Lipid Risk Factors of Coronary Heart Disease in Postmenopausal Women with Statins based on NMR Metabolomics

doi:10.21203/rs.3.rs-900583/v1

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Lipid Risk Factors of Coronary Heart Disease in Postmenopausal Women with Statins based on NMR Metabolomics

https://doi.org/10.21203/rs.3.rs-900583/v1

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Background The role of nuclear magnetic resonance (NMR) metabolomics in the prevention of coronary heart disease (CHD) in postmenopausal women is unclear.

Objective To explore the NMR measured risk factors of CHD and the correlation among Gensini score, proprotein convertase subtilisin/kexin type-9 (PCSK9) and NMR metabolomics.

Method 300 postmenopausal women who were under moderate intensity statins were enrolled and assigned into CHD Group (242) and non-CAHD Group (58). Multivariate Logistic regression and Spearman correlation analysis were conducted for the risk factors of CHD and the relationship among Gensini score, PCSK9 and NMR results in all patients as well as the patients with CHD, diabetes mellitus (DM) and metabolic syndrome (MS).

Results

Age, the particle of LDL-6, LDL-6- triglyceride (TG) and LDL-6-free cholesterol (FC) were risk factors of CHD, while, glycerol were the protective factors of CHD. Lipoprotein contents of very-low-density lipoprotein (VLDL)-2 ~ VLDL-5, intermediate-density lipoprotein (IDL), low-density lipoprotein (LDL)-1 and LDL-2 were positively related to Gensini score, while the lipoprotein contents, apolipoprotein A1 (ApoA1) and ApoA2 of high-density lipoprotein (HDL)-1 ~ HDL-4 showed negative correlations with Gensini score. PCSK9 was negatively correlated to the particles of VLDL, IDL and LDL, total cholesterol (TC), ApoB/A1, and nearly all the lipid contents in VLDL-3 ~ VLDL-5, IDL and LDL-1.

Conclusion

In postmenopausal women, under moderate intensity statins, age, and the NMR measured particle of LDL-6, LDL-6-TG and LDL-6-FC were risk factors of CHD, while glycerol were the protective factors of CHD. Lipoprotein contents of VLDL-2 ~ VLDL-5, IDL, LDL-1 and LDL-2 maybe the residual risk factors of CHD in postmenopausal women, who is under moderate intensive statin.

Cardiac & Cardiovascular Systems

Health Policy

coronary heart disease

nuclear magnetic resonance spectroscopy

postmenopausal females

PCKS9

Dyslipidemia, especially high level of low-density lipoprotein cholesterol (LDL-C), is an important risk factor of coronary heart disease (CHD)(1,2). Postmenopausal women are a special group of females, featured with increased LDL-C and CHD risk(3,4). Patients with diabetes mellitus (DM) and metabolic syndrome (MS) are also more susceptible to CHD due to abnormal lipid metabolism(5,6).

Proprotein convertase subtilisin/kexin type-9 (PCSK9) will bind to LDL receptor (LDL-R), resulting in the decrease of LDL-C metabolism, after synthesized and secreted from hepatocytes(7,8). PCSK9 has become a new target in LDL metabolism intervening in recent years. However, despite PCSK9 monoclonal antibodies, evolocumab and alirocumab, achieved approximate 50%-60% substantial reduction of LDL-C and 15% relative risk reduction of major adverse cardiac events (MACE)(9,10), statins are still the most widely used first-line lipid-lowering agent(11,12).

Nuclear magnetic resonance (NMR) spectroscopy is an advanced measurement, provides plenty metabolomics data, including lipid indexes, metabolites and amino acids. In terms of lipids, NMR can not only group different lipoproteins according to the size of lipoprotein particles, very low-density lipoprotein (VLDL)-1 ~ VLDL-5, intermediate density lipoprotein (IDL), LDL-1 ~ LDL-6, high-density lipoprotein (HDL)-1 ~ HDL-4, but also quantified the contents of lipoproteins, cholesteryl ester (CE), free cholesterol (FC), triglycerides (TG) and phospholipids (PL), according to different reactions of the substances in magnetic field. Several studies have reported the correlation between advanced lipid indexes and CHD risk(13-17). Sliz et al.(18) measured the lipid-lowering effect of statins with NMR, in a large group of elderly individuals at risk of cardiovascular disease. While Guardiola et al.(19) reported the correlation between PCSK9 and NMR results in a group of DM and MS patients, who were not under statin therapy. In this study, we combined NMR spectroscopy and laboratory tests to explore the risk factors of CHD in 148 NMR results and clinical characteristics, and try to find the relationship among NMR metabolomics, PCSK9 and coronary lesion in a group of postmenopausal women, who were under moderate intensity statins therapies.

