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BACKGROUND: The impact of sex-differences on the release of cardiac biomarkers after coronary artery bypass grafting (CABG) remains unknown. The aim of our study was to (1) investigate the impact of sex-differences in cardiac biomarker release after CABG and (2) determine sex-specific thresholds for high-sensitivity cardiac troponin (hs-cTn) and creatine kinase-myocardial band (CK-MB) associated with 30-day major adverse cardiovascular events (MACE) and mortality. METHODS: A consecutive cohort of 3687 patients, comprising 643 women (17.4%) and 3044 men (82.6%), undergoing CABG from 2008 to 2021 in 2 tertiary university centers with serial postoperative cTn and CK-MB measurement was analyzed. The composite primary outcome was MACE at 30 days. Secondary end points were 30-day mortality and 5-year mortality and MACE. Sex-specific thresholds for cTn and CK-MB were determined. RESULTS: Lower levels of cTn were found in women after CABG (69.18 vs 77.57 times the upper reference limit [URL]; P < .001). The optimal threshold value for cTn was calculated at 94.36 times the URL for female patients and 206.07 times the URL for male patients to predict 30-day MACE. Female patients missed by a general threshold had increased risk for MACE or death within 30 days (cTn: MACE: odds ratio [OR], 3.78; 95% CI, 1.03-13.08; P = .035; death: OR, 4.98; 95% CI, 1.20-20.61; P = .027; CK-MB: MACE: OR, 10.04; 95% CI, 2.07-48.75; P < .001; death: OR 13.59; 95% CI, 2.66-69.47; P = .002). CONCLUSIONS: We provide evidence for sex-specific differences in the outcome and biomarker release after CABG. Sex-specific cutoffs are necessary for the diagnosis of perioperative myocardial injury to improve outcomes of women after CABG.
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BACKGROUND AND AIMS: In chronic ischaemic heart failure, revascularisation strategies control symptoms but are less effective in improving left ventricular ejection fraction (LVEF). The aim of this trial is to investigate the safety of cardiac shockwave therapy (SWT) as a novel treatment option and its efficacy in increasing cardiac function by inducing angiogenesis and regeneration in hibernating myocardium. METHODS: In this single-blind, parallel-group, sham-controlled trial (cardiac shockwave therapy for ischemic heart failure, CAST-HF; NCT03859466) patients with LVEF ≤40% requiring surgical revascularisation were enrolled. Patients were randomly assigned to undergo direct cardiac SWT or sham treatment in addition to coronary bypass surgery. The primary efficacy endpoint was the improvement in LVEF measured by cardiac magnetic resonance imaging from baseline to 360 days. RESULTS: Overall, 63 patients were randomized, out of which 30 patients of the SWT group and 28 patients of the Sham group attained 1-year follow-up of the primary endpoint. Greater improvement in LVEF was observed in the SWT group (Δ from baseline to 360 days: SWT 11.3%, SD 8.8; Sham 6.3%, SD 7.4, P = .0146). Secondary endpoints included the 6-minute walking test, where patients randomized in the SWT group showed a greater Δ from baseline to 360 days (127.5â m, SD 110.6) than patients in the Sham group (43.6â m, SD 172.1) (P = .028) and Minnesota Living with Heart Failure Questionnaire score on day 360, which was 11.0 points (SD 19.1) for the SWT group and 17.3 points (SD 15.1) for the Sham group (P = .15). Two patients in the treatment group died for non-device-related reasons. CONCLUSIONS: In conclusion, the CAST-HF trial indicates that direct cardiac SWT, in addition to coronary bypass surgery improves LVEF and physical capacity in patients with ischaemic heart failure.
