Protective role of Gremlin-1 in myocardial function.

BACKGROUND: Gremlin-1 is a cystine knot protein and is expressed in organs developing fibrosis. Transient ischaemia leads to myocardial fibrosis, a major determinant of impaired myocardial function. MATERIALS AND METHODS: Expression of Gremlin-1 was investigated in infarcted myocardium by real-time PCR, Western blot analysis, histological and immunohistochemistry staining. We further elaborated the colocalization of Gremlin-1 and TGF-ß proteins by confocal microscopy and co-immunoprecipitation experiments. The interaction between Gremlin-1 and TGF-ß was analysed by photon correlation spectroscopy. Gremlin-1 modulation of the TGF-ß-dependent collagen I synthesis in fibroblasts was investigated using ELISA and immunohistochemistry experiments. The effect of prolonged administration of recombinant Gremlin-1 on myocardial function following ischaemia/reperfusion was accessed by echocardiography and immunohistochemistry. RESULTS: Gremlin-1 is expressed in myocardial tissue and infiltrating cells after transient myocardial ischaemia (P < .05). Gremlin-1 colocalizes with the pro-fibrotic cytokine transforming growth factor-ß (TGF-ß) expressed in fibroblasts and inflammatory cell infiltrates (P < .05). Gremlin-1 reduces TGF-ß-induced collagen production of myocardial fibroblasts by approximately 20% (P < .05). We found that Gremlin-1 binds with high affinity to TGF-ß (KD  = 54 nmol/L) as evidenced by photon correlation spectroscopy and co-immunoprecipitation. intravenous administration of m Gremlin-1-Fc, but not of equivalent amount of Fc control, significantly reduced infarct size by approximately 20%. In the m Gremlin-1-Fc group, infarct area was reduced by up to 30% in comparison with mice treated with Fc control (I/LV: 4.8 ± 1.2% vs 6.0 ± 1.2% P < .05; I/AaR: 15.2 ± 1.5% vs 21.1 ± 5%, P < .05). CONCLUSIONS: The present data disclose Gremlin-1 as an antagonist of TGF-ß and presume a role for Gremlin-1/TGF-ß interaction in myocardial remodelling following myocardial ischaemia.

Deceleration capacity of heart rate predicts 1-year mortality in patients undergoing transcatheter edge-to-edge mitral valve repair.

BACKGROUND: Risk stratification for transcatheter procedures in patients with severe mitral regurgitation is challenging. Deceleration capacity (DC) has already proven to be a reliable risk predictor in patients undergoing transcatheter aortic valve implantation. We hypothesized, that DC provides prognostic value in patients undergoing transcatheter edge-to-edge mitral valve repair (TEER). METHODS: We retrospectively analyzed electrocardiogram signals from 106 patients undergoing TEER at the University Hospital of Tübingen. All patients received continuous heart-rate monitoring to assess DC following the procedure. One-year all-cause mortality was defined as the primary end point. RESULTS: Sixteen patients (15.1%) died within 1 year. The DC in nonsurvivors was significantly reduced compared to survivors (5.1 ± 3.0 vs. 3.0 ± 1.6 ms, p = 0.002). A higher EuroSCORE II and impaired left ventricular function were furthermore associated with poor outcome. In Cox regression analyses, a DC < 4.5 ms was found a strong predictor of 1-year mortality (hazard ratio: 0.10, 95% confidence interval: 0.13-0.79, p = 0.029). Finally, a significant negative correlation was found between DC and residual mitral regurgitation after TEER (r = -0.41, p < 0.001). CONCLUSION: In patients with severe mitral regurgitation undergoing TEER, DC may serve as a new predictor of follow-up mortality.

Using Multiparametric Cardiac Magnetic Resonance to Phenotype and Differentiate Biopsy-Proven Chronic from Healed Myocarditis and Dilated Cardiomyopathy.

