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Background: Several studies have reported a relationship between elevated serum adiponectin levels and poor outcomes in patients with heart failure (HF). However, data on the activities of daily living (ADL) in elderly patients with HF are limited., Methods: We evaluated 218 hospitalized elderly (≥65 years) patients with HF who underwent a comprehensive cardiac rehabilitation (CR) program during hospitalization. Serum adiponectin levels were measured before discharge. The Barthel index (BI) score was evaluated at discharge. Low ADL was defined as a BI score < 85., Results: Serum adiponectin levels were significantly associated with low ADL [p = 0.03; odds ratio (OR), 1.024, per 1.0 μg/mL increase]. In logistic or regression analyses adjusted for age, sex, body mass index, and estimated glomerular filtration rate, high adiponectin levels (≥16.2 μg/mL) were significantly associated with low ADL (p = 0.04; OR, 2.53), malnutrition (p < 0.01; OR, 2.88), and 6-min walk distance (p = 0.04; β = -17.5). In the multivariate analysis adjusted for conventional risk factors of low ADL, high adiponectin levels were also significantly associated with low ADL (p = 0.03; OR, 2.68). In the stepwise forward selection procedure, a high adiponectin level was an independent determinant of low ADL (p = 0.02; R 2  = 0.0262). Both net reclassification improvement (0.53; p < 0.01) and integrated discrimination improvement (0.02; p = 0.01) improved significantly after the addition of high adiponectin level to conventional risk factors. In the regression analysis adjusted for age and sex, serum adiponectin levels were significantly (p < 0.0025) negatively associated with abdominal visceral and subcutaneous adipose tissue areas, body weight, body mass index, and serum triglyceride levels., Conclusions: High serum adiponectin levels were not only significantly associated with an increased risk of low ADL, but also with an increased risk of malnutrition and low physical activity in elderly patients with HF after the in-hospital CR program., Competing Interests: Declaration of competing interest The authors declare that there is no conflict of interest., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Objectives: In hypertrophic cardiomyopathy (HCM), specific ECG abnormalities are observed. Therefore, ECG is a valuable screening tool. Although several studies have reported on estimating the risk of developing fatal arrhythmias from ECG findings, the use of ECG to identify the severity of heart failure (HF) by applying deep learning (DL) methods has not been established., Methods: We assessed whether data-driven machine-learning methods could effectively identify the severity of HF in patients with HCM. A residual neural network-based model was developed using 12-lead ECG data from 218 patients with HCM and 245 patients with non-HCM, categorised them into two (mild-to-moderate and severe) or three (mild, moderate and severe) severities of HF. These severities were defined according to the New York Heart Association functional class and levels of the N-terminal prohormone of brain natriuretic peptide. In addition, the patients were divided into groups according to Kansas City Cardiomyopathy Questionnaire (KCCQ)-12. A transfer learning method was applied to resolve the issue of the low number of target samples. The model was trained in advance using PTB-XL, which is an open ECG dataset., Results: The model trained with our dataset achieved a weighted average F1 score of 0.745 and precision of 0.750 for the mild-to-moderate class samples. Similar results were obtained for grouping based on KCCQ-12. Through data analyses using the Guided Gradient Weighted-Class Activation Map and Integrated Gradients, QRS waves were intensively highlighted among true-positive mild-to-moderate class cases, while the highlighted part was highly variable among true-positive severe class cases., Conclusions: We developed a model for classifying HF severity in patients with HCM using a deep neural network algorithm with 12-lead ECG data. Our findings suggest that applications of this DL algorithm for using 12-lead ECG data may be useful to classify the HF status in patients with HCM., Competing Interests: Competing interests: YM reports receipt of scholarship funds or donations scholarship funds from Abbott Medical Japan and BIOTRONIK JAPAN. The other authors declare no conflicts of interest., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective The cardiac function, blood distribution, and oxygen extraction in the muscles as well as the pulmonary function determine the oxygen uptake (VO 2 ) kinetics at the onset of exercise. This factor is called the VO 2 time constant, and its prolongation is associated with an unfavorable prognosis for heart failure (HF). The mitochondrial function of skeletal muscle is known to reflect exercise tolerance. Morphological changes and dysfunction in cardiac mitochondria are closely related to HF severity and its prognosis. Although mitochondria play an important role in generating energy in cardiomyocytes, the relationship between cardiac mitochondria and the VO 2 time constant has not been elucidated. Methods We calculated the ratio of abnormal cardiac mitochondria in human myocardial biopsy samples using an electron microscope and measured the VO 2 time constant during cardiopulmonary exercise testing. The VO 2 time constant was normalized by the fat-free mass index (FFMI). Patients Fifteen patients with non-ischemic cardiomyopathy (NICM) were included. Patients were divided into two groups according to their median VO 2 time constant/FFMI value. Results Patients with a low VO 2 time constant/FFMI value had a lower abnormal mitochondria ratio than those with a high VO 2 time constant/FFMI value. A multiple linear regression analysis revealed that the ratio of abnormal cardiac mitochondria was independently associated with a high VO 2 time constant/FFMI. Conclusion An increased abnormal cardiac mitochondria ratio might be associated with a high VO 2 time constant/FFMI value in patients with NICM.

