Pathophysiologische Grundlagen der instabilen Koronarsyndrome

Hintergrund:

Das akute Koronarsyndrom ist die Manifestation einer Plaqueruptur in den Koronararterien, die zu einer intermittierenden oder anhaltenden regionalen Myokardischämie führt. Die Erfassung der zugrunde liegenden Mechanismen ist durch die Komplexität der ablaufenden Prozesse und durch die Komplexität einer komplizierten arteriosklerotischen Läsion erschwert. Deshalb ist eine systematische Analyse des akuten Koronarsyndroms problematisch, ein Tiermodell ist nicht vorhanden.

Pathomorphologische und klinische Studien: Wesentliche Erkenntnisse über die Grundlagen des akuten Koronarsyndroms verdanken wir pathomorphologischen Analysen, die eine Reihe von Kriterien für eine vulnerable Plaque identifizieren konnten. Klinische Studien konnten eine thrombotische Komponente als wesentlichen Aspekt der klinischen Manifestation identifizieren und haben dazu geführt, dass gerinnungshemmende Strategien heute einen festen Stellenwert in der Therapie akuter Koronarsyndrome haben.

Triggermechanismen:Was die Triggermechanismen zur Auslösung des akuten Koronarsyndroms angeht, so gibt es derzeit nur eine Reihe von Indizien; ein akutes Koronarsyndrom lässt sich im Einzelfall nicht sicher vorhersagen: Zu den möglichen Triggermechanismen gehören neben der spontanen Progression arteriosklerotischer Läsionen vor allem lokale inflammatorische Prozesse, die unter anderem auch von einer Matrixdegradation begleitet sind. Eine Beteiligung der pathologischen Plaqueangiogenese kann als wahrscheinlich angenommen werden.

Background:

The acute coronary syndrome is the manifestation of a plaque rupture in a coronary artery, which can lead to intermittent or prolonged regional myocardial ischemia. In such a situation, the underlying atherosclerotic lesion is a complex one. Moreover, the mechanisms leading to the instability of an atherosclerotic plaque are complex themselves. This makes it problematic to systematically analyze the nature of the acute coronary syndrome. Moreover, no animal model is available to study this process.

Pathomorphological and Clinical Studies: Substantial insights into the basis of the acute coronary syndrome have been gathered by pathomorphological analyses, which have helped to identify a number of criteria describing a vulnerable plaque. Clinical studies have helped to identify the thrombotic component as an important aspect of the clinical manifestation of the acute coronary syndrome. Based on such data, well-defined antithrombotic strategies play an important role in today's therapy of the acute coronary syndrome.

Triggering Mechanisms: Concerning the triggering mechanisms for an acute coronary syndrome, there is a number of suspected processes, the most important of which is local inflammation of the coronary plaque. Inflammatory processes have recently been recognized as important stimulators of vascular modelling during atherogenesis. These inflammatory mechanisms involve a number of different cytokines, cells of the immune system and other components of the immune systems such as the complement cascade. C-reactive protein may even be a link between systemic and local inflammatory processes, because it has been shown to be systemically elevated in patients with unstable angina and – most recently – has been shown to be involved in the initiation and progression of early atherosclerotic lesions. Local inflammation of the atherosclerotic plaques induces the expression of a number of growth factors and other potent molecules that contribute to vascular remodelling. These substances are acting on smooth muscle cells, fibroblasts as well as on the extracellular matrix and include growth factors, matrixmetalloproteinases and tissue inhibitors of metalloproteinase. Another component of potential significance within the unstable plaque is the process called plaque-angiogenesis. Plaque-angiogenesis occurs within complicated atherosclerotic plaques, the process of angiogenesis leads to destabilization of the extracellular matrix and, moreover, newly formed capillaries are more likely to rupture and may therefore be an important trigger of plaque rupture and of the acute coronary syndrome.

Therapeutic Approaches: A number of molecular strategies including inhibition of matrix metalloproteinasis or inhibitors of angiogenesis may turn out to stabilize the vulnerable plaque. Until these therapeutic concepts may be used in the clinic, our therapeutic repertoire will mostly consist of antithrombotic and entire antiinflammatory approaches.