It has been shown that the patency of an infarct-related artery (IRA) before primary percutaneous coronary intervention determines post-procedural success, better preservation of left ventricular function, and lower in-hospital mortality. However, the factors associated with pre-procedural Thrombolysis In Myocardial Infarction (TIMI) flow have not been fully investigated.

The Japanese registry of acute Myocardial INfarction diagnosed by Universal dEfiniTion (J-MINUET) is a prospective multicenter registry conducted at 28 Japanese medical institutions between July 2012 and March 2014. We enrolled 3,283 consecutive patients with acute myocardial infarction who were admitted to a participating institution within 48 hours of symptom onset. There were 2,262 patients (68.9%) with ST-elevation myocardial infarction (STEMI), among whom 2,182 patients underwent emergent or urgent coronary angiography.

Pre-procedural TIMI flow grade 3 was related to post-procedural TIMI flow grade 3 (P < 0.001), lower enzymatic infarct size (P < 0.001), lower ventricular tachycardia and ventricular fibrillation (P = 0.049), and lower in-hospital mortality (P = 0.020). A history of antiplatelet drug use was associated with pre-procedural TIMI flow.

Antiplatelet drug use on admission was associated with pre-procedural TIMI flow. The patency of the IRA in patients with STEMI was related to procedural success and decreased enzymatic infarct size, fatal arrhythmic events, and in-hospital mortality.

The aim of the study is to evaluate the association of pre-procedural N-terminal pro-B type natriuretic peptide (NT-proBNP) with contrast-induced acute kidney injury (CI-AKI) and long-term outcomes in elderly patients undergoing elective percutaneous coronary intervention (PCI).

A total of 540 patients aged ≥ 75 years who had undergone elective PCI between January 2012 and December 2015 were enrolled in this study. Admission NT-proBNP levels were measured before PCI. CI-AKI was defined as a relative increase in serum creatinine (SCr) of ≥50%, or an absolute increase of ≥ 0.3 mg/dL, occurring within 48 hours after contrast medium exposure. The predictive value of NT-proBNP for predicting CI-AKI was assessed by receiver operating characteristic (ROC) and multivariable logistic regression analysis.

A total of 54 (10.0%) patients developed CI-AKI. The best cutoff value of NT-pro-BNP for detecting CI-AKI was 1133 pg/mL with 66.7% sensitivity and 70.8% specificity according to the ROC analysis (C statistic = 0.719; 95% CI, 0.679-0.756). Multivariable analysis demonstrated that Lg-NT-proBNP is significantly related to CI-AKI (odds ratio [OR] = 3.892; 95% CI, 1.996-7.590; P < 0.001). Cox regression analysis showed that Lg-NT-proBNP is associated with long-term mortality (adjusted hazard ratio [HR] = 2.158; 95% CI, 1.246-3.740; P = 0.006) during follow-up.

Pre-procedural NT-proBNP is a significant and independent predictor of CI-AKI and long-term mortality in elderly patients following elective PCI, and the best cutoff point for predicting CI-AKI was 1133 pg/mL.

Increasing evidence is available for the use of percutaneous coronary intervention (PCI) in selected patients with unprotected left main (LM) bifurcation coronary lesions. However, little data have been reported on recurrent in-stent restenosis (ISR) for LM bifurcation lesions. The aim of this study was to evaluate the efficacy of a drug-eluting balloon (DEB) for LM bifurcation ISR compared with that of a drug-eluting stent (DES).

Between December 2011 and December 2015, 104 patients who underwent PCI for unprotected LM bifurcation ISR were enrolled. We separated the patients into 2 groups: (1) those underwent PCI with further DEB and (2) those underwent PCI with further DES. Clinical outcomes were analyzed.

Patients' average age was 67.14 ± 7.65 years, and the percentage of male patients was 76.0%. A total of 75 patients were enrolled in the DEB group, and another 29 patients were enrolled in the DES group. Similar target lesion revascularization (TLR) rate and recurrent myocardial infarction (MI) rate were noted for both groups. A significantly higher cardiovascular mortality rate was found in the DES group (10.7% versus 0%, P = 0.020), and a higher all-cause mortality rate was noted in the DES group (21.4% versus 6.8%, P = 0.067).

It is feasible to use DEB for LM bifurcation ISR. When comparing DEB with DES, similar TLR rates were found, but lower recurrent MI and lower cardiovascular death were noted for DEB treatment.

This retrospective follow-up study explored the status of patients with myocardial infarction with regard to the likelihood of being readmitted to the hospital within 30 days after undergoing coronary artery bypass surgery (CABG) and their survival status within one year of the procedure.

The rate of readmission within 30 days was 10.7% (167/1,575), primarily due to surgical wound infection (11.3% of readmission cases), ischemic heart disease (10.3%), and heart failure (8.7%). The readmission group consisted mainly of older males with a high comorbidity index. No significant differences existed between the two groups with regard to case distribution, hospital level, tenure of physicians, or teaching status of the hospitals. Most subsequent emergency department visits one month after surgery involved older male patients with a high comorbidity index. Compared to patients in the non-emergency group, those in the emergency group had longer hospital stays but lower mortality rates. Males constituted a higher proportion of survivors at one year post CABG, with age and comorbidity index being the primary variables affecting the risk of death.

The National Health Insurance may adopt the policy of increasing payments for medical institutions that avoid readmission within 30 days post CABG in order to encourage better patient care and avoid the costs associated with readmission.

In patients requiring an implantable cardioverter defibrillator (ICD), the combined use of a prior pacemaker and a subcutaneous ICD (S-ICD) could be an alternative treatment option to implantation of new leads or upgrading of pacemakers to an ICD if vascular access is limited. Here, we assessed the prevalence of S-ICD's eligibility according to surface electrogram screening in those receiving cardiac resynchronization therapy (CRT). S-ICD's eligibility was assessed in patients with a CRT pacemaker or a CRT defibrillator using the S-ICD template screening tool. Eligibility was defined as fulfillment of the template in both supine and upright positions in one or more leads during biventricular pacing. Among 44 patients (34 men, age: 67 ± 12), 36 (82%) were found to be eligible. The T/QRS amplitude ratio in lead II was significantly lower in those who were eligible (0.31 ± 0.16 versus 0.44 ± 0.18 in the ineligible group, P = 0.04). The lead position, underlying disease, and other electrocardiographic findings were not different between those who were eligible and those who were not. The majority of patients with biventricular pacing were eligible for S-ICD based on current screening tests and may benefit from this treatment. Further study is required.

