Rocco A. Montone

High Levels of Systemic Myeloperoxidase Are Associated With Coronary Plaque Erosion in Patients With Acute Coronary Syndromes A Clinicopathological Study

Background— Systemic levels of myeloperoxidase predict prognosis in patients with acute coronary syndromes and are considered a marker of plaque vulnerability. It is not known whether myeloperoxidase is associated with different coronary morphologies (ie, rupture or erosion of the culprit lesion) in patients with acute coronary syndrome. Methods and Results— Twenty-five consecutive patients (aged 67±11 years; 15 men [60%]; 13 [52%] with non-ST-segment elevation acute coronary syndrome and 12 [48%] with acute ST-segment elevation myocardial infarction) were enrolled. Optical coherence tomography classified the culprit lesion as ruptured in 18 (72%) or eroded in 7 patients (28%) and detected intraluminal thrombus in 89% of ruptured plaques and 100% of eroded plaques. Baseline systemic levels of serum myeloperoxidase were significantly higher in patients with an eroded plaque than in those with a ruptured plaque (median, 2500 ng/mL; 25th to 75th percentile, 1415 to 2920 versus median, 707 ng/mL; 25th to 75th percentile, 312 to 943; P=0.001), whereas C-reactive protein levels did not differ significantly (median, 11.3 mg/L; 25th to 75th percentile, 1.3 to 28.5 versus median, 3.9 mg/L; 25th to 75th percentile, 1.3 to 17.8; P=0.76, respectively). In addition, the density of myeloperoxidase-positive cells within thrombi overlying plaques in postmortem coronary specimens retrieved from sudden coronary death victims was significantly higher in lesions with erosion (n=11) than ruptures (n=11) (median, 1584; 25th to 75th percentile, 1088 to 2135 cells/mm2 versus median, 579; 25th to 75th percentile, 442 to 760 cells/mm2; P=0.0012). Conclusions— Systemic myeloperoxidase levels are significantly elevated in patients with acute coronary syndrome presenting with eroded culprit plaque compared with patients presenting with ruptured culprit plaque. Consistently, in postmortem coronary specimens, luminal thrombi superimposed on eroded plaques contain a higher density of myeloperoxidase-positive cells than thrombi superimposed on ruptured plaques. This study supports the concept that elevations in selective inflammatory biomarkers reflect specific acute complications of coronary atherosclerosis.

Plaque rupture and intact fibrous cap assessed by optical coherence tomography portend different outcomes in patients with acute coronary syndrome.

AIMS Patients presenting with acute coronary syndrome (ACS) may have different plaque morphologies at the culprit lesion. In particular, plaque rupture (PR) has been shown as the more frequent culprit plaque morphology in ACS. However, its prognostic value is still unknown. In this study, we evaluated the prognostic value of PR, compared with intact fibrous cap (IFC), in patients with ACS. METHODS AND RESULTS We enrolled consecutive patients admitted to our Coronary Care Unit for ACS and undergoing coronary angiography followed by interpretable optical coherence tomography (OCT) imaging. Culprit lesion was classified as PR and IFC by OCT criteria. Prognosis was assessed according to such culprit lesion classification. Major adverse cardiac events (MACEs) were defined as the composite of cardiac death, non-fatal myocardial infarction, unstable angina, and target lesion revascularization (follow-up mean time 31.58 ± 4.69 months). The study comprised 139 consecutive ACS patients (mean age 64.3 ± 12.0 years, male 73.4%, 92 patients with non-ST elevation ACS and 47 with ST-elevation ACS). Plaque rupture was detected in 82/139 (59%) patients. There were no differences in clinical, angiographic, or procedural data between patients with PR when compared with those having IFC. Major adverse cardiac events occurred more frequently in patients with PR when compared with those having IFC (39.0 vs. 14.0%, P = 0.001). Plaque rupture was an independent predictor of outcome at multivariable analysis (odds ratio 3.735, confidence interval 1.358-9.735). CONCLUSION Patients with ACS presenting with PR as culprit lesion by OCT have a worse prognosis compared with that of patients with IFC. This finding should be taken into account in risk stratification and management of patients with ACS.

