Abstract
Background
Little is known on the association of plasma adiponectin with blood pressure (BP) changes in African Americans (AAs). We evaluated the associations between plasma adiponectin and BP progression among AAs.
Methods
We analyzed data from 1,184 participants without hypertension at baseline (2000–2004) with ≥1 follow-up visits in the Jackson Heart Study. We used robust Poisson regression to generate risk ratios (RRs) for BP progression (an increase by ≥1 BP stage) and incident hypertension.
Results
Over a median of 7 years, 71% progressed to higher BP stage and 65% developed hypertension. We found evidence of interaction by sex (P-interaction = 0.088). Compared with those in the lowest quartile (Q1), male participants in the highest adiponectin quartile (Q4) had reduced risks of BP progression (RR 0.76 [95% confidence interval, CI, 0.60–0.96]) and incident hypertension (RR 0.74 [95% CI 0.56–0.97]). After accounting for body mass index, this relation persisted among obese men (RR for the highest [vs. lowest] adiponectin quartile: 0.59 [95% CI 0.36–0.97] for incident hypertension, and 0.69 [95% CI 0.45–1.06] for BP progression). Among women, adiponectin was not associated with BP outcomes (RR [95% CI] for Q4 vs. Q1: 1.03 [0.86–1.23] and 1.01 [0.83–1.23] for BP progression and incident hypertension, respectively). Our findings were consistent across both the American College of Cardiology (ACC)/American Heart Association (AHA) and Seventh Joint National Committee (JNC-7) BP categories.
Conclusions
In a large, community-based sample of AAs, higher adiponectin concentrations were associated with lower risks of BP progression and incident hypertension in men, but no significant association was observed in women.
Keywords: adiponectin, blacks, blood pressure, blood pressure progression, hypertension
Obesity and hypertension disproportionately affect African Americans (AAs).1,2 Measures of obesity such as body mass index (BMI) are positively associated with increases in blood pressure (BP) and a greater risk of hypertension.3,4 Adipose tissue is an endocrine organ that produces a variety of hormones known as adipokines.3,4 Adiponectin, one of the adipokines, is related to various cardiometabolic features including BMI, diabetes, coronary heart disease, and hypertension.4–7
Although plasma adiponectin concentrations have been shown to be inversely related to BP levels and hypertension in cross-sectional studies,7–9 there is a paucity of data on the relations of adiponectin to longitudinal BP changes and incident hypertension, specifically in AAs.8,10–12 Black individuals have higher rates of hypertension and BP levels compared with their white counterparts.13,14 Additionally, plasma adiponectin concentrations are lower in AAs compared with Caucasians.15,16 The Jackson Heart Study (JHS)17 allows a unique opportunity to assess whether relative hypoadiponectinemia accounts for the higher hypertension rates in AAs. We hypothesized that lower adiponectin concentrations will be associated with a greater progression of BP category and a higher incidence of hypertension in a community-based sample of AAs.
METHODS
Study design
The JHS is a longitudinal prospective study that recruited 5,306 AAs aged 21–94 years at the time of the baseline examination (2000–2004) from the Jackson, MS, metropolitan area.17 Two subsequent follow-up visits have been completed since baseline (2005–2008 and 2009–2013). Participants were excluded if they had hypertension at baseline (hypertension was defined as BP ≥130/80 mm Hg or use of blood antihypertensive medications),18 missing values of plasma adiponectin, missing BP measures, or missing information on the use antihypertensive medications. Supplementary Figure S1 online summarizes the exclusion process. The JHS study design and methods have been described previously.17 Informed consent was obtained from each participant, and the study protocol was approved by the institutional review board of the University of Mississippi Medical Center, Jackson State University, and Tougaloo College.
Adiponectin measurement
Plasma adiponectin was measured from venous blood samples collected from each participant at baseline after at least 8 hours of fasting, as described previously.17 Serum specimens were stored at the JHS repository in Minneapolis, MN, at −80 °C until they were assayed. The concentration of adiponectin was measured in 2008–2012 as total circulating adiponectin by ELISA (R&D Systems; Minneapolis, MN).19 The interassay coefficient of variation was 8.8%. No biological degradation has been reported using specimens, suggesting a high validity for our measurements.20
Blood pressure outcomes
At the first and second JHS examinations, systolic and diastolic BPs were obtained from the right arm twice using the random-0 BP sphygmomanometer (Hawksley and Sons Limited, Sussex, United Kingdom). The first BP was measured after allowing each participant to rest for 5 minutes in a seated position, and the second BP was measured after waiting 1 additional minute. The average of those two readings was used as the examination BP. At the third JHS examination, a semiautomatic oscillometric device (Omron HEM-907XL; Omron Healthcare, Lake Forest, IL) was used. A comparability study was conducted among the participants who had their BP measured concurrently using the random-zero sphygmomanometer and the oscillometric device at examination 2. The random-zero BP measurements were then calibrated to the semiautomated device using robust regression. The details of the calibration process have been described previously.21
