Pathogenic pathways and therapeutic targets of inflammation in heart diseases: A focus on Interleukin-1.

BACKGROUND: An exuberant and dysregulated inflammatory response contributes to the development and progression of cardiovascular diseases (CVDs). METHODS: This narrative review includes original articles and reviews published over the past 20 years and found through PubMed. The following search terms (or combination of terms) were considered: "acute pericarditis," "recurrent pericarditis," "myocarditis," "cardiac sarcoidosis," "atherosclerosis," "acute myocardial infarction," "inflammation," "NLRP3 inflammasome," "Interleukin-1" and "treatment." RESULTS: Recent evidence supports the role of inflammation across a wide spectrum of CVDs including myocarditis, pericarditis, inflammatory cardiomyopathies (i.e. cardiac sarcoidosis) as well as atherosclerotic CVD and heart failure. Interleukins (ILs) are the signalling mediators of the inflammatory response. The NACHT, leucine-rich repeat and pyrin-domain containing protein 3 (NLRP3) inflammasome play a key role in producing IL-1ß, the prototypical pro-inflammatory cytokine involved in CVDs. Other pro-inflammatory cytokines (e.g. tumour necrosis factor) have been implicated in cardiac sarcoidosis. As a proof of this, IL-1 blockade has been proven efficacious in pericarditis and chronic coronary syndrome. CONCLUSION: Tailored strategies aiming at quenching the inflammatory response have emerged as promising to treat CVDs. In this review article, we summarize recent evidence regarding the role of inflammation across a broad spectrum of CVDs. We also review novel evidence regarding targeted therapeutic strategies.

Mechanical Circulatory Support for High-Risk Percutaneous Coronary Intervention.

PURPOSE OF REVIEW: This review will focus on the indications of mechanical circulatory support (MCS) for high-risk percutaneous coronary intervention (PCI) and then analyze in detail all MCS devices available to the operator, evaluating their mechanisms of action, pros and cons, contraindications, and clinical data supporting their use. RECENT FINDINGS: Over the last decade, the interventional cardiology arena has witnessed an increase in the complexity profile of the patients and lesions treated in the catheterization laboratory. Patients with significant comorbidity burden, left ventricular dysfunction, impaired hemodynamics, and/or complex coronary anatomy often cannot tolerate extensive percutaneous revascularization. Therefore, a variety of MCS devices have been developed and adopted for high-risk PCI. Despite the variety of MCS available to date, a detailed characterization of the patient requiring MCS is still lacking. A precise selection of patients who can benefit from MCS support during high-risk PCI and the choice of the most appropriate MCS device in each case are imperative to provide extensive revascularization and improve patient outcomes. Several new devices are being tested in early feasibility studies and randomized clinical trials and the experience gained in this context will allow us to provide precise answers to these questions in the coming years.

Clinical and Pharmacological Implications of Time to Treatment with Interleukin-1 Blockade in ST-Segment Elevation Myocardial Infarction.

