Perspectives on non-obstructive coronary artery disease (NOCAD) have changed over the past decade. The prevalence of patients with NOCAD has been increasing in relation to obstructive coronary artery disease (CAD) [1]. Studies have demonstrated that patients with NOCAD have a high risk of myocardial infarction and all-cause mortality, compared to those without evidence of CAD on coronary computed tomography angiography (CCTA) [2, 3]. Moreover, when the calcified plaque burden is similar, the risk of major adverse cardiovascular events is comparable for both NOCAD and obstructive CAD patients [4]. Thus, the current paradigm of CAD management, which focuses on flow-limiting obstructive stenosis, is imperfect since a relationship exists between myocardial ischemia and coronary atherosclerosis, even in the absence of flow-limiting stenosis [5]. A Working Group for the European Society of Cardiology has suggested that approximately two-thirds of patients with suspected CAD and NOCAD may experience disease progression and the development of complications due to the presence of coronary microvascular dysfunction (CMD) [6]. Additionally, the 2024 European Society of Cardiology guidelines categorize patients with ischemia or angina in the context of NOCAD as a distinct subgroup of chronic coronary syndromes [7]. Consequently, a growing necessity exists to extend beyond anatomical evaluations of the coronary bed and to conduct comprehensive investigations into myocardial microcirculation.

CCTA is a modern, non-invasive tool that can identify coronary stenosis and quantify the extent of plaques. Comprehensive CCTA image processing software enables the assessment of total plaque volume and the burden of different plaque types, including calcified, non-calcified, and low-attenuation plaques [8].

Parameters of CCTA-derived coronary atherosclerosis correlate with myocardial ischemia on gated myocardial perfusion obtained by single-photon emission computed tomography (SPECT) in obstructive CAD patients [9, 10, 11]. Moreover, recent advances in the myocardial dynamic SPECT technique can enable the assessment of myocardial blood flow (MBF) and myocardial flow reserve (MFR) using cadmium–zinc–telluride single-photon emission computed tomography (CZT-SPECT) gamma cameras. The high diagnostic performance of this technique in assessing obstructive CAD and ischemia has been confirmed through the use of invasive coronary angiography, invasive fractional flow reserve (FFR), and positron emission tomography (PET) as reference methods [12, 13, 14, 15, 16]. However, data regarding the use of CZT-SPECT in NOCAD patients to identify those at increased cardiac risk due to CMD remain limited. Moreover, a gap exists in research concerning the associations between CCTA-based plaque quantification and MBF and MFR evaluations in NOCAD patients derived from dynamic CZT-SPECT. Patients with NOCAD who have decreased stress MBF and MFR are at higher risk for CMD and may benefit from additional risk stratification as well as a personalized, modern, and more intensive medication strategy.

Therefore, this study aimed to assess the influence of quantitative CCTA-derived atherosclerotic plaque features on myocardial perfusion and MBF obtained by dynamic CZT-SPECT in NOCAD patients.

A total of 49 patients (stenosis 50%, 29 men, mean age 57.4 $\pm$ 9.0 years) were included in the final analysis. Based on the MFR values obtained from dynamic CZT-SPECT, patients were divided into two groups. The patients enrolled in group 1 exhibited reduced MFR (2.0, n = 20; 9 men; mean age, 56.3 $\pm$ 9.0 years), while the patients in group 2 had normal MFR ($\ge$2.0, n = 29; 20 men; mean age, 58.2 $\pm$ 8.9 years).

The clinical and demographic characteristics of the patients did not differ between the groups (Table 1). Since patients were enrolled in the study at the early stages of the disease, these patients did not receive optimal medical therapy at the time of inclusion in the study. The groups did not differ significantly in the frequency of prescribed drugs. Subsequently, the treatment was corrected, and guided-derived medical therapy was prescribed in accordance with current clinical recommendations [7, 17, 18].

Patients with reduced MFR exhibited a significantly lower level of activated partial thromboplastin time compared to those with normal MFR. Other blood parameters were found to be negligible (Table 2).

