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Masked Hypertension and Atherogenesis: The Impact on Adiponectin and Resistin Plasma Levels

Masked Hypertension and Atherogenesis: The Impact on Adiponectin and Resistin Plasma Levels The phenomenon of masked hypertension (MH) is defined as a clinical condition in which patients’ office blood pressure (BP) values are <140/90 mm Hg but ambulatory or home BP readings are in the hypertensive range. Different BP thresholds have been proposed to define MH. It is difficult to compare the results from various laboratories. The prevalence of MH in the general population could be as high as 10%; data from several cross‐sectional studies have reported large differences with prevalence rates from a low of 8% to a high of 49%. A body of evidence indicates that MH is a significant predictor of cardiovascular disease, and MH is associated with increased left ventricular mass index and increased carotid intima‐media thickness. In longitudinal studies, MH has been shown to be a strong predictor of cardiovascular outcomes, mortality, and target organ damage. Adipocytes have recently been shown to secrete a variety of bioactive substances called adipocytokines, such as leptin, adiponectin, resistin, and visfatin, which have been recognized as endocrine cells. These adipocytokines contribute to the regulation of energy homeostasis by affecting insulin sensitivity, glucose and lipid metabolism, food intake, hemostatic/fibrinolytic balance, and inflammation. In contrast to many adipokines that are overproduced in obese individuals and exert deleterious effects on insulin sensitivity, lipoprotein metabolism, and the cardiovascular system, adiponectin seems to be a unique adipokine that is produced in smaller amounts in obese persons than in lean individuals and possesses predominantly beneficial characteristics (ie, increases insulin sensitivity, stimulates fatty acid oxidation, inhibits inflammatory reactions, and induces endothelium‐dependent nitric oxide–mediated vasorelaxation). Adiponectin knockout mice exhibit various manifestations of the metabolic syndrome such as insulin resistance, glucose intolerance, hyperlipidemia, impaired endothelium‐dependent vasorelaxation, and hypertension, as well as augmented neointima formation after vascular injury. Clinical studies indicate that plasma adiponectin concentration is lower in patients with essential hypertension and ischemic heart disease. Resistin belongs to a newly discovered protein family with no homology to any previously known proteins. These proteins are members of a cysteine‐rich secretory protein family called resistin‐like molecules found in inflammatory zones (FIZZ). FIZZ3 (resistin) is expressed exclusively in white adipose tissue. Resistin is detectable at a very low level in human adipose tissue, and there is no relationship between resistin expression and obesity. This protein is detected in peripheral blood monocytes, suggesting its possible role in inflammatory processes. The aim of our study was to examine adiponectin and resistin plasma levels in patients with MH and compare the findings with those of healthy normotensive persons matched for age, sex, body mass index, and other risk factors. Material and Methods The study was performed on 130 (60 men and 70 women) Greek participants with a mean age of 45±12 years who had clinic BP values <140/90 mm Hg and attended the cardiology department of our hospital. The whole study population underwent 24‐hour ambulatory BP monitoring (ABPM). According to the ABPM recordings, 24 individuals (8 men and 16 women) had MH (daytime systolic BP ≥135 mm Hg or daytime diastolic BP ≥85 mm Hg; group A), and the remaining 106 participants (52 men and 54 women) had normal ABPM findings (group B). The demographic characteristics of the participants as well as the variables included in the recent guidelines of the European Society of Hypertension to assess global cardiovascular risk are presented in Table I . Participants from both groups were taking no medication and were nonsmokers. All patients were on a usual diet before sampling, and none had any thyroid abnormalities. Alcohol consumption was expressed in grams per day and determined by a detailed questionnaire. Information concerning physical activity was obtained from a previously described questionnaire. Written informed consent was obtained from each participant; this was approved by the hospital review committee. At baseline, all participants underwent a physical examination with a medical history, laboratory assessment of risk factors for cardiovascular disease, and routine electrocardiography. I Demographic Characteristics and Laboratory Assessment