Kenichi Ishigami

Thin-cap fibroatheroma and microchannel findings in optical coherence tomography correlate with subsequent progression of coronary atheromatous plaques.

AIMS Morphological characteristics of non-significant coronary plaques (NSCPs) that develop rapid progression have not been fully elucidated. The aim of this study was to clarify the morphological characteristics of NSCPs in patients with coronary artery disease (CAD) using intravascular optical coherence tomography (OCT). METHODS AND RESULTS Fifty-three consecutive CAD patients undergoing percutaneous coronary intervention were enrolled and 69 NSCPs (per cent diameter stenosis <50%) were identified on baseline angiogram. Baseline characteristics of NSCPs were evaluated by OCT, and patients were followed-up prospectively. At the second coronary angiography, the baseline OCT characteristics and plaque progression were correlated. During the 7-month follow-up period, 13 NSCPs showed angiographic progression and 56 NSCPs did not. Baseline minimum lumen diameter and diametric stenosis were similar between NSCPs with and without progression. Compared with NSCPs without progression, those with progression showed a significantly higher incidence of intimal laceration (61.5 vs. 8.9%, P < 0.01), microchannel (76.9 vs. 14.3%, P < 0.01), lipid pools (100 vs. 60.7%, P = 0.02), thin-cap fibroatheroma (TCFA) (76.9 vs. 14.3%, P < 0.01), macrophage images (61.5 vs. 14.3%, P < 0.01), and intraluminal thrombi (30.8 vs. 1.8%, P < 0.01). Univariate regression analysis showed that TCFA and microchannel images showed high correlation with subsequent luminal progression [odds ratio (OR): 20.0, P < 0.01 and OR: 20.0, P < 0.01, respectively]. CONCLUSION Optical coherence tomography-based complex characteristics of TCFA and microchannel were the potential predictors of subsequent progression of NSCPs in patients with CAD.

Long-term follow-up of neointimal coverage of sirolimus-eluting stents--evaluation with optical coherence tomography.

BACKGROUND Late stent thrombosis related to delayed neointimal growth is a major concern after drug-eluting stent (DES) implantation. The time course of neointimal growth and risk factors of uncovered stent struts after sirolimus-eluting stent (SES) was studied using optical coherence tomography (OCT). METHODS AND RESULTS The 60 patients were enrolled and classified into G1 (follow-up period <9 months, n=27), G2 (9-24 months, n=18), and G3 (>25 months, n=15). The time elapsed since SES implantation was associated with a significant increase in mean neointimal area and neointimal thickness, and also with a significant decrease in the number of uncovered stent struts (G1: 14.8%, G2: 11.7%, and G3: 4.1%, P<0.001). However, only 17.6% of implanted SES was completely covered by neointima, even in the G3 period. Small-diameter SES, complex coronary lesions with lipid and calcium content adjacent to stent struts, and diabetes predicted delayed neointimal coverage of SES struts in G1. CONCLUSIONS Neointima inside SES progressively increases after the routine follow-up period, but only a few SES were completely covered at 3 years after implantation. OCT is a useful modality for assessing neointimal formation after SES implantation, and may give important information about the strategy of antiplatelet therapy after DES implantation.

Usefulness of soluble Fms-like tyrosine kinase-1 as a biomarker of acute severe heart failure in patients with acute myocardial infarction.

Placental growth factor and vascular endothelial growth factor increase angiogenesis and promote healing after acute myocardial infarction (MI), but the significance of soluble Fms-like tyrosine kinase-1 (sFlt-1), an antagonist of placental growth factor and vascular endothelial growth factor, in the setting of acute MI has not been elucidated. The development of acute heart failure in the immediate period after MI is a dreaded complication, but there are no useful biomarkers that identify patients at risk of acute heart failure. We wished to investigate the clinical significance of circulating sFlt-1 during acute MI. We enrolled 174 patients with acute MI, and arterial blood sampling was performed. Plasma levels of sFlt-1 were measured by enzyme-linked immunosorbent assay and their relation to clinical parameters was analyzed. Circulating levels of sFlt-1 on admission were significantly increased in patients with acute MI compared to controls (528.1 +/- 290.9 vs 355.7 +/- 205.0 pg/ml, p <0.001). Circulating levels of sFlt-1 on admission were significantly higher in patients who developed severe acute heart failure requiring mechanical circulatory support devices compared to those with stable hemodynamics (611.4 +/- 373.6 vs 494.6 +/- 243.9 pg/ml, p = 0.016). Moreover, circulating levels of sFlt-1 on admission were directly related to duration of hospitalization. Multivariate logistic analysis showed that hemodynamic instability was predicted by sFlt-1 on admission and left ventricular systolic pressure. In conclusion, the circulating level of sFlt-1 is increased in patients with acute MI, and the sFlt-1 level on admission is a promising biomarker for the development of severe acute heart failure after MI.

