Hyperleptinemia As a Risk Factor for High Blood Pressure in the Elderly
By Mendoza-Nez, Vctor Manuel; Correa-Muoz, Elsa; Garfias-Cruz, Elsa A; Snchez-Rodriguez, Martha A; Et al
Context.-Studies have demonstrated that high serum leptin levels are associated with aging. However, we do not know whether hyperleptinemia is a relevant risk factor for high blood pressure (HBP) in the elderly.
Objective.-To determine the relationship between hyperleptinemia and HBP in the elderly.
Design.-A comparative cross-sectional study was carried out in a convenience sample of 70 healthy elderly persons comprising 46 women (mean age, 67 5.8 years) and 24 men (mean age, 73 7.5 years), and a group of 91 elderly persons with HBP, comprising 62 women (mean age, 67 8.2 years) and 29 men (mean age, 70 0.3 years). We measured serum leptin levels through the radio-immunoassay method.
Results.-The elderly subjects with HBP had significantly higher leptin levels than the healthy elderly subjects (P = .02). Furthermore, in female elderly subjects we observed a statistically significant correlation between systolic blood pressure and leptin (r = 0.37, P = .003), as well as systolic blood pressure and age (r = 0.29, P = .02), but not with diastolic blood pressure. In male elderly subjects, there was no correlation between leptin and systolic blood pressure or leptin and diastolic blood pressure. However, hyperleptinemia as risk factor for HBP was nearly 5 times higher in men than in women (men, odds ratio = 18.0, 95% confidence interval 3.2-100.9, P < .001 vs women, odds ratio = 3.33, 95% confidence interval 1.4-7.4, P = .003).
Conclusions.-Our data suggest that hyperleptinemia was a significant risk factor for HBP elderly individuals, mainly in men.
(Arch Pathol Lab Med. 2006;130:170-175)
There is much evidence supporting the hypothesis that age- associated changes in cardiovascular structure and function are related to the markedly increased risk for cardiovascular disease in older persons, and that such changes involve a decrease in elasticity, large artery thickening and stiffness, as well as endothelial dysfunction in apparently healthy older persons. Some vascular changes that occur with aging are risk factors for an increase in systolic blood pressure (SBP) and diastolic blood pressure (DBP), and for the development of atherosclerosis and stroke.1-5 Likewise, it has been suggested that arterial hypertension could be an inflammatory disease with high leptin levels.6,7 This relationship has been found in older persons; however, it is not conclusive.8,9
Leptin, the product of the Lep gene (originally termed ob gene), was discovered through positional cloning techniques used to determine the genetic defect resulting in obesity in ob/ob mice.10 The ob gene encodes a peptide from 167 amino acids named leptin (from the Greek word leptos, meaning thin), whose crystal structure suggests that it belongs to the cytokine family.11 This hormone has been associated with obesity and weight loss, cachexia, inflammatory processes, oxidative stress, arterial hypertension, and aging.12-17
Furthermore, it has been noted that there is an increase in fat mass and abdominal adiposity during aging, as well as an increase in insulin resistance that is frequently associated with leptin resistance and high leptin levels. This situation is associated with a heightened expression of the cytokine signaling 3 suppressor (SOCS- 3), suggesting that it could be a mediator of leptin resistance in aging individuals.18,19 Likewise, studies in rats have revealed leptin resistance during aging, independent of fat mass.20
The aim of this study was to evaluate the influence of hyperleptinemia as a risk factor for high blood pressure (HBP) in the elderly.
MATERIALS AND METHODS
Subjects
A comparative cross-sectional study was carried out in a convenience sample of 70 healthy elderly persons (46 women [mean age, 67 5.8 years] and 24 men [mean age, 73 7.5 years]) and 91 elderly persons with HBP (62 women [mean age, 67 8.2 years] and 29 men [mean age, 70 0.3 years]). Subjects with HBP were found among 300 apparently healthy older persons in Mexico City.
Elderly persons without HBP were selected through clinical history; they were excluded if they were found to have high glucose levels (≥113 mg/dL) and/or any disease. Subjects gave their informed consent to participate in the study. The Ethics Committee of the Universidad Nacional Autonoma de Mexico (National Autonomous University of Mexico), Zaragoza Campus, approved the research protocol for this study.
Data Collection
All subjects underwent the following examinations: screening studies, complete clinical history, blood tests, liver function tests, complete blood count, and general urine examination. Those tests were used to exclude subjects with chronic subclinical problems and pseudohypertension.
