Optical coherence tomography in coronary atherosclerosis assessment and intervention.

Since optical coherence tomography (OCT) was first performed in humans two decades ago, this imaging modality has been widely adopted in research on coronary atherosclerosis and adopted clinically for the optimization of percutaneous coronary intervention. In the past 10 years, substantial advances have been made in the understanding of in vivo vascular biology using OCT. Identification by OCT of culprit plaque pathology could potentially lead to a major shift in the management of patients with acute coronary syndromes. Detection by OCT of healed coronary plaque has been important in our understanding of the mechanisms involved in plaque destabilization and healing with the rapid progression of atherosclerosis. Accurate detection by OCT of sequelae from percutaneous coronary interventions that might be missed by angiography could improve clinical outcomes. In addition, OCT has become an essential diagnostic modality for myocardial infarction with non-obstructive coronary arteries. Insight into neoatherosclerosis from OCT could improve our understanding of the mechanisms of very late stent thrombosis. The appropriate use of OCT depends on accurate interpretation and understanding of the clinical significance of OCT findings. In this Review, we summarize the state of the art in cardiac OCT and facilitate the uniform use of this modality in coronary atherosclerosis. Contributions have been made by clinicians and investigators worldwide with extensive experience in OCT, with the aim that this document will serve as a standard reference for future research and clinical application.

Resilience of the Internal Mammary Artery to Atherogenesis: Shifting From Risk to Resistance to Address Unmet Needs.

Fueled by the global surge in aging, atherosclerotic cardiovascular disease reached pandemic dimensions putting affected individuals at enhanced risk of myocardial infarction, stroke, and premature death. Atherosclerosis is a systemic disease driven by a wide spectrum of factors, including cholesterol, pressure, and disturbed flow. Although all arterial beds encounter a similar atherogenic milieu, the development of atheromatous lesions occurs discontinuously across the vascular system. Indeed, the internal mammary artery possesses unique biological properties that confer protection to intimal growth and atherosclerotic plaque formation, thus making it a conduit of choice for coronary artery bypass grafting. Its endothelium abundantly expresses nitric oxide synthase and shows accentuated nitric oxide release, while its vascular smooth muscle cells exhibit reduced tissue factor expression, high tPA (tissue-type plasminogen activator) production and blunted migration and proliferation, which may collectively mitigate intimal thickening and ultimately the evolution of atheromatous plaques. We aim here to provide insights into the anatomy, physiology, cellular, and molecular aspects of the internal mammary artery thereby elucidating its remarkable resistance to atherogenesis. We propose a change in perspective from risk to resilience to decipher mechanisms of atheroresistance and eventually identification of novel therapeutic targets presently not addressed by currently available remedies.

Fundamental Cardiovascular Research: Returns on Societal Investment: A Scientific Statement From the American Heart Association.

Recent decades have witnessed robust successes in conquering the acutely lethal manifestations of heart and vascular diseases. Many patients who previously would have died now survive. Lifesaving successes like these provide a tremendous and easily recognized benefit to individuals and society. Although cardiovascular mortality has declined, the devastating impact of chronic heart disease and comorbidities on quality of life and healthcare resources continues unabated. Future strides, extending those made in recent decades, will require continued research into mechanisms underlying disease prevention, pathogenesis, progression, and therapeutic intervention. However, severe financial constraints currently jeopardize these efforts. To chart a path for the future, this report analyzes the challenges and opportunities we face in continuing the battle against cardiovascular disease and highlights the return on societal investment afforded by fundamental cardiovascular research.

Combined non-invasive assessment of endothelial shear stress and molecular imaging of inflammation for the prediction of inflamed plaque in hyperlipidaemic rabbit aortas.

