3±15.1 vs. 124.8±11.9 ms, respectively; P=0.008) and non-carriers (127.7±17.3 ms, P=0.027). There were no differences in LVED among groups.

Conclusions:Using the simple, non-invasive echocardiographic parameter RVED revealed a more pronounced ‘electromechanical’ delay in BrS patients carrying T variants ofSCN5A.

Background:Severe hypothermia (SH) is known to be arrhythmogenic, but the effect of therapeutic hypothermia (TH) on arrhythmias is unclear. It is hypothesized that susceptibility to Ca-mediated arrhythmia triggers would be increased only by SH.

Methods and Results:Spontaneous Ca release (SCR) and resultant delayed afterdepolarizations (DADs) were evaluated by optical mapping in canine wedge preparations during normothermia (N, 36℃), TH (32℃) or SH (28℃; n=8 each). The slope (amplitude/rise time) of multicellular SCR (mSCR) events, a determinant of triggered activity, was suppressed in TH (24.4±3.4%/s vs. N: 41.5±6.0%/s), but significantly higher in SH (96.3±8.1%/s) producing higher amplitude DADs in SH (35.7±1.6%) and smaller in TH (5.3±1.0% vs. N: 10.0±1.1%, all P<0.05). Triggered activity was only observed in SH. In isolated myocytes, sarcoplasmic reticulum (SR) Ca release kinetics slowed in a temperature-dependent manner, prolonging Ca transient rise time [33±3 (N) vs. 50±6 (TH) vs. 88±12 ms (SH), P<0.05], which can explain the decreased mSCR slope and DAD amplitude in TH. Although the SR Ca content was similar in TH and SH, Ca spark frequency was markedly increased only in SH, suggesting that increased ryanodine receptor open probability could explain the increased triggered activity during SH.

Conclusions:Temperature dependence of Ca release can explain susceptibility to Ca-mediated arrhythmia triggers in SH. This may therefore explain the increased risk of lethal arrhythmia in SH, but not during TH.

Background:Atrial fibrillation (AF) can be initiated from arrhythmogenic foci within the muscular sleeves that extend not only into the pulmonary veins but also into both vena cavae. The superior vena cava (SVC) is a key target site for catheter ablation. Patients with SVC-derived AF often lack the clinical risk factors of AF.

Methods and Results:We conducted a meta-analysis of the clinical and genetic factors of 2,170 AF patients with and without SVC arrhythmogenicity. In agreement with previous reports, the left atrial diameter was smaller in AF patients with SVC arrhythmogenicity. Among 6 variants identified in a previous genome-wide association study in Japanese patients, rs2634073 and rs6584555 were associated with SVC arrhythmogenicity. This finding was confirmed in our meta-analysis using independent cohorts. We also found that SVC arrhythmogenicity was conditionally dependent on age, body mass index, and left ventricular ejection fraction.

Conclusions:Both clinical and genetic factors are associated with SVC arrhythmogenicity.

Background:Risk stratification of ventricular arrhythmias is vital to the optimal management in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC). We hypothesized that 64-channel magnetocardiography (MCG) would be useful to detect isolated late activation (ILA) by overcoming the limitations of conventional noninvasive predictors of ventricular tachyarrhythmias, including epsilon waves, late potential (LP), and right ventricular ejection fraction (RVEF), in ARVC patients.

Methods and Results:We evaluated ILA on MCG, defined as discrete activations re-emerging after the decay of main RV activation (%magnitude >5%), and conventional noninvasive predictors of ventricular tachyarrhythmias (epsilon waves, LP, and RVEF) in 40 patients with ARVC. ILA was noted in 24 (60%) patients. Most ILAs were found in RV lateral or inferior areas (17/24, 71%). We defined “delayed ILA” as ILA in which the conduction delay exceeded its median (50 ms). During a median follow-up of 42.5 months, major arrhythmic events (MAEs: 1 sudden cardiac death, 3 sustained ventricular tachycardias, and 4 appropriate implantable cardioverter defibrillator discharges) occurred more frequently in patients with delayed ILA (6/12) than in those without (2/28; log-rank: P=0.004). Cox regression analysis identified delayed ILA as the only independent predictor of MAEs (hazard ratio 7.63, 95% confidence interval 1.72–52.6, P=0.007), and other noninvasive parameters were not significant predictors.

Conclusions:MCG is useful to identify ARVC patients at high risk of future lethal ventricular arrhythmias.

Background:Left atrial appendage closure (LAAC) has been developed as an alternative treatment used for the prevention of strokes in high-risk patients with atrial fibrillation. Here, a novel LAAC prosthesis (LACBES^®device) is developed, and its translational potential is investigated by performing a pre-clinical study to evaluate its safety and effectiveness.