The degree or nature of functional mitral regurgitation (MR) is not necessarily correlated with the size or function of the left ventricle (LV). We hypothesized that the anatomical structure of the mitral valve (MV) complex might play a role in functional MR in ischemic or nonischemic dilated cardiomyopathy (DCM).

The structure of the LV and MV complex in DCM patients (n = 29) was assessed using electrocardiogram-gated 320-slice computed tomography and was compared with that in healthy patients (n = 12). Twenty-five DCM patients with mild or low MR (DCM-lowMR) had markedly greater length, diameter, and sphericity index of the LV and a larger tenting area than the controls. The distance between the papillary muscle (PM) tip and the mitral annular plane was not different between DCM-lowMR and normal hearts despite the greater LV length observed in DCM-lowMR. Furthermore, DCM-lowMR had markedly longer chordae tendineae (DCM-lowMR: 24 [20-26] mm; controls: 14 [13-16] mm; P < 0.01) and larger anterior leaflets (DCM-lowMR: 30 [27-31] mm; controls: 22 [20-24] mm; P < 0.01), thus suggesting the adaptive remodeling of the MV complex. Four DCM patients with moderate-severe MR had unbalanced remodeling, such as excessive LV dilatation, short anterior mitral leaflets, and short chordae tendineae.

The development of functional MR might be associated with the remodeling of LV and MV components, such as the PMs, chordae tendineae, or anterior MV leaflets. Detailed anatomical assessments of the LV and MV complex would contribute to the adequate staging of ischemic or nonischemic DCM.

The prognostic value of the right ventricular (RV) systolic to diastolic duration ratio (S/D ratio) in patients with advanced heart failure is not clear.

We enrolled 45 patients with DCM (40 ± 13 years, 33 male) who were admitted to our hospital for evaluation or treatment of heart failure. The RV systolic and diastolic durations were measured using continuous Doppler imaging of tricuspid regurgitation, and the RV S/D ratio was calculated. Cardiac events were defined as cardiac death or left ventricular assist device implantation within the first year. Twenty-eight cardiac events occurred. The RV S/D ratio was significantly higher in the event group than in the event-free group (1.8 ± 0.8 versus 1.2 ± 0.5, P = 0.008). Univariate analysis showed that the RV S/D ratio, plasma brain natriuretic peptide concentration, left atrial volume index, and mitral deceleration time were associated with these events. Receiver operating characteristic curve analysis revealed that the optimal RV S/D cutoff value to predict events was 1.2 (sensitivity 79%, specificity 65%, area under the curve 0.745). Kaplan-Meier analysis indicated a significantly higher event rate in patients with an RV S/D ratio > 1.2 (log-rank test, P = 0.003). The addition of an RV S/D ratio > 1.2 improved the prognostic utility of a model that included conventional variables (P = 0.014).

In patients with advanced heart failure with DCM, the RV S/D ratio was higher in patients with events than in those without events. The addition of the RV S/D ratio to conventional parameters may provide better prognostic information.

Hyperuricemia is an independent predictor of mortality in patients with chronic heart failure. The aim of the study is to determine whether a urate-lowering agent febuxostat, an inhibitor of xanthine oxidase, may improve the clinical outcomes in chronic heart failure patients with hyperuricemia when compared to conventional treatment. This multicenter, prospective, randomized, open-label, blinded endpoint study with a follow-up period of 24 weeks will enroll 200 Japanese chronic heart failure patients with hyperuricemia. The eligibility criteria include a diagnosis of chronic heart failure (New York Heart Association functional class II-III with a history of hospitalization due to worsening of heart failure within the last 2 years), reduced left ventricular systolic function (left ventricular ejection fraction < 40%) and increased plasma natriuretic peptide [plasma B-type natriuretic peptide (BNP) ≥ 100 pg/mL or N-terminal pro BNP (NT-proBNP) ≥ 400 pg/mL], and hyperuricemia (serum uric acid >7.0 mg/dL and ≤ 10 mg/dL) at the screening visit. The primary outcome is the difference in the plasma BNP levels between the baseline and 24 weeks of treatment. The plasma BNP levels are measured in the central laboratory in a blinded manner. This study investigates the efficacy and safety of febuxostat in chronic heart failure patients with hyperuricemia.

Ventricular assist devices (VADs) have become an important therapy for advanced heart failure, however, the prognosis of those who receive a biventricular assist device (BiVAD) is still poor. We enrolled 70 patients who underwent paracorporeal VAD (Nipro-VAD^®) implantation between 2004 and 2015 and studied the preoperative risk factors, including hemodynamic parameters for RVAD requirement. Furthermore, 2-year survival was compared between the BiVAD group and LVAD only group. Fourteen patients (20%) required RVAD. The BiVAD group had a significantly smaller left ventricular diastolic/systolic dimension, lower mean pulmonary artery wedge pressure (PAWP), lower cardiac index (CI), higher pulmonary vascular resistance (PVR), higher mean right atrial pressure (RAP), lower pulmonary artery pulsatility index (PAPi), lower right ventricular stroke work index (RVSWI), and higher mean RAP/mean PAWP ratio preoperatively. After multivariate analysis, only PVR > 4.5 Wood units: WU (P = 0.013, odds ratio: OR 7.9) and mean RAP/mean PAWP > 0.8 (P < 0.001, OR 14.4) were significant predictors for RVAD requirement. From these odds ratios, we assigned 1 point to PVR > 4.5 WU and 2 points to mean RAP/mean PAWP > 0.8. This simple scoring method adequately stratified the incidence of RVAD implantation (score 0: 4.4%, score 1: 28.6%, score 2: 41.7%, score 3: 83.3%). The cumulative survival rate at 2-year after VAD implantation was significantly worse among patients who required RVAD support compared to the LVAD only group (28.5% versus 74.4%, P = 0.009). RVAD requirement is associated with poor long-term survival, and this simple scoring system using PVR and mean RAP/mean PAWP may be useful for predicting RVAD requirement in such patients.

