Chronic defensiveness and neuroendocrine dysfunction reflect a novel cardiac troponin T cut point: The SABPA study

doi:10.1016/j.psyneuen.2017.07.492

Psychoneuroendocrinology

Volume 85, November 2017, Pages 20-27

https://doi.org/10.1016/j.psyneuen.2017.07.492 Get rights and content

Highlights

•
Central neural control systems exemplified a brain-heart stress pathway.
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Sympatho-adrenal responses are activated as an innate defense coping mechanism.
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Desensitization occurred with initial neural- (HRV) followed by neuroendocrine dysfunction (norepinephrine:creatinine) at cTnT 4.2 ng/L.
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Chronic defensiveness may drive desensitization or a physiological depression.
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Ischemic heart disease risk increases at a novel stress-related cTnT 4.2 ng/L cut-point.

Abstract

Background

Sympatho-adrenal responses are activated as an innate defense coping (DefS) mechanism during emotional stress. Whether these sympatho-adrenal responses drive cardiac troponin T (cTnT) increases are unknown. Therefore, associations between cTnT and sympatho-adrenal responses were assessed.

Methods

A prospective bi-ethnic cohort, excluding atrial fibrillation, myocardial infarction and stroke cases, was followed for 3 years (N = 342; 45.6 ± 9.0 years). We obtained serum high-sensitive cTnT and exposure measures [Coping-Strategy-Indicator, depression/Patient-Health-Questionnarie-9, 24 h BP, 24 h heart-rate-variability (HRV) and 24 h urinary catecholamines].

Results

Blacks showed moderate depression (45% vs. 16%) and 24 h hypertension (67% vs. 42%) prevalence compared to Whites. A receiver-operating-characteristics cTnT cut-point 4.2 ng/L predicting hypertension in Blacks was used as binary outcome measure in relation to exposure measures [AUC 0.68 (95% CI 0.60-0.76); sensitivity/specificity 63/70%; P ≤ 0.001]. Bi-ethnic cTnT-incidence was similar (Blacks=27%, Whites=25%) with cTnT-recovery better in Blacks (9%) compared to Whites (5%), P = 0.001. In cross-sectional analyses, elevated cTnT was related to DefS [OR 1.08 (95% CI 0.99–1.16); P = 0.06]; 24 h BP [OR 1.03–1.04 (95% CI 1.01–1.08); P ≤ 0.02] and depressed HRV [OR 2.19 (95% CI 1.09–4.41); P = 0.03] in Blacks, but not in Whites. At 3 year follow-up, elevated cTnT was related to attenuated urine norepinephrine:creatinine ratio in Blacks [OR 1.46 (95% CI 1.01–2.10); P = 0.04]. In Whites, a cut point of 5.6 ng/L cTnT predicting hypertension was not associated with exposure measures.

Conclusion

Central neural control systems exemplified a brain-heart stress pathway. Desensitization of sympatho-adrenal responses occurred with initial neural- (HRV) followed by neuroendocrine dysfunction (norepinephrine:creatinine) in relation to elevated cTnT. Chronic defensiveness may thus drive the desensitization or physiological depression, reflecting ischemic heart disease risk at a novel 4.2 ng/L cTnT cut-point in Blacks.

Graphical abstract

Brain-Heart stress pathway exemplifying chronic defensiveness and desensitized sympatho-adrenal responses in relation to cardiac injury. Where: Color coding: Green = Defensiveness in-control/homeostasis; Orange = Defensiveness loss-of-control/imbalance; *Social stress = interpersonal conflict; **Perception = Thalamus; Emotional response = Amygdala, Cognition = Prefrontal cortex; Sympathetic activation-PVN = Hypothalamus-paraventricular nucleus; HRV = heart rate variability.

Introduction

Coping with everyday stressors (Amirkhan, 1990) may disturb sympatho-adrenal activity and cardiac rhythmicity as indicated by changes in catecholamine turnover (De Kock et al., 2012) as well as heart-rate variability (HRV) (Malan et al., 2013). Particularly, defensive coping (DefS) or the fight-flight response encompassing perception of control and active problem solving, has been suggested as a promoter of health (Amirkhan, 1990). In spite of this view, DefS outcomes have also been linked with pathology and emotional distress related alterations (De Kock et al., 2012, Malan et al., 2008, Malan et al., 2013), in that attenuated sympatho-adrenal responses to acute mental stress in a cross-sectional analysis were associated with wall remodeling and silent myocardial ischemia in a Black male cohort (Malan and Malan, 2017). Therefore, it seems plausible that chronic defensiveness, reflecting emotional distress, may drive direct relationships between sympatho-adrenal activation and markers of cardiac injury (Lazzarino et al., 2013) such as elevated cardiac troponin (cTnT) levels.

