Background— Midkine (MK) is a heparin-binding growth factor involved in diverse biological phenomena, eg, neural survival, carcinogenesis, and tissue repair. MK could have a protective action against ischemia/reperfusion (I/R) injury in the heart, because MK was shown to have cytoprotective activity in cultured neurons and tumor cells. We investigated this hypothesis in mice with and without genetic MK deletion. Methods and Results— Myocardial injury after I/R was produced by transient occlusion of coronary arteries. In wild-type ( Mdk +/+ ) mice, MK expression was increased after I/R in the periinfarct area. Infarct size/area at risk 24 hours after I/R in MK-deficient ( Mdk −/− ) mice was larger than in Mdk +/+ mice (55.4±9.1% versus 32.1±5.3%, P <0.05). Terminal dUTP nick end-labeling–positive myocyte population in the periinfarct area in Mdk −/− mice was higher than in Mdk +/+ mice (6.8±0.9% versus 3.2±0.6%, P <0.05). Left ventricular fractional shortening 24 hours after I/R in Mdk −/− mice was significantly less than that in Mdk +/+ mice (34.3±4.4% versus 50.8±2.1%, P <0.05). Supplemental application of MK protein to left ventricle of Mdk −/− mice at the time of I/R resulted in reduction of the infarct size. Application of exogenous MK to cultured cardiomyocytes resulted in increased Bcl-2 expression and decreased apoptosis after hypoxia/reoxygenation. Conclusions— These results suggest that MK plays a protective role against I/R injury, most likely through a prevention of apoptotic reaction. MK is a potentially important new molecular target for treatment of ischemic heart disease.

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.

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.

Background Little information is available regarding the incidence of aortic dissection or rupture in patients with a dilated ascending aorta after aortic valve replacement (AVR). The present clinical study aimed to demonstrate the incidence of aortic complications after AVR in patients with a dilated ascending aorta and to clarify those risk factors associated with the progression of a dilated ascending aorta or late aortic events. Methods and Results A total of 35 patients with a dilated ascending aorta at the time of AVR were enrolled. A dilated ascending aorta was defined as 40 mm or greater in diameter by preoperative computed tomography or operative findings. The baseline ascending aorta diameter ranged from 40 to 55 mm with a mean of 44.8±4.4 mm. There was a high frequency of bicuspid valve disease in patients with a dilated ascending aorta (57%). The mean follow-up interval was 8.1±3.5 years (range: 2.3-13). Aortic events occurred in 5 patients (aortic dissection in 1, rupture in 2, reoperation in 2) during the follow-up. One aortic dissection developed at a baseline aortic size of 42 mm, whereas 2 aortic ruptures occurred at baseline aortic sizes of 47 mm and 50 mm. There was no statistically significant univariate association between any of the patient clinical characteristics and late aortic events or ascending aortic progression. Conclusion Although the clinical course of patients with a dilated ascending aorta is unpredictable, aortic events may occur even in patients with a baseline aortic diameter of <50 mm. Therefore, preventive aortic surgery at the time of AVR should be considered to prevent aortic dissection or rupture in patients with an even slightly dilated ascending aorta with a diameter of 40 to 50 mm, unless the patient has a high operative risk or older age. (Circ J 2005; 69: 392 -396)