Higher heart rate (HR) is independently related to worse outcomes in various cardiac diseases, including hypertension, coronary artery disease, and heart failure (HF). HR is determined by the pacemaker activity of cells within the sinoatrial node. The hyperpolarization-activated cyclic nucleotide-gated (HCN) 4 channel, one of 4 HCN isoforms, generates the I_f current and plays an important role in the regulation of pacemaker activity in the sinoatrial node. Ivabradine is a novel and only available HCN inhibitor, which can reduce HR and has been approved for stable angina and chronic HF in many countries other than Japan. In this review, we summarize the current knowledge of the HCN4 channel and ivabradine, including the function of HCN4 in cardiac pacemaking, the mechanism of action of I_f inhibition by ivabradine, and the pharmacological and clinical effects of ivabradine in cardiac diseases as HF, coronary artery disease, and atrial fibrillation.

The identification of corticotropin-releasing hormone (CRH) has led to the discovery of a growing family of ligands and receptors. CRH receptor 1 (CRHR1) and CRHR2 are mammalian G-protein coupled receptors (GPCRs) with high affinity for CRH and the CRH family of peptides. CRHR1 is predominantly expressed in the brain and plays a vital role in the hypothalamic-pituitary-adrenal (HPA) axis stress responses by secreting adrenal corticotropic hormone (ACTH). CRHR2 is predominantly expressed in the heart, and a CRHR2-specific ligand, urocortin 2 (UCN2), shows positive cardiac chronotropic and inotropic effects through 3´,5´-cyclic adenosine monophosphate (cAMP) signaling in response to CRHR2-mediated Gαs activation in mice and humans. Central administration of the CRH family of peptides increases mean arterial pressure through CRHR1 activation, whereas peripheral administration of the peptides decreases mean arterial pressure through CRHR2 activation. These observations have led to further investigations of CRHR2 as an important and unique GPCR in the physiological and pathological functioning of the cardiovascular (CV) system. Moreover, recent clinical trials demonstrate CRHR2 as a potentially therapeutic target in the treatment of heart failure. We present recent reviews of the role of CRHRs in basic CV physiology and in the pathophysiology of CV diseases.

Elevated plasma lipid levels are linked to atherosclerosis, a hallmark for coronary artery disease (CAD), documented by animal studies as well as angiographic and clinical studies. The ability to treat hyperlipidemia through lifestyle changes and lipid-lowering agents has been related to the slow progression of atherosclerosis and decreased incidence of major coronary events. Angiopoietin-like proteins (ANGPTLs) are a family of secreted glycoproteins expressed in the liver that share common domain characteristics with angiopoietins, the main regulators of angiogenesis. Although ANGPTLs cannot bind the angiopoietin receptors expressed on endothelial cells, 2 ANGPTL family members (ANGPTL3 and ANGPTL4) have clinical importance because of their unambiguous effects on lipoprotein metabolism in mice and humans. The regulation of plasma lipid levels by ANGPTL3 is controlled via affecting lipoprotein lipase and endothelial lipase-mediated hydrolysis of triglycerides (TGs) and phospholipids. ANGPTL 3, along with the other 2 members, 4 and 8, is a key to balancing the distribution of circulating TGs between white adipose tissue (WAT) and oxidative tissues. Thus, ongoing trials with newly discovered medications in the form of monoclonal antibodies or antisense oligonucleotides with novel targets are under analysis and may represent a fresh frontier in the treatment of hyperlipidemia and CAD.

Background: Outcomes of early-onset acute type A aortic dissection (ATAAD) associated with Marfan syndrome (MFS) are known, but not with other etiologies.

Methods and Results: ATAAD patients from 2 centers (n=1,001) were divided into 2 groups: age ≤45 years (n=93) and age >45 years (n=908). Although in-hospital death and 10-year survival were similar (12% vs. 7% and 62.6% vs. 67.3%), the 10-year aortic event-free survival differed (50.0% vs. 80.2%; P<0.01). ATAAD patients from 3 centers (n=132), all aged ≤45 years, were divided into 5 groups: lone hypertension (HTN, n=71), MFS (n=23), non-syndromic familial thoracic aortic aneurysm and dissection (NS-FTAAD, n=16), bicuspid aortic valve (BAV, n=11), and no known etiologic factor (n=11). The incidence of severe aortic insufficiency varied between groups (HTN: 11%, MFS: 39%, NS-FTAAD: 38%, BAV: 55%, no known factor: 46%; P<0.01), whereas in-hospital death did not (14%, 22%, 0%, 0%, and 9%; P=0.061). The 10-year survival was 52.2%, 64.7%, 83.6%, 100%, and 90.9%, respectively, and 10-year aortic event-free survival was 55.6%, 36.3%, 77.5%, 90.0%, and 30.0%. Median descending aorta growth (mm/year) was 1.1 (0.1–3.4), 2.3 (0.3–5.3), 1.9 (1.3–2.7), 0.9 (−0.1–2.0), and 1.0 (−0.2–2.9) (P=0.15), respectively.

