Posts Tagged: coronary artery disease

Environmental Determinants of Cardiovascular Disease

Environmental Determinants of Cardiovascular Disease

Aruni Bhatnagar

The effect of sunlight on cardiovascular health. The visible range of sunlight regulates the master clock located in the pacemaker neurons of the suprachiasmatic nucleus, which sets the intrinsic 24-h cycle and synchronizes the light-insensitive peripheral clocks to coordinate cycles of waking, sleeping, and feeding. The UVB radiation converts 7-dehydrocholesterol in the epidermis to pre–vitamin D3, which undergoes thermal isomerization to vitamin D. Vitamin D3 formed in the skin appear in the circulation and is then transported to the liver where it is converted to 25(OH)D3. In kidney, 25(OH) D3 undergoes hydroxylation to form biologically active 1,25(OH)2D. The UVA radiation induces photodegradation of nitrosothiols, such as S-nitrosylglutathione, which leads to the generation of NO, an important regulator of blood pressure. (Illustration credit: Ben Smith.) [Powerpoint File]

Neutrophil Extracellular Traps in Atherosclerosis and Atherothrombosis

Neutrophil Extracellular Traps in Atherosclerosis and Atherothrombosis

Yvonne Döring, Oliver Soehnlein, Christian Weber

Emerging roles of neutrophil extracellular traps (NETs) in atherosclerosis and atherothrombosis. (A) Luminally netting neutrophils activate leukocytes, platelets, and endothelial cells creating a proinflammatory milieu presumably resulting in endothelial dysfunction, the initial trigger of lesion development. (B/C) Lesional NETs may initiate a interleukin-1β/TH17 (T helper 17) and type I interferon response, which leads to further activation of lesional leukocytes, releasing more proinflammatory mediators. (D/E) Furthermore, it may be assumed that NET-driven proinflammatory responses will cause an inflammatory environment that favors plaque destabilization and rupture. During atherothrombosis, NETs may trigger activation of the coagulation cascade and increase thrombus stability thus orchestrating arterial occlusion. [Powerpoint File]

Prognostic Determinants of Coronary Atherosclerosis in Stable Ischemic Heart Disease: Anatomy, Physiology, or Morphology?

Prognostic Determinants of Coronary Atherosclerosis in Stable Ischemic Heart Disease: Anatomy, Physiology, or Morphology?

Amir Ahmadi, Gregg W. Stone, Jonathon Leipsic, Leslee J. Shaw, Todd C. Villines, Morton J. Kern, Harvey Hecht, David Erlinge, Ori Ben-Yehuda, Akiko Maehara, Eloisa Arbustini, Patrick Serruys, Hector M. Garcia-Garcia, Jagat Narula

Modification of the natural history of coronary disease by local implantation of a bioresorbable scaffold. From left to right: Intimal thickening (a), intimal xanthoma (b), pathological intimal thickening (c), fibroatheroma (d), thin-capped fibroatheroma (e) (reprinted from García-García et al92 with permission of the publisher. Copyright © 2009, Europa Digital & Publishing). As coronary disease progresses, does the endothelial function worsen. After the implantation of the scaffold, it can be seen that the 3-dimensional (3D) structure of the device can be delineated by means of optical coherence tomography (OCT) (f). In histology, it can be appreciated the polymeric struts overlying on the vessel wall (black arrow). On the 2D OCT image, the squared-shape struts are translucent and therefore their whole thickness can be appreciated (f′). At 5 o clock, the metallic marker can be seen (*). Invasive imaging by means of angiography and OCT allows the reconstruction of the scaffolded artery (f″). Thereafter, blood flow simulation was performed on the luminal surface and around struts at baseline and the local shear stress conditions were measured. As times goes by, the struts are integrated into the vessel wall and cover by neointima (g and g′). When the shear stress at baseline is portrayed into the follow-up OCT images (g″), it became apparent that the low shear stress areas at baseline (blue) correlate with thicker neointima thickness at follow-up as compared to high shear stress areas (on top of struts in red color), which showed thinner neointima thickness (reprinted from Bourantas et al93 with permission of the publisher. Copyright © 2014, American College of Cardiology Foundation. Published by Elsevier Inc.). Eventually, the polymeric struts will disappear (h) and somewhat vessel wall thinning is observed (i). As the bioresorbable vascular scaffold (BVS) integrates and dissolves, there is some vasomotion restoration (reprinted from Serruys et al94 with permission of the publisher. Copyright © 2014, American College of Cardiology Foundation. Published by Elsevier Inc.). EL indicates extracellular lipid; FC, fibrous cap; NC, necrotic core. BVS is a product of Abbott Vascular, Santa Clara, CA. [Powerpoint File]

