Determinants of high cardiovascular risk in relation to plaque-composition of a non-culprit coronary segment visualized by near-infrared spectroscopy in patients undergoing percutaneous coronary intervention.

AIM: The aim of this study was to determine the relationship between clinical and blood characteristics of a vascular inflammatory milieu and coronary plaque composition visualized by near-infrared spectroscopy (NIRS) in percutaneous coronary intervention (PCI) patients. METHODS AND RESULTS: Between April 2009 and January 2011, we performed NIRS in 208 patients who underwent PCI or invasive diagnostic coronary exploration for various indications. Imaging was performed of one non-intervened coronary segment after the initial procedure. Univariate and multivariate linear regression analyses were applied to evaluate the relationship between the acquired NIRS-derived lipid core burden index (LCBI) and clinical and blood (lipids and hs-C-reactive protein) characteristics. Patients with a history of hypercholesterolaemia [median 48 (inter-quartile range 21-101) vs. 38 (13-70), P = 0.043] and multi-vessel disease [55 (24-104) vs. 32 (12-71), P = 0.012] had higher LCBI levels. Men had higher LCBI than women [48 (21-95) vs. 27 (9-59), P = 0.003]. Hypercholesterolaemia and gender remained significant in multivariate regression analysis, whereas also a history of non-cardiac vascular disease and beta-blockers were positively associated with LCBI. Altogether 23.2% of the variability in LCBI could be explained by clinical and blood characteristics. CONCLUSION: Clinical characteristics reflecting patients with a high cardiovascular risk profile explained 23.2% of the variability in LCBI, whereas blood biomarkers added little. Further research is warranted to evaluate whether NIRS has the potential to provide additional prognostic information about patients' cardiovascular risk.

In vivo detection of high-risk coronary plaques by radiofrequency intravascular ultrasound and cardiovascular outcome: results of the ATHEROREMO-IVUS study.

AIMS: Acute coronary syndromes (ACS) are mostly caused by plaque rupture. This study aims to investigate the prognostic value of in vivo detection of high-risk coronary plaques by intravascular ultrasound (IVUS) in patients undergoing coronary angiography. METHODS AND RESULTS: Between November 2008 and January 2011, IVUS of a non-culprit coronary artery was performed in 581 patients who underwent coronary angiography for ACS (n = 318) or stable angina (n = 263). Primary endpoint was major adverse cardiac events (MACEs) defined as mortality, ACS, or unplanned coronary revascularization. Culprit lesion-related events were not counted. Cumulative Kaplan-Meier incidence of 1-year MACE was 7.8%. The presence of IVUS virtual histology-derived thin-cap fibroatheroma (TCFA) lesions (present 10.8% vs. absent 5.6%; adjusted HR: 1.98, 95% CI: 1.09-3.60; P = 0.026) and lesions with a plaque burden of ≥70% (present 16.2% vs. absent 5.5%; adjusted HR: 2.90, 95% CI: 1.60-5.25; P < 0.001) were independently associated with a higher MACE rate. Thin-cap fibroatheroma lesions were also independently associated with the composite of death or ACS only (present 7.5% vs. absent 3.0%; adjusted HR: 2.51, 95% CI: 1.15-5.49; P = 0.021). Thin-cap fibroatheroma lesions with a plaque burden of ≥70% were associated with a higher MACE rate within (P = 0.011) and after (P < 0.001) 6 months of follow-up, while smaller TCFA lesions were only associated with a higher MACE rate after 6 months (P = 0.033). CONCLUSION: In patients undergoing coronary angiography, the presence of IVUS virtual histology-derived TCFA lesions in a non-culprit coronary artery is strongly and independently predictive for the occurrence of MACE within 1 year, particularly of death and ACS. Thin-cap fibroatheroma lesions with a large plaque burden carry higher risk than small TCFA lesions, especially on the short term.

Circulating chemokines in relation to coronary plaque characteristics on radiofrequency intravascular ultrasound and cardiovascular outcome.

OBJECTIVE: To investigate relations of several circulating chemokines with extent and phenotype of coronary atherosclerosis and with 1-year clinical outcome. METHODS: Intravascular ultrasound virtual histology (IVUS-VH) imaging of a coronary artery was performed in 581 patients. Monocyte chemoattractant protein-1 (MCP-1), macrophage inflammatory protein-1α (MIP-1α), MIP-1ß and regulated upon activation normal T cell expressed and secreted (RANTES) were measured in plasma. RESULTS: Higher MCP-1, MIP-1α and lower RANTES were associated with coronary plaque burden. Higher MCP-1, MIP-1α and lower RANTES were associated with the presence of IVUS-VH-derived thin-cap fibroatheroma lesions. RANTES was associated with major adverse cardiac events. CONCLUSIONS: RANTES is a promising biomarker that is inversely associated with coronary plaque burden and vulnerability, as well as with death and acute coronary syndrome.

