Multi‐organ dysfunction syndrome in patients undergoing extracorporeal life support

Background Multiple organ failure is a common complication in patients undergoing ECLS significantly affecting patient outcomes. Gaining knowledge about the mechanisms of onset, clinical course, risk factors, and potential therapeutic targets is highly desirable. Methods Data of 354 patients undergoing ECLS with one-, two, three-, and four organ failures were retrospectively analyzed. Incidence of multiple organ dysfunction (MODS), its impact on survival, risk factors for its occurrence, and the impact of proinflammatory mediators on the occurrence of MODS in patients undergoing ECLS were investigated. Results The median follow-up was 66 (IQR 6; 820) days. 245 (69.2%) patients could be weaned from ECLS, 30-day survival and 1-year survival were 194 (54.1%) and 157 (44.4%), respectively. The duration of mechanical support was 4 (IQR 2; 7) days in the median. Increasing severity of MODS resulted in significant prolongation of mechanical circulatory support and worsening of the outcome. Liver dysfunction had the strongest impact on patient mortality (OR = 2.5) and survival time (19 vs 367 days). The serum concentration of analyzed interleukins rose significantly with each, additional organ affected by dysfunction (p < 0.001). All analyzed proinflammatory cytokines showed significant predictivity relative to the occurrence of MODS with interleukin 8 serum level prior to ECLS showing the strongest predictive potential for the occurrence of MODS (AUC 0.78). Conclusion MODS represents a frequent complication in patients undergoing ECLS with a significant impact on survival. Proinflammatory cytokines show prognostic capacity regarding the occurrence and severity of multi-organ dysfunction

Angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker treatment and haemodynamic factors are associated with increased cardiac mRNA expression of angiotensin-converting enzyme 2 in patients with cardiovascular disease

Aims Coronavirus disease 2019 (COVID-19) is a widespread pandemic with an increased morbidity and mortality, especially for patients with cardiovascular diseases. Angiotensin-converting enzyme 2 (ACE2) has been identified as necessary cell entry point for SARS-CoV-2. Previous animal studies have demonstrated an increased ACE2 expression following treatment with either angiotensin-converting enzyme inhibitors (ACEi) or angiotensin II receptor blockers (ARB) that have led to a massive precariousness regarding the optimal cardiovascular therapy during this pandemic. Methods and results We have measured ACE2 mRNA expression using real-time quantitative polymerase chain reaction in atrial biopsies of 81 patients undergoing coronary artery bypass grafting and we compared 62 patients that received ACEi/ARB vs. 19 patients that were not ACEi/ARB-treated. We found atrial ACE2 mRNA expression to be significantly increased in patients treated with an ACEi or an ARB, independent of potential confounding comorbidities. Interestingly, the cardiac ACE2 mRNA expression correlated significantly with the expression in white blood cells of 22 patients encouraging further evaluation if the latter may be used as a surrogate for the former. Similarly, analysis of 18 ventricular biopsies revealed a significant and independent increase in ACE2 mRNA expression in patients with end-stage heart failure that were treated with ACEi/ARB. On the other hand, cardiac unloading with a left ventricular assist device significantly reduced ventricular ACE2 mRNA expression. Conclusion Treatment with ACEi/ARB is independently associated with an increased myocardial ACE2 mRNA expression in patients with coronary artery disease and in patients with end-stage heart failure. Further trials are needed to test whether this association is deleterious for patients with COVID-19, or possibly protective. Nevertheless, haemodynamic factors seem to be equally important for regulation of cardiac ACE2 mRNA expression

Systemic inflammation predicts diastolic dysfunction in patients with sleep disordered breathing