Maximal left atrial volume (LAVmax) has been suggested to be an important indicator of left ventricular (LV) diastolic function and a prognosticator in patients with hypertrophic cardiomyopathy (HCM). However, LAVmax can be influenced by LV longitudinal systolic function, which causes systolic descent of the mitral plane. We investigated the prognostic role of LAVmin in patients with HCM and tested if LAVmin is better than LAVmax in predicting clinical outcome in these patients. A total of 167 consecutive patients with HCM were enrolled (age = 64.7 ± 13.5 years, male: female = 120:47). Clinical parameters and conventional echocardiographic measurement including tissue Doppler measurement were evaluated. Left atrial maximal and minimal volumes were measured just before mitral valve opening and at mitral valve closure respectively using the biplane disk method. The relationship between LAVmin and the clinical outcome of hospitalization for heart failure (HF), stroke or all-cause mortality was evaluated. During a median follow-up of 25.0 ± 17.8 months, the primary end point of HF hospitalization, stroke or death occurred in 35 patients (21%). Indexed LAVmin was predictive of HF, stroke or death after adjustment for age, diabetes, hypertension, atrial fibrillation, LV ejection fraction, and E/e'in a multivariate analysis (P = 0.001). The model including indexed LAVmin was superior to the model including indexed LAVmax in predicting a worse outcome in patients with HCM (P = 0.02). In conclusion, LAVmin was independently associated with increased risk of HF, stroke, or mortality in patients with HCM and was superior to LAVmax in predicting clinical outcome in this population.

Sarcoidosis is a systemic granulomatous disease including heart (cardiac sarcoidosis, CS). It has recently been reported that isolated CS, which presenting primarily cardiac symptoms without clinical evidence of sarcoid involvement in other organs. Diagnostic and prognostic biomarkers of CS, especially in isolated CS, have not yet been established.

We studied plasma levels of angiotensin-converting enzyme (ACE), soluble interleukin-2 receptor (sIL-2R), B-type natriuretic peptide (BNP) and cardiac troponin I (cTnI) in consecutive 172 patients with diagnosed sarcoidosis. We compared these markers between non-cardiac sarcoidosis (non-CS, n = 123, 71.5%) and CS patients (n = 49, 28.5%), including non-isolated CS (n = 30, 17.4%) and isolated CS (n = 19, 11.1%). ROC analysis revealed that BNP identified CS with AUC of 0.85 (P < 0.01) in sarcoidosis patients. In addition, ACE and sIL-2R levels were significantly higher in non-isolated CS than in isolated CS (P < 0.05). Furthermore, in the Cox proportional hazard analysis, cTnI, but not ACE, IL2R or BNP, was a predictor of fatal arrhythmia in sarcoidosis patients (HR 2.418, P = 0.003).

Higher ACE and sIL2-R are associated with systemic lesions, whereas BNP is a useful marker for detecting cardiac involvement in sarcoidosis patients. cTnI is a predictor of fatal arrhythmia in CS patients. A multiple biomarker approach supports comprehensive management of sarcoidosis.

Several studies have reported that the left ventricular (LV) lead implant success rate ranges between 88.0% and 92.4%. Coronary venous anatomy differs among patients thus, necessitating multiple types of leads. To date, the implant success rate among Japanese patients utilizing a pre-specified family LV leads (including bipolar and quadripolar) is not well known. The Attain Success Japan Study enrolled patients indicated for a de novo or an upgrade cardiac resynchronization therapy implant. Patients were followed for 3 months, and the implant success rates with Medtronic Attain family LV leads as well as the incidence of complications related to the LV lead were evaluated.

Three hundred 53 patients were enrolled from 29 sites in Japan; 346 patients had LV lead implant attempts. The LV lead was successfully implanted in 336 patients (97.1%). Bipolar and quadripolar LV lead implants were successful in 97.2% and 99.2% of patients, respectively (P = 0.43). Four complications (1.2%) related to the LV leads were reported; all of which occurred in patients receiving bipolar LV leads. The quadripolar LV leads were more frequently implanted in the apical segment compared with bipolar leads (21.6% versus 3.8%, P < 0.01). This study demonstrated a high implant success rate and a low LV lead-related complication rate, regardless of bipolar, or quadripolar in a Japanese cohort of patients.

The aim of this study was to evaluate hepatic dysfunction over 10 years following Fontan surgery. We assessed the clinical usefulness of diagnostic tools for the detection and follow-up of hepatic dysfunction in patients with Fontan circulation.

A total of 26 post-Fontan patients (median age 13 years, range 10-35 years; median duration from Fontan procedure 10.5 years, range 4-17 years) were enrolled in this study. Hepatic assessment was performed by ultrasonography, computed tomography (CT), and transient elastography (TE) with biochemical tests, echocardiography, and cardiac catheterization. Related parameters were compared on the basis of different findings in liver sonography, CT, and TE.

Liver CT and TE showed abnormal findings in all patients. Liver ultrasonography revealed abnormal results in 24 patients (92.3%). However, liver function test was normal and did not correlate with imaging studies. C-reactive protein was significantly correlated with severity of CT findings. White blood cell, platelet count, and N-terminal pro-brain natriuretic peptide were correlated with severity on TE. Post-Fontan high pulmonary vascular resistance (P = 0.046) and high mean pulmonary artery pressure (P = 0.046) correlated with hepatic changes on liver CT.

Changes in the liver post-Fontan surgery are common and occur even after 10 years the procedure. Liver imaging is more sensitive, and CT seems to be more useful for differentiation of severe hepatic changes.

