Association between abnormal myocardial fatty acid metabolism and cardiac-derived death among patients undergoing hemodialysis: results from a cohort study in Japan.

BACKGROUND: Detecting myocardial ischemia in hemodialysis patients is crucial given the high incidence of silent ischemia and the high cardiovascular mortality rates. Abnormal myocardial fatty acid metabolism as determined by imaging with (123)I-labeled BMIPP (ß-methyl iodophenyl-pentadecanoic acid) might be associated with cardiac-derived death in hemodialysis patients. STUDY DESIGN: Prospective observational study. SETTING & PARTICIPANTS: Asymptomatic hemodialysis patients with one or more cardiovascular risk factors, but without known coronary artery disease, were followed up for 3 years at 48 Japanese hospitals (406 men, 271 women; mean age, 64 years). PREDICTOR: Baseline BMIPP summed scores semiquantified using a 17-segment 5-point system (normal, 0; absent, 4). OUTCOMES: Cardiac-derived death, including cardiac and sudden death. MEASUREMENTS: HRs were estimated using a Cox model for associations between BMIPP summed scores and cardiac-derived death, adjusting for potential confounders of age, sex, body mass index, dialysis duration, and cardiovascular risk factors. RESULTS: Rates of all-cause mortality and cardiac-derived death were 18.5% and 6.8%, respectively. Cardiac-derived death (acute myocardial infarction [n = 10], congestive heart failure [n = 13], arrhythmia [n = 2], valvular heart disease [n = 1], and sudden death [n = 20]) accounted for 36.8% of all-cause deaths. Cardiac-derived death (n = 46) was associated with age, history of heart failure, and BMIPP summed scores of 4 or higher (HR, 2.9; P < 0.001). Three-year cardiac-derived death-free survival rates were 95.7%, 90.6%, and 78.8% when BMIPP summed scores were 3 or lower, 4-8, and 9 or higher, respectively. BMIPP summed score also was a predictor of all-cause death (HR, 1.6; P = 0.009). LIMITATIONS: Sudden death of unknown cause was considered to have been cardiac derived, although a coronary origin was not confirmed. CONCLUSIONS: Abnormal myocardial fatty acid metabolism is associated with cardiac-derived death in hemodialysis patients. BMIPP single-proton emission computed tomography appears clinically useful for predicting cardiac-derived death in this population.

Erythrocyte-rich thrombus aspirated from patients with ST-elevation myocardial infarction: association with oxidative stress and its impact on myocardial reperfusion.

AIMS: Recent studies have demonstrated that erythrocytes are a potential component in atheromatous lesions and thrombus formation in patients with ST-elevation myocardial infarction (STEMI). The purpose of this study was to determine the associations of red blood cell (RBC) component of coronary thrombi with oxidative stress and myocardial reperfusion. METHODS AND RESULTS: Aspirated thrombi from 178 STEMI patients within 12 h of symptom onset were investigated immunohistochemically using antibodies against platelets, RBCs, fibrin, macrophages, and neutrophils [myeloperoxidase (MPO)]. The thrombi were divided into tertiles according to the percentage of glycophorin-A-positive area: low (glycophorin-A-positive area <33%; n = 60), intermediate (<54 to 33%; n = 59), and high group (≥54%; n = 59). We also measured plasma MPO levels on admission. In the thrombi, the number of MPO-positive cells in the high-RBC group was significantly greater than that in the low-RBC group (high, 927 ± 385; intermediate, 765 ± 406; low, 279 ± 220 cells/mm(2); P< 0.0001). Plasma MPO levels were significantly higher in the high-RBC group than that in the low-RBC group [low 43.1 (25.0-71.6); intermediate 71.0 (32.9-111.2); high 74.3 (31.1-126.4)ng/mL; P< 0.005]. Distal embolization occurred more frequently in the high-RBC group (P= 0.0009). Moreover, the signs of impaired myocardial reperfusion, as indicated by incomplete ST-segment resolution (STR) and lower myocardial blush grades (MBG), and progression of left ventricular remodelling at 6 months were frequently observed in the high-RBC group (high vs. low: STR, P= 0.056; MBG, P< 0.01; remodelling, P< 0.01). CONCLUSION: The present study demonstrated that erythrocyte-rich thrombi contain more inflammatory cells and reflect high thrombus burden, leading to impaired myocardial reperfusion in STEMI patients.