A 56-year-old woman was referred to our hospital for the further evaluation of drug-refractory heart failure with a reduced ejection fraction. A family history interview revealed that men in her family had died of Duchenne muscular dystrophy (DMD), whereas she had no skeletal muscle disorder. Myocardial histopathology revealed a reduced dystrophin expression in the cardiomyocyte membrane, and a dystrophin (DMD) gene analysis identified a duplication in exon 8-9 on Xp21, suggesting that she had a cardiac-specific phenotype of dystrophinopathy, i.e. X-linked dilated cardiomyopathy (XLDCM). In conclusion, careful family history interviews and an investigation of dystrophinopathy are required to detect XLDCM in women.

About 30% of patients with hypertrophic cardiomyopathy have a significant left ventricular pressure gradient at rest, and 60%-70% of these patients are diagnosed with hypertrophic obstructive cardiomyopathy (HOCM) because an induced pressure gradient is also present. Percutaneous transluminal septal myocardial ablation (PTSMA) is a procedure in which ethanol is used to ablate the portion of the septal myocardium that is involved in the pathogenesis of the left ventricular outflow tract pressure gradient (LVOT PG). In 1995, Sigwart et al. reported three cases of PTSMA in The Lancet. The introduction of PTSMA into clinical practice has enabled the reduction of LVOT PG and improvement of heart failure symptoms in elderly and high-risk patients with symptomatic, drug-refractory HOCM. In 1998, Faber et al. published a report in Circulation on selective septal myocardial ablation using myocardial contrast echocardiography (MCE). MCE-guided PTSMA is now recognized as the standard method of PTSMA in many countries and regions, including Europe, North America, and Asia, and is estimated to be performed on about 300 to 400 patients per year in Japan based on reports from the Japanese Circulation Society's Clinical Practice Survey. The current problems with this technique are: 1) the outcome is greatly influenced by operators' and institutional experience, and 2) it is difficult to determine in advance whether the patient is a PTSMA responder or not. Recently, advancements in imaging modalities, including cardiac computed tomography and magnetic resonance imaging, have facilitated clarification of the mechanisms of LVOT obstruction. Therefore, more appropriate decisions regarding PTSMA and surgical myectomy (SM) are now made. Better treatment selection will undoubtedly improve the prognosis of patients with drug-refractory HOCM complicated by heart failure, and further elucidation of the pathogenesis of LVOT obstruction and technical advances in PTSMA and SM are eagerly awaited., (Copyright © 2021. Published by Elsevier Ltd.)