The Coronary Circulation as a Target of Cardioprotection

The Coronary Circulation as a Target of Cardioprotection

Gerd Heusch

Schematic diagram with the different manifestations of coronary vascular injury during acute myocardial ischemia/reperfusion and the protective interventions that attenuate these manifestations. IP indicates ischemic preconditioning; POCO, ischemic postconditioning; and RIC, remote ischemic conditioning. [Powerpoint File]

From Loci to Biology: Functional Genomics of Genome-Wide Association for Coronary Disease

From Loci to Biology: Functional Genomics of Genome-Wide Association for Coronary Disease

Sylvia T. Nurnberg*, Hanrui Zhang*, Nicholas J. Hand, Robert C. Bauer, Danish Saleheen, Muredach P. Reilly, Daniel J. Rader

Coronary heart disease (CHD) genome-wide association studies (GWAS) risk genes are active in selective cell types involved in atherosclerosis. Coronary heart disease follow-up studies have demonstrated roles for LIPA, SORT1, and TRIB1 as plasma lipid regulators in the liver, as well as in macrophages biology. Within the vessel wall, TCF21 is upregulated in dedifferentiated smooth muscle cells which migrate to the forming fibrous cap. Adamts7 is also a regulator of smooth muscle migration but also a role in endothelial cells has been suggested. [Powerpoint File]

From Loci to Biology: Functional Genomics of Genome-Wide Association for Coronary Disease

From Loci to Biology: Functional Genomics of Genome-Wide Association for Coronary Disease

Sylvia T. Nurnberg*, Hanrui Zhang*, Nicholas J. Hand, Robert C. Bauer, Danish Saleheen, Muredach P. Reilly, Daniel J. Rader

Mechanism by which noncoding risk single nucleotide polymorphisms (SNP) can affect phenotype. Top, Multiple SNPs associated with disease are located in the intergenic region proximal to genes A, B, and C. One of the SNPs with genome-wide significance is situated within a cis-regulatory element (orange tag). The lowest P value SNP (lead SNP, flag tag) lies outside the regulatory element. Bottom, Through bending of the DNA molecule, the regulatory element gets into physical contact with the promoter of its target gene, in this case gene C, which is not the gene in closest proximity, leading to regulation of its expression (activation or upregulation in case of an enhancer element). The SNP located within the regulatory element (functional SNP, orange tag) can now affect transcription by, for instance, altering transcription factor (TF)–binding affinity based on genotype via disruption of a TF-binding motif. [Powerpoint File]

MicroRNA Regulation of Atherosclerosis

MicroRNA Regulation of Atherosclerosis

Mark W. Feinberg, Kathryn J. Moore

MicroRNA (miRNA) orchestration of cholesterol homeostasis and macrophage activation in atherosclerosis. In the liver, miRNAs repress the expression of genes involved in lipoprotein packaging and secretion (eg, miR-30c and miR-27b), uptake (eg, miRNAs targeting LDLR and SRB1), and cholesterol efflux (eg, miRNA targeting ATP-binding cassette [ABC] transporter A1 [ABCA1]). MiRNA repression of ABCA1 decreases cholesterol efflux to lipid-poor apolipoprotein A-I (apoA-I), and biogenesis of high-density lipoprotein (HDL). As the nascent HDL particle mediates free cholesterol (FC) uptake and remodels because of lecithin-cholesterol acyltransferase (LCAT) conversion of FC to cholesterol ester (CE), secreted miRNAs, such as miR-223, miR-92a, and miR-126, are detected on the mature HDL particles. The HDL-carried miRNAs can mediate extracellular signaling by repressing genes in target tissues and HDL interaction with macrophages and endothelial cells may also result in miRNA exchange (ie, pick-up or delivery via scavenger receptor B1 [SR-B1]). MiRNA targeting of SR-B1 and the ABC11 and ATP8B1 transporters reduce selective cholesterol uptake by the liver and excretion, respectively. In macrophages, miRNA targeting of ABCA1 reduces cholesterol efflux and reverse cholesterol transport back to the liver. In addition, miRNAs regulate the polarization of macrophages toward classical M1 (eg, miR-33 and miR-155) or alternative M2 (eg, miR-223 and miR-27a) inflammatory activation and also regulate lipoprotein uptake and foam cell formation (Illustration Credit: Ben Smith). ANGPTL3 indicates angiopoietin like 3; CETP, cholesteryl ester transfer protein; GPAM, glycerol-3-phosphate acyltransferase mitochondrial; LDL, low-density lipoprotein; LDLR, LDL receptor; LPGAT1, lysophosphatidylglycerol acyltransferase 1; MTTP, microsomal triglyceride transfer protein; NDST1, N-deacetylase/N-sulfotransferase; oxLDL, oxidized LDL; TG, triglyceride; and VLDL, very low-density lipoprotein. [Powerpoint File]

