Physicians' Academy for Cardiovascular Education

Focus on stenosis restricts successes of prevention of acute coronary syndrome

Literature - Libby P - N Engl J Med. 2013 May 23;368(21):2004-13


Mechanisms of acute coronary syndromes and their implications for therapy.

 
Libby P
N Engl J Med. 2013 May 23;368(21):2004-13. doi: 10.1056/NEJMra1216063
 

Background

Although atherosclerotic lesions typically develop over the course of several years, thrombotic complications may occur suddenly. We here summarise this review that examines what is known about the mechanisms that may explain the abrupt transition from stable ischemic heart disease or asymptomatic atherosclerosis to acute coronary syndromes (ACS).
 

Pathogenesis of acute coronary syndromes

The traditional view that progressive stenosis leads to narrowing of the vessel lumen, which can subsequently cause occlusion by a platelet thrombus has been challenged by clinical and pathological studies. Angiographic studies demonstrated that the plaque at the site of the culprit lesion of a future acute myocardial infarction (MI) is often not the cause of stenosis severe enough to limit flow. Plaques associated with ACS appear to be characterised by low attenuation (little or no calcification) and outward expansion of the artery wall, which may accommodate growth of the plaque. Compensatory enlargement of the vessel by outward expansion can mask a severe burden of atheroma by preventing stenosis and its symptoms.
Revascularisation therapies are traditionally targeted at the site of maximal stenosis, although the culprit may lie elsewhere. This may also explain why MI is not always preceded by symptoms of angina as a result of severe stenosis.
 

Thrombotic  complications of atherosclerosis

Autopsy studies have long ascribed most fatal coronary events to a physical disruption of coronary arterial plaques. Rupture of the fibrous cap that typically overlies the lipid-rich centre of an atheromatous plaque, bring the coagulation factors from the blood in contact with the thrombogenic material in the lipid core. A recent autopsy study identified a fibrous cap thinner than 55 µm as the best morphologic indicator of plaques that had caused fatal ruptures.
 

Inflammation, collagen metabolism, and plaque rupture and thrombosis

The fibrous cap owes its tensile strength to interstitial collagen that is synthesised primarily by arterial smooth muscle cells. Disturbed collagen metabolism can impair the strength of the fibrous cap, such that it can no longer protect the plaque from rupture. Macrophages have been hypothesised to be involved in this process.
Collagen-production by smooth muscle cells is inhibited by exposure to interferon-γ produced by activated T cells. Macrophages produce vast amounts of all three matrix-metalloproteinases (MMP) that can degrade interstitial collagen in plaques (MMP-1, -8 and -13). Thus, the combination of T cells of the adaptive immune cells and innate immune effector cells (macrophages) inhibits the synthesis and decreases the degradation of interstitial collagen. Thus, inflammation is involved in thinning and rupture of the fibrous cap. A systemic inflammatory reaction to acute MI can even aggravate inflammation in the plaque. This explains why recurrent thrombotic events are common just after ACS, and why immediate revascularisation (limiting myocardial injury and thus inflammation) reduces the risk of recurrent events, but later intervention generally does not.
Local endothelial shear stress also seems to be involved in plaque rupture. Low shear stress was found to colocalise with coronary atheromata with thin fibrous caps, and high expression of matrix-degrading proteinases.
Experimental genetic and pharmacological studies interfering with interstitional collagenase activity have demonstrated the causal nature of the role for altered collagen metabolism in the collagen content of plaque.  
Thus, inflammatory signals cause decreased synthesis and increased degradation of collagen, yielding a frail cap prone to rupture and thrombosis. But this is not enough; coronary vasospasm and punctuate calcifications appear to further contribute to plaque rupture. Upon plaque rupture, tissue factor triggers thrombin generation and platelet activation and aggregation. Production of this procoagulant by macrophages is induced by the same proinflammatory signal (CD154) that increases collagenase activity. Thus, inflammation and the thrombotic complications of atherosclerosis are tightly linked.
 

Superficial erosion of plaques

Superficial erosion of coronary atheromata account for 20-25% of cases of fatal acute MI. These lesions may lack prominent inflammatory infiltrates, but instead these plaques exhibit proteoglycan accumulation. The underlying mechanisms have been less studied, but apoptosis of endothelial cells seems to contribute to desquamation. During apoptosis, endothelial cells produce the procoagulant tissue factor, thus promoting local thrombosis.  
 

Therapeutic implications of new mechanistic insights

Revascularisation procedures relieve angina symptoms, but do not consistently reduce the risk of ACS or death from CAD. Treatment with statins on the other hand reduces both first and recurrent ACS in broad categories of patients. However, these interventions hardly affect stenosis as assessed on angiography and cause only mild reductions in atheroma volume (intravascular ultrasonography).
Since reduction of events is not proportional to the shrinkage of stenoses, it has been proposed that lipid lowering alters qualitative characteristics of atheromata. Molecular and cellular processes could confer ‘stabilisation’ to the plaque. Studies in rabbits and mice have confirmed this hypothesis. Both a lipid-lowering diet and statin treatment reduced the content of inflammatory cells, augmented interstitial collagen accumulation, and reduced tissue factor antigen and activity, along with other effects that contrast with the features of human plaques prone to rupture and thrombosis. Also in humans, plaques in patients receiving statins have a more fibrous character, and show reduced lipid content and indexes of macrophage activity.
Still, despite the benefits of statin therapy, patients treated with statins are at considerable residual risk of ACS. Therapies that target other aspects of the lipid profile have proved disappointing. Given the role of inflammation in the pathophysiology of plaque rupture, anti-inflammatory strategies are worth exploring. The first clinical studies are underway.
 
These insights into the pathophysiological features of ACS expand the scope of treatment of this disease beyond the traditional focus on reducing stenoses.
 
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