Purpose: The diuretic effect of tolvaptan is largely blood level-dependent although it does exhibit interindividual differences according to cytochrome P450 (CYP) 3A5 genotype. This study aimed to investigate the pharmacokinetic relationship between plasma tolvaptan and its monohydroxylate enantiomers and the factors affecting their metabolism in heart failure patients., Methods: Japanese heart failure patients (n = 88) receiving oral tolvaptan (median dosage 7.5 mg/day) were enrolled. Blood samples were collected prior to the dosing on day 6 or later after first administration to determine the plasma concentrations of tolvaptan and its monohydroxylate enantiomers. Gene polymorphisms of CYP3A5, carbonyl reductase (CBR) 1/3, and ATP-binding cassette subfamily B member (ABCB) 1 were analyzed for their impact on tolvaptan pharmacokinetics. Serum laboratory test values and concomitant use of amiodarone were evaluated as factors related to tolvaptan metabolism., Results: The median of the sum of the 5S- and 5R-tolvaptan plasma concentrations was 48.9 (range, 15.3-100) ng/mL. CYP3A5 genotypes significantly affected the concentration ratio of all enantiomeric metabolites to tolvaptan, while the other metabolic-related gene polymorphisms had no influence. A negative correlation was found between serum albumin and the enantiomeric ratio of tolvaptan and monohydroxylate DM-4111. Concomitant use of amiodarone increased the plasma levels of whole tolvaptan but significantly decreased the metabolic ratios of 5R-tolvaptan. 5S-tolvaptan was selectively synthesized from ketone MOP-21826 by CBR1 with a substantially smaller reaction velocity compared to tolvaptan monohydroxylation by CYP3A4/5., Conclusion: This study clarified the racemic impact of CYP3A5 genotypes on tolvaptan metabolism. Amiodarone may stereoselectively interact with R-forms rather than S-forms of tolvaptan., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Implantation of a cardiac resynchronization therapy (CRT) device is usually scheduled in the compensated phase of heart failure; however, procedural safety may be sometimes disturbed in the decompensated phase. We report a case of a successful semi-urgent implantation of a CRT device temporary assisted with Impella in a patient with the decompensated phase of severe heart failure dependent on inotropic agents and who cannot maintain the supine position. Impella assistance with left ventricular (LV) unloading and maintenance of end-organ perfusion contributed to early recovery from acute heart failure. Furthermore, an acute effect of mechanical resynchronization by biventricular pacing plays an important role in weaning from the mechanical support or inotropic dependence. These mutual effects of mechanical support and CRT might contribute to a decrease in LV end-diastolic pressure and to a remarkable early recovery from a severely decompensated condition.

Objective: Hypertrophic cardiomyopathy (HCM) is a common genetic disease with diverse morphology, symptoms, and prognosis. Hypertrophied myocardium metabolism has not been explored in detail. We assessed the association between myocardium lipid metabolism and clinical severity of heart failure (HF) in HCM using imaging mass spectrometry (IMS)., Results: We studied 16 endomyocardial biopsy (EMB) specimens from patients with HCM. Analysis was conducted using desorption electrospray ionization IMS. The samples were assigned into two cohorts according to the period of heart biopsy (cohort 1, n = 9 and cohort 2, n = 7). In each cohort, samples were divided into two groups according to the clinical severity of HF in HCM: clinically severe and clinically mild groups. Signals showing a significant difference between the two groups were analyzed by volcano plot. In cohort 1, the volcano plot identified four signals; the intensity in the clinically severe group was more than twice that of the mild group. Out of the four signals, docosahexaenoic acid (DHA) showed significant differences in intensity between the two groups in cohort 2 (10,575.8 ± 2750.3 vs. 19,839.3 ± 4803.2, P = 0.025). The intensity of DHA was significantly higher in EMB samples from the clinically severe HCM group than in those from the mild group., (© 2022. The Author(s).)

