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Abstract Aims The identification of subjects at higher risk for incident heart failure (HF) with preserved ejection fraction (EF) suitable for more intensive preventive programmes remains challenging. We applied phenomapping to the DAVID‐Berg population, comprising subjects with preclinical HF, aiming to refine HF risk stratification. Methods The DAVID‐Berg study prospectively enrolled 596 asymptomatic outpatients with EF > 40% with hypertension, diabetes mellitus or known cardiovascular disease. In this cohort, we performed an unsupervised cluster analysis on 591 patients, including clinical, laboratory, electrocardiographic and echocardiographic parameters. We tested the association between each cluster and a composite outcome of HF/death. Results The median age was 70 years, 55.5% were males and the median EF was 61.0%. Phenomapping provided three different clusters. Subjects in Cluster 3 were the oldest and had the highest prevalence of atrial fibrillation, the lowest estimated glomerular filtration rate (eGFR), the highest N‐terminal pro‐brain natriuretic peptide (NT‐proBNP) and the largest left atrium. During a median follow‐up of 5.7 years, 13.4% of subjects experienced HF/death events (N = 79). Compared with Clusters 1 and 2, Cluster 3 had the worst prognosis (log‐rank test: Cluster 3 vs. 1 P 40% who deserve more efforts to prevent clinical HF.

Despite the withdrawal of the HeartWare Ventricular Assist Device (HVAD), hundreds of patients are still supported with this continuous-flow pump, and the long-term management of these patients is still under debate. This study aims to analyse 5 years survival and freedom from major adverse events in patients supported by HVAD and HeartMate3 (HM3). From 2010 to 2022, the MIRAMACS Italian Registry enrolled all-comer patients receiving a LVAD support at seven Cardiac Surgery Centres. Out of 447 LVAD implantation, 214 (47.9%) received HM3 and 233 (52.1%) received HVAD. Cox-regression analysis adjusted for major confounders showed an increased risk for mortality (HR 1.5 [1.2–1.9]; p = 0.031), for both ischemic stroke (HR 2.08 [1.06–4.08]; p = 0.033) and haemorrhagic stroke (HR 2.6 [1.3–4.9]; p = 0.005), and for pump thrombosis (HR 25.7 [3.5–188.9]; p < 0.001) in HVAD patients. The propensity-score matching analysis (130 pairs of HVAD vs. HM3) confirmed a significantly lower 5 years survival (41.7% vs. 64.1%; p 0.02), freedom from haemorrhagic stroke (90.5% vs. 70.1%; p < 0.001) and from pump thrombosis (98.5% vs. 74.7%; p < 0.001) in HVAD cohort. Although similar perioperative outcome, patients implanted with HVAD developed a higher risk for mortality, haemorrhagic stroke and thrombosis during 5 years of follow-up compared to HM3 patients.

Abstract Bone marrow megakaryocytes (MKs) undergo a maturation involving contacts with the microenvironment before extending proplatelets through sinusoids to deliver platelets in the bloodstream. We demonstrated that MKs assemble linear F-actin-enriched podosomes on collagen I fibers. Microscopy analysis evidenced an inverse correlation between the number of dot-like versus linear podosomes over time. Confocal videomicroscopy confirmed that they derived from each-other. This dynamics was dependent on myosin IIA. Importantly, MKs progenitors expressed the Tks4/5 adaptors, displayed a strong gelatinolytic ability and did not form linear podosomes. While maturing, MKs lost Tks expression together with digestive ability. However, those MKs were still able to remodel the matrix by exerting traction on collagen I fibers through a collaboration between GPVI, ß1 integrin and linear podosomes. Our data demonstrated that a change in structure and composition of podosomes accounted for the shift of function during megakaryopoiesis. These data highlight the fact that members of the invadosome family could correspond to different maturation status of the same entity, to adapt to functional responses required by differentiation stages of the cell that bears them.