The participants were classified according to their BP category defined by the 2017 American College of Cardiology (ACC)/American Heart Association (AHA) hypertension guidelines: normal (BP <120/80 mm Hg), and elevated (systolic 120–129 and diastolic <80 mm Hg).18
In the present investigation, we assessed 2 BP outcomes: (i) incident hypertension: defined as systolic BP ≥130 mm Hg, diastolic BP ≥80 mm Hg, or the use of antihypertensive medication at a follow-up visit; (ii) BP progression: defined as the increase in BP by at least 1 category during follow-up. BP categories considered in the analysis assessing BP progression are those from the 2017 ACC/AHA guidelines (normal BP <120/80 mm Hg, elevated BP [systolic 120–129 and diastolic <80 mm Hg], hypertension [BP ≥130/80 mm Hg or use of BP-lowering medications]).18
Assessment of covariates
Weight was measured to the nearest 0.1 kg and height to the nearest 1 cm. BMI (kg/m2) was calculated as weight in kilograms divided by height in meters squared. BMI was categorized as normal (BMI <25 kg/m2), overweight (BMI 25–29.9 kg/m2), and obese (BMI ≥30 kg/m2).22 Waist circumference was measured twice at the umbilicus with the participant in the upright position, to the nearest 1 cm and the average of 2 readings was used for the analysis. Abdominal obesity was defined as a waist circumference ≥88 cm in women and 102 in men.22 Current smoking was defined as self-reported smoking within the last 12 months (yes vs. no). Alcohol drinking was defined as regular drinking within the past year. Diabetes was defined as a self-report diagnosis of diabetes mellitus, fasting blood glucose ≥126 mg/dl or use of insulin or oral hypoglycemic agents.23 Ideal physical activity was defined based on the AHA guidelines as: (i) ≥150 minutes of moderate physical activity; or (ii) ≥75 minutes of vigorous physical activity; or (iii) ≥150 minutes of combined moderate and vigorous physical activity.24
Serum creatinine was measured using the rate Jaffe reaction, and the estimated glomerular filtration rate calculated by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation.25 Plasma total cholesterol, high-density lipoprotein cholesterol, and triglyceride levels were obtained using standard enzymatic techniques, on a Vitros 950 or 250, Ortho-Clinical Diagnostics analyzer (Raritan, NJ) in accordance with the College of American Pathologists Proficiency Testing Program.26 The Friedewald equation was used to calculate low-density lipoprotein cholesterol.27 High-sensitivity C-reactive protein was measured using standardized techniques.26 Data on medical history, medication use, current smoking, physical activity, and alcohol use were obtained using standardized questionnaires at the baseline visit.17
Statistical analyses
We performed sex-stratified analyses after finding statistically significant interaction by sex. Plasma adiponectin was analyzed both as continuous and categorical variables. For the analysis as a continuous variable, adiponectin values were log transformed as a result of their skewed distribution. Baseline characteristics of participants were compared across adiponectin quartiles using the analysis of variance or Kruskal–Wallis test for continuous variables, or the χ 2 test for categorical variables.
For each BP outcome, the follow-up time was calculated from the baseline examination to the earliest of visit at which the selected outcome occurred, death, or third examination. We performed two sets of analyses using Poisson regression with robust variance estimation. First, we assessed the relation of log-transformed adiponectin (continuous) or quartiles (categorical) to BP progression defined as an increase by ≥1 BP category. Second, we investigated the relation of log-adiponectin (continuous) or quartiles (categorical) to incident hypertension.
All regression models were constructed in a sequential fashion adjusting for age and sex (model 1); model 1 with further adjustment for current smoking, alcohol drinking, and physical activity (model 2); model 2 with further adjustment for estimated glomerular filtration rate, diabetes status, high-sensitivity C-reactive protein, statin use, and ratio of total to high-density lipoprotein cholesterol ratio (model 3). First-order statistical interaction terms were incorporated into the full model assessing the relation of adiponectin to BP outcomes according to sex. In additional analyses, we performed further adjustments for baseline BPs and stratified analyses by menopausal status among women, given that plasma adiponectin levels have been shown to vary by menopausal status.28 Furthermore, we conducted analyses stratified by BMI categories in order to explore the effect of plasma adiponectin across levels of adiposity.
Finally, we performed analyses using the Seventh Joint National Committee (JNC-7) guidelines instead of the 2017 ACC/AHA guidelines.29 The JNC-7 BP categories used in this analyses are: normal BP (systolic BP <120 mm Hg and diastolic BP<80 mm Hg), prehypertension (systolic BP 120–139 mm Hg and/or diastolic BP 80–89 mm Hg), and hypertension (systolic BP ≥140 mm Hg or diastolic BP ≥90 mm Hg self-reported use of BP-lowering medications).
Risk ratios (RRs) and their 95% confidence intervals (CIs) are presented. A 2-tailed probability value of <0.05 or <0.10 for interaction terms (in order to increase the power to detect interactions)30 was considered statistically significant. All analyses were performed using STATA 14.2 (Stata, College Station, TX).
RESULTS
The study sample consisted of participants (mean age, 48 [SD: 12] years, 64% women). Statistically significant effect modification by sex (P-interaction = 0.088). Thus, results are presented separately by sex. The baseline characteristics by sex-specific quartiles of plasma adiponectin are displayed in Tables 1 and 2.
Table 1.