Reduction of Circulating Soluble Fms-Like Tyrosine Kinase-1 Plays a Significant Role in Renal Dysfunction–Associated Aggravation of Atherosclerosis

Background— Renal dysfunction is commonly accompanied by a worsening of atherosclerosis; however, the underlying molecular mechanism is not fully understood. We examined the role played by soluble fms-like tyrosine kinase-1 (sFlt-1), an endogenous antagonist of the proatherogenic cytokine placental growth factor (PlGF), in the worsening of atherosclerosis in patients with renal dysfunction and in an animal model of renal failure. Methods and Results— In this study, 329 patients who received cardiac catheterization and 76 patients who underwent renal biopsy were enrolled. Both plasma sFlt-1 levels and renal sFlt-1 mRNA expression were positively correlated with estimated glomerular filtration rate (P<0.01). The PlGF/sFlt-1 ratio was negatively correlated with estimated glomerular filtration rate (P<0.01), whereas plasma PlGF levels were not affected by it. The PlGF/sFlt-1 ratio was significantly higher in patients with multivessel coronary artery disease than in patients with single-vessel or no coronary artery disease. The reduction of circulating sFlt-1 and renal sFlt-1 mRNA levels was confirmed in five-sixths (5/6)–nephrectomized apolipoprotein E–deficient mice that developed experimental renal dysfunction. Atherosclerotic plaque area and macrophage infiltration into the plaque were significantly higher in 5/6–nephrectomized apolipoprotein E–deficient mice than in control mice, but replacement therapy with recombinant sFlt-1 significantly reduced both plaque formation and macrophage infiltration. Conclusions— The present study demonstrates that a reduction in the circulating levels of sFlt-1 is associated with the worsening of atherosclerosis that accompanies renal dysfunction.

Morphological features of coronary arteries in patients with coronary spastic angina: Assessment with intracoronary optical coherence tomography

BACKGROUND Coronary spasm (CS) plays an important role in the pathogenesis of many types of ischemic heart disease, but morphological appearance of non-stenotic coronary segments with CS is not fully understood. We evaluate the morphological characteristics of coronary arteries in patients with coronary spastic angina (CSA) using intravascular optical coherence tomography (OCT). METHODS We evaluated 37 patients with resting chest pain whose coronary angiograms did not reveal significant stenosis. These patients underwent an acetylcholine (ACh) provocation test. OCT was performed after complete dilatation of coronary arteries, and additionally during ACh-induced CS in four patients. RESULTS Based on the ACh test, 23 patients were diagnosed as having CSA, and the remaining 14 patients without CS were referred to as CS-negative. OCT study revealed that coronary segments with ACh-induced CS had homogeneous intimal thickening, and quantitative analysis showed that CS-positive segments had a significantly greater intima area as compared with corresponding CS-negative segments without lipid or calcium content. By contrast, CS-positive segments had a significantly smaller intima area as compared with CS-negative segments with lipid or calcium deposit. During ACh-induced CS, lumen and total vascular areas were significantly decreased, whereas intima area did not change in comparison with complete vasodilatation. The luminal surface of the intima formed a markedly wavy configuration during CS. CONCLUSIONS Coronary artery segments involved in CS are characterized by diffuse intimal thickening without lipid or calcium content. High-resolution coronary OCT imaging could make it possible to analyze the vascular pathophysiology in patients with CS.

