Abstract
Emerging evidence supports a causal role for the immunoglobulin-M (IgM) as a protector of atherosclerosis. Since arterial stiffness is an index of subclinical atherosclerosis, we propose that IgM may play an important role in arterial stiffness. As the level of IgM differs between sexes, we investigate the sex-specific association of serum IgM with arterial stiffness in a Chinese population. The study subjects were recruited from Danyang in 2017. Using the Omron VP-1000 system, we measured brachial ankle pulse wave velocity (baPWV). Serum IgM concentration was measured by the immunoturbidimetry method. The 1030 study participants (mean age = 54.3 ± 9.0 years) included 407 men (39.5%), 428 hypertensive (41.6%), 80 diabetic (7.8%), and 512 arterial stiffness patients (49.7%). Serum IgM concentration was lower in men than women (0.97 vs. 1.26 μg/mL, P < 0.001) and negatively with alcohol intake (r = −0.11 in men and r = −0.07 in women, P ≤ 0.09). In multiple regression analyses, serum IgM concentration was negatively associated with baPWV in women (−0.82 m/s per 10-time increase in serum IgM concentration, P = 0.009) but not in men. In multivariable logistic regression analyses, elevated serum IgM concentration was associated with lower risks for arterial stiffness in women (OR = 0.26; 95% CI 0.08–0.82; P = 0.02) but not in men (OR = 0.66; 95% CI 0.17–2.62; P = 0.55). Categorical analyses produced similar results. Serum IgM is negatively associated with baPWV and accordingly associated with a lower risk of arterial stiffness in women.
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Introduction
Immunoglobulin-M (IgM) antibodies, mainly produced by B1 lymphocytes [1], have been shown to protect against atherosclerosis in recent animal experiments [2,3,4] and human studies [5,6,7]. The atheroprotective effects of IgM antibodies may be mediated by neutralizing the proinflammatory properties of oxidized low-density lipoproteins (ox-LDL), inhibiting the uptake of oxidized low-density lipoproteins by macrophages, and by promoting apoptotic cell clearance [8]. Arterial stiffness caused by decreased arterial compliance is one of the major signs of vascular aging [9]. Previous study showed that increased ox-LDL contributed to decreased arterial compliance [10], which might lead to arterial stiffness. In addition, elevated arterial stiffness was an index of subclinical atherosclerosis [11] because some studies have reported the reversibility of arterial stiffness after reduction of atherosclerotic risk factors. Taken together, serum IgM is, therefore, considered as a protector of arterial stiffness by regulation of ox-LDL and anti-atherosclerosis. To date, as to humans, evidence for IgM and arterial stiffness association is still lacking. On this point, an important notion has attracted increasing interests is that IgM may also play an important role in arterial stiffness. If the hypothesis is true, this would open a new pathway to a possible therapy of vascular aging.
Sex differences have been observed in serum IgM concentrations. Men have an absolute lower level of serum IgM than women [12]. Therefore, the association between serum IgM and arterial stiffness may differ between sexes. Accordingly, the present study aims to investigate sex-specific association of serum IgM with arterial stiffness in a Chinese population.
Methods
Study population
The Danyang Study is an ongoing, longitudinal, and multistage cohort study with the objective of investigating the comprehensive cardiovascular risk factors in Chinese. Subjects were recruited if they were (1) at least 30 years old, (2) local residents from communities in Danyang, and (3) available for long-term follow-up. Exclusion criteria included (1) severe cardiac disease or end-stage renal disease, (2) stroke history within 3 months, (3) autoimmune disease, and (4) malignant tumor with life expectancy <5 years. The Danyang Study was authorized and financially supported by the provincial government of Jiangsu (Grant ID BE2015730) and was approved by the Ethics Committee of Jiangsu Province Hospital of Traditional Chinese Medicine. All patients gave informed written consent prior to their inclusion in the study.