Methods and Results:LACBES^®occluders were implanted in 7 healthy canines percutaneously. Closure effect was evaluated by left atrial angiography. The canines were sacrificed post-procedure on days 45, 80 and 110; gross anatomy was examined subsequently. Endothelialization of device surface was evaluated by HE staining, immunofluorescence staining against CD31 and scanning electron microscope. LACBES^®occluders were implanted in all canines successfully; a small residual shunt was observed in 1 canine immediately post procedure. One canine died of groin hematoma within 36 h, which was related to the procedure, but there was no device-related death. A layer of white transparent tissue that failed to cover the nut was formed on the surface of the sealing disc on day 80, but the newborn tissue completely covered the sealing disc on day 110. Immunofluorescence staining against CD31 and scanning electron microscope confirmed complete intima formation and neovascularization within 4 months.

Conclusions:The current research suggested the LACBES^®device is feasible for LAAC, with a high success rate, few device-related complications and complete neointima formation in canines.

Background:This study investigated the consequences of recurrent mitral regurgitation (MR) after mitral valve (MV) repair in patients with degenerative MR and risk factors for recurrence.

Methods and Results:From January 1990 to December 2015, 792 patients underwent MV repair due to degenerative MR. Recurrent MR was defined as moderate-to-severe MR on follow-up echocardiography. Mean follow-up duration was 8.71±5.58 years. During the follow-up period, MR recurred in 133 (16.8%) patients, and the MR recurrence-free rate at 20 years was 77.5±2.0%. In the recurrence group, the degree of MR decreased in 8 (6.0%) patients and was aggravated in 46 (34.6%) patients. Recurrent MR was associated with increased mortality and adverse left ventricular (LV) remodeling. Independent risk factors for MR recurrence were MV repair performed before 2000, preoperative atrial fibrillation, high LV end-diastolic dimension (LVEDD), prolapse of the isolated anterior leaflet or multiple segments, and absence of ring annuloplasty. Predictors of MR progression were high LVEDD and repair without artificial chordae implantation.

Conclusions:Recurrent MR after MV repair in patients with degenerative MR showed a tendency to progress and was associated with increased mortality and adverse LV remodeling. Early referral for MV repair before development of atrial fibrillation and LV enlargement may reduce the risk of MR recurrence. Moreover, artificial chordae implantation and ring annuloplasty may assure the long-term durability of MV repair.

Background:To evaluate in-hospital and mid-term outcomes of sequential vs. separate grafting of in situ skeletonized left internal mammary artery (LIMA) to the left coronary system in a single-center, propensity-matched study.

Methods and Results:After propensity score-matching, 120 pairs of patients undergoing first scheduled isolated coronary artery bypass grafting (CABG) with in situ skeletonized LIMA grafting to the left anterior descending artery (LAD) territory were entered into a sequential group (sequential grafting of LIMA to the diagonal artery and then to the LAD) or a control group (separate grafting of LIMA to the LAD). The in-hospital and follow-up clinical outcomes and follow-up LIMA graft patency were compared. Both propensity score-matched groups had similar in-hospital and follow-up clinical outcomes. Sequential LIMA grafting was not found to be an independent predictor of adverse events. During a follow-up period of 27.0±7.3 months, 99.1% patency for the diagonal site and 98.3% for the LAD site were determined by coronary computed tomographic angiography after sequential LIMA grafting, both of which were similar with graft patency of separate grafting of in situ skeletonized LIMA to the LAD.

Conclusions:Revascularization of the left coronary system using a skeletonized LIMA resulted in excellent in-hospital and mid-term clinical outcomes and graft patency using sequential grafting.

Background:Intimal hyperplasia (IH) is a major cause of graft failure. Hemodynamic factors such as stagnation and disturbed blood flow are involved in IH formation. The aim of this study is to perform a comparative analysis of distal-end side-to-side (deSTS) and end-to-side (ETS) anastomoses using computational fluid dynamics (CFD) after validating the results via particle image velocimetry (PIV).

Methods and Results:We investigated the characteristics of our target flow fields using CFD under steady and pulsatile flows. CFD via PIV under steady flow in a 10-times-actual-size model was validated. The CFD analysis revealed a recirculation zone in the heel region in the deSTS and ETS anastomoses and at the distal end of the graft, and just distal to the toe of the host artery in the deSTS anastomoses. The recirculation zone sizes changed with the phase shift. We found regions of low wall shear stress and high oscillating shear index in the same areas. The PIV and CFD results were similar.

Conclusions:It was demonstrated that the hemodynamic characteristics of CFD and PIV is the difference between the deSTS and ETS anastomoses; that is, the deSTS flow peripheral to the distal end of the graft, at the distal end and just distal to the toe of the host artery is involved in the IH formation.

Background:Cardiovascular surgery is one of the highest risk procedures in the field of surgery. Preoperative assessment of endothelial function has been reported as useful for predicting postoperative adverse events (AEs). The aim of this study was to investigate the relationship between endothelial function assessed by reactive hyperemia index (RHI) and AEs after cardiovascular surgery.