A subunit of the troponin complex, namely cTnT is released in response to sympathetic activation or catecholamine overload and myocyte necrosis (Muthu et al., 2014). A decrease in the metabolic supply to the myocardial tissue results in ischemia and resultant cardiomyocyte necrosis of the myocardium (Muthu et al., 2014). Reduced metabolic supply when accompanied by catecholamine vascular responsiveness may further increase myocardial ischemia and cTnT-related damage (Mazzeo et al., 2014, Muthu et al., 2014). Resultant changes in cardiac autonomic modulation and blood pressure may therefore occur to counteract myocardial ischemia, in order to improve perfusion. Accumulative effects of higher chronic metabolic demands may also be taxing if emotional distress is present (Malan et al., 2016). To maintain metabolic homeostasis, central neural control and downstream adrenergic-related signaling will be apparent with either sensitization/upregulation in acute or desensitization/downregulation in chronic situations (Guilliams and Edwards, 2010). Therefore, we aimed to assess sympatho-adrenal exposure measures, including 24 h urinary catecholamines, 24 h heart-rate-variability (HRV), blood pressure and levels of coping and depression in a bi-ethnic cohort from South Africa. Sympatho-adrenal responses resembling emotional distress might translate to cTnT activity at a certain cut point indicative of future ischemic heart disease risk. Thus, the main aim was to examine prospective associations between binary outcome cTnT and sympatho-adrenal exposure measures.

Section snippets

Study design

The Sympathetic activity and Ambulatory Blood Pressure in Africans (SABPA) prospective study (Fig. 1) was conducted in 2008/9 and 2011/12 and included 409 Black and White teachers (Malan et al., 2015). For the current sub-study, we only included teachers participating in both phases and additionally excluded individuals with atrial fibrillation (N = 10), history of or current myocardial infarction or stroke (N = 3) and missing cTnT data at baseline (N = 4). The final study sample comprised of 342

Clinical characteristics

In Table 1, Blacks at baseline were younger, physically less active, consumed more alcohol (γ-GT), and had lower TSH and time-domain HRV values compared to Whites. More Blacks showed moderate depression (45.0% vs. 16.2%) and 24 h hypertension (67% vs. 42%) prevalence compared to Whites. Blacks further used more ACE inhibitors, diuretics and calcium channel blockers (P ≤ 0.05).

In Fig. 2, a receiver-operating-characteristics (ROC) cTnT cut-point of 4.2 ng/L predicted both clinic [AUC 0.64 (95% CI

Discussion

We assessed cross-sectional and longitudinal associations between cardiac injury (cTnT) and sympatho-adrenal responses in a bi-ethnic cohort of South African teachers. Major central neural control systems exemplified a brain-heart-axis stress pathway. The pathway demonstrated desensitized sympatho-adrenal responses in relation to elevated cTnT levels with initial neural- (HRV) followed by neuroendocrine dysfunction (norepinephrine:creatinine). Chronic defensiveness may drive this

Conflict of interest

None declared.

Financial disclosures

No conflicts of interest are declared. Any opinion, findings and conclusions or recommendations expressed in this material are those of the authors; therefore, funders do not accept any liability with regard to this study.

The laboratory of GL currently, or recently, has received research funding from the National Health and Medical Research Council of Australia (NHMRC), Medtronic, Abbott Pharmaceuticals, Servier Australia and Allergan. GL has acted as a consultant for Medtronic and has received

Acknowledgements

This study would not have been possible without all the participants who volunteered to be part of the SABPA study; and in-kind analyses of collaborators. Funding was obtained by the North-West University, Potchefstroom, South Africa; the National Research Foundation (NRF); the Department of Education, North-West Province, South Africa; ROCHE diagnostics; and the Metabolic Syndrome Institute, France.