Short- and long-term major adverse cardiac events in patients undergoing percutaneous coronary intervention with stenting for acute myocardial infarction complicated by cardiogenic shock.

OBJECTIVES: To determine the risk of short- and long-term mortality and major adverse cardiac events (MACE) in acute myocardial infarction (AMI) patients complicated by cardiogenic shock (CS) in the contemporary practice of primary percutaneous coronary intervention with stenting. METHODS: Of the 1,755 consecutive AMI patients undergoing percutaneous coronary intervention with stenting enrolled, 103 had CS at admission. Primary endpoints were early mortality (within 30 days after the index event) and late mortality (from day 31 up to 4 years). Secondary endpoints included MACE [all-cause death, myocardial infarction or target vessel revascularization (TVR)], myocardial infarction, TVR and stent thrombosis. RESULTS: Thirty-day mortality was higher among CS patients, and CS was a strong independent predictor of a higher risk of early death (adjusted HR 3.64, 95% CI 2.44-5.44). The late mortality rate was significantly higher in CS patients, and CS was also a predictor of higher risk of death at a 4-year follow-up (adjusted HR 1.95, 95% CI 1.11-3.45). Recurrent AMI, TVR and stent thrombosis rates were similar among patients with and without CS. CONCLUSION: CS complicating AMI is still a severe clinical event, mainly with regard to a significant higher risk of early mortality, but also associated with a worse prognosis in 30-day survivors.

Evaluating the 'all-comers' design: a comparison of participants in two 'all-comers' PCI trials with non-participants.

AIMS: We aimed to asses the generalizability of two 'all-comers' randomized clinical trials (AC-RCTs) in patients undergoing percutaneous coronary intervention (PCI). METHODS AND RESULTS: Recently two large AC-RCT's comparing drug-eluting stents were performed in our institution (LEADERS and RESOLUTE-III). During the inclusion period of these trials 1242 consecutive PCI patients were treated of whom 579 (48%) were actually included. The most important reasons for non-participation were inability to provide informed consent (33.5%), refused to participate (19%), or patient met one of the other exclusion criteria (26.9%). Trial participants more frequently had stable angina (42.5 vs. 34.4%) and less frequently acute myocardial infarction as indication for PCI (31.4 vs. 42.4%) than non-participants. Hypertension (52.8 vs. 49.1%) and hypercholesterolaemia (56.3 vs. 49.1%) were seen more frequently in trial participants; heart failure was less common (2.1 vs. 4.4%). A significant difference in 30-day mortality was observed between AC-RCT participants and non-participants [0.7 vs. 4.5% events; adjusted hazard ratio (aHR) 0.18 and 95% confidence interval (CI) 0.06-0.52]. One-year mortality was also lower (3.1 vs. 6.9% events; aHR: 0.51 and 95% CI: 0.29-0.91, but 1-year mortality in 48 h survivors was similar (3.1 vs. 4.2% events; aHR: 0.74 and 95% CI: 0.41-1.34). CONCLUSION: Applying the all-comers design did not result in inclusion of all consecutive patients, as only half of the target population was enrolled. It should be noted, however, that this design included more patients than observed in classical RCTs. AC-RCT participants and non-participants were different in terms of baseline characteristics and outcome.

High-risk patients with ST-elevation myocardial infarction derive greatest absolute benefit from primary percutaneous coronary intervention: results from the Primary Coronary Angioplasty Trialist versus thrombolysis (PCAT)-2 collaboration.