Methods and Results:A prospective observational study of 197 patients who underwent cardiovascular surgery was conducted. RHI was measured before the surgery. The primary endpoint was a composite of postoperative death, reoperation, stroke, newly required dialysis, deep sternum infection, and prolonged ventilation within 30 days. The secondary endpoint was new-onset atrial fibrillation (AF) within 30 days. Following cardiovascular surgery, 19 patients (9.6%) had AEs. New-onset AF was documented in 42 (25.9%) of 162 patients without a prior history of AF. In the receiver-operating characteristic curve analysis, RHI significantly predicted AEs (area under the curve [AUC] 0.67, best cutoff value 1.64, P=0.03), whereas RHI did not predict new-onset AF (AUC 0.53, P=0.93). Patients with RHI ≤1.64 had more AEs than those with RHI >1.64 (16.3% vs. 4.5%, P=0.005). Multiple logistic regression analysis showed the number of surgical procedures and RHI ≤1.64 as significant predictors of AEs.

Conclusions:Preoperative endothelial dysfunction assessed by RHI was associated with postoperative AEs in patients with cardiovascular surgery.

Background:The present study aimed to clarify the current use and outcomes of coronary artery bypass grafting (CABG) for acute coronary syndrome (ACS) based on the Japan Adult Cardiovascular Surgery Database (JACVSD) in stratified risk categories, and also to provide guidance on selection of optimal surgical strategies for ACS.

Methods and Results:From January 2008 through December 2012, 7,867 isolated CABG procedures for ACS were identifiedfrom the JACVSD. Patients were stratified into 3 subgroups (<2%, 2–9.9%, ≥10%) according to preoperative risk estimations based on this database. Off- and on-pump CABG surgical outcomes were evaluated in each subgroup. Off-pump CABG (OPCAB) was the predominant surgical strategy in all subgroups. The proportion of on-pump beating CABG increased in the higher-risk groups. Although average observed mortality rates were compatible with preoperative estimated risk in all subgroups, those after OPCAB were significantly lower in the medium (2–9.9%) risk group with lower incidence of major complications. In the low (<2%) and high (≥10%) risk groups, observed mortality rates did not show statistically significant differences between off- and on-pump CABG.

Conclusions:In this study in Japan, OPCAB was mainly performed in patients with ACS, particularly those with estimated risk <10%, with lower mortality rates, whereas on-pump beating CABG was selected for higher-risk patients with ACS, with reasonable mortality rates.

Background:Surgical treatment of functional mitral regurgitation (FMR) improves ventricular remodeling in patients with dilated cardiomyopathy (DCM). However, it is unclear whether surgical treatment improves long-term outcomes. We investigated the effects of mitral valve (MV) surgery in patients with DCM and FMR.

Methods and Results:Of 525 patients with DCM hospitalized due to heart failure between January 1996 and September 2014, 70 who had severe FMR despite receiving optimal medical therapy were enrolled in the study. Of these patients, 16 underwent surgery for FMR (surgery group; repair=14, replacement=2); the remaining 54 who refused or decided not to undergo surgery were classified as the medication group. There were no differences in age, sex, medication, or echocardiographic parameters between the 2 groups (P>0.05). During the mean follow-up period of 53.6±43.6 months, the occurrence of clinical outcomes (i.e., all-cause death or left ventricular assist device implantation) was 54.3%; the occurrence of clinical outcomes was lower in the surgery group (P=0.008, log-rank test). Multivariate Cox regression analysis using clinical data revealed that MV surgery (hazard ratio [HR] 0.257, 95% confidence interval [CI] 0.103–0.640; P=0.004) and diabetes mellitus (HR 2.924, 95% CI 1.243–6.876; P=0.014) were independent predictors of clinical outcomes after adjusting for age and sex.

Conclusions:Surgery for severe FMR provides better long-term outcomes in patients with DCM.

Background:TY-0201 (TY) is a transdermal formulation of bisoprolol that is the free base of bisoprolol fumarate (BO), a drug widely used to treat chronic heart failure (CHF). The objectives of this phase II study were to evaluate the efficacy and safety of TY when switching from oral BO to TY in patients with CHF whose drug therapy was optimized, and to determine the dose conversion rate of BO to TY.

Methods and Results:The efficacy and safety of once daily TY patch use for 16 weeks was investigated in 40 patients with CHF who were stabilized with an optimized drug treatment, including BO, after switching from BO to TY at the dose conversion rate of 5:8. The pre-switch left ventricular ejection fraction was 50.13±11.09% (mean±SD). The post-switch value was 50.87±10.79% after 16 weeks, which was not significantly different, with similar results for other efficacy and safety parameters. The 16-week study was continued for all patients without changing doses after switching to TY. No cardiovascular deaths, hospitalizations for worsening HF, or significant safety concerns were observed.

Conclusions:Efficacy was maintained without significant safety concerns in patients with CHF who were stabilized with BO treatment after switching to TY, suggesting the appropriateness of the dose conversion rate.

Background:The mineralocorticoid receptor antagonist eplerenone improved clinical outcomes among patients with heart failure with reduced ejection faction (HFrEF) in the EMPHASIS-HF (Eplerenone in Mild Patients Hospitalization And SurvIval Study in Heart Failure) study. However, similar efficacy and safety have not been established in Japanese patients. We evaluated the efficacy and safety of eplerenone in patients with HFrEF in a multicenter, randomized, double-blind placebo-controlled outcome study (ClinicalTrials.gov Identifier: NCT01115855). The aim of the study was to evaluate efficacy predefined as consistency of the primary endpoint with that of EMPHASIS-HF at a point estimate of <1 for the hazard ratio.