From 3 June 2017 to 29 June 2017, we visited five villages of Station Community randomly selected from Danyang County, a plain area approximately 70 km east of Nanjing. We invited all inhabitants aged at least 30 years to take part. Of the 1154 invited, 1035 (89.7%) participated. Of these 1035 participants, we excluded five subjects from this analysis because of missing information on brachial ankle pulse wave velocity (n = 3), or serum IgM (n = 2). Thus, the number of participants analyzed totaled 1030.
Anthropometric, biochemical, and immunoglobulin-M measurements
One trained physician measured each patient’s blood pressure 3 × consecutively using a validated Omron 7130 oscillometric blood pressure monitor (Omron, Kyoto, Japan) [13] after the patients had rested for at least 5 min in the sitting position. The same observer also administered a standardized questionnaire to collect information on sociodemographics medical history, lifestyle, and use of medications. A trained nurse measured body height and body weight. Body mass index (BMI) was calculated as the body weight in kilograms divided by the body height in meters squared.
Venous blood samples were drawn after overnight fasting for the measurement of plasma glucose, serum creatinine, total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, and triglycerides. Serum IgM was measured by the immunoturbidimetry method using IMMAGE 800 analyzers (Beckman Coulter Inc., Brea, CA, USA).
Hypertension was defined as a blood pressure of at least 140 mm Hg systolic or 90 mm Hg diastolic, or as the use of antihypertensive drugs. Diabetes mellitus was defined as a fasting plasma glucose of at least 7.0 mmol/L or as the use of anti-diabetic agents.
Brachial ankle pulse wave velocity measurements
Brachial ankle pulse wave velocity (baPWV) was measured using the Omron VP-1000 device (Omron HealthCare, Kyoto, Japan) as described previously [14, 15]. In brief, the travel path from body height was extrapolated and baPWV was computed automatically by dividing time difference between the pulse waves that were transmitted to the brachial and ankle arteries by the travel path with Omron Colin device [16]. Because no uniform cutoff values are available for baPWV, arterial stiffness was defined as a baPWV >14.88 m/s in current study [17].
Statistical methods
For database management and statistical analysis, we used SAS software (version 9.2, SAS institute, Cary, NC, USA). Serum IgM concentration was logarithmically transformed for statistical analysis. To compare means and proportions, we used the Student t-test and Fisher’s exact test, respectively. We searched for possible correlates of IgM and baPWV using stepwise multiple regression with the P-value for potential covariates to enter and stay in the model set at 0.10. We then performed sex-specific multiple linear and logistic regression analyses to study the association of serum IgM concentration with baPWV, with continuous and dichotomous variables, respectively, while controlling for the identified correlates. A two-sided value of P < 0.05 was considered statistically significant.
Results
Characteristics of the study participants
The 1030 participants (mean age 54.3 ± 9.0 years) included 407 men (39.5%), 428 had hypertension (41.6%), 80 had type 2 diabetes mellitus (7.8%), and 512 had arterial stiffness (49.7%). Table 1 summarizes the characteristics of the study participants by sex. Men and women had similar rates for diabetes and taking antihyperglycemic drugs, and LDL cholesterol levels. Men were older ( + 1.9 years) and had a greater BMI ( + 1.1 kg/m2), higher systolic/diastolic blood pressure ( + 5.1/5.2 mm Hg), higher serum creatinine ( + 17.8μmol/L), higher plasma glucose ( + 0.25 mmol/L), serum triglycerides ( + 0.12 mmol/L), lower serum total (−0.18 mmol/L), and HDL cholesterol concentrations (−0.18 mmol/L), and lower heart rate (−3.2 beats/minute), and higher rates for hypertension (51.4% vs. 35.2%) or taking antihypertensive drugs (29.0% vs. 19.4%) and higher proportions of current smoking (65.6% vs. 0.2%) and alcohol intake (55.3% vs. 4.5%) (P ≤ 0.005).
Men, compared with women, had lower serum IgM concentration (0.97 vs. 1.26 g/L; P < 0.001) but higher baPWV (15.6 vs. 15.0 m/s; P = 0.001) and proportion of arterial stiffness (54.8% vs. 46.4%; P = 0.008).
