Aims Takotsubo syndrome (TTS) is an acute heart failure, typically triggered by high adrenaline during physical or emotional stress. It is distinguished from myocardial infarction (MI) by a characteristic pattern of ventricular basal hypercontractility with hypokinesis of apical segments, and absence of coronary occlusion. We aimed to understand whether recently discovered circulating biomarkers miR-16 and miR-26a, which differentiate TTS from MI at presentation, were mechanistically involved in the pathophysiology of TTS. Methods and results miR-16 and miR-26a were co-overexpressed in rats with AAV and TTS induced with an adrenaline bolus. Untreated isolated rat cardiomyocytes were transfected with pre-/anti-miRs and functionally assessed. Ventricular basal hypercontraction and apical depression were accentuated in miR-transfected animals after induction of TTS. In vitro miR-16 and/or miR-26a overexpression in isolated apical (but not basal) cardiomyocytes produced strong depression of contraction, with loss of adrenaline sensitivity. They also enhanced the initial positive inotropic effect of adrenaline in basal cells. Decreased contractility after TTS-miRs was reproduced in non-failing human apical cardiomyocytes. Bioinformatic profiling of miR targets, followed by expression assays and functional experiments, identified reductions of CACNB1 (L-type calcium channel Cavβ subunit), RGS4 (regulator of G-protein signalling 4) and G-protein subunit Gβ (GNB1) as underlying these effects. Conclusion miR-16 and miR-26a sensitise the heart to TTS-like changes produced by adrenaline. Since these miRs have been associated with anxiety and depression, they could provide a mechanism whereby priming of the heart by previous stress causes an increased likelihood of TTS in the future. Translational perspective TTS-associated miRs have the potential to be active players predisposing to TTS. Feasibly, their measurement in recovered TTS patients during subsequent periods of stress could be used to predict likelihood of recurrence, a significant risk in this population, and allow preventative action. Since they have been reported as raised in anxiety and depression, they could be part of a priming mechanism where chronic stress predisposes to an acute episode. Understanding the mechanistic basis for the sensitisation may also allow design of other prophylactic pharmacological therapies, including the pre/anti-miR constructs which are now starting to reach the clinic.

Although more than 90% of children born with congenital heart disease (CHD) survive into adulthood, patients face significantly higher and premature morbidity and mortality. Heart failure as well as non-cardiac comorbidities represent a striking and life-limiting problem with need for new treatment options. Systemic chronic inflammation and immune activation have been identified as crucial drivers of disease causes and progression in various cardiovascular disorders and are promising therapeutic targets. Accumulating evidence indicates an inflammatory state and immune alterations in children and adults with CHD. In this review, we highlight the implications of chronic inflammation, immunity, and immune senescence in CHD. In this context, we summarize the impact of infant open-heart surgery with subsequent thymectomy on the immune system later in life and discuss the potential role of comorbidities and underlying genetic alterations. How an altered immunity and chronic inflammation in CHD influence patient outcomes facing SARS-CoV-2 infection is unclear, but requires special attention, as CHD could represent a population particularly at risk during the COVID-19 pandemic. Concluding remarks address possible clinical implications of immune changes in CHD and consider future immunomodulatory therapies.