Methods and Results:HFrEF patients with NYHA functional class II–IV and an EF ≤35% received eplerenone (n=111) or placebo (n=110) on top of standard therapy for at least 12 months. The primary endpoint was a composite of death from cardiovascular causes or hospitalization for HF. The primary endpoint occurred in 29.7% of patients in the eplerenone group vs. 32.7% in the placebo group [hazard ratio=0.85 (95% CI: 0.53–1.36)]. Hospitalization for any cause and changes in plasma BNP and LVEF were favorable with eplerenone. A total of 17 patients (15.3%) in the eplerenone group and 10 patients (9.1%) in the placebo group died. Adverse events, including hyperkalemia, were similar between the groups.

Conclusions:Eplerenone was well-tolerated in Japanese patients with HFrEF and showed results consistent with those reported in the EMPHASIS-HF study.

Background:Although diuretic resistance leading to residual congestion is a known predictor of a poorer heart failure (HF) prognosis, better therapeutic strategies for effective and safe decongestion have not been established.

Methods and Results:In this study, 81 HF patients with fluid retention (despite taking ≥40 mg/day furosemide (FUR)), with an estimated glomerular filtration rate <45 mL/min/1.73 m², were randomized into 2 groups and administered either ≤15 mg/day additive tolvaptan (TLV) or ≤40 mg/day increased FUR for 7 days. Changes in urine volume between baseline and mean urine volume during treatment were significantly higher in the TLV than FUR group (P=0.0003). Although there was no significant decrease in body weight or improved signs and symptoms of congestion between the 2 groups, the increase in serum creatinine on Day 7 from baseline was significantly smaller in the TLV than FUR group (P=0.038). Multiple logistic regression analysis revealed that additive TLV (odds ratio 0.157, 95% confidence interval 0.043–0.605, P=0.001) was an independent clinical factor for improved renal function during treatment compared with increased FUR.

Conclusions:In HF patients with residual congestion and renal dysfunction refractory to standard therapy, additive TLV increased urine volume without further renal impairment compared with patients who received an increased dose of FUR.

Background:Blood pressure is regulated by a network of diverse physiological pathways. The C-terminal Src kinase (CSK) locus (15q24) is associated with blood pressure in various ethnic groups. It was recently reported thatCskinsufficiency increases blood pressure through Src. The mechanisms of hypertension inCsk^+/−mice are examined further in this study.

Methods and Results:To identify a causal component responsible for hypertension inCsk^+/−, the heart rate was measured by electrocardiogram and plasma volume by Evans blue dilution. Plasma volume increased inCsk^+/−compared with wild-types, while the heart rate did not change. Plasma sodium and aldosterone levels rose consistently inCsk^+/−vs. wild-types, and spironolactone, a mineralocorticoid receptor antagonist, reduced blood pressure. The amounts of Sgk1 and Na⁺/K⁺-ATPase (NKA) increased in the kidney ofCsk^+/−compared with wild-types. It was also found that Cyp11b2 (aldosterone synthase) was upregulated in the adrenal glands ofCsk^+/−, and that Csk was enriched in the zona glomerulosa of adrenals, the major site of aldosterone production in the normal mouse.

Conclusions:The results of the present study identify a physiological pathway by which blood pressure is regulated, in which the insufficiency ofCskinduces aldosterone production with zonal specificity in the adrenal glands, increasing sodium reabsorption and plasma volume and thus resulting in hypertension.

Background:Previously, we developed an image-based modeling system (V-Modeler) to investigate geometric changes in stent grafts (SGs) following their implantation for abdominal aortic aneurysms (AAAs). The aims of the present study were to improve this system for clinical use, to chronologically analyze postoperative morphological changes in SGs, and to demonstrate scenarios of SG migration.

Methods and Results:Contrast-enhanced computed tomography data from 36 patients who underwent endovascular aneurysm repair (EVAR) for AAAs were used, with 72 centerline paths, in total, analyzed for bilateral SG legs. The existing V-modeler system was modified by introducing a penalty term, optimizing the number of control points using Akaike’s information criterion, and changing the degree of the function from 3 to 5. Geometric parameters were then analyzed immediately, as well as >1 year after EVAR. Eight migrations were found and although overall SG curvature and curvature at the distal (leg) site did not change, curvature at the proximal (trunk) site of SGs decreased over time. Subanalysis revealed that SGs with severe curvature showed the same trend, whereas distal curvature increased in the non-severe curvature group. In addition, proximal curvature decreased more in Excluder than Zenith devices.

Conclusions:The present study demonstrates SG behavior after implantation with numerical values for SG length and curvature.

