Stroke outcomes following durable left ventricular assist device implant in patients bridged with micro-axial flow pump: Insights from a large registry.

BACKGROUND: Stroke after durable left ventricular assist device (d-LVAD) implantation portends high mortality. The incidence of ischemic and hemorrhagic stroke and the impact on stroke outcomes of temporary mechanical circulatory support (tMCS) management among patients requiring bridge to d-LVAD with micro-axial flow-pump (mAFP, Abiomed) is unsettled. METHODS: Consecutive patients, who underwent d-LVAD implantation after being bridged with mAFP at 19 institutions, were retrospectively included. The incidence of early ischemic and hemorrhagic stroke after d-LVAD implantation (<60 days) and association of pre-d-LVAD characteristics and peri-procedural management with a specific focus on tMCS strategies were studied. RESULTS: Among 341 patients, who underwent d-LVAD implantation after mAFP implantation (male gender 83.6%, age 58 [48-65] years, mAFP 5.0/5.5 72.4%), the early ischemic stroke incidence was 10.8% and early hemorrhagic stroke 2.9%. The tMCS characteristics (type of mAFP device and access, support duration, upgrade from intra-aortic balloon pump, ECMELLA, ECMELLA at d-LVAD implantation, hemolysis, and bleeding) were not associated with ischemic stroke after d-LVAD implant. Conversely, the device model (mAFP 2.5/CP vs. mAFP 5.0/5.5: HR 5.6, 95%CI 1.4-22.7, p = 0.015), hemolysis on mAFP support (HR 10.5, 95% CI 1.3-85.3, p = 0.028) and ECMELLA at d-LVAD implantation (HR 5.0, 95% CI 1.4-18.7, p = 0.016) were associated with increased risk of hemorrhagic stroke after d-LVAD implantation. Both early ischemic (HR 2.7, 95% CI 1.9-4.5, p < 0.001) and hemorrhagic (HR 3.43, 95% CI 1.49-7.88, p = 0.004) stroke were associated with increased 1-year mortality. CONCLUSIONS: Among patients undergoing d-LVAD implantation following mAFP support, tMCS characteristics do not impact ischemic stroke occurrence, while several factors are associated with hemorrhagic stroke suggesting a proactive treatment target to reduce this complication.

Clinical Features and Outcomes of Takotsubo (Stress) Cardiomyopathy.

BACKGROUND: The natural history, management, and outcome of takotsubo (stress) cardiomyopathy are incompletely understood. METHODS: The International Takotsubo Registry, a consortium of 26 centers in Europe and the United States, was established to investigate clinical features, prognostic predictors, and outcome of takotsubo cardiomyopathy. Patients were compared with age- and sex-matched patients who had an acute coronary syndrome. RESULTS: Of 1750 patients with takotsubo cardiomyopathy, 89.8% were women (mean age, 66.8 years). Emotional triggers were not as common as physical triggers (27.7% vs. 36.0%), and 28.5% of patients had no evident trigger. Among patients with takotsubo cardiomyopathy, as compared with an acute coronary syndrome, rates of neurologic or psychiatric disorders were higher (55.8% vs. 25.7%) and the mean left ventricular ejection fraction was markedly lower (40.7±11.2% vs. 51.5±12.3%) (P<0.001 for both comparisons). Rates of severe in-hospital complications including shock and death were similar in the two groups (P=0.93). Physical triggers, acute neurologic or psychiatric diseases, high troponin levels, and a low ejection fraction on admission were independent predictors for in-hospital complications. During long-term follow-up, the rate of major adverse cardiac and cerebrovascular events was 9.9% per patient-year, and the rate of death was 5.6% per patient-year. CONCLUSIONS: Patients with takotsubo cardiomyopathy had a higher prevalence of neurologic or psychiatric disorders than did those with an acute coronary syndrome. This condition represents an acute heart failure syndrome with substantial morbidity and mortality. (Funded by the Mach-Gaensslen Foundation and others; ClinicalTrials.gov number, NCT01947621.).

