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Cardiac Troponin T as Early Marker of Subclinical Cardiovascular Deterioration in Black Hypertensive Women
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Heart, Lung and Circulation (2016) xx, 1–8 1443-9506/04/$36.00 http://dx.doi.org/10.1016/j.hlc.2016.11.010
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Cardiac Troponin T as Early Marker of Subclinical Cardiovascular Deterioration in Black Hypertensive Women R. Kruger a*, A.E. Schutte a,b, C.M.C. Mels a, W. Smith a, J.M. van Rooyen a, I.M. Kruger c, C.M.T. Fourie a a
Hypertension in Africa Research Team (HART), North-West University, Potchefstroom, South Africa Medical Research Council: Unit for Hypertension and Cardiovascular Disease, Faculty of Health Sciences, North-West University, Potchefstroom, South Africa c Africa Unit for Transdisciplinary Health Research (AUTHeR), North-West University, Potchefstroom, South Africa b
Received 13 May 2016; accepted 13 November 2016; online published-ahead-of-print xxx
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ORIGINAL ARTICLE
Background
Hypertensive heart disease is a rising concern, especially among black South African women. As high sensitivity cardiac troponin T (cTnT) is a marker of cardiomyocyte damage, we determined the potential link of (i) systemic endothelial dysfunction (reflected by urinary albumin-to-creatinine ratio), (ii) large artery stiffness, (iii) cardiac volume load (estimated by the N-terminal prohormone B-type natriuretic peptide (Nt-proBNP)), and (iv) ECG left ventricular hypertrophy in post-menopausal black women.
Methods
In 121 (50 normotensive and 71 hypertensive) black women (mean age: 60.6 years), basic cardiovascular assessments including blood pressure and ECG were performed, along with plasma and urinary biomarkers including cTnT.
Results
The cTnT levels (p=0.049) along with Nt-proBNP (p=0.003), pulse pressure (p<0.0001) and the Cornell product (p=0.030) were higher in hypertensive than normotensive women. Only in hypertensive women, was cTnT independently associated with urinary albumin-to-creatinine ratio (b=0.25; p=0.019), pulse pressure (b=0.31; p=0.019), Nt-proBNP (b=0.47; p<0.0001) and Cornell product (b=0.31; p=0.018). An independent association between albumin-to-creatinine ratio and cTnT was also evident in normotensive women (b=0.34; p=0.037).
Conclusion
We found cTnT to be a useful marker in an elderly black population relating to several measures of cardiovascular deterioration – from subclinical endothelial dysfunction to left ventricular hypertrophy.
Keywords
Troponin T Endothelial dysfunction Arterial stiffness Left ventricular hypertrophy Hypertension
Introduction Q3
The link between the heart and vasculature is apparent and therefore worth exploring in a population prone to hypertensive heart disease by assessing a reliable measure of cardiomyocyte injury. High sensitivity cardiac troponin T (cTnT) is described as a novel, noninvasive biomarker of
subclinical myocardial damage and relates to incident hypertension and an increasing risk of left ventricular hypertrophy in individuals free from cardiovascular disease (CVD).[1] The N-terminal prohormone B-type natriuretic peptide (Nt-proBNP) increases in hypertensive heart disease and indicates cardiac overload and augments with heart failure.[2,3] NT-proBNP was also shown to link with subclinical
*Corresponding author at: Hypertension in Africa Research Team (HART), North-West University, Potchefstroom, 2531, South Africa. Tel.: +27 18 299 2904; fax: +27 18 285 2432, Email: [email protected] © 2016 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: Kruger R, et al. Cardiac Troponin T as Early Marker of Subclinical Cardiovascular Deterioration in Black Hypertensive Women. Heart, Lung and Circulation (2016), http://dx.doi.org/10.1016/j. hlc.2016.11.010
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vascular extracellular matrix turnover and arterial stiffness in black individuals, posing a higher risk for future cardiovascular morbidity compared to their white counterparts.[4] Hypertension remains to a large extent one of the major public health problems in South Africa[5] with a prevalence range of hypertension between 78% and 82% in women over the age of 50 years.[6] Furthermore, our group indicated that 24% of South Africans of the North West province with optimal blood pressure developed hypertension within five years.[7] The low detection, treatment, and control of high blood pressure, especially in black communities, increase the risk of future adverse events such as cerebral bleeding, malignant hypertension, and/or kidney disease – all of which may lead to congestive heart failure.[8,9] Black women in particular are affected by hypertensive heart disease at a much younger age in sub-Saharan Africa than observed in developed countries.[10] The prevalence of high blood pressure and related arterial stiffness have also been shown to occur earlier in black South Africans than their white counterparts.[11] We therefore reviewed cTnT in a hypertension-prone population of urban, post-menopausal black women, and how it relates to (i) endothelial function; (ii) arterial stiffness; (iii) NtproBNP; and (iv) ECG derived left ventricular hypertrophy (Cornell product).
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Ethical Considerations
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All procedures were explained to each individual beforehand, in their home language when preferred. Written, informed consent was obtained from each participant through an independent person. Participation within the study was completely voluntarily, and participants could withdraw at any point without any consequences. Privacy and confidentiality was ensured throughout the entire research process by using a unique number assigned to each participant. The study protocol was approved by the Health Research Ethics Committee of the Faculty of Health Sciences, of the North-West University (Potchefstroom campus, South Africa) and complied with the Declaration of Helsinki.
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Methods
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Data from the South African leg of the Prospective Urban and Rural Epidemiology (PURE) study[7,12] conducted in the North West Province, Potchefstroom were used in this cross-sectional sub-study. During the baseline data collection (2005) of the South African PURE study 1004 randomly selected Africans (>35 years) from the Potchefstroom (urban) area partook in the study, of whom 66% were women. 152 women partook in the 2012 data collection and for this crosssectional analysis, individuals with incomplete data (n=28) and macro-albuminuria (n=3) were excluded, resulting in a total of 121 black women (50 normotensive and 71 hypertensive). Hypertensive status was determined according to the European Society of Hypertension guidelines.[13] A systolic 140 mmHg and/or diastolic blood pressure 90 mmHg
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were considered hypertensive. All individuals using antihypertensive drugs were also considered hypertensive. Research participants were transported to and from the Potchefstroom campus of the North-West University where the measurements and data collection took place. Participants were required to complete standardised, interviewbased questionnaires administered by trained fieldworkers in the language of their choice to collect demographic information. On the day of data collection the medication use was recorded by a pharmacist. We measured height and weight to the nearest decimal point with a calibrated Leicester stadiometer (Seca, Birmingham, UK) and an electronic Precision Health scale (model UC-300, Saitama, Japan), respectively. Waist circumference was also measured to the nearest decimal point using a steel measuring tape (Lufkin, Apex, NC, USA). Blood pressure was measured in duplicate on the right upper arm using an Omron automatic digital blood pressure monitor with appropriate cuff sizes (Omron M10-IT, Omron Healthcare, Tokyo, Japan). The participants were seated upright and relaxed with their right arm supported at heart level. Two measurements were taken with a five-minute interval and the second measurement of systolic and diastolic blood pressure, as well as heart rate, were recorded. Participants were instructed to refrain from eating, smoking, ingesting caffeine or undertaking exercise/physical activity such as climbing the stairs in the 30 minutes prior to the measurement. Pulse pressure was calculated and used as measure of arterial stiffness. A 12-lead standard ECG (Norav Medical Ltd, Kiryat Bialik, Israel) was recorded in a supine position. The Cornell product calculated as (RaVL+SV3 +0.8) * QRS duration for women was used as surrogate measure for left ventricular hypertrophy.[14,15] Participants were asked to fast for at least eight hours before data collection. Blood samples were obtained by a registered nurse and a midstream spot urine sample was collected for each individual. Urinary, serum and plasma samples were prepared according to appropriate methods, followed by storage at –80 8C in the bio-repository until analysis. Quantitative determination of serum creatinine, high density lipoprotein cholesterol, triglycerides, glucose, high sensitivity C-reactive protein as well as urinary albumin and creatinine levels were performed (Cobas Integra 400 Plus, Roche, Indianapolis, IN, USA). High sensitivity troponin T (cTnT), interleukin-6 and Nt-proBNP levels were measured with an Elecsys 2010 (Roche, Basel, Switzerland). The standard Elecsys-test for hs-cTnT has a Limit of Detection (LoD) at 5 pg/ml, and a 10%-Coefficient of Variance at 13 pg/ ml. Assuming this, >50% of patients in the normotensive group had cTnT levels below 5 pg/ml while the uncertainty of the measurements is quite high and most likely exceeds 20%. We assessed renal function by using the Chronic Kidney Disease Epidemiology Collaboration creatinine equation (CKD-EPI) as glomerular filtration rate estimation[16] along with urinary albumin excretion. All statistical analyses were performed using Statistica (data analysis software system), version 12 (StatSoft, Inc.
Please cite this article in press as: Kruger R, et al. Cardiac Troponin T as Early Marker of Subclinical Cardiovascular Deterioration in Black Hypertensive Women. Heart, Lung and Circulation (2016), http://dx.doi.org/10.1016/j. hlc.2016.11.010
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(2014), Tulsa, OK, USA) and G*Power version 3.1.9.2 software. In post hoc analysis, we computed the achieved power to determine differences between two independent groups. At an a error probability of 0.05, effect size of 50% and twotailed input method the achieved Power (1-b error probability) was estimated at 89.14%. Prior to any further statistical testing, variables were assessed for non-Gaussian tendency. Skewed variables were transformed to the logarithm with base 10. These variables were cTnT, Nt-proBNP, glucose, Creactive protein and interleukin 6. Independent samples T-tests along with Chi-squared tests were performed to illustrate the mean differences and proportions between groups, respectively. Linear bivariate correlations were explored using single regression analysis and thereafter partially adjusted for main confounding variables including age and glomerular filtration rate as a measure of kidney function. Forward stepwise multiple regression analyses were used to determine independent associations between measures of cardiovascular function and cTnT in each group. Variables considered for entry in the model
included age, body mass index, systolic or diastolic blood pressure, glucose, C-reactive protein, interleukin 6, estimated glomerular filtration rate and additionally for anti-hypertensive treatment in our hypertensive cohort.
