scholarly journals Interleukin-18 mediates interleukin-1-induced cardiac dysfunction

2014 ◽  
Vol 306 (7) ◽  
pp. H1025-H1031 ◽  
Author(s):  
Stefano Toldo ◽  
Eleonora Mezzaroma ◽  
Laura O'Brien ◽  
Carlo Marchetti ◽  
Ignacio M. Seropian ◽  
...  
Keyword(s):  
Systolic Dysfunction ◽  
Interleukin 1 ◽  
Left Ventricular ◽  
Wild Type ◽  
Blocking Antibody ◽  
Experimental Mouse Model ◽  
Patients With Heart Failure ◽  
Experimental Mouse ◽  
Genetic Deletion ◽  
Fractional Shortening

Patients with heart failure (HF) have enhanced systemic IL-1 activity, and, in the experimental mouse model, IL-1 induces left ventricular (LV) systolic dysfunction. Whether the effects of IL-1 are direct or mediated by an inducible cytokine, such as IL-18, is unknown. Recombinant human IL-18-binding protein (IL-18BP) or an IL-18-blocking antibody (IL-18AB) was used to neutralize endogenous IL-18 after challenge with the plasma of patients with HF or with recombinant murine IL-1β in adult male mice. Plasma levels of IL-18 and IL-6 (a key mediator of IL-1-induced systemic effects) and LV fractional shortening were measured in mice sedated with pentobarbital sodium (30–50 mg/kg). Mice with genetic deletion of IL-18 or IL-18 receptors were compared with matching wild-type mice. A group of mice received murine IL-18 to evaluate the effects on LV fractional shortening. Plasma from HF patients and IL-1β induced LV systolic dysfunction that was prevented by pretreatment with IL-18AB or IL-18BP. IL-1β failed to induce LV systolic dysfunction in mice with genetic deletion of IL-18 signaling. IL-1β induced a significant increase in plasma IL-18 and IL-6 levels. Genetic or pharmacological inhibition of IL-18 signaling failed to block the induction of IL-6 by IL-1β. In conclusion, IL-1 induces a release of active IL-18 in the mouse that mediates the LV systolic dysfunction but not the induction of IL-6. IL-18 blockade may therefore represent a novel and more targeted therapeutic approach to treat HF.

Abstract 71: STAT3 Affects Myofibrillar Structure and Its Loss May Contribute to Heart Failure in Hypertension

Hypertension ◽  
2012 ◽  
Vol 60 (suppl_1) ◽  
Author(s):  
Fouad Zouein ◽  
Carlos Zgheib ◽  
John Fuseler ◽  
John E Hall ◽  
Mazen Kurdi ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Myocytes ◽  
Transcriptional Activity ◽  
Cardiac Myocyte ◽  
Early Stage ◽  
Systolic Dysfunction ◽  
Wild Type ◽  
Patients With Heart Failure ◽  
Protective Proteins ◽  
Fractional Shortening

How hypertension causes heart failure is not known. Since patients with heart failure have reduced cardiac STAT3 and STAT3 KO mice develop heart failure with age, we tested the hypothesis that reduced STAT3 transcriptional activity contributes at an early stage to remodeling that precedes heart failure in hypertension using SA mice with a STAT3 S727A mutation. SA and wild type (WT) mice received angiotensin (A) II (1000 ng/kg/min) or saline (S) for 17 days. Hearts of WT and SA mice had similar levels of STAT3-induced protective proteins Bcl-xL and SOD2, and unlike STAT3 KO mice, cardiac miR-199a levels were not increased in SA mice. AII increased systolic blood pressure measured by telemetry in SA (124 ± 1 to 167 ± 3) and WT (122 ± 3 to 162 ± 3) mice to the same extent. AII increased cardiac levels of cytokines (pg/μg protein) associated with heart failure in both WT and SA mice, but significantly less so (P<0.05) in SA mice; IL-6, 13.6 ± 1.4 vs. 9.1 ± 0.6; TGFβ, 56 ± 4 vs. 38 ± 3 and MCP1 35 ± 2 vs. 22 ± 2. Compared to WT mice, hearts of SA mice showed signs of developing systolic dysfunction with AII as seen by a significant (P<0.05) reduction in ejection fraction (63.7 ± 7.1 to 51.7 ± 6.9) and fractional shortening (34.3 ± 4.9 to 26.4 ± 4.3). AII caused fibrosis in the left ventricle of both WT and SA mice characterized by cardiac myocyte loss and increased % collagen: WT+S, 5.59 ± 0.34; WT+AII, 15.70 ± 1.87; SA+S, 6.70 ± 0.40; SA+AII, 16.50 ± 1.91. In WT+AII mice there was a nonsignificant trend towards a loss of myofibrillar content of cardiac myocytes, but an increase in the mass of the myofibrils (IOD/myofibrillar area). In contrast, cardiac myocytes of SA+AII mice had a significant (P<0.001) % loss in myofibrils (5.71 ± 0.28) compared to SA+S (0.75 ± 0.07), WT+S (0.80 ± 0.06) and WT+AII (1.54 ± 0.10) mice. In addition, the mass of the myofibrils in SA+AII mice (6.01 ± 0.07) was significantly less (P<0.001) than those of SA+S mice (6.46 ± 0.04), although greater than WT+S (4.85 ± 0.06) or WT+AII (5.27 ± 0.08) mice. Our findings reveal that STAT3 transcriptional activity is important for proper morphology of the myofibrils of cardiac myocytes. Loss of STAT3 activity may impair cardiac function in the hypertensive heart due to defective myofibrillar structure and remodeling that may lead to heart failure.