Interleukin-1 (IL-1) blockade with anakinra given within 12 hours from reperfusion has been shown to reduce the inflammatory response as well as prevent heart failure (HF) events in patients with STEMI. We sought to determine whether time-to-treatment influences the efficacy of anakinra on systemic inflammation and incidence of HF events in patients with STEMI. We divided the cohort in two groups base6d on the median time from percutaneous coronary intervention (PCI) to investigational drug, and analyzed the effects of anakinra on the area-under-the-curve for C reactive protein (AUC-CRP) and on incidence of the composite endpoint of death or new onset HF. We analyzed data from 139 patients: 84 (60%) treated with anakinra and 55 (40%) with placebo. The median time from PCI to investigational treatment was 271 (182-391) minutes. The AUC-CRP was significantly higher in patients receiving placebo versus anakinra both in those with time from PCI to treatment <271 minutes (222.6 [103.9-325.2] vs. 78.4 [44.3-131.2], P < 0.001) and those with time from PCI to treatment ≥271 minute (235.2 [131.4-603.4] vs. 75.5 [38.9-171.9], P < 0.001) (P > 0.05 for interaction). Anakinra significantly reduced the combined endpoint of death or new onset HF in patients with time from PCI to treatment <271 minutes (5 [11%] vs. 9n[36%], log-rank χ 2 5.985, P = 0.014) as well as in patients with time from PCI to drug ≥271 minutes (2n[5%] vs. 7 [23%], log-rank χ 2 3.995, P = 0.046) (P > 0.05 for interaction). IL-1 blockade with anakinra blunts the acute systemic inflammatory response and prevents HF events independent of time-to-treatment. SIGNIFICANCE STATEMENT: In patients with ST segment elevation presenting within 12 hours of pain onset and treated within 12 hours of reperfusion, interleukin-1 blockade with anakinra blunts the acute systemic inflammatory response, a surrogate of interleukin-1 activity, and prevents heart failure events independent of time-to-treatment.

Chronic total occlusion percutaneous coronary intervention in heart transplant patients.

Cardiac allograft vasculopathy (CAV) is frequently observed after heart transplant (HT), and represents one of the main causes of chronic rejection, graft loss, and death. While the role of percutaneous coronary intervention (PCI) is well established in the management of CAV in cases of nonocclusive stenoses, the outcomes and technical aspects of this procedure in chronic total occlusions (CTOs) are unknown. We describe our experience with three cases in which CTO PCI was indicated to treat CAV in HT recipients, and we discuss the peculiarities and therapeutic approach to this challenging patient population. In particular, all patients were asymptomatic for angina, and CTO PCI was indicated to promote recovery of left ventricular function, extend graft survival, and/or protect from future ischemic events. CTO PCI was performed using hybrid techniques and was successful in all three cases. Intravascular imaging was used in all cases to maximize the durability of the procedure.

Comparative evaluation of intracardiac, transesophageal, and transthoracic echocardiography in the assessment of patent foramen ovale: A retrospective single-center study.

INTRODUCTION: Certain patent foramen ovale (PFO) characteristics, such as a large right-to-left shunt (RLS) or atrial septal aneurysm, identify patients who may receive the highest clinical benefit from percutaneous PFO closure. This study aimed to compare intracardiac echocardiography (ICE) with standard echocardiographic imaging in the evaluation of high-risk PFO characteristics and RLS severity in patients with PFO-associated stroke. METHODS: We conducted a retrospective review of all patients aged ≥18 years who underwent percutaneous PFO closure for PFO-associated stroke and received all three ultrasound-based cardiac imaging modalities and had interpretable results (N = 51). We then compared RLS severity, high-risk PFO characteristics, and the proportion of patients with a higher likelihood of PFO-associated stroke by ICE versus transthoracic echocardiogram (TTE) and transesophageal echocardiogram (TEE). RESULTS: The final cohort had a mean (±SE) age of 48.4 (±1.8) years and was predominantly female (58.8%). ICE was more likely to identify a large RLS versus TTE/TEE combined (66.7% vs. 45.1%; p = 0.03). The use of ICE resulted in significantly more patients being reclassified as having a higher likelihood of PFO-associated stroke (TTE vs. TEE vs. ICE: 10.4% vs. 14.6% vs. 25%; p = 0.03). A high-quality bubble study was found to be the single most important factor associated with identifying a larger RLS across all modalities (ρ [p]; TTE: 0.49 [<0.001], TEE: 0.60 [<0.001], ICE: 0.32 [0.02]). The presence of a hypermobile septum was associated with significantly greater RLS on ICE (ρ [p]: 0.3 [0.03]), especially with poor quality bubble studies (ρ [p]: 0.49 [0.02]). CONCLUSION: In this observational study of patients with PFO-associated stroke, ICE detected a large RLS more frequently than TTE and TEE; and reclassified some patients as having a higher likelihood of PFO-associated stroke.

