The endomyocardial biopsy (EMB) method was first developed by Japan's Dr. Souji Konno in 1962. Since then, this technique has been used worldwide in clinical cardiology for the recognition and diagnosis of cardiomyopathies, arrhythmias, and other heart conditions. Many studies relating to the EMB have been published at the global level, including a large review by Cooper, et al.,¹⁾ wherein a limited selection of Japanese papers were cited despite considerable pioneering work on the EMB having been done in Japan. Following this, the Cardiac Biopsy Conference (CABIC) organization, which was founded in Japan in 1979, conducted a nationwide survey of the English language literature on the EMB. Among the collection of 500 studies compiled, approximately 40 abstracts have been selected by the co-editors in CABIC for further discussion. This report aims to supplement Cooper's work and bring to light other prominent contributions of Japanese researchers on the EMB.

The quality-adjusted life year (QALY) and incremental cost-effectiveness ratio (ICER) are important concepts in cost-effectiveness analysis, which is becoming increasingly important in Japan. QALY is used to estimate quality of life (QOL) and life years, and can be used to compare the efficacies of cancer and cardiovascular treatments. ICER is defined as the difference in cost between treatments divided by the difference in their effects, with a smaller ICER indicating better cost-effectiveness. Here, we present a review of cost-effectiveness analyses in Japan as well other countries. A number of treatments were shown to be cost-effective, e.g., statin for secondary prevention of cardiovascular disease, aspirin for primary prevention of cardiovascular disease, DOAC for high-risk atrial fibrillation, beta blockers, ACE inhibitors, and ARB for heart failure, sildenafil and bosentan for pulmonary hypertension, CABG for multi-vessel coronary disease, ICD for ventricular tachycardia, and CRT for heart failure with low ejection fraction, while others were not cost-effective, e.g., epoprostenol for pulmonary hypertension and LVAD for end-stage heart failure. Further investigations are required regarding some treatments, e.g., PCSK-9 inhibitors for familial hypercholesterolemia, PCI for multi-vessel coronary disease, catheter ablation for atrial fibrillation, and TAVI for severe aortic stenosis. Ethical aspects should be taken into consideration when utilizing the results of cost-effectiveness analysis in medical policy.

It is not clear if anti-restonotic effect of cilostazol is consistent for different types of drug-eluting stents (DES).

The purpose of this study was to compare the anti-proliferative effect of cilostazol between DAT and TAT with consideration of confounding influences of DES type.

Nine hundred and fifteen patients were randomized to either dual antiplatelet therapy (DAT; aspirin and clopidogrel) or triple antiplatelet therapy (TAT; aspirin, clopidogrel, and cilostazol) in the previous CILON-T trial. After excluding 70 patients who received both or neither stents, we analyzed 845 patients who received exclusively PES or ZES, and compared in-stent late loss at 6 months between both antiplatelet regimens (DAT versus TAT).

Baseline angiographic and clinical characteristics were similar between the DAT (656 lesions in 425 patients) and the TAT group (600 lesions in 420 patients). The 6-month follow-up angiography was completed in 745 patients (88.2%). Quantitative coronary angiography showed that TAT significantly reduced in-stent late loss (DAT 0.62 ± 0.62 mm versus TAT 0.54 ± 0.49 mm, P = 0.015). Stent type, diabetes or lesion length did not interact with difference of late loss. However, reduction of late loss by cilostazol did not lead to a significant reduction in the rate of target lesion revascularization (TLR) (DAT 7.8% versus TAT 6.9%, P = 0.69) due to a nonlinear relationship found between late loss and TLR.

The TAT group showed less in-stent late loss as compared to the DAT group. This was consistently observed regardless of DES type, lesion length, or diabetic status. However, reduction of late loss by cilostazol did not lead to a significant reduction in TLR.

Although drug-eluting stents (DESs) reduce the rates of in-stent restenosis (ISR) and subsequent target lesion revascularization, stent fracture (SF) after DES implantation has become an important concern because of its potential association with restenosis and stent thrombosis. We aimed to assess the pathogenic impact of SF on in-stent restenotic neointimal tissue components after DES implantation. We analyzed 43 consecutive patients (14 with SF and 29 without SF) with ISR requiring revascularization after DES implantation between January 2008 and March 2014. For evaluation of in-stent tissue components, integrated backscatter intravascular ultrasound (IB-IVUS) was performed. SF was defined as complete or partial separation of stent segments observed using plain fluoroscopy or intravascular ultrasound. On volumetric IB-IVUS analyses, patients with SF had a significantly higher percentage of lipid tissue volume within the neointima and a significantly lower percentage of fibrous tissue volume than those without (37.3 ± 18.9% versus 24.9 ± 12.4%, P = 0.02, and 61.2 ± 18.3 versus 72.6 ± 12.1%, P = 0.04, respectively). Moreover, SF was positively correlated with the percentage of lipid volume on multiple linear regression analysis after adjustment for confounding factors (β = 0.36, P = 0.03). The interval from stent implantation was similar in both groups (47.0 ± 28.7 versus 37.7 ± 33.3 months; P = 0.39). In conclusion, SF is associated with larger lipid tissue volume within the neointima after DES placement, suggesting a contribution to the development of neoatherosclerosis and vulnerable neointima. Thus SF might lead to future adverse coronary events.

