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Attenuated NOx responses and myocardial ischemia, a possible risk for structural vascular disease in African men: the SABPA study

Abstract

Chronically elevated blood pressure has been associated with impaired NO-mediated vasodilation and structural vascular disease risk. This study aimed to determine whether significant associations exist regarding NO metabolite (NOx) responses, cardiovascular function and structural vascular disease in a cohort of African and Caucasian men. The study included 81 African and 94 Caucasian male teachers stratified via median splits into low and high NOx ethnic groups. Ambulatory blood pressure, electrocardiogram monitoring and ultrasound carotid intima-media thickness (CIMT) images were obtained. Cardiovascular measurements and fasting blood for NOx responses were measured during rest and on challenging the cardiovascular system with the Stroop colour-word conflict test. African men displayed significantly higher resting NOx as well as higher number of 24 h silent ischemic events than their Caucasian counterparts. Low NOx African men displayed enhanced α-adrenergic and ECG ST segment depression acute mental stress responses as well as 24 h silent ischemic events associated with CIMT (adjusted R2=0.47; β=0.25; confidence interval (CI)=0.13, 0.41). African men demonstrated a vulnerable cardiovascular profile. Novel findings revealed α-adrenergic-driven blood pressure responses and less NO bioavailability during acute stress. The association between myocardial ischemia and CIMT in this group emphasized their risk for future coronary artery disease and cerebrovascular events.

Introduction

Hypertension is a challenging health problem in South Africa,1 specifically for urban black African men.2 Chronic psychosocial stress because of everyday life demands, if residing in an urban environment, has been established as a contributing factor to the poor cardiovascular profile of this population group.3 Research has indicated that psychosocial stress and subsequent chronically elevated blood pressure is associated with impaired NO-mediated vasodilation.4 Reduced bioactivity of NO particularly reduces coronary artery dilation.5 In concert with a pro-atherogenic environment where leukocyte adhesion and platelet activation are no longer reduced by NO,6 the risk for coronary artery disease is significantly increased.7

Cardillo et al.8 indicated a possible link between a reduced sensitivity of the vascular smooth muscle for NO and reduced vasodilation during mental stress in African Americans. This positive association may have a significant role in the higher prevalence of hypertension among blacks. Whether this relationship also applies to urban black South African men is not known.

Reduced NO bioavailability during acute and chronic mental stress may contribute to a higher prevalence of myocardial ischemic responses in African men.5 Taking into account the poor cardiovascular profile, urban African men may be a highly susceptible group for structural vascular disease, particularly with an increased risk for coronary artery disease7 as well as future cardiovascular events.9 The aim of this study was to explore the relationship between NO metabolite (NOx) responses to a mental stressor, cardiovascular function and structural vascular disease in a cohort of African and Caucasian men.

Materials and methods

Study design and participants

The Sympathetic activity and Ambulatory Blood Pressure in Africans (SABPA) study was conducted in February–May in 2008 and 2009 as a target population comparative study. Our sub-study included 81 African and 94 Caucasian male teachers, working in the Dr Kenneth Kaunda Education district of the North West Province (South Africa). This participant selection was to obtain a homogenous sample from similar socio-economic class. Exclusion criteria were ear temperature >37.5 °C, vaccinated or blood donors in previous 3 months, HIV-positive status, clinically diagnosed diabetes mellitus and use of alpha-, beta blockers, statin medication and psychotropic substance use.

The study protocol complied with institutional guidelines as well as those of the Declaration of Helsinki (as revised in 2004) for investigation in human subjects. It was approved by the Ethics Review Board of the North-West University (Project number: NWU-00036-07-S6).

