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Inhibition of plaque development and inflammation to reduce risk of heart attack

Heart Research Institute

Grant:
  • Early-Mid Career Fellowship
Date Funded:
  • 1 February, 2017
Chief Investigator/s:
  • Associate Professor Sanjay Patel

Inflammation is central to the pathogenesis of atherosclerotic plaque progression and athero-thrombotic vascular events with systemic inflammatory markers correlating strongly with prognosis in acute coronary syndrome (ACS) patients. Indeed, these patients are particularly vulnerable to recurrent ischaemic events in the early post-ACS period, likely driven by pan-coronary inflammation, resulting in a higher prevalence of vulnerable non-culprit plaque.

Moreover, percutaneous coronary intervention (PCI) to treat culprit coronary stenoses in the setting of ACS, is strongly associated with a relatively high rate of peri-procedural myocardial infarction and adverse cardiovascular outcomes, due in part, to distal embolisation of inflamed plaque fragments with microvascular obstruction. Therefore, suppression of atherosclerosis-associated inflammation is of critical importance to stabilise vulnerable plaque (AIM 1); to decrease inflammatory mediator release after PCI of vulnerable lesions (AIM 2); and to reduce plaque progression/instability, which itself is strongly linked with adverse cardiovascular outcomes (AIM 3).

The principle aim of this project is to investigate a new, innovative, and cost-effective approach to reduce the deleterious effects of atherosclerosis-associated inflammation, based on our discovery that oral colchicine, a safe and well established drug, widely used in non-vascular inflammatory disorders, has marked anti-inflammatory properties in ACS patients. Notably, SP’s recent published studies have elucidated that colchicine, within hours of ingestion, markedly reduces (1) secretion of the pro-inflammatory cytokine IL-1β by circulating monocytes and (2) local coronary levels of the inflammatory cytokines IL-1β and IL-18, together with downstream IL-6, a cytokine strongly linked with future coronary events.

Based on these findings, colchicine’s acute effects on plaque stability will be studied, as well as its more long term effects on plaque volume/inflammatory content. Such studies have enormous clinical relevance as they have the potential to directly improve outcomes in patients presenting with unstable coronary syndromes, particular in the context of PCI, as well as ‘stable” patients with established atherosclerosis. Moreover, as colchicine is safe, readily available and cost-effective, it can be rapidly included as part of the standard therapy for both ACS and stable coronary disease patients.