Transcriptional Regulation and Epigenetics in Cardiovascular Cells: Role of the Mineralocorticoid Receptor

The mineralocorticoid receptor (MR), a ligand-activated transcription factor, plays an important role in the pathophysiology of cardiovascular disease. Epigenetic mechanisms such as DNA methylation or histone modifications in addition to the DNA sequence are decisive regulators of cell type-specific transcriptional activity and gene expression by controlling chromatin accessibility. In this review, we summarise the current knowledge about the impact of MR on gene expression in cardiovascular cells. We discuss studies investigating the interaction of MR with epigenetic mechanisms or other transcription factors and their implications for the cardiovascular system. Finally, we compare mechanisms of transcriptional regulation by MR and other nuclear transcription factors. In conclusion, MR is an important regulator of gene expression in cardiovascular cells. Potential mechanisms of cell type-specific transcriptional regulation by MR include interaction with other transcription factors or co-regulators, tethering and post-translational modifications of the MR. Further studies will be needed to clarify the interplay of MR and epigenetic mechanisms

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Approaches towards tissue‐selective pharmacology of the mineralocorticoid receptor

Mineralocorticoid receptor antagonists (MRAs) are highly effective therapies for cardiovascular and renal disease. However, the widespread clinical use of currently available MRAs in cardiorenal medicine is hampered by an increased risk of hyperkalaemia. The mineralocorticoid receptor (MR) is a nuclear receptor responsible for fluid and electrolyte homeostasis in epithelial tissues, whereas pathophysiological MR activation in nonepithelial tissues leads to undesirable pro-inflammatory and profibrotic effects. Therefore, new strategies that selectively target the deleterious effects of the MR but spare its physiological function are needed. In this review, we discuss recent pharmacological developments starting from novel non-steroidal MRAs, such as finerenone or esaxerenone, that are now entering clinical use, to concepts arising from the current knowledge of the MR signalling pathway, aiming at receptor-coregulator interaction, epigenetics or downstream effectors of the MR

Histone Deacetylase 6 Inhibitor JS28 Prevents Pathological Gene Expression in Cardiac Myocytes

Background Epigenetic modulators have been proposed as promising new drug targets to treat adverse remodeling in heart failure. Here, we evaluated the potential of 4 epigenetic drugs, including the recently developed histone deacetylase 6 (HDAC6) inhibitor JS28, to prevent endothelin‐1 induced pathological gene expression in cardiac myocytes and analyzed the chromatin binding profile of the respective inhibitor targets. Methods and Results Cardiac myocytes were differentiated and puromycin‐selected from mouse embryonic stem cells and treated with endothelin‐1 to induce pathological gene expression (938 differentially expressed genes, q<0.05). Dysregulation of gene expression was at least in part prevented by epigenetic inhibitors, including the pan‐BRD (bromodomain‐containing protein) inhibitor bromosporine (290/938 genes), the BET (bromodomain and extraterminal) inhibitor JQ1 (288/938), the broad‐spectrum HDAC inhibitor suberoylanilide hydroxamic acid (227/938), and the HDAC6 inhibitor JS28 (210/938). Although the 4 compounds were similarly effective toward pathological gene expression, JS28 demonstrated the least adverse effects on physiological gene expression. Genome‐wide chromatin binding profiles revealed that HDAC6 binding sites were preferentially associated with promoters of genes involved in RNA processing. In contrast, BRD4 binding was associated with genes involved in core cardiac myocyte functions, for example, myocyte contractility, and showed enrichment at enhancers and intronic regions. These distinct chromatin binding profiles of HDAC6 and BRD4 might explain the different effects of their inhibitors on pathological versus physiological gene expression. Conclusions In summary, we demonstrated, that the HDAC6 inhibitor JS28 effectively prevented the adverse effects of endothelin‐1 on gene expression with minor impact on physiological gene expression in cardiac myocytes. Selective HDAC6 inhibition by JS28 appears to be a promising strategy for future evaluation in vivo and potential translation into clinical application

Hemoadsorption eliminates remdesivir from the circulation: Implications for the treatment of COVID‐19

Abstract Both antiviral treatment with remdesivir and hemoadsorption using a CytoSorb® adsorption device are applied in the treatment of severe COVID‐19. The CytoSorb® adsorber consists of porous polymer beads that adsorb a broad range of molecules, including cytokines but also several therapeutic drugs. In this study, we evaluated whether remdesivir and its main active metabolite GS‐441524 would be adsorbed by CytoSorb®. Serum containing remdesivir or GS‐441524 was circulated in a custom‐made system containing a CytoSorb® device. Concentrations of remdesivir and GS‐441524 before and after the adsorber were analyzed by liquid chromatography‐tandem mass spectrometry. Measurements of remdesivir in the outgoing tube after the adsorber indicated almost complete removal of remdesivir by the device. In the reservoir, concentration of remdesivir showed an exponential decay and was not longer detectable after 60 mins. GS‐441524 showed a similar exponential decay but, unlike remdesivir, it reached an adsorption–desorption equilibrium at ~48 µg/L. Remdesivir and its main active metabolite GS‐441524 are rapidly eliminated from the perfusate by the CytoSorb® adsorber device in vitro. This should be considered in patients for whom both therapies are indicated, and simultaneous application should be avoided. In general, plasma levels of therapeutic drugs should be closely monitored under concurrent CytoSorb® therapy