Study Populations

Patients who met the inclusion and exclusion criteria were enrolled in the study. Inclusion criteria: 1. Female, age > 46 years, natural menopause over 1 year; 2. Continuous administration of atorvastatin 10mg QD. or rosuvastatin 20mg QD. over 6 months; 3. Conducted coronary angiography (CAG) between June 2019 and June 2020; 4. All necessary data for this study were available; 5. Clear awareness, able to sign informed consent and willing to take blood measurements. Exclusion criteria: 1. Previous percutaneous coronary intervention (PCI) or coronary artery bypass graft (CABG); 2. Ovariectomy on either side; 3. Under taking estrogen replacement medication; 4. Under treatment of any PCSK9 inhibitors; 5. Cirrhosis or decompensated liver function (Child-Pugh Score > 6); 6. Abnormal renal function (estimated glomerular filtration rate < 60mL/min/1.73m²); 7. Unstable hemodynamics or left ventricular ejection fraction (LVEF) less than 30%; 8. Rheumatoid or systemic diseases such as sepsis; 9. Severe progressive diseases such as tumors. This study is approved by the ethics committee and conducted with signed consent of all participants.

Study Design

This was a single-center cross-sectional clinical study. All enrolled patients were grouped according to three criteria. Patients with any coronary stenosis ≥ 50% were assigned into CHD Group, with all coronary stenosis < 50% were distributed into non-CHD Group, according to CAG results. In the same measure, patients were assigned to DM Group and non-DM Group, MS Group and non-MS Group, according to the diagnoses of DM and MS. The diagnoses of DM and MS were collected from the medical record system according to the standard diagnostic criteria(20,21). (Figure 1) Gensini scores were calculated based on CAG. The clinical characters were collected from medical record system, blood samples were collected for NMR spectroscopy, lipoprotein a (Lp(a)), PCSK9 and C-reactive protein (C-RP) test, once the patients were enrolled in this study. This study is approved by the ethics committee and conducted with signed consent of all participants in accordance with the Helsinki Declaration.

Laboratory Testing and NMR Spectroscopy Lipid Measurement

Fasting venues blood samples were collected the day before CAG, and stored at -70° C after centrifugation. PCSK9 and C-RP were measured with ELISA. Lp(a) were measured in nmol/L by particle-enhanced turbidimetric immunoassay with Tina-quant Lipoprotein (a) Gen.2 (Latex) (LPA2) Roche^® on Cobas system. NMR spectroscopy (AvanceIII IVDr, ProteinT^®, Bruker^®) was conducted according to the standard process.

CAG and Gensini Score

The CAGs were performed for patients who had typical or untypical unstable angina pectoris along with myocardial ischemic changes in electrocardiogram. Coronary plaque burden was evaluated by Gensini score(22), which could qualify the severity of the coronary lesions by 3 main parameters: severity score, region multiplying factor and collateral adjustment factor.

Statistical Analysis

Categorical variables were presented as n (%), and the differences between groups were assessed with chi-square test. The continuous variables were tested with Kolmogorov-Smirnov for the normality of distributions and presented as mean ± standard deviations when normally distributed, medians (25^th, 75^th percentile) when non-normally distributed. Student’s t-test was used to assess the differences of continuous variables between groups, among which, the non-normally distributed ones were converted into natural logarithm before assessment. Due to the multi-variables, the False Discovery Rate (FDR) was adapted for Multiple Hypothesis Testing after Student’s t-test. Variables with P-fdr < 0.1 and without collinearity with others, were entered into multivariate Logistic regression model. Heatmaps based on the Spearman correlation analysis of variables and Gensini score or PCSK9 were charted. All statistical analysis was performed with Stata version 15. Data were considered statistically significant when P value was less than 0.05.

Clinical Demography Characteristics, Routine and Advanced Lipid Indexes

300 patients were enrolled in this study, among which, 242 patients were diagnosed with CHD and assigned to CHD Group, 123 patients were diagnosed with DM and 75 patients were diagnosed with MS, assigned to DM Group and MS Group. As the Supplement Table 1 ~ 3 showed, 9 clinical information and 139 NMR results were compared between CHD Group and non-CHD Group, DM Group and non-DM Group, MS Group and non-MS Group.