Ambulatory blood pressure measurements (ABPMs)

ABPMs were conducted during working days of the week. Each morning at 0700–0800 participants were fitted with a British Hypertension Society validated Cardiotens CE12 apparatus (Meditech CE120, Budapest, Hungary), which measured 24-h blood pressure and two-channel electrocardiogram (ECG). Cuffs were applied to the non-dominant arms. ABPM was obtained oscillometrically in 30 min intervals during the day (0800–2200 h) and in 60-min intervals during the night (2200–0600 h). The mean successful inflation rate was 75% (±9.8%) for the African and 85% (±9.1%) for the Caucasian men. Ambulatory ECG was recorded in 5 min intervals for 20 s. Participants were also fitted with Actical accelerometers (Montréal, Québec, Canada) over the ambulatory period to measure physical activity with resting metabolic rate taken into account. Participants were asked to continue with their normal daily routine, recording in an ambulatory diary card, any abnormalities experienced such as headache, nausea, dizziness, visual disturbances and fatigue. At 1630 h, participants were transported to the Metabolic Unit Research Facility of the North-West University for an overnight stay. On arrival, they were introduced to the experimental setup to lessen anticipation stress,10 which included a brief introduction to the Stroop colour-word conflict test. Participants completed general health questionnaires on their medical history and prescribed medications. After having received a standardized dinner, participants were requested to go to bed at 2200 h, fasting overnight.

The following morning at 0600 h (after the last blood pressure measurement) the ABPM and Actical apparatus were disconnected. Following anthropometric measurements, participants remained in a semi-recumbent position for 2 h for a series of cardiovascular measurements. A resting 12-lead ECG was recorded for six cardiac cycles as well as a 5-min reading of beat-to-beat measurement of cardiovascular variables using the Finometer, which is validated for relative changes (Finapres Medical Systems, Amsterdam, the Netherlands). Hereafter, venous blood samples were obtained by a registered nurse, using a sterile winged infusion set was left in situ with a heparin block (0.5 ml of a Heparin Sodium-Fresenius 5000 IU ml−1 in 50 ml normal saline solution) to prevent blood clotting. A rest period was allowed for 5–10 min before participants were exposed to the Stroop colour-word conflict test, known to evoke a mixed α-β adrenergic response at the heart and vasculature.11 Successive series of five colour words written in incongruent colours on a cardboard were shown to the participant in a random order. The participants were instructed to recognize and verbally confirm the colour of a given word within a certain time limit. A monetary incentive was given as motivation on completing the test. The stressor was applied for 1 min, which was followed by blood sample collection after the infusion set was thoroughly flushed with 2–3 ml saline and 2 ml blood sampling was discarded before sampling was done 10 min poststress. A dominant α-adrenergic response pattern is characterized by an increase in total peripheral vascular resistance and diastolic blood pressure as well as a decrease of arterial compliance (Cw).12 An increase in heart rate, systolic blood pressure and cardiac output (CO) are all characteristic of a dominant β-adrenergic response pattern.11 Beat-to-beat cardiovascular (Finometer) and 12-lead ECG measurements were also obtained during stressor application. The last 15 s of the ECG and cardiovascular measurements obtained during stress exposure were used for data analyses.

To determine the presence of structural vascular disease, the carotid intima-media thickness of the far wall (CIMTf) was measured with a SonoSite Micromaxx ultrasound system (SonoSite, Bothell, WA, USA) and a 6–13 MHz linear array transducer. A high-resolution image of the left and right common carotid artery was obtained from two optimal angles.13 Images were digitized and imported into the Artery Measurement System II Version 1.139 automated software (Gothenberg, Sweden). From an image of good quality, the far wall of a 10-mm segment was chosen for CIMTf analysis. CIMTf of 0.9 mm indicates structural vascular disease14 and a CIMTf of 0.75 mm indicates an increased stroke risk.15

Anthropometric measurements

Registered anthropometrists obtained anthropometric measurements in triplicate according to standards of the International Society of the Advancement of Kinanthropometry.16 Body mass was measured to the nearest 0.1 kg with a digital scale and height was measured to the nearest 0.1 cm with a stadiometer. The body surface area was calculated using the Mosteller formula.17