The dynamic CZT-SPECT results are presented in Table 3. Patients did not exhibit severe myocardial perfusion abnormalities, as determined by standard myocardial perfusion imaging indexes. Patients with reduced MFR had significantly lower stress MBF and FD, and higher rest MBF compared to the group with normal MFR.

Analysis of the CCTA data demonstrated that patients were characterized by small atherosclerotic plaque volumes and burdens, which aligns with data reported in a large international cohort study [30]. Patients with a normal MFR presented only significantly higher calcium scores (Table 4). The study utilized exclusively coronary atherosclerosis volume and burden parameters, demonstrating good (0.75 ICC 0.90) to excellent (ICC $>$0.90) intra- and inter-observer reproducibility (Supplementary Table 1).

Stress and rest MBF values are associated with total and non-calcified (soft-tissue and fibrous) plaque volume and burden. Interestingly, MFR, FD, and standard indexes of myocardial perfusion impairment were not significantly associated with quantitative CCTA parameters. The heatmap graph of associations regarding atherosclerotic plaque features and MBF in NOCAD patients is shown in Fig. 2.

Fig. 2.

A heatmap graph of associations between atherosclerotic plaque features and myocardial blood flow in NOCAD patients. $\rho$, the Spearman’s correlation coefficient; FD, flow difference; MBF, myocardial blood flow; MFR, myocardial flow reserve; SDS, summed difference score; SRS, summed rest score; SSS, summed stress score.

Based on the univariate logistic regression analysis results, the following quantitative CCTA parameters were predictors of reduced stress MBF of less than 1.5 mL/min/g: total plaque volume (OR 1.01; 95% CI 1.00–1.02; p = 0.006); total plaque burden (OR 1.21; 95% CI 1.05–1.40; p = 0.009); non-calcified plaque volume (OR 1.01; 95% CI 1.00–1.02; p = 0.007); non-calcified plaque burden (OR 1.22; 95% CI 1.04–1.43; p = 0.013); soft-tissue plaque volume (OR 1.07; 95% CI 1.01–0.12; p = 0.018); fibrous plaque volume (OR 1.01; 95% CI 1.00–1.02; p = 0.008); fibrous plaque burden (OR 1.27; 95% CI 1.06–1.52; p = 0.009). Additional covariates, such as age, sex, risk factors, laboratory markers of lipid profile, complete blood count, blood biochemistry tests, hemostasis panel, echocardiographic parameters of left ventricular contractility, and other coronary computed tomography angiography characteristics, were not significant predictors of a reduced stress MBF of less than 1.5 mL/min/g (Supplementary Table 2). Based on the stepwise multivariate logistic regression analysis result, adjusted for age, sex, and aforementioned clinical, laboratory, and echocardiographic characteristics, only total plaque volume (OR 1.01; 95% CI 1.005–1.030; p 0.001; Nagelkerke R² = 0.505) was found to be an independent predictor of a reduced stress MBF of less than 1.5 mL/min/g.

The representative clinical case of the NOCAD patient with reduced stress MBF is shown in Fig. 3.

Fig. 3.

