Keiichi Hishikari

In vivo critical fibrous cap thickness for rupture-prone coronary plaques assessed by optical coherence tomography

AIMS The widely accepted threshold of <65 μm for coronary plaque fibrous cap thickness was derived from postmortem studies of ruptured plaques and may not be appropriate for in vivo rupture-prone plaques. We investigated the relationship between fibrous cap thickness and plaque rupture using optical coherence tomography (OCT). METHODS AND RESULTS We studied 266 lesions (103 from patients with acute coronary syndrome and 163 from patients with stable angina) before percutaneous coronary intervention using OCT. Ruptured and non-ruptured lipid-rich plaques were identified and the thinnest and most representative fibrous cap thickness were determined. Cap thickness was reliably measured in 71 ruptured and 111 non-ruptured plaques. From the ruptured plaques, the median thinnest cap thickness was 54 μm (50-60). The median most representative cap thickness was 116 μm (103-136). For non-ruptured plaques, the median thinnest cap thickness was 80 μm (67-104) and 182 μm (156-216) for most representative cap thickness. In 95% of ruptured plaques, the thinnest cap thickness and most representative cap thickness were <80 and <188 μm, respectively. The best cut-offs for predicting rupture were <67 μm (OR: 16.1, CI: 7.5-34.4, P < 0.001) for the thinnest cap thickness and <151 μm (OR: 35.6, CI: 15.0-84.3, P < 0.001) for most representative cap thickness. These two measures were modestly correlated (r(2) = 0.39) and both independently associated with rupture. CONCLUSION In vivo critical cap thicknesses were <80 μm for the thinnest and <188 μm for most representative fibrous cap thickness. Prospective imaging studies are required to establish the significance of these values.

Impact of Coronary Plaque Morphology Assessed by Optical Coherence Tomography on Cardiac Troponin Elevation in Patients With Elective Stent Implantation

Background—Mild elevations of cardiac troponin frequently occur after percutaneous coronary intervention (PCI), and patients with elevated post-PCI biomarkers have a worse prognosis. We used optical coherence tomography (OCT) to study the relationship between pre-PCI plaque morphology and post-PCI cardiac troponin I elevations. Methods and Results—One hundred thirty-one patients with normal pre-PCI cardiac troponin I levels underwent OCT before nonemergency stent implantation. Clinical and OCT findings were compared between patients with (n=31, 23.7%) and without (n=100, 76.3%) post-PCI cardiac troponin I of >3×upper reference limit (post-PCI myocardial infarction [MI]). After PCI, long-term follow-up data were collected. Post-PCI MI was associated with angiographic lesion length, type B2/C lesions, presence of thin-cap fibroatheroma, and fibrous cap thickness. In multivariable analysis, presence of thin-cap fibroatheroma (odds ratio, 10.47; 95% confidence interval, 3.74 to 29.28; P<0.001) and type B2/C lesions (odds ratio, 3.74; 95% confidence interval, 1.41 to 9.92; P=0.008) were predictors of post-PCI MI. At a median follow-up of 12 months, cardiac event-free survival was significantly worse in patients with post-PCI MI (log-rank test &khgr;2=8.9; P=0.003). Cox proportional hazards analysis showed that post-PCI MI (hazard ratio, 3.67; 95% confidence interval, 1.39 to 9.65; P=0.009) and ejection fraction (hazard ratio, 0.96; 95% confidence interval, 0.92 to 0.99; P=0.029) were independent predictors of adverse cardiovascular events during follow-up. Conclusions—Type B2/C lesions and the presence of OCT-defined thin-cap fibroatheroma can predict post-PCI MI in patients treated with elective stent implantation, who may require adjunctive therapy after otherwise successful PCI.