Admission blood glucose level and outcome in patients requiring venoarterial extracorporeal membrane oxygenation

Background!#!Patients with cardiogenic shock or cardiac arrest undergoing venoarterial extracorporeal membrane oxygenation (V-A ECMO) frequently present with blood glucose levels out of normal range. The clinical relevance of such findings in the context of V-A ECMO is unknown. We therefore investigated the prognostic relevance of blood glucose at time of cannulation for V-A ECMO.!##!Methods!#!We conducted a single-center retrospective registry study. All patients receiving V-A ECMO from October 2010 to January 2020 were included if blood glucose level at time of cannulation were documented. Patients were divided in five groups according to the initial blood glucose level ranging from hypoglycemic (&amp;lt; 80 mg/dl), normoglycemic (80-140 mg/dl), to mild (141-240 mg/dl), moderate (241-400 mg/dl), and severe (&amp;gt; 400 mg/dl) hyperglycemia, respectively. Clinical presentation, arterial blood gas analysis, and survival were compared between the groups.!##!Results!#!392 patients met inclusion criteria. Median age was 62 years (51.5-70.0), SAPS II at admission was 54 (43.5-63.0), and 108/392 (27.6%) were female. 131/392 were discharged alive (hospital survival 33.4%). At time of cannulation, survivors had higher pH, hemoglobin, calcium, bicarbonate but lower potassium and lactate levels compared to non-survivors (all p &amp;lt; 0.01). Outcome of patients diagnosed with particularly high (&amp;gt; 400 mg/dl) and low (&amp;lt; 80 mg/dl) blood glucose at time of V-A ECMO cannulation, respectively, was worse compared to patients with normoglycemic, mildly or moderately elevated values (p = 0.02). Glucose was independently associated with poor outcome after adjustment for other predictors of survival and persisted in all investigated subgroups.!##!Conclusion!#!Arterial blood glucose at time of V-A ECMO cannulation predicts in-hospital survival of patients with cardiac shock or after ECPR. Whether dysglycemia represents a potential therapeutic target requires further evaluation in prospective studies

Cytokine adsorption in patients with post-cardiac arrest syndrome after extracorporeal cardiopulmonary resuscitation (CYTER) - A single-centre, open-label, randomised, controlled trial

Aim: To investigate the effect of cytokine adsorption in patients receiving extracorporeal cardiopulmonary resuscitation (ECPR) after cardiac arrest. Methods: CYTER was a single-centre, open-label, randomised, controlled trial. Patients selected for ECPR at the University Medical Center Freiburg (Freiburg, Germany) were assigned to extracorporeal membrane oxygenation (ECMO) support with or without cytokine adsorption (1:1) using the CytoSorb adsorber, incorporated into the ECMO, replaced every 24 hours, and removed after 72 hours. The primary endpoint was serum interleukin (IL)-6 concentration at 72 hours (intention-to-treat analysis). Secondary endpoints included 30-day survival, vasopressor support and biomarkers of end-organ injury. Results: Of 50 patients enrolled in the trial, 26 (52%) were treated with cytokine adsorption and 24 (48%) without. Nine patients were excluded (informed consent could not be obtained); 41 patients were therefore included in the primary analysis. Median IL-6 levels (IQR) decreased from 408.0 (93.4-906.5) to 324.0 (134.3-4617.3) mu g/mL and increased from 133.0 (56.2-528.5) to 241.0 (132.8-718.0) mu g/mL in the cytokine adsorption and control group, respectively (linear regression for treatment [cytokine adsorption vs control]: p = 0.48). Three (14%) of 22 patients treated with cytokine adsorption and 8 (42%) of 19 patients treated without cytokine adsorption survived to day 30 (HR = 1.85, 95% CI 0.86-4.01; p = 0.10). Vasopressor support and NSE, S100b, troponin T, CRP and PCT levels were similar between groups. Conclusion: Cytokine adsorption in patients receiving ECPR did not reduce serum IL-6 and had no significant effect on survival, vasopressor support, or biomarkers of injury

Evaluation of Serum Serotonin as a Biomarker for Myocardial Infarction and Ischemia/Reperfusion Injury

Background: Activated platelets release serotonin during acute myocardial infarction (AMI), aggravating myocardial damage and ischemia/reperfusion (I/R) injury. However, serum serotonin and its potential role as a biomarker for myocardial infarction and I/R injury have not been studied so far. Methods: In this investigator-initiated pilot study, we examined 38 patients with ST-segment myocardial infarction (STEMI). We determined serum serotonin levels prior to percutaneous coronary intervention and 8, 16, and 24 h afterwards. We studied whether serum serotonin was associated with I/R injury assessed by ECG analysis and by analysis of TIMI myocardial perfusion grade (TMP) and myocardial blush grade (MGB). Serum serotonin levels were compared to an age-matched control group consisting of patients admitted to the emergency department for any other reason than STEMI. Results: Serum serotonin levels were not elevated in the myocardial infarction group compared to the control cohort and they did not show any timeline kinetics after STEMI. They were not associated with the severity of coronary artery disease, the outcome of coronary angiography, the extent of I/R injury, or the degree of heart failure. Conclusions: Serum serotonin is not suitable as a biomarker after myocardial infarction and in the assessment of I/R injury