Long-Term Follow-Up of Patients With Elevated Aldosterone-to-Renin Ratio but Negative Confirmatory Test: The Progression of Primary Aldosteronism Phenotypes.

BACKGROUND: About 10% of patients with arterial hypertension have a positive screening test for primary aldosteronism (PA) and 50% to 70% of them have a negative confirmatory test: the appropriate follow-up of these patients is currently unknown. We investigated the incidence of PA in patients with previous negative confirmatory testing, after at least a 2-year follow-up. METHODS: One hundred eighty-four patients with a previously elevated aldosterone-to-renin ratio followed by a negative confirmatory test were recruited in 2 hypertension centers (Torino and Munich). We repeated the screening test for PA and, if positive, the confirmatory test (seated saline infusion test or captopril challenge test). Primary end point of the study was the incidence of newly diagnosed overt PA, as defined by a positive confirmatory test. RESULTS: After a mean follow-up of 5 years, 20% of patients developed overt PA. When subtype diagnosis was offered systematically, one-third of patients displayed unilateral PA. Patients who developed PA showed worsening of blood pressure control and a higher rate of cardiac organ damage, despite similar implementation of antihypertensive therapy, compared with patients without PA. A mild progression of autonomous aldosterone secretion was evident even in patients without confirmed PA but with relatively stable control of blood pressure levels over time. CONCLUSIONS: About one-fifth of patients with a negative confirmatory test develop overt PA over time. A clinical follow-up of patients with a negative confirmatory test is advisable, along with the repetition of PA investigation, primarily in patients with worsening of blood pressure control.

Manual Compression versus Suture-Mediated Closure Device Technique for VA-ECMO Decannulation.

Background: The impact of devices for vessel closure on the safety and efficacy of cannula removal in VA-ECMO patients is unknown. Methods: We retrospectively analyzed 180 consecutive patients weaned from VA-ECMO after cardiac arrest or cardiogenic shock from January 2012 to June 2020. In the first period (historical technique group), from January 2012 to December 2018, primary decannulation strategy was manual compression. In the second period (current technique group), from January 2019 to June 2020, decannulation was performed either by a conventional approach with manual compression or by a suture-mediated closure device technique. Results: A femoral compression system was necessary in 71% of patients in the historical group compared to 39% in the current technique group (p < 0.01). Vascular surgery was performed in 12% in the historical cohort and 2% in the current technique cohort, which indicated a clear trend, albeit it did not reach significance (p = 0.07). Conclusion: We illustrated that a suture-mediated closure device technique for VA-ECMO decannulation was feasible, safe, and may have reduced the need of surgical interventions compared to manual compression alone.

Differences in Cell-Intrinsic Inflammatory Programs of Yolk Sac and Bone Marrow Macrophages.

BACKGROUND: Tissue-resident macrophages have mixed developmental origins. They derive in variable extent from yolk sac (YS) hematopoiesis during embryonic development. Bone marrow (BM) hematopoietic progenitors give rise to tissue macrophages in postnatal life, and their contribution increases upon organ injury. Since the phenotype and functions of macrophages are modulated by the tissue of residence, the impact of their origin and developmental paths has remained incompletely understood. METHODS: In order to decipher cell-intrinsic macrophage programs, we immortalized hematopoietic progenitors from YS and BM using conditional HoxB8, and carried out an in-depth functional and molecular analysis of differentiated macrophages. RESULTS: While YS and BM macrophages demonstrate close similarities in terms of cellular growth, differentiation, cell death susceptibility and phagocytic properties, they display differences in cell metabolism, expression of inflammatory markers and inflammasome activation. Reduced abundance of PYCARD (ASC) and CASPASE-1 proteins in YS macrophages abrogated interleukin-1ß production in response to canonical and non-canonical inflammasome activation. CONCLUSIONS: Macrophage ontogeny is associated with distinct cellular programs and immune response. Our findings contribute to the understanding of the regulation and programming of macrophage functions.

Synthesis, DNA-binding and antiproliferative properties of diarylquinolizinium derivatives.

