記述言語：英語   掲載種別：研究論文（学術雑誌）  

AIMS: The mechanism by which a sodium-glucose cotransporter inhibitor (SGLT2i) induces favorable effects on diabetes and cardiovascular diseases including heart failure (HF) remains poorly understood. Metabolomics including amino acid profiling enables detection of alterations in whole body metabolism. The aim of this study was to determine whether plasma amino acid profiles are modulated by SGLT2i use in HF patients with type 2 diabetes mellitus (T2DM). METHODS: We retrospectively examined 81 HF patients with T2DM (68 ± 11 years old; 78% male). Plasma amino acid concentrations in a fasting state after stabilization of HF were determined using ultraperformance liquid chromatography. To minimize potential selection bias in the retrospective analyses, the differences in baseline characteristics between patients receiving an SGLT2i and patients not receiving an SGLT2i were controlled by using an inverse probability of treatment weighting (IPTW)-adjusted analysis. RESULTS: Of amino acids measurable in the present assay, plasma β-aminoisobutyric acid (BAIBA), an exercise-induced myokine-like molecule also known as 3-aminoisobutyric acid or 3-amino-2-methyproponic acid, was detected in 77% of all patients and the proportion of patients in whom plasma BAIBA was detected was significantly higher in patients receiving an SGLT2i than in patients not receiving an SGLT2i (93% vs. 67%, p = 0.01). Analyses in patients in whom plasma BAIBA was detected showed that plasma BAIBA concentration was significantly higher in patients receiving an SGLT2i than in patients not receiving an SGLT2i (6.76 ± 4.72 vs. 4.56 ± 2.93 nmol/ml, p = 0.03). In multivariate logistic regression analyses that were adjusted for age and sex, SGLT2i use was independently associated with BAIBA detection. The independent association between BAIBA and SGLT2i use remained after inclusion of body mass index, HF with reduced ejection fraction, ischemic etiology, renal function, NT-proBNP, albumin, hemoglobin, and HbA1c into the Cox proportional hazards model. When the differences in baseline characteristics between patients receiving an SGLT2i and patients not receiving an SGLT2i were controlled by using an IPTW-adjusted analysis, least squares mean of plasma BAIBA concentration was significantly higher in patients receiving an SGLT2i than in patients not receiving an SGLT2i. CONCLUSION: SGLT2i use is closely associated with increased circulating BAIBA concentration in HF patients with T2DM.

DOI： 10.1186/s12933-022-01727-x

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

Pregnancy is associated with substantial physiological changes of the heart, and disruptions in these processes can lead to peripartum cardiomyopathy (PPCM). The molecular processes that cause physiological and pathological changes in the heart during pregnancy are not well characterized. Here, we show that mTORc1 was activated in pregnancy to facilitate cardiac enlargement that was reversed after delivery in mice. mTORc1 activation in pregnancy was negatively regulated by the mRNA-destabilizing protein ZFP36L2 through its degradation of Mdm2 mRNA and P53 stabilization, leading to increased SESN2 and REDD1 expression. This pathway impeded uncontrolled cardiomyocyte hypertrophy during pregnancy, and mice with cardiac-specific Zfp36l2 deletion developed rapid cardiac dysfunction after delivery, while prenatal treatment of these mice with rapamycin improved postpartum cardiac function. Collectively, these data provide what we believe to be a novel pathway for the regulation of mTORc1 through mRNA stabilization of a P53 ubiquitin ligase. This pathway was critical for normal cardiac growth during pregnancy, and its reduction led to PPCM-like adverse remodeling in mice.

DOI： 10.1172/JCI154491

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

AIMS: The clinical outcome of heart failure (HF) is complicated by the presence of multiple comorbidities including malnutrition and cachexia, and prediction of the outcome is still difficult in each patient. Metabolomics including amino acid profiling enables detection of alterations in whole body metabolism. The aim of this study was to determine whether plasma amino acid profiling improves prediction of clinical outcomes in patients with HF. METHODS AND RESULTS: We retrospectively examined 301 HF patients (70 ± 15 years old; 59% male). Blood samples for measurements of amino acid concentrations were collected in a fasting state after stabilization of HF. Plasma amino acid concentrations were measured using ultraperformance liquid chromatography. Clinical endpoint of this study was adverse event defined as all-cause death and unscheduled readmission due to worsening HF or lethal arrhythmia. During a mean follow-up period of 380 ± 214 days, 40 patients (13%) had adverse events. Results of analyses of variable importance in projection score, a measure of a variable's importance in partial least squares-discriminant analysis (PLS-DA) showed that the top five amino acids being associated with adverse events were 3-methylhistidine (3-Me-His), β-alanine, valine, hydroxyproline, and tryptophan. Multivariate Cox-proportional hazard analyses indicated that a high 3-Me-His concentration and low β-alanine and valine concentrations were independently associated with adverse events. When HF patients were divided according to the cut-off values of amino acids calculated from receiver operating characteristic curves, Kaplan-Meier survival curves showed that event-free survival rates were lower in HF patients with high 3-Me-His than in HF patients with low 3-Me-His (68% vs. 91%, P < 0.01). In a subgroup with high 3-Me-His, HF patients with low β-alanine and those with low valine had significantly lower event-free survival rates than did HF patients with high β-alanine and those with high valine, respectively. On the other hand, Kaplan-Meier curves of event-free survival rates did not differ between HF patients with and those without low β-alanine and low valine in subgroups of patients with low 3-Me-His. Inclusion of both high 3-Me-His and low β-alanine or low valine into the adjustment model including N-terminal pro-brain natriuretic peptide improved the accuracy of prediction of adverse events after discharge. 3-Me-His concentration was associated with muscle mass and nutritional status. CONCLUSIONS: Simple measurement of 3-Me-His with either β-alanine or valine improved the predictive ability for adverse events, indicating the utility of plasma amino acid profiling in risk stratification of hospitalized HF patients.

DOI： 10.1002/ehf2.13572

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Ischaemic heart disease limits oxygen and metabolic substrate availability to the heart, resulting in tissue death. Here, we demonstrate that the AMP-activated protein kinase (AMPK)-related protein Snf1-related kinase (SNRK) decreases cardiac metabolic substrate usage and mitochondrial uncoupling, and protects against ischaemia/reperfusion. Hearts from transgenic mice overexpressing SNRK have decreased glucose and palmitate metabolism and oxygen consumption, but maintained power and function. They also exhibit decreased uncoupling protein 3 (UCP3) and mitochondrial uncoupling. Conversely, Snrk knockout mouse hearts have increased glucose and palmitate oxidation and UCP3. SNRK knockdown in cardiac cells decreases mitochondrial efficiency, which is abolished with UCP3 knockdown. We show that Tribbles homologue 3 (Trib3) binds to SNRK, and downregulates UCP3 through PPARα. Finally, SNRK is increased in cardiomyopathy patients, and SNRK reduces infarct size after ischaemia/reperfusion. SNRK also decreases cardiac cell death in a UCP3-dependent manner. Our results suggest that SNRK improves cardiac mitochondrial efficiency and ischaemic protection.

DOI： 10.1038/ncomms14095

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

Type 2 diabetes mellitus (T2DM) is often complicated with diastolic heart failure, which decompensates under increased afterload. Focusing on cardiac metabolomes, we examined mechanisms by which T2DM augments ventricular diastolic stiffness in response to pressure overloading. Pressure-volume relationships (PVRs) and myocardial metabolomes were determined at baseline and during elevation of aortic pressure by phenylephrine infusion in a model of T2DM, OLETF, and its non-diabetic control, LETO. Pressure overloading augmented diastolic stiffness without change in systolic reserve in OLETF as indicated by a left-upward shift of end-diastolic PVR. In contrast, PVRs under cardioplegic arrest in buffer-perfused isolated hearts were similar in OLETF and LETO, indicating that extracellular matrix or titin remodeling does not contribute to the afterload-induced increase in stiffness of the beating ventricle of OLETF. Metabolome analyses revealed impaired glycolysis and facilitation of the pentose phosphate pathway in OLETF. Pressure overloading significantly reduced ATP and total adenine nucleotides by 34% and 40%, respectively, in OLETF but not in LETO, while NADH-to-NAD(+) ratios were similar in the two groups. The decline in ATP by pressure overloading in OLETF was associated with increased inosine 5-monophosphate and decreased adenosine levels, being consistent with the 2.5-times higher activity of cardiac AMP deaminase in OLETF. Tissue ATP level was negatively correlated with tau of LV pressure and LVEDP. These results suggest that ATP depletion due to excessive degradation of adenine nucleotides by up-regulated AMP deaminase underlies ventricular stiffening during acute pressure overloading in T2DM hearts.

DOI： 10.1016/j.yjmcc.2015.01.004

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Since diabetic cardiomyopathy was first reported four decades ago, substantial information on its pathogenesis and clinical features has accumulated. In the heart, diabetes enhances fatty acid metabolism, suppresses glucose oxidation, and modifies intracellular signaling, leading to impairments in multiple steps of excitation-contraction coupling, inefficient energy production, and increased susceptibility to ischemia/reperfusion injury. Loss of normal microvessels and remodeling of the extracellular matrix are also involved in contractile dysfunction of diabetic hearts. Use of sensitive echocardiographic techniques (tissue Doppler imaging and strain rate imaging) and magnetic resonance spectroscopy enables detection of diabetic cardiomyopathy at an early stage, and a combination of the modalities allows differentiation of this type of cardiomyopathy from other organic heart diseases. Circumstantial evidence to date indicates that diabetic cardiomyopathy is a common but frequently unrecognized pathological process in asymptomatic diabetic patients. However, a strategy for prevention or treatment of diabetic cardiomyopathy to improve its prognosis has not yet been established. Here, we review both basic and clinical studies on diabetic cardiomyopathy and summarize problems remaining to be solved for improving management of this type of cardiomyopathy.

DOI： 10.1007/s10741-012-9313-3

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

Our recent studies indicated that up-regulation of calcineurin activity and unfolded protein responses (UPRs) disrupt cytoprotective Akt- and ERK-signaling in OLETF, a model of obese type 2 diabetes (T2DM). To determine whether the mechanisms can be generalized, we used Goto-Kakizaki rats (GK), a model of non-obese T2DM, in this study. Infarct sizes after 20-min ischemia/2-h reperfusion were similar in GK and non-diabetic controls, Wistar rats (Wistar). However, erythropoietin (EPO) limited infarct size in Wistar (64.0±5.3% vs. 45.7±4.4%, p<0.05) but not in GK (56.2±2.2% vs. 52.6±2.3%). Levels of calcineurin activity and EPO-induced phosphorylation of Akt and ERK were similar in GK and Wistar, though cytosolic HSP70 level was 50% lower and mitochondrial HSP60 level was 60% higher in GK. EPO preserved mitochondrial calcium retention capacity (CRC), an index of the threshold for opening of the mitochondrial permeability transition pore (mPTP), after ischemia/reperfusion in Wistar but not in GK. Interaction of cyclophilin D (CypD) with mitochondrial inorganic phosphate carrier (PiC), which sensitizes the mPTP, was enhanced in GK. There was a negative exponential relationship between CypD-PiC interaction and CRC upon reperfusion, indicating that increase in CRC by reduction of CypD-PiC interaction is smaller when CypD-PiC interaction level is at a higher range. A chemical chaperone, 4-phenylbutyric acid, attenuated the changes in HSPs and CypD-PiC interaction and restored responses of CRC and infarct size to EPO in GK. These results suggest that cytoprotective regulation of the mPTP is impaired in GK by enhanced CypD-PiC interaction in which UPRs are involved.

DOI： 10.1016/j.yjmcc.2012.10.001

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Systolic reserve is an important compensatory mechanism against increasing afterload. Although longitudinal systolic dysfunction with preserved ejection fraction has been reported in hypertensive hearts, radial and circumferential function has not been fully examined. The aim of this study was to investigate three-directional systolic function and its relationships with left ventricular geometry in asymptomatic hypertensive patients using two-dimensional speckle-tracking imaging. METHODS: Echocardiographic evaluations were performed in 74 hypertensive patients and 55 age-matched control subjects. RESULTS: Longitudinal strain was significantly reduced in the hypertrophy groups compared with that in control subjects (concentric, -15.1 ± 4.0%; eccentric, -15.9 ± 4.4%; control, -18.9 ± 3.3%; P < .05). Conversely, radial strain was significantly higher in the normal geometry group than in control subjects (53.8 ± 19.4% vs 40.3 ± 15.1%, P < .05). However, this augmentation was attenuated in the other geometries. CONCLUSION: Hypertrophic remodeling attenuates compensatory augmentation of radial systolic function and is associated with latent longitudinal systolic dysfunction.

DOI： 10.1016/j.echo.2010.10.020

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

Pulmonary vascular resistance (PVR) is an important hemodynamic variable in the management of patients with pulmonary hypertension. To establish a method of estimating PVR in patients with pulmonary arterial hypertension (PAH), Doppler echocardiography was performed within 24 hours of right heart catheterization in 43 patients with PAH (idiopathic PAH, n = 20; chronic thromboembolic pulmonary hypertension, n = 9; congenital heart disease, n = 9; and others). Correlations between invasive PVR and Doppler variables of pulmonary artery flow and tricuspid regurgitation were examined. Mean invasive PVR was 1,294 +/- 680 dyne s cm(-5). Linear regression analysis revealed significant correlations with invasive PVR for the time-velocity integral (TVI; r = -0.63, p = 0.009) of right ventricular outflow and peak tricuspid regurgitant pressure gradient (TRPG; r = 0.77, p <0.001). The TRPG/TVI ratio, which approximated the ratio of pulmonary artery pressure to pulmonary blood flow, showed an improved correlation coefficient of 0.82 (PVR = 187 + TRPG/TVI x 118, p <0.001). After excluding 5 patients with an intracardiac shunt, 26 of the remaining 38 patients (68%) met the hemodynamic criteria in international guidelines for the selection of lung transplantation candidates and were defined as the poor-prognosis group. A TRPG/TVI >7.6 showed 85% sensitivity and 92% specificity for identifying patients in the poor-prognosis group. In conclusion, TRPG/TVI provides a reliable estimation of PVR over a wide range in patients with PAH with various underlying causes.

DOI： 10.1016/j.amjcard.2008.11.039

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Japanese Circulation Society  

DOI： 10.1253/circj.cj-25-0714

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掲載種別：研究論文（学術雑誌）  

DOI： 10.1186/s12877-026-07016-6

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

AIMS: Metabolic dysfunction-associated steatotic liver disease (MASLD) is characterized by the presence of hepatic steatosis and at least one of five cardiometabolic risk factors, leading to the development of cardiovascular-kidney-metabolic syndrome including chronic kidney disease (CKD). However, the impact of heterogeneity of MASLD on new onset of CKD remains unclear. We explored the relationship between subgroups of MASLD divided by using a machine learning (ML) model called supervised clustering and the development of CKD during a 10-year follow-up period. METHODS: A total of 12,168 Japanese subjects (men/women: 7927/4,241 and mean age: 48 years) who received annual health examinations including abdominal ultrasonography were recruited. RESULTS: Using the supervised clustering by SHapley Additive exPlanations (SHAP) and uniform manifold approximation and projection (UMAP) for steatotic liver diseases, 10 subclusters including 3 distinctive subgroups of MASLD were detected by a Gaussian mixture model. Kaplan-Meier survival curve analysis showed a significant difference in the cumulative incidence for new onset of CKD among the 3 subgroups of MASLD. Among the MASLD subclusters, an obese subgroup with an atherogenic profile of serum lipids as well as high levels of fatty liver index and uric acid was the worst subcluster for the development of CKD in individuals with MASLD. CONCLUSIONS: The supervised clustering of MASLD using a SHAP-converted matrix and UMAP reveals phenotypically distinct subpopulations that improved risk stratification for new onset of CKD. An obese subgroup with atherogenic lipid profiles and hyperuricemia in MASLD is associated with an increased risk for the development of CKD.