Competing Interests: Funding Support and Author Disclosures The authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Tolvaptan efficacy for heart failure has a large interindividual variation. This study aimed to evaluate the influence of CYP3A5 and ABCB1 genotypes on tolvaptan pharmacokinetics and their relationships with plasma markers of CYP3A activity and laboratory test values in heart failure patients. Fifty-eight heart failure patients receiving oral tolvaptan for volume overload were enrolled. Blood samples for determination of pre-dose plasma concentrations of tolvaptan and its metabolites were collected. CYP3A5 and ABCB1 genotypes, plasma 4β-hydroxycholesterol/total cholesterol ratio (4β-OHC/TC) and 25-hydroxyvitamin D (25-OHD), and serum laboratory test values were evaluated. The CYP3A5*3/*3 genotype was associated with a higher plasma concentration of tolvaptan but not with its metabolic ratios. The ABCB1 3435C > T, 2677G > T/A and 1236C > T polymorphisms affected neither tolvaptan pharmacokinetics nor its metabolism. Plasma 4β-OHC/TC and 25-OHD concentration were not correlated with plasma tolvaptan concentration. In a stratified analysis based on CYP3A5 genotype, plasma 4β-OHC/TC had a negative correlation with plasma tolvaptan concentration in the patients with the CYP3A5*1 allele, while the plasma concentration of 25-OHD did not. The CYP3A5*3/*3 genotype was associated with a higher serum sodium level in the patients with volume overload. The plasma concentration of 25-OHD had a positive correlation with the serum total bilirubin level. In conclusion, CYP3A5*3 but not ABCB1 genotypes elevated tolvaptan plasma exposure in heart failure patients. CYP3A5-deficient patients treated with tolvaptan had a higher serum sodium level. The CYP3A5 genotype altered the relationship between plasma tolvaptan and 4β-OHC., (© 2019 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).)

Racemic tolvaptan possessing an asymmetric carbon is metabolized to three pairs of monohydroxylate enantiomers of diol form with V 2 receptor antagonistic activity via CYP3A. This study aimed to develop a simultaneous quantitative liquid chromatography-tandem mass spectrometry method for 5R- and 5S-tolvaptan and their monohydroxylate enantiomers in human plasma and to apply it to patient samples. Deproteinized plasma specimens were separated using a polysaccharide derivative chiral column in a reversed-phase elution mode. The mass spectrometer was run in positive ion electrospray ionization mode. The chromatographic peaks of tolvaptan monohydroxylate enantiomers were identified by the recombinant CYP3A4/5 digestion of 5R- and 5S-tolvaptan. The calibration curves ranged over the plasma concentrations of 0.25-125 ng/mL for 5R- and 5S-tolvaptan, 0.025-12.5 ng/mL for 4R5R- and 4S5S-diols, and 0.025-38.15 ng/mL for 4S5R-, 4R5S-, 3S5R-, and 3R5S-diols with a large variation. Their pre-treatment recovery rates and matrix factors in human plasma were 85.2-112.9 % and 86.9-113.1 %, respectively. The intra- and inter-day accuracy and imprecision were 92.3-113.8 % and 3.5-14.6 % for all analytes, respectively. The plasma concentration ranges of 5R- and 5S-tolvaptan, 4R5R-, 4S5S-, 4S5R-, 4R5S-, 3S5R-, and 3R5S-diols in heart failure patients with a 5-fold dilution procedure were 0.634-28.4, 2.37-131, 0.525-15.4, 0.0970-4.08, 6.82-108, 0.271-6.49, 0.394-4.18, and 4.81-39.8 ng/mL, respectively. In conclusion, the present method has an acceptable analytical performance level and can be helpful for characterization of the plasma 5R- and 5S-tolvaptan and their monohydroxylate enantiomers in heart failure patients., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Some patients with hypertrophic cardiomyopathy (HCM) develop systolic dysfunction, called the dilated phase of HCM (d-HCM), which is associated with increased morbidity and mortality. We conducted a retrospective study using an HCM database to clarify the incidence, clinical characteristics, and long-term outcomes of d-HCM. We analyzed an HCM cohort consisting of 434 patients (273 with apical HCM and 161 with non-apical HCM; 18 had obstructive HCM, 16 had dilated HCM, and 127 had other HCM) diagnosed by echocardiography in our hospital between 1991 and 2010. The follow-up period was 8.4 ± 6.7 years. The mean age at final follow-up was 67 ± 14 years, and 304 patients (70%) were men. The mean age of the 16 d-HCM patients at the initial visit was 45 ± 17 years, the age at final follow-up was 59 ± 18 years, and 13 were men. Thirteen d-HCM patients developed atrial fibrillation and six patients developed ischemic stroke. Twelve d-HCM patients were implanted with cardiac devices: one pacemaker, nine implantable cardioverter-defibrillators, and two cardiac resynchronization therapy with defibrillator. Five patients died of progressive heart failure at the age of 61 ± 23 years. The age at the initial visit and final follow-up were lower and the NYHA class, brain natriuretic peptide levels, and left ventricular function at initial evaluation were worse in the d-HCM group. Univariate analysis demonstrated that a lower age at the initial visit was associated with d-HCM (hazard ratio 0.955/1 year increase; 95% CI 0.920-0.991, P = 0.015). In our HCM cohort, the incidence of d-HCM was 4%. A high prevalence of atrial fibrillation and cerebral infarction and poor prognosis were noted in this group, despite patients undergoing medication and device implantation.

