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We investigated whether miR143#12, a synthesized chemically modified miR-143-3p derivative, exerts therapeutic effects on acute myocardial infarction (AMI). Sprague-Dawley rats and Japanese white rabbits underwent 30 min of coronary occlusion followed by 2 weeks of reperfusion. The rat AMI model was intravenously administered with control miRNA (9 μg/kg), 3 μg/kg or 9 μg/kg of miR143#12 1 h after reperfusion, while the rabbit AMI model was intravenously administered with control miRNA (9 μg/kg) or 9 μg/kg of miR143#12. In the rat and rabbit AMI models, 9 μg/kg of miR143#12 significantly reduced infarct sizes and significantly improved cardiac function including LVEF and LVFS at 2 weeks. The tissue miR143 levels in infarct areas significantly decreased after AMI in both models. Electron microscopic study and immunohistochemistry suggested that miR143#12 suppressed autophagic cell death caused by AMI and induced neoangiogenesis in the infarct border. In cultured rat H9c2 cells, miR143#12 significantly inhibited H 2 O 2 -induced autophagic cell death by decreasing ROS levels and increased viable cell numbers more than the control by silencing COX-1, -2, and ATG7. Replacement treatment with miR143#12 in the infarct areas, where the expression levels of miR143 were significantly decreased, has a beneficial effect on AMI by silencing COX-1 and -2., Competing Interests: Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Background: The optimal treatment strategy for coronary calcified nodules (CN) remains uncertain. We aimed to evaluate the efficacy and safety of different calcium modification strategies, including rotational atherectomy (RA), orbital atherectomy (OA), and intravascular lithotripsy (IVL) for managing CN with optical coherence tomography (OCT) guidance., Methods: Consecutive patients undergoing OCT-guided percutaneous coronary intervention (PCI) for severely calcified lesions using RA, OA, or IVL between January 2017 and December 2022 were included. Primary endpoint was minimum stent area (MSA) post-PCI. Secondary endpoints included MSA at CN site and 1-year target vessel failure (TVF), defined as a composite of cardiac death, target-vessel myocardial infarction, or target vessel revascularization., Results: Among 154 patients and 158 lesions, CN was identified in 54 lesions (34.2%) and managed with RA (39%, n = 21), OA (33%, n = 18), or IVL (28%, n = 15). The IVL group exhibited a larger minimal lumen diameter, maximum calcium arc, and maximum calcium thickness. Post-PCI OCT demonstrated comparable MSA (RA: 6.23 ± 0.34 mm², OA: 5.75 ± 0.39 mm², IVL: 6.24 ± 0.46 mm²; p = 0.62) and MSA at CN site (7.17 ± 0.43 mm², 6.46 ± 0.49 mm², 7.86 ± 0.56 mm², respectively; p = 0.55) after adjusting for morphologic factors. The incidence of TVF at 1 year was similar among the group (RA: 19.0%, OA: 22.2%, IVL: 13.3%, p = 0.81)., Conclusions: In patients undergoing PCI for CN, similar procedural and clinical outcomes can be achieved using RA, OA, or IVL. These findings warrant further investigation in larger, prospective trials., (© 2024 Wiley Periodicals LLC.)

Background: Progranulin is a secreted glycoprotein that regulates inflammation and wound healing. However, plasma progranulin levels in the acute phase and their clinical significance in patients with acute myocardial infarction (AMI) remain to be elucidated., Objective: We aimed to investigate the relationship between the increase in plasma progranulin levels in the acute phase and the recovery of left ventricular function in the chronic phase in AMI patients., Method and Result: Eighteen AMI patients were followed up for 6 months. Blood samples were collected from the antecubital vein on day 0 (on admission) and day 7 in the acute phase. The control group consisted of patients without significant coronary artery stenosis, as assessed by cardiac catheterization (n = 16). Plasma progranulin levels were measured by enzyme-linked immunosorbent assay. Echocardiography was performed in the acute (within 7 days) and chronic (6 months) phases of AMI to evaluate left ventricular ejection fraction using the modified Simpson's method. Plasma progranulin levels in the AMI group on day 0 (69.5 ± 24.6 ng/mL) were similar to those in the control group (84.2 ± 47.1 ng/mL). There was a significant increase in progranulin levels in the AMI group on day 7 (104.2 ± 52.0 ng/mL) compared with day 0. The increase in plasma progranulin levels in the acute phase was positively correlated with the increase in left ventricular ejection fraction between the acute and chronic phases. Among various factors, only plasma progranulin levels were favorably correlated with left ventricular functional recovery in the chronic phase., Conclusion: The increase in plasma progranulin levels in the acute phase may serve as a predictive biomarker and a contributer for the recovery of left ventricular function in the chronic phase in patients with AMI., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Minatoguchi et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

MicroRNA(miR)-143 and miR-145 are mainly expressed in vascular smooth muscle cells. However, the relationship between plasma miR-143 or miR-145 levels and the left ventricular (LV) function in patients with heart diseases remains unclear. Blood samples were taken from the antecubital vein in patients with heart diseases (n = 52), such as coronary artery disease, old myocardial infarction, cardiomyopathy, and valvular heart disease, and controls without heart diseases (n = 22). We measured plasma miR-143 and -145 levels by quantitative RT-PCR using TaqMan MicroRNA Assays and THUNDERBIRD Probe qPCR Mix. Plasma BNP levels were also measured. Echocardiography was performed to measure the LV ejection fraction (LVEF) and LV dilation. Plasma miR-143 and miR-145 levels were significantly higher in patients with heart diseases than in controls, respectively. Plasma miR-143 and miR-145 levels were significantly higher in patients with LVEF < 50% than in those with LVEF ≧ 50%, respectively. Plasma miR-143 and miR-145 levels were inversely correlated with LVEF, respectively. Plasma miR-143 and miR-145 levels were positively correlated with LV end-systolic dimension, respectively. Plasma miR-143 and -145 levels were positively correlated with plasma BNP levels, respectively. Plasma BNP levels were inversely correlated with LVEF. Plasma miR-143 and miR-145 levels are elevated in patients with LV dysfunction and may counteract LV dysfunction., (© 2024. The Author(s).)

Background: Percutaneous coronary intervention (PCI) of calcified lesions remains challenging for interventionalists., Aims: We aimed to investigate whether combining rotational atherectomy (RA) with cutting balloon angioplasty (RA+CBA) results in more optimal stent expansion compared with RA followed by non-compliant balloon angioplasty (RA+NCBA)., Methods: ROTA-CUT is a prospective, multicentre, randomised trial of 60 patients with coronary artery disease undergoing PCI of moderately or severely calcified lesions with drug-eluting stent implantation. Patients were randomised 1:1 to either RA+CBA or RA+NCBA. The primary endpoint was the minimum stent area on intravascular ultrasound (IVUS). Secondary endpoints included minimum lumen area and stent expansion assessed by IVUS and acute lumen gain, final residual diameter stenosis and minimum lumen diameter assessed by angiography. Clinical endpoints were obtained at 30 days., Results: The mean age was 71.1±9.4 years, and 22% were women. The procedural details of RA were similar between groups, as were procedure duration and contrast use. Minimum stent area was similar with RA+CBA versus RA+NCBA (6.7±1.7 mm 2 vs 6.9±1.8 mm 2 ; p=0.685). Furthermore, there were no significant differences regarding the other IVUS and angiographic endpoints. Procedural complications were rare, and 30-day clinical events included 2 myocardial infarctions and 1 target vessel revascularisation in the RA+CBA group and 1 myocardial infarction in the RA+NCBA group., Conclusions: Combining RA with CBA resulted in a similar minimum stent area compared with RA followed by NCBA in patients undergoing PCI of moderately or severely calcified lesions. RA followed by CBA was safe with rare procedural complications and few clinical adverse events at 30 days.