MicroRNA Regulation of Atherosclerosis

MicroRNA Regulation of Atherosclerosis

Mark W. Feinberg, Kathryn J. Moore

Endothelial microRNAs (miRNAs) regulate vascular inflammation. In response to biochemical and biomechanical stimuli, miRNAs regulate specific targets in endothelial cells (ECs) that alter the balance of pro- or anti-inflammatory signaling pathways. Biochemical stimuli such as tumor necrosis factor (TNF)-α reduces the expression of miR-181b, whereas it increases the expression of miR-146. MiR-181b targets importin-α3 in ECs, an effect that prevents cytoplasmic-to-nuclear translocation of nuclear factor-κB (NF-κB) family members, p50 and p65, thereby reducing NF-κB–responsive gene expression such as adhesion molecules vascular cell adhesion molecule 1 (VCAM-1), intercellular adhesion molecule 1 (ICAM-1), or E-selectin. Induction of miR-146 targets the 3′-untranslated region of tumor necrosis factor (TNF) receptor–associated factor 6 (TRAF6) and interleukin 1 receptor associated kinase 1 (IRAK1), to regulate upstream NF-κB signaling and targets HuR, which regulates endothelial nitric oxide synthase (eNOS) expression. The expression of miR-92a and miR-712 is increased in response to disturbed flow (d-flow), whereas miR-126-5p expression is reduced. miR-92a targets the transcription factors Kruppel-like factor 2 (KLF2) and 4 (KLF4), and suppressor of cytokine signaling (SOCS5) expression, an effect that decreases anti-inflammatory pathways and increases monocyte chemoattractant protein (MCP)-1 and interleukin (IL)-6 that further promote EC activation. miR-712 suppresses tissue inhibitor of metalloproteinase-3 (TIMP3), thereby increasing the expression of matrix metalloproteinases (MMPs) and a disintegrin and MMP (ADAMs). In contrast, d-flow reduces expression of miR-126-5p, thereby derepressing its target gene delta-like 1 homolog (Dlk-1), a negative regulator of endothelial cell proliferation. Laminar flow induces the expression of the miR-143/miR-145 cluster, which may be packaged and released extracellularly in microvesicles and taken-up by neighboring vascular smooth muscle cells (VSMCs). Conversely, ECs may enable the passage of miR-143 and miR-145 released from VSMCs through specialized membrane protrusions known as tunneling nanotubes. HKII indicates hexokinase II; IKK, I-kappaB kinase; and ITG β8, integrin β8. [Powerpoint File]

