Limits...
Enhanced interleukin-1 activity contributes to exercise intolerance in patients with systolic heart failure.

Van Tassell BW, Arena RA, Toldo S, Mezzaroma E, Azam T, Seropian IM, Shah K, Canada J, Voelkel NF, Dinarello CA, Abbate A - PLoS ONE (2012)

Bottom Line: Interleukin-1β (IL-1β) is a pro-inflammatory cytokine that becomes chronically elevated in HF and exerts putative negative inotropic effects.We developed a model of IL-1β-induced left ventricular (LV) dysfunction in healthy mice that exhibited a 32% reduction in LV fractional shortening (P<0.001) and a 76% reduction in isoproterenol response (P<0.01) at 4 hours following a single dose of IL-1β 3 mcg/kg.The median peak oxygen consumption (VO(2)) improved from 12.3 [10.0, 15.2] to 15.1 [13.7, 19.3] mL · kg(-1) · min(-1) (P = 0.016 vs. baseline) and median ventilator efficiency (V(E)/VCO(2) slope) improved from 28.1 [22.8, 31.7] to 24.9 [22.9, 28.3] (P = 0.031 vs. baseline).

View Article: PubMed Central - PubMed

Affiliation: School of Pharmacy, Virginia Commonwealth University, Richmond, Virginia, United States of America. bvantassell@vcu.edu

ABSTRACT

Background: Heart failure (HF) is a complex clinical syndrome characterized by impaired cardiac function and poor exercise tolerance. Enhanced inflammation is associated with worsening outcomes in HF patients and may play a direct role in disease progression. Interleukin-1β (IL-1β) is a pro-inflammatory cytokine that becomes chronically elevated in HF and exerts putative negative inotropic effects.

Methods and results: We developed a model of IL-1β-induced left ventricular (LV) dysfunction in healthy mice that exhibited a 32% reduction in LV fractional shortening (P<0.001) and a 76% reduction in isoproterenol response (P<0.01) at 4 hours following a single dose of IL-1β 3 mcg/kg. This phenotype was reproducible in mice injected with plasma from HF patients and fully preventable by pretreatment with IL-1 receptor antagonist (anakinra). This led to the design and conduct of a pilot clinical to test the effect of anakinra on cardiopulmonary exercise performance in patients with HF and evidence of elevated inflammatory signaling (n = 7). The median peak oxygen consumption (VO(2)) improved from 12.3 [10.0, 15.2] to 15.1 [13.7, 19.3] mL · kg(-1) · min(-1) (P = 0.016 vs. baseline) and median ventilator efficiency (V(E)/VCO(2) slope) improved from 28.1 [22.8, 31.7] to 24.9 [22.9, 28.3] (P = 0.031 vs. baseline).

Conclusions: These findings suggest that IL-1β activity contributes to poor exercise tolerance in patients with systolic HF and identifies IL-1β blockade as a novel strategy for pharmacologic intervention.

Trial registration: ClinicalTrials.gov NCT01300650.

Show MeSH

Related in: MedlinePlus

Model of IL-1-induced systolic dysfunction in healthy mice.Healthy, adult, mice underwent baseline echocardiography followed by a single intraperitoneal injection of recombinant human IL-1β (0, 0.03, 0.3, 3, or 30 mcg/kg) and subsequent echocardiography at 4 hours. (A) All doses of IL-1β ≥0.3 mcg/kg produced a significant 28 – 32% reduction in left ventricular fractional shortening (LVFS) at 4 hours. Panels B (baseline) and C (4 hours) show representative echocardiographic images at 4 hours of mice injected with 3 mcg/kg IL-1β. Panels D – F show additional measures of LV function at 4 hours: (D) LV ejection fraction (LVEF); (E) FS/myocardial performance index (MPI) or FS-Tei index; (F) velocity of circumferential fiber shortening (Vcfc) corrected for heart rate. In all experiments, pre-treatment with anakinra 100 mg/kg 30 minutes prior to IL-1β was sufficient to prevent changes in LV function. (G) Isoproterenol 0.01 mcg/kg induced a reproducible 46% increase in LVFS that was significantly blunted by pre-treatment with IL-1β 3 mcg/kg. *P<0.01 versus control/baseline; †P<0.01 versus IL-1β.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC3306393&req=5

