In the present study, we investigated the possible relationship between the TG/HDL-C ratio and CSFP in patients undergoing elective coronary angiography. Our study results showed that the mean TG/HDL-C ratio was significantly higher in the CSFP patients than those with normal coronary flow. In addition, the mean TCF was positively and significantly correlated with the TG/HDL-C ratio. The ROC curve analysis showed that the cut-off value of TG/HDL-C ratio was sufficient to discriminate CSFP and non-CSFP individuals with a high sensitivity and specificity.
The CSFP is an angiographic evidence and should be considered as a distinct entity with specific characteristics, pathogenic mechanisms, and specified diagnostic criteria [1, 2]. Although the exact pathophysiology of CSFP is still unclear, endothelial dysfunction and atherosclerosis have been thought to be involved [3, 6]. Abnormally slow flow in the coronary arteries has been proposed to be an indicator of diffuse atherosclerosis related to the endothelial damage before angiographically visible coronary lesion, indicating an early manifestation involving both the microvascular system and epicardial coronary arteries [3, 11]. In a study, Avşar et al. [25]. examined the possible link between CSFP and carotid artery intima-media thickness (CIMT) and found the increased CIMT in CSFP patients. In this study, the CIMT and corrected TCF were also significantly correlated, implying that CSFP might be an early marker of both endothelial dysfunction and subclinical atherosclerosis. In another study investigating the epicardial coronary morphology and intracoronary pressure in CSFP patients using intravascular ultrasonography (IVUS) and flow rate measurements, Cin et al. [3] reported diffuse intimal thickening, widespread calcification through the vessel wall, and non-obstructive atheroma. Consistent with these findings, Pekdemir et al. [11] described longitudinally extended massive calcification along the epicardial arteries as evidenced by IVUS examination as the most common finding in CSFP patients. Furthermore, Camsari et al. [26] found the CIMT to be associated with IVUS indices in CSFP patients. Taken together, these findings support the notion that CSFP is an indicator of microvascular diseases and diffuse, non-obstructive atherosclerotic disease of the epicardial arteries.
Endothelial dysfunction is an early indicator of atherosclerosis [27]. Endothelial-dependent, flow-mediated dilatation (FMD) of the brachial artery has been shown to reduce in CSFP patients, indicating that CSFP may play a role in the etiology of endothelial dysfunction [5]. In addition, plasma homocysteine and endothelin levels increase in CSFP patients, both which have detrimental effects on endothelial function [4, 10]. In the light of existing data, CSFP seems to be a form of early diffuse coronary atherosclerosis, predominantly characterized by microvascular endothelial dysfunction.
It has been well established that lipid abnormalities contribute to the development of atherosclerosis [10]. An extensive number of studies have demonstrated that high TC and LDL-C and low HDL-C are strongly associated with ischemic heart disease, stroke, peripheral vascular disease, and atherosclerosis [12]. Elevated LDL-C levels with high TG and low HDL-C have been shown to increase the risk of CAD than elevated LDL-C levels alone [28, 29]. Review of the literature reveals that different subfractions of the lipid particles are involved in the atherogenesis. Small dense LDL particles are more atherogenic than larger particles [28]. Less dense HDL2 particles are protective, while small dense HDL3 particles are atherogenic [30]. High TG and low HDL-C levels are strongly associated with small dense LDL-C levels [18, 28]. The TG/HDL-C ratio has been shown to be an indirect indicator of small dense LDL particles and a superior predictor of coronary heart disease than conventional lipid parameters [15, 19]. This ratio has been also considered an independent predictor of CVD and all-cause mortality [20, 21]. In their study, Keles et al. [31] evaluated whether the TG/HDL-C ratio differed between patients with chronic inflammatory disease and healthy individuals. The authors concluded that increased TG/HDL-C ratio and low FMD values might indicate endothelial dysfunction and a higher risk of atherosclerosis in these patients. Consistent with previous studies showing a link between low HDL-C and high TG levels and CSFP [32–34], we found high TG levels low HDL-C levels in the CSFP group in our study.
Review of the literature reveals only one retrospective study investigating the relationship between proportional serum lipid parameters and CSFP. In this study including 54 CSFP patients and 39 controls, Kalayci et al. [34] found higher TG, TC/HDL-C, TG/HDL-C, LDL-C/HDL-C, and non-HDL-C levels to be associated with CSFP. In addition, there was a weak, but positive correlation between the TG and TG/HDL-C ratio and mean TFC. In our prospective study, we also found a significant correlation of the high TG, TG/HDL-C ratio, and low HDL-C and CSFP. Furthermore, we showed a weak, but positive correlation between the TG levels and mean TFC and a moderate, positive correlation between the TG/HDL-C ratio and mean TFC. These findings suggest that high TG/HDL-C ratio is an independent predictor of CSFP.
In the literature, several studies have shown the link between LDL-C levels and CSFP [35–37]. In a study investigating the clinical and angiographic properties of CSFP, Yilmaz et al. [35] found LDL-C levels to be correlated with CSFP. On the other hand, no significant correlation between these two variables was reported in some other studies [36, 37]. Similarly, in our study, the LDL-C levels were comparable between the two groups. Based on these findings, it can be speculated that TG and HDL-C levels are more valuable indicators of CSFP than LDL-C alone and TG/HDL-C ratio shows a higher correlation with the mean TFC, than TG and HDL-C levels.
Nonetheless, there are some limitations to this study. First, it has a single-center design with relatively small sample size. Second, we were unable to evaluate the atherosclerotic alterations in the coronary arteries via sophisticated imaging modalities such as IVUS or optic coherence tomography, precluding the evaluation of coexisting non-obstructive CAD in isolated CSFP patients. Of note, IVUS is not recommended in the routine daily practice for the evaluation of CSFP patients and the diagnosis is usually confirmed based on visible angiographic findings. Third, inflammatory biomarkers such as the high-sensitivity C-reactive protein, interleukin-6, and tumor necrosis factor-alpha were unable to be analyzed. Further large-scale, prospective, randomized-controlled studies are needed to confirm these findings.