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Results
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A comparison of basic descriptive data is provided in Table 1. We found no difference in age (p=0.077), body mass index (p=0.23), markers of renal function (all p>0.1), C-reactive protein (p=0.12) and heart rate (p=0.60) between normotensive and hypertensive women. About 6% of all cases had urinary albumin levels in the microalbuminuria range, equally distributed between the groups (p=0.94). Cardiac TnT levels along with Nt-proBNP, glucose and interleukin-6 were higher (all p<0.05) in hypertensive than normotensive women. Among the hypertensive women, almost 31% presented with hyperglycaemia compared to 10% in normotensives (p=0.009). Resting blood pressure, pulse
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Table 1 Population characteristics of black women stratified by blood pressure status. Normotensive
Hypertensive
n=50
n=71
p-value
Age, years
58.6 10.7
62.0 10.2
0.077
Body mass index, kg/m2
29.0 7.9
30.7 7.6
NS
Biochemical analyses Troponin T, pg/ml
4.96 (3.00 – 11.82)
6.01 (3.00 – 21.0)
0.049
Nt-proBNP, pg/ml
57.5 (8.06 – 172.7)
104.4 (20.9 – 883.7)
0.003
Urinary ACR, mg/g Serum creatinine, mmol/l
1.06 (0.32 – 9.22) 55.4 14.4
1.40 (0.35 –9.09) 56.2 16.9
NS NS
Glomerular filtration rate, ml/min/1.73m2
113.9 19.6
109.7 19.1
NS
Serum glucose, mmol/l
4.77 (2.09 – 7.45)
5.83 (2.90 – 8.84)
0.004
Interleukin-6, pg/ml
3.87 (1.61 – 6.03)
5.69 (3.64 – 7.92)
0.010
C-reactive protein, mg/l
3.28 (2.10 – 4.48)
4.69 (3.55 – 5.87)
NS
Systolic blood pressure, mmHg Diastolic blood pressure, mmHg
114 13.4 73.9 8.2
136 25.1 84.4 14.9
<0.0001 <0.0001
Pulse pressure, mmHg
40.4 9.7
51.1 15.0
<0.0001
Heart rate, bpm
72.4 13.0
73.7 12.4
NS
Cornell product, mm*ms
77.4 39.3
107.3 90.8
0.030
Antihypertensive treatment, n (%)
–
53 (75)
–
Obesity, n (%) Microalbuminuria, n (%)
22 (44) 3 (6)
41 (57.8) 4 (5.6)
NS NS
Hyperglycaemia, n (%)
5 (10)
21 (29.6)
0.009
Cardiovascular measurements
Comorbidities
Values are arithmetic mean SD, geometric mean (5th and 95th percentiles) or number of participants (percentage). Abbreviations: ACR – albumin to creatinine ratio; NS – not significant; Nt-proBNP – N-terminal prohormone B-type natriuretic peptide. Obesity was defined as a body mass index 30 kg/m2; Microalbuminuria was defined as urinary albumin 30 mg/dl; Hyperglycaemia was defined as fasting serum glucose 5.6 mmol/l.
Please cite this article in press as: Kruger R, et al. Cardiac Troponin T as Early Marker of Subclinical Cardiovascular Deterioration in Black Hypertensive Women. Heart, Lung and Circulation (2016), http://dx.doi.org/10.1016/j. hlc.2016.11.010
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Table 2 Unadjusted bivariate correlations of cardiac troponin T with measures of cardiovascular risk. Normotensive
Hypertensive
(n=50)
(n=71)
Troponin T, pg/ml Age, years
r=0.58; p<0.0001
Body mass index, kg/m2
r=0.011; p=0.94
r=–0.10; p=0.42
Systolic blood pressure, mmHg
r=0.19; p=0.19
r=0.23; p=0.055
Diastolic blood pressure, mmHg
r=–0.14; p=0.33
r=–0.005; p=0.97
Pulse pressure, mmHg
r=0.38; p=0.008
r=0.38; p=0.001
Cornell product, mm*ms
r=0.17; p=0.23
r=0.29; p=0.014
Nt-proBNP, pg/ml Serum glucose, mmol/l
r=0.37; p=0.008 r=0.038; p=0.79
r=0.48; p<0.0001 r=0.17; p=0.15
Urinary ACR, mg/g
r=0.18; p=0.21
r=0.30; p=0.010
Glomerular filtration rate, ml/min/1.73m2
r=–0.55; <0.0001
r=–0.50; p<0.0001
r=0.54; p<0.0001
Interleukin-6, pg/ml
r=0.31; p=0.032
r=0.094; p=0.44
C-reactive protein, mg/l
r=0.102; p=0.49
r=0.11; p=0.38
Abbreviations: ACR – albumin to creatinine ratio; Nt-proBNP – N-terminal prohormone B-type natriuretic peptide
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pressure (all p<0.0001) as well as Cornell product (p=0.030) were elevated in hypertensive compared to normotensive women. Table 2 summarises the single regression analysis of cTnT with measures of cardiovascular risk. Cardiac TnT correlated positively with age, pulse pressure and Nt-proBNP (all p<0.01) as well as inversely with glomerular filtration rate (p<0.0001) in both normotensive and hypertensive women. Cardiac TnT correlated positively with interleukin-6 in normotensive women only (p=0.032), whereas positive correlations with Cornell product (p=0.014) and urinary albumin-tocreatinine ratio (p=0.010) were only evident in hypertensive women. After partial adjustments for age, body mass index and kidney function (Table 3), all previous correlations in normotensive women disappeared while a positive link with
urinary albumin-to-creatinine ratio (r=0.35; p=0.017) emerged. In hypertensive women, cTnT correlated positively with urinary albumin to creatinine ratio, pulse pressure, NtproBNP and Cornell product (all p<0.05). We used multiple regression models to present independent associations of cardiovascular measures with cTnT (Table 4). The four models included urinary albumin-tocreatinine ratio, pulse pressure, Nt-proBNP and Cornell product as dependent variables. Variables that entered the models included age, body mass index, diastolic blood pressure (except for Model 2), glucose, interleukin-6, glomerular filtration rate, and in the hypertensive group antihypertensive treatment was additionally added. In normotensive women, the association of urinary albumin-to-creatinine ratio was confirmed (Adj. R2=0.19; b=0.34; p=0.037), but we found no association of pulse pressure, Nt-proBNP
Table 3 Partially adjusted bivariate correlations of cardiac troponin T with measures of cardiovascular risk. Normotensive (n=50)
Hypertensive (n=71)
Troponin T, pg/ml Systolic blood pressure, mmHg
r=0.16; p=0.28
r=0.21; p=0.093
Diastolic blood pressure, mmHg
r=0.008; p=0.96
r=0.11; p=0.39
Pulse pressure, mmHg
r=0.23; p=0.12
r=0.25; p=0.040
Cornell product, mm*ms
r=0.066; p=0.66
r=0.32; p=0.009
Nt-proBNP, pg/ml Urinary ACR, mg/g
r=0.22; p=0.15 r=0.35; p=0.017
r=0.39; p=0.001 r=0.25; p=0.044
Interleukin-6, pg/ml
r=0.21; p=0.16
r=0.056; p=0.65
Adjustments applied for age, body mass index and glomerular filtration rate. Abbreviations: ACR – albumin to creatinine ratio; Nt-proBNP – N-terminal prohormone B-type natriuretic peptide.