Myocardial Late Contrast Enhancement CT in Troponin-Positive Acute Chest Pain Syndrome.

Background Acute chest pain with mild troponin rise and inconclusive diagnosis after clinical evaluation represents a diagnostic challenge. Triple-rule-out (TRO) CT may exclude coronary artery disease (CAD), as well as acute aortic syndrome and pulmonary embolism, but cannot help identify other causes of myocardial injury. Purpose To investigate the diagnostic value of a comprehensive CT protocol including both an angiographic and a late contrast enhancement (LCE) scan in participants with troponin-positive acute chest pain. Materials and Methods In this prospective study, consecutive patients with troponin-positive acute chest pain or anginal equivalent and inconclusive diagnosis after clinical evaluation (symptoms, markers, electrocardiography, and echocardiography) who underwent TRO CT between June 2018 and September 2020 were enrolled. TRO CT was performed to evaluate the presence of obstructive CAD (stenosis ≥50%), acute aortic syndrome, and pulmonary embolism. If the findings on the TRO CT scan were negative, an LCE CT scan was acquired after 10 minutes to assess the presence and pattern of scar and quantify the myocardial extracellular volume fraction. CT-based diagnoses were compared with diagnoses obtained with reference standard methods, including invasive coronary angiography, cardiac MRI, and endomyocardial biopsy. Results Eighty-four patients (median age, 69 years [interquartile range, 50-77 years]; 45 men) were enrolled. TRO CT helped identify obstructive CAD in 35 participants (42%), acute aortic syndrome in one (1.2%), and pulmonary embolism in six (7.1%). LCE CT scans were acquired in the remaining 42 participants. The following diagnoses were reached with use of LCE CT: myocarditis (22 of 42 participants [52%]), takotsubo cardiomyopathy (four of 42 [10%]), amyloidosis (three of 42 [7.1%]), myocardial infarction with nonobstructed coronary arteries (three of 42 [7.1%]), dilated cardiomyopathy (two of 42 [4.8%]), and negative or inconclusive findings (eight of 42 [19%]). The addition of LCE CT improved the diagnostic rate of TRO CT from 42 of 84 participants (50% [95% CI: 38.9, 61.1]) to 76 of 84 (90% [95% CI: 82.1, 95.8]) (P < .001). Conclusion A CT protocol including triple-rule-out and late contrast enhancement CT scans improved diagnostic rate in participants presenting with acute chest pain syndrome. © RSNA, 2021 Online supplemental material is available for this article. See also the editorial by Nagpal and Bluemke in this issue.

Percutaneous approach to left ventricular assist device decommissioning.

OBJECTIVE: To assess the outcomes of a single-center experience with percutaneous left ventricular assist device (LVAD) decommissioning. BACKGROUND: Patients with LVADs may eventually require their removal, either due to recovery of left ventricular function or recurrent complications. Traditionally, withdrawal of LVAD support has been managed with surgical device explantation, which carries significant procedural risks. Transcatheter LVAD decommissioning, with outflow graft occlusion and driveline transection, has recently been described as an alternative to surgical removal. METHODS: Here, we report on a retrospective cohort of five consecutive cases treated with transcatheter LVAD decommissioning. RESULTS: The procedure was effective in all cases, and no patient experienced procedure-related complications. At midterm follow-up, the three patients who had myocardial function recovery were alive and had not experienced heart failure-related symptoms or complications. CONCLUSION: Percutaneous LVAD decommissioning appears to be a safe and effective approach to LVAD treatment discontinuation.

Outcomes of chronic total occlusion percutaneous coronary intervention in patients with prior coronary artery bypass graft surgery: Insights from the LATAM CTO registry.