pone-0033438-g001: Model of IL-1-induced systolic dysfunction in healthy mice.Healthy, adult, mice underwent baseline echocardiography followed by a single intraperitoneal injection of recombinant human IL-1β (0, 0.03, 0.3, 3, or 30 mcg/kg) and subsequent echocardiography at 4 hours. (A) All doses of IL-1β ≥0.3 mcg/kg produced a significant 28 – 32% reduction in left ventricular fractional shortening (LVFS) at 4 hours. Panels B (baseline) and C (4 hours) show representative echocardiographic images at 4 hours of mice injected with 3 mcg/kg IL-1β. Panels D – F show additional measures of LV function at 4 hours: (D) LV ejection fraction (LVEF); (E) FS/myocardial performance index (MPI) or FS-Tei index; (F) velocity of circumferential fiber shortening (Vcfc) corrected for heart rate. In all experiments, pre-treatment with anakinra 100 mg/kg 30 minutes prior to IL-1β was sufficient to prevent changes in LV function. (G) Isoproterenol 0.01 mcg/kg induced a reproducible 46% increase in LVFS that was significantly blunted by pre-treatment with IL-1β 3 mcg/kg. *P<0.01 versus control/baseline; †P<0.01 versus IL-1β.

Mentions: To the hypothesis that IL-1β induces systolic dysfunction, we injected healthy mice with increasing doses of IL-1β and measured changes in cardiac function by transthoracic echocardiography. At 4 hours after injection, IL-1β produced significant reductions in LVFS at all doses ≥0.3 mcg/kg (Figure 1A-1C). We further characterized IL-1β 3 mcg/kg as a standard dose in all subsequent experiments as this dose was 10X the minimum dose required to significantly impair contractile function and appeared to give the greatest numerical reduction in LVFS. In addition to changes in contractile indices such as the ratio of fractional shortening/myocardial performance index (FS/MPI) and circumferential shortening–both of which are less sensitive to changes in preload [21], [22]–IL-1β 3 mcg/kg significantly reduced LV stroke volume from 41±2 µL to 29±3 µL (–27%, P<0.001) and increased heart rate from 345±22 beats/min to 432±30 beats/min (+25%, P = 0.004). Estimated cardiac output remained unchanged. No effects were noted with IL-1β doses less than 0.3 mcg/kg. The effects of IL-1β 3 mcg/kg were reproduced by IP administration of IL-1α 3 mcg/kg (data not shown) and prevented by pre-administration of anakinra 100 mg/kg (Figure 1D-1F), suggesting conserved signaling through the IL-1 type 1 membrane receptor (IL-1R1).


Enhanced interleukin-1 activity contributes to exercise intolerance in patients with systolic heart failure.

Van Tassell BW, Arena RA, Toldo S, Mezzaroma E, Azam T, Seropian IM, Shah K, Canada J, Voelkel NF, Dinarello CA, Abbate A - PLoS ONE (2012)

Model of IL-1-induced systolic dysfunction in healthy mice.Healthy, adult, mice underwent baseline echocardiography followed by a single intraperitoneal injection of recombinant human IL-1β (0, 0.03, 0.3, 3, or 30 mcg/kg) and subsequent echocardiography at 4 hours. (A) All doses of IL-1β ≥0.3 mcg/kg produced a significant 28 – 32% reduction in left ventricular fractional shortening (LVFS) at 4 hours. Panels B (baseline) and C (4 hours) show representative echocardiographic images at 4 hours of mice injected with 3 mcg/kg IL-1β. Panels D – F show additional measures of LV function at 4 hours: (D) LV ejection fraction (LVEF); (E) FS/myocardial performance index (MPI) or FS-Tei index; (F) velocity of circumferential fiber shortening (Vcfc) corrected for heart rate. In all experiments, pre-treatment with anakinra 100 mg/kg 30 minutes prior to IL-1β was sufficient to prevent changes in LV function. (G) Isoproterenol 0.01 mcg/kg induced a reproducible 46% increase in LVFS that was significantly blunted by pre-treatment with IL-1β 3 mcg/kg. *P<0.01 versus control/baseline; †P<0.01 versus IL-1β.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3306393&req=5

