R3i Editorial

To date, cholesterol and inflammation are the main targets for managing residual vascular risk. Added to this, important findings from cardiovascular outcome trials with novel glucose-lowering therapies, i.e., sodium‐glucose cotransporter‐2 inhibitors ¹ and glucagon‐like peptide‐1 receptor agonists ², prompted a shift in guidelines to incorporate these agents in preventive approaches in patients with type 2 diabetes and atherosclerotic cardiovascular disease or risk factors ³. Less well investigated, however, is the interplay of microvascular and cardiovascular disease in residual vascular risk, despite evidence that microvascular dysfunction underlies many manifestations of cardiovascular disease.

Studies implicate dysfunction in the coronary microvasculature with the development of angina pectoris and heart failure ⁴. Women in particular exhibit a higher burden of microvascular dysfunction with more ischaemia with non-obstructive coronary disease than men ⁵. Mechanistically, it is thought that common risk factors such as dyslipidaemia promote microvascular endothelial dysfunction via increased inflammation and oxidative stress ⁶.

On the same theme, this month’s Focus highlights a role for microvascular dysfunction in adverse macrovascular and limb complications of peripheral artery disease (PAD) ⁷. This report, based on US national data from over 33 million people admitted to hospital with PAD and/or microvascular disease illustrated the magnitude of this issue. Over one in four of these patients had comorbid PAD and microvascular disease. Not only did these patients have more severe PAD, but the coexistence of microvascular disease exacerbated the risk of major and minor amputations, major adverse cardiovascular events, in-hospital mortality, and readmission to hospital. It is thought that impaired angiogenesis and serial ischaemic–reperfusion injuries may contribute to chronic inflammation in patients with comorbid PAD and microvascular disease, exacerbating their risk of adverse events ⁸. Comorbid PAD and microvascular disease not only poses a higher morbidity and mortality risk, but also impacts the economic burden of PAD, the third most common cardiovascular disease ⁹.

Why is this an issue? As illustrated in the report by Grubman et al ⁷, the prevalence of PAD, and associated complications, is increasing. Globally, the prevalence of PAD increased by over 70% between 1990-2019 (10). This contrasted with global trends for ischaemic heart disease and ischaemic stroke, which exhibited decreasing prevalence and disease-related mortality over the same time period (10). With aging populations, even in low- and middle-income countries, as well as an escalating type 2 diabetes pandemic, the prevalence of PAD will undoubtedly increase in the future. This scenario highlights the urgent need for new strategies to target modifiable residual risk factors , as well a renewed emphasis on recognising and detecting comorbid microvascular disease, to impact this escalating disease burden.

References
1. Dalan R. Sodium-Glucose Cotransporter-2 Inhibition in Type 2 Diabetes Mellitus: a review of large-scale cardiovascular outcome studies and possible mechanisms of benefit. Cardiol Rev 2018;26:312-20.
2. Sattar N, Lee MMY, Kristensen SL, et al. Cardiovascular, mortality, and kidney outcomes with GLP-1 receptor agonists in patients with type 2 diabetes: a systematic review and meta-analysis of randomised trials. Lancet Diabetes Endocrinol 2021;9:653–62.
3. Visseren FLJ, Mach F, Smulders YM, et al. 2021 ESC Guidelines on cardiovascular disease prevention in clinical practice. Eur Heart J 2021;42:3227-337.
4. Del Buono MG, Montone RA, Camilli M, et al. Coronary microvascular dysfunction across the spectrum of cardiovascular diseases: JACC State-of-the-Art Review. J Am Coll Cardiol 2021;78:1352-71.
5. Roeters van Lennep JE, Tokgözoğlu LS, Badimon L, et al. Women, lipids, and atherosclerotic cardiovascular disease: a call to action from the European Atherosclerosis Society. Eur Heart J 2023;44:4157-73.
6. Padró T, Vilahur G, Badimon L. Dyslipidemias and microcirculation. Current Pharm Design 2018;24:2921-6.
7. Grubman S, Algara M, Smolderen KG, et al. Examining outcomes in patients admitted with comorbid peripheral artery disease and microvascular disease. J Am Heart Assoc 2024;13:e030710.
8. Behroozian A, Beckman JA. Microvascular disease increases amputation in patients with peripheral artery disease. Arterioscler Thromb Vasc Biol 2020;40:534–40.
9. Timmis A, Vardas P, Townsend N, et al. European Society of Cardiology: cardiovascular disease statistics 2021. Eur Heart J 2022;43:716-99.
10. Eid MA, Mehta K, Barnes JA, et al. The global burden of peripheral artery disease. J Vasc Surg 2023;771119-1126.e1.