Publications by authors named "Maike Knorr"

43 Publications

Ethnic comparison in takotsubo syndrome: novel insights from the International Takotsubo Registry.

Clin Res Cardiol 2021 May 19. Epub 2021 May 19.

Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany.

Background: Ethnic disparities have been reported in cardiovascular disease. However, ethnic disparities in takotsubo syndrome (TTS) remain elusive. This study assessed differences in clinical characteristics between Japanese and European TTS patients and determined the impact of ethnicity on in-hospital outcomes.

Methods: TTS patients in Japan were enrolled from 10 hospitals and TTS patients in Europe were enrolled from 32 hospitals participating in the International Takotsubo Registry. Clinical characteristics and in-hospital outcomes were compared between Japanese and European patients.

Results: A total of 503 Japanese and 1670 European patients were included. Japanese patients were older (72.6 ± 11.4 years vs. 68.0 ± 12.0 years; p < 0.001) and more likely to be male (18.5 vs. 8.4%; p < 0.001) than European TTS patients. Physical triggering factors were more common (45.5 vs. 32.0%; p < 0.001), and emotional triggers less common (17.5 vs. 31.5%; p < 0.001), in Japanese patients than in European patients. Japanese patients were more likely to experience cardiogenic shock during the acute phase (15.5 vs. 9.0%; p < 0.001) and had a higher in-hospital mortality (8.2 vs. 3.2%; p < 0.001). However, ethnicity itself did not appear to have an impact on in-hospital mortality. Machine learning approach revealed that the presence of physical stressors was the most important prognostic factor in both Japanese and European TTS patients.

Conclusion: Differences in clinical characteristics and in-hospital outcomes between Japanese and European TTS patients exist. Ethnicity does not impact the outcome in TTS patients. The worse in-hospital outcome in Japanese patients, is mainly driven by the higher prevalence of physical triggers.

Trial Registration: URL: https://www.clinicaltrials.gov ; Unique Identifier: NCT01947621.
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http://dx.doi.org/10.1007/s00392-021-01857-4DOI Listing
May 2021

Prognostic impact of acute pulmonary triggers in patients with takotsubo syndrome: new insights from the International Takotsubo Registry.

ESC Heart Fail 2021 06 13;8(3):1924-1932. Epub 2021 Mar 13.

Department of Cardiology, Charité, Campus Rudolf Virchow, Berlin, Germany.

Aims: Acute pulmonary disorders are known physical triggers of takotsubo syndrome (TTS). This study aimed to investigate prevalence of acute pulmonary triggers in patients with TTS and their impact on outcomes.

Methods And Results: Patients with TTS were enrolled from the International Takotsubo Registry and screened for triggering factors and comorbidities. Patients were categorized into three groups (acute pulmonary trigger, chronic lung disease, and no lung disease) to compare clinical characteristics and outcomes. Of the 1670 included patients with TTS, 123 (7%) were identified with an acute pulmonary trigger, and 194 (12%) had a known history of chronic lung disease. The incidence of cardiogenic shock was highest in patients with an acute pulmonary trigger compared with those with chronic lung disease or without lung disease (17% vs. 10% vs. 9%, P = 0.017). In-hospital mortality was also higher in patients with an acute pulmonary trigger than in the other two groups, although not significantly (5.7% vs. 1.5% vs. 4.2%, P = 0.13). Survival analysis demonstrated that patients with an acute pulmonary trigger had the worst long-term outcome (P = 0.002). The presence of an acute pulmonary trigger was independently associated with worse long-term mortality (hazard ratio 2.12, 95% confidence interval 1.33-3.38; P = 0.002).

Conclusions: The present study demonstrates that TTS is related to acute pulmonary triggers in 7% of all TTS patients, which accounts for 21% of patients with physical triggers. The presence of acute pulmonary trigger is associated with a severe in-hospital course and a worse long-term outcome.
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http://dx.doi.org/10.1002/ehf2.13165DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8120351PMC
June 2021

Randomised, non-inferiority, controlled procedural outcomes TrIal comParing reverse T And Protrusion versus double-kissing and crush stenting: protocol of the TIP TAP I randomised trial.

BMJ Open 2020 06 16;10(6):e034264. Epub 2020 Jun 16.

Kardiologie I, Universitätsmedizin Mainz, Mainz, Rheinland-Pfalz, Germany

Introduction: To assess the impact of 'reverse T and Protrusion' (TAP) technique on the outcome after stenting of true bifurcation lesions of the left main (LM) or proximal epicardial vessels as compared with double kissing (DK)-crush technique.

Methods And Analysis: 50 consecutive patients with true coronary bifurcation lesion (Medina 1,1,1 or 0,1,1) of the LM or the proximal main vessels, requiring a two-stent technique as first-line strategy at University Medical Center Mainz, are randomised in a 1:1 ratio to reverse TAP or DK-crush stenting. As recommended by best clinical practice, final angiographic result is evaluated and optical coherence tomographic (OCT) intracoronary imaging is performed to assess and optimise the final result. The primary end point is defined as the percentage of stent expansion in the side branch. Secondary end points consist of angiographic and procedural success (assessed until patient's discharge), procedural parameters (procedural time, fluoroscopy time, use of devices, X-ray dose) and OCT parameters expressing expansion of the stents. Safety parameters include all adverse events up to 6 months after discharge. A clinical, angiographic and intracoronary imaging control at 6 months is planned.

Ethics And Dissemination: The protocol complies with good clinical practice and the ethical principles described in the Declaration of Helsinki and is approved by the local ethics committee. The results of the trial will be published as original article(s) in medical journals and/or as presentation at congresses.

Trial Registration Number: ClinicalTrials.gov Registry (NCT03714750).
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http://dx.doi.org/10.1136/bmjopen-2019-034264DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7304799PMC
June 2020

Coexistence and outcome of coronary artery disease in Takotsubo syndrome.

Eur Heart J 2020 09;41(34):3255-3268

Department of Cardiology, Kantonsspital Lucerne, Lucerne, Switzerland.

Aims: Takotsubo syndrome (TTS) is an acute heart failure syndrome, which shares many features with acute coronary syndrome (ACS). Although TTS was initially described with angiographically normal coronary arteries, smaller studies recently indicated a potential coexistence of coronary artery disease (CAD) in TTS patients. This study aimed to determine the coexistence, features, and prognostic role of CAD in a large cohort of patients with TTS.

Methods And Results: Coronary anatomy and CAD were studied in patients diagnosed with TTS. Inclusion criteria were compliance with the International Takotsubo Diagnostic Criteria for TTS, and availability of original coronary angiographies with ventriculography performed during the acute phase. Exclusion criteria were missing views, poor quality of angiography loops, and angiography without ventriculography. A total of 1016 TTS patients were studied. Of those, 23.0% had obstructive CAD, 41.2% had non-obstructive CAD, and 35.7% had angiographically normal coronary arteries. A total of 47 patients (4.6%) underwent percutaneous coronary intervention, and 3 patients had acute and 8 had chronic coronary artery occlusion concomitant with TTS, respectively. The presence of CAD was associated with increased incidence of shock, ventilation, and death from any cause. After adjusting for confounders, the presence of obstructive CAD was associated with mortality at 30 days. Takotsubo syndrome patients with obstructive CAD were at comparable risk for shock and death and nearly at twice the risk for ventilation compared to an age- and sex-matched ACS cohort.