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Pontage aortocoronarien , Défaillance cardiaque , Ischémie myocardique , Débit systolique , Humains , Mâle , Femelle , Défaillance cardiaque/thérapie , Défaillance cardiaque/physiopathologie , Méthode en simple aveugle , Adulte d'âge moyen , Ischémie myocardique/thérapie , Ischémie myocardique/physiopathologie , Ischémie myocardique/complications , Ischémie myocardique/chirurgie , Débit systolique/physiologie , Sujet âgé , Résultat thérapeutique , Association thérapeutique , Ondes de choc de haute énergie/usage thérapeutiqueRÉSUMÉ
OBJECTIVES: Barlow's disease is a specific sub-form of mitral valve (MV) disease, characterized by diffuse excessive tissue and multi segment prolapse. The anterolateral mini-thoracotomy represents the standard access for MV regurgitation in many centres. It still remains unclear which surgical technique provides the best results. Therefore, the aim of this study was to compare operative safety and mid-term outcomes after (i) isolated annuloplasty, (ii) use of additional artificial chordae or (iii) leaflet resection in patients suffering from Barlow's disease undergoing minimally invasive MV repair. METHODS: A consecutive series of patients suffering from Barlow's disease undergoing minimally invasive MV surgery between 2001 and 2020 were analysed (n = 246). Patients were grouped and analysed according to the used surgical technique. The primary outcome was a modified Mitral Valve Academic Research Consortium combined end-point of mortality, reoperation due to repair failure or reoccurrence of severe mitral regurgitation within 5 years. The secondary outcome included operative success and safety up to 30 days. RESULTS: No significant difference was found between the 3 surgical techniques with regard to operative safety (P = 0.774). The primary outcome did not differ between groups (P = 0.244). Operative success was achieved in 93.5% and was lowest in the isolated annuloplasty group (77.1%). Conversion to MV replacement was increased in patients undergoing isolated annuloplasty (P < 0.001). CONCLUSIONS: Isolated annuloplasty, use of additional artificial chordae and leaflet resection represent feasible techniques in Barlow patients undergoing minimally invasive MV surgery with comparable 5-year results. In view of the increased conversion rate in the annuloplasty group, the pathology should not be oversimplified.
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Interventions chirurgicales mini-invasives , Annuloplastie mitrale , Prolapsus de la valve mitrale , Valve atrioventriculaire gauche , Humains , Femelle , Mâle , Prolapsus de la valve mitrale/chirurgie , Interventions chirurgicales mini-invasives/méthodes , Adulte d'âge moyen , Valve atrioventriculaire gauche/chirurgie , Annuloplastie mitrale/méthodes , Annuloplastie mitrale/effets indésirables , Résultat thérapeutique , Études rétrospectives , Insuffisance mitrale/chirurgie , Sujet âgé , Adulte , Implantation de valve prothétique cardiaque/méthodes , Implantation de valve prothétique cardiaque/mortalité , Implantation de valve prothétique cardiaque/effets indésirablesRÉSUMÉ
Consciousness is lost within seconds upon cessation of cerebral blood flow. The brain cannot store oxygen, and interruption of oxidative phosphorylation is fatal within minutes. Yet only rudimentary knowledge exists regarding cortical partial oxygen tension (Po2) dynamics under physiological conditions. Here we introduce Green enhanced Nano-lantern (GeNL), a genetically encoded bioluminescent oxygen indicator for Po2 imaging. In awake behaving mice, we uncover the existence of spontaneous, spatially defined "hypoxic pockets" and demonstrate their linkage to the abrogation of local capillary flow. Exercise reduced the burden of hypoxic pockets by 52% compared with rest. The study provides insight into cortical oxygen dynamics in awake behaving animals and concurrently establishes a tool to delineate the importance of oxygen tension in physiological processes and neurological diseases.
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Cortex cérébral , Circulation cérébrovasculaire , Hypoxie cérébrale , Mesures de luminescence , Saturation en oxygène , Oxygène , Animaux , Souris , Cortex cérébral/vascularisation , Cortex cérébral/imagerie diagnostique , Cortex cérébral/métabolisme , Oxygène/sang , Oxygène/métabolisme , Pression partielle , Hypoxie cérébrale/sang , Hypoxie cérébrale/imagerie diagnostique , Hypoxie cérébrale/métabolisme , Vasodilatation , Mesures de luminescence/méthodes , Luciferases/génétique , Luciferases/métabolisme , Protéines de fusion recombinantes/génétique , Protéines de fusion recombinantes/métabolisme , Protéines à fluorescence verte/génétique , Protéines à fluorescence verte/métabolisme , Hypercapnie/sang , Hypercapnie/imagerie diagnostique , Hypercapnie/métabolismeRÉSUMÉ
Objective: In patients with complex coronary artery disease (CAD) undergoing cardiac surgery, myocardial protection might be impaired due to microvascular obstruction, resulting in myocardial injury and subsequent biomarker release. Therefore, this study investigated the correlation between the complexity of CAD, reflected by the SYNTAX Score, and the release of cardiac biomarkers after CABG. Methods: In a consecutive series of 919 patients undergoing isolated CABG SYNTAX scores I and II were calculated to assess the complexity of CAD. Levels of high sensitivity cardiac troponin T (hs-cTnT) and creatine kinase-myocardial band (CK-MB) were routinely measured once before and serially after surgery. Patients were divided into tertiles according to their SYNTAX Scores I and II. Spearman correlations and regression models were performed to measure the degree of association between the release of hs-cTnT and CK-MB and the SYNTAX Scores. Results: Patients with a higher SYNTAX Score I had more comorbidities reflected in a higher EuroSCORE II. Preoperatively, higher levels of cardiac biomarkers were found in patients with higher SYNTAX Score II. No correlation was observed between hs-cTnT, CK-MB and SYNTAX Score I or II. Regression models did not show any association between cardiac biomarkers and the complexity of CAD. Conclusion: The complexity of CAD is not associated with the release of cardiac biomarkers after CABG. Factors influencing postoperative biomarker release need to be elucidated in future trials to include postoperative biomarker release into risk stratification models predicting outcome after cardiac surgery.