Blood Pressure Measurement
Blood pressure was measured in both arms 3 times in the morning, in a fasting condition or 2 hours after breakfast, in sitting and standing positions. A mercurial manometer was used to measure the blood pressure. Subjects with pseudohypertension were identified by applying the Osier technique, that is, feeling the radial pulse when the manometer registered values above the true systolic pressure. Retinal and/or electrocardiographic changes were considered for the diagnosis of systolic normal blood pressure less than 140 mm Hg and diastolic normal blood pressure less than 90 mm Hg.1
Blood pressure was taken by medical technicians who had attended training sessions to standardize the procedures. The technicians were supervised to avoid possible biases in measurement.
Anthropometric Measurements
The following anthropometric measurements were obtained: weight, height, body mass index (BMI), and waist and hip circumferences. Weight was taken with the subject in underwear and a clinical smock, and in a fasted state (after evacuation). A Torino scale (Tecno Lgica, Mexicana, Mexico) was used in obtaining the subject’s weight, calibrated before each measurement. Height was measured with an aluminum cursor stadiometer, graduated in millimeters. The subject was barefoot with the back and head in contact with the stadiometer aligned in the Frankfurt horizontal plane.
Body mass index was calculated by dividing weight (in kilograms) by height (in square meters). Waist and hip circumferences were measured with a tape measure to the nearest 0.5 cm. The waist-to- hip ratio was calculated by dividing waist measurement (in centimeters) by hip measurement (in centimeters).
Laboratory Procedures
For biochemical measurements, a blood sample was taken from each subject at 8:00 AM after a 12-hour fast. Portions of each sample were placed in vacuum tubes (Becton Dickinson, Mexico City, Mexico) without anticoagulant, and the serum was obtained. Glucose was determined by the glucose oxidase method (Randox Laboratories, Ltd, Antrim, UK), total cholesterol was analyzed by the cholesterol oxidasa/4-amino-phenazone method (Randox Laboratories, Ltd), and triglycerides were quantified by the glycerol-phosphate oxidase Trinder method (Randox Laboratories, Ltd). High-density lipoprotein cholesterol was measured by the same method as cholesterol after having precipitated very low-density lipoproteins and low-density lipoprotein cholesterol with a solution of phosphotungstic acid/ magnesium chloride. Low-density lipoprotein cholesterol was obtained with the following formula:
LDLC = Total Cholesterol – [HDLC + (Triglycerides/5)]
where LDLC = low-density lipoprotein cholesterol and HDLC = high- density lipoprotein cholesterol.
Serum leptin was determined by radioimmunoassay (Pharmacia- Upjohn Diagnostics, Tokyo, Japan) using rabbit polyclonal antibodies against highly purified recombinant human leptin (Linco Research, Inc, St Charles, Mo).21 Men were considered to have hyperleptinemia if their serum leptin values were greater than 9.4 ng/mL, and women were considered to have hyperleptinemia if their values were greater than 27.4 ng/mL. The cut-off value was the 90th percentile of subjects with normal weight.22
Serum insulin was also quantified by radioimmunoassay.23 The cut- off value for hyperinsulinemia was a level greater than 29 ng/ mL, which agreed with the 90th percentile of subjects with normal weight and euglycemia.22
Insulin resistance was determined with the formula proposed by Matthews et al24:
IR = [Fasting Insulin X Fasting Glucose]/22.5
where IR = insulin resistance; fasting insulin is measured in microunits per milliliter and fasting glucose is measured in millimoles per liter.
Statistical Analysis
Data were processed using standard statistical software, SPSS 10.0 (SPSS, Inc, Chicago, Ill). Descriptive statistics were means SE. The variance-stabilizing transformation leptin natural logarithm was used to meet the necessary regression assumptions. Results were analyzed using the Student t test and simple linear regression. A P value <.05 was considered significant. Also, a multivariate analysis of logistic regression was calculated considering a risk factor when an odds ratio greater than 1 and a range of 95% confidence interval did not include the value 1.0 (P < .05).
RESULTS
Our data showed that elderly subjects with HBP had significantly higher leptin levels than healthy elderly persons (P = .02). In this regard, the increase in leptin levels was significantly higher in men than in women. Similarly\, BMI was significantly higher in the elderly persons with HBP than in the healthy elderly persons (Table 1).