of the Study Population G roup A ( n =24) G roup B ( n =106) P V alue Age, y 46±7 44±6 NS Sex (M/F) 11/13 52/54 NS BMI, kg/m 2 25.9±2.1 25.5±2.4 NS Clinic systolic BP, mm Hg 125±8 124±7 NS Clinic diastolic BP, mm Hg 80±3 79±4 NS Total cholesterol, mg/dL 234±26 232±25 NS HDL‐C, mg/dL 43±6 42±4 NS LDL‐C, mg/dL 160±30 156±27 NS Τriglycerides, mg/dL 99±31 102±32 NS Abbreviations: BMI, body mass index; BP, blood pressure; HDL‐C, high‐density lipoprotein cholesterol; LDL‐C, low‐density lipoprotein cholesterol; NS, not significant. Measurement of BP and Laboratory Assessment Systolic and diastolic BP were measured at the time of the first and fifth Korotkoff sounds, respectively. Measurements were made on the right arm to the nearest millimeter of mercury with the use of a mercury sphygmomanometer. All measurements were made in the supine position after the patient had rested for 15 minutes. Results recorded were the average of measurements obtained on at least 3 separate occasions by the same trained nurse, who was not aware of the history of the patients. The recruitment of persons with MH was performed according to the recently published guidelines of the European Society of Hypertension that define individuals with MH as those with clinic BP levels <140/90 mm Hg and daytime systolic BP values >135 mm Hg or daytime diastolic BP levels >85 mm Hg. BP measurements consisted of clinic BP (see above); home BP (average of morning and evening measurements, semiautomatic device); and ambulatory BP, with Spacelabs 90207 (Spacelabs Healthcare, Issaquah, WA), which recorded BP every 20 minutes during the daytime (between 10 am and 8 pm ) and every 30 minutes during the nighttime (between midnight and 6 am ) for 24 hours. Patients recorded a daily action profile from which information about the precise times of sleeping and waking were obtained. The onset of sleep was identified as the time that the participant went to bed. The participants were instructed to carry out normal daily activities during the monitoring period. Participants with normal BP values were recruited during preoperative (mainly orthopedic, ophthalmologic, etc) cardiac examination a few days prior to surgery. They were included if they were normotensive (clinic BP within normal values) and had no other serious illnesses; none were receiving any medication known to interfere with the studied parameters (eg, aspirin). Blood sampling was performed after 12 hours of fasting at 8 am to 9 am to determine adiponectin and resistin plasma levels. The adiponectin plasma levels (RD195023100; Human Adiponectin ELISA Bio Vendor Laboratory Medicine Inc, Brno, Czech Republic) and the resistin plasma levels (RD191016100; Human Resistin ELISA Bio Vendor Laboratory Medicine Inc.) were measured by immunoassay . Investigators performing the assays were not aware of the identity of the samples studied. Results are reported as concentrations of adiponectin (μg/mL) and as concentrations of resistin (ng/mL). Statistical Analysis Values are expressed as mean ± SD. Differences among the 3 groups were analyzed by one‐way analysis of variance (ANOVA). The variables that showed significant differences were compared afterward between each group by use of Bonferroni test for multiple comparisons. The correlations between variables were determined by use of Spearman’s correlation coefficient. A P value <.05 was accepted as statistically significant. Results Table I shows no statistical differences according to age, sex, or body mass index between the 2 groups. No differences were found concerning physical activity or alcohol consumption (data not shown). Table II summarizes significantly higher ( P <.01) resistin levels (12±4 vs 6.8±3.6 ng/mL) in group A compared with group B, while the adiponectin plasma levels were significantly lower in group A compared with group B (6±2.3 vs 11±2.7 μg/mL). II Resistin and Adiponectin Plasma Levels of the Study Groups G roup A ( n =24) G roup B ( n =106) P V alue Μean daytime systolic BP, mm Hg 138±6 122±7 <.01 Μean daytime diastolic BP, mm Hg 90±4 79±4 <.01 Adiponectin, μg/mL 6±2.3 11±2.7 <.001 Resistin, ng/mL 12±4 6.8±3.6 <.001 Abbreviation: BP, blood pressure. Discussion The current study demonstrated that mean adiponectin plasma levels were lower while mean resistin plasma levels were higher in patients with MH compared with healthy normotensive persons, even when age, sex, body mass index, and other laboratory markers for cardiovascular disease were matched for the 2 groups. Adipose tissue is now known as the largest endocrine organ of the human body. This tissue secretes a number of substances—adipocytokines—with multiple functions in the metabolic and immunologic