3D facial landmarks: Inter-operator variability of manual annotation.

BACKGROUND: Manual annotation of landmarks is a known source of variance, which exist in all fields of medical imaging, influencing the accuracy and interpretation of the results. However, the variability of human facial landmarks is only sparsely addressed in the current literature as opposed to e.g. the research fields of orthodontics and cephalometrics. We present a full facial 3D annotation procedure and a sparse set of manually annotated landmarks, in effort to reduce operator time and minimize the variance. METHOD: Facial scans from 36 voluntary unrelated blood donors from the Danish Blood Donor Study was randomly chosen. Six operators twice manually annotated 73 anatomical and pseudo-landmarks, using a three-step scheme producing a dense point correspondence map. We analyzed both the intra- and inter-operator variability, using mixed-model ANOVA. We then compared four sparse sets of landmarks in order to construct a dense correspondence map of the 3D scans with a minimum point variance. RESULTS: The anatomical landmarks of the eye were associated with the lowest variance, particularly the center of the pupils. Whereas points of the jaw and eyebrows have the highest variation. We see marginal variability in regards to intra-operator and portraits. Using a sparse set of landmarks (n=14), that capture the whole face, the dense point mean variance was reduced from 1.92 to 0.54 mm. CONCLUSION: The inter-operator variability was primarily associated with particular landmarks, where more leniently landmarks had the highest variability. The variables embedded in the portray and the reliability of a trained operator did only have marginal influence on the variability. Further, using 14 of the annotated landmarks we were able to reduced the variability and create a dense correspondences mesh to capture all facial features.

Impact of intra-aortic balloon counterpulsation on all-cause mortality among patients with Takotsubo syndrome complicated by cardiogenic shock: results from the German-Italian-Spanish (GEIST) registry.

Aims: Takotsubo syndrome (TTS) is an acute and reversible left ventricular dysfunction and can be complicated by cardiogenic shock (CS). However, few data are available on optimal care in TTS complicated by CS. Aim of this study was to evaluate short- and long-term impact of intra-aortic balloon pumping (IABP) on mortality in this setting. Methods and results: In a multi-centre, international registry on TTS, 2248 consecutive patients were enrolled from 38 centres from Germany, Italy, and Spain. Of the 2248 patients, 212 (9.4%) experienced CS. Patients with CS had a higher prevalence of diabetes (27% vs. 19%), male sex (25% vs. 10%), and right ventricular involvement (10% vs. 5%) (P < 0.01 in all cases). Forty-three patients with CS (20% of 212) received IABP within 8 h (interquartile range 4-18) after admission. No differences in terms of age, gender, cardiovascular risk factors, and admission left ventricular ejection fraction were found among patients with and without IABP. There were no significant differences in terms of 30-day mortality (16% vs. 17%, P = 0.98), length of hospitalization (18.9 vs. 16.7 days, P = 0.51), and need of invasive ventilation (35% vs. 41%, P = 0.60) among two groups: 30-day survival was not significantly different even after propensity score adjustment (log-rank P = 0.73). At 42-month follow-up, overall mortality in patients with CS and TTS was 35%, not significantly different between patients receiving IABP and not (37% vs. 35%, P = 0.72). Conclusions: In a large multi-centre observational registry, the use of IABP was not associated with lower mortality rates at short- and long-term follow-up in patients with TTS and CS.

Impact of national holidays and weekends on incidence of acute type A aortic dissection repair.

