Atherosclerosis Presentation
Atherosclerosis Presentation
Various immunodeficiencies
HLH
Variable course of disease Rapidly progressive leading to death within weeks Transient improvements with unspecific therapies Disappearance of symptoms without therapy Disappearance of symptoms with immunosuppressive/immunomodulatory drugs
HLH
Classification
Unknown mutations
HLH
Endogenous products - tissue damage - radical stress - metabolic products Rheumatic disorders
- Immune deficiencies
CHS Griscelli syndrome XLP SCID Malignancies
HLH Diagnostic criteria Histiocyte Society 1991 Clinical Fever > 38.5 Splenomegaly Laboratory Cytopenia of => 2/3 cell lines Hypertriglyceridemia and/or hypofibrinogenemia Histopathology Hemophagocytosis in bone marrow or spleen or liver or lymphnode Strong supportive evidence are spinal fluid pleocytosis, liver histology resembling chronic persistent hepatitis, low natural killer cell activity
HLH Therapy h Cytostatic and immunsuppressive/ immunomodulatory drugs: Corticosteroids, Cyclosporin A, Etoposide Immunoglobulins, Antithymocyte globulin h Bone marrow transplantation Prognosis In 20% no response to therapy After BMT 60-70% relapse-free survival
Introduction
Arteriosclerosis
Thickening and loss of elasticity of arterial walls Hardening of the arteries Greatest morbidity and mortality of all human diseases via Narrowing Weakening
Atherosclerotic Disease
Prevalence
In US there are 6 million with CAD 3 million Americans have had strokes
Mortality
1.5 million deaths/yr in US due to myocardial infarction 0.5 million deaths/yr in US due to strokes
Monckeberg medial calcific sclerosis Arteriolosclerosis small arteries and arterioles (hypertension and DM)
Gender
Men more prone than women, but by age 60-70 about equal frequency
Family History
Familial cluster of risk factors Genetic differences
Fig. 11.7
Normal Artery
Normal Artery
Atherosclerosis
A disease of the intima A disease of the intima A disease of the intima Atheromas, atheromatous/fibrofatty plaques, fibrous plaques Narrowing/occlusion; weakness of wall
Fatty Streak-Aorta
Consequence
Ischemia, turbulence Aneurysms, vessel rupture Narrowing, ischemia, embolization Athero-embolization Increase systolic blood pressure
Late Changes
Calcification
An example of dystrophic calcification
Thrombus formation
Caused by endothelial injury,ulceration, turbulence Organization of thrombus More thrombus
Encroachment
Weakens vessel wall
Bleeding
Ulceration, cracking and angiogenesis
Fibrous Plaques
Complicated Lesions
Ulceration/Hemorrhage/Cholesterol Crystals
Complicated Lesion/Calcification
Thrombosis/Complicated Lesion
Complicated Lesion/Ulceration/Thrombosis
Aortic Aneurysm
Aortic Aneurysm
Pathogenesis of Atherosclerosis
Cause?
Current hypothesis: Response to Injury
Initiated by endothelial dysfunction
Endothelial dysfunction
Induced by oxidized LDL, can be worsened by cigarette smoking, and can be reversed with correction of hyperlipidemia by diet or by therapy with a statin, which increases the bioavailability of nitric oxide, with ACE inhibitors, or with antioxidants such as vitamin C or flavonoids contained in red wine
Anderson et al., 1996; Harison et al 1987; John et al., 1998; Mancini et al 1996; Levine et al 1996
Endothelial dysfunction
Expression of VCAM-1 on endothelial surfaces is an early, and necessary, step in the pathogenesis of atherosclerosis. Increased cellular adhesion and associated endothelial dysfunction then sets the stage for the recruitment of inflammatory cells, release of cytokines and recruitment of lipid into the atherosclerotic plaque.
