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Zusammenfassung Hintergrund und Ziel Die kontinuierliche Erfassung von Augenverletzungen durch Pyrotechnik in den Tagen um Silvester über 6 Jahre ermöglicht uns, Verletzungszahlen, Verletzungsmuster und Unfallhergänge im Jahresvergleich zu untersuchen. Zur Entlastung der Krankenhäuser wurden in Deutschland im Rahmen der COVID-19-Pandemie für die Jahreswechsel 2020/21 und 2021/22 ein Verkaufsverbot für Pyrotechnikartikel und Versammlungsbegrenzungen umgesetzt. Wir untersuchen, welchen Einfluss diese Maßnahmen auf die Anzahl von feuerwerksbedingten Augenverletzungen hatten. Außerdem betrachten wir, ob dies zu einer Zunahme schwerer Verletzungen geführt hat und ob ein Zusammenhang mit einer vermehrten Nutzung selbst gebauter oder in Deutschland nicht zugelassener Pyrotechnik bestehen könnte. Methoden Mit unserem Online-Fragenbogen erfassen wir anonymisierte Daten zu Patienten, Unfallhergang und seit 2017/18 auch zur Beschaffung der eingesetzten Pyrotechnikartikel. Ergebnisse Unsere Auswertung umfasst Daten von 2151 Betroffenen. Während vor der Pandemie pro Jahr Daten von rund 500 Verletzten eingegeben worden waren, sank diese Zahl auf 79 am Jahreswechsel 2020/21 und 193 2021/22. Der Anteil schwerer, stationär zu versorgender Augenverletzungen lag in den Jahren vor der Pandemie zwischen 21 und 26 %, in den Pandemiejahren 2020 bis 2022 hingegen bei 27 % und 34 %. Gleichzeitig stieg unter dem Verkaufsverbot der Anteil von Pyrotechnikartikeln, die nach Aussagen der Patienten selbst gebaut oder inoffiziell erworben waren, von 3 % auf knapp 10 % an. Bei den absoluten Zahlen jedoch stehen 67 Unfälle mit nicht offiziell erworbener Pyrotechnik 1675 Zwischenfällen mit offiziell erworbenen oder nicht benennbaren Feuerwerkskörpern gegenüber. In etwa der Hälfte der Fälle konnte zum auslösenden Pyrotechnikartikel keine Aussage gemacht werden, was erklärbar ist durch den hohen Anteil (rund 50 %) verletzter Unbeteiligter. Schlussfolgerung Die absolute Zahl der Augenverletzungen durch Pyrotechnik sank unter den Pandemiebedingungen von rund 500 auf 79 bzw. 193. Die Nutzung von Feuerwerkskörpern, die als nicht offiziell erworben bezeichnet wurden, war auch unter dem Verkaufsverbot anteilsmäßig gering und spielt im Vergleich zu Verletzungen mit „offiziell erworbener“ Pyrotechnik eine untergeordnete Rolle.