DOI： 10.1111/hepr.70127

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

AIM: Metabolic dysfunction-associated steatotic liver disease (MASLD) is associated with an increased risk of atherosclerotic cardiovascular disease (ASCVD). Although small dense low-density lipoprotein cholesterol (sdLDL-C) is a highly atherogenic lipid fraction, the association of the sdLDL-C level with MASLD and other steatotic liver disease (SLD) subcategories remain unclear. We investigated the association between various SLDs and the sdLDL-C level calculated by Sampson's equation. METHODS: A total of 15,734 Japanese participants (men/women: 10,228/5,506, mean age: 49±9 years) who underwent annual health examinations including abdominal ultrasonography were recruited after the exclusion of subjects with triglycerides ≥ 800 mg/dL. RESULTS: Among SLD subcategories including MASLD, MASLD with increased alcohol consumption (MetALD) and alcohol-associated liver disease (ALD), the mean levels of sdLDL-C and non-high-density lipoprotein cholesterol (non-HDL-C) were the highest in participants with MASLD. Triglyceride levels were significantly lower in participants with MASLD than in those with MetALD and those with ALD. After adjustment for age, sex, body mass index, current smoking and alcohol drinking habits, treatment of hypertension, diabetes and dyslipidemia, and triglyceride level, MASLD and MetALD were independently associated with sdLDL-C level, and the association was stronger in MASLD than in other SLD subcategories. The sdLDL-C level was also independently associated with each SLD subcategory after adjustment for the same covariates. The addition of sdLDL-C to traditional risk factors significantly improved the discriminatory capacity for the presence of MASLD in comparison to the addition of non-HDL-C. CONCLUSION: MASLD is independently associated with elevated estimated sdLDL-C levels in Japanese individuals, leading to an increased risk of ASCVD.

DOI： 10.5551/jat.65939

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

An elevated level of small dense low-density lipoprotein cholesterol (sdLDL-C) is a risk factor for cardiovascular diseases, including hypertension. However, it remains unclear whether the sdLDL-C level is a predictor for the development of hypertension independent of LDL-C level. We investigated the associations of new onset of hypertension with four categorized groups of high (H-) and low (L-) levels of sdLDL-C calculated by the Sampson equation and LDL-C using cut-off values of sdLDL-C/LDL-C (29.6/114 mg/dL) by receiver operating characteristic curves in 15,204 Japanese participants (men/women: 9230/5794, mean age: 46 years) who received annual health checkups. During a 10-year follow-up period (median duration: 6.0 years), 3,054 subjects (men/women: 2332 [25.3%]/722 [12.5%]) newly developed hypertension. Kaplan-Meier survival curves showed a distinct difference in the cumulative incidence of hypertension between high (H-sdLDL-C/H-LDL-C and H-sdLDL-C/L-LDL-C) and low (L-sdLDL-C/H-LDL-C and L-sdLDL-C/L-LDL-C) sdLDL-C groups. Multivariable Cox proportional hazard model analysis adjusting for age, sex, family history of hypertension, systolic blood pressure, obesity, habits of current smoking and alcohol drinking, and diagnosis of diabetes mellitus and chronic kidney disease showed that hazard ratios [95% confidence intervals] were significantly higher in participants with H-sdLDL-C/H-LDL-C (1.21 [1.09-1.34]) and participants with H-sdLDL-C/L-LDL-C (1.25 [1.10-1.41]) than in participants with L-sdLDL-C/L-LDL-C as the reference. Linear mixed effects model analysis showed that there was a significant interaction of sdLDL-C, but not LDL-C, with systolic blood pressure for the follow-up period. In conclusion, a high level of estimated sdLDL-C can predict the development of hypertension regardless of LDL-C level in a general Japanese population.

DOI： 10.1038/s41440-025-02374-x

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

AIM: While sarcopenia affects functional independence in older patients with heart failure (HF), the differential impact of its components-including muscle mass (MM), muscle strength (MS), and physical function (PF)-remain underexplored. We investigated these components' independent and synergistic associations with functional independence in older patients with HF, including sex-specific differences. METHODS: We studied 587 older patients with HF (299 women; mean age, 79±7 years). MM, MS, and PF were assessed using dual-energy X-ray absorptiometry, handgrip strength, and physical performance tests (gait speed, five-times sit-to-stand test [FTSS], short physical performance battery [SPPB]), respectively. Cutoffs for each component followed the Asian Working Group for Sarcopenia 2019 criteria. Functional independence was assessed using the Barthel Index (BI). RESULTS: Sarcopenia was associated with lower BI scores. Poor PF independently predicted reduced BI scores (slow gait speed: 8.4 points; prolonged FTSS: 10.9 points; low SPPB: 14.8 points; all p < 0.001), whereas low MM and weak MS did not. Low MM amplified the negative impact of poor PF on BI scores consistently across sexes. Machine-learning analysis revealed MM status-specific predictors of PF: clinical factors (female sex, HF symptoms) and comorbidities predicted poor PF in patients with normal MM; renin-angiotensin system inhibition, and cardiomyopathy were associated with preserved PF in patients with low MM. CONCLUSIONS: In older patients with HF, sarcopenia is closely and negatively associated with BI score primarily through poor PF; MM potentially modifies this relationship independent of sex. MM status-specific factors associated with PF suggest the importance of phenotype-specific approaches in facilitating functional independence.

DOI： 10.1016/j.archger.2025.105933

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

AIM: Cardiovascular-kidney-metabolic (CKM) syndrome is a recently defined systemic condition linking cardiovascular disease, chronic kidney disease and metabolic disorders including type 2 diabetes (T2D). Although the CKM staging has been proposed for integrated risk assessment, its association with all-cause mortality in patients with T2D remains unclear. We investigated the prognosis in patients with T2D assigned by the CKM health stage. METHODS: A total of 632 Japanese patients with T2D were enrolled. The primary endpoint was all-cause death. RESULTS: The numbers of the recruited patients with stages 2, 3 and 4 were 353 (55.9 %), 116 (18.3 %) and 163 (25.8 %), respectively. During a median follow-up of 64 months (35,327 person-months), 62 patients (9.8 %) died. Kaplan-Meier survival curves analysis showed significant differences in cumulative mortality among CKM health stages (log-rank test: P < 0.001) with higher cumulative mortality in stages 3 and 4 than in stage 2. Multivariable Cox proportional hazard models after adjustment of age, sex, body mass index, current smoking habit, cancer, relevant medications and hemoglobin A1c showed that adjusted hazard ratios (HRs) [95 % confidence intervals] for all-cause death were significantly higher in patients with stages 3 (2.25[1.08-4.69]) and those with stage 4 (2.87[1.41-5.84]) than in those with stage 2 as the reference. After additional adjustment of N-terminal pro-brain natriuretic peptide and estimated glomerular filtration rate among definition criteria for staging, the association of stages with all-cause death remained statistically significant in only stage 4 (2.16[1.02-4.56]). CONCLUSION: The CKM health staging is useful for predicting all-cause mortality in Japanese patients with T2D.

DOI： 10.1016/j.jdiacomp.2025.109146

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Hypertrophic cardiomyopathy (HCM) is a primary myocardial disease characterized by unexplained left ventricular hypertrophy, often resulting from pathogenic variants of sarcomeric protein genes. Conventional treatments, such as the use of beta blockers or calcium channel blockers, focus on symptomatic control but do not address the underlying hypercontractility at the sarcomere level. Recent advances in molecular understanding have led to the development of cardiac myosin inhibitors that directly modulate sarcomeric function by reducing myosin-actin cross-bridge formation and adenosine triphosphatase (ATPase) activity. Mavacamten and aficamten have shown promising results in phase 2 and 3 clinical trials, improving symptoms, exercise capacity, and left ventricular outflow tract gradients in patients with obstructive HCM. This review summarizes the current understanding of HCM pathophysiology, diagnostic strategies, and conventional treatments with a focus on the mechanisms of action of myosin inhibitors, clinical evidence supporting their use, and future directions for improvement. We also discuss their potential applications in non-obstructive HCM and the importance of precision medicine guided by genetic profiling.

DOI： 10.3390/ijms26199347

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Cardiovascular-kidney-metabolic (CKM) syndrome is a recently proposed condition encompassing metabolic dysfunction, chronic kidney disease, and cardiovascular diseases including coronary artery disease (CAD). Although concomitant metabolic dysfunction-associated steatotic liver disease (MASLD) exacerbates CKM syndrome, MASLD is not included in the original stratification (stages 0-3) for predicting cardiovascular disease (stage 4). METHODS: We investigated whether the addition of MASLD in the original health stage of CKM syndrome improves the risk stratification of CAD in Japanese participants who underwent annual health checkups. A total of 18 358 participants were categorized by the original health stages (stages 0-3) or modified health stages incorporating MASLD without chronic kidney disease in stage 2 and MASLD with chronic kidney disease in stage 3 to analyze the predictive ability for CAD during a 10-year period. RESULTS: Kaplan-Meier survival curve analysis showed that the modified classification more effectively stratified the risk of CAD than did the original CKM health stage. In Cox hazard proportional analyses after adjustment of confounders, hazard ratios in the original and modified stages 2/3 were 1.63 (95% CI, 1.27-2.11; P<0.001), 2.41 (95% CI, 0.34-17.4; P=0.381), 1.58 (95% CI, 1.23-2.05; P<0.001), and 2.56 (95% CI, 1.66-3.95; P<0.001), respectively. Risk discrimination significantly improved in the modified classification evaluated by integrated discrimination improvement. Furthermore, machine learning-mediated feature importance analyses using random forest and extreme gradient boosting identified MASLD as a key predictor of CAD with a high value of the Shapley Additive Explanations, indicating strong contribution in models. CONCLUSIONS: The modified health stage classification of CKM syndrome incorporating MASLD improves the accuracy of predicting new onset of CAD in a Japanese general population.

DOI： 10.1161/JAHA.125.043173

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: The association of each of the recently classified steatotic liver diseases (SLDs), including metabolic dysfunction-associated SLD (MASLD), MASLD and increased alcohol intake (MetALD), and alcohol-associated liver disease (ALD), with new development of ischemic heart disease (IHD) remains unclear. METHODS AND RESULTS: We investigated the associations of various SLDs with the development of IHD during a 10-year follow-up period in 13,815 Japanese individuals without a history of IHD (men/women 8,933/4,882; mean age 48 years) who underwent annual health checkups including an abdominal ultrasound examination. Among the participants, 4,639 (33.6%) subjects were diagnosed as having SLDs, and the proportions of subjects with MASLD, MetALD and ALD were 25.4%, 4.7% and 1.9%, respectively. During the follow-up period, 1,963 (16.2%; men/women 1,374 [17.2%]/589 [14.2%]) subjects had new development of IHD. Multivariable Cox proportional hazard model analysis after adjustment of age, sex, estimated glomerular filtration rate (eGFR), current smoking habit, diabetes, hypertension and dyslipidemia showed that the adjusted risk for new onset of IHD was significantly higher in subjects with MASLD (hazard ratio 1.20 [95% confidence interval 1.01-1.55]; P=0.042) than in those without SLD. Other SLDs were not selected as independent risk factors for the development of IHD. CONCLUSIONS: The presence of MASLD, but not other SLDs, is an independent risk factor for new onset of IHD during a 10-year follow-up period.

DOI： 10.1253/circrep.CR-25-0019

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVES: The utility of the updated Asian Working Group for Sarcopenia (AWGS) criteria in diagnosing sarcopenia in older patients with heart failure (HF) remains unclear. OBJECTIVE: To analyze the prevalence and prognostic impact of sarcopenia diagnosed by the updated AWGS criteria in older patients with HF. DESIGN: Ambispective cohort study. SETTING & SUBJECTS: 534 older patients with HF from a university hospital in Japan. MEASUREMENTS: Sarcopenia was assessed using different versions of the AWGS criteria: AWGS 2014, AWGS 2019H (muscle mass relative to height squared), and AWGS 2019B (muscle mass relative to BMI). The primary endpoint was all-cause mortality at three years post-discharge. RESULTS: Of 534 patients, 42%, 57%, and 44% were diagnosed with sarcopenia according to AWGS 2014, AWGS 2019H, AWGS 2019B, respectively. Among patients without AWGS 2014-defined sarcopenia, 23% were reclassified as having sarcopenia by AWGS 2019H criteria. Forty-four percent of sarcopenic patients diagnosed by AWGS 2019H were re-classified as non-sarcopenic by AWGS 2019B, with lower fat mass and poorer nutritional status. After the multivariate Cox proportional hazard analyses, an association between all-cause death and sarcopenia remained significant for AWGS 2014 (hazard ratio [HR], 1.55; 95% confidence interval [CI], 1.01-2.37) and AWGS 2019H (HR, 1.65; 95% CI, 1.05-2.59), but not for AWGS 2019B (HR, 0.99; 95% CI, 0.64-1.51). CONCLUSION: The updated AWGS 2019H criteria detected more sarcopenic patients with HF while maintaining favorable predictive ability. The use of BMI-adjusted muscle mass reclassified underweight and malnourished patients as non-sarcopenic, limiting its impact on the mortality prediction in older patients with HF.

DOI： 10.1016/j.jnha.2024.100434

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

This case involved an 89-year-old woman with a history of left nephrectomy for left renal cell carcinoma at the age of 87 years. She had been gradually accumulating pericardial effusion for the past 4 years. She presented with signs of tachycardia and hypotension suggestive of cardiac tamponade due to pericardial effusion, and pericardiocentesis was performed below the xiphoid process in the cardiology department. Serous fluid was aspirated, and malignancy was ruled out by various tests. The patient subsequently developed recurrent pericardial effusion and was admitted to the hospital. Cardiovascular surgery was performed for pericardial drainage. A left intercostal incision was made for pericardiotomy and drainage of the pericardial effusion, allowing it to accumulate in the left pleural cavity in case of future accumulation. Pathological examination of the pericardium revealed no specific findings, and no cancer cells were present in the pericardial fluid. Prednisolone therapy was initiated for idiopathic pericarditis.

DOI： 10.1093/omcr/omae139

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

AIMS: The adverse effects of low daily protein intake (DPI) on clinical outcomes in patients with heart failure (HF) are known; however, an optimal DPI to predict event adverse outcomes remains undetermined. Moreover, whether protein restriction therapy for chronic kidney disease is applicable in patients with HF and renal dysfunction remains unclear. METHODS AND RESULTS: In this single-centre, ambispective cohort study, we included 405 patients with HF aged ≥65 years (mean age, 78.6 ± 7.5 years; 50% women). DPI was estimated from consumption over three consecutive days before discharge and normalized relative to the ideal body weight [IBW, 22 kg/m2 × height (m)2]. The primary outcome was a composite of all-cause mortality and HF-related readmission within the 2 year post-discharge period. RESULTS: During an average follow-up period of 1.49 ± 0.74 years, 100 patients experienced composite events. Kaplan-Meier survival curves revealed a significantly lower composite event-free rate in patients within the lowest quartile of DPI than in the upper quartiles (log-rank test, P = 0.02). A multivariate Cox proportional hazards analysis after adjusting for established prognostic markers and non-proteogenic energy intake revealed that patients in the lowest DPI quartile faced a two-fold higher risk of composite events than those in the highest quartile [hazard ratio (HR), 2.03; 95% confidence interval (CI), 1.08-3.82; P = 0.03]. The composite event risk linearly increased as DPI decreased (P for nonlinearity = 0.90), with each standard deviation (0.26 g/kg IBW/day) decrease in DPI associated with a 32% increase in composite event risk (HR, 1.32; 95% CI, 1.10-1.71; P = 0.04). There was significant heterogeneity in the effect of DPI, with the possible disadvantage of lower DPI in patients with HF with cystatin C-based estimated glomerular filtration rate <30 mL/min/1.73 m2. The cutoff value of DPI for predicting the occurrence of composite events calculated from the Youden index was 1.12 g/kg IBW/day. Incorporating a DPI < 1.12 g/kg IBW/day into the baseline model significantly improved the prediction of post-discharge composite events (continuous net reclassification improvement, 0.294; 95% CI, 0.072-0.516; P = 0.01). CONCLUSIONS: Lower DPI during hospitalization is associated with an increased risk of mortality and HF readmission independent of non-proteogenic energy intake, and the possible optimal DPI for predicting adverse clinical outcomes is >1.12 g/kg IBW/day in older patients with HF. Caution is warranted when protein restriction therapy is administered to older patients with HF and renal dysfunction.