Conclusions: Late aortic events are common in young ATAAD patients. Known etiologic factors, though not BAV, negatively influence late outcomes in these patients.

Background: It has been suggested that protein directly activated by cAMP (Epac), one of the downstream signaling molecules of β-adrenergic receptor (β-AR), may be an effective target for the treatment of arrhythmia. However, there have been no reports on the anti-arrhythmic effects or cardiac side-effects of Epac1 inhibitors in vivo.

Methods and Results: In this study, the roles of Epac1 in the development of atrial and ventricular arrhythmias are examined. In addition, we examined the usefulness of CE3F4, an Epac1-selective inhibitor, in the treatment of the arrhythmias in mice. In Epac1 knockout (Epac1-KO) mice, the duration of atrial fibrillation (AF) was shorter than in wild-type mice. In calsequestrin2 knockout mice, Epac1 deficiency resulted in a reduction of ventricular arrhythmia. In both atrial and ventricular myocytes, sarcoplasmic reticulum (SR) Ca²⁺ leak, a major trigger of arrhythmias, and spontaneous SR Ca²⁺ release (SCR) were attenuated in Epac1-KO mice. Consistently, CE3F4 treatment significantly prevented AF and ventricular arrhythmia in mice. In addition, the SR Ca²⁺ leak and SCR were significantly inhibited by CE3F4 treatment in both atrial and ventricular myocytes. Importantly, cardiac function was not significantly affected by a dosage of CE3F4 sufficient to exert anti-arrhythmic effects.

Conclusions: These findings indicated that Epac1 is involved in the development of atrial and ventricular arrhythmias. CE3F4, an Epac1-selective inhibitor, prevented atrial and ventricular arrhythmias in mice.

Background: The Substrate and Trigger Ablation for Reduction of Atrial Fibrillation Trial Part II (STAR-AF2) emphasized the importance of circumferential pulmonary vein isolation (CPVI) during AF ablation.

Methods and Results: This study involved 2,297 consecutive patients (mean age, 58±11 years; 73.1% male, 70.1% paroxysmal AF) undergoing AF ablation from 2009 to 2017. We investigated the ablation lesion set, ablation time, catheter type, and clinical outcomes. Over the 9 years, the extra-pulmonary vein (PV) left atrial (LA) ablation rate (76.8% to 19.4%, P<0.001 for trend) and ablation time (P<0.001 for trend) decreased dramatically, whereas the 1-year recurrence rates decreased (21.8% to 14.1%, P=0.04 for trend). In persistent AF patients, the extra-PV LA ablation rate (91.4% to 55.3%, P<0.001) and ablation time (P<0.001) decreased after the STAR-AF2 report, but the 1-year recurrence rates remained similar (22.1% to 17.9%, P=0.281). A mesh-type flexible tip (MFT) catheter with a moderately increased radiofrequency power was used since 2012, and the MFT catheter was independently associated with a lower clinical recurrence compared to other irrigated-tip catheters (HR, 0.670; 95% CI: 0.559–0.803, P<0.001; log rank P=0.002) without increasing the procedure-related complications (OR, 1.434; 95% CI: 0.937–2.194, P=0.097).

Conclusions: Over the 9 years the extra-PV LA ablation and 1-year recurrence rates in the AF ablation cohort decreased, in part due to improved catheter technology.

Background: There are few reports about the differences between drug-eluting stents (DES) and bare metal stents (BMS) in neoatherosclerosis associated with in-stent restenosis (ISR), so we compared the frequency and characteristics of neoatherosclerosis with ISR evaluated by optical coherence tomography (OCT) in the present study.

Methods and Results: Between March 2009 and November 2016, 98 consecutive patients with ISR who underwent diagnostic OCT were enrolled: 34 patients had a BMS, 34 had a 1st-generation DES, and 30 had a 2nd-generation DES. Neoatherosclerosis was defined as a lipid neointima (including a thin-cap fibroatheroma [TCFA] neointima, defined as a fibroatheroma with a fibrous cap <65 µm) or calcified neointima. As a result, lipid neointima, TCFA neointima and calcified neointima were detected in 39.8%, 14.3%, and 5.1%, respectively, of all patients. The frequency of neoatherosclerosis was significantly greater with DES than BMS (48.4% vs. 23.5%, P=0.018). The minimum fibrous cap thickness was significantly thicker with DES than BMS (110.3±41.1 µm vs. 62.5±17.1 µm, P<0.001). In addition, longitudinal extension of neoatherosclerosis in the stented segment was less with DES than BMS (20.2±15.1% vs. 71.8±27.1%, respectively, P=0.001).

