Clinical practice of continuous rhythm monitoring after embolic stroke of undetermined source.

AIMS: Embolic stroke of undetermined source (ESUS) accounts for up to 20% of ischemic strokes annually. Undetected atrial fibrillation (AF) is one important potential underlying cause. For AF, oral anticoagulation has evolved as the most preferable means of secondary stroke prevention. To detect unrecognized paroxysmal AF, long-term ECG monitoring is required, and implantable cardiac monitors (ICM) appear most suitable. Yet, ICMs are particularly costly, implantation is invasive, and remote monitoring places a personnel burden on health care providers. Here, we use data from a large cohort of ESUS patients to systematically analyze the effort of ICM remote monitoring for AF diagnosis and the strain on health care providers. METHODS AND RESULTS: From a prospective, single-center, observational ESUS registry, we analyzed all ICM-equipped patients post-ESUS (n = 172) between January 1st, 2018, and December 31st, 2019. Through January 2nd, 2023, 48 patients (27.9%) were diagnosed with AF by ICM remote monitoring. During follow-up, a total of 29,180 remote monitoring episodes were transmitted, of which 17,742 were alarms for AF. A systematic estimation of workload revealed that on average, 20.3 trained physician workhours are required to diagnose one patient with AF. CONCLUSION: ICM remote monitoring is useful to diagnose AF in cohort of post-ESUS patients. However, the number of ICM alarms is high, even in a cohort at known high risk of AF and in whom AF detection is therapeutically consequential. Improved automated event classification, clear recommendations for ICM interrogation after AF diagnosis, and a careful patient selection for ICM monitoring are warranted.

Major in-hospital complications after catheter ablation of cardiac arrhythmias: individual case analysis of 43 031 procedures.

AIMS: In-hospital complications of catheter ablation for atrial fibrillation (AF), atrial flutter (AFL), and ventricular tachycardia (VT) may be overestimated by analyses of administrative data. METHODS AND RESULTS: We determined the incidences of in-hospital mortality, major bleeding, and stroke around AF, AFL, and VT ablations in four German tertiary centres between 2005 and 2020. All cases were coded by the G-DRG- and OPS-systems. Uniform code search terms were applied defining both the types of ablations for AF, AFL, and VT and the occurrence of major adverse events including femoral vascular complications, iatrogenic tamponade, stroke, and in-hospital death. Importantly, all complications were individually reviewed based on patient-level source records. Overall, 43 031 ablations were analysed (30 361 AF; 9364 AFL; 3306 VT). The number of ablations/year more than doubled from 2005 (n = 1569) to 2020 (n = 3317) with 3 times and 2.5 times more AF and VT ablations in 2020 (n = 2404 and n = 301, respectively) as compared to 2005 (n = 817 and n = 120, respectively), but a rather stable number of AFL ablations (n = 554 vs. n = 612). Major peri-procedural complications occurred in 594 (1.4%) patients. Complication rates were 1.1% (n = 325) for AF, 1.0% (n = 95) for AFL, and 5.3% (n = 175) for VT. With an increase in complex AF/VT procedures, the overall complication rate significantly increased (0.76% in 2005 vs. 1.81% in 2020; P = 0.004); but remained low over time. Following patient-adjudication, all in-hospital cardiac tamponades (0.7%) and strokes (0.2%) were related to ablation. Major femoral vascular complications requiring surgical intervention occurred in 0.4% of all patients. The in-hospital mortality rate adjudicated to be ablation-related was lower than the coded mortality rate: AF: 0.03% vs. 0.04%; AFL: 0.04% vs. 0.14%; VT: 0.42% vs. 1.48%. CONCLUSION: Major adverse events are low and comparable after catheter ablation for AFL and AF (∼1.0%), whereas they are five times higher for VT ablations. In the presence of an increase in complex ablation procedures, a moderate but significant increase in overall complications from 2005-20 was observed. Individual case analysis demonstrated a lower than coded ablation-related in-hospital mortality. This highlights the importance of individual case adjudication when analysing administrative data.

Ontogeny of arterial macrophages defines their functions in homeostasis and inflammation.

Arterial macrophages have different developmental origins, but the association of macrophage ontogeny with their phenotypes and functions in adulthood is still unclear. Here, we combine macrophage fate-mapping analysis with single-cell RNA sequencing to establish their cellular identity during homeostasis, and in response to angiotensin-II (AngII)-induced arterial inflammation. Yolk sac erythro-myeloid progenitors (EMP) contribute substantially to adventitial macrophages and give rise to a defined cluster of resident immune cells with homeostatic functions that is stable in adult mice, but declines in numbers during ageing and is not replenished by bone marrow (BM)-derived macrophages. In response to AngII inflammation, increase in adventitial macrophages is driven by recruitment of BM monocytes, while EMP-derived macrophages proliferate locally and provide a distinct transcriptional response that is linked to tissue regeneration. Our findings thus contribute to the understanding of macrophage heterogeneity, and associate macrophage ontogeny with distinct functions in health and disease.

