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Acute cardiometabolic responses facilitating a state of chronic hyperglycemia and renal impairment: the SABPA study

Joosten, Liezla; Malan, Leonéa; Uys, Aletta S.a; Alkerwi, Ala’ab; Malan, Nico T.a

Cardiovascular Endocrinology & Metabolism: September 2014 - Volume 3 - Issue 3 - p 98–106
doi: 10.1097/XCE.0000000000000019
Original articles

Background Augmented α-adrenergic response patterns are associated with vascular risk in Africans. Therefore, the aims of this study were (a) to assess ethnic differences related to glucose and cardiovascular responses during acute laboratory stress, and (b) to assess whether these responses are associated with chronic hyperglycemia (HbA1c≥5.7%) and albumin : creatinine ratio (ACR).

Materials and methods Ambulatory blood pressure of 81 African and 100 Caucasian men was recorded. Beat-to-beat blood pressure was obtained during exposure to the Color Word Conflict (STROOP) and Cold Pressor Tests (CPT). Overnight 8 h fasting urine, basal and post-stress blood samples were collected for biochemical analyses.

Results Augmented glucose responses (P<0.001) were shown by the African men in response to the STROOP and CPT, in contrast to their Caucasian counterparts, who showed attenuated responses. In hyperglycemic African men, an enhanced α-adrenergic profile was revealed, with decreased stroke volume (P=0.07) and cardiac output responses (P=0.05). Augmented systolic blood pressure changes during the CPT predicted elevated ACR in African men [adjusted R 2 0.31: β, 0.54 (0.23, 0.85), P=0.002]. In hyperglycemic Caucasian men, however, metabolic changes, that is augmented glucose changes to the STROOP test, predicted elevated ACR [adjusted R 2 0.19: β, 0.33 (0.02, 0.64), P=0.04].

Conclusion An α-adrenergic-driven cardiovascular response profile acted in tandem with augmented glucose responses in African men when exposed to acute laboratory stress. Pressure overload in Africans in contrast to metabolic responses in Caucasians may suggest different underlying mechanisms for ACR, a marker of renal impairment, when in a state of chronic hyperglycemia.

aHypertension in Africa Research Team (HART), School for Physiology, Nutrition, and Consumer Science, North-West University, Potchefstroom, South Africa

bResearch Centre (CRP-Santé), Luxembourg city, Luxembourg

Correspondence to Leoné Malan, RN, PhD, Hypertension in Africa Research Team (HART), School for Physiology, Nutrition, and Consumer Science, North-West University (Potchefstroom Campus), Private Bag x6001, Potchefstroom, 2520, South Africa Tel: +27 18 299 2438; fax: +27 18 299 1053; e-mail: leone.malan@nwu.ac.za

Received June 28, 2013

Accepted December 11, 2013

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Introduction

Sub-Saharan Africa is faced with major health problems related to cardiovascular and renal diseases. Generally, urban Africans from South Africa have a higher prevalence of hypertension and the metabolic syndrome than Caucasians 1–4. Prolonged or exaggerated cardiovascular reactivity in response to a mental stressor can promote the development of cardiovascular disease 5, with subsequent renal complications 6. At rest, and while experiencing a stressor, urban Africans and African–Americans demonstrate higher sympathetic activity as well as higher peripheral resistance responses compared with Caucasians 7,8.

According to other studies, mainly in white populations, mental stressors such as the STROOP Color Word Conflict Test (STROOP) stimulate mixed α-adrenergic and β-adrenergic receptors, whereas the Cold Pressor Test (CPT) predominantly stimulates α-adrenergic receptors 9. Mixed α-adrenergic and β-adrenergic stimulation elicits a myocardial reaction through central mechanisms, whereas α-adrenergic stimulation elicits a vascular response pattern through vascular mechanisms 9,10. The CPT also produces a pain stimulus, releasing β-endorphins which have a hyperglycemic effect 11. The CPT elicits sympathetically mediated spontaneous vasoconstriction with subsequent increases in total peripheral resistance (TPR), cardiac afterload, and diastolic blood pressure (DBP) 12. Exposure to acute stress may cause opposite glycemic effects. According to a study carried out by Fairclough et al. 13, blood glucose levels decreased with the STROOP as a result of increased energy metabolism. However, in another study, contradicting these results, acute stress induced a hyperglycemic response 14. Furthermore, chronic elevated blood glucose levels are a cause of microalbuminuria, a marker of endothelial dysfunction, and has been identified as an independent predictor for renal and/or cardiovascular disease 15–18. Whether this holds true for the South African population is uncertain. We hypothesize that differing mechanisms for renal damage may be ethnicity related; the differences may be attributed to exaggerated adrenergic responses among Africans.