Conclusions: OCT imaging demonstrated that neoatherosclerosis with ISR was more frequent with DES than BMS and its pattern exhibited a more focal and thick fibrous cap as compared with BMS.

Background: Inflammation and platelet activation have been shown to be involved in acute thromobogenicity following venous occlusive conditions. The aim of this study was to identify the association of baseline platelet count and neutrophil/lymphocyte ratio (NLR) with venous stent failure.

Methods and Results: Patients who underwent technically successful iliocaval venous stent placement with available baseline complete blood count and follow-up stent patency data were selected (n=50). Stent failure was defined as >50% stenosis or occlusion at follow-up angiography, contrast-enhanced CT, MRI or duplex US. Median patient age was 49.5 years (range, 13–76 years), and 62% were female. Median follow-up time was 10.2 months (range, 0.1–76.4 months). Stent failure occurred in 13 patients (26%) after a median of 1.2 months (range, 1 day–76.4 months). On multivariable-adjusted Cox modeling, baseline platelets (HR, 2.28; P=0.004) and WBC count (HR, 2.03; P=0.013) were significantly associated with stent failure on follow-up; neutrophils (HR, 16.10; P=0.050); and NLR (HR, 12.19; P=0.050) had borderline significance. Compared with patients without stent failure, those with early, but not late, stent failure had higher baseline platelets (P=0.031) and neutrophils (P=0.025), and NLR (P=0.026).

Conclusions: Baseline platelet count and NLR are associated with early but not late failure of iliocaval venous stents. This suggests different pathophysiologic mechanisms and a role for both platelet activation and inflammatory mechanisms in early rather than late stent thrombosis. Future research is needed to better explain this novel finding.

Background: In the RE-DUAL PCI trial, dual anti-thrombotic therapy with dabigatran and a P2Y₁₂inhibitor had a lower risk of bleeding and similar risk reduction of thromboembolic events, compared with warfarin triple therapy, in patients with NVAF undergoing PCI. This subanalysis investigated whether the efficacy and safety of dabigatran dual therapy in Japanese and East-Asian patients enrolled in the RE-DUAL PCI trial were similar to those of the overall patient population of the trial.

Methods and Results: RE-DUAL PCI was a multicenter, randomized trial. The primary endpoint was the time to first International Society on Thrombosis and Hemostasis major or clinically relevant non-major bleeding events. Of the East-Asian patients (n=240) enrolled in the RE-DUAL PCI trial, 111 were Japanese and received dabigatran 110 mg (n=50) or 150 mg (n=13) dual therapy, or warfarin triple therapy (n=48). The incidence of the primary endpoint in Japanese patients was 26.0% and 29.2% with dabigatran 110-mg dual therapy and the corresponding warfarin triple therapy, and 23.1% and 30.8% with dabigatran 150-mg dual therapy and the corresponding warfarin triple therapy, respectively. Similar results were observed in the East-Asian population.

Conclusions: This subanalysis of the RE-DUAL PCI trial demonstrated that, like in the overall patient population, dabigatran dual therapy may offer physicians additional options for managing Japanese and East-Asian patients with NVAF receiving PCI.

Background: Low body mass index (BMI) is a relevant prognostic factor for heart failure (HF), but HF patients with low BMI are reported to be at risk of not receiving optimal drug treatment. We sought to evaluate the efficacy of cardiac rehabilitation (CR) in patients with low vs. normal BMI.

Methods and Results: We studied 152 consecutive patients (low BMI, n=32; normal BMI, n=119) who participated in a 3-month CR program. Low BMI was defined as <18.5 kg/m²and normal BMI, as 18.5≤BMI<25 kg/m². All patients underwent cardiopulmonary exercise testing and muscle strength testing at the beginning and end of the 3-month CR program. After CR, a significantly greater proportion of HF patients with low BMI had a positive change in peak V̇O₂than in the normal BMI group (91% vs. 70%; P=0.010). Average percent change in peak V̇O₂was significantly greater in patients with low vs. normal BMI (17.1±2.8% vs. 7.8±1.5%; P<0.001). In addition, on multivariable logistic regression, low BMI was an independent predictor of a positive change in peak V̇O₂after CR (OR, 3.97; 95% CI: 1.10–14.31; P=0.035).

Conclusions: CR has a greater effect in patients with low than normal BMI, and low BMI is an independent predictor of a positive change in peak V̇O₂. Thus, CR should be strongly recommended for HF patients with low BMI.

Background: Studies assessing the safety and effectiveness of Del Nido cardioplegia for adult cardiac surgery remain limited. We investigated early outcomes after coronary artery bypass grafting (CABG) using single-dose Del Nido cardioplegia vs. conventional multi-dose blood cardioplegia.

