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Journal of the American College of... Jan 2022Over the last 3 decades there have been substantial improvements in treatments aimed at reducing cardiovascular (CV) events. As these treatments have been developed,... (Review)
Review
Over the last 3 decades there have been substantial improvements in treatments aimed at reducing cardiovascular (CV) events. As these treatments have been developed, there have been parallel improvements in coronary imaging modalities that can assess plaque volumes and composition, using both invasive and noninvasive techniques. Plaque progression can be seen to precede CV events, and therefore, many studies have longitudinally assessed changes in plaque characteristics in response to various treatments, aiming to demonstrate plaque regression and improvements in high-risk features, with the rationale being that this will reduce CV events. In the past, decisions surrounding treatments for atherosclerosis have been informed by population-based risk scores for initiation in primary prevention and low-density lipoprotein cholesterol levels for titration in secondary prevention. If outcome data linking plaque regression to reduced CV events emerge, it may become possible to directly image plaque treatment response to guide management decisions.
Topics: Alcohol Drinking; Anticoagulants; Antihypertensive Agents; Cholesterol Ester Transfer Proteins; Colchicine; Coronary Artery Disease; Coronary Vessels; Diagnostic Imaging; Diet; Eicosapentaenoic Acid; Exercise; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypoglycemic Agents; Hypolipidemic Agents; Life Style; Plaque, Atherosclerotic; Smoking Cessation
PubMed: 34991791
DOI: 10.1016/j.jacc.2021.10.035 -
Arteriosclerosis, Thrombosis, and... Jan 2020Macrophages play a central role in the development of atherosclerotic cardiovascular disease (ASCVD), which encompasses coronary artery disease, peripheral artery... (Review)
Review
Macrophages play a central role in the development of atherosclerotic cardiovascular disease (ASCVD), which encompasses coronary artery disease, peripheral artery disease, cerebrovascular disease, and aortic atherosclerosis. In each vascular bed, macrophages contribute to the maintenance of the local inflammatory response, propagate plaque development, and promote thrombosis. These central roles, coupled with their plasticity, makes macrophages attractive therapeutic targets in stemming the development of and stabilizing existing atherosclerosis. In the context of ASCVD, classically activated M1 macrophages initiate and sustain inflammation, and alternatively activated M2 macrophages resolve inflammation. However, this classification is now considered an oversimplification, and a greater understanding of plaque macrophage physiology in ASCVD is required to aid in the development of therapeutics to promote ASCVD regression. Reviewed herein are the macrophage phenotypes and molecular regulators characteristic of ASCVD regression, and the current murine models of ASCVD regression.
Topics: Animals; Atherosclerosis; Coronary Artery Disease; Disease Progression; Humans; Leukocyte Count; Macrophage Activation; Macrophages; Phenotype; Plaque, Atherosclerotic
PubMed: 31722535
DOI: 10.1161/ATVBAHA.119.312802 -
Nature Reviews. Cardiology Apr 2022Nanotechnology could improve our understanding of the pathophysiology of atherosclerosis and contribute to the development of novel diagnostic and therapeutic strategies... (Review)
Review
Nanotechnology could improve our understanding of the pathophysiology of atherosclerosis and contribute to the development of novel diagnostic and therapeutic strategies to further reduce the risk of cardiovascular disease. Macrophages have key roles in atherosclerosis progression and, therefore, macrophage-associated pathological processes are important targets for both diagnostic imaging and novel therapies for atherosclerosis. In this Review, we highlight efforts in the past two decades to develop imaging techniques and to therapeutically manipulate macrophages in atherosclerotic plaques with the use of rationally designed nanoparticles. We review the latest progress in nanoparticle-based imaging modalities that can specifically target macrophages. Using novel molecular imaging technology, these modalities enable the identification of advanced atherosclerotic plaques and the assessment of the therapeutic efficacy of medical interventions. Additionally, we provide novel perspectives on how macrophage-targeting nanoparticles can deliver a broad range of therapeutic payloads to atherosclerotic lesions. These nanoparticles can suppress pro-atherogenic macrophage processes, leading to improved resolution of inflammation and stabilization of plaques. Finally, we propose future opportunities for novel diagnostic and therapeutic strategies and provide solutions to challenges in this area for the purpose of accelerating the clinical translation of nanomedicine for the treatment of atherosclerotic vascular disease.