DOI： 10.1002/ehf2.14812

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Necroptosis, necrosis characterized by RIPK3-MLKL activation, has been proposed as a mechanism of doxorubicin (DOX)-induced cardiomyopathy. We showed that rapamycin, an mTORC1 inhibitor, attenuates cardiomyocyte necroptosis. Here we examined role of MLKL in DOX-induced myocardial damage and protective effects of rapamycin. Cardiomyopathy was induced in mice by intraperitoneal injections of DOX (10 mg/kg, every other day) and followed for 7 days. DOX-treated mice showed a significant decline in LVEF assessed by cardiac MRI (45.5 ± 5.1% vs. 65.4 ± 4.2%), reduction in overall survival rates, and increases in myocardial RIPK3 and MLKL expression compared with those in vehicle-treated mice, and those changes were prevented by administration of rapamycin (0.25 mg/kg) before DOX injection. In immunohistochemical analyses, p-MLKL signals were detected in the cardiomyocytes of DOX-treated mice, and the signals were reduced by rapamycin. Mlkl+/- and Mlkl-/- mice were similarly resistant to DOX-induced cardiac dysfunction, indicating that a modest reduction in MLKL level is sufficient to prevent the development of DOX-induced cardiomyopathy. However, evidence of cardiomyocyte necrosis assessed by C9 immunostaining, presence of replacement fibrosis, and electron microscopic analyses was negligible in the myocardium of DOX-treated mice. Thus, MLKL-mediated signaling contributes to DOX-induced cardiac dysfunction primarily by a necrosis-independent mechanism, which is inhibitable by rapamycin.

DOI： 10.1016/j.jphs.2024.06.005

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

Rhabdomyolysis can lead to acute kidney injury (AKI), primarily due to myoglobin-induced tubular damage. We present a case of slowly progressive rhabdomyolysis following SARS-CoV-2 infection in a 28-year-old male who was monitored through serial serum creatine kinase (CK) and myoglobin levels. Despite prominent CK elevations, the patient did not develop AKI, probably due to disproportionately mild serum myoglobin elevation with distinctive cyclic spikes. This case underscores the informative value of frequent monitoring of both CK and myoglobin to assess muscle damage severity and AKI risk in rhabdomyolysis, particularly with viral infections like COVID-19 that can cause delayed-onset muscle injury.

DOI： 10.7759/cureus.68145

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記述言語：英語  

DOI： 10.1111/ggi.14879

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

AIMS: Osteoporosis is prevalent and is associated with poor prognosis in patients with heart failure (HF). However, bone mineral density measurement by a dual-energy X-ray absorptiometry (DEXA) scan is not always available in a daily clinical setting or large-scale population-based studies. METHODS AND RESULTS: A single-centre, cross-sectional observational study was conducted with 387 patients [median age: 77 years (interquartile range: 68-83 years); 37% women]. Bone mineral densities were measured by DEXA scans, and osteoporosis was diagnosed as ≤-2.5 standard deviation of the bone mineral densities in healthy young adults. Osteoporosis risk assessment score (ORAS) was developed using significant predictors from a logistic regression model for osteoporosis and was subsequently validated. Osteoporosis was found in 103 (27%) of the 387 HF patients. Multivariate logistic regression analyses yielded the ORAS based on sex, body mass index, handgrip strength, and anti-coagulant therapy utilization. The C-index of ORAS in the developmental set (0.796, 95% confidence interval: 0.747-0.845) was similar to the bootstrap validation of the prediction model (0.784) and tended to be higher than that of the osteoporosis self-assessment tool for Asians (OSTA). A nomogram of ORAS, established on the basis of the final logistic regression model, demonstrated 100% sensitivity at the lowest score (35 points), with an optimal cut-off point of 127 points, yielding 85% sensitivity and 62% specificity. CONCLUSION: Osteoporosis risk assessment score exhibits superior predictive performance to OSTA in predicting osteoporosis in HF patients, establishing itself as a valuable tool for early detection in both daily clinical practice and large-scale population-based studies.

DOI： 10.1093/eurjcn/zvad089

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Necroptosis, a form of necrosis, and alterations in mitochondrial dynamics, a coordinated process of mitochondrial fission and fusion, have been implicated in the pathogenesis of cardiovascular diseases. This study aimed to determine the role of mitochondrial morphology in canonical necroptosis induced by a combination of TNFα and zVAD (TNF/zVAD) in H9c2 cells, rat cardiomyoblasts. Time-course analyses of mitochondrial morphology showed that mitochondria were initially shortened after the addition of TNF/zVAD and then their length was restored, and the proportion of cells with elongated mitochondria at 12 h was larger in TNF/zVAD-treated cells than in non-treated cells (16.3 ± 0.9% vs. 8.0 ± 1.2%). The knockdown of dynamin-related protein 1 (Drp1) and fission 1, fission promoters, and treatment with Mdivi-1, a Drp-1 inhibitor, had no effect on TNF/zVAD-induced necroptosis. In contrast, TNF/zVAD-induced necroptosis was attenuated by the knockdown of mitofusin 1/2 (Mfn1/2) and optic atrophy-1 (Opa1), proteins that are indispensable for mitochondrial fusion, and the attenuation of necroptosis was not canceled by treatment with Mdivi-1. The expression of TGFβ-activated kinase (TAK1), a negative regulator of RIP1 activity, was upregulated and the TNF/zVAD-induced RIP1-Ser166 phosphorylation, an index of RIP1 activity, was mitigated by the knockdown of Mfn1/2 or Opa1. Pharmacological TAK1 inhibition attenuated the protection afforded by Mfn1/2 and Opa1 knockdown. In conclusion, the inhibition of mitochondrial fusion increases TAK1 expression, leading to the attenuation of canonical necroptosis through the suppression of RIP1 activity.

DOI： 10.3390/ijms25052905

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND AND AIMS: Low serum 25-hydroxyvitamin D (25 [OH]D) levels have been associated with sarcopenia, frailty, and risk of cardiovascular disease, whereas high levels negatively impact clinical outcomes. We determined optimal serum 25(OH)D concentrations to minimise the probability of sarcopenia in patients with heart failure (HF) by examining the dose-dependent relationship between serum 25(OH)D levels and sarcopenia. METHODS AND RESULTS: We enrolled 461 consecutive patients with HF (mean age, 72 ± 15 years; 39% female) who underwent dual-energy X-ray absorptiometry. Serum 25(OH)D levels were measured using a chemiluminescence immunoassay. Sarcopenia was diagnosed according to the 2019 Asian Working Group for Sarcopenia criteria. Overall, 49% of enrolled patients were diagnosed with sarcopenia. Adjusted logistic regression with restricted cubic spline function revealed that the odds ratio (OR) of sarcopenia increased in patients with HF presenting serum 25(OH)D levels <14.6 ng/ml or > 31.4 ng/ml, reaching the lowest OR at ∼20 ng/ml. Multivariate logistic regression revealed that a serum 25(OH)D level below 14.6 ng/mL was independently associated with the presence of sarcopenia (adjusted OR: 2.16, 95% confidence interval [CI]: 1.24-3.78). Incorporating serum 25(OH)D levels <14.6 ng/ml, but not <20.0 ng/ml, in the baseline model improved continuous net reclassification (0.334, 95% CI: 0.122-0.546) in patients with HF. CONCLUSION: A U-shaped relationship exists between serum 25(OH)D levels and sarcopenia probability in patients with HF. Maintaining serum 25(OH)D levels between 14.6 and 31.4 ng/ml may help prevent sarcopenia in patients with HF.

DOI： 10.1016/j.numecd.2023.10.003

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

AIMS: Iron deficiency (ID) is common in patients with heart failure (HF) and is reportedly associated with exercise intolerance and impaired quality of life. Iron supplementation therapy in HF patients with ID improves exercise capacity. Conversely, protective roles of iron depletion in the development of diabetes mellitus (DM) and its complications have been proposed. This study aimed to determine the impact of ID on physical function in HF patients with and without DM. METHODS AND RESULTS: We enrolled consecutive patients who were admitted to our institute for HF diagnosis and management. The short physical performance battery (SPPB) was used to evaluate physical function, and low physical function was defined as an SPPB score of <10 points as individuals with SPPB scores of <10 points are most likely to be classified as frail and are at high risk for disability and future adverse events, including death. ID was defined as serum ferritin < 100 or 100-299 ng/mL when transferrin saturation (TSAT) was <20% according to the HF guidelines. Among the 562 HF patients (72 ± 14 years old; 56% male), 329 patients (58%) and 191 patients (34%) had ID and low physical function, respectively. Multivariate logistic regression analysis showed that TSAT as a continuous variable, but not ID, was a predictor of low physical function (odds ratio: 0.980, P = 0.024). Subgroup analysis showed that a significant association between low TSAT and low physical function was lost in HF patients with DM (P for interaction < 0.001). A spline dose-response curve for the relationship between TSAT and risk of low physical function with adjustments for covariates associated with low physical function in non-DM patients was almost linear with an increase in the risk of low physical function as the TSAT increased, but such a relationship was not found in the analyses of DM patients. A lack of close TSAT-SPPB relationship in HF patients with DM was confirmed also in a propensity-score-matched cohort. CONCLUSIONS: TSAT as a continuous variable, but not ID, was independently associated with physical function in HF patients, and a significant association was lost in patients with HF and DM, suggesting a limited impact of iron supplementation therapy in HF patients with DM.

DOI： 10.1002/ehf2.14610

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

AIM: We examined whether the addition of self-reported weight loss improves the accuracy of prediction of mortality caused by sarcopenia in heart failure (HF) patients. METHODS: We enrolled 477 HF patients (mean age 77 years) who received combined assessment of sarcopenia and self-reported weight loss. Sarcopenia was diagnosed according to the criteria of the Asian Working Group for Sarcopenia. If the patients answered "yes" to the question "have you lost 2 kg or more in the past 6 months?", they were diagnosed as having self-reported weight loss. RESULTS: Sarcopenia and self-reported weight loss coexisted in 32% of patients. During a median follow-up period of 763 days, 65 patients (15%) died. Kaplan-Meier curves showed a significantly higher rate of mortality in HF patients with both sarcopenia and self-reported weight loss than in HF patients with sarcopenia alone. Multivariate Cox proportional hazards analysis showed that the coexistence of sarcopenia and self-reported weight loss is an independent predictor of mortality in HF patients. Inclusion of the coexistence of sarcopenia and self-reported weight loss in the baseline model consisting of established prognostic markers significantly improved both the net reclassification index and the integrated discrimination index. CONCLUSIONS: The coexistence of sarcopenia and self-reported weight loss is a powerful predictor of mortality in HF patients. Geriatr Gerontol Int 2024; 24: 95-101.

DOI： 10.1111/ggi.14778

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Results of experimental studies have shown that β-aminoisobutyric acid (BAIBA), an exercise-induced myokine-like molecule, is an endogenous negative regulator of fat mass in mice, but it remains unclear whether that is the case in humans, though an enhanced BAIBA concentration in patients receiving sodium-glucose cotransporter 2 inhibitors was found in our recent study. The objective of this study was to analyze the determinants of circulating BAIBA concentration in humans, with focus on the possible link between circulating BAIBA and body composition including fat mass. Data for 188 consecutive patients with heart failure (HF, 64 ± 13 years; 70% male) who received a dual energy X ray absorptiometry (DEXA) scan for assessment of body composition including fat mass index (FMI) and appendicular skeletal muscle mass index (ASMI) were used in this study. Plasma BAIBA concentration in a fasting state after stabilization of HF was determined using ultraperformance liquid chromatography. Plasma BAIBA was detected in 66% of the patients. In simple linear regression analyses of data from patients in whom plasma BAIBA was detected, plasma BAIBA concentration was positively correlated with uric acid and was negatively correlated with body mass index (BMI), estimated glomerular filtration rate (eGFR), FMI, and % body fat. There were no correlations between plasma BAIBA concentration and indexes of muscle mass and bone mass. The results of multiple linear regression analyses showed that FMI and % body fat in addition to BMI, but not ASMI, were independent explanatory factors for plasma BAIBA concentration. In conclusion, plasma BAIBA concentration is inversely correlated with indexes of fat mass, indicating that BAIBA may be a therapeutic target for excessive fat accumulation.

DOI： 10.1007/s00380-023-02308-y

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: The renin-angiotensin system (RAS) activation is a proposed mechanism of muscle wasting (MW i.e., reduction in muscle mass). Although we reported that RAS inhibitors (RASIs) were associated with lower prevalence of MW in heart failure (HF) patients, the relationship between mineralocorticoid receptor (MR) signaling and MW has not been analyzed. METHODS AND RESULTS: We analyzed data from 320 consecutive Japanese HF patients who underwent dual-energy X-ray absorptiometry scanning for assessment of appendicular skeletal muscle mass index (ASMI). In multiple linear regression analyses, plasma renin activity (PRA) was negatively correlated with ASMI in patients not receiving RASIs, indicating an untoward role of the RAS in MW. Results of analysis of covariance in which risk factors of MW served as covariates showed that use of MR antagonists (MRAs) was associated with lower ASMI and higher PRA in the non-RASIs group. The close relationship between use of MRAs and lower ASMI or higher PRA in the non-RASIs group was confirmed in analyses in which the differences in baseline characteristics between users and non-users of MRAs were minimized by using an inverse probability of treatment weighting. CONCLUSIONS: Increased PRA by MR inhibition without concurrent RAS inhibition, possibly contributing to upregulation of angiotensin II signaling, may be associated with reduction in muscle mass.

DOI： 10.1253/circj.CJ-23-0567

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Although proton pump inhibitors (PPIs) play a pivotal role in the prevention and treatment of gastric acid-related diseases and gastrointestinal adverse events caused by antiplatelet therapies, the safety of long-term use of PPIs has been questioned. OBJECTIVE: The aim of this study was to determine the effects of use of PPIs on muscle mass and bone mineral density in heart failure (HF) patients. METHODS: This was a single-center, ambispective (combined retrospective and prospective), observational study. HF patients (n = 747; 72 years of age; males, 54%) who received a dual-energy x-ray absorptiometry scan were enrolled. Muscle wasting was defined as appendicular skeletal muscle mass index (ASMI) < 7.0 kg/m2 in males and <5.4 kg/m2 in females. Propensity scores for the use of PPIs were calculated using a multivariate logistic regression model to minimize selection bias. RESULTS: Before propensity score matching, ASMI was significantly lower in patients receiving PPIs than in patients not receiving PPIs, resulting in a higher prevalence of muscle wasting in the PPI group. Such a relationship between use of PPIs and muscle wasting remained after propensity score matching. In multivariate Cox regression analyses, use of PPIs was independently associated with presence of muscle wasting (hazard ratio 1.68, 95% confidence interval 1.05-2.69) after adjustment for established risk factors of sarcopenia. On the other hand, there were no differences in bone mineral density between the PPI group and the no-PPI group. CONCLUSION: Use of PPIs is associated with a high risk of muscle wasting in HF patients. Caution is warranted when long-term PPI treatment is performed in sarcopenic HF patients and HF patients with several risk factors for muscle wasting.