Methods and Results: The 81 consecutive patients underwent isolated CABG performed by a single surgeon. The initial 27 patients received anterograde blood cardioplegia, while the subsequent 54 patients received anterograde Del Nido cardioplegia. There were no differences in the baseline characteristics of each group nor any differences in the 30-day incidences of myocardial infarction, all-cause death, and readmission following surgery. The use of Del Nido cardioplegia was associated with shorter cardiopulmonary bypass time (98 vs. 115 min, P=0.011), shorter cross-clamp time (74 vs. 87 min, P=0.006), and decreased need for intraoperative defibrillation (13.0% vs. 33.3%, P=0.030) compared with blood cardioplegia. To control for the difference in cross-clamp time, we performed propensity score matching with a logistical treatment model and confirmed that Del Nido cardioplegia provided similar outcomes as blood cardioplegia and also reduced the need for defibrillation independent of cross-clamp time.

Conclusions: Compared with conventional blood cardioplegia, Del Nido cardioplegia provided excellent myocardial protection with reduced need for intraoperative defibrillation, shorter bypass and cross-clamp times, and comparable early clinical outcomes for adult patients undergoing CABG.

Background: The clinical characteristics and outcomes of acute heart failure (AHF) according to left ventricular ejection fraction (LVEF) have not been fully elucidated, especially for patients with mid-range LVEF. We performed a comprehensive comparison of the epidemiology, patterns of in-hospital management, and clinical outcomes in AHF patients with different LVEF categories.

Methods and Results: The Korean Acute Heart Failure (KorAHF) registry is a prospective multicenter cohort of hospitalized AHF patients in Korea. A total of 5,374 patients enrolled in the KorAHF registry were classified according to LVEF based on the 2016 ESC guidelines. More than half of the HF patients (58%) had reduced EF (HFrEF), 16% had mid-range EF (HFmrEF), and 25% had preserved EF (HFpEF). The HFmrEF patients showed intermediate epidemiological profiles between HFrEF and HFpEF and had a propensity to present as de-novo HF with ischemic etiology. Patients with lower LVEF had worse short-term outcomes, and the all-cause in-hospital mortality, including urgent heart transplantation, of HFrEF, HFmrEF, and HFpEF was 7.1%, 3.6%, and 3.0%, respectively. Overall, discharged AHF patients showed poor 3-year all-cause death up to 38%, which was comparable between LVEF subgroups (P=0.623).

Conclusions: Each LVEF subgroup of AHF patients was a heterogeneous population with diverse characteristics, which have a significant effect on the clinical outcomes. This finding suggested that focused phenotyping of AHF patients could help identify the optimal management strategy and develop novel effective therapies.

Background: Statins might be associated with improved survival in patients with heart failure with preserved ejection fraction (HFpEF). The effect of statins in HFpEF without coronary artery disease (CAD), however, remains unclear.

Methods and Results: From the JASPER registry, a multicenter, observational, prospective cohort with Japanese patients aged ≥20 years requiring hospitalization with acute HF and LVEF ≥50%, 414 patients without CAD were selected for outcome analysis. Based on prescription of statins at admission, we divided patients into the statin group (n=81) or no statin group (n=333). We followed them for 25 months. The association between statin use and primary (all-cause mortality) and secondary (non-cardiac death, cardiac death, or rehospitalization for HF) endpoints was assessed in the entire cohort and in a propensity score-matched cohort. In the propensity score-matched cohort, 3-year mortality was lower in the statin group (HR, 0.21; 95% CI: 0.06–0.72; P=0.014). The statin group had a significantly lower incidence of non-cardiac death (P=0.028) and rehospitalization for HF (P<0.001), but not cardiac death (P=0.593). The beneficial effect of statins on mortality did not have any significant interaction with cholesterol level or HF severity.

Conclusions: Statin use has a beneficial effect on mortality in HFpEF without CAD. The present findings should be tested in an adequately powered randomized clinical trial.

Background: The rapid increase in the number of heart failure (HF) patients in parallel with the increase in the number of older people is receiving attention worldwide. HF not only increases mortality but decreases quality of life, creating medical and social problems. Thus, it is necessary to define molecular mechanisms underlying HF development and progression. HMGB2 is a member of the high-mobility group superfamily characterized as nuclear proteins that bind DNA to stabilize nucleosomes and promote transcription. A recent in vitro study revealed that HMGB2 loss in cardiomyocytes causes hypertrophy and increases HF-associated gene expression. However, it’s in vivo function in the heart has not been assessed.