OBJECTIVES: To evaluate the outcomes of chronic total occlusion (CTO) percutaneous coronary intervention (PCI) in patients with and without prior coronary artery bypass graft (CABG) surgery. BACKGROUND: Data on the outcomes of CTO PCI in patients with versus without CABG remains limited and with scarce representation from developing regions like Latin America. METHODS: We evaluated patients undergoing CTO PCI in 42 centers participating in the LATAM CTO registry between 2008 and 2020. Statistical analyses were stratified according to CABG status. The outcomes of interest were technical and procedural success and in-hospital major adverse cardiac and cerebrovascular events (MACCE). RESULTS: A total of 1662 patients were included (n = 1411 [84.9%] no-CABG and n = 251 [15.1%] prior-CABG). Compared with no-CABG, those with prior-CABG were older (67 ± 11 vs. 64 ± 11 years; p < 0.001), had more comorbidities and lower left ventricular ejection fraction (52.8 ± 12.8% vs. 54.4 ± 11.7%; p = 0.042). Anatomic complexity was higher in the prior-CABG group (J-CTO score 2.46 ± 1.19 vs. 2.10 ± 1.22; p < 0.001; PROGRESS CTO score 1.28 ± 0.89 vs. 0.91 ± 0.85; p < 0.001). Absence of CABG was associated with lower risk of technical and procedural failure (OR: 0.60, 95% CI: 0.43-0.85 and OR: 0.58, 95% CI: 0.40-0.83, respectively). No significant differences in the incidence of in-hospital MACCE (3.8% no-CABG vs. 4.4% prior-CABG; p = 0.766) were observed between groups. CONCLUSION: In a contemporary multicenter CTO-PCI registry from Latin America, prior-CABG patients had more comorbidities, higher anatomical complexity, lower success, and similar in-hospital adverse event rates compared with no-CABG patients.

Ischemic Cardiomyopathy and Heart Failure After Acute Myocardial Infarction.

PURPOSE OF REVIEW: Ischemic cardiomyopathy refers to systolic left ventricular dysfunction in the setting of obstructive coronary artery disease and represents the most common cause of heart failure worldwide. It is often the combination of an irreversible loss of viable mass following an acute myocardial infarction (AMI) with a dysfunctional, but still viable, myocardium in the context of a chronically reduced myocardial blood flow and reduced coronary reserve. Medical treatments aiming at modulating neurohumoral response and restoring blood flow to the ischemic cardiomyocytes were shown to dramatically abate the occurrence of ventricular dysfunction and adverse remodeling in ischemic cardiomyopathy. RECENT FINDINGS: Novel therapeutic approaches, such as mechanical unloading and modulation of the inflammatory response, appear to be promising. Furthermore, the understanding of the mechanisms by which, despite optimal treatment, heart failure ensues after AMI, with or without adverse remodeling and systolic dysfunction, is a critical step in the search for novel ways to tackle heart failure risk beyond preservation of left ventricular volumes and systolic function. In this review article, we explore the principal pathophysiological mechanisms and pathways of heart failure in ischemic cardiomyopathy, therapeutic opportunities, and knowledge gaps in this area.

State-of-the-Art of Endomyocardial Biopsy on Acute Myocarditis and Chronic Inflammatory Cardiomyopathy.

