Plasma microRNA-143 and microRNA-145 levels are elevated in patients with left ventricular dysfunction.

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.

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.

S1P-S1PR2 Axis Mediates Homing of Muse Cells Into Damaged Heart for Long-Lasting Tissue Repair and Functional Recovery After Acute Myocardial Infarction.

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.

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.

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.

(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.

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.

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.

Mobilized Muse Cells After Acute Myocardial Infarction Predict Cardiac Function and Remodeling in the Chronic Phase.

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.

Non-Invasive Pulmonary Capillary Wedge Pressure Assessment on Speckle Tracking Echocardiography as a Predictor of New-Onset Non-Valvular Atrial Fibrillation　- Four-Year Prospective Study (NIPAF Study).

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.

Endogenous Adenosine May Be Related to Left Ventricular Dysfunction, Dilation, and Wall Thinning in Patients With Heart Disease.

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.

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.

Antidiabetic Drug Alogliptin Protects the Heart Against Ischemia-reperfusion Injury Through GLP-1 Receptor-dependent and Receptor-independent Pathways Involving Nitric Oxide Production in Rabbits.

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.

Evaluation of systolic and diastolic properties of hypertensive heart failure using speckle-tracking echocardiography with high volume rates.

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.

Estimated pulmonary capillary wedge pressure assessed by speckle tracking echocardiography predicts successful ablation in paroxysmal atrial fibrillation.

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.

MicroRNA-145 repairs infarcted myocardium by accelerating cardiomyocyte autophagy.

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.

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.

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.

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.