Methods and Results: Western blotting analysis revealed increased HMGB2 expression in heart tissues undergoing pressure overload by transverse aorta constriction (TAC) in mice. Hmgb2 homozygous knockout (Hmgb2^−/−) mice showed cardiac dysfunction due to AKT inactivation and decreased sarco(endo)plasmic reticulum Ca²⁺-ATPase (SERCA)2a activity. Compared to wild-type mice, Hmgb2^−/− mice had worsened cardiac dysfunction after TAC surgery, predisposing mice to HF development and progression.

Conclusions: This study demonstrates that upregulation of cardiac HMGB2 is an adaptive response to cardiac stress, and that loss of this response could accelerate cardiac dysfunction, suggesting that HMGB2 plays a cardioprotective role.

Background: We evaluated clinical outcomes of left ventricular assist device (LVAD) support in patients with or without severe right heart failure, in order to determine what kind of organ allocation system could help severe biventricular failure patients to be safely bridged to heart transplantation (HTx), even in Japan where the waiting time for HTx is extremely long.

Methods and Results: One hundred and seventy consecutive patients who were implanted with continuous-flow LVAD at the present institution were included in this study. The patients were divided into 2 groups: 158 patients with isolated LVAD (group-LVF) and 12 patients who required long-term mechanical or inotropic right heart support (group-BVF). Post-LVAD survival in group-BVF was significantly worse than in group-LVF (P<0.0001). Given that many patients in group-BVF died between 1 and 2 years after LVAD implantation, Kaplan-Meier survival curve simulation was carried out under the condition that all the patients in group-BVF who died on LVAD support >1 year after LVAD implantation had received HTx at 365 days after LVAD implantation and survived thereafter. In this simulation, no significant difference in survival was seen between the groups (P=0.2424).

Conclusions: A new allocation system that allows severe right heart failure patients to receive HTx at around 1 year would enable rescue of the patients with severe right heart failure.

Background: Left ventricular (LV) torsion is an important aspect of cardiac mechanics and is altered in heart failure patients. Cardiac resynchronization therapy (CRT) has a positive effect on LV function, but the exact mechanisms through which it works are not completely depicted. Our aim was to investigate (1) the acute CRT effect on LV torsional mechanics in heart failure patients using 3D speckle tracking echocardiography (3DSTE) and (2) its effect on short-term LV remodeling.

Methods and Results: We considered 48 patients (age 72±11 years, 35 men) who received CRT. They underwent 3DSTE during CRT-on (biventricular stimulation) vs. CRT-off (intrinsic conduction/right atrial/ventricular stimulation alone), in a random fashion. Patients were classified as CRT responders based on LV systolic volume reduction ≥15% at 6 months (final population: 31 responders, 17 non-responders). Acute CRT positively affected responders in terms of LV torsion (from 0.32±0.06°/cm CRT-off to 0.41±0.06°/cm CRT-on), but adversely affected non-responders (from 0.54±0.08°/cm CRT-off to 0.28±0.08°/cm CRT-on, interaction P=0.02). A similar trend was confirmed for apical (interaction P<0.04), but not for basal torsion (interaction P=0.351).

Conclusions: CRT has a positive role in acute recovery of LV torsion (particularly in its apical component) in responders, likely modulating the improvement in LV remodeling at early follow-up.

Background: Few biomarkers, even B-type natriuretic peptide (BNP), can predict the long-term outcome in patients with acute decompensated heart failure (ADHF) on the first day of admission. Placental growth factor (PlGF), a member of the vascular endothelial growth factor family of cytokines, is a key molecule in cardiorenal syndrome and a predictor of adverse events in chronic kidney disease patients. However, its significance in ADHF patients remains poorly understood.

Methods and Results: We studied 408 ADHF patients admitted between April 2011 and December 2016 by measuring their PlGF levels on the first day of admission. Primary endpoints were all-cause and cardiovascular (CV) death. Patients were divided into 2 groups according to PlGF quartiles. Kaplan-Meier analysis revealed that the high PlGF group (quartile 4: ≥12.6 pg/mL) had a worse prognosis than the low PlGF group (quartiles 1–3; <12.6 pg/mL) in terms of all-cause (hazard ratio [HR], 1.56; 95% confidence interval [CI], 1.13–2.14; P<0.01) and CV death (HR, 1.68; 95% CI, 1.04–2.66; P<0.05). After adjustment for covariates, PlGF remained an independent predictor of all-cause and CV death.

Conclusions: PlGF on the first day of admission was significantly associated with both all-cause and CV death, suggesting that it provides novel prognostic information in the acute phase of ADHF.

Background: We used dual Doppler echocardiography to measure the time interval between the mitral and tricuspid valve opening (MO-TO time), which we expected would reflect the balance between left and right ventricular hemodynamics.