(1) Objectives: To discriminate biopsy-proven myocarditis (chronic vs. healed myocarditis) and to differentiate from dilated cardiomyopathy (DCM) using cardiac magnetic resonance (CMR). (2) Methods: A total of 259 consecutive patients (age 51 ± 15 years; 28% female) who underwent both endomyocardial biopsy (EMB) and CMR in the years 2008−2021 were evaluated. According to right-ventricular EMB results, patients were divided into either chronic (n = 130, 50%) or healed lymphocytic myocarditis (n = 60, 23%) or DCM (n = 69, 27%). The CMR protocol included functional, strain, and late gadolinium enhancement (LGE) imaging, T2w imaging, and T2 mapping. (3) Results: Left-ventricular ejection fraction (LV-EF) was higher, and the indexed end-diastolic volume (EDV) was lower in myocarditis patients (chronic: 42%, median 96 mL/m²; healed: 49%, 86 mL/m²) compared to the DCM patients (31%, 120 mL/m²), p < 0.0001. Strain analysis demonstrated lower contractility in DCM patients vs. myocarditis patients, p < 0.0001. Myocarditis patients demonstrated a higher LGE prevalence (68% chronic; 59% healed) than the DCM patients (45%), p = 0.01. Chronic myocarditis patients showed a higher myocardial edema prevalence and ratio (59%, median 1.3) than healed myocarditis (23%, 1.3) and DCM patients (13%, 1.0), p < 0.0001. T2 mapping revealed elevated values more frequently in chronic (90%) than in healed (21%) myocarditis and DCM (23%), p < 0.0001. T2 mapping yielded an AUC of 0.89 (sensitivity 90%, specificity 76%) in the discrimination of chronic from healed myocarditis and an AUC of 0.92 (sensitivity 86%, specificity 91%) in the discrimination of chronic myocarditis from DCM, both p < 0.0001. (4) Conclusions: Multiparametric CMR imaging, including functional parameters, LGE and T2 mapping, may allow differentiation of chronic from healed myocarditis and DCM and therefore help to optimize patient management in this clinical setting.

Comprehensive Cardiac Magnetic Resonance to Detect Subacute Myocarditis.

(1) Background: Compared to acute myocarditis in the initial phase, detection of subacute myocarditis with cardiac magnetic resonance (CMR) parameters can be challenging due to a lower degree of myocardial inflammation compared to the acute phase. (2) Objectives: To systematically evaluate non-invasive CMR imaging parameters in acute and subacute myocarditis. (3) Methods: 48 patients (age 37 (IQR 28−55) years; 52% female) with clinically suspected myocarditis were consecutively included. Patients with onset of symptoms ≤2 weeks prior to 1.5T CMR were assigned to the acute group (n = 25, 52%), patients with symptom duration >2 to 6 weeks were assigned to the subacute group (n = 23, 48%). CMR protocol comprised morphology, function, 3D-strain, late gadolinium enhancement (LGE) imaging and mapping (T1, ECV, T2). (4) Results: Highest diagnostic performance in the detection of subacute myocarditis was achieved by ECV evaluation either as single parameter or in combination with T1 mapping (applying a segmental or global increase of native T1 > 1015 ms and ECV > 28%), sensitivity 96% and accuracy 91%. Compared to subacute myocarditis, acute myocarditis demonstrated higher prevalence and extent of LGE (AUC 0.76) and increased T2 (AUC 0.66). (5) Conclusions: A comprehensive CMR approach allows reliable diagnosis of clinically suspected subacute myocarditis. Thereby, ECV alone or in combination with native T1 mapping indicated the best performance for diagnosing subacute myocarditis. Acute vs. subacute myocarditis is difficult to discriminate by CMR alone, due to chronological connection and overlap of pathologic findings.

Hybrid Cardiac Magnetic Resonance/Fluorodeoxyglucose Positron Emission Tomography to Differentiate Active From Chronic Cardiac Sarcoidosis.