Li et al., 1993
Dyslipidaemia
Lipid abnormalities play a critical role in the development of atherosclerosis Early experiments demonstrated accelerated atherosclerosis with a high cholesterol diet. Epidemiologic studies showed increasing incidence of atherosclerosis when serum cholesterol above 3.9 mM
Dyslipidaemia
High levels of LDL and low levels of HDL important risk factors for atherosclerosis Macrophage uptake of LDL may initially be adaptive response, which prevents LDL-induced endothelial injury However, cholesterol accumulation in foam cells leads to mitochondrial dysfunction, apoptosis, and necrosis, with resultant release of cellular proteases, inflammatory cytokines, and prothrombotic molecules
Dyslipidaemia
Oxidized LDL can cause disruption of the endothelial cell surface, promote inflammatory and immune changes via cytokine release from macrophages and antibody production and increase platelet aggregation
Dyslipidaemia
HDL, in contrast to LDL, has antiatherogenic properties that include reverse cholesterol transport, maintenance of endothelial function, protection against thrombosis, and maintenance of low blood viscosity through a permissive action on red cell deformability
Inflammation
Best evidence supporting the importance of inflammation in the pathogenesis of atherosclerosis comes from the observation that markers of increased or decreased systemic inflammation are directly associated with the risk of atherosclerosis
Atherosclerosis is initiated when leucocytes adhere to the endothelium as a result of expression of adhesive proteins.
Monocytes within the subendothelial space subsequently orchestrate the development of atherosclerosis through cytokine release. Crowther et al., 2005
Clinically apparent disease if first noted as a result of the accumulation of foam cells. Crowther et al., 2005
Inflammatory mediators
Include IL-1, TNF and , IL-6, M-CSF, MCP-1, IL-18 and CD-40L. The impact of these mediators is diverse and includes mitogenesis, intracellular matrix proliferation, angiogenesis and foam cell development
Crowther et al., 2005
The clinically important lesion is characterized by intimal narrowing, many foam cells, neovascularization and flow limiting narrowing. However, this stage of the disease is sufficiently advanced that treatments aimed at it do not impact the pathogenesis of the underlying disorder.
CRP
CRP may be only a marker of inflammation and thrombotic risk CRP binds to LDL, allowing LDL to be taken up by macrophages without the need for modification CRP induces adhesion molecule expression and production of IL-6 and MCP-1 in human endothelial cells; these effects might enhance a local inflammatory response within the atherosclerotic plaque by the recruitment of monocytes and lymphocytes
CRP
The proinflammatory and prothrombotic effects of CRP on monocytes and endothelial cells in vivo by subjecting wild-type mice, which do not express CRP, and human CRP-transgenic (CRPtg) mice to two models of arterial injury. In an arterial injury model complete thrombotic occlusion of the femoral artery at 28 days was seen in 17% of wild-type mice compared with 75% of CRPtg arteries.
Danenberg et al., 2003
Multivariable-adjusted relative risks of cardiovascular disease according to levels of CRP and the estimated 10-year risk based on the Framingham Risk Score. CHD indicates coronary heart disease. Data from Ridker and colleagues
Leukocyte activation
mRNA profiles showing increased levels of most inflammatory mRNAs in individuals with prior AMI
Toll-like receptor 4
Polymorphisms in the toll-like receptor 4 gene that confer differences in the inflammatory response to Gram negative pathogens Carriers of the Asp299Gly polymorphism, compared to wild-type alleles, have reduced circulating levels of inflammatory markers, including CRP, adhesion molecules, and IL-6, and a reduced incidence of carotid atherosclerosis
PPARs
Ligands of PPAR- include fatty acids and the oral hypoglycemic drugs belonging to the glitazone family PPAR- is expressed in numerous cell types found within the atherosclerotic lesion, including endothelial cells, smooth musclecells, macrophages, and T cells
Potential anti-atherogenic activities of peroxisome proliferator-activated receptors (PPARs) 1. Increased nitric oxide synthesis and release 2. Decreased recruitment of T cells 3. Reduced angiogenesis 4. Inhibition of smooth muscle cell (SMC) migration 5. Decreased SMC expression of matrix-degrading enzymes 6. Decreased macrophage-dependent expression of matrix metalloproteinase (MMP)-9 and osteopontin 7. Enhanced release of the interleukin-1 receptor antagonist 8. Enhanced reverse cholesterol transport
Angiogenesis
Angiogenic signaling and proliferation of microvessels within the plaque is only now beginning to be understood Plaque hemorrhage is likely attributable to bleeding from fragile microvessels that proliferate within the plaque itself, presumably in response to local angiogenic stimuli.
Angiogenesis
Kockx et al identified intraplaque hemorrhage from microvessels triggering macrophage activation and foam cell formation in carotid lesions These authors propose that intraplaque microhemorrhage may initiate platelet and erythrocyte deposition, lead to iron deposition, activate macrophages and contribute to foam cell formation.
