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Surgery remains the only recommended intervention for patients with native aortic regurgitation. A transcatheter therapy to treat patients at high risk for mortality and complications with surgical aortic valve replacement represents an unmet need. Commercial transcatheter heart valves in pure aortic regurgitation are hampered by unacceptable rates of embolisation and paravalvular regurgitation. The Trilogy transcatheter heart valve (JenaValve Technology, Irvine, CA, USA) provides a treatment option for these patients. We report outcomes with transfemoral transcatheter aortic valve implantation (TAVI) in patients with pure aortic regurgitation using this dedicated transcatheter heart valve.

ObjectivesThe association of pulmonary hypertension (PH) with the outcome after mitral transcatheter edge-to-edge repair (M-TEER) focusing on the new ESC/ERS guidelines definition for PH.BackgroundPH is frequently found in patients with mitral regurgitation and is associated with lower survival rates. Recent studies were based on echocardiographic parameters, but results based on invasive haemodynamics differentiating distinct types of PH using the new definition for PH are missing.Methods449 consecutive M-TEER-treated patients from December 2009 to February 2015 were included in this retrospective analysis. All patients were stratified by the distinct types of PH (no PH, precapillary PH, isolated postcapillary PH, combined post-PH and precapillary PH) according to the definitions of the ESC/ERS guidelines for the diagnosis of PH from 2015 (meanPA cut-off <25 mm Hg, pulmonary capillary wedge pressure (PCWP) cut-off ≤15 mm Hg, diastolic pulmonary gradient cut-off ≥7 mm Hg or pulmonary vascular resistance (PVR) >3 WU) and 2022 (meanPA cut-off ≤20 mm Hg, PCWP cut-off ≤15 mm Hg, PVR cut-off ≥3 WU).ResultsPatients with any type of PH (2015: meanPA cut-off 25 mm Hg; 2022: meanPA cut-off >20 mm Hg) showed a higher risk of death after M-TEER compared with patients with no PH (2015: HR 1.61 (95% CI 1.25 to 2.07); p<0.001 and 2022: HR 2.09 (95% CI 1.54 to 2.83); p<0.001). Based on the new PH definition, each PH subgroup showed a lower survival after M-TEER compared with patients with no PH. Echocardiographic estimated systolic PAP showed a correlation with invasively measured mean pulmonary artery pressure (mPAP) (r=0.29, p<0.001) and systolic pulmonary arterial pressure (r=0.34,p<0.001). Cox-regression analysis showed higher invasive diastolic, systolic and mean pulmonary pressures were associated with higher all-cause mortality (p<0.001). In addition, invasive measured higher right atrial pressure, lower pulmonary arterial compliance, higher PVR and higher wedge pressure were identified as predictors of all-cause mortality after M-TEER.ConclusionsThe new PH definition discriminates PH groups and mortality better than the old definition. The lower threshold of mPAP of 20mmHg improved prognostication in this cohort of patients.

Left ventricular reverse remodeling (LVRR) is associated with improved outcome in patients with heart failure. Factors associated with and predictive of LVRR in patients with low-flow low-gradient aortic stenosis (LFLG AS) after transcatheter aortic valve implantation (TAVI) and its impact on outcome were assessed.

Frailty and heart failure share pathophysiology and clinical characteristics.

Several supra-annular self-expanding transcatheter systems are commercially available for transcatheter aortic valve implantation (TAVI). Comparative data in large-scale multicenter studies are scant.