Previous studies have demonstrated that environmental and temporal factors may affect the incidence of acute type A aortic dissection (ATAAD). Here, we aimed to investigate the hypothesis that national holidays and weekends influence the incidence of surgery for ATAAD. For the period 1st of January 2005 until 31st of December 2019, we investigated a hypothesised effect of (country-specific) national holidays and weekends on the frequency of 2995 surgical repairs for ATAAD at 10 Nordic cities included in the Nordic Consortium for Acute Type A Aortic Dissection (NORCAAD) collaboration. Compared to other days, the number of ATAAD repairs were 29% (RR 0.71; 95% CI 0.54-0.94) lower on national holidays and 26% (RR 0.74; 95% CI 0.68-0.82) lower on weekends. As day of week patterns of symptom duration were assessed and the primary analyses were adjusted for period of year, our findings suggest that the reduced surgical incidence on national holidays and weekends does not seem to correspond to seasonal effects or surgery being delayed and performed on regular working days.

Toll-Like Receptor 3 Activator Preconditioning Enhances Modulatory Function of Adipose­Derived Mesenchymal Stem Cells in a Fully MHC-Mismatched Murine Model of Heterotopic Heart Transplantation.

BACKGROUND Donor-specific tolerance is the ultimate goal in organ transplantation. Diverse approaches, including the use of mesenchymal stem cells (MSCs), have been investigated to induce graft tolerance. Non-stimulated MSCs showed limited regulatory functions through interaction with multiple immune-regulatory cells, such as regulatory T cells (Tregs). To augment their functions, MSCs have been preconditioned with toll-like receptor (TLR3/4) agonist in autoimmune disease models, but results were conflicting. MATERIAL AND METHODS We evaluated the immunomodulatory effects of mouse adipose-derived mesenchymal stem cells (ADSCs) preconditioned with various combinations of TLR3/4 agonist and antagonists, including polyinosinic-polycytidylic acid poly(I:C)-TLR3 agonist, lipopolysaccharide (LPS) -TLR4 agonist, and TAK242-TLR4 antagonist. In vitro and in vivo experiments including mixed lymphocyte reaction, cytokines measurement, Tregs analysis, and a fully mismatched MHC heterotopic heart transplantation in mice (BALB/c to C57BL/6) were conducted. RESULTS ADSCs preconditioned with poly(I:C) showed the highest efficiency in inhibiting lymphocyte proliferation, which was correlated with the upregulation of fibrinogen-like protein 2 (FGL2), an effector molecule of Tregs. The mean survival of cardiac allografts was extended from 8 to 12 days by intravenous injection of a single dose of ADSCs preconditioned with TLR3 agonist. The proportion of Tregs in the recipient's spleen was significantly increased by injecting the poly(I:C)-stimulated ADSCs. CONCLUSIONS These results show that short-term TLR3 agonist preconditioning enhances the immunomodulatory efficacy of ADSCs, which can induce the generation of Tregs and upregulate the expression of FGL2, thereby improving the outcome of patients receiving organ transplantation.

Genome-wide association study in takotsubo syndrome - Preliminary results and future directions.

BACKGROUND: Takotsubo syndrome (TS) is an acute non-ischemic cardiomyopathy characterized by transient regional systolic dysfunction of the left and/or right ventricle with still unknown etiology. The aim of the current study was to conduct for the first time a genome-wide association study (GWAS) in a cohort of TS patients to identify potential genetic risk variants. METHODS: This single-center study was conducted at the University Heart Center Lübeck from 2008 to 2016. DNA isolation was done according to standard protocols. Imputation of genotypes were performed at the Michigan Imputation Server (https://imputationserver.sph.umich.edu) using the 1000G Phase 3 v5 reference panel. RESULTS: The study population consisted of 96 TS patients (91 females, 5 males) with a mean age of 71.9±10.4years and 475 healthy controls (268 males, 207 females). The results of GWAS analysis showed several promising candidate loci (68 loci after applying threshold of p<5∗10-4 and MAF>5%). Of these 68 loci, 18 loci contained top single nucleotide polymorphisms (SNPs) that were supported by SNPs in high Linkage Disequilibrium (r2>0.8) with p<10-3. Two out of the 18 loci contained SNP with hits in the GWAS catalog (traits: blood pressure, thyroid stimulating hormone). CONCLUSION: This first GWAS analysis in a larger cohort of patients with TS showed promising preliminary results. Further intensive research efforts of international collaborators are now necessary to enable deep-phenotyping of TS patients to ultimately assess a potential genetic cause of TS.