To date, no literature exists on cardiovascular and glucose mental stress responses in the black African population of South Africa. The aims of this study were, therefore, (a) to assess whether there are African–Caucasian ethnic differences in acute glucose and cardiovascular responses during acute mental stress, and (b) to assess whether these responses are associated with renal impairment when a chronic hyperglycemic state (HbA1C>5.7%) is present.

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Methods

Study population

Our substudy is nested in the Sympathetic Activity and Ambulatory Blood Pressure in Africans (SABPA), which is a multidisciplinary target comparative population study, involving teachers from the Dr Kenneth Kaunda Education District, North West Province South Africa 10. To avoid seasonal variations, the study was successively carried out in 2008 and 2009 between February and May. African (n=100) and Caucasian (n=101) men of similar socioeconomic and educational status, aged between 25 and 60 years, were recruited. Our final analyzed sample for the present substudy comprised 181 teachers, African (n=81) and Caucasian (n=100), after exclusion of individuals with ear temperature exceeding 37.5°C, users of α-blocking and β-blocking agents, clinically diagnosed diabetes, and individuals with HIV-positive status and renal impairment.

Trained black African fieldworkers, including postgraduate students and a clinical psychologist, were involved during the execution phases of SABPA. Their tasks comprised participant recruitment, ambulatory blood pressure and ECG measurement, urine sampling, providing a standardized dinner, completion of psychosocial battery, general health and medical history questionnaires and individual feedback.

Before recruitment, participants were fully informed about the objectives and procedures of the study, and an informed consent document was signed by each participant. The study conformed to the ethical guidelines of the World Medical Association declaration of Helsinki and the Ethics Review Board of the North-West University (Potchefstroom Campus, South Africa) approved the study (Ethics number: 000 36 07 S6).

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Materials and methods

Study design and participants

During the working week, at ∼07:00–08:00 h, four teachers were fitted daily with the Cardiotens (Meditech CE120 Cardiotens; Meditech, Budapest, Hungary) to measure their ambulatory blood pressure and with the Actical apparatus (Actical accelerometers; Actical, Montreal, Quebec, Canada) to record their physical activity index and energy expenditure. The participants were encouraged to continue with their usual daily activities, but were asked to record, on their ambulatory diary cards, any abnormalities experienced during the day, such as nausea, headache, or stress. At a∼16:30 h of day 1, the participants were transported to the Metabolic Unit Research Facility, situated on the Potchefstroom Campus (North-West University), where each participant was allocated his/her own room. To reduce anticipation stress, the participants were familiarized with the experimental procedures to be followed the next day. Then, a standardized dinner was served, after which the participants fasted from 22:00 h.

At ∼05:45 h of day 2, participants were woken and at 06:00 h the Cardiotens was disconnected after the last blood pressure measurement. Then, 8-h overnight fasting urine and blood samples were collected, followed by anthropometric measurements. Beat-to-beat blood pressures and blood samples at rest as well as 10 min poststress samples were obtained (Fig. 1). Before they were transported back to their respective schools, participants received individual feedback on their collected data and were thanked for their participation.