Expansion of CD4+CD28null T-lymphocytes in diabetic patients: exploring new pathogenetic mechanisms of increased cardiovascular risk in diabetes mellitus

AIMS Diabetes mellitus (DM) is associated with high incidence of first and recurrent cardiovascular events, especially acute coronary syndromes (ACSs); however, the mechanisms involved are still unknown. We sought to investigate the role of CD4(+)CD28(null)T-lymphocytes, a rare long-lived subset of T-lymphocytes with proatherogenic and plaque-destabilizing properties, in the increased cardiovascular risk associated with DM. METHODS AND RESULTS CD4(+)CD28(null)T-cell frequency was analysed by flow-cytometry in 60 DM patients without overt cardiovascular disease (cDM), in 166 ACS patients with or without DM (ACS/DM+, n= 51 and ACS/DM-, n= 115), and in 60 healthy individuals. The incidence of cardiovascular events (death, myocardial infarction, unstable angina) was assessed at 36 months follow-up. CD4+CD28(null)T-cell frequency (median, range) was higher in ACS/DM+ (12.7%, 0.1-48) vs. ACS/DM- (3.9%, 0.2-35), cDM (3.1%, 0.3-22.4), and controls (1.5%, 0.1-9.1) (P< 0.001 for all comparisons). Notably, cDM patients had significantly higher CD4+CD28(null)T-cell frequency than controls (P= 0.001). Glycosylated haemoglobin A(1c) was the only parameter independently associated with CD4+CD28(null)T-cells in cDM. The 36-month event-free survival was significantly lower in cDM patients with CD4+CD28(null)T-cells ≥4% (90th percentile of normal distribution) than in those with CD4+CD28(null)T-cells <4% (P= 0.039). Among ACS patients, the 36-month event-free survival was the lowest in those with DM and CD4+CD28(null)T-cells ≥4% and highest in those without DM and CD4+CD28(null)T-cells <4% (P< 0.001), being intermediate in those with only one of these features. CONCLUSIONS In DM patients, CD4+CD28(null)T-cells are expanded and are associated with poor glycaemic control; they also correlate with the occurrence of a first cardiovascular event and with a worse outcome after an ACS.

The Evolving Role of Inflammatory Biomarkers in Risk Assessment After Stent Implantation

The main adverse reactions to coronary stents are in-stent restenosis (ISR) and stent thrombosis. Along with procedural factors, individual susceptibility to these events plays an important role. In particular, inflammatory status, as assessed by C-reactive protein levels, predicts the risk of ISR after bare-metal stent implantation, although it does not predict the risk of stent thrombosis. Conversely, C-reactive protein levels fail to predict the risk of ISR after drug-eluting stent (DES) implantation, although they appear to predict the risk of stent thrombosis. Of note, DES have abated ISR rates occurring in the classical 1-year window, but new concern is emerging regarding late restenosis and thrombosis. The pathogenesis of these late events seems to be related to delayed healing and allergic reactions to polymers, a process in which eosinophils seem to play an important role by enhancing restenosis and thrombosis. The identification of high-risk individuals based on biomarker assessment may be important for the management of patients receiving stent implantation. In this report, we review the evolving role of inflammatory biomarkers in predicting the risk of ISR and stent thrombosis.

Coronary atherosclerotic burden in patients with infection by CagA-positive strains of Helicobacter pylori

ObjectivesCytotoxic associated gene-A (CagA)-positive strains of Helicobacter pylori emerged as a possible atherosclerotic stimulus. Nevertheless, whether CagA-positivity is associated with more extensive or severe atherosclerotic coronary burden has never been studied. MethodsForty consecutive patients with coronary artery disease (CAD) and twenty consecutive patients with normal coronary arteries undergoing coronary angiography were enrolled. All patients underwent evaluation of classical atherogenic risk factors and assessment of anti-urease B and anti-CagA antibodies titer. Either the severity of coronary stenosis (stenosis score) or the extent of coronary atherosclerosis (extent score) was evaluated in CAD patients. ResultsThe anti-CagA antibody titer was significantly higher in patients with CAD as compared with normal coronary arteries patients [85 (10–108.75) vs. 47.3 (17–64) RU/ml, P=0.02], whereas there were no differences in anti-urease B titer between the two groups. A significant correlation was found between anti-CagA antibody titer and extent score (R=0.35, P=0.03), whereas stenosis score was similar (R=0.25, P=0.11). On the contrary, no significant correlation was found between anti-urease B antibody titer and either extent or stenosis score. Moreover, CagA-positive patients had a more extensive CAD (P=0.029) when compared with CagA-negative patients. Interestingly, whereas serum glucose, LDL levels, anti-urease B, and anti-CagA antibodies were predictors of extent score at univariate analysis, at multivariate analysis anti-CagA antibody titer only was an independent predictor of the extent of coronary atherosclerosis (B=0.051, standard error of B=0.042, P=0.04). ConclusionThese results support the association between CagA-positive H. pylori infection and coronary atherosclerotic burden. Further studies are needed to better elucidate the mechanism by which CagA-positive strains may promote atherosclerosis.

