Abstract
Background and purpose
Cerebrovascular and cardiovascular disease share common risk factors. Our goal was to determine if levels of N-terminal brain natriuretic peptide (NT-proBNP) and cardiac troponin T measured with a highly sensitive assay (hs-cTnT) are associated with silent brain infarcts (BI) and white matter lesions (WML) on magnetic resonance imaging (MRI) in the Atherosclerosis Risk In Communities (ARIC) study.
Methods
1920 participants had brain MRI at ARIC visit 3 (1993–1995). NT-proBNP and hs-cTnT were measured in all individuals at ARIC visit 4 (1996-1998). Of 1920 individuals, 1112 had a follow-up MRI in 2004-2006. We analyzed the association of NT-proBNP and hs-cTnT with MRI-defined BI and WML on the initial MRI and incident BI and WML progression on the follow-up MRI in participants without heart failure, coronary heart disease, or stroke.
Results
In the adjusted model, individuals in the highest NT-proBNP quartile had significantly more BI (odds ratio [OR] 3.50, 95% confidence interval [CI]2.03-6.20) and WML (β-coefficient 0.09[standard error](SE) 0.03]) on the baseline MRI and more incident BI (OR 2.18, 95% CI [1.38-3.47]) and WML progression (β-coefficient 0.22 (SE 0.10)] on the follow-up MRI. Individuals in the highest hs-cTnT category had more BI (OR 3.03, 95% CI [1.57-5.82) and WML (β-coefficient 0.11 [SE 0.04]) on the initial MRI and more WML progression (β-coefficient 0.43 [0.17]) on the follow-up MRI.
Conclusion
NT-proBNP and hs-cTnT are independently associated with silent MRI-defined BI and WML suggesting that cardiovascular biomarkers may be useful to identify individuals with subclinical cerebral injury.
Keywords: cardiovascular biomarkers, subclinical brain injury, magnetic resonance imaging, brain infarcts, white matter lesions
Introduction
Cardiac troponin T and N-terminal brain natriuretic peptide (NT-proBNP) are biomarkers currently used in clinical settings in the assessment of chest pain and heart failure-related symptoms respectively1, 2. Recent studies in the healthy general population have shown that NT-proBNP and cardiac troponin T levels, measured with a newer highly sensitive assay (hs-cTnT), are associated with incident cardiovascular disease events (CVD) and incident heart failure hospitalizations (HF)3-5. Thus, hs-cTnT and NT-proBNP are considered to be biomarkers for subclinical cardiac injury in the general population.
It is well known that cerebrovascular and cardiovascular disease share common risk factors such as hypertension and diabetes 6-8. Thus, even before clinical manifestation of organ injury, subclinical brain injury expressed as silent brain infarcts (BI) and white matter lesions (WML) on magnetic resonance imaging (MRI) may be present and coexist with subclinical cardiac injury9. In healthy middle aged individuals the presence of BI and WML on an MRI is associated with higher risk of development of strokes and dementia, which in turn result in functional decline, long term disability and increased health care costs 10-12. Hence, early detection of subclinical brain damage is important. The possible co-existence of subclinical myocardial injury and subclinical brain injury suggests that cardiovascular biomarkers associated with future CVD and HF may also be associated with subclinical brain injury.
The purpose of this study is to investigate the association of hs-cTnT and NT-proBNP with MRI-defined WML and silent BI in the Atherosclerosis Risk in Communities (ARIC) Study.
Methods
Study population
The ARIC study is a prospective study of middle-aged predominantly black and white men and women who were 45–64 years of age at their baseline examination in 1987–1989. In all, 15,792 participants were sampled from 4 US communities: Forsyth County, NC; Jackson, MS; northwestern suburbs of Minneapolis, MN; and Washington County, MD.