process. Therefore, excessive fat mass may trigger metabolic and hemostatic disturbances as well as cardiovascular disease. Adipocytokines may act locally or distally as inflammatory, immune, or hormonal signallers. Adiponectin is the most abundant secretory protein in adipose tissue in humans with insulin‐sensitizing, anti‐inflammatory, and antiatherogenic properties. Recent cross‐sectional studies in humans have reported a significant negative correlation between adiponectin plasma levels and obesity, waist‐to‐hip ratio and insulin resistance, diabetic dyslipidemia, and cardiovascular disease. A negative correlation between adiponectin and BP levels has been observed in normotensive populations. Results of recent studies on adiponectin in hypertension have been inconsistent. High, low, or normal adiponectin levels (only in patients without insulin resistance) have been reported in patients with essential hypertension, while adiponectin plasma levels have been shown to be significantly lower in patients with prehypertension and in healthy offspring of hypertensive parents. These data are in agreement with our results. Resistin is a newly discovered adipocyte‐secreted polypeptide that has been implicated in the development of insulin resistance. It belongs to a family of cysteine‐rich secretory proteins collectively termed the resistin‐like molecules family and is also described as “adipose tissue secretory factor” or “FIZZ” found in inflammatory zones protein. In humans, resistin is expressed primarily in inflammatory cells and is detectable in adipose tissue at a very low level. There is no relationship between resistin expression and obesity. This protein is also detected in peripheral blood monocytes, suggesting a possible role in inflammatory processes. Recombinant resistin increases the expression of the adhesion molecules vascular cell adhesion molecule 1 and intracellular adhesion molecule 1, up‐regulates the monocyte chemoattractant chemokine‐1, and promotes endothelial cell activation via endothelin 1 release on human endothelial cells, suggesting a potential role in atherosclerosis. The relationship of resistin with inflammation, insulin resistance, and atherosclerosis in humans, however, remains largely unexplored. Studies concerning resistin levels in patients with hypertension are limited. Furuhashi and associates found that resistin levels are not related to insulin resistance, at least in patients with essential hypertension, while Zhang and colleagues pointed out a relationship between fasting serum resistin and blood glucose values in patients with essential hypertension and abnormal glucose tolerance. This suggests that resistin may be a mediator involved in the development of diabetes in humans. Recently, studies on healthy individuals with prehypertension and in healthy offspring of hypertensive parents have shown similar results. One limitation of our study is that we did not evaluate leptin and its receptors in plasma levels in our study population, given that accumulating evidence has suggested a close interaction between hyperleptinemia and hyperinsulinemia. Another limitation of our study is that we have not measured insulin resistance, which is a known factor influencing plasma adiponectin concentration. It should be stressed, however, that none of the studied participants were diabetic. The limitations of body mass index for estimating body fat are known, and it is possible that more accurate measures of adipose tissue mass might be necessary to categorically exclude obesity as a common antecedent. Therefore, we cannot exclude the possibility that patients with MH had greater body fat mass than normotensive participants and that increased body fat is the cause of the decreased plasma adiponectin concentration in patients with MH. Finally, we did not evaluate the adiponectin plasma concentrations according to sex because of the small sample size. To the best of our knowledge, this is the first study concerning adiponectin and resistin plasma levels in patients with MH. Conclusions Findings from the present study suggest that in the absence of major cardiovascular risk factors, patients with MH have significantly higher resistin plasma levels and lower adiponectin plasma levels compared with normotensive individuals, although we do not know the exact mechanism underlying these differences and recognize that they should be further investigated. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Clinical Hypertension Wiley

Masked Hypertension and Atherogenesis: The Impact on Adiponectin and Resistin Plasma Levels

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Publisher
Wiley
Copyright
© 2009 Wiley Periodicals, Inc.