pone-0033438-g001: Model of IL-1-induced systolic dysfunction in healthy mice.Healthy, adult, mice underwent baseline echocardiography followed by a single intraperitoneal injection of recombinant human IL-1β (0, 0.03, 0.3, 3, or 30 mcg/kg) and subsequent echocardiography at 4 hours. (A) All doses of IL-1β ≥0.3 mcg/kg produced a significant 28 – 32% reduction in left ventricular fractional shortening (LVFS) at 4 hours. Panels B (baseline) and C (4 hours) show representative echocardiographic images at 4 hours of mice injected with 3 mcg/kg IL-1β. Panels D – F show additional measures of LV function at 4 hours: (D) LV ejection fraction (LVEF); (E) FS/myocardial performance index (MPI) or FS-Tei index; (F) velocity of circumferential fiber shortening (Vcfc) corrected for heart rate. In all experiments, pre-treatment with anakinra 100 mg/kg 30 minutes prior to IL-1β was sufficient to prevent changes in LV function. (G) Isoproterenol 0.01 mcg/kg induced a reproducible 46% increase in LVFS that was significantly blunted by pre-treatment with IL-1β 3 mcg/kg. *P<0.01 versus control/baseline; †P<0.01 versus IL-1β.
Mentions: To the hypothesis that IL-1β induces systolic dysfunction, we injected healthy mice with increasing doses of IL-1β and measured changes in cardiac function by transthoracic echocardiography. At 4 hours after injection, IL-1β produced significant reductions in LVFS at all doses ≥0.3 mcg/kg (Figure 1A-1C). We further characterized IL-1β 3 mcg/kg as a standard dose in all subsequent experiments as this dose was 10X the minimum dose required to significantly impair contractile function and appeared to give the greatest numerical reduction in LVFS. In addition to changes in contractile indices such as the ratio of fractional shortening/myocardial performance index (FS/MPI) and circumferential shortening–both of which are less sensitive to changes in preload [21], [22]–IL-1β 3 mcg/kg significantly reduced LV stroke volume from 41±2 µL to 29±3 µL (–27%, P<0.001) and increased heart rate from 345±22 beats/min to 432±30 beats/min (+25%, P = 0.004). Estimated cardiac output remained unchanged. No effects were noted with IL-1β doses less than 0.3 mcg/kg. The effects of IL-1β 3 mcg/kg were reproduced by IP administration of IL-1α 3 mcg/kg (data not shown) and prevented by pre-administration of anakinra 100 mg/kg (Figure 1D-1F), suggesting conserved signaling through the IL-1 type 1 membrane receptor (IL-1R1).

Bottom Line: Interleukin-1β (IL-1β) is a pro-inflammatory cytokine that becomes chronically elevated in HF and exerts putative negative inotropic effects.We developed a model of IL-1β-induced left ventricular (LV) dysfunction in healthy mice that exhibited a 32% reduction in LV fractional shortening (P<0.001) and a 76% reduction in isoproterenol response (P<0.01) at 4 hours following a single dose of IL-1β 3 mcg/kg.The median peak oxygen consumption (VO(2)) improved from 12.3 [10.0, 15.2] to 15.1 [13.7, 19.3] mL · kg(-1) · min(-1) (P = 0.016 vs. baseline) and median ventilator efficiency (V(E)/VCO(2) slope) improved from 28.1 [22.8, 31.7] to 24.9 [22.9, 28.3] (P = 0.031 vs. baseline).

View Article: PubMed Central - PubMed

Affiliation: School of Pharmacy, Virginia Commonwealth University, Richmond, Virginia, United States of America. bvantassell@vcu.edu

ABSTRACT

Background: Heart failure (HF) is a complex clinical syndrome characterized by impaired cardiac function and poor exercise tolerance. Enhanced inflammation is associated with worsening outcomes in HF patients and may play a direct role in disease progression. Interleukin-1β (IL-1β) is a pro-inflammatory cytokine that becomes chronically elevated in HF and exerts putative negative inotropic effects.

Methods and results: We developed a model of IL-1β-induced left ventricular (LV) dysfunction in healthy mice that exhibited a 32% reduction in LV fractional shortening (P<0.001) and a 76% reduction in isoproterenol response (P<0.01) at 4 hours following a single dose of IL-1β 3 mcg/kg. This phenotype was reproducible in mice injected with plasma from HF patients and fully preventable by pretreatment with IL-1 receptor antagonist (anakinra). This led to the design and conduct of a pilot clinical to test the effect of anakinra on cardiopulmonary exercise performance in patients with HF and evidence of elevated inflammatory signaling (n = 7). The median peak oxygen consumption (VO(2)) improved from 12.3 [10.0, 15.2] to 15.1 [13.7, 19.3] mL · kg(-1) · min(-1) (P = 0.016 vs. baseline) and median ventilator efficiency (V(E)/VCO(2) slope) improved from 28.1 [22.8, 31.7] to 24.9 [22.9, 28.3] (P = 0.031 vs. baseline).

Conclusions: These findings suggest that IL-1β activity contributes to poor exercise tolerance in patients with systolic HF and identifies IL-1β blockade as a novel strategy for pharmacologic intervention.

Trial registration: ClinicalTrials.gov NCT01300650.

Show MeSH
Related in: MedlinePlus