Background: MicroRNA (miR)-143 and miR-145 are non-coding RNAs present in smooth muscle cells and the heart. However, their behavior and physiological role in patients with acute myocardial infarction (AMI) have not been clarified., Methods and results: Plasma miR-143 and miR-145 concentrations were measured on Day 0 (on admission) and on Day 7 in AMI patients who could be followed up for 6 months (n=25). The control group consisted of subjects without significant coronary stenosis (n=20). Blood samples were collected from the antecubital vein, and plasma miR-143 and miR-145 concentrations were measured by quantitative reverse transcription-polymerase chain reaction. In AMI patients (n=25), left ventricular ejection fraction (LVEF) was measured by echocardiography in the acute and chronic (6 months) phases. On Day 7, plasma miR-143 and miR-145 concentrations were significantly higher in AMI patients than in the control group and on Day 0 in AMI patients. Plasma miR-143 and miR-145 concentrations increased significantly from Day 0 to Day 7. The increase in plasma miR-143 concentrations (∆miR-143) in the acute phase was positively correlated with the increase in LVEF in the chronic phase. Among many factors, only ∆miR-143 was favorably correlated with left ventricle (LV) functional recovery in the chronic phase., Conclusions: An increase in plasma miR-143 concentrations in the acute phase may be a biomarker predicting recovery of LV function in the chronic phase in AMI patients.

Rapid percutaneous coronary intervention for acute myocardial infarction (AMI) reduces acute mortality, but there is an urgent need for treatment of left ventricular dysfunction and remodeling after AMI to improve the prognosis. The myocardium itself does not have a high regenerative capacity, and it is important to minimize the loss of cardiomyocytes and maintain the cardiac function after AMI. To overcome these problems, attention has been focused on myocardial regeneration therapy using cells derived from bone marrow. The clinical use of bone marrow stem cells is considered to have low safety concerns based on the experience of using bone marrow transplantation for blood diseases in clinical practice. It has been reported that bone marrow mononuclear cells (BM-MNC) and mesenchymal stem cells (BM-MSC) differentiate into cardiomyocytes both in vitro and in vivo, and they have been considered a promising source for stem cell therapy. To prevent heart failure after human AMI, studies have been conducted to regenerate myocardial tissue by transplanting bone marrow stem cells, such as BM-MSCs and BM-MNCs. Therapies using those cells have been administered to animal models of AMI, and were effective to some extent, but the effect in clinical trials was limited. Recently, it was reported that multilineage-differentiating stress enduring cells (Muse cells), which are endogenous pluripotent stem cells obtainable from various tissues including the bone marrow, more markedly reduced the myocardial infarct size and improved the cardiac function via regeneration of cardiomyocytes and vessels and paracrine effects compared with BM-MSCs. Here, we describe stem cell therapies using conventional BM-MNCs and BM-MSCs, and Muse cells which have potential for clinical use for the treatment of AMI., (Copyright © 2021. Published by Elsevier Ltd.)

Background: We recently reported that multilineage-differentiating stress enduring (Muse) cells intravenously administered after acute myocardial infarction (AMI), selectively engrafted to the infarct area, spontaneously differentiated into cardiomyocytes and vessels, reduced the infarct size, improved the left ventricular (LV) function and remodeling in rabbits. We aimed to clarify the efficiency of Muse cells in a larger animal AMI model of mini-pigs using a semi-clinical grade human Muse cell product., Method and Result: Mini-pigs underwent 30 min of coronary artery occlusion followed by 2 weeks of reperfusion. Semi-clinical grade human Muse cell product (1x107, Muse group, n = 5) or saline (Vehicle group, n = 7) were intravenously administered at 24 h after reperfusion. The infarct size, LV function and remodeling were evaluated by echocardiography. Arrhythmias were evaluated by an implantable loop recorder. The infarct size was significantly smaller in the Muse group (10.5±3.3%) than in the Vehicle group (21.0±2.0%). Both the LV ejection fraction and fractional shortening were significantly greater in the Muse group than in the Vehicle group. The LV end-systolic and end-diastolic dimensions were significantly smaller in the Muse group than in the Vehicle group. Human Muse cells homed into the infarct border area and expressed cardiac troponin I and vascular endothelial CD31. No arrhythmias and no blood test abnormality were observed., Conclusion: Muse cell product might be promising for AMI therapy based on the efficiency and safety in a mini-pig AMI., Competing Interests: The authors have declared that no competing interests exist.

Background: Autophagy is a cellular process that degrades a cell's own cytoplasmic components for energy provision and to maintain a proper intracellular environment. Left ventricular reverse remodeling (LVRR) promises a better prognosis for patients with dilated cardiomyopathy (DCM)., Objectives: The authors tested the hypothesis that autophagy is involved in LVRR and has prognostic value in the human failing heart., Methods: Using left ventricular endomyocardial biopsy specimens from 42 patients with DCM (21 LVRR-positive and 21 LVRR-negative) and 7 patients with normal cardiac function (control), the authors performed immunohistochemistry and immunofluorescent labeling of LC3 and cathepsin D and electron microscopic observation in addition to general morphometry under light microscopy., Results: The clinical characteristics of LVRR-positive patients were similar to those of the LVRR-negative patients, except for pulmonary artery pressure and left atrial dimension. Morphometry under light microscopy did not differ among specimens from DCM patients, regardless of their LVRR status. Electron microscopy revealed that autophagic vacuoles (autophagosomes and autolysosomes) and lysosomes were abundant within cardiomyocytes from DCM patients. Moreover, cardiomyocytes from LVRR-positive patients contained significantly more autophagic vacuoles with higher autolysosome ratios and cathepsin D expression levels than cardiomyocytes from LVRR-negative patients. Logistic regression analysis adjusted for age showed that increases in autophagic vacuole number and cathepsin D expression were predictive of LVRR. DCM patients who achieved LVRR experienced fewer cardiovascular events during the follow-up period., Conclusions: The authors show that autophagy is a useful marker predictive of LVRR in DCM patients. This provides novel pathologic insight into a strategy for treating the failing DCM heart., Competing Interests: Funding Support and Author Disclosures This study was supported in part by JSPS KAKENHI grant no. JP21K08077 from the Japan Society for the Promotion of Science and a research grant from Gifu University School of Medicine. The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objective: To examine the Cardiac Rehabilitation Gifu Network (CR-GNet) feasibility in managing diseases and assisting patients in attaining physical fitness, and its impact on long-term outcomes after acute coronary syndrome (ACS)., Methods: In this prospective observational study, we enrolled 47 patients with ACS registered in the CR-GNet between February 2016 and September 2019. 37, 29, and 21 patients underwent follow-up assessments for exercise capacity (peak oxygen uptake) at 3 months, 6 months, and 1 year after discharge, respectively. Major adverse cardiac events (MACE) were compared with controls not registered in the CR-GNet., Results: The coronary risk factors, except blood pressure, improved at 3 and 6 months, and 1 year after discharge. These risk factors in each patient significantly reduced from 2.9 at admission to 1.6, 1.4, and 1.9 at 3 months, 6 months, and 1 year after discharge (p<0.05), respectively. Peak oxygen uptake was significantly higher at 3 months (17.5±4.9 ml/kg/min), 6 months (17.9±5.1 ml/kg/min), and 1 year (17.5±5.5 ml/kg/min) after discharge than that at discharge (14.7±3.6 ml/kg/min) (p<0.05). During follow-up, there was no significant difference; MACE did not occur in any patients in the CR-GNet but occurred in controls., Conclusion: CR-GNet is a feasible option for the long-term management of ACS patients., Competing Interests: The authors have no conflicts of interest to declare, (2022, JAPANESE PHYSICAL THERAPY ASSOCIATION.)