Pulmonary hypertension (PH) is a disease with poor prognosis, caused by the obstruction/stenosis of small pulmonary arteries. Statin is known to have vasodilating and anti-inflammatory property and is considered to be a candidate of therapeutic agents for the treatment of PH, but its efficacy has not been verified in clinical trials. We have formulated pitavastatin incorporating nanoparticles composed of poly (lactic-co-glycolic acid) (NK-104-NP) to improve drug delivery to the pulmonary arteries and evaluated their safety and pharmacokinetics in healthy volunteers. To accomplish this purpose, phase I clinical trials were conducted. In the single intravenous administration regimen, 40 healthy subjects were enrolled and PK (pharmacokinetic) parameters in 4 groups (1, 2, 4, and 8 mg as pitavastatin calcium) were as follows: 1.00 hour after the administration, the plasma concentration of pitavastatin reached C_max (the maximum drug concentration) in all groups. C_max, AUC_0-t (area under the curve from time 0 to the last measurable concentration) and AUC_0-∞ (area under the curve from time 0 extrapolated to infinite time) were increased in a dose-dependent manner. Population pharmacokinetic analysis based on these results indicated no accumulation of pitavastatin after repeated administration of NK-104-NP for 7 days. In this 7-day administration trial, the mean C_max and AUC_0-∞ of pitavastatin were not significantly different between days 1 and 7, suggesting that pitavastatin is unlikely to accumulate after repeated administration. In these trials, three adverse events (AEs) were reported, but they were resolved without any complications and judged to have no causal relationships with NK-104-NP. These results indicate that the innovative nanotechnology-based medicine NK-104-NP exhibited dose-dependent pharmacokinetics and was well tolerated with no significant AEs in healthy volunteers.

Japan is facing problems associated with "heart failure (HF) pandemics" and bed shortages in core hospitals that can accommodate patients with acute HF. The prognosis is currently unknown for acute HF patients who were transferred from core hospitals to collaborating hospitals during the very early treatment phase and whose treatment strategies are in place.

We enrolled 166 acute HF patients who were hospitalized between January 1, 2015, and December 31, 2015, and compared the conditions of transferred patients (n = 53, median duration before transfer = 6 days) and nontransferred patients (n = 113). The transferred and nontransferred patients had similar one-year mortality rates (24.5% versus 19.5%, log-rank P = 0.27) and composite one-year mortality and HF readmission rates (35.8% versus 31.0%, log-rank P = 0.32). Multivariate analysis determined that patient transfers were not associated with a higher composite endpoint (hazard ratio, 1.08; 95% confidence interval, 0.58-1.99, P = 0.82). Transferred patients with low composite congestion scores (CCSs) had significantly lower composite endpoints than those with high CCSs (23.5% versus 57.9%, log-rank P = 0.005).

Acute HF patients who were transferred did not have inferior prognoses compared with nontransferred patients when the treatment strategies were correctly assumed by cardiologists. The implementation of early and strict decongestion strategies before transfer may be important for reducing cardiovascular events.

Cognitive impairment is frequently represented in elderly patients with cardiovascular disease (CVD); yet, the mechanism is uncertain. Recent studies have suggested the association between the vascular endothelial dysfunction and cognitive impairment. The aim of this study was to clarify the association between endothelial dysfunction and cognitive impairment in elderly patients with CVD.

A total of 80 elderly patients (> 70 years old) with CVD were included. Patients who had already pharmacologically intervened for cognitive impairment were excluded. The endothelial dysfunction was assessed by the reactive hyperemia-peripheral arterial tonometry (RH-PAT). Cognitive impairment was diagnosed by the Mini-mental state examination.

The RH-PAT index was significantly lower in cognitive impairment (median 1.60 [interquartile range (IQR) 1.34 to 1.89], n = 51) as compared with non-cognitive impairment (median 1.75 [IQR 1.55 to 2.30], n = 29, P = 0.005). By a multivariate analysis, the RH-PAT index was independently associated with cognitive impairment (odds ratio: 0.89; 95% confidence interval: 0.81 to 0.97; per 0.1, P = 0.044). In the receiver-operating characteristic analysis, the best cut-off of the RH-PAT index to identify cognitive impairment was 1.65 (area under the curve 0.67; P = 0.011) with limited the sensitivity (63%) and specificity (66%).

A lower RH-PAT index was significantly associated with the presence of cognitive impairment in elderly CVD patients. Further studies are required to clarify the mechanism and the causal relationship between the endothelial dysfunction and cognitive impairment in patients with CVD.

The prevalence of arteriosclerosis obliterans (ASO) and critical limb ischemia (CLI) is currently increasing, and arterial reconstruction is often attempted to salvage the limb. Some patients cannot undergo attempted revascularization because of contraindications, and they only receive conservative treatment. In this study, we investigate the comorbidities and survival rates of patients with CLI who receive conservative treatment. Thirty-five patients with CLI due to ASO, who had not undergone revascularization surgery (C group), were enrolled. As controls, 136 patients with CLI due to ASO who did undergo revascularization (R group), mainly via bypass surgery, were enrolled. Coronary artery disease, heart failure, and respiratory dysfunction were factors indicating conservative treatment. Limb salvage rates and survival rates were not significantly different between the two groups. Patients who had survived for less than two years after surgery had a higher prevalence of chronic heart failure, cardiovascular disease, and end-stage renal disease compared to patients who had survived for more than two years. The use of statins, dual antiplatelets, aspirin, or warfarin did not influence whether a patient survived for longer than two years. 77% of patients survived for more than two years after receiving only conservative therapies. Surgical revascularization did not improve the prognosis of patients with CLI as compared with the conservative therapy. Clinicians might start with conservative treatment while considering other treatment options for patients with CLI.