Pre-intervention eosinophil cationic protein serum levels predict clinical outcomes following implantation of drug-eluting stents

AIMS Eosinophils have been identified in post-mortem studies as important players of both restenosis and thrombosis after drug-eluting stent (DES) implantation. We aimed at assessing the association between baseline levels of eosinophil cationic protein (ECP), a marker of eosinophil activation, and recurrence of clinical events in a consecutive series of patients who underwent DES implantation. METHODS AND RESULTS Two hundred patients (age 63 +/- 10.4, males 75%) undergoing implantation of first-generation DES (Taxus or Cypher stents) were enrolled. We measured serum levels of ECP and total IgE by enzyme-linked immunosorbent assay and of C-reactive protein by high-sensitivity nephelometry prior to percutaneous coronary intervention. A clinical follow-up was planned 18 months after discharge. Major adverse cardiac events (MACEs), such as cardiac death, recurrent myocardial infarction, or clinically driven target lesion revascularization, were the endpoint of the study. Twenty-two patients (11%) had MACEs and showed higher serum levels of ECP compared with those without MACEs [30.5 (14.4-50) vs. 12.2 (4.4-31) microg/L, P = 0.004]. At simple Cox regression analysis, serum levels of ECP were a significant predictor of MACEs (hazard ratio 1.016, 95% confidence interval 1.003-1.03, P = 0.018). CONCLUSION This study shows for the first time an association between baseline ECP levels and the occurrence of MACEs in patients undergoing implantation of DES. Further studies are warranted to establish whether in this setting ECP is a risk marker or plays a contributory pathogenetic role.

Eosinophil cationic protein: A new biomarker of coronary atherosclerosis

AIMS Coronary atherosclerosis is a chronic inflammatory disease, but different inflammatory biomarkers may reflect different phases of atherosclerotic plaque evolution. We aimed at assessing the role of eosinophil cationic protein (ECP), a sensitive marker of eosinophil activation, and C-reactive protein (CRP) in coronary artery disease (CAD). METHODS AND RESULTS Consecutive anginal patients with angiographic evidence of CAD [stable angina (SA) or non-ST-elevation acute coronary syndrome (NSTE-ACS)], or with angiographically normal coronary arteries (NCA) were enrolled. The severity of CAD was graded according to Bogatys score and coronary lesion morphology was defined as smooth or complex. Baseline ECP and high sensitivity CRP were measured in all patients. Of 198 patients (64 + or - 10 years, male 74%), 91 had SA, 57 had NSTE-ACS and 50 had NCA. ECP levels were significantly higher in SA [30 microg/L (13.8-46.9), p<0.001] and NSTE-ACS [21.8 microg/L (5.5-46.3), p=0.016] compared to NCA [9.7 microg/L (6.1-13.6)], without significant difference between SA and NSTE-ACS (p=0.45). CRP levels were significantly higher in NSTE-ACS [2.38 mg/L (1.11-11.94)] compared to SA [1.48 mg/L (0.82-2.83), p=0.03], and NCA [1.09 mg/L (0.8-2.1), p<0.001], without significant difference between SA and NCA (p=0.20). The addition of ECP to main cardiovascular risk factors improved the area under the curve from 0.88 to 0.92, p=0.007 for the angiographic diagnosis of CAD; further addition of CRP increased the area to 0.94, p=0.014. At multiple linear regression analysis ECP levels independently predicted CAD severity (p=0.001), whereas CRP levels independently predicted lesion complexity (p=0.01). CONCLUSIONS Our study shows that ECP is a marker of CAD and that different inflammatory biomarkers reflect different phases of atherosclerotic plaque evolution.