Correlates of serum IgM concentration and baPWV
In sex-specific stepwise multiple regression analyses, age, body mass index, mean arterial pressure, heart rate, current smoking (not in women because of small numbers) and alcohol intake, the use of antihypertensive and antihyperglycemic drugs, the presence of hypertension and diabetes, plasma glucose, serum total, and high-density lipoprotein cholesterol were considered as potential correlates.
We identified that serum IgM concentration was associated with alcohol intake and baPWV with age, mean arterial pressure, heart rate and body mass index in men as well as women (r = 0.10 to 0.57 or −0.11 to −0.07, P ≤0.06, Table 2). IgM was additionally negatively associated with age in women (r = −0.15, P = 0.0003). BaPWV was additionally associated with the presence of diabetes and use of antihypertensive drugs in men (r = 0.08 to 0.11, P≤ 0.05, Table 2).
Relationship between IgM concentration and baPWV
Because men and women had different IgM and baPWV, we performed multiple regression analyses in men and women separately and adjusted for above-mentioned correlates, i.e., age, mean arterial pressure, heart rate, body mass index, current smoking (not in women because of small numbers) and alcohol intake, the use of antihypertensive and antihyperglycemic drugs, the presence of hypertension and diabetes, plasma glucose, serum total, and high-density lipoprotein cholesterol. These multiple regression analyses demonstrated that serum IgM concentration was significantly negatively associated with baPWV (0.82 m/s decrease per 10-time increase in serum IgM concentration, P = 0.009) in women but not in men (P > 0.10, Table 3). Similarly, compared to those in the lowest tertile of serum IgM level, subjects in the highest tertile had a significantly lower baPWV in women (14.9 vs. 15.3 m/s, P = 0.01) but not in men (15.5 vs. 15.7 m/s, P = 0.39, Fig. 1).
Relationship between IgM concentration and arterial stiffness
We next performed multiple logistic regression analysis to investigate whether serum IgM level was associated with the risks for arterial stiffness in men and women separately. After adjusted for aforementioned covariates, elevated serum IgM concentration was significantly associated with lower risks for arterial stiffness in women (OR = 0.26; 95% CI 0.08–0.82; P = 0.02) but not in men (OR = 0.66; 95% CI 0.17–2.62; P = 0.55), respectively (Table 4). Similar results were obtained by logistic regression using non-transformed IgM as a categorical variable (data not show).
Discussion
The main finding of our study is that IgM decreases with alcohol intake in both men and women and declines with age in women, and is negatively associated with baPWV and accordingly associated with a lower risk of arterial stiffness in women. As baPWV is a measure of arterial stiffness and is also predictive of cardiovascular events and mortality [14, 18, 19], our finding, therefore, may have clinical implications for arterial stiffness and cardiovascular events prevention by increasing the production of serum IgM in women.
To the best of our knowledge, our study is the first that has showed significant association of serum IgM concentration with a lower risk of arterial stiffness as assessed by baPWV in women. Among 623 Chinese women in our study, each logarithmically transformed increase in serum IgM concentrations are associated with −0.82 m/s lower baPWV, and 74% lower risk of arterial stiffness. This finding is in keeping with recent findings on inverse association between IgM autoantibodies to oxidized low-density lipoprotein and carotid artery atherosclerosis [5] and coronary artery disease [6]. Indeed, arterial stiffness is closely related to atherosclerosis [20]. Study conducted by Huynh et al. [21] suggested that arterial stiffening may affect endothelial function with aging and promote atherosclerosis. Arterial stiffness and atherosclerosis commonly coexist with aging and they share some common pathophysiological mechanisms. That to some extent explains why the association between IgM and atherosclerosis can partly translate to arterial stiffness.
The mechanism underlying the protective effect of serum IgM on arterial stiffness has not been clear. Mounting evidences from recent animal-based studies suggest that IgM plays an important role in atherosclerosis. Ldlr-/- mice deficient in serum IgM has accelerated cholesterol crystal formation and increases smooth muscle cell stiffness in aortic root lesions [2]. Moreover, Kyaw et al. [3] demonstrates that natural IgM secreted by B1 lymphocytes offered atheroprotection by depositing IgM in atherosclerotic lesions, which reduces the necrotic cores of lesions. As vascular smooth muscle cell stiffness [22] and inflammation [23] contribute to arterial stiffness, we therefore speculate that lower serum IgM might have a detrimental effect on arterial stiffness by above-mentioned mechanisms. However, future studies are needed to clarify the exact mechanisms of serum IgM in the development of arterial stiffness.