Effect of omega-3 fatty acids on cardiovascular events in high-risk patients with hypertriglyceridemia in Japan: a 3-year post-marketing surveillance study (OCEAN3 survey).

BACKGROUND: Studies on the efficacy of prescription omega-3 polyunsaturated fatty acids to reduce cardiovascular events have produced conflicting results. RESEARCH DESIGN AND METHODS: This 3-year prospective post-marketing surveillance study evaluated the effect of omega-3-acid ethyl esters (O3AEE; usual dosage 2 g/day) on cardiovascular events in high-risk statin-treated Japanese patients with hypertriglyceridemia. Statin-treated patients not receiving O3AEE were included as a reference cohort. The composite primary endpoint was cardiovascular death, myocardial infarction, stroke, angina requiring coronary revascularization, or peripheral arterial disease requiring surgery or peripheral arterial intervention. RESULTS: At 3 years, Kaplan-Meier estimated cumulative incidence of the primary endpoint was 2.5% (95% confidence interval, 2.1%-2.9%) in O3AEE-treated patients (N = 6,580) and 2.7% (2.4%-3.1%) in non-O3AEE-treated patients (N = 7,784; hazard ratio, 0.99; 95% confidence interval, 0.79-1.23). Incidence of heart failure requiring hospitalization was 0.4% with O3AEE versus 0.8% in non-O3AEE-treated patients (hazard ratio, 0.47; 95% confidence interval, 0.28-0.78; P < 0.05). CONCLUSIONS: Among patients receiving statins, cardiovascular event incidence did not differ significantly between O3AEE-treated patients and non-O3AEE-treated patients. Further studies are required before definitive conclusions can be drawn on the effect of O3AEE on cardiovascular event incidence in high-risk patients with hypertriglyceridemia. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02285166.

Three-year outcomes after sirolimus-eluting stent implantation for unprotected left main coronary artery disease: insights from the j-Cypher registry.

BACKGROUND: Long-term outcomes after stenting of an unprotected left main coronary artery (ULMCA) with drug-eluting stents have not been addressed adequately despite the growing popularity of this procedure. METHODS AND RESULTS: j-Cypher is a multicenter prospective registry of consecutive patients undergoing sirolimus-eluting stent implantation in Japan. Among 12 824 patients enrolled in the j-Cypher registry, the unadjusted mortality rate at 3 years was significantly higher in patients with ULMCA stenting (n=582) than in patients without ULMCA stenting (n=12 242; 14.6% versus 9.2%, respectively; P<0.0001); however, there was no significant difference between the 2 groups in the adjusted risk of death (hazard ratio 1.23, 95% confidence interval 0.95 to 1.60, P=0.12). Among 476 patients whose ULMCA lesions were treated exclusively with a sirolimus-eluting stent, patients with ostial/shaft lesions (n=96) compared with those with bifurcation lesions (n=380) had a significantly lower rate of target-lesion revascularization for the ULMCA lesions (3.6% versus 17.1%, P=0.005), with similar cardiac death rates at 3 years (9.8% versus 7.6%, P=0.41). Among patients with bifurcation lesions, patients with stenting of both the main and side branches (n=119) had significantly higher rates of cardiac death (12.2% versus 5.5%; P=0.02) and target-lesion revascularization (30.9% versus 11.1%; P<0.0001) than those with main-branch stenting alone (n=261). CONCLUSIONS: The higher unadjusted mortality rate of patients undergoing ULMCA stenting with a sirolimus-eluting stent did not appear to be related to ULMCA treatment itself but rather to the patients' high-risk profile. Although long-term outcomes in patients with ostial/shaft ULMCA lesions were favorable, outcomes in patients with bifurcation lesions treated with stenting of both the main and side branches appeared unacceptable.

Angiotensin receptor blocker-based therapy and cardiovascular events in hypertensive patients with coronary artery disease and impaired renal function.