Zusammenfassung Hintergrund Die Medien berichten über die erhöhte Gewaltbereitschaft von Patienten sowie Angehörigen gegenüber medizinischem Personal. Bislang wurden wenige Untersuchungen zu diesem Thema durchgeführt, entsprechend schwach ist die Datenlage. Gerade Augenärzte haben an der Spaltlampe engen Kontakt zum Patienten und sind oft mit Patienten allein. Methodik Auf Grundlage der Aggressions-Wahrnehmungsskala (POPAS Fragebogen, Oud 2000) sowie der Umfrage zu Aggressionen und Gewalt unter Allgemeinmedizinern (Vorderwülbecke et al. 2015) wurde ein Fragebogen entwickelt. Im Herbst 2018 erhielten alle Mitglieder der Deutschen Ophthalmologischen Gesellschaft (DOG) und des Berufsverbandes der Augenärzte (BVA) per Mail eine Einladung, um den Fragebogen online auszufüllen. Ergebnisse Von 9411 angeschriebenen Augenärzten nahmen insgesamt 1508 (Alter: 49 ± 12 Jahre) an der Befragung teil (16 %). 806 (53,7 %) Befragte waren weiblich. 1139 (75,5 %) Teilnehmer arbeiteten in Praxen. Insgesamt 1264 (83,3 %) der Augenärzte hatten Aggressionen/Gewalt in ihrer Tätigkeit erfahren. 986 (65 %) Befragte hatten verbale Übergriffe ohne Drohung erlebt. Von bedrohlich körperlichen Gewalterfahrungen berichteten 363 (24,1 %) Ärzte. 30 (2 %) Teilnehmer erhielten aufgrund schwerer körperlicher Gewalt eine ärztliche Behandlung. Sexuelle Einschüchterung/Belästigung bejahten 322 (21,4 %) der Befragten, von diesen waren 243 (75,5 %) weiblich. 533 (47,9 %) Ärzte empfanden, dass aggressive/gewalttätige Verhaltensweisen in den letzten 5 Jahren zugenommen haben. Schlussfolgerung Die hohe Teilnehmeranzahl weist auf die hohe Relevanz des Themas hin. Die Umfrage hat erstaunliche Ergebnisse geliefert, die weitere Diskussionen und Handlungen zur Folge haben sollten, um die Sicherheit der Mitarbeiter zu verbessern.

Intravitreal injection (IVI) of drugs for treatment of various macular diseases is now one of the most frequently performed surgical procedures worldwide. As mostly chronic diseases are treated, the indications for treatment often mean a continuous treatment over years with a corresponding effort regarding spatial, personnel and financial resources. The diagnosis and indications for treatment are nowadays mainly made by spectral domain optical coherence tomography (SD-OCT). The ability to clinically assess and evaluate a fluorescence angiography is less practiced, although these are still a component of the indications for intravitreal injections. Therefore, it can happen that despite all diligence patients may receive anti-vascular endothelial growth factor (VEGF) treatment, sometimes permanently, based on a misinterpretation of the macular diagnosis or disease activity and these indications, once made, are rarely questioned or retracted. Therefore, the aim of this manuscript is to point out possible and typical misinterpretations in the indications or continuation of IVI treatment with anti-VEGF by means of case studies and to sensitize for differential diagnoses.Die intravitreale operative Medikamenteneingabe (IVOM) bei verschiedenen Makulaerkrankungen ist heute eine der am häufigsten durchgeführten operativen Behandlungen weltweit. Da zumeist chronische Erkrankungen behandelt werden, bedeutet die Indikation zur Behandlung oft eine kontinuierliche Therapie über Jahre mit einem entsprechenden Aufwand bezüglich räumlicher, personeller und finanzieller Ressourcen. Dabei werden die Diagnose und Indikation zur Behandlung heute maßgeblich über die Spectral-Domain-optische Kohärenztomographie (SD-OCT) gestellt. Die Fähigkeit zur klinischen Beurteilung und Bewertung einer Fluoreszenzangiographie wird weniger geübt, obwohl diese immer noch Bestandteil der Indikationsstellung ist. So kann es passieren, dass Patienten zum Teil dauerhaft eine Anti-VEGF(„vascular endothelial growth factor“)-Therapie auf Basis einer Fehleinschätzung der makulären Diagnose oder der Aktivität der Erkrankung erhalten und diese Indikation – sobald einmal gestellt – selten hinterfragt oder zurückgenommen wird. Ziel dieses Manuskriptes ist es daher, anhand von Fallbeispielen auf mögliche und typische Fehlinterpretationen bei der Indikation oder Fortsetzung einer IVOM-Therapie mittels Anti-VEGF hinzuweisen und für Differenzialdiagnosen zu sensibilisieren.

