Blood-Based Cardiac Biomarkers and the Risk of Cognitive Decline, Cerebrovascular Disease, and Clinical Events

Bibek Gyanwali, PhD; Mitchell K.P. Lai, PhD; Benedict Lui, MB BCh; Oi Wah Liew, PhD; Narayanaswamy Venketasubramanian, MMed; Arthur Mark Richards, PhD; Christopher Chen, MRCP; Saima Hilal, PhD


Stroke. 2021;52(7):2275-2283. 

In This Article

Abstract and Introduction


Background and Purpose: Cardiac biomarkers, NT-proBNP (N-terminal probrain natriuretic peptide), hs-cTnT (high-sensitivity-cardiac troponin T), and GDF-15 (growth differentiation factor-15) have been proposed as important biomarkers of early vascular pathology. However, little is known of the longitudinal associations of these cardiac biomarkers with cerebrovascular disease and clinical events. We examine the association of blood-based cardiac biomarkers (NT-proBNP, hs-cTnT, and GDF-15) with cognitive decline, incident cerebrovascular disease, vascular events, and mortality.

Methods: Four hundred thirty-four memory-clinic patients provided blood samples at baseline, underwent 3 annual neuropsychological assessments and brain magnetic resonance imaging scans at baseline and follow-up. NT-proBNP and hs-cTnT concentrations were measured by electrochemiluminescence immunoassay and GDF-15 by quantitative sandwich immunoassay. Baseline and follow-up magnetic resonance imagings were graded for white matter hyperintensities, lacunes, cerebral microbleeds, cortical infarcts, and intracranial stenosis. Data on incident vascular events and mortality were obtained.

Results: Patients with higher levels of NT-proBNP, hs-cTnT, and GDF-15 showed greater decline in memory domain. Additionally, hs-cTnT was associated with decline in global cognition, executive function, and visuomotor speed. Higher levels of NT-proBNP were associated with incident cerebral microbleeds and hs-cTnT with incident cortical infarcts. During a mean follow-up of 3 years, 26 (5.9%) patients died and 35 (8.1%) developed vascular events. Patients with higher levels of NTpro-BNP and hs-cTnT were at increased risk of vascular events whereas those with higher levels of NT-proBNP and GDF-15 were at risk of mortality.

Conclusions: Higher levels of blood-based cardiac biomarkers were associated with decline in memory and risk of vascular events and mortality. Moreover, NT-proBNP and hs-cTnT were associated with incident cerebral microbleeds and cortical infarcts. Thus, these biomarkers are potentially useful in identifying patients at risk of adverse vascular events and death.


Subclinical vascular brain injury is associated with an increased risk of stroke and dementia.[1] This vascular damage may be detectable by brain magnetic resonance imaging (MRI) or by using extensive neuropsychological testing. However, large-scale screening utilizing such tests may not be practical in routine clinical settings. Thus, cost-effective, rapid, and minimally invasive biomarkers are needed as initial screening tool.[2]

Blood biomarkers of cardiovascular disease (CVD), such as NT-proBNP (N-terminal probrain natriuretic peptide), hs-cTnT (high-sensitivity-cardiac troponin T), and GDF-15 (growth differentiation factor-15), have recently gained greater interest in cardiovascular research because these biomarkers were found to be upregulated not only in myocardial injury and stress but also in the early stage of CVD.[3,4] NT-proBNP is excreted by cardiac myocytes in response to excessive cardiac wall stress and has been linked with coronary heart disease, stroke, and subclinical brain injury.[5–7] Similarly, hs-cTnT (released as a consequence of myocardial injury) has been associated with future cardiac events, stroke, and mortality.[8,9] GDF-15 has important regulatory roles in inflammation and pro/antiapoptosis in injured and diseased tissues and is predictive of CVD, worse cognition,[10,11] and mortality.[12,13]

Despite the verified predictive power of cardiac biomarkers for adverse CVD outcomes, it is unclear how overt cardiac diseases affect the association between NT-proBNP, hs-cTnT, and GDF-15 with brain changes and clinical outcomes. It is believed that persons with high cardiac biomarker concentrations, even in subclinical stage, may be affected from clinical heart disease, which eventually leads to subclinical brain injury.[14] By contrast, the corollary may also hold true where stroke-induced functional or structural alterations to the central neuronal network lead to imbalances in neural-cardiac control and myocardial injury, resulting in cardiac biomarker elevation. We investigated the association of circulating NT-proBNP, hs-cTnT, and GDF-15 levels with cognitive decline, incident cerebrovascular disease (CeVD), and clinical events (stroke, heart disease, and mortality) in a memory-clinic population.