Eiji Shinoda

Differential expression of three types of nitric oxide synthase in both infarcted and non-infarcted left ventricles after myocardial infarction in the rat

In the present report we investigated the differential expression of three types of nitric oxide synthase (NOS) in the left ventricle after myocardial infarction in rats. One, 3, 7, 14, 28 and 56 days (n=6-12 for each group) after ligation of a coronary artery, tissue samples were obtained from infarcted and non-infarcted tissues. The mRNA and protein levels of neuronal (n) NOS, endothelial (e) NOS and inducible (i) NOS were sequentially determined by semi-quantitative reverse transcription-polymerase chain reaction and Western blotting. Progressive left ventricular dilatation and gradual reduction in fractional shortening were confirmed by echocardiography. The expression levels of nNOS were significantly increased 1, 3 and 7 days post-infarct compared to those of sham-operated rats in both the infarcted (P<0.01) and non-infarcted regions (P<0.01). Immunohistochemical analysis showed that nNOS was localized in nerve fibers in the left ventricle and that the number of positive fibers after myocardial infarction had increased compared to that in sham-operated rats. With regard to eNOS, no significant changes in expression levels were detected between infarcted hearts and sham-operated controls. The level of iNOS expression peaked three days post-infarct and then decreased in the infarcted tissue, whereas it increased one day post-infarct, peaked at 14 and 28 days post-infarct and was still elevated in the chronic stage in the ventricular septum. iNOS immunoreactivity was detected in spared cardiomyocytes and macrophages in the infarcted region, and in cardiomyocytes in the ventricular septum. The expressions of three types of NOS were differentially regulated and iNOS produced in the non-infarcted region may contribute to the progression of heart failure after myocardial infarction in rats.

Late Adverse Events After Implantation of Sirolimus-Eluting Stent and Bare-Metal Stent Long-Term (5–7 Years) Follow-Up of the Coronary Revascularization Demonstrating Outcome Study-Kyoto Registry Cohort-2

Background—Late adverse events such as very late stent thrombosis (VLST) or late target-lesion revascularization (TLR) after first-generation sirolimus-eluting stents (SES) implantation have not been yet fully characterized at long term in comparison with those after bare-metal stent (BMS) implantation. Methods and Results—Among 13 058 consecutive patients undergoing first percutaneous coronary intervention in the Coronary REvascularization Demonstrating Outcome study-Kyoto registry Cohort-2, 5078 patients were treated with SES only, and 5392 patients were treated with BMS only. During 7-year follow-up, VLST and late TLR beyond 1 year after SES implantation occurred constantly and without attenuation at 0.24% per year and at 2.0% per year, respectively. Cumulative 7-year incidence of VLST was significantly higher in the SES group than that in the BMS group (1.43% versus 0.68%, P<0.0001). However, there was no excess of all-cause death beyond 1 year in the SES group as compared with that in the BMS group (20.8% versus 19.6%, P=0.91). Cumulative incidences of late TLR (both overall and clinically driven) were also significantly higher in the SES group than in the BMS group (12.0% versus 4.1%, P<0.0001 and 8.5% versus 2.6%, P<0.0001, respectively), leading to late catch-up of the SES group to the BMS group regarding TLR through the entire 7-year follow-up (18.8% versus 25.2%, and 10.6% versus 10.2%, respectively). Clinical presentation as acute coronary syndrome was more common at the time of late SES TLR compared with early SES TLR (21.2% and 10.0%). Conclusions—Late catch-up phenomenon regarding stent thrombosis and TLR was significantly more pronounced with SES than that with BMS. This limitation should remain the target for improvements of DES technology.

TISSUE FACTOR PATHWAY INHIBITOR-2 IS A NOVEL MITOGEN FOR VASCULAR SMOOTH MUSCLE CELLS

A mitogen for growth-arrested cultured bovine aortic smooth muscle cells was purified to homogeneity from the supernatant of cultured human umbilical vein endothelial cells by heparin affinity chromatography and reverse-phase high performance liquid chromatography. This mitogen was revealed to be tissue factor pathway inhibitor-2 (TFPI-2), which is a Kunitz-type serine protease inhibitor. TFPI-2 was expressed in baby hamster kidney cells using a mammalian expression vector. Recombinant TFPI-2 (rTFPI-2) stimulated DNA synthesis and cell proliferation in a dose-dependent manner (1–500 nm). rTFPI-2 activated mitogen-activated protein kinase (MAPK) activity and stimulated early proto-oncogene c-fos mRNA expression in smooth muscle cells. MAPK, c-fos expression and the mitogenic activity were inhibited by a specific inhibitor of MAPK kinase, PD098059. Thus, the mitogenic function of rTFPI-2 is considered to be mediated through MAPK pathway. TFPI has been reported to exhibit antiproliferative action after vascular smooth muscle injury in addition to the ability to inhibit activation of the extrinsic coagulation cascade. However, structurally similar TFPI-2 was found to have a mitogenic activity for the smooth muscle cell.

Quantitative coronary angiogram analysis: nifedipine retard versus angiotensin-converting enzyme inhibitors (JMIC-B side arm study).

