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Cardiac fibrosis is central to the pathology of heart failure, particularly heart failure with preserved ejection fraction (HFpEF). Irrespective of the underlying profibrotic condition (e.g. ageing, diabetes, hypertension), maladaptive cardiac fibrosis is defined by the transformation of resident fibroblasts to matrix‐secreting myofibroblasts. Numerous profibrotic factors have been identified at the molecular level (e.g. TGFβ, IL11, AngII), which activate gene expression programs for myofibroblast activation. A number of existing HF therapies indirectly target fibrotic pathways; however, despite multiple clinical trials in HFpEF, a specific clinically effective antifibrotic therapy remains elusive. Therapeutic inhibition of TGFβ, the master‐regulator of fibrosis, has unfortunately proven toxic and ineffective in clinical trials to date, and new approaches are needed. In this review, we discuss the pathophysiology and clinical implications of interstitial fibrosis in HFpEF. We provide an overview of trials targeting fibrosis in HFpEF to date and discuss the promise of potential new therapeutic approaches and targets in the context of underlying molecular mechanisms. Graphical Abstract This review discusses recent advances in novel therapeutic approaches against cardiac fibrosis in heart failure with preserved ejection fraction and their underlying molecular mechanisms.

Interleukin (IL)-11 evolved as part of the innate immune response. In the human lung, IL-11 upregulation has been associated with viral infections and a range of fibroinflammatory diseases, including idiopathic pulmonary fibrosis. Transforming growth factor-beta (TGFβ) and other disease factors can initiate an autocrine loop of IL-11 signaling in pulmonary fibroblasts, which, in a largely ERK-dependent manner, triggers the translation of profibrotic proteins. Lung epithelial cells also express the IL-11 receptor and transition into a mesenchymal-like state in response to IL-11 exposure. In mice, therapeutic targeting of IL-11 with antibodies can arrest and reverse bleomycin-induced pulmonary fibrosis and inflammation. Intriguingly, fibroblast-specific blockade of IL-11 signaling has anti-inflammatory effects, which suggests that lung inflammation is sustained, in part, through IL-11 activity in the stroma. Proinflammatory fibroblasts and their interaction with the damaged epithelium may represent an important but overlooked driver of lung disease. Initially thought of as a protective cytokine, IL-11 is now increasingly recognized as an important determinant of lung fibrosis, inflammation, and epithelial dysfunction.Lung disease: suppressing immune protein could reduce fibrosisAn immune protein that contributes to fibrosis, inflammation, and cellular dysfunction in the airways should be a target of therapies for severe lung diseases. Previously thought of as protective, the cytokine interleukin-11 (IL-11) evolved as part of the body’s immune system, and is highly expressed in the parenchyma and stroma of the diseased lung. Sebastian Schäfer at National Heart Centre Singapore and co-workers review recent research evidence indicating that IL-11 signaling is centrally important in pathological processes including the dysfunction of epithelial cells, inflammation of connective tissue, and the activation of cells that induce fibrotic scarring. Antibody therapies targeting IL-11 can reduce pulmonary fibrosis and inflammation in mice. Pharmacological companies may soon begin clinical trials of anti-IL-11 therapies on patients with idiopathic pulmonary fibrosis, a severe lung disease sharing several risk factors with COVID-19.

Dilated cardiomyopathy (DCM) affects approximately 1 in 250 individuals and is the leading indication for heart transplantation. DCM is often familial, and the most common genetic predisposition is a truncating variation in the giant sarcomeric protein, titin, which occurs in up to 15% of ambulant patients with DCM and 25% of end-stage or familial cases. In this article, we review the evidence for the role of titin truncation in the pathogenesis of DCM and our understanding of the molecular mechanisms and pathophysiological consequences of variation in the gene encoding titin (TTN). Such variation is common in the general population (up to 1% of individuals), and we consider key features that discriminate variants with disease-causing potential from those that are benign. We summarize strategies for clinical interpretation of genetic variants for use in the diagnosis of patients and the evaluation of their relatives. Finally, we consider the contemporary and potential future role for genetic stratification in cardiomyopathy and in the general population, evaluating titin variation as a predictor of outcome and treatment response for precision medicine.

