Innate Immune Cells – Heart Failure
A new study published in the journal Circulation Research is perhaps the first to show changes of the innate cells network and traffic in ischemic heart failure.
Heart failure (HF) remains a major health issue, and evidence accumulated over the last decade has established immune activation or inflammation as a major pathogenic factor in chronic HF.
However, anti- inflammatory strategies have produced modest results or no therapeutic benefit and to date, no large-scale immunomodulatory therapies have been successfully translated to clinical practice. This also includes clinical trials targeting inflammatory mediators such as tumor necrosis factor (TNF)-α, a major pro-inflammatory ‘hormone’ or cytokine (cf. U. Hofmann & Frantz S., Basic Res Cardiol, 2013; 108:356).
So far, the main research focus in HF has been directed toward pro-inflammatory mediators such as cytokines.
Lesser attention has been given to the role of immune and inflammatory cell networks in this condition. It is known that in acute myocardial infarction, monocytes and dendritic cells (DCs) are involved in early post-infarction remodeling.
Whether and how the myelomonocytic network between lymphoid tissue and the heart is altered in chronic HF still remains undefined.
Now the study by Mohamed Ismahil and colleagues, from the Department of Medicine, University of Alabama at Birmingham VAMC, Birmingham, AL in Circulation Research demonstrates extreme changes of the mononuclear phagocyte network in ischemic HF that include the failing heart, spleen, peripheral blood, and bone marrow. Moreover, it shows that mononuclear splenocytes in chronic HF are highly activated and traffic to the heart to induce immune cell-mediated injury.
The authors suggest that activation of innate immune cells may represent a major pathogenic mechanism in HF, where the splenic microenvironment may play a major role. According to the authors the progression of pathological cardiac remodeling is presumably and partially dependent on autoimmune heart damage induced by activated mononuclear phagocytes.
Source: Circ Res, 2014, 114:266. doi: 10.1161/CIRCRESAHA.113.301720. Epub 2013 Nov 1.
Read More: Circulation Research
Updates
A 2017 study by Bindiya Patel et al. tested the hypothesis that cardiac and splenic mononuclear phagocytes (MPs), i.e., monocytes, macrophages and dendritic cells (DCs) are required for the progression of remodeling in pressure-overload heart failure (HF), and that MP depletion would ameliorate remodeling.
Background: Pathological left ventricular (LV) remodeling is a hallmark of chronic pressure-overload. With the imposition of augmented pressure load, the LV initially remodels with concentric hypertrophy and preserved systolic function, but over time transitions to a phenotype of dilated cardiomyopathy and systolic heart failure (HF). The development of pressure-overload HF is accompanied by structural and metabolic changes within the myocardium, including cardiomyocyte hypertrophy, interstitial fibrosis, inflammation, and a switch toward a fetal-like metabolic profile.
The authors have shown that there is a phasic expansion of circulating LyC6hi monocytes, and pro-inflammatory CD206− macrophages and classical DCs in the heart, during mechanical pressure-overload. Pro-inflammatory monocyte and macrophage expansion occurs during early remodeling, prior to the development of significant hypertrophy and systolic dysfunction, and resolves late during chronic HF. In contrast, classical DC expansion is biphasic occurring both early, prior to systolic dysfunction, as well as late, during established HF.
Second, cardiac MP expansion occurs without significant expansion of DCs in the blood, or Ly6C+ monocytes and DCs in the spleen. Third, chronic depletion of MPs initiated at the compensated hypertrophy stage did not alter the subsequent course of LV remodeling and late HF. Fourth, the combination of adoptive transfer and splenectomy studies established that, unlike in chronic ischemic HF, a pathological cardiosplenic axis does not play a significant role in pressure-overload HF.
Taken together, authors concluded that mononuclear phagocytes are dispensable for the progression of pressure-overload HF, once significant cardiac hypertrophy and normalization of circulating pro-inflammatory monocytes are apparent.
A 2018 review by Farhan Shahid, Gregory Y H Lip and Eduard Shantsila aimed to illustrate the role of monocytes and their associated inflammatory cells in the pathogenesis of cardiac fibrosis. Particular focus was given to monocyte subsets and their associated immune response cells in the inflammation process of HF and AF.
Triggers for monocyte activation and subsequent function. HSP indicates xxx; LPS, lipopolysaccharide; LV, left ventricular; ROS, reactive oxygen species.
The authors argued that the beneficial effects of monocytes include their contribution to cardiac remodeling in response to physiological and pathological changes in hemodynamics, elimination of pathogens, involvement in apoptosis, and phagocytosis of necrotic tissues. However, excessive inflammatory response to cardiac insult can be harmful to the human body and can lead to cardiac fibrosis and heart failure.
Of note, an acute ischemic injury is accompanied by conversion from M1 to M2 macrophages, a type of macrophage known to provide a profibrotic inflammatory environment. The authors discussed that despite the relative scarcity of the data, it is likely that this monocyte/macrophage‐driven inflammatory environment is largely responsible for the fibrotic changes in preserved ejection fraction (HFpEF). Their increase number causes an increase in collagen deposition and conversion of cardiac fibroblasts to myofibroblasts.
Furthermore, the question remains of how important atrial fibrosis is as a causative factor for AF in humans. Most animal models show that atrial dilation is accompanied by both atrial fibrosis and conduction disturbances, although conduction disturbances could also be observed in the absence of atrial fibrosis.
The role of ventricular fibrosis in AF is less established. Patients with AF have more‐marked ventricular fibrosis than those with sinus rhythm. Although atrial and ventricular fibrosis are likely to share a common mechanism, there are much more‐limited findings of profibrotic gene expression in ventricular fibrosis in comparison with the atrium. TGF‐β seems to play a major role in ventricular fibrosis in AF, but further data are needed to establish the mechanisms that trigger its expression in the myocardium and the role of monocytes and macrophages as a source of TGF‐β in the heart.
Another 2018 review by Sumanth D Prabhu summarized the evidence that ischemic cardiomyopathy is a state of global immune activation, with robust expansion of macrophages, dendritic cells (DCs), and CD4+ T cells. Such activation is part of a proinflammatory and tissue-injurious cardiosplenic axis that promotes adverse LV remodeling. Hence, directly targeting specific leukocyte populations may represent a more fruitful approach to therapeutic immunomodulation in HF.
The author concluded that chronic inflammation in ischemic cardiomyopathy is characterized by profound remodeling of innate (monocyte, macrophages, and DCs) and adaptive (CD4+ and CD8+ T cells) immune cell networks in the heart, blood, and lymphoid organs. The spleen appears to be a particularly important site of immune activation, with cellular and tissue level changes that are consistent with augmented antigen processing and the triggering of immune memory.
A detrimental cardiosplenic axis develops in chronic ischemic HF with activated splenocytes homing to the heart and primed to induce tissue injury; this axis is both necessary and sufficient for the progression of adverse remodeling. Hence, ischemic cardiomyopathy is in part an immune cell-mediated cardiomyopathy.
Therefore, if confirmed in humans, targeting specific immune cell populations (e.g., CD4+ T cells), or the antigens responsible for their activation, may be a better approach to therapeutic immunomodulation in HF.
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