References (35)

A. De Kock et al.
Defensive coping and subclinical vascular disease risk – associations with autonomic exhaustion in Africans and Caucasians: the SABPA study
Atherosclerosis
(2012)
M. Hamer et al.
Psychophysiological risk markers of cardiovascular disease
Psychophysiol. Biomark. Health Special Ed.: Neurosci. Biobehav. Rev.
(2010)
A.I. Lazzarino et al.
The association between cortisol response to mental stress and high-sensitivity cardiac Troponin T plasma concentration in healthy adults
J. Am. Coll. Cardiol.
(2013)
L. Malan et al.
Coping with urbanization: a cardiometabolic risk?
Biol. Psychiatry
(2008)
L. Malan et al.
Defensive coping facilitates higher blood pressure and early sub-clinical structural vascular disease via alterations in heart rate variability: the SABPA study
Atherosclerosis
(2013)
L. Malan et al.
Chronic depression symptoms and salivary NOx are associated with retinal vascular dysregulation: the SABPA study
Nitric Oxide Biol. Chem.
(2016)
A.T. Mazzeo et al.
Brain–heart crosstalk: the many faces of stress-related cardiomyopathy syndromes in anaesthesia and intensive care
Br. J. Anaesth.
(2014)
V. Muthu et al.
Cardiac troponins: bench to bedside interpretation in cardiac disease
Am. J. Med. Sci.
(2014)
A. Rosengren et al.
INTERHEART investigators. Association of psychosocial risk factors with risk of acute myocardial infarction in 11119 cases and 13648 controls from 52 countries (the INTERHEART study): case-control study
Lancet
(2004)
A. Tawakol et al.
Relation between resting amygdalar activity and cardiovascular events: a longitudinal and cohort study
Lancet
(2017)

J.F. Thayer et al.

A meta-analysis of heart rate variability and neuroimaging studies: implications for heart rate variability as a marker of stress and health

Neurosci. Biobehav. Rev.

(2012)

C. Tsigos et al.

Hypothalamic-pituitary-adrenal axis, neuroendocrine factors and stress

J. Psychosom. Res.

(2002)

M. Abdalla et al.

Masked hypertension and incident clinic hypertension among Blacks in the Jackson Heart Study

Hypertension

(2016)

A. Adefurin et al.

African-Americans have a greater sensitivity to alpha₁-adrenoceptor-mediated venoconstriction compared to Caucasians

Hypertension

(2013)

J.H. Amirkhan

A factor analytically derived measure of coping: the Coping Strategy Indicator

J. Pers. Soc. Psychol.

(1990)

M. Griffiths et al.

Lower high-sensitivity cardiac Troponin T cut-points in Blacks predicted 24 h systolic hypertension: the SABPA study

J. Prev. Cardiol.

(2017)

T.G. Guilliams et al.

Chronic stress and the HPA-axis: clinical assessment and therapeutic considerations

Standard

(2010)