Please cite this article in press as: Kruger R, et al. Cardiac Troponin T as Early Marker of Subclinical Cardiovascular Deterioration in Black Hypertensive Women. Heart, Lung and Circulation (2016), http://dx.doi.org/10.1016/j. hlc.2016.11.010
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Table 4 Multiple regression analyses of cardiovascular measures with cardiac troponin T in black women stratified by hypertension status. Normotensive (n=50)
Hypertensive (n=71)
Urinary albumin-to-creatinine ratio, mg/g Adjusted R2 = 0.194
Adjusted R2 = 0.284
Standardised beta (95% CI)
p-value
Standardised beta (95% CI)
p-value
Troponin T, pg/ml
0.34 (0.030 to 0.657)
0.037
0.25 (0.047 to 0.447)
0.019
Body mass index, kg/m2
–0.30 (–0.566 to –0.036)
0.032
–0.31 (–0.512 to –0.107)
0.004
Diastolic BP, mmHg
–
–
0.34 (0.140 to 0.542)
0.001
Glomerular filtration rate, ml/min/1.73m2
0.43 (0.124 to 0.744)
0.009
–
–
Interleukin-6, pg/ml
0.29 (0.010 to 0.579)
0.049
0.27 (0.068 to 0.469)
0.011
Serum glucose, mmol/l
0.21 (–0.071 to 0.499) Pulse pressure. mmHg
0.15
–
–
Adjusted R2 = 0.223
Adjusted R2 = 0.209
Troponin T, pg/ml
0.19 (–0.128 to 0.505)
0.25
0.31 (0.056 to 0.553)
0.019
Age, years
0.20 (–0.105 to 0.513)
0.20
0.29 (0.028 to 0.528)
0.033
Body mass index, kg/m2
–0.31 (–0.567 to –0.045)
0.026
–
–
Interleukin-6, pg/ml
0.22 (–0.052 to 0.498)
0.12
–
–
Serum glucose, mmol/l
0.14 (–0.119 to 0.389)
0.30
–
–
Antihypertensive treatment
– Nt-proBNP, pg/ml
–
–0.20 (–0.414 to 0.020)
0.080
Adjusted R2 = 0.321
Adjusted R2 = 0.283
Troponin T, pg/ml
0.21 (–0.088 to 0.513)
0.17
0.47 (0.262 to 0.667)
<0.0001
Age, years
0.54 (0.220 to 0.868)
0.002
–
–
Body mass index, kg/m2
–0.14 (–0.379 to 0.092)
0.24
–0.17 (–0.374 to 0.033)
0.11
Diastolic BP, mmHg
–
–
0.20 (–0.006 to 0.397)
0.061
Glomerular filtration rate, ml/min/1.73m2
0.26 (–0.054 to 0.577)
0.11
–
–
Interleukin-6, pg/ml Serum glucose, mmol/l
– –0.27 (–0.509 to –0.033)
– 0.031
0.25 (0.040 to 0.468) –0.17 (–0.389 to 0.041)
0.023 0.12
Cornell product, mm*ms Adjusted R2 = 0.122
Adjusted R2 = 0.212
Troponin T, pg/ml
–
–
0.31 (0.059 to 0.550)
0.018
Age, years
0.17 (–0.109 to 0.457)
0.24
–
–
Body mass index, kg/m2
–
–
–0.29 (–0.501 to –0.079)
0.009
Diastolic blood pressure, mmHg
–0.30 (–0.586 to –0.020)
0.042
0.38 (0.129 to 0.627)
0.004
Glomerular filtration rate, ml/min/1.73m2 Interleukin-6, pg/ml
– –
– –
0.16 (–0.080 to 0.421) 0.14 (–0.074 to 0.351)
0.19 0.20
Antihypertensive treatment
–
–
0.17 (–0.082 to 0.415)
0.19
Variables that did not enter the model are indicated with ‘‘–’’ or omitted if applicable for both groups. Abbreviations: CI – confidence interval.
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and Cornell product with cTnT (Table 4). In hypertensive women, cTnT entered all four models and related to urinary albumin-to-creatinine ratio (b=0.25; p=0.019), pulse pressure (b=0.31; p=0.019), Nt-proBNP (b=0.47; p<0.0001) and Cornell product (b=0.31; p=0.018). Although the same number of cases with microalbuminuria was observed in each group, we performed the same regression analyses after excluding these seven cases from the models. No difference in the models shown in Table 4 was observed. Furthermore, we explored these associations in only hypertensive women using anti-hypertensive treatment (n=53) and confirmed all previous associations except
for the association with urinary albumin-to-creatinine ratio (Adj. R2=0.30; b=0.14; p=0.31).
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Discussion
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Our study confirmed a persistent link of urinary albumin-tocreatinine ratio, arterial stiffness (pulse pressure), cardiac volume overload (Nt-proBNP) and ECG derived left ventricular hypertrophy (Cornell product), with a biomarker of cardiomyocyte damage, namely cTnT, in black hypertensive women, despite >50% hypertensive treatment users. We
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Please cite this article in press as: Kruger R, et al. Cardiac Troponin T as Early Marker of Subclinical Cardiovascular Deterioration in Black Hypertensive Women. Heart, Lung and Circulation (2016), http://dx.doi.org/10.1016/j. hlc.2016.11.010
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further established an independent association between urinary albumin-to-creatinine ratio and cTnT in normotensive women, suggesting its potential as an early marker of subclinical organ damage in older normotensive individuals. To the best of our knowledge this is the first study indicating an association between albumin-to-creatinine ratio and cTnT in black women. Although albumin-to-creatinine ratio depicts renal injury, it is also considered a marker of systemic endothelial dysfunction and used to stratify risk in hypertensive patients.[17,18] Hypertension and endothelial dysfunction are interrelated regarding pathophysiologic mechanisms,[19] supporting the relevance of our findings in black women prone to develop hypertensive heart disease. [20] A study on the racial differences in endothelial function in postmenopausal women concluded that brachial artery flow-mediated dilation (as an indicator of endothelial dysfunction) is lower in African American women compared to white women.[21] This study further suggested these African American women may especially benefit from interventions designed to improve endothelial health. Antihypertensive therapy not only reduces blood pressure but also reverses hypertension-associated endothelial dysfunction.[19] Although we indicated a persistant link between systemic endothelial dysfunction and cTnT in our hypertensive cohort, this link disappeared after performing the analysis only in those on treatment. This may indicate the benefit of hypertensive treatment, however potential subclinical cardiovascular damage may already be present attributed by ineffective control and perhaps the lack of compliance and adherence to treatment prescribed to these black women. Apart from potentially ineffective treatment, subclinical endothelial dysfunction related to elevated blood pressure may be driven by inflammation[22] and increased obesity[23] in hypertensive black women. Several studies, in both population- and patient-based cohorts, demonstrated a link between increased arterial stiffness and the risk of cardiovascular complications such as heart failure, myocardial infarction, and stroke.[24,25] Measures of arterial stiffness (pulse wave velocity and pulse pressure) are associated with subclinical myocardial damage as reflected by increased cTnT levels in the elderly[26] and Nt-proBNP in black individuals.[27] Our study confirmed this association between pulse pressure and cTnT in black hypertensive women. Pulse pressure is a critical predictor of cardiovascular events, particularly in older individuals due to increased arterial stiffness and systolic blood pressure and decreasing diastolic pressure with advancing age.[28] The mean age of the hypertensive black women in our study was above 50 years, with high levels of inflammation (interleukin6), and presented with a large percentage of hyperglycaemia and obesity. These are all contributors to increased arterial stiffness above the high average pulse pressure in the hypertensive group. We unfortunately did not have data on femoral pulse wave velocity in this study. The link we observed with cTnT suggests not only do these individuals have potential subclinical endothelial dysfunction, but are also exposed to subclinical arteriosclerosis (arterial stiffness) inflicting a
high cardiac volume load, making them more prone to cardiac damage. Our study also confirmed an independent association of both Nt-proBNP and Cornell product with cTnT in hypertensive black women. A study concluded that cTnT relates to age, renal function, and cardiac hypertrophy in individuals presenting with treated essential hypertension.[29] Cardiac TnT release is also associated with wall stress in the damaged myocardium potentially in response to volume expansion and pressure overload associated with wall stress and depicted by Nt-proBNP.[30] The link between circulating cTnT levels and Nt-proBNP levels is evident in patients without heart failure confirming usefulness in the general population.[31] These findings signify cTnT as a useful tool to detect subclinical cardiovascular disease and assessing cardiovascular disease risk in the general population. Although our cohort of black women did not have overt hypertrophy and Nt-proBNP levels, our associations with cTnT indicate the potential for cardiovascular risk in these elderly black women. In light of the high incidence of obesity, inflammation and hyperglycaemia in this black female cohort, along with the established associations of urinary albumin-to-creatinine ratio, pulse pressure, Cornell product and Nt-proBNP with cTnT, potential future adverse cardiac events could be prevented by introducing intervention strategies in this population. The results from our study therefore confirm the urgency of early intervention strategies and more sensitive methods for detecting silent cardiovascular deterioration highlighted by LloydSherlock et al.[6] Although our method of measuring high sensitivity cTnT had limitations in terms of the Limit of Detection, our values in the hypertensive group were reliable. Our results in the normotensive group should however be interpreted with caution since more sensitive methods for detecting lower levels of cTnT are currently under development.[32] In addition, a previous study described the prevalence of detectable troponin in the general population to be low, but associated strongly with structural heart disease[33] and an increased risk of death and adverse cardiovascular events.[34] Furthermore, circulating cTnT has prognostic value in a community-dwelling population, making it possible to screen for the presence of subclinical silent myocardial damage in subjects without overt cardiovascular disease.[26,35] Cardiac TnT is also a more cost-effective tool compared to expensive imaging modalities including echocardiography and cardiac magnetic resonance imaging, especially in countries with low detection of hypertension and CVD. To our knowledge our study is the first to assess associations of markers of systemic endothelial dysfunction, arterial stiffness, left ventricular hypertrophy and Nt-proBNP with cTnT in black South African women. Although, a power calculation indicated our sample size as sufficient for the current analysis to test our hypothesis, our population sample was fairly small in numbers and we cannot exclude any residual findings impacting on the results. This
Please cite this article in press as: Kruger R, et al. Cardiac Troponin T as Early Marker of Subclinical Cardiovascular Deterioration in Black Hypertensive Women. Heart, Lung and Circulation (2016), http://dx.doi.org/10.1016/j. hlc.2016.11.010
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study also formed part of a larger longitudinal study, but some data from this sub-analysis study was not available at baseline. Therefore this study was of cross-sectional design and causality cannot be inferred, nor can we exclude any potential chance finding, but our results were robust after multiple adjustments. Our data further urges the importance of more sensitive early screening tools necessary to identify potential subclinical risk prior to clinically overt cardiovascular manifestations in which treatment and intervention strategies are likely to be ineffective or redundant.
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Conclusion
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In conclusion, our study highlights the potential usefulness of cTnT as an early marker of cardiovascular risk (from subclinical endothelial dysfunction to left ventricular hypertrophy) especially in an elderly black population independent of hypertension treatment and renal function.