ObjectiveAfter transcatheter aortic valve implantation (TAVI), the optimal regimen of anticoagulant therapy in patients with an additional indication for oral anticoagulation remains a matter of debate. This study investigates the efficacy of direct oral anticoagulants (DOACs) versus vitamin K antagonists (VKAs) in patients after TAVI in a real-world population.MethodsThe German Aortic Valve RegistrY (GARY) is a prospective, multicentre registry enrolling patients undergoing invasive treatment for aortic valve disease. From January 2011 to December 2019, 1 41 790 patients from 92 hospitals in Germany were enrolled. Anticoagulatory treatment regimens were assessed at hospital discharge for patients after TAVI procedures. All-cause mortality and the combined endpoint ‘cardiac and cerebrovascular events’ containing myocardial infarction, stroke, transient ischaemic attack, aortic prosthesis reintervention and all-cause mortality in the first year after TAVI were examined by treatment regimen.ResultsOf 45 598 patients (mean age 80.7±5.7 years, 49.3% males) undergoing TAVI, 16 974 patients (37.2%) received an anticoagulant regimen that included VKA or DOAC. Hereof, the majority of patients were prescribed VKA (n=11 333, 66.8%) compared with DOAC (n=5641, 33.2%) with an increase of DOAC use from 9.4% in 2011 to 69.9% in 2019. During the 1-year follow-up, the absolute event rates per 100 person-years for all-cause mortality and the combined endpoint cardiac and cerebrovascular events were 1.9 and 1.3 for VKA-treated and 1.7 and 1.2 for DOAC-treated patients, respectively. After adjustment for baseline confounders, all-cause mortality (HR 0.95, 95% CI 0.88 to 1.01, p=0.114) and cardiac and cerebrovascular event-free survival (HR 0.93, 95% CI 0.86 to 1.01, p=0.071) did not differ significantly between VKA and DOAC groups.ConclusionsThis study supports evidence of the efficacy of DOAC use after TAVI in patients with an indication for oral anticoagulation.

Hintergrund: Leitlinien zum Myokardinfarkt (MI) empfehlen eine blutverdünnende Therapie zum Diagnosezeitpunkt. Während der MI mit ST-Streckenhebung (STEMI) präklinisch sicher detektiert werden kann, ist das akute Koronarsyndrom ohne ST-Streckenhebung (NSTE-ACS) eine Arbeitsdiagnose. Zielsetzung: Erfassung von präklinischem Loading mit Acetylsalicylsäure (ASS) und Heparin stratifiziert nach ACS-Entität und in Abhängigkeit von oraler Antikoagulation. Methoden: Die PRELOAD-Studie wurde als deutschlandweite Online-Umfrage durchgeführt. STEMI/NSTE-ACS-Szenarien wurden mit folgender Variation präsentiert: I) ohne Vorbehandlung, II) Vorbehandlung mit neuem oralem Antikoagulan (NOAK), Vorbehandlung mit Vitamin-K-Antagonist (VKA). Loading-Strategien wurden erhoben und umfassten: a) ASS, b) unfraktioniertes Heparin (UFH), c) ASS + UFH, d) kein Loading. Ergebnisse: In die Studie wurden 708 Notfallmediziner*innen eingeschlossen. Beim NSTE-ACS ohne Vorbehandlung entschieden sich 79 % für ein Loading (p&lt; 0,001). ASS + UFH (71,4 %) war die häufigste Antwort. Beim STEMI entschlossen sich 100 % zum Loading, wobei 98,6 % ASS + UFH wählten. Beim NSTE-ACS mit NOAK-Vorbehandlung wählten 69,8 % Loading (p&lt; 0,001). Eine VKA-Einnahme führte in 72,3 % der Fälle zum Loading (p&lt; 0,001). ASS gefolgt von ASS + UFH waren die häufigsten Antworten. Beim STEMI war eine NOAK- bzw. VKA-Behandlung in 97,5 bzw. 96,8 % der Fälle mit einer Loading-Entscheidung verbunden (p&lt; 0,001) – vermehrt wurde eine ASS-Monotherapie eingesetzt. Schlussfolgerungen: Präklinisches Loading ist die präferierte Behandlungsstrategie, obwohl beim NSTE-ACS die Leitlinien eine Antikoagulation erst zum Zeitpunkt der Diagnose empfehlen. Im Fall vorbestehender oraler Antikoagulation wird präklinisches Loading gehäuft in Form einer ASS-Monotherapie durchgeführt. Beim STEMI mit Notwendigkeit der sofortigen invasiven Strategie bedeutet dies eine potenzielle Unterversorgung.

Die Leitlinien zur Behandlung von Herzklappenerkrankungen, erstellt von den Europäischen Gesellschaften für Kardiologie und Herz-Thorax-Chirurgie wurden im Jahr 2021 aktualisiert. Neuerungen in der frühzeitigen chirurgischen Therapie von Patienten mit asymptomatischen Herzklappenfehlern wie der Aortenstenose und -insuffizienz sowie der primären Mitralklappeninsuffizienz, die Indikation zum kathetergestützten Aortenklappenersatz, eine Aufwertung der segelbasierten transvenösen Rekonstruktion bei Mitralklappeninsuffizienz für definierte Patienten, die erstmalige Nennung der kathetergestützten Therapie der Trikuspidalklappeninsuffizienz sowie die Anpassung der Empfehlungen zur Antikoagulation nach Klappeneingriffen stellen die Schwerpunkte in dieser Leitlinie dar. In dem hier vorliegenden Papier werden diese Neuerungen von der Deutschen Gesellschaft für Kardiologie und der Deutschen Gesellschaft für Thorax‑, Herz- und Gefäßchirurgie kommentiert.