OBJECTIVES: The purpose of this study was to investigate the diagnostic value of simultaneous hybrid cardiac magnetic resonance (CMR) and 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) for detection and differentiation of active (aCS) from chronic (cCS) cardiac sarcoidosis. BACKGROUND: Late gadolinium enhancement (LGE) CMR and FDG-PET are both established imaging techniques for the detection of CS. However, there are limited data regarding the value of a comprehensive simultaneous hybrid CMR/FDG-PET imaging approach that includes CMR mapping techniques. METHODS: Forty-three patients with biopsy-proven extracardiac sarcoidosis (median age: 48 years, interquartile range: 37-57 years, 65% male) were prospectively enrolled for evaluation of suspected CS. After dietary preparation for suppression of myocardial glucose metabolism, patients were evaluated on a 3-T hybrid PET/MR scanner. The CMR protocol included T1 and T2 mapping, myocardial function, and LGE imaging. We assumed aCS if PET and CMR (ie, LGE or T1/T2 mapping) were both positive (PET+/CMR+), cCS if PET was negative but CMR was positive (PET-/CMR+), and no CS if patients were CMR negative regardless of PET findings. RESULTS: Among the 43 patients, myocardial glucose uptake was suppressed successfully in 36 (84%). Hybrid CMR/FDG-PET revealed aCS in 13 patients (36%), cCS in 5 (14%), and no CS in 18 (50%). LGE was present in 14 patients (39%); T1 mapping was abnormal in 10 (27%) and T2 mapping abnormal in 2 (6%). CS was diagnosed based on abnormal T1 mapping in 4 out of 18 CS patients (22%) who were LGE negative. PET FDG uptake was present in 17 (47%) patients. CONCLUSIONS: Comprehensive simultaneous hybrid CMR/FDG-PET imaging is useful for the detection of CS and provides additional value for identifying active disease. Our results may have implications for enhanced diagnosis as well as improved identification of patients with aCS in whom anti-inflammatory therapy may be most beneficial.

TRoponin of Unknown origin in STroke evaluated by multi-component cardiac Magnetic resonance Imaging - The TRUST-MI study.

Aims: Increased high-sensitive cardiac troponin I (hs-cTnI) levels are common in patients with acute ischemic stroke. However, only a minority demonstrates culprit lesions on coronary angiography, suggesting other mechanisms, e.g., inflammation, as underlying cause of myocardial damage. Late Gadolinium Enhancement (LGE)-cardiac magnetic resonance (CMR) with mapping techniques [T1, T2, extracellular volume (ECV)] allow the detection of both focal and diffuse myocardial abnormalities. We investigated the prevalence of culprit lesions by coronary angiography and myocardial tissue abnormalities by a comprehensive CMR protocol in troponin-positive stroke patients. Methods and results: Patients with troponin-positive acute ischemic stroke and no history of coronary artery disease were prospectively enrolled. Coronary angiography and CMR (LGE, T1 + T2 mapping, ECV) were performed within the first days of the acute stroke. Twenty-five troponin-positive patients (mean age 62 years, 44% females) were included. 2 patients (8%) had culprit lesions on coronary angiography and underwent percutaneous coronary intervention. 13 patients (52%) demonstrated LGE: (i) n = 4 ischemic, (ii) n = 4 non-ischemic, and (iii) n = 5 ischemic AND non-ischemic. In the 12 LGE-negative patients, mapping revealed diffuse myocardial damage in additional 9 (75%) patients, with a high prevalence of increased T2 values. Conclusions: Our data show a low prevalence of culprit lesions in troponin-positive stroke patients. However, > 50% of the patients demonstrated myocardial scars (ischemic + non-ischemic) by LGE-CMR. Mapping revealed additional myocardial abnormalities (mostly inflammatory) in the majority of LGE-negative patients. Therefore, a comprehensive CMR protocol gives important insights in the etiology of troponin which might have implications for the further work-up of troponin-positive stroke patients.

Closure or medical therapy of patent foramen ovale in cryptogenic stroke: prospective case series.