The sex differences on the association between serum IgM and baPWV that we found are probably explained by a difference in serum IgM between men and women. Women have a relatively higher level of IgM than men [12]. Indeed, women have a 0.29 g/L higher IgM concentration in our study. In addition, Lewis et al. [2] demonstrates that increased atherosclerosis is observed in female serum IgM deficient LDLR-/- mice compared to control irrespective of type of diet. Another possible explanation on the sex-specific association may be dependent on the status of menopause in women. Previous studies suggested that post-menopausal women had a lower level of IgM than pre-menopausal women [24] and menopause engendered the augmentation of arterial stiffness in an age-dependent manner [25,26,27]. Indeed, post-menopausal women, compared with pre-menopausal women, had lower IgM concentration (1.17 vs. 1.37 g/L; P < 0.001) but higher baPWV (16.0 vs. 13.4 m/s; P < 0.001) in our study. We therefore speculate that menopause status could partially explain the sex-specific association between IgM with baPWV.
Another interesting finding of the current study is a negative correlation between serum IgM and alcohol intake in general population, which is consistent with the results obtained by McMillan et al. [28]. and Nissinen et al. [29]. Nevertheless, our finding did not accord with a study performed by Gonzalez-Quintela et al. [30] in which alcohol consumption was not associated with significant changes in serum IgM. The disparities in association of alcohol intake and IgM between our finding and the results of a previous study [30] might be explained by the difference in the sample size. In 124 heavy drinkers and 137 abstainer controls, Gonzalez-Quintela et al. [30] reported similar levels of IgM (1.12 g/L in men vs. 1.47 g/L in women) as our study. However, in this previous study, serum IgM level was not significantly correlated with alcohol intake. This previous study apparently has insufficient power to show significant association of the size observed in our study because drinkers tended to have lower IgM concentration than abstainers (1.24 vs. 1.37 g/L) in their study.
The main strength of our current study is a relative large population study, which enable us to find the sex-specific differences because of sufficient sample size. A major limitation of our study is the cross-sectional nature of the design, which does not allow us to draw any casual inference. Another limitation of this study is that we only performed measurement of baPWV but not carotid femoral PWV in current study. The latter is considered as the golden standard for assessing arterial stiffness. Nonetheless, baPWV has been reported previously to be closely correlated with carotid femoral PWV [31]. Future studies are necessary to investigate the association of cfPWV and serum IgM. Finally, the studied subjects were aged at least 30 years, which are not fully representative of general population. Future studies including subjects aged between 18 and 30 years are warranted to further explore the relationship between serum IgM and arterial stiffness.
In summary, our study demonstrates serum IgM is negatively associated with baPWV and accordingly associated with a lower risk of arterial stiffness in Chinese women. One of the potential clinical implications of our study is that prospective observational and interventional studies are needed to study the modulation of IgM production in arterial stiffness and cardiovascular disease prevention.
References
Baumgarth N, Tung JW, Herzenberg LA. Inherent specificities in natural antibodies: a key to immune defense against pathogen invasion. Springe Semin Immunopathol. 2005;26:347–62.
Lewis MJ, Malik TH, Ehrenstein MR, Boyle JJ, Botto M, Haskard DO. Immunoglobulin M is required for protection against atherosclerosis in lowdensity lipoprotein receptor-deficient mice. Circulation. 2009;120:417–26.
Kyaw T, Tay C, Krishnamurthi S, Kanellakis P, Agrotis A, Tipping P, et al. B1a B lymphocytes are atheroprotective by secreting natural IgM that increases IgM deposits and reduces necrotic cores in atherosclerotic lesions. Circ Res. 2011;109:830–40.
