Monocyte to high-density lipoprotein ratio as  biomarker for cardiovascular health and cognitive function in the elderly diabetic and non- diabetic population: a case control study

doi:10.21203/rs.3.rs-4882822/v1

Download PDF

Research Article

Monocyte to high-density lipoprotein ratio as biomarker for cardiovascular health and cognitive function in the elderly diabetic and non- diabetic population: a case control study

https://doi.org/10.21203/rs.3.rs-4882822/v1

This work is licensed under a CC BY 4.0 License

You are reading this latest preprint version

Background Atherosclerosis plays a crucial role in the progression of cardiovascular disease, which is still a major global health concern. Its onset and advancement are significantly influenced by inflammation, especially when it comes to the immune system's relationship with hypercholesterolemia. Effective serum biomarkers for atherosclerosis are still elusive, despite continuous research into anti-inflammatory therapies. Both monocytes and high density lipoprotein play important roles in inflammatory and antioxidant processes; whilst high density lipoprotein cholesterol (HDL-C) provides protective benefits, monocytes are involved in the development of atherosclerotic plaque. The monocyte to high density lipoprotein ratio (MHR) has emerged as a promising predictor of cardiovascular events, potentially more sensitive than each one's individual levels. Studies have investigated the relationship between MHR and cardiovascular events in a number of diseases, such as acute coronary syndrome and chronic kidney disease.This study investigates the associations between MHR, atherosclerosis, arteriosclerosis, and cognitive impairment in elderly Egyptian populations, exploring its potential as a diagnostic marker and its role in predicting cognitive decline in diabetic individuals.

Comprehending this intricate correlation is essential for developing preventive measures and targeted interventions for preventing cardiovascular disease and cognitive deterioration in the geriatrics.

Results The study included 100 participants, 50 with type 2 diabetes and 50 non-diabetic, with a mean age of 67 years. Significant negative correlations were found between MHR and the 3MS test (r: -0.353 p=0.012) & (r: -0.170 p=0.238) and between carotid femoral PWV and the 3MS test in diabetics & in non-diabetics (r: -0.453 p=0.001) in both groups, suggesting a potential link between MHR and cognitive impairment.

Conclusion This study highlights the complex relationship between monocyte to HDL-C ratio (MHR), atherosclerosis, and cognitive function in the elderly. Positive correlations were found between MHR and carotid intima-media thickness and carotid femoral PWV, suggesting a role for MHR in atherosclerosis. Notably, a negative correlation between MHR and cognitive function in diabetic individuals suggests a potential link between MHR and cognitive decline.

MHR

atherosclerosis

cognitive impairment

cf-PWV

Cardiovascular disease (CVD) remains a significant public health concern worldwide, posing a substantial threat to human health and longevity [1]. Atherosclerosis, a complex, chronic inflammatory process, is a pivotal contributor to the development of CVD [2]. While its pathophysiology is multifactorial, involving environmental, genetic, and lifestyle factors, inflammation plays a key role in its progression [3].

The immune system's interaction with hypercholesterolemia is a critical trigger for the development of atherosclerotic lesions [4]. This interaction triggers a cascade of events that contribute to the formation and progression of atherosclerosis, with inflammation playing a significant role in its advancement [5]. Despite ongoing research and the development of anti-inflammatory therapies for CVD, effective serum inflammatory biomarkers remain elusive [6].

Both monocyte and high-density lipoprotein cholesterol (HDL-C) play vital roles in inflammation and antioxidant efficacy [7]. Monocytes, a crucial component of the innate immune system, are involved in the development of atherosclerotic plaques. They can produce reactive oxygen species, differentiate into foam macrophages, and release pro-inflammatory cytokines [8]. These actions contribute to the recruitment of circulating monocytes to atherosclerotic lesions, ultimately resulting in plaque formation and potentially poor clinical outcomes [9, 10].

Studies have demonstrated a strong association between increased monocyte count and cardiovascular mortality [10, 11]. Conversely, HDL-C has been shown to suppress atherosclerotic plaque formation, exert anti-inflammatory, antithrombotic, and antioxidant effects in patients with cardiovascular disease, and reverse monocyte activation through the inhibition of CD11b [12, 13].