At the third ARIC visit (1993–1995), 2,825 persons older than 56 years of age from Forsyth County or Jackson were invited for a brain MRI and 1,949 were imaged. Images were of sufficient quality for grading in 1,920 examinations. Hs-cTnT and NT-proBNP were measured from the blood samples collected at ARIC Visit 4 (1996-1998). After ARIC visit 4, a subset of those individuals who had the initial MRI at ARIC Visit 3 (N=1112) had a follow-up MRI between 2004 and 2006 (10.61 years later). For our study we selected those individuals without history of CVD or HF who had the initial MRI performed at ARIC visit 3 (Supplemental Figure 1). Individuals with missing covariate data (N=283) or those with a history of CVD (coronary heart disease [CHD] or stroke or heart failure, N=135) at the time of hs-cTnT and NT-proBNP measurement were excluded resulting in 1501 individuals for the NT-proBNP analysis and 1502 individuals for the hs-cTnT analysis. CHD and stroke were defined as self-reported myocardial infarction or stroke before ARIC visit 1, or silent myocardial infarction (diagnosed by electrocardiographic changes), validated myocardial infarction, coronary revascularization, or stroke between visits 1 and 4. A detailed description of CHD events is provided elsewhere.13 HF was identified from hospital discharge records and death certificates that showed an HF code in any position. International Classification of Diseases Code, Ninth Revision (ICD-9) code 428.x and deaths with ICD-9/10 codes of either 428.x or I50 were considered as HF. Medical history, demographic data, anthropometric data, blood pressure measurements, and fasting lipid assessments were obtained during visit 4 at the same time as the blood draw for hs-cTnT and NT-proBNP measurement. Each ARIC Field Center's institutional review board approved research protocols, and all participants provided written informed consent.
Biomarkers, MRI scans and outcome definitions
The specific details regarding biomarker assays for hs-cTnT14 and NT-proBNP15 are have been previously published. The MRI scanning protocol has also previously been described in detail elsewhere16. Participants were scanned on 1.5-Tesla scanners. MRI images were interpreted by trained readers at the ARIC MRI Reading Center at Johns Hopkins Medical Institutions in Baltimore.
WML were estimated as the total volume of periventricular and subcortical white matter-signal abnormality. The severity of WML was assessed with a grade from 0 to 9 scale by visual comparison with 8 templates that successively increased from barely detectable white matter lesions to extensive, confluent abnormalities. Subcortical and periventricular WMLs were visually evaluated together. This scale was initially developed and validated in the Cardiovascular Health Study (CHS) and it is in detail described elsewhere17.
Brain infarcts (BIs) were defined by size, type, and location and defined as focal, non-mass areas with an arterial vascular distribution and hyperintense to gray matter on both spin-density and T2-weighted images. BIs in the cerebral white matter and brain stem were defined as lesions with increased signal intensity on spin-density and T2-weighted images and decreased signal intensity on T1-weighted images, similar to the hypointensity of cerebrospinal fluid.18
Statistical analysis
Our analysis was aimed at answering the following two questions: 1) Are higher levels of hs-cTnT and NT-proBNP associated with pre-existent subclinical brain injury? 2) Are higher levels of hs-cTnT and NT-proNP levels associated with incident BI and WML progression? In order to answer question 1, we analyzed the association of hs-cTnT and NT-proBNP with MRI measures of BI and WML performed at ARIC visit 3 (initial MRI visit). In order to answer our second question, we analyzed the association of hs-cTnT and NT-proBNP with new BIs and WML progression on the follow up MRI, which was assessed by comparison to the initial MRI. The follow up MRI was performed approximately 8 years after the measurement of the biomarkers (2004-2006, see Supplemental Figure 1).
Hs-cTnT and NT-proBNP were modeled as categorical variables. For hs-cTnT, individuals were divided in categories as described in a previous publication 4 and are briefly described in the data supplement. For NT-proBNP quartile measures were used as cutpoints to obtain four groups. The lowest quartile was used as a reference group. The associations between hs-cTnT categories or NT-proBNP quartiles with BI were determined with logistic regression. For analyses of incident BI at the follow-up MRI examination, individuals with MRI-defined BI at the first visit were excluded (N=71). For the association between biomarkers and WML, the beta coefficient of hs-cTnT category or NT-proBNP quartile was obtained from the linear regression analysis modeling log-transformed WML grade (Log(WMG+1)). Log transformation of WML grade was performed to reduce skewness. Progression in WML burden between the initial and follow-up MRI visits for each individual was calculated as the difference in WML grade between the 2 exams. The categories and quartiles were modeled as dummy variables and the beta coefficient represents the difference in logWML grade relative to the 1st category of hs-cTnT or 1st quartile of NT-proBNP. Additionally, we used linear terms using quartile number or category number to obtain a p-value for trend and compare any linear trend in risks with each increasing quartile or category.