Background: Preoperative lymph node staging of lung cancer by CT relies on the premise that malignant lymph nodes are larger than benign ones. Lymph nodes > 1 cm in size [...]

ObjectivesThis study aimed to investigate early haemodynamic and clinical performance of the SAPIEN 3 Ultra (S3 Ultra) transcatheter heart valve (THV) system in comparison to its precursor, the SAPIEN 3 (S3). Previous studies have indicated potential haemodynamic differences between the S3 Ultra and S3. Such differences may impact clinical outcome after transcatheter aortic valve implantation (TAVI).MethodsPostprocedural haemodynamic performance and 30-day clinical outcome were compared in patients who underwent TAVI receiving either the S3 or the new S3 Ultra prostheses. Multivariable analysis and propensity score matching (PSM) were used to identify factors associated with higher mean transvalvular gradients.ResultsWe included 697 patients (S3 Ultra: n=314, S3: n=383) from the multicentre RhineHeart TAVI Registry. Patients receiving the S3 Ultra prosthesis showed significantly higher postprocedural mean transvalvular gradients (14.2±4.8 vs 10.2±4.4 mm Hg; p<0.01). Multivariable logistic regression analyses and additional PSM revealed the use of the S3 Ultra to be associated with higher postprocedural mean transvalvular gradients (p<0.01). 30-day clinical outcomes, such as mortality, myocardial infarction, permanent pacemaker implantation and vascular complications were comparable between the groups.ConclusionsThe new S3 Ultra THV was associated with a higher postprocedural mean transvalvular gradient compared with the S3 system, while there was no difference in mortality or adverse clinical outcomes at 30 days. These echocardiographic differences will require long-term studies to assess the clinical relevance of this finding.

Vertreter der Hochschulmedizin, Bildungs- und Forschungspolitik und der Industrie sind sich einig: Clinician Scientists, forschende Ärztinnen und Ärzte, sind Schlüssel und Antrieb der Translation und Implementierung innovativer Therapiekonzepte in die klinische Praxis. Der Forschung an kardiovaskulären Erkrankungen, welche weiterhin für die meisten Todesfälle weltweit verantwortlich sind, muss dabei eine herausragende Rolle beigemessen werden. Die Deutsche Gesellschaft für Kardiologie – Herz- und Kreislaufforschung e. V. hat im Rahmen interner Diskussionen und auf Basis von Umfragen unter Ärztinnen und Ärzten an deutschen Universitätskliniken und kliniknahen Forschungsinstituten die aktuelle und zukünftige Situation und Bedeutung forschender Kliniker*innen in der kardiovaskulären Medizin intensiv beleuchtet. Die Analyse ergab, dass die moderne Kardiologie an Universitätskliniken von einem hohen Maß an Arbeitsverdichtung bei steigenden Patientenfallzahlen, kürzeren Liegezeiten und immer komplexeren interventionellen Eingriffen geprägt ist, die viele forschungsinteressierte Ärztinnen und Ärzte und Einrichtungsleiter*innen vor große Herausforderungen bei der Integration wissenschaftlicher Tätigkeiten in den klinischen Alltag und die Ausbildung stellt. Mögliche Verbesserungen der Rahmenbedingungen und die Schaffung konkreter Karriereperspektiven für Clinician Scientistsin der kardiovaskulären Medizin werden in diesem Positionspapier erörtert.