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Grant Support
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We acknowledge the support of the Population Health Research Institute (PHRI), the North-West University and Roche Diagnostics, as well as the financial support of the South Africa - Netherlands Research Program on Alternatives in Development (SANPAD) (GUN number 08/15) and the South African National Research Foundation (NRF) (GUN number FA2006040700010 and 2069139).
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Q4
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Disclosure
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The authors have nothing to disclose.
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Conflict of Interest Statement
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The authors have no conflicts of interest to disclose.
367
Acknowledgements
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We are grateful towards the participants of this study, the PURE-SA research team, the field workers and supporting staff in the Africa Unit for Transdisciplinary Health Research (AUTHeR), North-West University, South Africa, as well as Dr S Yusuf (PURE-International) and the PURE project staff at the PHRI, Hamilton Health Sciences and McMaster University, ON, Canada. The authors also acknowledge funding for this study including the South African Medical Research Council and National Research Foundation. The conclusions of this study are those of the authors and not the funding bodies.
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References
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[1] McEvoy JW, Chen Y, Nambi V, Ballantyne CM, Sharrett AR, Appel LJ, et al. High-Sensitivity Cardiac Troponin T and Risk of Hypertension. Circulation 2015;132(9):825–33.
[2] Magga J, Marttila M, Mantymaa P, Vuolteenaho O, Ruskoaho H. Brain natriuretic peptide in plasma, atria, and ventricles of vasopressinand phenylephrine-infused conscious rats. Endocrinology 1994;134(6): 2505–15. [3] Raizada V, Thakore K, Luo W, McGuire PG. Cardiac chamber-specific alterations of ANP and BNP expression with advancing age and with systemic hypertension. Molecular and Cellular Biochemistry 2001; 216(1–2):137–40. [4] Kruger R, Schutte R, Huisman HW, Argraves WS, Rasmussen LM, Olsen MH, et al. NT-proBNP is associated with fibulin-1 in Africans: the SAfrEIC study. Atherosclerosis 2012;222(1):216–21. [5] Addo J, Smeeth L, Leon DA. Hypertension in sub-saharan Africa: a systematic review. Hypertension 2007;50(6):1012–8. [6] Lloyd-Sherlock P, Beard J, Minicuci N, Ebrahim S, Chatterji S. Hypertension among older adults in low- and middle-income countries: prevalence, awareness and control. International Journal of Epidemiology 2014;43(1):116–28. [7] Schutte AE, Schutte R, Huisman HW, van Rooyen JM, Fourie CM, Malan NT, et al. Are behavioural risk factors to be blamed for the conversion from optimal blood pressure to hypertensive status in Black South Africans?. A 5-year prospective study. International Journal of Epidemiology 2012;41(4):1114–23. [8] Opie LH, Seedat YK. Hypertension in sub-Saharan African populations. Circulation 2005;112(23):3562–8. [9] Seedat YK. Hypertension in black South Africans. Journal of Human Hypertension 1999;13(2):96–103. [10] Sliwa K, Ojji D, Bachelier K, Bohm M, Damasceno A, Stewart S. Hypertension and hypertensive heart disease in African women. Clinical Research in Cardiology: official journal of the German Cardiac Society 2014;103(7):515–23. [11] Schutte AE, Huisman HW, Schutte R, Van Rooyen JM, Malan L, Malan NT, et al. Arterial stiffness profiles: investigating various sections of the arterial tree of African and Caucasian people. Clinical and Experimental Hypertension (New York, NY: 1993) 2011;33(8):511–7. [12] Teo K, Chow CK, Vaz M, Rangarajan S, Yusuf S. The Prospective Urban Rural Epidemiology (PURE) study: examining the impact of societal influences on chronic noncommunicable diseases in low-, middle-, and high-income countries. American Heart Journal 2009; 158(1). 1-7.e1. [13] Mancia G, Fagard R, Narkiewicz K, Redon J, Zanchetti A, Bohm M, et al. 2013 ESH/ESC Practice Guidelines for the Management of Arterial Hypertension. Blood Press 2014;23(1):3–16. [14] Molloy TJ, Okin PM, Devereux RB, Kligfield P. Electrocardiographic detection of left ventricular hypertrophy by the simple QRS voltageduration product. Journal of the American College of Cardiology 1992;20 (5):1180–6. [15] Okin PM, Roman MJ, Devereux RB, Kligfield P. Electrocardiographic identification of increased left ventricular mass by simple voltage-duration products. Journal of the American College of Cardiology 1995;25 (2):417–23. [16] Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro 3rd AF, Feldman HI, et al. A new equation to estimate glomerular filtration rate. Annals of Internal Medicine 2009;150(9):604–12. [17] Furtner M, Kiechl S, Mair A, Seppi K, Weger S, Oberhollenzer F, et al. Urinary albumin excretion is independently associated with carotid and femoral artery atherosclerosis in the general population. European Heart Journal 2005;26(3):279–87. [18] Pedrinelli R, Dell’Omo G, Penno G, Mariani M. Non-diabetic microalbuminuria, endothelial dysfunction and cardiovascular disease. Vascular Medicine (London, England) 2001;6(4):257–64. [19] Dharmashankar K, Widlansky ME. Vascular endothelial function and hypertension: insights and directions. Current Hypertension Reports 2010;12(6):448–55. [20] Schutte R, Huisman HW, Ware LJ, Mels CM, Smith W, Malan NT, et al. Cornell product relates to albuminuria in hypertensive black adults independently of blood pressure: the SABPA study. Journal of the American Society of Hypertension 2015;9(2):115–22. [21] Loehr LR, Espeland MA, Sutton-Tyrrell K, Burke GL, Crouse 3rd JR, Herrington DM. Racial differences in endothelial function in postmenopausal women. American Heart Journal 2004;148(4):606–11. [22] Shoelson SE, Lee J, Goldfine AB. Inflammation and insulin resistance. The Journal of Clinical Investigation 2006;116(7):1793–801. [23] Schutte AE, Huisman HW, Van Rooyen JM, Schutte R, Malan L, Reimann M, et al. Should obesity be blamed for the high prevalence rates of hypertension in black South African women? Journal of Human Hypertension 2008;22(8):528–36.
Please cite this article in press as: Kruger R, et al. Cardiac Troponin T as Early Marker of Subclinical Cardiovascular Deterioration in Black Hypertensive Women. Heart, Lung and Circulation (2016), http://dx.doi.org/10.1016/j. hlc.2016.11.010
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[24] Boutouyrie P, Tropeano AI, Asmar R, Gautier I, Benetos A, Lacolley P, et al. Aortic stiffness is an independent predictor of primary coronary events in hypertensive patients: a longitudinal study. Hypertension 2002;39(1):10–5. [25] Mattace-Raso FU, van der Cammen TJ, Hofman A, van Popele NM, Bos ML, Schalekamp MA, et al. Arterial stiffness and risk of coronary heart disease and stroke: the Rotterdam Study. Circulation 2006;113(5):657–63. [26] Bai Y, Ye P, Luo L, Xiao W, Xu R, Wu H, et al. Arterial stiffness is associated with minimally elevated high-sensitivity cardiac, troponin T levels in a community-dwelling population. Atherosclerosis 2011;218 (2):493–8. [27] Kruger R, Schutte R, Huisman HW, Hindersson P, Olsen MH, Schutte AE. N-terminal prohormone B-type natriuretic peptide and cardiovascular function in Africans and Caucasians: the SAfrEIC study. Heart, Lung Circ 2012;21(2):88–95. [28] Franklin SS, Larson MG, Khan SA, Wong ND, Leip EP, Kannel WB, et al. Does the relation of blood pressure to coronary heart disease risk change with aging? The Framingham Heart Study. Circulation 2001;103(9):1245–9. [29] Sato Y, Yamamoto E, Sawa T, Toda K, Hara T, Iwasaki T, et al. Highsensitivity cardiac troponin T in essential hypertension. Journal of Cardiology 2011;58(3):226–31.
[30] Daniels LB, Maisel AS. Natriuretic peptides. Journal of the American College of Cardiology 2007;50(25):2357–68. [31] Saunders JT, Nambi V, de Lemos JA, Chambless LE, Virani SS, Boerwinkle E, et al. Cardiac troponin T measured by a highly sensitive assay predicts coronary heart disease, heart failure, and mortality in the Atherosclerosis Risk in Communities Study. Circulation 2011;123(13): 1367– 76. [32] Apple FS. A new season for cardiac troponin assays: it’s time to keep a scorecard. Clinical Chemistry 2009;55(7):1303–6. [33] Wallace TW, Abdullah SM, Drazner MH, Das SR, Khera A, McGuire DK, et al. Prevalence and determinants of troponin T elevation in the general population. Circulation 2006;113(16):1958–65. [34] Blankenberg S, Zeller T, Saarela O, Havulinna AS, Kee F, Tunstall-Pedoe H, et al. Contribution of 30 biomarkers to 10-year cardiovascular risk estimation in 2 population cohorts: the MONICA, risk, genetics, archiving, and monograph (MORGAM) biomarker project. Circulation 2010;121(22):2388–97. [35] Otsuka T, Kawada T, Ibuki C, Seino Y. Association between high-sensitivity cardiac troponin T levels and the predicted cardiovascular risk in middle-aged men without overt cardiovascular disease. American Heart Journal 2010;159(6):972–8.
