Extracorporeal membrane oxygenation (ECMO) is considered a life-saving treatment option for patients in cardiogenic shock or cardiac arrest undergoing cardiopulmonary resuscitation (CPR) due to acute pulmonary embolism (PE). We sought to analyze use and outcome of ECMO with or without adjunctive treatment strategies in patients with acute PE. We retrospectively analyzed data on patient characteristics, treatments, and in-hospital outcomes for all PE patients (ICD-code I26) undergoing ECMO in Germany between 2005 and 2018. At total of 1,172,354 patients were hospitalized with PE; of those, 2,197 (0.2%) were treated with ECMO support. Cardiac arrest requiring cardiopulmonary resuscitation was present in 77,196 (6.5%) patients. While more than one fourth of those patients were treated with systemic thrombolysis alone (n = 20,839 patients; 27.0%), a minority of patients received thrombolysis and VA-ECMO (n = 165; 0.2%), embolectomy and VA-ECMO (n = 385; 0.5%) or VA-ECMOalone (n = 588; 0.8%). A multivariable logistic regression analysis indicated the lowest risk for in-hospital death in patients who received embolectomy in combination with VA-ECMO (OR, 0.50 [95% CI, 0.41-0.61], p < 0.001), thrombolysis and VA-ECMO (0.60 [0.43-0.85], p = 0.003) or VA-ECMO alone (0.68 [0.57-0.82], p < 0.001) compared to thrombolysis alone (1.04 [0.99-1.01], p = 0.116). Our findings suggest that the use of VA-ECMO alone or as part of a multi-pronged reperfusion approach including embolectomy or thrombolysis might offer survival advantages compared to thrombolysis alone in patients with PE deteriorating to cardiac arrest.

Aim: We have reported earlier that a high salt intake triggered an aestivation‐like natriuretic‐ureotelic body water conservation response that lowered muscle mass and increased blood pressure. Here, we tested the hypothesis that a similar adaptive water conservation response occurs in experimental chronic renal failure.Methods: In four subsequent experiments in Sprague Dawley rats, we used surgical 5/6 renal mass reduction (5/6 Nx) to induce chronic renal failure. We studied solute and water excretion in 24‐hour metabolic cage experiments, chronic blood pressure by radiotelemetry, chronic metabolic adjustment in liver and skeletal muscle by metabolomics and selected enzyme activity measurements, body Na⁺, K⁺ and water by dry ashing, and acute transepidermal water loss in conjunction with skin blood flow and intra‐arterial blood pressure.Results: 5/6 Nx rats were polyuric, because their kidneys could not sufficiently concentrate the urine. Physiological adaptation to this renal water loss included mobilization of nitrogen and energy from muscle for organic osmolyte production, elevated norepinephrine and copeptin levels with reduced skin blood flow, which by means of compensation reduced their transepidermal water loss. This complex physiologic‐metabolic adjustment across multiple organs allowed the rats to stabilize their body water content despite persisting renal water loss, albeit at the expense of hypertension and catabolic mobilization of muscle protein.Conclusion: Physiological adaptation to body water loss, termed aestivation, is an evolutionary conserved survival strategy and an under‐studied research area in medical physiology, which besides hypertension and muscle mass loss in chronic renal failure may explain many otherwise unexplainable phenomena in medicine.

Aim: Recent evidence suggests that arterial hypertension could be alternatively explained as a physiological adaptation response to water shortage, termed aestivation, which relies on complex multi‐organ metabolic adjustments to prevent dehydration. Here, we tested the hypothesis that chronic water loss across diseased skin leads to similar adaptive water conservation responses as observed in experimental renal failure or high salt diet.Methods: We studied mice with keratinocyte‐specific overexpression of IL‐17A which develop severe psoriasis‐like skin disease. We measured transepidermal water loss and solute and water excretion in the urine. We quantified glomerular filtration rate (GFR) by intravital microscopy, and energy and nitrogen pathways by metabolomics. We measured skin blood flow and transepidermal water loss (TEWL) in conjunction with renal resistive indices and arterial blood pressure.Results: Psoriatic animals lost large amounts of water across their defective cutaneous epithelial barrier. Metabolic adaptive water conservation included mobilization of nitrogen and energy from muscle to increase organic osmolyte production, solute‐driven maximal anti‐diuresis at normal GFR, increased metanephrine and angiotensin 2 levels, and cutaneous vasoconstriction to limit TEWL. Heat exposure led to cutaneous vasodilation and blood pressure normalization without parallel changes in renal resistive index, albeit at the expense of further increased TEWL.Conclusion: Severe cutaneous water loss predisposes psoriatic mice to lethal dehydration. In response to this dehydration stress, the mice activate aestivation‐like water conservation motifs to maintain their body hydration status. The circulatory water conservation response explains their arterial hypertension. The nitrogen‐dependency of the metabolic water conservation response explains their catabolic muscle wasting.