Patienten mit hochgradiger TI stellen in der Vielzahl der Fälle ein Hochrisikokollektiv dar, dessen Behandlung besonders komplex ist. Die Auswahl eines geeigneten Therapiepfades für die Betroffenen erfordert daher zunächst die präzise Charakterisierung der Genese des Vitiums. Hierzu gehören eine transthorakale und transösophageale Echokardiographie, eine Rechtsherz- und Linksherzkatheteruntersuchung und bedarfsgerecht zusätzliche Bildgebung mittels CT und MRT. Die Therapie bedarf einer interdisziplinären Diskussion, wobei die Optimierung einer medikamentösen Therapie bei Linksherzinsuffizienz, die Diskussion antiarrhythmischer Therapieverfahren bei atrialer Genese der TI, der Ausschluss chirurgisch zu behandelnder Pathologien des Herzens und der Ausschluss einer Indikation für die gezielte Therapie bei pulmonal arterieller Hypertonie (PAH) erfolgen müssen. Insbesondere aufgrund der sehr häufigen Komorbidität der Patienten hat die interventionelle Therapie mittlerweile einen wichtigen Stellenwert. Die ESC-Leitlinien aus 2021 haben hierzu für die kathetergestützte Rekonstruktion erstmalig eine Empfehlung ausgesprochen. Die bisher noch eingeschränkte Erfahrung mit dieser komplexen Therapieform, fehlende randomisiert prospektive Studien zur Effektivität und Herausforderungen in der periprozeduralen Bildgebung haben die DGK bewogen, im Vorgriff auf konkrete Kriterien für eine zukünftige Zentrumszertifizierung die oben genannten Empfehlungen beim Vorhalten eines Programmes für die interventionelle Therapie der Trikuspidalklappeninsuffizienz zu formulieren. Dieses Papier soll dazu beitragen, den betroffenen Patienten diese so wichtige Therapie in Deutschland unter der Prämisse bestmöglicher Qualität zu ermöglichen.

ObjectiveA sizeable proportion of patients with secondary mitral regurgitation (SMR) do not receive guideline-directed medical therapy (GDMT) for heart failure (HF). We investigated the association between the use of GDMT and mortality in patients with SMR who underwent transcatheter edge-to-edge repair (TEER).MethodsWe retrospectively analysed patients with SMR and a left ventricular ejection fraction of <50% who underwent TEER at three centres. According to current HF guidelines, GDMT was defined as triple therapy consisting of beta-blockers, renin–angiotensin system (RAS) inhibitors and mineralocorticoid receptor antagonists (MRAs). Patients were divided into two groups: GDMT and non-GDMT groups. We calculated the propensity scores and carried out inverse probability of treatment weighting (IPTW) analyses to compare 2-year mortality between the two groups.ResultsOf 463 patients, 228 (49.2%) were treated with GDMT upon discharge. IPTW-adjusted Kaplan-Meier curve showed patients with GDMT had a lower incidence of mortality than those without GDMT (19.8% vs 31.1%, p=0.011). In IPTW-adjusted Cox proportional hazards analysis, GDMT was associated with a reduced risk of 2-year mortality (HR: 0.58; 95% CI: 0.35 to 0.95; p=0.030), which was consistent among clinical subgroups. Moreover, patients with GDMT had a higher rate of left ventricular reverse remodelling at 1 year after TEER than those without GDMT.ConclusionGDMT, defined as triple therapy consisting of beta-blockers, RAS inhibitors and MRAs, was associated with a reduced risk of 2-year mortality after TEER for SMR. Optimisation of medical therapy is crucial to improve clinical outcomes in patients undergoing TEER for SMR.

Purpose: Access-related vascular complications in transfemoral transcatheter aortic valve implantation (TAVI) can be treated endovascularly or surgically. The aim of this study was to evaluate the short- and long-term outcomes of endovascular treatment compared with surgical repair for access-related vascular complications.Methods: This retrospective study was performed from January 1, 2018, to December 31, 2020. All transfemorally treated TAVI patients in whom a surgical or endovascular treatment for an access site complication was needed were included. The primary outcome was the need for any related vascular re-operation.Results: In total, 1219 transfemoral TAVI procedures were conducted during the study period. 19 patients suffered an access complication requiring endovascular treatment, while 54 patients required surgical repair. No differences were seen with regard to re-operations (endovascular 15.8% vs surgical 14.8%; p=0.919), wound infections (endovascular 0% vs surgical. 11.1%; p=0.129), and wound healing disorders (endovascular 15.8% vs surgical 29.6%; p=0.237). Patients undergoing endovascular treatment were discharged earlier (endovascular 11.2 vs surgical 14.9 days; p=0.028). After surgical repair, patients received significantly more blood transfusions than endovascularly treated patients (endovascular 1.00 vs surgical 3.1 red blood cell concentrate bags; p<0.001). No differences were found regarding the new onset of walking pain, rest pain, and ischemic ulcers during follow-up.Conclusion: In this retrospective cohort, endovascular treatment of access-related vascular complications of transfemoral TAVI procedures was safe and feasible. During the hospital stay, endovascularly treated patients received fewer blood transfusions and were discharged faster than surgically treated patients. No differences regarding clinical outcomes and re-intervention rates were seen during the follow-up.Clinical Impact Given the in this retrospective study demonstrated safety and feasibility of endovascular treatment for major access-related vascular complications, along with the in-hospital benefits and absence of follow-up disadvantages compared to surgical treatment, endovascular treatment should be considered in cases of major access-related vascular complications in transfemoral TAVI patients.