BACKGROUND: Meta-analyses of randomized trials show that primary percutaneous coronary intervention (PPCI) results in lower mortality than fibrinolytic therapy in patients with myocardial infarction. We investigated which categories of patients with myocardial infarction would benefit most from the strategy of PPCI and, thus, have lowest numbers needed to treat to prevent a death. METHODS: Individual patient data were obtained from 22 (n = 6,763) randomized trials evaluating efficacy and safety of PPCI versus fibrinolysis. A risk score was developed and validated to estimate the probability of 30-day death in individuals. Patients were then divided in quartiles according to risk. Subsequent analyses were performed to evaluate if the treatment effect was modified by estimated risk. RESULTS: Overall, 446 patients (6.6%) died within 30 days after randomization. The mortality risk score contained clinical characteristics, including the time from symptom onset to randomization. The c-index was 0.76, and the Hosmer-Lemeshow test was nonsignificant, reflecting adequate discrimination and calibration. Patients randomized to PPCI had lower mortality than did patients randomized to fibrinolysis (5.3% vs 7.9%, adjusted odds ratio 0.63, 95% CI 0.42-0.84, P < .001). The interaction between risk score and allocated treatment interaction term had no significant contribution (P = .52) to the model, indicating that the relative mortality reduction by PPCI was similar at all levels of estimated risk. In contrast, the absolute risk reduction was strongly related to estimated risk at baseline: the numbers needed to treat to prevent a death by PPCI versus fibrinolysis was 516 in the lowest quartile of estimated risk compared with only 17 in the highest quartile. CONCLUSION: Primary percutaneous coronary intervention is consistently associated with a strong relative reduction in 30-day mortality, irrespective of patient baseline risk, and should therefore be considered as the first choice reperfusion strategy whenever feasible. If access to percutaneous coronary intervention is >2 hours, fibrinolysis remains a legitimate option in low-risk patients because of the small absolute risk reduction by PPCI in this particular cohort.

Fibrinogen in relation to degree and composition of coronary plaque on intravascular ultrasound in patients undergoing coronary angiography.

OBJECTIVE: The aim of this study was to provide additional insight into the role of fibrinogen in coronary artery disease by investigating the associations between plasma fibrinogen with both degree and composition of coronary atherosclerosis as determined by virtual histology-intravascular ultrasound. PATIENTS AND METHODS: In 581 patients undergoing coronary angiography for acute coronary syndrome (ACS) or stable angina pectoris, preprocedural blood samples were drawn for fibrinogen, C-reactive protein (CRP), interleukin-6, and plasminogen activator inhibitor-1 measurements, and virtual histology-intravascular ultrasound of a nonculprit coronary artery was performed. The degree [plaque volume, plaque burden (PB), and lesions with PB≥70%] and the composition of coronary atherosclerotic plaque (fibrous, fibrofatty, dense calcium, necrotic core tissue, and thin-cap fibroatheroma lesions) were assessed. RESULTS: Fibrinogen showed a tendency toward a positive association with PB [ß (95% CI): 2.55 (-0.52-5.61) increase in PB per ln(g/l) fibrinogen, P=0.09], which was driven significantly by an association in the ACS subgroup [ß (95% CI): 4.11 (0.01-8.21) increase in PB per ln(g/l) fibrinogen, P=0.049]. Fibrinogen was also related to the presence of lesions with PB 70% or more in both the full cohort [OR (95% CI): 2.27 (1.17-4.43), P=0.016] and ACS patients [OR (95% CI): 2.92 (1.17-7.29), P=0.022]. All associations were independent of established cardiovascular risk factors, but not CRP. Interleukin-6 and plasminogen activator inhibitor-1 did not provide incremental value to fibrinogen when examining the associations with degree of atherosclerosis. Substantial associations with plaque composition were absent. CONCLUSION: Fibrinogen is associated with degree of coronary atherosclerosis, especially in ACS patients. However, whether this association is independent of CRP might be questioned and needs further investigation.

Integrated Biomarker and Imaging Study 3 (IBIS-3) to assess the ability of rosuvastatin to decrease necrotic core in coronary arteries.

AIMS: Statins are highly effective in reducing major adverse clinical events, but the direct effects on coronary plaque composition remain debatable. Our aim was to mechanistically evaluate the treatment effect of high-intensity statin therapy on compositional coronary plaque changes. METHODS AND RESULTS: The third Integrated Biomarker and Imaging Study (IBIS-3) was a prospective, investigator-initiated, single-centre study. Serial radiofrequency intravascular ultrasound (RF-IVUS) measurements of a predefined non-stenotic segment in a non-culprit coronary artery were performed to evaluate the effect of rosuvastatin (intended dose: 40 mg daily) on necrotic core (NC) volume in patients with stable angina or acute coronary syndrome. Changes in lipid core burden index (LCBI) were evaluated through serial near-infrared spectroscopy (NIRS) imaging in a subset. Serial RF-IVUS (and NIRS) data of a median segment of 41 mm (interquartile range: 32 to 49 mm) were complete in 164 (103) patients. Follow-up measurements were performed at six and 12 months in 30 (26) and 134 (77) patients, respectively. Mean levels of low-density lipoprotein cholesterol decreased by 30%, from 2.49 mmol/l to 1.73 mmol/l at the end of follow-up. High-dose rosuvastatin therapy resulted in a non-significant change of -1.4 mm3 (95% CI: -3.0, 0.1) in NC volume during follow-up (p=0.074). The change in NC percentage of total plaque volume was -1.4% (95% CI: -2.4 to -0.4; p=0.006). A neutral effect was also observed on LCBI. Indications of significant regression of NC volume and LCBI in the highest baseline quartiles were observed, which should cautiously be regarded as hypothesis-generating. CONCLUSIONS: High-intensity rosuvastatin therapy during one year resulted in a neutral effect on NC and LCBI within non-stenotic, non-culprit coronary segments with a relatively low atheroma burden. This study has been registered in The Netherlands Trial Register (NTR) nr. 2872.