Recently, long-term outcomes of pre-capillary pulmonary hypertension (PH) have been improved, whereas morbidity and mortality are still high because of right-sided heart failure (HF). Right-sided HF is closely related to right ventricular (RV) function and hemodynamics such as RV stroke work index (RVSWI). However, the association between RVSWI and long-term outcomes in pre-capillary PH has not been well investigated. The aims of this study were to compare clinical characteristics between low RVSWI and high RVSWI and to investigate the association between low RVSWI and long-term outcomes in patients with pre-capillary PH. We included patients admitted to diagnose and evaluate PH by right heart catheterization between 2007 and 2015. Patients with pre-capillary PH were divided into two groups according to the median value of RVSWI (low RVSWI group: RVSWI < 19.7 g・m/m²/beat; high RVSWI group: RVSWI ≥ 19.7 g・m/m²/beat). Kaplan-Meier survival curves were applied to investigate whether the low RVSWI were associated with HF death or HF readmission in patients with pre-capillary PH. A total of 36 patients with pre-capillary PH who were diagnosed as pulmonary arterial hypertension (PAH) or chronic thromboembolic PH (CTEPH) were allocated into the low RVSWI group (n = 18) and high RVSWI group (n = 18). The event-free survival rate was significantly lower in the low RVSWI group as compared with the high RVSWI group (P = 0.02). In conclusion, lower RVSWI was significantly associated with HF death or HF readmission in patients with PAH or CTEPH.

Although hyponatremia during hospitalization for acute decompensated heart failure (ADHF) is reportedly related with poor prognosis, the available data regarding the impact of serum sodium level within the low-normal range at admission on clinical events in patients with ADHF is limited.

We studied eligible patients admitted to our institution in 2007-2011. All the patients were categorized into 3 groups according to the admission serum sodium levels of < 135 mmol/L (hyponatremia), ≥ 135 and < 140 mmol/L (low-normal range), or ≥ 140 mmol/L (normal range). The association between admission serum sodium levels and long-term clinical events, a composite of all-cause deaths and re-hospitalizations for ADHF, was assessed by multivariable Cox proportional analysis.

Of the 584 eligible patients, 208 (35.6%) were in the low-normal range and 99 (16.9%) had hyponatremia on admission. On multivariable analysis, compared with those with a sodium level ≥ 140 mmol/L, patients with hyponatremia were at increased risk for clinical events (hazard ratio [HR], 1.53; P = 0.041), whereas the HR of those in the low-normal range was attenuated and insignificant (HR, 1.08; P = 0.625). However, the HR of each category increased significantly as sodium level decreased (P value for HR trend, 0.024). In addition, when serum sodium level was treated as a continuous variable, the lower the serum sodium level, the greater the risk of clinical events (P = 0.012). The cut-off value of serum sodium level to predict mortality was < 138 mmol/L.

In conclusion, a low serum sodium level on admission for ADHF, even if low-normal, can increase the risk of long-term mortality and/or re-hospitalization for ADHF.

There are many inherited disorders associated with thoracic aortic aneurysms and dissections (TAADs), like Marfan syndrome and Loeys-Dietz syndrome (LDS). The 4 patients in this study all had TAADs and were initially diagnosed with suspected Marfan syndrome. We collected peripheral blood samples from the patients and their family members and then attempted to identify the causal mutation using different methods including PCR, Sanger sequencing, and next generation sequencing. We identified 3 novel heterozygous mutations including 2 splicing mutations of FBN1 and 1 missense mutation of TGFBR2 in our patients. Although these mutation sites have been reported in the Human Gene Mutation Database, the nucleotide changes are different. All novel mutations found in this study were confirmed to be absent in 50 unrelated normal individuals of the same ethnic background. The RT-PCR results of 2 splicing mutations verified that the mutations can lead to the skipping of exons. The RT-qPCR results indicated that FBN1 mRNA levels were nearly 50 percent lower in the patients than in normal controls, indicating that there is almost no expression of truncated fibrillin-1 because of the nonsense-mediated mRNA decay (NMD) mechanism. To the best of our knowledge, we are the first to report these 3 novel mutations. However, the pathogenicity of these mutations still needs further confirmation. Our study has confirmed or corrected the clinical diagnosis, and enlarged the mutation spectrum of FBN1 and TGFBR2. The results should be helpful for prenatal diagnosis and genetic counseling.

Exercise preconditioning (EP) attenuates pathological cardiac hypertrophy by increasing the functional capacity of the cardiovascular system; however, the underlying molecular mechanisms remain unclear. MicroRNAs (miRNAs) play important roles in various physiological and pathological processes by regulating the expression of the targeted gene. In this study, we aimed to screen the miRNAs involved in EP-attenuating pathological cardiac hypertrophy. The histological and echocardiographic parameters assessment showed that pathological cardiac hypertrophy induced by transverse aortic constriction (TAC) was significantly alleviated in EP treated rats. The left ventricular tissues (n = 3) from Sham, TAC and EP + TAC groups were subjected to small RNA deep sequencing. A total of 570 known mature miRNAs and 530 putative novel miRNAs were detected. DEGseq analysis showed that there were 37 and 88 differentially expressed miRNAs in the comparisons of TAC versus Sham and EP + TAC versus TAC, respectively. Among them, EP treatment could relieve the expression changes of 32 miRNAs, which were supposed to be involved in EP-attenuating pathological cardiac hypertrophy. After miRNAs target genes prediction by miRDB algorithm, pathway analysis showed that the most frequently represented pathways were involved in Calcium signaling pathway and MAPK signaling pathway. The results would provide valuable clues to finding therapeutic targets for the treatment of pathological cardiac hypertrophy.

In a canine rapid atrial stimulation model of atrial fibrillation (AF), we have demonstrated an increased production of reactive oxygen species (ROS) along with electrical and structural remodeling. In the present study, we hypothesized that antioxidants can suppress atrial remodeling canines with AF. We therefore evaluated the effect of febuxostat, a xanthine oxidase (XO) inhibitor and a pure antioxidant, on atrial remodeling.

AF was produced by performing a 3-week rapid atrial pacing (400 bpm) in 13 dogs divided into three groups: pacing + febuxostat group (n = 5; atrial pacing with 50 mg/day of febuxostat (administration); pacing control group (n = 5; atrial pacing without any drug administration); and non-pacing group (n = 3). Electrophysiological studies were conducted in the first 2 groups every week. Atrial tissue fibrosis was evaluated by Azan and immunofluorescent staining of fibronectin. Oxidative stress was evaluated by DHE and FCF-DA staining.

