Temporarily increased stroke rate after Takotsubo syndrome: need for an anticoagulation?

BACKGROUND: Previous studies have reported slightly higher stroke rates in Takotsubo Syndrome compared to acute myocardial infarction. Our goal was to evaluate the temporal course of stroke rates and left ventricular recovery in patients with Takotsubo Syndrome. METHODS: We retrospectively examined the clinical and imaging data of 72 patients with Takotsubo Syndrome. The data collected came from January 2005 to March 2017. Left ventricular performance was evaluated by cardiovascular magnetic resonance imaging (MRI) in all patients during the acute phase of Takotsubo Syndrome and in a follow-up scan 2 months later. Acute stroke and major adverse clinical events, such as myocardial infarction or recurrence of Takotsubo Syndrome and death, were also determined for each patient at 30 days and 12 months after initial presentation. RESULTS: The MRI scans performed during the acute phase of Takotsubo Syndrome demonstrated apical ballooning with anterior wall motion dysfunction in 65 (90%) patients. Imaging performed 2 months later demonstrated resolution of this in 97% of those patients. Median left ventricular ejection fraction also significantly increased between both scans (49.5% vs. 64.0%, P < 0.001). We observed 9 (12%) events in the study population within 12 months of the initial diagnosis of Takotsubo Syndrome. Stroke had an event rate of 2.8% after 30 days and 4.2% after 12 months. CONCLUSIONS: Apical ballooning was found in the majority of our Takotsubo Syndrome patients on the MRI scans performed at presentation. This finding was subsequently associated with higher than expected stroke rates within 30 days of diagnosis and with rapid recovery of left ventricular function within 2 months of diagnosis. This suggests that rapid improvement in left ventricular morphology and function may facilitate the formation of cardiac emboli and consequently increase stroke rates in Takotsubo Syndrome. Although no guidelines currently exist for the treatment of Takotsubo Syndrome, these results may point to a potential role for temporary oral anticoagulation in high-risk patients. Future studies should examine if stroke rates after Takotsubo Syndrome have been underestimated.

Evaluation of therapy management and outcome in Takotsubo syndrome.

BACKGROUND: To date there is no validated evidence for standardized treatment of patients with Takotsubo syndrome (TTS). Medication therapy after final TTS diagnosis remains unclear. Previous data on patient outcome is ambivalent. Aim of this study was to evaluate medication therapy in TTS and to analyze patient outcome. METHODS: Within an observational retrospective cohort study we analyzed our medical records and included 72 patients with TTS that underwent cardiovascular magnetic resonance imaging (CMR) after a median of 2 days interquartile range (IQR 1-3.5). We investigated medication therapy at discharge. Medication implementation and major adverse clinical events (MACE) were prospectively evaluated after a median follow-up of 24 months (IQR 6-43). Left ventricular function, myocardial oedema and late gadolinium enhancement were analyzed in a CMR follow-up if available. RESULTS: Antithrombotic therapy was recommended in 69 (96%) patients including different combinations. Antiplatelet monotherapy was prescribed in 28 (39%) patients. Dual antiplatelet therapy was recommended in 29 (40%) patients. Length of therapy duration varied from one to twelve months. Only in one case oral anticoagulation was prescribed due to apical ballooning with a left ventricular ejection fraction <30%. In all other cases oral anticoagulation was recommended due to other indications. ß-adrenoceptor antagonists and ACE inhibitors were recommended in 63 (88%), mineralocorticoid receptor antagonists were prescribed in 31 (43%) patients. After a median of 2 months (IQR 1.3-2.9) left ventricular function significantly recovered (49.1% ± 10.1 vs. 64.1% ± 5.7, P < 0.001) and myocardial oedema significantly decreased (13.5 ± 11.3 vs. 0.6% ± 2.4, P = <0.001) in the CMR follow-up. The 30-day mortality was 1%. MACE rate after 24 months was 12%. CONCLUSION: Although therapy guidelines for TTS currently do not exist, we found that the majority of patients were treated with antithrombotic and heart failure therapy for up to twelve months. Left ventricular function and myocardial oedema recovered rapidly within the first two months. Outcome analysis showed a low bleeding rate and a high short-term survival. Therefore, TTS patients might benefit from antithrombotic and heart failure therapy at least for the first two months.

Comparison of cardiac output estimates obtained from the Antares oscillometric pulse wave analysis algorithm and from Doppler transthoracic echocardiography.