DOI： 10.1007/s40266-023-01035-3

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background: A multidisciplinary team (MDT) approach is crucial for managing older patients with heart failure (HF). We investigated the impact on clinical outcomes of implementation of a conference sheet (CS) with an 8-component radar chart for visualizing and sharing patient information. Methods and Results: We enrolled 395 older inpatients with HF (median age 79 years [interquartile range 72-85 years]; 47% women) and divided them into 2 groups according to CS implementation: a non-CS group (before CS implementation; n=145) and a CS group (after CS implementation; n=250). The clinical characteristics of patients in the CS group were assessed using 8 scales (physical function, functional status, comorbidities, nutritional status, medication adherence, cognitive function, HF knowledge level, and home care level). In-hospital outcomes (Short Physical Performance Battery, Barthel Index score, length of hospital stay, and hospital transfer rate) were significantly better in the CS than non-CS group. During the follow-up period, 112 patients experienced composite events (all-cause death or admission for HF). Inverse probabilities of treatment-weighted Cox proportional hazard analyses demonstrated a 39% reduction in risk of composite events in the CS group (adjusted hazard ratio 0.65; 95% confidence interval 0.43-0.97). Conclusions: Radar chart-based information sharing among MDT members is associated with superior in-hospital clinical outcomes and a favorable prognosis.

DOI： 10.1253/circrep.CR-23-0049

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

AIMS/INTRODUCTION: We previously showed that upregulation of myocardial adenosine monophosphate deaminase (AMPD) is associated with pressure overload-induced diastolic dysfunction in type 2 diabetes hearts. Here, we examined involvement of AMPD localized in the endoplasmic reticulum-mitochondria interface in mitochondrial Ca2+ overload and its pathological significance. MATERIALS AND METHODS: We used type 2 diabetes Otsuka Long-Evans Tokushima Fatty rats (OLETF) and non-diabetes Long-Evans Tokushima Otsuka Fatty rats (LETO) as well as AMPD3-overexpressing H9c2 cells and human embryonic kidney 293 cells. RESULTS: OLETF, but not LETO, showed diastolic dysfunction under the condition of phenylephrine-induced pressure overload. The levels of 90-kDa AMPD3 in outer mitochondrial membranes/endoplasmic reticulum and mitochondria-associated endoplasmic reticulum membrane (MAM) fractions were significantly higher in OLETF than in LETO. The area of the MAM quantified by electron microscopic analysis was 57% larger, mitochondrial Ca2+ level under the condition of pressure overload was 47% higher and Ca2+ retention capacity in MAM-containing crude mitochondria isolated before the pressure overloading was 21% lower in OLETF than in LETO (all P-values <0.05). Transfection of FLAG-AMPD3 in cells resulted in significant enlargement of the MAM area, and impairment in pyruvate/malate-driven adenosine triphosphate-stimulated and uncoupler-stimulated mitochondrial respiration compared with those in control cells. CONCLUSIONS: The findings suggest that 90-kDa AMPD3 localized in the endoplasmic reticulum-mitochondria interface promotes formation of the MAM, inducing mitochondrial Ca2+ overload and dysfunction in type 2 diabetes hearts.

DOI： 10.1111/jdi.13982

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Preserved urinary excretion of aquaporin 2, an index for the function of vasopressin V2 receptor (V2-R), has been reported to predict a favorable response of heart failure patients to treatment with tolvaptan. In this study, we investigated the long-term effects of tolvaptan treatment on clinical outcomes and V2-R function in patients with acute decompensated heart failure (ADHF). We enrolled 90 consecutive patients who were hospitalized in Sapporo Medical University Hospital for ADHF and treated with tolvaptan in the BOREAS-ADHF registry and analyzed patients who continued taking tolvaptan after discharge. The effect of tolvaptan treatment on rehospitalization for HF or death was investigated according to whether the V2-R function was preserved (first morning urine osmolarity ≥ 352 mOsm/L, High-Uosm) or impaired (Uosm < 352 mOsm/L, Low-Uosm). During a median follow-up period of 443 days, significantly fewer patients in the High-Uosm group experienced adverse events than did patients in the Low-Uosm group (P < 0.001). Among the patients with High-Uosm, early commencement of tolvaptan administration (on or before day 7 of hospitalization, Early/High-Uosm) significantly reduced adverse events compared to late administration (after day 7 of hospitalization, Late/High-Uosm). Uosm measured during the long-term follow-up period after discharge was significantly reduced compared to that before commencement of tolvaptan administration in the Late/High-Uosm group (from 468 ± 88 to 395 ± 108 mOsm, -18.3 ± 19.6%, P < 0.05) but not in the Early/High-Uosm group (from 478 ± 115 to 455 ± 133 mOsm, -0.50 ± 35.3%, P = 0.66). These findings indicate that early commencement and long-term continuation of tolvaptan treatment attenuate functional impairment of V2-R and improve clinical outcomes in ADHF patients with preserved V2-R function.

DOI： 10.1536/ihj.22-321

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Accumulating evidence suggests that necroptosis of cardiomyocytes contributes to cardiovascular diseases. Lethal disruption of the plasma membrane in necroptosis is induced by oligomers of mixed lineage kinase domain-like (MLKL) that is translocated to the membrane from the cytosol. However, the role played by cytoplasmic-nuclear shuttling of MLKL is unclear. Here, we tested the hypothesis that translocation of MLKL to the nucleus promotes the necroptosis of cardiomyocytes. Activation of the canonical necroptotic signaling pathway by a combination of TNF-α and zVAD (TNF/zVAD) increased nuclear MLKL levels in a RIP1-activity-dependent manner in H9c2 cells, a rat cardiomyoblast cell line. By use of site-directed mutagenesis, we found a nuclear export signal sequence in MLKL and prepared its mutant (MLKL-L280/283/284A), though a search for a nuclear import signal was unsuccessful. MLKL-L280/283/284A localized to both the cytosol and the nucleus. Expression of MLKL-L280/283/284A induced necroptotic cell death, which was attenuated by GppNHp, an inhibitor of Ran-mediated nuclear import, but not by inhibition of RIP1 activity or knockdown of RIP3 expression. GppNHp partly suppressed H9c2 cell death induced by TNF/zVAD treatment. These results suggest that MLKL that is translocated to the nucleus via RIP1-mediated necroptotic signaling enhances the necroptosis of cardiomyocytes through a RIP1-/RIP3-independent mechanism.

DOI： 10.1016/j.jphs.2022.12.009

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

The primary pharmacological action of sodium-glucose co-transporter 2 (SGLT2) inhibitors is to inhibit the reabsorption of glucose and sodium ions from the proximal tubules of the kidney and to promote urinary glucose excretion. Notably, several clinical trials have recently demonstrated potent protective effects of SGLT2 inhibitors in patients with heart failure (HF) or chronic kidney disease (CKD), regardless of the presence or absence of diabetes. However, the impact of SGLT2 inhibitors on sudden cardiac death (SCD) or fatal ventricular arrhythmias (VAs), the pathophysiology of which is partly similar to that of HF and CKD, remains undetermined. The cardiorenal protective effects of SGLT2 inhibitors have been reported to include hemodynamic improvement, reverse remodeling of the failing heart, amelioration of sympathetic hyperactivity, correction of anemia and impaired iron metabolism, antioxidative effects, correction of serum electrolyte abnormalities, and antifibrotic effects, which may lead to prevent SCD and/or VAs. Recently, as possible direct cardiac effects of SGLT2 inhibitors, not only inhibition of Na+/H+ exchanger (NHE) activity, but also suppression of late Na+ current have been focused on. In addition to the indirect cardioprotective mechanisms of SGLT2 inhibitors, suppression of aberrantly increased late Na+ current may contribute to preventing SCD and/or VAs via restoration of the prolonged repolarization phase in the failing heart. This review summarizes the results of previous clinical trials of SGLT2 inhibitors for prevention of SCD, their impact on the indices of electrocardiogram, and the possible molecular mechanisms of their anti-arrhythmic effects.

DOI： 10.3389/fcvm.2023.1159953

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

Mitochondrial disease, most cases of which are caused by mitochondrial DNA (mtDNA) mutation, is present with multiple phenotypes including diabetes mellitus, sensorineural hearing loss, cardiomyopathy, muscle weakness, renal dysfunction, and encephalopathy, depending on the degree of heteroplasmy. While mitochondria play an important role in intracellular glucose and lactate metabolism in insulin-sensitive tissues such as muscles, appropriate strategies for glycemic control have not yet been established in a patient with mitochondrial disease, which is often complicated by myopathy. Here, we describe the history of a 40-year-old man with mtDNA 3243A > G who had sensorineural hearing loss, cardiomyopathy, muscle wasting, and diabetes mellitus with stage 3 chronic kidney disease. He developed mild diabetic ketoacidosis (DKA) in the process of treatment for poor glycemic control with severe latent hypoglycemia. According to the standard therapy for DKA, he was treated with continuous intravenous insulin infusion therapy, which unexpectedly resulted in an abrupt and transient elevation in blood lactate levels without exacerbation of heart failure and kidney function. Since blood lactate levels are determined by the balance between lactate production and consumption, an abrupt and transient lactate elevation following intravenous insulin injection therapy may reflect not only enhanced glycolysis in insulin-sensitive tissues with mitochondrial dysfunction but also decreased lactate consumption in the sarcopenic skeletal muscle and failing heart. Intravenous insulin infusion therapy in patients with mitochondrial disease may unmask derangements of intracellular glucose metabolism in response to insulin signaling.

DOI： 10.3389/fcvm.2023.1144925

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

AIMS: Reduction in appendicular skeletal muscle mass index (ASMI) assessed by dual-energy X-ray absorptiometry (DEXA) has been shown to be independently associated with a higher mortality rate in patients with heart failure (HF). However, DEXA is not suitable for measurement of muscle mass in a daily clinical setting and in large population-based studies. The aim of this study was to determine whether ASMI predicted from anthropometric indicators (predicted ASMI) serves as an alternative to DEXA-measured ASMI for predicting all-cause death in HF patients. METHODS AND RESULTS: Data for 539 HF patients who received a DEXA scan and measurements of calf circumferences (CC) and mid-arm circumferences (MAC) in our hospital were analysed. Predicted ASMI was calculated as we previously reported: predicted ASMI (kg/m2 ) = [0.214 × weight (kg) + 0.217 × CC (cm) - 0.189 × MAC (cm) + 1.098 (male = 1, female = -1) + 0.576]/height2 (m2 ). Low ASMI values were defined as <7.00 kg/m2 and <5.40 kg/m2 for men and women, respectively, according to the criteria of the Asian Working Group for Sarcopenia. The median follow-up period was 1.75 years (interquartile range, 0.96-2.37 years), and 79 patients (15%) died. Kaplan-Meier survival curves showed that patients with low DEXA-measured ASMI and patients with low predicted ASMI had significantly lower survival rates than those for patients with high ASMI. In multivariate Cox proportional hazard analyses adjusted for age, sex, logarithmic B-type natriuretic peptide, cystatin C based-estimated glomerular filtration rate, and gait speed, DEXA-measured ASMI [hazard ratio (HR), 0.982; 95% confidence interval (CI), 0.967-0.998; P = 0.026] and predicted ASMI (HR, 0.979; 95% CI, 0.962-0.996; P = 0.018) were independent predictors of all-cause mortality. Inclusion of predicted ASMI into the adjustment model significantly improved continuous net reclassification improvement (0.338; 95% CI, 0.103-0.572; P < 0.01) and integrated discrimination improvement (0.020; 95% CI, 0.004-0.035; P < 0.05) for predicting mortality after discharge. CONCLUSIONS: Predicted ASMI, as well as DEXA-measured ASMI, can predict all-cause death in HF patients, and calculation of predicted ASMI will be useful for detecting high-risk patients in a daily clinical setting and in large population-based studies.

DOI： 10.1002/ehf2.14121

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

AIMS: The role of necroptosis in dilated cardiomyopathy (DCM) remains unclear. Here, we examined whether phosphorylation of mixed lineage kinase domain-like protein (MLKL), an indispensable event for execution of necroptosis, is associated with the progression of DCM. METHODS AND RESULTS: Patients with DCM (n = 56, 56 ± 15 years of age; 68% male) were enrolled for immunohistochemical analyses of biopsies. Adverse events were defined as a composite of death or admission for heart failure or ventricular arrhythmia. Compared with the normal myocardium, increased signals of MLKL phosphorylation were detected in the nuclei, cytoplasm, and intercalated discs of cardiomyocytes in biopsy samples from DCM patients. The phosphorylated MLKL (p-MLKL) signal was increased in enlarged nuclei or nuclei with bizarre shapes in hypertrophied cardiomyocytes. Nuclear p-MLKL level was correlated negatively with septal peak myocardial velocity during early diastole (r = -0.327, P = 0.019) and was correlated positively with tricuspid regurgitation pressure gradient (r = 0.339, P = 0.023), while p-MLKL level in intercalated discs was negatively correlated with mean left ventricular wall thickness (r = -0.360, P = 0.014). During a median follow-up period of 3.5 years, 10 patients (18%) had adverse events. To examine the difference in event rates according to p-MLKL expression levels, patients were divided into two groups by using the median value of nuclear p-MLKL or intercalated disc p-MLKL. A group with high nuclear p-MLKL level (H-nucMLKL group) had a higher adverse event rate than did a group with low nuclear p-MLKL level (L-nucMLKL group) (32% vs. 4%, P = 0.012), and Kaplan-Meier survival curves showed that the adverse event-free survival rate was lower in the H-nucMLKL group than in the L-nucMLKL group (P = 0.019 by the log-rank test). Such differences were not detected between groups divided by a median value of intercalated disc p-MLKL. In δ-sarcoglycan-deficient (Sgcd-/- ) mice, a model of DCM, total p-MLKL and nuclear p-MLKL levels were higher than in wild-type mice. CONCLUSION: The results suggest that increased localization of nuclear p-MLKL in cardiomyocytes is associated with left ventricular diastolic dysfunction and future adverse events in DCM.

DOI： 10.1002/ehf2.14059

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

AIMS: Although the impact of physical frailty on prognosis and the effect of cardiac rehabilitation in HF patients has been well established, data for the prognostic impact of social frailty (SF) in HF patients are limited. In addition, the relative importance of each SF domain in clinical outcomes remains unclear. We aimed to get a new insight into the associations of SF with clinical outcomes in elderly hospitalized HF patients. METHODS: A single-center, retrospective cohort study was conducted using data from 310 in-hospital HF patients aged ≥ 65 years (mean age of 78 ± 8 years; 49% women). Makizako's five questions, a self-reported questionnaire, were used to define SF. The primary outcome was composite events defined by all-cause death and cardiovascular events. RESULTS: Of the 310 elderly HF patients, 188 patients (61%) had SF. Seventy-five patients (24%) had composite events during a mean follow-up period of 1.93 ± 0.91 years. Kaplan-Meier curves showed that patients with SF had a significantly higher composite event rate than patients without SF. In multivariate Cox regression analyses, SF was independently associated with a higher composite event rate after adjusting for prognostic markers [adjusted hazard ratio (HR), 2.01; 95% confidence interval (CI), 1.07-3.78; p = 0.04]. Of the 5 questions for defining SF, an answer of yes to the question about not feeling helpful toward friends or family, which indicates loss of perceived social role, was an independent predictor of composite events (adjusted HR, 2.28; 95% CI, 1.36-3.82; p < 0.01). Inclusion of loss of perceived social role into the baseline prognostic model improved both the continuous net reclassification improvement (0.562; 95% CI, 0.298-0.827; p < 0.01) and integrated discrimination improvement (0.031; 95% CI, 0.006-0.056; p = 0.02). CONCLUSION: Loss of perceived social role is associated with increased adverse event risk and provides additive prognostic information in elderly HF patients.

