R3i Editorials

March 2024
The microvascular-macrovascular interplay: the next target?
Prof. Jean-Charles Fruchart, Prof. Michel Hermans, Prof. Pierre Amarenco

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. GBD 2017 DALYs and HALE Collaborators. Global, regional, and national disability-adjusted life-years (DALYs) for 359 diseases and injuries and healthy life expectancy (HALE) for 195 countries and territories, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet 2018;392:1859–922.
    2. Timmis A, Vardas P, Townsend N, et al. European Society of Cardiology: cardiovascular disease statistics 2021. Eur Heart J 2022;43:716-99.
    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. Libby P. Triglycerides on the rise: should we swap seats on the seesaw? Eur Heart J 2015;36:774-6.
    5. Nordestgaard BG. Triglyceride-rich lipoproteins and atherosclerotic cardiovascular disease: new insights from epidemiology, genetics, and biology. Circ Res 2016;118:547-63.
    6. Matter MA, Paneni F, Libby P, et al. Inflammation in acute myocardial infarction: the good, the bad and the ugly. Eur Heart J 2024;45:89–103.
    7. Ridker PM, Everett BM, Thuren T, et al; CANTOS Trial Group. Antiinflammatory therapy with canakinumab for atherosclerotic disease. N Engl J Med 2017;377:1119–1131.
    8. Tardif JC, Kouz S, Waters DD, et al. Efficacy and safety of low-dose colchicine after myocardial infarction. N Engl J Med 2019;381:2497–505.
    9. Ridker PM. Targeting residual inflammatory risk: The next frontier for atherosclerosis treatment and prevention. Vascul Pharmacol 2023:153:107238.
    10. Ridker PM, Bhatt DL, Pradhan AD, et al. Inflammation and cholesterol as predictors of cardiovascular events among patients receiving statin therapy: a collaborative analysis of three randomized trials. Lancet 2023;401:1293–301.
    11. Ridker PM, Lei L, Louie MJ, et al. Inflammation and cholesterol as predictors of cardiovascular events among 13970 contemporary high-risk patients with statin intolerance. Circulation 2024;149:28–35.