Bilal B. Ayach

Dissecting mechanisms of innate and acquired immunity in myocarditis

Inflammation underlies the pathogenesis of some of the most common cardiovascular diseases. Myocarditis is a relevant clinical cause of heart failure, but also provides an excellent laboratory model to study the mechanisms of inflammation leading to heart failure. The availability of different inbred mouse strains for inducing myocarditis using viral or myosin as triggers provides an excellent platform for investigation. The recent use of genetically manipulated mouse models of transgenic overexpression or knockout or knockin targets have provided opportunity to pinpoint specific pathways underlying myocarditis. These pathways include the involvement of both innate and acquired immunity, as well as the role of viral receptors in disease phenotype. These different models also permit the evaluation of therapeutic strategies of candidates for clinical development.

Chlamydophila pneumoniae Inhibits Differentiation of Progenitor Adipose Cells and Impairs Insulin Signaling

BACKGROUND Recent clinical studies have shown Chlamydophila pneumoniae seropositivity to be related to overweight status and inversely related to insulin sensitivity. The present study was performed to investigate the potential effects of C. pneumoniae infection of adipocytes. METHODS 3T3-L1 cells and primary epididymal preadipocytes were infected with C. pneumoniae either before or after induction of differentiation, and the effects on adipogenesis and insulin signaling were determined. Tumor necrosis factor (TNF)-alpha signaling was examined by assessing the effects of C. pneumoniae infection in preadipocytes isolated from epididymal adipose tissue of both wild-type and TNF-alpha(-/-) mice. RESULTS C. pneumoniae successfully infected both undifferentiated and differentiated 3T3-L1 cells in vitro. The bacteria were also detected in adipose tissue of infected low-density lipoprotein receptor-deficient mice. TNF-alpha protein levels were significantly increased in cells infected with either live or heat-killed C. pneumoniae or treated with lipopolysaccharide or heat-shock protein 65; this increase was associated with inhibition of adipocyte differentiation and down-regulation of insulin-stimulated tyrosine-phosphorylated insulin receptor and its substrate. In contrast, C. pneumoniae infection in TNF-alpha(-/-) adipocytes produced no apparent changes, but addition of recombinant TNF-alpha reversed this effect. CONCLUSIONS We demonstrate for the first time that C. pneumoniae can infect murine pre- and postdifferentiated adipocytes and, through a TNF-alpha-mediated inflammatory mechanism, can impair differentiation and insulin signaling.

Direct injection of kit ligand-2 lentivirus improves cardiac repair and rescues mice post-myocardial infarction.

Myocardial infarction (MI) and subsequent adverse remodeling cause heart failure. Previously we demonstrated a role for Kit ligand (KL) in improving cardiac function post-MI. KL has two major isoforms; KL-1 is secreted whereas KL-2 is predominantly membrane bound. We demonstrate here first that KL-2-deficient mice have worse survival and an increased heart/bodyweight ratio post-MI compared to mice with reduced c-Kit receptor expression. Next we synthesized recombinant lentiviral vectors (LVs) that engineered functional expression of murine KL-1 and KL-2. For in vivo analyses, we directly injected these LVs into the left ventricle of membrane-bound KL-deficient Sl/Sl(d) or wild-type (WT) mice undergoing MI. Control LV/enGFP injection led to measurable reporter gene expression in hearts. Injection of LV/KL-2 attenuated adverse left ventricular remodeling and dramatically improved survival post-MI in both Sl/Sl(d) and WT mice (from 12 to 71% and 35 to 73%, respectively, versus controls). With regard toward beginning to understand the possible salutary mechanisms involved in this effect, differential staining patterns of Sca-1 and Ly49 on peripheral blood (PB) cells from therapeutically treated animals was found. Our data show that LV/KL-2 gene therapy is a promising treatment for MI.

End of life decisions in heart failure: to turn off the intracardiac device or not?

Purpose of review Heart failure is a significant public health concern around the world. Implantable cardioverter defibrillators with or without cardiac resynchronization therapy (CRT-D) have proven survival benefit. As patients progress to end-stage disease, management shifts to palliative care, and cardiologists are often confronted with how to best manage these devices. Recent findings Studies suggest that up to one-third of patients with an implantable cardioverter defibrillator receive painful shocks in the last 24 h of life. Disabling pacing or resynchronization devices may further weaken the heart function and expedite death, particularly if the patient has no underlying ventricular rhythm. Is it ethical or legal to discontinue functions of the implantable device? The discussion and the decision to be made are whether to continue both pacing and tachyarrhythmia therapies, disable tachyarrhythmia therapies while maintaining pacing, or discontinue both. Summary The decision to disable all or parts of the device function is ultimately up to the patient. To avoid painful shocks near the end of life, it is recommended that tachyarrhythmia therapies be turned off when the patient is being treated palliatively. After informed discussion, withdrawing the resynchronization or pacing device option is also acceptable if requested by the patient regardless of the potential outcomes.