Academic Editor: Vincent Figueredo
Background: In this study, we investigated whether the ratio of
non-high-density lipoprotein cholesterol to high-density lipoprotein cholesterol
(NHHR) is associated with the development of acute ST-segment elevation
myocardial infarction (STEMI). Methods: 889 STEMI patients who had not
previously received lipid-lowering therapy were selected as the test group and
120 patients with less than 50% coronary stenosis were selected as the control
group. All patients completed the related blood tests the morning after
admission, and Gensini scores were based on coronary angiography results. The
differences were compared using a t-test, rank sum test, chi-square test and
logistic regression analysis. Linear regression analysis was used to study the
correlation between variables. Receiver Operating Characteristic (ROC) curves were
used to validate the predictive value of NHHR for STEMI. Results: NHHR
was shown to be a significant independent risk factor for STEMI according to
binary logistic regression analysis (OR = 0.163, 95% CI: 0.065–0.411, p
Cardiovascular diseases (CVD) account for one-third of all deaths in the world, and two-thirds of them occur in developing countries. In recent years, CVD has accounted for more than 40% of all deaths among Chinese residents, about 45% in urban areas, and about 42% in rural areas, which is a significantly higher percentage than that of other diseases such as cancer. It has become the leading cause of death among Chinese residents and is still showing an upward trend [1]. Previous studies have recognized that low-density lipoprotein cholesterol (LDL-C) is significantly correlated with atherosclerosis, so LDL-C has always been the primary target of lipid-lowering therapy. However, although the LDL-C level of patients has been effectively controlled, the prevalence of atherosclerotic cardiovascular disease (ASCVD) is still high. Subsequent studies have begun to focus on non-high-density lipoprotein cholesterol (non-HDL-C). Some studies have found that compared with LDL-C, non-HDL-C has a stronger correlation with cardiovascular events and atherosclerosis and is a better predictor and prevention indicator [2, 3]. In 2016, the expert consensus committee of the American College of Cardiology (ACC) proposed that the non-HDL-C index can be used the same as the LDL-C index in patients with diabetes and elevated triglycerides. In 2017, the ACC expert consensus committee issued the latest guidelines on the role of non-statins in the prevention of coronary artery disease [4]. This is an updated version of the ACC guidelines from 2016, which considers non-HDL-C to be a target for all risk groups. In recent years, the ratio of non-high-density lipoprotein cholesterol to high-density lipoprotein cholesterol (NHHR) has attracted increasing attention, and many studies have proposed that it can reflect the relationship between mixed blood lipids, better reflect the balance between atherosclerosis and anti-atherosclerosis, and better reflect dyslipidemia than the traditional blood lipid spectrum. NHHR has been found to be significantly associated with a variety of lipid abnormality-related diseases such as atherosclerotic plaques [5], metabolic syndrome, insulin resistance [6, 7], nonalcoholic fatty liver [8], and chronic kidney disease [9]. Numerous studies have shown that NHHR can better assess the severity of coronary artery disease and cardiovascular adverse events than LDL-C, HDL-C, non-HDL-C, LDL-C/HDL-C, and other single indicators [10, 11]. This study focuses on STEMI, the most severe form of coronary heart disease, and provides additional guidance for lipids management in STEMI patients.
1226 STEMI patients with chest pain who had been hospitalized for coronary angiography were selected. All patients with a history of coronary heart disease, malignant tumor, severe infection, severe liver and kidney dysfunction, or of taking lipid-lowering drugs were excluded. 889 remaining STEMI patients served as the test group and 120 patients with less than 50% coronary stenosis were selected as the control group (Fig. 1). The diagnostic criteria refer to the “Global Definition of the Fourth Myocardial Infarction” promulgated in 2018 [12]. The sex, age, history of diabetes, history of hypertension, smoking habits, height, and weight of each patient was recorded. All of the selected patients underwent blood tests, electrocardiograms, and coronary angiography upon admission. A full lipid profile blood test was performed the next morning. Two doctors detailed the location and stenosis of each patient’s coronary artery disease. The degree of coronary artery disease was measured using the Gensini score. Whenever there was any disagreement, a third physician would join the discussion in order to help come to a decision. Non-HDL-C equals total cholesterol (TC) minus HDL-C, and NHHR equals non-HDL-C divided by HDL-C.