AIMS: To evaluate the incremental value of low endothelial shear stress (ESS) combined with high-resolution magnetic resonance imaging (MRI)- and computed tomography angiography (CTA)-based imaging for the prediction of inflamed plaque. METHODS AND RESULTS: Twelve hereditary hyperlipidaemic rabbits underwent quantitative analysis of plaque in the thoracic aorta with 256-slice CTA and USPIO-enhanced (ultra-small superparamagnetic nanoparticles, P904) 1.5-T MRI at baseline and at 6-month follow-up. Computational fluid dynamics using CTA-based 3D reconstruction of thoracic aortas identified the ESS patterns in the convex and concave curvature subsegments of interest. Subsegments with low baseline ESS exhibited significant increase in wall thickness and plaque inflammation by MRI, in non-calcified plaque burden by CTA, and developed increased plaque size, lipid and inflammatory cell accumulation (high-risk plaque features) at follow-up by histopathology. Multiple regression analysis identified baseline ESS and inflammation by MRI to be independent predictors of plaque progression, while receiver operating curve analysis revealed baseline ESS alone or in combination with inflammation by MRI as the strongest predictor for augmented plaque burden and inflammation (low ESS at baseline: AUC = 0.84, P < 0.001; low ESS and inflammation by molecular MRI at baseline: AUC = 0.89, P < 0.001). CONCLUSION: Low ESS predicts progression of plaque burden and inflammation as assessed by non-invasive USPIO-enhanced MRI. Combined non-invasive assessment of ESS and imaging of inflammation may serve to predict plaque with high-risk features.

Cardiovascular drug development: is it dead or just hibernating?

Despite the global burden of cardiovascular disease, investment in cardiovascular drug development has stagnated over the past 2 decades, with relative underinvestment compared with other therapeutic areas. The reasons for this trend are multifactorial, but of primary concern is the high cost of conducting cardiovascular outcome trials in the current regulatory environment that demands a direct assessment of risks and benefits, using clinically-evident cardiovascular endpoints. To work toward consensus on improving the environment for cardiovascular drug development, stakeholders from academia, industry, regulatory bodies, and government agencies convened for a think tank meeting in July 2014 in Washington, DC. This paper summarizes the proceedings of the meeting and aims to delineate the current adverse trends in cardiovascular drug development, understand the key issues that underlie these trends within the context of a recognized need for a rigorous regulatory review process, and provide potential solutions to the problems identified.

In vivo nanoparticle assessment of pathological endothelium predicts the development of inflow stenosis in murine arteriovenous fistula.

OBJECTIVE: In vivo assessment of pathological endothelium within arteriovenous fistula (AVF) could provide new insights into inflow stenosis, a common cause of AVF primary failure in end-stage renal disease patients. Here we developed nanoparticle-based imaging strategies to assess pathological endothelium in vivo and elucidate its relationship to neointimal hyperplasia formation in AVF. APPROACH AND RESULTS: Jugular-carotid AVFs were created in C57BL/6 mice (n=38). Pathological endothelium in the AVF was visualized and quantified in vivo using dextranated magnetofluorescent nanoparticles (CLIO-VT680 [cross-linked iron oxide-VivoTag680]). At day 14, CLIO-VT680 was deposited in AVF, but only minimally in sham-operated arteries. Transmission electron microscopy revealed that CLIO-VT680 resided within endothelial cells and in the intimal extracellular space. Endothelial cells of AVF, but not control arteries, expressed vascular cell adhesion molecule-1 and showed augmented endothelial permeability near the anastomosis. Intravital microscopy demonstrated that CLIO-VT680 deposited most intensely near the AVF anastomosis (P<0.0001). The day 14 intravital microscopy CLIO-VT680 signal predicted the subsequent site and magnitude of AVF neointimal hyperplasia at day 42 (r=0.58, P<0.05). CLIO-VT680 deposition in AVF was further visualized by ex vivo MRI. CONCLUSIONS: AVF develop a pathological endothelial response that can be assessed in vivo via nanoparticle-enhanced imaging. AVF endothelium is activated and exhibits augmented permeability, offering a targeting mechanism for nanoparticle deposition and retention in pathological endothelium. The in vivo AVF nanoparticle signal identified and predicted subsequent inflow neointimal hyperplasia. This approach could be used to test therapeutic interventions aiming to restore endothelial health and to decrease early AVF failure caused by inflow stenosis.