DOI： 10.3389/fcvm.2022.1051570

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Objective We recently reported a novel score for the detection of glomerular filtration rate (GFR) overestimation using a creatinine-based equation. We examined the utility of this score in patients with cardiovascular/renal diseases and diabetes mellitus. Methods We enrolled 1,425 patients (65±15 years old; 37% women) who were admitted to our hospital for the management of cardiovascular and renal diseases and their risk factors. Overestimation of the GFR (OE) was defined as a creatinine-based GFR (eGFRcre) ≥120% of the cystatin C-based estimated GFR. The OE score was calculated as the sum of the scores for the body weight, hemoglobin concentration, and blood urea nitrogen (BUN)/serum creatinine (Scr), totaling 1 point if the body weight was <63.0 kg in men or <42.0 kg in women, 1 point if the hemoglobin concentration was <12.4 g/dL in men or <11.0 g/dL in women, and 1 point if the BUN/Scr was >26.5. Results The proportion of patients with OE was 14.2%. The score predicted OE with a sensitivity of 70.8% and a specificity of 99.6%, and the sensitivity was increased in patients ≥75 years old (88.3%) and decreased in diabetics (58.6%). When patients were divided into subgroups by the total score, the frequencies of OE were 8% (59/754), 14% (72/502), 38% (58/151), and 72% (13/18) in patients with scores of 0, 1, 2, and 3, respectively. Conclusion The OE score is useful for detecting elderly cases of cardiovascular and renal diseases in which eGFRcre overestimates the GFR, although its utility is limited in diabetics.

DOI： 10.2169/internalmedicine.7388-21

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Diagnostic strategies for symptomatic transthyretin (ATTR) cardiac amyloidosis showing typical morphological features such as increased ventricular wall thickness and myocardial injury such as an elevation in serum troponin T level have been established, but those for subclinical cardiac amyloidosis are limited. In the era when effective therapies to suppress/delay progression of ATTR cardiac amyloidosis are available, early detection of cardiac involvement plays a crucial role in appropriate decision-making for treatment in TTR mutation carriers who have a family history of heart failure and death due to ATTR amyloidosis. Findings of three cases with known pathogenic transthyretin (TTR) mutations (p.Ser70Arg, p.Phe53Val, and p.Val50Met) and family histories of death for amyloidosis were presented. Two cases were asymptomatic, and a case carrying p.Phe53Val had gastrointestinal symptoms and autonomic neuropathy. Levels of plasma N-terminal fragment of pro-B-type natriuretic peptide and troponin T were within normal ranges in all cases, but results of cardiac magnetic resonance (CMR) and bone scintigraphy clearly revealed the presence of cardiac involvement in all cases, even in a case without echocardiographic abnormalities including left ventricular hypertrophy and relative apical sparing of longitudinal strain shown by two-dimensional speckle-tracking echocardiography. Electrocardiography revealed modest abnormalities including reduced R wave amplitude in V2 and a trend toward left axis deviation in all cases. In conclusion, CMR, bone scintigraphy, and electrocardiography are useful for early detection of ATTR cardiac amyloidosis in TTR mutation carriers. The role of comprehensive cardiac assessment in the early detection of cardiac amyloidosis in TTR mutation carriers is discussed.

DOI： 10.1536/ihj.21-336

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: A strategy to predict mortality in elderly heart failure (HF) patients has not been established. METHODS AND RESULTS: We retrospectively enrolled 413 HF patients aged ≥65 years (mean age 78 years) who had received comprehensive cardiac rehabilitation (CR) during hospitalization. Basic activities of daily life were assessed before discharge using the Barthel index (BI). Of 413 HF patients, 116 (28%) died during a median follow-up period of 1.90 years (interquartile range 1.20-3.23 years). An adjusted dose-dependent association analysis showed that the hazard ratio (HR) of mortality increased in an almost linear manner as the BI score decreased, and that a BI score of 85 corresponded to an HR of 1.0. Kaplan-Meier survival curves showed that the survival rate was lower for patients with a low BI (<85) than for those with a high BI (≥85; 65% vs. 74%, respectively; P=0.007). In multivariate Cox regression analyses, low BI was independently associated with higher mortality after adjusting for predictors, including B-type natriuretic peptide. Inclusion of the BI into the adjusted model improved the accuracy of the prediction of mortality. CONCLUSIONS: A BI score <85 at the time of discharge is associated with increased mortality independent of known prognostic markers, and achieving functional status with a BI score ≥85 by comprehensive CR during hospitalization may contribute to favorable outcomes in elderly HF patients.

DOI： 10.1253/circj.CJ-21-0584

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Sarcoidosis is a systemic inflammatory disease characterized by the formation of noncaseating epithelioid granulomas. Multiple organs, including the lung, eyes, and skin, are involved in this disorder, and cardiac involvement is a major cause of morbidity and mortality in patients with this disorder. We present the case history of a 22-year-old man with neurosarcoidosis complicated by abrupt onset of cardiac tamponade. Cardiac tamponade is a rare but potentially fatal manifestation of sarcoidosis, which is treatable with glucocorticoid therapy. Including the present case, previously reported cases of sarcoidosis with cardiac tamponade are reviewed to delineate its clinical characteristics.

DOI： 10.1536/ihj.21-167

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記述言語：英語  

DOI： 10.1177/2047487320904236

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Multiple factors regulate glucagon-like peptide-1 (GLP-1) secretion, but a group of apparently healthy subjects showed blunted responses of GLP-1 secretion in our previous study. In this study, we examined whether the reduction in GLP-1 secretory capacity is associated with increased extent of coronary artery stenosis in non-diabetic patients. Non-diabetic patients who were admitted for coronary angiography without a history of coronary interventions were enrolled. Coronary artery stenosis was quantified by Gensini score (GS), and GS ≥ 10 was used as an outcome variable based on its predictive value for cardiovascular events. The patients (mean age, 66.5 ± 8.8 years; 71% males, n = 173) underwent oral 75 g-glucose tolerant tests for determination of glucose, insulin and active GLP-1 levels. The area under the curve of plasma active GLP-1 (AUC-GLP-1) was determined as an index of GLP-1 secretory capacity. AUC-GLP-1 was not correlated with fasting glucose, AUC-glucose, serum lipids or indices of insulin sensitivity. In multivariate logistic regression analysis for GS ≥ 10, AUC-GLP-1 < median, age and hypertension were selected as explanatory variables, though fasting GLP-1 level was not selected. The findings suggest that reduction in GLP-1 secretory capacity is a novel independent risk factor of coronary stenosis.

DOI： 10.1038/s41598-021-95065-9

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

AIMS: Results of experimental studies have indicated the possibility of muscle and bone mass being negatively regulated by renin-angiotensin system (RAS) activation, but that possibility has not been analysed in patients with heart failure (HF). METHODS AND RESULTS: Data for HF patients who received a dual-energy X-ray absorptiometry scan in our hospital were reviewed. Propensity scores for the use of RAS inhibitors (RASIs) were calculated using a multivariate logistic regression model to minimize selection bias. One hundred sixty pairs of patients were extracted. Plasma aldosterone concentration was significantly lower in the RASIs group than in the no-RASIs group (119 [IQR 71-185] vs. 94 [IQR 60-131] pg/mL, P = 0.003), confirming RAS inhibition in the RASIs group. Skeletal muscle mass index tended to be higher in the RASIs group than in the non-RASIs group (15.6 [IQR 14.0-17.2] vs. 15.0 [IQR 13.3-16.6] pg/mL, P = 0.065). The proportion of patients with muscle wasting, defined as appendicular skeletal muscle mass indexes of <7.00 and <5.40 kg/m2 for males and females, respectively, was significantly lower in the RASIs group than in the non-RASIs group (53% vs. 64%, P = 0.041). Multivariate logistic regression analysis showed that the no use of RASIs was associated with presence of muscle wasting independently of age, presence of diabetes, renal function, and severity of HF. Bone mineral densities and proportions of patients with osteoporosis were similar in the two groups. CONCLUSIONS: Renin-angiotensin system inhibition is associated with a lower prevalence of muscle wasting in HF patients independently of established risk factors.

DOI： 10.1002/ehf2.13430

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVE: Malnutrition is associated with an increased risk of mortality in heart failure (HF) patients. Here, we examined the hypothesis that assessment of energy intake in addition to nutritional status improves the stratification of mortality risk in elderly HF patients. METHODS: We retrospectively examined 419 HF patients aged ≥ 65 years (median 78 years, 49% female). Nutritional status was assessed by the Mini Nutritional Assessment Short Form (MNA-SF), and daily energy intake was calculated from intake during 3 consecutive days before discharge. RESULTS: During a median 1.52-year period (IQR 0.96-2.94 years), 110 patients (26%) died. Kaplan-Meier survival curves showed that patients with low tertile of daily energy intake had a higher mortality rate than did patients with high or middle tertile of daily energy intake. In multivariate Cox regression analyses, low daily energy intake was independently associated with higher mortality after adjustment for the model including age, sex, BNP, Charlson Comorbidity Index, history of HF hospitalization, and cachexia in addition to MNA-SF. Inclusion of both MNA-SF and energy intake into the adjustment model improved the accuracy of prediction of the mortality after discharge (continuous net reclassification improvement, 0.355, p = 0.003; integrated discrimination improvement, 0.029, p = 0.003). Results of a fully adjusted dose-dependent association analysis showed that risk of all-cause mortality was lowest among HF patients who consumed 31.5 kcal/kg/day of energy. CONCLUSIONS: Energy intake during hospital stay is an independent predictor of the mortality in elderly HF patients, and its assessment together with established predictors improves the mortality risk stratification.

DOI： 10.1007/s00392-020-01774-y

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: We previously reported that upregulated AMP deaminase (AMPD) contributes to diastolic ventricular dysfunction via depletion of the adenine nucleotide pool in a rat model of type 2 diabetes (T2DM), Otsuka Long-Evans-Tokushima Fatty rats (OLETF). Meanwhile, AMPD promotes the formation of substrates of xanthine oxidoreductase (XOR), which produces ROS as a byproduct. Here, we tested the hypothesis that a functional link between upregulated AMPD and XOR is involved in ventricular dysfunction in T2DM rats. METHODS AND RESULTS: Pressure-volume loop analysis revealed that pressure overloading by phenylephrine infusion induced severer left ventricular diastolic dysfunction (tau: 14.7 ± 0.8 vs 12.5 ± 0.7 msec, left ventricular end-diastolic pressure: 18.3 ± 1.5 vs 12.2 ± 1.3 mmHg, p < 0.05) and ventricular-arterial uncoupling in OLETF than in LETO, non-diabetic rats, though the baseline parameters were comparable in the two groups. While the pressure overload did not affect AMPD activity, it increased XOR activity both in OLETF and LETO, with OLETF showing significantly higher XOR activity than that in LETO (347.2 ± 17.9 vs 243.2 ± 6.1 μg/min/mg). Under the condition of pressure overload, myocardial ATP level was lower, and levels of xanthine and uric acid were higher in OLETF than in LETO. Addition of exogenous inosine, a product of AMP deamination, to the heart homogenates augmented XOR activity. OLETF showed 68% higher tissue ROS levels and 47% reduction in mitochondrial state 3 respiration compared with those in LETO. Overexpression of AMPD3 in H9c2 cells elevated levels of hypoxanthine and ROS and reduced the level of ATP. Inhibition of XOR suppressed the production of tissue ROS and mitochondrial dysfunction and improved ventricular function under the condition of pressure overload in OLETF. CONCLUSIONS: The results suggest that increases in the activity of XOR and the formation of XOR substrates by upregulated AMPD contribute to ROS-mediated diastolic ventricular dysfunction at the time of increased cardiac workload in diabetic hearts.

DOI： 10.1016/j.yjmcc.2021.01.002

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Although high body mass index (BMI) is a risk factor of heart failure (HF), HF patients with a higher BMI had a lower mortality rate than that in HF patients with normal or lower BMI, a phenomenon that has been termed the "obesity paradox". However, the relationship between body composition, i.e., fat or muscle mass, and clinical outcome in HF remains unclear. METHODS: We retrospectively analyzed data for 198 consecutive HF patients (76 years of age; males, 49%). Patients who were admitted to our institute for diagnosis and management of HF and received a dual-energy X-ray absorptiometry scan were included regardless of left ventricular ejection fraction (LVEF) categories. Muscle wasting was defined as appendicular skeletal muscle mass index < 7.0 kg/m2 in males and < 5.4 kg/m2 in females. Increased percent body fat mass (increased FM) was defined as percent body fat > 25% in males and > 30% in females. RESULTS: The median age of the patients was 76 years (interquartile range [IQR], 67-82 years) and 49% of them were male. The median LVEF was 47% (IQR, 33-63%) and 33% of the patients had heart failure with reduced ejection fraction. Increased FM and muscle wasting were observed in 58 and 67% of the enrolled patients, respectively. During a 180-day follow-up period, 32 patients (16%) had cardiac events defined as cardiac death or readmission by worsening HF or arrhythmia. Kaplan-Meier survival curves showed that patients with increased FM had a lower cardiac event rate than did patients without increased FM (11.4% vs. 22.6%, p = 0.03). Kaplan-Meier curves of cardiac event rates did not differ between patients with and those without muscle wasting (16.5% vs. 15.4%, p = 0.93). In multivariate Cox regression analyses, increased FM was independently associated with lower cardiac event rates (hazard ratio: 0.45, 95% confidence interval: 0.22-0.93) after adjustment for age, sex, diabetes, muscle wasting, and renal function. CONCLUSIONS: High percent body fat mass is associated with lower risk of short-term cardiac events in HF patients.

DOI： 10.1186/s12877-020-01950-9

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Muscle wasting, that is, reduction in muscle mass, is frequently observed in patients with chronic heart failure (CHF) and diabetes mellitus (DM). METHODS: We retrospectively examined 185 patients with CHF (median age of 71 years [interquartile range, 61-78 years]; 64% male) who received a dual-energy X-ray absorptiometry scan for assessment of appendicular skeletal muscle mass index (ASMI). RESULTS: Seventy patients with CHF (38%) had DM. Patients with DM had higher prevalences of ischemic heart disease and hypertension, lower levels of estimated glomerular filtration rate (eGFR) and ASMI, and higher levels of plasma renin activity (PRA) than did patients without DM. In simple regression analyses, ASMI was positively correlated with the Mini Nutritional Assessment Short Form (MNA-SF) score and levels of hemoglobin, eGFR, and fasting plasma insulin and was negatively correlated with levels of N-terminal pro B-type natriuretic peptide, PRA, and cortisol. In multiple linear regression analyses, age, MNA-SF score, DM, fasting plasma insulin level, and PRA were independently associated with ASMI. When multiple linear regression analyses were separately performed in a non-DM group and a DM group, MNA-SF score and fasting plasma insulin level were independent variables for ASMI in both groups. PRA was independently associated with ASMI in the DM group but not in the non-DM group, whereas cortisol concentration was independently associated with ASMI only in the non-DM group. CONCLUSIONS: In addition to malnutrition and reduction in plasma insulin, renin-angiotensin system activation may be responsible for the development of muscle wasting in CHF patients with DM.