Methods and Results: We prospectively enrolled 60 patients with heart failure (HF) and sinus rhythm. The MO-TO time was measured in addition to routine echocardiography parameters, invasive hemodynamic parameters and plasma B-type natriuretic peptide (BNP) level in all patients. Patients were divided into 2 groups based on the MO-TO time: MOP (mitral opening preceding tricuspid opening), and TOP (tricuspid opening preceding mitral opening) groups. We followed up the predefined adverse outcomes (cardiovascular [CV] death and hospitalization due to worsening HF) for 1 year. Pulmonary artery wedge pressure (PAWP) and mean pulmonary artery pressure (mPAP) were higher in the MOP than in the TOP group (P<0.001; P<0.001, respectively). The probability of an adverse CV outcome was higher in the MOP than in the TOP group (log-rank test; P=0.002). Addition of MOP improved the predictive power of univariate predictors (mitral E/A ratio and BNP) in the bivariate Cox analysis (P=0.017, P=0.024, respectively).

Conclusions: MOP reflects pulmonary hypertension caused by left heart disease and has prognostic value in predicting adverse CV events in patients with HF.

Background: The differential prognostic impact of β-blocker dose after acute myocardial infarction (AMI) has been under debate. The current study sought to compare clinical outcome after AMI according to β-blocker dose using the Korea Acute Myocardial Infarction Registry-National Institutes of Health (KAMIR-NIH).

Methods and Results: Of the total population of 13,104 consecutive AMI patients enrolled in the KAMIR-NIH, the current study analyzed 11,909 patients. These patients were classified into 3 groups (no β-blocker; low-dose [<25% of target dose]; and high-dose [≥25% of target dose]). The primary outcome was cardiac death at 1 year. Compared with the no β-blocker group, both the low-dose and high-dose groups had significantly lower risk of cardiac death (HR, 0.435; 95% CI: 0.363–0.521, P<0.001; HR, 0.519; 95% CI: 0.350–0.772, P=0.001, respectively). The risk of cardiac death, however, was similar between the high- and low-dose groups (HR, 1.194; 95% CI: 0.789–1.808, P=0.402). On multivariable adjustment and inverse probability weighted analysis, the result was the same.

Conclusions: The use of β-blockers in post-AMI patients had significant survival benefit compared with no use of β-blockers. There was no significant additional benefit of high-dose β-blockers compared with low-dose β-blockers, however, in terms of 1-year risk of cardiac death.

Background: The aim of the present study was to determine whether instructors could accurately assess chest compression quality visually, considering the association between chest compression depth and rate.

Methods and Results: In this prospective, observational study, the quality of chest compressions performed by a simulated actor in a video was visually assessed by certified instructors. The film consisted of 14 case scenarios, each including a combination of depth (2 patterns: adequate, 5–6 cm; and inadequate, <5 cm) and rate (7 categories: compressions 90–150 times/min in increments of 10 times/min). The participants evaluated whether the compression depth was adequate, deep, or inadequate; and whether the compression rate was appropriate, fast, or slow. Of 198 instructors, 56% of participants misidentified adequate depth as deep at a chest compression rate of 120/min (the tendency toward this response increased as chest compression rate increased), and 64.1% of participants incorrectly determined 130/min to be appropriate. On generalized linear mixed-effects model analysis, perceived chest compression depth and rate were significant factors for a correct response (P<0.01, both). A significant interaction between chest compression depth and rate was observed (P<0.01).

Conclusions: In the visual assessment of chest compression quality, recognition of chest compression depth was closely associated with compression rate. Misidentification of adequate chest compression depth as deep increased as the compression rate increased.

Background: Despite the best efforts of pediatricians, healthcare for adult patients with congenital heart disease (ACHD) has proven challenging because of the increased numbers. This study presents the process of establishing an ACHD care system as a collaborative effort between Shinshu University Hospital and Nagano Children’s Hospital.

Methods and Results: Establishing an outpatient clinic for transition, a cooperation agreement for in-patient care between the 2 hospitals, and quality management of diagnostic imaging and educational meetings for adult cardiologists were the 3 major challenges. Of the 99 patients who visited the transition clinic in the children’s hospital between May 2014 and December 2016, 3 returned to the pediatrician’s clinic. Between June 2013 and December 2017, 273 patients visited the ACHD center in Shinshu University Hospital. Until December 2017, mortality and fatal arrhythmia were noted in 3 and 2 cases, respectively. Catheter ablation for arrhythmia was performed in 12 cases, and 4 cases of pregnancy with moderate/severe ACHD or estimated as high risk were managed with healthy livebirths. Surgical interventions for moderate/severe ACHD were performed in collaboration with the children’s hospital or Sakakibara Heart Institute.

Conclusions: Patients were successfully transferred to adult cardiology departments. Surgical and nonsurgical interventions for ACHD were provided. Collaboration between adult and pediatric cardiologists assists in the establishment of healthcare systems for ACHD.