Fig. 1

Fig. 1

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Anthropometric measurements

To ensure accuracy, triplicate anthropometric measurements were taken by trained personnel. For each participant, the maximum stature was measured to the nearest 0.1 cm with a stadiometer (Invicta Stadiometer; Invicta, London, UK), and the body weight was measured to the nearest 0.1 kg using a standardized calibrated digital electronic scale. These measurements were used to calculate the body surface area (BSA) according to the Mosteller formula [weight (kg)×height (cm)/3600]1/2 19. BSA is less affected by abnormal adipose mass and has been found to be a better indicator of metabolic mass than BMI 19.

In an upright standing position, the waist circumference was measured using a nonextensible and flexible anthropometric tape, at the midpoint between the lower costal rib and the iliac crest, perpendicular to the long axis of the trunk. Intraobserver and interobserver variability was less than 10%.

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Cardiovascular measurements

The Cardiotens is a 24-h blood pressure measurement (ABPM) apparatus validated by the British Hypertension Society. This apparatus was attached to the participant’s nondominant arm, using appropriate obese or nonobese cuff sizes, to measure blood pressure at 30 min intervals until 22:00 h and at 60 min intervals from 22:00 to 06:00 h. The ABPM data were analyzed using the CardioVisions 1.15.2 Personal Edition software (Meditech, Budapest, Hungary). The successful mean inflation rate was 82.7% (±3.8%) for African men and 94.6% (±3.7%) for Caucasian men.

Cardiovascular responses were recorded at rest and during exposure to the respective two mental stressors with the participant in a semirecumbent position for 10 min using the Finometer apparatus (Finapres Medical Systems, Amsterdam, the Netherlands). The Finometer has been validated for relative changes and measurements included systolic blood pressure (SBP), DBP, heart rate, cardiac output, stroke volume, TPR, and arterial compliance/Windkessel.

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Biochemical measurements

Resting plasma and serum samples were collected on the morning of day 2 by a registered nurse with a sterile winged infusion set from the brachial vein branches of the participant’s dominant arm and they were stored at −80°C till analyses. A small amount of anti-clotting solution (0.5 ml of a Heparin Sodium-Fresenius 5000 IU/ml in 50 ml isotonic saline solution) to prevent blood clotting was induced into the infusion set. The infusion set was flushed thoroughly with 2–3 ml saline and the 2 ml blood sample was discarded before poststress sampling was collected 10 min after stress. Fasting blood glucose samples were collected in sodium fluoride tubes and analyzed using a timed-end-point method (Unicel DXC 800; Beckman Coulter, Krefeld, Germany). The percentage glycosylated hemoglobin (HbA1c) was determined using the turbidimetric inhibition immunoassay with the Roche Integra 400 (Roche, Basil, Switzerland). According to the American Diabetes Association, the threshold level of HbA1c at 6.5% is sufficient to make a diagnosis of diabetes, whereas a level between 5.7 and 6.4% is an indicator of high-risk development of diabetes and cardiovascular diseases, and is known as a marker of ‘prediabetes’ 20. To assess the second study objective, we computed models to determine the interaction between main effects [ethnicity×HbA1c (HbA1c<5.7% and ≥5.7%)] in subsequent multivariate associations. Ultrahigh-sensitivity serum C-reactive protein (hs-CRP), cotinine (COT) as well as gamma glutamyl transferase (γ-GT) as markers of inflammation, smoking, and alcohol abuse, respectively, were analyzed using the sequential multiple analyzer computer (Konelab 20i; ThermoScientifica, Vantaa, Finland). The albumin : creatinine ratio (ACR), as a marker of microalbuminuria, was determined by analysis of an 8 h overnight fasting urine sample stored at 4°C for 1 h after collection and frozen at −80°C till analyses. Analysis was carried out using the sequential multiple analyzer involving the measurement of immunoprecipitation enhanced by polyethylene glycol at 450 nm.

