Luca Di Vito

OCT-Based Diagnosis and Management of STEMI Associated With Intact Fibrous Cap

In autopsy studies, at least 25% of thrombotic coronary occlusions are caused by plaque erosion in which thrombus often overlies atherosclerotic plaque without evident disruption of the fibrous cap. We performed optical coherence tomography imaging after aspiration thrombectomy and identified plaque erosion as the cause in 31 patients presenting with ST-segment elevation myocardial infarction. Plaque erosion was identified when the fibrous cap of the culprit lesion was intact. Based on clinical criteria, 40% of patients with subcritically occlusive plaque were treated with dual antiplatelet therapy without percutaneous revascularization (group 1), and the remaining 60% of patients underwent angioplasty and stenting (group 2). At a median follow-up of 753 days, all patients were asymptomatic, regardless of stent implantation. These observations support an alternative treatment strategy for patients with acute coronary events and optical coherence tomography-verified intact fibrous cap (or plaque erosion), where nonobstructive lesions might be managed without stenting.

MicroRNA signatures in peripheral blood mononuclear cells of chronic heart failure patients

MicroRNAs (miRNAs) are noncoding RNAs that act as negative regulators of gene expression. Interestingly, specific alterations of miRNA expression have been found in failing hearts of different etiologies. The aim of this study was to identify the miRNA expression pattern of peripheral blood mononuclear cells (PBMCs) derived from chronic heart failure (CHF) patients affected by ischemic (ICM) and nonischemic dilated (NIDCM) cardiomyopathy. The expression profile of 257 miRNAs was assessed in 7 NIDCM patients, 8 ICM patients, and 9 control subjects by quantitative real-time PCR. Significantly modulated miRNAs were validated by using an independent set of 34 CHF patients (NIDCM = 19, ICM = 15) and 19 control subjects. Three miRNAs (miR-107, -139, and -142-5p) were downmodulated in both NIDCM and ICM patients versus control subjects. Other miRNAs were deregulated in only one of the CHF classes analyzed compared with control subjects: miR-142-3p and -29b were increased in NIDCM patients, while miR-125b and -497 were decreased in ICM patients. Bioinformatic analysis of miRNA predicted targets and of gene expression modifications associated with CHF in PBMCs indicated a significant impact of the miRNA signature on the transcriptome. Furthermore, miRNAs of both the NIDCM and the ICM signature shared predicted targets among CHF-modulated genes, suggesting potential additive or synergistic effects. The present study identified miRNAs specifically modulated in the PBMCs of NIDCM and ICM patients. Intriguingly, most of these miRNAs were previously reported as deregulated in human and/or mouse failing hearts. The identified miRNAs might have a potential diagnostic and/or prognostic use in CHF.

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.

Predictors of Periprocedural (Type IVa) Myocardial Infarction, as Assessed by Frequency-Domain Optical Coherence Tomography

Background— Frequency-domain optical coherence tomography (FD-OCT) is easily able to define both pre- and post-stenting features of the atherosclerotic plaque that can potentially be related to periprocedural complications. We sought to examine which FD-OCT-defined characteristics, assessed both before and after stent deployment, predicted periprocedural (type IVa) myocardial infarction (MI). Methods and Results— FD-OCT was performed before and after coronary stenting in 50 patients undergoing percutaneous coronary intervention (PCI) for either non-ST segment elevation MI (NSTEMI) or stable angina. All patients underwent single-vessel stenting, and only drug-eluting stents were implanted. Troponin T was analyzed on admission, before PCI, and at 12 and 24 hours after PCI, and type IVa MI was defined in stable angina as a rise of at least 3× upper reference limit and in NSTEMI as a pre-PCI troponin T fall, followed by post-PCI troponin T rise >20%. Type IVa MI was diagnosed in 21 patients, while the remaining 29 represented the control group. FD-OCT analysis showed that thin-cap fibroatheroma (76.2% versus 41.4%; P=0.017) prior to PCI, intrastent thrombus (61.9% versus 20.7%; P=0.04), and intrastent dissection (61.9% versus 31%; P=0.03) after PCI were significantly more frequent in type IVa MI than in the control group. Multivariate logistic regression analysis confirmed thin-cap fibroatheroma (OR 29.7, 95% CI 1.4 to 32.1), intrastent thrombus (OR 5.5, CI 1.2 to 24.9) and intrastent dissection (OR 5.3, CI 1.2 to 24.3) as independent predictors of type IVa MI. Conclusions— In conclusion, presence of thin-cap fibroatheroma at pre-PCI FD-OCT and of intrastent thrombus and intrastent dissection at post-PCI FD-OCT predict type IVa MI in a contemporary sample of patients treated with second-generation drug-eluting stents. Interestingly, 2 of the 3 predictors of type IVa MI were not apparent at pre-PCI FD-OCT.