Diabetic cardiomyopathy, clinically diagnosed as ventricular dysfunction in the absence of coronary atherosclerosis or hypertension in diabetic patients, is a cardiac muscle-specific disease that increases the risk of heart failure and mortality. Its clinical course is characterized initially by diastolic dysfunction, later by systolic dysfunction, and eventually by clinical heart failure from an uncertain mechanism. Light microscopic features such as interstitial fibrosis, inflammation, and cardiomyocyte hypertrophy are observed in diabetic cardiomyopathy, but are common to failing hearts generally and are not specific to diabetic cardiomyopathy. Electron microscopic studies of biopsy samples from diabetic patients with heart failure have revealed that the essential mechanism underlying diabetic cardiomyopathy involves thickening of the capillary basement membrane, accumulation of lipid droplets, and glycogen as well as increased numbers of autophagic vacuoles within cardiomyocytes. Autophagy is a conserved mechanism that contributes to maintaining intracellular homeostasis by degrading long-lived proteins and damaged organelles and is observed more often in cardiomyocytes within failing hearts. Diabetes mellitus (DM) impairs cardiac metabolism and leads to dysregulation of energy substrates that contribute to cardiac autophagy. However, a "snapshot" showing greater numbers of autophagic vacuoles within cardiomyocytes may indicate that autophagy is activated into phagophore formation or is suppressed due to impairment of the lysosomal degradation step. Recent in vivo studies have shed light on the underlying molecular mechanism governing autophagy and its essential meaning in the diabetic heart. Autophagic responses to diabetic cardiomyopathy differ between diabetic types: they are enhanced in type 1 DM, but are suppressed in type 2 DM. This difference provides important insight into the pathophysiology of diabetic cardiomyopathy. Here, we review recent advances in our understanding of the pathophysiology of diabetic cardiomyopathy, paying particular attention to autophagy in the heart, and discuss the therapeutic potential of interventions modulating autophagy in diabetic cardiomyopathy., (Copyright © 2020. Published by Elsevier Ltd.)

Objectives: This study sought to assess the efficacy of oversized drug-coated balloon (DCB) inflation at low pressure for the prevention of acute dissections and late restenosis., Background: The major limitation of DCB coronary angioplasty is the occurrence of severe dissection after inflation of DCB., Methods: Between 2014 and 2018, 273 consecutive patients were retrospectively studied. 191 lesions (154 patients) treated by oversized DCB inflation at low pressure (<4 atm, 2.4 ± 1.2 atm, DCB/artery ratio 1.14 ± 0.22; LP group) were compared with 135 lesions (119 patients) treated by the standard DCB technique (7.1 ± 2.2 atm, DCB/artery ratio 1.03 ± 0.16; SP group)., Results: Although the lesions in the LP group were more complex than those in the SP group (smaller reference diameter (2.38 mm vs. 2.57 mm, P =0.011), longer lesions (11.7 mm vs. 10.5 mm, P =0.10), and more frequent use of rotational atherectomy (45.0% vs. 28.1%, P =0.003), there was no significant difference in the NHLBI type of dissections between the two groups (11.5%, 12.0%, 5.2% vs. 12.6%, 12.6%, 2.2% in type A , B , and C , P =0.61), and no bailout stenting was required. In 125 well-matched lesion pairs after propensity score analysis, the cumulative incidence of target lesion revascularization at 3 years was 4.5% vs. 7.0%, respectively ( P =0.60). Late lumen loss (-0.00 mm vs. -0.01 mm, P =0.94) and restenosis rates (7.4% vs. 7.1%, P =1.0) were similar in both of the groups., Conclusion: The application of oversized DCB at low pressure is effective and feasible for preventing late restenosis comparative to the standard technique of DCB., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2020 Katsumi Ueno et al.)

Objective: This study aimed to investigate the effect of combination of high-salt intake and hypertension on renal functional and histological damage, associated with renal (pro)renin receptor [(P)RR] and AT1 receptor in rats., Methods: Wistar Kyoto rats (WKYs) and spontaneously hypertensive rats (SHRs) received regular rat chow (normal-salt diet 0.9%) or high-salt rat chow (high-salt diet 8.9%) for 6 weeks from 6 to 12 weeks of age. Systolic blood pressure, serum creatinine and blood urea nitrogen (BUN) were measured. Histological analysis of the kidney was performed. Western blot analysis was performed on the expressions of (P)RR, angiotensinogen and AT1 receptor in the kidney., Results: High-salt intake significantly increased systolic blood pressure in WKYs and especially in SHRs. High-salt intake significantly increased serum creatinine and BUN, and accelerated renal tubulointerstitial fibrosis and glomerular sclerosis in SHRs. High-salt intake significantly enhanced the renal tissue expressions of (P)RR, angiotensinogen and AT1 receptor in SHRs., Conclusion: High-salt intake accelerates functional and histological renal damage associated with renal tissue overexpression of (P)RR and AT1 receptors in SHRs.

Aims: Glucagon-like peptide-1 (GLP-1) is a neuroendocrine hormone secreted by the intestine. Its receptor (GLP-1R) is expressed in various organs, including the heart. However, the dynamics and function of the GLP-1 signal in heart failure remains unclear. We investigated the impact of the cardio-intestinal association on hypertensive heart failure using miglitol, an α-glucosidase inhibitor known to stimulate intestinal GLP-1 production., Methods and Results: Dahl salt-sensitive (DS) rats fed a high-salt diet were assigned to miglitol, exendin (9-39) (GLP-1R blocker) and untreated control groups and treated for 11 weeks. Control DS rats showed marked hypertension and cardiac dysfunction with left ventricular dilatation accompanied by elevated plasma GLP-1 levels and increased cardiac GLP-1R expression as compared with age-matched Dahl salt-resistant (DR) rats. Miglitol further increased plasma GLP-1 levels, suppressed adverse cardiac remodelling, and mitigated cardiac dysfunction. In cardiomyocytes from miglitol-treated DS hearts, mitochondrial size was significantly larger with denser cristae than in cardiomyocytes from control DS hearts. The change in mitochondrial morphology reflected enhanced mitochondrial fusion mediated by protein kinase A activation leading to phosphorylation of dynamin-related protein 1, expression of mitofusin-1 and OPA-1, and increased myocardial adenosine triphosphate (ATP) content. GLP-1R blockade with exendin (9-39) exacerbated cardiac dysfunction and led to fragmented mitochondria with disarrayed cristae in cardiomyocytes and reduction of myocardial ATP content. In cultured cardiomyocytes, GLP-1 increased expression of mitochondrial fusion-related proteins and ATP content. When GLP-1 and exendin (9-39) were administered together, their effects cancelled out., Conclusions: Increased intestinal GLP-1 secretion is an adaptive response to heart failure that is enhanced by miglitol. This could be an effective strategy for treating heart failure through regulation of mitochondrial dynamics., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: journals.permissions@oup.com.)

Background: Levocarnitine has been reported to improve the left ventricular (LV) systolic function and decrease LV hypertrophy in hemodialysis (HD) patients. Its effect on LV diastolic dysfunction, however, has not yet been clarified. Methods and Results: HD patients (n=88) were given levocarnitine i.v. 1,000 mg for 12 months at the end of every dialysis session through the dialysis circuit of the venous site. LV ejection fraction (EF), E/A, E/e', left atrial volume index (LAVI) and LV mass index (LVMI) were measured before and 3, 6, 9, and 12 months after the start of levocarnitine on echocardiography. We regarded E/A≤0.8, E/e'>14 and LAVI>34 mL/m 2 as LV diastolic dysfunction, and LVEF<55% as LV systolic dysfunction. We also investigated the effect of levocarnitine on HFpEF. Plasma brain natriuretic peptide, total carnitine, free carnitine, and acyl-carnitine and biochemistry parameters were measured. Levocarnitine significantly improved LV diastolic function in HD patients with LV diastolic dysfunction, but did not affect LV diastolic function in those with normal LV diastolic function. Levocarnitine significantly improved HFpEF. Levocarnitine significantly improved the LV systolic function in HD patients with LV systolic dysfunction but did not affect the LV systolic function in those with normal LV systolic function. Levocarnitine significantly decreased LVMI and increased plasma total, free, and acyl-carnitine. Conclusions: Levocarnitine ameliorates LV diastolic as well as LV systolic dysfunction in HD patients., Competing Interests: Shinya M. is a member of Circulation Reports’ Editorial Team. The other authors declare no conflicts of interest., (Copyright © 2019, THE JAPANESE CIRCULATION SOCIETY.)