Baseline characteristics of participants across quartiles of plasma adiponectin level in men (N = 423)
| Characteristics | Quartiles of plasma adiponectin level, ng/ml | P value | |||
|---|---|---|---|---|---|
| <2,040 (n = 106) | 2,040–3,054 (n = 106) | 3,054–4,900 (n = 106) | >4,900 (n = 105) | ||
| Age, years | 47.6 (11.5) | 47.9 (11.6) | 46.9 (12.2) | 49.2 (13.4) | 0.589 |
| Body mass index, kg/m2 | 30.1 (5.3) | 29.1 (5.2) | 28.1 (4.3) | 26.3 (5.6) | <0.001 |
| Obesity, %a | 45.2 | 34.9 | 34.5 | 18.1 | <0.001 |
| Waist circumference, cm | 101.2 (13.3) | 98.8 (13.2) | 95.4 (12.1) | 90.7 (15.4) | <0.001 |
| Abdominal obesity, %b | 44.1 | 41.0 | 35.7 | 15.7 | <0.001 |
| Systolic blood pressure, mm Hg | 116.0 (6.8) | 114.7 (7.7) | 115.2 (9.0) | 115.2 (8.6) | 0.701 |
| Diastolic blood pressure, mm Hg | 73.3 (5.2) | 72.3 (5.8) | 71.6 (4.9) | 71.8 (5.8) | 0.134 |
| Total cholesterol, mg/dl | 195.6 (39.4) | 199.6 (40.9) | 194.3 (42.7) | 194.5 (36.3) | 0.780 |
| HDL-C, mg/dl | 40.7 (10.8) | 43.5 (8.4) | 46.6 (11.0) | 52.2 (13.1) | <0.001 |
| LDL-C, mg/dl | 129.6 (38.9) | 134.6 (38.2) | 129.2 (41.9) | 127.3 (34.5) | 0.593 |
| Triglyceride, mg/dl | 126.9 (67.1) | 109.1 (68.3) | 92.6 (45.1) | 75.5 (55.6) | <0.001 |
| Total/HDL cholesterol | 5.0 (1.3) | 4.8 (1.5) | 4.4 (1.3) | 4.0 (1.5) | <0.001 |
| Fasting plasma glucose, mg/dl | 100.5 (37.2) | 95.2 (31.5) | 93.2 (25.9) | 89.4 (10.9) | 0.051 |
| HbA1C, % | 6.1 (1.7) | 5.7 (1.1) | 5.5 (1.0) | 5.5 (0.9) | 0.002 |
| Type 2 diabetes, % | 20.2 | 13.3 | 9.5 | 9.6 | 0.059 |
| Current smokers, % | 13.1 | 18.1 | 14.3 | 19.3 | 0.508 |
| Alcohol drinking, % | 60.7 | 68.7 | 64.3 | 61.5 | 0.743 |
| Ideal physical activity, % | 25.0 | 27.7 | 35.7 | 36.1 | 0.112 |
| Use of statin medication, % | 4.8 | 4.8 | 4.8 | 6.0 | 0.972 |
| eGFR, ml/min/1.73 m2 | 99.0 (15.6) | 102.8 (15.5) | 102.1 (17.5) | 103.4 (18.6) | 0.248 |
| hs-CRP, mg/dl, median (IQR) | 0.1 (0.1–0.3) | 0.2 (0.1–0.4) | 0.1 (0.1–0.3) | 0.1 (0.0–0.2) | 0.008 |
Values are reported as mean (SD), median (IQR), or proportion (%) as appropriate. Abbreviations: BMI, body mass index; eGFR, estimated glomerular filtration rate; HbA1C, hemoglobin A1C; HDL-C, high-density lipoprotein cholesterol; hs-CRP, high-sensitivity C-reactive protein; IQR, interquartile range; LDL-C, low-density lipoprotein cholesterol.
aDefined as BMI ≥30 kg/m2.
bDefined as waist circumference ≥102 cm.
Table 2.
Baseline characteristics of participants across quartiles of plasma adiponectin level in women (N = 761)
| Characteristics | Quartiles of plasma adiponectin level, ng/ml | P value | |||
|---|---|---|---|---|---|
| <3,190 (n = 191) | 3,190–4,945 (n = 190) | 4,945–7,188 (n = 190) | >7,188 (n = 190) | ||
| Age, years | 45.2 (10.6) | 46.5 (10.7) | 47.5 (11.4) | 50.5 (13.3) | <0.001 |
| Body mass index, kg/m2 | 32.9 (7.8) | 32.6 (7.6) | 31.2 (6.4) | 28.5 (6.2) | <0.001 |
| Obesity, %a | 62.4 | 58.3 | 49.7 | 35.9 | <0.001 |
| Waist circumference, cm | 100.0 (15.0) | 98.0 (16.3) | 93.0 (15.3) | 88.9 (15.2) | <0.001 |
| Abdominal obesity, %b | 77.7 | 78.2 | 61.2 | 48.7 | <0.001 |
| Systolic blood pressure, mm Hg | 112.6 (7.7) | 113.8 (8.9) | 112.9 (9.7) | 114.0 (8.3) | 0.151 |
| Diastolic blood pressure, mm Hg | 70.0 (5.2) | 71.0 (5.6) | 70.8 (5.7) | 70.0 (6.2) | 0.376 |
| Total cholesterol, mg/dl | 195.7 (40.8) | 190.2 (38.4) | 195.2 (34.5) | 196.4 (38.4) | 0.380 |
| HDL cholesterol, mg/dl | 48.9 (10.5) | 52.4 (10.8) | 54.6 (12.3) | 62.4 (14.8) | <0.001 |
| LDL cholesterol | 126.8 (36.9) | 120.7 (35.3) | 124.2 (32.0) | 120.0 (35.1) | 0.141 |
| Triglyceride, mg/dl | 102.9 (59.9) | 85.6 (46.2) | 82.0 (44.5) | 69.7 (35.9) | <0.001 |
| Total/HDL cholesterol | 4.2 (1.3) | 3.7 (1.0) | 3.7 (1.0) | 3.3 (0.9) | <0.001 |
| Fasting plasma glucose, mg/dl | 92.8 (18.2) | 89.3 (14.3) | 86.7 (12.5) | 89.2 (22.5) | 0.552 |
| HbA1C, % | 5.7 (0.9) | 5.5 (0.6) | 5.4 (0.5) | 5.4 (0.8) | 0.004 |
| Type 2 diabetes, % | 12.7 | 5.1 | 1.3 | 7.1 | 0.021 |
| Current smokers, % | 15.9 | 10.3 | 7.6 | 9.6 | 0.140 |
| Alcohol drinking, % | 51.0 | 51.9 | 51.6 | 48.1 | 0.823 |
| Ideal physical activity, % | 19.8 | 18.6 | 25.5 | 21.8 | 0.376 |
| Use of statin medication, % | 2.6 | 3.2 | 3.2 | 5.1 | 0.214 |
| eGFR, ml/min/1.73 m2 | 107.8 (17.7) | 105.4 (17.8) | 103.5 (19.0) | 104.1 (17.7) | 0.079 |
| hs-CRP, mg/dl, median (IQR) | 0.4 (0.2–0.8) | 0.3 (0.1–0.7) | 0.3 (0.1–0.6) | 0.1 (0.1–0.3) | <0.001 |
Values are reported as mean (SD), median (IQR), or proportion (%) as appropriate. Abbreviations: BMI, body mass index; eGFR, estimated glomerular filtration rate; HbA1C, hemoglobin A1C; HDL-C, high-density lipoprotein cholesterol; hs-CRP, high-sensitivity C-reactive protein; IQR, interquartile range; LDL-C, low-density lipoprotein cholesterol.
aDefined as BMI ≥30 kg/m2.
bDefined as waist circumference ≥88 cm.