The model was adjusted for age, gender, race, ARIC center, hypertension, diabetes status, smoking status because of previous results that show an association between these factors and WML and BI on brain MRIs 12, 19. We also adjusted for glomerular filtration rate (eGFR) because of reports that patients with renal insufficiency may have higher cTnT levels and NT-proBNP levels 20, 21. There is no data to show an association between LDL-cholesterol or HDL-cholesterol with small vessel disease of the brain in ARIC.
Results
After exclusion of the individuals with CVD as well as those with missing covariates we included in the study a total of 1501 individuals who had an initial MRI performed at ARIC visit 3 and NT-proBNP measured at Visit 4. Table 1 presents the baseline characteristic of each NT-proBNP quartile. The individuals in the highest NT-proBNP quartile had more women and fewer African Americans, and these individuals had lower BMIs. They were also significantly older, more likely to be hypertensive and less likely to have diabetes. Individuals in the highest NT-proBNP quartile had higher high-density lipoprotein cholesterol (HDL-c) and lower low-density lipoprotein cholesterol (LDL-c) levels.
Table 1. Baseline characteristic of by NT-proBNP quartiles at ARIC Visit 4.
| Quartile 1 | Quartile 2 | Quartile 3 | Quartile 4 | P | |
|---|---|---|---|---|---|
| Quartiles cut-off (pg/mL) | 2.5 to ≤29.6 | 29.7 to ≤65.0 | 65.1 to ≤119.1 | >119.1 | |
| N | 377 | 375 | 374 | 375 | |
| Age (years) | 63.5(4.3) | 64.8(4.3) | 65.6(4.3) | 66.9(4.4) | <0.0001 |
| African Americans (%). | 66.8 | 53.9 | 41.4 | 35.2 | <0.0001 |
| Females (%) | 45.4 | 63.2 | 69.0 | 71.2 | <0.0001 |
| BMI (kg/m2) | 29.2(5.0) | 28.1(4.9) | 27.8(5.2) | 27.3(5.4) | <0.0001 |
| HDL-cholesterol (mg/dl) | 48.3(14.7) | 50.6(16.6) | 53.7(17.4) | 54.5(18.2) | <0.0001 |
| LDL-cholesterol (mg/dl) | 127.2(30.1) | 122.2(42.9) | 120.3(32.5) | 116.8(33.3) | 0.0004 |
| EGFR (ml/min/1.73m2) | 87.3(19.0) | 85.4(18.9) | 82.8(17.0) | 76.7(20.3) | <0.0001 |
| Current smokers (%) | 14.4 | 13.9 | 13.9 | 18.4 | 0.24 |
| Current drinkers (%) | 33.1 | 34.9 | 33.8 | 30.2 | 0.56 |
| Hypertension (%) | 40.0 | 40.0 | 37.4 | 53.0 | <0.0001 |
| Antihypertensive medications (%) | 43.0 | 42.1 | 39.6 | 58.7 | <0.0001 |
| Diabetes Mellitus (%) | 22.1 | 17.6 | 12.8 | 13.3 | 0.0019 |
| Infarct on MRI (%) | 5.8 | 7.5 | 10.7 | 18.7 | <0.0001 |
| Log White Matter Grade | 0.68(0.42) | 0.74(0.42) | 0.78(0.41) | 0.88(0.45) | <0.0001 |
We had a total of 1502 individuals without CVD who had an initial MRI examination at visit 3 and hs-cTnT measured at visit 4. Table 2 presents the baseline characteristics of the individuals by hs-cTnT category. Individuals in the highest category had significantly higher BMIs, more African Americans and less females. They were significantly older and more likely to be hypertensive, to have diabetes and less likely to be smokers or alcohol drinkers. They also had significantly lower levels of HDL-c.
