cardiology4 Flashcards
Major ASCVD Risk Factors
Cigarette smoking. Hypertension. Low HDL-C:
Emerging Risk Factors
Hypertriglyceridemia. Apolipoprotein B 100 (Apo B). LDL particle number. LDL particle size/density (small dense LDL). Lipoprotein (a) [Lp(a)]. Markers of Inflammation (hsCRP). Homocysteine. Prothrombotic Factors. Subclinical Atherosclerosis
4 Major Statin Benefit Groups
- Individuals with known clinical ASCVD. 2. Individuals with LDL ≥ 190 mg/dl. 3. Individuals with diabetes (>40 yo and LDL>70). 4. Individuals (>40 yo, LDL>70) without ASCVD or diabetes who have an estimated 10-year ASCVD risk ≥ 7.5%
Major Recommendations for Statin Therapy for ASCVD Prevention
In those whose 10-year risk is 5-7.5% or when the decision is unclear, other factors may be used to enhance the treatment decision making: Family History of Premature ASCVD, LDL-C > 160 mg/dl, hsCRP ≥ 2 mg/dl, Coronary Calcium Score ≥ 300 Agatston units or ≥ 75th percentile for age, sex, ethnicity, Ankle-Brachial Index
Hypertriglyceridemia
Severe hypertriglyceridemia is associated with acute pancreatitis. Moderate hypertriglyceridemia is associated with ASCVD. Biologically plausible associated risk factor. But unclear whether triglyceride lowering is beneficia. Associated with insulin resistance, metabolic syndrome, type 2 diabetes. “Risk factor” for ASCVD
HDL-C
Biologic Plausibility: HDL “removes” cholesterol from periphery and HDL has antioxidant and anti-inflammatory effects. Epidemiology: Low HDL levels are associated with increased risk for ASCVD. High HDL levels are associated with a protective effect against ASCVD. Randomized Trials: No evidence to date that HDL raising reduces ASCVD related events/death
Atherosclerosis HLD and LDL
Atherosclerosis is a slow, complex process. Elevated atherogenic lipoproteins (primarily LDL-C) are a critical component in the development of atherosclerosis and the progression to acute events. Cholesterol lowering therapy especially with statin therapy is effective in preventing acute atherosclerotic events, both acutely and chronically. What specific lipid goals should be is still not entirely clear. The “jury is still out” on whether HDL raising or TG lowering are clinically beneficial over and beyond LDL lowering
LDL particles
pose a risk for cardiovascular disease when they invade the endothelium and become oxidized, since the oxidized forms are more easily retained by the proteoglycans. A complex set of biochemical reactions regulates the oxidation of LDL particles, chiefly stimulated by presence of necrotic cell debris and free radicals in the endothelium. Increasing concentrations of LDL particles are strongly associated with increasing amounts of atherosclerosis within the walls of arteries over time, eventually resulting in sudden plaque ruptures and triggering clots within the artery opening, or a narrowing or closing of the opening, i.e. cardiovascular disease, stroke, and other vascular disease complications. LDL particles (though far different from cholesterol per se) are sometimes referred to as bad cholesterol because they can transport their content of fat molecules into artery walls, attract macrophages, and thus drive atherosclerosis. In contrast, HDL particles (though far different from cholesterol per se) are often called good cholesterol or healthy cholesterol because they can remove fat molecules from macrophages in the wall of arteries.
How Do Inflammation and Atherogenesis Overlap?
Subintimal LDL activates the endothelium. Activated leukocytes localize to sites of endothelial injury and initiate local inflammation. Intensified inflammation promotes plaque growth and eventual instability. LDL penetrates endothelium and is retained in the intima, where it undergoes oxidative modification. Proinflammatory lipids released from LDL stimulate endothelial cells to express adhesion molecules. Circulating monocytes adhere to endothelial cells expressing VCAM-1 and other adhesion molecules respond to chemokines (eg MCP-1) and migrate into the intima. Microphages begin taking up oxLDL and cholesterol accumulates in the cell, which develops into a lipid-laden foam cells and release proinflammatory mediators.
Why is Inflammation Implicated in Atherogenesis?
Evolution of host response to bacterial infection increases risk of sterile inflammation. Pathogen-associated molecular patterns (PAMPs). Danger-associated molecular patterns (DAMPs), such as Oxidized LDL and Cholesterol crystals
Monocytes
innate immune system leukocytes (2-10% of all leukocytes). Differentiate into tissue macrophages. Monocyte accumulation in atherogenesis is progressive and proportional to extent of disease. Monocyte adhesion to activated endothelium is an obligate step in atherogenesis. Inhibiting monocyte adhesion limits atherosclerosis initiation, such as VLA-4 and beta 2 integrins.