Conclusions: Coronary artery disease frequently coexists in TTS patients, presents with the whole spectrum of coronary pathology including acute coronary occlusion, and is associated with adverse outcome.

Trial Registration: ClinicalTrials.gov number: NCT01947621.
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http://dx.doi.org/10.1093/eurheartj/ehaa210DOI Listing
September 2020

Effectiveness of additional X-ray protection devices in reducing scattered radiation in radial intervention: the ESPRESSO randomised trial.

EuroIntervention 2020 10;16(8):663-671

Zentrum für Kardiologie, Kardiologie I, Universitätsmedizin Mainz and DZHK Standort Rhein-Main, Mainz, Germany.

Aims: We aimed to examine the impact of three different radiation protection devices in a real-world setting of radial artery catheterisation.

Methods And Results: In an all-comer randomised trial, consecutive coronary radial diagnostic and intervention procedures were assigned in a 1:1:1 ratio to shield-only protection (shield group), shield and overlapping 0.5 mm Pb panel curtain (shield+curtain group) or shield, curtain and additional 75x40 cm, 0.5 mm Pb drape placed across the waist of the patient (shield+curtain+drape group). A total of 614 radial procedures were randomised (n=193 shield, n=220 shield+curtain, n=201 shield+curtain+drape). There were no differences among the groups in patient or procedural characteristics. The primary endpoint (relative exposure ratio between the operators' exposure in μSv and the patient's exposure, dose area product in cGy·cm2) was significantly lower in the shield+curtain+drape group for both the first operator (20% reduction vs shield, 16% vs shield+curtain, p=0.025) and the assistant (39% reduction vs shield, 25% vs shield+curtain, p=0.009).

Conclusions: The use of an additional drape reduced the radiation exposure of both the first operator and the second operator during routine radial procedures; a shield-attached curtain alone was only partially effective. ClinicalTrials.gov identifier: NCT03634657
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http://dx.doi.org/10.4244/EIJ-D-19-00945DOI Listing
October 2020

Age-Related Variations in Takotsubo Syndrome.

J Am Coll Cardiol 2020 04;75(16):1869-1877

Krankenhaus "Maria Hilf" Medizinische Klinik, Stadtlohn, Germany.

Background: Takotsubo syndrome (TTS) occurs predominantly in post-menopausal women but is also found in younger patients.

Objectives: This study aimed to investigate age-related differences in TTS.

Methods: Patients diagnosed with TTS and enrolled in the International Takotsubo Registry between January 2011 and February 2017 were included in this analysis and were stratified by age (younger: ≤50 years, middle-age: 51 to 74 years, elderly: ≥75 years). Baseline characteristics, hospital course, as well as short- and long-term mortality were compared among groups.

Results: Of 2,098 TTS patients, 242 (11.5%) patients were ≤50 years of age, 1,194 (56.9%) were 51 to 74 years of age, and 662 (31.6%) were ≥75 years of age. Younger patients were more often men (12.4% vs. 10.9% vs. 6.3%; p = 0.002) and had an increased prevalence of acute neurological (16.3% vs. 8.4% vs. 8.8%; p = 0.001) or psychiatric disorders (14.1% vs. 10.3% vs. 5.6%; p < 0.001) compared with middle-aged and elderly TTS patients. Furthermore, younger patients had more often cardiogenic shock (15.3% vs. 9.1% vs. 8.1%; p = 0.004) and had a numerically higher in-hospital mortality (6.6% vs. 3.6% vs. 5.1%; p = 0.07). At multivariable analysis, younger (odds ratio: 1.60; 95% confidence interval: 0.86 to 3.01; p = 0.14) and older age (odds ratio: 1.09; 95% confidence interval: 0.66 to 1.80; p = 0.75) were not independently associated with in-hospital mortality using the middle-aged group as a reference. There were no differences in 60-day mortality rates among groups.

Conclusions: A substantial proportion of TTS patients are younger than 50 years of age. TTS is associated with severe complications requiring intensive care, particularly in younger patients.
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http://dx.doi.org/10.1016/j.jacc.2020.02.057DOI Listing
April 2020

Nox2+ myeloid cells drive vascular inflammation and endothelial dysfunction in heart failure after myocardial infarction via angiotensin II receptor type 1.

Cardiovasc Res 2021 01;117(1):162-177

Center for Thrombosis and Haemostasis, University Medical Center Mainz, Langenbeckstraße 1, 55131 Mainz, Germany.

Aims: Heart failure (HF) ensuing myocardial infarction (MI) is characterized by the initiation of a systemic inflammatory response. We aimed to elucidate the impact of myelomonocytic cells and their activation by angiotensin II on vascular endothelial function in a mouse model of HF after MI.

Methods And Results: HF was induced in male C57BL/6J mice by permanent ligation of the left anterior descending coronary artery. Compared to sham, HF mice had significantly impaired endothelial function accompanied by enhanced mobilization of Sca-1+c-Kit+ haematopoietic stem cells and Sca-1-c-Kit+ common myeloid and granulocyte-macrophage progenitors in the bone marrow as well as increased vascular infiltration of CD11b+Ly6G-Ly6Chigh monocytes and accumulation of CD11b+ F4/80+ macrophages, assessed by flow cytometry. Using mice with Cre-inducible expression of diphtheria toxin receptor in myeloid cells, we selectively depleted lysozyme M+ myelomonocytic cells for 10 days starting 28 days after MI. While the cardiac phenotype remained unaltered until 38 days post-MI, myeloid cell depletion attenuated vascular accumulation of Nox2+CD45+ cells, endothelial dysfunction, oxidative stress, and vascular expression of adhesion molecules and angiotensin II receptor type 1 (AT1R). Pharmacological blockade of this receptor for 4 weeks did not significantly alter cardiac function, but mimicked the effects of myeloid cell depletion: telmisartan (20 mg/kg/day, fed to C57BL/6J mice) diminished bone marrow myelopoesis and myeloid reactive oxygen species production, attenuated endothelial leucocyte rolling and vascular accumulation of CD11b+Ly6G-Ly6Chigh monocytes and macrophages, resulting in improved vascular function with less abundance of Nox2+CD45+ cells.

Conclusion: Endothelial dysfunction in HF ensuing MI is mediated by inflammatory Nox2+ myeloid cells infiltrating the vessel wall that can be targeted by AT1R blockade.
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http://dx.doi.org/10.1093/cvr/cvaa042DOI Listing
January 2021

Impact of aspirin on takotsubo syndrome: a propensity score-based analysis of the InterTAK Registry.

