Dror Luger

Inflammation as a Driver of Adverse Left Ventricular Remodeling After Acute Myocardial Infarction

Treatment of acute myocardial infarction (AMI) has improved significantly in recent years, but many patients have adverse left ventricular (LV) remodeling, a maladaptive change associated with progressive heart failure. Although this change is usually associated with large infarcts, some patients with relatively small infarcts have adverse remodeling, whereas other patients with larger infarcts (who survive the first several days after AMI) do not. This paper reviews the relevant data supporting the hypothesis that individual differences in the intensity of the post-AMI inflammatory response, involving 1 or more inflammatory-modulating pathways, may contribute to adverse LV remodeling. It concludes by outlining how individual variations in the inflammatory response could provide important novel therapeutic targets and strategies.

Mechanisms Contributing to the Progression of Ischemic and Nonischemic Dilated Cardiomyopathy: Possible Modulating Effects of Paracrine Activities of Stem Cells

Over the past 1.5 decades, numerous stem cell trials have been performed in patients with cardiovascular disease. Although encouraging outcome signals have been reported, these have been small, leading to uncertainty as to whether they will translate into significantly improved outcomes. A reassessment of the rationale for the use of stem cells in cardiovascular disease is therefore timely. Such a rationale should include analyses of why previous trials have not produced significant benefit and address whether mechanisms contributing to disease progression might benefit from known activities of stem cells. The present paper provides such a reassessment, focusing on patients with left ventricular systolic dysfunction, either nonischemic or ischemic. We conclude that many mechanisms contributing to progressive left ventricular dysfunction are matched by stem cell activities that could attenuate the myocardial effect of such mechanisms. This suggests that stem cell strategies may improve patient outcomes and justifies further testing.

Intravenously Delivered Mesenchymal Stem Cells

Rationale: Virtually all mesenchymal stem cell (MSC) studies assume that therapeutic effects accrue from local myocardial effects of engrafted MSCs. Because few intravenously administered MSCs engraft in the myocardium, studies have mainly utilized direct myocardial delivery. We adopted a different paradigm. Objective: To test whether intravenously administered MSCs reduce left ventricular (LV) dysfunction both post–acute myocardial infarction and in ischemic cardiomyopathy and that these effects are caused, at least partly, by systemic anti-inflammatory activities. Methods and Results: Mice underwent 45 minutes of left anterior descending artery occlusion. Human MSCs, grown chronically at 5% O2, were administered intravenously. LV function was assessed by serial echocardiography, 2,3,5-triphenyltetrazolium chloride staining determined infarct size, and fluorescence-activated cell sorting assessed cell composition. Fluorescent and radiolabeled MSCs (1×106) were injected 24 hours post–myocardial infarction and homed to regions of myocardial injury; however, the myocardium contained only a small proportion of total MSCs. Mice received 2×106 MSCs or saline intravenously 24 hours post–myocardial infarction (n=16 per group). At day 21, we harvested blood and spleens for fluorescence-activated cell sorting and hearts for 2,3,5-triphenyltetrazolium chloride staining. Adverse LV remodeling and deteriorating LV ejection fraction occurred in control mice with large infarcts (≥25% LV). Intravenous MSCs eliminated the progressive deterioration in LV end-diastolic volume and LV end-systolic volume. MSCs significantly decreased natural killer cells in the heart and spleen and neutrophils in the heart. Specific natural killer cell depletion 24 hours pre–acute myocardial infarction significantly improved infarct size, LV ejection fraction, and adverse LV remodeling, changes associated with decreased neutrophils in the heart. In an ischemic cardiomyopathy model, mice 4 weeks post–myocardial infarction were randomized to tail-vein injection of 2×106 MSCs, with injection repeated at week 3 (n=16) versus PBS control (n=16). MSCs significantly increased LV ejection fraction and decreased LV end-systolic volume. Conclusions: Intravenously administered MSCs for acute myocardial infarction attenuate the progressive deterioration in LV function and adverse remodeling in mice with large infarcts, and in ischemic cardiomyopathy, they improve LV function, effects apparently modulated in part by systemic anti-inflammatory activities.

Multimodality imaging demonstrates trafficking of liposomes preferentially to ischemic myocardium

INTRODUCTION Nanoparticles may serve as a promising means to deliver novel therapeutics to the myocardium following myocardial infarction. We sought to determine whether lipid-based liposomal nanoparticles can be shown through different imaging modalities to specifically target injured myocardium following intravenous injection in an ischemia-reperfusion murine myocardial infarction model. METHODS Mice underwent ischemia-reperfusion surgery and then either received tail-vein injection with gadolinium- and fluorescent-labeled liposomes or no injection (control). The hearts were harvested 24h later and underwent T1 and T2-weighted ex vivo imaging using a 7 Tesla Bruker magnet. The hearts were then sectioned for immunohistochemistry and optical fluorescent imaging. RESULTS The mean size of the liposomes was 100nm. T1-weighted signal intensity was significantly increased in the ischemic vs. the non-ischemic myocardium for mice that received liposomes compared with control. Optical imaging demonstrated significant fluorescence within the infarct area for the liposome group compared with control (163±31% vs. 13±14%, p=0.001) and fluorescent microscopy confirmed the presence of liposomes within the ischemic myocardium. CONCLUSIONS Liposomes traffic to the heart and preferentially home to regions of myocardial injury, enabling improved diagnosis of myocardial injury and could serve as a vehicle for drug delivery.

