see also:

• atherosclerosis and primary prevention;
• risk factors and molecular genetics of atherosclerosis

• in 2017, the inflammation hypothesis of atherothrombosis was proven with the 10 000-participant CANTOS (Canakinumab Anti-Inflammatory Thrombosis Outcomes Study) in which targeting IL-1b significantly lowered major cardiovascular events rates in the absence of any effect on cholesterol, blood pressure, or coagulation, and the magnitude of risk reduction observed in CANTOS was related directly to the magnitude of interleukin-6 (IL-6) reduction achieved.
• many studies have shown that the increase in risk per SD of inflammation measured either by hsCRP (high-sensitivity C-reactive protein) or interleukin-6 (IL-6) consistently exceeded that of a 1-SD increase in cholesterol or blood pressure
• 2023 discovery that the protein Piezo 1 plays a previously unidentified role in how the endothelial cells respond to vessel stiffening and shear stress ¹⁾
• traditional teaching was:
  • The building blocks are the same as those in conventional inflammatory response, but they are constructed in different ways & the mechanism is driven by lipids (mainly LDL).
  • It appears that following endothelial injury, a plaque characterised by cholesterol filled “foamy” macrophages develops & that this plaque is self-promoting once established by further entry of monocytes being encouraged by positive feedback

1. lesion initiation - occurs when endothelial cells, activated by risk factors such as hyperlipidaemia, express adhesion and chemoattractant molecules that recruit inflammatory leukocytes such as monocytes & T lymphocytes. Extracellular lipid begins to accumulate in the intima.
   • ⇒ incr. expression of ICAM-1 via:
     • IL-1, TNF both from macrophages
     • scavenger receptor ligands;
     • thrombin;
     • activated platelets;
   • ⇒ incr. monocyte chemoattractant protein (also from macrophages)
   • both lead to incr. migration of monocytes (via their beta-2 integrin -ICAM1)
     • inhibited by HDL & antioxidants;
2. evolution to fibrofatty change - monocytes recruited to artery wall become macrophages & express scavenger receptors that bind modified lipoproteins. Macrophages become lipid-laden foam cells by engulfing modified lipoproteins. Leukocytes & resident vascular wall cells can secrete inflammatory cytokines & growth factors that amplify leukocyte recruitment & cause smooth muscle cell migration & proliferation.
   • Extracellular oxidised LDL (also due to macrophages)
     • ⇒ uptake by macrophages via scavenger receptor that binds oxidised LDL
     • ⇒ “foamy cells”
     • functional HDL promotes efflux of cholesterol from these macrophages and thus reduces risk of coronary artery disease ²⁾
       • it seems that inflammatory processes may convert HDL into dysfunctional HDL which does not promote this efflux and thus is no longer cardio-protective.
   • Atherosclerotic macrophages:
     • ⇒ incr. c-fos
     • ⇒ incr. apo-lipoprotein E;
     • ⇒ ? incr. interleukin-6 (IL-6), IL-1 & TNF;
     • ⇒ incr. monocyte chemoattractant protein (see above)
     • ⇒ incr. platelet-derived growth factor (PDGF) ⇒ proliferation arterial sm. muscle cells;
       • ⇒ arterial wall thickening ⇒ ischaemia;
     • ⇒ incr. heparin-binding epidermal growth factor ⇒ proliferation art.sm.muscle cells;
     • ⇒ incr. oxidation of extracellular LDL ⇒ incr. uptake (see above)
   • ? role of thrombosis via incr. plasminogen activator inhibitor-1;
   • ? role of Chlamydial infection???
3. fibrous cap weakening - as lesion progresses, inflammatory mediators cause expression of tissue factor, a potent procoagulant, and of matrix-degrading proteinases that weaken the fibrous cap of the plaque
   • factors predictive of fibrous cap weakening:
     • presence of large lipid-rich core
     • thin fibrous cap with eccentric morphology less likely to withstand mechanical stresses of haemodynamic changes
     • heavy infiltration by inflammatory cells which weaken the cap by reducing its tensile strength
     • fewer smooth muscle cells
     • BUT NOT size of plaque or degree of resulting stenosis
   • there is a growing body of evidence that statin Rx can stabilise plaques and even induce plaque regression.
   • ACE inhibitors may also have plaque-stabilising effects by favourably influencing endothelial function & myocardial remodelling.