Background: Metformin is a popular antidiabetic agent that is also used to treat heart failure patients with type 2 diabetes mellitus. Several reports suggest that metformin may also have cardioprotective effects in patients without diabetes mellitus. In the present study, we investigated the possible therapeutic effect of metformin in heart failure and its underlying molecular mechanisms using a δ-sarcoglycan-deficient mouse model of dilated cardiomyopathy., Methods and Results: Thirty-two-week-old δ-sarcoglycan-deficient mice exhibiting established cardiomyopathy with extensive left ventricular dilatation and dysfunction were administered saline or metformin (200 mg/kg per day) for 4 weeks using osmotic mini-pumps. Metformin partially reversed the left ventricular dilatation (reverse remodeling) and significantly improved cardiac function. The hearts of metformin-treated mice showed less fibrosis, less cardiomyocyte hypertrophy, and fewer degenerative subcellular changes than saline-treated mice. These effects were accompanied by restored expression of the sarcomeric proteins myosin heavy chain and troponin I, and their transcription factor, GATA-4. Autophagy was enhanced in the hearts from metformin-treated mice, as indicated by increase of myocardial microtubule-associated protein-1 LC-3 (light chain 3)-II levels and LC3-II/-I ratios as well as levels of cathepsin D and ATP. In addition, increased numbers of autophagic vacuoles and lysosomes were accompanied increased AMP-activated protein kinase activity and suppression of mammalian target of rapamycin phosphorylation. Finally, autophagic flux assays using short-term chloroquine treatment revealed that autophagy was activated in δ-sarcoglycan-deficient hearts and was further augmented by metformin treatment., Conclusions: Metformin is a beneficial pharmacological tool that mitigates heart failure caused by δ-sarcoglycan deficiency in association with enhanced autophagy.

Background: The (pro)renin receptor [(P)RR)] is involved in the activation of local renin-angiotensin system and subsequent development of cardiovascular disease. We investigated the therapeutic effect of a (P)RR blocker, handle-region peptide (HRP), on chronic kidney disease (CKD)-associated heart failure., Methods and Results: CKD was induced in C57BL/6J mice by means of five-sixths nephrectomy. Eight weeks later, cardiac dysfunction and cardiac dilatation with hypertension developed. Mice were then assigned to 1 of the 3 following groups: vehicle, low-dose (0.01 mg·kg -1 ·d -1 ) HRP, or high-dose (0.3 mg·kg -1 ·d -1 ) HRP for 4 weeks. High-dose HRP treatment reversed left ventricular dilation and significantly improved cardiac dysfunction with ameliorated hypertension compared with the vehicle. The hearts with high-dose HRP treatment showed significant attenuation of cardiac fibrosis, cardiomyocyte hypertrophy, macrophage infiltration, and oxidative DNA damage. This treatment decreased the myocardial expressions of angiotensin (Ang) II, Ang II type 1 receptor, transforming growth factor β1, extracellular matrix-related proteins, and lipid peroxidation. Autophagy was activated in the cardiomyocyte from nephrectomized mice, but HRP treatment had no effect on cardiomyocyte autophagy., Conclusions: This study indicates that (P)PR blockade is a beneficial strategy by suppressing cardiac fibrosis and hypertrophy to ameliorate heart failure caused by CKD., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Changes in the plasma adenosine concentration and the effects on left ventricular (LV) function and remodeling in patients with acute myocardial infarction (AMI) remain unclear., Methods and results: In 58 patients with AMI and 14 subjects without cardiac disease (controls), we measured the plasma adenosine concentration by LC-MS/MS. Blood samples were taken from the antecubital vein on days 0, 1, 7, and 14 after AMI, and from the controls on admission. Cardiac echocardiography was performed in the acute (within 7 days) and chronic (6 months) phases of AMI. There were no significant differences in the plasma adenosine concentrations among days 0 (211.5±150.2 nmol/L), 1 (192.7±141.3 nmol/L), 7 (218.8±154.1 nmol/L), and the controls (136.0±50.9 nmol/L). The plasma adenosine concentration increased significantly on day 14 (321.1±195.4 nmol/L) after AMI as compared with days 0, 1 and 7. AMI patients with a greater increase in the plasma adenosine concentration in the subacute phase showed an attenuation of LV dilation in the chronic phase. The plasma adenosine concentration in the acute phase did not affect the LV ejection fraction in the chronic phase., Conclusions: The plasma adenosine concentration significantly increased 14 days after AMI, which may contribute to attenuation of LV dilation in the chronic phase.

Objectives: This study sought to assess the safety and long-term efficacy of drug-coated balloons (DCB) following aggressive intracoronary image-guided rotational atherectomy (iRA) for severe coronary artery calcification (CAC), and to compare this strategy with new generation drug-eluting stents (nDES) following iRA., Background: Ischemic events following the treatment of CAC is still relatively high. Thus, more innovative strategies are required., Methods: We evaluated 123 consecutive patients (166 lesions) with de novo CAC undergoing an iRA (burr size; 0.7 of the mean reference diameter by intracoronary imaging) followed by DCB (DCB-iRA; 54 patients, 68 lesions) or nDES (nDES-iRA; 69 patients, 98 lesions). Follow-up angiography was obtained at > 6 months., Results: The target vessels (right coronary and circumflex), bifurcation (67.6% versus 47.9%), reference diameter (2.28mm versus 2.49mm), and lesion length (11.89mm versus 18.78mm) were significantly different between the two groups. The median follow-up was 732 days. TLR and TVR in DCB-iRA and nDES-iRA at 3 years were similar: 15.6% versus 16.3% ( P =0.99) and 15.6% versus 23.3% ( P =0.38). In 41 well-matched lesion pairs after propensity score analysis, the cumulative incidence of TLR and TVR in DCB-iRA and nDES-iRA at 3 years was 12.9% versus 16.3% (P=0.70) and 12.9% versus 26.1% (P=0.17), respectively. On QCA analysis, although the acute gain was smaller in DCB-iRA (0.85 mm versus 1.53 mm, P<0.001), the minimum lumen diameter at follow-up was similar (1.69 mm versus 1.87 mm, P=0.29). The late lumen loss was lower (0.09 mm versus 0.52 mm, P=0.009) in DCB-iRA., Conclusions: DCB-iRA is feasible for CAC., Competing Interests: The authors have no conflicts of interest to declare., (Copyright © 2019 Katsumi Ueno et al.)

Background: Left ventricular (LV) torsion by contraction of inner and outer oblique muscles contributes to EF. Outer muscle plays a predominant role in torsion. We evaluated the impact of LV remodeling by hypertension (HTN) on torsion using 3-dimensional speckle tracking echocardiography (3D-STE). Methods and Results: LV strain, strain rate during systole (SR-S) and torsion at endocardium, mid-wall and epicardium were assessed on 3D-STE in 53 controls and 186 HTN patients. Torsion was defined as the difference between apical and basal rotation divided by long axis length. LVEF and strain, SR-S and torsion in all 3 layers in HTN without LV hypertrophy (LVH) were similar to those in controls. LV longitudinal strain at endocardium in HTN with LVH decreased, whereas LVEF was similar to that in controls and, which was associated with increased torsion at epicardium. Reduced LVEF in hypertensive HF was associated with reduced strain, SR-S and torsion in all layers and with LV dilation. On multivariate analysis, epicardial torsion was an independent determinant of LVEF. At epicardial torsion cut-off 0.41, the sensitivity and specificity for the identification of HFrEF were 88% and 68%. Conclusions: Torsion on 3D-STE may represent a compensatory mechanism to maintain LVEF despite reduced endocardial function, suggesting that the deterioration of torsion caused by insult to outer muscle and dilation may lead to HFrEF., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2019, THE JAPANESE CIRCULATION SOCIETY.)