As shown in Supplement Table 1, age, both the triglycerides of LDL and LDL-6 were higher in CHD group, while the ethanol was lower in the comparison with non-CHD group. In the comparison between DM and non-DM patients, shown in Supplement Table 2, there was little variables with significant differences. Most of the differences of clinical characteristics and NMR measured lipid indexes were statistically significant in the comparison between MS group and non-MS group (Supplement Table 3). In the clinical characteristics comparison, age, fasting plasma glucose (FPG), the rate of smoking, overweight, diabetes, hypertension and CHD family history were significantly higher in MS group, but the PCSK9 was much lower in MS patients, which was inconsistent with our cognition. Total cholesterol (TC), TG and apolipoprotein B (apoB) were higher in MS group, while HDL-C and apolipoprotein A2 (apoA2) were lower. Total lipoprotein particles, as well as the particles of VLDL, IDL, LDL were more in MS group and the higher LDL particle in MS group was mainly due to LDL-5 and LDL-6. Almost all TG, CE, FC and PL of VLDL and IDL were much higher in MS group, while the advantage of those contents of LDL in MS patients was mostly concentrated in LDL-3, LDL-4 and LDL-6. And even the TG of HDL were much higher in MS patients, while CE, FC and PL of HDL were higher in non-MS patients. In addition, higher glutamine in MS group was the only differentiated metabolites found in the comparison with non-MS patients.

Risk Factors of CHD

As Figure 2 showed the result of multiple Logistic regression, age (odds ratio (OR) = 2.520, 95% confidence interval (CI): 1.081 ~ 5.086, P = 0.032), the particle of LDL-6 (OR = 1.006, 95% CI: 1.001 ~ 1.012, P = 0.022), LDL-6-TG (OR = 1.200, 95% CI: 1.034 ~ 1.393, P = 0.016) and LDL-6-FC (OR = 1.330, 95% CI: 1.142 ~ 1.549, P < 0.001) were risk factors of CHD. While, glycerol (OR = 0.167, 95% CI: 0.032 ~ 0.868, P = 0.041) were the protective factors of CHD.

The Relation between Gensini Score and NMR Results

Heatmaps, Figure 3 and 4, showed the direction and intensity of the Spearman correlation between Gensini score and NMR results as well as PCSK9 and NMR results, in all postmenopausal women and the patients diagnosed with CHD, DM, and MS.

In general, Figure 3 showed that the positive correlation between Gensini score and NMR results deposited in VLDL-2 ~ VLDL-5, IDL, LDL-1 and LDL-2, while the negative correlations concentrated on ApoA1, ApoA2 and HDL-1 ~ HDL-4.

In all postmenopausal women enrolled in this study, the indexes with positive correlation with Gensini score including ApoB/A1, particles of VLDL and IDL, lipoprotein contents TG in VLDL-3 ~ VLDL-5, LDL-1 ~ LDL-2, LDL-5 ~ LDL-6, CE in VLDL-2 ~ VLDL4, IDL, FC in VLDL-2 ~ VLDL-4, IDL and LDL-1 and PH in VLDL-3 ~ VLDL-5, while the indexes with negative correlation were ApoA1, ApoA2, ApoA1, CE and PL in HDL-2 ~ HDL-4, FC in HDL-3 and ApoA2 in HDL-4. The NMR results of CHD and DM patients showed a similar but not identical trends with All patients. In the MS patients, the indexes positively related to Gensini score were confined only to the TG, CE and PL in VLDL-3 ~ VLDL-5, while the negative correlated indexes were ApoA1, FC and PL in LDL-1, and ApoA1, CE, PL in HDL-1. The PCSK9 was negatively correlated with Gensini score in all patients and DM patients.

The Relation between PCSK9 and NMR Results

Figure 4 showed correlations between plasma PCSK9 and NMR results. In all patients and CHD, DM subgroups, PCSK9 showed a similar trend that negatively correlated with total cholesterol (TC), ApoB/A1, the particles of VLDL, IDL and LDL, as well as nearly all the lipid contents in VLDL-3 ~ VLDL-5, IDL and LDL-1. In MS group, there was little correlation between PCSK9 and NMR results.