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OBJECTIVES: Myocardial hypertrophy results in increased levels of cardiac biomarkers in healthy individuals and in patients suffering from acute myocardial infarction. The influence of cardiac mass on postoperative cardiac biomarkers release remains unclear. This study investigated the correlation between myocardial mass and the release of high-sensitivity cardiac Troponin T (hs-cTnT) and creatine kinase-myocardial band (CK-MB) after isolated aortic valve replacement (AVR) or bypass surgery. METHODS: Myocardial mass of a consecutive retrospective series of patients was measured automatically using preoperative computer tomography scans (636 patients, AVR = 251; bypass surgery = 385). Levels of cardiac biomarkers were measured before and serially after surgery. Spearman and Pearson correlation and a multivariate regression model was performed to measure the degree of association between myocardial mass and the release of hs-cTnT and CK-MB. RESULTS: Patients were divided into 3 tertiles according to their myocardial mass index. Higher biomarker levels were measured preoperatively in the upper tertile of patients undergoing AVR (P = 0.004) or bypass surgery (P < 0.001). Patients with different heart sizes showed no differences in postoperative biomarker release neither after AVR nor bypass surgery. No statistical significant correlation was observed between myocardial mass index and postoperative release of hs-cTnT or CK-MB in any subgroup (ρ maximum 0.106). CONCLUSIONS: Postoperative biomarker release is not correlated with myocardial mass. Patient factors leading to increased postoperative biomarker levels need to be elucidated in future studies.
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BACKGROUND: The relevance of perioperative myocardial injury (PMI) after cardiac surgery for 30-day mortality and long-term survival remains to be determined. OBJECTIVES: This study assessed the association of PMI after cardiac surgery, reflected by postoperative troponin release, with 30-day mortality and long-term survival after: 1) coronary artery bypass grafting (CABG); 2) isolated aortic valve replacement (AVR) surgery; and 3) all other cardiac surgeries. METHODS: A consecutive cohort of 8,292 patients undergoing cardiac surgery with serial perioperative high-sensitivity cardiac troponin T (hs-cTnT) measurements was retrospectively analyzed. The relationship between postoperative hs-cTnT release and 30-day mortality or 5-year mortality was analyzed after adjustment with EuroSCORE II using a Cox proportional hazards model. hs-cTnT thresholds for 30-day and 5-year mortality were determined for isolated CABG (32.3%), AVR (14%), and other cardiac surgery (53.8%). RESULTS: High postoperative hs-cTnT levels were associated with higher 30-day mortality but not 5-year mortality. In CABG, median peak concentration of postoperative hs-cTnT was 1,044 ng/L, in AVR it was 502 ng/L, and in other cardiac surgery it was 1,110 ng/L. hs-cTnT thresholds defining mortality-associated PMI were as follows: for CABG, 2,385 ng/L (170× the upper reference limit of normal in a seemingly healthy population [URL]); for AVR, 568 ng/L (41× URL); and for other cardiac procedures, 1,873 ng/L (134× URL). hs-cTnT levels above the cutoffs resulted in an HR for 30-day mortality for CABG of 12.56 (P < 0.001), for AVR of 4.44 (P = 0.004), and for other cardiac surgery of 3.97 (P < 0.001). CONCLUSIONS: PMI reflected by perioperative hs-cTnT release is associated with the expected 30-day mortality but not 5-year mortality. Postoperative hs-cTnT cutoffs to identify survival-relevant PMI are higher than suggested in current definitions.