Heart failure with preserved ejection fraction (HFpEF) constitutes approximately half of all patients with heart failure and causes mortality similar to heart failure with reduced ejection fraction [1]. HFpEF is highly relevant as novel evidence-based therapies emerge but treatment options remain limited [1]. Diastolic dysfunction is a hallmark of HFpEF and is also very common in up to 80% of high-risk cardiovascular patients undergoing cardiac surgery [2]. Even without overt HFpEF, echocardiographic diastolic dysfunction is independently associated with increased mortality [3]. Another important characteristic of HFpEF is the frequent presence of comorbidities, with one of the most important being sleep disordered breathing (SDB). SDB affects over one billion patients in the general population and is highly prevalent in cardiovascular high-risk patients, which underscores its high socioeconomic relevance [4]. Interestingly, SDB patients frequently exhibit diastolic dysfunction [5]; however, the underlying mechanisms remain elusive thus far [6]. In this cross-sectional experimental study, we analysed the role of inflammation and fibrosis for diastolic dysfunction in cardiovascular high-risk patients stratified by the prevalence of SDB, which may provide a groundwork for future therapeutic strategies

Abnormal P‐wave terminal force in lead V 1 is a marker for atrial electrical dysfunction but not structural remodelling

Aims There is a lack of diagnostic and therapeutic options for patients with atrial cardiomyopathy and paroxysmal atrial fibrillation. Interestingly, an abnormal P-wave terminal force in electrocardiogram lead V1 (PTFV1) has been associated with atrial cardiomyopathy, but this association is poorly understood. We investigated PTFV1 as a marker for functional, electrical, and structural atrial remodelling. Methods and results Fifty-six patients with acute myocardial infarction and 13 kidney donors as control cohort prospectively underwent cardiac magnetic resonance imaging to evaluate the association between PTFV1 and functional remodelling (atrial strain). To further investigate underlying pathomechanisms, right atrial appendage biopsies were collected from 32 patients undergoing elective coronary artery bypass grafting. PTFV1 was assessed as the product of negative P-wave amplitude and duration in lead V1 and defined as abnormal if ≥4000 ms*μV. Activity of cardiac Ca/calmodulin-dependent protein kinase II (CaMKII) was determined by a specific HDAC4 pull-down assay as a surrogate for electrical remodelling. Atrial fibrosis was quantified using Masson's trichrome staining as a measure for structural remodelling. Multivariate regression analyses were performed to account for potential confounders. A total of 16/56 (29%) of patients with acute myocardial infarction, 3/13 (23%) of kidney donors, and 15/32 (47%) of patients undergoing coronary artery bypass grafting showed an abnormal PTFV1. In patients with acute myocardial infarction, left atrial (LA) strain was significantly reduced in the subgroup with an abnormal PTFV1 (LA reservoir strain: 32.28 ± 12.86% vs. 22.75 ± 13.94%, P = 0.018; LA conduit strain: 18.87 ± 10.34% vs. 10.17 ± 8.26%, P = 0.004). Abnormal PTFV1 showed a negative correlation with LA conduit strain independent from clinical covariates (coefficient B: −7.336, 95% confidence interval −13.577 to −1.095, P = 0.022). CaMKII activity was significantly increased from (normalized to CaMKII expression) 0.87 ± 0.17 to 1.46 ± 0.15 in patients with an abnormal PTFV1 (P = 0.047). This increase in patients with an abnormal PTFV1 was independent from clinical covariates (coefficient B: 0.542, 95% confidence interval 0.057 to 1.027, P = 0.031). Atrial fibrosis was significantly lower with 12.32 ± 1.63% in patients with an abnormal PTFV1 (vs. 20.50 ± 2.09%, P = 0.006), suggesting PTFV1 to be a marker for electrical but not structural remodelling. Conclusions Abnormal PTFV1 is an independent predictor for impaired atrial function and for electrical but not for structural remodelling. PTFV1 may be a promising tool to evaluate patients for atrial cardiomyopathy and for risk of atrial fibrillation

Empagliflozin inhibits increased Na influx in atrial cardiomyocytes of patients with HFpEF

