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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: Because ST-elevation myocardial infarction (STEMI) extensively damages the heart, regenerative therapy with pluripotent stem cells such as multilineage-differentiating stress enduring (Muse) cells is required., Methods and results: In a first-in-human study, 3 STEMI patients with a left ventricular ejection fraction (LVEF) ≤45% after successful percutaneous coronary intervention received intravenously 1.5×10 7 cells of a human Muse cell-based product, CL2020. The safety and efficacy on LVEF and wall motion score index (WMSI) were evaluated for 12 weeks. No adverse drug reaction was noted. LVEF and WMSI were markedly improved., Conclusions: The first-in-human intravenous administration of CL2020 was safe and markedly improved LV function in STEMI patients.

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.

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: 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.

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.

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: Extravascular smooth muscle cells are often observed in the endocardium of human failing hearts. Here, we characterized the phenotype of those cells and investigated their physiological significance., Methods and Results: We examined left ventricular biopsy specimens obtained from 44 patients with dilated cardiomyopathy and 6 nonfailing hearts. In Masson trichrome-stained histological preparations, bundles of smooth muscle cells were seen localized in the endocardium in 23 of the 44 specimens (none of the 6 controls). These cells were immunopositive for α-smooth muscle actin, type 2 smooth muscle myosin, desmin, and calponin, but were negative for embryonic smooth muscle myosin, vimentin, fibronectin, and periostin. This profile is indicative of a late differentiation (contractile) smooth muscle phenotype. Electron microscopy confirmed that phenotype, revealing the cells to contain abundant myofilaments with dense bodies but little rough endoplasmic reticulum or Golgi apparatus. In the endocardial smooth muscle-positive group, the left ventricular end-systolic volume index (73±34 versus 105±50 mL/m(2); P=0.021), left ventricular peak wall stress (164±47 versus 196±43 dynes 10(3)/cm(2); P=0.023), and left ventricular end-systolic meridional wall stress (97±38 versus 121±37 dynes 10(3)/cm(2); P=0.036) were all significantly smaller, and the ejection fraction was larger (41±8.8 versus 33±9.3%; P=0.005) than in the endocardial smooth muscle-negative group. However, no histological parameters differed between the 2 groups., Conclusions: Endocardial smooth muscle cell bundles in hearts with dilated cardiomyopathy exhibit a mature contractile phenotype and may play a compensatory role mitigating heart failure by reducing left ventricular wall stress and systolic dysfunction., (© 2014 American Heart Association, Inc.)

Background: We investigated the effects of asialoerythropoietin (asialoEPO), a nonerythrogenic erythropoietin derivative, on 3 murine models of heart failure with different etiologies., Methods and Results: Doxorubicin (15 mg/kg) induced heart failure within 2 weeks (toxic cardiomyopathy). Treatment with asialoEPO (6.9 μg/kg) for 2 weeks thereafter attenuated the associated left ventricular dysfunction and dilatation. In addition, the asialoEPO-treated heart showed less myocardial fibrosis, inflammation, and oxidative damage, and diminished atrophic cardiomyocyte degeneration, which was accompanied by restored expression of GATA-4 and sarcomeric proteins. Mice with large 6-week-old myocardial infarctions exhibited marked left ventricular dysfunction with adverse remodeling (ischemic cardiomyopathy). AsialoEPO treatment for 4 weeks significantly mitigated progression of the dysfunction and remodeling and reduced myocardial fibrosis, inflammation, and oxidative damage. Finally, 25-week-old δ-sarcoglycan-deficient mice (genetic cardiomyopathy) were treated with asialoEPO for 5 weeks. AsialoEPO mitigated the progressive cardiac remodeling and dysfunction through cardiomyocyte hypertrophy, and upregulated expression of GATA-4 and sarcomeric proteins. AsialoEPO appears to act by altering the activity of the downstream erythropoietin receptor signals extracellular signal-regulated protein kinase, Akt, signal transducer, and activator of transcription 3 and 5 in a model-specific manner., Conclusions: The findings suggest that asialoEPO exerts broad cardioprotective effects through distinct mechanisms depending on the model, which are independent of the erythrogenic action. This compound may be promising for the treatment of heart failure of various etiologies.

