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Review
. 2015 Jun;240(6):821-31.
doi: 10.1177/1535370215584931. Epub 2015 May 8.

Inosine and hypoxanthine as novel biomarkers for cardiac ischemia: from bench to point-of-care

Don E Farthing  1 , Christine A Farthing  2 , Lei Xi  3
Affiliations
Review

Inosine and hypoxanthine as novel biomarkers for cardiac ischemia: from bench to point-of-care

Don E Farthing et al. Exp Biol Med (Maywood). 2015 Jun.

Abstract

Cardiac ischemia associated with acute coronary syndrome and myocardial infarction is a leading cause of mortality and morbidity in the world. A rapid detection of the ischemic events is critically important for achieving timely diagnosis, treatment and improving the patient's survival and functional recovery. This minireview provides an overview on the current biomarker research for detection of acute cardiac ischemia. We primarily focus on inosine and hypoxanthine, two by-products of ATP catabolism. Based on our published findings of elevated plasma concentrations of inosine/hypoxanthine in animal laboratory and clinical settings, since 2006 we have originally proposed that these two purine molecules can be used as rapid and sensitive biomarkers for acute cardiac ischemia at its very early onset (within 15 min), hours prior to the release of heart tissue necrosis biomarkers such as cardiac troponins. We further developed a chemiluminescence technology, one of the most affordable and sensitive analytical techniques, and we were able to reproducibly quantify and differentiate total hypoxanthine concentrations in the plasma samples from healthy individuals versus patients suffering from ischemic heart disease. Additional rigorous clinical studies are needed to validate the plasma inosine/hypoxanthine concentrations, in conjunction with other current cardiac biomarkers, for a better revelation of their diagnostic potentials for early detection of acute cardiac ischemia.

Keywords: ATP breakdown by-products; Biomarker; cardiac ischemia; chemiluminescence; diagnostic methods; nucleoside.

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Figures

Figure 1
Figure 1
Illustrative summary of major metabolic pathways of ATP degradation during myocardial ischemia. Abbreviations: ATP: adenosine triphosphate; ADP: adenosine diphosphate; AMP: adenosine monophosphate; IMP: inosine monophosphate; ENT: equilibrative nucleoside transporters; CNT: concentrative nucleoside transporters. (A color version of this figure is available in the online journal.)
Figure 2
Figure 2
Overlay of HPLC–UV chromatograms representing (top to bottom) a calibration standard, healthy normal individual plasma sample, cardiac troponin T plasma samples (cTnT 6.64 and cTnT 0.55 µg/L), and non-traumatic chest pain patient samples (CP 294 and CP 307). Calibration standards included the components hypoxanthine (H, RT ∼5.2 min), uric acid (UA, RT ∼5.9 min), xanthine (X, RT ∼6.9 min), adenosine (A, RT ∼10.6 min), and inosine (I, RT ∼11.1 min)
Figure 3
Figure 3
HPLC-DAD (diode array detector) chromatogram representing a typical Krebs buffer eluent sample obtained and evaluated from a mouse heart undergoing ex vivo acute cardiac ischemia in Langendorff model. The samples were also evaluated using LC-ESI-MS, for confirmation that inosine (MW 268 Da) was the elevated component in the mouse-induced acute cardiac ischemia samples. Adapted with permission from Farthing et al. Biomarkers 2006.. (A color version of this figure is available in the online journal.)
Figure 4
Figure 4
Bar chart representing inosine (Ino) and hypoxanthine (Hypo) plasma concentrations from healthy individuals and ER non-traumatic chest pain patients. The ER patients had significantly elevated concentrations of inosine and hypoxanthine, as compared to the healthy normal individuals. As inosine is metabolized to hypoxanthine in the blood stream, the cumulative amounts (mole to mole) for these biomarkers in plasma are depicted in the bar chart as µM Ino + Hypo. (A color version of this figure is available in the online journal.)
Figure 5
Figure 5
Overlay of chemiluminescence scans representing plasma analysis from healthy individuals and non-traumatic chest pain patients. Sample equilibrium time is 120 s, followed by the xanthine oxidase (enzyme) injection. Time to RLU peak maximum signal was ∼5 s after XO enzyme injection, with ∼30 s required for completion of the luminescence reaction. (A color version of this figure is available in the online journal.)
See this image and copyright information in PMC

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