Activation of Mst1 causes dilated cardiomyopathy by stimulating apoptosis without compensatory ventricular myocyte hypertrophy.

Activation of mammalian sterile 20-like kinase 1 (Mst1) by genotoxic compounds is known to stimulate apoptosis in some cell types. The importance of Mst1 in cell death caused by clinically relevant pathologic stimuli is unknown, however. In this study, we show that Mst1 is a prominent myelin basic protein kinase activated by proapoptotic stimuli in cardiac myocytes and that Mst1 causes cardiac myocyte apoptosis in vitro in a kinase activity-dependent manner. In vivo, cardiac-specific overexpression of Mst1 in transgenic mice results in activation of caspases, increased apoptosis, and dilated cardiomyopathy. Surprisingly, however, Mst1 prevents compensatory cardiac myocyte elongation or hypertrophy despite increased wall stress, thereby obscuring the use of the Frank-Starling mechanism, a fundamental mechanism by which the heart maintains cardiac output in response to increased mechanical load at the single myocyte level. Furthermore, Mst1 is activated by ischemia/reperfusion in the mouse heart in vivo. Suppression of endogenous Mst1 by cardiac-specific overexpression of dominant-negative Mst1 in transgenic mice prevents myocyte death by pathologic insults. These results show that Mst1 works as both an essential initiator of apoptosis and an inhibitor of hypertrophy in cardiac myocytes, resulting in a previously unrecognized form of cardiomyopathy.

Coronary revascularization in Japan. Part 3: percutaneous coronary intervention during 1997.

A survey by the Japanese Coronary Intervention Study (JCIS) group revealed that 109,788 percutaneous coronary intervention (PCI) procedures were performed at 1,023 laboratories during 1997. The present study aimed to describe the demographic and clinical characteristics, treatment strategies, in-hospital outcomes, and long-term outcomes of these patients. A total of 10,642 PCIs performed in 8,814 patients, which corresponded to approximately 10% of the overall PCIs, were selected at random. The mean patient age was 65 years, and 75% were males. The patients often had extensive coronary risk factors. The most prevalent clinical diagnosis was stable angina (36%), followed by myocardial infarction (MI) excluding acute myocardial infarction (AMI; 28%) and AMI (25%). Plain old balloon angioplasty was used as the sole procedure in 58% of lesions for which an attempt to heal was made, and coronary stent placement in 38%. Angiographic success was achieved in 92% of attempted lesions. Mortality, MI and emergency coronary artery bypass grafting (CABG) rates during the hospitalization were 2.6%, 2.0% and 0.7%, respectively. In-hospital mortality rate for AMI was 7.6%, whereas that for elective PCI in cases without AMI was 0.6%. The overall mortality for 1.8 years was 8%. Repeat PCI was performed for 35% and CABG for 6% during the follow-up period. In Japan, PCI was performed in patients with coronary artery disease and extensive risk factors, but a high rate of angiographic success was achieved. The rates of in-hospital mortality and emergency CABG were low in non-AMI patients, but the 1-year rate of repeat PCI was as high as 32%.

Coronary revascularization in Japan. Part 4: coronary artery bypass surgery during 1997.

The Japanese Coronary Intervention Study (JCIS) has revealed that 17,667 coronary artery bypass grafting (CABG) procedures were performed at 477 facilities during 1997, and this report describes the demographic and clinical characteristics, treatment strategies, and the in-hospital and the long-term outcomes in patients treated with CABG in Japan. A total of 1,862 CABG cases, which corresponded to approximately 10% of the overall CABGs, were selected at random. The mean age was 65 years, and 76% of cases were males. The most prevalent clinical diagnosis was stable angina (54%), followed by myocardial infarction (MI) excluding acute myocardial infarction (AMI) (48%), unstable angina (25%), and AMI (5%). A large proportion of cases had multivessel coronary artery disease: 3-vessel disease (56%) and left main trunk disease (29%). The CABG procedures were emergency in 16%, and 93% of anastomotic sites were patent. In-hospital mortality and MI occurred in 5.1% and 3.5% of cases, respectively. The in-hospital mortality rate for emergency CABG was 12.0%, whereas that for elective CABG was 3.8%. The overall mortality rate during the follow-up period of 2.3 years was 10%. During the follow-up period, MI and angina occurred in 2% and 8% of cases, respectively. Percutaneous coronary intervention (PCI) was performed for 8%, and repeat CABG for 0.8%. In Japan, CABG was performed in patients with multivessel coronary artery disease with extensive risk factors. Angiographically determined success was achieved in 93% and the need for subsequent revascularization was relatively low.