A relationship between serum polyunsaturated fatty acids (PUFAs) and cardiovascular disease has been reported; however, the existence of a relationship between serum PUFAs and extent of vessel disease (VD) in patients with ST elevation myocardial infarction (STEMI) remains unclear.

Between July 2011 and June 2015, 866 consecutive STEMI patients underwent emergent percutaneous coronary intervention, 507 of whom were enrolled and classified into three groups according to the initial angiograms: 1VD, 294 patients; 2VD, 110 patients; and 3VD/left main trunk disease (LMTD), 103 patients. Serum levels of PUFAs, including eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and arachidonic acid, and other laboratory data during hospitalization were evaluated.

The serum EPA level in the 3VD/LMTD group was significantly lower than that in the 1VD group (55.5 ± 22.1 versus 66.2 ± 28.7, P = 0.002) and was slightly lower than that in the 2VD group (55.5 ± 22.1 versus 65.2 ± 28.9, P = 0.0167). Multivariate adjustment analysis revealed that age ≥ 70 years (odds ratio, 1.72; 95% confidence interval, 1.03-2.89; P = 0.038) and a low serum EPA level (odds ratio, 0.98; 95% confidence interval, 0.99-1.00; P = 0.023) were independent risk factors for 3VD/LMTD, while a low serum DHA level was not.

A low serum EPA level may be more strongly related than a low serum DHA level to the extent of VD in STEMI patients. Age ≥ 70 years and a low serum EPA level may be independent risk factors for 3VD/LMTD.

Defibrillation threshold (DFT) testing during implantable cardioverter defibrillator (ICD) implantations is considered necessary for appropriate shock therapy and to measure the safety margin. However, the relationship between the DFT with modern era devices and the clinical outcome, including the total mortality is limited, which may lead to DFT testing itself being questioned. This study aimed to evaluate the relationship between the DFT and clinical outcome in ICD recipients.

We enrolled 81 consecutive patients (66 males, aged 64.6 ± 13.8 years) who received an ICD implantation and underwent DFT testing. The DFT was measured with a step-by-step method in the patients upon implant. Further, we evaluated the relationship between the DFT and the clinical outcome, which included major cardiac adverse events and any cause of death.

The mean DFT was 11.6 ± 9.24J in total. In 40 patients (49.4%), VF was terminated by a low output (5J), whereas 11 patients (13.6%) had a high DFT. The rates of atrial fibrillation were significantly higher in the high DFT group (63.6% versus 24.2%, P = 0.007). During the observational period (median 432 days; range from 151 days to 1146 days), the incidence of clinical events occurred in 22 patients (27.2%) in total. In a multivariate analysis, a high DFT was the only predictive factor for the incidence of the clinical outcome (OR 4.54, 95% CI 1.03-21.9, P = 0.045).

Pulmonary vein isolation (PVI) is a cornerstone therapy for atrial fibrillation (AF). Although severe complications are rather rare, the development of an atrio-esophageal fistula (AEF) is a fatal complication with a very high mortality even after surgical treatment. The use of esophageal temperature probes (ETP) during PVI may protect the esophagus but it is still under debate since the ETP may also lead to esophageal lesions. The aim of this study was to evaluate the clinical safety of PVI using contact-force (CF) sensing catheter without esophageal temperature monitoring.

We investigated 70 consecutive patients who underwent point-by-point PVI without usage of ETP and who underwent esophago-gastro-duodenoscopy (EGD) with detailed evaluation of the esophagus after the index PVI procedure. The operator attempted to keep CF within the 10-40 g range. The incidences of esophageal lesions (EDEL) detected by endoscopy were then analyzed.

Two of 70 patients (2.9%) showed EDEL consisting of one longitudinal ulcer-like erythematous lesion with fibrin and a different one consisting of a round-shaped lesion surrounded by erythema and petechial hemorrhage. All EDEL healed within two weeks under high proton-pump inhibitor therapy without developing AEF as proven by a second EGD of the esophagus.

Point-by-point PVI without usage of ETP showed a low incidence of EDEL (2.9%); atrio-esophageal fistula was absent. Further studies on the necessity of ETP under CF control are necessary.