Comprehensive overview of definitions for optical coherence tomography-based plaque and stent analyses.

Optical coherence tomography (OCT) is the current state-of-the-art intracoronary imaging modality that allows visualization of detailed morphological characteristics of both atherosclerotic plaque and stent. So far, three expert review documents have been released for standardization of OCT image analysis. In the real world, a variety of definitions are being used by different groups and by different core laboratories to analyze OCT findings because of different clinical/procedural contexts in which OCT research has been carried out. This comprehensive overview is aimed to summarize different applicable definitions used by different research groups in plaque and stent analysis using OCT. In addition, it presents readers with a panoramic view to select the best definition of OCT measurement for ones own study purpose. We divided this review article into two parts: Part I - Plaque analysis, and Part II - Stent analysis. The plaque analysis section summarizes the definitions of plaque composition, rupture, erosion, protruding calcific nodules, macrophages, microvessels, and cholesterol crystal. The stent analysis section includes the classification of stent struts, features of neointimal hyperplasia, and other stent-related findings such as tissue protrusion, thrombus, intrastent, and stent edge dissections. In each case of controversy, an explanation for the specific context is provided.

Severity of coronary atherosclerosis in patients with a first acute coronary event: a diabetes paradox

AIMS We aimed to compare coronary artery disease (CAD) at the time of a first acute coronary syndrome (ACS) in type II diabetic and non-diabetic patients by coronary angiography and by optical coherence tomography (OCT). METHODS AND RESULTS Two different patient populations with a first ACS were enrolled for the angiographic (167 patients) and the OCT (72 patients) substudy. Angiographic CAD severity was assessed by Bogaty, Gensini, and Sullivan scores, whereas collateral development towards the culprit vessel was assessed by the Rentrop score. Optical coherence tomography plaque features were evaluated at the site of the minimum lumen area (MLA) and of culprit segment. In the angiographic substudy, at multivariate analysis, diabetes was associated with both the stenosis score and the extent index (P = 0.001). Furthermore, well-developed collateral circulation (Rentrop 2-3) towards the culprit vessel was more frequent in diabetic than in non-diabetic patients (73% vs. 16%, P = 0.001). In the OCT substudy, at MLA site lipid quadrants were less and the lipid arc was smaller in diabetic than in non-diabetic patients (2.3 ± 1.3 vs. 3.0 ± 1.2; P = 0.03 and 198° ± 121° vs. 260° ± 118°; P = 0.03). Furthermore, the most calcified cross-section along the culprit segment had a greater number of calcified quadrants and a wider calcified arc in diabetic than in non-diabetic patients (1.7 ± 1.0 vs. 1.2 ± 0.9; P = 0.03 and 126° ± 95° vs. 81° ± 80°; P = 0.03). Superficial calcified nodules were more frequently found in diabetic than in non-diabetic patients (79 vs. 54%, P = 0.04). CONCLUSIONS In spite of potent pro-inflammatory, pro-oxidant and pro-thrombotic stimuli operating in type II diabetes, diabetic patients exhibit substantially more severe coronary atherosclerosis than non-diabetic patients at the time of a first acute coronary event. Better collateral development towards the culprit vessel, a predominantly calcific plaque phenotype and, probably, yet unknown protective factors operating in diabetic patients may explain these intriguing paradoxical findings.

