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Heart failure with preserved ejection fraction (HFpEF) is a widespread syndrome with limited therapeutic options and poorly understood immune pathophysiology. Using a 2-hit preclinical model of cardiometabolic HFpEF that induces obesity and hypertension, we found that cardiac T cell infiltration and lymphoid expansion occurred concomitantly with cardiac pathology and that diastolic dysfunction, cardiomyocyte hypertrophy, and cardiac phospholamban phosphorylation were T cell dependent. Heart-infiltrating T cells were not restricted to cardiac antigens and were uniquely characterized by impaired activation of the inositol-requiring enzyme 1[alpha]/X-box-binding protein 1 (IRE1[alpha]/XBP1) arm of the unfolded protein response. Notably, selective ablation of XBP1 in T cells enhanced their persistence in the heart and lymphoid organs of mice with preclinical HFpEF. Furthermore, T cell IRE1[alpha]/XBP1 activation was restored after withdrawal of the 2 comorbidities inducing HFpEF, resulting in partial improvement of cardiac pathology. Our results demonstrated that diastolic dysfunction and cardiomyocyte hypertrophy in preclinical HFpEF were T cell dependent and that reversible dysregulation of the T cell IRE1[alpha]/ XBP1 axis was a T cell signature of HFpEF., Introduction Widely regarded as the greatest unmet need in cardiovascular medicine, heart failure with preserved ejection fraction (HFpEF) is a complex and heterogeneous syndrome accounting for roughly 50% of HF [...]

The immune and fibrotic responses have evolved to work in tandem to respond to pathogen clearance and promote tissue repair. However, excessive immune and fibrotic responses lead to chronic inflammation and fibrosis, respectively, both of which are key pathological drivers of organ pathophysiology. Fibroblasts and immune cells are central to these responses, and evidence of these two cell types communicating through soluble mediators or adopting functions from each other through direct contact is constantly emerging. Here, we review complex junctions of fibroblast-immune cell cross talk, such as immune cell modulation of fibroblast physiology and fibroblast acquisition of immune cell-like functions, as well as how these systems of communication contribute to organ pathophysiology. We review the concept of antigen presentation by fibroblasts among different organs with different regenerative capacities, and then focus on the inflammation-fibrosis axis in the heart in the complex syndrome of heart failure. We discuss the need to develop anti-inflammatory and antifibrotic therapies, so far unsuccessful to date, that target novel mechanisms that sit at the crossroads of the fibrotic and immune responses. [ABSTRACT FROM AUTHOR]

Sialomucin CD43 is a transmembrane protein differentially expressed in leukocytes that include innate and adaptive immune cells. Among a variety of cellular processes, CD43 participates in T cell adhesion to vascular endothelial cells and contributes to the progression of experimental autoimmunity. Sequential infiltration of myeloid cells and T cells in the heart is a hallmark of cardiac inflammation and heart failure (HF). Here, we report that CD43−/− mice have improved survival to HF induced by transverse aortic constriction (TAC). This enhanced survival is associated with improved systolic function, decreased cardiac fibrosis, and significantly reduced T cell cardiac infiltration in response to TAC compared to control wild-type (WT) mice. Lack of CD43 did not alter the number of myeloid cells in the heart, but resulted in decreased cardiac CXCL10 expression, a chemoattractant for T cells, and in a monocyte shift to anti-inflammatory macrophages in vitro. Collectively, these findings unveil a novel role for CD43 in adverse cardiac remodeling in pressure overload induced HF through modulation of cardiac T cell inflammation. [ABSTRACT FROM AUTHOR]