ISSN
1524-6175
eISSN
1751-7176
DOI
10.1111/j.1751-7176.2008.00070.x
pmid
19222669
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Abstract

The phenomenon of masked hypertension (MH) is defined as a clinical condition in which patients’ office blood pressure (BP) values are <140/90 mm Hg but ambulatory or home BP readings are in the hypertensive range. Different BP thresholds have been proposed to define MH. It is difficult to compare the results from various laboratories. The prevalence of MH in the general population could be as high as 10%; data from several cross‐sectional studies have reported large differences with prevalence rates from a low of 8% to a high of 49%. A body of evidence indicates that MH is a significant predictor of cardiovascular disease, and MH is associated with increased left ventricular mass index and increased carotid intima‐media thickness. In longitudinal studies, MH has been shown to be a strong predictor of cardiovascular outcomes, mortality, and target organ damage. Adipocytes have recently been shown to secrete a variety of bioactive substances called adipocytokines, such as leptin, adiponectin, resistin, and visfatin, which have been recognized as endocrine cells. These adipocytokines contribute to the regulation of energy homeostasis by affecting insulin sensitivity, glucose and lipid metabolism, food intake, hemostatic/fibrinolytic balance, and inflammation. In contrast to many adipokines that are overproduced in obese individuals and exert deleterious effects on insulin sensitivity, lipoprotein metabolism, and the cardiovascular system, adiponectin seems to be a unique adipokine that is produced in smaller amounts in obese persons than in lean individuals and possesses predominantly beneficial characteristics (ie, increases insulin sensitivity, stimulates fatty acid oxidation, inhibits inflammatory reactions, and induces endothelium‐dependent nitric oxide–mediated vasorelaxation). Adiponectin knockout mice exhibit various manifestations of the metabolic syndrome such as insulin resistance, glucose intolerance, hyperlipidemia, impaired endothelium‐dependent vasorelaxation, and hypertension, as well as augmented neointima formation after vascular injury. Clinical studies indicate that plasma adiponectin concentration is lower in patients with essential hypertension and ischemic heart disease. Resistin belongs to a newly discovered protein family with no homology to any previously known proteins. These proteins are members of a cysteine‐rich secretory protein family called resistin‐like molecules found in inflammatory zones (FIZZ). FIZZ3 (resistin) is expressed exclusively in white adipose tissue. Resistin is detectable at a very low level in human adipose tissue, and there is no relationship between resistin expression and obesity. This protein is detected in peripheral blood monocytes, suggesting its possible role in inflammatory processes. The aim of our study was to examine adiponectin and resistin plasma levels in patients with MH and compare the findings with those of healthy normotensive persons matched for age, sex, body mass index, and other risk factors. Material and Methods The study was performed on 130 (60 men and 70 women) Greek participants with a mean age of 45±12 years who had clinic BP values <140/90 mm Hg and attended the cardiology department of our hospital. The whole study population underwent 24‐hour ambulatory BP monitoring (ABPM). According to the ABPM recordings, 24 individuals (8 men and 16 women) had MH (daytime systolic BP ≥135 mm Hg or daytime diastolic BP ≥85 mm Hg; group A), and the remaining 106 participants (52 men and 54 women) had normal ABPM findings (group B). The demographic characteristics of the participants as well as the variables included in the recent guidelines of the European Society of Hypertension to assess global cardiovascular risk are presented in Table I . Participants from both groups were taking no medication and were nonsmokers. All patients were on a usual diet before sampling, and none had any thyroid abnormalities. Alcohol consumption was expressed in grams per day and determined by a detailed questionnaire. Information concerning physical activity was obtained from a previously described questionnaire. Written informed consent was obtained from each participant; this was approved by the hospital review committee. At baseline, all participants underwent a physical examination with a medical history, laboratory assessment of risk factors for cardiovascular disease, and routine electrocardiography. I Demographic Characteristics and Laboratory