Shortening of the refractory period and increase in AF inducibility appeared gradually in the pacing control group, but such changes were suppressed in the pacing + febuxostat group (P = 0.05). The pacing control group showed increase in fibrosis, which was suppressed in the febuxostat group. In DHE and DCF-DA staining, the pacing control group showed an increase in oxidative stress, which was suppressed in the pacing + febuxostat group. The pacing control group exhibited fibronectin expression, which was suppressed in the pacing + febuxostat group.

The antioxidant effect of febuxostat may achieve an inhibition of new-onset AF in canines.

Atherosclerosis is one of the most prevalent and important cardiac diseases, involving the heart and brain. This study aimed to explore the impacts of lncRNA Divergent to GSC induced by TGF-b family signaling (DIGIT) on vascular endothelial cells tube-formation capacity so as to reveal the potentials of DIGIT in atherosclerosis therapy. DIGIT expression in human microvascular endothelial HMEC-1 cells was silenced by transfection with shRNAs-targeted DIGIT. The effects of DIGIT silence on cell viability, migration, apoptosis, and tube formation were then assessed. Additionally, the cross-regulation between DIGIT and miR-134, and between miR-134 and Bmi-1 was detected to further reveal through which mechanism (s) DIGIT mediated HMEC-1 cells. The results showed that DIGIT silence significantly reduced cell viability, migration, tube-like structures formation, and induced apoptosis in HMEC-1 cells. DIGIT worked as a sponge for miR-134, and the anti-growth, anti-migratory, and anti-tube-formation functions of DIGIT silence on HMEC-1 cells were abolished by miR-134 suppression. Bmi-1 was a target of miR-134, and Bmi-1 upregulation abolished miR-134 overexpression-diminished cell growth, migration, and tube formation of HMEC-1 cells. Furthermore, Bmi-1 upregulation activated PI3K/AKT and Notch signaling pathways. In conclusion, our study demonstrated that lncRNA DIGIT accelerated tube formation of vascular endothelial cells through sponging miR-134. Our findings suggest that DIGIT and miR-134 may be promising molecular targets for atherosclerosis therapy.

Hypertrophic cardiomyopathy (HCM) is a genetic disorder that is characterized by hypertrophy of the myocardium. Some of the patients are diagnosed for HCM during infancy, and the prognosis of infantile HCM is worse than general HCM. Nevertheless, pathophysiology of infantile HCM is less investigated and remains largely unknown. In the present study, we generated induced pluripotent stem cells (iPSCs) from two patients with infantile HCM: one with Noonan syndrome and the other with idiopathic HCM. We found that iPSC-derived cardiomyocytes (iPSC-CMs) from idiopathic HCM patient were significantly larger and showed higher diastolic intracellular calcium concentration compared with the iPSC-CMs from healthy subject. Unlike iPSC-CMs from the adult/adolescent HCM patient, arrhythmia was not observed as a disease-related phenotype in iPSC-CMs from idiopathic infantile HCM patient. Phenotypic screening revealed that Pyr3, a transient receptor potential channel 3 channel inhibitor, decreased both the cell size and diastolic intracellular calcium concentration in iPSC-CMs from both Noonan syndrome and idiopathic infantile HCM patients, suggesting that the target of Pyr3 may play a role in the pathogenesis of infantile HCM, regardless of the etiology. Further research may unveil the possibility of Pyr3 or its derivatives in the treatment of infantile HCM.

The cardiac effects of exercise preconditioning (EP) are well established; however, the mechanisms involving cardiac ATP-sensitive potassium channel (K_ATP channel) subunits and autophagy are yet to be fully established. The present work aims to investigate the alterations of cardiac K_ATP channel subunits Kir6.2, SUR2A, and autophagy-related LC3 during the late cardioprotective phase of EP against exhaustive exercise-induced myocardial injury. Rats run on treadmill for four running time intervals, each with 10 minutes running and rest. Exhaustive exercise was performed 24 h after EP. Cardiac biomarkers, cTnI and NT-proBNP, along with the histological stain, were served as indicators of myocardial injury. Cardiac K_ATP channel subunits Kir6.2 and SUR2A were analyzed in this study, and autophagy was evaluated by LC3. The results revealed that EP reduced the exhaustive exercise-induced high level of serum cTnI and myocardial ischemia/hypoxia; however, it did not reveal any changes in the serum NT-proBNP level or cardiac BNP. Cardiac SUR2A mRNA significantly upregulated during the exhaustive exercise. The high levels of Kir6.2, SUR2A, LC3IIpuncta and LC3II turnover observed after exhaustive exercise were significantly mitigated by EP in the late phase. These results suggest that EP alleviates myocardial injury induced by exhaustive exercise through the downregulation of cardiac K_ATP channels and autophagy.

Atherosclerosis is an inflammatory disease; monocytes and macrophages play an important role in the progression of this disease. However, the mechanisms are not fully understood yet. Nicotinamide phosphate transferase (NAMPT) is the rate limiting enzyme in the synthesis of NAD, but extracellular NAMPT shows the characteristics of cytokines/adipokines, suggesting that it may be a link between metabolism and inflammation. In this study, we compared the expression levels of the NAMPT/NAD+/Sirt1 signaling pathway as well as NAMPT, CRP and IL-6 in the peripheral blood mononuclear cell (PBMC), and plasma in patients with acute coronary syndromes and healthy subjects, and analyzed their association with macrophage polarization. The relationship between eNAMPT and iNAMPT and the polarization of macrophages was analyzed by NAD+, NAMPT blocker, and neutralizing antibody treatment. The results showed that the expression of the NAMPT/NAD+/Sirt1 signaling pathway was up-regulated in the peripheral blood of patients with ACS. Inhibition of iNAMPT expression can reduce M1 polarization; however, there was no significant effect on eNAMPT secretion and M2 polarization. Neutralizing eNAMPT by neutralizing antibodies can reduce M2 polarization and decrease the expression levels of IL-10, IL-13, IL-4 and IL-1ra. The addition of NAD+ in the cell culture supernatant had no significant effect on the polarization of M1 but increased the M2 polarization and the expression levels of IL-10 and IL-1ra. Our findings suggested that NAMPT is involved in the pathogenesis of atherosclerosis; the increased expression of eNAMPT in ACS patients may play a protective role by the up regulation of the NAMPT/NAD+/Sirt1 signaling pathway.