Even in the era of intravitreal injection therapy (intravitreal operative injection of medication, IVOM) for the treatment of macular and retinal diseases, such as age-related macular degeneration (AMD), proliferative diabetic retinopathy (DR) and diabetic macular edema (DME) as well as proliferative stages and/or macular edema due to retinal vein occlusion (RVO), conventional retinal laser treatment is still of importance. It can be focally performed on an on-label basis for DME and macular edema due to branch RVO (BRVO) and its use as panretinal treatment for proliferative stages in retinal diseases as well as for the treatment of retinal holes is undisputed. The spectrum is extended by the treatment of less common diseases, such as retinal hemangioblastoma, macroaneurysms and subhyaloid macular hemorrhage. There is cause for concern that knowledge about the correct performance of retinal laser application might be shifted into the background due to an increase of IVOM treatment, which could lead to an increase in unnecessary errors. The aim of this manuscript is to increase awareness for the correct indications and execution of retinal laser treatment based on case examples of flawed or insufficient treatment.

Zusammenfassung Hintergrund Die Coronaviruserkrankung COVID-19 hat im Frühjahr 2020 zu einer deutlichen Minderleistung der elektiven Medizin in den Krankenhäusern geführt, wobei es für universitäre Polikliniken bisher keine entsprechenden Daten über das Ausmaß dieser Reduktion und die damit verbundenen Erlösminderungen gibt. Material und Methode Mithilfe der Daten des aus dem Krankenhausinformationssystems (IS-H/i.s.h.med unter SAP, Cerner Corporation, North Kansas City, MO, Vereinigte Staaten von Amerika und SAP SE, Walldorf, Deutschland) und der an unserer Klinik mitentwickelten Zeiterfassungs- und Managementsoftware TimeElement (Medizinische Hochschule Hannover, Hannover, Deutschland) wurden alle Patientenkontakte des COVID-19-Shutdowns über ca. 7 Wochen vom 18.03.2020 bis zum 08.05.2020 evaluiert und mit dem Vorjahreszeitraum 2019 verglichen. Zudem wurden die Fallzahlen für das erste und zweite Quartal 2019 und 2020 in Relation gesetzt. Ergebnisse Im COVID-19-Zeitraum reduzierte sich die Gesamtzahl der Patientenkontakte um 59,5 % gegenüber dem Vorjahr. Die Anzahl der abrechenbaren Fälle reduzierte sich um 74,8 %. Insbesondere der Hochschulambulanz‑/Selbstzahlerbereich verzeichnete mit einer Reduktion der Patientenkontakte auf 17,2 % des Ausgangswertes von 2019 den größten Patientenwegfall. Aus der reduzierten Arbeitsleistung resultierte ein Erlösverlust von mindestens 218.000 €. Über TimeElement ergab sich ein Rückgang aller diagnostischen Spezialleistungen von 69,4 %, wobei gerade auch Gesichtsfelduntersuchungen um ca. 75,3 % reduziert waren. OCT-Messungen verzeichneten einen Rückgang um 60,3 %. Das Patiententracking ergab allerdings auch eine Reduktion der durchschnittlichen Anwesenheitszeiten der Patienten um ca. 23 % (COVID-19: 145,8 ± 88,8 min vs. 2019: 189,6 ± 97,2 min). Diskussion Der COVID-19-Shutdown ließ die Arbeitsleistung unserer Poliklinik auf nur noch ca. 40 % der Patientenkontakte und die der funktionsdiagnostischen Untersuchungen auf nur noch ca. 30 %, verglichen zur Leistung aus dem Jahr 2019, einbrechen. Die Reduktion der Patientenzahl führte allerdings auch dazu, dass die Anwesenheitszeiten der Patienten deutlich geringer als bei regulärer Auslastung ausfielen. Die damit verbundenen finanziellen Verluste sind durchaus erheblich und offensichtlich nicht über gesetzlich geregelte Ausgleichszahlungen wie im stationären Bereich kompensiert.