Assessment of the Study Population G roup A ( n =24) G roup B ( n =106) P V alue Age, y 46±7 44±6 NS Sex (M/F) 11/13 52/54 NS BMI, kg/m 2 25.9±2.1 25.5±2.4 NS Clinic systolic BP, mm Hg 125±8 124±7 NS Clinic diastolic BP, mm Hg 80±3 79±4 NS Total cholesterol, mg/dL 234±26 232±25 NS HDL‐C, mg/dL 43±6 42±4 NS LDL‐C, mg/dL 160±30 156±27 NS Τriglycerides, mg/dL 99±31 102±32 NS Abbreviations: BMI, body mass index; BP, blood pressure; HDL‐C, high‐density lipoprotein cholesterol; LDL‐C, low‐density lipoprotein cholesterol; NS, not significant. Measurement of BP and Laboratory Assessment Systolic and diastolic BP were measured at the time of the first and fifth Korotkoff sounds, respectively. Measurements were made on the right arm to the nearest millimeter of mercury with the use of a mercury sphygmomanometer. All measurements were made in the supine position after the patient had rested for 15 minutes. Results recorded were the average of measurements obtained on at least 3 separate occasions by the same trained nurse, who was not aware of the history of the patients. The recruitment of persons with MH was performed according to the recently published guidelines of the European Society of Hypertension that define individuals with MH as those with clinic BP levels <140/90 mm Hg and daytime systolic BP values >135 mm Hg or daytime diastolic BP levels >85 mm Hg. BP measurements consisted of clinic BP (see above); home BP (average of morning and evening measurements, semiautomatic device); and ambulatory BP, with Spacelabs 90207 (Spacelabs Healthcare, Issaquah, WA), which recorded BP every 20 minutes during the daytime (between 10 am and 8 pm ) and every 30 minutes during the nighttime (between midnight and 6 am ) for 24 hours. Patients recorded a daily action profile from which information about the precise times of sleeping and waking were obtained. The onset of sleep was identified as the time that the participant went to bed. The participants were instructed to carry out normal daily activities during the monitoring period. Participants with normal BP values were recruited during preoperative (mainly orthopedic, ophthalmologic, etc) cardiac examination a few days prior to surgery. They were included if they were normotensive (clinic BP within normal values) and had no other serious illnesses; none were receiving any medication known to interfere with the studied parameters (eg, aspirin). Blood sampling was performed after 12 hours of fasting at 8 am to 9 am to determine adiponectin and resistin plasma levels. The adiponectin plasma levels (RD195023100; Human Adiponectin ELISA Bio Vendor Laboratory Medicine Inc, Brno, Czech Republic) and the resistin plasma levels (RD191016100; Human Resistin ELISA Bio Vendor Laboratory Medicine Inc.) were measured by immunoassay . Investigators performing the assays were not aware of the identity of the samples studied. Results are reported as concentrations of adiponectin (μg/mL) and as concentrations of resistin (ng/mL). Statistical Analysis Values are expressed as mean ± SD. Differences among the 3 groups were analyzed by one‐way analysis of variance (ANOVA). The variables that showed significant differences were compared afterward between each group by use of Bonferroni test for multiple comparisons. The correlations between variables were determined by use of Spearman’s correlation coefficient. A P value <.05 was accepted as statistically significant. Results Table I shows no statistical differences according to age, sex, or body mass index between the 2 groups. No differences were found concerning physical activity or alcohol consumption (data not shown). Table II summarizes significantly higher ( P <.01) resistin levels (12±4 vs 6.8±3.6 ng/mL) in group A compared with group B, while the adiponectin plasma levels were significantly lower in group A compared with group B (6±2.3 vs 11±2.7 μg/mL). II Resistin and Adiponectin Plasma Levels of the Study Groups G roup A ( n =24) G roup B ( n =106) P V alue Μean daytime systolic BP, mm Hg 138±6 122±7 <.01 Μean daytime diastolic BP, mm Hg 90±4 79±4 <.01 Adiponectin, μg/mL 6±2.3 11±2.7 <.001 Resistin, ng/mL 12±4 6.8±3.6 <.001 Abbreviation: BP, blood pressure. Discussion The current study demonstrated that mean adiponectin plasma levels were lower while mean resistin plasma levels were higher in patients with MH compared with healthy normotensive persons, even when age, sex, body mass index, and other laboratory markers for cardiovascular disease were matched for the 2 groups. Adipose tissue is now known as the largest endocrine organ of the human body. This tissue secretes