Pharmacological activation of the prostaglandin E2 receptor EP4 improves cardiac function after myocardial ischaemia/reperfusion injury

AIMS Increased expression of several subtypes of prostaglandin E(2) receptors (EP1-4) has recently been described in clinical and experimental myocardial ischaemia/reperfusion (I/R) injury. However, their pathophysiological significance in I/R remains obscure. Thus, we determined whether the activation of the prostanoid receptor, EP4, suppresses myocardial I/R injury. METHODS AND RESULTS To analyse the role of EP4, we administered an EP4 selective agonist (EP4RAG, 1 or 3 mg/kg) or vehicle to rats with myocardial I/R injury. After 7 days of reperfusion, I/R rats exhibited left ventricular (LV) dilatation and contractile dysfunction with myocyte hypertrophy and interstitial fibrosis. EP4RAG significantly reduced infarction area/ischaemic myocardium (72.4 +/- 0.7 vs. 23.3 +/- 0.6%; P < 0.05) and improved LV contraction and dilatation compared with that of the vehicle. EP4RAG also attenuated the recruitment of inflammatory cells, especially macrophages, and interstitial fibrosis in hearts. Monocyte chemoattractant protein (MCP)-1 and other cytokines were increased in both non-ischaemic (area not at risk, ANAR) and ischaemic (area at risk, AAR) myocardium; however, western blot analysis and RNase protection assay showed that EP4RAG suppressed these changes. Gelatin zymography revealed EP4RAG significantly reduced matrix metalloproteinase-2 and -9 activities in both ANAR and AAR. Chemoattractant assay demonstrated that EP4RAG suppressed the migration of cytokine-stimulated macrophages and decreased the level of MCP-1 production in the supernatant (587.3 +/- 55.3 vs. 171.5 +/- 47.5 pg/mL; P < 0.05). CONCLUSION The data suggest that the EP4 agonist is effective for attenuation of I/R injury by suppressing MCP-1 and the infiltration of inflammatory cells, especially macrophages.

Clarithromycin Attenuates Acute and Chronic Rejection Via Matrix Metalloproteinase Suppression in Murine Cardiac Transplantation

OBJECTIVES Clarithromycin (CAM), a major macrolide antibiotic, has many biological functions, including matrix metalloproteinases (MMPs) regulation. However, little is known about the effect of CAM in heart transplantation via MMP-9. The purpose of this study was to clarify the role of MMPs regulated by CAM in the progression of rejection. BACKGROUND The MMPs are critical in the development of inflammation and tissue remodeling. The MMP-9 level is associated with the rejection of heart transplantation. METHODS We orally administered CAM into murine cardiac allograft recipients. Total allomismatch combination and class II mismatch combination were used for the analysis of graft survival, pathology and molecular. RESULTS Clarithromycin improved acute rejection judged by graft survival and by myocardial cell infiltrating area in a total allomismatch combination. The CAM-treated allografts showed affected expression of T-cells, macrophages, and MMP-9 in immunohistochemistry. Zymography indicated that enhanced MMPs activities were observed in nontreated hearts, whereas CAM suppressed the levels. In chronic rejection, CAM suppressed the development of graft arterial disease and myocardial remodeling compared with that of nontreatment. Clarithromycin inhibited the expression of MMP-9, whereas the treatment did not alter the expression of MMP-2 and tissue inhibitor metalloproteinase-1 in macrophages and smooth muscle cells. Inhibition of MMP-9 by CAM was associated with suppression of smooth muscle cell migration and proliferation. CONCLUSIONS Clarithromycin is useful to suppress allograft remodeling, because it is critically involved in the prevention of cardiac rejection through the suppression of MMP-9.

Early treatment with clarithromycin attenuates rat autoimmune myocarditis via inhibition of matrix metalloproteinase activity

Background Matrix metalloproteinase (MMP) activity is upregulated in the hearts with myocarditis, and its activation contributes to the changes in left ventricular function. A major macrolide antibiotic, clarithromycin (CAM), has many biological functions including MMP regulation. However, little is known about the effect of CAM in myocarditis via MMPs. Objective To clarify the role of MMPs regulated by CAM in the progression of myocarditis. Design CAM was given to experimental rats with autoimmune myocarditis (EAM) from day –7 to day 21 (early treated group, n=6) or from day 1 to day 21 (late treated group, n=6) twice a day. Results Although the non-treated rats showed blood pressure decline and impaired cardiac function, early CAM treatment prevented this progression. Pathologically, severe myocardial cell infiltration (30.5±4.2%) and fibrosis (32.2±1.1%) were detected in the non-treated group, while early CAM treatment significantly suppressed these changes (infiltration 6.5±0.2%, fibrosis 5.9±3.9%). Zymography showed that non-treated EAM resulted in enhanced ventricular activities of MMP-9, while early CAM treatment reduced the alteration. However, late CAM treatment was less effective than the early treatment. Conclusions Early CAM treatment is effective to attenuate myocarditis by suppressing MMP-9.