Plasma concentrations of molecular lipid species in relation to coronary plaque characteristics and cardiovascular outcome: Results of the ATHEROREMO-IVUS study.

BACKGROUND AND AIMS: Previous lipidomics analyses have demonstrated that several lipid molecules in plasma are associated with fatal outcome in patients with coronary artery disease (CAD). This study aims to investigate the associations of previously identified high risk lipid molecules in plasma with coronary plaque characteristics derived from intravascular ultrasound virtual histology (IVUS-VH) imaging, with coronary lipid core burden index (LCBI) on near-infrared spectroscopy (NIRS), and with one year cardiovascular outcome in patients with CAD. METHODS: Between 2008 and 2011, IVUS-VH imaging of a non-culprit coronary artery was performed in 581 patients who underwent coronary angiography for acute coronary syndrome (ACS) or stable CAD. NIRS imaging was additionally performed in 191 patients. Plasma concentrations of molecular lipids were measured with mass spectrometry. RESULTS: Several cholesteryl ester, ceramide and lactosylceramide species and ceramide ratios were associated with vulnerable plaque characteristics on IVUS-VH and NIRS imaging and with 1-year major adverse cardiac events (MACE, defined as all-cause mortality, ACS and unplanned coronary revascularization). In particular, ceramide d18:1/16:0 was consistently associated with higher necrotic core fraction on IVUS-VH (p = 0.001), higher LCBI (p = 0.024) on NIRS and higher MACE rate (adjusted HR 1.79 per standard deviation increase in log-transformed lipid concentration, 95%CI 1.24-2.59, p = 0.002). CONCLUSION: Several molecular lipid species, and particularly ceramide(d18:1/16:0), are associated with the fraction of necrotic core tissue and lipid core burden in coronary atherosclerosis, and are predictive for 1-year clinical outcome after coronary angiography. These molecular lipids may improve risk stratification in CAD and may also be interesting therapeutic targets for the treatment of atherosclerotic disease.

Smoking in Relation to Coronary Atherosclerotic Plaque Burden, Volume and Composition on Intravascular Ultrasound.

BACKGROUND: This study aimed to evaluate the relationship between cigarette smoking and coronary atherosclerotic burden, volume and composition as determined in-vivo by grayscale and virtual histology (VH) intravascular ultrasound (IVUS). METHODS AND RESULTS: Between 2008 and 2011, (VH-)IVUS of a non-culprit coronary artery was performed in 581 patients undergoing coronary angiography. To account for differences in baseline characteristics, current smokers were matched to never smokers by age, gender and indication for catheterization, resulting in 280 patients available for further analysis. Coronary atherosclerotic plaque volume, burden, composition (fibrous, fibro-fatty, dense calcium and necrotic core) and high-risk lesions (VH-IVUS derived thin-cap fibroatheroma (TCFA), plaque burden ≥70%, minimal luminal area ≤4.0 mm2) were assessed. Cigarette smoking showed a tendency towards higher coronary plaque burden (mean±SD, 38.6±12.5% in current versus 36.4±11.0% in never smokers, p = 0.080; and odds ratio (OR) of current smoking for plaque burden above versus below the median 1.69 (1.04-2.75), p = 0.033). This effect was driven by an association in patients presenting with an acute coronary syndrome (ACS) (current smokers, plaque burden 38.3±12.8% versus never smokers, plaque burden 35.0±11.2%, p = 0.049; OR 1.88 (1.02-3.44), p = 0.042). Fibrous tissue tended to be lower in current smokers (mean±SD, 57.7±10.5% versus 60.4±12.6%, p = 0.050) and fibro-fatty tissue was higher in current smokers (median[IQR], 9.6[6.0-13.7]% versus 8.6[5.8-12.2]%, p = 0.039). However, differences in percentage necrotic core and dense calcium could not be demonstrated. Also, no differences were found with regard to high-risk lesions. CONCLUSIONS: An association between smoking and degree of coronary atherosclerosis was present in patients undergoing coronary angiography who presented with ACS. Although smoking was associated with higher fibro-fatty percentage, no associations could be demonstrated with percentage necrotic core, nor with VH-IVUS derived TCFA lesions. Since the magnitude of the differences in both degree and composition of atherosclerosis was modest, clinical relevance of the findings may be questioned.

