Hiroyuki Mizukami

Serum tenascin-C level is associated with coronary plaque rupture in patients with acute coronary syndrome

Tenascin-C, a large oligometric glycoprotein of the extracellular matrix, increases the expression of matrix metalloproteinases that lead to plaque instability and rupture, resulting in acute coronary syndrome (ACS). We hypothesized that a high serum tenascin-C level is associated with plaque rupture in patients with ACS. Fifty-two consecutive ACS patients who underwent emergency percutaneous coronary intervention (PCI) and, as a control, 66 consecutive patients with stable angina pectoris (SAP) were enrolled in this study. Blood samples were obtained from the ascending aorta just prior to the PCI procedures. After coronary guide-wire crossing, intravascular ultrasonography (IVUS) was performed for assessment of plaque characterization. Based on the IVUS findings, ACS patients were assigned to two groups according to whether there was ruptured plaque (ruptured ACS group) or not (nonruptured ACS group). There were 23 patients in the ruptured group and 29 patients in the nonruptured group. Clinical characteristics and IVUS measurements did not differ between the two groups. Tenascin-C levels were significantly higher in the ruptured ACS group than in the SAP group, whereas there was no significant difference between the nonruptured ACS and SAP groups. Importantly, in the ruptured ACS group, tenascin-C levels were significantly higher than in the nonruptured ACS group (71.9 ± 34.9 vs 50.5 ± 20.5 ng/ml, P < 0.005). Our data demonstrate that tenascin-C level is associated with pathologic conditions in ACS, especially the presence of ruptured plaque.

Long-term clinical outcomes after deferral of percutaneous coronary intervention of intermediate coronary stenoses based on coronary pressure-derived fractional flow reserve.

Coronary pressure-derived fractional flow reserve (FFR) has been used to evaluate functional severity of coronary artery stenoses. The cut-off point of 0.75 was considered to be the indication for percutaneous coronary intervention (PCI). In this study, we examined the prognosis of patients in whom PCI was deferred because the lesion was not significant by FFR (≥0.75). We measured FFR of 44 patients (50 lesions with angiographically intermediate stenoses by pressure wire between 2002 and 2009. Out of 44 patients (50 lesions), functionally non-significant stenoses with FFR≥0.75 were 29 patients (33 lesions) and PCI was deferred. In the remaining 15 patients (17 lesions), FFR was <0.75 and PCI was performed. Patients were followed up for an average period of 53 months with endpoints of major adverse cardiac events (MACE; cardiac death, acute coronary syndrome, PCI, and coronary artery bypass grafting). The rate of MACE was 2/29 (6.9%) in patients with FFR≥0.75 and 2/15 (13.3%) in those with FFR<0.75, and it was not statistically different between the two groups. Since long-term clinical outcomes after deferral of PCI of intermediate coronary stenoses based on FFR were excellent (annual event rate 1.6%/year), FFR is a useful index to judge the indication of PCI and risk-stratify patients for MACE.

Intravascular ultrasound predictors of acute side branch occlusion in coronary artery bifurcation lesions just after single stent crossover.

We aimed to assess the intravascular ultrasound (IVUS) predictors of acute side branch (SB) occlusions just after single stent crossover in percutaneous coronary intervention (PCI) for coronary bifurcation lesions.

Coronary Artery Spasm Related to Thiol Oxidation and Senescence Marker Protein-30 in Aging

BACKGROUND Senescence marker protein-30 (SMP30) decreases with aging, and SMP30 knockout (KO) mice show a short life with increased oxidant stress. AIMS We assessed the effect of oxidant stress with SMP30 deficiency in coronary artery spasm and clarify its underlying mechanisms. RESULTS We measured vascular responses to acetylcholine (ACh) and sodium nitroprusside (SNP) of isolated coronary arteries from SMP30 KO and wild-type (WT) mice. In SMP30 KO mice, ACh-induced vasoconstriction occurred, which was changed to vasodilation by dithiothreitol (DTT), a thiol-reducing agent. However, Nω-nitro-L-arginine-methyl ester, nitric oxide (NO) synthase inhibitor, or tetrahydrobiopterin did not change the ACh response. In isolated coronary arteries of WT mice, ACh-induced vasodilation occurred. Inhibition of glutathione reductase by 1, 3-bis(2-chloroethyl)-1-nitrosourea decreased ACh-induced vasodilation (n=10, p<0.01), which was restored by DTT. To evaluate the thiol oxidation, we measured the fluorescence of monochlorobimane (MCB) in coronary arteries, which covalently labels the total. The fluorescence level to MCB decreased in SMP30 KO mice, but with DTT treatment restored to a level comparable to that of WT mice. The reduced glutathione and total thiol levels were also low in the aorta of SMP30 KO mice compared with those of WT mice. Administration of ACh into the aortic sinus in vivo of SMP30 KO mice induced coronary artery spasm. INNOVATION The thiol redox state is a key regulator of endothelial NO synthase activity, and thiol oxidation was associated with endothelial dysfunction in the SMP30 deficiency model. CONCLUSION These results suggest that chronic thiol oxidation by oxidant stress is a trigger of coronary artery spasm, resulting in impaired endothelium-dependent vasodilation.

