The diagnostic value of serum C-reactive protein/high-density lipoprotein in microvascular angina

doi:10.21203/rs.3.rs-4973475/v1

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The diagnostic value of serum C-reactive protein/high-density lipoprotein in microvascular angina

https://doi.org/10.21203/rs.3.rs-4973475/v1

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Objective This study aimed to explore the relation ship between the serum ratio of C-reactive protein (CRP) to high density lip opro tein cholesterol (HDL-C) with microvascular angina(MVA).It also aimed to evaluate the predictive value of serum CRP /HDL-C in relation to MVA.

Methods The observation group consisted of 70 patients diagnosed with MVA ,while the control group included 68 patients with normal or minimal (< 50%) stenosis on coronary angiography, negative ECG exercise test and normal coronary blood flow randomly selected using a random number table method.Serum CRP,HCY,HDL-C and other relevant parameters were measured in both groups, with CRP /HDL-C calculated.Logistic regression analysis, and receiver operating characteristic (ROC) curve analysis were performed to identify independent risk factors for microvascular angina.

Results CRP/HDL-C levels were significantly elevated in MVA patients with statistical significance (P < 0.001).The parameterswas identified as independent risk factor for predicting MVA occurrence.The results of ROC analysis indicated that CRP /HDL-C showed high predictive value for diagnosing MVA .The CRP/HDL-C had a higher area under the curve (AUC) for diagnosing microvascular angina compared to individual parameters ,with a statisticallysignificantdifference(P<0.05).

Conclusions Elevated CRP /HDL-C levels can serve as positive predictors for diagnosing MVA.The parameters can enhance diagnostic accuracy and aid in the early identification of MVA patients..

C-reactive protein

high density liptein cholesterol

microvascular angina pectoris

Microvascular angina pectoris (microvascular angina, MVA) is a clinical syndrome^[1], Which is characterized by structural and functional abnormalities of anterior coronary arterioles, arterioles and capillaries. It is precisely because of these abnormalities in microvascular structure and function that MVA patients are at a significantly increased risk of major cardiovascular adverse events such as heart failure and acute coronary syndrome, so timely identification and intervention of MVA patients is crucial. At present, common methods for MVA diagnosis include invasive methods such as coronary angiography, intra-coronary Doppler blood flow guide wire, noninvasive methods such as cardiac magnetic resonance imaging, positron emission computed tomography imaging and single-photon emission computed tomography imaging^[2], But these inspection techniques are difficult to popularize, mainly because of their high cost and high technical requirements. Therefore, it is urgent to develop a simple, non-invasive and reliable serological diagnostic method. According to studies, the pathogenesis of MVA is closely related to the inflammatory response and dysfunction of coronary microvessels^[3]。C-reactive protein (C-reactive protein, CRP) is an acute time-phase inflammatory marker, and its level is positively correlated with the inflammatory status of the body, which can reflect the diagnosis and prognosis of coronary heart disease (coronary heart disease, CHD) to some extent^[4]. High-density lipoprotein cholesterol (HDL-C) not only participates in cholesterol reverse, but also slows the progression of atherosclerosis through antioxidant, anti-inflammatory and improvement of endothelial cell function^[5]. Studies have shown that CRP and HDL-C are closely related to the occurrence and development of cardiovascular diseases. Multiple studies have established risk prediction models for cardiovascular disease and found inflammation and cholesterol index as high risk factors for occurrence and development. Due to the inflammation and the lipid metabolism^[6]correlation, the use of inflammatory-lipid indicators may predict the prognosis of cardiovascular disease, while a single inflammatory index or a single lipid index is susceptible to various confounders and is not independently and accurately predicted. Therefore, CRP/HDL-C is able to reflect the vascular damage caused by abnormal lipid metabolism, and both markers are inexpensive and simple to use in clinical practice. There are few reported studies on the association of CRP/HDL-C with MVA. Therefore, this study intends to evaluate the value of CRP/HDL-C in the diagnosis of MVA by measuring the CRP and HDL-C levels in the serum of MVA patients, in order to provide a reference for the early diagnosis of MVA and patients, which is reported below.

2.1 General information

In this study, 70 patients diagnosed with MVA in the Department of Cardiovascular Medicine of the Second Affiliated Hospital of Dalian Medical University between September 2022 and December 2/2023 were selected as the observation group, Including 33 cases, female, and 37 male, The mean age was 58.78 ± 9.27 years old; At the same time, 68 patients with "chest pain" were selected, Patients with normal coronary angiography or stenosis < 50% and negative exercise plate test results were used as the control group, Including both 33 females and 35 males, The mean age was 60.62 ± 10.11 years; The study protocol was approved by the Ethics Committee of the Second Affiliated Hospital of Dalian Medical University.