Eur J Heart Fail 2020 02 20;22(2):330-337. Epub 2019 Dec 20.

Department of Internal Medicine III, Heart Center University of Cologne, Cologne, Germany.

Aims: The aim of the present study was to investigate the impact of aspirin on prognosis in takotsubo syndrome (TTS).

Methods And Results: Patients from the International Takotsubo (InterTAK) Registry were categorized into two groups based on aspirin prescription at discharge. A comparison of clinical outcomes between groups was performed using an adjusted analysis with propensity score (PS) stratification; results from the unadjusted analysis were also reported to note the effect of the PS adjustment. Major adverse cardiac and cerebrovascular events (MACCE: a composite of death, myocardial infarction, TTS recurrence, stroke or transient ischaemic attack) were assessed at 30-day and 5-year follow-up. A total of 1533 TTS patients with known status regarding aspirin prescription at discharge were included. According to the adjusted analysis based on PS stratification, aspirin was not associated with a lower hazard of MACCE at 30-day [hazard ratio (HR) 1.24, 95% confidence interval (CI) 0.50-3.04, P = 0.64] or 5-year follow-up (HR 1.11, 95% CI 0.78-1.58, P = 0.58). These results were confirmed by sensitivity analyses performed with alternative PS-based methods, i.e. covariate adjustment and inverse probability of treatment weighting.

Conclusion: In the present study, no association was found between aspirin use in TTS patients and a reduced risk of MACCE at 30-day and 5-year follow-up. These findings should be confirmed in adequately powered randomized controlled trials. ClinicalTrials.gov Identifier: NCT01947621.
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http://dx.doi.org/10.1002/ejhf.1698DOI Listing
February 2020

Intraventricular Thrombus Formation and Embolism in Takotsubo Syndrome: Insights From the International Takotsubo Registry.

Arterioscler Thromb Vasc Biol 2020 01 26;40(1):279-287. Epub 2019 Nov 26.

Service de cardiologie, Hôpitaux Universitaires de Genève, Switzerland (P. Meyer, J.D.A.).

Objective: Takotsubo syndrome (TTS) is characterized by acute left ventricular dysfunction, which can contribute to intraventricular thrombus and embolism. Still, prevalence and clinical impact of thrombus formation and embolic events on outcome of TTS patients remain unclear. This study aimed to investigate clinical features and outcomes of patients with and without intraventricular thrombus or embolism. Additionally, factors associated with thrombus formation or embolism, as well as predictors for mortality, were identified. Approach and Results: TTS patients enrolled in the International Takotsubo Registry at 28 centers in Australia, Europe, and the United States were dichotomized according to the occurrence/absence of intraventricular thrombus or embolism. Patients with intraventricular thrombus or embolism were defined as the ThrombEmb group. Of 1676 TTS patients, 56 (3.3%) patients developed intraventricular thrombus and/or embolism following TTS diagnosis (median time interval, 2.0 days [range, 0-38 days]). Patients in the ThrombEmb group had a different clinical profile including lower left ventricular ejection fraction, higher prevalence of the apical type, elevated levels of troponin and inflammatory markers, and higher prevalence of vascular disease. In a Firth bias-reduced penalized-likelihood logistic regression model apical type, left ventricular ejection fraction ≤30%, previous vascular disease, and a white blood cell count on admission >10×10 cells/μL emerged as independent predictors for thrombus formation or embolism.

Conclusions: Intraventricular thrombus or embolism occur in 3.3% of patients in the acute phase of TTS. A simple risk score including clinical parameters associated with intraventricular thrombus formation or embolism identifies patients at increased risk.

Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01947621.
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http://dx.doi.org/10.1161/ATVBAHA.119.313491DOI Listing
January 2020

Clinical Predictors and Prognostic Impact of Recovery of Wall Motion Abnormalities in Takotsubo Syndrome: Results From the International Takotsubo Registry.

J Am Heart Assoc 2019 11 1;8(21):e011194. Epub 2019 Nov 1.

Department of Cardiology Kantonsspital Lucerne Lucerne Switzerland.

Background Left ventricular (LV) recovery in takotsubo syndrome (TTS) occurs over a wide-ranging interval, varying from hours to weeks. We sought to investigate the clinical predictors and prognostic impact of recovery time for TTS patients. Methods and Results TTS patients from the International Takotsubo Registry were included in this study. Cut-off for early LV recovery was determined to be 10 days after the acute event. Multivariable logistic regression was used to assess factors associated with the absence of early recovery. In-hospital outcomes and 1-year mortality were compared for patients with versus without early recovery. We analyzed 406 patients with comprehensive and serial imaging data regarding time to recovery. Of these, 191 (47.0%) had early LV recovery and 215 (53.0%) demonstrated late LV improvement. Patients without early recovery were more often male (12.6% versus 5.2%; =0.011) and presented more frequently with typical TTS (76.3% versus 67.0%, =0.040). Cardiac and inflammatory markers were higher in patients without early recovery than in those with early recovery. Patients without early recovery showed unfavorable 1-year outcome compared with patients with early recovery (=0.003). On multiple logistic regression, male sex, LV ejection fraction <45%, and acute neurologic disorders were associated with the absence of early recovery. Conclusions TTS patients without early LV recovery have different clinical characteristics and less favorable 1-year outcome compared with patients with early recovery. The factors associated with the absence of early recovery included male sex, reduced LV ejection fraction, and acute neurologic events. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT01947621.
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http://dx.doi.org/10.1161/JAHA.118.011194DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6898832PMC
November 2019

Clinical Features and Outcomes of Patients With Malignancy and Takotsubo Syndrome: Observations From the International Takotsubo Registry.

J Am Heart Assoc 2019 08 17;8(15):e010881. Epub 2019 Jul 17.

Clinic for Cardiology and Pneumology Georg August University Goettingen Goettingen Germany.

Background Clinical characteristics and outcomes of takotsubo syndrome (TTS) patients with malignancy have not been fully elucidated. This study sought to explore differences in clinical characteristics and to investigate short- and long-term outcomes in TTS patients with or without malignancy. Methods and Results TTS patients were enrolled from the International Takotsubo Registry. The TTS cohort was divided into patients with and without malignancy to investigate differences in clinical characteristics and to assess short- and long-term mortality. A subanalysis was performed comparing long-term mortality between a subset of TTS patients with or without malignancy and acute coronary syndrome (ACS) patients with or without malignancy. Malignancy was observed in 16.6% of 1604 TTS patients. Patients with malignancy were older and more likely to have physical triggers, but less likely to have emotional triggers compared with those without malignancy. Long-term mortality was higher in patients with malignancy (P<0.001), while short-term outcome was comparable (P=0.17). In a subanalysis, long-term mortality was comparable between TTS patients with malignancies and ACS patients with malignancies (P=0.13). Malignancy emerged as an independent predictor of long-term mortality. Conclusions A substantial number of TTS patients show an association with malignancy. History of malignancy might increase the risk for TTS, and therefore, appropriate screening for malignancy should be considered in these patients. Clinical Trial Registration URL: http://www.clinicaltrial.gov. Unique identifier: NCT01947621.
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http://dx.doi.org/10.1161/JAHA.118.010881DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6761645PMC
August 2019

Effectiveness of additional X-ray protection devices in reducing Scattered radiation in radial interventions: protocol of the ESPRESSO randomised trial.