Table 2. Baseline characteristic of by hs-cTnT categories at ARIC Visit 4.
| Category 1 | Category 2 | Category 3 | Category 4 | Category 5 | P | |
|---|---|---|---|---|---|---|
| Category cat-off (μg/L) | <0.003 | 0.003 to ≤0.005 | 0.006 to ≤0.008 | 0.009 to ≤0.013 | ≥0.014 | |
| N | 454 | 375 | 322 | 221 | 130 | |
| Age (years) | 63.7(4.2) | 65.4(4.3) | 65.8(4.5) | 66.1(4.6) | 66.8(4.2) | <0.0001 |
| African Americans (%) | 45.2 | 48.5 | 48.5 | 52.0 | 64.6 | 0.002 |
| Females (%) | 83.5 | 70.7 | 50.6 | 37.6 | 33.1 | <0.0001 |
| BMI (kg/m2) | 27.4(5.2) | 28.2(5.6) | 28.4(4.7) | 28.1(4.5) | 29.3(5.3) | 0.002 |
| HDL-cholesterol (mg/dl) | 55.7(17.0) | 53.0(16.6) | 49.9(17.01) | 47.2(13.9) | 47.6(17.8) | <0.0001 |
| LDL-cholesterol (mg/dl) | 120.3(36.0) | 124.1(32.9) | 122.2(32.9) | 122.2(33.3) | 116.0(33.3) | 0.31 |
| EGFR(ml/min/1.73m2) | 86.6(18.1) | 84.6(16.7) | 83.0(19.5) | 78.9(17.9) | 75.6(24.8) | <0.0001 |
| Current smokers (%) | 22.2 | 12.9 | 10.9 | 12.3 | 12.3 | <0.0001 |
| Current drinkers (%) | 36.6 | 34.1 | 33.2 | 27.9 | 27.9 | 0.15 |
| Hypertension (%) | 36.9 | 36.6 | 45.2 | 47.3 | 67.4 | <0.0001 |
| Antihypertensive medications (%) | 40.1 | 40.3 | 47.5 | 50.2 | 70.0 | <0.0001 |
| Diabetes Mellitus (%) | 12.1 | 12.8 | 12.7 | 23.1 | 40.0 | <0.0001 |
| Infarct on MRI (%) | 6.8 | 9.3 | 12.1 | 11.2 | 23.1 | <0.0001 |
| Log White Matter Grade | 0.72(0.40) | 0.73(0.42) | 0.78(0.43) | 0.82(0.46) | 0.93(0.46) | <0.0001 |
NT-proBNP and MRI findings
After adjustment for risk factors, when compared to the first quartile, individuals in the highest NT-proBNP quartile were more likely to have BIs (odds ratio [OR] 3.50, 95% confidence interval [CI] (2.03-6.20)) and more WML (β-coefficient 0.09 (standard error [SE] 0.03); p<0.01) on the initial MRI (Table 3). Of these individuals, 891 had a follow up MRI 10.61 years later at the follow-up visit (2004-2006). Among these 891 participants, those who were in the highest NT-proBNP quartile had significantly more incident BIs (OR 2.18 95% CI [1.38-3.47]) and more WML progression (β-coefficient 0.22 (SE 0.11); p<0.05] on the follow-up MRI when compared to those in the lowest quartile (Table 3).
Table 3. Association of NT-proBNP and hs-cTnT with MRI findings.