Quantitative assessment of tissue prolapse on optical coherence tomography and its relation to underlying plaque morphologies and clinical outcome in patients with elective stent implantation.

BACKGROUND Tissue prolapse (TP) is sometimes observed after percutaneous coronary intervention (PCI), but its clinical significance remains unclear. We investigated the relationship between TP volume on optical coherence tomography (OCT) after PCI and underlying plaque morphologies and the impact of TP on clinical outcomes. METHODS We investigated 178 native coronary lesions with normal pre-PCI creatine kinase-myocardial band (CK-MB) values (154 lesions with stable angina; 24 with unstable angina). TP was defined as tissue extrusion from stent struts throughout the stented segments. All lesions were divided into tertiles according to TP volume. The differences in plaque morphologies and 9-month clinical outcomes were evaluated. RESULTS TP volume was correlated with lipid arc (r=0.374, p<0.0001) and fibrous cap thickness (r=-0.254, p=0.001) at the culprit sites. The frequency of thin-cap fibroatheroma (TCFA) was higher in the largest TP tertile (≥ 1.38 mm(3)) (p=0.015). In multivariate analysis, right coronary artery lesion (odds ratio [OR]: 2.779; p=0.005), lesion length (OR: 1.047; p=0.003), and TCFA (OR: 2.430; p=0.022) were related to the largest TP tertile. Lesions with post-PCI CK-MB elevation (>upper reference limit) had larger TP volume than those without (1.28 [0.48 to 3.97] vs. 0.70 [0.16 to 1.64] mm(3), p=0.007). The prevalence of cardiac events during the 9-month follow-up was not significantly different according to TP volume. CONCLUSIONS TP volume on OCT was related to plaque morphologies and instability, and post-PCI myocardial injury, but not to worse 9-month outcomes.

Association of Intravascular Ultrasound- and Optical Coherence Tomography-Assessed Coronary Plaque Morphology With Periprocedural Myocardial Injury in Patients With Stable Angina Pectoris

BACKGROUND Periprocedural myocardial injury (PMI) is not an uncommon complication and is related to adverse cardiac events after percutaneous coronary intervention (PCI). We investigated the predictors of PMI in patients with stable angina pectoris (SAP) on intravascular imaging. METHODSANDRESULTS We enrolled 193 SAP patients who underwent pre-PCI intravascular ultrasound (IVUS) and optical coherence tomography (OCT). Clinical characteristics, lesion morphology, and long-term follow-up data were compared between patients with and without PMI, defined as post-PCI elevation of high-sensitivity cardiac troponin-T. PMI were observed in 79 patients (40.9%). Estimated glomerular filtration rate (odds ratio [OR], 0.973; 95% confidence interval [CI]: 0.950-0.996; P=0.020), ≥2 stents (OR, 3.100; 95% CI: 1.334-7.205; P=0.009), final myocardial blush grade 0-2 (OR, 4.077; 95% CI: 1.295-12.839; P=0.016), and IVUS-identified echo-attenuated plaque (EA; OR, 3.623; 95% CI: 1.700-7.721; P<0.001) and OCT-derived thin-cap fibroatheroma (OCT-TCFA; OR, 3.406; 95% CI: 1.307-8.872; P=0.012) were independent predictors of PMI on multivariate logistic regression analysis. A combination of EA and OCT-TCFA had an 82.4% positive predictive value for PMI. On Cox proportional hazards analysis, PMI was an independent predictor of adverse cardiac events during 1-year follow-up (hazard ratio, 2.984; 95% CI: 1.209-7.361; P=0.018). CONCLUSIONS Plaque morphology assessment using pre-PCI IVUS and OCT may be useful for predicting PMI in SAP patients.