R2804 --> 10.3 --> Introduction: Heart Failure with Preserved Ejection Fraction (HFpEF) is an uncurable widespread syndrome characterized by impaired cardiac relaxation (diastolic function), preserved cardiac contractility (systolic function), and the concordance of several comorbidities, such as obesity and hypertension. While T cell inflammation is known to contribute to HF with reduced cardiac contractility (HF with reduced EF), whether T cell inflammation occurs in HFpEF remains elusive. Recently, downregulation of the unfolded protein response (UPR) in cardiomyocytes was identified as a cardiometabolic HFpEF‐unique molecular signature. Interestingly, downregulation of the UPR has been reported to improve T cell anti‐tumor inflammatory responses. We hypothesized T cells contribute to diastolic dysfunction in HFpEF following T cell UPR downregulation in response to metabolic and nitrosative stress. Methods: We modeled cardiometabolic HFpEF in male C57/Bl6 (WT), Nur77‐GFP mice, reporter mice for T cell antigen engagement, and T cell receptor‐a (Tcra−/−) mice using high‐fat diet (HFD) and L‐NAME‐supplemented drinking water to mimic obesity and hypertension, respectively. Mice fed standard chow (STD) were used as controls. Invasive hemodynamic analyses were used to measure cardiac function. Immune populations in the heart, mediastinal lymph nodes (MdLN), and spleen were characterized using flow cytometry. CD4+ T cells from MdLN and spleen were isolated using magnetic‐assisted cell sorting, and UPR gene expression was assessed using qPCR. Results: We observed significant increases in cardiac CD4+ T cells in WT mice fed HFD/L‐NAME, concordant with diastolic dysfunction and preserved EF, compared to STD mice. We found increased effector CD4+CD62LloCD44hiIFNγ+ T cells in spleens and MdLN isolated from WT HFD/L‐NAME mice compared to STD controls. Nur77‐GFP mice revealed no antigen recognition by CD4+ T cells in the heart following HFD/L‐NAME. Tcra−/−mice fed HFD/L‐NAME did not develop diastolic dysfunction or cardiomyocyte hypertrophy. Strikingly, qPCR analysis of splenic T cells of WT HFD/L‐NAME mice revealed significantly decreased expression of spliced X box‐binding protein 1 (XBP1s), compared to controls, with no significant changes in unspliced XBP1 or activating transcription factor 4 (ATF4). ATF6 and C/EBP homologous protein (CHOP) gene expression was also reduced compared to T cells from control mice. Conclusion: Our data demonstrate that diastolic dysfunction and cardiomyocyte hypertrophy are T cell dependent in preclinical cardiometabolic HFpEF and reveal downregulation of two branches of the T cell UPR as a potential novel mechanism that contributes to T cell inflammation in HFpEF. [ABSTRACT FROM AUTHOR]

R1600 --> Heart Failure with Preserved Ejection Fraction (HFpEF) is a prevalent and heterogenous cardiovascular syndrome characterized by impaired cardiac relaxation (diastolic function) with preserved contractility (systolic function), generally as a result of the presentation of several comorbidities. Despite its high and increasing prevalence, there are no therapies available to directly treat or cure HFpEF. Obesity and hypertension, the two dominant risk factors of HFpEF, have been independently associated with T cell inflammation, however, the inflammatory mechanisms driving HFpEF by these two comorbidities together, and T cell contributions, remain elusive. We hypothesized that T cell immune responses and cardiotropism promote diastolic dysfunction and HFpEF. C57/BL6 (wild‐type, WT) and T cell receptor alpha‐deficient (Tcra‐/‐) male mice were fed a high fat diet (HFD) with L‐NAME‐treated water (0.5 g/L) for 5 weeks to mimic obesity and hypertension, respectively, a recently established model of HFpEF. Age‐ and sex‐matched mice were fed standard chow (STD) as controls. Cardiac function was assessed using hemodynamic analyses, and plasma was collected to evaluate systemic levels of pro‐ and anti‐inflammatory cytokines. The heart, mediastinal lymph nodes, inguinal lymph nodes, and spleen were harvested to characterize cardiac and systemic immune cell populations by flow cytometry. Cardiac tissue was also collected for gene expression analysis by qPCR of markers of adverse cardiac remodeling and HFpEF. WT mice fed HFD/L‐NAME had increased cardiac CD11b+ cell abundance and increased CD4+ T cell infiltration compared to controls. Furthermore, in contrast to control mice, HFD/L‐NAME‐treated mice had an increased abundance of CD44hi/CD62Llo effector T cells in the mediastinal lymph nodes and spleen. This was associated with increased passive chamber stiffness (end‐diastolic pressure volume relationship, EDPVR) and decreased expression of the unfolded protein response (UPR) proteins spliced form of X‐box binding protein 1 and binding immunoglobulin protein (XBP1s and BIP), hallmarks of HFpEF. Additionally, HFD/L‐NAME induced a 2.5‐fold increase in plasma levels of IL‐17, without altering the levels of interferon‐gamma or IL‐2. Strikingly, Tcra‐/‐ mice did not develop diastolic dysfunction when fed HFD/L‐NAME, supporting a causal role of T cells in HFpEF pathology. We conclude that T cell activation and recruitment to the heart contribute to diastolic dysfunction in HFpEF. Further studies will interrogate the mechanisms by which combined risk factors prime T cells for cardiac infiltration and effector function in the heart to induce and drive HFpEF. [ABSTRACT FROM AUTHOR]