MVA diagnostic criteria: MVA diagnostic criteria established by the 2018 International Coronary Momotor Disorder Study Group (Coronary Vasomotion Disorders International Study Group, COVADIS)^[7]: ① Myocardial ischemia symptoms such as angina pectoris, but no specific ischemia on ECG; ② coronary angiography showed normal coronary or stenosis < 50%; ③ positive exercise test or exercise plate test (ST level shift 0.1 mV during and after exercise for at least 2 minutes; typical angina symptoms during exercise; ST back elevation 0.1 mV, for more than 1 minute; blood pressure decreased by 10mmHg during exercise)^[8]; ④ Slow flow phenomenon in coronary arteries: at least one coronary artery corrected TIMI (Thrombolysis In Myocardial Infarction) flow frame number > 27 frames^[9]。

Inclusion criteria were: (1) patients with "chest pain" aged between 37 and 85 years; and (2) patients who were conscious and able to communicate normally.(3) Compliance with the MVA diagnosis.

Exclusion criteria:①Previous acute myocardial infarction, revascularization such as coronary stent implantation and coronary bypass grafting; ② hypertensive heart disease, rheumatic heart disease, heart failure and other organic heart disease; ③ severe liver and kidney insufficiency; ④ non-cardiac chest pain caused by intercostal neuralgia, pleural disease; ⑤ uncontrolled or abnormal hemodynamics; ⑥ with active inflammation; ⑦ malignant tumor; ⑧ recent use of amiodarone, digoxin, propafenone and other drugs that affect test results.

2.2 Methods

2.2.1 Collect data and collect detailed clinical data of patients, including gender, age, physical constitution index (Body Mass Index BMI), history of diabetes, history of hypertension, smoking history, etc. Early morning fasting venous blood was collected for liver function, including albumin (ALB), aspartate aminotransferase (AST), alanine aminotransferase (ALT), etc. Automatic biochemical instrument (Beckman) for high density lipoprotein cholesterol (HDL-C), C reactive protein (CRP), blood creatinine (sCr), and CRP/HDL-C was calculated. Left ventricular ejection fraction (Left ventricular ejection fraction LVEF) was measured in all patients using color Doppler ultrasound instruments. Blood collection was completed before the use of therapeutic myocardial ischemic drugs, such as antiplatelet aggregation drugs, nitrates, β -blockers, etc.

2.2.2 According to the results of coronary angiography, patients with no obvious abnormality or stenosis < 50% and exercise plate test or positive 12 leads (0.1 mv) were included in the observation group (n = 70), vascular stenosis was also less than 50% or no obvious abnormality, and negative exercise plate test or Holter test were included in the control group (n = 68).

2.3 Statistical Processing The data of this study were IBM SPSS 26.0 and Graphpad prism 9.5 and analyzed by statistical software.‾first, Use the Shapiro-Wilk test to determine whether the measurement data follows the normal distribution; Using x ± s representation for measurement data meeting a normal distribution, And perform the group t-test; For non-normally distributed measurements using M (Q1, Q3) representation, And performed a Manne-Whitney U test; The count data is expressed as [cases (%)], And perform a chi-square test; Multivariate Logistic regression method was also used for multivariate screening; at the same time, Mapping the Subject-subject operating characteristics (receiver operating characteristic, ROC) curve, Calculate the area under the curve (area under the curve, AUC) to assess the predictive value of CRP / HDL for MVA, And to determine the optimal cutoff value. The results were statistically significant when P < 0.05.

3.1 General Data The differences between the observation and control groups in age, sex, BMI, history of hypertension, smoking and diabetes (P > 0.05). See Table 1.

3.2 Comparison of laboratory data, the differences in AST, ALT, ALB, sCr, LDL-C, HDL-C, and LVEF were not significant (P > 0.05); however, the differences in CRP and CHR were significant (P < 0.001), in which the observation group had higher CRP and CHR than the control group. See Table 1.

3.3 Comparison of serum CHR levels between the observation and control groups, the serum CHR in the observation group (13.59 ± 5.36) and the control group (11.15 ± 2.83), and these differences were statistically significant (P < 0.001). See Table 1, Fig. 1.