The aim of this study was to assess the effects of angiotensin receptor blocker (ARB)-based therapy on cardiovascular events in high-risk hypertensive patients with coronary artery disease (CAD) and impaired renal function in post hoc analysis of HIJ-CREATE (Heart Institute of Japan Candesartan Randomized Trial for Evaluation in Coronary Artery Disease). Patients (n=2049) were randomly assigned to candesartan-based or non-ARB treatment arms; 1022 patients (age 70 ± 6 years, 28% female) with impaired renal function, defined as creatinine clearance <60 ml/min at baseline. There was no difference in major adverse cardiac event (MACE), a composite of cardiovascular death, non-fatal myocardial infarction, unstable angina, heart failure, stroke and other cardiovascular events requiring hospitalization between the two arms in patients without impaired renal function. However, there was a lower incidence of MACE in the candesartan-based treatment arm than in the non-ARB treatment arm (HR=0.79, 95% CI 0.63-0.99, p=0.039) in patients with impaired renal function. Among the MACE, candesartan-based treatment reduced hospitalization for unstable angina (HR=0.71, 95% CI 0.52-0.96, p=0.028). Although candesartan-based treatment was not superior to non-ARB treatment in prevention of cardiac mortality, ARB-based therapy may be beneficial in reducing risk of coronary events in hypertensive patients with CAD and impaired renal function.

Angiotensin II receptor blocker-based vs. non-angiotensin II receptor blocker-based therapy in patients with angiographically documented coronary artery disease and hypertension: the Heart Institute of Japan Candesartan Randomized Trial for Evaluation in Coronary Artery Disease (HIJ-CREATE).

AIMS: To test whether angiotensin II receptor blockers (ARBs) therapy can reduce the incidence of cardiovascular events compared with non-ARB-based standard pharmacotherapy in coronary artery disease (CAD) patients with hypertension. METHODS AND RESULTS: Angiographically documented CAD patients with hypertension were randomly assigned to receive either candesartan-based (n= 1024) or non-ARB-based pharmacotherapy including angiotensin-converting enzyme-inhibitors (n = 1025). The primary endpoint was the occurrence of a first major adverse cardiovascular event (MACE). There were 552 primary events during a median follow-up of 4.2 years: 264 (25.8%) in the candesartan group and 288 (28.1%) in the non-ARB group (hazard ratio, 0.89; 95% confidence interval, 0.76-1.06). No significant differences existed between groups in terms of cardiovascular death (2.7 vs. 2.4%, 1.14; 0.66-1.95), non-fatal myocardial infarction (2.8 vs. 2.5%, 1.12; 0.66-1.88), or heart failure (3.9 vs. 4.3%, 0.91; 0.59-1.40). New-onset diabetes was diagnosed significantly less frequently with candesartan than with non-ARBs (0.37; 0.16-0.89). Incidence of study drug discontinuation due to adverse events was lower with candesartan than with non-ARBs (5.7 vs. 12.2%, P < 0.001). CONCLUSION: Although candesartan showed no significant differences in MACE compared with the non-ARB treatment group, the drug significantly reduced the incidence of new-onset diabetes and was better tolerated. This study is registered as International Standard Randomised Controlled Trial No. UMIN000000790.

Enhanced expression of haemoglobin scavenger receptor in accumulated macrophages of culprit lesions in acute coronary syndromes.

AIMS: Effective clearance of extracellular haemoglobin (Hb) is thought to limit systemic oxidative heme toxicity, which is presumed to contribute to the pathogenesis of plaque instability. We immunohistochemically examined the relationship between intraplaque haemorrhage, 4-HNE (4-hydroxy-2-nonenal), an index of lipid peroxidation, and the Hb scavenger receptor (CD163), using coronary atherectomy specimens from 74 patients with stable angina pectoris (SAP, n = 39) or unstable angina pectoris (UAP, n = 35). METHODS AND RESULTS: Atherectomy samples were stained with antibodies against glycophorin A (a protein specific to erythrocyte membranes), CD31, 4-HNE, and CD163. Quantitative analysis demonstrated that glycophorin A-positive areas, 4-HNE-positive macrophage score, and CD163-positive macrophage score in UAP patients were significantly higher (glycophorin A, P < 0.0001; 4-HNE-positive macrophage score, P < 0.0001; CD163-positive macrophage score, P < 0.0005) than in SAP patients. The percentage of the glycophorin A-positive area showed a significant positive correlation with the number of CD31-positive microvessels and the 4-HNE-positive macrophage score (microvessels, R = 0.59, P < 0.0001; 4-HNE, R = 0.59, P < 0.0001). Moreover, the CD163-positive macrophage score was positively correlated with glycophorin A-positive area and the 4-HNE-positive macrophage score (glycophorin A, R = 0.58, P < 0.0001; 4-HNE, R = 0.53, P < 0.0001). CONCLUSION: These findings suggest a positive association among intraplaque haemorrhage, enhanced expression of Hb scavenger receptor, and lipid peroxidation in human unstable plaques.