Diagnostic accuracy of dual-source computed tomography in the characterization of coronary atherosclerotic plaques: Comparison with intravascular optical coherence tomography

BACKGROUND Dual-source computed tomography (DSCT) has enabled us to non-invasively visualize coronary artery stenosis, but its ability to characterize coronary atherosclerotic plaques (ASPs) has not been evaluated. Intravascular optical coherence tomography (OCT) provides tissue images of coronary artery wall that are validated by pathohistological studies. We studied the diagnostic accuracy of DSCT in the characterization of coronary ASPs, especially lipid-rich ASP with thin fibrous cap (TCFA), in comparison with OCT. METHODS DSCT and OCT were used to image non-stenotic ASPs in non-culprit coronary arteries of 17 acute coronary syndrome (ACS) patients, and 162 coronary regions were enrolled. RESULTS The mean CT values of fibrous ASP, ASP with lipid core, and ASP with calcium deposit were 77.5, 28.9, and 515.9 HU, respectively (P<0.0001). ASP with calcium deposit was detected with a sensitivity of 88.9% and a specificity of 98.6%, while ASP with lipid core was detected by DSCT with a relatively low sensitivity of 73.1% and a high specificity of 94.0%. In TCFA, cross-sectional areas of both ASP and lipid core were significantly larger, mean CT value of ASP was significantly lower, and concomitant calcification was more frequently observed compared with lipid-rich ASP with thick fibrous cap (ThCFA). The combination of these CT parameters seems to be a useful index for the differentiation of TCFA from ThCFA. CONCLUSION DSCT is useful for non-invasive evaluation of calcified and fibro-fatty tissue characters in coronary artery plaque, but it is still not able to differentiate TCFA, one of the features of vulnerable plaque.

A New Drug Delivery System for Intravenous Coronary Thrombolysis With Thrombus Targeting and Stealth Activity Recoverable by Ultrasound

OBJECTIVES The purpose of this study was to develop a new intelligent drug delivery system for intracoronary thrombolysis with a strong thrombolytic effect without increasing bleeding risk. BACKGROUND Rapid recanalization of an occluded coronary artery is essential for better outcomes in acute myocardial infarction. Catheter-based recanalization is widely accepted, but it takes time to transport patients. Although the current fibrinolytic therapy can be started quickly, it cannot achieve a high reperfusion rate. Recently, we generated nanoparticles comprising tissue-type plasminogen activator (tPA), basic gelatin, and zinc ions, which suppress tPA activity by 50% with 100% recovery by ultrasound (US) in vitro. METHODS The thrombus-targeting property of nanoparticles was examined by an in vitro binding assay with von Wilbrand factor and with a mouse arterial thrombosis model in vivo. The thrombolytic efficacy of nanoparticles was evaluated with a swine acute myocardial infarction model. RESULTS Nanoparticles bound to von Wilbrand factor in vitro and preferentially accumulated at the site of thrombus in a mouse model. In a swine acute myocardial infarction model, plasma tPA activity after intravenous injection of nanoparticles was approximately 25% of tPA alone and was recovered completely by transthoracic US (1.0 MHz, 1.0 W/cm(2)). During US application, plasma tPA activity near the affected coronary artery was recovered and was higher than that near the femoral artery. Although treatment with tPA alone (55,000 IU/kg) recanalized the occluded coronary artery in only 1 of 10 swine, nanoparticles containing the same dose of tPA with US achieved recanalization in 9 of 10 swine within 30 min. CONCLUSIONS We developed an intelligent drug delivery system with promising potential for better intravenous coronary thrombolysis.

Clinical significance of papillary muscle late enhancement detected via cardiac magnetic resonance imaging in patients with single old myocardial infarction