Table 1

Comparison of clinical data and laboratory indicators between the two groups
Clinical indicators	Observation group (n = 70)	Control group (n = 68)	t/z/x2	P price
Age (years, x ± s)	57.66 ± 10.02	60.62 ± 10.11	-1.727	0.086
Gender [example (%)]	37(52.9)	35(51.5)	0.027	0.871
Smoking [example (%)]	34(48.6)	24(35.3)	2.496	0.114
Hypertension [Case (%)]	37(52.9)	39(57.4)	0.282	0.596
Diabetes mellitus [for example, (%)]	17(24.3)	21(30.9)	0.752	0.386
BMI(x ± s)	25.16 ± 2.91	25.25 ± 2.96	-0.714	0.862
AST[U/L,M(Q1, Q3)]	22.56(16,28)	22.74(18,26)	-0.781	0.435
ALT[U/L,M(Q1, Q3)]	23.89(15,26.25)	23.03(16,25.75)	-0.200	0.841
Scr[mg/dl,M(Q1, Q3)]	67.36(55.32,77.97)	66.92(51.94,83.31)	-0.635	0.526
LVEF[%,M(Q1, Q3)]	60(58,62)	60(61,59)	-1.308	0.191
LDL-C[mmol/L, M(Q1, Q3)]	2.94(2.28,3.42)	2.75(2.24,3.23)	-0.488	0.626
HDL-C[mmol/L, M(Q1, Q3)]	1.31(1.04,1.60)	1.22(1.11,1.32)	-0.914	0.361
ALB(g/l,x ± s)	41.74 ± 3.13	42.18 ± 3.42	-0.765	0.446
CRP(mg/dl,x ± s)	5.13 ± 1.69	3.57 ± 0.87	6.733	< 0.001
CHR (x ± s)	4.17 ± 1.75	2.96 ± 0.85	-5.169	< 0.001
BMI: Body mass index; AST: aspartate aminotransferase; ALT: alanine aminotransferase; Scr: serum creatinine; LVEF: left ventricular ejection fraction; LDL-C; LDL-C: high-density lipoprotein cholesterol; ALB: albumin; CRP: C-reactive protein; CHR: C-reactive protein / high-density lipoprotein cholesterol

3.4 Logistic regression analysis of MVA risk factors These statistically significant variables such as CRP and CHR were taken as independent variables, and whether MVA was taken as the dependent variable (assigned 0 = control group, 1 = MVA group, observation group) was included in the multivariate Logistic regression analysis. The results showed that CRP and CHR were independent risk factors for MVA, and the increased level of serum CHR increased the risk of MVA. See Table 2.

Table 2

Multivariate Logistic regression analysis of MVA risk factors
variable	β	OR price	95%CI	P price
CRP	0.056	1.057	0.640 ~ 1.745	< 0.001
CHR	0.720	2.055	1.481 ~ 2.851	< 0.001
CRP: C-reactive protein; CHR: C-reactive protein / HDL cholesterol

3.5 Prediction analysis of serum CHR on MVA as a clinical indicator of predicting MVA, ROC, curve analysis showed that the area under the curve (AUC) of serum CHR was 0.724, the optimal cut-off value of 13.36, sensitivity of 45.7% and specificity of 85.3%. These results indicate that the serum CHR is able to more accurately predict the occurrence of MVA. See Table 3, Fig. 2.

Table 3

Serum CAR, HCY / HDL-C and the combination predicted MVA Results of the ROC curve analysis
variable	The Cut Off value	sensibility (%)	specificity (%)	AUC	95%CI
CRP	5.05	52.9	98.5	0.771	0.693 ~ 0.849
CHR	13.36	65.7	85.3	0.724	0.638 ~ 0.810
CRP: C-reactive protein; CHR: C-reactive protein / HDL cholesterol

MVA is common in patients with cardiovascular risk factors and is associated with an elevated risk of adverse cardiovascular events, which is characterized by high morbidity, a low diagnostic rate and a low poor prognosis^[10–12]。Relevant studies have shown that^[13], In the myocardial ischemia population, the prevalence of MVA is about 40% – 64%, but only about 6.3% of the population has received timely diagnosis and treatment. While MVA is a special form of coronary heart disease, its diagnostic criteria^[14]Is: symptoms of myocardial ischemia, reduced coronary flow reserve or microvasospasm, and recordable myocardial ischemia. In order to confirm MVA, patients need multiple coronary angiography, which is a heavy medical burden for the patient. The National Heart, Lung, and Blood Institute Research Study^[2]It is considered that MVA patients have a poor prognosis, and that MVA is also a reliable and independent predictor of adverse cardiovascular events. Therefore, early screening and intervention for MVA appear particularly important. This study confirmed that CRP / HDL-C is an independent predictor of MVA diagnosis and can provide more possibilities for early diagnosis and early intervention treatment. CRP/HDL-C in the evaluation of coronary lesions will receive more attention.

