[Out-of-hospital cardiac arrest during lockdown]. / Prähospitaler Kreislaufstillstand im Lockdown: Auswirkungen der übergreifenden Infektionspräventionsmaßnahmen während der ersten SARS-CoV-2-Welle.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread worldwide. Consequences of infection prevention measures during such contagion events can cause disadvantages especially for patients in out-of-hospital cardiac arrest (OHCA). METHODS: Retrospective analysis of OHCAs in one county from January-May in 2018, 2019 and 2020, with the first appearance of the SARS-CoV­2 pandemic in 2020 and a high incidence of the influenza virus in 2018. RESULTS: A total of 497 OHCAs were investigated (2018 n = 173; 2019 n = 149; 2020 n = 175). In this study, a constant resuscitation incidence (85-99 resuscitations/100,000 population/year) and locally typical patients (mean 70 years, 66% male; median PES 3) were found. There were no statistically significant differences in the initial situation of the patients (number of observed OHCAs, frequency of lay resuscitations, suspected causes of OHCAs, initial ECG rhythm) and the treatment course (frequency of return of spontaneous circulation [ROSC]/hospital admission/survival to hospital discharge, neurological outcome). None of the OHCA patients in 2020 tested positive for SARS-CoV­2 and 3 patients in 2018 tested positive for the influenza virus. DISCUSSION: The lockdown during the first wave of SARS-CoV­2 pandemic does not seem to have affected the outcome of OHCA patients without coronavirus disease 2019 (COVID-19) in the end.

Multimodal Elimination for Intoxication with a Lethal Dose of Organic Mercury.

We here report on a case of massive organic mercury intoxication in a 40-year-old man that resulted in progressive multiorgan failure. We treated the patient intravenously and enterally with the chelating agent (RS)-2,3-bis(sulfanyl) propane-1-sulfonic acid (DMPS) in addition to hemodialysis. The patient was treated for 6 weeks and could successfully be weaned from mechanical ventilation and hemodialysis. He awoke and was sent to rehabilitation, but unfortunately died 7 months later from refractory status epilepticus. Autopsy revealed severe brain atrophy consistent with organ damage from massive mercury intoxication. The present case illustrates that bimodal DMPS application is sufficient for detoxification from lethal mercury levels, with an associated chance for weaning of organ support and survival to discharge. The case further reminds us of intoxication as a cause of multiorgan dysfunction. We propose to immediately initiate combined parenteral and enteral detoxification in cases of methyl mercury intoxication, especially in cases of high doses.

[Cardiac causes of chest pain]. / Kardiologische Ursachen für Thoraxschmerz.

Because of the life-threatening character and a high prevalence in emergency rooms, cardiac causes are important differential diagnoses of acute chest pain with the need for rapid clarification. In this context the working diagnosis "acute coronary syndrome" (ACS) plays a major role. In a synopsis of the clinical presentation, medical history, electrocardiogram and analysis of cardiac biomarkers, ST-segment elevation myocardial infarction (STEMI), non-ST-segment elevation myocardial infarction (NSTEMI) and unstable angina pectoris can be specified as entities of ACS. The treatment of ACS consists of an immediate anti-ischemic therapy, anti-thrombotic therapy and invasive coronary diagnostics with subsequent interventional or operative revascularization therapy. The timing of invasive management is essentially determined by the individual patient risk, with the exception of STEMI where interventional revascularization must be undertaken within 120 min of diagnosis. In this context the GRACE 2.0 and TIMI risk score have become established as reliable tools. Another rare but fatal cause of acute chest pain is aortic dissection. An abrupt onset of tearing and sharp chest pains, deficits in pulse as well as the presence of high-risk factors, such as advanced age, arterial hypertension, atherosclerosis, known collagenosis and previous aortic or coronary artery procedures are highly indicative for aortic dissection and additional diagnostic imaging and the highly sensitive D­dimer should be undertaken. Additionally, inflammatory diseases, such as pericarditis and myocarditis can be associated with chest pains and mimic the character of ACS and should also be considered in the differential diagnostics.

Deficiency of MAPK-activated protein kinase 2 (MK2) prevents adverse remodelling and promotes endothelial healing after arterial injury.