Cardiovascular measurements

ABPM data were downloaded into a database and processed using the CardioVisions 1.15.2 software. Before analysis, ABPM and ECG data are automatically cleaned by the CardioVisions 1.15.2 (Meditech CE120, Budapest, Hungary) software to remove noise. From the two-channel ECG recording, ischemic events were recorded according to the 1-1-1 rule, which entails a horizontal or descending ST-segment depression by 1 mm; duration of the ST-segment episode of at least 1 min and a 1 min interval from previous episodes.18 ST-segment abnormalities defined as deviation of greater than 1 mm were assessed from the 12-lead ECG reading. Depression of the ST-segment is an indication of myocardial ischemia.19 Finometer measurements were processed with Beatscope 1.1 software (Finapres Medical Systems, Amsterdam, the Netherlands) to obtain systolic blood pressure, diastolic blood pressure, heart rate, CO, stroke volume, total peripheral resistance and Windkessel arterial compliance.20

Biochemical sampling and analyses

Fasting serum and plasma samples were dealt with according to standardized procedures and stored at −80 °C until analyses. From serum samples, gamma-glutamyl transferase (γ-GT), high-sensitivity C-reactive protein (CRP) and total cholesterol were determined with the Konelab TM 20i Sequential Multiple Analyser Computer (Thermo Scientific, Vantaa, Finland). Cotinine levels were determined by homogenous immunoassay with the Roche Modular System (Roche, Basil, Switzerland). Levels of γ-GT and cotinine were used to indicate alcohol abuse21 and of smoking status.22 The concentration of nitric oxide metabolites (NOx), the sum of plasma nitrite and reduced nitrate were determined with an R&D systems Inc kit (Parameter, Catalogue number: KGE001, R&D systems, Minneapolis, MN, USA), Universal ELX800 Plate reader and GEN5 software (BioTek Instruments Inc, Winooski, VT, USA). Intra-assay variability was 5.5%. Inter-assay variability ranged between 8.2 and 13.5%.

Statistical analyses

Stress responses (%) were calculated with the following formula as changes from baseline (delta, Δ): %=(X stressor—X resting)/X resting) × 100. Data analyses were performed with Statistica Version 10 (Statsoft Inc., 2012, Johannesburg, South Africa). Distribution of data was determined by means of the Shapiro–Wilk’s test. Subsequently, logarithmic transformation of CRP and γ-GT was deemed necessary because of skewed distribution. Means and proportions were compared between the two ethnic groups, using Student’s t-tests and χ2 tests, respectively. Interaction on the main effects was tested with a single 2 × 2 (ethnic × NOx response) analysis of covariance independent of co-variates age, body surface area, cotinine, log γ-GT, physical activity and resting responses. Cardiovascular measurements of African and Caucasian men were compared by means of one-way analysis of covariance independent of co-variates.

Multiple linear regression analyses, applying the forward stepwise method, were used to analyse the variance in CIMTf (dependent variable) in ethnic groups as well as in low and high NOx ethnic groups. Independent variables included NOx and ST-segment responses, age, body surface area, cotinine, log γ-GT, physical activity, log CRP, cholesterol and 24 h mean arterial pressure. Statistical significance was indicated by a two-sided α level of 0.05 or less.

Sensitivity analyses

Sensitivity analyses were performed first, to determine if waist circumference, as independent variable, predicted structural vascular disease. Second, we adjusted for the presence of mental illness and its impact on acute mental stress responses (Diagnostic and Statistical Manual for mental disorders (DSMIV) criteria)23 as well as in the prediction of structural vascular disease.

Results

The study population characteristics are depicted in Table 1. The African men demonstrated lower cholesterol, physical activity levels and smaller waist circumference (P<0.001) than their Caucasian counterparts. Significantly higher γ-GT levels were found in the African men, which may indicate alcohol abuse (γ-GT0.65 ul−1).21 Despite the higher use of anti-hypertensive medication among the African men (P=0.024), higher mean ambulatory blood pressure (P<0.001), heart rate (P<0.001) and more silent ischemic events (P=0.001) were revealed. African men also exhibited higher CRP (P=0.018) and resting NOx levels (P<0.001) compared with Caucasian men.