Plasma adiponectin concentrations and BP progression
Over a median follow-up of 7 years (range: 4–11 years), 71.0% (n = 840) of study participants (71% of women) progressed to a higher BP category. Those with BP progression were older, more likely to be smokers and had lower baseline adiponectin levels (Supplementary Table S1 online). Table 3 illustrates the relation of log-adiponectin to BP progression by sex with increasing levels of adjustment. After adjustment for demographic and lifestyle variables, each SD increase in log-adiponectin was associated with a RR of 0.91 (95% CI 0.84–0.99, P = 0.026) of BP progression in men, although this association was unchanged after full adjustment (RR of 0.92 [95% CI 0.84–1.02], P = 0.108). In models assessing adiponectin as quartiles, a dose–response relation with BP progression was observed among male participants (Table 4). After full multivariable adjustment, men in the highest quartile (Q4) of adiponectin had a significantly lower risk of BP progression (RR 0.76 [95% CI 0.60–0.96], Ptrend = 0.039) compared with those in the lowest quartile (Q1), but no association was observed among women (RR for Q4 vs. Q1 was 1.03 [0.86–1.23], Ptrend = 0.631).
Table 3.
Relation of plasma adiponectin to blood pressure progression or incident hypertension stratified by sex (N = 1,184)
| Blood pressure progression | Incident hypertension | |||||||
|---|---|---|---|---|---|---|---|---|
| Men | Women | Men | Women | |||||
| Risk ratio (95% CI) | P value | Risk ratio (95% CI) | P value | Risk ratio (95% CI) | P value | Risk ratio (95% CI) | P value | |
| Model 1 | 0.92 (0.85–1.00) | 0.043 | 0.97 (0.92–1.03) | 0.376 | 0.91 (0.82–0.99) | 0.038 | 0.98 (0.92–1.04) | 0.502 |
| Model 2 | 0.91 (0.84–0.99) | 0.026 | 0.97 (0.92–1.03) | 0.374 | 0.90 (0.82–0.99) | 0.030 | 0.98 (0.91–1.04) | 0.450 |
| Model 3 | 0.92 (0.84–1.02) | 0.108 | 0.99 (0.93–1.06) | 0.852 | 0.90 (0.81–1.01) | 0.082 | 1.00 (0.93–1.07) | 0.951 |
Risk ratios are reported per 1-SD increase in ln(adiponectin). Abbreviation: CI, confidence interval. Blood pressure progression represents advancing upward by ≥1 category of blood pressure (BP) at a follow-up visit based on the 2017 American College of Cardiology (ACC)/American Heart Association (AHA) Guidelines. Incident hypertension is defined as BP ≥130/80 mm Hg or use of antihypertensive medication at a follow-up visit. Model 1 includes age and sex. Model 2: model 1 + current smoking, alcohol drinking (yes/no), physical activity. Model 3: model 2 + glomerular filtration rate, diabetes status, use of statin medication, high-sensitivity C-reactive protein, total cholesterol/(high-density lipoprotein cholesterol) ratio.
Table 4.
Incidence and risk ratios (95% CI) for blood pressure progression or incident hypertension by sex-specific quartiles of plasma adiponectin (N = 1,184)
| Adiponectin, ng/ml | Men | Women | ||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| <2,040 | 2,040–3,054 | 3,054–4,900 | >4,900 | P trend | <3,180 | 3,180–4,943 | 4,945–7,186 | >7,186 | P trend | |
| Blood pressure progression | ||||||||||
| Cases/no at risk | 86/106 | 73/106 | 75/106 | 68/105 | … | 130/191 | 148/190 | 124/190 | 136/190 | … |
| Model 1 | 1 (Reference) | 0.81 (0.67–0.98)* | 0.83 (0.69–1.01) | 0.74 (0.61–0.90)† | 0.007 | 1 (Reference) | 1.13 (0.97–1.31) | 0.93 (0.78–1.09) | 0.98 (0.83–1.15) | 0.282 |
| Model 2 | 1 (Reference) | 0.79 (0.65–0.96)* | 0.84 (0.69–1.02) | 0.72 (0.59–0.89)† | 0.006 | 1 (Reference) | 1.15 (1.00–1.34) | 0.94 (0.79–1.11) | 0.98 (0.83–1.15) | 0.278 |
| Model 3 | 1 (Reference) | 0.82 (0.67–1.01) | 0.87 (0.71–1.08) | 0.76 (0.60–0.96)* | 0.039 | 1 (Reference) | 1.17 (1.01–1.37)* | 0.97 (0.81–1.16) | 1.03 (0.86–1.23) | 0.631 |
| Incident hypertension | ||||||||||
| Cases/no at risk | 78/106 | 69/106 | 66/106 | 59/105 | … | 120/191 | 129/190 | 116/190 | 127/190 | … |
| Model 1 | 1 (Reference) | 0.85 (0.68–1.05) | 0.82 (0.65–1.03) | 0.71 (0.56–0.91)† | 0.007 | 1 (Reference) | 1.02 (0.86–1.21) | 0.92 (0.77–1.11) | 0.96 (0.81–1.15) | 0.453 |
| Model 2 | 1 (Reference) | 0.85 (0.68–1.05) | 0.83 (0.66–1.05) | 0.72 (0.56–0.91)† | 0.009 | 1 (Reference) | 1.04 (0.87–1.23) | 0.93 (0.78–1.12) | 0.96 (0.80–1.14) | 0.402 |
| Model 3 | 1 (Reference) | 0.89 (0.71–1.12) | 0.86 (0.67–1.10) | 0.74 (0.56–0.97)* | 0.034 | 1 (Reference) | 1.07 (0.90–1.27) | 0.97 (0.80–1.18) | 1.01 (0.83–1.23) | 0.829 |
Values reported are risk ratios (95% CI). Abbreviation: CI, confidence interval. Blood pressure progression represents advancing upward by ≥1 category of blood pressure (BP) at a follow-up visit based on the 2017 American College of Cardiology (ACC)/American Heart Association (AHA) Guidelines. Incident hypertension is defined as BP ≥130/80 mm Hg or use of antihypertensive medication at a follow-up visit. Model 1 includes age and sex. Model 2: model 1 + current smoking, alcohol drinking (yes/no), physical activity. Model 3: model 2 + glomerular filtration rate, diabetes status, use of statin medication, high-sensitivity C-reactive protein, total cholesterol/(high-density lipoprotein cholesterol) ratio.