BACKGROUND: Results of randomized controlled trials (RCT) do not provide definite guidance for secondary prevention after ischemic stroke (IS)/transient ischemic attack (TIA) attributed to patent foramen ovale (PFO). No recommendations can be made for patients > 60 years. We aimed to compare interventional and medical PFO-management in cryptogenic IS/TIA patients, including patients > 60 years. METHODS: Prospective case series including consecutive cryptogenic IS/TIA patients with PFO at Tuebingen university stroke unit, Germany. 'PFO-closure' was recommended in patients ≤70 years when featuring high-risk PFO (i.e., with atrial septal aneurysm, spontaneous, or high-grade right-to-left shunt during Valsalva). Primary (recurrent IS/intracranial hemorrhage) and secondary endpoints (e.g., disability) were assessed during ≥1-year follow-up; planned subgroup analyses of patients ≤60/> 60 years. RESULTS: Among 236 patients with median age of 58 (range 18-88) years, 38.6% were females and median presenting National Institutes of Health Stroke Scale score was 1 (IQR 0-4). Mean follow-up was 2.8 ± 1.3 years. No intracranial hemorrhage was observed. Recurrent IS rate after 'PFO-closure' was 2.9% (95%CI 0-6.8%) and 7% (4-16.4) in high-risk PFO patients ≤60 (n = 103) and > 60 years (n = 43), respectively, versus 4% (0-11.5) during 'medical therapy alone' MTA (n = 28). 42 low-risk PFO patients treated with MTA experienced no recurrent IS/TIA. CONCLUSIONS: In our real-world study, IS recurrence rate in 'PFO-closure' high-risk PFO patients ≤60 years was comparable to that observed in recent RCT. High-risk PFO patients > 60 years who underwent PFO-closure had similar IS recurrence rates than those who received MTA. MTA seems the appropriate treatment for low-risk PFO. TRIAL REGISTRATION: ClinicalTrials.gov, registration number: NCT04352790 , registered on: April 20, 2020 - retrospectively registered.

Predictors of Mortality in Patients With Biopsy-Proven Viral Myocarditis: 10-Year Outcome Data.

Background There is scarce data about the long-term mortality as well as the prognostic value of cardiovascular magnetic resonance and late gadolinium enhancement (LGE) in patients with biopsy-proven viral myocarditis. We sought to investigate: (1) mortality and (2) prognostic value of LGEcardiovascular magnetic resonance (location, pattern, extent, and distribution) in a >10-year follow-up in patients with biopsy-proven myocarditis. Methods and Results Two-hundred three consecutive patients with biopsy-proven viral myocarditis and cardiovascular magnetic resonance were enrolled; 183 patients were eligible for standardized follow-up. The median follow-up was 10.1 years. End points were all-cause death, cardiac death, and sudden cardiac death (SCD). We found substantial long-term mortality in patients with biopsy-proven myocarditis (39.3% all cause, 27.3% cardiac, and 10.9% SCD); 101 patients (55.2%) demonstrated LGE. The presence of LGE was associated with a more than a doubled risk of death (hazard ratio [HR], 2.40; 95% CI], 1.30-4.43), escalating to a HR of 3.00 (95% CI, 1.41-6.42) for cardiac death, and a HR of 14.79 (95% CI, 1.95-112.00) for SCD; all P≤0.009. Specifically, midwall, (antero-) septal LGE, and extent of LGE were highly associated with death, all P<0.001. Septal LGE was the best independent predictor for SCD (HR, 4.59; 95% CI, 1.38-15.24; P=0.01). Conclusions In patients with biopsy-proven viral myocarditis, the presence of midwall LGE in the (antero-) septal segments is associated with a higher rate of mortality (including SCD) compared with absent LGE or other LGE patterns, underlining the prognostic benefit of a distinct LGE analysis in these patients.

Time-Dependent Myocardial Necrosis in Patients With ST-Segment-Elevation Myocardial Infarction Without Angiographic Collateral Flow Visualized by Cardiac Magnetic Resonance Imaging: Results From the Multicenter STEMI-SCAR Project.

