Hisaaki Ishiguro

Midkine gene transfer after myocardial infarction in rats prevents remodelling and ameliorates cardiac dysfunction

AIM We have previously reported that therapy with midkine (MK) has a protective effect in mouse models of myocardial infarction (MI) and ischemia/reperfusion. The underlying mechanism was proved to be anti-apoptosis and prevention of left ventricular (LV) remodelling following angiogenesis. Here we investigated the effects of overexpression of MK by adenoviral gene transfer on cardiac function and remodelling in an experimental rat MI model. METHODS AND RESULTS MI was created in male Wistar rats. Adenoviral vectors encoding mouse MK (AdMK) or beta-galactosidase (AdLacZ; as controls) were injected in myocardium at the onset of MI. One week after injection, in vivo adenoviral gene expression was assessed by western blot and histological analysis. After echocardiographic analysis at 4 weeks and haemodynamic analysis at 6 weeks after MI, AdMK animals had better cardiac function compared with AdLacZ animals. Heart weight (HW) and relative HW of AdMK animals were not different from sham-operated animals after 6 weeks, pointing to a very potent effect in the prevention of ischemic cardiomyopathy. In histological studies at 6 weeks after MI, AdMK animals had less fibrosis in the non-infarcted myocardium and higher vascular density in the border-zone area compared with AdLacZ animals. AdMK animals had strongly upregulated levels of phosphorylated extracellular signal-regulated kinase, Akt, PI 3-kinase, and Bcl-2, whereas the level of Bax was downregulated compared with AdLacZ animals. CONCLUSION Overexpression of MK prevents LV remodelling and ameliorates LV dysfunction by anti-apoptotic and pro-angiogenic effects. MK gene transfer may provide a new therapeutic modality in ischemic cardiomyopathy and ischemic heart failure.

Midkine prevents ventricular remodeling and improves long-term survival after myocardial infarction

Cardiac remodeling is thought to be the major cause of chronic heart dysfunction after myocardial infarction (MI). However, molecules involved in this process have not been thoroughly elucidated. In this study we investigated the long-term effects of the growth factor midkine (MK) in cardiac remodeling after MI. MI was produced by ligation of the left coronary artery. MK expression was progressively increased after MI in wild-type mice, and MK-deficient mice showed a higher mortality. Exogenous MK improved survival and ameliorated left ventricular dysfunction and fibrosis not only of MK-deficient mice but also of wild-type mice. Angiogenesis in the peri-infarct zone was also enhanced. These in vivo changes induced by exogenous MK were associated with the activation of phosphatidylinositol 3-kinase (PI3K)/Akt and MAPKs (ERK, p38) and the expression of syndecans in the left ventricular tissue. In vitro experiments using human umbilical vein endothelial cells confirmed the potent angiogenic action of MK via the PI3K/Akt pathway. These results suggest that MK prevents the cardiac remodeling after MI and improves the survival most likely through an enhancement of angiogenesis. MK application could be a new therapeutic strategy for the treatment of ischemic heart failure.

A single intracoronary injection of midkine reduces ischemia/reperfusion injury in Swine hearts: a novel therapeutic approach for acute coronary syndrome

Several growth factors are effective for salvaging myocardium and limiting infarct size in experimental studies with small animals. Their benefit in large animals and feasibility in clinical practice remains to be elucidated. We investigated the cardioprotective effect of midkine (MK) in swine subjected to ischemia/reperfusion (I/R). I/R was created by left anterior descending coronary artery occlusion for 45 min using a percutaneous over-the-wire balloon catheter. MK protein was injected as a bolus through the catheter at the initiation of reperfusion [MK-treated (MKT) group]. Saline was injected in controls (CONT). Infarct size/area at risk (24 h after I/R) in MKT was almost five times smaller than in CONT. Echocardiography in MKT revealed a significantly higher percent wall thickening of the interventricular septum, a higher left ventricular (LV) fractional shortening, and a lower E/e′ (ratio of transmitral to annular flow) compared with CONT. LV catheterization in MKT showed a lower LV end-diastolic pressure, and a higher dP/dtmax compared with CONT. Terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end-labeling-positive myocytes and CD45-positive cell infiltration in the peri-infarct area were significantly less in MKT than in CONT. Here, we demonstrate that a single intracoronary injection of MK protein in swine hearts at the onset of reperfusion dramatically reduces infarct size and ameliorates systolic/diastolic LV function. This beneficial effect is associated with a reduction of apoptotic and inflammatory reactions. MK application during percutaneous coronary intervention may become a promising adjunctive therapy in acute coronary syndromes.