As for nonvalvular atrial fibrillation (NVAF) patients with left atrial thrombus or spontaneous echo contrast (LAT/SEC), we evaluated the additional predictive value of serum uric acid (SUA) and Left atrial diameter (LAD) for CHADS₂ and CHA₂DS₂-VASc, and explored the influence from the level of SUA and LAD to LAT/SEC in moderate risk group. Thus, we put forward the concept of a borderline high risk group to guide clinical anticoagulant therapy in patients with NVAF.

A total of 284 NVAF patients without the history of anticoagulant prior to hospitalization were enrolled. They were divided into LAT/SEC group or No LAT/SEC group according to transesophageal echocardiography (TEE). Then, we explored and compared the additional predictive value of serological and ultrasonic indexes after combining them to CHADS₂/CHA₂DS₂-VASc.

61 patients (21.48%) had LAT/SEC. SUA and LAD were the independent risk factors of LAT/SEC. After being added with LAD and SUA, the predictive value of CHADS₂ and CHA₂DS₂-VASc were increased much more than others. In the moderate risk group, the incidence of LAT/SEC rose significantly when SUA or LAD was higher than cut-off values.

SUA and LAD enhanced the predictive ability of CHADS₂ and CHA₂DS₂-VASc for LAT/SEC as additional factors. For patients in moderate risk group, if SUA or LAD was higher than cut-off values, the risk of thromboembolism events would rise accompanied by the elevated risk of LAT/SEC.

Totally thoracosopic mitral valve replacement (MVR) has been applied to mitral stenosis for many years. Three working ports are usually necessary, among which the longest port ranges from 6 to 8 cm. This study aimed to determine the safety and feasibility of the two-incision totally thoracoscopic approach for MVR, with the longest incision of 3 cm.

From January 2014 to February 2016, 90 patients with mitral valve stenosis were retrospectively analyzed. Thirty-six (40%) patients were included in the two-incision group and 54 patients were operated on using the sternotomy approach. Perioperative variables and postoperative 3-month follow-up data were analyzed.

All patients underwent MVR. Tricuspid valvuloplasty was performed in 23 (25.5%) patients with the Kay technique. The mean total surgery time, cardiopulmonary bypass, and cross-clamp times were longer in the two-incision group (266 ± 42 versus 200 ± 38 minutes; 156 ± 23 versus 121 ± 21 minutes; 100 ± 17 versus 80 ± 17 minutes, respectively) (P < 0.05). The mean postoperative mechanical ventilation time was shorter in the two-incision group (8.6 ± 2.5 versus 11.2 ± 2.6 hours, respectively) (P < 0.05). The mean volume of blood drainage was less in the two-incision group (497 ± 120 versus 730 ± 198 mL, respectively) (P < 0.05). Reopening occurred in one (sternotomy group, 1.8%) patient. No deaths, perivalvular leakage, infectious endocarditis, atelectasis of the lungs, or moderate tricuspid regurgitation were found at the 3-month follow-up.

The two-incision totally thoracoscopic approach for MVR is safe and feasible. Concomitant tricuspid valvuloplasty can be conveniently performed. However, further clinical data are needed in future studies.

As Japan has one of the most rapidly aging populations in the world, transcatheter aortic valve implantation (TAVI) is likely to be performed in increasing numbers of older people. There is little information on either the efficacy or the safety of TAVI in nonagenarians in Asia.

From October 2013 to June 2015, 112 consecutive patients underwent TAVI with Edwards SAPIEN XT valves in our institution. We compared 25 patients aged at least 90 years (mean 91.6 ± 1.7 years) with 87 patients aged under 90 years (mean 82.5 ± 6.0 years) at the time of TAVI. All definitions of clinical endpoints and adverse events were based on the Valve Academic Research Consortium 2 definitions.

The median follow-up interval was 561.5 days (the first and third quarters, 405.0 and 735.8 days). Nonagenarians had a higher logistic European System for Cardiac Operative Risk Evaluation (EuroSCORE), Euro II score, and the Society of Thoracic Surgeons predictive risk of mortality (STS) score, and a prevalence of clinical frailty scale ≥ 4. The rate of device success, and the 30-day and 6-month mortalities were not different between patients aged ≥ 90 years and < 90 years (96.0% versus 92.0%, P = 0.68; both 0%, P = 1.00; 4.0% versus 3.5%, P = 0.32, respectively). At six months, clinical efficacy and time-related valve safety were also similar in the two groups (12.5% versus 13.4%, P = 1.00; 4.5% versus 10.3%, P = 0.68, respectively). The cumulative 1-year mortalities were not significantly different between the two groups (8.4% versus 9.4%, P = 0.94, respectively).

TAVI can contribute to acceptable clinical results and benefits in a carefully selected group of nonagenarians in Asia.

