The Diagnostic Accuracy of Cardiac Enzymes-Lipid Profile Ratio for Diagnosing Coronary Heart Disease in Chest Pain Patients

Background: Lipid abnormalities increase Coronary Heart Disease (CHD) risk. Our developed indexes 1,2 were reported in scientific Journals. Here, we verified and evaluated the cardiac enzymes-lipid profile ratio's diagnostic value for diagnosing CHD patients.


INTRODUCTION
CHD is the leading cause of premature mortality and death worldwide, poses a severe global health burden [1]. Among CHD, Acute Coronary Syndrome (ACS) is the most common cause, a very complex complaint with pathologies encompassing tissue inflammation, remodeling, thrombosis, and necrosis [2]. ACS includes a wide spectrum of diseases because of acute myocardial ischemia secondary to a diminu-now the gold standard biomarker [6]. Troponin I is very specific for the myocardium because it is found solely in cardiac myocytes, while troponin T is found in several cells [7]. On the other hand, the ACS reasons are multi-factorial, containing some non-modifiable risk factors, like gender and age, several modifiable risk factors, as hypertension, diabetes mellitus, dyslipidemia, smoking, low physical activity, and dietary habits [8]. ACS patients are at very high risk of suffering an adverse cardiovascular incident. Such risk can be diminished by good controlling of associated modifiable risk factors [9]. Lipid abnormality, for example, high concen-tration of triglycerides or Low-Density Lipoprotein (LDL) and low level of HDL, are famous for being highly widespread in ACS patients [10].
Meanwhile, a repetitive estimation of lipid profile indexes is performed only in 50% of patients with ACS [3]. After ACS, lipid abnormality has focused primarily on raising HDL or lowering LDL to diminish recurrent CHD risk among the patients [11]. The correlation between obstructive CHD and serum levels of lipid profile is well known [12] but, the studies that assessed the critical role of lipoprotein concentration as biomarkers of ACS severity are still limited in the literature [13]. Therefore, the purpose of our study was to evaluate the diagnostic value of troponin I-lipid profile ratio and CKMBlipid profile ratio for detecting the severity of coronary atherosclerotic disease in CHD patients.

Patients
A total of 400 chest pain patients aged 30-74 years, included 336 patients with CHD [SA (n= 72), UA (n= 90), and AMI (n= 174)] and 64 patients with NCCP. The diagnosis of AMI patients is according to the study [4,14]. The patients excluded were those who have cardiogenic shock, cardiomyopathy, or chronic kidney failure. The study protocol conforms to the ethical guidelines of the 1975 Declaration of Helsinki. Blood samples were taken from all patients, and the serum was separated. The routine laboratory investigations were determined on an automated biochemistry analyzer (BT1500; Biotecnica instruments S.P.A, Italy). Troponin I was measured using a one-step sandwich enzyme-linked fluorescent immunoassay assay (bioMerieux's Vidas Troponin I Ultra, France). Myeloperoxidase and monocyte chemoattractant protein-1 were measured, according to Omran et al. [15].

Statistical Analysis
All data were analyzed using the Statistical Package for the Social Sciences (SPSS) (SPSS Inc., Chicago, IL, USA) software, version 15.0. The variables were presented as the mean ± standard error (SE), and P-value <0.05 was considered significant. Analysis of variance (ANOVA) and student's t-test was used to compare chest pain groups patients' markers. Receiver-Operating Characteristic (ROC) curves were processed for indexes to evaluate these indexes' diagnostic performances for differentiating between the different groups of chest pain patients. Our previously developed indexes were constructed to discriminate between the different groups of the chest pain patient; the first was; Index 1 = 2.236 (numeric constant) + 0.001 × myeloperoxidase + 0.002 × CK-MB +0.074 × troponin I [16]. and the second was; Index 2 = -0.051 (numeric constant) + 0.001* myeloperoxidase + 0.001* monocyte chemoattractant protein-1 + 0.009* CKMB + 2.5* Troponin I [15]. Table 1 shows the levels of lipid profile and biomarkers within groups of chest pain patients. There were extremely significant differences (P < 0.0001) in cholesterol, HDL, LDL, CK-MB, myeloperoxidase, monocyte chemoattractant protein-1 and Troponin I within the groups. But, there were no significant differences (P > 0.05) of Aspartate Aminotransferase (AST) and triglycerides levels within the groups. Furthermore, there were various significant differences (P < 0.01-P < 0.0001) of CK-MB-lipid profile ratio and Troponin Ilipid profile ratio within the groups.

Comparison between Levels of Routine Investigations between Chest Pain Patient Groups
The value of CK-MB-lipid profile ratio and Troponin Ilipid profile ratio in the different chest pain groups, showed no significant differences between NCCP and SA groups for all indexes values. However, the CK-MB-HDL ratio has the highest significant difference between SA and UA groups and between SA and AMI groups. Both CK-MB-HDL ratio and Troponin I-HDL ratio have the highest significant differences between UA and AMI groups, between NCCP and UA, and between NCCP and AMI groups.