PURPOSE OF REVIEW: Histologic evidence of myocardial inflammatory infiltrate not secondary to an ischemic injury is required by current diagnostic criteria to reach a definite diagnosis of myocarditis. Endomyocardial biopsy (EMB) is therefore often indicated for the diagnosis of myocarditis, although it may lack sufficient sensitivity considering the limited possibility of myocardial sampling. Improving the diagnostic yield and utility of EMB is of high priority in the fields of heart failure cardiology and myocarditis in particular. The aim of the present review is to highlight indications, strengths, and shortcomings of current EMB techniques, and discuss innovations currently being tested in ongoing clinical studies, especially in the setting of acute myocarditis and chronic inflammatory cardiomyopathy. RECENT FINDINGS: EMB provides unique diagnostic elements and prognostic information which can effectively guide the treatment of myocarditis. Issues affecting the diagnostic performance in the setting of acute myocarditis and chronic inflammatory cardiomyopathies will be discussed in this review in the light of recent expert consensus documents on the management of these conditions and on indication to EMB. Recent innovations using electroanatomic mapping (EAM)-guided EMB and fluoroscopic-guided EMB during temporary mechanical circulatory support have improved the utility of the procedure. EMB remains an important diagnostic test whose results need to be interpreted in the context of (1) clinical pre-test probability, (2) timing of sampling, (3) quality of sampling (4) site of sampling, (5) histologic type of myocarditis, and (6) analytic methods that are applied. Herein we will review these caveats as well as perspectives and innovations related to the use of this diagnostic tool.

Use of extracorporeal membrane oxygenation in high-risk acute pulmonary embolism: A systematic review and meta-analysis.

Extracorporeal membrane oxygenation (ECMO) represents a therapeutic option for cardiopulmonary support in patients with high-risk pulmonary embolism (PE); however, no definite consensus exists on ECMO use in high-risk PE. Hence, we aim to provide insights into its real-world use pooling together all available published experiences. We performed a systematic review and pooled analysis of all published studies (up to April 17, 2020) investigating ECMO support in high-risk PE. All studies including at least four patients were collectively analyzed. Study outcomes were early all-cause death (primary endpoint) and relevant in-hospital adverse events. A total of 21 studies were included in the pooled analysis (n = 635 patients). In this population (mean age 47.8 ± 17.3 years, 44.5% females), ECMO was indicated for cardiac arrest in 62.3% and immediate ECMO support was pursued in 61.9% of patients. Adjunctive reperfusion therapies were implemented in 57.0% of patients. Pooled estimate rate of early all-cause mortality was 41.1% (95% CI 27.7%-54.5%). The most common in-hospital adverse event was major bleeding, with an estimated rate of 28.6% (95%CI 21.0%-36.3%). At meta-regression analyses, no significant impact of multiple covariates on the primary endpoint was found. In this systematic review of patients who received ECMO for high-risk PE, pooled all-cause mortality was 41.1%. Principal indication for ECMO was cardiac arrest, cannulation was chiefly performed at presentation, and major bleeding was the most common complication.

Relief of Ischemia in Ischemic Cardiomyopathy.

PURPOSE OF THE REVIEW: Ischemic heart disease is among the most common causes of morbidity and mortality worldwide. In its stable manifestation, obstructing coronary artery stenoses prevent myocardial blood flow from matching metabolic needs of the heart under exercise conditions, which manifests clinically as dyspnea or chest pain. Prolonged bouts of ischemia may result in permanent myocardial dysfunction, heart failure, and eventually reduced survival. The aim of the present work is to review currently available approaches to provide relief of ischemia in stable coronary artery disease (CAD). RECENT FINDINGS: Several pharmacological and interventional approaches have proven effectiveness in reducing the burden of ischemia in stable CAD and allow for symptom control and quality of life improvement. However, substantial evidence in favor of improved survival with ischemia relief is lacking, and recently published randomized controlled trial suggests that only selected groups of patients may substantially benefit from this approach. Pharmacological treatments aimed at reducing ischemia were shown to significantly reduce ischemic symptoms but failed to provide prognostic benefit. Myocardial revascularization is able to re-establish adequate coronary artery flow and was shown to improve survival in selected groups of patients, i.e., those with significant left main CAD or severe left ventricular dysfunction in multivessel CAD. Outside the previously mentioned categories, revascularization appears to improve symptoms control over medical therapy, but does not confer prognostic advantage. More studies are needed to elucidate the role of systematic invasive functional testing to identify individuals more likely to benefit from revascularization and to evaluate the prognostic role of chronic total occlusion recanalization.

