Ulrich Hofmann

Background—: Activation of innate immunity, especially infiltration of monocytes, is critical for proper wound healing and scar formation after myocardial infarction (MI). Therefore, we tested the hypothesis that interleukin-13 (IL-13), which influences the differentiation of monocytes/macrophages and has profibrotic properties, modulates wound healing and remodeling after MI. Methods and Results—: MI was induced by permanent ligation of the left coronary artery in both male and female wild-type (WT)/IL-13 ^−/− mice. Real-time polymerase chain reaction demonstrated that expression of IL-13 was induced in left and right ventricular myocardium of WT mice within days in response to MI. Fifty-six–day survival was significantly impaired (65% in WT versus 34% in IL-13 ^−/− ) in male but not female IL-13 ^−/− (55% in WT versus 54% in IL-13 ^−/− ) mice. Serial echocardiography showed significantly increased left ventricular dilation in male IL-13 ^−/− compared with WT mice starting from day 1 after MI, despite comparable infarct size. Fluorescence-activated cell sorter analysis revealed less leukocyte infiltration in male IL-13 ^−/− mice on day 3. Real-time polymerase chain reaction analysis demonstrated reduced expression of marker genes of alternative activation in monocytes sorted from the infarct zone of male IL-13 ^−/− in comparison with WT mice on day 3 after MI. Conclusions—: Genetic deficiency of IL-13 worsens outcome after MI in male mice. Our data indicate that IL-13 regulates leukocyte recruitment and induces M2-like monocyte/macrophage differentiation, which modifies wound healing within the infarct zone.

Rationale: An exaggerated or persistent inflammatory activation after myocardial infarction (MI) leads to maladaptive healing and subsequent remodeling of the left ventricle. Foxp3⁺CD4⁺regulatory T cells (T_regcells) contribute to inflammation resolution. Therefore, T_regcells might influence cardiac healing post-MI.Objective: Our aim was to study the functional role of T_regcells in wound healing post-MI in a mouse model of permanent left coronary artery ligation.Methods and Results: Using a model of genetic T_reg-cell ablation (Foxp3^DTRmice), we depleted the T_reg-cell compartment before MI induction, resulting in aggravated cardiac inflammation and deteriorated clinical outcome. Mechanistically, T_reg-cell depletion was associated with M1-like macrophage polarization, characterized by decreased expression of inflammation-resolving and healing-promoting factors. The phenotype of exacerbated cardiac inflammation and outcome in T_reg-cell–ablated mice could be confirmed in a mouse model of anti-CD25 monoclonal antibody–mediated depletion. In contrast, therapeutic T_reg-cell activation by superagonistic anti-CD28 monoclonal antibody administration 2 days after MI led to improved healing and survival. Compared with control animals, CD28-SA–treated mice showed increased collagen de novo expression within the scar, correlating with decreased rates of left ventricular ruptures. Therapeutic T_reg-cell activation induced an M2-like macrophage differentiation within the healing myocardium, associated with myofibroblast activation and increased expression of monocyte/macrophage-derived proteins fostering wound healing.Conclusions: Our data indicate that T_regcells beneficially influence wound healing after MI by modulating monocyte/macrophage differentiation. Moreover, therapeutic activation of T_regcells constitutes a novel approach to improve healing post-MI.

The prevalence of chronic heart failure is still increasing making it a major health issue in the 21st century. Tremendous evidence has emerged over the past decades that heart failure is associated with a wide array of mechanisms subsumed under the term “inflammation”. Based on the great success of immuno-suppressive treatments in auto-immunity and transplantation, clinical trials were launched targeting inflammatory mediators in patients with chronic heart failure. However, they widely lacked positive outcomes. The failure of the initial study program directed against tumor necrosis factor-α led to the search for alternative therapeutic targets involving a broader spectrum of mechanisms besides cytokines. We here provide an overview of the current knowledge on immune activation in chronic heart failure of different etiologies, summarize clinical studies in the field, address unresolved key questions, and highlight some promising novel therapeutic targets for clinical trials from a translational basic science and clinical perspective.