Abstract 5920: Usefulness of Late Gadolinium Enhancement as Non-invasive Arrhythmic Risk Marker in Patients with Heart Failure and Systolic Dysfunction

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Alfonso Valle ◽  
Mercedes Nadal ◽  
Jordi Estornell ◽  
Nieves Martinez ◽  
Miguel Corbi ◽  
...  
Keyword(s):  
Heart Failure ◽  
Late Gadolinium Enhancement ◽  
Risk Stratification ◽  
Systolic Dysfunction ◽  
Total Mortality ◽  
Left Ventricular ◽  
Gadolinium Enhancement ◽  
Non Invasive ◽  
Patients With Heart Failure

The identification of prognostic markers in patients with heart failure of both ischemic and non ischemic etiology is an increasing need in the era of devices therapy. Risk stratification for sudden cardiac death (SCD) remains problematic with reliance on left ventricular function which predicts total mortality rather than arrhythmic events (AE). Recently cardiac magnetic resonance was employed to predict susceptibility for malignant arrhythmias. This study sought to determine the utility of late gadolinium enhancement (LGE) to predict AE. Three hundred consecutive patients with symptomatic heart failure and systolic dysfunction of both ischemic and non ischemic cause undergoing CMR, were classified into two groups attending to the presence (n 160) or absence of LGE (n 140), and were followed prospectively during 842 days. The primary endpoint was the combined of SCD or Ventricular tachycardia (VT). 23 patients had AE (8 SCD/15 VT) during the follow-up, 19 of them presenting LGE (83%). The presence of LGE was associated to a significantly higher AE rate (11.8.% vs 2.8% p< 0.001)(figure ). Compared to patients without LGE, midwall fibrosis and an ischemic pattern of LGE predicted AE. (3% vs 5% vs 14%, p= 0.001) LGE is a new non-invasive predictor of AE in patients with heart failure and systolic dysfunction. This suggest a potential role for risk stratification and better selection of patients who needs device therapy

Abstract 18294: Left Ventricular Systolic Dysfunction Early After Resuscitation From Cardiac Arrest is Associated With Shockable Arrest Rhythm

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Jacob C Jentzer ◽  
Hussein Abu-Daya ◽  
Asher Shafton ◽  
Meshe Chonde ◽  
Didier Chalhoub ◽  
...  
Keyword(s):  
Cardiac Arrest ◽  
Hospital Mortality ◽  
Troponin I ◽  
Left Ventricular Systolic Dysfunction ◽  
Systolic Dysfunction ◽  
Mitral Annulus ◽  
Left Ventricular ◽  
Ventricular Systolic Dysfunction ◽  
Mitral Annulus Velocity ◽  
Fractional Shortening

Introduction: Left ventricular systolic dysfunction (LVSD) is common after resuscitation from cardiac arrest (CA). The association of echocardiographic LVSD with cardiac rhythm during CA is not well described. Hypothesis: Patients with a shockable rhythm (VT/VF) will have a greater degree of LVSD by echocardiography after CA. Methods: Prospective registry of patients resuscitated from CA underwent transthoracic echocardiography (TTE) within 24 hours after CA. We determined 2D measurements, LVEF, spectral Doppler of mitral inflow and LV outflow, systolic and diastolic tissue Doppler of the mitral annulus velocity, and tricuspid plane annular excursion (TAPSE). We collected data on in-hospital mortality as well as vasopressor doses and troponin I levels. TTE parameters and clinical characteristics were compared between patients with a shockable (VT/VF) arrest rhythm and a non-shockable (asystole/PEA) arrest rhythm and between survivors and non-survivors using t-tests and ANOVA. Results: Of the 55 patients, the 23 (42%) with shockable CA rhythms had significantly higher LV end-systolic dimension (4.1cm vs. 3.3cm, p = 0.0073), lower LV fractional shortening (0.15 vs. 0.28, p <0.0001), and lower LVEF both by visual estimate (36.2% vs. 52.3%, p = 0.0012) and by Simpson’s biplane method (37.5% vs. 52.3%, p = 0.0506). Other measured TTE parameters did not differ between groups, including TAPSE (shockable 1.53 vs. non-shockable 1.82, p = 0.1731). Admission and peak 24 hour vasopressor requirements did not differ between groups. Peak troponin levels were higher (22.26 vs. 3.88, p = 0.0198) in patients with shockable CA rhythms, but admission troponin levels were no different (0.88 vs. 0.51, p = 0.1527). TTE parameters did not differ between survivors and non-survivors (visual LVEF 47.0% vs. 44.2%, p = 0.5968; LV fractional shortening 0.19 vs. 0.25, p = 0.0916). Conclusions: Patients with shockable CA rhythms have more severe LVSD on 24 hour echocardiography despite similar vasopressor requirements and admission troponin levels. Echocardiographic parameters at 24 hours did not predict in-hospital mortality. Early echocardiography after CA appears more useful for differentiating primary CA rhythm than for predicting mortality.

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