Maladaptive remodelling of the arterial wall after mechanical injury (e. g. angioplasty) is characterised by inflammation, neointima formation and media hypertrophy, resulting in narrowing of the affected artery. Moreover, mechanical injury of the arterial wall causes loss of the vessel protecting endothelial cell monolayer. Mitogen-activated protein kinase (MAPK)-activated protein kinase 2 (MK2), a major downstream target of p38 MAPK, regulates inflammation, cell migration and proliferation, essential processes for vascular remodelling and re-endothelialisation. Therefore, we investigated the role of MK2 in remodelling and re-endothelialisation after arterial injury in genetically modified mice in vivo. Hypercholesterolaemic low-density-lipoprotein-receptor-deficient mice (ldlr-/-) were subjected to wire injury of the common carotid artery. MK2-deficiency (ldlr-/-/mk2-/-) nearly completely prevented neointima formation, media hypertrophy, and lumen loss after injury. This was accompanied by reduced proliferation and migration of MK2-deficient smooth muscle cells. In addition, MK2-deficiency severely reduced monocyte adhesion to the arterial wall (day 3 after injury, intravital microscopy), which may be attributed to reduced expression of the chemokine ligands CCL2 and CCL5. In line, MK2-deficiency significantly reduced the content of monocytes, neutrophiles and lymphocytes of the arterial wall (day 7 after injury, flow cytometry). In conclusion, in a model of endothelial injury (electric injury), MK2-deficiency strongly increased proliferation of endothelial cells and improved re-endothelialisation of the arterial wall after injury. Deficiency of MK2 prevents adverse remodelling and promotes endothelial healing of the arterial wall after injury, suggesting that MK2-inhibition is a very attractive intervention to prevent restenosis after percutaneous therapeutic angioplasty.

Drug-eluting stents and perioperative risk - more than matters of the heart?

The introduction of drug-eluting stents (DES) to interventional cardiology has been a breakthrough in the treatment of in-stent restenosis. However, the downside of reduced restenosis is a significantly prolonged and practically incalculable time to reendothelialization of thrombogenic stent-surfaces with an increased risk for coronary thrombosis. As the use of DES in non-coronary arteries (e.g. carotid, renal, infrainguinal and even cerebral arteries) is increasing, new vascular beds might be put at risk of ischemia. The practice of stopping antiplatelet drugs in a perioperative setting is highly problematic and contemporary guidelines released by scientific societies from different medical specialties have recently addressed this problem. While many case reports have reported alarming incidents of stent thrombosis, prospective clinical data are scarcely available to guide anticoagulation during the perioperative phase. This review summarizes information on the vascular biology of DES and associated adverse events based on a systematic search of the available literature in public data bases. An emphasis is put on the growing use of DES in non-coronary vessels and the associated danger of putting new vascular beds at risk of thrombotic complications.

Catheter fragmentation and local lysis in two lung transplant patients with pulmonary embolism.

In conjunction with the rising number of lung transplant operations in the past decade, an increased predisposition to venous thrombosis (VT), particularly within the first year posttransplantation has been observed. Previous studies have revealed that between 8.6% and 12% of patients develop VT, which can ultimately result in pulmonary emboli (PE).Transplanted lungs pose a much greater infarction risk due to their lack of collateral vascularisation, relying entirely on the vasa publica--the pulmonary artery--in the absence of vasa privata. Such losses in viable lung parenchyma are always serious, but carry still greater risks for single-lung transplant recipients, an early diagnosis and treatment remain critical. Here we report on two cases of PE after lung transplantation, both of whom were managed with catheter fragmentation and local thrombolysis. In our opinion, this approach represents a viable treatment for symptomatic PE in lung transplant recipients. The benefits and risks of the alternative treatment options in these special cases will be reviewed and the definitive therapy was described. In the patients treated, catheter fragmentation with localized thrombolysis resulted in short term improvements in graft function, but could not prevent later lung infarction in one case.

Angiotensin II type 1 receptor blockade: high hopes sent back to reality?

