Prognostic significance of cold pressor test myocardial perfusion imaging in patients with ischemia and nonobstructive coronary arteries

Introduction

Angina is the most common symptom of coronary artery disease (CAD), which affects approximately 112 million people globally. Up to 70% of patients undergoing invasive coronary angiography (CAG) do not have obstructive CAD, which has been recently termed ischemia with nonobstructive coronary arteries (INOCA) (1). INOCA is linked to a higher rate of major adverse cardiovascular events (MACEs), frequent hospital readmissions, diminished life quality, and elevated healthcare expenses (2). Two key factors within INOCA are coronary artery spasm (CAS) and coronary microvascular dysfunction (CMD). It was reported that nearly 66.6% patients with INOCA experience CAS, which is promoted by endothelial dysfunction (3).

Endothelial integrity is critical for vascular physiology. Endothelial dysfunction not only precedes coronary atherosclerosis but is also exacerbated by it, constituting a vicious cycle (4). In the event of endothelial damage, acetylcholine (ACh) induces vasoconstriction through direct activation of muscarinic receptors on vascular smooth muscle cells (5). Diagnosing endothelial dysfunction remains challenging, as the gold standard—intracoronary ACh infusion during invasive procedures and numerous adverse reactions—limits its clinical applicability (6). A noninvasive and easily conducted provocative test that does not involve the administration of pharmacological agents would be extremely advantageous for assessing endothelial function in patients with INOCA.

Cold pressor test (CPT) may offer this potential, as it is a feasible, noninvasive, easily applicable, and safe diagnostic tool for assessing endothelial function in patients with INOCA, eliminating the need for pharmacologic agent administration (7). For patients with healthy endothelium, CPT can facilitate coronary dilation through the release of nitric oxide (NO). During endothelial dysfunction, α1-adrenergic receptor–mediated vascular smooth muscle contraction predominates, mimicking the vasoconstrictive effects observed with ACh stimulation (8). The CPT is a relatively straightforward procedure to conduct, as the physiological response to cold stimulation is rapid and generally well-tolerated by individuals. The CPT-myocardial perfusion imaging (MPI) is a novel diagnostic strategy for noninvasively assessing the coronary artery endothelial-dependent function via single-photon emission computed tomography (SPECT) (9). However, in a study of normal stress-rest MPI, 38.2% patients were positive on CPT-MPI, and these patients exhibited severe endothelial dysfunction and were at a heightened risk of experiencing cardiovascular events (10). However, a definite relationship between positivity on CPT and cardiovascular outcomes in patients with INOCA has not been established.

The aim of this study was thus to analyze the fundamental traits of patients with positive CPT and investigate the potential of the CPT to identify individuals at high risk of MACEs among patients with INOCA. We present this article in accordance with the STROBE reporting checklist (available at https://qims.amegroups.com/article/view/10.21037/qims-2025-33/rc).

Methods

Study population

This retrospective cohort study was conducted at Xuzhou Central Hospital from January 2019 to September 2023 and received approval by the Ethics Committee of Xuzhou Central Hospital (approval No. XZXY-LJ-20180118-016). This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The requirement for informed consent was waived due to the retrospective nature of the analysis. Patients with INOCA who fulfilled the following criteria were included: (I) angina pectoris, chest tightness, heart palpitations, and other symptoms; (II) presence of nonobstructive coronary arteries, defined as <50% stenosis in the major epicardial coronary arteries on coronary angiography (CAG) or computed tomography angiography (CTA) (11); and (III) evidence of myocardial ischemia, as detected through an electrocardiogram (ECG) or cardiac imaging techniques (such as echocardiography, nuclear imaging, magnetic resonance imaging), either at rest or during stress induced by exercise or pharmacological agents (12). All patients enrolled underwent CPT and resting MPI examination. Data on traditional cardiovascular risk factors were gathered, including body mass index (BMI), hypertension, hyperlipidemia, diabetes mellitus (DM), active smoking, and related symptoms. Upon admission, fasting plasma markers were assessed for all patients, including for triglycerides (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C). The 12-lead ECG examination was carried out at the time of admission. T-wave inversion and ST-segment depression were considered to indicate ST-T changes (13). Coronary atherosclerosis was defined as a degree of maximal coronary diameter stenosis between 1% and 49%, while the degree of maximal coronary diameter stenosis of 0% indicated no coronary atherosclerosis (14). The exclusion criteria for participants were as follows: (I) the presence of ≥50% luminal stenosis in the major coronary artery in CAG or a history of percutaneous coronary intervention (PCI) or coronary artery bypass graft (CABG) surgery; (II) heart failure; (III) acute coronary syndrome; (IV) valvular heart disease or cardiomyopathy; and (V) non-sinus rhythm. The flowchart of patient inclusion is presented in Figure 1.