We investigated whether combination therapy of G-CSF and erythropoietin (EPO)-liposome with Siaryl Lewis X (SLX) is more cardioprotective than G-CSF or EPO-liposome with SLX alone. For the purpose of generating myocardial infarction (MI), rabbits underwent 30 minutes of coronary occlusion and 14 days of reperfusion. We administered saline (control group, i.v.,), G-CSF (G group, 10 μg/kg/day × 5 days, i.c., starting at 24 hours after reperfusion), EPO-liposome with SLX (LE group, i.v., 2500 IU/kg EPO containing liposome with SLX, immediately after reperfusion), and G-CSF + EPO-liposome with SLX (LE + G group) to the rabbits. The MI size was the smallest in the LE+G group (14.7 ± 0.8%), and smaller in the G group (22.4 ± 1.5%) and LE group (18.5 ± 1.1%) than in the control group (27.8 ± 1.5%). Compared with the control group, the cardiac function and remodeling of the G, LE, and LE + G groups were improved, and LE + G group tended to show the best improvement. The number of CD31-positive microvessels was the greatest in the LE + G group, greater in the G and LE groups than in the control group. Higher expressions of phosphorylated (p)-Akt and p-ERK were observed in the ischemic area of the LE and LE + G groups. The number of CD34 + /CXCR4 + cells was significantly higher in the G and LE + G groups. The cardiac SDF-1 was more expressed in the G and LE + G groups. In conclusion, Post-MI combination therapy with G-CSF and EPO-liposome with SLX is more cardioprotective than G-CSF or EPO-liposome with SLX alone through EPCs mobilization, neovascularization, and activation of prosurvival signals.

Background: Given that residual congestion is a predictor of poor outcome in patients with heart failure (HF), a therapeutic strategy for decongestion is required. Methods and Results: Eighteen HF patients with fluid retention despite oral furosemide >20 mg/day, with chronic kidney disease (CKD; estimated glomerular filtration rate [eGFR], <59 mL/min/1.73 m 2 ) were enrolled. Patients were randomized into 2 groups: a tolvaptan group (tolvaptan, 7.5 mg/day, n=10) and a furosemide group (additional furosemide 20 mg/day, n=8), and followed up for 7 days. The urine volume significantly increased on day 3 in the tolvaptan group but not in the furosemide group. The body weight significantly decreased in the tolvaptan compared with the furosemide group on days 3 and 5. Although there was no difference in serum creatinine or eGFR in the 7 days between the 2 groups, serum cystatin C significantly decreased on day 7 in the tolvaptan group compared with the furosemide group. The residual congestion was more improved in the tolvaptan group than in the furosemide group. Conclusions: Adding tolvaptan but not furosemide significantly increased urine volume, decreased body weight and improved residual congestion without affecting the renal function or electrolytes in patients with HF with CKD under furosemide treatment., Competing Interests: The authors declare no conflict of interest., (Copyright © 2019, THE JAPANESE CIRCULATION SOCIETY.)

Background: It is still unclear whether dynamic exercise increases the number of Muse cells, pluripotent stem cells, in the peripheral blood. Methods and Results: The number of Muse cells, SSEA3 + and CD105 + double-positive cells, in the peripheral blood was measured using FACS before and after 40 min of cardiac rehabilitation with dynamic exercise in 6 patients with heart disease. The number of Muse cells significantly increased after cardiac rehabilitation in all patients. Muse cell mobilization may be related to the beneficial clinical outcome of cardiac rehabilitation. Conclusions: Cardiac rehabilitation increases the number of Muse cells in the peripheral blood., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2019, THE JAPANESE CIRCULATION SOCIETY.)

Background: Although new-onset atrial fibrillation (AF) increases with ageing, the prediction of new-onset AF is complicated. We previously reported that pulmonary capillary wedge pressure (ePCWP) estimated by the combination of left atrial volume index (LAVI) and active left atrial emptying function (aLAEF) had a strong relationship with PCWP on catheterization (r=0.92): ePCWP=10.8-12.4×log (aLAEF/minimum LAVI). We sought to determine the usefulness of ePCWP to predict new-onset AF., Methods and results: We measured LAVI, aLAEF and ePCWP on speckle tracking echocardiography (STE) in 566 consecutive elderly patients (72±6 years) without a history of AF. A total of 63 patients (73±6 years) developed electrocardiographically confirmed AF during a mean follow-up period of 50 months. Baseline aLAEF was significantly lower in patients with than without new-onset AF (17.9±6.5 vs. 28.2±7.5%), whereas ePCWP was significantly higher (14.8±3.7 vs. 10.3±3.1 mmHg). In multivariate logistic regression analysis, ePCWP and aLAEF were strong independent predictors of AF. Using ePCWP >13 mmHg or aLAEF ≤22% on univariate Cox regression analysis, the HR for new-onset AF were 3.53 (95% CI: 1.68-7.44, P<0.001) and 4.06 (95% CI: 1.90-8.65, P<0.001), respectively. By combining these 2 criteria (>13 mmHg and ≤22%), the HR increased to 11.84 (95% CI: 6.85-20.5, P<0.001)., Conclusions: ePCWP and aLAEF measured on STE are useful predictors of new-onset AF. ePCWP provides added value for risk stratification of new-onset AF.

We examined whether the stimulation of the angiotensin II AT1 receptor increases the expression of the cardiac (pro)renin receptor ((P)RR) and its downstream signals and whether the blockade of the angiotensin II AT1 receptor by azilsartan decreases the expression of the cardiac (P)RR and its signaling in spontaneously hypertensive rats (SHRs) with a high-salt intake. Rats received normal-salt (0.9%) chow, high-salt (8.9%) chow, normal-salt chow with 1 mg/day of azilsartan, and high-salt chow with 1 mg/day of azilsartan from 6 to 12 weeks of age. Rats with normal-salt chow were administered 100 ng/kg/min of angiotensin II by osmotic minipump from 6 to 12 weeks of age. A high-salt diet and angiotensin II significantly increased the systolic blood pressure; overexpressed cardiac (P)RR, phosphorylated (p)-ERK1/2, p-p38MAPK, p-HSP27, and TGF-ß1; enhanced cardiac interstitial and perivascular fibrosis, cardiomyocyte size, interventricular septum (IVS) thickness, and left ventricular (LV) end-diastolic dimension; and decreased LV fractional shortening. Azilsartan decreased systolic blood pressure, cardiac expressions of (P)RR, p-ERK1/2, p-p38MAPK, p-HSP27, and TGF-ß1, cardiac interstitial and perivascular fibrosis, cardiomyocyte size, and LV diastolic dimension, and improved LV fractional shortening. In conclusion, azilsartan attenuates cardiac damage caused by high salt intake through the downregulation of the cardiac (pro)renin receptor and its downstream signals in SHRs.