research finding^[15], MVA is the result of multifactorial, multiple mechanisms, including vascular endothelial dysfunction, inflammatory response, abnormal hemodynamics, and cardiac autonomic dysfunction are the causes of abnormal coronary microcirculation. Recent studies have shown that the^[16]The impairment of vascular endothelial function is one of the main causes of coronary microcirculation diseases, in which inflammatory response plays a key role. Some inflammatory markers such as CRP can promote the activation and abnormal function of endothelial cells, and then lead to the occurrence of abnormal microcirculation function. Research proved that^[17–18]C-reactive protein (CRP) has significant negative effects on various physiological processes, including activation of the complement system, damage to endothelial cells, inhibition of fibrinolysis, and participation in the uptake of LDL-C by macrophages, prompting conversion into foam cells. In addition, it adversely affects the vasomotor function of blood vessels and inducinflammatory reactions in vascular endothelial cells, which plays a key role in the development and development of coronary heart disease.research finding^[19–20]CRP is a biomarker of inflammation, and elevated CRP is more likely associated with the occurrence of CAD. Binding of the CRP and the lipid markers^[21–22], Such as CRP and triglyceride-glucose binding, CRP and residual lipoprotein cholesterol index binding, have been used clinically as prognostic predictors of CHD.

The interplay between lipid metabolism and inflammation is very important in the development and progression of cardiovascular diseases.research finding^[23]The main effects of HDL-C in cardiovascular diseases are manifested in anti-inflammatory, anti-oxidation, vasodilation, anti-thrombosis, etc. HDL can mediate the clearance of lipid macrophage cholesterol by reversing cholesterol transport, and participate in the intermediate process of inhibiting atherosclerosis. Other studies have found that^[24]The anti-inflammatory effect of HDL prevents oxidative modification of LDL, and HDL also reduces CRP, induced the expression of adhesion molecules on the surface of endothelial cells, thus conferring anti-inflammatory capability.research finding[25–26]HDL prevents T lymphocytes and monocytes from adhering to the vascular endothelium and migrate to atherosclerotic areas.by contraries^[27], Inflammation leads to the reduction of HDL and structural changes, and the related proteins and enzymes involved in HDL metabolism are significantly altered. There is a study[28]Believe that a negative interaction between abnormal blood lipid levels and CRP may reduce the cardiovascular risk. From a large cohort study showed that[29], High CRP /HDL-C ratio is an important risk factor for cardiovascular disease and cardiac problems, and early intervention in patients with elevated CRP/HDL-C ratio may further reduce the incidence of cardiovascular disease.

This study found that the serum level of CRP /HDL-C (4.17 ± 1.7 ± 1.75 vs 2.172.96 ± 0.85, P < 0.001) was significantly higher in patients in the control group, with a statistically significant difference. Multivariate Logistic regression analysis showed that the serum CRP / HDL-C (OR = 2.055,95%CI: 1.481–2.851, P < 0.001) level was an independent risk factor for MVA. In addition, the ROC curve and AUC analysis showed that serum CRP / HDL-C could effectively predict MVA and provide good positive predictive value (AUC = 0.724), with sensitivity of 65.7% and specificity of 85.3%.

In conclusion, CRP/HDL-C may have a key role in the occurrence and development of MVA.yet, There are still some limitations to this study: First, This study is a single-center case-control study, All study subjects were from patients attending the same hospital during the same period, There may be a selection bias; next, The small sample size, Limited geographical scope, Limiting the persuasion of the study conclusions, Therefore, further multi-center and large-sample studies are needed to provide more sufficient evidence; besides, The data for CRP and HDL-C were obtained from single blood sample tests before coronary angiography, Dynamic detection has not been continuously, Whether the CRP/HDL-C will change after coronary angiography deserves further attention and investigation.

Overall, CRP/ HDL-C reflects the inflammatory reaction and abnormal lipid metabolism, respectively, enabling better prediction of microvascular angina, which may be a potential, easily measured and affordable parameter for the diagnosis of MVA.

Author Contribution

wxz wrote the main manuscript text and prepared figures 1-3. lw ,yxc and xfz reviewed the manuscript

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The diagnostic value of serum C-reactive protein/high-density lipoprotein in microvascular angina

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Abstract

Figures

1. Introduction

2. Data and methods

2.1 General information

2.2 Methods

3 Results

4. Discussion

5. Conclusion

Declarations

Author Contribution

References

Additional Declarations

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