Figure 1 Flowchart of patient inclusion. CABG, coronary artery bypass graft; CAG, coronary angiography; CPT, cold pressor test; INOCA, ischemia with nonobstructive coronary arteries; MPI, myocardial perfusion imaging; PCI, percutaneous coronary intervention.

Resting MPI

Following the indications and the 2-day standard imaging protocol, each patient underwent CPT and resting MPI. Resting MPI commenced 90 minutes after an intravenous injection of 555 MBq of 99mTc-MIBI (radiochemical purity >95%). Before the MPI examination, patients were required to fast for 4 hours and discontinue the intake of cardiovascular active medications for 24 hours.

CPT

One day after resting MPI, patients were instructed to immerse their foot in a container of cold water (0–5 ℃) for 1.5 minutes, during which blood pressure and heart rate were monitored (10). Subsequently, 555–740 MBq of 99mTc-MIBI was administered intravenously, and cardiac imaging was performed 90 minutes after with the same procedure and parameters as those of the rest test. SPECT images were captured using a dual-head camera set at a 90° angle (Siemens Healthineers, Erlangen, Germany) equipped with a high-resolution low-energy parallel-hole collimator and a 180° orbit (ranging from 45° right anterior oblique to 45° left posterior oblique). Attenuation correction was not applied. Images of MPI were produced with a matrix of 128×128, a magnification of 2.0, and 20% window centered on the 140-keV peak energy. All images were reconstructed using an ordered subset-expectation maximization algorithm (OSEM), and horizontal long-axis, vertical long-axis, and short-axis images were acquired. Figure 2 presents the flowchart for the CPT procedure.

Figure 2 A flowchart of the CPT procedure. CPT, cold pressor test; SPECT/CT, single-photon emission computed tomography/computed tomography; 99mTc-MIBI, Technetium-99m Methoxyisobutyl Isonitrile.

Imaging analysis

The interpretation of SPECT/MPI images was conducted semiquantitatively via computer assistance and visual analysis by two experienced nuclear medicine physicians who were blinded to the patients’ clinical information. In cases of divergence in the assessments by the two experts, a third specialist was consulted to achieve a consensus, and that result was then documented. The myocardial perfusion images were segmented into 17 distinct parts and evaluated under a five-tier scoring system, with 0, indicating normalcy and 4 indicating a complete lack of uptake in the segment. The stress-induced and rest-induced abnormalities were quantified through the summed stress score (SSS) and summed rest score (SRS), respectively, through the aggregation of scores from all affected segments during stress and rest. The summed difference score (SDS) was derived by subtracting the SRS from the SSS. A positive CPT-MPI result was characterized by the presence of a reversible perfusion defect with an SDS of 2 or higher (15). The effective radiation dose was approximately 6–8 mSv.

Follow-up

Follow-up data were obtained from patient clinical records or telephone interviews. All endpoints were determined through consensus between two independent reviewers who were blinded to the study data. The follow-up deadline was April 2024. MACEs were defined as all-cause mortality or coronary revascularization performed at least 3 months after SPECT-MPI, including CABG and PCI, nonfatal myocardial infarction, as diagnosed based on symptoms, enzyme levels (creatine kinase, troponin T), ECG findings, and rehospitalization due to angina, heart failure, and stroke (16). Heart failure was defined as the first heart failure hospitalization in any position of the hospital discharge list (17).