Background Acute complete occlusion of a coronary artery results in progressive ischemia, moving from the endocardium to the epicardium (ie, wavefront). Dependent on time to reperfusion and collateral flow, myocardial infarction ( MI ) will manifest, with transmural MI portending poor prognosis. Late gadolinium enhancement cardiac magnetic resonance imaging can detect MI with  high diagnostic accuracy. Primary percutaneous coronary intervention is the preferred reperfusion strategy in patients with ST -segment-elevation MI with <12 hours of symptom onset. We sought to visualize time-dependent necrosis in a population with ST -segment-elevation MI by using late gadolinium enhancement cardiac magnetic resonance imaging (STEMI-SCAR project). Methods and Results ST -segment-elevation MI patients with single-vessel disease, complete occlusion with TIMI (Thrombolysis in Myocardial Infarction) score 0, absence of collateral flow (Rentrop score 0), and symptom onset <12 hours were consecutively enrolled. Using late gadolinium enhancement cardiac magnetic resonance imaging, the area at risk and infarct size, myocardial salvage index, transmurality index, and transmurality grade (0-50%, 51-75%, 76-100%) were determined. In total, 164 patients (aged 54±11 years, 80% male) were included. A receiver operating characteristic curve (area under the curve: 0.81) indicating transmural necrosis revealed the best diagnostic cutoff for a symptom-to-balloon time of 121 minutes: patients with >121 minutes demonstrated increased infarct size, transmurality index, and transmurality grade (all P<0.01) and decreased myocardial salvage index ( P<0.001) versus patients with symptom-to-balloon times ≤121 minutes. Conclusions In MI with no residual antegrade and no collateral flow, immediate reperfusion is vital. A symptom-to-balloon time of >121 minutes causes a high grade of transmural necrosis. In this pure ST -segment-elevation MI population, time to reperfusion to salvage myocardium was less than suggested by current guidelines.

Previous TAVR in patients undergoing percutaneous edge-to-edge mitral valve repair (PMVR) affects improvement of MR.

BACKGROUND: Patients after transcatheter aortic valve replacement (TAVR) and persistent severe mitral regurgitation (MR) are increasingly treated with percutaneous edge-to-edge mitral valve repair (PMVR). The impact of a former TAVR on PMVR procedures is not clear. METHODS AND RESULTS: We retrospectively analyzed 332 patients undergoing PMVR using the MitraClip system with respect to procedural and clinical outcome. 21 of these 332 patients underwent TAVR before PMVR. Intra-procedural transthoracic (TTE) and transesophageal echocardiograms (TEE) immediately before and after clip implantation as well as invasive hemodynamic measurements were evaluated. At baseline, we found a significantly smaller mitral valve anterior-posterior diameter in the TAVR cohort (p < 0.001). A reduction of MR by at least three grades was achieved in a smaller fraction in the TAVR cohort as compared to the cohort with a native aortic valve (p = 0.02). Accordingly, we observed a smaller post-procedural cardiac output in the TAVR cohort (p = 0.02). CONCLUSION: PMVR in patients who had a TAVR before, is associated with altered MR anatomy before and a reduced improvement of MR after the procedure. Future larger and prospective studies will have to determine, whether a previous TAVR influences long-term clinical outcome of patients undergoing PMVR.

High Plasma Levels of Gremlin-1 and Macrophage Migration Inhibitory Factor, but Not Their Ratio, Indicate an Increased Risk for Acute Coronary Syndrome in Patients With Type 2 Diabetes Mellitus.