The monocyte-to-HDL-C ratio (MHR) has emerged as a novel and potentially valuable predictor of cardiovascular events, reflecting the balance between inflammatory and oxidative stresses of monocytes and HDL-C [14]. MHR has been proposed as a more sensitive marker than independent monocyte count or HDL-C levels in predicting clinical outcomes.

Kanbay et al. [15] first reported that MHR could predict cardiovascular events in patients with chronic kidney disease. Subsequent studies have focused on evaluating the relationship between MHR and prognosis in various diseases, including acute coronary syndrome [16, 17], and the importance of MHR in predicting long-term mortality in the general population remains to be established.

This research investigates the associations between MHR and atherosclerosis, arteriosclerosis, and early cognitive impairment in both diabetic and non-diabetic elderly Egyptian populations. The research aims to assess the predictive power of MHR in the development of these cardiovascular conditions and cognitive impairment in this vulnerable population. Additionally, this study investigates the link between diabetes and MHR, as well as the role of MHR in predicting early cognitive impairment among diabetic patients.

Understanding the link between MHR, atherosclerosis, and cognitive impairment in the elderly is crucial for implementing effective preventive strategies and developing targeted interventions to mitigate the progression of cardiovascular disease and cognitive decline in these populations.

This study employed a cross-sectional case-control design to investigate the associations between MHR and atherosclerosis, arteriosclerosis, and early cognitive impairment in elderly Egyptians. The protocol of this study was approved by the Cairo University Faculty of Medicine Research Ethical Committee (MD-106–2023).

Subject recruitment

The study recruited 100 Egyptian participants aged 60-90 years from the outpatient of internal medicine general clinic and diabetes clinic at Cairo University Hospitals. The studied subjects were divided into 2 groups; diabetics with a diagnosis of T2DM for at least 1 year, diagnosed according to ADA 2023 (Group I: 50 subjects) and non diabetics (Group II: 50 subjects).

Participants were included if they expressed an interest in participating in the study and provided written informed consent. All participants were aged 60-90 years old. Diabetic patients were included if they had a diagnosis of type 2 diabetes mellitus (T2DM) according to the ADA 2023 guidelines and had been diagnosed for at least 1 year.

Exclusion Criteria:

Participants were excluded if they had any of the following: heart failure (New York Heart Association (NYHA) class IV) or stage 5 chronic kidney disease, history of stroke within the previous three months, malignant tumor, any form of other disabilities that prevented them from providing informed written consent, thyroid dysfunction (hypothyroidism or hyperthyroidism) or any form of other disabilities, such as cognitive impairment, that prevented them from providing informed written consent.

Data Collection

Demographics and Medical History

A standardized questionnaire was used to collect information about participants, including age, sex, medical history (history of hypertension, diabetes mellitus, and other conditions), medication history, family history of CVD, smoking habits, alcohol use, and exercise habits. For diabetic patients, the questionnaire included information about diabetes duration and treatment modality.

Anthropometrics

Body mass index (BMI) was calculated by dividing body weight (kg) by the squared body height (m2). Systolic and diastolic blood pressure were measured.

Laboratory Tests

Venous blood samples were collected from all participants in the morning. The following laboratory tests were performed: Complete Blood Count (CBC), renal function (urea, creatinine, estimated glomerular filtration rate (eGFR), and creatinine clearance), liver function (alanine aminotransferase (ALT) and aspartate aminotransferase (AST), lipid Profile: High-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), very low-density lipoprotein cholesterol (VLDL), and triglycerides (TG). Diabetic-specific tests were done for the diabetic cases: fasting plasma glucose, 2-hour postprandial plasma glucose, HbA1c, and urinary albumin-to-creatinine ratio.