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Cardiac Troponin T as Early Marker of Subclinical Cardiovascular Deterioration in Black Hypertensive Women R. Kruger a*, A.E. Schutte a,b, C.M.C. Mels a, W. Smith a, J.M. van Rooyen a, I.M. Kruger c, C.M.T. Fourie a a
Hypertension in Africa Research Team (HART), North-West University, Potchefstroom, South Africa Medical Research Council: Unit for Hypertension and Cardiovascular Disease, Faculty of Health Sciences, North-West University, Potchefstroom, South Africa c Africa Unit for Transdisciplinary Health Research (AUTHeR), North-West University, Potchefstroom, South Africa b
Received 13 May 2016; accepted 13 November 2016; online published-ahead-of-print xxx
13 14 15 16
ORIGINAL ARTICLE
Background
Hypertensive heart disease is a rising concern, especially among black South African women. As high sensitivity cardiac troponin T (cTnT) is a marker of cardiomyocyte damage, we determined the potential link of (i) systemic endothelial dysfunction (reflected by urinary albumin-to-creatinine ratio), (ii) large artery stiffness, (iii) cardiac volume load (estimated by the N-terminal prohormone B-type natriuretic peptide (Nt-proBNP)), and (iv) ECG left ventricular hypertrophy in post-menopausal black women.
Methods
In 121 (50 normotensive and 71 hypertensive) black women (mean age: 60.6 years), basic cardiovascular assessments including blood pressure and ECG were performed, along with plasma and urinary biomarkers including cTnT.
Results
The cTnT levels (p=0.049) along with Nt-proBNP (p=0.003), pulse pressure (p<0.0001) and the Cornell product (p=0.030) were higher in hypertensive than normotensive women. Only in hypertensive women, was cTnT independently associated with urinary albumin-to-creatinine ratio (b=0.25; p=0.019), pulse pressure (b=0.31; p=0.019), Nt-proBNP (b=0.47; p<0.0001) and Cornell product (b=0.31; p=0.018). An independent association between albumin-to-creatinine ratio and cTnT was also evident in normotensive women (b=0.34; p=0.037).
Conclusion
We found cTnT to be a useful marker in an elderly black population relating to several measures of cardiovascular deterioration – from subclinical endothelial dysfunction to left ventricular hypertrophy.
Keywords
Troponin T Endothelial dysfunction Arterial stiffness Left ventricular hypertrophy Hypertension
Introduction Q3
The link between the heart and vasculature is apparent and therefore worth exploring in a population prone to hypertensive heart disease by assessing a reliable measure of cardiomyocyte injury. High sensitivity cardiac troponin T (cTnT) is described as a novel, noninvasive biomarker of
subclinical myocardial damage and relates to incident hypertension and an increasing risk of left ventricular hypertrophy in individuals free from cardiovascular disease (CVD).[1] The N-terminal prohormone B-type natriuretic peptide (Nt-proBNP) increases in hypertensive heart disease and indicates cardiac overload and augments with heart failure.[2,3] NT-proBNP was also shown to link with subclinical
*Corresponding author at: Hypertension in Africa Research Team (HART), North-West University, Potchefstroom, 2531, South Africa. Tel.: +27 18 299 2904; fax: +27 18 285 2432, Email: [email protected] © 2016 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: Kruger R, et al. Cardiac Troponin T as Early Marker of Subclinical Cardiovascular Deterioration in Black Hypertensive Women. Heart, Lung and Circulation (2016), http://dx.doi.org/10.1016/j. hlc.2016.11.010
21 22 23 24 25 26 27
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51 52
vascular extracellular matrix turnover and arterial stiffness in black individuals, posing a higher risk for future cardiovascular morbidity compared to their white counterparts.[4] Hypertension remains to a large extent one of the major public health problems in South Africa[5] with a prevalence range of hypertension between 78% and 82% in women over the age of 50 years.[6] Furthermore, our group indicated that 24% of South Africans of the North West province with optimal blood pressure developed hypertension within five years.[7] The low detection, treatment, and control of high blood pressure, especially in black communities, increase the risk of future adverse events such as cerebral bleeding, malignant hypertension, and/or kidney disease – all of which may lead to congestive heart failure.[8,9] Black women in particular are affected by hypertensive heart disease at a much younger age in sub-Saharan Africa than observed in developed countries.[10] The prevalence of high blood pressure and related arterial stiffness have also been shown to occur earlier in black South Africans than their white counterparts.[11] We therefore reviewed cTnT in a hypertension-prone population of urban, post-menopausal black women, and how it relates to (i) endothelial function; (ii) arterial stiffness; (iii) NtproBNP; and (iv) ECG derived left ventricular hypertrophy (Cornell product).
53
Ethical Considerations
54
All procedures were explained to each individual beforehand, in their home language when preferred. Written, informed consent was obtained from each participant through an independent person. Participation within the study was completely voluntarily, and participants could withdraw at any point without any consequences. Privacy and confidentiality was ensured throughout the entire research process by using a unique number assigned to each participant. The study protocol was approved by the Health Research Ethics Committee of the Faculty of Health Sciences, of the North-West University (Potchefstroom campus, South Africa) and complied with the Declaration of Helsinki.
29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50
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66
Methods
67
Data from the South African leg of the Prospective Urban and Rural Epidemiology (PURE) study[7,12] conducted in the North West Province, Potchefstroom were used in this cross-sectional sub-study. During the baseline data collection (2005) of the South African PURE study 1004 randomly selected Africans (>35 years) from the Potchefstroom (urban) area partook in the study, of whom 66% were women. 152 women partook in the 2012 data collection and for this crosssectional analysis, individuals with incomplete data (n=28) and macro-albuminuria (n=3) were excluded, resulting in a total of 121 black women (50 normotensive and 71 hypertensive). Hypertensive status was determined according to the European Society of Hypertension guidelines.[13] A systolic 140 mmHg and/or diastolic blood pressure 90 mmHg
68 69 70 71 72 73 74 75 76 77 78 79 80
were considered hypertensive. All individuals using antihypertensive drugs were also considered hypertensive. Research participants were transported to and from the Potchefstroom campus of the North-West University where the measurements and data collection took place. Participants were required to complete standardised, interviewbased questionnaires administered by trained fieldworkers in the language of their choice to collect demographic information. On the day of data collection the medication use was recorded by a pharmacist. We measured height and weight to the nearest decimal point with a calibrated Leicester stadiometer (Seca, Birmingham, UK) and an electronic Precision Health scale (model UC-300, Saitama, Japan), respectively. Waist circumference was also measured to the nearest decimal point using a steel measuring tape (Lufkin, Apex, NC, USA). Blood pressure was measured in duplicate on the right upper arm using an Omron automatic digital blood pressure monitor with appropriate cuff sizes (Omron M10-IT, Omron Healthcare, Tokyo, Japan). The participants were seated upright and relaxed with their right arm supported at heart level. Two measurements were taken with a five-minute interval and the second measurement of systolic and diastolic blood pressure, as well as heart rate, were recorded. Participants were instructed to refrain from eating, smoking, ingesting caffeine or undertaking exercise/physical activity such as climbing the stairs in the 30 minutes prior to the measurement. Pulse pressure was calculated and used as measure of arterial stiffness. A 12-lead standard ECG (Norav Medical Ltd, Kiryat Bialik, Israel) was recorded in a supine position. The Cornell product calculated as (RaVL+SV3 +0.8) * QRS duration for women was used as surrogate measure for left ventricular hypertrophy.[14,15] Participants were asked to fast for at least eight hours before data collection. Blood samples were obtained by a registered nurse and a midstream spot urine sample was collected for each individual. Urinary, serum and plasma samples were prepared according to appropriate methods, followed by storage at –80 8C in the bio-repository until analysis. Quantitative determination of serum creatinine, high density lipoprotein cholesterol, triglycerides, glucose, high sensitivity C-reactive protein as well as urinary albumin and creatinine levels were performed (Cobas Integra 400 Plus, Roche, Indianapolis, IN, USA). High sensitivity troponin T (cTnT), interleukin-6 and Nt-proBNP levels were measured with an Elecsys 2010 (Roche, Basel, Switzerland). The standard Elecsys-test for hs-cTnT has a Limit of Detection (LoD) at 5 pg/ml, and a 10%-Coefficient of Variance at 13 pg/ ml. Assuming this, >50% of patients in the normotensive group had cTnT levels below 5 pg/ml while the uncertainty of the measurements is quite high and most likely exceeds 20%. We assessed renal function by using the Chronic Kidney Disease Epidemiology Collaboration creatinine equation (CKD-EPI) as glomerular filtration rate estimation[16] along with urinary albumin excretion. All statistical analyses were performed using Statistica (data analysis software system), version 12 (StatSoft, Inc.
Please cite this article in press as: Kruger R, et al. Cardiac Troponin T as Early Marker of Subclinical Cardiovascular Deterioration in Black Hypertensive Women. Heart, Lung and Circulation (2016), http://dx.doi.org/10.1016/j. hlc.2016.11.010
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138 139 140 141 142 143 144 145 146 147 148 149 150 151 152 153 154 155 156 157
(2014), Tulsa, OK, USA) and G*Power version 3.1.9.2 software. In post hoc analysis, we computed the achieved power to determine differences between two independent groups. At an a error probability of 0.05, effect size of 50% and twotailed input method the achieved Power (1-b error probability) was estimated at 89.14%. Prior to any further statistical testing, variables were assessed for non-Gaussian tendency. Skewed variables were transformed to the logarithm with base 10. These variables were cTnT, Nt-proBNP, glucose, Creactive protein and interleukin 6. Independent samples T-tests along with Chi-squared tests were performed to illustrate the mean differences and proportions between groups, respectively. Linear bivariate correlations were explored using single regression analysis and thereafter partially adjusted for main confounding variables including age and glomerular filtration rate as a measure of kidney function. Forward stepwise multiple regression analyses were used to determine independent associations between measures of cardiovascular function and cTnT in each group. Variables considered for entry in the model
included age, body mass index, systolic or diastolic blood pressure, glucose, C-reactive protein, interleukin 6, estimated glomerular filtration rate and additionally for anti-hypertensive treatment in our hypertensive cohort.