R3672 --> Gut dysbiosis has recently been associated with the severity of the complex syndrome of heart failure (HF) in patients. The mechanisms of action involving gut microbes and immune responses are starting to be characterized in experimental models of HF. More than 50% of HF patients present with HF with preserved ejection fraction (HFpEF), characterized by impaired relaxation (diastolic function) and preserved contractility (systolic function), which do not respond to any of the available treatments for HF. Obesity and hypertension are major risk factors for HFpEF, and have been independently associated with gut dysbiosis, and modulation of the microbiota in experimental models of these risk factors has revealed mechanistic insights. However, whether and how the microbiota contributes to HFpEF is unknown. Recently, a novel mouse model of HFpEF induced by a combination of high‐fat diet (HFD) and L‐NAME, to mimic obesity and hypertension, respectively. We hypothesize that specific microbiota and derived metabolites, are altered in HFpEF and contribute to systemic inflammation and diastolic dysfunction. C57/BL6 WT mice were fed HFD and L‐NAME (H/L) to induce HFpEF. We used invasive hemodynamics to determine diastolic and systolic function, and 16S rRNA sequencing in fecal samples to characterize gut bacteria and perform metabolic pathway analysis. The heart, the intestine and plasma were collected and evaluated for indicators of cardiac remodeling and gut permeability using flow cytometry and qPCR. As expected, H/L triggered diastolic dysfunction at 5 weeks. At this time, H/L intestinal epithelial cells (iECs) showed downregulation in gene expression of the junctional markers cadherin‐1, ZO‐1 and occludin, suggesting the induction of leaky gut. We also found increased concentration of proinflammatory molecules in serum (e.g. IL‐6, IL‐17 and CXCL1). Strikingly, H/L treatment resulted in gut dysbiosis in H/L mice compared to those that received standard diet (STD). The main phyla analysis showed a higher Firmicutes/Bacteroidetes ratio in H/L, which has been associated with obesity, compared to STD. At the family level, Ruminococcaceae, also linked to obesity in humans, showed elevated relative abundance in H/L group compared to STD, and Rikenellaceae and Christensenellaceae significantly decreased their numbers. Interestingly, gut bacteria from H/L‐treated mice revealed an enrichment of metabolic pathways related to synthesis and degradation of fatty acids. We studied the gene expression of the main short‐chain fatty acid (SCFA) receptors, associated with improvement in cardiovascular health. FFAR2 (GPR43) expression did not change in the heart neither the gut, but strikingly, FFAR3 (GPR41) expression was significantly upregulated in the heart in the H/L group compared to STD, but not in iECs. In conclusion, we demonstrated that a novel mouse model of HFpEF induced gut dysbiosis and alterations in gut permeability, and identified a dysregulation of fatty acid synthesis and degradation metabolic pathways. Mechanistic studies are needed to see the role of fatty acids and its receptors in cardiac inflammation during diastolic dysfunction. [ABSTRACT FROM AUTHOR]

The fibrotic response has evolutionary worked in tandem with the inflammatory response to facilitate healing following injury or tissue destruction as a result of pathogen clearance. However, excessive inflammation and fibrosis are key pathological drivers of organ tissue damage. Moreover, fibrosis can occur in several conditions associated with chronic inflammation that are not directly caused by overt tissue injury or infection. In the heart, in particular, fibrotic adverse cardiac remodeling is a key pathological driver of cardiac dysfunction in heart failure. Cardiac fibroblast activation and immune cell activation are two mechanistic domains necessary for fibrotic remodeling in the heart, and, independently, their contributions to cardiac fibrosis and cardiac inflammation have been studied and reviewed thoroughly. The interdependence of these two processes, and how their cellular components modulate each other's actions in response to different cardiac insults, is only recently emerging. Here, we review recent literature in cardiac fibrosis and inflammation and discuss the mechanisms involved in the fibrosis-inflammation axis in the context of specific cardiac stresses, such as myocardial ischemia, and in nonischemic heart conditions. We discuss how the search for anti-inflammatory and anti-fibrotic therapies, so far unsuccessful to date, needs to be based on our understanding of the interdependence of immune cell and fibroblast activities. We highlight that in addition to the extensively reviewed role of immune cells modulating fibroblast function, cardiac fibroblasts are central participants in inflammation that may acquire immune like cell functions. Lastly, we review the gut-heart axis as an example of a novel perspective that may contribute to our understanding of how immune and fibrotic modulation may be indirectly modulated as a potential area for therapeutic research. • Cardiac fibroblast activation and immune cell activation are two mechanistic domains necessary for fibrotic remodeling in the heart. We discuss their interdependence in modulating each other's actions in response to different cardiac insults. • We highlight the pro-fibrotic role of immune cells as well as the less explored pro-inflammatory role of cardiac fibroblasts, which adopt "immune cell like" functions that have an impact on cardiac and immune cells, and discuss therapeutic opportunities that modulate these responses. • We review the gut-heart axis as an example of a novel perspective that may contribute to our understanding of how immunity and fibrosis may be indirectly modulated as a potential area for therapeutic research. [ABSTRACT FROM AUTHOR]