Background: The aim of this prospective study was to determine whether statin therapy (pitavastatin) has a beneficial effect on the prevention of new-onset atrial fibrillation (AF) in elderly patients with hypertension (HTN) and to evaluate the relationships among statin treatment, the development of AF, and left atrial (LA) and ventricular (LV) structure and function., Methods and Results: We enrolled eligible elderly patients (≥65 years old) with HTN and LV hypertrophy until the number of patients reached 110 in both groups. The 110 patients with HTN who needed statin therapy (HTN with statin group) were started on pitavastatin (1-2 mg/day), and both groups continued with appropriate medication for HTN. LV and LA structure and function were examined by conventional and speckle-tracking echocardiography at baseline and after 1 year. LA volume and function in the HTN with statin group improved more than in the HTN without statin group. There was a significant difference in survival free of new-onset AF in the patients with and without statin therapy during the 2-year follow-up (hazard ratio: 0.32, P=0.027)., Conclusions: Pitavastatin had a beneficial effect on LV diastolic function and LA structure and function in elderly patients with HTN. Pitavastatin treatment may be associated with a lower incidence of new-onset AF.

Aims: Autophagy is activated in cardiomyocytes in ischaemic heart disease, but its dynamics and functional roles remain unclear after myocardial infarction. We observed the dynamics of cardiomyocyte autophagy and examined its role during postinfarction cardiac remodelling., Methods and Results: Myocardial infarction was induced in mice by ligating the left coronary artery. During both the subacute and chronic stages (1 and 3 weeks postinfarction, respectively), autophagy was found to be activated in surviving cardiomyocytes, as demonstrated by the up-regulated expression of microtubule-associated protein-1 light chain 3-II (LC3-II), p62 and cathepsin D, and by electron microscopic findings. Activation of autophagy, specifically the digestion step, was prominent in cardiomyocytes 1 week postinfarction, especially in those bordering the infarct area, while the formation of autophagosomes was prominent 3 weeks postinfarction. Bafilomycin A1 (an autophagy inhibitor) significantly aggravated postinfarction cardiac dysfunction and remodelling. Cardiac hypertrophy was exacerbated in this group and was accompanied by augmented ventricular expression of atrial natriuretic peptide. In these hearts, autophagic findings (i.e. expression of LC3-II and the presence of autophagosomes) were diminished, and activation of AMP-activated protein kinase was enhanced. Treatment with rapamycin (an autophagy enhancer) brought about opposite outcomes, including mitigation of cardiac dysfunction and adverse remodelling. A combined treatment with bafilomycin A1 and rapamycin offset each effect on cardiomyocyte autophagy and cardiac remodelling in the postinfarction heart., Conclusion: These findings suggest that cardiomyocyte autophagy is an innate mechanism that protects against progression of postinfarction cardiac remodelling, implying that augmenting autophagy could be a therapeutic strategy.

Background: We investigated whether postinfarct treatment with oxytocin (OT) improves left ventricular (LV) function and remodeling via cardiac repair of myocardial ischemia-reperfusion injury., Methods and Results: Experiments were performed with 30 minutes of coronary occlusion and 2 or 14 days of reperfusion rabbit model of myocardial infarction. LV function and remodeling were significantly improved in the OT group. The infarct size was significantly reduced in the OT group. The number of CD31-positive microvessels was increased significantly in the OT group. There were no Ki67-positive myocytes in either group. The expression of the OT receptor, phosphorylated (p)-Akt protein kinase, p-extracellular signal-regulated protein kinase, p-enodthelial NO synthase, p-signal transducer and activator of transcription 3, vascular endothelial growth factor, B-cell lymphoma 2, and matrix metalloproteinase-1 (MMP-1) were markedly increased in the OT group days 2 and 14 post myocardial infarction., Conclusions: Postinfarct treatment with OT reduces myocardial infarct size and improves LV function and remodeling by activating OT receptors and prosurvival signals and by exerting antifibrotic and angiogenic effects through activation of MMP-1, endothelial NO synthase, and vascular endothelial growth factor. These findings provide new insight into therapeutic strategies for ischemic heart disease.

