Sanneke P.M. de Boer

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.

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).

NIRS and IVUS for characterization of atherosclerosis in patients undergoing coronary angiography

OBJECTIVES The aim of this study was to compare the findings of near-infrared spectroscopy (NIRS), intravascular ultrasound (IVUS) virtual histology (VH), and grayscale IVUS obtained in matched coronary vessel segments of patients undergoing coronary angiography. BACKGROUND Intravascular ultrasound VH has been developed to add tissue characterization to the grayscale IVUS assessment of coronary plaques. Near-infrared spectroscopy is a new imaging technique able to identify lipid core-containing coronary plaques (LCP). METHODS We performed NIRS and IVUS-VH pullbacks in a consecutive series of 31 patients with a common region of interest (ROI) between 2 side branches. For each ROI, we analyzed the chemogram blocks by NIRS, plaque area and plaque burden by grayscale IVUS, and tissue types by IVUS-VH. The chemogram block is a summary metric of a 2-mm vertical slice of the chemogram. The value ranges from 0 to 1 according to the presence of lipids and represents the probability of LCP with a color scale from red (low probability) through orange and tan to yellow (high probability). RESULTS Plaque area (mm(2)) increases as percentage VH derived-necrotic core (NC) content (4.6 ± 2.7 vs. 7.4 ± 3.5 vs. 8.6 ± 3.4 vs. 7.9 ± 3.3, grouped in percentage NC quartiles, p<0.001) and chemogram block probability color bin thresholds increase (4.9 ± 3.8 red, 7.3 ± 3.6 orange, 8.1 ± 3.4 tan, and 8.7 ± 3.4 yellow, p<0.001). The correlation between the block chemogram detection of lipid core and percentage NC content by VH was weak (r=0.149). Correction for the presence of calcium does not improve this correlation. CONCLUSIONS Larger plaque area by grayscale IVUS was more often associated with either elevated percentage VH-NC or LCP by NIRS; however, the correlation between the detection of LCP by NIRS and necrotic core by VH is weak.

Mortality and Morbidity Reduction by Primary Percutaneous Coronary Intervention Is Independent of the Patient's Age

OBJECTIVES The aim of this study was to obtain a valid estimate of the clinical effects of primary percutaneous coronary intervention (PPCI) in relation to age. BACKGROUND Treatment with PPCI is most beneficial in high-risk myocardial infarction patients. Paradoxically, elderly patients, who are at increased risk of adverse outcome, are often withheld PPCI. METHODS Individual patient data were obtained from 22 randomized trials (n = 6,763) evaluating the clinical effects of PPCI versus fibrinolysis (FL). Differences in 30-day death, repeat myocardial infarction, and stroke between patients randomized to FL and PPCI were determined in 5 age-strata: < or =50, >50 to 60, >60 to 70, >70 to 80, and >80 years. Treatment effects are reported as odds ratios (ORs) and 95% confidence intervals (CI). Multivariable logistic regression analyses, which included age x treatment interaction, were applied to examine evidence of heterogeneity in age-specific ORs. RESULTS Thirty-day death increased with increasing age and ranged from 1.1% (FL) and 1.8% (PPCI) in patients < or =50 years to 26.4% and 18.3% in patients >80 years of age. The point estimate of treatment effect (overall adjusted OR: 0.65; 95% CI: 0.52 to 0.79) was compatible with a mortality reduction favoring PPCI in all age-strata (except in patients < or =50 years of age), and 95% CIs were largely overlapping. There was no evidence of heterogeneity in ORs between age categories. Similar results were observed for repeat myocardial infarction and stroke. CONCLUSIONS In this analysis of randomized trials, the reduction in clinical end points by PPCI was not influenced by age. Hence, age per se should not be considered an exclusion criterion for the application of PPCI.

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.

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).

Short- and long-term outcomes in octogenarians undergoing percutaneous coronary intervention with stenting

AIMS To investigate the incidence of cardiac events in octogenarians who underwent percutaneous coronary intervention (PCI) with stenting, as well as to evaluate the efficacy and safety of drug-eluting stents (DES) in this population. METHODS AND RESULTS The study included 6,129 consecutive patients who underwent PCI with stenting from 2000 to 2005 in our centre, of whom 291 (4.7%) were octogenarians. After adjusting for confounders, age ≥80 years appeared a significant predictor of high mortality at 30 days (adjusted hazard ratio [aHR] 1.92, 95% CI 1.23-3.01), and four years (aHR 2.25, 95% CI 1.77-2.85). No differences were seen with respect to incident myocardial infarction (MI), but target lesion (63.2 vs. 32.6 per 1,000 person-years at one year and 27.9 vs. 16.6 per 1,000 person-years at four years) and vessel (83.1 vs. 52.9 per 1,000 person-years at one year and 37.7 vs. 25.0 per 1,000 person-years at four years) revascularisation rates were lower in octogenarians. When comparing DES with bare metal stents (BMS) in octogenarians, mortality and MI rates were comparable, but there was a significantly lower incidence of target lesion revascularisation at one- (9.5 vs. 0.6 per 1,000 person-years, aHR 0.07, 95% CI 0.01-0.57) and four-year (3.4 vs. 0.7 per 1,000 person-years, aHR 0.16, 95% CI 0.04-0.59) follow-up in patients who received a DES. CONCLUSIONS Octogenarians undergoing PCI with stenting have an increased mortality risk, whereas the rates of repeat revascularisation in octogenarians are lower. This study suggests that the benefit of DES in reducing revascularisation rates is extended to elderly patients.

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 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.

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.