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Results
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A comparison of basic descriptive data is provided in Table 1. We found no difference in age (p=0.077), body mass index (p=0.23), markers of renal function (all p>0.1), C-reactive protein (p=0.12) and heart rate (p=0.60) between normotensive and hypertensive women. About 6% of all cases had urinary albumin levels in the microalbuminuria range, equally distributed between the groups (p=0.94). Cardiac TnT levels along with Nt-proBNP, glucose and interleukin-6 were higher (all p<0.05) in hypertensive than normotensive women. Among the hypertensive women, almost 31% presented with hyperglycaemia compared to 10% in normotensives (p=0.009). Resting blood pressure, pulse
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Table 1 Population characteristics of black women stratified by blood pressure status. Normotensive
Hypertensive
n=50
n=71
p-value
Age, years
58.6 10.7
62.0 10.2
0.077
Body mass index, kg/m2
29.0 7.9
30.7 7.6
NS
Biochemical analyses Troponin T, pg/ml
4.96 (3.00 – 11.82)
6.01 (3.00 – 21.0)
0.049
Nt-proBNP, pg/ml
57.5 (8.06 – 172.7)
104.4 (20.9 – 883.7)
0.003
Urinary ACR, mg/g Serum creatinine, mmol/l
1.06 (0.32 – 9.22) 55.4 14.4
1.40 (0.35 –9.09) 56.2 16.9
NS NS
Glomerular filtration rate, ml/min/1.73m2
113.9 19.6
109.7 19.1
NS
Serum glucose, mmol/l
4.77 (2.09 – 7.45)
5.83 (2.90 – 8.84)
0.004
Interleukin-6, pg/ml
3.87 (1.61 – 6.03)
5.69 (3.64 – 7.92)
0.010
C-reactive protein, mg/l
3.28 (2.10 – 4.48)
4.69 (3.55 – 5.87)
NS
Systolic blood pressure, mmHg Diastolic blood pressure, mmHg
114 13.4 73.9 8.2
136 25.1 84.4 14.9
<0.0001 <0.0001
Pulse pressure, mmHg
40.4 9.7
51.1 15.0
<0.0001
Heart rate, bpm
72.4 13.0
73.7 12.4
NS
Cornell product, mm*ms
77.4 39.3
107.3 90.8
0.030
Antihypertensive treatment, n (%)
–
53 (75)
–
Obesity, n (%) Microalbuminuria, n (%)
22 (44) 3 (6)
41 (57.8) 4 (5.6)
NS NS
Hyperglycaemia, n (%)
5 (10)
21 (29.6)
0.009
Cardiovascular measurements
Comorbidities
Values are arithmetic mean SD, geometric mean (5th and 95th percentiles) or number of participants (percentage). Abbreviations: ACR – albumin to creatinine ratio; NS – not significant; Nt-proBNP – N-terminal prohormone B-type natriuretic peptide. Obesity was defined as a body mass index 30 kg/m2; Microalbuminuria was defined as urinary albumin 30 mg/dl; Hyperglycaemia was defined as fasting serum glucose 5.6 mmol/l.
Please cite this article in press as: Kruger R, et al. Cardiac Troponin T as Early Marker of Subclinical Cardiovascular Deterioration in Black Hypertensive Women. Heart, Lung and Circulation (2016), http://dx.doi.org/10.1016/j. hlc.2016.11.010
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Table 2 Unadjusted bivariate correlations of cardiac troponin T with measures of cardiovascular risk. Normotensive
Hypertensive
(n=50)
(n=71)
Troponin T, pg/ml Age, years
r=0.58; p<0.0001
Body mass index, kg/m2
r=0.011; p=0.94
r=–0.10; p=0.42
Systolic blood pressure, mmHg
r=0.19; p=0.19
r=0.23; p=0.055
Diastolic blood pressure, mmHg
r=–0.14; p=0.33
r=–0.005; p=0.97
Pulse pressure, mmHg
r=0.38; p=0.008
r=0.38; p=0.001
Cornell product, mm*ms
r=0.17; p=0.23
r=0.29; p=0.014
Nt-proBNP, pg/ml Serum glucose, mmol/l
r=0.37; p=0.008 r=0.038; p=0.79
r=0.48; p<0.0001 r=0.17; p=0.15
Urinary ACR, mg/g
r=0.18; p=0.21
r=0.30; p=0.010
Glomerular filtration rate, ml/min/1.73m2
r=–0.55; <0.0001
r=–0.50; p<0.0001
r=0.54; p<0.0001
Interleukin-6, pg/ml
r=0.31; p=0.032
r=0.094; p=0.44
C-reactive protein, mg/l
r=0.102; p=0.49
r=0.11; p=0.38
Abbreviations: ACR – albumin to creatinine ratio; Nt-proBNP – N-terminal prohormone B-type natriuretic peptide
175 176 177 178 179 180 181 182 183 184 185 186 187 188 189 190
pressure (all p<0.0001) as well as Cornell product (p=0.030) were elevated in hypertensive compared to normotensive women. Table 2 summarises the single regression analysis of cTnT with measures of cardiovascular risk. Cardiac TnT correlated positively with age, pulse pressure and Nt-proBNP (all p<0.01) as well as inversely with glomerular filtration rate (p<0.0001) in both normotensive and hypertensive women. Cardiac TnT correlated positively with interleukin-6 in normotensive women only (p=0.032), whereas positive correlations with Cornell product (p=0.014) and urinary albumin-tocreatinine ratio (p=0.010) were only evident in hypertensive women. After partial adjustments for age, body mass index and kidney function (Table 3), all previous correlations in normotensive women disappeared while a positive link with
urinary albumin-to-creatinine ratio (r=0.35; p=0.017) emerged. In hypertensive women, cTnT correlated positively with urinary albumin to creatinine ratio, pulse pressure, NtproBNP and Cornell product (all p<0.05). We used multiple regression models to present independent associations of cardiovascular measures with cTnT (Table 4). The four models included urinary albumin-tocreatinine ratio, pulse pressure, Nt-proBNP and Cornell product as dependent variables. Variables that entered the models included age, body mass index, diastolic blood pressure (except for Model 2), glucose, interleukin-6, glomerular filtration rate, and in the hypertensive group antihypertensive treatment was additionally added. In normotensive women, the association of urinary albumin-to-creatinine ratio was confirmed (Adj. R2=0.19; b=0.34; p=0.037), but we found no association of pulse pressure, Nt-proBNP
Table 3 Partially adjusted bivariate correlations of cardiac troponin T with measures of cardiovascular risk. Normotensive (n=50)
Hypertensive (n=71)
Troponin T, pg/ml Systolic blood pressure, mmHg
r=0.16; p=0.28
r=0.21; p=0.093
Diastolic blood pressure, mmHg
r=0.008; p=0.96
r=0.11; p=0.39
Pulse pressure, mmHg
r=0.23; p=0.12
r=0.25; p=0.040
Cornell product, mm*ms
r=0.066; p=0.66
r=0.32; p=0.009
Nt-proBNP, pg/ml Urinary ACR, mg/g
r=0.22; p=0.15 r=0.35; p=0.017
r=0.39; p=0.001 r=0.25; p=0.044
Interleukin-6, pg/ml
r=0.21; p=0.16
r=0.056; p=0.65
Adjustments applied for age, body mass index and glomerular filtration rate. Abbreviations: ACR – albumin to creatinine ratio; Nt-proBNP – N-terminal prohormone B-type natriuretic peptide.
Please cite this article in press as: Kruger R, et al. Cardiac Troponin T as Early Marker of Subclinical Cardiovascular Deterioration in Black Hypertensive Women. Heart, Lung and Circulation (2016), http://dx.doi.org/10.1016/j. hlc.2016.11.010
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Table 4 Multiple regression analyses of cardiovascular measures with cardiac troponin T in black women stratified by hypertension status. Normotensive (n=50)
Hypertensive (n=71)
Urinary albumin-to-creatinine ratio, mg/g Adjusted R2 = 0.194
Adjusted R2 = 0.284
Standardised beta (95% CI)
p-value
Standardised beta (95% CI)
p-value
Troponin T, pg/ml
0.34 (0.030 to 0.657)
0.037
0.25 (0.047 to 0.447)
0.019
Body mass index, kg/m2
–0.30 (–0.566 to –0.036)
0.032
–0.31 (–0.512 to –0.107)
0.004
Diastolic BP, mmHg
–
–
0.34 (0.140 to 0.542)
0.001
Glomerular filtration rate, ml/min/1.73m2
0.43 (0.124 to 0.744)
0.009
–
–
Interleukin-6, pg/ml
0.29 (0.010 to 0.579)
0.049
0.27 (0.068 to 0.469)
0.011
Serum glucose, mmol/l
0.21 (–0.071 to 0.499) Pulse pressure. mmHg
0.15
–
–
Adjusted R2 = 0.223
Adjusted R2 = 0.209
Troponin T, pg/ml
0.19 (–0.128 to 0.505)
0.25
0.31 (0.056 to 0.553)
0.019
Age, years
0.20 (–0.105 to 0.513)
0.20
0.29 (0.028 to 0.528)
0.033
Body mass index, kg/m2
–0.31 (–0.567 to –0.045)
0.026
–
–
Interleukin-6, pg/ml
0.22 (–0.052 to 0.498)
0.12
–
–
Serum glucose, mmol/l
0.14 (–0.119 to 0.389)
0.30
–
–
Antihypertensive treatment
– Nt-proBNP, pg/ml
–
–0.20 (–0.414 to 0.020)
0.080
Adjusted R2 = 0.321
Adjusted R2 = 0.283
Troponin T, pg/ml
0.21 (–0.088 to 0.513)
0.17
0.47 (0.262 to 0.667)
<0.0001
Age, years
0.54 (0.220 to 0.868)
0.002
–
–
Body mass index, kg/m2
–0.14 (–0.379 to 0.092)
0.24
–0.17 (–0.374 to 0.033)
0.11
Diastolic BP, mmHg
–
–
0.20 (–0.006 to 0.397)
0.061
Glomerular filtration rate, ml/min/1.73m2
0.26 (–0.054 to 0.577)
0.11
–
–
Interleukin-6, pg/ml Serum glucose, mmol/l
– –0.27 (–0.509 to –0.033)
– 0.031
0.25 (0.040 to 0.468) –0.17 (–0.389 to 0.041)
0.023 0.12
Cornell product, mm*ms Adjusted R2 = 0.122
Adjusted R2 = 0.212
Troponin T, pg/ml
–
–
0.31 (0.059 to 0.550)
0.018
Age, years
0.17 (–0.109 to 0.457)
0.24
–
–
Body mass index, kg/m2
–
–
–0.29 (–0.501 to –0.079)
0.009
Diastolic blood pressure, mmHg
–0.30 (–0.586 to –0.020)
0.042
0.38 (0.129 to 0.627)
0.004
Glomerular filtration rate, ml/min/1.73m2 Interleukin-6, pg/ml
– –
– –
0.16 (–0.080 to 0.421) 0.14 (–0.074 to 0.351)
0.19 0.20
Antihypertensive treatment
–
–
0.17 (–0.082 to 0.415)
0.19
Variables that did not enter the model are indicated with ‘‘–’’ or omitted if applicable for both groups. Abbreviations: CI – confidence interval.
