In our study, 315 patients were identified with CSF out of 8780 patients who underwent angiography, resulting in an incidence rate of 3.59%, consistent with the previously reported range of 1–7% [1]. Following a median follow-up period of 25 months, CSF patients meeting the inclusion criteria exhibited a high incidence rate (18.9%) of MACE, with rehospitalization due to unstable angina accounting for the majority (15.4%). Our analysis suggests that LpPLA2 may independently predict the occurrence of MACE during follow-up in CSF patients. The risk of MACE incidence remained relatively stable until approximately 247.7 ng/ml of predicted LpPLA2 level and then began to increase thereafter, displaying an overall linear trend in the restricted cubic spline analysis. In addition to LpPLA2, multiple Cox regression analyses indicated that mTFC, LDL-C, and diabetes were also associated with the occurrence of MACE in CSF patients.
Common characteristics of CSF were usually identified by comparing clinical data between patients with CSF and those with normal coronary artery flow though several observational studies. Most studies have reported a higher prevalence of CSF in men, smokers, and patients with high CV risks [2]. A cross-sectional study involving 124 patients revealed that CSF patients were predominantly male, had a history of smoking and hypertension, as well as elevated laboratory indicators such as lipids and mean platelet volume. Furthermore, these subjects displayed subtle declines in diastolic function alongside an overall reduction in longitudinal strain during cardiac ultrasound assessments [18]. Notably highlighted by Yilmaz et al. [19], within the context of suspected atherosclerotic heart disease necessitating coronary angiography procedures, those affected by CSF exhibited an increased likelihood of presenting metabolic syndrome hallmarked by hyperglycemia, hyperlipidemia, and overweight when compared to counterparts demonstrating normal coronary blood flow velocities.
Cohort studies have shown that around two-thirds of patients with CSF present with acute coronary syndrome [2], typically characterized by recurrent chest pain, mainly at rest, and accompanied by electrocardiogram changes. While most CSF patients have a favorable prognosis in terms of major cardiovascular events, the persistent episodes of chest pain can significantly impact their quality of life. Additionally, several cases have reported that clinical manifestations of CSF also include malignant arrhythmias and sudden death [5, 20]. Further studies have identified CSF as a risk predictor for myocardial ischemia, myocardial infarction, arrhythmia, and sudden cardiac death [21–23].
Although CSF has been found to be associated with vascular endothelial dysfunction, microvascular disease, insulin resistance, oxidative stress, and adipocytokines, the exact mechanisms remain unclear [1]. Increasing evidence suggests that endothelial cells play a crucial role in the regulation of vascular tension, platelet activity, white blood cell adhesion, vascular smooth muscle hyperplasia, and are closely associated with the development of atherosclerosis. A reduction in endothelium-dependent flow-mediated dilation of the brachial artery has been observed in patients with CSF, suggesting a link between endothelial dysfunction and the etiology of CSF [24]. Kanar et al. [25] utilized optical coherence tomography to identify thinner nerve fiber layers in the subfoveal choroid and perioptic disc in patients with CSF, indicating extensive endothelial dysfunction and increased microvascular resistance. The coronary artery system contains not only epicardial large vessels but also a significant number of microvessels smaller than 400 µm which play a role in regulating myocardial blood flow. Microvascular dysfunction has been identified as a key factor in the pathogenesis of CSF. Mangieri et al. [26] provided direct evidence of microvascular disease in endocardial muscle biopsy samples from CSF patients including thickening of the microvascular walls, reduction in lumen size, mitochondrial abnormalities, and decreased glycogen content. Pekdemir et al. [27] utilized intravascular ultrasound (IVUS) technology and flow rate measurements to demonstrate diffuse intimal thickening, extensive calcification of coronary artery walls, and nonobstructive atherosclerosis changes in patients with CSF, suggesting an early involvement of atherosclerosis in the development of CSF.
Inflammation plays a crucial role in the human immune response, serving dual functions in defense mechanisms. Initially, it protects physiological homeostasis against infection and tissue damage but should be promptly resolved once infectious agents are eliminated or initial tissue injuries are repaired. Failure to resolve inflammation can lead to tissue dysfunction and other adverse consequences [28]. Studies have confirmed that inflammation is a risk factor for various cardiovascular diseases [29], and inflammatory responses have also been observed in CSF [1, 7]. Plasma soluble adhesion molecules and inflammatory markers were found to be significantly elevated in CSF patients, including C-reactive protein [30], interleukin-6 [30], platelet to lymphocyte ratio [31], neutrophil to lymphocyte ratio [32], matrix metallopro-teinase-9 and soluble CD40 ligand [33], etc.