ENDOGENOUS CARBON MONOXIDE CONCENTRATION IN BLOOD ELEVATES IN ACUTE CORONARY SYNDROME OF NONSMOKER POPULATION

BACKGROUND Carbon monoxide (CO) was previously only considered as a highly toxic pollutant since it binds to hemoglobin with high affinity. Recently, however, it has been recognized as a signaling molecule with regulatory roles in many physiological and pathophysiological processes within the cardiovascular system. The aim of this study was to clarify the behavior of CO in patients with acute coronary syndrome (ACS). METHODS We assessed 235 patients with suspected ACS, 98 smokers (88 male, 62 ± 14 years) and 137 nonsmokers (77 male, 72 ± 13 years), who had undergone emergent cardiac catheterization and blood sampling for calculation of carboxyhemoglobin (COHb). Patients were categorized into 4 groups: smoking patients with ACS (n=77), smoking patients without ACS (n=21), non-smoking patients with ACS (n=97), and non-smoker patients without ACS (n=40). We investigated whether biomarkers were related to COHb levels. RESULTS LogCOHb was significantly higher in the smoking patients compared to non-smoking patients (0.30 ± 0.12 vs. 0.45 ± 0.18, P < 0.01). Interestingly, among the non-smoking patients, COHb was increased in the ACS patients compared to the non ACS patients (0.31 ± 0.12 vs. 0.25 ± 0.12 P < 0.01). In contrast, among the smoking patients, there was no difference in COHb between the ACS and non-ACS patients (0.45 ± 0.18 vs. 0.44 ± 0.18, n.s.). There were no correlations between COHb and any of the biomarkers. CONCLUSIONS These results suggest that endogenous CO may be useful to assess the risk of cardiovascular stress.

Age-related oxidant stress with senescence marker protein-30 deficiency plays a pivotal role in coronary artery spasm.

ObjectivesWe examined the mechanism of coronary artery spasm related to oxidant stress with aging in senescence marker protein-30 (SMP30)-deficient mice because SMP30 decreases with aging and SMP30 knockout (KO) mice show a short life with increased oxidant stress. MethodsTo examine the effect of SMP30 on coronary artery vasomotor tone, we measured the endothelium-dependent [5-hydroxytryptamine (5-HT)] response of isolated, pressurized coronary arteries from SMP30 KO and wild-type (WT) mice (n=10 each). ResultsIn SMP30 KO mice, 5-HT-induced vasoconstriction occurred, which altered vasodilation with dithiothreitol, a thiol-reducing agent. In WT mice, 5-HT-induced vasodilation occurred. Administration of 5-HT from the aortic sinus induced a coronary artery spasm in SMP30 KO mice, which was prevented by the intravenous administration of Y-27632, rho-kinase inhibitor. The fluorescence level of monochlorobimane in coronary arteries, which covalently labels the reduced total thiols, decreased in SMP30 KO mice, but reverted to a level comparable with that of WT mice on treatment with Y-27632. From these results, SMP30 provides protection against coronary artery spasm. ConclusionChronic oxidant stress associated with aging plays an important role in coronary artery spasm related to thiol oxidation and rho-kinase signaling.

STENTING STRATEGY AND FOLLOW-UP RESULTS OF MULTI-CENTER REGISTRY IN FUKUSHIMA CITY FOR LEFT MAIN CORONARY ARTERY DISEASE: BARE METAL STENT VERSUS DRUG-ELUTING STENT

An appropriate treatment strategy for left main trunk (LMT) lesions is still controversial in the drug-eluting stent (DES) era. Consecutive LMT stenting cases (n = 155) between January 2008 and January 2013 in 4 hospitals in Fukushima city were retrospectively analyzed. We excluded the patients suffering from cardiogenic shock before the stenting procedure. Among those cases, 60 patients had acute coronary syndrome, and remaining 95 had stable angina pectoris. Out of 155 cases, 45 patients were treated with bare metal stents (BMSs) and 110 patients were treated with DESs. All cases were succeeded in the initial procedure. Mean stent size of BMS was 3.85 ± 0.34 mm while that of DES was 3.46 ± 0.17 mm (P<0.001). At the follow up coronary angiography (255-day on average), % stenosis of BMS group was 26.6 ± 15.0% and that of DES group was 20.4 ± 12.6% (P = 0.006). The mean observation period for clinical events was 738.8 ± 480.3 days. Major adverse cardiac events-free rates for each group were compared and no significant differences were evident between the 2 groups (11.1% vs. 19.1%, ns). The present study demonstrated that use of BMSs would be a viable option in the treatment of LMT lesions when it is possible to use a large-sized stent (>3.5 mm).

ELEVATED SOLUBLE LECTIN-LIKE OXIDIZED LDL RECEPTOR-1 (LOX-1) IN CORONARY CIRCULATION OF PATIENTS WITH ACUTE CORONARY SYNDROME

Results: Soluble LOX-1 levels in Ao and CS were signiicantly higher in ACS than in EAP (P<0.0001, each). We found the positive correlation between Ao and CS LOX-1 values in ACS (R=0.676, P<0.0001), but not in EAP, suggesting that elevated LOX-1 was derived from coronary cir culation. The LOX1 values increased earlier after the onset compared to other markers for ACS such as CK-MB and troponin I. Correlations between LOX-1 and CK-MB, troponin I or CRP were not observed in ACS. Conclusions: This study showed that soluble LOX-1 levels in coronary circulation were elevated in ACS, suggesting that soluble LOX-1 is a speciic biomarker of vulnerable plaque in ACS.