MicroRNA Regulation of Atherosclerosis

MicroRNA Regulation of Atherosclerosis

Mark W. Feinberg, Kathryn J. Moore

MicroRNA (miRNA) regulation of vascular smooth muscle cell phenotype. In response to vascular wall injury or atherosclerosis, the expression of the miR-143/miR-145 cluster is markedly reduced in vascular smooth muscle cells (VSMCs). MiR-143 and miR-145 target the transcriptional regulators Krüppel-like factor (KLF)-4, KLF5, myocardin, and ETS domain-containing protein-1 (ELK-1) important for VSMC phenotypic switching from a contractile, mature, and differentiated cell type to a dedifferentiated synthetic, and proliferative cell type. In addition, miR-143/miR-145 target genes important to the regulation of blood pressure such as angiotensin-converting enzyme (ACE). In contrast, vascular wall injury increases expression of miR-221 and miR-222, an effect that decreases the expression of the cell cycle regulator c-Kit, p27(Kip1), and p57(Kip2). Induction of miR-21 expression targets phosphatase and tensin homolog (PTEN), thereby increasing the antiapoptotic regulator B-cell lymphoma 2 (Bcl-2). Microvesicles or exosomes released by neighboring endothelial cells, and carrying miRNAs such as miR-143/miR-145 or miR-126 (bound to Argonaute2 [Ago2]), may be taken up by VSMCs enabling suppression of target genes and altering VSMC functional responses. BCL2 indicates B-cell lymphoma 2; EC, endothelial cell; FOXO3, Forkhead Box O3; IRS1, insulin receptor substrate 1; SM, smooth muscle; and SMMHC, smooth muscle myosin heavy chain. [Powerpoint File]

Imaging Atherosclerosis

Imaging Atherosclerosis

Jason M. Tarkin, Marc R. Dweck, Nicholas R. Evans, Richard A.P. Takx, Adam J. Brown, Ahmed Tawakol, Zahi A. Fayad, James H.F. Rudd

Multimodal approach to atherosclerosis imaging. A representative illustration of current and emerging atherosclerosis imaging modalities. Each modality offers unique measurements of disease severity. Together, this information can be used to determine anatomic and hemodynamic consequences of atherosclerosis, complimented by detail on plaque composition, overall disease burden, and current metabolic activity acting within an individual patient. A, X-ray angiography showing multiple right coronary artery atherosclerotic lesions (arrows) resulting in significant luminal narrowing; B, virtual histology intravascular ultrasound (VH-IVUS) demonstrating coronary plaque with high content of necrotic core (red), as well as dense calcium (white) and fibro-fatty regions (dark/light green); C, Computed tomographic (CT) angiography showing noncalcified plaque in the left anterior descending artery with positive remodeling (dashed line); D, single-photon emission computed tomography (SPECT) myocardial perfusion scan with stress-induced perfusion defect (arrow); E, 3D volume rendered CT whole-heart image; F, optical coherence tomography (OCT) image of a coronary plaque showing lipid (*), characterized as signal-poor regions with poorly demarcated borders; G, OCT image of a lipid-rich coronary plaque displaying thin overlying fibrous cap (arrow), indicative of thin-cap fibroatheroma; H, Fused 18F-NaF positron emission tomography (PET)–CT image showing high left anterior descending artery tracer uptake (arrow) revealing active plaque microcalcification; I, 3-T magnetic resonance (MR) contrast-angiography performed with dual ECG and respiratory navigator gating showing clear delineation of the proximal left-sided coronary vessels. Panel H adapted from Joshi et al.5 [Powerpoint File]

Imaging Atherosclerosis

Imaging Atherosclerosis

Jason M. Tarkin, Marc R. Dweck, Nicholas R. Evans, Richard A.P. Takx, Adam J. Brown, Ahmed Tawakol, Zahi A. Fayad, James H.F. Rudd

Shear stress simulation and plaque progression. 3D coronary reconstruction at baseline (A) and 3-year follow-up (C); outer vessel-wall shown in a semitransparent fashion to allow visualization of plaque distribution. B, E, Shear stress simulation performed at baseline; low stress shown in blue and high in red. Plaque burden at baseline (D) and follow-up (F); green indicates minimal thickness and red increased plaque thickness. There is significant plaque progression in the region of low shear stress at baseline (circle). Image courtesy of Dr Christos Bourantas. [Powerpoint File]

Imaging Atherosclerosis

Imaging Atherosclerosis

Jason M. Tarkin, Marc R. Dweck, Nicholas R. Evans, Richard A.P. Takx, Adam J. Brown, Ahmed Tawakol, Zahi A. Fayad, James H.F. Rudd