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Procédures de chirurgie cardiaque , Lésions traumatiques du coeur , Humains , Troponine T , Études rétrospectives , Pontage aortocoronarien/effets indésirables , MyocardeRÉSUMÉ
BACKGROUND: Calcific aortic valve disease (CAVD) is characterized by a phenotypic switch of valvular interstitial cells to bone-forming cells. Toll-like receptors (TLRs) are evolutionarily conserved pattern recognition receptors at the interface between innate immunity and tissue repair. Type I interferons (IFNs) are not only crucial for an adequate antiviral response but also implicated in bone formation. We hypothesized that the accumulation of endogenous TLR3 ligands in the valvular leaflets may promote the generation of osteoblast-like cells through enhanced type I IFN signaling. METHODS: Human valvular interstitial cells isolated from aortic valves were challenged with mechanical strain or synthetic TLR3 agonists and analyzed for bone formation, gene expression profiles, and IFN signaling pathways. Different inhibitors were used to delineate the engaged signaling pathways. Moreover, we screened a variety of potential lipids and proteoglycans known to accumulate in CAVD lesions as potential TLR3 ligands. Ligand-receptor interactions were characterized by in silico modeling and verified through immunoprecipitation experiments. Biglycan (Bgn), Tlr3, and IFN-α/ß receptor alpha chain (Ifnar1)-deficient mice and a specific zebrafish model were used to study the implication of the biglycan (BGN)-TLR3-IFN axis in both CAVD and bone formation in vivo. Two large-scale cohorts (GERA [Genetic Epidemiology Research on Adult Health and Aging], n=55 192 with 3469 aortic stenosis cases; UK Biobank, n=257 231 with 2213 aortic stenosis cases) were examined for genetic variation at genes implicated in BGN-TLR3-IFN signaling associating with CAVD in humans. RESULTS: Here, we identify TLR3 as a central molecular regulator of calcification in valvular interstitial cells and unravel BGN as a new endogenous agonist of TLR3. Posttranslational BGN maturation by xylosyltransferase 1 (XYLT1) is required for TLR3 activation. Moreover, BGN induces the transdifferentiation of valvular interstitial cells into bone-forming osteoblasts through the TLR3-dependent induction of type I IFNs. It is intriguing that Bgn-/-, Tlr3-/-, and Ifnar1-/- mice are protected against CAVD and display impaired bone formation. Meta-analysis of 2 large-scale cohorts with >300 000 individuals reveals that genetic variation at loci relevant to the XYLT1-BGN-TLR3-interferon-α/ß receptor alpha chain (IFNAR) 1 pathway is associated with CAVD in humans. CONCLUSIONS: This study identifies the BGN-TLR3-IFNAR1 axis as an evolutionarily conserved pathway governing calcification of the aortic valve and reveals a potential therapeutic target to prevent CAVD.
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Sténose aortique , Calcinose , Adulte , Animaux , Humains , Souris , Valve aortique/anatomopathologie , Sténose aortique/anatomopathologie , Biglycane/métabolisme , Calcinose/métabolisme , Cellules cultivées , Récepteur de type Toll-3/génétique , Récepteur de type Toll-3/métabolisme , Danio zébréRÉSUMÉ
AIMS/HYPOTHESIS: Sodium-glucose cotransporter 2 (SGLT2) inhibitors are widely used in the treatment of type 2 diabetes, heart failure and chronic kidney disease. Their role in the prevention of diet-induced metabolic deteriorations, such as obesity, insulin resistance and fatty liver disease, has not been defined yet. In this study we set out to test whether empagliflozin prevents weight gain and metabolic dysfunction in a mouse model of diet-induced obesity and insulin resistance. METHODS: C57Bl/6 mice were fed a western-type diet supplemented with empagliflozin (WDE) or without empagliflozin (WD) for 10 weeks. A standard control diet (CD) without or with empagliflozin (CDE) was used to control for diet-specific effects. Metabolic phenotyping included assessment of body weight, food and water intake, body composition, hepatic energy metabolism, skeletal muscle mitochondria and measurement of insulin sensitivity using hyperinsulinaemic-euglycaemic clamps. RESULTS: Mice fed the WD were overweight, hyperglycaemic, hyperinsulinaemic and insulin resistant after 10 weeks. Supplementation of the WD with empagliflozin prevented these metabolic alterations. While water intake was significantly increased by empagliflozin supplementation, food intake was similar in WDE- and WD-fed mice. Adipose tissue depots measured by MRI were significantly smaller in WDE-fed mice than in WD-fed mice. Additionally, empagliflozin supplementation prevented significant steatosis found in WD-fed mice. Accordingly, hepatic insulin signalling was deteriorated in WD-fed mice but not in WDE-fed mice. Empagliflozin supplementation positively affected size and morphology of mitochondria in skeletal muscle in both CD- and WD-fed mice. CONCLUSIONS/INTERPRETATION: Empagliflozin protects mice from diet-induced weight gain, insulin resistance and hepatic steatosis in a preventative setting and improves muscle mitochondrial morphology independent of the type of diet.