Cardiovascular disease (CVD) is the leading cause of death in women(23). We conducted this study in a group of postmenopausal women who received moderate intensity statins, which was proved with lower risk of MACE and re-ischemia events in Chinese population(24). The result of this study indicated that age, the particles of LDL-6, LDL-6-TG and LDL-6-FC were risk factors of CHD, while glycerol were the protective factor. The correlation analysis of Gensini score and NMR results showed positive correlations with VLDL-2 ~ VLDL-5, IDL, LDL-1 and LDL-2, and negative correlations with ApoA1, ApoA2 and HDL-1 ~ HDL-4. PCSK9 was negatively related to TC, ApoB/A1, the particles of VLDL, IDL and LDL, as well as nearly all the lipid contents in VLDL-3 ~ VLDL-5, IDL and LDL-1. These results of this study indicated that LDL-6 was the risk factor of CHD, but we should also pay attention to VLDL-2~VLDL-5, IDL, LDL-1 and LDL-2, which may be the residual risk of CHD, under the moderate intensity statins.

The population we studied in this research was a group of postmenopausal women, which was considered of low to very-high 10-year CVD risk, and recommended of systematic cardiovascular risk assessment even with no known cardiovascular risk factors by the recently published 2021 European society of cardiology (ESC) guideline(25). Age is an important influencing factor of 10-year CVD risk, in the systematic coronary risk estimation 2 model, and the 10-year CVD risk increases by 0.2% per year for women aged 50 to 60 and 0.3% per year for women aged 60 to 70, when other risk factors are all in an ideal state(25). Beside age, we also proved LDL-6 particle, LDL-6-TG, LDL-6-FC were risk factors of CHD. LDL-6 was the smallest and densest subgroup of LDL. It had been reported in the Cardiovascular Health Study(26), that LDL particles and smaller LDL particle size were associated with the incidence of CHD, especially in elderly women. Mackey et al.(27) also reported that LDL- particle, small, dense LDL, and large VLDL were positively associated with coronary artery calcification in healthy postmenopausal women. Compared with bigger LDLs, smaller and denser LDL particles are more susceptible to oxidative modification and more easily engulfed by macrophages(28). And the greater levels of oxidized-LDL particles would lead to more instable plaque in coronary artery disease(29). Glycerol was proved to be a protective factor of CHD in this study. Glycerol was mainly released from the hydrolysis of TG. It was reported that inflammation and homocysteine would inhibit the metabolic of TG(30,31). But we didn’t find any evidence of the direct protective effect of glycerol on CHD. We tend to that glycerol is just a marker of the decreased TG hydrolysis.

Lipoproteins are the spherical containers of CE, FC, TG and PL. The traditional lipid measurements focused on the pathogenic effect of lipoprotein and cholesterol on CHD. But studies proved the amount and structure of lipoprotein particles were also risk factors of CVD(32,33). The TG in VLDL is exchanged for CE from LDL and HDL by the cholesteryl ester transport protein, produced CE-depleted LDL and HDL. The TG in the core of VLDL, LDL and HDL are then hydrolyzed by hepatic lipases, producing IDL and smaller, denser LDL and HDL. NMR measured lipoprotein subfractions, VLDL-1 ~ VLDL-5, IDL, LDL-1 ~ LDL-6 and HDL-1 ~ HDL-4, arranged in a smaller, denser way with less TG and more PL. Dr. Sliz measured the specific effect of pravastatin 40mg per day on the particle concentration and contents of lipoprotein with NMR(18), which showed a "V" relationship between the lipid-lowering effect and the size of lipoprotein particles. In detail, the most reduced lipoprotein particle was extremely large VLDL (nearly 45%), then the degree of reduction declined with the decrease of particle size to the lowest point of small VLDL (nearly 15%), then rose to medium LDL (over 30%). The downward trends of lipoprotein contents (CE, FC and TG) were similar, but the overall decreases of TG and FC in LDL were much lower (15% to 30%). In the correlation analysis session of this study, we noticed that the positive correlation between Gensini score and NMR results focused on the lipoprotein contents of VLDL-2 ~ VLDL-5, IDL and LDL-1 and LDL-2, which all proved with lower degree of reductions (15% ~ 30%) under moderate intensity statins in Dr. Sliz’s study. Although the statins in the two studies were different, there is a high consistency between the results. Based on the results of these two studies, we hypothesized that VLDL-2~VLDL-5, IDL, LDL-1 and LDL-2 were residual risk factors of CHD related to blood lipid, in postmenopausal women treated with moderate intensity statins.