Heart failure (HF) is a rapidly growing global public health problem. Since HF results in high mortality and re-hospitalization, new effective treatments are desired. Although it remains controversial, omega 3 polyunsaturated fatty acids (n-3 PUFAs), such as the eicosapentaenoic acid and docosahexaenoic acid, have been widely recognized to have benefits for HF. In a large-scale clinical trial regarding secondary prevention of HF by n-3 PUFA (GISSI-HF trial), the supplementation of n-3 PUFA significantly reduced cardiovascular mortality and hospitalization. Other small clinical studies proposed that n-3 PUFA potentially suppresses the ventricular remodeling and myocardial fibrosis, which thereby improves the ventricular systolic and diastolic function both in ischemic and non-ischemic HF. Basic investigations have further supported our understanding regarding the cardioprotective mechanisms of n-3 PUFA against HF. In these reports, n-3 PUFA has protected hearts through (1) anti-inflammatory effects, (2) intervention of cardiac energy metabolism, (3) modification of cardiac ion channels, (4) improvement of vascular endothelial response, and (5) modulation of autonomic nervous system activity. To clarify the pros and cons of n-3 PUFA on HF, we summarized recent evidence regarding the beneficial effects of n-3 PUFA on HF both from the clinical and basic studies.

Heart failure (HF) frequently coexists with conditions associated with glucose insufficiency, such as insulin resistance and type 2 diabetes mellitus (T2DM), and patients with T2DM have a significantly high incidence of HF. These two closely related diseases cannot be separated on the basis of their treatment. Some antidiabetic drugs failed to improve cardiac outcomes in T2DM patients, despite lowering glucose levels sufficiently. This may be, at least in part, due to a lack of understanding of cardiac insulin resistance. Basic investigations have revealed the significant contribution of cardiac insulin resistance to the pathogenesis and progression of HF; however, there is no clinical evidence of the definition or treatment of cardiac insulin resistance. Mitochondrial dynamics play an important role in cardiac insulin resistance and HF because they maintain cellular homeostasis through energy production, cell survival, and cell proliferation. The innovation of diagnostic tools and/or treatment targeting mitochondrial dynamics is assumed to improve not only the insulin sensitivity of the myocardium and cardiac metabolism, but also the cardiac contraction function. In this review, we summarized the current knowledge on the correlation between cardiac insulin resistance and progression of HF, and discussed the role of mitochondrial dynamics on the pathogenesis of cardiac insulin resistance and HF. We further discuss the possibility of mitochondria-targeted intervention to improve cardiac metabolism and HF.