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and Cornell product with cTnT (Table 4). In hypertensive women, cTnT entered all four models and related to urinary albumin-to-creatinine ratio (b=0.25; p=0.019), pulse pressure (b=0.31; p=0.019), Nt-proBNP (b=0.47; p<0.0001) and Cornell product (b=0.31; p=0.018). Although the same number of cases with microalbuminuria was observed in each group, we performed the same regression analyses after excluding these seven cases from the models. No difference in the models shown in Table 4 was observed. Furthermore, we explored these associations in only hypertensive women using anti-hypertensive treatment (n=53) and confirmed all previous associations except
for the association with urinary albumin-to-creatinine ratio (Adj. R2=0.30; b=0.14; p=0.31).
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Discussion
221
Our study confirmed a persistent link of urinary albumin-tocreatinine ratio, arterial stiffness (pulse pressure), cardiac volume overload (Nt-proBNP) and ECG derived left ventricular hypertrophy (Cornell product), with a biomarker of cardiomyocyte damage, namely cTnT, in black hypertensive women, despite >50% hypertensive treatment users. We
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Please cite this article in press as: Kruger R, et al. Cardiac Troponin T as Early Marker of Subclinical Cardiovascular Deterioration in Black Hypertensive Women. Heart, Lung and Circulation (2016), http://dx.doi.org/10.1016/j. hlc.2016.11.010
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further established an independent association between urinary albumin-to-creatinine ratio and cTnT in normotensive women, suggesting its potential as an early marker of subclinical organ damage in older normotensive individuals. To the best of our knowledge this is the first study indicating an association between albumin-to-creatinine ratio and cTnT in black women. Although albumin-to-creatinine ratio depicts renal injury, it is also considered a marker of systemic endothelial dysfunction and used to stratify risk in hypertensive patients.[17,18] Hypertension and endothelial dysfunction are interrelated regarding pathophysiologic mechanisms,[19] supporting the relevance of our findings in black women prone to develop hypertensive heart disease. [20] A study on the racial differences in endothelial function in postmenopausal women concluded that brachial artery flow-mediated dilation (as an indicator of endothelial dysfunction) is lower in African American women compared to white women.[21] This study further suggested these African American women may especially benefit from interventions designed to improve endothelial health. Antihypertensive therapy not only reduces blood pressure but also reverses hypertension-associated endothelial dysfunction.[19] Although we indicated a persistant link between systemic endothelial dysfunction and cTnT in our hypertensive cohort, this link disappeared after performing the analysis only in those on treatment. This may indicate the benefit of hypertensive treatment, however potential subclinical cardiovascular damage may already be present attributed by ineffective control and perhaps the lack of compliance and adherence to treatment prescribed to these black women. Apart from potentially ineffective treatment, subclinical endothelial dysfunction related to elevated blood pressure may be driven by inflammation[22] and increased obesity[23] in hypertensive black women. Several studies, in both population- and patient-based cohorts, demonstrated a link between increased arterial stiffness and the risk of cardiovascular complications such as heart failure, myocardial infarction, and stroke.[24,25] Measures of arterial stiffness (pulse wave velocity and pulse pressure) are associated with subclinical myocardial damage as reflected by increased cTnT levels in the elderly[26] and Nt-proBNP in black individuals.[27] Our study confirmed this association between pulse pressure and cTnT in black hypertensive women. Pulse pressure is a critical predictor of cardiovascular events, particularly in older individuals due to increased arterial stiffness and systolic blood pressure and decreasing diastolic pressure with advancing age.[28] The mean age of the hypertensive black women in our study was above 50 years, with high levels of inflammation (interleukin6), and presented with a large percentage of hyperglycaemia and obesity. These are all contributors to increased arterial stiffness above the high average pulse pressure in the hypertensive group. We unfortunately did not have data on femoral pulse wave velocity in this study. The link we observed with cTnT suggests not only do these individuals have potential subclinical endothelial dysfunction, but are also exposed to subclinical arteriosclerosis (arterial stiffness) inflicting a
high cardiac volume load, making them more prone to cardiac damage. Our study also confirmed an independent association of both Nt-proBNP and Cornell product with cTnT in hypertensive black women. A study concluded that cTnT relates to age, renal function, and cardiac hypertrophy in individuals presenting with treated essential hypertension.[29] Cardiac TnT release is also associated with wall stress in the damaged myocardium potentially in response to volume expansion and pressure overload associated with wall stress and depicted by Nt-proBNP.[30] The link between circulating cTnT levels and Nt-proBNP levels is evident in patients without heart failure confirming usefulness in the general population.[31] These findings signify cTnT as a useful tool to detect subclinical cardiovascular disease and assessing cardiovascular disease risk in the general population. Although our cohort of black women did not have overt hypertrophy and Nt-proBNP levels, our associations with cTnT indicate the potential for cardiovascular risk in these elderly black women. In light of the high incidence of obesity, inflammation and hyperglycaemia in this black female cohort, along with the established associations of urinary albumin-to-creatinine ratio, pulse pressure, Cornell product and Nt-proBNP with cTnT, potential future adverse cardiac events could be prevented by introducing intervention strategies in this population. The results from our study therefore confirm the urgency of early intervention strategies and more sensitive methods for detecting silent cardiovascular deterioration highlighted by LloydSherlock et al.[6] Although our method of measuring high sensitivity cTnT had limitations in terms of the Limit of Detection, our values in the hypertensive group were reliable. Our results in the normotensive group should however be interpreted with caution since more sensitive methods for detecting lower levels of cTnT are currently under development.[32] In addition, a previous study described the prevalence of detectable troponin in the general population to be low, but associated strongly with structural heart disease[33] and an increased risk of death and adverse cardiovascular events.[34] Furthermore, circulating cTnT has prognostic value in a community-dwelling population, making it possible to screen for the presence of subclinical silent myocardial damage in subjects without overt cardiovascular disease.[26,35] Cardiac TnT is also a more cost-effective tool compared to expensive imaging modalities including echocardiography and cardiac magnetic resonance imaging, especially in countries with low detection of hypertension and CVD. To our knowledge our study is the first to assess associations of markers of systemic endothelial dysfunction, arterial stiffness, left ventricular hypertrophy and Nt-proBNP with cTnT in black South African women. Although, a power calculation indicated our sample size as sufficient for the current analysis to test our hypothesis, our population sample was fairly small in numbers and we cannot exclude any residual findings impacting on the results. This
Please cite this article in press as: Kruger R, et al. Cardiac Troponin T as Early Marker of Subclinical Cardiovascular Deterioration in Black Hypertensive Women. Heart, Lung and Circulation (2016), http://dx.doi.org/10.1016/j. hlc.2016.11.010
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study also formed part of a larger longitudinal study, but some data from this sub-analysis study was not available at baseline. Therefore this study was of cross-sectional design and causality cannot be inferred, nor can we exclude any potential chance finding, but our results were robust after multiple adjustments. Our data further urges the importance of more sensitive early screening tools necessary to identify potential subclinical risk prior to clinically overt cardiovascular manifestations in which treatment and intervention strategies are likely to be ineffective or redundant.
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Conclusion
350
354
In conclusion, our study highlights the potential usefulness of cTnT as an early marker of cardiovascular risk (from subclinical endothelial dysfunction to left ventricular hypertrophy) especially in an elderly black population independent of hypertension treatment and renal function.
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Grant Support
356
We acknowledge the support of the Population Health Research Institute (PHRI), the North-West University and Roche Diagnostics, as well as the financial support of the South Africa - Netherlands Research Program on Alternatives in Development (SANPAD) (GUN number 08/15) and the South African National Research Foundation (NRF) (GUN number FA2006040700010 and 2069139).
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Disclosure
364
The authors have nothing to disclose.
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Conflict of Interest Statement
366
The authors have no conflicts of interest to disclose.
