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The heart, the first organ to develop in the embryo, undergoes complex morphogenesis that when defective results in congenital heart disease (CHD). With current therapies, more than 90% of patients with CHD survive into adulthood, but many suffer premature death from heart failure and non-cardiac causes 1 . Here, to gain insight into this disease progression, we performed single-nucleus RNA sequencing on 157,273 nuclei from control hearts and hearts from patients with CHD, including those with hypoplastic left heart syndrome (HLHS) and tetralogy of Fallot, two common forms of cyanotic CHD lesions, as well as dilated and hypertrophic cardiomyopathies. We observed CHD-specific cell states in cardiomyocytes, which showed evidence of insulin resistance and increased expression of genes associated with FOXO signalling and CRIM1 . Cardiac fibroblasts in HLHS were enriched in a low-Hippo and high-YAP cell state characteristic of activated cardiac fibroblasts. Imaging mass cytometry uncovered a spatially resolved perivascular microenvironment consistent with an immunodeficient state in CHD. Peripheral immune cell profiling suggested deficient monocytic immunity in CHD, in agreement with the predilection in CHD to infection and cancer 2 . Our comprehensive phenotyping of CHD provides a roadmap towards future personalized treatments for CHD. Single-nuclear transcriptomic and proteomic analyses identify molecular characteristics shared by multiple classes of congenital heart disease, including phenotypes associated with insulin resistance.

Myocarditis can develop into inflammatory cardiomyopathy through chronic stimulation of myosin heavy chain 6–specific T helper (TH)1 and TH17 cells. However, mechanisms governing the cardiotoxicity programming of heart-specific T cells have remained elusive. Using a mouse model of spontaneous autoimmune myocarditis, we show that progression of myocarditis to lethal heart disease depends on cardiac myosin–specific TH17 cells imprinted in the intestine by a commensal Bacteroides species peptide mimic. Both the successful prevention of lethal disease in mice by antibiotic therapy and the significantly elevated Bacteroides-specific CD4⁺ T cell and B cell responses observed in human myocarditis patients suggest that mimic peptides from commensal bacteria can promote inflammatory cardiomyopathy in genetically susceptible individuals. The ability to restrain cardiotoxic T cells through manipulation of the microbiome thereby transforms inflammatory cardiomyopathy into a targetable disease.

Plasminogen activator inhibitor-1 (PAI-1) has a cardioprotective function in mice by repressing cardiac fibrosis through TGF-β and plasminogen-mediated pathways. In addition it is known to be involved in the recruitment and polarization of monocytes/macrophages towards a M2 phenotype in cancer. Here, we investigated the expression of PAI-1 in human dilated cardiomyopathy (DCM) and inflammatory dilated cardiomyopathy (DCMi) and its effect on cardiac fibrosis and macrophage polarization. We retrospectively analyzed endomyocardial biopsies (EMBs) of patients with DCM or DCMi for PAI-1 expression by immunohistochemistry. Furthermore, EMBs were evaluated for the content of fibrotic tissue, number of activated myofibroblasts, TGF-β expression, as well as for M1 and M2 macrophages. Patients with high-grade DCMi (DCMi-high, CD3+ lymphocytes > 30 cells/mm2) had significantly increased PAI-1 levels compared to DCM and low-grade DCMi patients (DCMi-low, CD3+ lymphocytes = 14–30 cells/mm2) (15.5 ± 0.4% vs. 1.0 ± 0.1% and 4.0 ± 0.1%, p ≤ 0.001). Elevated PAI-1 expression in DCMi-high subjects was associated with a diminished degree of cardiac fibrosis, decreased levels of TGF-β and reduced number of myofibroblasts. In addition, DCMi-high patients revealed an increased proportion of non-classical M2 macrophages towards classical M1 macrophages, indicating M2 macrophage-favoring properties of PAI-1 in inflammatory cardiomyopathies. Our findings give evidence that elevated expression of cardiac PAI-1 in subjects with high-grade DCMi suppresses fibrosis by inhibiting TGF-β and myofibroblast activation. Moreover, our data indicate that PAI-1 is involved in the polarization of M2 macrophages in the heart. Thus, PAI-1 could serve as a potential prognostic biomarker and as a possible therapeutic target in inflammatory cardiomyopathies.