The treatment of macular edema with intravitreal injections has revolutionized the treatment of associated diseases in ophthalmology. However, with a few exceptions, this is a chronic treatment where patients require many injections and usually need to stay in treatment for years. Patient adherence and control of patient flow are critical to treatment success. In this manuscript, we describe the development of a patient-oriented organization management for intravitreal injections in a university hospital.In 2015, the intravitreal treatment in our clinic was switched to the treat-and-extend regime. At the same time, the optimization of the previous organizational processes in perioperative management was evaluated. For the period 2015 to 2018, we analyzed and gradually optimized the procedures of our intravitreal injection therapy in a survey with a specialized service provider.Through the analysis of the original processes, the patient appointment was optimized, work processes were summarized, spatially reorganized and there was only a slight increase in the number of staff involved compared with the significant increase in the number of injections. Through these measures, the total in-hospital-time of the patients could be drastically reduced and at the same time the number of patients on one operation day could be multiplied.In the context of chronic treatment with intravitreal injections, the care of an increased number of patients is a logistical challenge. By optimizing processes, existing resources can be better used to meet the increased demands. An optimized system offers the patient greater adherence and a better visual outcome largely independent of the medication used.Die Behandlung eines Makulaödems mittels intravitrealer Injektionen hat die Behandlung der assoziierten Krankheitsbilder in der Augenheilkunde revolutioniert. Abgesehen von einigen wenigen Ausnahmen handelt es sich jedoch um eine chronische Behandlung, bei der die Patienten viele Injektionen benötigen und i. d. R. über Jahre in Behandlung bleiben müssen. Die Adhärenz der Patienten und die Steuerung des Patientenflusses ist mit entscheidend für den Behandlungserfolg. In diesem Manuskript beschreiben wir die Entwicklung eines patientennahen Organisationsmanagements für intravitreale Injektionen in einer Universitätsklinik.Im Jahr 2015 wurde in unserer Klinik die intravitreale Behandlung auf das Treat-and-Extend-Regime umgestellt. Zugleich erfolgte die Evaluation der Optimierung der bisherigen Organisationsabläufe im perioperativen Management. Für den Zeitraum 2015 bis 2018 haben wir im Rahmen einer Erhebung mit einem spezialisierten Dienstleister die Abläufe unserer intravitrealen Injektionstherapie analysiert und schrittweise optimiert.Durch die Analyse der ursprünglichen Abläufe wurde die Patienteneinbestellung optimiert, Arbeitsabläufe wurden zusammengefasst sowie räumlich neu geordnet und es fand eine verglichen mit der deutlichen Erhöhung der Injektionszahlen nur geringfügige Erhöhung der beteiligten Mitarbeiterzahl statt. Durch diese Maßnahmen konnte sowohl die Gesamtaufenthaltszeit der Patienten deutlich reduziert werden als auch zugleich die Patientenzahl bei guter Adhärenz und guten Visusergebnissen an einem Operationstag vervielfacht werden.Im Rahmen der chronischen Behandlung mittels intravitrealer Injektionen ist die Versorgung einer gestiegenen Anzahl an Patienten eine logistische Herausforderung. Durch Optimierung von Abläufen können vorhandene Ressourcen besser genutzt werden, um den gestiegenen Anforderungen gerecht zu werden. Ein optimiertes System bietet für den Patienten eine höhere Adhärenz und ein besseres Visusergebnis weitgehend unabhängig von dem verwendeten Medikament.

Even in the era of intravitreal injection therapy (intravitreal operative injection of medication, IVOM) for the treatment of macular and retinal diseases, such as age-related macular degeneration (AMD), proliferative diabetic retinopathy (DR) and diabetic macular edema (DME) as well as proliferative stages and/or macular edema due to retinal vein occlusion (RVO), conventional retinal laser treatment is still of importance. It can be focally performed on an on-label basis for DME and macular edema due to branch RVO (BRVO) and its use as panretinal treatment for proliferative stages in retinal diseases as well as for the treatment of retinal holes is undisputed. The spectrum is extended by the treatment of less common diseases, such as retinal hemangioblastoma, macroaneurysms and subhyaloid macular hemorrhage. There is cause for concern that knowledge about the correct performance of retinal laser application might be shifted into the background due to an increase of IVOM treatment, which could lead to an increase in unnecessary errors. The aim of this manuscript is to increase awareness for the correct indications and execution of retinal laser treatment based on case examples of flawed or insufficient treatment.