Screening of patients in this study.
All data were analyzed and processed using IBM SPSS Statistics version 26 (IBM
SPSS Inc., Chicago, IL, USA). Non-normal distribution data between the two groups
were expressed by rank sum test, results by M (Q1, Q3), counting data by
Chi-square test, and results by
The patients were divided into a test group (STEMI group) and a control group (less than 50% coronary stenosis) based on coronary angiography results. There were 889 patients in the test group, of which 676 were male and 213 were female, and there were 120 patients in the control group. Table 1 summarizes the clinical data of all patients.
Variables | Test group (n = 889) | Control group (n = 120) | p | |
---|---|---|---|---|
age | 62.71 (53.00, 72.00) | 58.98 (50.00, 69.00) | –2.745 | 0.006 |
Sex (%) | Male 676 (76%) | Male 80 (67%) | 4.940 | 0.026 |
Female 213 (24%) | Female 40 (33%) | |||
BMI (Kg/m |
23.72 (22.00, 26.00) | 22.52 (20.00, 24.00) | –4.163 | 0.000 |
Hypertension (%) | 512 (58%) | 55 (46%) | 5.934 | 0.015 |
Diabetes (%) | 367 (43%) | 33 (28%) | 8.438 | 0.004 |
Smoking (%) | 516 (58%) | 43 (36%) | 21.086 | 0.000 |
ANC ( |
6.20 (4.59, 7.00) | 4.00 (3.26, 4.50) | –11.587 | 0.000 |
TLC ( |
1.88 (1.48, 2.26) | 2.12 (1.53, 2.64) | –3.969 | 0.000 |
MONOC ( |
0.60 (0.42, 0.73) | 0.43 (0.31, 0.50) | –7.899 | 0.000 |
RBC ( |
4.38 (3.96, 4.84) | 4.38 (3.93, 4.78) | –0.026 | 0.979 |
RDW | 13.21 (12.50, 13.50) | 13.18 (12.50, 13.50) | –0.196 | 0.845 |
TC (mmol/L) | 4.42 (3.73, 4.98) | 3.69 (3.09, 4.37) | –7.621 | 0.000 |
TG (mmol/L) | 1.66 (1.04, 1.89) | 1.39 (0.92, 1.66) | –2.897 | 0.004 |
HDL-C (mmol/L) | 0.93 (0.78, 1.04) | 1.12 (0.92, 1.23) | –7.262 | 0.000 |
LDL-C (mmol/L) | 2.66 (20.7, 3.18) | 1.86 (1.49, 2.30) | –10.342 | 0.000 |
VLDL-C (mmol/L) | 0.70 (0.44, 0.85) | 0.61 (0.38, 0.75) | –2.843 | 0.017 |
Non-HDL-C (mmol/L) | 3.49 (2.81, 4.03) | 2.56 (2.00, 3.14) | –9.803 | 0.000 |
LDL-C/HDL-C | 2.99 (2.27, 3.51) | 1.73 (1.29, 2.14) | –8.68 | 0.000 |
NHHR | 3.97 (2.96, 4.69) | 2.43 (1.69, 3.09) | –11.328 | 0.000 |
Gensini score | 71.32 (50.00, 88.00) | 19.46 (16.00, 30.00) | –17.629 | 0.000 |
Remarks: ANC, Absolute Neutrophil Count; TLC, Total Lymphocyte Count; MONOC, Monocyte Count; RBC, Red Blood Cell Count; RDW, Red blood cell distribution width; TG, triglyceride; BMI, Body Mass Index. |
It is evident that there are significant differences in blood lipid indicators between the two groups.