Heart failure is a major health burden, affecting 40 million people globally. One of the main causes of systolic heart failure is dilated cardiomyopathy (DCM), the leading global indication for heart transplantation. Our understanding of the genetic basis of both DCM and systolic heart failure has improved in recent years with the application of next-generation sequencing and genome-wide association studies (GWAS). This has enabled rapid sequencing at scale, leading to the discovery of many novel rare variants in DCM and of common variants in both systolic heart failure and DCM. Identifying rare and common genetic variants contributing to systolic heart failure has been challenging given its diverse and multiple etiologies. DCM, however, although rarer, is a reasonably specific and well-defined condition, leading to the identification of many rare genetic variants. Truncating variants in titin represent the single largest genetic cause of DCM. Here, we review the progress and challenges in the detection of rare and common variants in DCM and systolic heart failure, and the particular challenges in accurate and informed variant interpretation, and in understanding the effects of these variants. We also discuss how our increasing genetic knowledge is changing clinical management. Harnessing genetic data and translating it to improve risk stratification and the development of novel therapeutics represents a major challenge and unmet critical need for patients with heart failure and their families.

Purpose Whole-exome and whole-genome sequencing have transformed the discovery of genetic variants that cause human Mendelian disease, but discriminating pathogenic from benign variants remains a daunting challenge. Rarity is recognized as a necessary, although not sufficient, criterion for pathogenicity, but frequency cutoffs used in Mendelian analysis are often arbitrary and overly lenient. Recent very large reference datasets, such as the Exome Aggregation Consortium (ExAC), provide an unprecedented opportunity to obtain robust frequency estimates even for very rare variants. Methods We present a statistical framework for the frequency-based filtering of candidate disease-causing variants, accounting for disease prevalence, genetic and allelic heterogeneity, inheritance mode, penetrance, and sampling variance in reference datasets. Results Using the example of cardiomyopathy, we show that our approach reduces by two-thirds the number of candidate variants under consideration in the average exome, without removing true pathogenic variants (false-positive rate<0.001). Conclusion We outline a statistically robust framework for assessing whether a variant is “too common” to be causative for a Mendelian disorder of interest. We present precomputed allele frequency cutoffs for all variants in the ExAC dataset.

Human mutations that truncate the massive sarcomere protein titin [TTN-truncating variants (TTNtvs)] are the most common genetic cause for dilated cardiomyopathy (DCM), a major cause of heart failure and premature death. Here we show that cardiac microtissues engineered from human induced pluripotent stem (iPS) cells are a powerful system for evaluating the pathogenicity of titin gene variants. We found that certain missense mutations, like TTNtvs, diminish contractile performance and are pathogenic. By combining functional analyses with RNA sequencing, we explain why truncations in the A-band domain of TTN cause DCM, whereas truncations in the I band are better tolerated. Finally, we demonstrate that mutant titin protein in iPS cell–derived cardiomyocytes results in sarcomere insufficiency, impaired responses to mechanical and β-adrenergic stress, and attenuated growth factor and cell signaling activation. Our findings indicate that titin mutations cause DCM by disrupting critical linkages between sarcomerogenesis and adaptive remodeling.

Interleukin 11 (IL11) is upregulated in inflammatory conditions, where it is mostly believed to have anti-inflammatory activity. However, recent studies suggest instead that IL11 promotes inflammation by activating fibroblasts. Here, we assessed whether IL11 is pro- or anti-inflammatory in fibroblasts. Primary cultures of human kidney, lung or skin fibroblasts were stimulated with IL11 that resulted in the transient phosphorylation of signal transducer and activator of transcription 3 (STAT3) and the sustained activation of extracellular signal-regulated protein kinases (ERK). RNA sequencing over a time course of IL11 stimulation revealed a robust but short-lived transcriptional response that was enriched for gene set hallmarks of inflammation and characterized by the upregulation of SERPINB2, TNFRSF18, Interleukin 33 (IL33), CCL20, IL1RL1, CXCL3/5/8, ICAM1 and IL11 itself. IL33 was the most upregulated signaling factor (38-fold, p = 9.8 × 10−5), and IL1RL1, its cognate receptor, was similarly increased (18-fold, p = 1.1 × 10−34). In proteomic studies, IL11 triggered a proinflammatory secretome with the notable upregulation of IL8, IL6, MCP1, CCL20 and CXCL1/5/6, which are important chemotaxins for neutrophils, monocytes, and lymphocytes. IL11 induced IL33 expression across fibroblast types, and the inhibition of STAT3 but not of MEK/ERK prevented this. These data establish IL11 as pro-inflammatory with specific importance for priming the IL33 alarmin response in inflammatory fibroblasts across tissues.