Statistical analysis

Statistical analysis was performed with SPSS version 25; IBM Corp., Armonk, NY, USA). The Kolmogorov-Smirnov test was used to assess whether continuous variable distributions were normal. Continuous variables are presented as the mean ± standard deviation (SD) or as the median and interquartile range and were compared with the Student t-test or the Mann-Whitney test. Categorical variables are presented as percentages and were analyzed with the Chi-squared test or Fisher exact test. A binary logistic regression model was applied to identify factors influencing positive CPT-MPI results. Event-free survival rates over time were assessed with the Kaplan-Meier method, and the log-rank test was applied to analyze the differences between the survival curves. Predictors of poor prognosis were determined via Cox proportional hazards regression models, with hazard ratios (HRs) and 95% confidence intervals (CIs) being calculated. The factors that had clinical significance were included in the multivariate Cox regression analysis. Statistical significance was assigned to P values below 0.05.

Results

Patient characteristics

A total of 124 inpatients with INOCA (mean age 51.03±13.61 years; males 59.7%) were enrolled, and the details of their characteristic are presented in Table 1. The number of positive CPT-MPI cases was 49 (39.5%), and the number of negative CPT-MPI cases was 75 (60.5%). No serious adverse reactions (such as severe pain, severe arrhythmias, hypertensive crises, or syncope) related to CPT were reported. Compared with the negative CPT-MPI group, the positive CPT-MPI group had higher percentage of DM [16 (32.7%) vs. 13 (17.3%)], coronary atherosclerosis [33 (67.3%) vs. 32 (42.7%)], and ECG at admission ST changes [37 (75.5%) vs. 42 (56.0%)] (all P values <0.05).

Factors related to positive CPT-MPI

Univariate and multivariate logistic regression analyses indicated that coronary atherosclerosis was an independent risk factors of positive CPT-MPI [odds ratio (OR) 2.68; 95% CI: 1.22–5.90; P=0.014] (Table 2).

Association between positive CPT and poor prognosis

All patients were followed up for a median 28 (IQR, 19–35) months. MACEs occurred in 22 patients (17.7%) and included 2 revascularizations, 16 angina-related rehospitalizations, 4 heart failures (3 had heart failure with reduced ejection fraction and 1 had preserved ejection fraction). The proportion of positive CPT-MPI was higher in in patients with MACEs than in those without MACEs [6 (32.7%) vs. 16 (8%); P<0.05] (Table 3). Kaplan-Meier survival curve analysis showed that patients with positive CPT-MPI had a significantly lower event-free survival rate than did those with negative CPT-MPI, with a notable difference between the curves as indicated by the log-rank test (Figure 3). In the univariate analysis with Cox proportional hazards regression model, age (HR 1.05, 95% CI: 1.01–1.08) and positive CPT-MPI (HR 3.80, 95% CI: 1.48–9.76) were associated with MACEs (both P values <0.05). In the multivariate Cox proportional hazards regression, only positive CPT-MPI (HR 2.97, 95% CI: 1.02–8.58; P=0.04) was significantly associated with MACE occurrence (Table 4). Figure 4 provides a case example.

Figure 3 Kaplan-Meier survival curves for patients with INOCA with negative and positive CPT. CPT, cold pressor test; MACE, major adverse cardiovascular event; INOCA, ischemia with nonobstructive coronary arteries.

Figure 4 Case example. A 40-year-old female was admitted to the hospital with chest tightness for half a year and a history of diabetes for 1 year. The patient was diagnosed with INOCA (no significant stenosis was observed in CAG; exercise ECG results showed ST-T changes suggestive of myocardial ischemia) and received CPT-MPI. (A) The odd rows depict CPT, while the even rows show rest for short-axis, vertical long-axis, and horizontal long-axis images, and indicated a reversible perfusion defect at the inferior wall (red arrows). (B) The patient was instructed to immerse her foot in a container of cold water (0–5 ℃) for 1.5 minutes. (C-E) The CAG images of the LAD, LCX, and RCA, respectively, demonstrating a 20–30% stenosis in the proximal-to-middle segment of the RCA (white arrow). At 1-month follow-up, the patient was readmitted for recurrent chest pain. CAG, coronary angiography; CPT-MPI, cold pressor test myocardial perfusion imaging; ECG, electrocardiogram; INOCA, ischemia with nonobstructive coronary arteries; LAD, left anterior descending; LCX, left circumflex; RCA, right coronary artery.