Chronic activation of the renin-angiotensin system (RAS) plays a crucial role in the development of various cardiovascular diseases (CVD). Thus, effective RAS inhibition has been a major achievement to improve the treatment of patients at risk for CVDs, such as myocardial infarction, heart failure and stroke. Three substance classes that block RAS-activation are currently available, angiotensin converting enzyme (ACE) inhibitors, angiotensin II type 1 receptor blockade (ARB) and renin inhibitors. Although the overall goal of these drugs remains the blockade of RAS activation, their individual targets in this system vary and may substantially influence the clinical benefit derived from the long term use of these substances. Here, we summarize the evidence available for the use of ARBs in different cardiovascular pathologies and the impact of this evidence on current treatment guidelines for patients at risk for CVD. Today, ARBs represent a good alternative in case of ACE-inhibitor intolerance due to their outstanding tolerability. ARBs in comparison to ACE-inhibitors have been proven to exert similar effective in the treatment of systolic heart failure, primary prevention of stroke, new onset of diabetes mellitus (DM) type 2 and DM type 2 dependent macroalbuminuria. ARBs should be considered as alternatives to ACE-inhibitors in subjects post-myocardial infarction. Overall however, there is no profound proof for a specific cardiovascular protection by blockade of the angiotensin II Type 1 (AT1) receptor that exceeds the impact of ACE-inhibition or synergises with ACE-blockade. In fact, combination of ARBs and ACE-inhibitor result in an increased rate of adverse effects and, therefore, this combination should not be encouraged. To summarize, the initial hope for a more specific impact on cardiovascular diseases by inhibition of the AT1-receptor in comparison to ACE-inhibition has not come true. However, ARBs have been proven to be equally effective as ACE-blockade in a large variety of clinical settings.

Eprosartan in the primary prevention of cardiac allograft vascular disease: a double-blind prospectively randomized study using intravascular ultrasound.

The angiotensin blocker (ARB) eprosartan (600 mg once daily) and the calcium antagonist diltiazem (90 mg twice daily) were studied in a 24-month prospective, randomized, double-blind trial involving 53 heart transplant patients. The study compared their effects on the development of post-transplant cardiac allograft vasculopathy, a condition that frequently impairs long-term post-transplantation survival and where angiotensin blockers might be expected to play a preventive role. From baseline to month 12, the mean plaque volume increased by 7.7 mm(3) for eprosartan-treated patients and by 34.4 mm(3) for diltiazem-treated patients, but the eprosartan-related trend for reduced myointimal hyperplasia was not statistically significant. The trend in favour of eprosartan for secondary parameters (mean intimal index, vessel volume, lumen volume and coronary flow reserve) also failed to reach significance. The lack of effect might be due to a lower than planned sample size and observation periods due to recruitment difficulties. A larger study is required to confirm these preliminary findings.

Role of G beta-subunit in angiotensin II-type 1 receptor signaling.

The G-protein-coupled angiotensin II-type 1 (AT1) receptor activates the mitogen-activated protein (MAP) kinase cascade and the Janus kinase 2/signal transducers and activators of transcription (JAK2/STAT) cascade via tyrosine phosphorylation. Recent observations indicated that the G beta-subunit of heterotrimeric G-proteins interacts with tyrosine phosphorylated proteins. We investigated whether angiotensin II (ANG II) activates MAP-kinases and JAK/STAT cascades via the G beta-subunit. In rat aortic smooth muscle (RASM) cells we found phosphorylated proteins associated with the G beta-subunit SHC (Sequence Homology of Collagen) and JAK2. We demonstrate that JAK2 activity increased upon G beta-binding. The activity of pp60(c-src) kinase also increased, but upon activation pp60(c-src) dissociates from the G beta-complex. Immunoprecipitations revealed that SHC forms a complex with JAK2. Blockade of JAK2 with AG490 abolished this complex formation; therefore, JAK2 may be the kinase responsible for SHC phosphorylation. Thus, the G beta-subunit may play a pivotal role in AT1-receptor signaling by connecting signaling cascades leading to cell growth and differentiation.

Expression of angiotensin II and interleukin 6 in human coronary atherosclerotic plaques: potential implications for inflammation and plaque instability.