Conversely, the result of correlation analysis between PCSK9 and NMR results was the opposite of Dr. Guardiola’s study(19). Dr. Guardiola’s study indicated that circulating PCSK9 level was positively correlated with large particles of VDLD, IDL, small and very small particles of LDL, small particles of HDL and VLDL particle size, and the negative correlation deposited on LDL size and HDL size. We believe that the use of statins is the main reason why our results are contrary to Dr. Guardiola’s. It has been reported that statin can abolish the correlation between PCSK9 and the LDL-C(34). Several studies had proved the PCSK9-elevate effect of statins(35,36). It has also been reported that serum PCSK9 level could be affected by latitude, gender, HDL-C, TG and physical activity(37-39). We think that statins reduced lipid levels while increasing circulating PCSK9, resulting in a negative correlation between PCSK9 and the NMR results.

There are several limitations of this study. First, due to the lack of the patients without statins treatment as the control group, it is difficult to draw a solid conclusion in the correlation analysis between PCSK9 and NMR results. However, if compared with other studies, the heterogeneity of research population and methods will also affect the credibility of the results. Second, the population in this study is patients under statins, which cannot represent the overall characteristics of postmenopausal women. Third, the number of people in this study is relatively insufficient, for further exploring the risk factors of MS. Fourth, limited by the cross-sectional design, reversal causality is possible. Finally, further research is needed to confirm the stability of lipid indexes in frozen samples and repeatability of the advanced lipid measurement.

In this study, we explored the risk factors of CHD with NMR spectroscopy, in a group of postmenopausal women who received statins. The results indicated that age, the particle of LDL-6, LDL-6-TG and LDL-6-FC were risk factors of CHD, while glycerol were the protective factors. The positive correlation between Gensini score and NMR results concentrated in lipoprotein contents of VLDL-2 ~ VLDL-5, IDL, LDL-1 and LDL-2, which maybe the residual risk factors of CHD in postmenopausal women, who is under moderate intensive statin. The clinical significance and value of these findings need to be further studied.

CHD, coronary heart disease; CVD, cardiovascular disease; DM, diabetes mellitus; MS, metabolic syndrome; MACE, major adverse cardiac events; PCSK9, proprotein convertase subtilisin/kexin type-9; NMR, nuclear magnetic resonance; CAG, coronary angiography; PCI, percutaneous coronary intervention; CABG, coronary artery bypass graft; LVEF, left ventricular ejection fraction; TC, total cholesterol; LDL-C, low-density lipoprotein cholesterol; LDL-R, LDL receptor; IDL, intermediate-density lipoprotein; VLDL, very-low-density lipoprotein; HDL, high-density lipoprotein; CE, cholesteryl ester; FC, free cholesterol; TG, triglycerides; PL, phospholipids; Lp(a), lipoprotein a; C-RP, c-reactive protein; FPG, fasting plasma glucose; ApoA2, apolipoprotein A2; ApoB, apolipoprotein B.

Ethics approval and consent to participate: This study has been approved by the Ethics Committee of Special Medical Center of Chinese Armed Police Force. All the patients had been informed about the rights and obligations in this study and signed in informed consent before took part in.

Consent for publication: Not applicable.

Availability of data and material: All data generated or analyzed during this study are included in this published article.

Competing interests: There was no competing interests to be declared.

Funding: This study was supported by Key Projects of Tianjin Natural Science Foundation, Tianjin, China (No. 16JCZDJC31900) and Special Project on Health Care of Logistics Support Department of the Central Military Commission, China (No. 20BJZ50).

Authors' contributions: Dr. MZ put forward research ideas and was responsible for the organization of research. Dr. YS C, XN and WC provided parts of patients and data sources. CL was responsible for data collection and article writing. Dr. JX C, FP M, JY W, J L, and Dr. Y Y helped to collect patients’ information and provided comments on article revision. Miss. SY W helped with the statistical analysis.

Acknowledgement: The authors thank the participated patients, the director and researchers of the Cardiovascular Institute of Special Medical Center of Chinese People’s Armed Police Force.

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No competing interests reported.

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Lipid Risk Factors of Coronary Heart Disease in Postmenopausal Women with Statins based on NMR Metabolomics

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