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Diabète de type 2 , Insulinorésistance , Stéatose hépatique non alcoolique , Souris , Animaux , Insulinorésistance/physiologie , Diabète de type 2/métabolisme , Obésité/métabolisme , Foie/métabolisme , Stéatose hépatique non alcoolique/métabolisme , Prise de poids , Insuline/métabolisme , Régime occidental , Souris de lignée C57BL , Alimentation riche en graisseRÉSUMÉ
BACKGROUND: Coronary artery disease (CAD) remains a severe socio-economic burden in the Western world. Coronary obstruction and subsequent myocardial ischemia result in the progressive replacement of contractile myocardium with dysfunctional, fibrotic scar tissue. Post-infarctional remodelling is causal for the concomitant decline of left-ventricular function and the fatal syndrome of heart failure. Available neurohumoral treatment strategies aim at the improvement of symptoms. Despite extensive research, therapeutic options for myocardial regeneration, including (stem)-cell therapy, gene therapy, cellular reprogramming or tissue engineering, remain purely experimental. Thus, there is an urgent clinical need for novel treatment options for inducing myocardial regeneration and improving left-ventricular function in ischemic cardiomyopathy. Shockwave therapy (SWT) is a well-established regenerative tool that is effective for the treatment of chronic tendonitis, long-bone non-union and wound-healing disorders. In preclinical trials, SWT regenerated ischemic myocardium via the induction of angiogenesis and the reduction of fibrotic scar tissue, resulting in improved left-ventricular function. METHODS: In this prospective, randomized controlled, single-blind, monocentric study, 80 patients with reduced left-ventricular ejection fraction (LVEF≤ 40%) are subjected to coronary-artery bypass-graft surgery (CABG) surgery and randomized in a 1:1 ratio to receive additional cardiac SWT (intervention group; 40 patients) or CABG surgery with sham treatment (control group; 40 patients). This study aims to evaluate (1) the safety and (2) the efficacy of cardiac SWT as adjunctive treatment during CABG surgery for the regeneration of ischemic myocardium. The primary endpoints of the study represent (1) major cardiac events and (2) changes in left-ventricular function 12 months after treatment. Secondary endpoints include 6-min walk test distance, improvement of symptoms and assessment of quality of life. DISCUSSION: This study aims to investigate the safety and efficacy of cardiac SWT during CABG surgery for myocardial regeneration. The induction of angiogenesis, decrease of fibrotic scar tissue formation and, thus, improvement of left-ventricular function could lead to improved quality of life and prognosis for patients with ischemic heart failure. Thus, it could become the first clinically available treatment strategy for the regeneration of ischemic myocardium alleviating the socio-economic burden of heart failure. TRIAL REGISTRATION: ClinicalTrials.gov NCT03859466. Registered on 1 March 2019.
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Cardiomyopathies , Maladie des artères coronaires , Défaillance cardiaque , Ondes de choc de haute énergie , Ischémie myocardique , Humains , Débit systolique , Fonction ventriculaire gauche , Études prospectives , Qualité de vie , Méthode en simple aveugle , Résultat thérapeutique , Ischémie myocardique/complications , Ischémie myocardique/thérapie , Pontage aortocoronarien/effets indésirables , Défaillance cardiaque/étiologie , Maladie des artères coronaires/complications , Maladie des artères coronaires/thérapie , Cicatrice/étiologie , Cicatrice/thérapie , Cicatrice/anatomopathologie , Cardiomyopathies/étiologie , Cardiomyopathies/chirurgie , Essais contrôlés randomisés comme sujetRÉSUMÉ
BACKGROUND: The prognosis of COVID-19 patients with cardiac involvement is unfavorable and it remains unknown which patients are at risk. The virus enters cells via its receptor angiotensin-converting enzyme 2 (ACE2). Myocardial ACE2 expression is increased in structural heart disease (SHD). We, therefore, aimed to analyze correlations between structural heart disease and cardiac SARS-CoV-2 manifestation. METHODS: The clinical course of COVID-19 in patients with structural heart disease was assessed in a prospective cohort of 152 patients. The primary endpoints consisted of hospitalization and survival. Cardiac tissue of 23 autopsy cases with lethal COVID-19 course was obtained and analyzed for (a) the presence of SHD, (b) myocardial presence of SARS-CoV-2 via RT,-PCR, and (c) levels of ACE2 expression using immunofluorescence staining. RESULTS: Structural heart disease is found in 67 patients, of whom 56 (83.60%) are hospitalized. The myocardium is positive for SARS-CoV-2 in 15 patients (65%) in 23 autopsy cases of lethal COVID-19. Moreover, most hearts with evidence of myocardial SARS-CoV-2 have structural heart disease [11 (91,67%) vs. 1 (8,33%), p = 0.029]. Myocardial presence of SARS-CoV-2 is correlated with a significant downregulation of ACE2 compared to negative control hearts (6.545 ± 1.1818 A.U. vs. 7.764 ± 2.411 A.U., p = 0.003). The clinical course of patients with cardiac SARS-CoV-2 manifestation is unfavorable, resulting in impaired survival (median, 12 days and 4.5 days, respectively, HR 0.30, 95% CI, 0.13 to 0.73, p = 0.0005) CONCLUSIONS: We provide evidence for a correlation between SHD, altered ACE2 receptor expression, and cardiac SARS-CoV-2 manifestation. Consequently, structural heart disease may be considered a distinct risk factor for a severe clinical course after infection with SARS-CoV-2. REGISTRATION NUMBER LOCAL IRB: Ethics Committee of Northwestern and Central Switzerland ID 2020-00629; Ethics Committee of the Medical University Innsbruck EK Nr: 1103/2020. GOV NUMBER: NCT04416100.