BACKGROUND: Patients with an activated renin-angiotensin system (RAS) or genetic alterations of the RAS are at increased risk of myocardial infarction (MI). Administration of ACE inhibitors reduces the risk of MI, and acute coronary syndromes are associated with increased interleukin 6 (IL-6) serum levels. Accordingly, the present study evaluated the expression of angiotensin II (Ang II) in human coronary atherosclerotic plaques and its influence on IL-6 expression in patients with coronary artery disease. METHODS AND RESULTS: Immunohistochemical colocalization of Ang II, ACE, Ang II type 1 (AT(1)) receptor, and IL-6 was examined in coronary arteries from patients with ischemic or dilated cardiomyopathy undergoing heart transplantation (n=12), in atherectomy samples from patients with unstable angina (culprit lesion; n=8), and in ruptured coronary arteries from patients who died of MI (n=13). Synthesis and release of IL-6 was investigated in smooth muscle cells and macrophages after Ang II stimulation. Colocalization of ACE, Ang II, AT(1) receptor, and IL-6 with CD68-positive macrophages was observed at the shoulder region of coronary atherosclerotic plaques and in atherectomy tissue of patients with unstable angina. Ang II was identified in close proximity to the presumed rupture site of human coronary arteries in acute MI. Ang II induced synthesis and release of IL-6 shortly after stimulation in vitro in macrophages and rat smooth muscle cells. CONCLUSIONS: Ang II, AT(1) receptor, and ACE are expressed at strategic sites of human atherosclerotic coronary arteries, suggesting that Ang II is produced primarily by ACE within coronary plaques. The observation that Ang II induces IL-6 and their colocalization with the AT(1) receptor and ACE is consistent with the notion that the RAS may contribute to inflammatory processes within the vascular wall and to the development of acute coronary syndromes.

Role of NAD(P)H oxidase in angiotensin II-induced JAK/STAT signaling and cytokine induction.

Inflammatory processes involve both synthesis of inflammatory cytokines, such as interleukin-6 (IL-6), and the activation of their distinct signaling pathways, eg, the janus kinases (JAKs) and signal transducers and activators of transcription (STAT). Superoxide (O(2)(-)) anions activate this signaling cascade, and the vasoconstrictor angiotensin II (Ang II) enhances the formation of O(2)(-) anions via the NAD(P)H oxidase system in rat aortic smooth muscle cells. Ang II activates the JAK/STAT cascade via its type 1 (AT(1)) receptor and induces synthesis and release of IL-6. Therefore, we investigated the role of O(2)(-) anions generated by the NAD(P)H oxidase system on the Ang II activation of the JAK/STAT cascade and its impact on IL-6 synthesis. Ang II stimulation of rat aortic smooth muscle cells induced a rapid increase in O(2)(-) anions determined by laser fluoroscopy, which can be abolished by DPI, a flavoprotein inhibitor. Ang II-induced phosphorylation of JAK2, STAT1alpha/ss, STAT3, and IL-6-synthesis can be abolished by DPI, as determined by immunoprecipitations and Northern blot analysis. Electroporation of neutralizing antisera targeted against p47(phox), a NAD(P)H oxidase subunit, abolished Ang II-induced JAK/STAT activation and IL-6 synthesis. Inhibition of JAK2 by its inhibitor AG490 (10 micromol/L) blocked not only JAK2 activation but also IL-6 synthesis. These results suggest that stimulation of the JAK/STAT cascade by Ang II requires O(2)(-) anions generated by the NAD(P)H oxidase system, and O(2)(-) anion-dependent activation of the JAK/STAT cascade seems to be additionally involved in Ang II-induced IL-6 synthesis. Thus, Ang II-induced inflammatory effects seem to require O(2)(-) anions generated by the NAD(P)H oxidase system.

Angiotensin II-induced association of phospholipase Cgamma1 with the G-protein-coupled AT1 receptor.

An early event in signaling by the G-protein-coupled angiotensin II (Ang II) AT1 receptor in vascular smooth muscle cells is the tyrosine phosphorylation and activation of phospholipase Cgamma1 (PLCgamma1). In the present study, we show that stimulation of this event by Ang II in vascular smooth muscle cells is accompanied by binding of PLCgamma1 to the AT1 receptor in an Ang II- and tyrosine phophorylation-dependent manner. The PLCgamma1-AT1 receptor interaction appears to depend on phosphorylation of tyrosine 319 in a YIPP motif in the C-terminal intracellular domain of the AT1 receptor and binding of the phosphorylated receptor by the most C-terminal of two Src homology 2 domains in PLCgamma1. PLCgamma1 thus binds to the same site in the receptor previously identified for binding by the SHP-2 phosphotyrosine phosphatase.JAK2 tyrosine kinase complex. A single site in the C-terminal tail of the AT1 receptor can, therefore, be bound in a ligand-dependent manner by two different downstream effector proteins. These data demonstrate that G-protein-coupled receptors can physically associate with intracellular proteins other than G proteins, creating membrane-delimited signal transduction complexes similar to those observed for classic growth factor receptors.