DOI： 10.1111/1753-0407.13090

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: The clinical significance of osteoporosis in chronic heart failure (CHF) remains unclear. METHODS AND RESULTS: A total of 303 CHF patients (75 years, [interquartile range (IQR) 66-82 years]; 41% female) were retrospectively examined. Bone mineral densities (BMDs) at the lumbar spine, femoral neck, and total femur were measured by using dual-energy X-ray absorptiometry (DEXA), and osteoporosis was diagnosed when the BMD at any of the 3 sites was <70% of the Young Adult Mean percentage (%YAM). The prevalence of osteoporosis in CHF patients was 40%. Patients with osteoporosis were older (79 [IQR, 74-86] vs. 72 [IQR, 62-80] years), included a large percentage of females, had slower gait speed and had a lower body mass index. Multivariate logistic regression analysis indicated that sex, BMI, gait speed, loop diuretics use and no use of direct oral anticoagulants (DOACs) were independently associated with osteoporosis. Kaplan-Meier survival curves showed that the rate of death and heart failure hospitalization was higher in patients with osteoporotic BMD at 2 or 3 sites than in patients without osteoporosis (hazard ratio 3.45, P<0.01). In multivariate Cox regression analyses, osteoporotic BMD at 2 or 3 sites was an independent predictor of adverse events after adjustment for prognostic markers. CONCLUSIONS: Loop diuretics use and no DOACs use are independently associated with osteoporosis in CHF patients. Osteoporosis is a novel predictor of worse outcome in patients with CHF.

DOI： 10.1253/circj.CJ-20-0593

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記述言語：英語  

DOI： 10.1111/ggi.14001

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

AIMS: A high prevalence of muscle wasting, that is, reduction in muscle mass, in patients with peripheral artery disease (PAD) and heart failure (HF) has been reported. However, whether the association between PAD and muscle wasting is independent of shared risk factors such as diabetes mellitus has not been examined. METHODS AND RESULTS: We retrospectively enrolled 440 HF patients (mean age, 74 years; inter-quartile range, 64-82 years; 52% male). Muscle wasting was defined as an appendicular skeletal muscle mass index (ASMI) of <7.0 kg/m2 in men and <5.4 kg/m2 in women. PAD was defined as an ankle brachial index (ABI) of <0.9 in either leg. The prevalence of PAD in HF patients was 21%. ASMI was positively correlated with ABI in HF patients. In multivariate logistic regression analysis, ASMI and muscle wasting were selected as independent explanatory factors of the presence of PAD after adjustment for age, sex, diabetes mellitus, hypertension, dyslipidaemia, estimated glomerular filtration rate, and smoking status, established risk factors of atherosclerosis. In propensity score-matched analysis, frequency of muscle wasting was higher in patients with PAD than in patients with an ABI of ≧1.1 (72.1% vs. 52.5%, P = 0.04). CONCLUSIONS: The results suggest that there is an independent link between PAD and muscle wasting in HF patients.

DOI： 10.1002/ehf2.12951

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

A 14-year-old girl with cardiopulmonary arrest was referred to our hospital. She had received an injection of inactivated influenza vaccine 7 days before the referral. Her cardiac rhythm was pulseless wide QRS tachycardia, and mechanical circulatory support was immediately begun. Results of endomyocardial biopsy showed that there was massive infiltration of CD3- and CD68-positive cells and various degrees of cardiomyocyte necrosis in all of 3 endomyocardial specimens, whereas infiltration of eosinophils or giant cells was not observed. A histologic diagnosis of lymphocytic myocarditis was made. Acute myocarditis is a rare but potentially fatal complication of the influenza vaccination.

DOI： 10.1016/j.cjca.2020.05.005

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

AIMS: Creatinine-based estimated glomerular filtration rate (eGFRcre) has been shown to overestimate the glomerular filtration rate (GFR) when it is compared with cystatin C-based estimated GFR (eGFRcys) in older people. We investigated clinical determinants of GFR overestimation by eGFRcre and developed a score for prediction of GFR overestimation (OE) in heart failure patients. METHODS: We retrospectively examined 244 Japanese heart failure patients (aged 72.2 ± 13.1 years; 48% women) who had no known extrarenal factors that affect serum cystatin C concentration. eGFR OE by eGFRcre was defined as eGFRcre being ≥120% of cystatin C-based eGFR. RESULTS: The proportion of heart failure patients with OE was 14.3%. Patients with OE were older, had lower body weight and total skeletal muscle mass than those in patients without OE. Laboratory examinations showed that hemoglobin concentration was lower, and the ratio of blood urea nitrogen-to-creatinine was higher in patients with OE than in patients without OE. In multivariate regression analysis, body weight (<63.0 kg in men and <42.0 kg in women), hemoglobin level (<12.4 g/dL in men and <11.0 g/dL in women) and ratio of blood urea nitrogen-to-creatinine (>26.5) in addition to skeletal muscle mass were independently associated with OE. A score calculated by using cut-off levels of body weight, hemoglobin concentration and ratio of blood urea nitrogen-to-creatinine predicted OE with a sensitivity of 97.1% and a specificity of 98.1%. CONCLUSION: Overestimation of GFR by eGFRcre is predictable by a novel scoring system, which might be useful for the detection of patients who require cystatin C-based eGFR measurement for accurate assessment of renal function. Geriatr Gerontol Int 2020; 20: 752-758.

DOI： 10.1111/ggi.13959

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Although the benefit of updated therapeutic regimens, including bortezomib, on the survival of immunoglobulin light chain (AL) amyloidosis patients with heart failure (HF) has been reported, predictors of mortality in the patients treated with the updated therapy remain unclear. We retrospectively enrolled AL amyloidosis patients who had severe HF at the time of diagnosis and received the updated therapy, including bortezomib (n = 19, 61 ± 6 years old, 68% male). Severe HF was defined as the presence of both NYHA functional class III or IV and BNP > 200 pg/ml or NT-pro-BNP > 900 pg/ml. One-year mortality rate during follow-up after commencement of the treatment was 37%. Left ventricular morphological parameters and indexes of left ventricular diastolic function on admission were similar in the non-survivors and survivors. However, non-survivors had higher incidences of atrial fibrillation and ventricular tachycardia, higher serum total bilirubin levels (1.34 ± 0.55 vs. 0.61 ± 0.29 mg/dl), higher right atrial volume index (RAVI 49.7 ± 29.9 vs. 27.3 ± 6.8 ml/m2), lower tricuspid annular peak velocities during systole (RVs' 8.0 ± 1.8 vs. 11.6 ± 3.7 cm/sec) and late diastole (RVa' 3.4 ± 0.9 vs. 11.4 ± 5.3 cm/sec), and larger inferior vena cava dimension (22.7 ± 6.4 vs. 16.3 ± 4.9 mm) than those in survivors. Kaplan-Meier curve analyses showed that larger RAVI and lower RVs' and RVa', but not left ventricular systolic/diastolic dysfunction, predicted higher mortality during 1-year follow-up. The present results suggest that the presence of right-sided heart abnormality on admission is associated with high 1-year mortality in AL amyloidosis patients with severe HF under the updated therapeutic regimens.

DOI： 10.1007/s00380-019-01513-y

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Accumulating evidence indicates that necroptosis contributes to cardiovascular diseases. We recently reported suppression of autophagy by necroptotic signals in cardiomyocytes and protective action of rapamycin. Here we examined the mechanism by which mTORC1 inhibition protects cardiomyocytes from necroptosis. Necroptosis of H9c2 cells was induced by treatment with tumor necrotic factor-α (TNF) and z-VAD-fmk (zVAD), and the extent of necroptosis was determined as the level of LDH release (as % of total). TNF/zVAD increased RIP1-RIP3 interaction and LDH release from 3.4 ± 1.3% to 46.1 ± 2.3%. The effects of TNF/zVAD were suppressed by an mTORC1 inhibitor, rapamycin, and an mTORC1/2 inhibitor, Ku-0063794, but not by a p70s6K inhibitor, PF-4708671. Protection by rapamycin was not abolished by inhibitors of TAK1, IKKα/β, and cIAP, endogenous necroptosis suppressors upstream of RIP1. Rapamycin and Ku-0063794 suppressed TNF/zVAD-induced RIP1-Ser166 phosphorylation and increased phosphorylation of RIP1-Ser320, an inhibitory phosphorylation site, though such an effect on RIP1-Ser320 was not observed for PF-4708671. Protective effects of rapamycin on TNF/zVAD-induced RIP1-RIP3 binding and necroptosis were undetected in cells transfected with RIP1-S320A. In TNF/zVAD-treated cells, rapamycin and a RIP1 inhibitor, necrostatin-1, increased nuclear localization of transcriptional factor EB (TFEB) and promoted autolysosome formation from autophagosomes in a TFEB-dependent manner. Knockdown of TFEB expression attenuated rapamycin-induced protection from necroptosis in TNF/zVAD-treated cells. The results suggest that mTORC1 inhibition promotes autophagy and protects cardiomyocytes from necroptosis by a TFEB-dependent mechanism and that inhibition of RIP1 by increased phosphorylation at Ser320 is crucial in the cardiomyocyte protection afforded by mTORC1 inhibition.

DOI： 10.1016/j.bbadis.2019.165552

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Which combination of clinical parameters improves the prediction of prognosis in patients with pulmonary arterial hypertension (PAH) remains unclear. We examined whether combined assessment of pulmonary vascular resistance and right ventricular function by echocardiography is useful for classifying risks in PAH. In 41 consecutive patients with PAH (mean age of 48.9 ± 17.3 years, 31 females), a 6-min walk test, pulmonary function test, and echocardiography were performed at baseline and during PAH-specific therapies. The study endpoint was defined as a composite of cardiovascular death and hospitalization for PAH and/or right ventricular failure. During a follow-up period of 9.2 ± 8.7 months, 18 patients reached the endpoint. Multivariate regression analysis showed that the ratio of tricuspid regurgitation pressure gradient to the time-velocity integral of the right ventricular outflow tract (TRPG/TVI) and tricuspid annular plane systolic excursion (TAPSE) during PAH-specific treatment were independent prognostic predictors of the endpoint. Using cutoff values indicated by receiver operating characteristic analysis, the patients were divided into four subsets. Multivariate analyses by Cox's proportional hazards model adjusted for age, sex and body mass index indicated that subset 4 (TRPG/TVI ≥ 3.89 and TAPSE ≤ 18.9 mm) had a significantly higher event risk than did subset 1 (TRPG/TVI < 3.89 and TAPSE > 18.9 mm): HR = 25.49, 95% CI 4.70-476.97, p < 0.0001. Combined assessment of TRPG/TVI and TAPSE during adequate PAH-specific therapies enables classification of risks for death and/or progressive right heart failure in PAH.

DOI： 10.1007/s00380-019-01429-7

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1161/CIRCIMAGING.119.009689

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Takayasu arteritis (TA) is a large vessel vasculitis of unknown aetiology characterized by chronic inflammatory changes of the aorta and its major branches. We report the active TA case who had severe heart failure due to acute myocardial infarction and aortic regurgitation. Bentall procedure was successfully performed, but he had severely depressed left ventricular function and muscle wasting together with vascular inflammation. The treatment with tocilizumab, an interleukin-6 receptor monoclonal antibody, in addition to prednisolone and standard heart failure therapy led to prompt remission of TA activity and improvement of left ventricular function and muscle wasting. Taken together with possible involvement of interleukin-6 in the pathogenesis of heart failure and muscle wasting, inhibition of interleukin-6 receptor signalling by tocilizumab may be a safe and reasonable approach in the treatment of active TA with heart failure and muscle wasting.

DOI： 10.1002/ehf2.12487

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

The etiology of peripartum cardiomyopathy (PPCM) remains unestablished, but the involvement of abnormal autoimmunity has been suggested. We report a case of PPCM that was triggered by postpartum thyroiditis. Despite the presence of myocardial damage indicated by cardiac magnetic resonance imaging, the patient's cardiac function completely recovered with the addition of bromocriptine to standard therapies. We discuss the role of thyroid hormones in the development of PPCM through aggravation of a prolactin-dependent antiangiogenic effect, and we argue that more attention should be paid to postpartum thyroiditis as a novel risk factor for PPCM.

DOI： 10.1016/j.cjca.2019.03.013

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Cells respond to iron deficiency by activating iron-regulatory proteins to increase cellular iron uptake and availability. However, it is not clear how cells adapt to conditions when cellular iron uptake does not fully match iron demand. Here, we show that the mRNA-binding protein tristetraprolin (TTP) is induced by iron deficiency and degrades mRNAs of mitochondrial Fe/S-cluster-containing proteins, specifically Ndufs1 in complex I and Uqcrfs1 in complex III, to match the decrease in Fe/S-cluster availability. In the absence of TTP, Uqcrfs1 levels are not decreased in iron deficiency, resulting in nonfunctional complex III, electron leakage, and oxidative damage. Mice with deletion of Ttp display cardiac dysfunction with iron deficiency, demonstrating that TTP is necessary for maintaining cardiac function in the setting of low cellular iron. Altogether, our results describe a pathway that is activated in iron deficiency to regulate mitochondrial function to match the availability of Fe/S clusters.

DOI： 10.1073/pnas.1804701115

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

AMP deaminase (AMPD) plays a crucial role in adenine nucleotide metabolism. Recently we found that upregulated AMPD activity is associated with ATP depletion and contractile dysfunction under the condition of pressure overloading in the heart of a rat model of type 2 diabetes mellitus (T2DM), OLETF. Here we examined the mechanism of AMPD upregulation by T2DM. The protein level of 90-kDa full-length AMPD3 was increased in whole myocardial lysates by 55% in OLETF compared to those in LETO, a non-diabetic control. In contrast, the mRNA levels of AMPD3 in the myocardium were similar in OLETF and LETO. AMPD3 was comparably ubiquitinated in OLETF and LETO, and its degradation ex vivo was more sensitive to MG-132, a proteasome inhibitor, in OLETF than in LETO. MicroRNA array analysis revealed downregulation (>50%) of 57 microRNAs in OLETF compared to those in LETO, among which miR-301b was predicted to interact with the 3'UTR of AMPD3 mRNA. AMPD3 protein level was significantly increased by a miR-301b inhibitor and was decreased by a miR-301b mimetic in H9c2 cells. A luciferase reporter assay confirmed binding of miR-301b to the 3'UTR of AMPD3 mRNA. Transfection of neonatal rat cardiomyocytes with a miR-301b inhibitor increased 90-kDa AMPD3 and reduced ATP level. The results indicate that translational regulation by miR-301b mediates upregulated expression of cardiac AMPD3 protein in OLETF, which potentially reduces the adenine nucleotide pool at the time of increased work load. The miR-301b-AMPD3 axis may be a novel therapeutic target for intervening enegy metabolism in diabetic hearts.

DOI： 10.1016/j.yjmcc.2018.05.003

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

This corrects the article DOI: 10.1038/ncomms14095.

DOI： 10.1038/ncomms16155

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

CASE: Sibutramine is a weight loss agent that was withdrawn from the market in the USA and European Union because it increases adverse events in patients with cardiovascular diseases. However, non-prescription weight loss pills containing sibutramine can be still easily purchased over the Internet. UNLABELLED: A 21-year-old woman without history of cardiovascular diseases developed cardiac arrest. She was a user of a weight loss pills, containing sibutramine and hypokalemia-inducing agents, imported from Thailand over the Internet. OUTCOME: She was successfully resuscitated without any neurological deficits by using extracorporeal membrane oxygenation for refractory ventricular fibrillation. CONCLUSION: This case indicates that sibutramine can cause cardiac arrest even in subjects without pre-existing cardiovascular disease when combined with agents that promote QT prolongation.