There has been no established echocardiographic parameter to accurately assess left ventricular (LV) relaxation. Impaired LV relaxation assessed by the time constant of LV pressure decline (Tau) is one of the major components of diastolic dysfunction. We sought to noninvasively estimate Tau (eTau) by speckle tracking echocardiography (STE) and to validate the eTau against Tau by catheterization. Tau was reported to be calculated using the isovolumic relaxation time (IVRT), LV end-systolic pressure, and left atrial (LA) pressure. We reported that pulmonary capillary wedge pressure (ePCWP) can be noninvasively and accurately estimated as 10.8 - 12.4 × Log (LA active emptying function/minimum LA volume index). Therefore, the eTau by STE is noninvasively calculated using the formula: eTau = IVRT / (ln 0.9 × systolic blood pressure-ln ePCWP). Echocardiographic parameters were measured just before catheterization in 110 patients with cardiac disease (age 72 ± 8). There was a good correlation between the eTau and Tau by catheterization (r = 0.69, p <0.001), whereas IVRT and the e' had a poor correlation with Tau (r = 0.33 and -0.33, respectively). The sensitivity and specificity of the eTau to predict prolonged Tau (>48 ms) was 77% and 91%, respectively, with area under curve of 0.87 using an optimal cutoff of 48 ms. Bland-Altman analysis revealed a good agreement between the eTau and Tau. In conclusion, this study demonstrated that the eTau by our noninvasive method has a good correlation with Tau obtained by cardiac catheterization. LV relaxation may be noninvasively and accurately estimated by STE., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: The role of endogenous adenosine in cardiac patients is still unclear, so we investigated the relationship between the plasma adenosine concentration and left ventricular (LV) function, LV dilation and LV wall thinning in cardiac patients., Methods and results: In 97 cardiac patients, with angina pectoris, old myocardial infarction, dilated or hypertrophic cardiomyopathy, and valvular heart disease, plasma adenosine concentrations were measured using the LC-MS/MS system, and the LV function, LV end-diastolic dimension (LVDd), LV posterior wall thickness (LVPWth), and interventricular septum thickness (IVSth) were assessed by echocardiography. The plasma adenosine concentration was significantly higher in patients with a LV ejection fraction (EF), an indicator of the LV systolic function, <47% compared with those with LVEF ≥47% (P=0.027). There was no difference between the plasma adenosine concentration and E/e', an indicator of LV diastolic function. The plasma adenosine concentration was significantly higher in patients with LVDd ≥50 mm than in those with LVDd <50 mm (P=0.030). The plasma adenosine concentration was inversely correlated with IVSth (P=0.003) and LVPWth (P=0.0007). The plasma adenosine concentration was significantly higher in patients with IVSth <8 mm than in those with IVSth ≥8 mm (P=0.015), and was significantly higher in patients with LVPWth <8 mm than in those with LVPWth ≥8 mm (P=0.020)., Conclusions: Endogenous adenosine may be related to LV dysfunction, dilation, and wall thinning in cardiac patients.

Rationale: Multilineage-differentiating stress enduring (Muse) cells, pluripotent marker stage-specific embryonic antigen-3 + cells, are nontumorigenic endogenous pluripotent-like stem cells obtainable from various tissues including the bone marrow. Their therapeutic efficiency has not been validated in acute myocardial infarction., Objective: The main objective of this study is to clarify the efficiency of intravenously infused rabbit autograft, allograft, and xenograft (human) bone marrow-Muse cells in a rabbit acute myocardial infarction model and their mechanisms of tissue repair., Methods and Results: In vivo dynamics of Nano-lantern-labeled Muse cells showed preferential homing of the cells to the postinfarct heart at 3 days and 2 weeks, with ≈14.5% of injected GFP (green fluorescent protein)-Muse cells estimated to be engrafted into the heart at 3 days. The migration and homing of the Muse cells was confirmed pharmacologically (S1PR2 [sphingosine monophosphate receptor 2]-specific antagonist JTE-013 coinjection) and genetically (S1PR2-siRNA [small interfering ribonucleic acid]-introduced Muse cells) to be mediated through the S1P (sphingosine monophosphate)-S1PR2 axis. They spontaneously differentiated into cells positive for cardiac markers, such as cardiac troponin-I, sarcomeric α-actinin, and connexin-43, and vascular markers. GCaMP3 (GFP-based Ca calmodulin probe)-labeled Muse cells that engrafted into the ischemic region exhibited increased GCaMP3 fluorescence during systole and decreased fluorescence during diastole. Infarct size was reduced by ≈52%, and the ejection fraction was increased by ≈38% compared with vehicle injection at 2 months, ≈2.5 and ≈2.1 times higher, respectively, than that induced by mesenchymal stem cells. These effects were partially attenuated by the administration of GATA4 -gene-silenced Muse cells. Muse cell allografts and xenografts efficiently engrafted and recovered functions, and allografts remained in the tissue and sustained functional recovery for up to 6 months without immunosuppression., Conclusions: Muse cells may provide reparative effects and robust functional recovery and may, thus, provide a novel strategy for the treatment of acute myocardial infarction., (© 2018 American Heart Association, Inc.)

Background: Multilineage differentiating stress-enduring (Muse) cells are SSEA3 + and CD105 + double-positive pluripotent-like stem cells. We aimed to examine the mobilization of Muse cells into peripheral blood after acute myocardial infarction (AMI) and their effects on left ventricular (LV) function and remodeling., Methods and results: In 79 patients with AMI, 44 patients with coronary artery disease (CAD), and 64 normal subjects (Control), we measured the number of Muse cells in the peripheral blood by fluorescence-activated cell sorting. Muse cells were measured on days 0, 1, 7, 14, and 21 after AMI. Plasma sphingosine-1-phosphate (S1P) levels were measured. Cardiac echocardiography was performed in the acute (within 7 days) and chronic (6 months) phases of AMI. Muse cell number on day 1 was significantly higher in the AMI (276±137 cells/100 μL) than in the CAD (167±89 cells/100 μL) and Control (164±125 cells/100 μL) groups. Muse cell number peaked on day 1, and had gradually decreased on day 21. Muse cell number positively correlated with plasma S1P levels. Patients with a higher increase in the number of Muse cells in the peripheral blood but not those with a lower increase in number of Muse cells in the acute phase showed improved LV function and remodeling in the chronic phase., Conclusions: Endogenous Muse cells were mobilized into the peripheral blood after AMI. The number of Muse cells could be a predictor of prognosis in patients with AMI.

Acute myocardial infarction (AMI) is a common cause of morbidity and mortality worldwide. Severe MI leads to heart failure due to a marked loss of functional cardiomyocytes. First-line treatment for AMI is to reperfuse the occluded coronary artery by PCI as soon as possible. Besides PCI, there are several therapies to reduce the infarct size and improve the cardiac function and remodeling. These are drug therapies such as pharmacological pre- and postconditioning, cytokine therapies, and stem cell therapies. None of these therapies have been clinically developed as a standard treatment for AMI. Among many cell sources for stem cell therapies, the Muse cell is an endogenous non-tumorigenic pluripotent stem cell, which is able to differentiate into cells of all three germ layers from a single cell, suggesting that the Muse cell is a potential cell source for regenerative medicine. Endogenous Muse cell dynamics in the acute phase plays an important role in the prognosis of AMI patients; AMI patients with a higher number of Muse cells in the peripheral blood in the acute phase show more favorable improvement of the cardiac function and remodeling in the chronic phase, suggesting their innate reparative function for the heart. Intravenously administered exogenous Muse cells engrafted preferentially and efficiently to infarct border areas via the S1P-S1PR2 axis and differentiated spontaneously into working cardiomyocytes and vessels, showed paracrine effects, markedly reduced the myocardial infarct size, and delivered long-lasting improvement of the cardiac function and remodeling for 6 months. These findings suggest that Muse cells are reparative stem cells, and thus their clinical application is warranted.