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Ineffective stress-coping in Africans is associated with cardiac ischemia during acute mental stress. Ischemic conditions may be worsened by stress-induced release of glial-derived S100‑calcium-binding-protein β (S100B), which is pro-apoptotic for cardiomyocytes. Whether estradiol as coping regulator and cardio-protective factor will protect against pro-apoptotic effects, remains unclear. Therefore, we aimed to investigate stress-induced associations between cardiac troponin T/cTnT (cardiac ischemic marker), S100B and estradiol in a bi-ethnic cohort of defensive copers of both sexes. The target population study included African and Caucasian teachers of both sexes (n = 344; aged 20–65 years). The Stroop-color-word-conflict-test was administrated for 1 min to induce acute mental stress in the participants. A chronic stress risk phenotype score was obtained. The Coping Strategy Indicator determined habitual defensive/avoidance/seeking social support coping scores. Fasting blood samples were obtained prior to and 10 min post-Stroop-stress to assess cTnT, S100B and estradiol levels. An interaction between ethnicity, sex and defensive coping (p < 0.05) was found for acute stress-induced percentage changes in estradiol. In defensive coping African men, the Stroop-color-word-conflict-test elicited decreases in S100B and increases in estradiol. Again, in this group, S100B decreases were related to unchanged cTnT, a chronic stress risk phenotype and acute estradiol increases (p < 0.05). No associations among main markers were apparent in the African women or the Caucasian defensive copers of both sexes. In the defensive coping African men, the markers studied may play a relevant role in the brain-cardiovascular system interaction during stress exposure. Further research is needed to elaborate on potential mechanisms and to establish clinical relevance.
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Psychobiological processes linking stress and vascular diseases remain poorly understood. The retina and the brain share a common embryonic-diencephalon origin and blood-barrier physiology e.g. ongoing ischemia facilitates S100B release with astrocytic activity and glial-fibrillary-acidic-protein expression (GFAP). However, GFAP decreases revealed astrocyte pathology in the prefrontal cortex of depression/suicide cases; and might be a key mechanism in stress – disease pathways.
A chronic emotional stress phenotype independent of age, ethnicity or sex was used to stratify the current prospective cohort (N = 359; aged 46 ± 9 years) into Stress (N = 236) and no-Stress groups (N = 123). Prospective data for glia ischemia risk markers were obtained, including 24 h BP, fasting S100B, GFAP, HbA_1C and tumor-necrosis-factor-α (TNF-α). At 3-yr follow-up: diastolic-ocular-perfusion-pressure (indicating hypo-perfusion risk) was measured and retinal vessel calibers were quantified from digital images in the mydriatic eye.
Higher hypertension (75% vs. 16%), diabetes (13% vs. 0%) and retinopathy (57% vs. 45%) prevalence was observed in Stress compared to no-Stress individuals. Stressed individuals had consistently raised S100B, TNF-α, HbA_1C and higher diastolic-ocular-perfusion-pressure, but decreases in GFAP and GFAP:S100B. Furthermore stroke risk markers, arterial narrowing and venous widening were associated with consistently raised S100B, GFAP:S100B (p = 0.060), TNF-α and higher diastolic-ocular-perfusion-pressure [Adj. R² 0.39–0.41, p ≤ 0.05]. No retinal-glia associations were evident in the no-Stress group.
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Coping facilitated troponin T increases and hypo-responsivity in the copeptin-HPA-axis during acute mental stress in a black cohort: The SABPA study
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Citation Excerpt :
However, published data from the Sympathetic activity and Ambulatory Blood Pressure in Africans (SABPA) study, has proved DefS to be physiologically ineffective for blacks. Despite reporting a behavioural in-control profile, DefS in blacks was associated with a perception of emotional distress or poorer well-being, sympathetic hyperactivity, α-adrenergic vascular hyper-responsiveness [2] and myocardial injury at cardiac troponin T (cTnT) cut-points of 4.2 ng/L [5,11]. They also had higher cardiac stress responses during acute mental stress testing compared to whites [12,13].
Defensive coping (DefS) was associated with a vulnerable cardiovascular profile in blacks. The copeptin/vasopressin system is a manifestation of hypothalamic-pituitary-adrenal-axis activity and may act as an acute compensatory mechanism when there is a disruption in volume-loading homeostasis, i.e. when cardiac stress is evident. Whether DefS will influence associations between copeptin and cardiac stress markers, remains unclear. Here we aimed to determine associations between acute mental stress responses of copeptin, vascular responsiveness and biomarkers of cardiomyocyte injury [cardiac troponin T (cTnT)] and cardiac wall-stress [N-terminal pro-brain natriuretic peptide (NT-proBNP)] in DefS race groups.
South African black and white teachers (n = 378) of both sexes, participated in this target population study. Cases with a history of myocardial infarction, stroke and atrial fibrillation were excluded. We obtained coping scores (Coping Strategy Indicator), beat-to-beat blood pressure and fasting blood samples at rest and after 1-min exposure to the Stroop-Colour-Word-Conflict-test.
Interaction effects (p < .05) for copeptin percentage change (%) during the Stroop-Colour-Word-Conflict-test determined stratification of participants into race and DefS (≥26, above-median score) groups. In DefS blacks, Stroop-Colour-Word-Conflict-test exposure elicited increases in cTnT%, NT-proBNP% and diastolic-blood pressure%. Again, in these individuals, multiple regression analyses showed positive associations between copeptin% and total peripheral resistance%; with inverse associations between copeptin% and cTnT% (p < .05). None of these associations were found in DefS whites.
Utilisation of DefS in blacks provoked vascular hyper-responsiveness and cardiac wall stress (elevated cTnT and NT-proBNP); possibly mediated via the copeptin/vasopressin system. However, a presumably hypo-responsive hypothalamic-pituitary-adrenal-axis during stress exposure could not counteract coronary perfusion deficits via additional copeptin/vasopressin release. The presence of defensiveness may have clinical implications in preventive cardiology.
Coping and Cardiac Troponin T – A Risk for Hypertension and Sub-Clinical ECG Left Ventricular Hypertrophy: The SABPA Study
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Citation Excerpt :
HRV time domain measures included the standard deviation of the normal-to-normal (NN) intervals between adjacent QRS complexes (SDNN). The HRV-SDNN reflects vagus nerve-mediated autonomic control of the heart and is the best overall prognostic tool to detect depressed HRV (<100 ms) [20], which was also related to endothelial dysfunction and cardiomyocyte damage [7,21,22]. Data analyses were completed using the computer software package Statistica® version 13.1 (Dell, Round Rock, TX, USA, 2017).
Defensive coping (DefS) was associated with cardiovascular disease (CVD) susceptibility in Blacks. Whether coping strategies will associate with sub-clinical left ventricular hypertrophy (electrocardiographic-left ventricular hypertrophy [ECG-LVH] or Cornell product), cardiomyocyte injury and blood pressure (BP), is unclear. Therefore, we assessed relationships between ECG-LVH, cardiac troponin T (cTnT) and 24-hour BP in bi-ethnic groups when habitually utilising a certain coping style, and these groups when having a stress-related cTnT cut-point of 4.2 ng/L.
A target population study included a Black (n = 190) and White (n = 204) teachers’ gender cohort (20–65 years) from South Africa. The Coping Strategy Indicator determined DefS, social support and avoidance coping scores. Fasting blood samples, 10-lead ECG, 24-hour BP and ECG data were obtained.
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Defensive coping facilitated autonomic hyperactivity, myocardial injury and subsequent compensatory BP elevations as possible homeostatic reflexes to alleviate myocardial perfusion deficits. The resulting pressure overload increased sub-clinical wall remodelling and ischaemic heart disease risk in Blacks utilising habitual defensiveness. We therefore recommend regular ECG and high sensitivity cTnT screening in asymptomatic patients with emotional stress susceptibility. Longitudinal evidence is needed to confirm causality and progression of cardiomyopathy risk.
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We included 195 Black and White teachers (43.7 ± 9 years) from a South African 3-year prospective study. Hypertension medication users, diabetics and human immunodeficiency virus infected individuals were excluded. Depression symptoms (Patient-Health-Questionnaire-9/PHQ-9), 24 h blood pressure measurements and fasting blood samples were obtained.
Blacks had lower renin but higher DBP and eGFR levels at baseline (p ≤ .01) when compared to Whites. Blacks and Whites with depression (PHQ-9 ≥ 10) at baseline developed co-morbidity for having both depression plus DBP-HT at follow-up (Blacks, 49.1%; Whites, 13.1%). At 3-year follow-up, chronic depression symptoms were related to chronic lower renin in Blacks [Adjusted R² 0.20; β −0.37 (−0.66, −0.08), p = .02]. Chronic depression symptoms also predicted DBP hypertension in Blacks [ROC AUC = 0.61 (0.48–0.75); sensitivity/specificity 78.1/46.3%]. No prospective associations existed between depression symptoms, aldosterone and eGFR.
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Chronic defensiveness and neuroendocrine dysfunction reflect a novel cardiac troponin T cut point: The SABPA study

