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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Limited evidence suggests that specificity of cardiac troponin T (cTnT), a highly sensitive biomarker of myocardial injury, is reduced in patients with skeletal myopathies. Whether amyotrophic lateral sclerosis (ALS)-the most common motor neuron disease-could be also associated with abnormal plasma or serum cTnT levels remains unclear. Our objective was to assess cTnT levels in patients with ALS without known cTnT elevating conditions. Among ALS patients seen at our institution until 2012 we identified those who had their cTnT measured. Patients who suffered from conditions known to elevate cTnT were excluded. A case-control analysis comparing cTnT levels of these ALS patients to matched non-ALS controls fulfilling the same inclusion criteria was performed. We included 40 ALS patients of whom 27 (68 %) patients had a positive cTnT. In the control group (n = 40), 2 (5 %) tested as cTnT positive (p < 0.001). Among the ALS patients who underwent cTnT evaluation on more occasions (n = 7; median follow-up = 1.08 years), 2 (29 %) patients tested positive during the initial measurement while 6 (86 %) of them had positive cTnT at the subsequent evaluations. ALS patients with increased cTnT had been diagnosed with ALS significantly earlier than those without the elevation. Our findings raise the possibility that ALS may cause cTnT elevations. Further studies are needed to confirm these findings, clarify the pathophysiological mechanism, and establish the significance of cTnT elevations in patients with ALS.

One of the most relevant findings of this study was the marked decrease in EAT levels of TNF-α, AFABP, leptin and adiponectin after the CPB termination. Our results suggest that EAT might serve as a pool of cytokines which are released into the circulation in reaction to surgery with CPB. Should these novel findings be confirmed, new strategies to assess and possibly reduce EAT contribution on adverse outcomes of cardiac surgery may be developed.

A 36-year-old man with chronic renal insufficiency secondary to type 1 diabetes mellitus was on hemodialysis via central venous catheter (CVC), newly placed into the right subclavian vein after his arteriovenous fistula became dysfunctional. Seven days after CVC insertion, the patient developed fever and on day 11 echocardiography showed a large nearly occluding thrombus in the superior vena cava (SVC) extending into the right atrium (RA). Emergency surgical thrombectomy was successfully performed and an 11 cm long thrombus extending from the RA cranially into the SVC occupying majority of the vein's lumen was removed. Cultures from the thrombus and CVC were negative, but polymerase chain reaction was positive for Staphylococcus aureus. This particular case was interesting for a marked discrepancy between large SVC occluding thrombosis and a relatively mild clinical presentation with fever, and it highlights the importance of correct timing of echocardiography exam which might prevent potentially fatal consequences such as pulmonary embolism.

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