The Diagnostic Value of the Novel Indexes; CK-MB-HDL Ratio and Troponin I-HDL in Comparison with our Previous Developed Indexes for Discriminating the Different Groups of the Chest Pain Patient
ROC curves assessing the diagnostic values of the novel indexes CK-MB-HDL ratio and Troponin I-HDL ratio compared with our previous indexes [15,16], were constructed to discover the best index to discriminate the different groups of chest pain patients ( Table 3).
The AUCs were the greatest of CK-MB-HDL ratio (0.62) and Troponin I-HDL (0.62) for discriminating between NCCP and SA groups. Meanwhile, the greatest CK-MB-HDL ratio (0.97) was for discriminating between NCCP and UA groups. Also, AUC was the greatest of index 2 (0.99) for discriminating between NCCP and AMI groups. Similarly, AUC was the greatest of CK-MB-HDL ratio (0.90) for discriminating between SA and UA groups. The AUC was the greatest of index 2 (0.97) for discriminating between SA and AMI groups. Finally, AUC was the greatest of index 2 (0.78) for discriminating between UA and AMI groups.

DISCUSSION
It is well-established that ACS patients are at extremely high risk for cardiovascular incidents [10]. Also, dyslipidemia is a well-recognized risk factor for CHD progression, and this has been confirmed in many clinical studies [17]. High serum LDL levels are directly correlated with CHD progression, and low HDL levels have been considered one of the potent independent risk factors for the atherosclerotic disease [18]. The mild elevation in triglycerides causes an increased risk of coronary events and CHD development [1]. In the present study, we observed up-regulation of levels of lipid profiles in addition to cardiac enzymes within the different groups of chest pain patients, yielding extremely significant differences in levels of cholesterol, HDL, LDL, CK-MB, and Troponin I within these groups. Our present study represents the first study that assesses the cardiac enzyme-lipid profile ratio for diagnosing CHD patients in the Egyptian population. Our data showed significant differences in CK-MB-lipid profile ratio and Troponin I-lipid profile ratio within the different chest pain patients. Our previous study has discussed the significant upregulation of cardiac enzymes, including Troponin I and CK-MB, within the different chest pain patients [15,16]. Zhong et al. demonstrated that there were significant differences (P< 0.05) in the serum lipid levels among various age groups for both males and female AMI patients [13]. Several early studies have demonstrated that the increase in cholesterol levels in AMI due to the occurrence of an acute phase response [8].
Several studies observed significantly higher LDL levels, VLDL, and cholesterol, and lowers HDL levels in AMI patients than in the control group [8,19]. Dissimilar to our findings, Khan et al. noted that cholesterol, HDL, and LDL were significantly lower in descending order from controls, UA, AMI groups [20]. In our present study, we assessed these markers' diagnostic accuracy for diagnosing ACS patients in chest pain patients and observed that CK-MB-HDL ratio and Troponin I-HDL ratio were the perfect suitable indexes for diagnosing ACS patients with good efficiencies were 77% and 77.5%, respectively. Dyrbus et al. reported that the different ACS patients have significantly higher LDL levels than SA patients [21]. Gitt et al. reported that the mean LDL serum level was low at 108 mg/dl for premature ACS in 10661 patients aged below 18 years [18]. Islam et al. observed that triglycerides' level (mean ± standard deviation) was 168.2 ± 88.0 and 141.2 ± 45.3 in ACS patients and controls, respectively.
Similarly, the levels of HDL were 41.3 ± 5.1 and 34.2 ± 3.4, respectively. Also, triglycerides /HDL ratios were 4.2 ± 1.7 and 4.1 ± 1.3, respectively [1]. Our present study noted that the CK-MB-HDL and Troponin I-HDL ratios were the most efficient indexes than the other indexes for differentiating between NCCP and SA groups.In addition, CK-MB-HDL ratio was the most efficient index for differentiating between UA and (NCCP or SA) groups. Similarly, index 2 was the most efficient index than other indexes for differentiating between AMI and (NCCP, SA, or UA) groups. Stengaard et al. improved a model based on Troponin I and copeptin's combination to improve the efficiency of diagnosing AMI patients at early admission [22]. Also, Yanishi et al. developed a score based on several laboratory investigations for diagnosing AMI patients with AUC was 0.81 [23].
Moreover, O'Donoghue et al. used a multimarker strategy to predict CHD or heart failure [24]. The limit of this study was the sample size, especially the number of NCCP. In the coming research paper, we will consider examining a large number of NCCP patients.

CONCLUSION
The cardiac enzymes-lipid profile ratio may be used as a good index based on the simple routine investigations for diagnosing CHD patients and discriminating between the different chest pain patients.

ETHICS APPROVAL AND CONSENT TO PARTI-CIPATE
The study was approved by the Ethics Committee of Damietta Faculty of Medicine, Al-Azhar University, New Damietta, Egypt (Code #. IRB0012367-1609-002).

HUMAN AND ANIMAL RIGHTS
All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) in compliance with the ethical guidelines of the 1975 Helsinki Declaration as revised in 2013.

CONSENT FOR PUBLICATION
Informed written consent was signed by all patients.

AVAILABILITY OF DATA AND MATERIALS
Authors declare that all generated and analyzed data are included in the article.

FUNDING
None.