Thyroid dysfunction is prevalent in patients with heart failure (HF) and hypothyroidism is related to the adverse prognosis of HF subjects receiving cardiac resynchronization therapy (CRT). We aim to investigate whether low-normal free triiodothyronine (fT3) level is related to CRT response and the prognosis of euthyroid patients with HF after CRT implantation.

One hundred and thirteen euthyroid patients who received CRT therapy without previous thyroid disease and any treatment affecting thyroid hormones were enrolled. All of patients were evaluated for cardiac function and thyroid hormones (serum levels of fT3, free thyroxine [fT4] and thyroid-stimulating hormone [TSH]). The end points were overall mortality and hospitalization for HF worsening. During a follow-up period of 39 ± 3 weeks, 36 patients (31.9%) died and 45 patients (39.8%) had hospitalization for HF exacerbation. A higher rate of NYHA III/IV class and a lower fT3 level were both observed in death group and HF event group. Multivariate Cox regression analyses disclosed that a lower-normal fT3 level (HR = 0.648, P = 0.009) and CRT response (HR = 0.441, P = 0.001) were both independent predictors of overall mortality. In addition, they were also both related to HF re-hospitalization event (P < 0.01 for both). Patients with fT3 < 3.00 pmol/L had a significantly higher overall mortality than those with fT3 ≥ 3.00 pmol/L (P = 0.027). Meanwhile, a higher HF hospitalization event rate was also found in patients with fT3 < 3.00 pmol/L (P < 0.001).

A lower-normal fT3 level is correlated with a worse cardiac function an adverse prognosis in euthyroid patients with HF after CRT implantation.

Arterial stiffness is an important risk factor for cardiovascular disease (CVD) in patients with end-stage renal failure. However, little is known about the factors that contribute to arterial rigidity in peritoneal dialysis (PD) patients. The aim of this study was to define the pattern and determinants of the longitudinal change in arterial stiffness after PD initiation.

Arterial stiffening was estimated for 46 PD patients by using brachial-ankle pulse wave velocity (baPWV) and carotid intima-media thickness (cIMT). The cross-sectional relationship between the arterial markers and their clinical determinants was studied. The longitudinal effects of blood pressure (BP), body fluid status, and glucose were studied over the two years after initiating PD.

Multivariate analysis showed that higher baPWV was associated positively with urinary protein excretion (P < 0.001), systolic BP (P = 0.001), and hemoglobin A1c (P = 0.003). In contrast, increased cIMT correlated with smoking (P = 0.004) and hypoalbuminemia (P = 0.04), suggesting that endothelial dysfunction is implicated in the atherogenic process. Neither cIMT nor baPWV correlated significantly with other PD-related covariates of volume overload, peritoneal solute transport, kidney function, and C-reactive protein. Longitudinal observation demonstrated that BP had a greater influence on baPWV changes than hyperglycemia or fluid status.

Our study indicates that 1) baPWV represent an arterial marker that integrates multifactorial interaction between modifiable variables including BP and plasma glucose; and 2) intervention aimed at controlling BP as well as nutritional conditions (glucose and albumin) may reduce CVD risk in PD patients.

Glucosamine, used to treat osteoarthritis, has been shown to have anti-inflammatory and anti-atherosclerotic effects in experimental studies. A recent cohort study has demonstrated that the use of glucosamine was significantly associated with decreased total mortality. Vascular endothelial function is a potent surrogate marker of atherosclerosis and cardiovascular mortality where oxidative stress could participate. Therefore, we investigated whether glucosamine improves vascular endothelial function and intracellular redox state. We examined the effects of oral glucosamine administration (3000 mg/day) for 4 weeks on flow-mediated vasodilation (FMD) and intraerythrocyte glutathione parameters in 20 volunteers. Nineteen age-matched volunteers served as controls. Glucosamine administration significantly increased FMD (from 7.0 ± 2.3 to 8.7 ± 2.3%, P = 0.022). In the control group, FMD did not change. Glucosamine administration significantly increased intraerythrocyte total glutathione levels (from 212.9 ± 46.2 to 240.6 ± 49.4 μmol/L, P = 0.006), intraerythrocyte reduced form of glutathione (GSH) levels (from 124.7 ± 42.6 to 155.2 ± 47.7 μmol/L; P = 0.004) and intraerythrocyte GSH/oxidized form of glutathione (GSSG) ratios (from 3.18 ± 1.64 to 3.88 ± 1.61, P = 0.04). In the control group, any glutathione parameters did not change. Moreover, a stepwise multivariate analysis revealed percent change of GSH/GSSG is the only independent predictor for those of FMD (standardized β = 0.58, P = 0.007) in the glucosamine group. Glucosamine administration improved FMD in association with amelioration of intraerythrocyte GSH/GSSG ratios. These results suggest that oral glucosamine administration might improve vascular endothelial function by modulating intracellular redox state.