Background The subconjunctival anesthesia with local anesthetics is considered as a low-risk procedure allowing ocular surgery without serious complications typical for retro- or parabulbar anesthesia, especially in patients with preexisting Optic Nerve damage. We report development of ipsilateral transient amaurosis accompanied with mydriasis and both, direct and consensual light response absence. Case presentation Three patients with advanced refractory glaucoma undergoing laser cyclophotocoagulation (CPC) for intraocular pressure lowering experienced these adverse effects just few minutes after subconjunctival injection of mepivacaine 2% solution (Scandicaine® 2%, without vasoconstrictor supplementation). The vision was completely recovered to usual values in up to 20 h after mepivacaine application. Extensive ophthalmological examination, including cranial magnetic resonance imaging (MRI), revealed no further ocular abnormalities, especially no vascular constriction or thrombotic signs as well as no retinal detachment. The oculomotor function remained intact. The blockade of ipsilateral ciliary ganglion parasympathetic fibers by mepivacaine may be the responsible mechanism. Systemic pathways as drug-drug interactions seem to be unlikely involved. Importantly, all three patients tolerated the same procedure previously or at a later date without any complication. Overall, our thoroughly elaborated risk management could not determine the causative factor explaining the observed ocular complications just in the current occasion and not at other time points. Conclusions Doctors should be aware and patients should be informed about such rare complications after subconjunctival local anesthetics administration. Adequate risk management should insure patients’ safety.

Background Intravitreal injections are a mandatory treatment for macular edema due to nAMD, DME and RVO. These chronic diseases usually need chronic treatment using intravitreal injections with anti-VEGF agents. Thus, many trials were performed to define the best treatment interval using pro re nata regimes (PRN), fixed regimes or treat-and-extend regimes (TE). However, real-world studies reveal a high rate of losing patients within a 2-year interval of treatment observation causing worse results. In this study we analyzed retrospectively 2 years of real-world experience with an individualized treat-and-extend injection scheme. Methods Since 2015 our treatment scheme for intravitreal injections has been switched from PRN to TE. Out of 102 patients 59 completed a follow up time of 2 years. Every patient received visual acuity testing, SD-OCT and slit lamp examination prior to every injection. At each visit an injection was performed and the treatment interval was adjusted mainly on SD-OCT based morphologic changes by increasing or reducing in 2-week steps. Individual changes of the treatment protocol by face-to-face communication between physician and patient were possible. Results After 1 year of treatment visual acuity gain in nAMD was 7.4 ± 2.2 ETDRS letters (n = 34; injection frequency: 7.4 ± 0.4) respectively 6.1 ± 4.7 in DME (n = 9; injection frequency: 8.4 ± 1.1) and 9.7 ± 4.5 in RVO (n = 16; injection frequency: 7.6 ± 0.5). After 2 years of treatment results were as following: nAMD: visual acuity gain 6.9 ± 2.1 (injection frequency: 12.6 ± 0.7); DME: 11.1 ± 5.1 (injection frequency: 14.0 ± 1.0); RVO: 7.5 ± 5.0 (injection frequency: 11.2 ± 0.9). Planned treatment exit after 2 year was achieved in 29.4% of patients in nAMD (0% after 1 year); 0% in DME (0% after 1 year); and 31.3% in RVO (0% after 1 year). Patients’ persistence was 94.1% during the follow-up. Conclusion Using a consequent and individualized TE regime in daily practice may lead to a high patients’ persistence and visual acuity gains nearly comparable to those of large prospective clinical trials. Crucial factors are face-to-face communication with the patient as well as a stringent management regime. At this time TE may be the only instrument for proactive therapy which should therefore be regarded as a first-line tool in daily practice.