Discussion

The principal findings of this study were as follows: (I) among patients with INOCA, as compared with the negative CPT-MPI group, the positive CPT-MPI group had a higher percentage of patients with DM, coronary atherosclerosis, and ST changes on admission ECG. (II) Univariate and multivariate logistic regression analyses identified coronary atherosclerosis as an independent risk factor for positive CPT. (III) The proportion of patients with positive CPT-MPI was higher in the MACE group than in the non-MACE group. Kaplan-Meier survival curve analysis revealed that the MACE-free survival rate was significantly lower in patients with positive CPT-MPI than in those with negative CPT-MPI. (IV) In multivariate Cox proportional hazards regression, only positive CPT was significantly associated with poor prognosis, and patients with positive CPT were found to be twice as likely to experience MACEs than were those with a negative result.

INOCA has garnered growing recognition within the medical community, with epidemiological studies suggesting a prevalence that ranges from 3 to 4 million affected individuals (18). INOCA is associated with a higher risk of adverse clinical outcome as compared to the general population, and effective treatment remains elusive (19). Coronary endothelial dysfunction is known to be highly prevalent in patients with INOCA, yet it is not routinely assessed. It was reported that a total of 79% of patients with INOCA had endothelial dysfunction according to assessment with ACh-mediated vasodilation (3). Endothelial dysfunction is characterized by impaired endothelium-dependent vasodilation, heightened oxidative stress, chronic inflammation, leukocyte adhesion, vascular hyperpermeability, and endothelial senescence (20). Reduced endothelial NO activity and impaired endothelial function are closely linked to coronary spasm, the incidence of which is higher in Asian populations than in White populations (21,22). Moreover, the initial irregularity in the progression of coronary atherosclerosis is endothelial dysfunction, which is also linked independently to future cardiovascular incidents (23). Some clinical therapeutic approaches aim to prevent and treat atherosclerosis by improving endothelial function. Commonly used medications to enhance endothelial function in clinical practice include statins, renin-angiotensin system inhibitors (angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker inhibitor), antioxidants, β-blockers, insulin sensitizers, and NO donors, among others (24). Early detection of endothelial dysfunction and timely initiation of medications to enhance endothelial function can provide additional benefits, particularly given the high prevalence of this condition in patients with INOCA.

The intracoronary infusion of ACh, known as the ACh test, is regarded as the gold standard for assessing endothelial dysfunction (25). However, its feasibility is often limited due to its frequent adverse reactions, high incidence of severe cardiac complications, and high procedural risks. CPT can serve as a noninvasive alternative to the intracoronary ACh test, offering higher sensitivity and better safety (26). When individuals immerse their foot in ice water, activation of the sympathetic nervous system stimulates endothelial α2-adrenergic receptors, resulting in the release of NO and endothelium-derived hyperpolarizing factors (EDHFs), which subsequently induce vasodilation in healthy endothelia. Conversely, in the presence of endothelial dysfunction, the response is dominated by an α1-adrenergic receptor-mediated constriction of vascular smooth muscle cells, closely resembling the vasoconstrictive responses observed following ACh stimulation (27). Furthermore, the metabolically mediated increase in blood flow following the CPT, which results from an elevated myocardial oxygen demand due to increased heart rate and contractility, is a critical determinant of the coronary vasomotor response to sympathetic activation (28).

In this study, we found that the positive CPT-MPI group had a higher percentage of DM and coronary atherosclerosis. DM is associated with an elevation in free-radical production, which adversely affects endothelial function (29). Additional mechanisms may also trigger diabetic endothelial dysfunction, for example inflammatory conditions, oxidative excess, and insulin resistance (30). Similarly, Kjaer et al. found that in patients with non-insulin-dependent DM without evidence of epicardial coronary disease, endothelial dysfunction is strongly suggested by an impaired increase in coronary blood flow in the CPT (31). We further found that coronary atherosclerosis was the independent risk factor for positive CPT-MPI, which is consistent with a previous report suggesting that vascular segments with atheroma plaques exhibit increased sensitivity to vasoconstriction (32). Endothelial cells lining blood vessels sense shear stress and inflammatory stimuli, playing a pivotal role in the initiation and progression of atherosclerosis (33). Endothelial dysfunction manifests at an early stage in the development of atherosclerotic disease (34). Concurrently, during the development of atherosclerosis, a variety of stimuli increase oxidative stress, reduce NO levels, and diminish the bioavailability of NO in endothelial cells, ultimately leading to endothelial dysfunction (35). Unexpectedly, there was no correlation between other conventional risk factors and positive CPT. This lack of association may be explained by the low risk of CAD in this population, as all patients were free of obstructive CAD. Additionally, males accounted for 59.7% of all patients enrolled in this study. The reasons for the slightly higher proportion of males are as follows: male patients with cardiovascular symptoms are more frequently referred for advanced diagnostic evaluations such as MPI or coronary angiography as compared to females. This bias may stem from the long-standing perception that males are at a higher risk of cardiovascular disease. Given the relatively small sample size of 124 participants, random variation might have contributed to the observed male predominance.