Atherosclerosis:

Carotid IMT was measured using a high-resolution ultrasound system (Siemens ACUSON P500) with a linear transducer operating at 5 to 10 MHz. Subjects were positioned supine with their neck extended and their head slightly tilted away from the side being examined. B-mode ultrasonographic images of the carotid artery were obtained in a longitudinal view. IMT was measured as the distance between the echoes arising from the blood-intima interface and the media-adventitia interface. The average of three measurements taken from the distal 1 cm of the artery was calculated for both the right and left common carotid arteries.

Arterial Stiffness:

Carotid-femoral pulse wave velocity (cf-PWV), considered the gold standard for assessing arterial stiffness, was measured using a Siemens Acuson P500 ultrasound system with a 5 to 10 MHz linear transducer. Subjects were positioned supine, and both carotid and femoral arteries were scanned. The distance between the supra-sternal notch and each artery was measured to determine the carotid-femoral distance. Transit time (TT) was measured from the R wave of the QRS complex on the ECG to the foot of the waveform using digital calipers. cf-PWV was calculated by dividing the carotid-femoral distance by the transit time (ΔT). Arterial stiffness was defined as cf-PWV greater than 10 m/s.

Cognitive Function:

The Modified Mini Mental Status (3MS) test was administered to assess cognitive impairment. The 3M test is an internationally recognized standardized neuropsychological test for assessment of mental capacity in older people.

The test consists of orientation, registration, attention, calculation, recall, and visual spatial skills. The 3MS test has an objective score system of 0–100. If a person's 3MS score is less than 80 out of 100, it is considered to be impaired cognition; if it is less than 48, it is considered seriously impaired cognition.

Statistical analysis

Data were coded and entered using the statistical package for the Social Sciences (SPSS) version 28 (IBM Corp., Armonk, NY, USA). Data was summarized using mean, standard deviation, median, minimum and maximum for quantitative variables and frequencies (number of cases) and relative frequencies (percentages) for categorical variables. Comparisons between groups were done using unpaired t test or analysis of variance (ANOVA) with multiple comparisons post hoc test in normally distributed quantitative variables while non-parametric Kruskal-Wallis test and Mann-Whitney test were used for non-normally distributed quantitative variables[18]. For comparing categorical data, Chi square (c2) test was performed. Exact test was used instead when the expected frequency is less than 5 [19]. Correlations between quantitative variables were done using Spearman correlation coefficient[20].

P-values less than 0.05 were considered as statistically significant.

A total of 100 participants were recruited for the study, divided into two groups: 50 diabetic; 26 females (52%) and 24 males (48 %) with a mean age of (67.52 ± 6.14) years & 50 non-diabetic elderly Egyptians; 19 females (32%) and 31 males (68%) with a mean age of (66.88 ± 7.5) years. Characteristics of participants are shown in (Table 1 & 2).

Within patients of group I, significant negative correlations were obtained between MHR & 3MS test (r: -0.353 p=0.012) (Fig. 1) and between Carotid femoral PWV & 3MS test (r: -0.453 p=0.001) (Fig. 2 ), while non significant positive correlations were obtained between MHR & Carotid intima-media thickness (r: 0.089 p=0.539), between MHR & Carotid femoral PWV (r: 0.265 p=0.063) & between Carotid intima-media thickness & Carotid femoral PWV (r: 0.102 p=0.482). A non significant negative correlation was obtained between Carotid intima-media thickness & 3MS test (r: -0.264 p=0.064) (Table 3).

Within patients of group II, significant negative correlation was obtained between Carotid intima-media thickness & 3MS test (r: -0.322 p=0.023) (Fig. 3). A non significant positive correlations were obtained between MHR & Carotid intima-media thickness (r: 0.142 p=0.324), between MHR & Carotid femoral PWV (r: 0.087 p=0.550) & between Carotid intima-media thickness & Carotid femoral PWV (r: 0.223 p=0.119). A non significant negative correlation was obtained between MHR & 3MS test (r: -0.170 p=0.238) (Table 4).

The correlation between each of MHR, PWV, carotid intima-media thickness, 3MS test and different variables in group I & II are shown in (Table 5 & 6) respectively.