Table 1 Characteristics of the study group

After adjusting for covariates, NOx levels (P<0.001), blood pressure (P<0.001), heart rate (P=0.05) and the number of ischemic events (P=0.01) remained higher in the African men than in the Caucasian men (Table 2). CRP levels of the African men indicated low-grade inflammation and risk for cardiovascular disease development (>3.0 mg l−1).24

Table 2 Comparison of adjusted NOx and cardiovascular measurements between African and Caucasian men

Mental stress test responses

The Stroop colour-word conflict test evoked an α-adrenergic response in the African men with lower heart rate (P=0.008) and CO (P=0.027; Table 3). This study group also showed a reduced NOx response compared with the Caucasian men (P=0.016).

Table 3 Comparing acute mental stress NOx and cardiovascular responses in African and Caucasian men

Comparison of high and low NOx response groups

The augmented resting NOx in the African men substantiated interaction main effects for ethnicity × NOx. A significant interaction on the main effects (ethnicity × NOx responses) existed for stroke volume (F(1, 154)=6.45; P=0.012) and a marginal significant interaction for CO responses (F(1, 154)=3.64; P=0.058) to the Stroop colour-word conflict test. Hereafter, the African and Caucasian groups were stratified into low and high NOx response groups via median split (NOx=159.02 μmol l−1). The low-response group of the African men was characterized by lower stroke volume (P=0.003) and CO (P=0.007) responses to mental stress and a significant ST-segment depression (P=0.012; Figure 1).

Figure 1
figure1

A comparison of cardiovascular responses between high and low NO response groups in African (a) and Caucasian (b) men. Adjusted for age, body surface area, physical activity, γ-GT, cotinine and resting values. CO, cardiac output; SV, stroke volume; ST, ST-segment depression. *P0.05

In the sensitivity analyses, waist circumference first did not predict structural vascular disease. Second, depressive symptoms did not influence acute stress responses or predict structural vascular disease. No further discussion on mental illness is made.

Predictors of CIMTf

Depression of the ST-segment was significantly associated with CIMTf (adjusted R2=0.32; β=−0.28, 95% CI=−0.49; −0.05) in the African men (Figure 2). Furthermore (Figure 3), in the low NOx African men (adjusted R2=0.54; β=0.25; 95% CI=0.13; 0.41), ambulatory silent ischemia was significantly associated with CIMTf.

Figure 2
figure2

Associations between carotid intima-media thickness of the far wall (CIMTf; mm) and cardiovascular function using stepwise multiple linear regression in African (model 1) and Caucasian (model 2) men. Values are indicated as standard β (95% CI); *P0.05. γ-GT, gamma-glutamyl transferase; MAP, mean arterial pressure.

Figure 3
figure3

Associations between carotid intima-media thickness of the far wall (CIMTf; mm) and cardiovascular function using stepwise multiple linear regression in low NOx African (model 1) and low NOx Caucasian (model 2) men. Values are indicated as standard β (95% CI); *P0.05. γ-GT, gamma-glutamyl transferase.

Discussion

The main objective of our study was to determine associations between NOx responses, cardiovascular function and structural vascular disease in a cohort of African and Caucasian men. Our findings revealed less NO availability coupled with dominant α-adrenergic and ST depression acute mental stress responses in African men. Only in this population group, acute mental stress ST-segment depression responses were associated with CIMTf. These events were supported by chronic 24 h ischemic events being positively associated with CIMTf as well.

A significant reduction of NO bioavailability is often found in hypertension, probably due to endothelial dysfunction and/or increased oxidative stress.12, 25 Despite elevated mean blood pressure levels, the African men exhibited higher resting NOx levels than the Caucasians. Cardillo et al.8 suggested a desensitization of vascular smooth muscle cells to NO, rather than a reduction of bioavailability in African-Americans. This finding is substantiated by our study, where excessive levels of NOx may indicate an attempt of the cardiovascular system to compensate for the elevated blood pressure in the African men. Conversely, our findings are in accordance with the concept of the brain–heart connection. Although the brain makes up only 2% of the total body weight, it receives 15% of the resting CO.26 If blood flow to the brain is compromised, vasodilation is triggered immediately to return oxygen supply back to normal. Local blood flow control mechanisms are almost identical in the brain as in other parts of the circulatory system, including the coronary circulation.26 Therefore, when the system is challenged and attenuated NOx responses occur, blood pressure may act as homeostatic mechanism to upregulate NOx, resulting in augmented resting NOx.