Background:Inhibition of cholesteryl ester transfer protein by evacetrapib when added to atorvastatin may provide an additional treatment option for patients who do not reach their low-density lipoprotein cholesterol (LDL-C) goal.

Methods and Results:This multicenter, randomized, 12-week, double-blind, parallel-group, placebo-controlled, outpatient, phase 3 study evaluated the efficacy of evacetrapib with atorvastatin in reducing LDL-C in 149 Japanese patients (evacetrapib/atorvastatin, n=53; ezetimibe/atorvastatin, n=50; placebo/atorvastatin, n=46) with primary hypercholesterolemia. The primary efficacy measure was percent change from baseline to week 12 in LDL-C (β quantification). Treatment with evacetrapib 130 mg daily for 12 weeks resulted in a statistically significant treatment difference of −25.70% compared with placebo in percentage decrease in LDL-C (95% CI: −34.73 to −16.68; P<0.001). Treatment with evacetrapib 130 mg also resulted in a statistically significant difference of 126.39% in the change in high-density lipoprotein cholesterol (HDL-C) compared with placebo (95% CI: 113.54–139.24; P<0.001). No deaths or serious adverse events were reported. Four patients (3 in the evacetrapib group and 1 in the ezetimibe group) discontinued due to adverse events.

Conclusions:Evacetrapib daily in combination with atorvastatin was superior to placebo in lowering LDL-C after 12 weeks, and resulted in a statistically significant increase of HDL-C compared with placebo. Also, no new safety risks were identified.

Background:The process of cardiomyocyte swelling involves changes of biomechanical properties and profiles of cellular genes. Although many genes have been proved to regulate cell edema of cardiomyocyte, the mechanisms involved in this event, as well as the biomechanical properties of swelling cell, remain unknown.

Methods and Results:Whether histone deacetylase 1 (HDAC1) inhibition protects against hypoxia-induced H9c2 cardiomyocyte swelling is examined in this study. Hypoxia-induced changes in the biomechanical properties and cytoskeletal structure that are relevant to cell swelling were also determined. H9c2 cells were treated under a chemical hypoxia situation (cobalt chloride) with HDAC1 inhibition (chemical inhibitor or siRNA) for 5 h, followed by in vitro biological and mechanical characterization. The results showed that expression of HDAC1 instead of HDAC4 was upregulated by chemical hypoxia. HDAC1 inhibition protects H9c2 cells against chemical hypoxia-induced hypoxic injury and cell swelling. HDAC1 inhibition improved cell viability, decreased lactate dehydrogenase leakage, cell apoptosis, malondialdehyde concentration, cell volume, and particles on the cell surface, and increased superoxide dismutase activity. Moreover, chemical hypoxia induced a decrease of Young’s modulus, accompanied by alterations in the integrity of acetylated histone and organization of the cytoskeletal network. HDAC1 inhibition significantly reversed these processes.

Conclusions:Based on the ideal physical model, HDAC1 inhibition protects against hypoxia-induced swelling in H9c2 cardiomyocytes through enhancing cell stiffness. Overall, HDAC1 is a potential therapeutic target for myocardial edema.

Background:Prior studies have shown that routine follow-up coronary angiography (CAG) following percutaneous coronary intervention (PCI) increases the incidence of revascularization without a clear reduction in major adverse clinical events. However, none of these prior studies were adequately powered to evaluate hard clinical endpoints such as myocardial infarction (MI) or death and thus the clinical utility of such practice remains to be determined.

Methods and Results:We conducted a systematic review and meta-analysis of randomized trials that compared clinical outcomes after PCI between patients who underwent routine follow-up CAG and those who only had clinical follow-up. Five randomized trials, totaling 4,584 patients met our inclusion criteria, including studies that used sub-randomization and ones that assigned consecutive patients per study protocol. Our results showed that routine follow-up CAG was associated with a lower rate of MI (odds ratio [OR] 0.65; 95% confidence interval [CI] 0.46–0.91; P=0.01) without reduction in all-cause mortality (OR 0.87; 95% CI 0.59–1.28; P=0.48), and a higher rate of target lesion revascularization (OR 1.73; 95% CI 1.42–2.11; P<0.001).

Conclusions:Our meta-analysis demonstrated that routine follow-up CAG after PCI was associated with a higher rate of revascularization, but also with a reduction in the rate of subsequent MI. Further studies investigating the potential role of routine follow-up angiography may be warranted.

Background:Stent fracture (SF) and peri-stent contrast staining (PSS) after sirolimus-eluting stent (SES) implantation are considered to be related to very late stent thrombosis (VLST). How dual antiplatelet therapy (DAPT) beyond 1 year affects the clinical outcomes of patients with SF or PSS remains unclear.