Background The heterogeneous subtypes in dilated cardiomyopathy (DCM) are poorly characterized, thus posing challenges to risk stratification. This study aimed to establish a DCM subtype framework based on metabolic and immunoinflammatory factors. Methods DCM subtypes were identified using unsupervised clustering based on the expression patterns of metabolism-related genes in the left ventricular myocardium of 89 DCM patients. By comparing metabolic pathways, clinical characteristics, immune cell infiltration, inflammatory responses, and immunotherapy efficacy between the subtypes, key metabolic genes were identified through correlation analysis and validated at both bulk and single-cell levels. The alterations in gene expression were verified using the DCM mouse model. Molecular docking was performed to assess the binding affinity between the target protein and potential therapeutic small molecules. Results Two subtypes were identified; subtypes 1 and 2 were characterized by increased amino acid metabolism and decreased glucose and energy-related metabolisms, respectively. Subtype 2 displayed worse left ventricular structure and function, higher levels of immune and inflammatory activity, and a more favorable response to immunotherapy. The integrative analysis identified DHRS7C as a key regulator of glucose/energy metabolism; its expression was inversely correlated with left ventricular impairment. The DCM mice showed downregulated DHRS7C expression, which positively correlated with cardiac dysfunction. Additionally, molecular docking identified 17beta-estradiol as a potential therapeutic agent targeting DHRS7C. Conclusions This study suggested two heterogeneous DCM subtypes with different metabolic and immunoinflammatory profiles. Furthermore, DHRS7C was inversely correlated with DCM indices and could be targeted by 17beta-estradiol. Graphical abstract

Recent multiomics advancements have improved our understanding of immune dysregulation in dilated cardiomyopathy (DCM). However, specific immune cell subsets and their regulatory genes are still ambiguous. This study aimed to explore immune cell imbalances and regulatory genes in DCM, discover diagnostic biomarkers, and identify potential therapeutic targets. Immune cell infiltration in DCM patients was quantified via deconvolution algorithms and single-cell RNA sequencing. Flow cytometry validation in 40 DCM patients and 40 healthy controls confirmed a notable increase in CD4+ effector memory T cells (CD4+ TEM cells) in DCM patients. Differential expression analysis of the GSE101585 dataset revealed 1783 genes. Weighted gene coexpression network analysis (WGCNA) identified a core immune-regulatory gene set, and protein–protein interaction (PPI) analysis highlighted 36 hub genes. Machine learning cross-validation identified four diagnostic biomarkers (LRRTM4, PTPN22, FAM175B, and PROM2) whose transcriptional changes had been validated by qPCR. Among these genes, PTPN22 was strongly correlated with CD4+ TEM cell abundance. Additionally, DSigDB analysis predicted 87 potential therapeutic drugs, with PTPN22 being the target of the most drugs. This study reveals a CD4+ T cell subset-centered immunoregulatory network in DCM, identifying novel diagnostic biomarkers and druggable targets to guide precision immunomodulatory strategies for DCM management.

Recent evidence indicates that toll-like receptor (TLR) 2 and 4 are involved in the pathogenesis of dilated cardiomyopathy (DCM), but the exact mechanisms of their actions have not been elucidated. We explored the therapeutic potential of blocking TLRs in mice with established cardiomyopathy. Cardiomyopathy was generated by a single intraperitoneal injection of doxorubicin (10 mg/kg). Two weeks later, the mice were treated with TLR2 or TLR4 neutralizing antibody. Blocking TLR2, but not TLR4, activity not only reduced mortality, but also attenuated doxorubicin-induced cardiac dysfunction by 20% and inhibited myocardial fibrosis. To determine the differential effects of blocking TLR2 and TLR4 in chronic cardiomyopathy, mice were injected with doxorubicin (3.5 mg/kg) once a week for 8 weeks, followed by treatment with TLR2 or TLR4 neutralizing antibody for 40 days. Blocking TLR2 activity blunted cardiac dysfunction by 13% and inhibited cardiac fibrosis, which was associated with a significant suppression of myocardial inflammation. The underlying mechanism involved interrupting the interaction of TLR2 with its endogenous ligands, resulting in attenuation of inflammation and fibrosis. In contrast, blocking TLR4 exacerbated cardiac dysfunction and fibrosis by amplifying inflammation and suppressing autophagy. Our studies demonstrate that TLR2 and TLR4 play distinct roles in the progression of doxorubicin-induced DCM. TLR4 activity is crucial for the resolution of inflammation and cardiac fibrosis, while blocking TLR2 activity has therapeutic potential for the treatment of DCM.