Small coronary calcium deposits and elevated plasma levels of oxidized low density lipoprotein are characteristic of acute myocardial infarction.

AIM: Predictions of the onset of acute myocardial infarction (AMI) in high risk individuals are of great clinical importance. Among various risk factors, elevated levels of oxidized low density lipoprotein (ox-LDL) in plasma have been shown to reflect unstable coronary plaques. Coronary calcification is a common finding in the elderly, however, its clinical implications as a risk factor for plaque rupture are controversial. This study was designed to investigate the clinical implications of plasma ox-LDL levels and coronary calcification detected by electron-beam computed tomography (EBCT), by comparing patients with AMI with those with stable angina pectoris (SAP). METHODS: We measured plasma ox-LDL levels in AMI (n=34) and SAP (n=49) patients. In addition, a coronary calcium score was quantified with the Agatston system. The total coronary calcium score (TCS) was defined as the sum of the scores for each lesion. RESULTS: TCS and total calcium area were significantly smaller in patients with AMI than in those with SAP. On the other hand, plasma ox-LDL levels were significantly higher in AMI patients than in SAP patients (p<0.0005). CONCLUSION: These results suggest that a combined assessment of coronary calcium and plasma ox-LDL levels may be useful for screening patients with unstable coronary plaques.

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.

Effect of early statin treatment at standard doses on long-term clinical outcomes in patients with acute myocardial infarction (the Heart Institute of Japan, Department of Cardiology Statin Evaluation Program).

Long-term preventive effects of standard statin therapy in patients with acute myocardial infarction (AMI) against a secondary cardiac event remain unclear. The aims of this study were to evaluate and clarify characteristics of patients with AMI in whom standard statin therapy has beneficial effects against a secondary event in a real-world setting. Between 1999 and 2004, 4,075 patients with AMI were registered and followed prospectively, of whom 1,404 (matched by propensity scores) were analyzed. Statin use was defined as prescription on discharge from the hospital, and the control group was not prescribed statins at discharge. The primary end point was total mortality rate. Final follow-up was performed in June 2006 (median 4.1 years), and follow-up rate was 97.2%. During follow-up, 139 patients died, including 87 (12.4%) from the control group and 52 (7.4%) from the statin group. The hazard ratio for statin therapy was 0.64 (95% confidence interval 0.45 to 0.90, p = 0.011) throughout the study. Early statin therapy was strongly correlated with a lower risk of cardiovascular death, less recurrence of AMI, and less heart failure. Statin therapy was particularly beneficial for men, patients > or =60 years of age, and patients with a high low-density lipoprotein cholesterol level > or =155 mg/dl. In conclusion, these findings suggest that initiating standard rather than intensive statin therapy immediately after AMI decreases long-term mortality and subsequent cardiac events.

Comparison of clinical characteristics and arterial remodeling by intravascular ultrasonic imaging in three age groups (< or =55, 56 to 69 and > or =70 years) of Japanese patients with acute myocardial infarction.