Rationale Many processes in endothelial cells including angiogenic responses are regulated by microRNAs. However, there is limited information available about their complex cross-talk in regulating certain endothelial functions. Aim The objective of this study is to identify endothelial functions of the pro-hypertrophic miR-212/132 cluster and its cross-talk with other microRNAs during development and disease. Methods and results We here show that anti-angiogenic stimulation by transforming growth factor-beta activates the microRNA-212/132 cluster by derepression of their transcriptional co-activator cAMP response element-binding protein (CREB)-binding protein (CBP) which is a novel target of a previously identified pro-angiogenic miRNA miR-30a-3p in endothelial cells. Surprisingly, despite having the same seed-sequence, miR-212 and miR-132 exerted differential effects on endothelial transcriptome regulation and cellular functions with stronger endothelial inhibitory effects caused by miR-212. These differences could be attributed to additional auxiliary binding of miR-212 to its targets. In vivo , deletion of the miR-212/132 cluster increased endothelial vasodilatory function, improved angiogenic responses during postnatal development and in adult mice. Conclusion Our results identify (i) a novel miRNA-cross-talk involving miR-30a-3p and miR-212, which led to suppression of important endothelial genes such as GAB1 and SIRT1 finally culminating in impaired endothelial function; and (ii) microRNAs may have different biological roles despite having the same seed sequence.

Circulating microRNAs (miRNAs/miRs) are used as novel biomarkers for diseases. miR-21, miR-126, and miR-210 are known to be deregulated in vivo or in vitro under diabetic conditions.The aim of this study was to investigate the circulating miR-21, miR-126, and miR-210 in plasma and urine from pediatric patients with type 1 diabetes and to link our findings to cardiovascular and diabetic nephropathy risk factors in children with type 1 diabetes.miR-21, miR-126, and miR-210 concentrations were measured with quantitative RT-PCR in plasma and urine samples from 68 pediatric patients with type 1 diabetes and 79 sex- and age-matched controls.The study consisted of clinical pediatric patients with type 1 diabetes.Inclusion criterion for patients was diagnosed type 1 diabetes. Exclusion criteria were febrile illness during the last 3 months; chronic inflammatory or rheumatic disease; hepatitis; HIV; glucocorticoid treatment; liver, renal, or cardiac failure; or hereditary dyslipidemia. Patients were age and sex matched to controls.Main outcome parameters were changes in miR-21, miR-126, and miR-210 concentration in plasma and urine from type 1 diabetic patients compared with corresponding controls.Circulating miRNA levels of miR-21 and miR-210 were significantly up-regulated in the plasma and urine of the type 1 diabetic patients. Urinary miR-126 levels in diabetic patients were significantly lower than in age- and gender-matched controls and negatively correlated between the patient's glycated hemoglobin mean and miR-126 concentration value. In contrast, circulating miR-126 levels in plasma were comparable in both cohorts. For urinary miR-21, we found by an adjusted receiver-operating characteristic-curve analysis with an area under the curve of 0.78.Type 1 diabetic pediatric patients revealed a significant deregulation of miR-21, miR-126, and miR-210 in plasma and urinary samples, which might indicate an early onset of diabetic-associated diseases.

Rationale: Transforming growth factor (TGF)-β was linked to abnormal vessel function and can mediate impairment of endothelial angiogenic responses. Its effect on microRNAs and downstream targets in this context is not known. Objective: To study the role of microRNAs in TGF-β–mediated angiogenic activity. Methods and Results: MicroRNA profiling after TGF-β treatment of endothelial cells identified miR-30a-3p, along with other members of the miR-30 family, to be strongly silenced. Supplementation of miR-30a-3p restored function in TGF-β–treated endothelial cells. We identified the epigenetic factor methyl-CpG-binding protein 2 (MeCP2) to be a direct and functional target of miR-30a-3p. Viral overexpression of MeCP2 mimicked the effects of TGF-β, suggesting that derepression of MeCP2 after TGF-β treatment may be responsible for impaired angiogenic responses. Silencing of MeCP2 rescued detrimental TGF-β effects on endothelial cells. Microarray transcriptome analysis of MeCP2-overexpressing endothelial cells identified several deregulated genes important for endothelial cell function including sirtuin1 (Sirt1). In vivo experiments using endothelial cell–specific MeCP2 null or Sirt1 transgenic mice confirmed the involvement of MeCP2/Sirt1 in the regulation of angiogenic functions of endothelial cells. Additional experiments identified that MeCP2 inhibited endothelial angiogenic characteristics partly by epigenetic silencing of Sirt1. Conclusions: TGF-β impairs endothelial angiogenic responses partly by downregulating miR-30a-3p and subsequent derepression of MeCP2-mediated epigenetic silencing of Sirt1.