Kockx et al.,2003
Angiogenesis
The importance of angiogenesis in the pathogenesis of plaque growth was recently bolstered by the finding that intra-plaque microvessels were an independent predictor of plaque rupture The potential importance of angiogenesis in the development of atherosclerosis is found in experiments that demonstrate that antiangiogenic therapy reduced atherosclerotic lesion development in a placebo controlled trial in atherosclerosis prone mice
Moreno et al., 2004; Chew
General features of insulin signal transduction pathways. PI 3-kinase branch of insulin signaling regulates GLUT4 translocation and glucose uptake in skeletal muscle and NO production and vasodilation in vascular endothelium. MAPkinase branch of insulin signaling generally regulates growth and mitogenesis and controls secretion of ET-1 in vascular Endothelium Kim et al., 2006
Shared and interacting mechanisms of glucotoxicity, lipotoxicity, and inflammation underlie reciprocal relationships between insulin resistance and endothelial dysfunction that contribute to linkage between metabolic and cardiovascular diseases. CAD indicates coronary artery disease
Mechanisms for the contribution of insulin resistance to atherosclerosis. VSMC indicates vascular smooth muscle cell; CHF, congestive heart failure. Kim et al., 2006
Tissue factor: A key regulator of coagulation. Tissue factor (TF) is a key initiator of the coagulation cascade. Formation of a complex with factor VIIa (FVIIa) leads to activation of factor IX (FIX) and factor X (FX), resulting in thrombin generation and, ultimately, clot formation. Tissue factor pathway inhibitor (TFPI), the endogenous inhibitor of TF activity, is synthesized and secreted mainly by endothelial cells. TFPI binds to FXa and thereby inhibits TF/FVIIa activity.
Induction of tissue factor expression and activity. Induction of tissue factor (TF) is exemplified in an endothelial cell. Various mediators induce TF expression through activation of their receptors. Induction of TF primarily occurs at the transcriptional level, resulting in an increase in TF mRNA and, eventually, TF protein expression. TF is distributed in three cellular pools as cytoplasmatic TF, surface TF, and encrypted TF. Moreover, TF-containing microparticles are released from the cell. Alternative splicing results in a soluble secreted form of TF (asTF). IL-1 indicates interleukin-1; LPS, lipopolysaccharide; TNF-, tumor necrosis factor ; VEGF, vascular endothelial growth factor; HB1B, histamine HB1B-receptor; 5-HTB2aB, 5-hydroxytryptamineB2aB receptor; IL1-R, interleukin-1 receptor; TLR-4, toll-like receptor 4; PAR, proteaseSteffel et al; 2006 activated receptor; KDR, VEGF receptor-2.
Tissue factor in the atherosclerotic plaque. In the inflammatory environment of atherosclerotic plaques, tissue factor (TF) is present at high levels in endothelial cells, vascular smooth muscle cells, macrophages/foam cells, and in the necrotic core. TF induction is exemplified by selected mediators in endothelial cells (EC, left panel), macrophages (M, middle panel), and vascular smooth muscle cells (VSMC, right panel). On plaque rupture, highly procoagulant material including TF-containing microparticles is released into the blood, leading to rapid initiation of coagulation, platelet aggregation, and, ultimately, thrombus formation with vessel occlusion. Steffel et al; 2006
Therapeutic approaches. Several therapeutic strategies have been developed to specifically interfere with the action of tissue factor (TF). Molecular approaches such as ribozymes or antisense oligonucleotides specifically inhibit TF production. Monoclonal or polyclonal anti-TF antibodies directly target and inactivate the TF protein. Site-inactivated factor VIIa (FVIIai) binds to TF but lacks catalytic activity for conversion of factor X (FX) or factor IX (FIX). Recombinant tissue factor pathway inhibitor (rTFPI) interferes with the activity of the TF/FVIIa complex by binding to the active site of factor Xa (FXa), leading to formation of a quaternary inhibitory complex with TF/FVIIa. Similarly, recombinant nematode anticoagulant protein c2 (rNAPc2) interferes with the TF/FVIIa complex by binding to FXa or FX before formation of a quarternary inhibitory complex with TF/FVIIa.
Response to Injury
Endothelial Dysfunction
Fatty Streak
Fibro-fatty Atheroma
Is Atherosclerosis Reversible
Primate experiments
High fat diet discontinued; atherosclerotic lesions regress
Humans
Decrease fat and caloric intake (wars, famine, wasting disease), atheromas decrease. Angiography after cholesterol lowering, plaque size decreases