Inflammation, fibrosis and metabolic stress critically promote heart failure with preserved ejection fraction (HFpEF). Exposure to high-fat diet and nitric oxide synthase inhibitor N[w]-nitro-l-arginine methyl ester (L-NAME) recapitulate features of HFpEF in mice. To identify disease specific traits during adverse remodeling, we profiled interstitial cells in early murine HFpEF using single-cell RNAseq (scRNAseq). Diastolic dysfunction and perivascular fibrosis were accompanied by an activation of cardiac fibroblast and macrophage subsets. Integration of fibroblasts from HFpEF with two murine models for heart failure with reduced ejection fraction (HFrEF) identified a catalog of conserved fibroblast phenotypes across mouse models. Moreover, HFpEF specific characteristics included induced metabolic, hypoxic and inflammatory transcription factors and pathways, including enhanced expression of Angiopoietin-like 4 next to basement membrane compounds. Fibroblast activation was further dissected into transcriptional and compositional shifts and thereby highly responsive cell states for each HF model were identified. In contrast to HFrEF, where myofibroblast and matrifibrocyte activation were crucial features, we found that these cell-states played a subsidiary role in early HFpEF. These disease-specific fibroblast signatures were corroborated in human myocardial bulk transcriptomes. Furthermore, we found an expansion of pro-inflammatory Ly6Chigh macrophages in HFpEF, and we identified a potential cross-talk between macrophages and fibroblasts via SPP1 and TNFα. Finally, a marker of murine HFpEF fibroblast activation, Angiopoietin-like 4, was elevated in plasma samples of HFpEF patients and associated with disease severity. Taken together, our study provides a comprehensive characterization of molecular fibroblast and macrophage activation patterns in murine HFpEF, as well as the identification of a novel biomarker for disease progression in patients.

No abstract

Heart failure involves a complex interplay between diverse populations of immune cells that dynamically shift across the natural history of disease. Within this context, the character of the immune response is a key determinant of clinical outcomes. Recent technological advances in single-cell transcriptomic, spatial, and proteomic technologies have fueled an explosion of new and clinically relevant insights into distinct immune cell populations that reside within the diseased heart including potential targets for molecular imaging and therapy. In this review, we will discuss the immune cell types and their respective functions with respect to myocardial infarction remodeling, dilated cardiomyopathy, and heart failure with preserved ejection fraction. In addition, we give a brief overview regarding myocarditis and cardiac sarcoidosis as inflammatory heart failure etiologies. We will highlight markers and cell populations as targets for molecular imaging to visualize inflammation and tissue healing and discuss clinical implications including the development and implementation of precision medicine approaches.

Background Heart failure (HF) is a leading cause of mortality in adults with congenital heart disease (ACHD). ACHD is characterized by predominant right heart disease. In non-congenital heart disease inflammation and its mediators such as monocytes/macrophages play an important pathophysiological role in HF. We aimed to evaluate the role of circulating monocyte subsets in ACHD-HF. Methods This cross-sectional study includes 209 ACHD outpatients (mean age: 35.3±11.0 years; NYHA class I/II/III-IV 58.3%/19.6%/13%; male: 59.8%) and 21 healthy controls (age: 29.8±12.6 years; male: 47.6%). Patients with clinical signs of infection, inflammatory diseases or malignancies were excluded. Multivariate analysis was used to relate blood monocyte subsets to NYHA class and echocardiographically derived parameters of right and left ventricular function. Results Compared to control, ACHD had significantly higher circulating levels of pro-inflammatory HLA-DR+CD14++CD16+ intermediate monocytes (24.0±3.3 vs. 43.6±1.7 cells/μL; p<0.001). NT-proBNP was independently associated with reduced left (p<0.0001) and right (p<0.001) ventricular function, diastolic dysfunction (p=0.04) and vena cava diameter (p=0.02). Independent predictors of NYHA class were intermediate monocytes (p=0.022), plasma noradrenaline (p=0.002), albumin (p=0.001) and NT-proBNP (p<0.001). Elevated right ventricular systolic pressure (>35 mmHg) was independently associated with both, higher intermediate monocyte counts (OR 1.36; 95% CI: 1.13–1.62; p=0.001) and low oxygen saturation (OR 0.8; 95% CI: 0.7–0.92; p=0.001), even after multivariable adjustment for age, sex and NYHA class. Conclusions Right ventricular pressure and oxygen saturation are linked to elevated intermediate monocytes, suggesting an important link between inflammation and HF in ACHD. Circulating blood intermediate monocytes represent a promising biomarker in ACHD. Acknowledgement/Funding German Heart Foundation (Deutsche Herzstiftung e.V.)