Gene expression profiles in peripheral blood mononuclear cells of chronic heart failure patients

The present study was aimed at identifying chronic heart failure (CHF) biomarkers from peripheral blood mononuclear cells (PBMCs) in patients with ischemic (ICM) and nonischemic dilated (NIDCM) cardiomyopathy. PBMC gene expression profiling was performed by Affymetrix in two patient groups, 1) ICM (n = 12) and 2) NIDCM (n = 12) New York Heart Association (NYHA) III/IV CHF patients, vs. 3) age- and sex-matched control subjects (n = 12). Extracted RNAs were then pooled and hybridized to a total of 11 microarrays. Gene ontology (GO) analysis separated gene profiling into functional classes. Prediction analysis of microarrays (PAM) and significance analysis of microarrays (SAM) were utilized in order to identify a molecular signature. Candidate markers were validated by quantitative real-time polymerase chain reaction. We identified a gene expression profiling that distinguished between CHF patients and control subjects. Interestingly, among the set of genes constituting the signature, chemokine receptor (CCR2, CX(3)CR1) and early growth response (EGR1, 2, 3) family members were found to be upregulated in CHF patients vs. control subjects and to be part of a gene network. Such findings were strengthened by the analysis of an additional 26 CHF patients (n = 14 ICM and n = 12 NIDCM), which yielded similar results. The present study represents the first large-scale gene expression analysis of CHF patient PBMCs that identified a molecular signature of CHF and putative biomarkers of CHF, i.e., chemokine receptor and EGR family members. Furthermore, EGR1 expression levels can discriminate between ICM and NIDCM CHF patients.

Altered SDF-1-mediated differentiation of bone marrow-derived endothelial progenitor cells in diabetes mellitus

In diabetic patients and animal models of diabetes mellitus (DM), circulating endothelial progenitor cell (EPC) number is lower than in normoglycaemic conditions and EPC angiogenic properties are inhibited. Stromal cell derived factor‐1 (SDF‐1) plays a key role in bone marrow (BM) c‐kit+ stem cell mobilization into peripheral blood (PB), recruitment from PB into ischemic tissues and differentiation into endothelial cells. The aim of the present study was to examine the effect of DM in vivo and in vitro, on murine BM‐derived c‐kit+ cells and on their response to SDF‐1. Acute hindlimb ischemia was induced in streptozotocin‐treated DM and control mice; circulating c‐kit+ cells exhibited a rapid increase followed by a return to control levels which was significantly faster in DM than in control mice. CXCR4 expression by BM c‐kit+ cells as well as SDF‐1 protein levels in the plasma and in the skeletal muscle, both before and after the induction of ischemia, were similar between normoglycaemic and DM mice. However, BM‐derived c‐kit+ cells from DM mice exhibited an impaired differentiation towards the endothelial phenotype in response to SDF‐1; this effect was associated with diminished protein kinase phosphorylation. Interestingly, SDF‐1 ability to induce differentiation of c‐kit+ cells from DM mice was restored when cells were cultured under normoglycaemic conditions whereas c‐kit+ cells from normoglycaemic mice failed to differentiate in response to SDF‐1 when they were cultured in hyperglycaemic conditions. These results show that DM diminishes circulating c‐kit+ cell number following hindlimb ischemia and inhibits SDF‐1‐mediated AKT phosphorylation and differentiation towards the endothelial phenotype of BM‐derived c‐kit+ cells.