Aims Takotsubo cardiomyopathy (TTC) remains a potentially life-threatening disease, which is clinically indistinguishable from acute myocardial infarction (MI). Today, no established biomarkers are available for the early diagnosis of TTC and differentiation from MI. MicroRNAs (miRNAs/miRs) emerge as promising sensitive and specific biomarkers for cardiovascular disease. Thus, we sought to identify circulating miRNAs suitable for diagnosis of acute TTC and for distinguishing TTC from acute MI. Methods and results After miRNA profiling, eight miRNAs were selected for verification by real-time quantitative reverse transcription polymerase chain reaction in patients with TTC ( n = 36), ST-segment elevation acute myocardial infarction (STEMI, n = 27), and healthy controls ( n = 28). We quantitatively confirmed up-regulation of miR-16 and miR-26a in patients with TTC compared with healthy subjects (both, P < 0.001), and up-regulation of miR-16, miR-26a, and let-7f compared with STEMI patients ( P < 0.0001, P < 0.05, and P < 0.05, respectively). Consistent with previous publications, cardiac specific miR-1 and miR-133a were up-regulated in STEMI patients compared with healthy controls (both, P < 0.0001). Moreover, miR-133a was substantially increased in patients with STEMI compared with TTC ( P < 0.05). A unique signature comprising miR-1, miR-16, miR-26a, and miR-133a differentiated TTC from healthy subjects [area under the curve (AUC) 0.835, 95% CI 0.733–0.937, P < 0.0001] and from STEMI patients (AUC 0.881, 95% CI 0.793–0.968, P < 0.0001). This signature yielded a sensitivity of 74.19% and a specificity of 78.57% for TTC vs. healthy subjects, and a sensitivity of 96.77% and a specificity of 70.37% for TTC vs. STEMI patients. Additionally, we noticed a decrease of the endothelin-1 (ET-1)-regulating miRNA-125a-5p in parallel with a robust increase of ET-1 plasma levels in TTC compared with healthy subjects ( P < 0.05). Conclusion The present study for the first time describes a signature of four circulating miRNAs as a robust biomarker to distinguish TTC from STEMI patients. The significant up-regulation of these stress- and depression-related miRNAs suggests a close connection of TTC with neuropsychiatric disorders. Moreover, decreased levels of miRNA125a-5p as well as increased plasma levels of its target ET-1 are in line with the microvascular spasm hypothesis of the TTC pathomechanism.

Aims Impaired myocardial sarcoplasmic reticulum calcium ATPase 2a (SERCA2a) activity is a hallmark of failing hearts, and SERCA2a gene therapy improves cardiac function in animals and patients with heart failure (HF). Deregulation of microRNAs has been demonstrated in HF pathophysiology. We studied the effects of therapeutic AAV9.SERCA2a gene therapy on cardiac miRNome expression and focused on regulation, expression, and function of miR-1 in reverse remodelled failing hearts. Methods and results We studied a chronic post-myocardial infarction HF model treated with AAV9.SERCA2a gene therapy. Heart failure resulted in a strong deregulation of the cardiac miRNome. miR-1 expression was decreased in failing hearts, but normalized in reverse remodelled hearts after AAV9.SERCA2a gene delivery. Increased Akt activation in cultured cardiomyocytes led to phosphorylation of FoxO3A and subsequent exclusion from the nucleus, resulting in miR-1 gene silencing. In vitro SERCA2a expression also rescued miR-1 in failing cardiomyocytes, whereas SERCA2a inhibition reduced miR-1 levels. In vivo , Akt and FoxO3A were highly phosphorylated in failing hearts, but reversed to normal by AAV9.SERCA2a, leading to cardiac miR-1 restoration. Likewise, enhanced sodium–calcium exchanger 1 (NCX1) expression during HF was normalized by SERCA2a gene therapy. Validation experiments identified NCX1 as a novel functional miR-1 target. Conclusion SERCA2a gene therapy of failing hearts restores miR-1 expression by an Akt/FoxO3A-dependent pathway, which is associated with normalized NCX1 expression and improved cardiac function.