DOI： 10.1002/ams2.275

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Chronic kidney disease (CKD) increases myocardial infarct size by an unknown mechanism. Here we examined the hypothesis that impairment of protective PI3K-PDK1-Akt and/or mTORC-Akt signaling upon reperfusion contributes to CKD-induced enlargement of infarct size. CKD was induced in rats by 5/6 nephrectomy (SNx group) 4 weeks before myocardial infarction experiments, and sham-operated rats served as controls (Sham group). Infarct size as a percentage of area at risk after ischemia/reperfusion was significantly larger in the SNx group than in the Sham group (56.3 ± 4.6 vs. 41.4 ± 2.0%). In SNx group, myocardial p-Akt-Thr308 level at baseline was elevated, and reperfusion-induced phosphorylation of p-Akt-Ser473, p-p70s6K and p-GSK-3β was significantly suppressed. Inhibition of Akt-Ser473 phosphorylation upon reperfusion by Ku-0063794 significantly increased infarct size in the Sham group but not in the SNx group. There was no difference between the two groups in activities of mTORC2 and PDK1 and protein level of PTEN. However, the PP2A regulatory subunit B55α, which specifically targets Akt-Thr308, was reduced by 24% in the SNx group. Knockdown of B55α by siRNA increased baseline p-Akt-Thr308 and blunted Akt-Ser473 phosphorylation in response to insulin-like growth factor-1 (IGF-1) in H9c2 cells. A blunted response of Akt-Ser473 to IGF-1 was also observed in HEK293 cells transfected with a p-Thr308-mimetic Akt mutant (T308D). These results indicate that increased Akt-Thr308 phosphorylation by down-regulation of B55α inhibits Akt-Ser473 phosphorylation upon reperfusion in CKD and that the impaired Akt activation by insufficient Ser473 phosphorylation upon reperfusion contributes to infarct size enlargement by CKD.

DOI： 10.1007/s00395-017-0621-6

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVE: Chronic kidney disease is a risk factor of coronary events, however, its impact on coronary artery stenosis has not yet been clarified with the use of a large database. We examined the association between a reduced glomerular filtration rate (GFR) and the overall severity of coronary stenosis. METHODS: We enrolled 1,150 patients [mean age, 68±12 (SD) years; 66.6% men] who consecutively underwent coronary angiography for suspected stable angina pectoris. The overall severity of stenosis in the coronary arteries was assessed by the Gensini score (GS), and its logarithmic values (log-GS) were used for statistical analyses since the GS does not follow a normal distribution. RESULTS: The log-GS was significantly larger in men than in women (2.5±1.5 vs. 1.9±1.7), while the estimated GFR (eGFR) and comorbidities were comparable between both sexes. A multivariate regression analysis indicated that age, smoking, eGFR, HDL-cholesterol and HbA1c were independent explanatory variables of the log-GS in men, although the eGFR explained only 1.2% of the log-GS variation. In women, the eGFR was not included in the significant explanatory variables shown by the multivariate analysis. However, the sex difference in the regression for the eGFR-log-GS relationship was not statistically significant. CONCLUSION: A reduced eGFR is a significant, but minor, determinant of the overall severity of coronary artery stenosis in men and potentially women.

DOI： 10.2169/internalmedicine.55.5198

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Whether an intervendor discordance of myocardial velocities determined by tissue Doppler echocardiography (TDE) can be generalized remains unclear. We compared intervendor variabilities of left ventricular (LV) and right ventricular (RV) myocardial velocities among three TDE systems. METHODS: Examinations with TDE were performed in 41 healthy subjects and 11 patients with cardiovascular risk factors (CVR) using α-7 (V1, Hitachi Aloka Medical), Artida (V2, Toshiba Medical Systems), and Vivid E9 (V3, GE Healthcare) on the same day. Peak systolic (s'), early diastolic (e'), and late diastolic (a') myocardial velocities at medial and lateral sites of the mitral annulus and lateral site of the tricuspid annulus were measured using both pulsed-wave TDE and color TDE. Intra-observer and inter-observer variabilities were determined in 10 subjects and test-retest variability in 14 subjects. RESULTS: As for test-retest variability, reproducibilities of LV and RV myocardial velocities determined by pulsed-wave TDE and color TDE were relatively low but comparable between V1, V2, and V3. Myocardial velocities in healthy subjects determined by both pulsed-wave TDE and color TDE were significantly different among the three TDE systems. Myocardial velocities by pulsed-wave TDE in V3 were 2-12% lower (P < 0.05) than those by V2 and 5-14% lower (P < 0.05) than those by V1. Similar differences in myocardial velocities determined by both pulsed-wave TDE and color TDE were found in patients with CVR. CONCLUSIONS: LV and RV myocardial velocities determined by both pulsed-wave TDE and color TDE are vendor dependent, and reproducibility of the myocardial velocities determined by both TDE systems is relatively low.

DOI： 10.1111/echo.12962

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Whether different patterns of ventricular ballooning in takotsubo cardiomyopathy (TCM) reflect differences in trigger mechanisms or clinical outcomes is unclear. Here we examined differences in the clinical characteristics of typical and atypical forms of TCM. TCM patients (n = 251) in the BOREAS Registry were enrolled for comparison of TCM with apical ballooning (type A, n = 217) and TCM with non-apical ballooning (type non-A, n = 34). The percentage of females was significantly lower in the type non-A group (58.8 vs. 75.6 %), while other demographic parameters and triggers of TCM were similar in the two groups. Rate of mid-ventricular obstruction (MVO) was lower (2.9 vs. 14.3 %) in the type non-A group than in the type A group, though left ventricular ejection fractions in the two groups were comparable. During a follow-up period of 2.6 ± 2.8 years, TCM recurred in 2.9 % of the patients and cardiac death occurred in 4.0 %. Cox proportional hazard analysis indicated that body mass index (hazard ratio [HR]: 0.75, 95 % confidence interval [CI] 0.54-0.99) and MVO (HR: 14.71, CI 1.87-304.66) were determinants of TCM recurrence and that advanced age (HR: 1.09, CI 1.02-1.17) and cardiogenic shock (HR: 4.27, CI 1.07-18.93) were significantly associated with cardiac death. In conclusion, approximately 20 % of TCM patients show non-apical left ventricular ballooning, and female sex and MVO are less frequent in this type than in apical ballooning type TCM. Low body mass index and MVO are risk factors of recurrence, and advanced age and cardiogenic shock are risk factors of cardiac death in TCM.

DOI： 10.1007/s00380-014-0548-x

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Type 2 diabetes mellitus (T2DM) worsens the outcome after myocardial infarction (MI). Here, we hypothesized that inhibition of dipeptidyl peptidase-4 (DPP-4) improves survival after MI in T2DM by modifying autophagy in the non-infarcted region of the heart. METHODS AND RESULTS: Under baseline conditions, there was no significant difference between levels of myocardial autophagy marker proteins in OLETF, a rat model of T2DM, and in LETO, a non-diabetic control. However, in contrast to the response in LETO, LC3-II protein and LC3-positive autophagosomes in the non-infarcted region of the myocardium were not increased after MI in OLETF. The altered autophagic response in OLETF was associated with lack of AMPK/ULK-1 activation, attenuated response of Akt/mTOR/S6 signaling and increased Beclin-1-Bcl-2 interaction after MI. Treatment with vildagliptin (10 mg/kg/day s.c.), a DPP-4 inhibitor, suppressed Beclin-1-Bcl-2 interaction and increased both LC3-II protein level and autophagosomes in the non-infarcted region in OLETF, though it did not normalize AMPK/ULK-1 or mTOR/S6 signaling. Plasma insulin level, but not glucose level, was significantly reduced by vildagliptin at the dose used in this study. Survival rate at 48 h after MI was significantly lower in OLETF than in LETO (32 vs. 82%), despite similar infarct sizes. Vildagliptin improved the survival rate in OLETF to 80%, the benefit of which was abrogated by chloroquine, an autophagy inhibitor. CONCLUSIONS: The results indicate that vildagliptin reduces T2DM-induced increase in post-MI acute mortality possibly by restoring the autophagic response through attenuation of Bcl-2-Beclin-1 interaction.

DOI： 10.1186/s12933-015-0264-6

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Glycogen synthase kinase-3β (GSK-3β) is a major positive regulator of the mitochondrial permeability transition pore (mPTP), a principle trigger of cell death, under the condition of oxidative stress. However, the mechanism by which cytosolic GSK-3β translocates to mitochondria, promoting mPTP opening, remains unclear. Here we addressed this issue by analyses of the effect of site-directed mutations in GSK-3β on mitochondrial translocation and protein/protein interactions upon oxidative stress. H9c2 cardiomyoblasts were transfected with GFP-tagged GSK-3β (WT), a mutant GSK-3β insensitive to inhibitory phosphorylation (S9A), or kinase-deficient GSK-3β (K85R). Time lapse observation revealed that WT and S9A translocated from the cytosol to the mitochondria more promptly than did K85R after exposure to oxidative stress. H2O2 increased the density of nine spots on two-dimensional gel electrophoresis of anti-GSK-3β-immunoprecipitates by more than 3-fold. MALDI-TOF/MS analysis revealed that one of the spots contained voltage-dependent anion channel 2 (VDAC2). Knockdown of VDAC2, but not VDAC1 or VDAC3, by siRNA attenuated both the mitochondrial translocation of GSK-3β and mPTP opening under stress conditions. The mitochondrial translocation of GSK-3β was attenuated also when Lys-15, but not Arg-4 or Arg-6, in the N-terminal domain of GSK-3β was replaced with alanine. The oxidative stress-induced mitochondrial translocation of GSK-3β was associated with an increase in cell death, which was suppressed by lithium chloride (LiCl), a GSK-3β inhibitor. These results demonstrate that GSK-3β translocates from the cytosol to mitochondria in a kinase activity- and VDAC2-dependent manner in which an N-terminal domain of GSK-3β may function as a mitochondrial targeting sequence.

DOI： 10.1074/jbc.M114.563924

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Inter-vendor discordance in three-dimensional speckle-tracking echocardiography (3DS) remains uncharacterized. We aimed to examine inter-vendor discordance of left ventricular (LV) volumes, and functional parameters and their reproducibilities between two commercially available 3DS systems. METHODS: Echocardiographic examinations with 3DS were performed in 26 healthy subjects (age 34 ± 13 years, 85% men) using a Vivid E9 system (V1) with 4V probe (GE Health Care) and Artida (V2) with PST-25SX probe (Toshiba Medical Systems) on the same day. LV variables and global LV longitudinal, circumferential, radial, and area strains were measured by vendor-specific softwares, 4D strain EchoPAC BT11 (for V1) and 3D WMT (for V2), respectively. Reproducibility of data was assessed by an intra-class correlation coefficient (ICC). RESULTS: The mean time required for 3DS analysis was 5.4 ± 1.5 min for V1, being 21% less than that for V2 (6.8 ± 1.9 min, P < 0.01). Reproducibilities of all LV strains were comparable between V1 (ICC 0.50-0.82) and V2 (ICC 0.51-0.76), except for intra-observer and inter-observer reproducibilities of radial strain being lower in V2 (ICC for V1 0.82 and 0.82 and ICC for V2 0.44 and 0.40, respectively). LV strains in all directions and area were significantly different between V1 and V2, though LV volumes and ejection fraction were comparable. CONCLUSIONS: Global longitudinal, circumferential, and area LV strains are reproducible in both 3DS vendors. However, values of three-dimensional LV strains by 3DS are highly vendor-dependent.

DOI： 10.1111/echo.12432

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

In the present study, we examined if and how cardiac ion channels are modified by type 2 diabetes mellitus (T2DM). Subendocardial (Endo) myocytes and subepicardial (Epi) myocytes were isolated from left ventricles of Otsuka-Long-Evans-Tokushima Fatty rats (OLETF) rats, a rat model of T2DM, and Otsuka-Long-Evans-Tokushima (LETO) rats (nondiabetic control rats). Endo and Epi myocytes were used for whole cell patch-clamp recordings and for protein and mRNA analyses. Action potential durations in Endo and Epi myocytes were longer in OLETF rats than in LETO rats, and the difference was larger in Endo myocytes. Steady-state transient outward K+ current (Ito) density was reduced in Endo but not Epi myocytes of OLETF rats compared with LETO rats, although the contribution of the fast component of Ito recovery from inactivation was smaller in both Endo and Epi myocytes of OLETF rats than in LETO rats. Kv4.2 protein was reduced only in Endo myocytes in OLETF rats, although voltage-gated K+ channel-interacting protein 2 (KChIP2) protein levels in both Endo and Epi myocytes were lower in OLETF rats than in LETO rats. Corresponding regional differences in mRNA levels of KChIP2 and Kv4.2 were observed between OLETF and LETO rats. mRNA levels of Iroquois homeobox 5 in Endo myocytes were 53% higher in OLETF rats than in LETO rats. Densities of inward rectifier K+ current and L-type Ca2+ current and mRNA levels of Kv4.3 and Kv1.4 were similar in OLETF and LETO rats. In conclusion, T2DM induces Endo-predominant prolongation of the action potential duration via a reduction of the fast component of Ito recovery from inactivation and reduced steady-state Ito, in which downregulation of Kv4.2 and KChIP2 may be involved. Increased Iroquois homeobox 5 expression may underlie Kv4.2 downregulation in T2DM.

DOI： 10.1152/ajpheart.00414.2013

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: A considerable number of patients with atrial fibrillation (AF) develop cardioembolic stroke (CE) despite low CHADS2 score. We examined the possibility that use of the atrial electromechanical interval (AEMI) improves prediction of CE in patients with paroxysmal AF (PAF), particularly those with low CHADS2 score. METHODS: We consecutively enrolled 108 patients with nonvalvular PAF and 52 healthy subjects as controls. The PAF patients were divided into 2 groups depending on presence (n = 36) or absence (n = 72) of the history of CE. Left atrial (LA) volume index (LAVI), peak myocardial velocity during late diastole (a'), and AEMI as time from onset of P-wave to onset of lateral a' were measured. RESULTS: Patients with PAF had significantly larger LAVI, longer AEMI, and lower lateral a' than those in controls. Area under the curves for LAVI, lateral a', and AEMI for identifying patients with PAF were 0.70, 0.69, and 0.88, respectively. Multivariate logistic regression analysis indicated that age, use of antiarrhythmic drugs, and AEMI, but not LAVI or a', were independently associated with history of CE in patients with PAF. PAF patients were categorized into low risk by CHADS2 score (i.e. CHADS2 score = 0 or 1, n = 60), those with prolonged AEMI (>82 msec) had significantly higher rates of CE than those with ≤ 82 msec (48% vs. 15%, P < 0.05). CONCLUSION: As compared with echocardiographic parameters of LA size and LA function, AEMI appears to be more useful for identifying PAF patients. AEMI may enable to detect high risk PAF patients, especially those categorized into low risk by CHADS2 score.

