Pathogenic variants in genes that cause dilated cardiomyopathy (DCM) and arrhythmogenic cardiomyopathy (ACM) convey high risks for the development of heart failure through unknown mechanisms. Using single-nucleus RNA sequencing, we characterized the transcriptome of 880,000 nuclei from 18 control and 61 failing, nonischemic human hearts with pathogenic variants in DCM and ACM genes or idiopathic disease. We performed genotype-stratified analyses of the ventricular cell lineages and transcriptional states. The resultant DCM and ACM ventricular cell atlas demonstrated distinct right and left ventricular responses, highlighting genotype-associated pathways, intercellular interactions, and differential gene expression at single-cell resolution. Together, these data illuminate both shared and distinct cellular and molecular architectures of human heart failure and suggest candidate therapeutic targets.
A cell's function is defined by its intrinsic characteristics and its niche: the tissue microenvironment in which it dwells. Here, we combine single-cell and spatial transcriptomic data to discover cellular niches within eight regions of the human heart. We map cells to micro-anatomic locations and integrate knowledge-based and unsupervised structural annotations. For the first time, we profile the cells of the human cardiac conduction system, revealing their distinctive repertoire of ion channels, G-protein coupled receptors, and cell interactions using a custom CellPhoneDB.org module. We show that the sinoatrial node is compartmentalised, with a core of pacemaker cells, fibroblasts and glial cells supporting paracrine glutamatergic signalling. We introduce a druggable target prediction tool, drug2cell, which leverages single-cell profiles and drug-target interactions, providing unexpected mechanistic insights into the chronotropic effects of drugs, including GLP-1 analogues. In the epicardium, we show enrichment of both IgG+ and IgA+ plasma cells forming immune niches which may contribute to infection defence. We define a ventricular myocardial-stress niche enriched for activated fibroblasts and stressed cardiomyocytes, cell states that are expanded in cardiomyopathies. Overall, we provide new clarity to cardiac electro-anatomy and immunology, and our suite of computational approaches can be deployed to other tissues and organs.
ObjectiveTo describe the population, heart failure (HF) diagnosis rate, and 1-year hospitalisation and mortality of patients with suspected HF and elevated N-terminal pro B-type natriuretic peptide (NTproBNP) investigated according to UK National Institute for Health and Care Excellence (NICE) guidelines.MethodsNICE recommends patients with suspected HF, based on clinical presentation and elevated NTproBNP, are referred for specialist assessment and echocardiography. Patients should be seen within 2 weeks when NTproBNP is >2000 pg/mL (2-week pathway: 2WP) or within 6 weeks when NTproBNP is 400–2000 pg/mL (6-week pathway: 6WP). This is a retrospective, multicentre, observational study of consecutive patients with suspected HF referred from primary care between 2014 and 2016 to dedicated secondary care HF clinics based on the NICE 2WP and 6WP. Data were obtained from hospital records and episode statistics. Mortality and hospitalisation rates were calculated 1 year from NTproBNP measurement.Results1271 patients (median age 80; IQR 73–85) were assessed, 680 (53%) of whom were female. 667 (53%) were referred on the 2WP and 604 (47%) on the 6WP. 698 (55%) were diagnosed with HF (369 HF with reduced ejection fraction) and 566 (45%) as not HF (NHF). 1-year mortality was 10% (n=129) and hospitalisation was 33% (n=413). Patients on the 2WP had higher mortality and hospitalisation rates than those on the 6WP, 14% vs 6% (p<0.001) and 38% vs 27% (p<0.001), respectively. All-cause mortality (11% vs 9%; p=0.306) and hospitalisation rates (35% vs 29%; p=0.128) did not differ between HF and NHF patients, respectively.ConclusionsOutcomes using the NICE approach of short waiting time targets for specialist assessment of patients with suspected HF and raised NTproBNP are not known. The model identifies an elderly population a high proportion of whom have HF. Irrespective of diagnosis, patients have high rates of adverse outcomes. These contemporary real-world data provide a platform for discussions with patients and shaping HF services.
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