Inflammation and atherosclerosis: role of C-reactive protein in risk assessment.

Inflammation participates critically in atherosclerosis. Circulating levels of several inflammatory markers rise in individuals at risk for atherosclerotic events. In particular, elevation of plasma C-reactive protein (CRP), a nonspecific acute-phase reactant that is easily and reliably measured, has strong predictive power for cardiovascular events. Indeed, measurements of high-sensitivity CRP (hs-CRP) plasma levels add to both the prognostic information gleaned from assay of plasma lipid risk factors and the risk levels estimated by means of Framingham study-based criteria. Retrospective data suggest the hypothesis that hs-CRP plasma levels may be useful for guiding use of lipid-lowering therapy in individuals who appear to be at low risk according to traditional risk assessment. A large-scale, randomized clinical trial-Justification for the Use of Statins in Primary Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER)-will test whether rosuvastatin therapy will reduce incident cardiovascular disease in subjects with elevated plasma hs-CRP concentrations who do not meet current criteria for initiation of lipid-lowering drug therapy. Such clinical trial data may provide an evidence base for the use of plasma CRP assay as an adjuvant guide to therapy to complement the established traditional risk factors such as plasma lipid levels. Thus, medical practitioners are ushering in an era in which the biology of inflammation in atherosclerosis will find its way into clinical application.

From vulnerable plaque to vulnerable patient: a call for new definitions and risk assessment strategies: Part II.

Atherosclerotic cardiovascular disease results in >19 million deaths annually, and coronary heart disease accounts for the majority of this toll. Despite major advances in treatment of coronary heart disease patients, a large number of victims of the disease who are apparently healthy die suddenly without prior symptoms. Available screening and diagnostic methods are insufficient to identify the victims before the event occurs. The recognition of the role of the vulnerable plaque has opened new avenues of opportunity in the field of cardiovascular medicine. This consensus document concludes the following. (1) Rupture-prone plaques are not the only vulnerable plaques. All types of atherosclerotic plaques with high likelihood of thrombotic complications and rapid progression should be considered as vulnerable plaques. We propose a classification for clinical as well as pathological evaluation of vulnerable plaques. (2) Vulnerable plaques are not the only culprit factors for the development of acute coronary syndromes, myocardial infarction, and sudden cardiac death. Vulnerable blood (prone to thrombosis) and vulnerable myocardium (prone to fatal arrhythmia) play an important role in the outcome. Therefore, the term "vulnerable patient" may be more appropriate and is proposed now for the identification of subjects with high likelihood of developing cardiac events in the near future. (3) A quantitative method for cumulative risk assessment of vulnerable patients needs to be developed that may include variables based on plaque, blood, and myocardial vulnerability. In Part I of this consensus document, we cover the new definition of vulnerable plaque and its relationship with vulnerable patients. Part II of this consensus document will focus on vulnerable blood and vulnerable myocardium and provide an outline of overall risk assessment of vulnerable patients. Parts I and II are meant to provide a general consensus and overviews the new field of vulnerable patient. Recently developed assays (eg, C-reactive protein), imaging techniques (eg, CT and MRI), noninvasive electrophysiological tests (for vulnerable myocardium), and emerging catheters (to localize and characterize vulnerable plaque) in combination with future genomic and proteomic techniques will guide us in the search for vulnerable patients. It will also lead to the development and deployment of new therapies and ultimately to reduce the incidence of acute coronary syndromes and sudden cardiac death. We encourage healthcare policy makers to promote translational research for screening and treatment of vulnerable patients.

From vulnerable plaque to vulnerable patient: a call for new definitions and risk assessment strategies: Part I.