Relation of C-reactive protein to coronary plaque characteristics on grayscale, radiofrequency intravascular ultrasound, and cardiovascular outcome in patients with acute coronary syndrome or stable angina pectoris (from the ATHEROREMO-IVUS study).

The relation between C-reactive protein (CRP) and coronary atherosclerosis is not fully understood. This study aims to investigate the associations among high-sensitivity CRP, coronary plaque burden, and the presence of high-risk coronary lesions as measured by intravascular ultrasound (IVUS) and 1-year cardiovascular outcome. Between 2008 and 2011, grayscale and virtual histology IVUS imaging of a nonculprit coronary artery was performed in 581 patients who underwent coronary angiography for acute coronary syndrome (ACS) or stable angina pectoris. Primary end point consisted of 1-year major adverse cardiac events (MACEs), defined as all-cause mortality, ACS, or unplanned coronary revascularization. After adjustment for established cardiac risk factors, baseline CRP levels were independently associated with higher coronary plaque burden (p = 0.002) and plaque volume (p = 0.002) in the imaged coronary segment. CRP was also independently associated with the presence of large lesions (plaque burden ≥70%; p = 0.030) but not with the presence of stenotic lesions (minimal luminal area ≤4.0 mm(2); p = 0.62) or IVUS virtual histology-derived thin-cap fibroatheroma lesions (p = 0.36). Cumulative incidence of 1-year MACE was 9.7%. CRP levels >3 mg/L were independently associated with a higher incidence of MACE (hazard ratio 2.17, 95% confidence interval [CI] 1.01 to 4.67, p = 0.046) and of all-cause mortality and ACS only (hazard ratio 3.58, 95% CI 1.04 to 13.0, p = 0.043), compared with CRP levels <1 mg/L. In conclusion, in patients who underwent coronary angiography, high-sensitivity CRP is a marker of coronary plaque burden but is not related to the presence of virtual histology-derived thin-cap fibroatheroma lesions and stenotic lesions. CRP levels >3 mg/L are predictive for adverse cardiovascular outcome at 1 year.

Antibodies to periodontal pathogens are associated with coronary plaque remodeling but not with vulnerability or burden.

OBJECTIVE: Previous studies have suggested positive associations between periodontal infection and cardiovascular disease. We aimed to investigate the associations of circulating antibodies against periodontal pathogens with 1-year cardiovascular outcome, as well as the extent of coronary atherosclerosis, plaque vulnerability and lesion remodeling on intravascular ultrasound (IVUS) imaging. METHODS: Between 2008 and 2011, radiofrequency IVUS imaging of a non-culprit coronary artery was performed in 581 patients who underwent coronary angiography. Immunoglobulin G (IgG) and A (IgA) against Porphyromonas gingivalis, Aggregatibacter actinomycetemcomitans, Tannerella forsythia and Prevotella intermedia were measured in plasma. RESULTS: None of the antibody levels were associated with coronary plaque burden, radiofreqeuncy-IVUS-derived thin-cap fibroatheroma lesion morphology or 1-year incidence of major adverse cardiac events (MACE), which included all-cause mortality, acute coronary syndrome and unplanned coronary revascularization. IgA against A. actinomycetemcomitans, T. forsythia and P. intermedia were inversely associated with extent of positive lesion remodeling (OR for highest versus lowest tertile 0.55, 95%CI 0.35-0.88, p = 0.012; 0.53, 95%CI 0.32-0.87, p = 0.012; and 0.64, 95%CI 0.40-1.02, p = 0.061, respectively). In diabetic patients specifically, IgG against P. gingivalis tended to be associated with coronary plaque burden (p = 0.080), while IgA against P. gingivalis tended to be associated with incident MACE (p = 0.060). CONCLUSION: Plasma IgG and IgA against major periodontal pathogens were not associated with the extent of coronary atherosclerosis (with the exception of a trend in diabetics) nor with coronary plaque vulnerability. IgA against periodontal pathogens were inversely associated with extent of coronary remodeling. Altogether, these results do not add evidence for a substantial role of systemic exposure to periodontal pathogens in coronary artery disease.