In the test group, we found that TC, TG, HDL-C, LDL-C, non-HDL-C, LDL-C/HDL-C and NHHR were significantly correlated with Gensini score (Table 2).
Variables | r | p |
---|---|---|
TC (mmol/L) | 0.318 | 0.000 |
TG (mmol/L) | 0.068 | 0.042 |
HDL-C (mmol/L) | –0.171 | 0.000 |
LDL-C (mmol/L) | 0.403 | 0.000 |
VLDL-C (mmol/L) | 0.004 | 0.902 |
Non-HDL-C (mmol/L) | 0.361 | 0.000 |
LDL-C/HDL-C | 0.475 | 0.000 |
NHHR | 0.394 | 0.000 |
Age, sex, hypertension, diabetes, and smoking are all important risk factors for
coronary heart disease. We used the Gensini scores of the test group as a factor
and used all of the relevant indicators, as well as age, sex, smoking,
hypertension, and diabetes as independent variables for a step-by-step
multivariate linear regression analysis. Although LDL-C/HDL-C was found to have a
stronger correlation with Gensini score (Table 3b Model 2), NHHR was also shown to
have a significant correlation with Gensini score (Table 3a Model 1) (R
Variables | SD | t | 95% CI | p | |
---|---|---|---|---|---|
Age | 0.058 | 0.075 | 2.554 | 0.035, 0.264 | 0.011 |
Hypertension | 1.546 | 0.089 | 2.999 | 1.602, 7.669 | 0.003 |
Diabetes | 1.549 | 0.067 | 2.284 | 0.498, 6.576 | 0.023 |
LDL-C (mmol/L) | 1.425 | 0.412 | 9.071 | 10.127, 15.719 | 0.000 |
Non-HDL-C (mmol/L) | 1.713 | –0.285 | –4.404 | –10.906, –4.182 | 0.000 |
NHHR | 0.845 | 0.431 | 8.700 | 5.694, 9.012 | 0.000 |
Model 1: Research factors included (age, sex, hypertension, diabetes, smoking, TC, TG, HDL-C, LDL-C, non-HLD-C, NHHR). |
Variables | SD | t | 95% CI | p | |
---|---|---|---|---|---|
Age | 0.059 | 0.076 | 2.574 | 0.036, 0.266 | 0.010 |
Hypertension | 1.547 | 0.090 | 3.025 | 1.643, 7.717 | 0.003 |
Diabetes | 1.539 | 0.069 | 2.338 | 0.578, 6.618 | 0.020 |
TC (mmol/L) | 0.914 | 0.077 | 2.205 | 0.221, 3.808 | 0.028 |
LDL-C/HDL-C | 0.801 | 0.433 | 12.335 | 8.307, 11.450 | 0.000 |
Model 2: Research factors included (age, sex, hypertension, diabetes, smoking, TC, TG, HDL-C, LDL-C, non-HLD-C, LDL-C/HDL-C, NHHR). |
We performed a multi-factor binary logistic regression analysis on age, sex,
hypertension, diabetes, smoking, TC, TG, LDL-C, HDL-C, non-HDL-C, LDL-C/HDL-C,
and NHHR in the test group and the control group. NHHR was found to be an
important independent risk factor for STEMI (OR = 0.163, 95% CI: 0.065–0.411, p
Variables | SE | Wald | OR | 95% CI | p | |
---|---|---|---|---|---|---|
Sex | –0.740 | 0.297 | 6.198 | 0.477 | 0.477, 0.267 | 0.013 |
Age | –0.039 | 0.010 | 14.964 | 0.961 | 0.942, 0.981 | 0.000 |
Hypertension | –0.901 | 0.253 | 12.720 | 0.406 | 0.248, 0.666 | 0.000 |
Diabetes | –0.204 | 0.271 | 0.783 | 0.787 | 0.463, 1.338 | 0.376 |
Smoking | –0.450 | 0.278 | 2.627 | 0.638 | 0.370, 1.099 | 0.105 |
TC (mmol/L) | 2.221 | 1.008 | 4.854 | 9.217 | 1.278, 66.468 | 0.028 |
TG (mmol/L) | –0.124 | 0.164 | 0.566 | 0.884 | 0.641, 1.219 | 0.452 |
HDL-C (mmol/L) | –1.838 | 1.473 | 1.556 | 0.159 | 0.009, 2.856 | 0.212 |
LDL-C (mmol/L) | –3.603 | 1.702 | 4.481 | 0.027 | 0.001, 0.766 | 0.034 |
LDL-C/HDL-C | 0.797 | 1.639 | 0.237 | 2.219 | 0.089, 55.102 | 0.627 |
NHHR | –2.182 | 0.907 | 5.792 | 0.113 | 0.019, 0.667 | 0.016 |
LDL-C, non-HDL-C, and NHHR were used as ROC curves between the test and control groups (Table 5, Fig. 2). NHHR better predicts whether patients with chest pain have STEMI.