BACKGROUND Contrast-enhanced cardiac magnetic resonance imaging (MRI) can depict papillary muscle (PM) necrosis or fibrosis by late enhancement (LE) of PM, but its clinical significance in old myocardial infarction (OMI) has been little understood. METHODS Myocardial LE and PM-LE were detected with contrast imaging in 60 patients with OMI caused by a single culprit coronary artery lesion. Left ventricular (LV) morphology and function, mitral valve geometry, and severity of mitral regurgitation were also evaluated by cine imaging. Sphericity index was calculated for the assessment of LV remodeling. RESULTS PM-LE was detected in 32 of 60 (53.3%) OMI patients. Unilateral PM-LE was detected in 22 patients and bilateral PM-LE in 10 patients. Patients with bilateral PM-LE demonstrated more severe LV remodeling and functional mitral regurgitation than those with unilateral or no PM-LE (sphericity index; bilateral PM-LE, 1.60±0.15, unilateral PM-LE, 1.71±0.29, no PM-LE, 1.85±0.27, p≤0.05) (mitral regurgitation; bilateral PM-LE, 1.10±0.57, unilateral PM-LE, 0.41±0.73, no PM-LE, 0.54±0.84, p≤0.05). In cases of unilateral PM-LE, posteromedial PM-LE resulting from right coronary artery-related OMI was accompanied by less severe mitral regurgitation, while anterolateral PM-LE resulting from left coronary artery-related OMI was not associated with severity of mitral regurgitation. CONCLUSIONS More than half of patients with OMI showed unilateral or bilateral PM-LE, and bilateral PM-LE was closely related to more severe LV remodeling and functional mitral regurgitation.

Prognostic value of B-type natriuretic peptide and its amino-terminal proBNP fragment for cardiovascular events with stratification by renal function.

BACKGROUND Brain natriuretic peptide (BNP) and amino-terminal proBNP (NT-proBNP) are useful biomarkers for diagnosis and prediction of prognosis. Both of these peptides are elevated in patients with chronic kidney disease (CKD), but there is no evidence as to which peptide is the more suitable biomarker in patients with severe renal dysfunction. METHODS AND RESULTS This retrospective cohort study evaluated patients with cardiovascular diseases (64.9±11.7 years, mean±SD). The end points were all-cause death and a composite end point of all-cause death, nonfatal myocardial infarction, nonfatal stroke, hospitalization for severe heart failure, and initiation of hemodialysis. Baseline plasma BNP and NT-proBNP levels, expressed as log-transformed data, were closely correlated in patients with CKD stages 1-3 (n=998) (r2=0.870, p<0.001), whereas for CKD stages 4-5 (n=85) there was a significant but weaker correlation (r2=0.209, p<0.001). During follow-up periods (51.3±0.4 months), 132 patients died and 202 patients reached the composite end point. The area under the receiver operating characteristic curve (AUROC) for BNP and NT-proBNP were similar for CKD stages 1-3. However, for CKD stages 4-5, the AUC for mortality for BNP was 0.713 and that for NT-proBNP was 0.760, while the AUC for the composite end point for BNP was 0.666 and that for NT-proBNP was 0.720. CONCLUSIONS Both BNP and NT-proBNP are useful biomarkers for mortality and cardiovascular events, but NT-proBNP may be superior to BNP for CKD stages 4-5.

Proteinuria and Reduced Estimated Glomerular Filtration Rate Are Independent Risk Factors for Contrast-Induced Nephropathy After Cardiac Catheterization

BACKGROUND The aim of this study was to investigate the incidence of contrast-induced nephropathy (CIN) according to renal function in patients with or without proteinuria after cardiac catheterization in Japan. METHODS AND RESULTS: We conducted a multicenter prospective observational study involving 27 hospitals from all over Japan, which enrolled 906 patients with cardiac catheterization. CIN was defined as increase in serum creatinine ≥0.5 mg/dl or ≥25% from baseline between 48 and 72 h after exposure to contrast. The incidence of CIN in patients with estimated glomerular filtration rate (eGFR) <30 ml/min/1.73 m2was significantly higher than that in patients with eGFR ≥60 ml/min/1.73 m2. In patients without proteinuria, the incidence of CIN did not increase as eGFR decreased, but such a trend was observed in patients with proteinuria. Proteinuria was highly significantly associated with CIN in patients with eGFR 30-44 ml/min/1.73 m2(OR, 12.1; 95% CI: 2.81-82.8; P=0.0006) and eGFR <30 ml/min/1.73 m2(OR, 17.4; 95% CI: 3.32-321; P=0.0001). On multivariate logistic regression analysis, proteinuria (OR, 4.09; 95% CI: 1.66-10.0), eGFR (OR, 1.02; 95% CI: 1.00-1.04), contrast volume/eGFR (OR, 1.31; 95% CI: 1.04-1.65), and Ca antagonist use (OR, 3.79; 95% CI: 1.52-10.8) were significant predictors of CIN. CONCLUSIONS Proteinuria and reduced eGFR are independent risk factors for CIN after cardiac catheterization.