Although multiple myeloma (MM) had been an incurable hematological malignancy with a poor prognosis, recent advances in novel anti-neoplastic agents, including carfilzomib (a proteasome inhibitor), have improved the prognosis. We herein report two cases of congestive heart failure in patients treated with carfilzomib. Although there are some reports on the cardiotoxicity of carfilzomib, to our knowledge, this is the first report on the cardiac involvement of carfilzomib in Japanese MM patients. We review the critical points from our two cases, with the aim of avoiding carfilzomib-associated heart failure in MM patients.

The coexistence of sleep-disordered breathing (SDB) and hypertrophic obstructive cardiomyopathy (HOCM) has widely been recognized; however, the impact of percutaneous transluminal septal myocardial ablation (PTSMA) for HOCM on SDB remains unknown. Herein, we examine cardiorespiratory polygraph parameters in patients with drug-refractory HOCM before and after PTSMA. Forty consecutive drug-refractory HOCM patients, admitted to Keio University Hospital, and who underwent cardiorespiratory polygraphy were retrospectively analyzed. Cardiorespiratory polygraphy was performed before and after PTSMA if patients underwent PTSMA. Patients with an apnea-hypopnea index (AHI) ≥5/h were considered to have SDB. The total number of central sleep apneas, obstructive sleep apneas, and hypopnea events was evaluated. Thirty-two out of 40 patients (80%) with drug-refractory HOCM had SDB. All patients experienced relief of heart failure-associated symptoms after PTSMA. The severity of SDB was found to be correlated with left atrial diameter. The AHI decreased after PTSMA [before 15.4 (range 10.9-23.5)/h vs. after 13.1 (8.3-17.8)/h, P = 0.02]. Especially, the hypopnea index decreased after PTSMA. The average and lowest arterial oxygen saturation also increased after PTSMA (94.2 ± 1.9-95.7 ± 1.6%, P = 0.009; 81.3 ± 5.7-85.8 ± 4.8%, P = 0.012, respectively). In patients with drug-refractory HOCM, PTSMA decreased the AHI and improved arterial oxygen saturation measures. Thus, invasive treatment of the left ventricular obstruction ameliorates the severity of SDB, in addition to improving heart failure status.

Background: Preprocedural dual antiplatelet therapy (DAPT) in percutaneous coronary interventions (PCI) has been shown to improve outcomes; however, the efficacy of the procedure and its complications in Japanese patients remain largely unexplored, so we examined the risks and benefits of DAPT before PCI and its association with in-hospital outcomes., Methods and results: We analyzed data from patients who had undergone PCI at 12 centers within the metropolitan Tokyo area between September 2008 and September 2013.Our study group comprised 6,528 patients, of whom 2,079 (31.8%) were not administered preprocedural DAPT. Non-use of preprocedural DAPT was associated with death, postprocedural shock, or heart failure (odds ratio [OR]: 1.47, 95% confidence interval [CI]: 1.10-1.96, P=0.009), and postprocedural myocardial infarction (OR: 1.41, 95% CI: 1.18-1.69, P<0.001) after adjusting propensity scores for known predictors of in-hospital complications. Non-use of DAPT was not associated with procedure-related bleeding complications (OR: 0.98, 95% CI: 0.71-1.59, P=0.764)., Conclusions: Approximately one-third of the patients who underwent PCI did not receive preprocedural DAPT despite guideline recommendations. Our results indicate that patients undergoing PCI with DAPT have a lower risk of postprocedural cardiac events without any increased bleeding risk. Further studies are needed to implement the use of DAPT in real-world PCI.

