Significance of flow-mediated dilation in evaluating endothelial dysfunction in vasospastic angina

Abstract

A previous retrospective cohort study evaluated flow-mediated dilation (FMD) as a marker of endothelial-dependent vasodilation and nitroglycerin-induced dilation as a marker of endothelial-independent vasodilation in vasospastic angina patients. The study demonstrated that low FMD (< 3.7%) was significantly associated with major adverse cardiovascular events, whereas low nitroglycerin-induced dilation (< 14%) was not. Multivariable Cox proportional hazards modeling was carefully limited to three covariates to avoid overfitting in the setting of a small number of events. Important contributors to endothelial dysfunction, including smoking, chronic kidney disease, and inflammatory status, were acknowledged, and baseline use of endothelial-protective medications did not differ between groups. Despite limitations related to its retrospective design and sample size, the study supports the prognostic value of FMD in vasospastic angina and highlights endothelial dysfunction as a key determinant of adverse outcomes.

Key Words: Flow-mediated dilation; Vasospastic angina; Endothelial dysfunction; Coronary artery disease; Prognosis

Core Tip: This study emphasizes the prognostic importance of endothelial-dependent vasodilation assessed by flow-mediated dilation (FMD) in patients with vasospastic angina. Unlike nitroglycerin-induced dilation, FMD was independently associated with major adverse cardiovascular events, underscoring the pivotal role of endothelial dysfunction rather than vascular smooth muscle impairment. Careful model construction avoided overfitting despite limited events. Given its non-invasive nature, FMD may serve as a valuable risk-stratification and potentially diagnostic tool in vasospastic angina, warranting further prospective validation.

INTRODUCTION

The retrospective study conducted by Teragawa et al[1] identified flow-mediated dilation (FMD) as an important and reliable measure of endothelial dysfunction. In addition, the authors evaluated endothelium-independent vasodilation using nitroglycerin-induced dilation (NID), which further enriched the clinical context of the study as both parameters evaluate different pathophysiological mechanisms of endothelial dysfunction[2]. They demonstrated a significant association between low FMD (cutoff < 3.7%) and major adverse cardiovascular events, whereas low NID (cutoff < 14%) was not associated with adverse outcomes. Importantly, the authors adjusted for potential confounders using Cox proportional hazards models and deliberately limited the model to three variables to avoid overfitting, given the relatively small number of events. This methodological consideration is highly commendable.

The findings of this study are clinically compelling, particularly considering that FMD is a non-invasive examination that may have broader clinical implications, especially in patients with suspected vasospastic angina who demonstrate normal coronary arteries after exclusion of significant epicardial stenosis. These findings suggest that FMD may have the potential—pending further validation through larger and more robust studies—to reduce reliance on acetylcholine provocation testing for confirming microvascular dysfunction in vasospastic angina.

FMD AND VASOSPASTIC ANGINA

At present, studies evaluating the role of FMD in detecting endothelial dysfunction in vasospastic angina remain limited, with most originating from earlier investigations[3-5]. Nevertheless, FMD continues to be an attractive diagnostic modality due to its non-invasive nature and its established association with endothelial dysfunction, a fundamental mechanism underlying numerous cardiovascular diseases[6]. These conditions include coronary artery disease, peripheral arterial disease, chronic venous insufficiency, and other vascular disorders, several of which have demonstrated associations with impaired FMD in prior studies[7-9].

Several important factors related to endothelial dysfunction—such as smoking, obesity, chronic kidney disease, and C-reactive protein—were also reported[10], even though they were not included in the multivariate Cox model. Moreover, the authors emphasized the use of vasodilators and medications known to improve endothelial function, such as renin-angiotensin system inhibitors. Notably, baseline use of these medications did not differ significantly between the high- and low-FMD groups, thereby reducing the likelihood of treatment-related confounding.

Despite the promising association between FMD and major adverse cardiovascular events in patients with vasospastic angina, several caveats warrant consideration. First, the inherent limitations and potential biases associated with a retrospective design cannot be ignored. Second, other comorbidities known to influence endothelial dysfunction—such as peripheral artery disease[11]—could have been described in greater detail. Although the small sample size and limited number of events restricted the complexity of the multivariate model, a more explicit justification for the selection of covariates would have strengthened the analysis.