Tsiantoulas D, Bot I, Ozsvar-Kozma M, Göderle L, Perkmann T, Hartvigsen K, et al. Increased plasma IgE accelerate atherosclerosis in secreted IgM deficiency. Circ Res. 2017;120:78–84.
Karvonen J, Päivänsalo M, Kesäniemi YA, Hörkkö S. Immunoglobulin M type of autoantibodies to oxidized low-density lipoprotein has an inverse relation to carotid artery atherosclerosis. Circulation. 2003;108:2107–12.
Tsimikas S, Brilakis ES, Lennon RJ, Miller ER, Witztum JL, McConnell JP, et al. Relationship of IgG and IgM autoantibodies to oxidized low density lipoprotein with coronary artery disease and cardiovascular events. J Lipid Res. 2007;48:425–33.
Tsimikas S, Willeit P, Willeit J, Anter P, Mayr M, Xu Q, et al. Oxidation-specific biomarkers, prospective 15-year cardiovascular and stroke outcomes, and net reclassification of cardiovascular events. J Am Coll Cardiol. 2012;60:2218–29.
Tsiantoulas D, Diehl CJ, Witztum JL, Binder CJ. B cells and humoral immunity in atherosclerosis. Circ Res. 2014;114:1743–56.
Redheuil A, Yu WC, Wu CO, Mousseaux E, de Cesare A, Yan R, et al. Reduced ascending aortic strain and distensibility: earliest manifestations of vascular aging in humans. Hypertension. 2010;55:319–26.
Toikka JO, Niemi P, Ahotupa M, Niinikoski H, Viikari JS, Rönnemaa T, et al. Large-artery elastic properties in young men: relationships to serum lipoproteins and oxidized low-density lipoproteins. Arterioscler Thromb Vasc Biol. 1999;19:436–41.
Yu KJ, Zhang JR, Li Y, Huang X, Liu T, Li C, et al. Gallstone disease is associated with arterial stiffness progression. Hypertens Res. 2017;40:31–4.
McGue M, Borecki IB, Gerrard JW, Rao DC. Sex-linked determinants for IgM? Hum Hered. 1990;40:231–4.
Takahashi H, Yoshika M, Yokoi T. Validation of three automatic devices for the self-measurement of blood pressure according to the European Society of Hypertension International Protocol revision 2010: the Omron HEM-7130, HEM-7320F, and HEM-7500F. Blood Press Monit. 2015;20:92–7.
Liu M, Li Y, Wei FF, Zhang L, Han JL, Wang JG. Is blood pressure load associated, independently of blood pressure level, with target organ damage? J Hypertens. 2013;31:1812–8.
Sheng CS, Li Y, Li LH, Huang QF, Zeng WF, Kang YY, et al. Brachial-ankle pulse wave velocity as a predictor of mortality in elderly Chinese. Hypertension. 2014;64:1124–30.
Kohara K, Tabara Y, Tachibana R, Nakura J, Miki T. Microalbuminuria and arterial stiffness in a general population: the Shimanami Health Promoting Program (J-SHIPP) study. Hypertens Res. 2004;27:471–7.
Vlachopoulos C, Aznaouridis K, Terentes-Printzios D, Ioakeimidis N, Stefanadis C. Prediction of cardiovascular events and all-cause mortality with brachial-ankle elasticity index: a systematic review and meta-analysis. Hypertension. 2012;60:556–62.
Takashima N, Turin TC, Matsui K, Rumana N, Nakamura Y, Kadota A, et al. The relationship of brachialankle pulse wave velocity to future cardiovascular disease events in the general Japanese population: the Takashima Study. J Hum Hypertens. 2014;28:323–7.
Ninomiya T, Kojima I, Doi Y, Fukuhara M, Hirakawa Y, Hata J. et al. Brachial-ankle pulse wave velocity predicts the development of cardiovascular disease in a general Japanese population: the Hisayama Study. J Hypertens. 2013;31:477–83.
Oberoi S, Schoepf UJ, Meyer M, SHenzler T, Rowe GW, Costello P, et al. Progression of arterial stiffness and coronary atherosclerosis: longitudinal evaluation by cardiac CT. Progression of arterial stiffness and coronary atherosclerosis: longitudinal evaluation by cardiac CT. Am J Roentgenol. 2013;200:798–804.