Variables | AUC | Cutoff value | Sensitivity | Specificity | 95% CI | p |
---|---|---|---|---|---|---|
LDL-C (mmol/L) | 0.790 | 2.35 | 0.603 | 0.817 | 0.752, 0.829 | 0.000 |
Non-HDL-C (mmol/L) | 0.776 | 2.52 | 0.868 | 0.550 | 0.731, 0.820 | 0.000 |
NHHR | 0.818 | 2.68 | 0.826 | 0.692 | 0.777, 0.859 | 0.000 |
ROC curves of patients’ LDL-C, non-HDL-C, and NHHR.
With the deepening of the study, we also found differences in blood lipids in the different genders of STEMI patients. We divided all STEMI patients into two groups according to gender and compared the differences in blood lipids between the two groups. We found that the blood lipid level in male STEMI patients was lower than in female patients, and that the difference was statistically significant (Table 6). This indicates that male STEMI patients need more strict lipid management.
Variables | Male group (n = 676) | Female group (n = 213) | z | p |
---|---|---|---|---|
TC (mmol/L) | 4.40 (3.72, 4.98) | 4.49 (3.86, 5.01) | –0.839 | 0.401 |
TG (mmol/L) | 1.66 (1.02, 1.88) | 1.66 (1.07, 1.93) | –1.118 | 0.264 |
HDL-C (mmol/L) | 0.93 (0.78, 1.03) | 0.94 (0.78, 1.08) | –0.741 | 0.459 |
LDL-C (mmol/L) | 2.65 (2.06, 3.16) | 2.70 (2.11, 3.22) | –0.963 | 0.336 |
Non-HDL-C (mmol/L) | 3.47 (2.80, 4.02) | 3.55 (2.82, 4.13) | –1.233 | 0.218 |
LDL-C/HDL-C | 2.98 (2.27, 3.50) | 3.01 (2.27, 3.55) | –0.137 | 0.891 |
NHHR | 3.95 (2.94, 4.68) | 4.04 (3.02, 4.74) | –1.663 | 0.096 |
We divided 1009 patients into a male group and a female group for a separate
study, and each group (male and female) was divided into a test group and a
control group. Male patients with STEMI served as the male test group 1 (n = 676)
and male patients with less than 50% coronary stenosis served as the male
control group 1 (n = 80). Female patients with STEMI served as the female test
group 2 (n = 213), and female patients with less than 50% coronary stenosis
served as the female control group 2 (n = 40). Using NHHR as an independent
variable, the ROC curves of male and female classification were drawn
respectively (Fig. 2). In the male category, The ROC curve of the NHHR was (AUC:
0.833, 95% CI: 0.785–0.881; p
ROC curve of NHHR under male and female classification.
It is evident that lipid abnormality is an important risk factor for coronary heart disease (CHD). LDL-C is an important risk factor for CHD and can also serve as an important index to evaluate the management of blood lipids in CHD.
Even if the LDL-C of the patient drops below 1.4 mmol/L, as is recommended by the
guidelines, the patient is still likely to suffer from coronary heart disease.
