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. 2015 Oct 27;10(10):e0141394.
doi: 10.1371/journal.pone.0141394. eCollection 2015.

Left Ventricular Dysfunction and CXCR3 Ligands in Hypertension: From Animal Experiments to a Population-Based Pilot Study

Free PMC article

Left Ventricular Dysfunction and CXCR3 Ligands in Hypertension: From Animal Experiments to a Population-Based Pilot Study

Raffaele Altara et al. PLoS One. .
Free PMC article


Detecting left ventricular (LV) dysfunction at an early stage is key in addressing the heart failure epidemic. In proteome profiling experiments in mice subjected either to aortic banding or sham, the circulating CXCR3 ligands monokine induced by interferon-γ (MIG) and interferon-γ inducible protein 10 (IP10) were 5 to 40 fold up-regulated at eight weeks. We assessed the diagnostic value of circulating NT-pro BNP and CXCR3 ligands (MIG, IP10, Interferon-inducible T-cell alpha chemo-attractant [I-TAC]) in patients with hypertension (≥140/90 mm Hg) associated with subclinical (n = 19) or symptomatic (n = 16) diastolic LV dysfunction on echocardiography and healthy controls. NT-pro BNP, MIG, IP10, I-TAC all increased (p ≤ 0.014) across the categories of worsening left ventricular dysfunction. In patients with symptomatic disease, MIG, IP10, and I-TAC increased 210% (p = 0.015), 140% (p = 0.007) and 120% (p = 0.035) more than NT-pro BNP. The optimal discrimination limits, obtained by maximizing Youden's index were 246 pmol/L, 65 pg/mL, 93 pg/mL, and 24 pg/mL, respectively. The odds ratios associated with the four biomarkers were significant (p ≤ 0.010), ranging from 4.00 for IP10 to 9.69 for MIG. With adjustment for NT-pro BNP, the CXCR3 ligands retained significance (p ≤ 0.028). Adding optimized thresholds for the CXCR3 ligands to NT-pro BNP enhanced (p ≤ 0.014) the integrated discrimination improvement and the net reclassification improvement. In conclusion, congruent with the concept that inflammation plays a key role in the pathogenesis of LV dysfunction, MIG, IP10 and I-TAC add diagnostic accuracy over and beyond NT-pro BNP.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.


Fig 1
Fig 1. Expression profiles of the five most up-regulated cytokines in mice 4 and 8 weeks after aortic banding compared with sham operated animals.
After transverse aortic constriction (TAC), expression profiles increased at least twice (dashed line). MIG, IP10, MIP–2, IL–16 and sICAM–1 indicate monokine induced by interferon–γ (CXCL9), interferon–γ inducible protein 10 (CXCL10), murine macrophage inflammatory protein–2, interleukin 16, and soluble intercellular adhesion molecule 1, respectively.
Fig 2
Fig 2. Circulating biomarkers in patients with subclinical and symptomatic left ventricular dysfunction, normalized to each marker’s mean in healthy controls.
The vertical axis therefore expresses the average ratio in patients relative to the mean in all healthy controls combined.

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The experimental work was partly supported by the Center for Translational Molecular Medicine (; TRIUMPH grant 01C-103) and the Dutch Heart Foundation. The European Union (HEALTH-2011.2.4.2-2-EU-MASCARA, HEALTH-F7-305507 HOMAGE and the European Research Council Advanced Researcher Grant-2011-294713-EPLORE), the Fonds voor Wetenschappelijk Onderzoek Vlaanderen, Ministry of the Flemish Community, Brussels, Belgium (G.0881.13 and G.088013), and the International Zinc and Lead Research Organization currently support the Studies Coordinating Centre in Leuven.