Efficiency of statin treatment on EPC recruitment depends on baseline EPC titer and does not improve angiographic outcome in coronary artery disease patients treated with the Genous stent.

The objective of this study was to assess the effect of high-dose atorvastatin treatment on endothelial progenitor cell (EPC) recruitment and angiographic and clinical outcome in coronary artery disease (CAD) patients treated with the Genous EPC-capturing stent. The HEALING IIB study was a multicenter, open-label, prospective trial that enrolled 100 patients. Patients were started on 80 mg atorvastatin qd, at least 2 weeks before the index procedure and continued for at least 4 weeks after the index procedure. Eighty-seven patients were included in this analysis. EPC levels significantly increased as early as 2 weeks after the start of atorvastatin. Remarkably, among this group, 31 patients proved to be nonresponders to atorvastatin treatment (i.e., no increase in EPC levels), while 56 patients were responders (i.e., rise in EPC count between week -2 and 0). Compared to responders, nonresponders had a significantly higher baseline EPC count (76 ± 10 vs. 41 ± 5, p < 0.01) with a lower late luminal loss (LLL) at 6- and 18-month follow-up (FU) (0.61 ± 0.07 vs. 0.88 ± 0.08, p < 0.05, and 0.50 ± 0.08 vs. 0.82 ± 0.08, p < 0.01 respectively). Furthermore, baseline EPC count was inversely correlated with LLL at 6-month FU (R = -0.42, p < 0.001). Patients with a higher EPC count at baseline showed no increase in EPC recruitment in response to statin treatment but had favorable LLL at 6- and 18-month FU, whereas patients with lower EPC count were responsive to statin therapy, but EPCs might be less functional as they had higher LLL at 6- and 18-month FU. These data imply that although statin treatment can enhance EPC titer in patients with low baseline levels, there is no indication for a possible beneficial clinical effect with EPC capture stents.

Relation of genetic profile and novel circulating biomarkers with coronary plaque phenotype as determined by intravascular ultrasound: rationale and design of the ATHEROREMO-IVUS study.

AIMS: The European Collaborative Project on Inflammation and Vascular Wall Remodeling in Atherosclerosis - Intravascular Ultrasound (ATHEROREMO-IVUS) study aims to investigate the relations of genetic profile and novel circulating biomarkers with coronary plaque phenotype and vulnerability as determined by intravascular ultrasound (IVUS). METHODS AND RESULTS: ATHEROREMO-IVUS is a prospective, observational cohort study of 846 patients with stable angina pectoris or acute coronary syndrome (ACS) who are referred for coronary angiography. Prior to the catheterisation procedure, blood samples are drawn for biomarker measurements and genetic analyses. During the catheterisation procedure, IVUS is performed in a non-culprit coronary artery. The primary endpoint is the presence of vulnerable plaque as determined by IVUS virtual histology. Secondary endpoints include the incidence of major adverse cardiac events during long-term follow-up. CONCLUSIONS: Results from ATHEROREMO-IVUS are expected to improve our knowledge of the role of genetic profile and circulating biomarkers in relation to the development of atherosclerosis and vulnerable plaques. Assessment and early validation of the prognostic value of novel biomarkers and intracoronary imaging techniques will be performed. (ClinicalTrials.gov number: NCT01789411).

Excess mortality in women compared to men after PCI in STEMI: an analysis of 11,931 patients during 2000-2009.

BACKGROUND: Ambiguity exists whether gender affects outcome in patients undergoing percutaneous coronary intervention (PCI). METHODS: To evaluate the relationship between gender and outcome in a large cohort of PCI patients, 11,931 consecutive patients who underwent PCI for various indications during 2000-2009 were studied using survival analyses and Cox regression models. RESULTS: Most patients (n=8588; 72%) were men. Women were older and more often had a history of hypertension and diabetes mellitus. Men smoked more frequently, had a more extensive cardiovascular history (previous MI, PCI and CABG), a higher prevalence of renal impairment and multi-vessel disease. In STEMI patients, women had higher 31-day mortality rates than men (11.6% vs. 6.5%, respectively, p<0.001). This difference remained after adjustment for confounders (aHR at 30-days 1.54 and 95% CI 1.22-1.96). Likewise, higher mortality was observed at 1-year (15.1% vs. 9.3%) and 4-year follow-up (21.6% vs. 15.0%, aHR 1.30 and 95% CI 1.10-1.53). There were no differences in mortality between women and men in NSTE-ACS (aHR at 4-years 1.05 and 95% CI 0.85-1.28) or stable angina (HR at 4-years 0.85 and 95% CI 0.68-1.08). CONCLUSION: Women undergoing PCI for STEMI had higher mortality than men. The excess mortality in women appeared in the first month after PCI and could only partially be explained by a difference in baseline characteristics. No gender differences in outcome in patients undergoing PCI for NSTE-ACS and stable angina were observed.