Atherosclerotic cardiovascular disease results in >19 million deaths annually, and coronary heart disease accounts for the majority of this toll. Despite major advances in treatment of coronary heart disease patients, a large number of victims of the disease who are apparently healthy die suddenly without prior symptoms. Available screening and diagnostic methods are insufficient to identify the victims before the event occurs. The recognition of the role of the vulnerable plaque has opened new avenues of opportunity in the field of cardiovascular medicine. This consensus document concludes the following. (1) Rupture-prone plaques are not the only vulnerable plaques. All types of atherosclerotic plaques with high likelihood of thrombotic complications and rapid progression should be considered as vulnerable plaques. We propose a classification for clinical as well as pathological evaluation of vulnerable plaques. (2) Vulnerable plaques are not the only culprit factors for the development of acute coronary syndromes, myocardial infarction, and sudden cardiac death. Vulnerable blood (prone to thrombosis) and vulnerable myocardium (prone to fatal arrhythmia) play an important role in the outcome. Therefore, the term "vulnerable patient" may be more appropriate and is proposed now for the identification of subjects with high likelihood of developing cardiac events in the near future. (3) A quantitative method for cumulative risk assessment of vulnerable patients needs to be developed that may include variables based on plaque, blood, and myocardial vulnerability. In Part I of this consensus document, we cover the new definition of vulnerable plaque and its relationship with vulnerable patients. Part II of this consensus document focuses on vulnerable blood and vulnerable myocardium and provide an outline of overall risk assessment of vulnerable patients. Parts I and II are meant to provide a general consensus and overviews the new field of vulnerable patient. Recently developed assays (eg, C-reactive protein), imaging techniques (eg, CT and MRI), noninvasive electrophysiological tests (for vulnerable myocardium), and emerging catheters (to localize and characterize vulnerable plaque) in combination with future genomic and proteomic techniques will guide us in the search for vulnerable patients. It will also lead to the development and deployment of new therapies and ultimately to reduce the incidence of acute coronary syndromes and sudden cardiac death. We encourage healthcare policy makers to promote translational research for screening and treatment of vulnerable patients.

Diabetes and atherosclerosis: epidemiology, pathophysiology, and management.

CONTEXT: Complications of atherosclerosis cause most morbidity and mortality in patients with diabetes mellitus. Despite the frequency and severity of disease, proven medical therapy remains incompletely understood and underused. OBJECTIVE: To review the epidemiology, pathophysiology, and medical and invasive treatment of atherosclerosis in patients with diabetes mellitus. DATA SOURCES: Using the index terms diabetes mellitus, myocardial infarction, peripheral vascular diseases, cerebrovascular accident, endothelium, vascular smooth muscle, platelets, thrombosis, cholesterol, hypertension, hyperglycemia, insulin, angioplasty, and coronary artery bypass, we searched the MEDLINE and EMBASE databases from 1976 to 2001. Additional data sources included bibliographies of identified articles and preliminary data presented at recent cardiology conferences. STUDY SELECTION: We selected original investigations and reviews of the epidemiology, pathophysiology, and therapy of atherosclerosis in diabetes. We selected randomized, double-blind, controlled studies, when available, to support therapeutic recommendations. Criteria for data inclusion (168 of 396) included publication in a peer-reviewed journal or presentation at a national cardiovascular society-sponsored meeting. DATA EXTRACTION: Data quality was determined by publication in peer-reviewed literature. Data extraction was performed by one of the authors. DATA SYNTHESIS: Diabetes mellitus markedly increases the risk of myocardial infarction, stroke, amputation, and death. The metabolic abnormalities caused by diabetes induce vascular dysfunction that predisposes this patient population to atherosclerosis. Blood pressure control, lipid-lowering therapy, angiotensin-converting enzyme inhibition, and antiplatelet drugs significantly reduce the risk of cardiovascular events. Although diabetic patients undergo revascularization procedures because of acute coronary syndromes or critical limb ischemia, the outcomes are less favorable than in nondiabetic cohorts. CONCLUSIONS: Since most patients with diabetes die from complications of atherosclerosis, they should receive intensive preventive interventions proven to reduce their cardiovascular risk.