Rotational atherectomy combined with cutting balloon to optimise stent expansion in calcified lesions: the ROTA-CUT randomised trial.

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 mm2 vs 6.9±1.8 mm2; 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.

An Increase in Plasma MicroRNA-143 Levels in the Acute Phase Is Positively Correlated With Recovery of Cardiac Function in the Chronic Phase in Patients With Acute Myocardial Infarction.

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.

The Feasibility of a Newly Developed Local Network System for Cardiac Rehabilitation (the CR-GNet) in Disease Management and Physical Fitness after Acute Coronary Syndrome.

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.

Human Muse cells reduce myocardial infarct size and improve cardiac function without causing arrythmias in a swine model of acute myocardial infarction.

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.

Impact of Autophagy on Prognosis of Patients With Dilated Cardiomyopathy.

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.

Stem cell therapy for acute myocardial infarction - focusing on the comparison between Muse cells and mesenchymal stem cells.

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.

Morphological characteristics in diabetic cardiomyopathy associated with autophagy.

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.

High-salt intake accelerates functional and histological renal damage associated with renal tissue overexpression of (pro)renin receptors and AT1 receptors in spontaneously hypertensive rats.

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.

Efficacy of Low-Pressure Inflation of Oversized Drug-Coated Balloon for Coronary Artery Disease.

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.

Safety and Long-Term Efficacy of Drug-Coated Balloon Angioplasty following Rotational Atherectomy for Severely Calcified Coronary Lesions Compared with New Generation Drug-Eluting Stents.

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.

Metformin Enhances Autophagy and Provides Cardioprotection in δ-Sarcoglycan Deficiency-Induced Dilated Cardiomyopathy.

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.

Increased Plasma Adenosine Concentration in the Subacute Phase May Contribute to Attenuation of Left Ventricular Dilation in the Chronic Phase in Patients With Acute Myocardial Infarction.

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.

(Pro)renin Receptor Blockade Ameliorates Heart Failure Caused by Chronic Kidney Disease.

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 ß1, 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.

Post-MI treatment with G-CSF and EPO-liposome with SLX repairs infarcted myocardium through EPCs mobilization and activation of prosurvival signals in rabbits.

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.

The intestine responds to heart failure by enhanced mitochondrial fusion through glucagon-like peptide-1 signalling.

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.

Long-Term Levocarnitine Ameliorates Left Ventricular Diastolic as Well as Systolic Dysfunction in Hemodialysis Patients　- Multi-Center Study.

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/m2 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.

Left Ventricular Torsion in Hypertension and Hypertensive Heart Failure　- 3-Dimensional Speckle Tracking Echocardiography Assessment.

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.

Acute Myocardial Infarction, Cardioprotection, and Muse Cells.

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.