Background: Pulmonary embolism (PE) is a serious complication during the perioperative period. However, because most previous studies on the incidence of postoperative PE are based on symptoms, asymptomatic occurrences of PE have been overlooked, and the absolute incidence of postoperative PE remains unknown. The aim of this study was to investigate the incidence of perioperative PE, regardless of its symptoms, by reviewing the clinical interpretations of the diagnostic images obtained during the postoperative period.

Methods and Results: This study included all patients aged at least 18 years who underwent operations under general and/or neuraxial anesthesia in our institution from 2013 to 2016. We reviewed all interpretations of the diagnostic imaging performed in the postoperative period. We analyzed the 90-day cumulative incidence of postoperative PE and the characteristics, risk factors, and symptoms of patients with and without postoperative PE. Among 21,763 operations, postoperative diagnostic imaging was performed in 1,168 patients, which found PE in 217 patients. Symptoms appeared in 11.1% (24/217) of the PE patients, and 66.7% of these symptoms were decreased levels of SpO₂alone. Mortality from PE was 0.5% (1/217).

Conclusions: Diagnostic imaging found a number of postoperative PE cases, regardless of the presence of symptoms. Although symptomatic PE was not a frequent occurrence, these findings suggest that clinicians should be aware of postoperative PE even under current prophylaxis.

Background: Because the efficacy and safety of anticoagulant therapy in patients with acute intracerebral hemorrhage (ICH) are not fully known, present study aimed to elucidate the current status and the safety of anticoagulant therapy, mainly direct oral anticoagulants (DOACs), for acute ICH and anticoagulant-indicated patients.

Methods and Results: From September 2014 through March 2017, consecutive patients with acute (<7 days from onset), spontaneous ICH were retrospectively enrolled from a prospective registry. Whether to start anticoagulation was at the attending physicians’ discretion, and thromboembolic or hemorrhagic events during hospitalization were analyzed. A total of 236 patients (80 women [34%]; median age 69 [interquartile range 61–79] years; National Institutes of Health stroke scale score 7 [3–16]) were enrolled. Of them, 47 patients (20%) had an indication for anticoagulant therapy (33 had atrial fibrillation, 14 developed deep vein thrombosis), and 41 of 47 patients (87%) were actually treated with anticoagulant therapy (DOACs were used in 34 patients) after a median of 7 days from ICH onset. There was neither hematoma expansion nor excessive hemorrhagic complications during hospitalization after starting anticoagulant therapy.

Conclusions: Anticoagulant therapy was conducted for approximately 90% of anticoagulation-indicated patients after a median of 7 days from ICH onset. The predominant anticoagulant medications were DOACs. Anticoagulant therapy started from the acute phase of ICH should be safe.

Background: Although careful monitoring of asymptomatic severe aortic stenosis (AS) is recommended to prevent missing the optimal timing of surgical or transcatheter aortic valve replacement, prophylactic treatment that could extend the asymptomatic period remains unknown. In a hypertensive population, high blood pressure (BP) measured at the doctor’s office is known to be associated with B-type natriuretic peptide (BNP) level, a surrogate marker for symptomatic deterioration in AS. Little is known regarding the association between nocturnal BP variables and BNP in severe AS with preserved ejection fraction (EF).

Methods and Results: The subjects consisted of 78 severe AS patients (mean age, 79±6 years) with preserved EF. Nocturnal BP was measured hourly using a home BP monitoring device. On multiple regression analysis, nocturnal mean systolic BP (SBP) remained independently associated with BNP after adjustment for age, sex, body mass index, estimated glomerular filtration rate, antihypertensive medication class, early diastolic mitral annular velocity, and left ventricular mass index (P=0.03), whereas diastolic BP (DBP) and variables of BP variability were not.

Conclusions: Higher nocturnal SBP rather than DBP or indices of BP variability was independently associated with BNP in AS patients with preserved EF. Intervention for nocturnal SBP may therefore extend the asymptomatic period and improve prognosis.

Background: Infective endocarditis (IE) in cancer patients is increasing, but because little is known about it in these patients, we analyzed patient characteristics and outcomes and compared these factors in IE patients with and without cancer.

Methods and Results: This retrospective cohort study included 170 patients with IE newly diagnosed between January 2011 and December 2015. Among 170 patients, 30 (17.6%) had active cancer. The median age of IE patients with cancer was higher than that of non-cancer patients. Nosocomial IE was more common in cancer patients. Non-dental procedures, such as intravenous catheter insertion and invasive endoscopic or genitourinary procedures, were more frequently performed before IE developed in cancer patients. Staphylococcus was the most common pathogen in cancer patients, whereas Streptococcus was the most common in non-cancer patients. In-hospital mortality was significantly higher in cancer patients with IE (34.4% vs. 12.4%, P<0.001). IE was an important reason for discontinuing antitumor therapy and withholding additional aggressive treatment in nearly all deceased cancer patients.