In the Japanese population, the electrocardiographic (ECG) Cornell voltage and product predict cardiovascular events at lower values (Cornell voltage of 2.04 mV in males and 1.71 mV in females, and Cornell product of 158.7 mV× msec) than in the guidelines (2.8 mV, 2.0 mV, and 244 mV× msec, respectively). We evaluated the ECG criteria for left ventricular hypertrophy (LVH) corresponding to echocardiographic LVH (Echo-LVH) in Japanese patients.

We reviewed data on 345 consecutive hypertensive patients who underwent echocardiography, and evaluated the Cornell voltage (S in leads V3 + R in leads aVL), Cornell product [ (Cornell voltage + 0.6 mV for females) × QRS duration], and left ventricular mass index (LVMI) (Echo-LVH: LVMI ≥ 116 g/m² in males and ≥ 96 g/m² in females).

The mean age was 63.8 ± 12.5 years (174 males/172 females). Echo-LVH was found in 22.7% of males and 37.2% of females. The equations for estimating LVMI from the Cornell voltage were (1) LVMI = 14.5 × Cornell voltage + 78.9 for males and (2) LVMI = 21.5 × Cornell voltage + 61.5 for females. The Cornell voltage corresponding to Echo-LVH was 2.6 mV in males and 1.6 mV in females, which were below the guideline levels and close to the values indicating cardiovascular risk. The equation for estimating LVMI from the Cornell product was LVMI = 0.15 × Cornell product + 68.8. The Cornell product corresponding to Echo-LVH was 170 mV× msec (sensitivity: 0.730, specificity: 0.601), which was also close to the cardiovascular risk level.

Cornell voltage and product values indicating Echo-LVH are lower than those in the current guidelines and closer to the cardiovascular risk levels.

DTNA encoding dystrobrevin-α (α-DB) is a putative causal gene associated with left ventricular noncompaction cardiomyopathy (LVNC). The aim of the study was to investigate the causal role of DTNA in LVNC using a transgenic mouse model.

A missense mutation (c.146A > G, p.N49S) of DTNA was identified in a patient with LVNC by Sanger sequencing. Six independent lines of transgenic mice expressing the mutant DTNA under a myosin heavy chain 6 (Myh6) promoter were generated (Myh6:Dtna^N49S). Phenotypic characteristics of DTNA-p.N49S mutations were evaluated by echocardiography, histological observation, and immunoblotting. Multiple trabeculation and a higher ratio of non-compacted to compact myocardial layer were found in the Myh6:Dtna^N49S mice compared to the controls. The transgenic mice also showed left ventricular (LV) dilation and cardiac systolic dysfunction. In conclusion, overexpression of the DTNA-p.N49S mutation in a mouse heart can be responsible for the phenotype of deep trabeculation, dilated cardiomyopathy, and cardiac dysfunction, which resembles the phenotype of LVNC.

Pulmonary arterial hypertension (PAH) is characterized by pulmonary vascular remodeling leading to right ventricular hypertrophy (RVH) and failure. Peroxisome proliferator-activated receptor γ (PPARγ), a member of nuclear receptors, has been proved to ameliorate PAH. However, its effect on PAH-induced right ventricular failure (RVF) remains unknown. Therefore, we investigated the therapeutic potential of PPARγ in preventing monocrotaline (MCT)-induced RV dysfunction. The PAH model was induced by MCT administration. Male rats were administered with MCT to develop PAH and RVF formed by approximately day 30. Significant increase in RV area, RVAW resulted in an ascending RV index. However, the LV function including EF, FS, and LVID did not change significantly. PPARγ agonist prevented PAH-induced RVF by preserving RV index and preventing RVH. PPARγ's beneficial effects seem to result from various factors, including anti-apoptosis, preservation RV index, reversal of inflammation, improvement of glucolipid metabolism, reduction of ROS. In a word, PPARγ agonist prevents the development of RVF.

Ryanodine receptor type 2 (RyR-2), the main Ca²⁺ release channel from sarcoplasmic reticulum in cardiomyocytes, plays a vital role in the regulation ofmyocardial contractile function and cardiac hypertrophy. However, the role of RyR-2 in cardiac fibrosis during the development of cardiac hypertrophy remains unclear.

In this study, we examined whether RyR-2 regulates TGFβ1, which is secreted from cardiomyocytes and exerts on cardiac fibrosis using cultured cardiomyocytes and cardiac fibroblasts of neonatal rats. The expression of RyR-2 was found only in cardiomyocytesbut not in cardiac fibroblasts. Mechanical stretch induced upregulation of TGFβ1 in cardiomyocytes and RyR-2 knockdown significantly suppressed the upregulation of TGFβ1 expression. The transcript levels of collagen genes were also decreased in fibroblasts compare with wild type, although the expression of both two kinds was higher than those in stationary cardiomyocytes (non-stretch). With the inhibition of the TGFβ1-neutralizing antibody, the expression of collagen genes has no significant difference between the mechanically stretched cardiomyocytes and non-stretchedones. These results indicate that RyR-2 regulated TGFβ1 expression in mechanically stretched cardiomyocytes and TGFβ1 promoted collagen formation of cardiac fibroblasts by a paracrine mechanism.