This study was performed to compare the effects of nifedipine retard and angiotensin-converting enzyme (ACE) inhibitors on the progression of coronary atherosclerosis by means of quantitative coronary angiogram. Coronary angiogram was performed before the start of the study and during the 3-year treatment period. This study was conducted on the assumption that possible coronary vasodilation, which may be caused by nifedipine, was excluded by administration of sufficient isosorbide dinitrate. The changes from the baseline in the minimum lumen diameter of the coronary artery in all measured segments were negligible in the nifedipine group (+0.02±0.27 mm; P=0.543), whereas they were significantly reduced in the ACE inhibitor group (−0.12±0.27 mm; P<0.001), with a significant difference observed between the groups (P=0.002). The number of progressors in the nifedipine group was significantly lower than that in the ACE inhibitor group (P=0.019), and there was also a significant difference between the groups in the number of patients in whom ≥1 lesion developed after treatment (P=0.040). However, the changes of minimum lumen diameter stratified by baseline percent diameter stenosis demonstrated that progression of coronary atherosclerosis was suppressed in the nifedipine group for lesions with a percent diameter stenosis of ≤40 but was suppressed in both groups for those with a percent diameter stenosis of ≥41. This study suggests that nifedipine retard and ACE inhibitors may be effective in suppression of progression of coronary atherosclerosis, and that nifedipine in particular may be effective for mild to moderate stenosis.

Nifedipine retard prevents hospitalization for angina pectoris better than angiotensin-converting enzyme inhibitors in hypertensive Japanese patients with previous myocardial infarction (JMIC-B substudy)

Objectives and background We previously reported that nifedipine retard showed comparable efficacy to angiotensin-converting enzyme (ACE) inhibitors for the prevention of cardiac events in hypertensive patients with coronary artery disease during the Japan Multicenter Investigation for Cardiovascular Diseases B study. In the nifedipine group, patients with a history of myocardial infarction (MI) showed a significant reduction in hospitalization for angina pectoris compared with the ACE inhibitor group. We investigated whether this difference was related to the progression of coronary arteriosclerosis. Methods To evaluate coronary arteriosclerosis, we performed coronary angiography (CAG) and a quantitative analysis of coronary angiograms. Results The cumulative incidence of hospitalization for angina was significantly lower in the nifedipine group (log-rank test P = 0.013). The etiology of angina requiring hospitalization was determined on the basis of CAG findings. Its incidence secondary to the development of new lesions or the progression of existing lesions was significantly lower in the nifedipine group than in the ACE inhibitor group (log-rank test P = 0.042 and P = 0.028, respectively). Using quantitative coronary analysis, changes in the coronary artery luminal diameter were compared between the nifedipine and ACE inhibitor groups. The minimum coronary lumen diameter did not show a significant change in the nifedipine group, whereas it decreased significantly in the ACE inhibitor group (paired t-test P = 0.002), and there was a significant difference between the two groups by analysis of covariance (P = 0.047). Conclusion These results indicate that nifedipine more effectively prevented admission for angina pectoris by inhibiting the progression of coronary artery disease in patients with a history of MI.

Antiplatelet Therapy Discontinuation and the Risk of Serious Cardiovascular Events after Coronary Stenting: Observations from the CREDO-Kyoto Registry Cohort-2

Relation of antiplatelet therapy (APT) discontinuation with the risk of serious cardiovascular events has not been fully addressed yet. This study is aimed to evaluate the risk of ischemic event after APT discontinuation based on long-term APT status of large cohort. In the CREDO-Kyoto Registry Cohort-2 enrolling 15939 consecutive patients undergoing first coronary revascularization, 10470 patients underwent percutaneous coronary intervention either with bare-metal stents (BMS) only (N=5392) or sirolimus-eluting stents (SES) only (N=5078). Proportions of patients taking dual-APT were 67.3% versus 33.4% at 1-year, and 48.7% versus 24.3% at 5-year in the SES and BMS strata, respectively. We evaluated daily APT status (dual-, single- and no-APT) and linked the adverse events to the APT status just 1-day before the events. No-APT as compared with dual- or single-APT was associated with significantly higher risk for stent thrombosis (ST) beyond 1-month after SES implantation (cumulative incidence rates beyond 1-month: 1.23 versus 0.15/0.29, P<0.001/P<0.001), while higher risk of no-APT for ST was evident only until 6-month after BMS implantation (incidence rates between 1- and 6-month: 8.43 versus 0.71/1.20, P<0.001/P<0.001, and cumulative incidence rates beyond 6-month: 0.31 versus 0.11/0.08, P=0.16/P=0.08). No-APT as compared with dual- or single-APT was also associated with significantly higher risk for spontaneous myocardial infarction (MI) and stroke regardless of the types of stents implanted. Single-APT as compared with dual-APT was not associated with higher risk for serious adverse events, except for the marginally higher risk for ST in the SES stratum. In conclusion, discontinuation of both aspirin and thienopyridines was associated with increased risk for serious cardiovascular events including ST, spontaneous MI and stroke beyond 1-month after coronary stenting.