Increased gene expression levels of sodium-glucose cotransporter 1 (SGLT1) are associated with hypertrophic and ischemic cardiomyopathy. However, it remains unclear whether chronic pressure overload increases SGLT1 expression, which in turn induces hypertrophic cardiomyopathy. We hypothesized that pressure overload could increase SGLT1 gene expression, leading to the development of hypertrophic cardiomyopathy.

To create pressure overload-induced cardiomyopathy, transverse aortic constriction (TAC) was performed in SGLT1-deficient (SGLT1^-/-) and wild-type (WT) mice. Six weeks after surgery, all mice were investigated. We observed a reduction of left ventricular fractional shortening and left ventricular dilatation in TAC-operated WT but not in TAC-operated SGLT1^-/- mice. SGLT1, interleukin 18, connective tissue growth factor, and collagen type 1 gene expression levels were increased in TAC-operated WT mouse hearts compared with that of sham-operated WT mouse hearts. Moreover, heart/body weight ratio and ventricular interstitial fibrosis were increased in TAC-operated WT mice compared with that of sham-operated WT mice. Interestingly, these factors did not increase in TAC-operated SGLT1^-/- mice compared with that of sham-operated WT and SGLT1^-/- mice. Phenylephrine, an adrenergic α₁ receptor agonist, caused cardiomyocyte hypertrophy in neonatal WT mouse hearts to a significantly larger extent than in neonatal SGLT1^-/- mouse hearts.

In conclusion, the results indicate that chronic pressure overload increases SGLT1 and IL-18 gene expressions, leading to the development of hypertrophic cardiomyopathy. These results make SGLT1 a potential candidate for the therapeutic target for hypertension-induced cardiomyopathy.

For the suppression of inflammation in the aneurysm development, we focused on inhibition of an important transcription factor, nuclear factor-kappa B (NF-κB), using a decoy strategy. We newly developed a novel bioabsorbable sheet that delivers NF-κB decoy oligodeoxynucleotide (ODN).

We treated 5-week-old SD rats that were induced with abdominal aortic aneurysm (AAA) using 0.5 M CaCl₂ with an NF-κB decoy sheet. Four weeks after AAA induction, aortic tissue was excised for further examinations. We showed that this bioabsorbable sheet could deliver the decoy ODN into the target tissues and dissolve within a week. Treatment with the NF-κB decoy sheet reduced the aneurysm size compared with the controls. It also suppressed inflammation due to the effect of NF-κB decoy ODN. Immunohistochemistry revealed that the expression of CD31, CD4, and CD11b in the NF-κB decoy sheet group was significantly lower than in the control sheet group. The NF-κB decoy sheet was absorbed on the target tissue.

We have revealed that the bioabsorbable sheet mediated decoy ODN is effective for transfection into target organs. We have also indicated that NF-κB decoy ODN transfection using this sheet has the potential to suppress the dilatation of aneurysm. The bioabsorbable sheet mediated transfection of the decoy ODN can be beneficial for the clinical treatment of AAA and other NF-κB-related cardiovascular diseases.

A 53-year-old male presented with acute myocardial infarction and was subsequently implanted with a 4.0 × 28 mm everolimus-eluting platinum chromium stent in his proximal left anterior descending artery. Eight months after the implantation, he developed exertional angina and underwent coronary angiography, which revealed significant in-stent restenosis (ISR). Percutaneous coronary intervention was performed 1 month later, and the pre-procedural optical coherence tomography (OCT) revealed a diffusely bordered and rapidly attenuated signal-poor region with invisible stent struts at ISR site, potentially indicating a "lipid-laden" neointima. The ISR lesion was excised using a novel directional coronary atherectomy catheter. The histological analysis of the retrieved restenotic tissues revealed substantial inflammation characterized by abundant foamy macrophages and T-cell infiltration. This "inflammatory" neointimal tissue with numerous macrophages (without a necrotic core) detected on OCT was not expected owing to the absence of a known feature of macrophages on OCT (i.e., high backscattering with remarkable attenuation). The current histological confirmation of in vivo OCT findings of restenotic neointima indicated that a "lipid-laden" neointima on OCT may not necessarily reflect necrotic core accumulation, and this could be attributed to substantial inflammation with abundant macrophages.

Hemoptysis is a rare complication of acute aortic dissection. A 77-year-old woman was admitted to our department with epigastralgia and hemoptysis. Computed tomography showed Stanford A acute aortic dissection and massive posterior mediastinal hematoma which extended along the right pulmonary artery. Hemoptysis is a lethal sign of aortic dissection, therefore, emergency ascending aortic replacement was performed with a good clinical outcome.

A 74-year-old man was admitted for preoperative screening of aortic stenosis. Five months before this admission, he was found to have elevated serum immunoglobulin G4 (IgG4; 2,010 mg/dL). Computed tomography (CT) showed a soft tissue mass surrounding the abdominal aorta, suggestive of IgG4-related periaortitis. CT coronary angiography showed perivascular thickening of the right coronary artery, and subsequent coronary angiography showed a multi-vessel disease. The patient underwent aortic valve replacement and coronary bypass surgery. Immunohistochemical analysis showed IgG4-positive plasmacytic infiltration in specimens from the aortic valve, epicardium, and aortic adventitia, suggestive of the possible role of IgG4-related immune inflammation for the pathogenesis.