Methods and Results:Based on their DAPT status, 1,962 patients undergoing SES implantation were classified as on-thienopyridine (n=1,404) or off-thienopyridine (n=558). The 6-year incidence of VLST was significantly lower in the on-thienopyridine patients (0.56% vs. 1.8%, P=0.01), whereas cardiac death and myocardial infarction (MI) were similar (5.0% vs. 6.2%, P=0.31; 3.2% vs. 4.0%, P=0.33; respectively). The 1,962 patients were also classified as having SF/PSS (n=256) or non-SF/PSS (n=1,706). In the SF/PSS group, VLST and MI were significantly lower in on-thienopyridine patients (1.9% vs. 10.1%, P=0.003; 3.5% vs. 10.3%, P=0.02; respectively). In the non-SF/PSS group, VLST and MI were similar (0.36% vs. 0.45%, P=0.78; 3.2% vs. 3.0%, P=0.93; respectively). In both groups, cardiac death was similar (3.6% vs. 4.3%, P=0.78; 5.2% vs. 6.5%, P=0.32; respectively).

Conclusions:Prolonged DAPT was associated with significantly lower incidences of VLST and MI in the SF/PSS group, but had no effect on cardiac death, VLST, or MI in the non-SF/PSS group.

Background:Familial hypercholesterolemia (FH) is associated with premature atherosclerotic cardiovascular disease (ASCVD). The introduction of potent therapeutic agents underlies the importance of improving clinical diagnosis and treatment gaps in FH.

Methods and Results:A regional database of 1,690 adult patients with high-probability FH based on age-dependent peak-low-density lipoprotein cholesterol (LDL-C) cut-offs and exclusion of secondary causes of severe hypercholesterolemia, was examined to explore the clinical manifestations and current needs in the management of ASCVD, which was present in 248 patients (15%), of whom 83% had coronary artery disease (CAD); 19%, stroke; and 13%, peripheral artery disease. ASCVD was associated with male gender, higher peak LDL-C, lower high-density lipoprotein cholesterol (HDL-C), and traditional risk factor burden. Despite high-intensity statin (prescribed in 83% and combined with ezetimibe in 42%), attainment of LDL-C treatment goals was low, and associated with treatment intensity and drug adherence. Multivessel CAD (adjusted hazard ratios (HR), 3.05; 95% CI: 1.65–5.64), myocardial infarction, and the presence of ≥1 traditional risk factor (HR, 2.59; 95% CI: 1.42–4.71), were associated with repeat coronary revascularizations, in contrast with peak LDL-C >300 mg/dL (HR, 1.13; 95% CI: 0.66–1.91).

Conclusions:Main manifestations of ASCVD in FH patients were premature, multivessel CAD with need for recurrent revascularization, associated with classical cardiovascular risk factors but not with peak LDL-C. In spite of intensive therapy with lipid-lowering agents, treatment gaps were significant, with low attainment of LDL-C treatment goals.

Background:In the present study we investigated the effects of genetic variations in the C-C motif chemokine ligand 17 (CCL17) gene on serum CCL17 levels and risk of coronary artery disease (CAD).

Methods and Results:A case-control study was conducted to determine causal inferences amongCCL17single-nucleotide polymorphisms (SNPs), serum CCL17 levels, and risk of CAD. Luciferase assays, electrophoretic mobility shift assays (EMSA), and allele-specific quantitative chromatin immunoprecipitation (ChIP) assays were used to assess the function of the SNPs. In all, 947 participants (794 with CAD, 153 without CAD) were included in the study. The T allele in rs223828, located in intron of theCCL17gene, was associated with increased serum CCL17 levels as well as increased CAD risk. A causal inference test using mediation analysis suggested that rs223828 had a significant indirect casual effect on the increased risk of CAD mediated via serum CCL17 levels. Luciferase assays confirmed that the rs223828T allele enhancesCCL17promoter activity. Protein-DNA binding studies using EMSA and allele-specific quantitative ChIP assays indicated preferential activator protein-1 (AP-1) complex formation and recruitment with the rs223828 T allele compared with the C allele.

Conclusions:We propose that theCCL17SNP rs223828 is associated with increased risk of CAD, and that this site may be a potential AP-1 binding site.

Background:Congenital heart defects (CHD) are known to cluster within families, but existing evidence varies for the estimates of familial relative risk (RR). We aimed to examine familial aggregation and heritability of CHD in the general population of Taiwan.

Methods and Results:We conducted a population-based family study using the Taiwan National Health Insurance (NHI) research database. Individuals with affected first-degree (n=295,636) or second-degree (n=73,985) relatives were identified from all NHI beneficiaries (n=23,422,955) registered in 2012. Diagnoses of CHD for all study subjects were ascertained between January 1, 1996 and December 31, 2012. Having a twin, a first-degree relative and an affected second-degree relative were associated with an adjusted RR of 12.03 (11.59–12.49), 4.91 (4.85–4.97) and 1.21 (1.14–1.28) for CHD, respectively. Individuals with 1 affected first-degree relative had a RR of 4.78 (4.72–4.84), and those with ≥2 had an RR of 7.10 (6.77–7.45) for CHD. The estimated accountability for phenotypic variance of CHD was 37.3% for familial transmission and 62.8% for non-shared environmental factors.

Conclusions:Our results indicated that CHD tend to cluster within families, and approximately one-third of phenotypic variance was explained by familial factors.