Circulating cytokines in relation to the extent and composition of coronary atherosclerosis: results from the ATHEROREMO-IVUS study.

OBJECTIVE: We investigated whether concentrations of TNF-α, TNF-ß, TNF-receptor 2, interferon-γ, IL-6, IL-8, IL-10 and IL-18 are associated with extent and composition of coronary atherosclerosis determined by grayscale and virtual histology (VH)- intravascular ultrasound (IVUS). METHODS: Between 2008 and 2011, IVUS(-VH) imaging of a non-culprit coronary artery was performed in 581 patients (stable angina pectoris (SAP), n = 261; acute coronary syndrome (ACS), n = 309) undergoing coronary angiography from the ATHEROREMO-IVUS study. Plaque burden, presence of VH-IVUS-derived thin-cap fibroatheroma (TCFA) lesions, and presence of VH-TCFA lesions with plaque burden ≥70% were assessed. Blood samples for cytokine measurement were drawn from the arterial sheath prior to the angiography procedure. We applied linear and logistic regression. RESULTS: TNF-α levels were positively associated with plaque burden (beta (ß) [95%CI]: 4.45 [0.99-7.91], for highest vs lowest TNF-α tertile) and presence of VH-TCFA lesions (odds ratio (OR) [95%CI] 2.30 (1.17-4.52), highest vs lowest TNF-α tertile) in SAP patients. Overall, an inverse association was found between IL-10 concentration and plaque burden (ß [95%CI]: -1.52 [-2.49 to -0.55], per Ln (pg/mL) IL-10) as well as IL-10 and VH-TCFA lesions with plaque burden ≥70% (OR: 0.31 [0.12-0.80],highest vs lowest IL-10 tertile). These effects did not reach statistical significance in the separate SAP and ACS groups. CONCLUSION: Higher circulating TNF-α was associated with higher plaque burden and VH-TCFA lesions in SAP patients. Lower circulating IL-10 was associated with higher plaque burden and large VH-TCFA lesions. These in-vivo findings suggest a role for these cytokines in extent and vulnerability of atherosclerosis.

Circulating acute phase proteins in relation to extent and composition of coronary atherosclerosis and cardiovascular outcome: results from the ATHEROREMO-IVUS study.

INTRODUCTION: We examined whether the acute phase proteins (APPs): Alpha-1-Antitrypsin, Alpha-2-Macroglobulin, Complement C3, ferritin, haptoglobin, and Plasminogen Activator Inhibitor 1 (PAI-1) are associated with cardiovascular outcome, as well as with the extent and composition of coronary atherosclerosis as determined by intravascular ultrasound (IVUS) virtual histology (VH). METHODS: In 2008-2011, IVUS(-VH) imaging of a non-culprit coronary artery was performed in 581 patients from the ATHEROREMO-IVUS study undergoing coronary angiography for acute coronary syndrome (ACS) (n=318) or stable angina pectoris (SAP) (n=263). Coronary atherosclerotic plaque volume, composition (fibrous, fibro-fatty, dense calcium and necrotic core) and vulnerability (VH-derived thin-cap fibroatheroma (TCFA) lesions) were assessed. Major adverse cardiac events (MACE; all-cause mortality, ACS or unplanned coronary revascularization) were assessed during 1-year follow-up. We applied linear, logistic and Cox regression. RESULTS: Mean age was 61.5 ± 11.4 years and 75.4% were men. Higher ferritin was associated with higher coronary plaque volume (beta [95% CI]: 0.19 [0.07-0.31] percent atheroma volume), for the highest vs the lowest tertile of ferritin; p for linear association=0.013. Higher PAI-1 was associated with higher rates of all-cause mortality or ACS (hazard ratio [95% CI]: 2.98 [1.10-8.06]), for the highest vs the lowest tertile of PAI-1. No clear-cut associations could be demonstrated between APPs and composition of atherosclerosis or plaque vulnerability. CONCLUSIONS: Higher circulating ferritin was associated with higher coronary plaque volume, and higher PAI-1 was associated with higher incidence of all-cause mortality or ACS. None of the APPs displayed consistent associations with composition of atherosclerosis or plaque vulnerability.

Near-infrared spectroscopy predicts cardiovascular outcome in patients with coronary artery disease.