Aims Heart failure with preserved ejection fraction (HFpEF) causes substantial morbidity and mortality. Importantly, atrial remodelling and atrial fibrillation are frequently observed in HFpEF. Sodium–glucose cotransporter 2 inhibitors (SGLT2i) have recently been shown to improve clinical outcomes in HFpEF, and post-hoc analyses suggest atrial anti-arrhythmic effects. We tested if isolated human atrial cardiomyocytes from patients with HFpEF exhibit an increased Na influx, which is known to cause atrial arrhythmias, and if that is responsive to treatment with the SGTL2i empagliflozin. Methods and results Cardiomyocytes were isolated from atrial biopsies of 124 patients (82 with HFpEF) undergoing elective cardiac surgery. Na influx was measured with the Na-dye Asante Natrium Green–2 AM (ANG-2). Compared to patients without heart failure (NF), Na influx was doubled in HFpEF patients (NF vs. HFpEF: 0.21 ± 0.02 vs. 0.38 ± 0.04 mmol/L/min (N = 7 vs. 18); P = 0.0078). Moreover, late INa (measured via whole-cell patch clamp) was significantly increased in HFpEF compared to NF. Western blot and HDAC4 pulldown assay indicated a significant increase in CaMKII expression, CaMKII autophosphorylation, CaMKII activity, and CaMKIIdependent NaV1.5 phosphorylation in HFpEF compared to NF, whereas NaV1.5 protein and mRNA abundance remained unchanged. Consistently, increased Na influx was significantly reduced by treatment not only with the CaMKII inhibitor autocamtide- 2-related inhibitory peptide (AIP), late INa inhibitor tetrodotoxin (TTX) but also with sodium/hydrogen exchanger 1 (NHE1) inhibitor cariporide. Importantly, empagliflozin abolished both increased Na influx and late INa in HFpEF. Multivariate linear regression analysis, adjusting for important clinical confounders, revealed HFpEF to be an independent predictor for changes in Na handling in atrial cardiomyocytes. Conclusion We show for the first time increased Na influx in human atrial cardiomyocytes from HFpEF patients, partly due to increased late INa and enhanced NHE1-mediated Na influx. Empagliflozin inhibits Na influx and late INa, which could contribute to anti-arrhythmic effects in patients with HFpEF

COVID-19 among heart transplant recipients in Germany: a multicenter survey

Abstract Aims Heart transplantation may represent a particular risk factor for severe coronavirus infectious disease 2019 (COVID-19) due to chronic immunosuppression and frequent comorbidities. We conducted a nation-wide survey of all heart transplant centers in Germany presenting the clinical characteristics of heart transplant recipients with COVID-19 during the first months of the pandemic in Germany. Methods and results A multicenter survey of all heart transplant centers in Germany evaluating the current status of COVID-19 among adult heart transplant recipients was performed. A total of 21 heart transplant patients with COVID-19 was reported to the transplant centers during the first months of the pandemic in Germany. Mean patient age was 58.6 ± 12.3 years and 81.0% were male. Comorbidities included arterial hypertension (71.4%), dyslipidemia (71.4%), diabetes mellitus (33.3%), chronic kidney failure requiring dialysis (28.6%) and chronic-obstructive lung disease/asthma (19.0%). Most patients received an immunosuppressive drug regimen consisting of a calcineurin inhibitor (71.4%), mycophenolate mofetil (85.7%) and steroids (71.4%). Eight of 21 patients (38.1%) displayed a severe course needing invasive mechanical ventilation. Those patients showed a high mortality (87.5%) which was associated with right ventricular dysfunction (62.5% vs. 7.7%; p = 0.014), arrhythmias (50.0% vs. none; p = 0.012), and thromboembolic events (50.0% vs. none; p = 0.012). Elevated high-sensitivity cardiac troponin T- and N-terminal prohormone of brain natriuretic peptide were significantly associated with the severe form of COVID-19 (p = 0.017 and p < 0.001, respectively). Conclusion Severe course of COVID-19 was frequent in heart transplanted patients. High mortality was associated with right ventricular dysfunction, arrhythmias, thromboembolic events, and markedly elevated cardiac biomarkers

Outcome after veno‐venous extracorporeal membrane oxygenation in elderly compared to younger patients: A 14‐year retrospective observational study