Objective: A high salt intake causes hypertension and leads to cardiovascular disease. Therefore, a low salt diet is now recommended to prevent hypertension and cardiovascular disease. However, it is still unknown whether an excessively low salt diet is beneficial or harmful for the heart., Methods: Wistar Kyoto rats (WKYs) and spontaneously hypertensive rats (SHRs) received normal salt chow (0.9% salt diet) and excessively low salt chow (0.01% salt diet referred to as saltless diet) for 8 weeks from 8 to 16 weeks of age. The effects of the excessively low salt diet on the cardiac (pro) renin receptor, renin-angiotensin-aldosterone, and sympatho-adrenal systems were investigated., Results: The excessively low salt diet did not affect the systolic blood pressure but significantly increased the heart rate both in WKYs and SHRs. The excessively low salt diet significantly elevated plasma renin activity, plasma angiotensin I, II and aldosterone concentrations, and plasma noradrenaline and adrenaline concentrations both in WKYs and SHRs. Cardiac expressions of renin, prorenin, (P)RR, angiotensinogen, and angiotensin II AT1 receptor and phosphorylated (p)-ERK1/2, p-HSP27, p-38MAPK, and TGF-ß1 were significantly enhanced by the excessively low salt diet in both WKYs and SHRs. The excessively low salt diet accelerated cardiac interstitial and perivascular fibrosis and increased the cardiomyocyte size and interventricular septum thickness in WKYs and SHRs but the extent was greater in SHRs., Conclusion: An excessively low salt diet damages the heart through activation of plasma renin-angiotensin-aldosterone and sympatho-adrenal systems and activation of cardiac (P)RR and angiotensin II AT1 receptor and their downstream signals both in WKYs and SHRs.

GLP-1 has been reported to be cardioprotective against ischemia-reperfusion injury. We aimed to examine the effect of alogliptin, which may produce GLP-1, on ischemia-reperfusion injury and its mechanisms. Rabbits were fed a normal chow (control group) and a chow containing alogliptin (2 mg·kg·d: alogliptin-L group and 20 mg·kg·d: alogliptin-H group) for 7 days. The rabbits underwent 30 minutes of coronary occlusion and 48 hours of reperfusion. Exendin (9-39) [5 or 50 μg/kg, i.v., alogliptin-H+exendin (9-39)-L group and alogliptin-H+exendin (9-39)-H group] or L-NAME (10 mg/kg, i.v., alogliptin-H+L-NAME group) was administered to the alogliptin-H group. Alogliptin dose-dependently reduced the infarct size, which was partially blocked by exendin (9-39), but completely blocked by L-NAME. Exendin (9-39) or L-NAME alone did not affect the infarct size for themselves. The left ventricular ejection fraction and ±dP/dt were higher in the alogliptin-L group and alogliptin-H group than in the control group. Alogliptin increased the serum NOx and plasma GLP-1 levels, and those levels inversely correlated with the infarct size. Alogliptin upregulated the expressions of phosphorylated (p)-Akt and p-eNOS, which were inhibited by exendin (9-39) and L-NAME, respectively. In conclusion, alogliptin protects the heart against ischemia-reperfusion injury through GLP-1 receptor-dependent and receptor-independent pathways which involve nitric oxide production in rabbits.

Left ventricular (LV) properties in hypertension (HTN) could be deteriorated by pressure overload, especially in endocardium, resulting in hypertensive heart failure (HHF). We sought to noninvasively examine LV systolic and diastolic functions at three myocardial layers in HTN and elucidate features of HHF by speckle-tracking echocardiography (STE) with high volume rates. We examined normotensive controls (n = 54), HTN patients without LV hypertrophy (LVH) (n = 50), and HTN patients with LVH (n = 40) and HHF patients (n = 45). The HHF group was divided into two subgroups based on their LVEF (20 heart failure with preserved ejection fraction: HFpEF and 25 heart failure with reduced ejection fraction: HFrEF). LV layer systolic function was assessed by strain rate during systole. Pulmonary capillary wedge pressure (PCWP) was estimated (ePCWP) using kinetics-tracking index (KT index) that we previously reported. HTN patients with LVH had a significant deterioration of systolic and diastolic properties compared with normotensive controls in the absence of a significant reduction in LVEF. Patients with HHF had further deterioration of systolic and diastolic properties compared with HTN patients with LVH. LV strain at entire myocardium and ePCWP in HFrEF was deteriorated compared with those in HFpEF. Deterioration of LV layer SR was more typical during systole, isovolumic relaxation, and early diastole compared with control. LV dilation was independently associated with LVEF (r = -0.48, p < 0.001) and ePCWP (r = 0.47, p < 0.001), and LVH (LV mass index) was independently associated with E/e' (r = 0.37, p = 0.025), LVEF (r = -0.44, p < 0.001), and ePCWP (r = 0.67, p < 0.001). LV layer analysis by STE could detect subtle impairments in systolic function before the deterioration of LVEF in patients with HTN. The ePCWP that was estimated using KT index was the independent factor associated with HHF. The ePCWP may be useful to noninvasively detect the early stage of HHF.

Risk stratification in heart failure (HF) among patients and healthy subjects using pulmonary capillary wedge pressure (PCWP) is important for understanding when and why HF develops. The aim of the present study was to evaluate the impact of gender and healthy aging on estimated PCWP using a kinetics-tracking index in patients and in healthy subjects without hypertension. The study population consisted of 198 healthy subjects without cardiovascular or other systemic diseases and who were not taking any medications. Echocardiographic studies were performed using an ACUSON Sequoia 512 ultrasound system. Active left atrial (LA) emptying function (EF) was defined as (pre-atrial contraction LA volume-minimum LA volume)/pre-atrial contraction LA volume × 100%. With an increase in age, the E/A and E/e' ratios (markers of left ventricular (LV) diastolic dysfunction (DD)) showed a similar decrease in males and females. PCWP was maintained at 8.3±1.8 mm Hg in males and 8.2±2.3 mm Hg in females because of compensation by an increase in active LA EF. In contrast, the compensation for LV DD with an increase in active LA EF in females tended to be more gradual (slope=0.11) than in males (slope=0.18, P=0.060 vs. female). The parameters that indicated LV DD deteriorated with advancing age. PCWP might be maintained because of compensation, namely an increase in active LA EF in both males and females. The compensation in female septuagenarians and octogenarians was weaker than in male septuagenarians and octogenarians. This difference in compensation may explain why HF with preserved LV ejection fraction occurs more frequently in females than in males.

Background: Atrial fibrillation (AF) is associated with left atrial (LA) remodeling caused by pressure and/or volume (LAV) overload. Increased pulmonary capillary wedge pressure (PCWP) represents LA pressure overload. We recently reported that pulmonary capillary wedge pressure (ePCWP) can be estimated by the kinetics-tracking (KT) index that combines LA function and volume using speckle tracking echocardiography (STE), and has a strong correlation with PCWP measured by right heart catheterization (r = 0.92). Therefore, we hypothesized that ePCWP is the best echocardiographic predictor of successful AF ablation., Methods: We enrolled 137 patients with paroxysmal AF (age: 61 ± 10 years) who underwent pulmonary vein isolation. We measured LAV index, LA emptying function (EF) and LA stiffness during sinus rhythm before ablation using STE. PCWP was noninvasively estimated by STE as we previously reported. Parameters were compared between a group with AF recurrence (n = 30, age: 59 ± 11 years) and a group with successful ablation (sinus rhythm maintained for >1 year) (n = 107, age 61 ± 11 years)., Results: The ePCWP was correlated with PCWP measured by right heart catheterization (r = 0.76, p < 0.01). Compared with the non-recurrence group (n = 107, age: 61 ± 11), the AF recurrence group had significantly increased ePCWP (10.6 ± 3.5 vs 14.6 ± 2.9 mmHg, p < 0.01), minimum LAV index (29 ± 12 ml/m(2) vs 37 ± 14 ml/m(2), p < 0.01) and LA stiffness (0.47 ± 0.33 vs 0.83 ± 0.59, p < 0.01), but lower total LA EF (44 ± 11% vs 39 ± 13%, p < 0.01) before ablation. In multivariate logistic regression analysis, ePCWP was the most significant independent predictor of successful ablation. Using 13 mmHg of PCWP as the optimal cutoff value, the sensitivity and specificity for successful ablation were 73 and 77% (area under the curve = 0.81), respectively., Conclusion: The ePCWP that is measured by the combination of LA function and volume before ablation was a better predictor of the successful ablation compared with LA function and volume separately. The ePCWP estimated by STE is useful to predict the successful ablation in paroxysmal AF, and could be useful to improve candidate selection for AF ablation.