Background:Giant coronary aneurysm is the most severe sequela in Kawasaki disease, occurring in approximately 0.2% of patients in Japan. Regression is rare, while myocardial infarction (MI) and sudden death are relatively common. Herein, we reviewed patients with giant coronary aneurysm in a 10-year period.

Methods and Results:A nationwide questionnaire survey was conducted based on a national epidemiological database from 1999 to 2010. We identified 355 giant coronary aneurysm patients, of whom 209 were analyzed. The 5- and 10-year total cardiac event-free rates were 0.72 and 0.68, respectively. Twelve patients died, and MI was observed in 32 patients (18.1%). Five and 6 deaths were due to coronary rupture and MI, respectively. All ruptures occurred within 1 month of onset, while most MI occurred within 18 months. There was no death beyond 2 years. Aneurysm size was significantly related to the occurrence of MI in both the right and left coronary arteries. At the time of writing, 55% of patients had no exercise limitations. And including patients who cannot perform strenuous exercises, 81% of patients were leading ordinary lives.

Conclusions:Severe cardiac events are likely to occur within 2 years from onset of Kawasaki disease, while no deaths occurred beyond this time. Hence, careful monitoring is needed especially for the first 2 years. Most patients with giant coronary aneurysms can lead ordinary lives with appropriate management.

Background:In the present study we used echocardiography to investigate coronary artery diameter at the time of diagnosis of Kawasaki disease (KD), before the start of treatment.

Methods and Results:Diameters of the right, left main, left anterior descending, and left circumflex coronary arteries were determined in 410 patients before KD treatment commenced. The maximum Z-score was considered to be the pretreatment, maximum coronary artery Z-score (preZmax). The cumulative probability of coronary arterial dilatation was analyzed using the Kaplan-Meier method. In the present study, 31 patients (7.6%) had a preZmax ≥3.0, 56 (13.7%) had a preZmax ≥2.5, and 96 (23.4%) had a preZmax ≥2.0. The cumulative probability of a preZmax ≥2.0 was >20% on Day 5 of illness, 40% on Day 7, and 70% on Day 10. The positive predictive value (PPV) of a preZmax of 2.0 was approximately 0.9 on Day 5 of illness.

Conclusions:The present study demonstrates that the coronary arteries may dilate before Day 5 of illness, and that the rate of dilatation increases gradually until Day 10. Because preZmax 2.0 has high PPV after Day 5 of illness, it is a useful marker of coronary artery dilatation in the early phase of KD.

Background:Daily activity should be an important factor to consider when deciding on a treatment strategy for critical limb ischemia (CLI), and we hypothesized that there was a close relationship between activities of daily living (ADL) and prognosis. The aim of this study was to investigate the association between ADL and outcomes of open bypass for CLI.

Methods and Results:A total of 226 patients undergoing infrainguinal bypass for CLI between January 2005 and December 2015 were reviewed. They were divided into 2 groups based on Barthel index (BI) at admission (pre-BI; ≥60 and <60) and compared with respect to the incidence of early adverse events and 3-year overall survival and amputation-free survival. Adverse events were more frequently observed in patients with pre-BI <60. Patients with pre-BI <60 had worse long-term outcomes. On multivariable analysis, hypoalbuminemia, end-stage renal disease, and BI at discharge <60 were significant predictors of 3-year outcomes, whereas pre-BI <60 was not a significant predictor of either outcome.

Conclusions:It is not BI at admission, but BI at discharge that determines long-term outcome.

Background:Unstable atherosclerotic carotid plaques cause cerebral thromboemboli and ischemic events. However, this instability has not been pathologically quantified, so we sought to quantify it in patients undergoing carotid endarterectomy (CEA).

Methods and Results:Carotid plaques were collected during CEA from 67 symptomatic and 15 asymptomatic patients between May 2015 and August 2016. The specimens were stained with hematoxylin-eosin and elastica-Masson. Immunohistochemistry was performed using an endothelial-specific antibody to CD31, CD34 and PDGFRβ. The histopathological characteristics of the plaques were studied. By multiple-variable logistic regression analysis, plaque instability correlated with the presence of plaque rupture [odds ratio (OR), 9.75; P=0.013], minimum fibrous cap thickness (OR per 10 μm 0.70; P=0.025), presence of microcalcifications in the fibrous cap (OR 7.82; P=0.022) and intraplaque microvessels (OR 1.91; P=0.043). Receiver-operating characteristics analyses showed that these factors combined into a single score diagnosed symptomatic carotid plaques in patients with carotid artery stenosis with a high level of accuracy (area under the curve 0.92; 95% confidence interval 0.85–0.99 vs. asymptomatic).

Conclusions:This analysis of carotid plaque instability strongly suggested that the diagnostic scoring of carotid plaque instability improves the understanding and treatment of carotid artery disease in patients undergoing CEA.

Background:Most patients with critical limb ischemia (CLI) exhibit severe comorbidities accompanied by frailty. This study assessed and risk-stratified mortality after infrainguinal bypass (IB) in CLI and investigated the effects of frailty.