Patients with acute myocardial infarction and non-obstructive coronary arteries: safety and prognostic relevance of invasive coronary provocative tests

Aims Functional alterations of epicardial coronary arteries or coronary microcirculation represent a frequent cause of myocardial infarction and non-obstructive coronary arteries (MINOCA). We aimed at assessing the prognostic value of intracoronary provocative tests in patients presenting with MINOCA and in which other causes of MINOCA have been excluded. Methods and results We prospectively evaluated patients with a diagnosis of MINOCA, excluding patients with aetiologies other than suspected coronary vasomotor abnormalities. Immediately after coronary angiography, an invasive provocative test using acetylcholine or ergonovine was performed. The incidence of death from any cause, cardiac death, and recurrence of acute coronary syndrome (ACS) was assessed at follow-up. We also assessed angina status using Seattle Angina Questionnaires (SAQ). We enrolled 80 consecutive patients [mean age 63.0 ± 10.7 years, 40 (50%) male]. Provocative test was positive in 37 (46.2%) patients without any complication. Among patients with a positive test, epicardial spasm was detected in 24 (64.9%) patients and microvascular spasm in 13 (35.1%) patients. After a median follow-up of 36.0 (range 12.0-60.0) months, patients with a positive test had a significantly higher occurrence of death from any cause [12 (32.4%) vs. 2 (4.7%); P = 0.002], cardiac death [7 (18.9%) vs. 0 (0.0%); P = 0.005], and readmission for ACS [10 (27.0%) vs. 3 (7.0%); P = 0.015] as well as a worse angina status as assessed by SAQ [Seattle score: 88.0 (33.0-100.0) vs. 100.0 (44.0-100.0); P = 0.001] when compared with patients with a negative test. Conclusions We demonstrate that in patients presenting with MINOCA and suspected coronary vasomotor abnormalities, a positive provocative test for spasm is safe and identifies a high-risk subset of patients.

Inflammatory Mechanisms of Adverse Reactions to Drug-Eluting Stents

In-stent restenosis and stent thrombosis represent the main adverse reactions to coronary stents and individual susceptibility appears to play an important role in their onset. In particular, inflammatory status, classically assessed by C-reactive protein levels, predicts the risk of in-stent restenosis after bare-metal stent implantation but not after drug-eluting stent (DES) implantation. On the other hand, C-reactive protein seems to predict the risk of stent thrombosis after treatment with DES but not with bare-metal stent. If DES have considerably reduced, as compared to bare-metal stent, the rate of adverse reaction in the first year after implantation, concern is emerging about late events that seem to be related to delayed healing and allergic reactions to polymers, a process in which eosinophils play an important role by enhancing restenosis and thrombosis.

Predictive value of C-reactive protein after drug-eluting stent implantation

During the last few decades, with the evolution of techniques and materials and the increasing experience of operators, percutaneous coronary interventions (PCI) have become an equally efficient alternative to coronary artery bypass grafts for the treatment of most coronary stenoses. Bare-metal stent implantation represented a major step forward, compared with plain old balloon angioplasty (POBA), by improving the immediate angiographic success. However, the incidence of in-stent restenosis (ISR) remained unacceptably high. Development of the drug-eluting stent (DES) significantly improved the outcome of PCI by dramatically abating the rate of ISR and reducing the incidence of target lesion revascularization. However, ISR has not been eliminated and the persistence of metal vessel scaffolding also raises concern regarding the occurrence of late or very late stent thrombosis. POBA and stent implantation have been shown to induce a local and systemic inflammatory response, whose magnitude is associated with worse clinical outcome, and they increase the risk of ISR. C-reactive protein, a marker of systemic inflammation, has been demonstrated to predict clinical and angiographic outcome after POBA or bare-metal stent implantation. However, conflicting data regarding the prognostic value of C-reactive protein following DES implantation are available. In this paper, we review the literature regarding the clinical and pathophysiological association between inflammation and prognosis after DES implantation and suggest some possible therapeutic approaches to reduce inflammatory burden with the aim to improve clinical and angiographic outcome after PCI.