BACKGROUND: In cardiology, cardiac output (CO) is an important parameter for assessing cardiac function. While invasive thermodilution procedures are the gold standard for CO assessment, transthoracic Doppler echocardiography (TTE) has become the established method for routine CO assessment in daily clinical practice. However, a demand persists for non-invasive approaches, including oscillometric pulse wave analysis (PWA), to enhance the accuracy of CO estimation, reduce complications associated with invasive procedures, and facilitate its application in non-intensive care settings. Here, we aimed to compare the TTE and oscillometric PWA algorithm Antares for a non-invasive estimation of CO. METHODS: Non-invasive CO data obtained by two-dimensional TTE were compared with those from an oscillometric blood pressure device (custo med GmbH, Ottobrunn, Germany) using the integrated algorithm Antares (Redwave Medical GmbH, Jena, Germany). In total, 59 patients undergoing elective cardiac catheterization for clinical reasons (71±10 years old, 76% males) were included. Agreement between both CO measures were assessed by Bland-Altman analysis, Student's t-test, and Pearson correlations. RESULTS: The mean difference in CO was 0.04 ± 1.03 l/min (95% confidence interval for the mean difference: -0.23 to 0.30 l/min) for the overall group, with lower and upper limits of agreement at -1.98 and 2.05 l/min, respectively. There was no statistically significant difference in means between both CO measures (P = 0.785). Statistically significant correlations between TTE and Antares CO were observed in the entire cohort (r = 0.705, P<0.001) as well as in female (r = 0.802, P<0.001) and male patients (r = 0.669, P<0.001). CONCLUSIONS: The oscillometric PWA algorithm Antares and established TTE for a non-invasive estimation of CO are highly correlated in male and female patients, with no statistically significant difference between both approaches. Future validation studies of the Antares CO are necessary before a clinical application can be considered.

γ-Interferon-regulated chaperone governs human lymphocyte antigen class II expression.

Antigen presentation by human lymphocyte antigen (HLA) class II peptide receptors alerts the immune system to infections. In antigen-presenting cells (APCs), HLA class II, HLA-DM, and associated invariant chain-encoding genes are exclusively regulated by the interferon γ (IFNγ)-inducible class II transactivator (CIITA). Control of CIITA expression could therefore govern expression of class II peptide receptors in the diverse group of APCs. We discovered that elevation of the HLA class III region encoded B-associated transcript 3 (BAT3) increases and depletion of BAT3 decreases expression of HLA class II, HLA-DM, and invariant chain. IFNγ strongly elevates BAT3 transcription in various tumor cell lines and in primary macrophages. BAT3 chaperones the simultaneously IFNγ-induced CIITA. Following IFNγ-treatment, both CIITA and BAT3 translocate from the cytosol to the nucleus. The nuclear import of CIITA mediated by IFNγ controls activation of HLA class II genes. BAT3 is a novel key regulator of components of the HLA class II processing pathway. We present a mechanism explaining how parallel IFNγ-mediated regulation of CIITA and of its chaperone BAT3 controls the level of components of the HLA class II processing pathway.

[Correlation between comorbidities and thoracic CT manifestations of COVID-19 pneumonia]. / Korrelation zwischen Komorbiditäten und Veränderungen des Lungenparenchyms im CT des Thorax bei Patienten mit COVID-19-Pneumonie.

BACKGROUND AND OBJECTIVES: Pulmonary manifestation of coronavirus disease 2019 (COVID-19) is described using standardized computed tomography (CT) morphologic criteria. In this study, we investigated possible associations between thoracic CT manifestations in COVID-19 pneumonia and typical comorbidities, as well as clinical course. METHODS: We analyzed clinical data and pulmonary imaging of 61 patients with positive PCR test. Pulmonary changes were categorized and reviewed for associations with pre-existing comorbidities and clinical course. RESULTS: Compared to patients with atypical infiltrate patterns (2/19, 10.5%), 25 patients with typical infiltrate patterns (25/42, 59.5%) were significantly more likely to receive intensive care (p<0.001). In addition, patients with typical infiltrate patterns were more likely to receive non-invasive ventilation (12/42, 28.6%, p=0.040) and high-flow therapy (8/42, 19%, p=0.041) compared to patients with atypical infiltrate patterns. Mortality was also higher in patients with typical infiltrate patterns, with 15 patients (15/42, 35.7%) dying during follow-up compared to only 1 patient with atypical infiltrate pattern (1/19, 10.5%, p=0.012). No significant association between specific comorbidities and the resulting infiltrate pattern could be demonstrated. CONCLUSIONS: Patients with a typical COVID-19 infiltrate pattern are more likely to receive intensive care and show higher mortality rates. Further analysis with larger patient collectives is needed to identify specific risk factors for typical COVID-19 pneumonia.

Value of CT in COVID-19-pandemia: A systematic analysis of CT-findings and outcomes in patients with COVID-19 pneumonia.