RyR-2 in mechanical stretch could promote the development of cardiac fibrosis involving TGFβ1-dependent paracrine mechanism. Our findings provided more insight into comprehensively understanding the molecular role of RyR-2 in regulating cardiac fibrosis.

We determined the factors associated with the expression of c-kit in the heart and the proliferation of c-kit-positive (c-kit^pos) cardiac stem cells among the outgrowth cells cultured from human cardiac explants.

Samples of the right atrium (RA), left atrium (LA), and left ventricle obtained from patients during open-heart surgery were processed for cell culture of outgrowth cells and tissue analysis. The total number of growing cells and the population of c-kit^pos cells were measured and compared with c-kit expression in native tissues and characteristics of the patients according to the region of the heart.

We analyzed 452 samples from 334 patients. Atrial fibrillation (AF) in the patients reduced the number of outgrowth cells from the RA and LA, and aging was a co-factor for the LA. The c-kit^pos population from the RA was associated with serum brain natriuretic peptide (BNP). C-kit expression in native tissue was also associated with BNP expression. However, we observed no relationship in expression between outgrowth cells and native tissue. In addition, the RA tissue provided the highest number of c-kit^pos cells, and the left ventricle provided the lowest.

C-kit was weakly expressed in response to damage. In addition, no correlation between outgrowth cells and native tissue was found for c-kit expression.

Ryanodine receptors (RyRs), the large homotetrameric protein complexes, regulate the release of calcium from intracellular stores into the cytosol and play vital roles in the excitation-contraction coupling of cells. However, the evolutionary relationship of RyRs in vertebrates has yet to be elucidated. We identified 22 RyRs from Homo sapiens, Mus musculus, Rattus norvegicus, Gallus gallus, Anolis carolinensis, Rana catesbeiana, and Danio rerio. The phylogenetic relationship, motifs analysis and reconstruction of ancestral RyRs showed that the members of RyR family in vertebrates were grouped into three clades: the RyR1 clade, the RyR2 clade, and the RyR3 clade. Positive selection existed in RyR gene evolution, which is consistent in three site models, and gene ontology (GO) analysis showed that the evolution of RyR family in vertebrates promotes RyRs function differentiation. At last, we predicted 140 mutation sites which may be involved in diseases and 57 phosphorylation sites among RyR1 sequence in human, as well as 61 mutation sites and 70 phosphorylation sites in human RyR2 sequences. Most of these potential sites are arranged in clusters. Our work provides insight into the origin and evolutionary process of RyRs in vertebrates, facilitating their functional investigations in the future.

Patients with stage D heart failure (HF) frequently become dependent on high doses of diuretics and inotropic agents. Recently, a sodium-glucose cotransporter 2 inhibitor (SGLT2i), an oral antidiabetic agent, has been demonstrated to have favorable effects in preventing HF. However, it remains unknown whether SGLT2i is reliable for patients with decompensated HF. We experienced a case of a patient with stage D HF for whom attempting intravenous dobutamine withdrawal was difficult even after the administration of all conventional pharmacological treatment. Administration of canagliflozin produced an additive diuretic action and correction of volume overload in combination with azosemide and tolvaptan, and resulted in successful withdrawal of dobutamine. Thus, SGLT2i might be promising for the treatment of patients with congestive HF who are refractory to conventional diuretic treatment.

Percutaneous coronary intervention for the treatment of a severe calcified lesion is still one of the most technically challenging areas of interventional cardiology. Calcified lesions are a cause of stent underexpansion, which significantly increases the subsequent risks of in-stent restenosis and thrombosis, even when drug-eluting stents are used. In this report, we describe the usefulness of prolonged inflations using a scoring balloon catheter (Scoreflex) for severe calcified lesions. Prolonged inflation using a scoring balloon enables an adequate dilation for treatment of a severe calcified plaque that was unresponsive to conventional technique with or without rotational atherectomy.

