Plasmacytoid dendritic cells control homeostasis of megakaryopoiesis.

Platelet homeostasis is essential for vascular integrity and immune defence1,2. Although the process of platelet formation by fragmenting megakaryocytes (MKs; thrombopoiesis) has been extensively studied, the cellular and molecular mechanisms required to constantly replenish the pool of MKs by their progenitor cells (megakaryopoiesis) remains unclear3,4. Here we use intravital imaging to track the cellular dynamics of megakaryopoiesis over days. We identify plasmacytoid dendritic cells (pDCs) as homeostatic sensors that monitor the bone marrow for apoptotic MKs and deliver IFNα to the MK niche triggering local on-demand proliferation and maturation of MK progenitors. This pDC-dependent feedback loop is crucial for MK and platelet homeostasis at steady state and under stress. pDCs are best known for their ability to function as vigilant detectors of viral infection5. We show that virus-induced activation of pDCs interferes with their function as homeostatic sensors of megakaryopoiesis. Consequently, activation of pDCs by SARS-CoV-2 leads to excessive megakaryopoiesis. Together, we identify a pDC-dependent homeostatic circuit that involves innate immune sensing and demand-adapted release of inflammatory mediators to maintain homeostasis of the megakaryocytic lineage.

Pacing Using Cardiac Implantable Electric Device During TAVR: 10-Year Experience of a High-Volume Center.

BACKGROUND: Transcatheter aortic valve replacement (TAVR) is an effective and safe therapy for severe aortic stenosis. Rapid or fast pacing is required for implantation, which can be performed via a pre-existing cardiac implantable electric device (CIED). However, safety data on CIEDs for pacing in TAVR are missing. OBJECTIVES: The aim of this study was to elucidate procedural safety and feasibility of internal pacing with a CIED in TAVR. METHODS: Patients undergoing TAVR with a CIED were included in this analysis. Baseline characteristics, procedural details, and complications according to Valve Academic Research Consortium 3 (VARC-3) criteria after TAVR were compared between both groups. RESULTS: A total of 486 patients were included. Pacing was performed using a CIED in 150 patients and a transient pacemaker in 336 patients. No differences in technical success according to VARC-3 criteria or procedure duration occurred between the groups. The usage of transient pacers for pacing was associated with a significantly higher bleeding rate (bleeding type ≥2 according to VARC-3-criteria; 2.0% vs 13.1%; P < 0.01). Furthermore, impairment of the CIED appeared in 2.3% of patients after TAVR only in the group in which pacing was performed by a transient pacer, leading to surgical revision of the CIED in 1.3% of all patients when transient pacemakers were used. CONCLUSIONS: Internal pacing using a CIED is safe and feasible without differences of procedural time and technical success and might reduce bleeding rates. Furthermore, pacing using a CIED circumvents the risk of lead dislocation. Our data provide an urgent call for the use of a CIED for pacing during a TAVR procedure in general.

Single-Cell Dissection of the Immune Response After Acute Myocardial Infarction.

BACKGROUND: The immune system's role in ST-segment-elevated myocardial infarction (STEMI) remains poorly characterized but is an important driver of recurrent cardiovascular events. While anti-inflammatory drugs show promise in reducing recurrence risk, their broad immune system impairment may induce severe side effects. To overcome these challenges, a nuanced understanding of the immune response to STEMI is needed. METHODS: For this, we compared peripheral blood mononuclear single-cell RNA-sequencing (scRNA-seq) and plasma protein expression over time (hospital admission, 24 hours, and 6-8 weeks post-STEMI) in 38 patients and 38 controls (95 995 diseased and 33 878 control peripheral blood mononuclear cells). RESULTS: Compared with controls, classical monocytes were increased and CD56dim natural killer cells were decreased in patients with STEMI at admission and persisted until 24 hours post-STEMI. The largest gene expression changes were observed in monocytes, associating with changes in toll-like receptor, interferon, and interleukin signaling activity. Finally, a targeted cardiovascular biomarker panel revealed expression changes in 33/92 plasma proteins post-STEMI. Interestingly, interleukin-6R, MMP9 (matrix metalloproteinase-9), and LDLR (low-density lipoprotein receptor) were affected by coronary artery disease-associated genetic risk variation, disease status, and time post-STEMI, indicating the importance of considering these aspects when defining potential future therapies. CONCLUSIONS: Our analyses revealed the immunologic pathways disturbed by STEMI, specifying affected cell types and disease stages. Additionally, we provide insights into patients expected to benefit most from anti-inflammatory treatments by identifying the genetic variants and disease stage at which these variants affect the outcome of these (drug-targeted) pathways. These findings advance our knowledge of the immune response post-STEMI and provide guidance for future therapeutic studies.