Methods and Results:The study retrospectively reviewed 107 consecutive CLI patients who had undergone de novo IB due to atherosclerotic disease. Data regarding patient age, comorbidities, laboratory data, and functional status were collected; functional status was evaluated using the Barthel index (BI) and nutritional status was evaluated using albumin concentrations and body mass index (BMI). Mean (±SD) BI and BMI were 75±16 and 22±4 kg/m², respectively. BI (hazard ratio [HR] 0.96; 95% confidence interval [CI] 0.94–0.99, P=0.004), BMI (HR 0.85; 95% CI 0.75–0.95, P=0.003), atrial fibrillation (AF; HR 5.31; 95% CI 2.12–13.30, P<0.001), and ejection fraction (EF; HR 0.94; 95% CI 0.91–0.98, P=0.003) were independent predictors of mortality. Patients were divided into 2 groups based on BI (BI >75, n=71; and BI <70, n=36). Survival after IB was significantly lower for the lower BI group (P<0.001, log-rank test). After propensity score matching, post-IB survival remained significantly lower in the lower BI group (P=0.02).

Conclusions:BI, BMI, AF, and EF were independently associated with all-cause mortality after IB for CLI. BI and BMI may be useful in identifying and optimizing treatment for high-risk frail patients.

Background:The trend of the initial treatment strategy for pulmonary arterial hypertension (PAH) has changed from monotherapies to upfront combination therapies. This study analyzed treatments and outcomes in Japanese patients with PAH, using data from the Japan PH Registry (JAPHR), which is the first organized multicenter registry for PAH in Japan.

Methods and Results:We studied 189 consecutive patients (108 treatment-naïve and 81 background therapy patients) with PAH in 8 pulmonary hypertension (PH) centers enrolled from April 2008 to March 2013. We performed retrospective survival analyses and analyzed the association between upfront combination and hemodynamic improvement, adjusting for baseline NYHA classification status. Among the 189 patients, 1-, 2-, and 3-year survival rates were 97.0% (95% CI: 92.1–98.4), 92.6% (95% CI: 87.0–95.9), and 88.2% (95% CI: 81.3–92.7), respectively. In the treatment-naïve cohort, 33% of the patients received upfront combination therapy. In this cohort, 1-, 2-, and 3-year survival rates were 97.6% (95% CI: 90.6–99.4), 97.6% (95% CI: 90.6–99.4), and 95.7% (95% CI: 86.9–98.6), respectively. Patients on upfront combination therapy were 5.27-fold more likely to show hemodynamic improvement at the first follow-up compared with monotherapy (95% CI: 2.68–10.36).

Conclusions:According to JAPHR data, initial upfront combination therapy is associated with improvement in hemodynamic status.

Background:The monocyte to high-density lipoprotein cholesterol ratio (MHR) appears to be a newly emerging inflammatory marker. However, its prognostic value in patients with infective endocarditis (IE) and normal left ventricular ejection fraction (LVEF) has been unclear.

Methods and Results:We enrolled consecutive patients with IE and normal LVEF and divided into 3 groups based on the tertiles of MHR. Of 698 included patients, 44 (6.3%) died while in hospital. The occurrence of in-hospital death (3.9%, 4.3%, and 10.8%, P=0.003) and of major adverse clinical events (MACEs) (15.6%, 20.9%, and 30.6%, P<0.001) increased from the lowest to the highest MHR tertiles, respectively. Receiver-operating characteristic analysis demonstrated that MHR had good predictive value for in-hospital death (area under the curve [AUC] 0.670, 95% confidence interval [CI] 0.58–0.76, P<0.001) and was similar to C-reactive protein (AUC 0.670 vs. 0.702, P=0.444). Furthermore, MHR >21.3 had a sensitivity of 74.4% and specificity of 57.6% for predicting in-hospital death. Multiple analysis showed that MHR >21.3 was an independent predictor of both in-hospital (odds ratio 3.98, 95% CI 1.91–8.30, P<0.001) and long-term death (hazard ratio 2.29, 95% CI 1.44–3.64, P<0.001) after adjusting for age, female, diabetes mellitus, estimated glomerular filtration rate <90 mL/min/1.73 m², and surgical treatment. Kaplan-Meier survival curves showed that patients with MHR >21.3 had an increased rate of long-term death compared to those without (P=0.002).

Conclusions:Elevated MHR was independently associated with in-hospital and long-term death in patients with IE and normal LVEF.

Background:The valve-in-valve procedure, in which a transcatheter heart valve (THV) is implanted over a prosthetic valve, has been shown to be safe and therapeutically effective, depending on the size of the replacement valve.

Methods and Results:We report 3 cases of successful valve-in-valve procedure to replace a degenerated 19-mm stented prosthetic aortic valve. Balloon-expanding THVs were implanted: 20-mm in the 1st case and 23-mm in the next 2. Aortic stenosis was almost completely resolved in all patients, who recovered promptly and without cardiac adverse events.

Conclusions:Using the valve-in-valve procedure for a 19-mm degenerated bioprosthesis was feasible and safe.