Aims: The identification of subjects at higher risk for incident heart failure (HF) with preserved ejection fraction (EF) suitable for more intensive preventive programmes remains challenging. We applied phenomapping to the DAVID‐Berg population, comprising subjects with preclinical HF, aiming to refine HF risk stratification. Methods: The DAVID‐Berg study prospectively enrolled 596 asymptomatic outpatients with EF > 40% with hypertension, diabetes mellitus or known cardiovascular disease. In this cohort, we performed an unsupervised cluster analysis on 591 patients, including clinical, laboratory, electrocardiographic and echocardiographic parameters. We tested the association between each cluster and a composite outcome of HF/death. Results: The median age was 70 years, 55.5% were males and the median EF was 61.0%. Phenomapping provided three different clusters. Subjects in Cluster 3 were the oldest and had the highest prevalence of atrial fibrillation, the lowest estimated glomerular filtration rate (eGFR), the highest N‐terminal pro‐brain natriuretic peptide (NT‐proBNP) and the largest left atrium. During a median follow‐up of 5.7 years, 13.4% of subjects experienced HF/death events (N = 79). Compared with Clusters 1 and 2, Cluster 3 had the worst prognosis (log‐rank test: Cluster 3 vs. 1 P < 0.001; Cluster 3 vs. 2 P = 0.008). Cluster 3 was associated with a risk of HF/death 2.5 times higher than Cluster 1 [adjusted hazard ratio (HR) = 2.46, 95% confidence interval (CI) 1.24–4.90]. Conclusions: Based on phenomapping, older patients with lower kidney function and worse diastolic function might represent a subset of preclinical HF with EF > 40% who deserve more efforts to prevent clinical HF. [ABSTRACT FROM AUTHOR]

OBJECTIVES The use of ventricular assist devices (VADs) in children is increasing. However, absolute numbers in individual centres and countries remain small. Collaborative efforts such as the Paedi-European Registry for Patients with Mechanical Circulatory Support (EUROMACS) are therefore essential for combining international experience with paediatric VADs. Our goal was to present the results from the fourth Paedi-EUROMACS report. METHODS All paediatric (<19 years) patients from the EUROMACS database supported by a VAD were included. Patients were stratified into a congenital heart disease (CHD) group and a group with a non-congenital aetiology. End points included mortality, a transplant and recovery. Cox proportional hazard models were used to explore associated factors for mortality, cerebrovascular accident and pump thrombosis. RESULTS A total of 590 primary implants were included. The congenital group was significantly younger (2.5 vs 8.0 years, respectively, P  < 0.001) and was more commonly supported by a pulsatile flow device (73.5% vs 59.9%, P  < 0.001). Mortality was significantly higher in the congenital group (30.8% vs 20.4%, P  = 0.009) than in the non-congenital group. However, in multivariable analyses, CHD was not significantly associated with mortality [hazard ratio (HR) 1.285; confidence interval (CI) 0.8111–2.036, P  = 0.740]. Pump thrombosis was the most frequently reported adverse event (377 events in 132 patients; 0.925 events per patient-year) and was significantly associated with body surface area (HR 0.524, CI 0.333–0.823, P  = 0.005), CHD (HR 1.641, CI 1.054–2.555, P  = 0.028) and pulsatile flow support (HR 2.345, CI 1.406–3.910, P  = 0.001) in multivariable analyses. CONCLUSIONS This fourth Paedi-EUROMACS report highlights the increasing use of paediatric VADs. The patient populations with congenital and non-congenital aetiologies exhibit distinct characteristics and clinical outcomes. [ABSTRACT FROM AUTHOR]

Heart failure (HF) is a pandemic syndrome characterised by raised morbidity and mortality. An acute HF event requiring hospitalisation is associated with a poor prognosis, in both the short and the long term. Moreover, early rehospitalisation after discharge negatively affects HF management and survival rates. Cardiovascular and non-cardiovascular conditions combine to increase rates of HF hospital readmission at 30 days. A tailored approach for HF pharmacotherapy while the patient is in hospital and immediately after discharge could be useful in reducing early adverse events that cause rehospitalisation and, consequently, prevent worsening HF and readmission during the vulnerable phase after discharge.

Since the beginning of the SARS-CoV-2 outbreak, few cases of COVID-19 pneumonia in patients with pulmonary arterial hypertension have been reported. We present four patients with known history of PAH admitted to our hospital with SARS-CoV-2 pneumonia to analyze the impact of this disease on their clinical outcome.

Treatment of chronic diseases, such as heart failure, requires complex protocols based on early diagnosis; self-monitoring of symptoms, vital signs and physical activity; regular medication intake; and education of patients and caregivers about relevant aspects of the disease. Smartphones and mobile health applications could be very helpful in improving the efficacy of such protocols, but several barriers make it difficult to fully exploit their technological potential and produce clear clinical evidence of their effectiveness. App suppliers do not help users distinguish between useless/dangerous apps and valid solutions. The latter are few and often characterised by rapid obsolescence, lack of interactivity and lack of authoritative information. Systematic reviews can help physicians and researchers find and assess the ‘best candidate solutions’ in a repeatable manner and pave the way for well-grounded and fruitful discussion on their clinical effectiveness. To this purpose, the authors assess 10 apps for heart failure self-care using the Intercontinental Marketing Statistics score and other criteria, discuss the clinical effectiveness of existing solutions and identify barriers to their use in practice and drivers for change.