Furthermore, the role of NID could have been discussed in greater depth. Although NID was positively correlated with FMD, the correlation was weak, and NID did not demonstrate prognostic significance. This discrepancy between NID and FMD may support the hypothesis that endothelial-dependent dysfunction, rather than smooth muscle dysfunction, plays a central role in the pathophysiology of vasospastic angina. In addition, the discussion could have been expanded to address different types of coronary spasm and the specific coronary vessels involved. Such insights would be valuable, although they could not be fully explored in the study of Teragawa et al[1], as only focal spasm characteristics were evaluated (Figure 1).

Figure 1 Flow-mediated dilation and vasospastic angina. FMD: Flow-mediated dilation.

EXPANDED ROLE OF ENDOTHELIAL DYSFUNCTION IN VASOSPASTIC ANGINA

Recent work in vascular biology continues to reinforce the central role of endothelial dysfunction in vasospastic angina, particularly through impaired nitric oxide (NO) signaling, increased oxidative stress, and abnormal vasomotor responses. Dysfunction of endothelial NO synthase—whether related to reduced activity, altered regulation, or uncoupling—leads to reduced NO availability and increased production of reactive oxygen species, ultimately favoring vasoconstriction[12-16]. This mechanism is highly relevant in vasospastic angina, where marked vasoconstriction can occur even in the absence of significant structural coronary disease[17,18]. In this setting, FMD may reflect the overall integrity of endothelial function and NO-mediated vasodilation, which provides a plausible explanation for its observed prognostic value[13,14].

Inflammation also appears to play an important role. Elevated levels of inflammatory markers such as C-reactive protein and interleukin-6 have been associated with impaired endothelial function and a higher likelihood of coronary spasm[19-21]. These inflammatory processes may further reduce NO bioavailability and promote oxidative stress[14,21]. From a clinical perspective, this suggests that FMD is not simply capturing structural vascular abnormalities, but may also reflect dynamic changes in vascular function driven by inflammatory activity[22].

Another point worth emphasizing is that endothelial dysfunction in vasospastic angina is likely not limited to the coronary circulation. Several studies have demonstrated that abnormalities in peripheral endothelial function, as assessed by FMD, are associated with coronary vasomotor dysfunction identified through invasive testing[23,24]. This supports the concept of a more systemic vascular disorder rather than an isolated coronary phenomenon. Clinically, this has practical implications, particularly in patients with angina and non-obstructive coronary arteries, where non-invasive tools such as FMD could contribute to risk stratification and diagnostic evaluation[25,26].

Concerns regarding the variability and operator dependency of FMD have been raised in the past, but these limitations have been partially addressed with advances in imaging techniques and standardized protocols[27-30]. Nevertheless, variability between centers remains an issue, and adherence to standardized protocols remains essential for reliable interpretation[27].

The contrast between endothelial-dependent and endothelial-independent vasodilation is also of interest[1,7]. As NID and FMD reflect different pathophysiological process, observations from clinical studies can enhance the understanding of the involved abnormalities in endothelial signaling pathways[31]. However, further studies are needed to better understand how these mechanisms interact across different clinical phenotypes.

From a broader perspective, combining FMD with other biomarkers and diagnostic approaches may provide a more comprehensive assessment of vascular health. Biomarkers such as endothelin-1, asymmetric dimethylarginine, and E-selectin may offer additional insight into endothelial activation and dysfunction[12,32]. Similarly, integrating FMD with functional imaging modalities—such as coronary flow reserve or advanced perfusion imaging—may help contextualize its findings within a more complete cardiovascular assessment[33,34]. Such an approach could be particularly useful for improving phenotyping and guiding management strategies.

Finally, the potential role of FMD in monitoring treatment response remains an area of interest. Therapies known to improve endothelial function—including statins, renin-angiotensin system inhibitors, and calcium channel blockers—may lead to measurable improvements in FMD, although the clinical significance of these changes is not yet fully established[22,34]. Prospective studies evaluating longitudinal changes in FMD in relation to outcomes would help clarify whether it can be used not only as a prognostic marker, but also as a tool for treatment monitoring.

CONCLUSION

The study of Teragawa et al[1] contributes to the growing body of evidence supporting the role of FMD in assessing endothelial dysfunction across multiple cardiovascular pathologies, the prevalence of which is expected to increase. Given its ability to directly evaluate endothelial function in a non-invasive manner, FMD may hold significant clinical value in cardiovascular risk stratification and disease monitoring. Future investigations integrating FMD with established biomarkers of endothelial dysfunction, such as endothelin, E-selectin, and matrix metalloproteinases[12], may further enhance its diagnostic and prognostic utility.