SARS-CoV-2, the virus that causes COVID-19, binds to ACE2 receptors to gain entry into cells. The ACE2 receptor is a cell surface protein found in many tissues, including the heart. Studies suggest that people with heart disease are likely to have higher levels of ACE2 receptors, which may explain why they are more susceptible to severe illness from COVID-19. In this study, we identified heart disease as a risk factor for hospitalization in 152 patients who tested positive for SARS-CoV-2. The presence of SARS-CoV-2 in the heart was associated with altered levels of ACE2 receptors and with a shortened survival time in patients. These findings provide evidence for a potential link between heart disease, ACE2 receptor levels, and SARS-CoV-2 infection of the heart, and may help doctors to understand the clinical course of patients with heart disease who contract COVID-19.
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OBJECTIVES: Mechanical strain plays a major role in the development of aortic calcification. We hypothesized that (i) valvular calcifications are most pronounced at the localizations subjected to the highest mechanical strain and (ii) calcification patterns are different in patients with bicuspid and tricuspid aortic valves. METHODS: Multislice computed tomography scans of 101 patients with severe aortic stenosis were analysed using a 3-dimensional post-processing software to quantify calcification of tricuspid aortic valves (n = 51) and bicuspid aortic valves (n = 50) after matching. RESULTS: Bicuspid aortic valves exhibited higher calcification volumes and increased calcification of the non-coronary cusp with significantly higher calcification of the free leaflet edge. The non-coronary cusp showed the highest calcium load compared to the other leaflets. Patients with annular calcification above the median had an impaired survival compared to patients with low annular calcification, whereas patients with calcification of the free leaflet edge above the median did not (P = 0.53). CONCLUSIONS: Calcification patterns are different in patients with aortic stenosis with bicuspid and tricuspid aortic valves. Patients with high annular calcification might have an impaired prognosis.
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Sténose aortique , Maladie de la valve aortique bicuspide , Calcinose , Humains , Valve aortique/imagerie diagnostique , Sténose aortique/imagerie diagnostique , Calcinose/imagerie diagnostique , Valve atrioventriculaire droite/imagerie diagnostiqueRÉSUMÉ
Background Spinal cord ischemia (SCI) remains a devastating complication after aortic dissection or repair. A primary hypoxic damage is followed by a secondary damage resulting in further cellular loss via apoptosis. Affected patients have a poor prognosis and limited therapeutic options. Shock wave therapy (SWT) improves functional outcome, neuronal degeneration and survival in murine spinal cord injury. In this first-in-human study we treated 5 patients with spinal cord ischemia with SWT aiming to prove safety and feasibility. Methods and Results Human neurons were subjected to ischemic injury with subsequent SWT. Reactive oxygen species and cellular apoptosis were quantified using flow cytometry. Signaling of the antioxidative transcription factor NRF2 (nuclear factor erythroid 2-related factor 2) and immune receptor Toll-like receptor 3 (TLR3) were analyzed. To assess whether SWT act via a conserved mechanism, transgenic tlr3-/- zebrafish created via CRISPR/Cas9 were subjected to spinal cord injury. To translate our findings into a clinical setting, 5 patients with SCI underwent SWT. Baseline analysis and follow-up (6 months) included assessment of American Spinal Cord Injury Association (ASIA) impairment scale, evaluation of Spinal Cord Independence Measure score and World Health Organization Quality of Life questionnaire. SWT reduced the number of reactive oxygen species positive cells and apoptosis upon ischemia via induction of the antioxidative factor nuclear factor erythroid 2-related factor 2. Inhibition or deletion of tlr3 impaired axonal growth after spinal cord lesion in zebrafish, whereas tlr3 stimulation enhanced spinal regeneration. In a first-in-human study, we treated 5 patients with SCI using SWT (mean age, 65.3 years). Four patients presented with acute aortic dissection (80%), 2 of them exhibited preoperative neurological symptoms (40%). Impairment was ASIA A in 1 patient (20%), ASIA B in 3 patients (60%), and ASIA D in 1 patient (20%) at baseline. At follow-up, 2 patients were graded as ASIA A (40%) and 3 patients as ASIA B (60%). Spinal cord independence measure score showed significant improvement. Examination of World Health Organization Quality of Life questionnaires revealed increased scores at follow-up. Conclusions SWT reduces oxidative damage upon SCI via immune receptor TLR3. The first-in-human application proved safety and feasibility in patients with SCI. SWT could therefore become a powerful regenerative treatment option for this devastating injury.