Topics: Atherosclerosis; Humans; Macrophages; Nanomedicine; Nanoparticles; Plaque, Atherosclerotic
PubMed: 34759324
DOI: 10.1038/s41569-021-00629-x -
JAMA Cardiology Feb 2023Recent clinical and imaging studies underscore that major adverse cardiac events (MACE) outcomes are associated not solely with severe coronary obstructions (ischemia... (Review)
Review
IMPORTANCE
Recent clinical and imaging studies underscore that major adverse cardiac events (MACE) outcomes are associated not solely with severe coronary obstructions (ischemia hypothesis or stenosis hypothesis), but with the plaque burden along the entire coronary tree. New research clarifies the pathobiologic mechanisms responsible for plaque development/progression/destabilization leading to MACE (plaque hypothesis), but the translation of these insights to clinical management strategies has lagged. This narrative review elaborates the plaque hypothesis and explicates the current understanding of underlying pathobiologic mechanisms, the provocative destabilizing influences, the diagnostic and therapeutic implications, and their actionable clinical management approaches to optimize the management of patients with chronic coronary disease.
OBSERVATIONS
Clinical trials of management strategies for patients with chronic coronary artery disease demonstrate that while MACE rate increases progressively with the anatomic extent of coronary disease, revascularization of the ischemia-producing obstruction does not forestall MACE. Most severely obstructive coronary lesions often remain quiescent and seldom destabilize to cause a MACE. Coronary lesions that later provoke acute myocardial infarction often do not narrow the lumen critically. Invasive and noninvasive imaging can identify the plaque anatomic characteristics (plaque burden, plaque topography, lipid content) and local hemodynamic/biomechanical characteristics (endothelial shear stress, plaque structural stress, axial plaque stress) that can indicate the propensity of individual plaques to provoke a MACE.
CONCLUSIONS AND RELEVANCE
The pathobiologic construct concerning the culprit region of a plaque most likely to cause a MACE (plaque hypothesis), which incorporates multiple convergent plaque features, informs the evolution of a new management strategy capable of identifying the high-risk portion of plaque wherever it is located along the course of the coronary artery. Ongoing investigations of high-risk plaque features, coupled with technical advances to enable prognostic characterization in real time and at the point of care, will soon enable evaluation of the entire length of the atheromatous coronary artery and broaden the target(s) of our therapeutic intervention to include all regions of the plaque (both flow limiting and nonflow limiting).
Topics: Humans; Coronary Artery Disease; Plaque, Atherosclerotic; Myocardial Ischemia; Myocardial Infarction; Risk Factors
PubMed: 36515941
DOI: 10.1001/jamacardio.2022.3926 -
Genes Apr 2022The implication of the heterogeneous spectrum of pro- and anti-inflammatory macrophages (Macs) has been an important area of investigation over the last decade. The... (Review)
Review
The implication of the heterogeneous spectrum of pro- and anti-inflammatory macrophages (Macs) has been an important area of investigation over the last decade. The polarization of Macs alters their functional phenotype in response to their surrounding microenvironment. Macs are the major immune cells implicated in the pathogenesis of atherosclerosis. A hallmark pathology of atherosclerosis is the accumulation of pro-inflammatory M1-like macrophages in coronary arteries induced by pro-atherogenic stimuli; these M1-like pro-inflammatory macrophages are incapable of digesting lipids, thus resulting in foam cell formation in the atherosclerotic plaques. Recent findings suggest that the progression and stability of atherosclerotic plaques are dependent on the quantity of infiltrated Macs, the polarization state of the Macs, and the ratios of different types of Mac populations. The polarization of Macs is defined by signature markers on the cell surface, as well as by factors in intracellular and intranuclear compartments. At the same time, pro- and anti-inflammatory polarized Macs also exhibit different gene expression patterns, with differential cellular characteristics in oxidative phosphorylation and glycolysis. Macs are reflective of different metabolic states and various types of diseases. In this review, we discuss the major differences between M1-like Macs and M2-like Macs, their associated metabolic pathways, and their roles in atherosclerosis.
Topics: Atherosclerosis; Humans; Macrophage Activation; Macrophages; Phenotype; Plaque, Atherosclerotic
PubMed: 35627141
DOI: 10.3390/genes13050756 -
Journal of the American College of... Jul 2021Atherosclerosis starts early in life and progresses silently for decades. Considering atherosclerosis as a "systemic disease" invites the use of noninvasive... (Review)
Review
Atherosclerosis starts early in life and progresses silently for decades. Considering atherosclerosis as a "systemic disease" invites the use of noninvasive methodologies to detect disease in various regions before symptoms appear. The PESA-(Progression of Early Subclinical Atherosclerosis) CNIC-SANTANDER study is an ongoing prospective cohort study examining imaging, biological, and behavioral parameters associated with the presence and progression of early subclinical atherosclerosis. Between 2010 and 2014, PESA enrolled 4,184 asymptomatic middle-aged participants who undergo serial 3-yearly follow-up examinations including clinical interviews, lifestyle questionnaires, sampling, and noninvasive imaging assessment of multiterritorial subclinical atherosclerosis (carotids, iliofemorals, aorta, and coronaries). PESA tracks the trajectories of atherosclerosis and associated disorders from early stages to the transition to symptomatic phases. A joint venture between the CNIC and the Santander Bank, PESA is expected to run until at least 2029, and its significant contributions to date are presented in this review paper.