IgG4-related disease (IgG4-RD) is a fibro-inflammatory disorder characterized by lymphoplasmacytic infiltration of numerous IgG4-positive plasma cells, leading to fibrous thickening in the affected tissue. Typical cardiovascular manifestations of IgG4-RD are periaortitis, coronary arteritis, and pericarditis. Rare cases of myocardial involvement in IgG4-RD have been reported, but surgical resection or open biopsy was required for the diagnosis in those cases. Here, we report a case in which percutaneous transcatheter biopsy under the guidance of intracardiac echocardiography was useful for diagnosis of IgG4-RD manifested as an intracavitary right atrial mass, extending into the superior vena cava. Successful transcatheter diagnosis of myocardial involvement of IgG4-RD led to immediate favorable response to steroid therapy. Including the present case, previous IgG4-RD cases with myocardial involvement are reviewed to delineate its clinical characteristics.

Hemodynamically significant patent ductus arteriosus (PDA) in preterm infants increases morbidity and mortality. Here we describe a 12-day-old neonate with a huge PDA who developed pulmonary hemorrhage following disseminated intravascular clotting and multiple organ failure. Medical treatment or surgical ligation could not be performed because of the patient's poor condition. Transcatheter closure using a commercially available device (Amplatzer Vascular Plug II) successfully treated the huge PDA without major complications. The Amplatzer Vascular Plug II approach might become a new option for PDA closure in small infants, including those who are critically ill.

Pulmonary artery damage is difficult to estimate in a patient with one pulmonary artery from the aorta, and the pulmonary artery of anomalous origin is usually damaged. We describe a newborn patient with anomalous origin of the right pulmonary artery from the aorta who presented with significant lung perfusion at the anastomotic site 6 months postoperatively; the left/right perfusion ratio was 10:90 on a scintigram. The unbalanced left/right lung perfusion gradually improved over a number of years. In a newborn patient with anomalous origin of one pulmonary artery from the aorta, unbalanced lung perfusion may improve.

It is widely known that β-blockers exert beneficial effects on non-ischemic and ischemic systolic heart failure (sHF) in nonstructural hearts. However, whether β-blockers exert similar effects on sHF associated with congenital heart disease (CHD), particularly in an anatomical right ventricle, remains under debate.

Here we report the case of an adult man with repaired tetralogy of Fallot suffering from biventricular heart failure. Treatment with carvedilol directly improved the systolic function of the right and left ventricles. This case report strongly suggests there is potential for carvedilol to exert a beneficial effect on heart failure in CHD. The appropriate titration of carvedilol and patient follow-up for long-term effects are important when treating adult patients with CHD with β-blockers.

Angiogenesis inhibitors, such as sorafenib and axitinib, which target vascular endothelial growth factor (VEGF) signaling, are widely used for renal cell carcinoma, including metastasis. In this study, we report a case of cardiovascular adverse events of aortic dissection and cardiac dysfunction during treatment with sorafenib and axitinib for metastatic renal cell carcinoma. A 66-year-old man had been administered sorafenib for 2 years after nephrectomy due to renal cell carcinoma. To control the progression of metastatic lung tumor, axitinib was started after sorafenib for four years. During the treatment, angiotensin II type 1 receptor blockers and Ca antagonists were used to strictly control the axitinib-induced hypertension and proteinuria. Aortic dissection and cardiac dysfunction occurred coincidentally. Considering the critical role of VEGF signaling in the homeostasis of the cardiovascular system, we speculated that the long-term use of axitinib and sorafenib directly influenced the initiation of aortic dissection and cardiac dysfunction. Although the precise mechanisms underlying the aortic dissection and cardiac dysfunction induced by angiogenesis inhibition are still elusive, onco-cardiologists and oncologists should pay careful attention to cardiovascular toxicity and complications in patients with cancer, particularly patients undergoing long-term cancer treatment.

Vascular Ehlers-Danlos syndrome (vEDS), a genetic disorder caused by mutations in procollagen type III gene (COL3A1), may lead to fatal vascular complication during peripartum period because of the arterial fragility. We experienced a case of vEDS with peripartum life-threatening arterial rapture diagnosed by next-generation sequencing (NGS) and successfully treated the vascular complications. A 25-year-old female in pregnancy at 34 weeks had sudden and acute pain in the left lower abdomen. After successful delivery, her computed tomography scan showed a dissecting aneurysm of the left common iliac artery (CIA). Four days after delivery, she presented in hemorrhagic shock induced by arterial rupture in the CIA. Since her clinical presentations inferred vEDS even in the absence of familial history, we performed NGS-based genetic screening for inherited connective tissue disorders including vEDS with informed consent. Even though we started intensive medication, her iliac aneurysm was progressively enlarging within 3 weeks. After an urgent molecular diagnosis for vEDS (a splice-site mutation), cautious endovascular therapy for her CIA aneurysm was successfully performed. This is the first report for pretreatment molecular diagnosis of vEDS using NGS in an emergent situation of severe vascular complications.

Riociguat, a soluble guanylate cyclase stimulator, induces pulmonary artery dilatation through blood flow and is effective in treating chronic thromboembolic pulmonary hypertension (CTEPH). There are two types of vasculopathies in CTEPH based upon its location, in other words, proximal or distal to the thrombus-medicated obstruction. Distal vasculopathy is characterized by intrapulmonary shunts due to diminished blood flow. While other therapeutic interventions for CTEPH including pulmonary endarterectomy and balloon pulmonary angioplasty achieve reperfusion to the distal vasculopathy vessels, the effects of riociguat on distal vasculopathy vessels remain undetermined. Herein, we describe a case of a 66-year-old woman who exhibited deterioration of mean pulmonary artery pressure and exercise tolerance after a 4-month treatment with riociguat. She received balloon pulmonary angioplasty prior to riociguat administration. Her lung perfusion scintigraphy and pulmonary angiography findings did not change over the course of treatment. Notably, after the discontinuation of riociguat, her clinical values returned to their levels prior to riociguat administration. Her intrapulmonary shunt ratio followed a similar course as her hemodynamic status. We demonstrate that riociguat can deteriorate hemodynamic status, which may mediate the dilatation of intrapulmonary shunts. We should perform close monitoring of symptoms and hemodynamic status after riociguat administration, especially in patients in whom the reperfused DVs occurred due to invasive treatment.