We also discovered that only positive CPT-MPI was significantly associated with poor prognosis after adjustment were made for various cardiovascular risk factors. This finding highlights the importance of incorporating additional endothelial function testing into INOCA protocols given the clinical and therapeutic relevance of endothelial dysfunction in influencing patient outcomes. Similarly, Schächinger et al. demonstrated that the coronary vasomotor response to CPT serves as predictor of the progression of CAD and the occurrence of cardiovascular events (36). Another study reported that 38.2% of patients with no known CAD and normal MPI had a positive CPT; additionally, the positive CPT group had a fourfold higher risk of cardiovascular events as compared with the negative CPT group. Notably, all cardiovascular events in the negative CPT group occurred after 30 months of follow-up (10).

Limitations

The study still involved several limitations which should be acknowledged. First, we employed a single-center design with a small sample size which may limit the generalizability of the findings. Moreover, as we enrolled patients without obstructive CAD, our results can not be extrapolated to the population with obstructive CAD, and the relevance of our findings for clinical application needs to be verified by large-sample clinical studies. Second, we did not evaluate the endothelial function via ACh testing, which is the gold standard for invasive evaluation. A multicenter trial combining CPT-MPI and intracoronary ACh testing is warranted to refine the risk stratification protocols. Furthermore, the procedures and guidelines for using the CPT require standardization to facilitate its implementation in daily clinical practice. Third, the absolute quantification of myocardial blood flow and coronary flow reserve was not performed due to the lack of access to positron emission tomography (PET), which could have enabled us to further examine the mechanisms of microvascular dysfunction. Future studies integrating PET-based flow quantification may validate the prognostic value of CPT-MPI and determine the correlations with flow parameters. Fourth, due to the specific focus of endothelial function in INOCA and the practical constraints of conducting both tests in our patient population, we were unable to include standard stress MPI in this analysis. Future studies should explore the potential synergies and differences between CPT-MPI and standard stress MPI more comprehensively across CAD subtypes. Finally, no analyses related to pharmacological or nonpharmacological interventions were conducted.

Conclusions

In our study, 39.5% of patients with INOCA had positive CPT, which was significantly associated with MACE occurrence. In patients with positive CPT, the risk of MACEs increased twofold. Coronary atherosclerosis was an independent risk factor for positive CPT. CPT-MPI offers valuable insights for risk stratification and treatment decision-making in patients with INOCA, particularly in identifying those at higher risk of adverse cardiovascular events.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://qims.amegroups.com/article/view/10.21037/qims-2025-33/rc

Data Sharing Statement: Available at https://qims.amegroups.com/article/view/10.21037/qims-2025-33/dss

Funding: This research was supported by the Key Research and Development Program of Jiangsu Province (Social Development) (No. BE2021638; PI: Y.W.); the Changzhou Clinical Medical Center (Nuclear Medicine) (No. CZZX202204; PI: Y.W.); Clinical Medical Science and Technology, High-end Platform and Transformation Base Construction Project of Soochow University (Characteristic Discipline) Nuclear Medicine (PI: Y.W.); the Outstanding Talent of Changzhou “The 14th Five Year Plan” High-Level Health Talents Training Project (No. 2022-260; PI: Y.W.); the Young Talent Development Plan of Changzhou Health Commission (No. CZQM2023008; PI: W.Y.); and the Changzhou Science and Technology Plan Project (Applied Basic Research Special Program) (No. CJ20244010; PI: W.Y.).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-2025-33/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. This study was approval by the Ethics Committee of the Xuzhou Central Hospital (approval No. XZXY-LJ-20180118-016) and was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The requirement for informed consent was waived due to the retrospective nature of the analysis.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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