Aortic valve area calculation using 3D transesophageal echocardiography: Implications for aortic stenosis severity grading.

AIMS: Aortic stenosis (AS) grading by 2D-transthoracic echocardiography (2D-TTE) aortic valve area (AVA) calculation is limited by left ventricular outflow tract (LVOT) area underestimation. The combination of Doppler parameters with 3D LVOT area obtained by multidetector computed tomography (MDCT) can improve AS grading, reconciling discordant 2D-TTE findings. This study aimed to systematically evaluate the role of 3D-transesophageal echocardiography (3D-TEE) in AS grading using MDCT as reference standard. METHODS AND RESULTS: 288 patients (81 ± 6.3 years, 52.4% female) with symptomatic AS underwent 2D-TTE, 3D-TEE, and MDCT for transcatheter aortic valve implantation. Doppler parameters were combined with 3D LVOT areas measured by manual and semi-automated software 3D-TEE and by MDCT to calculate AVA, reassessing AS severity. Both 3D-TEE modalities demonstrated good correlation with MDCT, with excellent intra-observer and inter-observer variability. Compared to MDCT, 3D-TEE measurements significantly underestimated AVA (PANOVA  < .0001), although the difference was clinically acceptable. Compared to 2D-TTE, 3D-TEE manual and semi-automated software reclassified severe AS in 21.9% and 25.2% of cases, respectively (P < .0001), overcame grading parameters discordance in more than 40% of cases in patients with low-gradient AS (P < .0001) and reduced the proportion of low-flow states in nearly 75% of cases when combined to stroke volume index assessment (P < .0001). 3D-TEE imaging modalities showed a reduction in the proportion of patients with low-gradient and pathological AVA as defined by 2D-TTE, and improved AVA and mean pressure gradient agreement with current guidelines cutoff values. CONCLUSION: 3D-TEE AVA calculation is a reliable tool for AS grading with excellent reproducibility and good correlation with MDCT measurements.

The Role of Monocytes and Macrophages in Human Atherosclerosis, Plaque Neoangiogenesis, and Atherothrombosis.

Atherosclerosis is one of the leading causes of death and disability worldwide. It is a complex disease characterized by lipid accumulation within the arterial wall, inflammation, local neoangiogenesis, and apoptosis. Innate immune effectors, in particular monocytes and macrophages, play a pivotal role in atherosclerosis initiation and progression. Although most of available evidence on the role of monocytes and macrophages in atherosclerosis is derived from animal studies, a growing body of evidence elucidating the role of these mononuclear cell subtypes in human atherosclerosis is currently accumulating. A novel pathogenic role of monocytes and macrophages in terms of atherosclerosis initiation and progression, in particular concerning the role of these cell subsets in neovascularization, has been discovered. The aim of the present article is to review currently available evidence on the role of monocytes and macrophages in human atherosclerosis and in relation to plaque characteristics, such as plaque neoangiogenesis, and patients' prognosis and their potential role as biomarkers.

Acute and Fulminant Myocarditis: a Pragmatic Clinical Approach to Diagnosis and Treatment.

PURPOSE OF REVIEW: To review the clinical features of acute myocarditis, including its fulminant presentation, and present a pragmatic approach to the diagnosis and treatment, considering indications of American and European Scientific Statements and recent data derived by large contemporary registries. RECENT FINDINGS: Patients presenting with acute uncomplicated myocarditis (i.e., without left ventricular dysfunction, heart failure, or ventricular arrhythmias) have a favorable short- and long-term prognosis: these findings do not support the indication to endomyocardial biopsy in this clinical scenario. Conversely, patients with complicated presentations, especially those with fulminant myocarditis, require an aggressive and comprehensive management, including endomyocardial biopsy and availability of advanced therapies for circulatory support. Although several immunomodulatory or immunosuppressive therapies have been studied and are actually prescribed in the real-world practice, their effectiveness has not been clearly demonstrated. Patients with specific histological subtypes of acute myocarditis (i.e., giant cell and eosinophilic myocarditis) or those affected by sarcoidosis or systemic autoimmune disorders seem to benefit most from immunosuppression. On the other hand, no clear evidence supports the use of immunosuppressive agents in patients with lymphocytic acute myocarditis, even though small series suggest a potential benefit. Acute myocarditis is a heterogeneous condition with distinct pathophysiological pathways. Further research is mandatory to identify factors and mechanisms that may trigger/maintain or counteract/repair the myocardial damage, in order to provide a rational for future evidence-based treatment of patients affected by this condition.