*P < 0.05.
† P < 0.01.
Plasma adiponectin concentrations and incident hypertension
Over the 7-year follow-up, the incidence of hypertension was 64.5% (64.3% among men [n = 272] and 64.7% among women [n = 492]). Compared with those who did not develop hypertension, participants with incident hypertension were older, more likely to be smokers and had lower adiponectin levels at baseline (Supplementary Table S2 online). After adjustment for demographic and lifestyle variables, each SD increment in log-adiponectin was associated with reduced risk (RR 0.90 [95% CI 0.82–0.99], P = 0.030, Table 3) of hypertension in men, and this association was relatively unchanged after full adjustment (RR of 0.90 [95% CI 0.81–1.01], P = 0.082). A dose–response relation was noted for incident hypertension among men; with those in the higher quartile of adiponectin having a significantly reduced risk of incident hypertension compared with those in Q1 (RR 0.74 [95% CI 0.56–0.97], Ptrend = 0.034, Table 4). However, no significant association was noted among women (RR for Q4 vs. Q1 was 1.01 [95% CI 0.83–1.23], Ptrend = 0.829, Table 4).
In stratified analyses that further accounted for BMI, among obese men, we observed that higher adiponectin levels were associated with decreased risks of incident hypertension (Supplementary Table S3 online), with those in the highest (vs. lowest) adiponectin quartile having RRs of 0.59 (95% CI 0.36–0.97) for incident hypertension, and 0.69 (95% CI 0.45–1.06) for BP progression (Supplementary Table S4 online). Consistent with our main results, no significant association was found among women after stratification by BMI (Supplementary Tables S5 and S6 online).
Secondary analyses
In secondary analyses, we performed additional adjustments for baseline BP. These did not materially alter the direction or magnitude of our results (Supplementary Tables S7–S10 online). Notably, among obese men, the highest (compared with the lowest) adiponectin quartile was associated with RRs of 0.57 (95% CI 0.35–0.92) for incident hypertension, and 0.67 (95% CI 0.44–1.04) for BP progression after additional adjustment for baseline systolic and diastolic BPs. Among the 474 women with data on their menopausal status, in analyses stratified analyses by menopausal status, the estimates of association between plasma adiponectin and BP outcomes did not appear to differ between premenopausal and postmenopausal women (Supplementary Tables S11 and S12 online).
Finally, we used JNC-7 guidelines29 to define BP progression and incident hypertension (systolic BP ≥140 mm Hg, diastolic BP ≥90 mm Hg, or the use of antihypertensive medication). Consistent with our findings using the ACC/AHA guidelines to define BP elevation, log-adiponectin was negatively associated with BP progression and incident hypertension in men, but not in women (Supplementary Table S13 online). Using the JNC-7 classification of BP, male participants in the highest adiponectin quartile had a significantly lower risk of BP progression (RR 0.71 [95% CI 0.58–0.88], Ptrend = 0.003) and incident hypertension (RR 0.72 [95% CI 0.55–0.93], Ptrend = 0.014) compared with those in the lowest quartile (Supplementary Tables S14–S18 online).
Discussion
Our study prospectively investigated the effect of plasma adiponectin on BP tracking in a large entirely black cohort. Our results indicate sex differences in the association between plasma adiponectin concentrations and longitudinal BP progression. We observed a negative relation in men, mainly among obese individuals, but no association in women. These findings were consistent for both BP progression and hypertension incidence, and across the ACC/AHA and the JNC hypertension-based definitions of elevated BP.
Despite multiple mechanistic animal-based studies demonstrating antihypertensive properties of adiponectin,4,31 the evidence from prospective epidemiologic studies is still scant. Our findings of an inverse association between plasma adiponectin and longitudinal BP progression in men are consistent with several prior reports including US-based (Dallas Heart Study12) and non-US studies (Chinese and Japanese cohorts).32,33 Our finding of a lack of association between plasma adiponectin and BP changes among women is congruent with observations from the Danish Copenhagen City Heart Study (included 620 women),11 but is at odds with results from the Women’s Health Initiative-Observational Study (WHI-OS)10 and Dallas Heart Study12 which described an inverse association between plasma adiponectin and incident hypertension in women. However, none of these prior studies were done in an entirely black cohort. Furthermore, women in the WHI-OS study were all postmenopausal with an average age of 58 vs. 48 years in our study sample. This suggests that adiponectin may become protective against hypertension after they have reached menopause.