Background—: The role of adaptive immunity, especially CD4 ⁺ T-helper cells, has not yet been systematically investigated in wound healing and remodeling after myocardial infarction (MI). Therefore, we studied whether CD4 ⁺ T cells become activated and influence wound healing after experimental MI in mice. Methods and Results—: When we compared sham versus MI in wild-type (WT) mice, T-cell receptor–dependent activation of both conventional Foxp3 ⁻ and regulatory Foxp3 ⁺ CD4 ⁺ T cells could be demonstrated in heart-draining lymph nodes within the first week after MI. Concomitantly, we found infiltration of CD4 ⁺ T cells in infarcted myocardium. To study the role of CD4 ⁺ T cells in wound healing and remodeling, CD4 ⁺ T-cell–deficient mice (CD4 knockout [KO], MHCII ^Δ/Δ ) and T-cell receptor–transgenic OT-II mice recognizing an irrelevant ovalbumin-derived peptide were studied. Serial echocardiography up to day 56 after MI revealed increased left ventricular dilation in CD4 KO compared with WT mice. Within the infarcted myocardium, CD4 KO mice displayed higher total numbers of leukocytes and proinflammatory monocytes (18.3±3.0 10 ⁴ /mg WT versus 75.7±17.0 10 ⁴ /mg CD4 KO, P Δ/Δ and OT-II mice displayed significantly greater mortality (21% WT versus 48% OT-II, P Δ/Δ , P Δ/Δ mice, as well as in OT-II mice. Conclusions—: The present study provides the first evidence that CD4 ⁺ T cells become activated after MI, presumably driven by recognition of cardiac autoantigens, and facilitate wound healing of the myocardium.

The case presented here is intended to raise awareness of two uncommon coronary angiographic findings in the clinical context of acute coronary syndrome. The prevalence of patients presenting with spontaneous coronary dissection as the underlying cause of an ST-elevation myocardial infarction is low. It is typically found in women, often occurring during the peripartum period. There is some debate as to whether spontaneous dissection could also be managed conservatively without coronary intervention. As for spontaneous dissection, knowledge of a culprit lesion within the distal left anterior descending artery (LAD) causing inferior ST elevation (wrap around of the LAD) is not prevalent. Patient characteristics and treatment options are discussed on the basis of the recent literature on both clinical entities.

The innate immune system can detect the highly conserved, relatively invariant structural motifs of pathogens. The most important innate immune receptors, Toll-like receptors (TLRs), represent a first line of defense against infectious pathogens, and play a pivotal role in initiating and shaping innate and adaptive immune responses. TLRs are not only expressed in immune cells, but also in cardiovascular cells. In addition to their role in response to microbial infections, evidence suggests that TLRs can also recognize endogenous ligands and may play a role in mediating cardiomyocyte cell death and survival after non-infectious injury. TLRs could be a link between cardiovascular diseases and the immune system. Experimentally, there is good evidence that TLR activation contributes to development and progression of both acute cardiac injury and chronic heart failure. The role of TLRs in myocardial ischemia-reperfusion, remodeling, septic cardiomyoparthy, autoimmune- and viral myocarditis, anthracycline-induced cardiomyopathy and cardiac hypertrophy, in basic as well as clinical science are discussed. Evidence, mainly from animal experiments, indicates that TLRs contribute to all of the myocardial disease states reviewed in this paper. However, the relevance of TLRs as therapeutic targets remains to be defined as clinical data is sparse.

Several experimental studies have demonstrated protection against cardiac ischaemia–reperfusion injury achieved by pre-treatment with exogenous sphingosine-1-phosphate (S1P). We tested the hypothesis that pharmacological S1P receptor agonists improve recovery of function when applied with reperfusion. Isolated rat cardiomyocytes were stimulated with exogenous S1P, the selective S1P1 receptor agonist SEW2871, or the S1P1/3 receptor agonist FTY720. Western blot analysis was performed to analyse downstream signalling pathways. Ischaemia–reperfusion studies were conducted in rat cardiomyocytes, isolated Langendorff-perfused rat hearts, and in human myocardial muscle strip preparations to evaluate the effect of S1P receptor agonists on cell death and recovery of mechanical function. All S1P receptor agonists were able to activate Akt. This was associated with transactivation of the epidermal growth factor receptor. In isolated cardiomyocytes, selective stimulation of the S1P1 receptor by SEW2871 induced protection against cell death when administered either before or after ischaemia–reperfusion. In isolated rat hearts, treatment with FTY720 during reperfusion attenuated the rise in left ventricular end-diastolic pressure (LVEDP) and improved the recovery of left ventricular developed pressure without limiting infarct size. However, selective S1P1 receptor stimulation did not improve functional recovery but rather increased LVEDP. Additional experiments employing a human myocardial ischaemia–reperfusion model also demonstrated improved functional recovery induced by FTY720 treatment during reperfusion. Pharmacological S1P receptor agonists have distinct effects on ischaemia–reperfusion injury. Their efficacy when applied during reperfusion makes them potential candidates for pharmaceutical postconditioning therapy after cardiac ischaemia.