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Acknowledgements
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We are grateful towards the participants of this study, the PURE-SA research team, the field workers and supporting staff in the Africa Unit for Transdisciplinary Health Research (AUTHeR), North-West University, South Africa, as well as Dr S Yusuf (PURE-International) and the PURE project staff at the PHRI, Hamilton Health Sciences and McMaster University, ON, Canada. The authors also acknowledge funding for this study including the South African Medical Research Council and National Research Foundation. The conclusions of this study are those of the authors and not the funding bodies.
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References
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[1] McEvoy JW, Chen Y, Nambi V, Ballantyne CM, Sharrett AR, Appel LJ, et al. High-Sensitivity Cardiac Troponin T and Risk of Hypertension. Circulation 2015;132(9):825–33.
[2] Magga J, Marttila M, Mantymaa P, Vuolteenaho O, Ruskoaho H. Brain natriuretic peptide in plasma, atria, and ventricles of vasopressinand phenylephrine-infused conscious rats. Endocrinology 1994;134(6): 2505–15. [3] Raizada V, Thakore K, Luo W, McGuire PG. Cardiac chamber-specific alterations of ANP and BNP expression with advancing age and with systemic hypertension. Molecular and Cellular Biochemistry 2001; 216(1–2):137–40. [4] Kruger R, Schutte R, Huisman HW, Argraves WS, Rasmussen LM, Olsen MH, et al. NT-proBNP is associated with fibulin-1 in Africans: the SAfrEIC study. Atherosclerosis 2012;222(1):216–21. [5] Addo J, Smeeth L, Leon DA. Hypertension in sub-saharan Africa: a systematic review. Hypertension 2007;50(6):1012–8. [6] Lloyd-Sherlock P, Beard J, Minicuci N, Ebrahim S, Chatterji S. Hypertension among older adults in low- and middle-income countries: prevalence, awareness and control. International Journal of Epidemiology 2014;43(1):116–28. [7] Schutte AE, Schutte R, Huisman HW, van Rooyen JM, Fourie CM, Malan NT, et al. Are behavioural risk factors to be blamed for the conversion from optimal blood pressure to hypertensive status in Black South Africans?. A 5-year prospective study. International Journal of Epidemiology 2012;41(4):1114–23. [8] Opie LH, Seedat YK. Hypertension in sub-Saharan African populations. Circulation 2005;112(23):3562–8. [9] Seedat YK. Hypertension in black South Africans. Journal of Human Hypertension 1999;13(2):96–103. [10] Sliwa K, Ojji D, Bachelier K, Bohm M, Damasceno A, Stewart S. Hypertension and hypertensive heart disease in African women. Clinical Research in Cardiology: official journal of the German Cardiac Society 2014;103(7):515–23. [11] Schutte AE, Huisman HW, Schutte R, Van Rooyen JM, Malan L, Malan NT, et al. Arterial stiffness profiles: investigating various sections of the arterial tree of African and Caucasian people. Clinical and Experimental Hypertension (New York, NY: 1993) 2011;33(8):511–7. [12] Teo K, Chow CK, Vaz M, Rangarajan S, Yusuf S. The Prospective Urban Rural Epidemiology (PURE) study: examining the impact of societal influences on chronic noncommunicable diseases in low-, middle-, and high-income countries. American Heart Journal 2009; 158(1). 1-7.e1. [13] Mancia G, Fagard R, Narkiewicz K, Redon J, Zanchetti A, Bohm M, et al. 2013 ESH/ESC Practice Guidelines for the Management of Arterial Hypertension. Blood Press 2014;23(1):3–16. [14] Molloy TJ, Okin PM, Devereux RB, Kligfield P. Electrocardiographic detection of left ventricular hypertrophy by the simple QRS voltageduration product. Journal of the American College of Cardiology 1992;20 (5):1180–6. [15] Okin PM, Roman MJ, Devereux RB, Kligfield P. Electrocardiographic identification of increased left ventricular mass by simple voltage-duration products. Journal of the American College of Cardiology 1995;25 (2):417–23. [16] Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro 3rd AF, Feldman HI, et al. A new equation to estimate glomerular filtration rate. Annals of Internal Medicine 2009;150(9):604–12. [17] Furtner M, Kiechl S, Mair A, Seppi K, Weger S, Oberhollenzer F, et al. Urinary albumin excretion is independently associated with carotid and femoral artery atherosclerosis in the general population. European Heart Journal 2005;26(3):279–87. [18] Pedrinelli R, Dell’Omo G, Penno G, Mariani M. Non-diabetic microalbuminuria, endothelial dysfunction and cardiovascular disease. Vascular Medicine (London, England) 2001;6(4):257–64. [19] Dharmashankar K, Widlansky ME. Vascular endothelial function and hypertension: insights and directions. Current Hypertension Reports 2010;12(6):448–55. [20] Schutte R, Huisman HW, Ware LJ, Mels CM, Smith W, Malan NT, et al. Cornell product relates to albuminuria in hypertensive black adults independently of blood pressure: the SABPA study. Journal of the American Society of Hypertension 2015;9(2):115–22. [21] Loehr LR, Espeland MA, Sutton-Tyrrell K, Burke GL, Crouse 3rd JR, Herrington DM. Racial differences in endothelial function in postmenopausal women. American Heart Journal 2004;148(4):606–11. [22] Shoelson SE, Lee J, Goldfine AB. Inflammation and insulin resistance. The Journal of Clinical Investigation 2006;116(7):1793–801. [23] Schutte AE, Huisman HW, Van Rooyen JM, Schutte R, Malan L, Reimann M, et al. Should obesity be blamed for the high prevalence rates of hypertension in black South African women? Journal of Human Hypertension 2008;22(8):528–36.
Please cite this article in press as: Kruger R, et al. Cardiac Troponin T as Early Marker of Subclinical Cardiovascular Deterioration in Black Hypertensive Women. Heart, Lung and Circulation (2016), http://dx.doi.org/10.1016/j. hlc.2016.11.010
383 384 385 386 387 388 389 390 391 392 393 394 395 396 397 398 399 400 401 402 403 404 405 406 407 408 409 410 411 412 413 414 415 416 417 418 419 420 421 422 423 424 425 426 427 428 429 430 431 432 433 434 435 436 437 438 439 440 441 442 443 444 445 446 447 448 449 450 451 452 453 454 455 456 457 458
HLC 2252 1–8
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459 460 461 462 463 464 465 466 467 468 469 470 471 472 473 474 475 476 477 478 479
R. Kruger et al.
[24] Boutouyrie P, Tropeano AI, Asmar R, Gautier I, Benetos A, Lacolley P, et al. Aortic stiffness is an independent predictor of primary coronary events in hypertensive patients: a longitudinal study. Hypertension 2002;39(1):10–5. [25] Mattace-Raso FU, van der Cammen TJ, Hofman A, van Popele NM, Bos ML, Schalekamp MA, et al. Arterial stiffness and risk of coronary heart disease and stroke: the Rotterdam Study. Circulation 2006;113(5):657–63. [26] Bai Y, Ye P, Luo L, Xiao W, Xu R, Wu H, et al. Arterial stiffness is associated with minimally elevated high-sensitivity cardiac, troponin T levels in a community-dwelling population. Atherosclerosis 2011;218 (2):493–8. [27] Kruger R, Schutte R, Huisman HW, Hindersson P, Olsen MH, Schutte AE. N-terminal prohormone B-type natriuretic peptide and cardiovascular function in Africans and Caucasians: the SAfrEIC study. Heart, Lung Circ 2012;21(2):88–95. [28] Franklin SS, Larson MG, Khan SA, Wong ND, Leip EP, Kannel WB, et al. Does the relation of blood pressure to coronary heart disease risk change with aging? The Framingham Heart Study. Circulation 2001;103(9):1245–9. [29] Sato Y, Yamamoto E, Sawa T, Toda K, Hara T, Iwasaki T, et al. Highsensitivity cardiac troponin T in essential hypertension. Journal of Cardiology 2011;58(3):226–31.
[30] Daniels LB, Maisel AS. Natriuretic peptides. Journal of the American College of Cardiology 2007;50(25):2357–68. [31] Saunders JT, Nambi V, de Lemos JA, Chambless LE, Virani SS, Boerwinkle E, et al. Cardiac troponin T measured by a highly sensitive assay predicts coronary heart disease, heart failure, and mortality in the Atherosclerosis Risk in Communities Study. Circulation 2011;123(13): 1367– 76. [32] Apple FS. A new season for cardiac troponin assays: it’s time to keep a scorecard. Clinical Chemistry 2009;55(7):1303–6. [33] Wallace TW, Abdullah SM, Drazner MH, Das SR, Khera A, McGuire DK, et al. Prevalence and determinants of troponin T elevation in the general population. Circulation 2006;113(16):1958–65. [34] Blankenberg S, Zeller T, Saarela O, Havulinna AS, Kee F, Tunstall-Pedoe H, et al. Contribution of 30 biomarkers to 10-year cardiovascular risk estimation in 2 population cohorts: the MONICA, risk, genetics, archiving, and monograph (MORGAM) biomarker project. Circulation 2010;121(22):2388–97. [35] Otsuka T, Kawada T, Ibuki C, Seino Y. Association between high-sensitivity cardiac troponin T levels and the predicted cardiovascular risk in middle-aged men without overt cardiovascular disease. American Heart Journal 2010;159(6):972–8.
Please cite this article in press as: Kruger R, et al. Cardiac Troponin T as Early Marker of Subclinical Cardiovascular Deterioration in Black Hypertensive Women. Heart, Lung and Circulation (2016), http://dx.doi.org/10.1016/j. hlc.2016.11.010
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