BACKGROUND: Near-infrared spectroscopy (NIRS) is capable of identifying lipid core-containing plaques, which can subsequently be quantified as a lipid core burden index (LCBI). Currently, no data are available on the long-term prognostic value of NIRS in patients with coronary artery disease (CAD). OBJECTIVES: This study sought to determine the long-term prognostic value of intracoronary NIRS as assessed in a nonculprit vessel in patients with CAD. METHODS: In this prospective, observational study, NIRS imaging was performed in a nonculprit coronary artery in 203 patients referred for angiography due to stable angina pectoris (SAP) or acute coronary syndrome (ACS). The primary endpoint was the composite of all-cause mortality, nonfatal ACS, stroke, and unplanned coronary revascularization. RESULTS: The 1-year cumulative incidence of the primary endpoint was 10.4%. Cumulative 1-year rates in patients with an LCBI equal to and above the median (43.0) versus those with LCBI values below the median were 16.7% versus 4.0% (adjusted hazard ratio: 4.04; 95% confidence interval: 1.33 to 12.29; p = 0.01). The relation between LCBI and the primary endpoint was similar in SAP and ACS patients (p value for heterogeneity = 0.14). Similar differences between high and low LCBI were observed in pre-specified secondary endpoints. CONCLUSION: CAD patients with an LCBI equal to or above the median of 43.0, as assessed by NIRS in a nonculprit coronary artery, had a 4-fold risk of adverse cardiovascular events during 1-year follow-up. This observation warrants confirmation by larger studies with extended follow-up. (The European Collaborative Project on Inflammation and Vascular Wall Remodeling in Atherosclerosis - Intravascular Ultrasound Study [AtheroRemoIVUS]; NCT01789411).

Trial participation as a determinant of clinical outcome: differences between trial-participants and Every Day Clinical Care patients in the field of interventional cardiology.

BACKGROUND: This study examines differences in clinical outcome between trial-participants and non-participants after percutaneous coronary intervention (PCI). METHODS AND RESULTS: This study compromised of 11,931 consecutive patients who underwent PCI in a high volume center, during the period 2000 - 2009. Of these patients, 1787 (15%) participated in an interventional clinical trial with a follow-up period of at least six months. The maximum follow-up duration was 11.8 years, with a median of 3.8 years (IQR: 2.6 - 6.5). Baseline and procedural characteristics differed between trial-participants and non-participants. Trial-participants were more often male, were younger, had more cardiovascular risk factors and were treated more often for stable angina pectoris and single vessel disease. Overall mortality at maximum follow-up was lower for trial-participants compared to non-participants (8.1% versus 17.6%, p<0.001, adjusted HR, 0.62, 95% CI: 0.52-0.74). There was no difference in the incidence of non-fatal MI and CABG. Repeat PCI was seen more often in trial-participants (18.1% versus 30.7%, p<0.001, adjusted HR 1.91, 95%CI 1.73-2.10). Consequently, a higher incidence of the composite of mortality, repeat revascularization, and non-fatal MI was seen in the trail-participants (adjusted HR.1.36 95% CI 1.25 - 1.47), but this association was primarily driven by the occurrence of repeat PCI. CONCLUSION: Participants in clinical trials in the field of interventional cardiology with a follow-up of at least six months differed considerably from non-participants in baseline and procedural characteristics. Trial-participants had better survival than non-participants. In contrast, a two-fold higher incidence of repeat PCI was observed in trial-participants.

Life-years gained by smoking cessation after percutaneous coronary intervention.

Previous studies have shown that smoking cessation after a cardiac event reduces the risk of subsequent mortality in patients. The aim of this study was to describe the effect of smoking cessation in terms of prolonged life-years gained. The study sample comprised 856 patients who underwent percutaneous coronary intervention (PCI; balloon angioplasty) during 1980 to 1985. Patients were followed up for 30 years and smoking status at 1 year could be retrieved in 806 patients. The 27 patients who died within 1 year were excluded from the analysis. The median follow-up was 19.5 years (interquartile range 6.0 to 23.0). Cumulative 30-year survival rate was 29% in the group of patients who quit smoking and 14% in persistent smokers (p = 0.005). After adjustment for baseline characteristics at the time of PCI, smoking cessation remained an independent predictor of lesser mortality (adjusted hazard ratio 0.57, 95% confidence interval 0.46 to 0.71). The estimated life expectancy was 18.5 years in those who quit smoking and 16.4 years in the persistent smokers (p <0.0001). In conclusion, in patients with coronary heart disease who underwent PCI in the late 1980s, smoking cessation resulted in at least 2.1 life-years gained.