In women with HBP, we observed a statistically significant correlation between leptin (leptin natural logarithm) and SBP (r = 0.37, P = .003), as well as age and SBP (r = 0.29, P = .02); however, there was no statistically significant association between BMI and SBP (r = 0.19, P = .15). Also, there was no correlation between any variable and DBP (Table 2). Likewise, in women with normal blood pressure we found no association between SBP and leptin (leptin natural logarithm), age and BMI, or between DBP and other variables (Table 3).
In men with HBP, we did not observe a correlation between SBP and leptin (leptin natural logarithm), as well as SBP and BMI, or DBP and these parameters; however, there was a statistically significant relationship between age and SBP (r = 0.30, P = .03) (Table 4). Furthermore, in men with normal blood pressure there was a statistically significant correlation between waist-to-hip ratio and DBP (r = 0.52, P = .03), but we found no correlation between other variables and SBP or DBP (Table 5).
In logistic regression analysis, we found hyperleptineinia and BMI were risk factors for HBP in both sexes. However, hyperleptinemia as a risk factor was nearly 5 times higher in men than in women (men, odds ratio = 18.0, P < .001 vs women, odds ratio = 3.33, P = .003). The results for BMI were similar (women, odds ratio = 2.2, P = .04 vs men, odds ratio 2.4, P = .01). Conversely, none of the following were found to be risk factors for DBP and/or SBP in either sex: high levels of low-density lipoprotein cholesterol, low levels of high-density lipoprotein cholesterol, high levels of triglycerides, hyperinsulinemia, waist-to-hip ratio, waist circumference, smoking, drinking alcohol, or age (Table 6).
COMMENT
Leptin is a circulating hormone secreted mainly from adipose tissue, which is involved in the control of body weight through its effect on food intake and energy expenditure.25 In addition, plasma concentrations are correlated with BMI and are reported to be high in patients with insulin resistance, one of the major risk factors for cardiovascular disease. Nevertheless, this is controversial, given that contradictory results have been reported regarding the effect of leptin on glucose homeostasis as well as its ability to induce or intensify insulin resistance.26-28
Table 1. Anthropometric and Biochemical Characteristics in Elderly Persons With High and Normal Blood Pressure*
Table 2. Simple Linear Regression Between Anthropometric and Biochemical Characteristics With Systolic and DiastoTic Blood Pressure in Elderly Women With High Blood Pressure*
Table 3. Simple Linear Regression Between Anthropometric and Biochemical Characteristics With Systolic and Diastolic Blood Pressure in Elderly Women With Normal Blood Pressure*
Table 4. Simple Linear Regression Between Anthropometric and Biochemical Characteristics With Systolic and Diastolic Blood Pressure in Elderly Men With High Blood Pressure*
Table 5. Simple Linear Regression Between Anthropometric and Biochemical Characteristics With Systolic and Diastolic Blood Pressure in Elderly Men With Normal Blood Pressure*
Recent studies indicate that oxidative stress and inflammation are causal factors for atherosclerosis and arterial hypertension,29,30 whereas hyperleptinemia has been associated with HBP.9,31 Our results show that serum leptin levels were higher in the elderly persons with HBP than in healthy elderly individuals of both sexes (women, P = .02; men, P < .001). This association has been observed previously by our research group and by other authors.7,8,22,32,33 In this regard, a strong positive correlation has been noted between SBP and serum leptin, insulin concentrations, and percentage of body fat separately, as well as between these biochemical markers and DBP, in normotensive and hypertensive subjects.34-36 Nonetheless, we found a statistically significant correlation only between SBP and leptin levels, and SBP and age, in elderly women with HBP, but not in elderly women with normal blood pressure or in elderly men, with and without HBP. This finding suggests that leptin levels in the elderly were associated with SBP, which is linked with women prohably because of the higher percentage of body fat observed in women than in men.37 In this regard, a selective, obesity-related leptin resistance has been proven to be a factor in HBP by means of its sympathoexcitatory action,38 although there is also evidence that hyperleptinemia associated with hypertension is independent of obesity.39 The lack of correlation observed between blood pressure and leptin in the men could have been the result of the sample size, which must still be confirmed.