4. fibrous cap rupture - if fibrous cap ruptures at point of weakening, coagulation factors in the blood gain access to thrombogenic, tissue factor-containing lipid core causing thrombosis on non-occlusive plaque. If balance between prothrombotic & fibrinolytic mechanisms prevailing at that particular region and at that particular time is unfavorable, occlusive thrombus causing acute coronary syndromes may result.
   • it was shown in the 1990's that 60% of all ACS actually involved plaque lesions that were only mildly-moderately obstructive and were due to de-stabilisation of the plaque
   • high risk lesions are not necessarily the angiographically “tight” stenoses that have been the focus of cardiologists in the era of angiography, but it is generally the mild to mod. stenosis lesions that result in plaque rupture!
   • 1-12% of AMI pts have “normal” angiograms - but presumably have mild plaques that ruptured.
   • plaque rupture occurs when intraplaque stress exceeds the material strength of the overlying fibrous cap with important risk factors being:
     • necrotic core size > 10%
     • fibrous cap thickness, especially thin-cap fibroatheromas (TCFAs) and those infiltrated by foam cells (macrophages)
     • presence of microcalcification
     • but reduced by dense calcium ≥10%
     • luminal area
       • plaques causing mild or moderate stenosis may be under greater stress and therefore more prone to rupture compared with plaques that cause greater lumen stenosis
       • Laplace’s law (σ = Pr/h, where σ = circumferential stress, P = intra-arterial pressure, r = vessel radius, and h = vessel wall thickness)
       • cyclical stretching and relaxation of systole and diastole may be particularly important to induce plaque “fatigue“
       • plaques with minimal luminal area ≤4 mm² do not predict major cardiac events
     • eccentricity
     • location - 80% of coronary plaque ruptures occur within the 1st 33mm of the artery; 59% in RCA, 40% in LAD and 16% in L circumflex A ³⁾
   • it appears serum bilirubin may be protective in preventing plaque rupture
     • those with Gilbert's disease have a 3-4x lower risk of heart attacks
     • bilirubin deficiency further destabilises unstable atherosclerotic plaque ⁴⁾
       • future possibility of strategies to inhibit the activity of bilirubin UDP-glucuronosyltransferase to raise bilirubin levels
   • Virchow's triad for occlusive thrombus formation:
     • vessel wall factors:
       • tissue factor rich lipid core; active inflammatory infiltration; weakening fibrous cap; endothelial dysfunction; vasoconstriction;
     • blood factors:
       • thrombogenic factors eg. hyperlipidaemia; lipoprotein a; hyperglycaemia; cell aggregation; hypertension; hyperinsulinaemia; hypo-HDL;
       • increased platelet reactivity & hyperaggregability eg. diabetes
       • defective fibrinolysis eg. PAI-1 (due to hyperTG & insulin resistance)
     • blood flow factors:
       • plasma viscosity;
       • shear stress is directly related to flow velocity & inversely related to the 3rd power of luminal diameter, thus vasoconstriction, plaque disruption & thrombus formation increase shear stress;
       • circumferential tensile stress is directly related to BP & radius of lumen, thus fibrous caps with larger lumen are subject to more tension than flow-limiting stenosed plaques with smaller residual lumen.
       • local stasis eg. intimal dissection, coronary artery aneuryms or complex lesions may cause local stasis.
5. healing phase - when thrombus resorbs, products associated with thrombosis such as thrombin & mediators released from degranulating platelets, including platelet-derived growth factor & transforming growth factor beta, can cause healing response, leading to increased collagen accumulation and smooth muscle cell growth. In this manner, the fibrofatty lesion can evolve into advanced fibrous & often calcified plaque, one that may cause significant stenosis and produce symptoms of stable angina pectoris.
6. mural thrombus - in some cases, occlusive thrombi arise not from fracture of the fibrous cap but from superficial erosion of the endothelial layer resulting in a mural thrombus, again dependent on local prothrombotic & fibrinolytic balance, that can cause acute myocardial infarction.