A previous study indicated that sympathetic hyperactivity was present together with a dominant α-adrenergic response pattern in this specific cohort of African men.27 The vasoconstrictory profile and the reduced NOx stress response seem to support our assumption of sympathetic predominance and possible attenuation of parasympathetic influence on cardiovascular function in the African men of this study.27 The African men with a lower NOx stress response showed significant ST-segment depression during acute mental stress exposure. Conversely, only chronic ambulatory silent ischemic events mediated CIMTf in these men in the linear regression model, independent of co-variates. Hence, it appears that these African men tend to have attenuated NOx responses accompanied not only by systemic vasoconstriction but also possibly by myocardial ischemia when exposed to mental stress. It may further imply that if their ambulatory silent ischemic responses are simulated by everyday environmental stress,3 their future risk for coronary artery disease and cerebro-vascular events may increase.28

Previous studies have indicated a link between reduced NO bioavailability, increased vascular inflammation29 and smooth muscle cell proliferation,30 proving to be a major causal factor in atherogenesis.31, 32 The specific region mostly affected is the coronary circulation.33 Quyyumi et al.34 indicated reduced NO bioavailability in the presence of coronary risk factors. Some of these factors are also highly prevalent in the group of African men, including high blood pressure, chronic stress,3 lower physical activity and elevated CRP levels.35, 36 The reduced NO bioavailability, supported by low-grade inflammatory levels during acute and chronic mental stress, may further contribute to the higher prevalence of myocardial ischemic responses in the African men, making them vulnerable to structural vascular disease. Accordingly, Drexler33 noted that the common presence of coronary atherosclerosis reduced systemic NO bioavailability and inevitably results in myocardial ischemia. Results demonstrated in the African low NOx response group are in support of the postulated lack of NO sensitivity of vascular smooth muscle as possible promoting factor in increased occurrence of silent ischemia associated with structural vascular disease during everyday life.

Our findings may therefore be of clinical importance as the reduced NO bioavailability during acute and chronic stress can desensitize smooth muscle for NO. If supported by sympathetic-driven responses, it may enhance these effects and increase myocardial ischemic events constituting risk for coronary artery disease in our cohort of African men.

The strengths and limitations of this study must be recognized. Owing to the cross-sectional design, it was not possible to examine the causal relationship between disturbed NO bioavailability and structural vascular disease in this group of African men. With stratification of ethnic groups according to NOx responses, the sample size was reduced and could therefore have decreased statistical power. However, the unique sample of African and Caucasian men of similar social standing and the application of gold standard methods ensure highly reliable results. Further study with longitudinal design is necessary to elucidate possible trends indicated by our findings.

Conclusion

The African men demonstrated a vulnerable cardiovascular profile. Novel findings revealed α-adrenergic-driven blood pressure responses and less NO bioavailability during acute stress. Furthermore, the association between ambulatory myocardial ischemia and carotid intima-media thickness in this group emphasized their risk for future coronary artery disease and cerebrovascular events.

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Acknowledgements

We thank the participants of the SABPA study as well as the members of PhasRec (anthropometric measurements), M Glyn (NOx analysis), C Lessing (data collection) and S Péter (data collection) for their invaluable input. This study was supported by North-West University (Potchefstroom), North-West Department of Education, Roche Diagnostics, National Research Foundation (UID 65607), South Africa and the Metabolic Syndrome Institute, France.

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Uys, A., Malan, L., van Rooyen, J. et al. Attenuated NOx responses and myocardial ischemia, a possible risk for structural vascular disease in African men: the SABPA study. J Hum Hypertens 28, 438–443 (2014). https://doi.org/10.1038/jhh.2013.128

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Keywords

  • African
  • cardiovascular function
  • myocardial ischemia
  • nitric oxide
  • structural vascular disease

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