Coronary Endothelial Function Screening Before Structural Disease: Clinical Relevance and Emerging Strategies

Abstract

Coronary endothelial dysfunction is increasingly recognized as a pivotal early event in the pathogenesis of atherosclerotic cardiovascular disease (ASCVD), often preceding detectable structural abnormalities. The screening and assessment of coronary endothelial function prior to the development of overt structural disease present a critical opportunity for early risk stratification, prevention, and tailored management of at-risk individuals. This review critically examines the epidemiology, pathophysiological mechanisms, clinical implications, and current as well as emerging strategies for screening coronary endothelial function in asymptomatic or minimally symptomatic individuals. Recent evidence and guideline recommendations are highlighted to inform best practices for clinicians and healthcare professionals.

Introduction

Coronary artery disease (CAD) remains a leading cause of morbidity and mortality worldwide. Traditionally, diagnosis and intervention have focused on the detection of structural lesions, such as stenotic atherosclerotic plaques. However, a growing body of evidence implicates endothelial dysfunction as an early, potentially reversible precursor to structural coronary disease. The endothelium, a dynamic interface between circulating blood and the vascular wall, regulates vascular tone, platelet activity, leukocyte adhesion, and smooth muscle proliferation. Its dysfunction heralds a pro-atherogenic milieu long before anatomical changes are apparent. Early identification of endothelial dysfunction, therefore, offers a window for preventive strategies. This review synthesizes current knowledge on the burden, mechanisms, risk factors, clinical presentation, diagnostic modalities, management strategies, advances in the field, and guideline-based recommendations for coronary endothelial function screening before the onset of structural disease.

Epidemiology / Disease Burden

Cardiovascular disease accounts for approximately one-third of all global deaths, with CAD constituting the majority. Traditional risk assessment often underestimates risk in certain populations, particularly those with non-obstructive coronary disease or atypical symptoms. Studies suggest that up to 40% of patients with angina and non-obstructive coronary arteries (ANOCA) exhibit significant endothelial dysfunction. Subclinical endothelial impairment is prevalent in individuals with risk factors such as diabetes mellitus, hypertension, smoking, and dyslipidemia. The true burden is underestimated due to lack of routine screening, yet the PROSPECT and WISE studies demonstrate that endothelial dysfunction predicts future cardiovascular events independently of angiographic findings.

Pathophysiology

The vascular endothelium maintains homeostasis via production of vasodilators (notably nitric oxide [NO]), anti-inflammatory mediators, and antithrombotic factors. Endothelial dysfunction is characterized by reduced NO bioavailability, increased oxidative stress, enhanced expression of adhesion molecules, and a shift toward vasoconstriction, inflammation, and thrombosis. This dysfunctional state promotes lipid infiltration, smooth muscle cell migration, and plaque development, setting the stage for atherosclerosis. Mechanistically, risk factors such as hyperglycemia, smoking, and hyperlipidemia induce oxidative modification of low-density lipoproteins (LDL), impairing endothelial signaling and promoting vascular injury. Importantly, endothelial dysfunction is a dynamic and potentially reversible process, underscoring the rationale for early detection and intervention.

Risk Factors

Risk factors for coronary endothelial dysfunction parallel those of conventional atherosclerosis but may manifest earlier in the disease continuum. Major contributors include age, male sex, hypertension, diabetes mellitus, dyslipidemia, tobacco use, obesity, metabolic syndrome, sedentary lifestyle, chronic inflammation, and certain genetic predispositions. Non-traditional factors such as sleep apnea, psychosocial stress, and chronic inflammatory conditions (e.g., rheumatoid arthritis, systemic lupus erythematosus) have also been implicated. Identification of these risk factors is crucial for selecting candidates for screening and preventive interventions.

Clinical Features

Endothelial dysfunction is frequently asymptomatic or associated with non-specific symptoms such as atypical chest pain, exertional dyspnea, or microvascular angina. In women and younger patients, symptoms may be mistaken for non-cardiac etiologies, leading to underdiagnosis. Importantly, patients with ANOCA and endothelial dysfunction are at increased risk for adverse cardiovascular outcomes, including myocardial infarction and heart failure, despite the absence of obstructive lesions. Recognition of the subtle clinical presentations is essential for appropriate referral and management.

Diagnosis

Assessment of coronary endothelial function can be performed invasively or non-invasively. Invasive testing, considered the gold standard, involves intracoronary infusion of acetylcholine or other agonists during coronary angiography to assess vasomotor response. Non-invasive modalities include brachial artery flow-mediated dilation (FMD), peripheral arterial tonometry (PAT), and cardiac magnetic resonance imaging (MRI) with endothelial-dependent vasodilation protocols. Emerging biomarkers (e.g., asymmetric dimethylarginine, circulating endothelial microparticles) and advanced imaging techniques are under investigation. The choice of diagnostic modality depends on patient risk, local expertise, and availability. Early diagnosis facilitates risk stratification and guides therapy before irreversible structural changes occur.

Treatment & Management

Management focuses on aggressive modification of cardiovascular risk factors, lifestyle intervention, and pharmacologic therapy. Statins, angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), and certain antidiabetic agents (e.g., SGLT2 inhibitors, GLP-1 receptor agonists) have been shown to improve endothelial function independent of their primary therapeutic effects. Lifestyle measures such as exercise, dietary modification, weight reduction, smoking cessation, and stress management are foundational. In selected high-risk individuals, early pharmacologic intervention may delay or prevent progression to structural disease. Tailoring therapy based on endothelial function assessment represents a paradigm shift in personalized cardiovascular prevention.

Recent Advances / Emerging Therapies

Recent advances include the development of high-resolution imaging for detection of microvascular and endothelial dysfunction, identification of novel endothelial biomarkers, and the use of regenerative therapies such as endothelial progenitor cell mobilization. Gene therapy targeting endothelial nitric oxide synthase (eNOS) and strategies to enhance endogenous antioxidant defenses are in early clinical trials. Additionally, machine learning algorithms integrating endothelial function data with traditional risk factors show promise for refined risk prediction. Ongoing research is exploring the role of anti-inflammatory biologics and targeted immunomodulation to restore endothelial health.

Guideline Recommendations

Leading cardiovascular societies acknowledge the prognostic importance of endothelial dysfunction, particularly in patients with persistent symptoms and non-obstructive CAD. The European Society of Cardiology (ESC) and American Heart Association (AHA) recommend consideration of endothelial function testing in selected populations, especially those with high-risk profiles or persistent angina despite normal coronary angiograms. Routine screening in the general population is not yet advocated due to cost and accessibility constraints; however, focused screening in high-risk individuals is gaining acceptance, particularly as non-invasive modalities become more widely available.

Conclusion

Screening for coronary endothelial function before the onset of structural disease is a clinically relevant, evidence-based strategy that holds promise for improving cardiovascular outcomes through early detection and intervention. Advances in diagnostic modalities and therapeutic approaches are expanding the potential for personalized medicine in cardiovascular prevention. Integration of endothelial function assessment into routine clinical practice for high-risk patients may represent a transformative step in mitigating the global burden of coronary artery disease.