Background: Congestive physical findings such as pulmonary rales and third heart sound (S3) are hallmarks of acute heart failure (AHF). However, their role in outcome prediction remains unclear. We sought to investigate the association between congestive physical findings upon admission, steady-state biomarkers at the time of discharge, and long-term outcomes in AHF patients., Methods: We analyzed the data of 133 consecutive AHF patients with an established diagnosis of ischemic or non-ischemic (dilated or hypertrophic) cardiomyopathy, admitted to a single-center university hospital between 2006 and 2010. The treating physician prospectively recorded major symptoms and congestive physical findings of AHF: paroxysmal nocturnal dyspnea, orthopnea, pulmonary rales, jugular venous distension (JVD), S3, and edema. The primary endpoint was defined as rehospitalization for HF., Results: Majority (63.9%) of the patients had non-ischemic etiology and, at the time of admission, S3 was seen in 69.9% of the patients, JVD in 54.1%, and pulmonary rales in 43.6%. The mean follow-up period was 726 ± 31 days. Patients with pulmonary rales (p < 0.001) and S3 (p  =  0.011) had worse readmission rates than those without these findings; the presence of these findings was also associated with elevated troponin T (TnT) levels at the time of discharge (odds ratio [OR] 2.8; p  =  0.02 and OR 2.6; p  =  0.05, respectively)., Conclusion: Pulmonary rales and S3 were associated with inferior readmission rates and elevated TnT levels on discharge. The worsening of the readmission rate owing to congestive physical findings may be a consequence of on-going myocardial injury.

A 74-year-old female was admitted to our hospital due to hyperkinetic congestive heart failure. Noninvasive positive pressure ventilation, continuous hemodialysis and inotropic support were needed preoperatively. Computed tomography revealed saccular aortic arch aneurysm with aortopulmonary fistula toward the left pulmonary artery. Cardiac catheterization revealed severe left to right shunt with the pulmonary flow/systemic flow (Qp/Qs) ratio of 6.2.Emergency operation was performed under hypothermic circulatory arrest followed by selective cerebral perfusion and lower body perfusion. The aortopulmonary fistula was directly closed, reinforced with the aneurysmal wall, and total arch replacement was performed. Although the patient temporarily recovered by endoscopic suction of the blood from the lungs and continuous hemodialysis filtration, she died because of multiple organ failure due to mesenteric ischemia on postoperative day 34.

Serum C-reactive protein (CRP) elevation is associated with poor clinical outcome in patients with heart failure (HF). We previously reported that CRP exacerbates the development of pressure overload-induced cardiac remodeling through an enhanced inflammatory response and oxidative stress. In the present study, we examined the effect of eicosapentaenoic acid (EPA), a suppressor of inflammatory response and oxidative stress, on pressure overload-induced cardiac remodeling. Transverse aortic constriction (TAC) was performed on transgenic mice overexpressing CRP (CRPtg) and nontransgenic littermates (TAC/CON). CRPtg with TAC operation were randomly assigned to be fed a standard diet (TAC/CRPtg) or an EPA-enriched diet (7 % of total energy) (TAC/CRPtg/EPA). Myocardial mRNA level of transforming growth factor-β1, proinflammatory cytokines, and oxidative stress markers were increased in TAC/CRPtg in comparison with TAC/CON 1 and 4 weeks after the operation. These parameters were significantly suppressed in TAC/CRPtg/EPA compared with TAC/CRPtg. In addition, after 4 weeks of EPA treatment, as compared with TAC/CRPtg, TAC/CRPtg/EPA mice demonstrated reduced heart and lung weights, increased left ventricular fractional shortening, and decreased left ventricular end-diastolic pressure, together with decreased cardiac hypertrophy, fibrosis, and improved cardiac function. In conclusion, the anti-inflammatory and antioxidative properties of EPA may make it an effective therapeutic strategy for adverse cardiac remodeling associated with CRP overexpression.