A series of ten 2,7- and 2,8-diarylquinolizinium derivatives was synthesized and their DNA-binding and cytotoxic properties were investigated. Except for one nitro-substituted derivative all tested diarylquinolizinium ions bind to DNA with sufficient affinity (2 × 104 M-1-2 × 105 M-1). It was shown with photometric, fluorimetric and polarimetric titrations as well as with flow-LD analysis that the ligands bind mainly by intercalation to duplex DNA, however, depending on the ligand-DNA ratio, groove binding and backbone association were also observed with some derivatives. The biological activity was further investigated with tests of cytotoxicity and antiproliferative properties towards non-tumor cells and selected cancer cells, along with cell cycle analysis and an annexin-V assay. Notably, substrates that carry donor-functionalities in the 4-position of the phenyl substituents revealed a strong, and in some cases selective, antiproliferative activity as quantified by the growth inhibition, GI50, at very low micromolar and even submicromolar level both in leukemia and solid tumors.

Two populations of self-maintaining monocyte-independent macrophages exist in adult epididymis and testis.

Macrophages are the principal immune cells of the epididymis and testis, but their origins, heterogeneity, development, and maintenance are not well understood. Here, we describe distinct populations of epididymal and testicular macrophages that display an organ-specific cellular identity. Combining in vivo fate-mapping, chimeric and parabiotic mouse models with in-depth cellular analyses, we found that CD64hiMHCIIlo and CD64loMHCIIhi macrophage populations of epididymis and testis arise sequentially from yolk sac erythro-myeloid progenitors, embryonic hematopoiesis, and nascent neonatal monocytes. While monocytes were the major developmental source of both epididymal and testicular macrophages, both populations self-maintain in the steady-state independent of bone marrow hematopoietic precursors. However, after radiation-induced macrophage ablation or during infection, bone marrow-derived circulating monocytes are recruited to the epididymis and testis, giving rise to inflammatory macrophages that promote tissue damage. These results define the layered ontogeny, maintenance and inflammatory response of macrophage populations in the male reproductive organs.

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.

Hydroxychloroquine in COVID-19 Therapy: Protection Versus Proarrhythmia.

In recent months, the new coronavirus SARS-CoV-2 has emerged as a worldwide threat with about 4.2 million confirmed cases and almost 300 000 deaths. Its major clinical presentation is characterized by respiratory symptoms ranging from mild cough to serve pneumonia with fever and potentially even death. Until today, there is no known medication to improve clinical symptoms or even prevent or fight the infection. The search for a useful vaccination is ongoing and it will probably not be available before the end of 2020. In this review, we highlight hydroxychloroquine (HCQ) as a potential agent to prevent coronavirus disease 2019 (COVID-19) and reduce as well as shorten clinical symptoms. Moreover, it might serve as a potential post-exposition prophylaxis. Although it has been used in the treatment of rheumatoid arthritis, discoid or systemic lupus erythematosus, and malaria prophylaxis and therapy for decades, knowledge on HCQ as a potential treatment for COVID-19 is limited and multiple clinical trials have just emerged. Especially, rare HCQ side effects which were of minor importance for use in selected indications might gain major relevance with population-wide application. These rare side effects include retinopathy and-even more important-QT prolongation leading to sudden cardiac death by malignant arrhythmias.

[COVID-19: a cardiological point-of-view]. / COVID-19 aus Sicht der Kardiologie.

The SARS-CoV-2 pandemic has rapidly spread around the world and has led to a substantial morbidity and mortality in many countries. Although Corona Virus Disease 19 (COVID-19) is primarily a respiratory tract infection, there is growing evidence that other organs including the cardiovascular system are affected by COVID-19. In this review, we summarize the association of myocardial injury with in-hospital mortality of COVID-19 patients. Furthermore, we discuss potential mechanisms of myocardial injury including myocarditis and vascular thrombosis. Last, we review the current evidence on drugs which have been evaluated or are currently tested for the treatment of COVID-19 patients.

CD163 expression defines specific, IRF8-dependent, immune-modulatory macrophages in the bone marrow.