Highlights

Abstract

Background

Methods

Results

Conclusion

Graphical abstract

Introduction

Section snippets

Study design

Clinical characteristics

Discussion

Conflict of interest

Financial disclosures

Acknowledgements

Atherosclerosis

Psychophysiol. Biomark. Health Special Ed.: Neurosci. Biobehav. Rev.

J. Am. Coll. Cardiol.

Biol. Psychiatry

Atherosclerosis

Nitric Oxide Biol. Chem.

Br. J. Anaesth.

Am. J. Med. Sci.

Lancet

Lancet

Neurosci. Biobehav. Rev.

J. Psychosom. Res.

Masked hypertension and incident clinic hypertension among Blacks in the Jackson Heart Study

Hypertension

African-Americans have a greater sensitivity to alpha1-adrenoceptor-mediated venoconstriction compared to Caucasians

Hypertension

A factor analytically derived measure of coping: the Coping Strategy Indicator

J. Pers. Soc. Psychol.

Lower high-sensitivity cardiac Troponin T cut-points in Blacks predicted 24 h systolic hypertension: the SABPA study

J. Prev. Cardiol.

Chronic stress and the HPA-axis: clinical assessment and therapeutic considerations

Standard

African-Americans have a greater sensitivity to alpha₁-adrenoceptor-mediated venoconstriction compared to Caucasians