Recent epidemiologic, pathologic, and intravascular ultrasound (IVUS) studies have shown that there are differences in coronary risk factors or plaque morphology between younger and older patients with acute myocardial infarctions (AMIs). This study examined clinical background and plaque morphology using IVUS in younger and older adults with AMIs in Japan. The study population consisted of 96 patients with AMIs, for whom preinterventional IVUS images were obtained. Patients were classified into 3 groups: a young group (aged < or =55 years), a middle-aged group (aged 56 to 69 years), and an old group (aged > or =70 years). The remodeling index was defined as the ratio of the external elastic membrane area at the culprit lesion to the external elastic membrane area at the proximal reference site. Expansive remodeling was defined as a remodeling index >1.05 and constrictive remodeling as a remodeling index <0.95. The frequency of hypercholesterolemia was significantly different among the 3 age groups. Total cholesterol (p <0.001), low-density lipoprotein cholesterol (p <0.005), and triglyceride (p <0.05) levels and body mass index (p <0.001) in the young group were significantly higher than in the old group. On IVUS images, constrictive remodeling was most common in the young group, whereas expansive remodeling occurred most commonly in the middle-aged and old groups. In conclusion, this study demonstrated that patients with AMIs in the young group had higher levels of hypercholesterolemia, obesity, and constrictive remodeling compared with those in the old group. The differences in arterial remodeling of the culprit lesions between younger and older patients with AMIs may reflect different biologic mechanisms of plaque activation and destabilization.

Persistent high levels of plasma oxidized low-density lipoprotein after acute myocardial infarction predict stent restenosis.

OBJECTIVE: Recently, elevated levels of plasma oxidized low-density lipoprotein (LDL) have been shown to relate to plaque instability in human atherosclerotic lesions. We investigated prospectively patients admitted with acute myocardial infarction (AMI) who underwent primary coronary stenting to evaluate whether the 6-month outcome could be predicted by measuring plasma oxidized LDL (ox-LDL) levels at the time of hospital discharge. METHODS AND RESULTS: Plasma ox-LDL levels were measured in 102 patients with AMI undergoing primary coronary stenting using a highly sensitive ELISA method. Measurements were taken on admission and at discharge, and the findings related to the clinical outcome. At 6-month follow-up, angiographic stent restenosis occurred in 25 (25%) of the 102 AMI patients. Plasma ox-LDL levels at discharge were significantly (P=0.0074) higher in the restenosis group than those in the no-restenosis group (1.03+/-0.65 versus 0.61+/-0.34 ng/5 microg LDL protein). Multiple regression analysis showed that only plasma ox-LDL levels at discharge were a statistically significant independent predictor for late lumen loss after stenting (beta=0.645; P<0.0001). CONCLUSIONS: This prospective study demonstrates that persistence of an increased level of plasma ox-LDL at discharge is a strong independent predictor of stent restenosis at 6-month follow-up in AMI patients.

Pre-Load-Induced Changes in Forward LV Stroke and Functional Mitral Regurgitation: Echocardiographic Detection of the Descending Limb of Starling's Curve.

OBJECTIVES: The purpose of this study was to clarify the prognostic significance of diagnosing whether the failing heart is functioning on the descending limb of the Starling curve by using echocardiography with passive leg lifting (PLL). BACKGROUND: Patients with advanced heart failure can shift to the descending limb of the Starling curve, in which pre-load does not lead to an expected increase in forward left ventricular stroke volume (LVSV). METHODS: Thirty-five consecutive patients with left ventricular (LV) ejection fraction of <40% underwent echocardiography at rest during baseline and during PLL to increase pre-load. RESULTS: Despite PLL, a paradoxical decrease in forward LVSV was observed in 15 (43%) patients. Changes in forward LVSV inversely correlated with those in functional mitral regurgitation (r = -0.56). The primary endpoint of cardiac death or hospitalization due to worsening heart failure occurred in 15 (43%) patients during follow-up (2.8 ± 2.2 years). There were a number of significant predictors of the primary endpoint in the univariate Cox analysis: baseline E/A ratio (p = 0.0002), paradoxical decrease in LVSV despite PLL (hazard ratio: 4.44; 95% confidence interval: 1.41 to 14.0; p = 0.011), baseline LV end-systolic volume (p = 0.023), and baseline LV ejection fraction (p = 0.034). In the bivariate Cox analysis, an addition of the paradoxical decrease in LVSV significantly enhanced the predictive power of all other univariate predictors. CONCLUSIONS: Heart failure patients with LV systolic dysfunction on the descending limb of the Starling curve can be recognized by the paradoxical decrease in LVSV despite PLL, and the prognostic predicting power is additive to the other traditional echocardiographic predictors. Also, our results suggest that functional mitral regurgitation is an important reason for the descending limb of the Starling curve, which is clinically recognized as the pre-load-induced decrease in forward LVSV.