We investigated whether microRNA-145 (miR-145) has a cardioprotective effect in a rabbit model of myocardial infarction (MI) and in H9c2 rat cardiomyoblasts. Rabbits underwent 30 min of coronary occlusion, followed by 2 days or 2 wk of reperfusion. Control microRNA (control group; 2.5 nmol/kg, n = 10) or miR-145 (miR-145 group, 2.5 nmol/kg, n = 10) encapsulated in liposomes was intravenously administered immediately after the start of reperfusion. H9c2 rat cardiomyoblasts were transfected with miR-145. The MI size was significantly smaller in the miR-145 group than in the control group at 2 days and 2 wk post-MI. miR-145 had improved the cardiac function and remodeling at 2 wk post-MI. These effects were reversed by chloroquine. Western blot analysis showed that miR-145 accelerated the transition of LC3B I to II and downregulated p62/SQSTM1 at 2 days or 2 wk after MI, but not at 4 wk, and activated Akt in the ischemic area at 2 days after MI. miR-145 inhibited the growth of H9c2 cells, accelerated the transition of LC3B I to II, and increased phosphorylated Akt in the H9c2 cells at 2 days after miR-145 transfection. Antagomir-145 significantly abolished the morphological change, the transition of LC3B I to II, and the increased phosphorylated Akt induced by miR-145 in H9c2 cells. We determined fibroblast growth factor receptor substrate 2 mRNA to be a target of miR-145, both in an in vivo model and in H9c2 cells. In conclusion, post-MI treatment with miR-145 protected the heart through the induction of cardiomyocyte autophagy by targeting fibroblast growth factor receptor substrate 2., (Copyright © 2015 the American Physiological Society.)

Background: We hypothesized that a development of a novel index based on the combination of left atrial volume (LAV) and left atrial (LA) function evaluated by the time-LA volume curve using speckle tracking echocardiography (STE) would be accurate and useful to estimate pulmonary capillary wedge pressure (PCWP). Our goal was to develop a novel index of PCWP based on a combination of LAV and LA function using STE., Methods: A cross-validation study was performed with the patients divided into a training study to define the novel index (n=50) and a testing study to validate the index (n=196). PCWP was measured by right heart catheterization, and phasic LAV and emptying function (EF) were measured by STE., Results: Simple linear regression analysis in the training study revealed that the novel index that best estimated PCWP was the kinetics-tracking index [KT index=log10 (active LAEF/minimum LAV index)]. Multiple regression analysis revealed that the KT index was the most reliable predictor of PCWP. It had the strongest correlation with PCWP (r=-0.86, p<0.001) among all echocardiographic parameters. In the testing study, PCWP estimated by the KT index was also strongly correlated with measured PCWP (r=0.92, p<0.001). These correlations were also strong in the patients with reduced left ventricular ejection fraction (<50%), chronic heart failure, and chronic atrial fibrillation (r=0.92, r=0.91, r=0.79, p<0.001, respectively)., Conclusions: A novel index (KT index) using a combination of LAV and LA function was a powerful and useful predictor of PCWP and may be valuable in routine clinical practice., (Copyright © 2014 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

Objective: It has not yet been fully elucidated whether cardiac tissue levels of prorenin, renin and (P)RR are activated in hypertension with a high salt intake. We hypothesized that a high salt intake activates the cardiac tissue renin angiotensin system and prorenin-(pro)renin receptor system, and damages the heart at an early stage of hypertension., Methods: Wistar Kyoto rats (WKY) and spontaneously hypertensive rats (SHR) received regular (normal-salt diet, 0.9%) and high-salt (8.9%) chow for 6 weeks from 6 to 12 weeks of age. The systolic blood pressure, plasma renin activity (PRA) and plasma angiotensin II concentration were measured, and the protein expressions of prorenin, (pro)renin receptor, angiotensinogen, angiotensin II AT1 receptor, ERK1/2, TGF-β, p38MAPK and HSP27 in the myocardium were investigated. The cardiac function was assessed by echocardiography, and histological analysis of the myocardium was performed., Results: The high-salt diet significantly increased the systolic blood pressure, and significantly reduced the PRA and plasma angiotensin II concentration both in the WKYs and SHRs. Cardiac expressions of prorenin, renin, (P)RR, angiotensinogen, angiotensin II AT1 receptor, phosphorylated (p)-ERK1/2, p-p38MAPK, TGF-β and p-HSP27 were significantly increased by the high salt diet both in the WKYs and SHRs. The high-salt diet significantly increased the interventricular septum thickness and cardiomyocyte size, and accelerated cardiac interstitial and perivascular fibrosis both in the WKYs and SHRs. On the other hand, dilatation of left ventricular end-diastolic dimension and impairment of left ventricular fractional shortening was shown only in salt loaded SHRs., Conclusion: The high-salt diet markedly accelerated cardiac damage through the stimulation of cardiac (P)RR and angiotensin II AT1 receptor by increasing tissue prorenin, renin and angiotensinogen and the activation of ERK1/2, TGF-β, p38MAPK and HSP27 under higher blood pressure.

Background: Three-dimensional speckle tracking echocardiography (3D-STE) has a major advantage in the improvement of accuracy in the evaluation of cardiac chamber volume without any geometrical assumption. Thus, the aim of this study was to use 3D-STE to elucidate the features of left atrial (LA) volume and function that are altered by hypertension (HTN) by comparing well-controlled HTN patients with normal subjects., Methods: Conventional echocardiographic parameters and LA phasic volume and function were measured from apical view by 3D-STE in 40 patients with well-controlled HTN [systolic blood pressure (BP) <140 and diastolic BP <90mmHg for more than one year] and 40 normotensive subjects., Results: The passive LA emptying function (EF) in the patients with well-controlled HTN significantly decreased (16±7% vs. 22±8%, p=0.0013) and the active LAEF in patients with well-controlled HTN significantly increased (35±10% vs. 30±9%, p=0.029) compared with the values in normotensive subjects. Multivariate logistic regression analysis revealed that E/e' was an independent determinant of well-controlled HTN. The maximum LA volume index was correlated with elevated E/e' (r=0.30, p=0.0064), whereas the maximum LA volume index was not correlated with LV mass index or systolic BP. This change was independent of age., Conclusions: These results suggest that LV diastolic dysfunction occurs before structural changes of left atrium and left ventricle even in patients with well-controlled HTN., (Copyright © 2013 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

Background: The aim of this study was to validate the accuracy of three-dimensional (3D) speckle tracking echocardiography (STE) and two-dimensional (2D)-STE for the assessment of left atrial (LA) volume and function by comparison with 3D-computed tomography (CT) performed on the same day as STE., Methods: LA phasic volume and emptying function (EF) were measured in 28 patients with paroxysmal atrial fibrillation undergoing catheter ablation (62±11 years old) using both 3D-STE and 2D-STE during sinus rhythm. LA phasic volume and function measured by 3D-STE and 2D-STE were validated using 3D-CT as a gold standard., Results: The intraobserver correlation coefficient and variability in maximum LA volume assessed by 3D-STE were 0.99 and 1.4±6.0%, respectively. The interobserver correlation coefficient and variability in maximum LA volume assessed by 3D-STE were 0.99 and 0.2±4.5%, respectively. There were strong correlations between LA phasic volume measured by 3D-CT and those measured by 3D-STE (r=0.98, p<0.001). There were correlations between LA phasic function measured by 3D-CT and those measured by 3D-STE (r=0.85-0.88, p<0.001). There was a better agreement between 3D-CT and 3D-STE in the assessment of LA phasic volumes and function than between 3D-CT and 2D-STE in apical 2- and 4-chamber view., Conclusions: 3D-STE allows more accurate measurement of LA volume and function than 2D-STE and has high reproducibility., (Copyright © 2013 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)