Clinical case of a NOCAD patient with reduced stress MBF. Patient K., female, 56 years old, arterial hypertension, dyslipidemia. CCTA ((A) three-dimensional reconstruction of the coronary tree; (B) MIP of the LAD; (C) MIP of the LCX; (D) MIP of the RCA): diffuse NOCAD; maximum stenosis 40% in the proximal segment of the LAD; total plaque volume 288.2 mm³; total plaque burden 15.2%; non-calcified plaque volume 239.1 mm³; non-calcified plaque burden 12.6%; soft tissue plaque volume 9.5 mm³; soft tissue plaque burden 0.5%; fibrous plaque volume 229.6 mm³; fibrous plaque burden 12.1%; calcified plaque volume 49.1 mm³; calcified plaque burden 2.6%. MPI (E): normal myocardial perfusion; SSS 0; SRS 0; SDS 0. Myocardial dynamic CZT-SPECT (F): reduced stress MBF 0.91 mL/min/g, rest MBF 0.74 mL/min/g, reduced MFR 1.23, FD 0.17 mL/min/g. Green indicates the lumen of the coronary arteries, yellow indicates the calcified structural components of the plaque, and purple indicates the fibrous structural components of the plaque. CAD, coronary artery disease; CCTA, coronary computed tomography angiography; CZT, cadmium–zinc–telluride detectors; FD, flow difference; LAD, left anterior descending artery; LCX, left circumflex artery; MBF, myocardial blood flow; MIP, maximum intensity projection; MFR, myocardial flow reserve; MPI, myocardial perfusion imaging; NOCAD, non-obstructive coronary artery disease; RCA, right coronary artery; SDS, summed difference score; SPECT, single-photon emission computed tomography; SRS, summed rest score; SSS, summed stress score.

The results of this exploratory study support the notion that CCTA-derived total plaque volume is an independent predictor of a reduced stress MBF of less than 1.5 mL/min/g obtained by dynamic CZT-SPECT, even in the absence of obstructive CAD. Non-calcified (soft-tissue and fibrous) plaque volume and burden were linked with impaired MBF compared with calcified components. These findings support the concept that plaque volume and burden cause myocardial perfusion abnormalities to a greater extent than the degree of stenosis. Moreover, non-calcified plaques, in contrast to calcified ones, were associated with more severe myocardial perfusion abnormalities. These findings are significant in the context of developing an effective treatment strategy and improving prognoses.

Several studies have shown that the influence of stenosis severity on MBF may not be certain [4, 31, 32]. For instance, Schuijf et al. [31] reported that 15% of the patients with no stenosis $\ge$50% assessed by CCTA had perfusion abnormalities in the SPECT analysis. Vattay et al. [32] utilized a segment-based analysis to investigate the associations between quantitative plaque characteristics derived from CCTA and segmental myocardial ischemia using dynamic perfusion computed tomography. The authors demonstrated that an increase in total plaque volume was associated with a reduction in MBF, even after adjusting for clinical risk factors, luminal area stenosis, and high-risk plaque characteristics. Moreover, lumen area stenosis and the presence of high-risk plaques were not linked to ischemia. Our findings align with these previous results, as we reported that certain plaque characteristics may be associated with MBF impairment, even in the absence of CAD. However, semiquantitative myocardial perfusion parameters did not show such associations. These results may be explained by endothelial dysfunction, a mechanism currently considered a key contributor to CMD. This leads to impaired nitric oxide release, making it impossible to achieve vasodilation and decreasing MBF [33]. Recent research has shown that morphological atherosclerotic plaque features, particularly the necrotic core volume, can affect MBF and potentially lead to ischemia [34]. In addition, the morphological structure of plaques leads to impairment of FFR regardless of the severity of luminal stenosis [34].

The non-calcified plaque contains a significant amount of cholesterol, making the plaque susceptible to rupture and potentially leading to cardiac events [35]. Recent studies have reported that components in an atherosclerotic plaque, such as lipid necrotic core, low-density non-calcified plaque, may predict myocardial ischemia or decrease MBF [12, 36, 37]. Diaz-Zamudio et al. [36] demonstrated this in a cohort of 184 patients with suspected CAD who underwent hybrid CCTA and stress and rest myocardial perfusion imaging scans on the CZT camera.