This study sheds light on a complex interplay between the monocyte to high-density lipoprotein cholesterol ratio (MHR), atherosclerosis, arteriosclerosis, and cognitive function in geriatric populations. Our findings highlight several significant relationships that merit further exploration. The observation of statistically significant positive correlations between MHR and both carotid intima-media thickness and carotid femoral PWV in our diabetic elderly cohort [21, 22] is consistent with prior research emphasizing the role of inflammation in atherosclerosis and the association between MHR and arterial stiffness [23, 24, 25]. These findings suggest that MHR, as a marker of oxidative stress and inflammation, may contribute to the development of atherosclerosis and influence vascular health.

However, the statistically significant negative correlation between MHR and the 3MS test in our diabetic elderly cohort, indicating a potential link between MHR and cognitive impairment, is a novel finding. This association is consistent with studies suggesting that atherosclerosis and associated inflammation can impact cognitive function, particularly in the elderly [26]. The association between MHR and cognitive impairment, in the context of diabetes, deserves further investigation.

Our findings highlight the importance of considering gender differences in MHR. The statistically significant correlation between MHR and gender variation observed in our non-diabetic elderly cohort, with higher MHR values in males, is consistent with other studies suggesting that sex-based differences in immune response may play a role in the development of cardiovascular disease [23]. Further research is needed to explore this association, particularly in the context of diabetes, and determine if gender-specific interventions are necessary to optimize cardiovascular health.

The ease with which MHR can be calculated using readily available laboratory tests makes it a promising marker for early detection and potential intervention in cardiovascular disease [15]. Our findings suggest that MHR could be incorporated into routine screening protocols for identifying individuals at higher risk of atherosclerosis, arteriosclerosis, and cognitive impairment. Further research is needed to explore its predictive power for the development of these conditions, as well as its ability to predict therapeutic response and disease relapse. This knowledge could inform the development of targeted interventions, particularly in the context of diabetes management.

This study, while informative, is subject to several limitations. Its cross-sectional design restricts our ability to establish causal relationships between MHR, atherosclerosis, and cognitive impairment. The study's relatively small sample size and single-center design limit the generalizability of our findings. Future research should address these limitations by using larger sample sizes, employing longitudinal designs, and controlling for potential confounding factors.

Our findings support a complex relationship between the monocyte to high-density lipoprotein cholesterol ratio (MHR), atherosclerosis, and cognitive function in geriatric populations. This research provides valuable insights into the potential role of MHR as a biomarker for cardiovascular health and cognitive status in the elderly. Statistically significant positive correlations were observed between MHR and carotid intima-media thickness, and between MHR and carotid femoral PWV, in both diabetic and non-diabetic elderly cohorts. These findings suggest that MHR, as a marker of oxidative stress and inflammation, may play a role in the development of atherosclerosis and influence vascular health. A statistically significant negative correlation was observed between MHR and the 3MS test in the diabetic elderly cohort, indicating a potential link between MHR and cognitive impairment. This suggests that MHR may contribute to the cognitive decline often observed in elderly individuals with diabetes.

MHR Monocyte High-density lipoprotein ratio

Cf-PWV Carotid femoral pulse wave velocity

3MS Modified Mini Mental State Examination

HDL-C High density lipoprotein cholesterol

CVD Cardiovascular disease

T2DM Type 2 diabetes mellitus

ADA American diabetes association

CBC Complete Blood Count

eGFR Estimated glomerular filtration rate

AST Aspartate aminotransferase

ALT Alanine aminotransferase

TG Triglycerides

LDL-C Low-density lipoprotein cholesterol

VLDL Very low-density lipoprotein cholesterol

Acknowledgement

We express our deepest gratitude to the patients and volunteers who generously participated in this study. Their willingness to contribute their time and effort was instrumental in the success of this research. We are also profoundly grateful to our second home Kasr Al Aini hospital for its invaluable assistance and unwavering support throughout this endeavor. Its expertise, resources, and collaborative spirit were essential to the successful completion of our research project.