Conclusions: IE is common in cancer patients and is associated with poorer outcomes. Patients with IE and cancer have different clinical characteristics. Additional studies regarding antibiotic prophylaxis before non-dental invasive procedures in cancer patients are needed, as cancer patients are not considered to be at higher risk of IE.

Background: Underfilled transcatheter aortic-valve implantation with ad hoc post-dilation is a therapeutic option for patients with borderline annuli to avoid acute complication. The effects of this technique on valve leaflet behavior, hydrodynamic performances, and paravalvular leakage (PVL) using patient-specific three-dimensional (3D) aortic-valve models were investigated.

Methods and Results: A female octogenarian patient was treated with this technique by using a 23-mm Sapien-XT. Patient-specific models were constructed from pre-procedure computed tomography (CT) data. Change in aortic annulus areas during systolic/diastolic phases and post-procedure stent areas were adjusted to those of the patient. The following was performed: (1) −3 cc initial and −2 cc underfilled post-dilation to the scale-down model by adjusting percent oversizing; and (2) −1 cc initial underfilling, nominal volume, and repeat nominal volume post-dilation using the patient-specific model. Underfilling was associated with higher %PVL. Observation using a high-speed camera revealed distorted leaflets after underfilled implantation, with a longer valve-closing time and smaller effective orifice areas, especially in the −3 cc underfilled implantation. Micro-CT analysis revealed that the transcatheter valves shifted to the opposite side of the large annulus calcification after post-dilation and reduced the malapposition there.

Conclusions: Excessive underfilled implantation showed unacceptable acute hemodynamics. Abnormal leaflet motions after underfilled implantation raised concerns about durability. Flow simulations using patient-oriented 3D models could help to investigate hemodynamics, leaflet motions, and the PVL mechanism.

Background: Warfarin is an anticoagulant drug used to prevent thromboembolic disorders, but its pharmacological effect is affected by co-administered drugs. Therefore, careful management of warfarin-related drug-drug interactions (DDIs) is necessary for its safety and effectiveness. Recently, intestinal vitamin K₁absorption through the Niemann-Pick C1-like 1 (NPC1L1)-mediated pathway was found to affect the pharmacological effect of warfarin. This study aimed to identify high-frequency warfarin-related DDIs in a clinical setting and elucidate their mechanism(s) in terms of changes in NPC1L1 expression and/or activity.

Methods and Results: Prednisolone was the most frequently suspected drug in retrospective surveys of medical records of patients who experienced warfarin-related DDIs. Prednisolone significantly increased the international normalized ratio of prothrombin time (PT-INR) values in warfarin-treated patients. To demonstrate the involvement of NPC1L1 in warfarin-prednisolone DDI, we conducted an in vitro vitamin K₁uptake assay using NPC1L1-overexpressing cells and found that prednisolone inhibited NPC1L1-mediated vitamin K₁uptake. Additionally, we found that prednisolone downregulates NPC1L1 in a glucocorticoid receptor α-dependent manner.

Conclusions: Co-administration of warfarin and prednisolone frequently enhanced the anticoagulant effect of warfarin in a clinical setting. Prednisolone-mediated suppression of NPC1L1 expression and activity could be the mechanism of DDI between warfarin and prednisolone. To manage warfarin therapy, the potential of concomitant drugs to change its anticoagulant effect through NPC1L1-related mechanisms merits consideration.

Background: Although we and others have reported cases of patients with Anderson-Fabry disease (AFD) complicated by coronary spastic angina (CSA), the prevalence of CSA in these patients remains unknown.

Methods and Results: We performed the acetylcholine-induced provocation test, according to the Japanese guidelines for the diagnosis and treatment of patients with CSA, in 9 consecutive patients having 5 independent AFD pedigrees. Coronary spasms were provoked in conjunction with symptoms and ECG ischemic changes in 8 of 9 (89%) patients with AFD.

Conclusions: We found an unexpectedly high prevalence of CSA in patients with AFD.

Background: Rapid deployment aortic valve replacement has been developed to shorten procedural times and to facilitate minimally invasive cardiovascular surgery.

Methods and Results: As a representative rapid-deployment valve, the balloon-expanding INTUITY Elite (the 2nd-generation Edwards INTUITY Valve System) was uneventfully implanted via a right lateral mini-thoracotomy in 2 patients with severe aortic valve stenosis. Both of them recovered quickly and were discharged from hospital without significant adverse events.

Conclusions: Implantation of the INTUITY Elite valve via right mini-thoracotomy is feasible and safe.