Chest-computer tomography (CT) is a crucial factor in the clinical course and evaluation of patients with COVID-pneumonia. In the initial phase of the COVID-19 pandemic little information was known on the prognostic value of the initially taken thoracic CTs. The purpose of this study was to determine predictive values for clinical outcome based on CT classification of the pulmonary pathologies in patients with COVID-pneumonia. This single center study included 51 non-immunized patients during the first COVID-19 outbreak in Germany. The patients underwent a clinically indicated chest-CT. Using the radiological society of North America (RSNA)-report template, chest-CTs were classified into 4 categories (typical, atypical, indeterminate, and no changes). We analyzed the outcomes based on these imaging classifications and relevant comorbidities. Among the 51 patients of our study population 14 (27.5%) patients had a lethal outcome. Typical radiological COVID-19 pattern was found in 92.9% of the deceased patients and in 59.5% of the surviving patients (P = .022). The lethal group showed a significant higher proportion of diabetes mellitus (50% vs 10.8%; P = .003) and arterial hypertension (aHTN) (85.7% vs 54.1%; P = .037). Male sex, higher age and coronary heart disease (CHD) were also seen more often in the lethal group. In patients with clinically proven COVID-19 pneumonia, typical chest CT findings show a negative outcome. A classification system used in this study is helpful for classifying imaging features and is recommended as a standardized CT reporting tool. It could also help in triaging of the therapy of patients with COVID-19 pneumonia. Especially the comorbidities, diabetes and arterial hypertonia triggered a negative outcome in our study population.

MRI findings in patients with acute coronary syndrome and unobstructed coronary arteries.

PURPOSE: The underlying diagnosis in patients with acute coronary syndrome (ACS) and unobstructed coronary arteries remains a diagnostic challenge. We analyzed the value of magnetic resonance imaging (MRI) in this clinical setting. METHODS: A total of 213 patients with ACS and unobstructed coronary arteries underwent MRI within a median of 2 days after initial presentation. Clinical, laboratory, and MRI data were analyzed. A consensus diagnosis was established for each case by an independent panel after reviewing the individual clinical, laboratory, and MRI data. Standardized interviews to determine patient outcomes were carried out after a median follow-up of 24 months. Clinical events were defined as a composite of death, stroke, myocardial infarction or recurrence of Takotsubo syndrome (TTS), new onset of heart failure with a left ventricular ejection fraction (LVEF) <30%, and occurrence of a new left ventricular thrombus formation. RESULTS: Final diagnoses included acute myocardial infarction (AMI) (40%), acute myocarditis (24%) and TTS (33%). In 3% of patients, nonspecific findings lead to an indeterminate diagnosis. Patients with TTS showed a significantly impaired LVEF during the index event (50% vs. 60% in AMI and 60% in myocarditis, P = 0.001). The extent of myocardial edema was most pronounced in patients with TTS (13.4%±11.4 vs. 4.6%±7.9 in AMI and 1.8%±2.7 in myocarditis, P < 0.001). TTS patients had the highest event rate (16.9%). CONCLUSION: Our study emphasizes the diagnostic utility of timely MRI in patients with ACS and unobstructed coronary arteries. We found a high prevalence of TTS patients, who had poorer outcomes compared with patients with a final diagnosis of AMI or myocarditis.

Clinical predictors for the manifestation of late gadolinium enhancement after acute myocardial infarction.

Despite prompt revascularization, some patients with acute myocardial infarction (AMI) develop myocardial scars, which can be visualized by late gadolinium enhancement (LGE) in cardiovascular magnetic resonance imaging (CMR). Our goal was to identify angiographic findings that were predictive for scar development in patients after reperfused AMI.We examined 136 patients after first ST-elevated myocardial infarction by CMR after a median of 4 days (range: 2-7). Patients with manifestation of LGE were matched to patients without LGE by means of age and gender. Clinical follow-up with a combined primary endpoint including myocardial reinfarction, congestive heart failure, stroke, death and development of left ventricular thrombus was reported after 24 months.Patients with manifestation of LGE had a significant longer time of symptom-to-intervention, a higher prevalence of anterior AMI, and more proximal culprit lesions. Furthermore, left ventricular ejection fraction was significantly decreased, and peak values of infarct markers were significantly higher in these patients. Preinterventional thrombolysis in myocardial infarction-0-flow was significantly more frequent in patients with LGE manifestation. The presence of 3-vessel disease (odds ratio 53.99, 95% confidence interval 8.22-354.63, P <.001), a proximal culprit lesion, and high creatine kinase myocardial band (CK-MB) values were identified as independent predictors of LGE. Follow-up demonstrated a higher incidence of clinical events in the group with LGE, with the most common cause of heart failure (38.2% vs 7.4%, P <.001).The extent of angiographic findings in AMI plays a major role in the manifestation of LGE. The presence of a multivessel disease, a proximal culprit lesion, and high values of CK-MB are strong independent predictors for LGE manifestation.