DOI： 10.1111/echo.12329

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: The aim of this study was to examine whether left atrial (LA) strain and synchrony can be assessed using three-dimensional (3D) speckle-tracking echocardiography (STE) and how 3D STE parameters are modified by atrial fibrillation (AF). METHODS: LA peak ventricular systolic longitudinal strain (LSs), circumferential strain (CSs), and area strain (ASs) and LA peak pre-atrial contraction longitudinal strain, circumferential strain (CSa), and area strain were determined using 3D STE, and SDs of times to peaks of regional LA strain were calculated as indices of LA dyssynchrony. Three-dimensional speckle-tracking was able to measure LA strain in 75 of the 77 healthy subjects and in all 47 patients with AF (31 with paroxysmal AF [PAF] and 16 with permanent AF). RESULTS: The mean time for analysis with 3D STE was 18% shorter than with two-dimensional (2D) STE (P < .05). On 3D STE, values of interobserver and intraobserver variability of LA strain were <10% and <12%, respectively. LSs, CSs, ASs, and 2D STE LSs were reduced in patients with PAF compared with controls, and further reductions of these parameters were observed in patients with permanent AF. SDs of LSs, CSs, and ASs were similarly larger in patients with PAF and in those with permanent AF compared with controls. Patients with PAF showed smaller LA peak pre-atrial contraction longitudinal strain, CSa, and LA peak pre-atrial contraction area strain and larger SDs of CSa and LA peak pre-atrial contraction area strain compared with controls. In multivariate analysis, 2D STE LSs (P = .044), LSs (P = .040), ASs (P = .007), and CSa (P = .020) were independent predictors of PAF. CONCLUSIONS: Three-dimensional speckle-tracking enables the measurement of both LA strain and synchrony with excellent reproducibility. Three-dimensional LA strain appears to be beneficial compared with 2D LA strain for identifying patients with PAF.

DOI： 10.1016/j.echo.2012.10.003

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記述言語：英語  

DOI： 10.1111/pin.12017

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Visceral injury is a life-threatening complication of cardiopulmonary resuscitation (CPR); however, the clinical significance has been masked by the lethal outcome of out-of-hospital cardiac arrest (OHCA). OBJECTIVE: The objective is to share our experience of successful treatment of OHCA patients with serious, CPR-related visceral complications. CASE REPORTS: We report two cases of cardiac-origin OHCA with liver injury exacerbated by heparinization during mechanical circulatory support. Although both patients presented with delayed massive liver bleeding (intrahepatic or peritoneal) that compromised hemodynamic status, one patient was successfully treated by selective transcatheter arterial embolization and the other by a surgical procedure. CONCLUSION: Preventive measures such as careful CPR, as well as interventional or surgical repair after the early diagnosis of visceral injury, are required to improve the outcome in some cases of OHCA.

DOI： 10.1016/j.jemermed.2010.05.074

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Sarcolemmal connexin-43 (Cx43) and mitochondrial Cx43 play distinct roles: formation of gap junctions and production of reactive oxygen species (ROS) for redox signaling. In this study, we examined the hypothesis that Cx43 contributes to activation of a major cytoprotective signal pathway, phosphoinositide 3-kinase (PI3K)-Akt-glycogen synthase kinase-3β (GSK-3β) signaling, in cardiomyocytes. A δ-opioid receptor agonist {[d-Ala(2),d-Leu(5)]enkephalin acetate (DADLE)}, endothelin-1 (ET-1), and insulin-like growth factor-1 (IGF-1) induced phosphorylation of Akt and GSK-3β in H9c2 cardiomyocytes. Reduction of Cx43 protein to 20% of the normal level by Cx43 small interfering RNA abolished phosphorylation of Akt and GSK-3β induced by DADLE or ET-1 but not that induced by IGF-1. DADLE and IGF-1 protected H9c2 cells from necrosis after treatment with H(2)O(2) or antimycin A. The protection by DADLE or ET-1, but not that by IGF-1, was lost by reduction of Cx43 protein expression. In contrast to Akt and GSK-3β, PKC-ε, ERK and p38 mitogen-activated protein kinase were phosphorylated by ET-1 in Cx43-knocked-down cells. Like diazoxide, an activator of the mitochondrial ATP-sensitive K(+) channel, DADLE and ET-1 induced significant ROS production in mitochondria, although such an effect was not observed for IGF-1. Cx43 knockdown did not attenuate the mitochondrial ROS production by DADLE or ET-1. Cx43 was coimmunoprecipitated with the β-subunit of G protein (Gβ), and knockdown of Gβ mimicked the effect of Cx43 knockdown on ET-1-induced phosphorylation of Akt and GSK-3β. These results suggest that Cx43 contributes to activation of class I(B) PI3K in PI3K-Akt-GSK-3β signaling possibly as a cofactor of Gβ in cardiomyocytes.

DOI： 10.1152/ajpheart.00940.2011

PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

UNLABELLED: We examined prognostic interactions among cardiac autonomic function assessed by (123)I-labeled metaiodobenzylguanidine ((123)I-MIBG) activity, hemoglobin, and kidney function in chronic heart failure patients. Anemia, chronic kidney disease, and impairment of cardiac sympathetic function have been shown as determinants of prognosis in heart failure patients, but there has been little information on their synergistic correlations with cardiac mortality. METHODS: After evaluations of hemoglobin and estimated glomerular filtration rate (GFR), 468 heart failure patients with left ventricular ejection fraction less than 50% underwent cardiac (123)I-MIBG imaging before discharge and were then followed up for a mean interval of 60.5 mo with a primary endpoint of cardiac death. Cardiac (123)I-MIBG activity was quantified using heart-to-mediastinum ratio (HMR) and washout rate. RESULTS: For 89 fatal cardiac events documented (19.0%), besides New York Heart Association class, multivariate Cox analysis revealed HMR, hemoglobin, and estimated GFR as significant independent determinants, with hazard ratios of 0.215 (P = 0.0129; 95% confidence interval [CI], 0.064-0.718), 0.821 (P = 0.0062; 95% CI, 0.708-0.946), and 0.984 (P = 0.0243; 95% CI, 0.970-0.998), respectively. Receiver-operating-characteristic analysis determined the thresholds for identifying patients at increased risk for cardiac death to be 1.57 for HMR, 11.9 g/dL for hemoglobin, and 46.4 mL/min/1.73 m(2) for estimated GFR. Combining the 4 independent predictors incrementally (P < 0.05) improved prognostic powers maximally up to a global χ(2) value of 97.3 compared with sole or other combinations. CONCLUSION: Hemoglobin, kidney function, and alterations of cardiac sympathetic nerve activity are independently and synergistically associated with increased cardiac mortality in chronic heart failure patients, together with New York Heart Association functional class.

DOI： 10.2967/jnumed.111.095786

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Diabetes mellitus (DM) is associated with an increased risk of ischemic heart disease and of adverse outcomes following myocardial infarction (MI). Here we assessed the role of endoplasmic reticulum (ER) stress in ventricular dysfunction and outcomes after MI in type 2 DM (T2DM). METHODOLOGY AND PRINCIPAL FINDINGS: In hearts of OLETF, a rat model of T2DM, at 25∼30 weeks of age, GRP78 and GRP94, markers of ER stress, were increased and sarcoplasmic reticulum calcium ATPase (SERCA)2a protein was reduced by 35% compared with those in LETO, a non-diabetic control. SERCA2a mRNA levels were similar, but SERCA2a protein was more ubiquitinated in OLETF than in LETO. Left ventricular (LV) end-diastolic elastance (Eed) was higher in OLETF than in LETO (53.9±5.2 vs. 20.2±5.6 mmHg/µl), whereas LV end-systolic elastance and positive inotropic responses to β-adrenergic stimulation were similar in OLETF and LETO. 4-Phenylbutyric acid (4-PBA), an ER stress modulator, suppressed both GRP up-regulation and SERCA2a ubiquitination and normalized SERCA2a protein level and Eed in OLETF. Sodium tauroursodeoxycholic acid, a structurally different ER stress modulator, also restored SERCA2a protein level in OLETF. Though LV dysfunction was modest, mortality within 48 h after coronary occlusion was markedly higher in OLETF than in LETO (61.3% vs. 7.7%). Telemetric recording showed that rapid progression of heart failure was responsible for the high mortality rate in OLETF. ER stress modulators failed to reduce the mortality rate after MI in OLETF. CONCLUSIONS: ER stress reduces SERCA2a protein via its augmented ubiquitination and degradation, leading to LV diastolic dysfunction in T2DM. Even at a stage without systolic LV dysfunction, susceptibility to lethal heart failure after infarction is markedly increased, which cannot be explained by ER stress or change in myocardial response to sympathetic nerve activation.

DOI： 10.1371/journal.pone.0039893

PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVES: This study tested whether cardiac sympathetic innervation assessed by metaiodobenzylguanidine (MIBG) activity has long-term prognostic value in combination with left ventricular hypertrophy (LVH) and left atrial size in heart failure (HF) patients without reduced left ventricular ejection fraction (LVEF). DESIGN: A single-centre prospective cohort study. SETTING/PARTICIPANTS: With primary endpoints of cardiac death and rehospitalisation due to HF progression, 178 consecutive symptomatic HF patients with 74% men, mean age of 56 years and mean LVEF of 64.5% were followed up for 80 months. The entry criteria consisted of LVEF more than 50%, completion of predischarge clinical evaluations including cardiac MIBG and echocardiographic studies and at least more than 1-year follow-up when survived. RESULTS: Thirty-four patients with cardiac evens had larger left atrial dimension (LAD), increased LV mass index, reduced MIBG activity quantified as heart-to-mediastinum ratio (HMR) than did the others. Multivariable Cox analysis showed that LAD and HMR were significant predictors (HR of 1.080 (95% CI 1.00 to 1.16, p=0.044) and 0.107 (95% CI 0.01 to 0.61, p=0.012, respectively). Thresholds of HMR (1.65) and LAD (37 mm) were closely related to identification of high-risk patients. In particular, HMR was a significant determinant of cardiac events in both patients with and without LV hypertrophy. Reduced HMR with enlarged LAD or LV hypertrophy identified patients at most increased risk; overall log-rank value, 11.5, p=0.0032 for LAD and 17.5, p=0.0002, respectively. CONCLUSIONS: In HF patients without reduced LV ejection fraction, impairment of cardiac sympathetic innervation is related to cardiac outcomes independently and synergistically with LA size and LV hypertrophy. Cardiac sympathetic innervation assessment can contribute to better risk-stratification in combination with evaluation of LA size and LV mass but is needed to be evaluated for establishing aetiology-based risk assessment in HF patients at increased risk.

DOI： 10.1136/bmjopen-2012-001015

PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

The objective of this study was to examine the hypothesis that hypertensive hypertrophy is vulnerable to infarction and defective in cytoprotective mechanisms by modification of intracellular signaling and mitochondrial proteins. Myocardial infarction was induced by 20-minute coronary occlusion/reperfusion in spontaneously hypertensive stroke-prone rats (SHR-SPs) and their controls (Wistar-Kyoto rats [WKYs]). Infarct size expressed as a percentage of area-at-risk was larger by 29% in SHR-SPs than in WKYs. Pretreatment with erythropoietin (EPO) significantly limited infarct size in WKYs but not in SHR-SPs. Ca(2+) retention capacity of mitochondria, an index of the threshold for opening of the mitochondrial permeability transition pore, on reperfusion was reduced in SHR-SPs compared with that in WKYs. Suppression of reactive oxygen species by N-(2-mercaptopropionyl)-glycine increased Ca(2+) retention capacity after reperfusion and limited infarct size in SHR-SPs to levels in WKYs. EPO induced phosphorylation of Akt, extracellular signal-related kinase, and glycogen synthase kinase-3β in the myocardium in both WKYs and SHR-SPs. EPO enhanced interaction of phospho-glycogen synthase kinase-3β and adenine nucleotide translocase on reperfusion in WKYs, although such an effect of EPO was not detected in SHR-SPs. The results suggest that enhanced opening of mitochondrial permeability transition pores by reactive oxygen species and modification of the signal downstream of phospho-glycogen synthase kinase-3β in the mitochondria underlie the increased vulnerability to infarction and the lack of anti-infarct tolerance by EPO, respectively, in hypertensive hypertrophied hearts.

DOI： 10.1161/HYPERTENSIONAHA.110.158469

PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: The purpose of this study was to clarify the clinical characteristics and prognostic implications of left atrial (LA) dilation evaluated echocardiographic volume in patients with normal LA dimension (LAD). METHODS: A total of 140 consecutive patients (81 men, mean age: 57 ± 18 years) with normal LAD (<39 mm for women and <41 mm for men) who underwent conventional echocardiography and tissue Doppler imaging were enrolled. LA volume (LAV) ≥29 ml/m(2) was defined as abnormal LAV. Hospitalization for heart failure (HF) and cardiac death were defined as cardiac events. RESULTS: Eighty-seven (62%) of the patients had LA dilation, defined as a normal LAD but an abnormal LAV. Patients with LA dilation were significantly older and had a significantly higher left ventricular (LV) mass index (LVMI) and incidences of hypertension and HF than did patients with both normal LAD and normal LAV. Logistic regression analysis revealed that increased LVMI was an independent (p < 0.01) determinant of LA dilatation. During a follow-up period of 16 ± 10 months, ten patients had cardiac events. Patients with cardiac events had a higher incidence of LA dilation than those without cardiac events (100 vs. 59%, p < 0.05). A Kaplan-Meier survival curve showed that patients with LA dilation had a significantly lower survival rate than those with both normal LAD and normal LAV (log rank 6.1, p = 0.014). CONCLUSIONS: LV hypertrophy is an independent determinant of LA dilation in patients with normal LAD. Assessment of LA morphology using LAV can contribute to risk stratification in patients with normal LAD.

DOI： 10.1007/s12574-009-0015-3

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Japanese Society of Internal Medicine  

DOI： 10.2169/internalmedicine.44.1074

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVE: Adiponectin, an adipocyte-derived protein, has been suggested to enhance insulin sensitivity and prevent atherosclerosis. Circulating adiponecin levels are reduced in states of insulin resistance such as type 2 diabetes. We examined transcardiac utilization of adiponectin in patients with and without type 2 diabetes. RESEARCH DESIGN AND METHODS: A total of 17 male type 2 diabetic patients and 17 male nondiabetic patients were investigated. Venous blood samples were taken to measure glucose and lipid variables. Blood samples for the measurement of adiponectin were collected simultaneously from the aortic root and coronary sinus. Angiographic semiquantitative stenosis score of coronary artery was also evaluated. RESULTS: The adiponectin levels in both the aortic root and coronary sinus in the diabetic patients were significantly lower than those in the nondiabetic patients. The adiponectin level was significantly lower in the coronary sinus than in the aortic root in the nondiabetic patients, but there was no significant difference between adiponectin levels in the aortic root and coronary sinus in the diabetic patients. The total stenosis score, as an index of severity of coronary artery stenosis, was significantly higher in the diabetic patients than in the nondiabetic patients. The stenosis score was correlated with the degree of transcardiac utilization of adiponectin from the aortic root to coronary sinus in the nondiabetic patients but not in the diabetic patients. CONCLUSIONS: Diabetic patients not only have a decreased adiponectin level in the basal state compared with nondiabetic patients but also have impaired utilization of adiponectin in the coronary artery and/or the heart, which may promote the development of atherosclerosis.

PubMed

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J-GLOBAL

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J-GLOBAL

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J-GLOBAL

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J-GLOBAL

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J-GLOBAL

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記述言語：日本語   出版者・発行元：医歯薬出版(株)  

その他リンク:： https://search.jamas.or.jp/default/link?pub_year=2020&ichushi_jid=J00060&link_issn=&doc_id=20200214030010&doc_link_id=issn%3D0039-2359%26volume%3D272%26issue%3D7%26spage%3D608&url=http%3A%2F%2Fwww.pieronline.jp%2Fopenurl%3Fissn%3D0039-2359%26volume%3D272%26issue%3D7%26spage%3D608&type=PierOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00005_2.gif

医中誌

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