BMJ Open 2019 07 3;9(7):e029509. Epub 2019 Jul 3.

Kardiologie I, University Medical Center Mainz, Mainz, Germany.

Background: A number of devices have been developed to minimise operator radiation exposure in the setting of cardiac catheterisation. The effectiveness of these devices has traditionally been explored in transfemoral coronary procedures; however, less is known for the transradial approach. We set out to examine the impact of three different radiation protection devices in a real-world setting.

Methods And Design: Consecutive coronary diagnostic and intervention procedures are randomised in a 1:1:1 ratio to a shield-only protection (shield group), shield and overlapping 0.5 mm Pb panel curtain (curtain group) or shield, curtain and additional 75×40 cm, 0.5 mm Pb drape placed across the waist of the patient (drape group).The primary outcome is the difference in relative exposure of the primary operator among groups. Relative exposure is defined as the ratio between operator's exposure (E in μSv) and patient exposure (dose area product in cGy·cm).

Ethics And Dissemination: The protocol complies with good clinical practice and the ethical principles described in the Declaration of Helsinki and is approved by the local ethics committee. The results of the trial will be published as original article(s) in medical journals and/or as presentation at congresses.

Trial Registration Number: NCT03634657.
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http://dx.doi.org/10.1136/bmjopen-2019-029509DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6615829PMC
July 2019

Cardiac arrest in takotsubo syndrome: results from the InterTAK Registry.

Eur Heart J 2019 07;40(26):2142-2151

Department of Internal Medicine/Cardiology, University of Leipzig-Heart Center, Leipzig, Germany.

Aims: We aimed to evaluate the frequency, clinical features, and prognostic implications of cardiac arrest (CA) in takotsubo syndrome (TTS).

Methods And Results: We reviewed the records of patients with CA and known heart rhythm from the International Takotsubo Registry. The main outcomes were 60-day and 5-year mortality. In addition, predictors of mortality and predictors of CA during the acute TTS phase were assessed. Of 2098 patients, 103 patients with CA and known heart rhythm during CA were included. Compared with patients without CA, CA patients were more likely to be younger, male, and have apical TTS, atrial fibrillation (AF), neurologic comorbidities, physical triggers, and longer corrected QT-interval and lower left ventricular ejection fraction on admission. In all, 57.1% of patients with CA at admission had ventricular fibrillation/tachycardia, while 73.7% of patients with CA in the acute phase had asystole/pulseless electrical activity. Patients with CA showed higher 60-day (40.3% vs. 4.0%, P < 0.001) and 5-year mortality (68.9% vs. 16.7%, P < 0.001) than patients without CA. T-wave inversion and intracranial haemorrhage were independently associated with higher 60-day mortality after CA, whereas female gender was associated with lower 60-day mortality. In the acute phase, CA occurred less frequently in females and more frequently in patients with AF, ST-segment elevation, and higher C-reactive protein on admission.

Conclusions: Cardiac arrest is relatively frequent in TTS and is associated with higher short- and long-term mortality. Clinical and electrocardiographic parameters independently predicted mortality after CA.
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http://dx.doi.org/10.1093/eurheartj/ehz170DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6612368PMC
July 2019

A sequential interferon gamma directed chemotactic cellular immune response determines survival and cardiac function post-myocardial infarction.

Cardiovasc Res 2019 Nov;115(13):1907-1917

Center for Cardiology-Cardiology I, University Medical Center Mainz, Langenbeckstraße 1, Mainz, Germany.

Aims: Myelomonocytic cells are critical in injury and healing post-myocardial infarction (MI). Mechanisms of regulation, however, are incompletely understood. The aim of the study was to elucidate the role of interferon gamma (IFN-γ) in the orchestrated inflammatory response in a murine model of MI.

Methods And Results: MI was induced in 8- to 12-week-old male mice (C57BL/6 background) by permanent ligation of the left anterior descending (LAD) coronary artery. Lysozyme M (LysM)+ cell-depleted LysMiDTR transgenic mice displayed a reduced influx of CD45.2+/CD3-/CD11b+/Gr-1high neutrophils into infarcted myocardium 1 day post-MI compared with infarcted controls, paralleled by decreased cardiac mRNA levels of IFN-γ and tumour necrosis factor alpha (TNF-α). Mortality after MI was significantly increased in LysM+ cell-depleted mice within 28 days post-MI. To more specifically address the role of neutrophils, we depleted C57BL/6 mice with a monoclonal anti-Gr-1 antibody and found increased mortality, deteriorated cardiac function as well as decreased cardiac IFN-γ mRNA expression early after MI. Ccl2, Cxcl1, Cx3cl1, and Il12b mRNA were reduced 3 days after MI, as was the amount of CD11b+/Ly-6G-/Ly-6Chigh inflammatory monocytes. LAD-ligated Cramp-/- mice lacking cathelicidin important in neutrophil-dependent monocyte chemotaxis as well as IFNγ-/- and TNFα-/- mice phenocopied Gr-1+ cell-depleted mice, supporting a regulatory role of IFN-γ impacting on both the sequence of inflammatory cell invasion and cardiac outcome early after MI. The use of conditional IFN-γ receptor deficient mice indicated a direct effect of IFN-γ on LysM+ cells in cardiac injury post-MI. Using IFN-γ reporter mice and flow cytometry, we identified cardiac lymphoid cells (CD4+ and CD8+ T cells and natural killer cells) as primary source of this cytokine in the cardiac inflammatory response post-MI.

Conclusion: IFN-γ directs a sequential chemotactic cellular immune response and determines survival and cardiac function post-MI.
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http://dx.doi.org/10.1093/cvr/cvz092DOI Listing
November 2019

Hypoxia evokes increased PDI and PDIA6 expression in the infarcted myocardium of ex-germ-free and conventionally raised mice.

Biol Open 2019 Jan 2;8(1). Epub 2019 Jan 2.

