When coronary spasm reflects systemic vascular disease: Prognostic insights from endothelial dysfunction

Abstract

Vasospastic angina (VSA) has traditionally been regarded as a largely benign coronary syndrome when treated with vasodilator therapy and lifestyle modification. However, a subset of patients experiences recurrent ischemic events, heart failure or even sudden cardiac death, underscoring the need for reliable and clinically accessible prognostic markers. In this context, the study by Teragawa et al published in the World Journal of Cardiology provides important evidence that peripheral vascular endothelial dysfunction, assessed noninvasively by brachial artery flow-mediated dilation (FMD), is independently associated with adverse long-term outcomes in patients with angiographically confirmed VSA. This retrospective analysis demonstrates that reduced FMD (< 3.7%) identifies a higher-risk VSA phenotype characterized by advanced age, elevated natriuretic peptide levels and significantly increased rates of major adverse cardiovascular events. Notably, endothelial dysfunction outperformed several traditional spasm-related angiographic markers, including focal spasm, in multivariable prognostic modeling. These findings reinforce the concept that VSA is not merely a focal epicardial disorder but rather a manifestation of systemic vascular pathology, in which endothelial health plays a central role. Beyond its mechanistic implications, the study has important clinical ramifications. FMD is widely available, noninvasive and reproducible when performed according to established standards, making it an attractive tool for risk stratification in everyday practice. Incorporating endothelial function assessment into the evaluation of patients with VSA may allow for more individualized surveillance strategies and more aggressive modification of cardiovascular risk factors in those at highest risk. While the single-center, retrospective design necessitates cautious interpretation, this work meaningfully advances the field by bridging vascular biology with clinical outcomes. Future multicenter and prospective studies will be essential to validate optimal FMD thresholds and to determine whether therapeutic strategies aimed at improving endothelial function can translate into improved prognosis in VAS.

Key Words: Vasospastic angina; Endothelial dysfunction; Flow-mediated dilation; Coronary spasm; Prognosis; Risk stratification; Microvascular dysfunction

Core Tip: In patients with vasospastic angina, impaired brachial artery flow-mediated dilation independently predicts adverse cardiovascular events and outperforms conventional angiographic spasm markers. These data support the concept that coronary spasm reflects systemic endothelial pathology rather than isolated epicardial hyperreactivity, highlighting the potential role of endothelial function testing in clinical risk stratification.

This editorial refers to “Prognostic significance of vascular endothelial dysfunction in patients with vasospastic angina” by Teragawa et al, 2026; https://doi.org/10.4330/wjc.v18.i3.116661.

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INTRODUCTION

Vasospastic angina (VSA) results from episodic constriction of the epicardial coronary arteries, producing transient myocardial ischemia[1,2]. In recent years, it has gained recognition as a major mechanism underlying angina and even myocardial infarction in patients without flow-limiting coronary stenoses, including those with angina with non-obstructive coronary arteries and myocardial infarction with non-obstructive coronary arteries. Clinically, VSA most commonly presents with rest angina, often occurring at night or in the early morning, while exertional symptoms are less frequently reported[3-6]. Although most patients achieve good symptom control and an overall favorable prognosis with vasodilator therapy and lifestyle interventions, serious events, including ventricular arrhythmias and cardiac arrest, can still occur in a subset of cases[7]. Multiple clinical and angiographic predictors of adverse outcomes have been proposed, such as variant angina, spasm involving the left anterior descending artery, beta-blocker use, prior out-of-hospital cardiac arrest, multivessel or focal spasm, coexisting organic coronary stenosis and suboptimal use of statins or calcium-channel blockers[3,8-12]. In this context, identifying markers that reflect the systemic vascular substrate rather than solely angiographic features is of increasing clinical importance.

The pathogenesis of VSA is multifactorial, with both vascular endothelial dysfunction and enhanced coronary smooth muscle contractility playing central roles[12-17]. Several approaches are available to evaluate endothelial function. But brachial artery flow-mediated dilation (FMD) remains one of the most established, noninvasive and clinically applicable techniques[17-20]. While FMD has been extensively studied in patients with VSA, the prognostic implications of endothelial dysfunction in this population have not been adequately defined[17]. Registries and observational studies have demonstrated that a meaningful proportion of patients experience recurrent angina, heart failure hospitalization, myocardial infarction or even sudden cardiac death, despite appropriate therapy[18,21]. The persistent challenge has been the identification of patients at highest risk. However, prior studies have largely focused on the presence of endothelial dysfunction rather than its prognostic implications. The study by Teragawa et al[22] published in the World Journal of Cardiology is distinctive in that it links FMD-derived endothelial function with long-term clinical outcomes and directly compares its prognostic value against established angiographic spasm characteristics within a multivariable framework. This positions endothelial dysfunction not only as a mechanistic contributor but as a clinically actionable risk marker.

In this context, the study by Teragawa et al[22] provides mechanistically coherent and clinically relevant evidence that vascular endothelial dysfunction, assessed noninvasively by FMD, independently predicts long-term adverse outcomes in VSA. Among 244 patients with angiographically confirmed coronary spasm, those with FMD < 3.7% exhibited a significantly higher incidence of major adverse cardiovascular events (MACE) over extended follow-up. In multivariable Cox analysis, low FMD and older age remained independent predictors, whereas focal spasm, previously considered a prognostic marker, did not retain significance. These findings deserve careful consideration.