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Mental stress testing

Following the measurement of resting blood pressure and blood sampling, blood pressure was stabilized to resting state after ∼5–10 min (Fig. 1). The participants were then exposed to mental stressors applied in a counterbalanced design. Throughout mental stress testing, beat-to-beat blood pressure responses were obtained. The STROOP and the CPT were each applied for 1 min. The STROOP test requires identification by the participant of the ink color of the word rather than the name of the color spelled by the word, under time pressure. The participants received a small monetary motivational reward in line with performance. Another blood sample was collected 10 min after stress and the second stressor commenced after a 20 min rest period. If resting blood pressure was ensured, the second stressor, for example the CPT, was applied. The participant had to immerse his/her foot up to the ankle in 4°C ice water. To prevent erratic breathing and hyperventilation because of the cold exposure, the participants were encouraged to count quietly to themselves. Further poststress blood samples were collected.

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Statistical analysis

Statistica version 10 (Statsoft Inc., Tulsa, Oklahoma, USA) was used for database management and statistical analysis. The Shapiro–Wilk test computed normality distributions and hs-CRP and γ-GT were logarithmic transformed. Means and proportions for ethnic groups were compared using independent t-tests and χ 2-test, respectively. Significant differences, computed using independent t-tests, identified the covariates as BSA, physical activity, and log γ-GT. Analysis of covariance (ANCOVA), using least square means, was carried out to determine significant differences between ethnic groups for glucose and cardiovascular variables during each stressor. Glucose and cardiovascular responses during the mental stressors were determined as percentage change from the resting state using the formula (stressor−rest)/(rest×100). Resting values were added as covariates for glucose and cardiovascular responses.

Two-way ANCOVA interactions on main effects (ethnicity×HbA1c) were computed for all glucose and cardiovascular variables. Subsequent one-way ANCOVA analyses, using least square means, were carried out on glucose and cardiovascular responses for each stressor. The aforementioned covariates were considered.

Univariate and multivariate regression analyses were carried out, independent of confounding markers (BSA, physical activity, and log γ-GT), for each stressor. Forward stepwise linear regression analysis models were used to determine associations between the dependent variable, ACR, and the independent variables, that is glucose and cardiovascular responses. Models 1 (CPT) and 2 (STROOP) included the total ethnic male groups. Models 3–4 included associations between ACR and independent variables, that is glucose and cardiovascular responses in hyperglycemic African men (HbA1c≥5.7%) for each stressor. Models 5–6 included associations between ACR and independent variables, that is glucose and cardiovascular responses, in hyperglycemic Caucasian men (HbA1c≥5.7%) for each stressor. In all models, the following independent covariates were included: BSA, physical activity, log γ-GT, log CRP, glucose, and cardiovascular changes as well as resting responses. Results were considered to be significant at the 5% critical level (P<0.05) and trend set at the 1% level (P<0.1).

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Results

Characteristics of the participants

Table 1 describes the characteristics of the African and Caucasian men. Compared with the Caucasians, the Africans had significantly lower BSA (P<0.001) and waist circumference (P=0.001), were less physically active (P<0.001), consumed more alcohol (P<0.001), had higher C-reactive protein levels (P=0.002), higher ACR (P<0.001), and higher ambulatory systolic (P<0.001) and diastolic (P<0.001) blood pressures.

Table 1

Table 1

In response to the CPT and STROOP tests (Fig. 2), African men showed significantly augmented glucose responses (P<0.01) compared with their Caucasian counterparts, who showed attenuated responses, independent of covariates. The African men showed elevated heart rate responses (P<0.01) during the CPT as well as higher α-adrenergic vascular and lower β-adrenergic responses 10 for both mental stressors, independent of potential confounders and resting values. African men showed lower cardiac output and stroke volume changes as well as a trend for DBP changes (P=0.08) (latter not shown).

Fig. 2

Fig. 2

A single two-way significant interaction on main effects (ethnicity×HbA1c) was evident for ACR [F(1,171), 3.90; P=0.05]. Ethnic groups were then stratified into high (≥5.7%) and low (<5.7%) hyperglycemic groups. A similar trend to that observed in the total ethnic male groups were evident in the hyperglycemic men. In Fig. 3, African men showed a smaller elevation in heart rate responses (P=0.03) during the STROOP as well as more α-adrenergic vascular response and lower β-adrenergic responses 10 for both mental stressors, independent of potential confounders and resting values. They also showed smaller increases in cardiac output responses (P=0.05), a trend toward lower stroke volume (P=0.07), and higher DBP responses (hyperglycemic Africans, 15.28% vs. hyperglycemic Caucasians, 9.98%; P=0.06) (not shown). Nonsignificant TPR enhanced responses were also evident in African men, but huge variations in changes were mostly responsible for the lack of significance (26–52%).