The main indications for right ventricular assist device (RVAD) support are right heart failure after implantation of a left ventricular assist device (LVAD) or early graft failure following heart transplantation. We sought to study the effects induced by different RVAD connections when right ventricular elastance (EesRIGHT) was modified using numerical simulations based on atrial and ventricular pressure–volume analysis. We considered the effects induced by continuous-flow RVAD support on left/right ventricular/atrial loops when EesRIGHT changed from 0.3 to 0.8 mmHg/mL during in-series or parallel pump connection. Pump rotational speed was also addressed. Parallel RVAD support at 4000 rpm with EesRIGHT = 0.3 mmHg/mL generated percentage changes up to 60% for left ventricular pressure–volume area and external work; up to 20% for left ventricular ESV and up to 25% for left ventricular EDV; up to 50% change in left atrial pressure-volume area (PVLAL-A) and only a 3% change in right atrial pressure–volume area (PVLAR-A). Percentage variation was lower when EesRIGHT = 0.8 mmHg/mL. Early recognition of right ventricular failure followed by aggressive treatment is desirable, so as to achieve a more favourable outcome. RVAD support remains an option for advanced right ventricular failure, although the onset of major adverse events may preclude its use.

Perilipins are abundant lipid droplet (LD) proteins present in all metazoans and also in Amoebozoa and fungi. Humans express five perilipins, which share a similar domain organization: an amino‐terminal PAT domain and an 11‐mer repeat region, which can fold into amphipathic helices that interact with LDs, followed by a structured carboxy‐terminal domain. Variations of this organization that arose during vertebrate evolution allow for functional specialization between perilipins in relation to the metabolic needs of different tissues. We discuss how different features of perilipins influence their interaction with LDs and their cellular targeting. PLIN1 and PLIN5 play a direct role in lipolysis by regulating the recruitment of lipases to LDs and LD interaction with mitochondria. Other perilipins, particularly PLIN2, appear to protect LDs from lipolysis, but the molecular mechanism is not clear. PLIN4 stands out with its long repetitive region, whereas PLIN3 is most widely expressed and is used as a nascent LD marker. Finally, we discuss the genetic variability in perilipins in connection with metabolic disease, prominent for PLIN1 and PLIN4, underlying the importance of understanding the molecular function of perilipins. [ABSTRACT FROM AUTHOR]

Background The role of macrophages in the development of rhabdomyolysis-induced acute kidney injury (RM-AKI) has been established, but an in-depth understanding of the changes in the immune landscape could help to improve targeted strategies. Whereas senescence is usually associated with chronic kidney processes, we also wished to explore whether senescence could also occur in AKI and whether senolytics could act on immune cells. Methods Single-cell RNA sequencing was used in the murine glycerol-induced RM-AKI model to dissect the transcriptomic characteristics of CD45+ live cells sorted from kidneys 2 days after injury. Public datasets from murine AKI models were reanalysed to explore cellular senescence signature in tubular epithelial cells (TECs). A combination of senolytics (dasatinib and quercetin, DQ) was administered to mice exposed or not to RM-AKI. Results Unsupervised clustering of nearly 17 000 single-cell transcriptomes identified seven known immune cell clusters. Sub-clustering of the mononuclear phagocyte cells revealed nine distinct cell sub-populations differently modified with RM. One macrophage cluster was particularly interesting since it behaved as a critical node in a trajectory connecting one major histocompatibility complex class IIhigh (MHCIIhigh) cluster only present in Control to two MHCIIlow clusters only present in RM-AKI. This critical cluster expressed a senescence gene signature, that was very different from that of the TECs. Senolytic DQ treatment blocked the switch from a F4/80highCD11blow to F4/80lowCD11bhigh phenotype, which correlated with prolonged nephroprotection in RM-AKI. Conclusions Single-cell RNA sequencing unmasked novel transitional macrophage subpopulation associated with RM-AKI characterized by the activation of cellular senescence processes. This work provides a proof-of-concept that senolytics nephroprotective effects may rely, at least in part, on subtle immune modulation. [ABSTRACT FROM AUTHOR]