Comparison Between 1- and 2-Stent Strategies in Unprotected Distal Left Main Disease: The Milan and New-Tokyo Registry

Background—There are only little data available on the comparison of clinical outcomes between a 1-stent strategy (1-SS) and a 2-stent strategy (2-SS) for percutaneous coronary intervention in unprotected distal left main disease. Methods and Results—Between April 2005 and August 2011, we recruited 937 consecutive unprotected distal left main patients treated with drug-eluting stents (1-SS, 608 patients; 2-SS, 329 patients). Major adverse cardiovascular events were defined as all-cause death, myocardial infarction, or target lesion revascularization (TLR) during the median follow-up period of 1592 days. Furthermore, the individual components of major adverse cardiovascular events, cardiac death, and stent thrombosis were evaluated. More complex lesions were seen with 2-SS than with 1-SS. Cardiac death occurred more frequently with 1-SS than with 2-SS (propensity score–adjusted hazard ratio, 0.52; 95% confidence interval, 0.29–0.64; P=0.03), whereas TLR occurred more frequently with 2-SS than with 1-SS (propensity score–adjusted hazard ratio, 1.59; 95% confidence interval, 1.15–2.20; P=0.005). TLR was mainly driven by revascularizations after restenosis at the ostial left circumflex artery (propensity score–adjusted hazard ratio, 1.94; 95% confidence interval, 1.33–2.82; P=0.001). However, there were no differences in major adverse cardiovascular events, all-cause death, stent thrombosis, and myocardial infarction. Of the 139 pairs that were propensity score matched, only TLRs were significantly higher in the 2-SS group (hazard ratio, 1.59; 95% confidence interval, 1.00–2.53; P=0.05). Conclusions—The difference between 1-SS and 2-SS in percutaneous coronary intervention for unprotected distal left main disease may be summarized by the high incidence of TLR, mainly because of restenosis at the ostial left circumflex artery in the 2-SS group.

Comparison between Plain Old Balloon Angioplasty and Drug-Eluting Stent Implantation for the Treatment of Stent Fracture.

OBJECTIVES The aim of this study was to evaluate clinical outcomes after percutaneous coronary intervention (PCI) for stent fracture (SF). BACKGROUND SF has been reported as a predictor of in-stent restenosis (ISR) and stent thrombosis (ST). METHODS Between January 2009 and December 2012, consecutive SF cases treated with either drug-eluting stent (DES) or plain old balloon angioplasty (POBA) were retrospectively enrolled in this study. The study endpoints were all-cause death, cardiac death, myocardial infarction (MI), target vessel revascularization (TVR), target lesion revascularization (TLR), ST, re-stent fracture (re-SF), and major adverse cardiac events (MACE) defined as the composite of cardiac death, MI, and TLR. RESULTS Of 135 SF cases, 67 (49.6%) cases were treated with DES, whereas 68 (50.4%) cases with POBA. Median follow-up period was 1,401 (IQR: 967-1,771) days. The estimated MACE rate at 3 years was significantly lower in the DES group as compared with the POBA group largely driven by less TLR (25.7 vs. 55.8%, P < 0.001). Moreover, 1-year landmark analysis after PCI for SF revealed that MACE continued to occur even after 1 year irrespective of the treatment option (P = 0.47). On multivariable Cox regression analysis, POBA and large post-procedure angle (Δ) defined as the degree difference between the end systolic and diastolic angle were identified as independent predictors for TLR. CONCLUSIONS DES implantation for SF is associated with better clinical outcomes as compared to POBA alone, due to a lower need for TLR. Large post-procedural angle (Δ) appears to be an independent predictor of TLR.