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, Traitement par ondes de choc extracorporelles , Traumatismes de la moelle épinière , Ischémie de la moelle épinière , Humains , Souris , Animaux , Sujet âgé , Récepteur de type Toll-3/métabolisme , Récepteur de type Toll-3/usage thérapeutique , Facteur-2 apparenté à NF-E2 , Danio zébré , Études de faisabilité , Espèces réactives de l'oxygène , Qualité de vie , Ischémie de la moelle épinière/étiologie , Ischémie de la moelle épinière/prévention et contrôle , Ischémie de la moelle épinière/anatomopathologie , Traumatismes de la moelle épinière/thérapie , Traumatismes de la moelle épinière/anatomopathologie , Moelle spinale/métabolisme , Stress oxydatif , Ischémie , /anatomopathologieRÉSUMÉ
Visual snow syndrome is characterized by a continuous visual disturbance resembling a badly tuned analogue television and additional visual and non-visual symptoms causing significant disability. The natural course of visual snow syndrome has not hitherto been studied. In this prospective longitudinal study, 78 patients with the diagnosis of visual snow syndrome made in 2011 were re-contacted in 2019 to assess symptom evolution using a semi-structured questionnaire. Forty patients (51% of 78) were interviewed after 84 ± 5 months (mean ± SD). In all patients, symptoms had persisted. Visual snow itself was less frequently rated as the most disturbing symptom (72 versus 42%, P = 0.007), whereas a higher proportion of patients suffered primarily from entopic phenomena (2 versus 17%, P = 0.024). New treatment was commenced in 14 (35%) patients, of whom in seven, visual snow syndrome was ameliorated somewhat. Three (7%) experienced new visual migraine aura without headache, and one (2%) had new migraine headache. There were no differences in the levels of anxiety and depression measured by the Patient Health Questionnaire 8 and the Generalized Anxiety Disorder Scale 7. Thirty-eight patients (49%) were lost to follow-up. In visual snow syndrome, symptoms can persist over 8 years without spontaneous resolution, although visual snow itself might become less bothersome.
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Over the past decades, shockwave therapy (SWT) has gained increasing interest as a therapeutic approach for regenerative medicine applications, such as healing of bone fractures and wounds. More recently, pre-clinical studies have elucidated potential mechanisms for the regenerative effects of SWT in myocardial ischemia. The mechanical stimulus of SWT may induce regenerative effects in ischemic tissue via growth factor release, modulation of inflammatory response, and angiogenesis. Activation of the innate immune system and stimulation of purinergic receptors by SWT appears to enhance vascularization and regeneration of injured tissue with functional improvement. Intriguingly, small single center studies suggest that SWT may improve angina, exercise tolerance, and hemodynamics in patients with ischemic heart disease. Thus, SWT may represent a promising technology to induce cardiac protection or repair in patients with ischemic heart disease.
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OBJECTIVES: The need to ration medical equipment and interventions during the coronavirus disease 2019 pandemic translated to an ever-lengthening wait list for surgical care. Retrospective analysis of lockdowns is of high importance to learn from the current situation for future pandemics. This monocentric study assessed the impact of lockdown periods on cardiac surgery cases and outcomes. METHODS: The single-centre cross-sectional descriptive observational study was conducted to investigate the first lockdown period and the following post-lockdown period in comparison to the same periods during the previous 3 years at the Department of Cardiac Surgery at the Medical University of Innsbruck. Data were prospectively collected and retrospectively analysed from the department-specific quality management system. The primary objective was to compare the number of open-heart procedures between the prelockdown and the lockdown period. The secondary objectives were to analyse the characteristics and the outcomes of open-heart procedures. RESULTS: There were no differences in patient demographics. A significant decrease of 29% in weekly surgical procedures was observed during the lockdown period. The surgical case-mix was unaffected: The numbers of aortic valve replacements, coronary artery bypass grafts, mitral valve repair or replacement procedures and others remained stable. The urgency of cases increased significantly, and the general health conditions of patients appeared to be worse. However, outcomes were unchanged. CONCLUSIONS: By implementing a rational patient selection process, the quality of open-heart procedures was maintained even though patients who underwent surgery during lockdown were sicker and more symptomatic.