Cardiac motion-corrected 18F-NaF positron emission tomography (PET). 3D cardiac computed tomographic (CT) rendering with superimposed 18F-NaF cardiac-gated PET image reconstruction using a single bin (25% of PET counts) vs (B) motion corrected PET with 10-gated bin method (consecutive 10% segments), resulting in less noise and improved target to background ratio. Adapted from Rubeaux et al208 with permission of the publisher. Copyright ©2016, Society of Nuclear Medicine and Molecular Imaging, Inc. LAD indicates left anterior descending artery; LCx, left circumflex artery; and RCA, right coronary artery. [Powerpoint File]

Do Plaques Rapidly Progress Prior to Myocardial Infarction? The Interplay Between Plaque Vulnerability and Progression

Do Plaques Rapidly Progress Prior to Myocardial Infarction? The Interplay Between Plaque Vulnerability and Progression

Amir Ahmadi, Jonathon Leipsic, Ron Blankstein, Carolyn Taylor, Harvey Hecht, Gregg W. Stone, Jagat Narula

Possible mechanism for rapid plaque progression before MI. This figure illustrates a biologically plausible mechanism for rapid plaque progression before MI. The plaque depicted here is going through outward expansion (positive remodeling) in the first 6 measurements (A–F). During this time, the degree of luminal narrowing is relatively stable, despite active plaque growth, emphasizing that a stable degree of luminal narrowing is not equivalent to lack of plaque growth. Between stages F and G, the plaque reaches the limit of outward expansion (dotted line) and intraluminal growth ensues causing accelerated luminal narrowing. The possible mechanisms for this rapid expansion include intraplaque neovascularization with incompetent vessels that leak red blood cells at the borders of the necrotic core (F–H), intraplaque hemorrhage (G–I), and subclinical cycles of rupture and healing (H) causing accelerated plaque growth. Finally, a rapidly grown plaque ruptures and causes intraluminal thrombus formation resulting in a myocardial infarction (I). It should be noted that histological and behavioral features that allow plaques to undergo such rapid progression are the same features that are known to be characteristics of vulnerable plaques. It is also known that most MIs are result of ruptures of plaques with these features. Therefore, in order for a plaque to grow rapidly before causing MI, it should already possess or acquire these features of vulnerability. MI indicates myocardial infarction. [Powerpoint File]

Acute Coronary Syndromes Compendium: Genetics of Coronary Artery Disease

Acute Coronary Syndromes Compendium: Genetics of Coronary Artery Disease

Robert Roberts

Low-density lipoproteinn (LDL) and its cholesterol (LDL-C) are synthesized in the liver, and by binding to the LDL receptor (LDL-R), LDL-C is removed from the circulation. Statin X indicates that the class of drugs known as statins inhibits the synthesis of LDL-C. PCSK9 normally delays removal of LDL-C from the circulation. Inhibition of PCSK9 leads to faster removal of LDL-C and lower levels of circulating LDL-C. Reprinted from Roberts99 with permission of the publisher. Copyright ©2008, Elsevier. Authorization for this adaptation has been obtained both from the owner of the copyright in the original work and from the owner of copyright in the translation or adaptation. [Powerpoint FIle]

Acute Coronary Syndromes Compendium: Imaging Plaques to Predict and Better Manage Patients With Acute Coronary Events


Acute Coronary Syndromes Compendium: Imaging Plaques to Predict and Better Manage Patients With Acute Coronary Events

Hector M. Garcia-Garcia, Ik-Kyung Jang, Patrick W. Serruys, Jason C. Kovacic, Jagat Narula, Zahi A. Fayad

Photomicrographic cross section of human coronary plaque rupture (PR), thin-capped fibroatheromas (TCFA), and fibroatheromas (FA) with varying degree of luminal stenosis (A–C). PR with mild, moderate, and severe luminal stenosis, respectively. Nonocclusive thrombus (Thr) is observed in the microphotograph A, whereas occlusive Thr is occupying the lumen in B and C. D, E, and F, TCFA with mild, moderate, and severe luminal stenosis, respectively. Necrotic core (NC) is covered by a thin fibrous cap, and Thr is not present in the lumen. G, H, and I, Stable plaque or FA with mild, moderate, and severe luminal stenosis, respectively. The size of necrotic core is relatively small when present, and calcification (Ca++) is frequently seen. Reprinted from Narula et al12 with permission of the publisher. [Powerpoint File]