Translating Knowledge of Inflammatory Pathways to the Personalized Approach of Patients at Increased Risk of Coronary Artery Disease

Coronary artery disease can have multifactorial etiologies and devastating outcomes for those affected. Given a global prevalence that exceeds 300 million cases [1], significant investment in basic science and clinical investigations have been well warranted. Studies completed to date have identified and confirmed many classic risk factors for atherosclerosis, including advancing age, diabetes mellitus, obesity, hypertension, and tobacco use, as well as newer considerations such as preterm birth or early-life growth restriction [2]. The pathways linking those antecedents and progressive coronary artery occlusion are now known to often include inflammatory cascades [3].Localized acute or chronic vascular inflammation is consistently demonstrated in coronary artery plaques. In addition to cellular infiltrates, there is activation of immune cells and elaboration of multiple proinflammatory cytokines [4]. Beyond the local environment, the presence of cytokines in the peripheral circulation suggests the presence of systemic inflammation, and those cytokines are attractive targets for coronary artery disease surveillance and the development of interventions to potentially mitigate the detrimental effects of immune activation. While studies in this area are ongoing, there has been a need for nuanced understanding of the influence of age and sex on cytokine levels within the context of traditional coronary artery disease risk factors.In this issue of Cardiology, Zhou et al. [5] retrospectively analyzed the cytokine profiles and percutaneous coronary angiography results of 2,208 patients that underwent testing for suspected coronary artery disease at a single center, following their presentation with typical or atypical chest discomfort. The authors recapitulated the importance of traditional risk factors in showing increased rates of coronary artery disease, prospectively defined by having 50% or more stenosis of a major vessel, in those diagnosed with hypertension or diabetes, men, and individuals over 65 years old. More importantly, they demonstrated strong associations between a number of cytokines and the imaging results with elevations in IL-4, IL-6, and IL-10 among those with coronary artery disease.When the authors interrogated the cytokine levels in the context of the known co-morbidities [5], it was not surprising that many of the observed associations were dampened, suggesting that the presence of proinflammatory conditions like obesity and diabetes may have contributed to some of the univariate observations. For example, the anti-inflammatory cytokine IL-10 was significantly increased among male patients that screened positive for coronary artery disease, but that was attenuated after adjustment. The association of IL-10 with previously undiagnosed coronary artery disease is consistent with the findings in the PROSPER study [6]. In that investigation, IL-10 levels added prognostic value to traditional risk factors, but marginally so. Notably, reminiscent of the elevation in both IL-10 and IL-6 among those with coronary artery disease observed in the study by Zhou et al. [5], the PROSPER investigators found a strong correlation between IL-6 and IL-10 in their cohort, reemphasizing the importance of expanded cytokine panels in the context of risk factor assessment to advance our scientific understanding.Regarding the proinflammatory cytokine IL-6, it is noteworthy the study in this issue of Cardiology by Zhou and colleagues [5] found not just a univariate association with coronary artery disease but that association persisted even after risk factor-based adjustment. This finding is interesting in light of the existing literature demonstrating enhanced IL-6 expression in atherosclerotic plaques [7] and increased IL-6 levels in patients with cardiovascular disease [8]. Even more so, the independent association of IL-6 levels with coronary artery disease within the highest risk population, men over 65 years old, further promotes IL-6 as an attractive candidate for ongoing investigations [4, 5]. Notably, a recent randomized controlled trial by Broch and colleagues tested acute infusion of an IL-6 receptor blocker in patients with acute ST-segment elevation myocardial infarction, and they did identify significant improvement in shorter-term cardiac outcomes but not a reduction in final infarct size [9]. Interestingly, men tended to benefit from IL-6 receptor blockade more than women, but the study was not powered for that subgroup analysis, and the interaction between sex and treatment did not reach statistical significance (p = 0.05) [9]. Along this line of inquiry, there are extensive basic science and clinical data supporting a role for the relative testosterone deficiency present in elderly males contributing to increased circulating IL-6 levels [10]. Additional studies have shown elevated IL-6 levels can serve as an independent predictor of cardiovascular risk in even healthy men [11]. Finally, as a key regulator of c-reactive protein production, which is also a major early marker of coronary artery disease risk, IL-6 levels could provide an even earlier indicator of evolving vascular inflammation, and prospective longitudinal studies across at risk populations are therefore warranted [4].The final pattern of intriguing results from the investigation by Zhou et al. [5] are those cytokine levels that were not statistically significant by univariate analysis across the entire cohort, but significant following the a priori subgrouping by age and sex. Principal among those results was the increase in IL-5 seen only among women that were diagnosed with coronary artery disease. Given the important role IL-5 plays in autoimmune disease and atopic conditions [12], it is interesting that the association was still seen despite the exclusion of patients with previously diagnosed autoimmune or active inflammatory disease [5]. If replicated, there is possibility that IL-5 plays a causative role in the pathogenesis of a subset of coronary artery disease, and both basic science and clinical investigations could help clarify the role of subclinical autoimmunity or eosinophil-mediated vasculitis in women with coronary artery disease out of proportion with the presence of traditional cardiovascular risk factors.Like all retrospective investigations, the study of Zhou et al. [5] has some limitations. Beyond the need for prospective studies earlier in the course of disease progression, it will be important to expand the investigation to other cardiac care centers to clarify the potential role of unknown cofounders. Given the low levels of many cytokines, those investigations could benefit from assay methods with higher sensitivity. Finally, while it was logical to exclude patients with pre-existing inflammation or anti-inflammatory medications, those individuals might most benefit from expanded cytokine and cardiac monitoring, and they should be considered for inclusion in future studies.In conclusion, coronary artery disease clearly has multifactorial origins, but many of them converge on inflammatory pathways. Every investigation in this area helps bring clarity to disease pathogenesis and monitoring, but like all good studies, they also stimulate important discussion and opportunities for further pathway interrogation. From a clinical perspective, the analyses performed by Zhou and colleagues show that IL-5 and IL-6 were independent risk factors for coronary artery disease in women and elderly men, respectively [5]; this provides important signals that should be assessed in other populations for generalized implementation into prospective monitoring protocols. For example, if replicated, increased levels of the respective cytokines could suggest the need for enhanced coronary imaging and possibly anti-inflammatory therapy. As disease pathogenesis is further clarified, primary preventative strategies, tailored to individual risk factors, could include the maintenance of optimal sex hormone levels, as well as the diagnosis and management of co-morbid conditions that could lead to immune system dysregulation and life-threatening coronary artery occlusion.The author has no conflicts of interest to declare.This study was not supported by any sponsor or funder.R. Roghair conceived, wrote, and revised the manuscript.