Center for Thrombosis and Hemostasis (CTH), University Medical Center Mainz, Johannes Gutenberg University Mainz, Langenbeckstrasse 1, 55131 Mainz, Germany

The prototypic protein disulfide isomerase (PDI), encoded by the gene, has been described as a survival factor in ischemic cardiomyopathy. However, the role of protein disulfide isomerase associated 6 (PDIA6) under hypoxic conditions in the myocardium remains enigmatic, and it is unknown whether the gut microbiota influences the expression of PDI and PDIA6 under conditions of acute myocardial infarction. Here, we revealed that, in addition to the prototypic PDI, the PDI family member PDIA6, a regulator of the unfolded protein response, is upregulated in the mouse cardiomyocyte cell line HL-1 when cultured under hypoxia. , in the left anterior descending artery (LAD) ligation mouse model of acute myocardial infarction, similar to PDI, PDIA6 protein expression was enhanced in the infarcted area (LAD+) relative to uninfarcted sham tissue or the neighbouring area at risk (LAD-) of C57BL/6J mice. Interestingly, we found that ex-germ-free (ex-GF) mice subjected to the LAD ligation model for 24 h had a reduced ejection fraction compared with their conventionally raised (CONV-R) SPF controls. Furthermore, the LAD+ area in the infarcted heart of ex-GF mice showed reduced PDIA6 expression relative to CONV-R controls, suggesting that the presence of a gut microbiota enhanced LAD ligation-triggered PDIA6 expression. Collectively, our results demonstrate that PDIA6 is upregulated in cardiomyocytes as a consequence of hypoxia. In the LAD mouse model, PDIA6 was also increased in the infarcted area under conditions, but this increase was suppressed in ex-GF mice relative to CONV-R controls.This article has an associated First Person interview with the first author of the paper.
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http://dx.doi.org/10.1242/bio.038851DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6361221PMC
January 2019

Long-Term Prognosis of Patients With Takotsubo Syndrome.

J Am Coll Cardiol 2018 08;72(8):874-882

Deutsches Herzzentrum München, Technische Universität München, Munich, Germany; DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany.

Background: Prognosis of Takotsubo syndrome (TTS) remains controversial due to scarcity of available data. Additionally, the effect of the triggering factors remains elusive.

Objectives: This study compared prognosis between TTS and acute coronary syndrome (ACS) patients and investigated short- and long-term outcomes in TTS based on different triggers.

Methods: Patients with TTS were enrolled from the International Takotsubo Registry. Long-term mortality of patients with TTS was compared to an age- and sex-matched cohort of patients with ACS. In addition, short- and long-term outcomes were compared between different groups according to triggering conditions.

Results: Overall, TTS patients had a comparable long-term mortality risk with ACS patients. Of 1,613 TTS patients, an emotional trigger was detected in 485 patients (30%). Of 630 patients (39%) related to physical triggers, 98 patients (6%) had acute neurologic disorders, while in the other 532 patients (33%), physical activities, medical conditions, or procedures were the triggering conditions. The remaining 498 patients (31%) had no identifiable trigger. TTS patients related to physical stress showed higher mortality rates than ACS patients during long-term follow-up, whereas patients related to emotional stress had better outcomes compared with ACS patients.

Conclusions: Overall, TTS patients had long-term outcomes comparable to age- and sex-matched ACS patients. Also, we demonstrated that TTS can either be benign or a life-threating condition depending on the inciting stress factor. We propose a new classification based on triggers, which can serve as a clinical tool to predict short- and long-term outcomes of TTS. (International Takotsubo Registry [InterTAK Registry]; NCT01947621).
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http://dx.doi.org/10.1016/j.jacc.2018.06.016DOI Listing
August 2018

Basic in vitro Characterization of the Vasodilatory Potential of 2-Aminoethyl Nitrate Fixed-Dose Combinations with Cilostazol, Metoprolol and Valsartan.

Pharmacology 2018 7;101(1-2):54-63. Epub 2017 Oct 7.

Center for Cardiology, Cardiology I, University Medical Center Mainz, Mainz, Germany.

Background/aims: 2-aminoethyl nitrate (CLC-1011) is a member of the class of organic nitrates that cause vasodilation by the generation of nitric oxide (•NO). These drugs are mainly used for the treatment of angina pectoris and ischemic heart disease. The aim of this study was to characterize the vasodilatory potency of this organic nitrate alone and in combination with clinically established cardiovascular drugs.

Methods: Vasodilation by CLC-1011 was tested by isometric tension studies, either alone or combined with cilostazol, valsartan, and metoprolol. Induction of oxidative stress in isolated heart mitochondria was measured by enhanced chemiluminescence. Bioactivation of CLC-1011 in aortic tissue was measured by electron paramagnetic resonance spectroscopy using an iron-based spin trap for •NO.

Results: We observed potent vasodilation by CLC-1011 and additive effects for all three drug combinations. In contrast to nitroglycerin (GTN), CLC-1011 did not stimulate mitochondrial oxidative stress. CLC-1011 was bioactivated to •NO in aortic tissue.

Conclusion: In summary, the experiments described in this report demonstrate that CLC-1011 does not induce oxidative stress, is a more potent vasodilator than isosorbide-5-mononitrate and dinitrate ISDN, and displays synergistic vasodilation with other cardiovascular drugs. CLC-1011 fixed dose combinations could be used in the management of cardiovascular diseases.
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http://dx.doi.org/10.1159/000480434DOI Listing
August 2018

Platelet-localized FXI promotes a vascular coagulation-inflammatory circuit in arterial hypertension.

Sci Transl Med 2017 02;9(375)

Center for Thrombosis and Hemostasis Mainz, University Medical Center Mainz, Langenbeckstrasse 1, 55131 Mainz, Germany.

Multicellular interactions of platelets, leukocytes, and the blood vessel wall support coagulation and precipitate arterial and venous thrombosis. High levels of angiotensin II cause arterial hypertension by a complex vascular inflammatory pathway that requires leukocyte recruitment and reactive oxygen species production and is followed by vascular dysfunction. We delineate a previously undescribed, proinflammatory coagulation-vascular circuit that is a major regulator of vascular tone, blood pressure, and endothelial function. In mice with angiotensin II-induced hypertension, tissue factor was up-regulated, as was thrombin-dependent endothelial cell vascular cellular adhesion molecule 1 expression and integrin αβ- and platelet-dependent leukocyte adhesion to arterial vessels. The resulting vascular inflammation and dysfunction was mediated by activation of thrombin-driven factor XI (FXI) feedback, independent of factor XII. The FXI receptor glycoprotein Ibα on platelets was required for this thrombin feedback activation in angiotensin II-infused mice. Inhibition of FXI synthesis with an antisense oligonucleotide was sufficient to prevent thrombin propagation on platelets, vascular leukocyte infiltration, angiotensin II-induced endothelial dysfunction, and arterial hypertension in mice and rats. Antisense oligonucleotide against FXI also reduced the increased blood pressure and attenuated vascular and kidney dysfunction in rats with established arterial hypertension. Further, platelet-localized thrombin generation was amplified in an FXI-dependent manner in patients with uncontrolled arterial hypertension, suggesting that platelet-localized thrombin generation may serve as an inflammatory marker of high blood pressure. Our results outline a coagulation-inflammation circuit that promotes vascular dysfunction, and highlight the possible utility of FXI-targeted anticoagulants in treating hypertension, beyond their application as antithrombotic agents in cardiovascular disease.
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http://dx.doi.org/10.1126/scitranslmed.aah4923DOI Listing
February 2017

NOX2 amplifies acetaldehyde-mediated cardiomyocyte mitochondrial dysfunction in alcoholic cardiomyopathy.