A low-density non-calcified plaque burden has been associated with ischemia in vessels with stenosis of 30–69% [36]. A similar result has been reported with FFR derived from CCTA for the detection of myocardial ischemia. Gaur et al. [37] found that a low-density non-calcified plaque volume of $\ge$30 mm³ predicted ischemia independently of other plaque characteristics and stenosis severity. Wang et al. [12] demonstrated that necrotic core volume on the CCTA singly anticipated myocardial ischemia on PET, beyond diameter stenosis alone. Driessen et al. [38] examined 208 patients with suspected CAD who underwent CCTA and PET myocardial perfusion imaging. Morphological features such as non-calcified plaque volume and positive remodeling predicted impaired hyperemic MBF and FFR, independent of lesion severity. Indeed, atherosclerotic plaques significantly affect MBF by altering the coronary artery function and structure. The first mechanism is that plaques can directly cause anatomical obstruction of the coronary arteries, and the second mechanism is related to plaque morphology and progression. Thus, coronary atherosclerosis is influenced by CMD, even in the early stages of CAD. Atherosclerotic plaque features might be a pathogenetic link in the development of vascular inflammation and endothelial dysfunction, which may lead to severe myocardial ischemia in the future [38].

Interestingly, the current study revealed no correlation between calcified plaque volume and MBF. This finding aligns with the results of Feuchtner et al. [39], who investigated 106 patients with NOCAD undergoing both CCTA and FFR. The authors revealed that an increasing plaque density, in particular calcified lesions, is associated with declining ischemia. Although it is well known that the influence of calcification on the plaque can be different, namely, leading to stability or rupture of the plaque. Wu et al. [40] described the mechanisms through which calcifications may play a positive role in plaque stability, and their negative effect depends on the localization of calcifications within the plaque. This finding warrants further investigation in future studies.

The main limitations of this study stem from the single-center design and relatively small sample size, which limit the diversity of patients and the spectrum of disease severity, reduce statistical power, and increase the risk of type II errors—potentially affecting the generalizability of the findings. Thus, this study can be considered preliminary and hypothesis-generating. Larger, multi-center studies with more heterogeneous populations are needed to validate and generalize these findings.

Total plaque volume, derived from quantitative CCTA data, is an independent predictor of a reduced stress MBF of less than 1.5 mL/min/g obtained by dynamic CZT-SPECT, even in the absence of obstructive CAD. These findings suggest that total plaque volume may serve as an early marker of CMD related to atherosclerosis in NOCAD patients, potentially identifying those at increased risk of developing CMD. The combined quantitative assessment of CCTA parameters and stress MBF could enhance the stratification of cardiovascular risk in the NOCAD population. Nonetheless, further studies are needed to obtain more data related to CZT MBF assessment, which could lead to the development of a model for early and accurate risk assessment of clinical status, treatment dynamics, and the likelihood of major adverse cardiovascular events.

1CAC, the one-compartment (single-component) model; CAD, coronary artery disease; CI, 95% confidence interval; CMD, coronary microvascular dysfunction; CCTA, coronary computed tomography angiography; CZT, cadmium-zinc-telluride; ECG, electrocardiographic-gated; EDV, end diastolic volume; EF, ejection fraction; ESV, end systolic volume; FD, flow difference; FFR, fractional flow reserve; ICC, intraclass correlation coefficient; LV, left ventricular; MBF, myocardial blood flow; MFR, myocardial flow reserve; NOCAD, non-obstructive coronary artery disease; OR, odds ratio; PET, positron emission tomography; SDS, summed difference score; SPECT, single-photon emission computed tomography; SRS, summed rest score; SSS, summed stress score.

The datasets used and analyzed during the current study are available from the corresponding author on reasonable request.

ANM and KVZ designed the research study. ANM, RVD, KVK, ASD, AVM, EVG, and KVZ performed the research. ANM, and RVD analyzed the data. ANM, RVD, KVK, and KVZ wrote the manuscript. All authors read and approved the final manuscript. All authors contributed to the conception and editorial changes in the manuscript. All authors have participated sufficiently in the work and agreed to be accountable for all aspects of the work.

The research protocol was approved by the Local Ethical Committee of Cardiology Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences (protocol No. 204, dated 18 November 2020), and all of the participants provided signed informed consent. The study responded to the Declaration of Helsinki for all human research.

This research received no external funding.

The authors declare no conflict of interest.

Supplementary material associated with this article can be found, in the online version, at https://doi.org/10.31083/RCM39291.