Introduction Purinergic receptor-7 (P2X7R), primarily expressed on lymphocytes, senses adenosine 5'-triphosphate (ATP) (1) released extracellularly during cell damage (2, 3) and has been shown to regulate T cell activation (4-6). [...], Purinergic receptor-7 (P2X7R) signaling controls Th17 and Th1 generation/differentiation, while NOD-like receptor P3 (NLRP3) acts as a Th2 transcriptional factor. Here, we demonstrated the existence of a P2X7R/NLRP3 pathway in T cells that is dysregulated by a P2X7R intracellular region loss-of-function mutation, leading to NLRP3 displacement and to excessive Th17 generation due to abrogation of the NLRP3-mediated Th2 program. This ultimately resulted in poor outcomes in cardiac-transplanted patients carrying the mutant allele, who showed abnormal Th17 generation. Transient NLRP3 silencing in nonmutant T cells or overexpression in mutant T cells normalized the Th profile. Interestingly, IL-17 blockade reduced Th17 skewing of human T cells in vitro and abrogated the severe allograft vasculopathy and abnormal Th17 generation observed in preclinical models in which P2X7R was genetically deleted. This P2X7R intracellular region mutation thus impaired the modulatory effects of P2X7R on NLRP3 expression and function in T cells and led to NLRP3 dysregulation and Th17 skewing, delineating a high-risk group of cardiac-transplanted patients who may benefit from personalized therapy.

Platelets derive from large precursor cells (megakaryocytes) in the bone marrow. Düttinget al. show that megakaryocyte polarization and platelet biogenesis in the bone-marrow sinusoids are directed by adhesion receptor GPIb signalling and resulting balanced antagonism between RhoA (stop-signal) and Cdc42 (go-signal).

Abstract Gut microbiota dysbiosis has been implicated in a variety of systemic disorders, notably metabolic diseases including obesity and impaired liver function, but the underlying mechanisms are uncertain. To investigate this question, we transferred caecal microbiota from either obese or lean mice to antibiotic‐free, conventional wild‐type mice. We found that transferring obese‐mouse gut microbiota to mice on normal chow (NC) acutely reduces markers of hepatic gluconeogenesis with decreased hepatic PEPCK activity, compared to non‐inoculated mice, a phenotypic trait blunted in conventional NOD2 KO mice. Furthermore, transferring of obese‐mouse microbiota changes both the gut microbiota and the microbiome of recipient mice. We also found that transferring obese gut microbiota to NC‐fed mice then fed with a high‐fat diet (HFD) acutely impacts hepatic metabolism and prevents HFD‐increased hepatic gluconeogenesis compared to non‐inoculated mice. Moreover, the recipient mice exhibit reduced hepatic PEPCK and G6Pase activity, fed glycaemia and adiposity. Conversely, transfer of lean‐mouse microbiota does not affect markers of hepatic gluconeogenesis. Our findings provide a new perspective on gut microbiota dysbiosis, potentially useful to better understand the aetiology of metabolic diseases.

Summary: Under caloric restriction, bone marrow adipocytes (BM-Ads) do not decrease in size compared to white adipocytes, suggesting they harbor unique metabolic properties. We compare human primary BM-Ads with paired subcutaneous adipocytes (SC-Ads) using proteomic and lipidomic approaches. We find that, although SC-Ads and BM-Ads share similar morphological features, they possess distinct lipid metabolism. Although BM-Ad shows enrichment in proteins involved in cholesterol metabolism, correlating with increased free cholesterol content, proteins involved in lipolysis were downregulated. In particular, monoacylglycerol lipase expression is strongly reduced in BM-Ads, leading to monoacylglycerol accumulation. Consequently, basal and induced lipolytic responses are absent in BM-Ads, affirming their differences in metabolic fitness upon caloric restriction. These specific metabolic features are not recapitulated in vitro using common protocols to differentiate bone marrow mesenchymal stem cells. Thus, contrary to classical SC-Ads, BM-Ads display a specific lipid metabolism, as they are devoid of lipolytic activity and exhibit a cholesterol-orientated metabolism. : Attané et al. show that, although human bone marrow adipocytes (BM-Ads) resemble classic white adipocytes on a morphological level, their lipid metabolism is highly specific. They are devoid of lipolytic activity, one of the main metabolic functions of white adipocytes, which explains why they behave like a preserved lipid source under energy-demanding conditions. Keywords: bone marrow adipocytes, cholesterol, lipolysis, monoacylglycerol lipase, proteomic, adipose tissue, bone marrow fat

Lo possiamo chiamare in molti modi, collage, cut-up, sampling, détournement, ma la sostanza non cambia: c'è un atto elementare praticato da più di cento anni che non perde la propria carica sovversiva di estrarre dei frammenti della realtà per ricomporli in configurazioni di senso che aprono a nuovi orizzonti.