Sci Rep 2016 09 14;6:32554. Epub 2016 Sep 14.

Cardiology 1, Center for Cardiology, University Medical Center Mainz, Langenbeckstr. 1, 55131 Mainz, Germany.

Alcoholic cardiomyopathy (ACM) resulting from excess alcohol consumption is an important cause of heart failure (HF). Although it is assumed that the cardiotoxicity of the ethanol (EtOH)-metabolite acetaldehyde (ACA) is central for its development and progression, the exact mechanisms remain obscure. Murine cardiomyocytes (CMs) exposed to ACA or EtOH showed increased superoxide (O2(•-)) levels and decreased mitochondrial polarization, both being normalized by NADPH oxidase (NOX) inhibition. C57BL/6 mice and mice deficient for the ACA-degrading enzyme mitochondrial aldehyde dehydrogenase (ALDH-2(-/-)) were fed a 2% EtOH diet for 5 weeks creating an ACA-overload. 2% EtOH-fed ALDH-2(-/-) mice exhibited a decreased cardiac function, increased heart-to-body and lung-to-body weight ratios, increased cardiac levels of the lipid peroxidation product malondialdehyde (MDA) as well as increased NOX activity and NOX2/glycoprotein 91(phox) (NOX2/gp91(phox)) subunit expression compared to 2% EtOH-fed C57BL/6 mice. Echocardiography revealed that ALDH-2(-/-)/gp91(phox-/-) mice were protected from ACA-overload-induced HF after 5 weeks of 2% EtOH-diet, demonstrating that NOX2-derived O2(•-) contributes to the development of ACM. Translated to human pathophysiology, we found increased gp91(phox) expression in endomyocardial biopsies of ACM patients. In conclusion, ACM is promoted by ACA-driven mitochondrial dysfunction and can be improved by ablation of NOX2/gp91(phox). NOX2/gp91(phox) therefore might be a potential pharmacological target to treat ACM.
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http://dx.doi.org/10.1038/srep32554DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5021994PMC
September 2016

Gut Microbiota Promote Angiotensin II-Induced Arterial Hypertension and Vascular Dysfunction.

J Am Heart Assoc 2016 08 30;5(9). Epub 2016 Aug 30.

Center for Thrombosis and Hemostasis Mainz, Partner Site RheinMain, Mainz, Germany Center for Cardiology, Partner Site RheinMain, Mainz, Germany German Center for Cardiovascular Research (DZHK), Partner Site RheinMain, Mainz, Germany

Background: The gut microbiome is essential for physiological host responses and development of immune functions. The impact of gut microbiota on blood pressure and systemic vascular function, processes that are determined by immune cell function, is unknown.

Methods And Results: Unchallenged germ-free mice (GF) had a dampened systemic T helper cell type 1 skewing compared to conventionally raised (CONV-R) mice. Colonization of GF mice with regular gut microbiota induced lymphoid mRNA transcription of T-box expression in T cells and resulted in mild endothelial dysfunction. Compared to CONV-R mice, angiotensin II (AngII; 1 mg/kg per day for 7 days) infused GF mice showed reduced reactive oxygen species formation in the vasculature, attenuated vascular mRNA expression of monocyte chemoattractant protein 1 (MCP-1), inducible nitric oxide synthase (iNOS) and NADPH oxidase subunit Nox2, as well as a reduced upregulation of retinoic-acid receptor-related orphan receptor gamma t (Rorγt), the signature transcription factor for interleukin (IL)-17 synthesis. This resulted in an attenuated vascular leukocyte adhesion, less infiltration of Ly6G(+) neutrophils and Ly6C(+) monocytes into the aortic vessel wall, protection from kidney inflammation, as well as endothelial dysfunction and attenuation of blood pressure increase in response to AngII. Importantly, cardiac inflammation, fibrosis and systolic dysfunction were attenuated in GF mice, indicating systemic protection from cardiovascular inflammatory stress induced by AngII.

Conclusion: Gut microbiota facilitate AngII-induced vascular dysfunction and hypertension, at least in part, by supporting an MCP-1/IL-17 driven vascular immune cell infiltration and inflammation.
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http://dx.doi.org/10.1161/JAHA.116.003698DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5079031PMC
August 2016

Airborne disease: a case of a Takotsubo cardiomyopathie as a consequence of nighttime aircraft noise exposure.

Eur Heart J 2016 10 19;37(37):2844. Epub 2016 Jul 19.

II. Medizinische Klinik und Poliklinik, Kardiologie, Johannes Gutenberg Universität, Langenbeckstrasse 1, Mainz 55131, Germany.

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http://dx.doi.org/10.1093/eurheartj/ehw314DOI Listing
October 2016

Heme oxygenase-1 suppresses a pro-inflammatory phenotype in monocytes and determines endothelial function and arterial hypertension in mice and humans.

Eur Heart J 2015 Dec 29;36(48):3437-46. Epub 2015 Oct 29.

Department of Medicine 2, University Medical Center Mainz, Langenbeckstr. 1, 55131 Mainz, Germany German Center for Cardiovascular Research (DZHK), Partner Site RhineMain, University Medical Center Mainz, Langenbeckstr. 1, 55131 Mainz, Germany.

Aims: Heme oxygenase-1 (HO-1) confers protection to the vasculature and suppresses inflammatory properties of monocytes and macrophages. It is unclear how HO-1 determines the extent of vascular dysfunction in mice and humans.

Methods And Results: Decreased HO-1 activity and expression was paralleled by increased aortic expression and activity of the nicotinamide dinucleotide phosphate oxidase Nox2 in HO-1 deficient Hmox1⁻/⁻ and Hmox1(⁺/⁻) compared with Hmox1⁺/⁺ mice. When subjected to angiotensin II-infusion, streptozotocin-induced diabetes mellitus and aging, HO-1 deficient mice showed increased vascular dysfunction inversely correlated with HO activity. In a primary prevention population-based cohort, we assessed length polymorphisms of the HMOX1 promoter region and established a bipolar frequency pattern of allele length (long vs. short repeats) in 4937 individuals. Monocytic HMOX1 mRNA expression was positively correlated with flow-mediated dilation and inversely with CD14 mRNA expression indicating pro-inflammatory monocytes in 733 hypertensive individuals of this cohort. Hmox1⁻/⁻ mice showed drastically increased expression of the chemokine receptor CCR2 in monocytes and the aorta. Angiotensin II-infused Hmox1⁻/⁻ mice had amplified endothelial inflammation in vivo, significantly increased aortic infiltration of pro-inflammatory CD11b⁺ Ly6C(hi) monocytes and Ly6G⁺ neutrophils and were marked by Ly6C(hi) monocytosis in the circulation and an increased blood pressure response. Finally, individuals with unfavourable HMOX1 gene promoter length had increased prevalence of arterial hypertension and reduced cumulative survival after a median follow-up of 7.23 years.