Die Bestimmung des hochsensitiven Troponins ist der Goldstandard bei Patienten mit akutem Thoraxschmerz und erlaubt die zeitnahe Diagnosestellung und Therapieeinleitung bei Patienten mit akutem Myokardinfarkt (AMI). Erhöhte kardiale Troponinspiegel sind hochspezifisch für das Vorliegen einer akuten myokardialen Schädigung. Hingegen beruht nicht jede myokardiale Schädigung auf einem AMI, sodass bei der Interpretation erhöhter Troponinspiegel immer die Klinik und das 12-Kanal-Elektrokardiogramm mitberücksichtigt werden müssen. Neben dem AMI finden sich bei zahlreichen Erkrankungen erhöhte Troponinspiegel, sodass nicht jeder Patient zwangsläufig einer invasiven Koronardiagnostik unterzogen werden muss.

Supplemental Digital Content is available in the text.

AbstractPurpose:Established diagnostic thresholds for high-sensitivity cardiac troponins (hs-cTn) might not apply for elderly patients as they are elevated irrespective of the presence of an acute myocardial infarction (AMI). Aim of the present study was to investigate hs-cTnI in elderly patients with suspected AMI and to calculate optimized diagnostic cutoffs.Material and methods:Data from a prospective multi-centre study and from a second independent prospective single-centre cohort study were analysed. A number of 2903 patients were eligible for further analysis. Patients > 70 years were classified as elderly. hs-cTnI was measured upon admission.Results:Around 34.7% of 2903 patients were classified as elderly. Around 22.5% of elderly patients were finally diagnosed with AMI. Elderly patients had higher hs-cTnI levels at admission irrespective of the final diagnosis (p < 0.001). According to the AUROC, hs-cTnI was a strong marker for detection of AMI in elderly patients. Application of the 99th percentile cutoffs showed a substantially lower specificity in elderly. By using optimized thresholds, specificity was improved to levels as in younger patients in both cohorts but accompanied with a decrease in sensitivity.Conclusions:hs-cTnI levels have a lower specificity for detecting AMI in elderly patients. This lower specificity can be improved by using hs-cTnI thresholds optimized for elderly patients.

Supplemental Digital Content is available in the text.

Supplemental Digital Content is available in the text.

Background: The determination of cardiac troponin is essential for diagnosing myocardial infarction. A troponin I assay has recently been developed that provides the highest analytical sensitivity to date.Methods: The analysis included 1560 patients with chest pain, of whom 1098 were diagnosed with non-coronary chest pain, 189 with unstable angina pectoris and 273 with non-ST-segment elevation myocardial infarction. The troponin I concentration was determined on admission (0 hours) and 3 hours later. The diagnostic algorithm incorporated troponin I elevation above the gender-specific 99th percentile as well as predefined relative or absolute 3-hour changes in the troponin I concentration (delta).Results: The diagnostic criterion of troponin I above the 99th percentile resulted in a negative predictive value of 98.0% and 98.2% in men and women, respectively. For rule-in of non-ST-segment elevation myocardial infarction, the use of absolute deltas yielded higher positive predictive values and sensitivities compared to relative deltas. With detection rates of about 85% and 82% in men and women, respectively, non-ST-segment elevation myocardial infarction was diagnosed with a positive predictive value close to 84% in men and 80% in women.Conclusions: The investigational troponin I assay provides an excellent non-ST-segment elevation myocardial infarction rule out. With gender-specific differences, the application of absolute changes in troponin concentration was superior to relative changes to rule in patients with non-ST-segment elevation myocardial infarction.