| Association of NT-proBNP with silent BI and WML | |||||||
|---|---|---|---|---|---|---|---|
| Quartiles(pg/mL) | Quartile 1 2.5 to 29.6 | Quartile 2 29.7 to ≤65.0 | Quartile 3 65.1 to ≤119.1 | Quartile 4 > 119.1 | p for trend | ||
| Initial MRI | N | 377 | 375 | 374 | 375 | ||
| BI OR (95% CI) | Ref | 1.28 (0.71-2.34) | 2.03 (1.16-3.65) | 3.50 (2.03-6.20) | <0.0001 | ||
| Log WML Beta(SE) | Ref | 0.03(0.03) | 0.05(0.03) | 0.09(0.03)* | 0.05 | ||
| Follow up MRI | N | 249 | 241 | 230 | 180 | ||
| Incident BI OR(95% CI) | Ref | 0.92 (0.59-1.43) | 1.33 (0.85-2.09) | 2.18 (1.38-3.47) | 0.001 | ||
| WML progression Beta(SE) | Ref | 0.10(0.09) | 0.06(0.10) | 0.22(0.10)* | 0.23 | ||
| Association of hs-cTnT with silent BI and WML | |||||||
| Categories (μg/L) | <0.003 | 0.003 to ≤ 0.005 | 0.006 to ≤ 0.008 | 0.009 to ≤ 0.013 | ≥ 0.014 | p for trend | |
| Initial MRI | N | 454 | 375 | 322 | 221 | 130 | |
| BI OR (95% CI) | Ref. | 1.35 (0.79-2.30) | 1.74 (1.02-2.99) | 1.63 (0.87-3.00) | 3.03 (1.57-5.82) | 0.019 | |
| Log WML Beta(SE) | Ref. | -0.027(0.03) | 0.01(0.03) | 0.04 (0.04) | 0.11(0.04)* | 0.02 | |
| Follow up MRI | N | 299 | 235 | 190 | 121 | 56 | |
| Incident BI OR(95% CI) | Ref. | 1.32 (0.88-1.98) | 1.04 (0.65-1.66) | 2.31 (1.40-3.81) | 1.63 (0.78-3.31) | 0.01 | |
| WML progression Beta(SE) | Ref. | 0.01(0.09) | 0.00(0.10) | 0.05(0.12) | 0.43(0.17)* | 0.11 | |
Adjusted for age, sex, race, ARIC center estimated glomerular filtration rate, hypertension, diabetes mellitus, smoking status for both NT-proBNP and hs-cTnT
p<0.05, are marked only for the WML. For BI we present the confidence intervals.
Hs-cTnT and MRI findings
When compared to individuals in the lowest category, individuals in the highest hs-cTnT category had significantly more BIs (OR 3.03, 95% CI [1.57-5.82]) and more WML (β-coefficient 0.11 [SE 0.04]; p=0.01) on the initial MRI (Table 3). Of these, 892 individuals had a second MRI later at the follow-up visit (2004-2006). Among these, individuals in the highest hs-cTnT category had significantly more WML progression (β-coefficient 0.43 [SE 0.17]; p=0.01) on the follow up MRI when compared to the lowest category. When compared to the lowest category, individuals in the higher hs-cTnT categories tended to have significantly more incident BIs (P trend=0.01), although statistical significance was reached only for the category of hs-cTnT values between 0.009 to 0.013 μg/L (Table 3).
Discussion
In the present study we investigated the association of NT-proBNP and hs-cTnT with silent BIs and WML on brain MRI in participants from the ARIC study free of CVD. Our study shows a positive association between biomarkers of subclinical cardiac injury, such as NT-proBNP and hs-cTnT, and subclinical brain disease diagnosed by the presence of BIs and WML on MRI.
Several clinical studies have reported coexistence of heart disease and cerebral disease in elderly individuals 22, 23. NT-proBNP and hs-cTnT are both associated with increased risk of incident HF 4, 24. A small cross sectional study by Reinhard et al. shows that NT-proBNP was positively correlated with WML in diabetic patients 25. Our study extends the findings to a large healthy population-based cohort showing that patients in the highest quartiles of NT-proBNP are more likely to have BIs and have more WML on the brain MRI. Additionally we show that, prospectively, higher NT-proBNP levels are associated with increased incident BIs and WML progression over 8 years of follow up. In addition to that we also show hs-cTnT levels are associated with silent BIs and WML as well as with WML progression. Previous studies have shown that up to 20 to 50% of individuals with HF have cognitive impairment 26, but individuals with advanced cardiovascular disease and symptomatic heart failure may have cerebral hypoperfusion from reduced cardiac output, or subclinical stroke due to embolization from a dysfunctional left ventricle or other mechanisms by which advanced cardiovascular disease could impact the brain directly.