A 62-year-old Japanese man presented with chest pain indicating that acute myocardial infarction had occurred. Eleven years earlier, he underwent a splenectomy due to idiopathic portal hypertension. Coronary angiography revealed diffuse stenosis, with calcification in the left anterior descending coronary artery (LAD). We performed a primary percutaneous coronary intervention (PCI). We deployed two drug-eluting stents with sufficient minimal cross-sectional stent area by intravascular ultrasound and thrombolysis in myocardial infarction (TIMI) 3 flow. The initial laboratory examination revealed chronic disseminated intravascular coagulation (DIC). On the 8th hospital day, he developed chest pain indicating early coronary stent thrombosis, although he had been prescribed dual antiplatelet therapy. We performed an emergent second PCI, and the TIMI flow grade improved from 0 to 3. Clopidogrel was replaced with prasugrel. On the 18th hospital day, we detected a repeated coronary stent thrombosis again. We performed a third PCI and the TIMI flow grade improved from 0 to 3. After anticoagulation therapy with warfarin, the DIC was improved and his condition ran a benign course without the recurrence of stent thrombosis for 1 month. Contrast-enhanced CT showed portal vein thrombosis. This patient's case reveals the possibility that the condition of chronic DIC can lead to recurrent stent thrombosis. Stent thrombosis is infrequent, but remains a serious complication in terms of morbidity and mortality. Although stent thrombosis is multifactorial, the present case suggests that DIC is a factor in stent thrombosis. To prevent stent thrombosis after PCI under DIC, anticoagulation might be a treatment option in addition to antiplatelet therapy.

We report the case of a 51-year-old female, in whom coronary artery disease such as occlusion of septal perforators was manifested, on the occasion of hospitalization with congestive heart failure. The patient had a history of radiation therapy for a mediastinal tumor 19 years previously. As she had no conventional coronary risk factors, the cause of the coronary artery disease is thought to have been related to the radiation therapy. As survival rates of cancer patients improve as a consequence of therapeutic advances, we should be aware of the possibility of coronary artery disease as a very late complication of radiation therapy, even in patients who have no coronary risk factors.

The progression of heart failure with reduced ejection fraction is promoted by sympathovagal imbalance. Baroreflex activation therapy (BAT) by the electrical stimulation of baroreceptors at the carotid sinus significantly improved exercise capacity and NT-proBNP levels in a randomized trial; however, no significant difference in left ventricular ejection fraction (LV-EF) between groups was found. Here, we report the case of a 30-year-old man with a long history of dilated cardiomyopathy and severely reduced LV-EF despite optimal medical therapy, who was treated with BAT since October 2014 and showed a remarkable improvement in both symptoms and LV-EF under this treatment.

Loeffler endocarditis is a rare comprehensive cardiac manifestation caused by eosinophilic cell infiltrations and is present in 50%-60% of patients with hypereosinophilic syndrome (HES). Left ventricle (LV) endocardial systolic dysfunction is a major cause of morbidity and mortality in HES and Loeffler endocarditis. We present a case of Loeffler endocarditis, whose left ventricular (LV) systolic dysfunction and endocardial systolic dysfunction were first neglected by conventional transthoracic echocardiography (TTE), but were later pointed out by layer-specific longitudinal strain analysis. With timely initial therapeutic management, the patient's outcome was remarkable. Thus, we strongly recommend strain analysis as a necessary supplementary test of conventional TTE in all patients with Loeffler endocarditis.

A 43-year-old man was referred to our hospital in June 2014 because of severe heart failure. He was diagnosed with familial dilated cardiomyopathy and was administered oral tolvaptan and amiodarone for atrial and ventricular tachycardia. Since up-titration of carvedilol had failed and he was dependent on dobutamine, a left ventricular assist device (LVAD) was implanted. Tolvaptan and furosemide were both discontinued after LVAD implantation and he was discharged from the hospital. Thirteen months later, he was hospitalized for lethargy and hyponatremia of 108 mEq/L, with an antidiuretic hormone level of 2.5 pg/mL, which suggested syndrome of inappropriate antidiuretic hormone secretion (SIADH). We discontinued amiodarone and administered fludrocortisones. However, hyponatremia persisted for a few more days, eventually resulting in delirium and damage to the LVAD driveline. He received an urgent pump exchange and hyponatremia was gradually improved. We considered the possibility that amiodarone-induced SIADH was masked by tolvaptan therapy before LVAD implantation.

A 54-year-old woman with a history of multiple cardiac surgeries suffered from hypoxemia caused by a right-to-left intra-cardiac shunt due to coronary sinus (CS) anomaly with persistent left superior vena cava (PLSVC). Both the contrast echocardiography and enhanced computed tomography (CT) provided conclusive diagnosis of this rare congenital anomaly, which was overlooked for a long time. However, an important diagnostic clue was left-arm injection of the contrast media. In the present case, previously performed enhanced CT with its routine manner, i.e., contrast through the right arm, missed this anomaly. It is crucial to note that the unusual type of unroofed CS with PLSVC, presenting with an entirely right-to-left intra-cardiac shunt, cannot be delineated on an enhanced routine chest CT if the contrast media is injected through the right arm.