Epidemiological evidence indicates that up to 50% of systemic lupus erythematosus (SLE) patients exhibit cardiac involvement, suggesting a potential strong association between SLE and dilated cardiomyopathy (DCM). This study aims to identify SLE-related genes that may contribute to DCM development and to discover potential biomarkers for early DCM diagnosis in SLE patients. We obtained expression profile datasets for dilated cardiomyopathy DCM and SLE from the Gene Expression Omnibus (GEO) database. Through differential expression analysis and weighted gene co-expression network analysis (WGCNA), we screened for candidate biomarkers shared between DCM and SLE and constructed a diagnostic nomogram. The diagnostic performance and effectiveness of the nomogram were evaluated using external datasets and qPCR. Additionally, we performed single-gene set enrichment analysis (GSEA) on key genes to elucidate their potential roles in SLE-related DCM. Finally, we applied the CIBERSORT algorithm to assess immune cell infiltration in both DCM and SLE patients. Through DEG and WGCNA in the DCM and SLE datasets, we identified a total of 141 key module genes and 24 commonly expressed differentially expressed genes. Enrichment analysis revealed that these 24 genes were primarily involved in inflammation, cell apoptosis, and immune regulation. Through machine learning algorithms and dataset validation, we further identified the HERC6 and IFI44L genes as important diagnostic markers for SLE-related DCM. Experimental validation supports the key role of HERC6, IFI44L, and RSAD2 in SLE-related cardiac dysfunction. Additionally, we developed a nomogram for DCM based on these two genes, and the results showed that both genes exhibited AUC values greater than 0.84. Simultaneously, single-GSEA and immune infiltration analysis indicated immune dysfunction in both DCM and SLE, with both HERC6 and IFI44L significantly associated with immune cell infiltration. Furthermore, connectivity map (cMAP) analysis identified α-linolenic acid as a potential therapeutic agent for treating DCM. Our study identifies HERC6 and IFI44L as diagnostic markers for DCM in SLE and suggests α-linolenic acid as a potential therapeutic agent.

Previous studies have suggested the involvement of CD4 + T lymphocytes in cardiac remodelling. T-bet can direct Th1 lineage commitment. This study aimed to investigate the functional significance of T-bet in cardiac remodelling induced by pressure overload using T-bet global knockout rats. Increased T-bet levels were observed in rodent and human hypertrophied hearts. T-bet deficiency resulted in a less severe hypertrophic phenotype in rats. CD4 + T-lymphocyte reconstitution in T-bet−/− rats resulted in aggravated cardiac remodelling. T-cell homing molecule expression and cytokine secretion were altered in T-bet-deficient rat hearts. Administration of exogenous interferon-γ (IFN-γ) offset T-bet deficiency-mediated cardioprotection. Cardiomyocytes cultured in T-bet−/− CD4 + T-cell-conditioned media showed a reduced hypertrophic response after hypertrophic stimuli, which was abolished by an IFN-γ-neutralizing antibody. Taken together, our findings show that T-bet deficiency attenuates pressure overload-induced cardiac remodelling in rats. Specifically, targeting T-bet in T cells may be of great importance for the treatment of pathological cardiac remodelling and heart failure.

The immune system plays a crucial role in cardiac homeostasis and disease, and the innate and adaptive immune systems can be beneficial or detrimental in cardiac injury. The pleiotropic proinflammatory cytokine macrophage migration inhibitory factor (MIF) is involved in the pathogenesis of many human disease conditions, including heart diseases and inflammatory cardiomyopathies. Inflammatory cardiomyopathies are frequently observed after microbial infection but can also be caused by systemic immune-mediated diseases, drugs, and toxic substances. Immune cells and MIF are implicated in many of these conditions and may affect progression of inflammatory cardiomyopathy (ICM) to myocardial remodeling and dilated cardiomyopathy (DCM). The potential for targeting MIF therapeutically in patients with inflammatory diseases is an active area of investigation. Here we review the current literature supporting the role(s) of MIF in ICM and cardiac dysfunction. We posit that future research to further elucidate the underlying functions of MIF in cardiac pathologies is warranted.

Cardiosphere‐derived cells (CDCs) have been shown to reduce scar size and increase viable myocardium in human patients with mild/moderate myocardial infarction. Studies in rodent models suggest that CDC therapy may confer therapeutic benefits in patients with non‐ischaemic dilated cardiomyopathy (DCM). We sought to determine the safety and efficacy of allogeneic CDC in a large animal (canine) model of spontaneous DCM. Canine CDCs (cCDCs) were grown from a donor dog heart. Similar to human CDCs, cCDCs express CD105 and are slightly positive for c‐kit and CD90. Thirty million of allogeneic cCDCs was infused into the coronary vessels of Doberman pinscher dogs with spontaneous DCM. Adverse events were closely monitored, and cardiac functions were measured by echocardiography. No adverse events occurred during and after cell infusion. Histology on dog hearts (after natural death) revealed no sign of immune rejection from the transplanted cells.