Background The outcome after veno-venous extracorporeal membrane oxygenation in elderly patients is supposed to be unsatisfactory. Our primary aim was to determine the influence of advanced age on short- and long-term outcomes; the secondary aim was to analyze risk factors for impaired outcomes. Methods Between January 2006 and June 2020, 755 patients received V-V ECMO support at our department. Patients were grouped according to age (18–49.9, 50–59.9, 60–69.9, ≥70 years old), and then retrospectively analyzed for short- and long-term outcomes. Risk factors for in-hospital mortality and death during follow-up were assessed using multivariate regression analysis. Results Duration of V-V ECMO support was comparable between all groups median (8–10 days, p = 0.256). Likewise, the weaning rate was comparable in all age groups 68.2%–76.5%; (p = 0.354), but in-hospital mortality was significantly climbing with increasing age (<50 years 30.1%/n = 91 vs. 50–59.9 years 37.1%/n = 73, vs. 60–69.9 years 45.6%/n = 78 vs. ≥70 years 51.8%/n = 44; p < 0.001). Older age groups also showed significantly reduced cerebral performance category scores. The multivariate logistic analysis yielded age, acute and chronic hemodialysis, bilirubin on day 1 of support, malignancy, and primary lung disease as relevant risk factors for in-hospital mortality. Age, coronary artery disease, presence of another primary lung disease, malignancy, and immunosuppression were risk factors for death during follow-up. Conclusion In V-V ECMO patients, advanced age is associated with more comorbidity, impaired short- and long-term outcome, and worse neurological outcome

Outcome after veno‐arterial extracorporeal membrane oxygenation in elderly patients: A 14‐year single‐center experience

Background Use of veno-arterial extracorporeal membrane oxygenation (VA-ECMO) in elderly patients is controversial because of presumed poor outcome. Our primary aim was to determine the influence of advanced age on short- and long-term outcome; the secondary aim was to analyze risk factors for impaired outcome. Methods Between January 2006 and June 2020, 645 patients underwent VA-ECMO implantation in our department. The patients were categorized into four groups:<50, 50–59.9, 60–69.9 and ≥70 years old. Data were retrospectively analyzed for short- and long-term outcome. Risk factors for in-hospital mortality and mortality during follow-up were assessed using multivariate regression analysis. Results VA-ECMO support duration was comparable in all age groups (median 3 days). Weaning rates were 60.8%/n = 104 (<50 years), 51.4%/n = 90 (50–59.9 years), 58.8%/n = 107 (60–69.9), and 67.5%/n = 79 (≥70, p = 0.048). Hospital mortality was highest in the patients aged 50–59.9 years (68%/n = 119), but not in the elderly patients (60–69.9, ≥70:62.1%/n = 113, 58,1%/n = 68). At discharge, the cerebral performance category scores were superior in the patients <50 years. Multivariate logistic regression analysis revealed chronic kidney failure requiring hemodialysis, duration of cardiopulmonary resuscitation, and elevated blood lactate levels before VA-ECMO, but not age as predictors of in-hospital mortality. Cox's regression disclosed age as relevant risk factor for death during follow-up. The patients' physical ability was comparable in all age groups. Conclusion VA-ECMO support should not be declined in patients only because of advanced age. Mortality and neurological status at hospital discharge and during follow-up were comparable in all age groups

Perforation of myocardial wall and great vessels after cardiovascular interventions—a 5-year analysis

Background: Less invasive procedures have replaced open surgical treatment in many cardiovascular disorders. During these interventions, iatrogenic cardiac perforation may ensue, which is a severe complication and requires immediate diagnostic assessment and treatment. Methods: From March 2011 to April 2016, all patients referred to the Dept. of Cardio-thoracic Surgery with the diagnosis of iatrogenic perforation of myocardial wall or great vessels were included into the retrospective study. Complications during transapical transcutaneous aortic valve replacements (TAVR) procedures and percutaneous coronary intervention (PCI) were excluded from analysis. Symptoms, therapeutic strategy, intraoperative findings, and outcome were evaluated. Results: Forty-four patients suffered from myocardial wall or vessel perforation. Most common site of perforation were right (n=26; 59.1%) and left (n=8; 18.2%) ventricle. Other structures were involved in ten cases (22.7%). Open surgical treatment was required in 27 cases (61.4%). Mortality after left and right ventricular laceration was 75.0% and 11.5%, respectively. Most common cause of death was cardiocirculatory failure (n=5). Conclusions: Iatrogenic perforation of myocardial wall or central vessels during percutaneous interventional procedures is a rare but life-threatening complication. Despite immediate treatment efforts, mortality is high, particularly after left ventricular laceration