Suboptimal stent deployment is associated with subacute stent thrombosis: Optical coherence tomography insights from a multicenter matched study. From the CLI Foundation investigators: the CLI-THRO study

BACKGROUND Acute or subacute stent thrombosis (ST) is a well-described complication usually causing acute coronary syndromes and, in the worst case scenario, sudden cardiac death. In this study, we aimed at exploring the potential role of optical coherence tomography (OCT) in the understanding of the mechanism of ST. METHODS Twenty-one consecutive patients, after acute coronary syndromes due to a definite subacute ST, were assessed with OCT and matched 1:2 with 42 patients undergoing OCT for scheduled follow-up. Optical coherence tomography assessment was focused on features indicative of nonoptimal stent deployment: underexpansion, malapposition, edge dissection, and reference lumen narrowing. RESULTS Optical coherence tomography revealed a minimum stent area sensibly smaller in the ST group (5.6 ± 2.6 vs 6.8 ± 1.7 mm(2); P = .03) with a higher incidence of stent underexpansion when compared with the control group (42.8% vs 16.7%; P = .05). Dissection at stent edges was more commonly detected in ST group (52.4% vs 9.5%; P < .01). No significant differences between the 2 groups were observed for malapposition (52.4% vs 38.1%; P = .651) and reference lumen narrowing (19.0% vs 4.8%; P = .172). At least 1 OCT finding indicative of suboptimal stent deployment was detectable in 95.2% of patients experiencing ST versus 42.9% of the control group (P < .01). CONCLUSIONS Optical coherence tomography assessment in patients experiencing subacute ST revealed nonoptimal stent deployment in almost all cases with higher incidence of stent underexpansion and edge dissection, potentially explaining the cause of this adverse event. The adoption of an OCT-guided percutaneous coronary intervention protocol could have a potential for the prevention of ST in complex cases.

Increase of plasma IL-9 and decrease of plasma IL-5, IL-7, and IFN-γ in patients with chronic heart failure

BackgroundSeveral cytokines are associated with the development and/or progression of chronic heart failure (CHF). Our aim was to look more closely at the cytokine networks involved in CHF, and to assess whether disease etiology affects cytokine expression. The study population was comprised of a) 69 patients with stable CHF, New York Heart Association (NYHA) II/IV classes, secondary to ischaemic (ICM) and non ischaemic dilated (NIDCM) cardiomyopathy and b) 16 control subjects. We analyzed and compared the plasma levels of 27 pro- and anti-inflammatory mediators, in the study population and assessed for any possible correlation with echocardiographic parameters and disease duration.Methods27 cytokines and growth factors were analyzed in the plasma of ICM- (n = 42) and NIDCM (n = 27) NYHA class II-IV patients vs age- and gender-matched controls (n = 16) by a beadbased multiplex immunoassay. Statistical analysis was performed by ANOVA followed by Tukey post-hoc test for multiple comparison.ResultsMacrophage inflammatory protein (MIP)-1β, Vascular endothelial growth factor (VEGF), interleukin (IL)-9, Monocyte chemotactic protein (MCP)-1, and IL-8 plasma levels were increased in both ICM and NIDCM groups vs controls. In contrast, IL-7, IL-5, and Interferon (IFN)-γ were decreased in both ICM and NIDCM groups as compared to controls. Plasma IL-6 and IL-1 β were increased in ICM and decreased in NIDCM, vs controls, respectively.IL-9 levels inversely correlated, in ICM patients, with left ventricular ejection fraction (LVEF) while IL-5 plasma levels inversely correlated with disease duration, in NYHA III/IV ICM patients.This is the first time that both an increase of plasma IL-9, and a decrease of plasma IL-5, IL-7 and IFN-γ have been reported in ICM as well as in NIDCM groups, vs controls. Interestingly, such cytokines are part of a network of genes whose expression levels change during chronic heart failure. The altered expression levels of MIP-1 β, VEGF, MCP-1, IL-1 β, IL-6, and IL-8, found in this study, are in keeping with previous reports.ConclusionsThe increase of plasma IL-9, and the decrease of plasma IL-5, IL-7 and IFN-γ in ICM as well as in NIDCM groups vs controls may contribute to get further insights into the inflammatory pathways involved in CHF.