Role of Janus kinase/signal transducer and activator of transcription and mitogen-activated protein kinase cascades in angiotensin II- and platelet-derived growth factor-induced vascular smooth muscle cell proliferation.

In vascular smooth muscle cells, the induction of early growth response genes involves the Janus kinase (JAK)/signal transducer and activators of transcription (STAT) and the Ras/Raf-1/mitogen-activated protein kinase cascades. In the present study, we found that electroporation of antibodies against MEK1 or ERK1 abolished vascular smooth muscle cell proliferation in response to either platelet-derived growth factor or angiotensin II. However, anti-STAT1 or -STAT3 antibody electroporation abolished proliferative responses only to angiotensin II and not to platelet-derived growth factor. AG-490, a specific inhibitor of the JAK2 tyrosine kinase, prevented proliferation of vascular smooth muscle cells, complex formation between JAK2 and Raf-1, the tyrosine phosphorylation of Raf-1, and the activation of ERK1 in response to either angiotensin II or platelet-derived growth factor. However, AG-490 had no effect on angiotensin II- or platelet-derived growth factor-induced Ras/Raf-1 complex formation. Our results indicate that: 1) STAT proteins play an essential role in angiotensin II-induced vascular smooth muscle cell proliferation, 2) JAK2 plays an essential role in the tyrosine phosphorylation of Raf-1, and 3) convergent mitogenic signaling cascades involving the cytosolic kinases JAK2, MEK1, and ERK1 mediate vascular smooth muscle cell proliferation in response to both growth factor and G protein-coupled receptors.

G protein-coupled receptors control vascular smooth muscle cell proliferation via pp60c-src and p21ras.

The binding of vasoactive peptides to their respective G protein-coupled receptors has been implicated in the pathogenesis of vascular smooth muscle cell proliferation, leading to the development of hypertension, arteriosclerosis, and restenosis after vascular injury. We previously showed that the cytosolic tyrosine kinase pp60c-src is crucial for angiotensin II (ANG II)-induced activation of the protooncogene p21ras. Therefore, we investigated the role of pp60c-src and p21ras in rat aortic smooth muscle cell proliferation induced by several G protein-coupled receptors. ANG II, endothelin-1, or thrombin increased cell proliferation and DNA synthesis. Electroporation of anti-pp60c-src antibodies into cells abolished proliferation in response to these G protein-coupled receptor ligands but not in response to platelet-derived growth factor-BB (PDGF-BB). In contrast, electroporation of anti-p21ras antibody completely blocked DNA synthesis and cell proliferation in response to ANG II, endothelin-1, thrombin, and PDGF-BB. Our data indicate that the pp60c-src tyrosine kinase is necessary and specific for vascular smooth muscle cell proliferation and DNA synthesis in response to G protein-coupled receptors but not classic growth factor receptors.

Angiotensin II stimulates tyrosine phosphorylation and activation of insulin receptor substrate 1 and protein-tyrosine phosphatase 1D in vascular smooth muscle cells.

Angiotensin II (Ang II) and insulin-like growth factor I (IGF I) stimulate intracellular signaling events through binding to their respective G-protein-coupled and growth factor receptors. In rat aortic vascular smooth muscle cells, IGF I (20 ng/ml) induced a sustained (>30 min) increase in the tyrosine phosphorylation of both Src-homology 2 domain-docking insulin receptor substrate 1 (IRS-1) and Src-homology 2-binding tyrosine phosphatase 1D (PTP-1D). In addition, IGF I stimulated PTP-1D phosphatase activity. Ang II (10(-7) M) also increased the tyrosine phosphorylation of IRS-1 (4-fold), PTP-1D (5-fold), and PTP-1D activity (3-4-fold), but with a more transient time course. Ang II also induced PTP-1D.IRS-1 complex formation. These Ang II-induced events were not affected by preincubation with an anti-IGF I antibody, suggesting that Ang II's actions were not mediated via the autocrine secretion of IGF I. Anti-PTP-1D antibody electroporation attenuated Ang II-induced PTP-1D.IRS-1 complex formation and PTP-1D tyrosine phosphorylation and activation. Our findings show that the tyrosine phosphorylation of IRS-1 and PTP-1D represents a convergent intracellular signaling cascade stimulated by both growth factor (i.e. IGF I) and G-protein-coupled (i.e. AT1) receptors.