BACKGROUND: Chronic inflammation promotes atherosclerosis and is a prognostic factor in coronary artery disease (CAD). Patients with type 2 diabetes mellitus (DM2) are at risk for progressive atherosclerosis. Macrophage migration inhibitory factor (MIF) is a key player in atherosclerosis, mediating pro-inflammatory responses. Its endogenous antagonist Gremlin-1 inhibits foam-cell formation and atheroprogression by binding MIF, neutralizing its proatherosclerotic functions. HYPOTHESIS: Plasma levels of MIF and Gremlin-1 correlate with the stability of CAD in patients with DM2. METHOD: We assessed plasma levels of Gremlin-1 and MIF in 198 nondiabetic and 88 diabetic patients with symptomatic CAD using enzyme-linked immunosorbent assays. RESULTS: Plasma levels of Gremlin-1 were higher DM2 patients (278.8 ± 16.6 vs 224.7 ± 6.7 ng/mL; P = 0.001). MIF levels were elevated but not significantly increased in DM2 (P = 0.098). Interestingly, we found that Gremlin-1 plasma levels were significantly higher in diabetic patients with stable angina pectoris (SAP; n = 53) or acute coronary syndrome (ACS; n = 35) compared with nondiabetic patients with SAP (P = 0.008 and P = 0.011, respectively). MIF levels were significantly higher in diabetic patients with ACS compared with SAP (P < 0.001). Although the single plasma parameters showed an association with DM2 and CAD status, we could not confirm that the Gremlin-1/MIF ratio is significantly different in patients stratified by DM2 and CAD (P = 0.072). Hence, Gremlin-1/MIF ratio was significantly lower in patients with ACS compared with SAP (1.1 ± 0.1 vs 4.4 ± 1.1; P = 0.003). CONCLUSIONS: Diabetic patients with ACS show increased levels of Gremlin-1 and MIF, leading to unfavorable Gremlin-1/MIF ratios. However, DM2 alone is not associated with low Gremlin-1/MIF ratios.

Periprocedural platelet inhibition with cangrelor in P2Y12-inhibitor naïve patients with acute coronary syndromes - A matched-control pharmacodynamic comparison in real-world patients.

BACKGROUND: Effective inhibition of platelet aggregation during PCI in high risk patients with ACS is of utmost importance. The new intravenous short acting P2Y12-receptor inhibitor cangrelor is available for use in PCI-treated patients. We aimed to study platelet inhibition during treatment with cangrelor and transition phase with oral P2Y12-receptor inhibitors in patients with acute coronary syndromes (ACS). METHODS: Cangrelor was administered during PCI to 21 P2Y12-inhibitor naïve patients with ACS. Patients received a loading dose of ticagrelor at the time of procedure or prasugrel 30min before end of the cangrelor infusion. Platelet inhibition was measured by multiple electrode aggregometry (MEA) and thromboelastography (TEG), before and after PCI, immediately and 2h after stopping the infusion. Platelet inhibition after PCI was compared to a matched cohort of patients treated with oral P2Y12-inibitors only. RESULTS: There was a significant reduction of platelet reactivity measured by MEA-ADP from 46.7U to 17.9U and by TEG MA ADP from 43.1mm to 22.0mm before infusion and after PCI respectively (p<0.001). There was also sustained platelet inhibition after stopping of cangrelor infusion and 2h later. Significant higher platelet inhibition was observed at the end of PCI in comparison to control cohort without cangrelor (MEA 17.9U vs. 54.2U, p=0.001). CONCLUSION: We demonstrate significantly improved platelet inhibition during PCI in ACS patients treated with cangrelor in comparison to early treatment with potent oral P2Y12-inhibitors. Cangrelor should be considered for periprocedural treatment of high risk patients with acute coronary syndrome.

Platelets, inflammation and anti-inflammatory effects of antiplatelet drugs in ACS and CAD.