Fig. 3

Fig. 3

In Table 2, in models 1 and 2 for the total African male groups, only resting glucose predicted elevated ACR. No associations existed between resting glucose and ACR in Caucasian men. In model 3, augmented SBP responses to the CPT were associated with elevated ACR in hyperglycemic African men (HbA1c≥5.7%). However, in model 6, blunted SBP and enhanced glucose responses to the STROOP test were associated with elevated ACR in hyperglycemic Caucasian men (HbA1c≥5.7%).

Table 2

Table 2

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Discussion

We aimed to assess whether there are African–Caucasian ethnic differences in acute glucose and cardiovascular responses during exposure to acute mental stress. Furthermore, we assessed whether these responses are associated with chronic elevated glucose levels, as well as ACR, which may lead to target organ damage. The main findings from the present study indicated that a more α-adrenergic-driven cardiovascular response profile acted in tandem with augmented glucose responses in African men when exposed to acute laboratory stress. Pressure overload in Africans, in contrast to enhanced metabolic responses in Caucasians, suggests different underlying mechanisms for the development of renal impairment when in a state of chronic hyperglycemia.

Inconsistent with the reports of Moan et al. 21 and Armanio et al. 22, where hyperglycemia was induced in Caucasians by various mental stressors, our study showed blunted responses induced during mental stress in the Caucasian men even in a hyperglycemic state. Fairclough et al. 13 obtained similar results on exposure to the STROOP test. In contrast, augmented responses were observed in the Africans irrespective of the stressor. In-vivo studies carried out on rodents showed that blood glucose levels are elevated by α-adrenergic stimulation of the liver 23. This is in agreement with our findings, where a more α-adrenergic response pattern shown by the Africans was coupled to augmented blood glucose responses. Glucose response patterns were also the same in both ethnic races, independent of the glycemic state. The role of the perception of pain during the CPT, however, must also not be underestimated as it could elevate blood glucose levels through the release of β-endorphins, stimulating hyperglycemia 11,24,25. Reimann et al. 11 reported that black Africans show a more pronounced CPT-induced increase in heart rate and blood pressure, which may be attributed to greater pain-related increments in blood pressure. A higher cognitive appraisal of pain and a blunted baroreflex-mediated dampening of autonomic structures may, therefore, contribute toward the exaggerated blood pressure reactivity in black Africans.

In both ethnic groups, considerably higher mean SBP to the CPT compared with the STROOP indicated the association between high blood pressure, pain, and/or temperature 26. The hyperglycemic responses observed in the Africans may also be as a result of urban Africans experiencing more psychosocial stress and coping disability 27. Therefore, their augmented cardiovascular responses may reflect heightened sympathetic activity, possibly promoting insulin resistance 24,28.

These findings are supported by the African men showing a more dominant α-adrenergic-driven response pattern, with a trend of augmented DBP responses during the CPT, and smaller heart rate responses to the STROOP. These vascular response patterns 10 were significantly stronger when observed in a state of chronic hyperglycemia, with HbA1c higher than the ‘prediabetic’ indicator of 5.7%. Significantly lower responses of the African men with respect to β-adrenergic responses, that is heart rate, cardiac output, and stroke volume to the STROOP test, are coupled to a trend of higher DBP responses compared with their Caucasian counterparts. This indicates a strong α-adrenergic driven response pattern by the African men, even though the STROOP normally evokes mixed α-adrenergic and β-adrenergic responses 10.