Prediction of aortic stenosis-related events in patients with systolic ejection murmur using pocket-sized echocardiography.

BACKGROUND: We have previously reported the usefulness of our newly developed visual aortic stenosis (AS) score in screening for AS using pocket-sized echocardiography. The objective of this study was to investigate whether the visual AS score and/or conventional aortic valve calcification score derived from pocket-sized echocardiography can be used to predict AS-related events. METHODS: One hundred and nine patients with systolic ejection murmur (SEM) or known AS (64 males, age 75±9 years) were enrolled and a visual AS score and an aortic valve calcification score were assessed using pocket-sized echocardiography. The primary endpoint was defined as AS-related events, including cardiac death and aortic valve replacement, during the follow-up period. RESULTS: In a multivariate Cox proportional hazards analysis, AS-related events were independently predicted by an aortic valve calcification score ≥3 (HR, 3.5; 95% CI, 1.1-11; p=0.033) and a visual AS score ≥3 (HR, 15; 95% CI, 1.8-125; p=0.013). During 18±9 months of follow-up, the event-free survival rate was 98% in patients with both a visual AS score <3 and an aortic valve calcification score <3, 90% in patients with either a visual AS score ≥3 or an aortic valve calcification score ≥3 (p<0.0001), and 62% in patients with both a visual AS score ≥3 and an aortic valve calcification score ≥3 (p<0.0001). CONCLUSIONS: The combination of visual AS score and aortic valve calcification score derived from pocket-sized echocardiography is useful for predicting AS-related events in patients with SEM.

Expression of endothelin-converting enzyme, endothelin-1 and endothelin receptors at the site of percutaneous coronary intervention in humans.

OBJECTIVE: The repair process at the site of injury after percutaneous coronary intervention (PCI) is dominated by neointimal formation composed mainly of smooth muscle cells (SMC). Endothelin-1 (ET-1) is a powerful vasoconstrictor and SMC mitogen. Endothelin-converting enzyme (ECE) is the final key enzyme of endothelin processing. The effects of ET-1 are mediated by binding to endothelin type A (ETA) and endothelin type B (ETB) receptors. The ligand/receptor/ligand-producing system (ET system) could be involved in the pathogenesis of neointimal formation in humans. METHODS: Fifteen post-PCI sites obtained at autopsy and eight atherectomy specimens obtained from restenotic sites were investigated using immunohistochemical single and double staining techniques. Frozen sections were stained with antibodies against ECE, ET-1, ETA and ETB receptors, SMC, macrophages and endothelial cells. RESULTS: At the early stage, less than 3 months after PCI, neointimal SMC were positive for ECE, ET-1, ETA and ETB receptors. The expression of ECE, ET-1, ETA and ETB receptors in these neointimal SMC decreased markedly from 6 months onwards. The ECE, ET-1, ETA and ETB receptor-positive cell areas were significantly (P < 0.005) greater in the first 3 months after PCI compared with 6 months or more after PCI. Atherectomy specimens also showed similar positivity. CONCLUSIONS: These observations strongly suggest that the expression of ECE, ET-1, ETA and ETB receptors is enhanced in neointimal SMC at early stages after PCI injury in human coronary arteries. The increased expression of the ET system may contribute to SMC proliferation/migration and vasoconstriction in human post-PCI coronary lesions.

Spotty calcification typifies the culprit plaque in patients with acute myocardial infarction: an intravascular ultrasound study.