Huynh J, Nishimura N, Rana K, Peloquin JM, Califano JP, Montague CR, et al. Age-related intimal stiffening enhances endothelial permeability and leukocyte transmigration. Sci Transl Med. 2011;3:112ra122.
Sehgel NL, Vatner SF, Meininger GA. “Smooth Muscle Cell Stiffness Syndrome” – revisiting the structural basis of arterial stiffness. Front Physiol. 2015;6:335.
Tomiyama H, Shiina K, Matsumoto-Nakano C, Ninomiya T, Komatsu S, Kimura K, et al. The contribution of inflammation to the development of hypertension mediated by increased arterial stiffness. J Am Heart Assoc. 2017;6:e005729.
Yilmazer M, Fenkci V, Fenkci S, Aktepe O, Sonmezer M, Kurtay G. Association of serum complement (C3, C4) and immunoglobulin (IgG, IgM) levels with hormone replacement therapy in healthy post-menopausal women. Hum Reprod. 2003;18:1531–5.
Takahashi K, Miura S, Mori-Abe A, Kawagoe J, Takata K, Ohmichi M, et al. Impact of menopause on the augmentation of arterial stiffness with aging. Gynecol Obstet Invest. 2005;60:162–6.
Zaydun G, Tomiyama H, Hashimoto H, Arai T, Koji Y, Yambe M, et al. Menopause is an independent factor augmenting the age-related increase in arterial stiffness in the early postmenopausal phase. Atherosclerosis. 2006;184:137–42.
Tsai SS, Lin YS, Hwang JS, Chu PH. Vital roles of age and metabolic syndrome- associated risk factors in sex-specific arterial stiffness across nearly lifelong ages: possible implication of menopause and andropause. Atherosclerosis. 2017;258:26–33.
Mcmillan SA, Douglas JP, Archbold GP, Mccrum EE, Evans AE. Effect of low to moderate levels of smoking and alcohol consumption on serum immunoglobulin concentrations. J Clin Pathol. 1997;50:819–22.
Nissinen AE, Laitinen LM, Kakko S, Helander A, Savolainen MJ, Hörkkö S. Low plasma antibodies specific for phosphatidylethanol in alcohol abusers and patients with alcoholic pancreatitis. Addict Biol. 2012;17:1057–67.
Gonzalez-Quintela A, Alende R, Gude F, Campos J, Rey J, Meijide LM, et al. Serum levels of immunoglobulins (IgG, IgA, IgM) in a general adult population and their relationship with alcohol consumption, smoking and common metabolic abnormalities. Clin Exp Immunol. 2007;151:42–50.
Tanaka H, Munakata M, Kawano Y, Ohishi M, Shoji T, Sugawara J, et al. Comparison between carotid-femoral and brachial-ankle pulse wave velocity as measures of arterial stiffness. J Hypertens. 2009;27:2022–7.
Acknowledgements
We gratefully acknowledge the voluntary participation of all study subjects and the technical assistance of the nurses of Mei Huang, Jie Xu (Nanjing, Jiangsu), and Lei Yue (Danyang, Jiangsu).
Funding
The present study was in part supported by grants from National Natural Science Foundation of China (grant 81573909) and Social Development Key Programs of Science and Technology Commission Foundation of Jiangsu Province (grant BE2015730) to Zhu-yuan Fang, and Six Talent Peaks Project of Jiangsu Province (grant WSN-050) and Peak Academic Talent Project of Jiangsu Province Hospital of Traditional Chinese Medicine (grant y2018rc31) to Ming Liu.
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Liu, M., Yao, Y., Zhu, T. et al. Sex-specific association between serum immunoglobulin-M and brachial ankle pulse wave velocity in a Chinese population: Danyang Study. Hypertens Res 42, 385–391 (2019). https://doi.org/10.1038/s41440-018-0156-8
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DOI: https://doi.org/10.1038/s41440-018-0156-8