Paracrine-Mediated Systemic Anti-Inflammatory Activity of Intravenously Administered Mesenchymal Stem Cells: A Transformative Strategy for Cardiac Stem Cell Therapeutics

Stem cell therapy as a treatment option for acute myocardial infarction or heart failure caused by ischemic or nonischemic cardiomyopathy has focused on direct cardiac delivery of stem cells to facilitate cardiac engraftment. Once engrafted, it was believed that these cells would either transdifferentiate into new functioning myocytes or stimulate the expansion of resident myocardial stem cells. However, a sea change in thinking about cell therapy in cardiovascular disease has occurred as mounting evidence indicates that (1) inflammation is a major mechanism contributing to the progressive myocardial dysfunction seen in patients post-acute myocardial infarction and in patients with cardiomyopathy, and (2) systemic paracrine-mediated anti-inflammatory effects of stem cells can drive beneficial cardiac effects in these diseases. These concepts lead to a potentially transformative strategy that intravenous delivery of stem cells, through systemic anti-inflammatory mechanisms, improves myocardial function and thereby obviates the need for invasive methods of stem cell delivery. Until recently, the prevailing view of the mechanism responsible for any potential benefit of stem cells in patients with acute myocardial infarction (AMI) or with heart failure (HF) caused by ischemic or nonischemic cardiomyopathy (ICM/NICM) was that benefit derived from local effects—once engrafted in damaged myocardium, the stem cells either transdifferentiate into functional myocardium, stimulate resident myocardial stem cells to expand, and repopulate the heart with functioning myocytes or secrete substances leading to myocardial healing. This mechanistic perspective implied that the greater the number of engrafted cells in the myocardium, the greater the cardiac benefit. Because few intravenously administered stem cells engraft in injured myocardium, invasive strategies providing direct delivery of stem cells to the heart were uniformly adopted. This necessarily involved either catheter-based delivery (intracoronary or transendocardial injection) or surgical delivery (direct intramyocardial injection). A transformative concept relating to stem cell treatment of patients with AMI or ICM/NICM has recently …

Mesenchymal Stem Cell Therapy for the Treatment of Heart Failure Caused by Ischemic or Non-ischemic Cardiomyopathy: Immunosuppression and Its Implications

HF patients with signs and symptoms of worsening heart failure (HF), despite optimal medical therapy, have a poor prognosis. The pathways contributing to HF are multiple, probably accounting, in part, for current treatment approaches not being more effective. Stem cells, particularly mesenchymal stem cells (MSCs), have a broad range of activities, making them particularly interesting candidates for a new HF therapeutic. This review presents an overview of the studies examining the efficacy of stem cell studies administered to HF patients, focusing mainly on MSCs. It examines the issues surrounding autologous vs. allogenic stem cells, the results of different routes of administration, and implications deriving from the belief that for stem cells to be effective, they must engraft in the myocardium and exert local effects. Since intravenous administration of stem cells leads to sparse cardiac engraftment, stem cell delivery strategies have uniformly involved catheter-based delivery systems. This becomes problematic in a disease that will almost certainly require delivery of the therapeutic throughout the course of the disease. Importantly, it appears that a critical contributing cause of the progressive cardiac dysfunction experienced by HF patients is the existence of a persistent inflammatory response. Since MSCs exert potent anti-inflammatory effects through paracrine mechanisms, it is possible that intravenous delivery of MSCs may be therapeutically effective. If this concept is valid, it could lead to a transformational change in stem cell delivery strategies.

Large Animal Model Efficacy Testing Is Needed Prior to Launch of a Stem Cell Clinical Trial: An Evidence-Lacking Conclusion Based on Conjecture.

Stem cell therapeutics, as other therapeutic strategies, must surmount multiple requirements before reaching the phase of clinical trials. These requirements can be onerous in terms of time and funding and could, thereby, lead to abandonment of many promising therapeutics. One of these requirements is the perceived necessity of conducting large animal efficacy studies—especially pig studies—prior to initiating a clinical trial. The value of such a strategy, despite acceptance by experts, has never been demonstrated scientifically, raising the question of whether bias rather than evidence hampers the development of new therapeutic strategies. Of the questions facing investigators involved in developing new treatment strategies, one is common across disease disciplines and therapeutic approaches: What animal models should be used to determine whether the likelihood a therapeutic will be clinically successful is high enough to justify spending years of effort and tens, or even hundreds, of millions of dollars in clinical trials? A particularly vexing extension of this question is whether it is necessary to test efficacy in a large animal model prior to clinical trial launch. The purpose of this Viewpoint is to challenge the prevailing view, epitomized by the following quote: “Translational studies in large animal models (usually pigs) are rare because they are expensive, complex, time-consuming, technically demanding, slow, and usually not suitable for mechanistic investigations; nevertheless, because they are conducted in settings closer to the human situation than those found in rodent models, these studies are essential to justify the risks and costs of clinical trials.”1 This quote reflects current unofficial dogma that once efficacy of an intervention is established in mouse or other rodent models, efficacy needs confirmation in a large animal model—the most popular one being the pig.1–3 This is not a trivial conclusion because adequately powered pig studies are expensive from both …