Objective— MicroRNAs are a class of small ribonucleotides regulating gene/protein targets by transcript degradation or translational inhibition. Transforming growth factor-β (TGF-β) is involved in cardiac fibrosis partly by stimulation of endothelial-to-mesenchymal transition (EndMT). Here, we investigated whether microRNA (miR)-21, a microRNA enriched in fibroblasts and involved in general fibrosis, has a role in cardiac EndMT. Methods and Results— TGF-β treatment of endothelial cells significantly increased miR-21 expression and induced EndMT characterized by suppression of endothelial and increase of fibroblast markers. Overexpression of miR-21 alone also stimulated EndMT. Importantly, miR-21 blockade by transfection of specific microRNA inhibitors partly prevented TGF-β-induced EndMT. Mechanistically, miR-21 silenced phosphatase and tensin homolog in endothelial cells, resulting in activation of the Akt-pathway. Akt inhibition partly restored TGF-β-mediated loss of endothelial markers during EndMT. In vivo, pressure overload of the left ventricle led to increased expression of miR-21 in sorted cardiac endothelial cells, which displayed molecular and phenotypic signs of EndMT. This was attenuated by treatment of mice subjected to left ventricular pressure overload with an antagomir against miR-21. Conclusion— TGF-β-mediated EndMT is regulated at least in part by miR-21 via the phosphatase and tensin homolog/Akt pathway. In vivo, antifibrotic effects of miR-21 antagonism are partly mediated by blocking EndMT under stress conditions.

The small regulatory RNA microRNA-21 (miR-21) plays a crucial role in a plethora of biological functions and diseases including development, cancer, cardiovascular diseases and inflammation. The gene coding for pri-miR-21 (primary transcript containing miR-21) is located within the intronic region of the TMEM49 gene. Despite pri-miR-21 and TMEM49 are overlapping genes in the same direction of transcription, pri-miR-21 is independently transcribed by its own promoter regions and terminated with its own poly(A) tail. After transcription, primiR- 21 is finally processed into mature miR-21. Expression of miR-21 has been found to be deregulated in almost all types of cancers and therefore was classified as an oncomiR. During recent years, additional roles of miR-21 in cardiovascular and pulmonary diseases, including cardiac and pulmonary fibrosis as well as myocardial infarction have been described. MiR-21 additionally regulates various immunological and developmental processes. Due to the critical functions of its target proteins in various signaling pathways, miR-21 has become an attractive target for genetic and pharmacological modulation in various disease conditions.

Rationale: Long noncoding RNAs represent a novel class of molecules regulating gene expression. Long noncoding RNAs are present in body fluids, but their potential as biomarkers was never investigated in cardiovascular disease. Objective: To study the role of long noncoding RNAs as potential biomarkers in heart disease. Methods and Results: Global transcriptomic analyses were done in plasma RNA from patients with or without left ventricular remodeling after myocardial infarction. Regulated candidates were validated in 3 independent patient cohorts developing cardiac remodeling and heart failure (788 patients). The mitochondrial long noncoding RNA uc022bqs.1 (LIPCAR) was downregulated early after myocardial infarction but upregulated during later stages. LIPCAR levels identified patients developing cardiac remodeling and were independently to other risk markers associated with future cardiovascular deaths. Conclusions: LIPCAR is a novel biomarker of cardiac remodeling and predicts future death in patients with heart failure.