Aims: We investigated the effect of an erythropoietin (EPO)-gelatin hydrogel drug delivery system (DDS) applied to the heart on myocardial infarct (MI) size, left ventricular (LV) remodelling and function., Methods and Results: Experiments were performed in a rabbit model of MI. The infarct size was reduced, and LV remodelling and function were improved 14 days and 2 months after MI but not at 2 days after MI in the EPO-DDS group. The number of cluster of differentiation 31(CD31)-positive microvessels and the expression of erythropoietin receptor (EPO-R), phosphorylated-Akt (p-Akt), phosphorylated glycogen synthase kinase 3beta (p-GSK-3beta), phosphorylated extracellular signal-regulated protein kinase (p-ERK), phosphorylated signal transducer and activator of transcription 3 (p-Stat3), vascular endothelial growth factor (VEGF), and matrix metalloproteinase-1 (MMP-1) were significantly increased in the myocardium of the EPO-DDS group., Conclusion: Post-MI treatment with an EPO-DDS improves LV remodelling and function by activating prosurvival signalling, antifibrosis, and angiogenesis without causing any side effect.

Background: Aspirin and anti-platelet drugs are used commonly for patients with coronary heart disease. Proton pump inhibitor (PPI) and high-dose H2-blocker were recommended for preventing NSAIDs-related ulcer. Previously H2-blocker reported to have some negative cardiovascular effects. Additionally, a recent in vitro study showed that PPI reduced cardiac contractility. In this study, we evaluated whether chronic administration of PPI and high-dose H2-blocker affects left ventricular function., Method: Fifty-two stable angina patients were enrolled and classified into PPI group ([P]; lansoprazole: 15 mg/day, n=28), H2-blocker group ([H]; famotidine: 40 mg/day, n=8), and control ([C]; none or mucosal-defense drug, n=16). Eligible patients showed normal cardiac function in initial catheterization without administrated PPI or H2-blocker. They received percutaneous coronary intervention and follow-up catheterization. We compared changes in ejection fraction (EF: %), end diastolic/systolic volume index (EDVI/ESVI: ml/m(2)), and peak positive/negative dp/dt (+/-dp/dt: mmHg/s) in left ventricular angiography series., Result: There were no significant differences among three groups regarding patient characteristics, backgrounds of angiographic and intervention, except for fewer smokers in [C]. Other drugs such as beta- and Ca-blocker did not have effects on cardiac function except for aspirin during 255+/-115 days follow-up. Rate of EF changes significantly decreased in [P], and tended to decrease in [H] (C: 3.8+/-9.8%, H: -1.6+/-7.6%, P: -2.1+/-5.9%; p<0.05 for [C] vs. [P]). Those of ESVI changes were significantly greater in [P], and tended to be greater in [H] (C: -4.5+/-16.2%, H: 4.9+/-15.5%, P: 7.3+/-16.2%; p<0.05 for [C] vs. [P]), though, EDVI changes' were similar (C: 2.5+/-8.9%, H: 2.6+/-3.6%, P: 1.6+/-6.1%; p=ns). Rate of +/-dp/dt-changes tended to decrease in [H] (+dp/dt: C: 3.9+/-15.5%, H: -10.0+/-25.2%, P: 0.3+/-19.6%; p=ns, -dp/dt: C: -0.1+/-19.5%, H: -8.5+/-20.4%, P: 5.7+/-27.7%; p=ns)., Conclusion: In this study, PPI and high-dose H2-blocker have EF-reducing tendency. However, these changes were small and these drugs seemed to exhibit little influence clinically.

Recent studies suggest transplanted bone marrow cells (BMCs) can be used to reconstitute coronary vessels and myocardium following acute myocardial infarction, thereby improving cardiac function. We sought to investigate the therapeutic potential of BMC transplantation in the treatment of nonischemic cardiomyopathy. Experimental cardiomyopathy was produced by treating rabbits for 8 weeks with doxorubicin (2 mg/kg per week). Two weeks after the treatment was finished, freshly aspirated BMCs or an equivalent volume of phosphate-buffered saline was injected directly into the left ventricular free wall. Four weeks later, heart function was examined during perfusion on a Langendorff apparatus. Left ventricular developed pressure and +/-dp/dt were significantly better in the transplantation group, among which echocardiography also showed significantly better ejection fractions. In addition, left ventricular weights as a fraction of body weight and left ventricular wall thicknesses were both lower in rabbits transplanted with BMCs than in controls. Immunohistochemical analyses carried out 2 weeks after transplantation showed no new myocardium and a very small number of endothelial cells originating from BMCs. On the other hand, immunoblotting revealed upregulated expression of transforming growth factor-beta1 and downregulated expression of matrix metalloproteinase-1 and tumor necrosis factor-alpha following BMC transplantation. In conclusion, autologous BMC transplantation into cardiomyopathic rabbit hearts ameliorates the decline in ventricular function without regenerating cardiomyocytes, most likely by altering expression of various cytokines.