Background: Cardiac inflammation in heart failure is characterized by the presence of damage-associated molecular patterns, myeloid cells, and T cells. Cardiac damage-associated molecular patterns provide continuous proinflammatory signals to myeloid cells through TLRs (toll-like receptors) that converge onto the adaptor protein MyD88 (myeloid differentiation response 88). These induce activation into efficient antigen-presenting cells that activate T cells through their TCR (T-cell receptor). T-cell activation results in cardiotropism, cardiac fibroblast transformation, and maladaptive cardiac remodeling. T cells rely on TCR signaling for effector function and survival, and while they express MyD88 and damage-associated molecular pattern receptors, their role in T-cell activation and cardiac inflammation is unknown., Methods: We performed transverse aortic constriction in mice lacking MyD88 in T cells and analyzed remodeling, systolic function, survival, and T-cell activation. We profiled wild type versus Myd88 -/- mouse T cells at the transcript and protein level and performed several functional assays., Results: Analysis of single-cell RNA-sequencing data sets revealed that MyD88 is expressed in mouse and human cardiac T cells. MyD88 deletion in T cells resulted in increased levels of cardiac T-cell infiltration and fibrosis in response to transverse aortic constriction. We discovered that TCR-activated Myd88 -/- T cells had increased proinflammatory signaling at the transcript and protein level compared with wild type, resulting in increased T-cell effector functions such as adhesion, migration across endothelial cells, and activation of cardiac fibroblast. Mechanistically, we found that MyD88 modulates T-cell activation and survival through TCR-dependent rather than TLR-dependent signaling., Conclusions: Our results outline a novel intrinsic role for MyD88 in limiting T-cell activation that is central to tune down cardiac inflammation during cardiac adaptation to stress., Competing Interests: Disclosures None.

The stimulator of IFN genes (STING) protein senses cyclic dinucleotides released in response to double-stranded DNA and functions as an adaptor molecule for type I IFN (IFNI) signaling by activating IFNI-stimulated genes (ISG). We found impaired T cell infiltration into the peritoneum in response to TNF-α in global and EC-specific STING-/- mice and discovered that T cell transendothelial migration (TEM) across mouse and human endothelial cells (EC) deficient in STING was strikingly reduced compared with control EC, whereas T cell adhesion was not impaired. STING-/- T cells showed no defect in TEM or adhesion to EC, or immobilized endothelial cell-expressed molecules ICAM1 and VCAM1, compared with WT T cells. Mechanistically, CXCL10, an ISG and a chemoattractant for T cells, was dramatically reduced in TNF-α-stimulated STING-/- EC, and genetic loss or pharmacologic antagonisms of IFNI receptor (IFNAR) pathway reduced T cell TEM. Our data demonstrate a central role for EC-STING during T cell TEM that is dependent on the ISG CXCL10 and on IFNI/IFNAR signaling.

Despite the existing association of gut dysbiosis and T cell inflammation in heart failure (HF), whether and how gut microbes contribute to T cell immune responses, cardiac fibrosis and dysfunction in HF remains largely unexplored. Our objective was to investigate whether gut dysbiosis is induced by cardiac pressure overload, and its effect in T cell activation, adverse cardiac remodeling, and cardiac dysfunction. We used 16S rRNA sequencing of fecal samples and discovered that cardiac pressure overload-induced by transverse aortic constriction (TAC) results in gut dysbiosis, characterized by a reduction of tryptophan and short-chain fatty acids producing bacteria in WT mice, but not in T cell-deficient mice ( Tcra -/- ) mice. These changes did not result in T cell activation in the gut or gut barrier disruption. Strikingly, microbiota depletion in WT mice resulted in decreased heart T cell infiltration, decreased cardiac fibrosis, and protection from systolic dysfunction in response to TAC. Spontaneous reconstitution of the microbiota partially reversed these effects. We observed decreased cardiac expression of the Aryl hydrocarbon receptor (AhR) and enzymes associated with tryptophan metabolism in WT mice, but not in Tcra -/- mice, or in mice depleted of the microbiota. These findings demonstrate that cardiac pressure overload induced gut dysbiosis and T cell immune responses contribute to adverse cardiac remodeling, and identify the potential contribution of tryptophan metabolites and the AhR to protection from adverse cardiac remodeling and systolic dysfunction in HF.