LpPLA2 has been proposed as a novel independent inflammatory marker and has been associated with various vascular diseases in epidemiological studies [12, 34]. Numerous studies have established LpPLA2 activity as an independent predictor of CHD outcomes in the general population [14, 35]. Recent research has shown that elevated plasma LpPLA2 levels are also linked to the onset and severity of CSF [8, 9]. Our study suggests that LpPLA2 can function as an independent prognostic indicator for poor outcomes in CSF patients. LpPLA2, originally known as platelet-activating factor acetylhydrolase due to its hydrolytic activity on platelet-activating factor [36], is primarily secreted by macrophages and circulates in the bloodstream bound to LDL and HDL [37]. LpPLA2 has the ability to hydrolyze and oxidize LDL into two biologically active products, oxidized nonesterified fatty acids and lysophosphatidylcholine, which act as proinflammatory substances derived from LpPLA2, inducing immune responses and oxidative stress [38]. These inflammatory effects may contribute to the development of atherosclerotic plaques [14]. In our study, when LpPLA2 was divided into quartiles, the results of multi-model Cox regression indicated that the highest level of LpPLA2 was associated with a higher incidence of MACE compared to the lowest level in CSF patients. When considered as a continuous variable, although the RCS curve suggests a overall linear relationship between LpPLA2 and MACE rate, the linear relationship becomes more pronounced when plasma levels of LpPLA2 exceed 247.7 ng/ml. The mechanisms underlying the association between LpPLA2 and poor prognosis in CSF are not fully understood. The most plausible hypothesis is that unresolved inflammatory responses mediated by LpPLA2 may lead to vascular endothelial dysfunction, contributing to the onset and progression of CSF.
In addition to LpPLA2, multiple Cox regression analyses have shown that mTFC, LDL-C, and diabetes are associated with the occurrence of MACE in CSF patients. HDL-C also demonstrated a statistically significant association when analyzed using data after multiple imputation. Previous studies have found that dyslipidemia [6, 17](2,3) and mTFC [17] are associated with the occurrence of MACE in CSF patients, which is consistent with our findings. Isik T et al. [39] identified diabetes as a potential predictor of CSF. Jiang Yu et al. [4] demonstrated that diabetes was an independent prognostic predictor of MACE in patients with normal coronary artery during a mean 3.5 years of follow-up. Our study suggests that diabetes is linked to poor prognosis in CSF patients. Previous studies have indicated that hypertension independently predicts MACE in patients with CSF[6, 17], leading to a certain number of cardiovascular deaths over a relatively long follow-up period. However, our study suggests that there is no significant correlation between hypertension and the occurrence of MACE in patients with CSF, this may be due to insufficient follow-up time and a limited number of cases of cardiovascular death.
Limitations of this study: Despite suggesting that LpPLA2 may have predictive value for clinical outcomes in patients with CSF, there are several limitations that should be acknowledged. Firstly, this was a single-center retrospective study primarily relying on telephone follow-up, which could result in incomplete information, recall bias, and the omission of crucial details regarding clinical outcomes and events. Secondly, the study had a small sample size and a short follow-up period due to our hospital only commencing clinical testing of LpPLA2 in 2019, leading to a low incidence of clinical events such as cardiovascular death that could impact the statistical power of the results and may restrict the generalizability and extensibility of our findings. Lastly, as coronary artery stenosis is often not apparent in patients with CSF, only a few patients underwent repeated coronary angiography tests resulting in an inadequate assessment of coronary artery stenosis and mTFC during CSF follow-up
In conclusion, elevated levels of LpPLA may function as an independent predictor of risk for the occurrence of MACE in patients with CSF, potentially offering a novel therapeutic target for CSF treatment. In addition to LpPLA2, this study suggests that dyslipidemia, diabetes, and mTFC may also be associated with the prognosis of CSF. However, further investigation is needed to elucidate the exact pathophysiological mechanism of LpPLA2 in CSF, and prospective studies involving multiple centers and large sample sizes are required to validate our findings.