Atherosclerotic Plaque Disruption and Healing

If it ever occurs the final result of this research should provide interventions that make sure your plaque is the extinct version. What is your stroke hospital doing to ensure this research is followed up and creates protocols?

Atherosclerotic Plaque Disruption and Healing

As with geologists, cardiovascular researchers have long studied the mechanisms governing atherosclerotic plaque formation, disruption, and thrombosis (i.e. the ‘volcanoes’ eruption’), and the ascertained knowledge has guided our traditional approaches to atherosclerosis therapy. Yet the ability to predict plaque instability and the development of acute coronary syndrome (ACS) or sudden coronary death remains weak, suggesting that other potential pathogenic mechanisms should also be explored.²

In our review article recently published in the New England Journal of Medicine,³ we explored the hidden side of the moon: mechanisms of atherosclerotic plaque healing and their clinical and potential therapeutic implications. We know from historical pathology studies that healed plaques can be frequently found at the non-culprit coronary sites of patients dying from sudden cardiac death, and even in subjects dying from other causes.⁴ These plaques can be considered as ‘inactive volcanoes’ within the vasculature, either ‘extinct’ or ‘dormant’. By definition, an ‘extinct volcano’ is a volcano that has not erupted for at least 10 000 years and is not supposed to erupt again in the future, while a ‘dormant’ one is a volcano that is not erupting, but is expected to erupt again.¹

As with volcanoes, the healing process can either pacify the disrupted plaque so that it remains silent for the rest of the patient’s life, or instead, stabilize it for a variable time period before a new disruption occurs. Both pathology and in vivo imaging studies in fact suggest that atherosclerotic plaques may undergo multiple episodes of disruption and healing, and that accumulation of new granulation tissue may contribute to an increase in plaque burden and to progressive luminal narrowing.^4,5

Recent optical coherence tomography studies showed an association between the presence of healed coronary plaques and higher non-target lesion, ischaemia-driven revascularization rates, in the absence of acute events.⁶ These data confirm our original observation that patients with healed plaques are more likely to evolve towards a long-standing chronic coronary syndrome (CCS), while those without evidence of healed plaques more frequently experience a recurrence of ACS.⁵ These observations have led us to propose the ‘double hit’ theory of atherosclerosis as a possible explanation of the pathogenesis of ACS.^3,5,7 This is somewhat reminiscent of what happened in oncology where, after studying oncogenes for decades, it was discovered that half of all human cancers were prompted by a mutation in oncogene suppressor genes. In atherosclerosis, the first hit is the acute destabilization of an atherosclerotic plaque by either rupture or erosion, whereas the second hit is an impaired healing capacity.³

Why are these findings important for patients with ischaemic heart disease? Because they may help to better predict the natural history of coronary atherosclerosis and, most importantly, they may pave the way towards novel therapeutic strategies. While traditional therapies have focused almost exclusively on preventing atherosclerosis progression and on treating its acute thrombotic complications, new therapies may point strongly towards strategies of improving healing. Patients with an effective healing capacity seem to have more potent endogenous fibrinolytic and thrombolytic systems as well as polarization of inflammation towards a reparative phenotype, including the production of anti-inflammatory cytokines and the overexpression of alternative M2 macrophages.³

Therapeutic options might come from existing drugs as well as from novel agents. Intensive antithrombotic therapy has already proved effective in promoting healing of coronary plaque erosion,⁸ and the beneficial effects of aggressive lipid-lowering agents (e.g. high-dose statins, proprotein convertase subtilisin–kexin type 9 inhibitors) on plaque stabilization have been largely documented.³

Promising results may come from the use of anti-inflammatory agents, such as interleukin-1β antagonists (e.g. canakinumab) or low-dose colchicine.^9,10 Recently, low-dose colchicine has been demonstrated to significantly lower the risk of cardiovascular events in a randomized trial involving patients with CCS compared to placebo.¹⁰ Although the mechanisms behind this benefit have not been elucidated, they may be at least in part related to an improvement in a plaque healing capacity. Another intriguing approach may be the modulation of macrophage polarization towards a reparative phenotype through CD31-targeting molecules or epigenetic therapies, including DNA methylation, histone modifications, or modulation of microRNAs and long non-coding RNAs.³

In conclusion, although primary prevention and traditional therapies provide a key to stemming the worldwide spread of the atherosclerotic disease epidemic and its thrombotic complications, the recognition of the healing process as an active player, rather than an innocent bystander, in the pathogenesis of ischaemic heart disease may provide ground for novel treatment options. We must strive to move beyond the classic approach of focusing on the mechanisms of plaque instability only, and try to elucidate the hidden protective mechanisms, with the aim of converting ‘poor healers’ into ‘good healers’.

During the Second World War, Sir Winston Churchill stated: ‘Now this is not the end. It is not even the beginning of the end. But it is, perhaps, the end of the beginning’. In the current era, we might be at the same turning point in the war against atherosclerosis. Promoting plaque healing in addition to preventing plaque disruption might considerably potentiate our armamentarium in the battle against cardiovascular diseases.