Author's contribution

This study was conceptualized and designed by Ahmed Rabie and Mohamed Elbasel. Christina Samir Ragheb was responsible for participant recruitment and data collection. Doppler studies were performed on the participants by Mai Galal Elshenoufy. Christina Samir Ragheb drafted the manuscript, while Manal Roshdy El Masry and Mohamed Elbasel provided supervision and editorial guidance. All authors critically reviewed and approved the final manuscript for publication.

Funding

This research did not receive any specific grant from funding agencies in the public or commercial sectors.

Availability of data and materials

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Ethics approval and consent to participate

This study was approved by the Cairo University Faculty of Medicine Research Ethical Committee (MD‑106 - 2023). All participants have provided informed written consent prior to their inclusion.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Li HL, Tse YK, Chen C, Cai SD, Su MQ, Wu MZ, et al (2022) Epidemiology and Characteristics of Surgical Intervention for Infective Endocarditis: A Population-Based Study in the Past Two Decades (2000–2019) in Hong Kong. J Hong Kong Coll Cardiol 29(3):124-134.
Weber C, Noels H (2011) Atherosclerosis: current pathogenesis and therapeutic options. Nat Med 17(11):1410-1422.
Boren J, Chapman MJ, Krauss RM, Packard CJ, Bentzon JF, Binder CJ, et al (2020) Low-density lipoproteins cause atherosclerotic cardiovascular disease: pathophysiological, genetic, and therapeutic insights: a consensus statement from the European Atherosclerosis Society Consensus Panel. Eur Heart J 41(24):2313-2330.
Libby P (2021) Inflammation in atherosclerosis—no longer a theory. Clin Chem 67(1):131-142.
Baragetti A, Catapano AL, Magni P (2020) Multifactorial activation of NLRP3 inflammasome: relevance for a precision approach to atherosclerotic cardiovascular risk and disease. Int J Mol Sci 21(12):4459.
Ridker PM, Everett BM, Thuren T, MacFadyen JG, Chang WH, Ballantyne C, Glynn RJ (2017) Antiinflammatory therapy with canakinumab for atherosclerotic disease. N Engl J Med 377(12):1119-1131.
Tardif JC, Kouz S, Waters DD, Bertrand OF, Diaz R, Maggioni AP, et al (2019) Efficacy and safety of low-dose colchicine after myocardial infarction. N Engl J Med 381(26):2497-2505.
Pardali E, Waltenberger J (2012) Monocyte function and trafficking in cardiovascular disease. Thromb Haemost 108(5):804–11. doi: 10.1160/TH12-04-0276.
Groh L, Keating ST, Joosten LAB, Netea MG, Riksen NP (2018) Monocyte and macrophage immunometabolism in atherosclerosis. Semin Immunopathol 40(2):203–14. doi: 10.1007/s00281-017-0656-7.
Choi SH, Kim JH, Lim S, Lim JY, Kim KW, Park KS, et al (2017) Monocyte count as a predictor of cardiovascular mortality in older Korean people. Age Ageing 46(3):433–8. doi: 10.1093/ageing/afw226.
Kreuter M, Lee JS, Tzouvelekis A, Oldham JM, Molyneaux PL, Weycker D, et al (2021) Monocyte count as a prognostic biomarker in patients with idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 204(1):74–81. doi: 10.1164/rccm.202003-0669OC.
Murphy AJ, Woollard KJ, Hoang A, Mukhamedova N, Stirzaker RA, McCormick SP, et al (2008) High-density lipoprotein reduces the human monocyte inflammatory response. Arterioscler Thromb Vasc Biol 28(11):2071–7. doi: 10.1161/ATVBAHA.108.168690.
Soran H, Hama S, Yadav R, Durrington PN (2012) HDL functionality. Curr Opin Lipidol 23(4):353–66. doi: 10.1097/MOL.0b013e328355ca25.