a number of substances—adipocytokines—with multiple functions in the metabolic and immunologic process. Therefore, excessive fat mass may trigger metabolic and hemostatic disturbances as well as cardiovascular disease. Adipocytokines may act locally or distally as inflammatory, immune, or hormonal signallers. Adiponectin is the most abundant secretory protein in adipose tissue in humans with insulin‐sensitizing, anti‐inflammatory, and antiatherogenic properties. Recent cross‐sectional studies in humans have reported a significant negative correlation between adiponectin plasma levels and obesity, waist‐to‐hip ratio and insulin resistance, diabetic dyslipidemia, and cardiovascular disease. A negative correlation between adiponectin and BP levels has been observed in normotensive populations. Results of recent studies on adiponectin in hypertension have been inconsistent. High, low, or normal adiponectin levels (only in patients without insulin resistance) have been reported in patients with essential hypertension, while adiponectin plasma levels have been shown to be significantly lower in patients with prehypertension and in healthy offspring of hypertensive parents. These data are in agreement with our results. Resistin is a newly discovered adipocyte‐secreted polypeptide that has been implicated in the development of insulin resistance. It belongs to a family of cysteine‐rich secretory proteins collectively termed the resistin‐like molecules family and is also described as “adipose tissue secretory factor” or “FIZZ” found in inflammatory zones protein. In humans, resistin is expressed primarily in inflammatory cells and is detectable in adipose tissue at a very low level. There is no relationship between resistin expression and obesity. This protein is also detected in peripheral blood monocytes, suggesting a possible role in inflammatory processes. Recombinant resistin increases the expression of the adhesion molecules vascular cell adhesion molecule 1 and intracellular adhesion molecule 1, up‐regulates the monocyte chemoattractant chemokine‐1, and promotes endothelial cell activation via endothelin 1 release on human endothelial cells, suggesting a potential role in atherosclerosis. The relationship of resistin with inflammation, insulin resistance, and atherosclerosis in humans, however, remains largely unexplored. Studies concerning resistin levels in patients with hypertension are limited. Furuhashi and associates found that resistin levels are not related to insulin resistance, at least in patients with essential hypertension, while Zhang and colleagues pointed out a relationship between fasting serum resistin and blood glucose values in patients with essential hypertension and abnormal glucose tolerance. This suggests that resistin may be a mediator involved in the development of diabetes in humans. Recently, studies on healthy individuals with prehypertension and in healthy offspring of hypertensive parents have shown similar results. One limitation of our study is that we did not evaluate leptin and its receptors in plasma levels in our study population, given that accumulating evidence has suggested a close interaction between hyperleptinemia and hyperinsulinemia. Another limitation of our study is that we have not measured insulin resistance, which is a known factor influencing plasma adiponectin concentration. It should be stressed, however, that none of the studied participants were diabetic. The limitations of body mass index for estimating body fat are known, and it is possible that more accurate measures of adipose tissue mass might be necessary to categorically exclude obesity as a common antecedent. Therefore, we cannot exclude the possibility that patients with MH had greater body fat mass than normotensive participants and that increased body fat is the cause of the decreased plasma adiponectin concentration in patients with MH. Finally, we did not evaluate the adiponectin plasma concentrations according to sex because of the small sample size. To the best of our knowledge, this is the first study concerning adiponectin and resistin plasma levels in patients with MH. Conclusions Findings from the present study suggest that in the absence of major cardiovascular risk factors, patients with MH have significantly higher resistin plasma levels and lower adiponectin plasma levels compared with normotensive individuals, although we do not know the exact mechanism underlying these differences and recognize that they should be further investigated.

Journal

Journal of Clinical HypertensionWiley

Published: Feb 1, 2009

References