Conclusions: Heme oxygenase-1 is a regulator of vascular function in hypertension via determining the phenotype of inflammatory circulating and infiltrating monocytes with possible implications for all-cause mortality.
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http://dx.doi.org/10.1093/eurheartj/ehv544DOI Listing
December 2015

Heme Oxygenase-1 Gene Therapy Provides Cardioprotection Via Control of Post-Ischemic Inflammation: An Experimental Study in a Pre-Clinical Pig Model.

J Am Coll Cardiol 2015 Jul;66(2):154-65

Medizinische Klinik I, Klinikum Grosshadern, Ludwig Maximilian University, Munich, Germany; Medizinische Klinik I, Klinikum Rechts der Isar, Technical University of Munich, and German Center for Cardiovascular Research, partner site Munich Heart Alliance, Munich, Germany; Walter-Brendel-Centre for Experimental Medicine, Munich, Germany. Electronic address:

Background: Heme oxygenase-1 (HO-1) is an inducible stress-responsive enzyme converting heme to bilirubin, carbon monoxide, and free iron, which exerts anti-inflammatory and antiapoptotic effects. Although efficient cardioprotection after HO-1 overexpression has been reported in rodents, its role in attenuating post-ischemic inflammation is unclear.

Objectives: This study assessed the efficacy of recombinant adenoassociated virus (rAAV)-encoding human heme oxygenase-1 (hHO-1) in attenuating post-ischemic inflammation in a murine and a porcine ischemia/reperfusion model.

Methods: Murine ischemia was induced by 45 min of left anterior descending occlusion, followed by 24 h of reperfusion and functional as well as fluorescent-activated cell sorting analysis. Porcine hearts were subjected to 60 min of ischemia and 24h of reperfusion before hemodynamic and histologic analyses were performed.

Results: Human microvascular endothelial cells transfected with hHO-1 displayed an attenuated interleukin-6 and intercellular adhesion molecule 1 expression, resulting in reduced monocytic THP-1 cell recruitment in vitro. In murine left anterior descending occlusion and reperfusion, the post-ischemic influx of CD45(+) leukocytes, Ly-6G(+) neutrophils, and Ly-6C(high) monocytes was further exacerbated in HO-1-deficient hearts and reversed by rAAV.hHO-1 treatment. Conversely, in our porcine model of ischemia, the post-ischemic influx of myeloperoxidase-positive neutrophils and CD14(+) monocytes was reduced by 49% and 87% after rAAV.hHO-1 transduction, similar to hHO-1 transgenic pigs. Functionally, rAAV.hHO-1 and hHO-1 transgenic left ventricles displayed a smaller loss of ejection fraction than control animals.

Conclusions: Whereas HO-1 deficiency exacerbates post-ischemic cardiac inflammation in mice, hHO-1 gene therapy attenuates inflammation after ischemia and reperfusion in murine and porcine hearts. Regional hHO-1 gene therapy provides cardioprotection in a pre-clinical porcine ischemia/reperfusion model.
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http://dx.doi.org/10.1016/j.jacc.2015.04.064DOI Listing
July 2015

Interleukin 17 drives vascular inflammation, endothelial dysfunction, and arterial hypertension in psoriasis-like skin disease.

Arterioscler Thromb Vasc Biol 2014 Dec 23;34(12):2658-68. Epub 2014 Oct 23.

From the Institute for Molecular Medicine (S.K., A.L.C., R.S., N.Y., A.N., S.R., A.W.), Department of Medicine 2 (S.K., M.O., D.M., M.K., P. Wild, A.D., P. Wenzel, T.M.), Department of Dermatology (J.W., L.K., E.v.S.), Department of Pharmacology (H.L., Z.W.), Institute for Pathology (C.B.), Center for Thrombosis and Hemostasis (P. Wild, P. Wenzel, T.M.), German Center for Cardiovascular Research (DZHK), partner site RhineMain (A.U., P.W.), and Department of Medicine 3 (M.R.), University Medical Center of the Johannes-Gutenberg University of Mainz, Germany; Department of Internal Medicine I, University Hospital Erlangen, Germany (M.W., M.F.N.); Institute of Anatomy, University of Leipzig, Germany (C.P., I.B.); Institute for Biochemistry, Christian-Albrechts-University of Kiel, Germany (S.R.-J.); Institute of Biochemistry and Molecular Biology II, Medical Faculty, Heinrich-Heine University, Düsseldorf, Germany (J.S.).

Objective: Interleukin (IL)-17A is regarded as an important cytokine to drive psoriasis, an inflammatory skin disease marked by increased cardiovascular mortality. We aimed to test the hypothesis that overproduction of IL-17A in the skin leading to dermal inflammation may systemically cause vascular dysfunction in psoriasis-like skin disease.

Approach And Results: Conditional overexpression of IL-17A in keratinocytes caused severe psoriasis-like skin inflammation in mice (K14-IL-17A(ind/+) mice), associated with increased reactive oxygen species formation and circulating CD11b(+) inflammatory leukocytes in blood, with endothelial dysfunction, increased systolic blood pressure, left ventricular hypertrophy, and reduced survival compared with controls. In K14-IL-17A(ind/+) mice, immunohistochemistry and flow cytometry revealed increased vascular production of the nitric oxide/superoxide reaction product peroxynitrite and infiltration of the vasculature with myeloperoxidase(+)CD11b(+)GR1(+)F4/80(-) cells accompanied by increased expression of the inducible nitric oxide synthase and the nicotinamide dinucleotide phosphate (NADPH) oxidase, nox2. Neutrophil depletion by anti-GR-1 antibody injections reduced oxidative stress in blood and vessels. Neutralization of tumor necrosis factor-α and IL-6 (both downstream of IL-17A) reduced skin lesions, attenuated oxidative stress in heart and blood, and partially improved endothelial dysfunction in K14-IL-17A(ind/+) mice.

Conclusions: Dermal overexpression of IL-17A induces systemic endothelial dysfunction, vascular oxidative stress, arterial hypertension, and increases mortality mainly driven by myeloperoxidase(+)CD11b(+)GR1(+)F4/80(-) inflammatory cells. Depletion of the GR-1(+) immune cells or neutralization of IL-17A downstream cytokines by biologicals attenuates the vascular phenotype in K14-IL-17A(ind/+) mice.
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http://dx.doi.org/10.1161/ATVBAHA.114.304108DOI Listing
December 2014

Interplay of NK cells and monocytes in vascular inflammation and myocardial infarction.

Front Physiol 2014 14;5:295. Epub 2014 Aug 14.

Department of Medicine 2 and Center for Thrombosis and Hemostasis University Medical Center Mainz, Mainz, Germany.