VLA-4
responsible for monocyte tight adhesion to VCAM-1. Knockout limits atherogenesis
ß2 integrins
include CD11a/CD18, CD11b/CD18, CD11c/CD18, CD11d/CD18. Knockout of all 4 CD18 integrins. Specific knockout of CD11c
Adaptive Immunity in Atherogenesis
Dendritic cell antigen presentation with subsequent T cell activation promotes clonal T cell expansion. Th1 response promotes IFN-gamma elaboration and atherosclerosis. TH17 cells may promote plaque instability and neoangiogenesis. Elaborate IL-17A, IL-22, and IL-21. Blockade of IL-17A may reduce atherosclerosis.
Inflammation and Atherogenesis: Summary
Immune response to injury initiates atherogenesis. Innate immune cell interaction with endothelium drives initial plaque formation. T cells promote further lesion expansion and plaque vulnerability.
T lymphocytes in Atherosclerosis
The major class of T lymphocytes present in atherosclerotic lesions is CD4+. In response to the local milieu of cytokines, CD4+ cells differentiate into the Th1 or Th2 lineage. Among the principal inducers of the Th1 and Th2 cells are interleukin (IL)-12 and IL-10, respectively. Activated T lymphocytes are functionally defined by the cytokines produced with interferon (IFN)-γ secreted from the Th1 cells and IL-4 from the Th2 cells. Much of the emphasis in atherosclerosis research in relation to T lymphocytes has focused on the role of Th1-type responses. The evidence for the role of Th1 cells includes the detection of IFN-γ mRNA and protein in lesions. A direct role in the disease process has been defined in atherosclerotic-susceptible mice that are deficient in either IFN-γ receptors7 or the cytokine itself. Conversely, injection of IFN-γ or the IFN-γ–releasing factors IL-12 and IL-18 enhances the extent of disease in apolipoprotein E −/− mice.
Progression of Atherosclerosis
After establishment of fatty streak, inflammatory mediators drive additional plaque expansion. Th1 mediated process in conjunction with macrophage apoptosis. Plaque growth transitions from stable plaque to unstable/ruptured plaque. Interplay of atherosclerosis and thrombosis.
What are the Major Drivers of Plaque Instability?
Macrophage apoptosis and necrosis promotes a “necrotic core”. Matrix metalloproteinases degrade the fibrous cap. Intra-plaque hemorrhage further weakens core.
Plaque Progression and Vulnerability
Progression from atherosclerotic plaque to myocardial infarction involves: Lesion expansion, Macrophage apoptosis and necrosis, Weakening of fibrotic cap, and Eventual plaque rupture
Can a Biomarker of Inflammation Predict Cardiovascular Risk?
Inflammatory underpinning of atherogenesis suggests inflammatory markers may predict residual risk. Add additional prognostic information on top of standard risk factors.
C Reactive Protein
Pentraxin acute phase reactant is produced by hepatocytes. It is possibly also expressed by macrophages and smooth muscle cells. Binds to modified membranes, apoptotic cells, and lipoproteins. Activates classical complement pathway
Mechanisms of Accelerated Atherogenesis in Autoimmune Diseases
Increased monocyte/macrophage activation, which is a potential common mechanism underlying all IMIDs. Impaired endothelial vasodilator function. This is observed in rheumatoid arthritis. Proatherogenic Lipoproteins include pro-inflammatory HDL, which increases LDL oxidation, and observed in RA, psoriasis. Plaque instability. RA associated with similar extent of CAD, but increased plaque vulnerability
HDL
and its protein and lipid constituents help to inhibit oxidation, inflammation, activation of the endothelium, coagulation, and platelet aggregation. All these properties may contribute to the ability of HDL to protect from atherosclerosis, and it is not yet known which are the most important. In the stress response, serum amyloid A, which is one of the acute-phase proteins and an apolipoprotein, is under the stimulation of cytokines (IL-1, IL-6), and cortisol produced in the adrenal cortex and carried to the damaged tissue incorporated into HDL particles. At the inflammation site, it attracts and activates leukocytes. In chronic inflammations, its deposition in the tissues manifests itself as amyloidosis.
Inflammation and HDL Function
Endotoxemia alters HDL size and decreases reverse cholesterol transport capacity. In chronic inflammation, HDL may lose its anti-atherogenic functions or become pro-atherogenic. HDL cholesterol efflux capacity is inversely associated with carotid intima-media thickness and risk of coronary artery disease. Relationship remains significant even after adjusting for HDL level or levels of apolipoprotein A-I. Impaired HDL efflux associated with more severe psoriasis. Those with rheumatoid arthritis have a similar overall prevalence of vessel DAC and had significantly more vulnerable plaque in LAD.