Influence of donor age and donor-recipient age difference on intimal hyperplasia in pediatric patients with young and adult donors vs. adult patients after heart transplantation.

AIM: Optimal selection and allocation of donor hearts is a relevant aspect in transplantation medicine. Donor age and cardiac allograft vasculopathy (CAV) affect post-transplant mortality. To what extent donor age impacts intimal hyperplasia (CAVIH) in pediatric and adult patients after heart transplantation (HTx) is understudied. METHODS: In a cohort of 98 HTx patients, 58 pediatric (24.1% with adult donors) and 40 adult patients, we assessed the effect of donor age and donor-recipient age difference (D-R) on the continuous parameter of maximal intima thickness (mIT) in optical coherence tomography. We evaluated their predictive value regarding higher mIT and the prevalence of CAVIH, defined as mIT > 0.3 mm, and compared it to established CAV risk factors. RESULTS: In the overall population, donor age correlated with mIT (p < 0.001), while in the pediatric subpopulation, both donor age and D-R correlated with mIT (p < 0.001 and p = 0.002, respectively). In the overall population, donor age was a main predictor of higher mIT and CAVIH (p = 0.001 and p = 0.01, respectively) in addition to post-transplant interval, arterial hypertension, and dyslipidemia. In the pediatric patients, dyslipidemia remained a main predictor of both higher mIT and CAVIH (p = 0.004 and p = 0.040, respectively), while donor age and D-R were not. CONCLUSION: While there was an effect of the non-modifiable parameter of donor age regarding maximal intimal thickness, a stronger association was seen between the modifiable risk factor dyslipidemia and higher maximal intimal thickness and CAVIH in both the overall population and the pediatric subpopulation.

Multiomic analyses uncover immunological signatures in acute and chronic coronary syndromes.

Acute and chronic coronary syndromes (ACS and CCS) are leading causes of mortality. Inflammation is considered a key pathogenic driver of these diseases, but the underlying immune states and their clinical implications remain poorly understood. Multiomic factor analysis (MOFA) allows unsupervised data exploration across multiple data types, identifying major axes of variation and associating these with underlying molecular processes. We hypothesized that applying MOFA to multiomic data obtained from blood might uncover hidden sources of variance and provide pathophysiological insights linked to clinical needs. Here we compile a longitudinal multiomic dataset of the systemic immune landscape in both ACS and CCS (n = 62 patients in total, n = 15 women and n = 47 men) and validate this in an external cohort (n = 55 patients in total, n = 11 women and n = 44 men). MOFA reveals multicellular immune signatures characterized by distinct monocyte, natural killer and T cell substates and immune-communication pathways that explain a large proportion of inter-patient variance. We also identify specific factors that reflect disease state or associate with treatment outcome in ACS as measured using left ventricular ejection fraction. Hence, this study provides proof-of-concept evidence for the ability of MOFA to uncover multicellular immune programs in cardiovascular disease, opening new directions for mechanistic, biomarker and therapeutic studies.

Peripheral priming induces plastic transcriptomic and proteomic responses in circulating neutrophils required for pathogen containment.

Neutrophils rapidly respond to inflammation and infection, but to which degree their functional trajectories after mobilization from the bone marrow are shaped within the circulation remains vague. Experimental limitations have so far hampered neutrophil research in human disease. Here, using innovative fixation and single-cell-based toolsets, we profile human and murine neutrophil transcriptomes and proteomes during steady state and bacterial infection. We find that peripheral priming of circulating neutrophils leads to dynamic shifts dominated by conserved up-regulation of antimicrobial genes across neutrophil substates, facilitating pathogen containment. We show the TLR4/NF-κB signaling-dependent up-regulation of canonical neutrophil activation markers like CD177/NB-1 during acute inflammation, resulting in functional shifts in vivo. Blocking de novo RNA synthesis in circulating neutrophils abrogates these plastic shifts and prevents the adaptation of antibacterial neutrophil programs by up-regulation of distinct effector molecules upon infection. These data underline transcriptional plasticity as a relevant mechanism of functional neutrophil reprogramming during acute infection to foster bacterial containment within the circulation.