ObjectiveIn patients with pulmonary arterial hypertension (PAH), supportive therapies may be beneficial in addition to targeted medical treatment. Here, we evaluated the effectiveness and safety of oscillatory whole-body vibration (WBV) in patients on stable PAH therapy.MethodsTwenty-two patients with PAH (mean PAP≥25 mm Hg and pulmonary arterial wedge pressure (PAWP)≤15 mm Hg) who were in world health organization (WHO)-Functional Class II or III and on stable PAH therapy for≥3 months, were randomised to receive WBV (16 sessions of 1-hour duration within 4 weeks) or to a control group, that subsequently received WBV. Follow-up measures included the 6-min walking distance (6MWD), cardiopulmonary exercise testing (CPET), echocardiography, muscle-power, and health-related quality of life (HRQoL; SF-36 and LPH questionnaires).ResultsWhen compared to the control group, patients receiving WBV exhibited a significant improvement in the primary endpoint, the 6MWD (+35.4±10.9 vs −4.4±7.6 m), resulting in a net benefit of 39.7±7.8 m (p=0.004). WBV was also associated with substantial improvements in CPET variables, muscle power, and HRQoL. The combined analysis of all patients (n=22) indicated significant net improvements versus baseline in the 6MWD (+38.6 m), peakVO2 (+65.7 mL/min), anaerobic threshold (+40.9 mL VO2/min), muscle power (+4.4%), and HRQoL (SF-36 +9.7, LPH −11.5 points) (all p<0.05). WBV was well tolerated in all patients, and no procedure-related severe adverse events (SAEs) occurred.ConclusionsWBV substantially improves exercise capacity, physical performance, and HRQoL in patients with PAH who are on stable targeted therapy. This methodology may be utilised in structured training programmes, and may be feasible for continuous long-term physical exercise in these patients.Trial registration numberNCT01763112; Results.

Cardiac computed tomography angiography was used to identify anatomical characteristics of the aortic root in patients with severe aortic regurgitation (AR) as compared to those with aortic stenosis (AS) to judge feasibility of transcatheter aortic valve replacement (TAVR) with the JenaValve Trilogy system.

Aims Besides early percutaneous coronary intervention (PCI) long-term medical treatment is crucial for outcomes after ST-elevation myocardial infarction (STEMI). The present study aimed to identify predictors of adherence to evidence-based medication in this high risk population.Methods and results A total of 1025 consecutive patients with adjudicated STEMI treated by primary PCI in a single centre as part of the Cologne Infarction Model (KIM) were prospectively analysed. Gender-specific multivariate predictors of long-term medication adherence were identified. Follow-up with available information on drug use was completed for 610 of 738 (82.7%) patients confirmed to be alive after a median period of 36 months. Adherence was persistently high for evidence-based medication with 90.8% for acetylsalicylic acid (ASA), 88.2% for statins, 87.5% for beta-blockers and 79.2% for ACE-inhibitors or angiotensin-receptor blockers (ARBs). Patients with a history of heart failure had a higher medication adherence to beta-blockers, ACE-inhibitors/ARBs and diuretics, whereas long-term prescription rates for calcium channel blockers (CCBs) were lower in patients with reduced versus preserved ejection fraction. Patients with a history of hypertension presented higher medication adherence to CCBs, ACE-inhibitors/ARBs and diuretics but not to beta-blockers. On multivariate analysis, age, body mass index (BMI), hypertension, chronic kidney disease and lack of PCI were independently associated with prescription of diuretics at follow-up. In women, adherence was lower to beta-blockers and higher to CCBs compared to men.Conclusion In the high risk population of STEMI patients long-term adherence to evidence-based medication is high. The lower adherence to beta-blockers and higher prescription rate for CCBs in women needs particular attention.

Supplemental Digital Content is available in the text.

Supplemental Digital Content is available in the text.