Leptin resistance has been associated with an increased expression of cytokine signaling 3 suppressors (SOCS-3), which become higher with aging.18,40 It has also been proven to be independent of fat mass during aging.20,27 Therefore, although aging predisposes individuals to hyperleptinemia by leptin resistance, studies show that leptin could be a physiologic regulator of cardiovascular functions, whereas high plasma-leptin levels could act as a pathophysiologic trigger of HBP.16,41 In this regard, our results demonstrated that hyperleptinemia was higher in elderly men than elderly women with HBP, despite the fact that there was no statistically significant correlation between leptin and SBP, and leptin and DBF in the elderly men with and without HBP. Hyperleptinemia (≥9.4 ng/mL) predisposed the elderly men to suffer from HBP 17 times more than the elderly men with leptin levels less than 9.4 ng/mL; however, in the elderly women, hyperleptinemia (≥27.4 ng/mL) predisposed them only to experience HBP 2.3 times more than the elderly women with leptin levels less than 27.4 ng/dL. In this sense, several studies have shown that men are more vulnerable to HBP linked with hyperleptinemia.42,43
Table 6. Risk Factors for High Blood Presure in Women and Men*
Studies have shown that SBP increases with age, and DBP rises until 50 years of age and then levels off or even decreases slightly.44 In this respect, we found a higher percentage of subjects with isolated systolic HBP than with diastolic HBP; this has also been observed by Schutte et al.37
In general, hyperleptinemia as a causal factor of HBP is poorly understood. However, authors have also reported that leptin induces endothelin-1, a potent vasoconstrictor, and mitogen.45-47 This mechanism could explain the development of HBP in elderly persons with hyperleptinemia. Furthermore, studies have established that leptin promotes angiogenesis, which could contribute to the modulation of endothelial cell proliferation under pathophysiologic conditions in atherosclerosis.48-49 Thus, authors have suggested that atherosclerotic lesions are the result of an excessively proliferative and inflammatory response that involves several cellular events, including smooth-muscle cell migration and proliferation, inflammatory cell infiltration, neovascularization, production of an extracellular matrix, and accumulation of lipids. In this regard, research has shown that oxidative stress could play a central role in regulating such events; furthermore, several authors have reported that leptin induces oxidative stress.15,50,51 Another known mechanism of leptin linked to HBP is its stimulatory effect on the sympathetic nervous system, which could be a significant factor in raising blood pressure.52
Several studies have demonstrated that aging is accompanied by an increase in leptin serum levels. This condition leads to a high percentage of subjects with hyperleptinemia whose metabolic alteration has been associated with diverse organic disorders of geriatric importance: myocardial infarction, renal problems, immunity alterations, sexual hormone alterations, chronic obstructive pulmonary disease, syndrome X, cachexia, frailty syndrome, and Alzheimer disease.12,13,53-56
In conclusion, in the present study we observed that hyperleptinemia was a significant risk factor for HBP in elderly individuals, mainly in men, independent of BMI and age. This suggests that risk factors such as high serum levels of triglycerides and low-density lipoprotein, low levels of high- density lipoprotein, smoking, and the intake of alcohol could have less effect in old age than during youth and adulthood. However, sample size and the cross-sectional aspect must be considered as limitations of the study. To confirm these findings, it is necessary to conduct cross-longitudinal studies in subjects that are representative of adults and elderly individuals, and in a larger sample size.
This work was supported by a grant from the Direccion General de Asuntos del Personal Acadmico (PAPIIT-IN204301, PAPIIT-IN226404), Universidad Nacional Autnoma de Mxico (UNAM), Mexico City.
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Victor Manuel Mendoza-Nez, MD, PhD; Elsa Correa-Muoz, MD; Elsa A. Garfias-Cruz, BD; Martha A. Snchez-Rodriguez, MD; Rosa Elba Galvn- Duarte, MD; Raquel Retana-Ugalde, MD
Accepted for publication October 26, 2005.
From Unidad de Investigacin en Gerontologa, Universidad Nacional Autonoma de Mexico (FES Zaragosa), Mxico, D.F., Mexico (Drs Mendoza- Nez, Correa-Muoz, Garfias-Cruz, Snchez-Rodriguez, and Retana- Ugalde); and the Institute Mexicano del Seguro Social, Unidad de Investigacin Medica Endocrinolgica, Hospital de Especialidades, Mxico, D.F., Mexico (Dr Galvn-Duarte).
The authors have no relevant financial interest in the products or companies described in this article.
Reprints: Vctor Manuel Mendoza-Nez, MD, PhD, FES Zaragoza, UNAM, Batalla 5 de mayo s/n, Esq. Fuerte de Eoreto, Col. Ejrcito de Oriente, Mxico City 09230, Mxico (e-mail: mendovic@servidor. unam.mx).
Copyright College of American Pathologists Feb 2006