Interestingly, a strong significant difference was found in the heart rate responses during the CPT, with the African men showing higher responses compared with the Caucasian men. MacArthur and MacArthur 9 maintained that with the CPT, moderate increases in heart rate indicating β-adrenergic-like patterns may be observed, especially when the individuals hyperventilate. However, significantly higher heart rate responses were observed in the Africans compared with Caucasians. Another possible explanation to these findings is that CRP levels in the African men could also alter β-adrenergic signaling, possibly lowering β-adrenergic responsiveness, favoring the α-vascular responses. Malan et al. 10 reported that this may be the case as time-domain depressed heart rate variability confirmed increased α-adrenergic responses. Our main findings are consistent with previous research that Africans are more prone to a vascular response pattern in comparison with their Caucasian counterparts 7,29.

The metabolic responses in the Caucasian men predicted elevated ACR, additionally underscoring the possible development of metabolic syndrome. The Caucasian men showed significantly higher mean waist circumference values in a crude analysis. However, after adjusting for BSA, physical activity, and alcohol abuse, the African men had significantly higher mean waist circumference values. Following the guidelines of the Joint Interim Statement Consensus 30, Hoebel et al. 3 found a higher prevalence of the metabolic syndrome in the African men (65%) compared with Caucasian men (47%). The Joint Interim Statement Consensus suggested a waist circumference cut-point of 94 cm for Europids 30. So far, no ethnic-specific cut-points for sub-Saharan Africans exist. Recently, Prinsloo et al. 31 took up the challenge of developing new ethnicity-specific proposed models to indicate waist circumference cut-points with receiver operating characteristics (area under the curve) analyses. It was proposed that in the African men, their blood pressure responses predicted the best waist circumference cut-point, namely 90 cm 31. If these findings are coupled to significantly higher C-reactive protein levels, indicating inflammatory responses, an increased risk for cardiometabolic morbidity and events may be indicated in these African men 32,33.

Microalbuminuria is a marker of endothelial dysfunction and associated with cardiovascular disease and diabetes mellitus. It is measured by the urinary albumin excretion and can be expressed as the ACR 18,20,34. In a 24-year follow-up study, Meigs et al. 35 showed that chronically elevated blood glucose levels were indicated as a causal factor of microalbuminuria. To determine independent predictors of ACR, associations between acute mental stress cardiometabolic responses and ACR in a state of chronic hyperglycemia, models were computed. In the African men, augmented SBP changes to the CPT were associated with ACR, whereas blunted SBP changes to the STROOP test were associated with ACR in the Caucasian men. Heightened blood pressure changes coupled to chronic hyperglycemia could lead to endothelial damage 36. Modification of the glycocalyx because of glycation of the membrane proteins leads to charge selectivity loss, as well as glomerular hyperfusion and hyperfiltration 37,38. Subsequent albumin leakage through the glomerular capillaries will elevate the ACR 39.

A major limitation of the present study is related to the cross-sectional design, which precludes any causal relationship, particularly for long-term renal damage, emphasizing therefore the need for a follow-up study to show causal relationships. However, the strength of the study is that novel data were obtained in a well-controlled design and setting. To conclude, our study showed proneness for a more α-adrenergic-driven cardiovascular response in tandem with an augmented glucose response profile in African men when exposed to acute laboratory stress. Caucasian men, however, showed blunted glucose responses whereas, when in a hyperglycemic state, their glucose responses to the STROOP test were associated with ACR. It seems that pressure overload in Africans, in contrast to metabolic responses in Caucasians, suggests different underlying mechanisms for ACR, a marker of renal impairment, when in a state of chronic hyperglycemia. Elevated ACR as an indicator of endothelial dysfunction, therefore, poses an increased risk for hypertension and renal damage in the men 18.

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Acknowledgements

The authors acknowledge the voluntary collaboration of the participants. This study was funded by the North-West University, the National Research Foundation, Roche Diagnostics, South Africa, South African Medical Research Council, and the Metabolic Syndrome Institute, France.

The funding organizations played no role in the design and conduct of the study; collection, management, analysis and interpretation of the data; preparation, review, or approval of the manuscript.

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Conflicts of interest

There are no conflicts of interest.

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Keywords:

Africans; albumin; blood pressure; creatinine; glucose

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