Inflammatory monocytes and macrophages have been identified as key players in the pathogenesis of atherosclerosis, arterial hypertension, and myocardial infarction (MI). They become powerful mediators of vascular inflammation through their capacity to secrete and induce the production of proinflammatory cytokines, chemokines and adhesion molecules and through the production of reactive oxygen species mainly via their NADPH oxidase. Importantly, a crosstalk exists between NK cells and monocytes that works via a feedforwad amplification loop of T-bet/Interferon-gamma/interleukin-12 signaling, that causes mutual activation of both NK cells and monocytes and that fosters recruitment of inflammatory cells to sites of inflammation. Recently, we have discovered that this crosstalk is crucial for the unrestricted development of angiotensin II (ATII) induced vascular injury in arterial hypertension, the most important risk factor for atherosclerosis and cardiovascular disease worldwide. In this review, we will also discuss possible implications of this interplay between NK cells and monocytes for the pathogenesis of coronary atherosclerosis and myocardial infarction and potential therapeutic options.
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http://dx.doi.org/10.3389/fphys.2014.00295DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4132269PMC
September 2014

Inflammatory monocytes determine endothelial nitric-oxide synthase uncoupling and nitro-oxidative stress induced by angiotensin II.

J Biol Chem 2014 Oct 20;289(40):27540-50. Epub 2014 Aug 20.

From the 2nd Medical Clinic, Center for Thrombosis and Hemostasis, and

Endothelial nitric-oxide synthase (eNOS) uncoupling and increased inducible NOS (iNOS) activity amplify vascular oxidative stress. The role of inflammatory myelomonocytic cells as mediators of these processes and their impact on tetrahydrobiopterin availability and function have not yet been defined. Angiotensin II (ATII, 1 mg/kg/day for 7 days) increased Ly6C(high) and CD11b(+)/iNOS(high) leukocytes and up-regulated levels of eNOS glutathionylation in aortas of C57BL/6 mice. Vascular iNOS-dependent NO formation was increased, whereas eNOS-dependent NO formation was decreased in aortas of ATII-infused mice as assessed by electron paramagnetic resonance (EPR) spectroscopy. Diphtheria toxin-mediated ablation of lysozyme M-positive (LysM(+)) monocytes in ATII-infused LysM(iDTR) transgenic mice prevented eNOS glutathionylation and eNOS-derived N(ω)-nitro-L-arginine methyl ester-sensitive superoxide formation in the endothelial layer. ATII increased vascular guanosine triphosphate cyclohydrolase I expression and biopterin synthesis in parallel, which was reduced in monocyte-depleted LysM(iDTR) mice. Vascular tetrahydrobiopterin was increased by ATII infusion but was even higher in monocyte-depleted ATII-infused mice, which was paralleled by a strong up-regulation of dihydrofolate reductase expression. EPR spectroscopy revealed that both vascular iNOS- and eNOS-dependent NO formation were normalized in ATII-infused mice following monocyte depletion. Additionally, deletion as well as pharmacologic inhibition of iNOS prevented ATII-induced endothelial dysfunction. In summary, ATII induces an inflammatory cell-dependent increase of iNOS, guanosine triphosphate cyclohydrolase I, tetrahydrobiopterin, NO formation, and nitro-oxidative stress as well as eNOS uncoupling in the vessel wall, which can be prevented by ablation of LysM(+) monocytes.
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http://dx.doi.org/10.1074/jbc.M114.604231DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4183794PMC
October 2014

In vitro and in vivo characterization of a new organic nitrate hybrid drug covalently bound to pioglitazone.

Pharmacology 2014 7;93(5-6):203-15. Epub 2014 Jun 7.

Molekulare Kardiologie, II. Medizinische Klinik und Poliklinik, Klinikum der Johannes Gutenberg-Universität Mainz, Mainz, Germany.

Background/aims: Organic nitrates represent a group of nitrovasodilators that are clinically used for the treatment of ischemic heart disease. The new compound CLC-3000 is an aminoethyl nitrate (AEN) derivative of pioglitazone, a thiazolidinedione antidiabetic agent combining the peroxisome proliferator-activated receptor γ agonist activity of pioglitazone with the NO-donating activity of the nitrate moiety.

Methods: In vitro and in vivo characterization was performed by isometric tension recording, platelet function, bleeding time and detection of oxidative stress.

Results: In vitro, CLC-3000 displayed more potent vasodilation than pioglitazone alone or classical nitrates. In vitro, some effects on oxidative stress parameters were observed. Authentic AEN or the AEN-containing linker CLC-1275 displayed antiaggregatory effects. In vivo treatment with CLC-3000 for 7 days did neither induce endothelial dysfunction nor nitrate tolerance nor oxidative stress. Acute or chronic administration of AEN increased the tail vein bleeding time in mice.

Conclusion: In summary, the results of these studies demonstrate that CLC-3000 contains a vasodilative and antithrombotic activity that is not evident with pioglitazone alone, and that 7 days of exposure in vivo showed no typical signs of nitrate tolerance, endothelial dysfunction or other safety concerns in Wistar rats.
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http://dx.doi.org/10.1159/000361052DOI Listing
April 2015

Angiotensin II-induced vascular dysfunction depends on interferon-γ-driven immune cell recruitment and mutual activation of monocytes and NK-cells.

Arterioscler Thromb Vasc Biol 2013 Jun 21;33(6):1313-9. Epub 2013 Mar 21.

2nd Medical Clinic, Center for Thrombosis and Hemostasis, University Medical Center of Johannes Gutenberg-University, Mainz, Germany.

Objective: Immune cells contribute to angiotensin II (ATII)-induced vascular dysfunction and inflammation. Interferon-γ (IFN-γ), an inflammatory cytokine exclusively produced by immune cells, seems to be involved in ATII-driven cardiovascular injury, but the actions and cellular source of IFN-γ remain incompletely understood.

Approach And Results: IFN-γ(-/-) and Tbx21(-/-) mice were partially protected from ATII-induced (1 mg/kg per day of ATII, infused subcutaneously by miniosmotic pumps) vascular endothelial and smooth muscle dysfunction, whereas mice overexpressing IFN-γ showed constitutive vascular dysfunction. Absence of T-box expressed in T cells (T-bet), the IFN-γ transcription factor encoded by Tbx21, reduced vascular superoxide and peroxynitrite formation and attenuated expression of nicotinamide adenosine dinucleotide phosphate oxidase subunits as well as inducible NO synthase, monocyte chemoattractant protein 1, and interleukin-12 in aortas of ATII-infused mice. Compared with controls, IFN-γ(-/-) and Tbx21(-/-) mice were characterized by reduced ATII-mediated vascular recruitment of both natural killer (NK)1.1(+) NK-cells as the major producers of IFN-γ and CD11b(+)Gr-1(low) interleukin-12 secreting monocytes. Selective depletion and adoptive transfer experiments identified NK-cells as essential contributors to vascular dysfunction and showed that T-bet(+)lysozyme M(+) myelomonocytic cells were required for NK-cell recruitment into vascular tissue and local IFN-γ production.

Conclusions: We provide first evidence that NK-cells play an essential role in ATII-induced vascular dysfunction. In addition, we disclose the T-bet-IFN-γ pathway and mutual monocyte-NK-cell activation as potential therapeutic targets in cardiovascular disease.
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http://dx.doi.org/10.1161/ATVBAHA.113.301437DOI Listing
June 2013