There are several potential mechanisms via which adiponectin is thought to have BP-lowering properties.4,34–44 One mechanism is related to the effect of adiponectin on endothelial function, which extant evidence suggesting that hypoadiponectinemia leads to endothelial dysfunction.4,34 Adiponectin is known to stimulate the activity of endothelial nitric oxide synthase, which increases the production of nitric oxide, a vasodilatory molecule.4,34 In animal studies, adiponectin-deficient mice exhibited an impaired nitric oxide production and endothelium-dependent vasodilation.35,36 Similarly, in humans, low adiponectin levels were associated with lower vasodilation response.37 Another mechanism is through the interaction of adiponectin with the renin–angiotensin system. Obesity is associated with overproduction of angiotensin II,4 which in turns inhibits the production of adiponectin via angiotensin receptor subtype 1.41 Indeed, clinical studies have shown that angiotensin II receptor blockers increase circulating adiponectin levels.38–40 In rats, angiotensin II infusion led to a significant reduction in circulating adiponectin levels.41 Another potential mechanism through which adiponectin may influence BP is via interaction with the sympathetic nervous system. The obese state is associated with a disproportionate activation of the sympathetic nervous system, which increases the heart rate, the peripheral vascular resistance, and eventually the BP.42 Sympathetic nervous system hyperactivity has been shown to suppress the expression of adiponectin.43 In a group of hypertensive patients, treatment with sympathetic nervous system blockers led to better BP control and increased circulating levels of adiponectin by 30%, independent of insulin resistance.44
Our results need to be interpreted in the context of a few limitations. One limitation is that plasma adiponectin was measured at baseline only. Therefore, we could not account for change in adiponectin in evaluating the relation of adiponectin with BP change. Additionally, we evaluated total adiponectin, but we did not assess the effects of high molecular weight adiponectin on BP outcomes.45 Notwithstanding these limitations, our study has multiple strengths. These strengths include the prospective design, the large community-based sample of nonhypertensive participants, the standardized measurements of adiponectin, BP and other covariates, and the robust adjustment for factors known to influence adiponectin and BP change.
The prevalence of hypertension in AAs in the United States is among the highest and is increasing at higher rates compared with other ethnicities.46,47 Cardiovascular sequelae of long-standing hypertension are also worse in AAs.48 Adiponectin appears as a biomarker that can be used to enhance early detection of individuals at risk for BP progression, thus improving the risk stratification and prevention of cardiovascular disease this high-risk group. Our results indicate that plasma adiponectin levels may already be reduced early in the course of hypertensive disease in black men, thus may have utility as a potential biomarker for BP progression in the clinical setting,49 but such a role remains to be investigated. Given that plasma adiponectin increases after treatment with certain BP medications,4 it carries a potential as therapeutic target for BP-reducing drugs.
In this large community-based cohort of middle-aged AAs, over an 8-year follow-up period, higher plasma adiponectin concentrations were independently associated with reduced hypertension incidence and BP progression in men, but not in women. Our findings point to the potential utility of adiponectin in predicting and preventing BP progression.
Supplementary Material
Acknowledgments
The authors wish to thank the staff and participants of the Jackson Heart Study for their valuable contributions.
Funding
The Jackson Heart Study is supported and conducted in collaboration with Jackson State University (HHSN268201800013I), Tougaloo College (HHSN268201800014I), the Mississippi State Department of Health (HHSN268201800015I), and the University of Mississippi Medical Center (HHSN268201800010I, HHSN268201800011I, and HHSN268201800012I) contracts from the National Heart, Lung, and Blood Institute (NHLBI) and the National Institute for Minority Health and Health Disparities (NIMHD). The views expressed in this manuscript are those of the authors and do not necessarily represent the views of the National Heart, Lung, and Blood Institute; the National Institutes of Health; or the U.S. Department of Health and Human Services. Dr Echouffo-Tcheugui was supported by NIH/NHLBI grant K23 HL153774.
DISCLOSURE
The authors declared no conflict of interest.
References
- 1. Flegal KM, Kruszon-Moran D, Carroll MD, Fryar CD, Ogden CL. Trends in obesity among adults in the United States, 2005 to 2014. JAMA 2016; 315:2284–2291. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2. Dorans KS, Mills KT, Liu Y, He J. Trends in prevalence and control of hypertension according to the 2017 American College of Cardiology/American Heart Association (ACC/AHA) Guideline. J Am Heart Assoc 2018; 7: e008888. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3. Bogaert YE, Linas S. The role of obesity in the pathogenesis of hypertension. Nat Clin Pract Nephrol 2009; 5:101–111. [DOI] [PubMed] [Google Scholar]
- 4. Wang ZV, Scherer PE. Adiponectin, cardiovascular function, and hypertension. Hypertension 2008; 51:8–14. [DOI] [PubMed] [Google Scholar]
- 5. Hui X, Lam KS, Vanhoutte PM, Xu A. Adiponectin and cardiovascular health: an update. Br J Pharmacol 2012; 165:574–590. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6. Ohashi K, Ouchi N, Matsuzawa Y. Adiponectin and hypertension. Am J Hypertens 2011; 24:263–269. [DOI] [PubMed] [Google Scholar]