CCL22 controls immunity by promoting regulatory T cell communication with dendritic cells in lymph nodes.

Chemokines have crucial roles in organ development and orchestration of leukocyte migration. The chemokine CCL22 is expressed constitutively at high levels in the lymph node, but the functional significance of this expression is so far unknown. Studying a newly established CCL22-deficient mouse, we demonstrate that CCL22 expression by dendritic cells (DCs) promotes the formation of cell-cell contacts and interaction with regulatory T cells (T reg) through their CCR4 receptor. Vaccination of CCL22-deficient mice led to excessive T cell responses that were also observed when wild-type mice were vaccinated using CCL22-deficient DCs. Tumor-bearing mice with CCL22 deficiency showed prolonged survival upon vaccination, and further, CCL22-deficient mice had increased susceptibility to inflammatory disease. In conclusion, we identify the CCL22-CCR4 axis as an immune checkpoint that is crucial for the control of T cell immunity.

Cancer cell-derived IL-1α induces CCL22 and the recruitment of regulatory T cells.

In cancer patients, immunosuppression through regulatory T cells (Treg) is a crucial component of tumor immune evasion and contributes to disease progression. Tumor-infiltrating Treg in particular suppress local effector T cell responses and are associated with poor prognosis in tumors such as human pancreatic cancer or hepatocellular carcinoma (HCC). The chemokine CCL22 is known to recruit Treg into the tumor tissue and many types of human tumors are known to express high levels of CCL22. The mechanisms leading to intratumoral secretion of CCL22 are so far unknown. We demonstrate here that intratumoral CCL22 is induced in tumor-infiltrating immune cells through cancer cell-derived interleukin-1 (IL-1α). In pancreatic cancer and HCC, CCL22 is produced by intratumoral dendritic cells, while the cancer cells themselves do not secrete CCL22 in vitro and in vivo. Incubation of human peripheral blood mononuclear cells (PBMC) or murine splenocytes with tumor cells or tumor cell supernatants strongly induced CCL22 secretion in vitro. Tumor cell supernatants contained IL-1 and CCL22 induction in PBMC could be specifically prevented by the IL-1 receptor antagonist anakinra or by transfection of tumor cell lines with IL-1 siRNA, leading to a suppression of Treg migration. In conclusion, we identify here tumor cell-derived IL-1α as a major inducer of the Treg attracting chemokine CCL22 in human cancer cells. Therapeutic blockade of the IL-1 pathway could represent a promising strategy to inhibit tumor-induced immunosuppression.

Suppression of intratumoral CCL22 by type i interferon inhibits migration of regulatory T cells and blocks cancer progression.

The chemokine CCL22 is abundantly expressed in many types of cancer and is instrumental for intratumoral recruitment of regulatory T cells (Treg), an important subset of immunosuppressive and tumor-promoting lymphocytes. In this study, we offer evidence for a generalized strategy to blunt Treg activity that can limit immune escape and promote tumor rejection. Activation of innate immunity with Toll-like receptor (TLR) or RIG-I-like receptor (RLR) ligands prevented accumulation of Treg in tumors by blocking their immigration. Mechanistic investigations indicated that Treg blockade was a consequence of reduced intratumoral CCL22 levels caused by type I IFN. Notably, stable expression of CCL22 abrogated the antitumor effects of treatment with RLR or TLR ligands. Taken together, our findings argue that type I IFN blocks the Treg-attracting chemokine CCL22 and thus helps limit the recruitment of Treg to tumors, a finding with implications for cancer immunotherapy.

Long-term outcome of patients with severe biventricular heart failure and severe mitral regurgitation after percutaneous edge-to-edge mitral valve repair.

OBJECTIVE: To assess long-term outcome and parameters associated with poor and favorable outcome in patients with a left ventricular ejection fraction (LV-EF) ≤25% and severe mitral regurgitation (MR) after percutaneous edge-to-edge mitral valve repair (pMVR). BACKGROUND: There is no data on long-term outcome in this cohort of patients. METHODS: We analyzed all 34 patients with a LV-EF ≤25% and severe MR treated with pMVR in 2 university hospitals from 2009 to 2012. RESULTS: Mitral regurgitation could be successfully reduced to grade ≤2 in 30 patients (88%). Long-term follow-up (up to 5 years) revealed a steep decline of the survival curve reaching 50% already 8 month after pMVR. In contrast, estimated survival of the remaining patients showed a favorable long-term outcome. Patients deceased during the first year presented with higher right ventricular tricuspid pressure gradient (RVTG) (44.5 ± 8.4 mmHg vs. 35.2 ± 15.4 mmHg, P = 0.035) and worse RV-function (P = 0.014) prior to the procedure. One-year mortality of patients with pulmonary hypertension and depressed RV-function (n = 22) was very high (77%) compared to the remaining patients (n = 12, mortality rate of 0%, P = 0.0001). CONCLUSIONS: Although pMVR lead to a successful reduction of MR in patients with a LV-EF ≤25%, 1-year mortality in this cohort was very high. However, a subgroup of patients showed a favorable long-term outcome after pMVR. Especially the right ventricular parameters sustained RV-function and absence of pulmonary hypertension-easily assessed with echocardiography-might be used to identify this subgroup and encourage pMVR in these patients.