Coronary to pulmonary artery fistulas (CPAFs) are abnormal communications between the coronary and pulmonary arteries. They are an uncommon congenital heart disease and usually remain asymptomatic until later in life. However, there is no consensus on their management. We present four adult patients who required surgery for coronary to pulmonary artery fistulas to illuminate this issue. The clinical presentations were variable depending on the anatomical features of coronary to pulmonary artery fistulas and the presence or absence of other cardiac diseases. We successfully performed surgical closure of the coronary to pulmonary artery fistulas in each of the cases. In this report, we describe our experience with these cases and outline the available therapeutic strategies and treatment options for coronary to pulmonary artery fistulas.

We present a case of an infectious pseudoaneurysm after patent ductus arteriosus (PDA) closure with a ventricular septal defect (VSD) occluder in a two-year-old child. The aneurysm grew rapidly but was successfully removed in time and the patient survived. To our knowledge, this is the first report of an infectious pseudoaneurysm caused by VSD occluder in PDA closure.

Here, we report on a healthy 30-year-old man with no significant medical history, who tested negative for human immunodeficiency virus antigenemia but developed Aspergillus pancarditis. A case of this kind is extremely rare, and to the best of our knowledge, this is the first report of a patient with Aspergillus pancarditis, which generally leads to a very poor outcome, who had a long-term favorable clinical course. A biopsy from the right atrium of hypertrophied atrial septum was essential for obtaining the definitive diagnosis. Long-term administration of an effective antifungal oral agent might account for the patient's favorable outcome.

Primary cardiac osteosarcomas are rare entities, mostly arising from the left atrium. Because of their rarity, few reports have described this uncommon lesion. We herein report a case of primary cardiac osteosarcoma originating from the left atrium in a 34-year-old woman, who underwent tumor debulking surgery and died 3 months after being diagnosed.

We describe the case of a 45-year-old Japanese man who developed acute pericarditis following an acute pulmonary thromboembolism. He had developed shortness of breath 7 days prior to hospitalization and was admitted with severe dyspnea. Echocardiography and laboratory results were compatible with acute pulmonary thromboembolism, which was confirmed by contrast-enhanced chest computed tomography. On the third hospital day, he experienced chest pain exacerbated by inspiration. On the fourth hospital day, his body temperature increased to 39°C and echocardiography revealed circumferential pericardial effusion. A diagnosis of acute pericarditis was made and the patient was treated with colchicine and aspirin. On the fifth hospital day, his symptoms largely subsided. Auscultation revealed pericardial friction rub. Electrocardiography demonstrated diffuse ST-segment elevations. Twenty-four days later, computed tomography revealed the disappearance of both the pericardial effusion and pulmonary arterial emboli. This case was thought to be one of acute pericarditis following acute pulmonary thromboembolism.

We are pleased to announce that the following 4 articles have been selected for the the UEDA Heart Awards for the Year 2017.

First Place

Generation of Induced Pluripotent Stem Cells From Patients With Duchenne Muscular Dystrophy and Their Induction to Cardiomyocytes

Akihito Hashimoto, Atsuhiko T. Naito, Jong-Kook Lee, Rika Kitazume-Taneike, Masamichi Ito, Toshihiro Yamaguchi, Ryo Nakata, Tomokazu Sumida, Katsuki Okada, Akito Nakagawa, Tomoaki Higo, Yuki Kuramoto, Taku Sakai, Koji Tominaga, Takeshi Okinaga, Shigetoyo Kogaki, Keiichi Ozono, Shigeru Miyagawa, Yoshiki Sawa, Yasushi Sakata, Hiroyuki Morita, Akihiro Umezawa, Issei Komuro

Int Heart J 2016 ; 57 (1) : 112-117

Second Place

Effect of Allopurinol on Myocardial Energy Metabolism in Chronic Heart Failure Rats After Myocardial Infarct

Zhenzhen Wang, Juan Ding, Xiang Luo, Siliang Zhang, Gang Yang, Que Zhu, Dichuan Liu

Int Heart J 2016 ; 57 (6) : 753-759

Third Place

Plasma Levels of Receptor for Advanced Glycation End-Products and High-Mobility Group Box 1 in Patients With Pulmonary Hypertension

Satoshi Suzuki, Kazuhiko Nakazato, Koichi Sugimoto, Akiomi Yoshihisa, Takayoshi Yamaki, Hiroyuki Kunii, Hitoshi Suzuki, Shu-ichi Saitoh, Yasuchika Takeishi

Int Heart J 2016 ; 57 (2) : 234-240

Tolvaptan Reduces Long-Term Total Medical Expenses and Length of Stay in Aquaporin-Defined Responders

Teruhiko Imamura, Koichiro Kinugawa, Daisuke Nitta, Issei Komuro

Int Heart J 2016 ; 57 (5) : 593-599

November 2017

International Heart Journal Association