Provisional T-Stenting With Bioresorbable Vascular Scaffolds In Vivo: Insights From Optical Frequency Domain Imaging

Provisional single-stenting is the preferred strategy for the treatment of coronary bifurcation lesions [(1)][1]. In cases where the side branch (SB) suffers from flow compromise following main-branch (MB) stenting, stent implantation in the SB ought to be considered [(2)][2]. Currently, the use of

Independent predictors of in-stent restenosis after drug-eluting stent implantation for ostial right coronary artery lesions

OBJECTIVES We evaluated the angiographic patterns and predictors of in-stent restenosis (ISR) for ostial lesions of the right coronary artery (RCA) to clarify the mechanism of insoluble restenosis. BACKGROUND Although ISR of the RCA still occurs, limited data is available regarding the associated angiographic findings. METHODS Between January 2005 and September 2013, we recruited consecutive patients undergoing routine angiography 6-18months after implantation of a drug-eluting stent (DES). Multiple logistic regression analysis was used to determine the independent predictors of ISR, and the adjusted odds ratios (aOR) and 95% confidence intervals (95% CI) were calculated. RESULTS Routine angiography revealed that 45 of 131 patients (34.3%) had RCA-ISR, which were classifiable by occlusion type into ostial (24 cases), proximal (17 cases), diffuse (3 cases), and total (1 case). By multivariable analysis, early generation DES was the only independent predictor of overall ISR (aOR, 3.54; 95% CI, 1.59-7.87; p=0.002). In a subgroup analysis of each focal ISR pattern, early generation DES (aOR, 7.76; 95% CI, 2.15-28.0; p=0.002) was associated with increased risk of ostial ISR. On the contrary, larger stent (aOR, 0.21; 95% CI, 0.05-0.84; p=0.027) was associated with decreased risk of ostial ISR. Furthermore, a ratio of the stent to post-balloon size >1.10 (aOR, 3.93; 95% CI, 1.30-11.8; p=0.002) and good left ventricular contractility (ejection fraction >60%) (aOR, 8.27; 95% CI, 1.76-39.0; p=0.008) were associated with increased risk of proximal ISR when stent fracture was observed. CONCLUSION The focal pattern of RCA-ISR was mostly observed after DES implantation, and the mechanisms of proximal and ostial ISR differed.

Potential advantages of the GuideLiner ® catheter: insights from optical coherence tomography

Optical coherence tomography (OCT) has been reported as promising not only for the evaluation of lesion morphology, but also for better clinical outcomes; however, in some cases with severe vessel tortuosity or angulated bifurcation, it is difficult to advance an intravascular imaging catheter. We report a case in which a GuideLiner® catheter facilitated obtaining better angiographic and OCT images with the sub-selective injection of minimal contrast medium, even in a case with a tortuous vessel or angulated bifurcation. Furthermore, OCT assessment of a vessel through the catheter may be other potential advantage of this device.

Recanalized Thrombus Treated With a Paclitaxel-Coated Balloon: Insights from Optical Coherence Tomography.

A 56-year-old man with a medical history of hypertension and diabetes was referred by his primary care physician to our hospital for an electrocardiographic abnormality. An echocardiogram showed moderately reduced left ventricular function (ejection fraction 45%). Coronary angiography revealed a

High prevalence of coronary artery events and non-coronary events in patients with coronary artery aneurysm in the observational group

Background Coronary artery aneurysm (CAA) is occasionally detected on a small percentage of coronary angiography or multi-detector computed tomography (MDCT). CAA itself is considered benign entity despite the potential risks of rupture, thromboembolism, and compression of surrounding structures. However, the optimal management including other vascular comorbidity has yet to be fully clarified. Objective The aim of this study was to evaluate cardiovascular events in the patients with CAA in the observational group. Methods Between January 2010 and August 2015, 48 CAAs were identified in 37 patients out of consecutive 10,010 patients (0.37%) by MDCT. Twenty-eight patients treated conservatively were included in this study. Their major adverse cardiovascular events (MACE) were evaluated retrospectively: death, non-fatal myocardial infarction (MI), revascularizations; coronary artery bypass grafting (CABG) and percutaneous coronary intervention (PCI), and other vascular events. Results The average age was 62.0 ± 15.5 year sold, and median follow-up period was 49.6 months (IQR 23.6 to 78.1). Mean CAA diameter was 7.5 ± 2.8 mm. Twenty-two MACE occurred in 15 patients (53.6%): 1 sudden death, 4 MI, 1 CABG for CAA, 3 PCI for CAA, 7 PCI for non-CAA lesions, and 6 other vascular treatments for aorta and cerebral and peripheral artery. Follow-up MDCT was performed for 22 CAAs in 16 patients. In 9 CAAs of them, the maximal diameter increased significantly (Δ diameter: 1.5 ± 1.1 mm). Conclusions Presence of CAA may be associated with adverse vascular events including non-coronary diseases. This study could suggest the management for CAA should include the evaluation of not only CAA itself but also other vascular diseases.