Topics: Arteries; Atherosclerosis; Disease Progression; Humans; Longitudinal Studies; Middle Aged; Plaque, Atherosclerotic; Tomography, X-Ray Computed; Ultrasonography
PubMed: 34238438
DOI: 10.1016/j.jacc.2021.05.011 -
JAMA Cardiology Aug 2023Recurrent coronary events in patients with recent myocardial infarction remain a major clinical problem. Noninvasive measures of coronary atherosclerotic disease...
IMPORTANCE
Recurrent coronary events in patients with recent myocardial infarction remain a major clinical problem. Noninvasive measures of coronary atherosclerotic disease activity have the potential to identify individuals at greatest risk.
OBJECTIVE
To assess whether coronary atherosclerotic plaque activity as assessed by noninvasive imaging is associated with recurrent coronary events in patients with myocardial infarction.
DESIGN, SETTING, AND PARTICIPANTS
This prospective, longitudinal, international multicenter cohort study recruited participants aged 50 years or older with multivessel coronary artery disease and recent (within 21 days) myocardial infarction between September 2015 and February 2020, with a minimum 2 years' follow-up.
INTERVENTION
Coronary 18F-sodium fluoride positron emission tomography and coronary computed tomography angiography.
MAIN OUTCOMES AND MEASURES
Total coronary atherosclerotic plaque activity was assessed by 18F-sodium fluoride uptake. The primary end point was cardiac death or nonfatal myocardial infarction but was expanded during study conduct to include unscheduled coronary revascularization due to lower than anticipated primary event rates.
RESULTS
Among 2684 patients screened, 995 were eligible, 712 attended for imaging, and 704 completed an interpretable scan and comprised the study population. The mean (SD) age of participants was 63.8 (8.2) years, and most were male (601 [85%]). Total coronary atherosclerotic plaque activity was identified in 421 participants (60%). After a median follow-up of 4 years (IQR, 3-5 years), 141 participants (20%) experienced the primary end point: 9 had cardiac death, 49 had nonfatal myocardial infarction, and 83 had unscheduled coronary revascularizations. Increased coronary plaque activity was not associated with the primary end point (hazard ratio [HR], 1.25; 95% CI, 0.89-1.76; P = .20) or unscheduled revascularization (HR, 0.98; 95% CI, 0.64-1.49; P = .91) but was associated with the secondary end point of cardiac death or nonfatal myocardial infarction (47 of 421 patients with high plaque activity [11.2%] vs 19 of 283 with low plaque activity [6.7%]; HR, 1.82; 95% CI, 1.07-3.10; P = .03) and all-cause mortality (30 of 421 patients with high plaque activity [7.1%] vs 9 of 283 with low plaque activity [3.2%]; HR, 2.43; 95% CI, 1.15-5.12; P = .02). After adjustment for differences in baseline clinical characteristics, coronary angiography findings, and Global Registry of Acute Coronary Events score, high coronary plaque activity was associated with cardiac death or nonfatal myocardial infarction (HR, 1.76; 95% CI, 1.00-3.10; P = .05) but not with all-cause mortality (HR, 2.01; 95% CI, 0.90-4.49; P = .09).
CONCLUSIONS AND RELEVANCE
In this cohort study of patients with recent myocardial infarction, coronary atherosclerotic plaque activity was not associated with the primary composite end point. The findings suggest that risk of cardiovascular death or myocardial infarction in patients with elevated plaque activity warrants further research to explore its incremental prognostic implications.
Topics: Humans; Male; Female; Plaque, Atherosclerotic; Prospective Studies; Cohort Studies; Sodium Fluoride; Coronary Artery Disease; Myocardial Infarction; Death
PubMed: 37379010
DOI: 10.1001/jamacardio.2023.1729 -
Circulation Apr 2020Physical activity and exercise training are effective strategies for reducing the risk of cardiovascular events, but multiple studies have reported an increased... (Review)
Review
Physical activity and exercise training are effective strategies for reducing the risk of cardiovascular events, but multiple studies have reported an increased prevalence of coronary atherosclerosis, usually measured as coronary artery calcification, among athletes who are middle-aged and older. Our review of the medical literature demonstrates that the prevalence of coronary artery calcification and atherosclerotic plaques, which are strong predictors for future cardiovascular morbidity and mortality, was higher in athletes compared with controls, and was higher in the most active athletes compared with less active athletes. However, analysis of plaque morphology revealed fewer mixed plaques and more often only calcified plaques among athletes, suggesting a more benign composition of atherosclerotic plaques. This review describes the effects of physical activity and exercise training on coronary atherosclerosis in athletes who are middle-aged and older and aims to contribute to the understanding of the potential adverse effects of the highest doses of exercise training on the coronary arteries. For this purpose, we will review the association between exercise and coronary atherosclerosis measured using computed tomography, discuss the potential underlying mechanisms for exercise-induced coronary atherosclerosis, determine the clinical relevance of coronary atherosclerosis in middle-aged athletes and describe strategies for the clinical management of athletes with coronary atherosclerosis to guide physicians in clinical decision making and treatment of athletes with elevated coronary artery calcification scores.