Left Ventricular Thrombi in Takotsubo Syndrome: Incidence, Predictors, and Management: Results From the GEIST (German Italian Stress Cardiomyopathy) Registry.

BACKGROUND: Left ventricular (LV) thrombi during Takotsubo syndrome represent a potential complication and can be associated with cerebrovascular embolic events. The aim of this study was to evaluate the exact incidence, predictors, and management strategies of LV thrombi in patients with Takotsubo syndrome. METHODS AND RESULTS: We enrolled 541 consecutive patients in a multicenter international registry. Clinical features and echocardiographic data at admission, during hospitalization, and after 3 months were evaluated. Survival rates for long-term follow-up (mean 984±908 days) were recorded. Twelve Takotsubo syndrome patients (2.2%) developed LV thrombi (all female presenting with apical ballooning pattern). All patients with LV thrombi were treated with oral anticoagulation therapy; however, 2 (17%) had a stroke before treatment initiation. These patients were characterized by a higher prevalence of ST-elevation (56% versus 16%; P<0.001) and higher troponin I levels (10.8±18.3 ng/mL versus 3.5±4.3 ng/mL; P=0.001) as compared with those without LV thrombi. At multivariate analysis including age, sex, LV ejection fraction, ST-elevation at admission, and apical ballooning pattern, troponin I level >10 ng/mL was the only predictor for LV thrombosis (hazard ratio 6.6, confidence interval, 1.01-40.0; P=0.04). After 3 months all LV thrombi disappeared. Oral anticoagulation therapy was interrupted in all patients except 1. At long-term follow-up, the survival rate was not different between patients with and without LV thrombi (84% versus 85%; P=0.99). CONCLUSIONS: LV thrombi have a relatively low incidence among patients with Takotsubo syndrome and were detected in female patients with apical ballooning pattern and increased troponin levels. Oral anticoagulation therapy for 3 months seems reasonable in these high-risk patients.

Long-term excess mortality in takotsubo cardiomyopathy: predictors, causes and clinical consequences.

AIMS: Despite increasing research efforts, the prognostic consequences of takotsubo cardiomyopathy (TTC) remain largely unknown. The aim of this study was therefore to compare the long-term mortality rate of TTC patients with high-risk patients presenting with ST-segment elevation myocardial infarction (STEMI). METHODS AND RESULTS: A total of 286 patients with TTC were matched for age and gender with 286 STEMI patients. Outcome was obtained with a standardized telephone follow-up. The primary analysis determined long-term mortality. A secondary analysis was performed evaluating 28-day and 1-year mortality. Follow-up was available for 96% of patients after a mean of 3.8 ± 2.5 years. In TTC patients, long-term mortality was significantly higher compared with the matched STEMI cohort [24.7% vs. 15.1%, hazard ratio (HR) 1.58, 95% confidence interval (CI) 1.07-2.33; P = 0.02]. There was no significant difference in the rates of 28-day (5.5% vs. 5.7%, HR 0.96, 95% CI 0.47-1.94; P = 0.91) and 1-year mortality (12.5% vs. 9%, HR 1.42, 95% CI 0.85-2.38; P = 0.18). In multivariable regression analysis, male sex, a high Killip class on admission, and diabetes mellitus were identified as independent predictors of mortality in TTC patients. A risk score consisting of these factors showed a higher mortality with an increasing number of risk factors. CONCLUSION: Mortality rates in TTC patients are higher than previously expected and long-term mortality exceeded that of patients with STEMI. A simple risk score may provide an approach to identify high-risk patients and predict clinical prognosis.