Rizwan Kalani, MD

Greisenegger S, Segal HC, Burgess AI, Poole DL,  Mehta Z, and Rothwell PM. Biomarkers and Mortality After Transient Ischemic Attack and Minor IschemicStroke: Population-Based Study. Stroke. 2015

Premature death after stroke or TIA is more often a consequence of cardiac disease or malignancy than the cerebrovascular event itself. Prior studies evaluating various serologic biomarkers for predicting recurrent vascular events or death after stroke/TIA have shown mixed results. Greisenegger et al evaluated the association of several biomarkers with all-cause mortality (particularly cardiac or cancer death) in those with minor stroke or TIA.

The cohort studied came from an ongoing population based-study of vascular disease incidence and outcomes in Oxfordshire, UK (Oxford Vascular Study). TIA was defined according to the WHO definition (<24 hours of focal neurological deficit suspected to be of vascular cause – not imaging-based definition that excludes tissue injury) and minor stroke included those with NIHSS<3. Patient death was classified into vascular (stroke, cardiac, etc.) and non-vascular (cancer, other systems) causes. The panel of biomarkers collected are implicated in 1. the inflammatory response – IL-6, CRP, neutrophil-gelatinase associated lipocalin (NGAL), soluble tumor necrosis factor receptor-1 (sTNFR-1); 2. thrombosis – thrombomodulin (TM), fibrinogen, P-selectin, D-dimer, von Willebrand factor (vWF), protein-Z; 3. cardiac function – nt-proBNP; 4. cardiac/neuronal injury – neuron-specific enolase (NSE), heart-type fatty acid binding protein (HFABP); and 5. neural regeneration – BDNF.

929 patients with TIA (47%) and minor stroke (53%) were enrolled. The median age was 74 years and 51% were female. Biomarkers were drawn on average 5 days after the cerebrovascular event; the median follow-up of patients was 6.4 years. 39% (361/929) of patients died during the follow-up period – 151 of vascular cause, 184 non-vascular cause, and 26 unclear etiology. None of the biomarkers correlated with recurrent non-fatal stroke or MI. sTNFR-1, NGAL, CRP, IL-6, vWF, nt-proBNP, and hFABP were predictive of all-cause mortality after adjusting for demographics, risk factors, and prior medical therapy. The strongest associations were for sTNFR-1 (HR 1.45), nt-proBNP (HR 1.44), and hFABP (HR 1.37). sTNFR-1, NGAL, vWF, nt-proBNP, and hFABP were predictive of vascular death in multivariate analysis with the strongest association detected for nt-proBNP (HR 1.8). Among those, all but NGAL were predictive of cardiac death. Nt-proBNP was strongest predictor of stroke-related death. IL-6, CRP, NGAL, sTNFR-1, and hFABP were predictive of non-vascular death. The strongest associations were for hFABP (HR 1.5) and sTNFR-1 (HR 1.47); these two were also predictive of cancer-related death (hFABP HR 1.61, sTNFR-1 HR 1.41). Taken together, sTNFR-1, vWF, hFABP, and nt-proBNP added more prognostic information in comparison to outcome prediction models based on clinical risk factors. These four markers remained predictive of all-cause mortality at 2, 3, and 5 year follow-up.

This study demonstrates that biomarkers related to the inflammatory response, cardiac function, cardiac/neuronal injury, and thrombosis are independent predictors of death in patients with minor stroke or TIA. Those with highest predictive value were sTNFR-1, vWF, nt-proBNP and hFABP. The value of nt-proBNP was shown to be specifically predictive of vascular death and may assist in guiding further cardiac evaluation after stroke. hFABP may be of value for identifying occult malignancy after cerebrovascular ischemia, but this needs to be evaluated in independent cohorts. Future studies will have to validate this and assess the utility of incorporating these biomarkers in clinical care.