- 7. Iwashima Y, Katsuya T, Ishikawa K, Ouchi N, Ohishi M, Sugimoto K, Fu Y, Motone M, Yamamoto K, Matsuo A, Ohashi K, Kihara S, Funahashi T, Rakugi H, Matsuzawa Y, Ogihara T. Hypoadiponectinemia is an independent risk factor for hypertension. Hypertension 2004; 43:1318–1323. [DOI] [PubMed] [Google Scholar]
- 8. Kim DH, Kim C, Ding EL, Townsend MK, Lipsitz LA. Adiponectin levels and the risk of hypertension: a systematic review and meta-analysis. Hypertension 2013; 62:27–32. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9. Adamczak M, Wiecek A, Funahashi T, Chudek J, Kokot F, Matsuzawa Y. Decreased plasma adiponectin concentration in patients with essential hypertension. Am J Hypertens 2003; 16:72–75. [DOI] [PubMed] [Google Scholar]
- 10. Wang L, Manson JE, Gaziano JM, Liu S, Cochrane B, Cook NR, Ridker PM, Rifai N, Sesso HD. Plasma adiponectin and the risk of hypertension in white and black postmenopausal women. Clin Chem 2012; 58:1438–1445. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11. Asferg C, Møgelvang R, Flyvbjerg A, Frystyk J, Jensen JS, Marott JL, Appleyard M, Jensen GB, Jeppesen J. Leptin, not adiponectin, predicts hypertension in the Copenhagen City Heart Study. Am J Hypertens 2010; 23:327–333. [DOI] [PubMed] [Google Scholar]
- 12. Peri-Okonny PA, Ayers C, Maalouf N, Das SR, de Lemos JA, Berry JD, Turer AT, Neeland IJ, Scherer PE, Vongpatanasin W. Adiponectin protects against incident hypertension independent of body fat distribution: observations from the Dallas Heart Study. Diabetes Metab Res Rev 2017; 33: 10. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13. Musemwa N, Gadegbeku CA. Hypertension in African Americans. Curr Cardiol Rep 2017; 19:129. [DOI] [PubMed] [Google Scholar]
- 14. Abraham PA, Kazman JB, Zeno SA, Deuster PA. Obesity and African Americans: physiologic and behavioral pathways. ISRN Obes 2013; 2013:314295. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15. Hulver MW, Saleh O, MacDonald KG, Pories WJ, Barakat HA. Ethnic differences in adiponectin levels. Metabolism 2004; 53:1–3. [DOI] [PubMed] [Google Scholar]
- 16. Khan UI, Wang D, Sowers MR, Mancuso P, Everson-Rose SA, Scherer PE, Wildman RP. Race-ethnic differences in adipokine levels: the Study of Women’s Health Across the Nation (SWAN). Metabolism 2012; 61:1261–1269. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17. Taylor HA Jr, Wilson JG, Jones DW, Sarpong DF, Srinivasan A, Garrison RJ, Nelson C, Wyatt SB. Toward resolution of cardiovascular health disparities in African Americans: design and methods of the Jackson Heart Study. Ethn Dis 2005; 15:S6-4-17. [PubMed] [Google Scholar]
- 18. Whelton PK, Carey RM, Aronow WS, Casey DE Jr, Collins KJ, Dennison Himmelfarb C, DePalma SM, Gidding S, Jamerson KA, Jones DW, MacLaughlin EJ, Muntner P, Ovbiagele B, Smith SC Jr, Spencer CC, Stafford RS, Taler SJ, Thomas RJ, Williams KA Sr, Williamson JD, Wright JT Jr. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Hypertension 2018; 71:1269–1324. [DOI] [PubMed] [Google Scholar]
- 19. Bidulescu A, Liu J, Musani SK, Fox ER, Samdarshi TE, Sarpong DF, Vaccarino V, Wilson PW, Arnett DK, Din-Dzietham R, Taylor HA, Gibbons GH. Association of adiponectin with left ventricular mass in blacks: the Jackson Heart Study. Circ Heart Fail 2011; 4:747–753. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20. Shand B, Elder P, Scott R, Frampton C, Willis J. Biovariability of plasma adiponectin. Clin Chem Lab Med 2006; 44:1264–1268. [DOI] [PubMed] [Google Scholar]
- 21. Seals SR, Colantonio LD, Tingle JV, Shimbo D, Correa A, Griswold ME, Muntner P. Calibration of blood pressure measurements in the Jackson Heart Study. Blood Press Monit 2019; 24:130–136. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22. Jensen MD, Ryan DH, Apovian CM, Ard JD, Comuzzie AG, Donato KA, Hu FB, Hubbard VS, Jakicic JM, Kushner RF, Loria CM, Millen BE, Nonas CA, Pi-Sunyer FX, Stevens J, Stevens VJ, Wadden TA, Wolfe BM, Yanovski SZ; American College of Cardiology/American Heart Association Task Force on Practice Guidelines; Obesity Society . 2013 AHA/ACC/TOS guideline for the management of overweight and obesity in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and The Obesity Society. J Am Coll Cardiol 2014; 63:2985–3023. [DOI] [PubMed] [Google Scholar]
- 23. American Diabetes Association. 2. Classification and diagnosis of diabetes: standards of medical care in diabetes-2021. Diabetes Care 2021; 44(Suppl 1):S15–S33. [DOI] [PubMed] [Google Scholar]
- 24. Lloyd-Jones DM, Hong Y, Labarthe D, Mozaffarian D, Appel LJ, Van Horn L, Greenlund K, Daniels S, Nichol G, Tomaselli GF, Arnett DK, Fonarow GC, Ho PM, Lauer MS, Masoudi FA, Robertson RM, Roger V, Schwamm LH, Sorlie P, Yancy CW, Rosamond WD; American Heart Association Strategic Planning Task Force and Statistics Committee . Defining and setting national goals for cardiovascular health promotion and disease reduction: the American Heart Association’s strategic Impact Goal through 2020 and beyond. Circulation 2010; 121:586–613. [DOI] [PubMed] [Google Scholar]
- 25. Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF III, Feldman HI, Kusek JW, Eggers P, Van Lente F, Greene T, Coresh J; CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) . A new equation to estimate glomerular filtration rate. Ann Intern Med 2009; 150:604–612. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26. Carpenter MA, Crow R, Steffes M, Rock W, Heilbraun J, Evans G, Skelton T, Jensen R, Sarpong D. Laboratory, reading center, and coordinating center data management methods in the Jackson Heart Study. Am J Med Sci 2004; 328:131–144. [DOI] [PubMed] [Google Scholar]