Temporal course of microvascular obstruction after myocardial infarction assessed by MRI.

PURPOSE: We aimed to analyze the extent of microvascular obstruction (MO) after the index event compared with the follow-up at a median of three months. METHODS: We identified 31 patients with MO after primary percutaneous coronary intervention of acute myocardial infarction by cardiac magnetic resonance imaging. The initial examination was performed after the index event, and 27 patients had the follow-up exam after a median of three months (interquartile range, 2-4 months). In addition, we examined 10 patients without MO after transmural myocardial infarction, as a control group. RESULTS: MO disappeared in 23 of 27 patients (85%) in the follow-up and transformed into transmural late gadolinium enhancement. In patients with persistent MO, mean MO size decreased from 2.25% to 1.25%. In patients with MO, mean infarct size decreased significantly from 20.8% to 14.7% (P < 0.001). In the control group, mean infarct size decreased from 12.7% to 10.5% in the follow-up scan (P = 0.137). CONCLUSION: MO is significantly reduced during the follow-up after acute myocardial infarction.

Long-term Effect of Optimized Sedation and Pain Management after Sudden Cardiac Arrest.

BACKGROUND AND AIMS: Appropriate use of sedatives and analgesics is essential to keep critically ill patients comfortable and to prevent prolonged mechanical ventilation time and length of stay in ICU. Aim of this study was to analyse the long-term effect of an algorithm-based individual analgesic-sedative protocol on mechanical ventilation time and ICU length of stay in critically ill patients after sudden cardiac arrest due to ST-elevated myocardial infarction. SUBJECT AND METHODS: We examined a total of 109 patients before and after implementation of an algorithm-based sedation management. Our sedation protocol included individual defined sedation goals achieved by standardized sedation strategies. Mechanical ventilation time and ICU length of stay were analysed for three groups of patients: before and after the intervention and in the long-term follow-up. RESULTS: We observed shorter median mechanical ventilation time and ICU length of stay in the interventional and longterm follow-up group compared to the standard-care group without statistical significance. CONCLUSION: Our results demonstrate a long-term reduction of mechanical ventilation time and ICU length of stay achieved by implementation of an individual sedation management. This suggests sedation guidelines as effective tools to reduce the mechanical ventilation time and ICU length of stay in patients after sudden cardiac arrest in ST-elevated myocardial infarction. Investigations with a larger patient number and higher statistical power are required to confirm these findings.

Diffusion-weighted MRI findings of treated and untreated retroperitoneal fibrosis.

PURPOSE: We aimed to evaluate diffusion-weighted imaging (DWI) findings in patients with treated and untreated retroperitoneal fibrosis (RPF). METHODS: We analyzed magnetic resonance imaging examinations of 44 RPF patients (36 male, 8 female), of which 15 were untreated and 29 were under therapy. Qualitative DWI and T1 postcontrast signal intensities and the largest perivascular extent of RPF were compared between treated and untreated groups and correlated to erythrocyte sedimentation rate and C-reactive protein values. Quantitative DWI signal intensities and apparent-diffusion-coefficients were calculated in regions-of-interest, together with a relative index between signal intensities of RPF and psoas muscle in 15 untreated patients and 14 patients under treatment with remaining perivascular fibrosis of more than 5 mm. RESULTS: The extent of RPF in untreated patients was significantly larger compared with the extent of RPF in treated patients (P <0.0001). DWI signal intensities were significantly higher in untreated patients than in patients under therapy (mean, 27 s/mm2 vs. 20 s/mm2; P = 0.009). The calculated DWI-index was significantly higher in untreated patients than in patients under therapy (P = 0.003). CONCLUSION: Our data show significant differences in the DWI findings (b800 signal intensities and relative DWI-index) of patients with treated and untreated RPF. DWI is a promising technique in the assessment of disease activity and the selection of patients suitable for medical therapy.

Assembly of matched alpha/beta subunits to HLA class II peptide receptors.

Human antigen presenting cells express three human leukocyte antigen (HLA) class II isotypes (DR, DP, and DQ), which are composed of polymorphic α and ß subunits. The combination of polymorphic α- and ß-chains results in cis (encoded on the same chromosome) or trans (encoded on different chromosomes) combinations. Since some of the α-ß combinations may yield mismatched non-functional α-ß heterodimers, it is not entirely clear which type of HLA class II peptide receptors are found on the cell surface of antigen presenting cells. We have developed a combination of biochemical techniques for inspection of the assembly and intracellular transport of isotype matched and mismatched class II heterodimers.