In contrast to these prior studies, we have examined the association of NT-proBNP and hs-cTnT in individuals without any history of HF, CHD or stroke. One possible explanation for our findings may be that cerebrovascular disease and cardiac disease share several common risk factors such as hypertension and diabetes, which, over time, may produce damage in both organs. When present, these risk factors may promote early changes in the heart that result in alteration in myocardial structure and function, which may lead to increased levels of biomarkers such as hs-cTnT and NT-proBNP in blood before clinical symptoms of heart failure are evident.27-29 Eventually progression of disease leads to development of clinically symptomatic heart failure. In parallel these risk factors promote changes in the brain that produce silent BIs and WML which in time lead to “symptomatic” cognitive impairment. In the presence of risk factors, subclinical injury to the brain and heart may occur through mechanisms other than atherosclerosis. Recent studies have shown that arterial stiffness is associated with clinical and subclinical brain disease 30-32. At the same time arterial stiffness was also proven to be associated with NT-proBNP levels in healthy individuals and in individuals with heart failure 33-35. These data are consistent with the hypothesis that arterial stiffness may be a common risk factor for subclinical disease of the heart and brain, which may also explain our findings. Several authors have shown that the pathology of WML and BI reflects arteriolosclerosis of the small vessels in the brain.7 In hypertensives the smooth muscle cells in the small vessels walls are replaced by fibro-hyaline material with thickening of the wall and narrowing of the vascular lumen (arteriolosclerosis) resulting in BI and WML 6, 7. In diabetic patients, microvascular disease and lipotoxic mechanisms in the heart may lead to myocardial damage and cTnT leak while in the brain high blood glucose produces neuronal dysfunction and restriction of axon regeneration resulting in WML and BI 36, 37.
One major limitation in our study is that the initial MRI readings performed at ARIC visit 3 were performed 3 years before the troponin and NT-proBNP were measured. Another limitation is the small numbers of individuals with follow up MRI performed after ARIC visit 4.
Conclusion
NT-proBNP and hs-cTnT are associated with MRI-defined BIs and WML. These cardiovascular biomarkers, which were initially used for diagnosis in the presence of symptoms such as chest pain or shortness of breath, have now been shown to identify individuals who are asymptomatic but at high risk for developing symptomatic CVD3, 4. The concept of identifying high-risk individuals with screening blood biomarkers, followed by an imaging test and then therapies directed by a specialist to prevent disease progression, has been recently tested in the cardiovascular field. A study that was recently presented at the American College of Cardiology Scientific Session showed that early measurement of NT-proBNP followed by an echocardiogram for those individuals with values greater than 50 pg/ml and subsequent targeted therapy by a specialist resulted in 46% relative risk reduction in cardiovascular hospitalizations (http://www.theheart.org/article/1518637.do). Perhaps early measurement of the cardiovascular biomarkers NT-proBNP and hs-cTnT followed by an MRI may also help in early detection of cerebrovascular disease prior to development of symptoms, at a time when interventions directed by a specialist may be beneficial for the prevention of cognitive decline.
Supplementary Material
Data Supplement with Supplemental Figure 1: Study diagram.
Acknowledgments
Sources of Funding: The Atherosclerosis Risk in Communities Study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100012C). Neurocognitive data is collected by U01 HL096812, HL096814, HL096899, HL096902, HL096917 with previous brain MRI examinations funded by R01-HL70825.
Disclosures: Dr. Virani is supported by a Department of Veterans Affairs Health Services Research and Development Career Development Award (09-028). The authors thank the staff and participants of the ARIC study for their important contributions. Dr. Nambi is supported by a National Heart, Lung, and Blood Institute grant (5K23HL096893-02). Roche provided a grant to Baylor College of Medicine (Christie M. Ballantyne, MD and Ron C. Hoogeveen, PhD) to support measurement of NT-proBNP and hs -TnT with assays developed by Roche. Roche had no part in study design, analysis or manuscript preparation.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Supplement with Supplemental Figure 1: Study diagram.