Relationship Between Subclinical Cardiac Troponin I Elevation and Culprit Lesion Characteristics Assessed by Optical Coherence Tomography in Patients Undergoing Elective Percutaneous Coronary Intervention

Background—The prevalence of subclinical, cardiac troponin I (cTnI) elevation in stable patients undergoing elective percutaneous coronary intervention and its relationship to culprit lesion characteristics assessed by optical coherence tomography (OCT) are unknown. Methods and Results—We studied 206 native de novo culprit coronary lesions from 206 patients with stable angina pectoris who underwent OCT before elective percutaneous coronary intervention. Patients were divided into 2 groups according to the presence (cTnI group; n=47; 22.8%) or absence (non-cTnI group; n=159; 77.2%) of cTnI ≥0.03 ng/mL at admission. The clinical and OCT findings were compared between these 2 groups. No significant difference was found in the clinical presentation between the groups except for the serum C-reactive protein levels and presence of multivessel disease. By OCT, cTnI elevation was associated with the presence of thin-cap fibroatheromas, a greater lipid arc, and a longer lipid length. In a multivariable analysis, the presence of positive C-reactive protein levels (odds ratio, 4.38; 95% confidence interval, 1.90–10.08; P=0.001) and OCT-derived thin-cap fibroatheromas (odds ratio, 2.89; 95% confidence interval, 1.22–6.86; P=0.016) were independent predictors of cTnI elevation. Periprocedural myocardial injury, defined as postpercutaneous coronary intervention peak cTnI levels >1.0 ng/mL (5× the upper reference limit), occurred more often in patients with cTnI elevation at admission (cTnI group: 41% versus non-cTnI group: 18%; P=0.001). Conclusions—The presence of subclinical cTnI elevation at admission was not uncommon and was associated with OCT-derived unstable plaque morphology in patients undergoing elective percutaneous coronary intervention, and may help to identify patients with stable angina pectoris at high risk for periprocedural myocardial injury.

Severe coronary artery spasm during radiofrequency ablation for atrial fibrillation

☆ This is an open-access article distributed under the t Attribution–NonCommercial–No Derivative Works License, use, distribution, and reproduction in any medium, provide are credited. ☆☆ Author contributions: Data collection: Taishi Ku interpretation: Atsushi Takahashi M.D., Mitsuaki Isobe* ⁎ Corresponding author at: Cardiovascular Center, Yo Yonegahama-dori, Yokosuka, Kanagawa, Japan. Tel.: +81 2103. E-mail address: hishikari_86@yahoo.co.jp (K. Hishika

Different roles of PPAR-γ activity on physiological and pathological alteration after myocardial ischemia.

Background: Telmisartan is an angiotensin II receptor blocker, which acts as a partial agonist of peroxisome proliferator activator receptor-&ggr; (PPAR-&ggr;). Because PPAR-&ggr; initiates a variety of antiinflammatory responses, the effect on myocardial ischemia is to be elucidated. Methods and Results: The left anterior descending arteries were ligated to induce myocardial infarction in rats. The animals were assigned to 4 groups: (1) control (saline, n = 6), (2) telmisartan (10 mg·kg−1·d−1, n = 6), (3) telmisartan + GW9662 (PPAR-&ggr;-antagonist) (10 mg·kg−1·d−1 of telmisartan and 1 mg·kg−1·d−1 of GW9662, n = 6), and (4) amlodipine (10 mg·kg−1·d−1, n = 8) groups. Telmisartan reduced mean blood pressure compared with that in the control group. There was no statistical difference among the telmisartan, telmisartan + GW9662 and amlodipine groups. The end-diastolic left ventricular diameter was smaller in telmisartan group compared with that in the control group; GW9662 negated the effect of telmisartan. The thickness of the ventricular septum was kept in the telmisartan group compared with that in the control group; GW9662 negated the effect. Histopathologic analyses showed that telmisartan suppressed myocardial fibrosis compared with that of the control, whereas GW9662 negated the telmisartan effect. Conclusions: Telmisartan suppresses pathological remodeling by PPAR-&ggr; agonistic activities independent of its antihypertensive effects.