BACKGROUND: Calcification is a common finding in human coronary arteries; however, the relationship between calcification patterns, plaque morphology, and patterns of remodeling of culprit lesions in a comparison of patients with acute coronary syndromes (ACS) and those with stable conditions has not been documented. METHODS AND RESULTS: Preinterventional intravascular ultrasound (IVUS) images of 178 patients were studied, 61 with acute myocardial infarction (AMI), 70 with unstable angina pectoris (UAP), and 47 with stable angina pectoris (SAP). The frequency of calcium deposits within an arc of less than 90 degrees for all calcium deposits was significantly different in culprit lesions of patients with AMI, UAP, and SAP (P<0.0001). Moreover, the average number of calcium deposits within an arc of <90 degrees per patient was significantly higher in AMI than in SAP (P<0.0005; mean+/-SD, AMI 1.4+/-1.3, SAP 0.5+/-0.8). Conversely, calcium deposits were significantly longer in SAP patients (P<0.0001; mean+/-SD, AMI 2.2+/-1.6, UAP 1.9+/-1.8, and SAP 4.3+/-3.2 mm). In AMI patients, the typical pattern was spotty calcification, associated with a fibrofatty plaque and positive remodeling. In ACS patients showing negative remodeling, no calcification was the most frequent observation. Conversely, SAP patients had the highest frequency of extensive calcification. CONCLUSIONS: Our observations show that IVUS allows the identification of vulnerable plaques in coronary arteries, not only by identifying a fibrofatty plaque and positive remodeling, but also by identifying a spotty pattern of calcification.

Neutrophil infiltration of culprit lesions in acute coronary syndromes.

BACKGROUND: Neutrophils in unstable atherosclerotic lesions have not received much consideration, despite accumulating evidence suggesting a link between systemic inflammation and acute coronary syndromes. METHODS AND RESULTS: Coronary artery segments were obtained at autopsy from 13 patients with acute myocardial infarction (AMI); 8 had a ruptured and 5 an eroded plaque. Patients (n=45) who had died of noncardiovascular diseases served as reference. Atherectomy specimens were obtained from 35 patients with stable angina pectoris (SAP) and from 32 patients with unstable angina pectoris (UAP). Antibodies against CD66b, elastase, myeloperoxidase, and CD11b identified neutrophils; CD10 identified neutral endopeptidase (NEP). CD66b-positive and NEP-positive neutrophils were counted and expressed as a number per square millimeter of tissue. All specimens with plaque rupture or erosion showed distinct neutrophil infiltration; the number did not differ between ruptured and eroded plaques. However, the number of NEP-positive neutrophils was significantly higher (P<0.0001) in ruptured plaques than in eroded plaques. UAP patients showed neutrophils in 14 of 32 culprit lesions; in SAP only 2 of 35 lesions contained neutrophils. The number of neutrophils and NEP-positive cells in patients with UAP was significantly higher (neutrophils, P<0.0005; NEP-positive cells, P<0.005) than in patients with SAP. CONCLUSIONS: The observations suggest that neutrophil infiltration is actively associated with acute coronary events. The high number of NEP-positive neutrophils in ruptured plaques, compared with eroded plaques, may reflect differences in the underlying pathophysiological mechanisms.

C-Type natriuretic peptide and natriuretic peptide receptors are expressed by smooth muscle cells in the neointima after percutaneous coronary intervention.

Understanding restenosis after percutaneous coronary intervention (PCI) remains a challenge. Neointimal proliferation is the main cause of restenosis. C-Type natriuretic peptide (CNP) plays a role in relaxation and growth inhibition of vascular smooth muscle cells (SMCs); the effects depend on the presence of specific natriuretic peptide receptors (NPRs) consisting of NPR-A, NPR-B, and NPR-C. To test the hypothesis that CNP and NPRs may be involved in restenosis, we immunohistochemically studied the expression of CNP and NPRs during the post-PCI healing process; 10 sites after PCI obtained at autopsy and 14 atherectomy specimens obtained from restenotic sites were investigated. Frozen sections were stained with antibodies against CNP, NPRs, SMCs, macrophages, and endothelial cells. Within 2 months after PCI, most neointimal SMCs expressed CNP and NPR-A. The expression of CNP and NPR-A in these neointimal SMCs decreased from 6 months onward. In contrast, NPR-C was strongly expressed in neointimal SMCs from 1 to 9 months after PCI. In atherectomy specimens, most neointimal SMCs showed weak positivity for CNP and NPR-A, but NPR-C was strongly expressed in the neointimal SMCs. These findings strongly suggest that a paracrine and autocrine system of CNP and NPRs may be important in controlling neointimal growth after PCI in humans.