The Group’s goal is to develop novel therapies to target atherosclerosis (arterial blockages) and its consequences (heart attack).
We aim to develop dedicated agents that specifically target the inflammation that drives coronary plaque instability. Our work is performed in collaboration with the Clinical, Vascular Complications and Atherosclerosis and Vascular Remodeling Groups within the HRI, drawing upon their expertise in each area of research.
One Australian dies from an acute coronary syndrome (ACS) every 51 minutes. Failure to specifically target persistent coronary inflammation, which drives high rates of recurrent events, is likely a major factor.
To address this problem, our research program’s overarching aim is to (1) elucidate new inflammatory pathways in ACS patients and (2) re-purpose established anti-inflammatory drugs that target these pathways.
We have focussed on colchicine, a safe, cheap and effective anti-inflammatory agent. Our program was the first to show that colchicine has striking athero-protective effects. Our findings are recognised internationally, with 20 papers and 25 presentations (at national and international scientific symposia) in the last five years. Notably, this program’s work has been cited 202 times by groups in 16 countries (Google Scholar), demonstrating its reach. We have also received significant national and international media attention (Sydney Morning Herald, national evening news, TCTmd, heart.org).
Our research identified the potential of colchicine in the treatment of ACS patients.
We developed a safer and more robust technique for sampling blood from the coronary sinus in order to measure trans-coronary cytokine gradients (Martinez et al, IJC 2014). This provided the basis for ongoing studies. In 2015, we showed that a single dose of oral colchicine significantly reduces trans-coronary gradients of key inflammatory cytokines, all of which are highly predictive of future events in coronary artery disease patients (Martinez et al JAHA 2016).
To address mechanism and strengthen research impact, we described monocyte inflammasome activation in ACS patients and how colchicine attenuates this (Robertson et al, Clin Sci 2016). We currently have two papers under review demonstrating inhibitory effects of colchicine on chemokines and miRNA, relevant to inflammation and atherosclerosis.
In 2017, we established a computerised tomography coronary angiography program at Royal Prince Alfred Hospital, resulting in our third major colchicine publication, further strengthening our proposal that colchicine is athero-protective, through plaque stabilisation, independent of statin use (Vaidya et al, JACC imaging 2017). As acute stroke and ACS share common pathophysiologic mechanisms, we recently conducted a meta-analysis of the effects of colchicine on stroke incidence (accepted for publication in Clinical Therapeutics).
Taken together, our work provides compelling mechanistic evidence for a therapeutic role of colchicine in acutely suppressing athero-inflammation, stabilising vulnerable plaque and improving clinical outcomes.
Martínez GJ, et al. Colchicine acutely suppresses local cardiac production of inflammatory cytokines in patients with an acute coronary syndrome. JAHA 2015, 4(8):e002128.
Robertson S, et al. Colchicine therapy in acute coronary syndrome patients acts on caspase-1 to suppress NLRP3 inflammasome monocyte activation. Clin Sci 2016, 130(14):1237-46.
Vaidya K, et al. Colchicine therapy and plaque stabilization in patients with acute coronary syndrome JACC. Cardiovasc imaging, 2017.08.013.
Martínez GJ, et al. The NLRP3 inflammasome and the emerging role of colchicine to inhibit atherosclerosis-associated inflammation. Atherosclerosis. 2017, 269:262-271.
Choteau SA, et al. Transcoronary Gradients of HDL-Associated MicroRNAs in Unstable Coronary Artery Disease. Int J Cardiol. 2018, 253:138-144.