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

<div><p>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 (<i>n</i> = 19) or symptomatic (<i>n</i> = 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.</p></div

Circulating biomarkers in patients with subclinical and symptomatic left ventricular dysfunction, normalized to each marker’s mean in healthy controls.

<p>The vertical axis therefore expresses the average ratio in patients relative to the mean in all healthy controls combined.</p

Expression profiles of the five most up-regulated cytokines in mice 4 and 8 weeks after aortic banding compared with sham operated animals.

<p>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.</p

Clinical Characteristics of Controls and Cases.

<p>LV indicates left ventricle. Mean arterial pressure was diastolic blood pressure plus one third of the difference between systolic and diastolic blood pressure. Inhibitors of the renin-angiotensin system included angiotensin-converting enzyme inhibitors and angiotensin type–1 receptor blockers. Vasodilators were calcium channel blockers and α–blockers. P–values for trend across categories were significant (p ≤ 0.025) except for the proportion of women and smokers and the mean values of heart rate and serum cholesterol (p ≥ 0.39). Significance of the difference with left adjacent group:</p><p>* p ≤ 0.05</p><p>† p ≤ 0.01; and</p><p>‡ p ≤ 0.001.</p><p>Clinical Characteristics of Controls and Cases.</p

Circulating CXCR3 Ligands and NT–pro BNP in Controls and Cases.

<p>LV indicates left ventricle. Biomarker levels are geometric means (interquartile ranges).</p><p>Significance with healthy controls:</p><p>* p ≤ 0.05</p><p>† p ≤ 0.01; and</p><p>‡ p ≤ 0.001.</p><p>Circulating CXCR3 Ligands and NT–pro BNP in Controls and Cases.</p

Sequenced peptides constituting the HFrEF-related peptide panel and their differential excretion between HFrEF and Controls.

<p>Sequenced peptides constituting the HFrEF-related peptide panel and their differential excretion between HFrEF and Controls.</p

Forty-four WHR_adjBMI loci showing significant sex-differences.

<p>Chr: Chromosome; Pos: position; EAF: Effect Allele Frequency; EA: Effect allele; OA: Other allele</p><p>^a ‘Yes’ if the locus is mentioned as WHR_adjBMI locus for the first time</p><p>^b ‘Yes’ if the sex-difference in the effect on WHR_adjBMI is reported for the first time</p><p>^c Effect allele is according to the WHR_adjBMI increasing allele according to the associated sex.</p><p>The table shows the sex-specific (age-group combined) results, ordered by largest, positive effect in women to largest, negative effect in women. The age- and sex-specific results (four strata), more detailed information on the loci and on the screens for which they were detected are given in <b><a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1005378#pgen.1005378.s021" target="_blank">S5 Table</a></b>.</p

Fifteen BMI loci showing significant age-differences in adults ≤50y compared to adults >50y.

<p>Chr: Chromosome; Pos: position; EAF: Effect Allele Frequency; EA: Effect allele; OA: Other allele</p><p>^a ‘Yes’ if the locus is mentioned as BMI locus for the first time</p><p>^b Effect allele is according to the BMI increasing allele according to the associated sex.</p><p>The table shows the age-group specific (sex-combined) results, ordered by largest to smallest effect in adults ≤50y. All loci were detected by the screen on age-difference that included the a-priori filter on <i>P</i>_{<i>Overall</i>} < 10⁻⁵. The age- and sex-specific results (four strata) and more detailed information on the loci are given in <b><a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1005378#pgen.1005378.s020" target="_blank">S4 Table</a></b>.</p

Age-dependent BMI loci.

<p>Effect estimates (beta ±95CI) per standard deviation in BMI and risk allele for loci showing age-differences in men & women ≤50y compared to men & women >50y. Loci are ordered by greater magnitude of effect in men & women ≤50y compared to men & women >50y. (95%CI: 95% confidence interval; BMI: body mass index; SD: standard deviation, *Newly identified loci).</p