Dangerous liaison: successful percutaneous edge-to-edge mitral valve repair in patients with end-stage systolic heart failure can cause left ventricular thrombus formation.

AIMS: To evaluate the characteristics and clinical outcome of patients with new formation of left ventricular (LV) thrombus after percutaneous edge-to-edge mitral valve repair. METHODS AND RESULTS: Between 2009 and 2012 we intended to treat 150 patients with severe mitral regurgitation (MR) with percutaneous edge-to-edge mitral valve repair in our centre. Post-procedural transthoracic echocardiographic examinations scheduled during the hospital stay revealed the new formation of LV thrombi in three out of 150 patients. All three patients suffered from end-stage systolic heart failure with a LV ejection fraction (LVEF) below 20% and were successfully treated in terms of MR reduction (reduction of at least two MR grades). No thrombus formation was observed in patients with a LVEF >20% treated in our centre (a total of 136 patients). The frequency of new LV thrombus formation in the cohort of patients with a LVEF ≤20% treated in our centre was 21% (three out of 14 patients). CONCLUSIONS: New formation of LV thrombus was detected in patients with severely depressed LVEF (≤20%) after successful reduction of MR following percutaneous edge-to-edge mitral valve repair. This phenomenon could be a play of chance, but percutaneous edge-to-edge mitral valve repair using the MitraClip¨ system is a new procedure. Special care is needed when performing new procedures, and the unexpected post-procedural finding of LV thrombus formation in approximately 20% in this cohort is worth reporting.

Immunostimulatory RNA blocks suppression by regulatory T cells.

The role of immune suppression by regulatory T (Treg) cells in the maintenance of immune homeostasis is well established. However, little is known about how Treg cell function is inhibited on viral infection to allow the development of a protective immune response. As viral RNA is a crucial mediator for activation of antiviral immunity, we examined the effects of immunostimulatory RNA and infection with RNA viruses on Treg cell function. We show that synthetic RNA oligonucleotides potently inhibit Treg cell-induced suppression in a sequence-dependent manner. This effect is entirely dependent on TLR7 activation of APCs and subsequent IL-6 production. In addition, stimulation with the RNA viruses encephalomyocarditis virus and Sendai virus that specifically activate the RNA-sensing helicases melanoma differentiation-associated gene 5 (MDA-5) and retinoic acid-inducible gene I (RIG-I) also blocks Treg cell function. Interestingly, this effect is seen even in the absence of APCs. Consistent with this, both Treg and T effector cells express RIG-I and MDA-5. Using MDA-5-deficient mice, we demonstrate that the loss of Treg cell function on infection with encephalomyocarditis virus is strictly dependent on MDA-5 expression by Treg cells. Thus, we show in this study for the first time that activation of a RIG-I-like helicase on Treg cells blocks their suppressive function.

Activation of melanoma differentiation-associated gene 5 causes rapid involution of the thymus.

In the course of infection, the detection of pathogen-associated molecular patterns by specialized pattern recognition receptors in the host leads to activation of the innate immune system. Whereas the subsequent induction of adaptive immune responses in secondary lymphoid organs is well described, little is known about the effects of pathogen-associated molecular pattern-induced activation on primary lymphoid organs. Here we show that activation of innate immunity through the virus-sensing melanoma differentiation-associated gene 5 (MDA-5) receptor causes a rapid involution of the thymus. We observed a strong decrease in thymic cellularity associated with characteristic alterations in thymic subpopulations and microanatomy. In contrast, immune stimulation with potent TLR agonists did not lead to thymic involution or induce changes in thymic subpopulations, demonstrating that thymic pathology is not a general consequence of innate immune activation. We determined that suppression of thymocyte proliferation and enhanced apoptosis are the essential cellular mechanisms involved in the decrease in thymic size upon MDA-5 activation. Further, thymic involution critically depended on type I IFN. Strikingly however, no direct action of type I IFN on thymocytes was required, given that the decrease in thymic size was still observed in mice with a selective deletion of the type I IFN receptor on T cells. All changes observed were self-limiting, given that cessation of MDA-5 activation led to a rapid recovery of thymic size. We show for the first time that the in vivo activation of the virus-sensing MDA-5 receptor leads to a rapid and reversible involution of the thymus.