Topics: Athletes; Computed Tomography Angiography; Coronary Angiography; Coronary Artery Disease; Exercise; Female; Humans; Male; Plaque, Atherosclerotic; Prevalence; Risk Factors; Vascular Calcification
PubMed: 32310695
DOI: 10.1161/CIRCULATIONAHA.119.044467 -
Journal of the American College of... Sep 2019It has been believed that most acute coronary events result from the rupture of mildly stenotic plaques, based on studies in which angiographic information was available... (Review)
Review
It has been believed that most acute coronary events result from the rupture of mildly stenotic plaques, based on studies in which angiographic information was available from many months to years before the event. However, serial studies in which angiographic data were available from the past as also within 1 to 3 months of myocardial infarction have clarified that nonobstructive lesions progressively enlarged relatively rapidly before the acute event occurred. Noninvasive computed tomography angiography imaging data have confirmed that lesions that did not progress voluminously over time rarely led to events, regardless of the extent of luminal stenosis or baseline high-risk plaque morphology. Therefore, plaque progression could be proposed as a necessary step between early, uncomplicated atherosclerosis and plaque rupture. On the other hand, it has been convincingly demonstrated that intensive lipid-lowering therapy (to a low-density lipoprotein cholesterol level of <70 mg/dl) halts plaque progression. Given the current ability to noninvasively detect the presence of early atherosclerosis, the importance of plaque progression in the pathogenesis of myocardial infarction, and the efficacy of maximum lipid-lowering therapy, it has been suggested that plaque progression is a modifiable step in the evolution of atherosclerotic plaque. A personalized approach based on the detection of early atherosclerosis can trigger the necessary treatment to prevent plaque progression and hence plaque instability. Therefore, this approach can redefine the traditional paradigm of primary and secondary prevention based on population-derived risk estimates and can potentially improve long-term outcomes.
Topics: Acute Coronary Syndrome; Acute Disease; Atherosclerosis; Disease Progression; Humans; Plaque, Atherosclerotic
PubMed: 31537271
DOI: 10.1016/j.jacc.2019.08.012 -
The Journal of Clinical Investigation Aug 2021Endothelial-mesenchymal transition (EndMT) is associated with various cardiovascular diseases and in particular with atherosclerosis and plaque instability. However, the...
Endothelial-mesenchymal transition (EndMT) is associated with various cardiovascular diseases and in particular with atherosclerosis and plaque instability. However, the molecular pathways that govern EndMT are poorly defined. Specifically, the role of epigenetic factors and histone deacetylases (HDACs) in controlling EndMT and the atherosclerotic plaque phenotype remains unclear. Here, we identified histone deacetylation, specifically that mediated by HDAC9 (a class IIa HDAC), as playing an important role in both EndMT and atherosclerosis. Using in vitro models, we found class IIa HDAC inhibition sustained the expression of endothelial proteins and mitigated the increase in mesenchymal proteins, effectively blocking EndMT. Similarly, ex vivo genetic knockout of Hdac9 in endothelial cells prevented EndMT and preserved a more endothelial-like phenotype. In vivo, atherosclerosis-prone mice with endothelial-specific Hdac9 knockout showed reduced EndMT and significantly reduced plaque area. Furthermore, these mice displayed a more favorable plaque phenotype, with reduced plaque lipid content and increased fibrous cap thickness. Together, these findings indicate that HDAC9 contributes to vascular pathology by promoting EndMT. Our study provides evidence for a pathological link among EndMT, HDAC9, and atherosclerosis and suggests that targeting of HDAC9 may be beneficial for plaque stabilization or slowing the progression of atherosclerotic disease.
Topics: Animals; Atherosclerosis; Endothelium; Histone Deacetylases; Human Umbilical Vein Endothelial Cells; Humans; Mice; Mice, Knockout, ApoE; Plaque, Atherosclerotic; Repressor Proteins
PubMed: 34338228
DOI: 10.1172/JCI131178