- 27. Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem 1972; 18:499–502. [PubMed] [Google Scholar]
- 28. Jürimäe J, Jürimäe T. Plasma adiponectin concentration in healthy pre- and postmenopausal women: relationship with body composition, bone mineral, and metabolic variables. Am J Physiol Endocrinol Metab 2007; 293:E42–E47. [DOI] [PubMed] [Google Scholar]
- 29. Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL Jr, Jones DW, Materson BJ, Oparil S, Wright JT Jr, Roccella EJ; National Heart, Lung, and Blood Institute Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure; National High Blood Pressure Education Program Coordinating Committee . The seventh report of the Joint National Committee on prevention, detection, evaluation, and treatment of high blood pressure: the JNC 7 report. JAMA 2003; 289:2560–2572. [DOI] [PubMed] [Google Scholar]
- 30. Marshall SW. Power for tests of interaction: effect of raising the Type I error rate. Epidemiol Perspect Innov 2007; 4:4. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31. Ohashi K, Kihara S, Ouchi N, Kumada M, Fujita K, Hiuge A, Hibuse T, Ryo M, Nishizawa H, Maeda N, Maeda K, Shibata R, Walsh K, Funahashi T, Shimomura I. Adiponectin replenishment ameliorates obesity-related hypertension. Hypertension 2006; 47:1108–1116. [DOI] [PubMed] [Google Scholar]
- 32. Chow WS, Cheung BM, Tso AW, Xu A, Wat NM, Fong CH, Ong LH, Tam S, Tan KC, Janus ED, Lam TH, Lam KS. Hypoadiponectinemia as a predictor for the development of hypertension: a 5-year prospective study. Hypertension 2007; 49:1455–1461. [DOI] [PubMed] [Google Scholar]
- 33. Imatoh T, Miyazaki M, Momose Y, Tanihara S, Une H. Adiponectin levels associated with the development of hypertension: a prospective study. Hypertens Res 2008; 31:229–233. [DOI] [PubMed] [Google Scholar]
- 34. Hattori Y, Suzuki M, Hattori S, Kasai K. Globular adiponectin upregulates nitric oxide production in vascular endothelial cells. Diabetologia 2003; 46:1543–1549. [DOI] [PubMed] [Google Scholar]
- 35. Ouchi N, Ohishi M, Kihara S, Funahashi T, Nakamura T, Nagaretani H, Kumada M, Ohashi K, Okamoto Y, Nishizawa H, Kishida K, Maeda N, Nagasawa A, Kobayashi H, Hiraoka H, Komai N, Kaibe M, Rakugi H, Ogihara T, Matsuzawa Y. Association of hypoadiponectinemia with impaired vasoreactivity. Hypertension 2003; 42:231–234. [DOI] [PubMed] [Google Scholar]
- 36. Ouedraogo R, Gong Y, Berzins B, Wu X, Mahadev K, Hough K, Chan L, Goldstein BJ, Scalia R. Adiponectin deficiency increases leukocyte-endothelium interactions via upregulation of endothelial cell adhesion molecules in vivo. J Clin Invest 2007; 117:1718–1726. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 37. Tan KC, Xu A, Chow WS, Lam MC, Ai VH, Tam SC, Lam KS. Hypoadiponectinemia is associated with impaired endothelium-dependent vasodilation. J Clin Endocrinol Metab 2004; 89:765–769. [DOI] [PubMed] [Google Scholar]
- 38. Furuhashi M, Ura N, Higashiura K, Murakami H, Tanaka M, Moniwa N, Yoshida D, Shimamoto K. Blockade of the renin-angiotensin system increases adiponectin concentrations in patients with essential hypertension. Hypertension 2003; 42:76–81. [DOI] [PubMed] [Google Scholar]
- 39. Watanabe S, Okura T, Kurata M, Irita J, Manabe S, Miyoshi K, Fukuoka T, Murakami K, Higaki J. The effect of losartan and amlodipine on serum adiponectin in Japanese adults with essential hypertension. Clin Ther 2006; 28:1677–1685. [DOI] [PubMed] [Google Scholar]
- 40. Yilmaz MI, Sonmez A, Caglar K, Celik T, Yenicesu M, Eyileten T, Acikel C, Oguz Y, Yavuz I, Vural A. Effect of antihypertensive agents on plasma adiponectin levels in hypertensive patients with metabolic syndrome. Nephrology (Carlton) 2007; 12:147–153. [DOI] [PubMed] [Google Scholar]
- 41. Ran J, Hirano T, Fukui T, Saito K, Kageyama H, Okada K, Adachi M. Angiotensin II infusion decreases plasma adiponectin level via its type 1 receptor in rats: an implication for hypertension-related insulin resistance. Metabolism 2006; 55:478–488. [DOI] [PubMed] [Google Scholar]
- 42. Mancia G, Bousquet P, Elghozi JL, Esler M, Grassi G, Julius S, Reid J, Van Zwieten PA. The sympathetic nervous system and the metabolic syndrome. J Hypertens 2007; 25:909–920. [DOI] [PubMed] [Google Scholar]
- 43. Imai J, Katagiri H, Yamada T, Ishigaki Y, Ogihara T, Uno K, Hasegawa Y, Gao J, Ishihara H, Sasano H, Oka Y. Cold exposure suppresses serum adiponectin levels through sympathetic nerve activation in mice. Obesity (Silver Spring) 2006; 14:1132–1141. [DOI] [PubMed] [Google Scholar]
- 44. Nowak Ł, Adamczak M, Wiecek A. Blockade of sympathetic nervous system activity by rilmenidine increases plasma adiponectin concentration in patients with essential hypertension. Am J Hypertens 2005; 18:1470–1475. [DOI] [PubMed] [Google Scholar]
- 45. Kadowaki T, Yamauchi T. Adiponectin and adiponectin receptors. Endocr Rev 2005; 26:439–451. [DOI] [PubMed] [Google Scholar]
- 46. Friedewald VE, Nesbitt SD, Ram CV, Roberts WC. The editor’s roundtable: hypertension in African Americans and other non-Caucasian ethnic groups. Am J Cardiol 2010; 106:1466–1472. [DOI] [PubMed] [Google Scholar]
- 47. Fiscella K, Holt K. Racial disparity in hypertension control: tallying the death toll. Ann Fam Med 2008; 6:497–502. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 48. Howard G, Prineas R, Moy C, Cushman M, Kellum M, Temple E, Graham A, Howard V. Racial and geographic differences in awareness, treatment, and control of hypertension: the REasons for Geographic And Racial Differences in Stroke study. Stroke 2006; 37:1171–1178. [DOI] [PubMed] [Google Scholar]
- 49. Kishida K, Funahashi T, Shimomura I. Adiponectin as a routine clinical biomarker. Best Pract Res Clin Endocrinol Metab 2014; 28:119–130. [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.