Background: Cardiac resynchronization therapy (CRT)has been accepted broadly as an alternative to medical treatment in managing severe heart failure patients. Despite advance in CRT, the presence of a significant valvular heart disease was currently specific exclusion criteria and a response to this therapy remains unclear. The purpose of this study was to determine the effectiveness of CRT in heart failure patients undergoing valvular operation simultaneously., Patients and Methods: Between July 2010 and May 2012, 8 heart failure patients who underwent CRT in conjunction with valvular surgery were experienced. Right and left ventricular and atrial epicardial leads were implanted after completion of valvular procedures. In patients with chronic atrial fibrillation(Af),maze procedure was performed in order to eliminate Af. To evaluate the improvement of ventricular mechanical dyssynchrony, the echocardiographic assessment was repeated on admission and 1 month after the CRT implantation., Results: There was no operative death. One patient of ischemic cardiomyopathy died of sustained ventricular tachycardia 2 months after the operation. Postoperative course of severe heart failure patients was uneventful and all patients except 1 discharged on foot with improved New York Heart Association (NYHA) class. Echocardiographic parameters of dyssynchrony did not reach to statistical significance, but several parameters, left ventricular( LV)-pre-ejectionperiod( PEP) and interventricular mechanical delay (IVMD) showing time delay of cardiac contraction, tended to be improve, suggesting contribution to satisfactory postoperative course., Conclusion: The acceptable outcome was demonstrated with our concept to recover the intraventricular and atrioventricular synchrony. Although it might be difficult to establish the patient selection criteria for concomitant CRT and valvular surgery, our strategy is considered to be a feasible procedure to improve the morbidity and mortality in patients with severe heart failure due to valvular disease.

Gelsolin, a calcium-regulated actin severing and capping protein, is highly expressed in murine and human hearts after myocardial infarction and is associated with progression of heart failure in humans. The biological role of gelsolin in cardiac remodeling and heart failure progression after injury is not defined. To elucidate the contribution of gelsolin in these processes, we randomly allocated gelsolin knockout mice (GSN(-/-)) and wild-type littermates (GSN(+/+)) to left anterior descending coronary artery ligation or sham surgery. We found that GSN(-/-) mice have a surprisingly lower mortality, markedly reduced hypertrophy, smaller late infarct size, less interstitial fibrosis, and improved cardiac function when compared with GSN(+/+) mice. Gene expression and protein analysis identified significantly lower levels of deoxyribonuclease (DNase) I and reduced nuclear translocation and biological activity of DNase I in GSN(-/-) mice. Absence of gelsolin markedly reduced DNase I-induced apoptosis. The association of hypoxia-inducible factor (HIF)-1alpha with gelsolin and actin filaments cleaved by gelsolin may contribute to the higher activation of DNase. The expression pattern of HIF-1alpha was similar to that of gelsolin, and HIF-1alpha was detected in the gelsolin complex by coprecipitation and HIF-1alpha bound to the promoter of DNase I in both gel-shift and promoter activity assays. Furthermore, the phosphorylation of Akt at Ser473 and expression of Bcl-2 were significantly increased in GSN(-/-) mice, suggesting that gelsolin downregulates prosurvival factors. Our investigation concludes that gelsolin is an important contributor to heart failure progression through novel mechanisms of HIF-1alpha and DNase I activation and downregulation of antiapoptotic survival factors. Gelsolin inhibition may form a novel target for heart failure therapy.

Apelin constitutes a novel endogenous peptide system suggested to be involved in a broad range of physiological functions, including cardiovascular function, heart development, control of fluid homeostasis, and obesity. Apelin is also a catalytic substrate for angiotensin-converting enzyme 2, the key severe acute respiratory syndrome receptor. The in vivo physiological role of Apelin is still elusive. Here we report the generation of Apelin gene-targeted mice. Apelin mutant mice are viable and fertile, appear healthy, and exhibit normal body weight, water and food intake, heart rates, and heart morphology. Intriguingly, aged Apelin knockout mice developed progressive impairment of cardiac contractility associated with systolic dysfunction in the absence of histological abnormalities. We also report that pressure overload induces upregulation of Apelin expression in the heart. Importantly, in pressure overload-induced heart failure, loss of Apelin did not significantly affect the hypertrophy response, but Apelin mutant mice developed progressive heart failure. Global gene expression arrays and hierarchical clustering of differentially expressed genes in hearts of banded Apelin(-/y) and Apelin(+/y) mice showed concerted upregulation of genes involved in extracellular matrix remodeling and muscle contraction. These genetic data show that the endogenous peptide Apelin is crucial to maintain cardiac contractility in pressure overload and aging.