Aims. The neutrophil recruiting cytokine Interleukin-17A (IL-17A) is a key component in vascular dysfunction and arterial hypertension. Moreover, IL-17A has a central role for the vascular infiltration of myeloid cells into the arterial wall in Angiotensin II-induced vascular inflammation. The intention of our study was to analyze the impact of T cell-derived IL-17A on hypertension, vascular function, and inflammation.Methods and Results. Chronic IL-17A overexpression in T cells (CD4-IL-17A^ind/+mice) resulted in elevated reactive oxygen species in the peripheral blood and a significant vascular dysfunction compared to control mice. The vascular dysfunction seen in the CD4-IL-17A^ind/+mice was only accompanied by a modest and nonsignificant accumulation of inflammatory cells within the vessel wall. Therefore, infiltrating myeloid cells did not serve as an explanation of the vascular dysfunction seen in a chronic IL-17A-driven mouse model. In addition to vascular dysfunction, CD4-IL-17A^ind/+mice displayed vascular fibrosis with highly proliferative fibroblasts. This fibroblast proliferation was induced by exposure to IL-17A as confirmed byin vitroexperiments with primary murine fibroblastic cells. We also found that the^⋅NO/cGMP pathway was downregulated in the vasculature of the CD4-IL-17A^ind/+mice, while levels of protein tyrosine kinase 2 (PYK2), an oxidative stress-triggered process associated with T cell activation, were upregulated in the perivascular fat tissue (PVAT).Conclusions. Our data demonstrate that T cell-derived IL-17A elicits vascular dysfunction by mediating proliferation of fibroblasts and subsequent vascular fibrosis associated with PYK2 upregulation.

Heart failure (HF) ensuing myocardial infarction (MI) is characterized by the initiation of a systemic inflammatory response. We aimed to elucidate the impact of myelomonocytic cells and their activation by angiotensin II on vascular endothelial function in a mouse model of HF after MI. HF was induced in male C57BL/6J mice by permanent ligation of the left anterior descending coronary artery. Compared to sham, HF mice had significantly impaired endothelial function accompanied by enhanced mobilization of Sca-1⁺c-Kit⁺ haematopoietic stem cells and Sca-1⁻c-Kit⁺ common myeloid and granulocyte-macrophage progenitors in the bone marrow as well as increased vascular infiltration of CD11b⁺Ly6G⁻Ly6C^high monocytes and accumulation of CD11b⁺ F4/80⁺ macrophages, assessed by flow cytometry. Using mice with Cre-inducible expression of diphtheria toxin receptor in myeloid cells, we selectively depleted lysozyme M⁺ myelomonocytic cells for 10 days starting 28 days after MI. While the cardiac phenotype remained unaltered until 38 days post-MI, myeloid cell depletion attenuated vascular accumulation of Nox2⁺CD45⁺ cells, endothelial dysfunction, oxidative stress, and vascular expression of adhesion molecules and angiotensin II receptor type 1 (AT1R). Pharmacological blockade of this receptor for 4 weeks did not significantly alter cardiac function, but mimicked the effects of myeloid cell depletion: telmisartan (20 mg/kg/day, fed to C57BL/6J mice) diminished bone marrow myelopoesis and myeloid reactive oxygen species production, attenuated endothelial leucocyte rolling and vascular accumulation of CD11b⁺Ly6G⁻Ly6C^high monocytes and macrophages, resulting in improved vascular function with less abundance of Nox2⁺CD45⁺ cells. Endothelial dysfunction in HF ensuing MI is mediated by inflammatory Nox2⁺ myeloid cells infiltrating the vessel wall that can be targeted by AT1R blockade.

Despite major advances in acute interventions for myocardial infarction (MI), adverse cardiac remodeling and excess fibrosis after MI causing ischemic heart failure (IHF) remain a leading cause of death worldwide. Here we identify a profibrotic coagulation signaling pathway that can be targeted for improved cardiac function following MI with persistent ischemia. Quantitative phosphoproteomics of cardiac tissue revealed an upregulated mitogen-activated protein kinase (MAPK) pathway in human IHF. Intervention in this pathway with trametinib improves myocardial function and prevents fibrotic remodeling in a murine model of non-reperfused MI. MAPK activation in MI requires myeloid cell signaling of protease-activated receptor 2 linked to the cytoplasmic domain of the coagulation initiator tissue factor (TF). They act upstream of pro-oxidant NOX2 NADPH oxidase, ERK1/2 phosphorylation, and activation of profibrotic TGF-β1. Specific targeting with the TF inhibitor nematode anticoagulant protein c2 (NAPc2) starting 1 day after established experimental MI averts IHF. Increased TF cytoplasmic domain phosphorylation in circulating monocytes from patients with subacute MI identifies a potential thromboinflammatory biomarker reflective of increased risk for IHF and suitable for patient selection to receive targeted TF inhibition therapy.