Vascular dysfunction importantly contributes to mortality and morbidity in various cardiac and metabolic diseases. Among endogenous molecules regulating vascular tone is adenosine, with the adenosine A3receptor (A3AR) exerting cardioprotective properties in ischemia and reperfusion. However, overexpression of A3AR is suggested to result in vascular dysfunction and inflammation. The leukocyte enzyme myeloperoxidase (MPO) is an important modulator of vascular function with nitric oxide-consuming and proinflammatory properties. Increased MPO plasma levels are observed in patients with cardiovascular disorders like heart failure, acute coronary syndromes, and arrhythmias. Given that vascular dysfunction and inflammation are also hallmarks of diabetes, the role of MPO in adenosine-dependent vasomotor function was investigated in a murine model of diabetes mellitus. Wild-type (WT) and MPO-deficient (Mpo−−) mice were treated with Streptozotocin (STZ), which induced an increase of MPO plasma levels in WT mice and led to enhanced aortic superoxide generation as assessed by dihydroethidium staining in STZ-treated WT mice as compared with controls. The vasoconstriction of aortic segments in response to the A3AR agonist Cl-IB-MECA (2-Chloro-N6-(3-iodobenzyl)-N-methyl-5-carbamoyladenosine) as determined by isometric force measurements was augmented in diabetic WT as compared with diabetic Mpo−−mice. Moreover, A3AR protein expression was enhanced in STZ-treated mice but was attenuated by MPO deficiency. The current data reveal an MPO-mediated increase of vascular A3AR expression under diabetic conditions, which leads to enhanced vasoconstriction in response to A3AR agonists and discloses an additional mechanism of MPO-mediated vascular dysfunction.

Myeloperoxidase (MPO) is an enzyme expressed in neutrophils and monocytes/macrophages. Beside its well-defined role in innate immune defence, it may also be responsible for tissue damage. To identify the role of MPO in the progression of chronic kidney disease (CKD), we investigated CKD in a model of renal ablation in MPO knockout and wild-type mice. CKD was induced by 5/6 nephrectomy. Mice were followed for 10 wk to evaluate the impact of MPO deficiency on renal morbidity. Renal ablation induced CKD in wild-type mice with increased plasma levels of MPO compared with controls. No difference was found between MPO-deficient and wild-type mice regarding albuminuria 1 wk after renal ablation, indicating similar acute responses to renal ablation. Over the next 10 wk, however, MPO-deficient mice developed significantly less albuminuria and glomerular injury than wild-type mice. This was accompanied by a significantly lower renal mRNA expression of the fibrosis marker genes plasminogen activator inhibitor-I, collagen type III, and collagen type IV as well as matrix metalloproteinase-2 and matrix metalloproteinase-9. MPO-deficient mice also developed less renal inflammation after renal ablation, as indicated by a lower infiltration of CD3-positive T cells and F4/80-positive monocytes/macrophages compared with wild-type mice. In vitro chemotaxis of monocyte/macrophages isolated from MPO-deficient mice was impaired compared with wild-type mice. No significant differences were observed for mortality and blood pressure after renal ablation. In conclusion, these results demonstrate that MPO deficiency ameliorates renal injury in the renal ablation model of CKD in mice.

The True Infection Rate (TIR) in the whole population of each country and the Infection Fatality Rate (IFR) for coronavirus disease 2019 (COVID-19) are unknown although they are important parameters. We devised a simple method to infer TIR and IFR based on the open data. The prevalence rate of the polymerase chain reaction (PCR) tests among the population (Examination Rate; ER) and the positive rate of PCR tests (Infection Rate; IR) for 66 countries were picked up at a website 5 times from April 10th to June 13th, 2020, and the trajectory of each country was drawn over the IR vs. ER plot. IR and ER showed a strong negative correlation for some countries, and TIR was estimated by extrapolating the regression line when the correlation coefficient was between -0.99 and -1. True/Identified Case Ratio (TICR) and IFR were also calculated using the estimated TIR. The estimated TIR well coincided with local antibody surveys. Estimated IFR took on a wide range of values up to 10%: generally high in the Western countries. The estimated IFR of Singapore was very low (0.018%), which may be related to the reported gene mutation causing the attenuation of the viral virulence.

Nitroxyl (HNO) donors have potential benefit in the treatment of heart failure and other cardiovascular diseases. 1-Nitrosocyclohexyl acetate (NCA), a new HNO donor, in contrast to the classic HNO donors Angeli's salt and isopropylamine NONOate, predominantly releases HNO and has a longer half-life. This study investigated the vasodilatative properties of NCA in isolated aortic rings and human platelets and its mechanism of action. NCA was applied on aortic rings isolated from wild-type mice and apolipoprotein E-deficient mice and in endothelial-denuded aortae. The mechanism of action of HNO was examined by applying NCA in the absence and presence of the HNO scavenger glutathione (GSH) and inhibitors of soluble guanylyl cyclase (sGC), adenylyl cyclase (AC), calcitonin gene-related peptide receptor (CGRP), and K(+) channels. NCA induced a concentration-dependent relaxation (EC(50), 4.4 µM). This response did not differ between all groups, indicating an endothelium-independent relaxation effect. The concentration-response was markedly decreased in the presence of excess GSH; the nitric oxide scavenger 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide had no effect. Inhibitors of sGC, CGRP, and voltage-dependent K(+) channels each significantly impaired the vasodilator response to NCA. In contrast, inhibitors of AC, ATP-sensitive K(+) channels, or high-conductance Ca(2+)-activated K(+) channels did not change the effects of NCA. NCA significantly reduced contractile response and platelet aggregation mediated by the thromboxane A(2) mimetic 9,11-dideoxy-11α,9α-epoxymethanoprostaglandin F(2)(α) in a cGMP-dependent manner. In summary, NCA shows vasoprotective effects and may have a promising profile as a therapeutic agent in vascular dysfunction, warranting further evaluation.