BACKGROUND: Scavenger receptor CD163 is exclusively expressed on monocytes/macrophages and is widely used as a marker for alternatively activated macrophages. However, the role of CD163 is not yet clear. OBJECTIVES: We sought to examine the function of CD163 in steady-state as well as in sterile and infectious inflammation. METHODS: Expression of CD163 was analyzed under normal and inflammatory conditions in mice. Functional relevance of CD163 was investigated in models of inflammation in wild-type and CD163-/- mice. RESULTS: We describe a subpopulation of bone marrow-resident macrophages (BMRMs) characterized by a high expression of CD163 and functionally distinct from classical bone marrow-derived macrophages. Development of CD163+ BMRMs is strictly dependent on IFN regulatory factor-8. CD163+ BMRMs show a specific transcriptome and cytokine secretion pattern demonstrating a specific immunomodulatory profile of these cells. Accordingly, CD163-/- mice show a stronger inflammation in allergic contact dermatitis, indicating a regulatory role of CD163. However, CD163-/- mice are highly susceptible to S aureus infections, demonstrating the relevance of CD163 for antimicrobial defense as well. CONCLUSIONS: Our data indicate that anti-inflammatory and immunosuppressive mechanisms are not necessarily associated with a decreased antimicrobial activity. In contrast, our data define a novel macrophage population that controls overwhelming inflammation on one hand but is also necessary for an effective control of infections on the other hand.

The Kidney Contains Ontogenetically Distinct Dendritic Cell and Macrophage Subtypes throughout Development That Differ in Their Inflammatory Properties.

BACKGROUND: Mononuclear phagocytes (MPs), including macrophages, monocytes, and dendritic cells (DCs), are phagocytic cells with important roles in immunity. The developmental origin of kidney DCs has been highly debated because of the large phenotypic overlap between macrophages and DCs in this tissue. METHODS: We used fate mapping, RNA sequencing, flow cytometry, confocal microscopy, and histo-cytometry to assess the origin and phenotypic and functional properties of renal DCs in healthy kidney and of DCs after cisplatin and ischemia reperfusion-induced kidney injury. RESULTS: Adult kidney contains at least four subsets of MPs with prominent Clec9a-expression history indicating a DC origin. We demonstrate that these populations are phenotypically, functionally, and transcriptionally distinct from each other. We also show these kidney MPs exhibit unique age-dependent developmental heterogeneity. Kidneys from newborn mice contain a prominent population of embryonic-derived MHCIInegF4/80hiCD11blow macrophages that express T cell Ig and mucin domain containing 4 (TIM-4) and MER receptor tyrosine kinase (MERTK). These macrophages are replaced within a few weeks after birth by phenotypically similar cells that express MHCII but lack TIM-4 and MERTK. MHCII+F4/80hi cells exhibit prominent Clec9a-expression history in adulthood but not early life, indicating additional age-dependent developmental heterogeneity. In AKI, MHCIInegF4/80hi cells reappear in adult kidneys as a result of MHCII downregulation by resident MHCII+F4/80hi cells, possibly in response to prostaglandin E2 (PGE2). RNA sequencing further suggests MHCII+F4/80hi cells help coordinate the recruitment of inflammatory cells during renal injury. CONCLUSIONS: Distinct developmental programs contribute to renal DC and macrophage populations throughout life, which could have important implications for therapies targeting these cells.

Heterogeneity of Macrophages in Atherosclerosis.

Atherosclerosis is a prevalent inflammatory condition and a frequent cause of morbidity and mortality worldwide. Macrophages are among the key immune cells driving lesion formation in the arterial wall. They have therefore evolved as potential targets for therapeutic strategies. Understanding of the different macrophage phenotypes and functions seems to be of pivotal importance for the development of treatments to target these immune cells. This review highlights the complexity of the mononuclear phagocyte system and summarizes important features of macrophage biology contributing to atherosclerosis.

The Kindlin protein family: new members to the club of focal adhesion proteins.

Kindlins are a group of proteins that have recently attracted attention for their ability to bind and activate integrins. Moreover, they have also been linked to inherited and acquired human diseases including Kindler syndrome, leukocyte adhesion deficiency, and cancer. Although most studies have focused on kindlins as key regulatory components of cell-extracellular matrix junctions such as focal adhesions, preliminary data suggest the involvement of additional cellular compartments in mediating their functions, particularly at cell-cell contacts and the nucleus. Investigating the many roles of kindlins is likely to expand and sharpen our view on the versatility of integrin-mediated cell adhesion, the nuclear function of focal adhesion proteins, and the crosstalk between cell-cell and cell-matrix adhesions in health and disease.