This is called residual risk. Clinicians are still looking for better indicators
to manage the residual risk of CHD [13]. Therefore LDL-C/HDL-C, non-HDL-C, and
the NHHR are factors of concern. Changes in these ratios are proven indicators
for assessing the risk of coronary heart disease [14, 15]. Non-HDL-C refers to
cholesterol carried by apolipoprotein B (apo B) particles that promote
atherosclerosis, reflecting the content of TG-rich lipoproteins including LDL C,
medium-density lipoprotein, very low-density lipoprotein cholesterol (VLDL-C),
and its byproducts. TG-rich lipoproteins participate in the occurrence and
development of atherosclerotic lesions through a variety of mechanisms. One of
these mechanisms is the entering of the arterial endothelium, where they are
phagocytized by macrophages to form foam cells, thus triggering the occurrence
and development of atherosclerotic lesions. All these lipoproteins can bring
cholesterol into the arterial wall and lead to atherosclerotic lesions [3]. The
guidelines also suggest that attention should be paid to non-HDL-C, especially in
patients with diabetes, obesity, or metabolic syndrome, in whom the symptoms are
often manifested as non-HDL-C, TG level increase, and HDL-C level decrease, while
their LDL-C level may not be high [4]. In addition, the calculation method of
non-HDL-C is simple. HDL-C is subtracted from TC, and it is not affected by
fasting conditions, which is convenient for patients. Also, it is not affected by
TG variation, which makes it highly reliable. The newly published 2019 European
Society of Cardiology/European Society of Atherosclerosis (ESAC/EAS) guidelines
further adjusted their recommendations regarding LDL-C and non-LDL-C. For
patients with extremely high cardiovascular risk, the recommended primary target
is LDL-C
At present, there have been many studies on NHHR. Studies have proven that NHHR
can effectively predict diabetes [16]. Compared with non-HDL-C, NHHR can more
accurately represent the balance between proatherogenic lipoproteins and
antiatherogenic lipoproteins, indicating a more comprehensive lipid
dysregulation. Recent studies have found that TC and LDL-C levels in patients
with acute coronary syndrome decrease with age [17]. These results suggests that
it may be unreasonable for people of different ages to define their degree of
dyslipidemia by referring to the same LDL-C or non-HDL-C standard reference
range, and it may not be an accurate way to evaluate the occurrence, severity, or
prognosis of coronary heart disease. In comparison, the lipid ratio, especially
the NHHR, may provide a more objective basis for evaluation. Previous studies
have mostly focused on the broad field of coronary heart disease. Our study
focused specifically on STEMI, the most severe form of coronary heart disease. We
found a positive correlation between NHHR and the severity of coronary artery
disease in STEMI patients (r = 0.394, p
This is a single-center retrospective study with small sample size and few indicators. A lack of follow-up resulted in high patient loss rates and a lack of sufficient longitudinal study. There have been no further studies on the differences in NHHR in STEMI patients of different genders.
We found that NHHR was positively correlated with the severity of coronary lesions in STEMI patients, and was also an independent risk factor for STEMI, especially for patients who have not received lipid-lowering treatment in the past. We also found that the NHHR was different in STEMI patients of different genders, and male STEMI patients need more strict lipid management. We need more research to prove whether it is feasible to use NHHR to guide STEMI patients to manage blood lipids.
The data used to support the findings of this study are available from the corresponding authors upon request.
XF was responsible for the design of the study, JZ was responsible for the funding of the study, PG was responsible for the collection and analysis of the research data, and completed the writing of the manuscript. XF and JZ both provided guidance and suggestions for the study. All authors read and approved the final manuscript.
The study was conducted in accordance with the Declaration of Helsinki. The study protocol was approved by the Ethics Committees of Hefei Second People’s Hospital (approval No. 2020-Ke-058). All individuals have signed informed consent.
Not applicable.
The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was supported by the An Hui Province Science Foundation of China (No. 202104j07020058).
The authors declare no conflict of interest.