Disruptions in the ubiquitin protein ligase E3A (UBE3A) gene cause Angelman syndrome (AS). Whereas AS model mice have associated synaptic dysfunction and altered plasticity with abnormal behavior, whether similar or other mechanisms contribute to network hyperactivity and epilepsy susceptibility in AS patients remains unclear. Using human neurons and brain organoids, we demonstrate that UBE3A suppresses neuronal hyperexcitability via ubiquitin-mediated degradation of calcium- and voltage-dependent big potassium (BK) channels. We provide evidence that augmented BK channel activity manifests as increased intrinsic excitability in individual neurons and subsequent network synchronization. BK antagonists normalized neuronal excitability in both human and mouse neurons and ameliorated seizure susceptibility in an AS mouse model. Our findings suggest that BK channelopathy underlies epilepsy in AS and support the use of human cells to model human developmental diseases.

IL11 is important for fibrosis in non-alcoholic steatohepatitis (NASH) but its role beyond the stroma in liver disease is unclear. Here, we investigate the role of IL11 in hepatocyte lipotoxicity. Hepatocytes highly express IL11RA and secrete IL11 in response to lipid loading. Autocrine IL11 activity causes hepatocyte death through NOX4-derived ROS, activation of ERK, JNK and caspase-3, impaired mitochondrial function and reduced fatty acid oxidation. Paracrine IL11 activity stimulates hepatic stellate cells and causes fibrosis. In mouse models of NASH, hepatocyte-specific deletion of Il11ra1 protects against liver steatosis, fibrosis and inflammation while reducing serum glucose, cholesterol and triglyceride levels and limiting obesity. In mice deleted for Il11ra1 , restoration of IL11 cis-signaling in hepatocytes reconstitutes steatosis and inflammation but not fibrosis. We found no evidence for the existence of IL6 or IL11 trans-signaling in hepatocytes or NASH. These data show that IL11 modulates hepatocyte metabolism and suggests a mechanism for NAFLD to NASH transition. IL11 contributes to the development of non-alcoholic steatohepatitis (NASH) through incompletely understood mechanisms. Here, the authors report that lipotoxicity-driven autocrine IL11 activity underlies hepatocyte metabolic dysfunction and death via a NOX4/ERK-mediated mechanism while paracrine IL11 activity stimulates hepatic stellate cells contributing to fibrosis and inflammation in the context of NASH.

The kidney has large regenerative capacity, but this is compromised when kidney damage is excessive and renal tubular epithelial cells (TECs) undergo SNAI1-driven growth arrest. Here we investigate the role of IL11 in TECs, kidney injury and renal repair. IL11 stimulation of TECs induces ERK- and p90RSK-mediated GSK3β inactivation, SNAI1 upregulation and pro-inflammatory gene expression. Mice with acute kidney injury upregulate IL11 in TECs leading to SNAI1 expression and kidney dysfunction, which is not seen in Il11 deleted mice or in mice administered a neutralizing IL11 antibody in either preemptive or treatment modes. In acute kidney injury, anti-TGFβ reduces renal fibrosis but exacerbates inflammation and tubule damage whereas anti-IL11 reduces all pathologies. Mice with TEC-specific deletion of Il11ra1 have reduced pathogenic signaling and are protected from renal injury-induced inflammation, fibrosis, and failure. In a model of chronic kidney disease, anti-IL11 therapy promotes TEC proliferation and parenchymal regeneration, reverses fibroinflammation and restores renal mass and function. These data highlight IL11-induced mesenchymal transition of injured TECs as an important renal pathology and suggest IL11 as a therapeutic target for restoring stalled endogenous regeneration in the diseased kidney. Repair processes in kidney are impaired in severe disease. Here, the authors show that in kidney failure, genetic or pharmacologic inhibition of IL11 releases the brake on regeneration, reverses tissue damage and restores kidney function.