Quantifying cardiovascular risk: will measuring endothelial function suffice?

This editorial refers to ‘Association between cardiovascular risk profile and impaired microvascular function in a Swedish middle-aged cohort (the SCAPIS study)’, by S. Bergstrand et al., https://doi.org/10.1093/eurjpc/zwae052 Cardiovascular diseases (CVDs) are the most common cause of death, accounting for ∼18 million deaths each year. This is almost one-third of all deaths,1 and with the current pandemic of obesity in adults and more worrisome in children, we are facing a serious threat to our health care systems. A recent study estimated the total cost of CVD in Europe to be €282 billion annually, and coronary heart disease alone costs €77 billion each year.2 Cardiovascular diseases can be prevented by the treatment of classical cardiovascular risk factors such as an unhealthy diet, obesity, physical inactivity, and smoking. Yet, despite the tremendous efforts of clinicians and scientists, we need to step up even more, and early detection of CV risk is essential. A crucial role in the pathogenesis of CVD is laid out for the endothelium, a cell layer with a thickness of just one cell that lines the luminal side of the arteries. In response to stimuli that indicate increased blood flow demand (e.g. increased shear stress), endothelial cells will fine-tune vascular smooth muscle relaxation and thus result in vasodilation and the supply of oxygen and nutrients. In addition, healthy endothelium will also prevent platelet aggregation, proliferation of vascular smooth muscle cells, and adhesion and subsequent diapedesis of leukocytes through the vascular wall.3 In the case of endothelial dysfunction, the atheroprotective role of the endothelium is failing. Endothelial dysfunction is a first step in the development of CVD and could serve as a targetable risk factor since it is affected by all the commonly known cardiovascular risk factors, such as obesity, physical inactivity,4 hypertension,5 dyslipidaemia,6 insulin resistance or diabetes,7 chronic low-grade inflammation,8 adipokines,9 and sleep apnoea10 (Figure 1), and is even present in childhood obesity.11 Luckily, endothelial dysfunction is still a reversible process at all phases of the clinical spectrum, from early phase such as childhood obesity12 to even patients with severe coronary artery disease planned for coronary artery bypass graft.13 Technological advancements have made it possible to assess microvascular endothelial function in a non-invasive way for a reasonable price.14 Allowing us to start dreaming of a measurement of endothelial function as a quick way to assess cardiovascular risk. Studies in patient groups with distinct cardiovascular risk factors are optimistic about the possible role of endothelial function, and the question arises whether assessment of endothelial function could discriminate cardiovascular risk in a population with relatively low risk of CVD. Cardiovascular risk factors affecting microvascular endothelial dysfunction directly or indirectly. Created with BioRender.com. Bergstrand et al.15 have investigated the correlation between microvascular endothelial function and cardiovascular risk scores and subclinical atherosclerosis in 2857 asymptomatic participants aged 50–65 years with relatively low risk, namely without CVD or diabetes mellitus. All participants underwent extensive clinical investigations, including venous blood samples for established CV risk factors, and the SCORE2 algorithm was used to predict the 10-year risk of CVDs. Their atherosclerotic burden was assessed using coronary computed tomography and carotid vascular ultrasound. Microvascular endothelial function was assessed from the volar side of the forearm. and the correlations with SCORE2, coronary calcification, and carotid plaques were investigated. Firstly, participants were separated into quartiles of microvascular endothelial function: those with the worst endothelial function were generally older and had a higher blood pressure, non-LDL cholesterol, and C-reactive protein. These participants had an average 10-year CV risk of nearly 6% vs. 4% in participants in the quartile with the best endothelial function. There was a large proportion of participants in the lowest quartile of endothelial function in individuals with a SCORE2 risk > 10% and coronary calcification, yet no significant difference was found for carotid plaques. This would indicate that microvascular endothelial dysfunction is more sensitive to predict coronary calcification and, thus, acute myocardial infarction and even cardiovascular death. The question arises: will we be able to use endothelial function assessment in clinical practice for patient-specific risk stratification? Endothelial function certainly fulfils criteria for a good screening tool.16 Cardiovascular disease is a serious health problem. There is treatment available, and the test is easily available, cheap, and non-invasive. There is a good correlation between endothelial dysfunction and cardiovascular risk in high-risk populations and apparently healthy populations, as the current study demonstrates. Endothelial function also predicts the progression of CVD, such as carotid plaque formation, better than conventional risk factors.17 In addition, endothelial function assessment is also useful in secondary prevention since it also provides prognostic information in patients with peripheral vascular disease18 and predicts cardiovascular events in patients with acute coronary syndrome without ST elevation.19 Unfortunately, the clinical application of endothelial function assessment is still limited after years of research by the lack of standard protocols and reference values. The present study certainly underscores that endothelial function measurement could improve CV risk stratification. But in addition, it could also be used to improve treatment monitoring. Until now, there is insufficient evidence to support the application of endothelial function assessment in clinical practice. Future studies should be well designed to demonstrate whether the endothelial function provides additional information over classic CV risk factors and whether it is cost-effective. For this reason, a close collaboration between scientists, cardiologists, and also paediatricians and paediatric cardiologists will be essential since the long-term aim should be to detect and tackle CV risk as early as possible. All authors contributed to the writing of this paper. None declared.