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COVID-19 , COVID-19/épidémiologie , Contrôle des maladies transmissibles , Études transversales , Humains , Études rétrospectives , SARS-CoV-2RÉSUMÉ
Shockwave therapy (SWT) shows promising regenerative effects in several different tissues. However, the underlying molecular mechanisms are poorly understood. Angiogenesis, a process of new blood vessel formation is a leading driver of regeneration in softer tissues as well as a recently discovered effect of SWT. How the mechanical stimulus of SWT induces angiogenesis and regeneration and which pathways are involved is not fully understood. To further improve the clinical use of SWT and gain valuable information about how mechanical stimulation can affect tissue and tissue regeneration, a standardized model of SWT is needed. We, hereby, describe a standardized, easy to implement murine model of shockwave therapy induced regeneration, utilizing the hind-limb ischemia model.
Sujet(s)
Traitement par ondes de choc extracorporelles , Ischémie myocardique , Animaux , Modèles animaux de maladie humaine , Ischémie , Souris , Néovascularisation pathologiqueRÉSUMÉ
Characterizing the human leukocyte antigen (HLA) bound ligandome by mass spectrometry (MS) holds great promise for developing vaccines and drugs for immune-oncology. Still, the identification of non-tryptic peptides presents substantial computational challenges. To address these, we synthesized and analyzed >300,000 peptides by multi-modal LC-MS/MS within the ProteomeTools project representing HLA class I & II ligands and products of the proteases AspN and LysN. The resulting data enabled training of a single model using the deep learning framework Prosit, allowing the accurate prediction of fragment ion spectra for tryptic and non-tryptic peptides. Applying Prosit demonstrates that the identification of HLA peptides can be improved up to 7-fold, that 87% of the proposed proteasomally spliced HLA peptides may be incorrect and that dozens of additional immunogenic neo-epitopes can be identified from patient tumors in published data. Together, the provided peptides, spectra and computational tools substantially expand the analytical depth of immunopeptidomics workflows.
Sujet(s)
Apprentissage profond , Peptides/immunologie , Spectrométrie de masse en tandem/méthodes , Lignée cellulaire , Épitopes , Protéines de la matrice extracellulaire/métabolisme , Antigènes HLA/immunologie , Antigènes d'histocompatibilité de classe I/métabolisme , Antigènes d'histocompatibilité de classe II/métabolisme , Humains , Ligands , Spectrométrie de masse , Médecine moléculaire , Peptides/métabolisme , ProtéomiqueRÉSUMÉ
Database search engines for bottom-up proteomics largely ignore peptide fragment ion intensities during the automated scoring of tandem mass spectra against protein databases. Recent advances in deep learning allow the accurate prediction of peptide fragment ion intensities. Using these predictions to calculate additional intensity-based scores helps to overcome this drawback. Here, we describe a processing workflow termed INFERYS™ rescoring for the intensity-based rescoring of Sequest HT search engine results in Thermo Scientific™ Proteome Discoverer™ 2.5 software. The workflow is based on the deep learning platform INFERYS capable of predicting fragment ion intensities, which runs on personal computers without the need for graphics processing units. This workflow calculates intensity-based scores comparing peptide spectrum matches from Sequest HT and predicted spectra. Resulting scores are combined with classical search engine scores for input to the false discovery rate estimation tool Percolator. We demonstrate the merits of this approach by analyzing a classical HeLa standard sample and exemplify how this workflow leads to a better separation of target and decoy identifications, in turn resulting in increased peptide spectrum match, peptide and protein identification numbers. On an immunopeptidome dataset, this workflow leads to a 50% increase in identified peptides, emphasizing the advantage of intensity-based scores when analyzing low-intensity spectra or analytes with very similar physicochemical properties that require vast search spaces. Overall, the end-to-end integration of INFERYS rescoring enables simple and easy access to a powerful enhancement to classical database search engines, promising a deeper, more confident and more comprehensive analysis of proteomic data from any organism by unlocking the intensity dimension of tandem mass spectra for identification and more confident scoring.