A novel BAT3 sequence generated by alternative RNA splicing of exon 11B displays cell type-specific expression and impacts on subcellular localization.

BACKGROUND: The human lymphocyte antigen (HLA) encoded BAT3/BAG6 recently attracted interest as a regulator of protein targeting and degradation, a function that could be exerted in the cytosol and in the nucleus. The BAT3 gene was described to consist of 25 exons. Diversity of transcripts can be generated by alternative RNA splicing, which may control subcellular distribution of BAT3. METHODOLOGY/PRINCIPAL FINDINGS: By cDNA sequencing we identified a novel alternatively spliced sequence of the BAT3 gene located between exons 11 and 12, which was designated as exon 11B. Using PCR and colony hybridization we identified six cDNA variants, which were produced by RNA splicing of BAT3 exons 5, 11B and 24. In four examined cell types the content of BAT3 splice variants was examined. Most of the cDNA clones from monocyte-derived dendritic cells contain exon 11B, whereas this sequence was almost absent in the B lymphoma Raji. Exon 5 was detected in most and exon 24 in approximately half of the cDNA clones. The subcellular distribution of endogenous BAT3 largely correlates with a cell type specific splicing pattern. In cells transfected with BAT3 variants, full-length and Δ24 BAT3 displayed nearly exclusive nuclear staining, whereas variants deleted of exon 11B showed substantial cytosolic expression. We show here that BAT3 is mainly expressed in the cytosol of Raji cells, while other cell types displayed both cytosolic and nuclear staining. Export of BAT3 from the nucleus to the cytosol is inhibited by treatment with leptomycin B, indicating that the Crm1 pathway is involved. Nuclear expression of BAT3 containing exon 11B suggests that this sequence plays a role for nuclear retention of the protein. CONCLUSIONS/SIGNIFICANCE: Cell type-specific subcellular expression of BAT3 suggests distinct functions in the cytosol and in the nucleus. Differential expression of BAT3 variants may reconcile the multiple roles described for BAT3.

Influence of algorithm-based analgesia and sedation in patients after sudden cardiac arrest.

PURPOSE: The aim of this study was to analyse the effect of an algorithm-based analgesic-sedative management on mechanical ventilation time and length of stay in a cardiological ICU with critical ill patients after sudden cardiac arrest. METHODS: We examined 100 patients after successful resuscitation in a retrospective-prospective single-centre trial by introducing an algorithm-based sedation management. Demographic data, severity of illness classified by APACHE II score (Acute Physiology and Chronic Health Evaluation II), neurological outcome and data for mechanical ventilation time and length of stay were acquired for both groups. RESULTS: We found a shorter ventilation time for young patients without severe illness, whereby significant longer ventilation time was observed for patients with higher APACHE II score. Between both groups, we found no significant differences in mechanical ventilation time and length of stay. CONCLUSIONS: Our results demonstrate a tendency towards a reduction of mechanical ventilation time for patients without severe illness after sudden cardiac arrest achieved by implementation of a new sedation management, whereby significant longer ventilation time was observed for severe ill patients. Because of lack of statistical significance of our present study, a randomized study with sufficient power is necessary to demonstrate positive effects of a standardized sedation management and its influence on severity of illness.

A membrane-destabilizing peptide in capsid protein L2 is required for egress of papillomavirus genomes from endosomes.

Papillomaviruses are internalized via clathrin-dependent endocytosis. However, the mechanism by which viral genomes pass endosomal membranes has not been elucidated. In this report we show that the minor capsid protein L2 is required for egress of viral genomes from endosomes but not for initial uptake and uncoating and that a 23-amino-acid peptide at the C terminus of L2 is necessary for this function. Pseudogenomes encapsidated by L1 and L2 lacking this peptide accumulated in vesicular compartments similar to that observed with L1-only viral particles, and these mutant pseudoviruses were noninfectious. This L2 peptide displayed strong membrane-disrupting activity, induced cytolysis of bacteria and eukaryotic cells in a pH-dependent manner, and permeabilized cells after exogenous addition. Fusions between green fluorescent protein and the L2 peptide integrated into cellular membranes like the wild type but not like C-terminal mutants of L2. Our data indicate that the L2 C terminus facilitates escape of viral genomes from the endocytic compartment and that this feature is conserved among papillomaviruses. Furthermore, the characteristic of this peptide differs from the classical virus-encoded membrane-penetrating peptides.