Journal of Pediatric Cardiology and Cardiac Surgery

Activation of the immune system is a well-described mechanism in HF patients. In the early nineties, upregulation of proinflammatory cytokines in patients with HF was first discovered.^4） In particular, in depth investigation on the role of TNF has discovered that TNF was upregulated in the plasma of humans with HF^4）; that animals with cardiac overexpression of TNF developed HF^5）; and that development of HF in animals can be blocked by TNF antagonism.^6） Despite these findings, the mechanism for immune system activation remained obscure because the etiology of HF, except that which is caused by viral myocarditis, is usually not infection. Subsequently, it was discovered that the initial immune activation happens through the innate immune system,^7） which is the first line of defense that is evolutionary conserved and recognizes specific pathogenic patterns through so-called pattern recognition receptors (PRRs). The PRRs can be activated not only by patterns from pathogens, but also by the so-called danger associated patterns (DAMPs). As the name implies, DAMPs are factors that indicate danger, such as when they are released from dying cells. One example could be the different heat shock proteins that are released from the cytoplasm of dying cells and can subsequently bind to toll-like receptors (TLRs). Therefore, the function of the innate immune system is not limited to infection; it can also be viewed as form of reaction to stress.

The different innate immune system receptors, like the TLRs, are expressed in the heart and are upregulated in patients with HF.^8） These receptors are of pathophysiologic importance; for example, activation of TLRs subsequently leads to signaling events in the heart. Furthermore, the cellular constituents of the innate immune system, like the neutrophils and macrophages, can be found in the heart upon injury and are necessary for adequate healing response. Macrophages infiltrate the heart within hours after an episode of myocardial infarction (MI) and are necessary for formation of granulation tissue and scar. Depletion of macrophages has been shown to lead to increased mortality and inadequate healing after MI.^9） These findings indicate that a proinflammatory response after MI is not essentially adverse, but is necessary for an appropriate healing response.

Once the innate immune system is activated, mechanisms to downregulate the proinflammatory response have to be launched since a continuous immune activation is maladaptive. Subsequently, the innate immune system activates the adaptive immune system, wherein T-cells have the capability to decrease the innate immune response.^10, 11） Indeed, we were able to show that after MI, the T-cells, which are the most important cellular parts of the adaptive immune response, were activated and increased in the lymph nodes than drain the heart. Therefore, T-cells are essential for adequate healing. For example, mice lacking CD4⁺ T-cells were observed to have healing defects after MI.^12） In addition, animals without T-cells were observed to have heightened innate immune response.

Regulatory T-cells (T_reg), in particular, seem to be important for the above-mentioned process, as demonstrated by the fact that T_reg depletion increased mortality, whereas activation of T_reg rescued the phenotype and decreased immune activation. These findings were potentially mediated by an interaction with macrophages. We demonstrated that activated T_reg can induce the development of M2 macrophages, which are important for adequate healing, a process that may be paracrine mediated (e.g., through TGF).^13）

In summary, after cardiac injury, such as MI, the initial response of the body is activation of the proinflammatory innate immune system. This is followed by activation of the adaptive immune system, which can, in turn, downregulate the proinflammatory response. This cycle of activation and deactivation of the immune response is necessary for adequate healing.

Activation of the immune system is not localized to the heart, but it can also be found in different organs. For example, upregulation of cytokines were demonstrated in the muscle of patients with HF.^14） In such cases, the source of the circulating cytokines is not only cardiac. Moreover, only a small portion of the monocytes/macrophages that are found in the heart after an MI are secreted from the heart itself; rather, these infiltrating inflammatory cells come from other sources, such as the spleen and the bone marrow.^15） Therefore, in HF, the immune system manages a complex interaction of different organs.

HF patients have a substantial number of comorbidities. We hypothesize that the presence of active comorbidities is, at least, partially mediated by inadequate activation of the immune system. For example, HF patients are often well-known to have muscle wasting, which is induced directly by proinflammatory cytokines.^16） The above-mentioned association between depression and HF could also be mediated by the immune system. The role of the immune system in the development of depression has already been proven and is independent of HF. In one of our studies on an experimental mice model of HF, activation of the immune system in the brain was shown to produce anxiety.^17） These data implied that interaction of the immune system with the other organs is likely to predispose individuals with HF to develop comorbidities.