Alterations in the Interleukin-1/Interleukin-1 Receptor Antagonist Balance Modulate Cardiac Remodeling following Myocardial Infarction in the Mouse

Background Healing after acute myocardial infarction (AMI) is characterized by an intense inflammatory response and increased Interleukin-1 (IL-1) tissue activity. Genetically engineered mice lacking the IL-1 receptor (IL-1R1-/-, not responsive to IL-1) or the IL-1 receptor antagonist (IL-1Ra, enhanced response to IL-1) have an altered IL-1/IL-1Ra balance that we hypothesize modulates infarct healing and cardiac remodeling after AMI. Methods IL-1R1-/- and IL-1Ra-/- male mice and their correspondent wild-types (WT) were subjected to permanent coronary artery ligation or sham surgery. Infarct size (trichrome scar size), apoptotic cell death (TUNEL) and left ventricular (LV) dimensions and function (echocardiography) were measured prior to and 7 days after surgery. Results When compared with the corresponding WT, IL-1R1-/- mice had significantly smaller infarcts (−25%), less cardiomyocyte apoptosis (−50%), and reduced LV enlargement (LV end-diastolic diameter increase [LVEDD], −20%) and dysfunction (LV ejection fraction [LVEF] decrease, −50%), whereas IL-1Ra-/- mice had significantly larger infarcts (+75%), more apoptosis (5-fold increase), and more severe LV enlargement (LVEDD increase,+30%) and dysfunction (LVEF decrease, +70%)(all P values \u3c0.05). Conclusions An imbalance in IL-1/IL-1Ra signaling at the IL-1R1 level modulates the severity of cardiac remodeling after AMI in the mouse, with reduced IL-1R1 signaling providing protection and unopposed IL-1R1 signaling providing harm

The Antioxidant Potential of the Mediterranean Diet in Patients at High Cardiovascular Risk: An In-Depth Review of the PREDIMED

Cardiovascular disease (CVD) is the leading global cause of death. Diet is known to be important in the prevention of CVD. The PREDIMED trial tested a relatively low-fat diet versus a high-fat Mediterranean diet (MedDiet) for the primary prevention of CVD. The resulting reduction of the CV composite outcome resulted in a paradigm shift in CV nutrition. Though many dietary factors likely contributed to this effect, this review focuses on the influence of the MedDiet on endogenous antioxidant systems and the effect of dietary polyphenols. Subgroup analysis of the PREDIMED trial revealed increased endogenous antioxidant and decreased pro-oxidant activity in the MedDiet groups. Moreover, higher polyphenol intake was associated with lower incidence of the primary outcome, overall mortality, blood pressure, inflammatory biomarkers, onset of new-onset type 2 diabetes mellitus (T2DM), and obesity. This suggests that polyphenols likely contributed to the lower incidence of the primary event in the MedDiet groups. In this article, we summarize the potential benefits of polyphenols found in the MedDiet, specifically the PREDIMED cohort. We also discuss the need for further research to confirm and expand the findings of the PREDIMED in a non-Mediterranean population and to determine the exact mechanisms of action of polyphenols

Mesenchymal stromal cells inhibit NLRP3 inflammasome activation in a model of Coxsackievirus B3-induced inflammatory cardiomyopathy

Inflammation in myocarditis induces cardiac injury and triggers disease progression to heart failure. NLRP3 inflammasome activation is a newly identified amplifying step in the pathogenesis of myocarditis. We previously have demonstrated that mesenchymal stromal cells (MSC) are cardioprotective in Coxsackievirus B3 (CVB3)-induced myocarditis. In this study, MSC markedly inhibited left ventricular (LV) NOD2, NLRP3, ASC, caspase-1, IL-1β, and IL-18 mRNA expression in CVB3-infected mice. ASC protein expression, essential for NLRP3 inflammasome assembly, increased upon CVB3 infection and was abrogated in MSC-treated mice. Concomitantly, CVB3 infection in vitro induced NOD2 expression, NLRP3 inflammasome activation and IL-1β secretion in HL-1 cells, which was abolished after MSC supplementation. The inhibitory effect of MSC on NLRP3 inflammasome activity in HL-1 cells was partly mediated via secretion of the anti-oxidative protein stanniocalcin-1. Furthermore, MSC application in CVB3-infected mice reduced the percentage of NOD2-, ASC-, p10- and/or IL-1β- positive splenic macrophages, natural killer cells, and dendritic cells. The suppressive effect of MSC on inflammasome activation was associated with normalized expression of prominent regulators of myocardial contractility and fibrosis to levels comparable to control mice. In conclusion, MSC treatment in myocarditis could be a promising strategy limiting the adverse consequences of cardiac and systemic NLRP3 inflammasome activation

Pharmacologic and Surgical Interventions to Improve Functional Capacity in Heart Failure.

Heart failure (HF) is a clinical syndrome of breathlessness, lower extremity swelling, fatigue, and exercise intolerance affecting a large portion of the population worldwide, and associated with premature death. Despite improvement in the management of HF, many patients remain unable to complete activities of daily living without experiencing exertional symptoms. Although prevention of death in patients with HF is imperative, treatment of symptoms and improving functional capacity are equally important goals. This article discusses treatments (medical and surgical) associated with improved functional capacity in HF

Inflammatory markers in ST-elevation acute myocardial infarction

After acute myocardial infarction, ventricular remodeling is characterized by changes at the molecular, structural, geometrical and functional level that determine progression to heart failure. Inflammation plays a key role in wound healing and scar formation, affecting ventricular remodeling. Several, rather different, components of the inflammatory response were studied as biomarkers in ST-elevation acute myocardial infarction. Widely available and inexpensive tests, such as leukocyte count at admission, as well as more sophisticated immunoassays provide powerful predictors of adverse outcome in patients with ST-elevation acute myocardial infarction. We review the value of inflammatory markers in ST-elevation acute myocardial infarction and their association with ventricular remodeling, heart failure and sudden death. In conclusion, the use of these biomarkers may identify subjects at greater risk of adverse events and perhaps provide an insight into the mechanisms of disease progression

Heart failure with preserved ejection fraction: Refocusing on diastole.

Heart failure (HF) with preserved ejection fraction (HFpEF) is a clinical syndrome of exercise intolerance and/or congestion, in the presence of a left ventricular (LV) ejection fraction within the normal limits (i.e. LVEF>50%). Determining the presence of impaired LV relaxation and/or filling (diastolic dysfunction) in HFpEF is needed to pragmatically to distinguish it from other cardiac and non-cardiac conditions where symptoms are not due to HF. There are multiple mechanisms for diastolic dysfunction ranging from structural abnormalities to functional derangements in HFpEF yet tailored therapies are lacking. Treatments proven effective in HF with systolic dysfunction have failed to show significant benefit in patients with HFpEF, which prognosis remains poor. This review will discuss the challenges inherent to the use of diagnostic criteria for HFpEF, differential diagnosis, prognostic evaluation, and treatment, highlighting the need for more research in this field