Here we evaluated the prevalence and prognostic impact of epithelial cell adhesion molecule (EpCAM)-positive disseminated tumor cells (DTCs) in stage I rectal cancer. Further we tested the association of these single tumor cells or small tumor cell groups with the extent of peritumoral lymphangiogenesis. A total of 845 regional lymph nodes (LN) of 44 patients classified as negative on conventional histopathology were retrospectively reanalyzed with immunohistochemistry (IHC) using the monoclonal antibody Ber-Ep4 directed against EpCAM for the detection of DTCs. The degree of lymphangiogenesis in the primary tumors was assessed by IHC of the primary tumor tissue using the monoclonal antibody D2-40, which reacts with the lymphatic endothelium. The IHC results were correlated with clinico-pathologic parameters and clinical follow-up data. EpCAM-positive DTCs in LNs were detected in 8 (18.2) of the 44 patients. During a median follow-up of 59 months, 3 (37.5) of the 8 patients with EpCAM-positive DTCs relapsed, whereas none of the DTC-negative patients developed tumor recurrence (P=0.004). Survival analysis revealed a significant effect of the prevalence of DTCs on overall survival (P=0.0009) and on recurrence-free survival (P=0.0001). Finally, the prevalence of EpCAM-positive DTCs in perirectal LNs was significantly correlated with a high density of peritumoral lymphatic vessels (P=0.015). Our results show that DTCs may occur in stage I of rectal cancer and are associated with poor prognosis. Their occurrence seems to be linked to a high density of newly formed lymphatic vessel at the primary tumor site. According to our data, patients with DTCs in their LN might benefit from adjuvant therapy.

Activation of leukocytes with release of myeloperoxidase (MPO) has been linked to acute coronary disease. To date, studies investigating the diagnostic and prognostic performance of circulating MPO in patients with chest pain (CP) are mainly retrospective, of low size, and lack a cut-off value for MPO. Herein, we prospectively assess the diagnostic and prognostic properties of MPO compared with sensitive troponin I (sTNI) in patients admitted to the emergency room with CP.

Recruitment of polymorphonuclear neutrophils (PMNs) remains a paramount prerequisite in innate immune defense and a critical cofounder in inflammatory vascular disease. Neutrophil recruitment comprises a cascade of concerted events allowing for capture, adhesion and extravasation of the leukocyte. Whereas PMN rolling, binding, and diapedesis are well characterized, receptor-mediated processes, mechanisms attenuating the electrostatic repulsion between the negatively charged glycocalyx of leukocyte and endothelium remain poorly understood. We provide evidence for myeloperoxidase (MPO), an abundant PMN-derived heme protein, facilitating PMN recruitment by its positive surface charge. In vitro, MPO evoked highly directed PMN motility, which was solely dependent on electrostatic interactions with the leukocyte's surface. In vivo, PMN recruitment was shown to be MPO-dependent in a model of hepatic ischemia and reperfusion, upon intraportal delivery of MPO and in the cremaster muscle exposed to local inflammation or to intraarterial MPO application. Given MPO's affinity to both the endothelial and the leukocyte's surface, MPO evolves as a mediator of PMN recruitment because of its positive surface charge. This electrostatic MPO effect not only displays a so far unrecognized, catalysis-independent function of the enzyme, but also highlights a principal mechanism of PMN attraction driven by physical forces.

Detection rates of gastric cancer in 18F-fluorodeoxyglucose (FDG)-PET depend on the histopathological characteristics of the primary tumor. To clarify this observation, FDG uptake in gastric carcinoma was analyzed by focusing on histopathology and on the expression of the glucose transporter (GLUT-1) in the primary tumor.