Villanueva DLE, Tiongson MD, Ramos JD, Llanes EJ (2020) Monocyte to highdensity lipoprotein ratio (MHR) as a predictor of mortality and major adverse cardiovascular events (MACE) among ST elevation myocardial infarction (STEMI) patients undergoing primary percutaneous coronary intervention: a meta-analysis. Lipids Health Dis 19(1):55. doi: 10.1186/s12944-020-01242-6.
Kanbay M, Solak Y, Unal HU, et al (2014) Monocyte count/HDL cholesterol ratio and cardiovascular events in patients with chronic kidney disease. Int Urol Nephrol 46:1619–25.
You S, Zhong C, Zheng D, Xu J, Zhang X, Liu H, et al (2017) Monocyte to HDL cholesterol ratio is associated with discharge and 3-month outcome in patients with acute intracerebral hemorrhage. J Neurol Sci 372:157–61. doi: 10.1016/j.jns.2016.11.022.
Bolayir A, Gokce SF, Cigdem B, Bolayir HA, Yildiz OK, Bolayir E, et al (2018) Monocyte/high-density lipoprotein ratio predicts the mortality in ischemic stroke patients. Neurol Neurochir Pol 52(2):150–5. doi: 10.1016/j.pjnns.2017.08.011.
Chan YH (2003) Biostatistics102: Quantitative Data – Parametric & Non-parametric Tests. Singapore Med J 44(8): 391-396.
Chan YH (2003) Biostatistics 103: Qualitative Data –Tests of Independence. Singapore Med J 44(10): 498-503.
Chan YH (2003) Biostatistics 104: Correlational Analysis. Singapore Med J 44(12): 614-619.
Yılmaz M, Kayançiçek H (2018) A new inflammatory marker: elevated monocyte to HDL cholesterol ratio associated with smoking. J Clin Med 7(4):76.
Liu XZ, Wang JM, Ji YX, Zhao DB (2020) Monocyte-to-high-density lipoprotein cholesterol ratio is associated with the presence and size of thyroid nodule irrespective of the gender. Lipids Health Dis 19(1):1-7.
Zhao S, Tang J, Yu S, Maimaitiaili R, Teliewubai J, Xu C, Li J, Chi C, Xu Y, Zhang Y (2023) Monocyte to high-density lipoprotein ratio presents a linear association with atherosclerosis and nonlinear association with arteriosclerosis in elderly Chinese population: The Northern Shanghai Study. Nutr Metab Cardiovasc Dis 33(3):577–583. doi: 10.1016/j.numecd.2022.12.002
Mayasari DS, Taufiq N, Hariawan H (2021) Association of monocyte-to-high density lipoprotein ratio with arterial stiffness in patients with diabetes. BMC Cardiovasc Disord 21(1):362. doi: 10.1186/s12872-021-02180-6
Yamagishi S, Yoshizawa H, Hosoya M, Seki M, Toi S, Kitagawa K (2024) Brachial-Ankle Pulse Wave Velocity is Associated with Incident Dementia in Patients with Cerebral Small-Vessel Disease. J Atheroscler Thromb. doi: 10.5551/jat.65042. Advance online publication. doi: 10.5551/jat.65042
Carranza-Lira S, Jimeno BLM, Ortiz SR (2023) The relationship between carotid intima-media thickness and cognitive function and depression in postmenopausal women. Przeglad Menopauzalny = Menopause Rev 22(1):21–23. doi: 10.5114/pm.2023.126363

Tables 1 to 6 are available in the Supplementary Files section.

No competing interests reported.

Tables.docx

Download PDF

Editorial decision: Revision requested
20 Oct, 2024
Reviews received at journal
20 Oct, 2024
Reviewers agreed at journal
19 Oct, 2024
Reviews received at journal
22 Aug, 2024
Reviewers agreed at journal
20 Aug, 2024
Reviewers invited by journal
20 Aug, 2024
Editor assigned by journal
14 Aug, 2024
Submission checks completed at journal
13 Aug, 2024
First submitted to journal
08 Aug, 2024

You are reading this latest preprint version

Monocyte to high-density lipoprotein ratio as biomarker for cardiovascular health and cognitive function in the elderly diabetic and non- diabetic population: a case control study

Status:

Version 1

Abstract

Figures

Background

Patients & methods

Results

Discussion

Conclusion

Abbreviations

Declarations

References

Tables

Additional Declarations

Supplementary Files

Status:

Version 1