Determinants of outcome in patients with chronic ischemic left ventricular dysfunction undergone percutaneous coronary interventions.

BACKGROUND: Percutaneous coronary interventions (PCI) in patients with ischemic systolic left ventricular dysfunction (SLVD) are routinely performed although their impact on prognosis remains unclear. METHODS: We retrospectively evaluated 385 consecutive patients (76 % male, 66 ± 9 years) with SLVD (left ventricular ejection fraction [LVEF] ≤40 %) due to chronic coronary artery disease, who underwent PCI between 1999 and 2009, and explored clinical factors associated with higher risk of death or of a composite of death and hospitalization for acute decompensated heart failure (ADHF). RESULTS: The median follow-up was 28 months (inter-quartile range 14-46 months). Death and the composite outcome of death and hospitalization for ADHF occurred in 80 (21 %) and 109 (28 %) patients respectively (8.4 and 11.5 per 100 patient-years of follow-up). Insulin-dependent diabetes mellitus (IDDM), multivessel disease, LVEF < 35 %, symptoms of heart failure (HF) emerged both as independent predictors of death (adjusted hazard ratios [HR] 2.64; 1.92, 1.88 and 1.67 respectively) and composite outcome of death and hospitalization for ADHF (adjusted HR 2.22, 1.92, 1.79 and 1.94 respectively). Furthermore advanced age (HR = 1.03) emerged as independent predictors of death and having performed a stress test before PCI correlated with reduced number of deaths and ADHF hospitalizations (HR = 0.60). Of note, PCI significantly reduced the symptom of angina from 63.2 % at baseline to 16.3 % at the last follow up (p < 0.0001). CONCLUSIONS: IDDM, symptoms of HF, multivessel disease and LVEF < 35 % appear to be associated with worse outcome patients with ischemic SLVD undergoing PCI, and may be taken into account for optimal risk stratification. On the other hand, performing a stress testing before PCI seems to be associated with a more favorable outcome.

Markers of inflammation associated with plaque progression and instability in patients with carotid atherosclerosis.

Atherosclerosis is the focal expression of a systemic disease affecting medium- and large-sized arteries, in which traditional cardiovascular risk factor and immune factors play a key role. It is well accepted that circulating biomarkers, including C-reactive protein and interleukin-6, reliably predict major cardiovascular events, including myocardial infarction or death. However, the relevance of biomarkers of systemic inflammation to atherosclerosis progression in the carotid artery is less established. The large majority of clinical studies focused on the association between biomarkers and subclinical atherosclerosis, that is, carotid intima-media thickening (cIMT), which represents an earlier stage of the disease. The aim of this work is to review inflammatory biomarkers that were associated with a higher atherosclerotic burden, a faster disease progression, and features of plaque instability, such as inflammation or neovascularization, in patients with carotid atherosclerotic plaque, which represents an advanced stage of disease compared with cIMT. The association of biomarkers with the occurrence of cerebrovascular events, secondary to carotid plaque rupture, will also be presented. Currently, the degree of carotid artery stenosis is used to predict the risk of future cerebrovascular events in patients affected by carotid atherosclerosis. However, this strategy appears suboptimal. The identification of suitable biomarkers could provide a useful adjunctive criterion to ensure better risk stratification and optimize management.