Sandy Manzanera

Introduction:  Ischemia with no obstructive coronary arteries (INOCA) or Cardiac Syndrome X (CSX) is a condition in which patients present with signs and symptoms of ischemic heart disease but upon examination obstruction or stenosis of the coronary artery lumen diameter is found.¹ The mechanisms contributing to INOCA are considered multifactorial with two proposed mechanisms including coronary microvascular dysfunction and epicardial coronary artery spasms.²  This paper focuses on the literature present supporting the role of C-reactive protein (CRP,) an inflammatory biomarker, in inducing microvascular dysfunction, specifically endothelial dysfunction. Methods: CSX patients and a control group were examined to determine the relative concentration of endothelial and platelet microparticles among each group and their relationship with CRP, if any.³ Mice models were used to determine the effect of C reactive protein on macrophage profile levels and proinflammatory macrophage cytokine release.^4,5 Proinflammatory macrophage impairment of endothelial-dependent vasodilation were measured via coincubation of mesenteric arterioles with macrophages purified from either lean or obese mice. Macrophages from obese and lean mice displayed increased proinflammatory and anti-inflammatory polarization profiles respectively. Endothelial function was assessed by measuring acetylcholine induced vasodilatory response between lean and obese groups and later compared.⁶  Results: Endothelial-dependent vasodilation in mesenteric arterioles vessels isolated from lean mice that were cocultured with macrophages isolated from the peritoneum of obese mice was impaired.⁶ Macrophages obtained from obese mice were cocultured with mesenteric arterioles from obese mice exhibited endothelial dependent vasodilation impairment as well. Macrophages obtained from lean mice cultured with macrophages obtained from lean mice did not exhibit any endothelial dependent impairment. Lastly cocultured vessels from obese mice with macrophages from lean animals improved vasodilation.⁶ CRP upregulated the number of pro-inflammatory macrophages and their respective proinflammatory cytokines.^4,5 Stimulation of macrophage cells with PC:CRP and Pam induces a strong synergistic increase in proinflammatory cytokine TNF-a, IL-1B and (IL-23) production.⁵ Positive CRP was significantly more prevalent among CSX patients than the control group.³ While the mean percentage of the microparticles with expression pattern of  CD26E+ (E-Selectin) , CD144+ (VE-Cadherin) CD31+(PECAM-1), CD31+CD41−, and CD31+CD41+ among the CSX patients was significantly higher compared to the control group.³   Conclusion: This article discusses the evidence gathered that supports the role of CRP in inducing endothelial dysfunction and its possible attribution in the pathology of INOCA. CRPs role in increasing proinflammatory macrophages and their respective cytokine in addition to pro proinflammatory plasma microparticles are two of the few mechanisms that may induce the endothelial dysfunction among coronary arterioles in patients with CSX.

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2. Beltrame JF, Tavella R, Jones D, Zeitz C. Management of ischaemia with non-obstructive coronary arteries (INOCA). BMJ. 2021;375:e060602. Published 2021 Nov 26. doi:10.1136/bmj-2021-060602
3. Ghaffari F, Rasmi Y, Seyed Mohammadzad MH, et al. Increased circulating platelet and endothelial-derived microparticles in patients with cardiac syndrome X. ARYA Atheroscler. 2021;17(1):1-10. doi:10.22122/arya.v17i0.2094
4.  Zha Z, Cheng Y, Cao L, et al. Monomeric CRP Aggravates Myocardial Injury After Myocardial Infarction by Polarizing the Macrophage to Pro-Inflammatory Phenotype Through JNK Signaling Pathway. J Inflamm Res. 2021;14:7053-7064. Published 2021 Dec 18. doi:10.2147/JIR.S316816
5.  Newling M, Sritharan L, van der Ham AJ, et al. J Immunol. 2019;203(1):225-235. doi:10.4049/jimmunol.1900172
6.  Candela J, Wang R, White C. Microvascular Endothelial Dysfunction in Obesity Is Driven by Macrophage-Dependent Hydrogen Sulfide Depletion. Arterioscler Thromb Vasc Biol. 2017;37(5):889-899. doi:10.1161/ATVBAHA.117.309138