Historically, VSA has been conceptualized primarily as a disorder of coronary smooth muscle hyperreactivity[23]. However, endothelial dysfunction, particularly impaired nitric oxide bioavailability, has long been implicated in its pathophysiology. Genetic variants in endothelial nitric oxide synthase and invasive studies demonstrating reduced endothelium-dependent vasodilation have supported this paradigm.

The present analysis extends this biological understanding into the prognostic domain. By demonstrating that peripheral endothelial dysfunction correlates with adverse cardiovascular outcomes, the authors strengthen the argument that VSA is not merely a localized epicardial phenomenon but a manifestation of systemic vascular pathology. In other words, coronary spasm may represent the visible expression of a broader endothelial disease state.

BEYOND ANGIOGRAPHIC PHENOTYPING

Traditional risk markers in VSA have included variant angina presentation, multivessel spasm, left anterior descending artery involvement and focal spasm morphology. While clinically informative, these features reflect anatomical distribution rather than underlying vascular biology[24].

The observation that low FMD outperformed focal spasm in multivariable modeling suggests that endothelial health may capture risk more comprehensively than angiographic descriptors. This distinction is clinically meaningful. Angiographic features describe “where” the spasm occurs, whereas endothelial dysfunction reflects “why” the vasculature is vulnerable.

Moreover, the association between low FMD, advanced age and higher brain natriuretic peptide levels identifies a phenotype characterized by cumulative vascular injury and subclinical myocardial stress. Although left ventricular systolic function was preserved, elevated natriuretic peptide levels may reflect diastolic dysfunction, microvascular ischemia or increased arterial stiffness, conditions closely linked to endothelial impairment. In addition, systemic inflammation and oxidative stress may represent a unifying biological substrate linking endothelial dysfunction, myocardial stress and electrical instability. These processes impair nitric oxide bioavailability, promote vascular dysfunction and may contribute to arrhythmogenic vulnerability, which is particularly relevant in high-risk VSA phenotypes[25].

FMD offers several practical advantages. It is noninvasive, reproducible when performed according to established standards and widely available in tertiary centers[17]. A threshold near 4% is broadly consistent with contemporary vascular biology literature and guideline-based interpretations and the < 3.7% cutoff used in this study appears clinically plausible[17,18]. However, this value should be interpreted as a reference point rather than a universally applicable threshold, as FMD measurements are influenced by population characteristics, comorbidity burden and technical factors. Local validation and standardization will be important before routine adoption of a fixed cutoff in clinical practice.

Incorporating endothelial function assessment into the evaluation of VSA could refine risk stratification. Patients with markedly impaired FMD may warrant closer follow-up, aggressive risk factor modification and optimization of adjunctive therapies such as statins or renin-angiotensin system inhibitors. However, whether such strategies alter outcomes remains unproven.

The study’s retrospective and single-center design necessitates caution. The total number of events was modest and although statistical modeling was appropriately constrained, residual confounding cannot be excluded. Serial assessment of endothelial function was not performed and the potential dynamic evolution of FMD under therapy remains unexplored. Additionally, extrapolation to other populations requires validation, as endothelial function is influenced by ethnicity, comorbidity burden and methodological variability. Importantly, nitroglycerin-induced dilation did not independently predict MACE, suggesting that smooth muscle responsiveness alone does not account for adverse prognosis. This distinction reinforces the centrality of endothelium-dependent mechanisms in determining clinical trajectory.

FUTURE DIRECTIONS

The findings of Teragawa et al[22] open several important avenues for future investigation. Large, prospective, multicenter registries are needed to confirm the prognostic value of FMD in diverse populations and healthcare systems. Standardization of acquisition protocols, core laboratory adjudication and predefined FMD thresholds will be essential to ensure external validity. Furthermore, endothelial function is modifiable. Serial FMD measurements could determine whether improvement over time correlates with reduced event rates. Such data would clarify whether FMD serves merely as a risk marker or also as a modifiable risk factor. Randomized trials should evaluate whether targeted intensification of endothelial-protective therapies in low-FMD VSA patients reduces MACE. Potential strategies include high-intensity statins, renin–angiotensin system blockade, sodium-glucose cotransporter 2 inhibitors, structured exercise programs and comprehensive lifestyle interventions. Mechanistic sub-studies integrating inflammatory and oxidative stress biomarkers may provide additional insight. The interplay between epicardial spasm, coronary microvascular dysfunction and systemic endothelial impairment remains incompletely defined. Combining peripheral FMD with invasive coronary function testing, such as acetylcholine reactivity and coronary flow reserve, may allow refined phenotyping and precision-based therapeutic approaches. Finally, the observed association between low FMD and elevated natriuretic peptide levels suggests that multi-marker risk models may outperform single-parameter assessment. Integration of endothelial function, myocardial stress markers and possibly imaging-derived indices of arterial stiffness could yield a comprehensive prognostic framework.

CONCLUSION

Impaired FMD independently identifies a higher-risk phenotype in VSA and challenges the traditional view of the disorder as predominantly focal and benign. These data underscore the systemic nature of endothelial dysfunction in coronary vasomotor disease and highlight the potential clinical value of endothelial function testing. Future prospective and interventional studies will determine whether targeting endothelial health can meaningfully alter the long-term prognosis of patients with VSA.