Platelets play a pivotal role in chronic inflammation leading to progression of atherosclerosis and acute coronary events. Recent discoveries on novel mechanisms and platelet-dependent inflammatory targets underpin the role of platelets to maintain a chronic inflammatory condition in cardiovascular disease. There is strong and clinically relevant crosslink between chronic inflammation and platelet activation. Antiplatelet therapy is a cornerstone in the prevention and treatment of acute cardiovascular events. The benefit of antiplatelet agents has mainly been attributed to their direct anti-aggregatory impact. Some anti-inflammatory off-target effects have also been described. However, it is unclear whether these effects are secondary due to inhibition of platelet activation or are caused by direct distinct mechanisms interfering with inflammatory pathways. This article will highlight novel platelet associated targets that contribute to inflammation in cardiovascular disease and elucidate mechanisms by which currently available antiplatelet agents evolve anti-inflammatory capacities, in particular by carving out the differential mechanisms directly or indirectly affecting platelet mediated inflammation. It will further illustrate the prognostic impact of antiplatelet therapies by reducing inflammatory marker release in recent cardiovascular trials.

Evaluation of clinical risk factors to predict high on-treatment platelet reactivity and outcome in patients with stable coronary artery disease (PREDICT-STABLE).

OBJECTIVES: This study was designed to identify the multivariate effect of clinical risk factors on high on-treatment platelet reactivity (HPR) and 12 months major adverse events (MACE) under treatment with aspirin and clopidogrel in patients undergoing non-urgent percutaneous coronary intervention (PCI). METHODS: 739 consecutive patients with stable coronary artery disease (CAD) undergoing PCI were recruited. On-treatment platelet aggregation was tested by light transmittance aggregometry. Clinical risk factors and MACE during one-year follow-up were recorded. An independent population of 591 patients served as validation cohort. RESULTS: Degree of on-treatment platelet aggregation was influenced by different clinical risk factors. In multivariate regression analysis older age, diabetes mellitus, elevated BMI, renal function and left ventricular ejection fraction were independent predictors of HPR. After weighing these variables according to their estimates in multivariate regression model, we developed a score to predict HPR in stable CAD patients undergoing elective PCI (PREDICT-STABLE Score, ranging 0-9). Patients with a high score were significantly more likely to develop MACE within one year of follow-up, 3.4% (score 0-3), 6.3% (score 4-6) and 10.3% (score 7-9); odds ratio 3.23, P=0.02 for score 7-9 vs. 0-3. This association was confirmed in the validation cohort. CONCLUSIONS: Variability of on-treatment platelet function and associated outcome is mainly influenced by clinical risk variables. Identification of high risk patients (e.g. with high PREDICT-STABLE score) might help to identify risk groups that benefit from more intensified antiplatelet regimen. Additional clinical risk factor assessment rather than isolated platelet function-guided approaches should be investigated in future to evaluate personalized antiplatelet therapy in stable CAD-patients.

Gremlin-1 inhibits macrophage migration inhibitory factor-dependent monocyte function and survival.

BACKGROUND: Monocyte migration and their differentiation into macrophages critically regulate vascular inflammation and atherogenesis and are governed by macrophage migration inhibitory factor (MIF). Gremlin-1 binds to MIF. Current experimental evidences present Gremlin-1 as a potential physiological agent that might counter-regulate the inflammatory attributes of MIF. METHODS AND RESULTS: We found that Gremlin-1 inhibited MIF-dependent monocyte migration and adhesion to activated endothelial cells in flow chamber perfusion assay in vitro and to the injured carotid artery of WT and ApoE-/- mice in vivo as deciphered by intravital microscopy. Intravenous administration of Gremlin-1, but not of control protein, significantly reduced leukocyte recruitment towards the inflamed carotid artery of ApoE-/- mice. Besides, leukocytes from MIF-/- when administered into ApoE-/- mice showed lesser adhesion as compared to wild type. In the presence of Gremlin-1 however, adhesion of wild type, but not of MIF-/- leukocytes, to the carotid artery was significantly inhibited as compared to control. Gremlin-1 also inhibited the MIF-induced differentiation of monocytes into macrophages. Gremlin-1 substantially inhibited the anti-apoptotic impact of MIF on monocytes against BH3 mimetic ABT-737-induced apoptosis as verified by Annexin V-binding, caspase 3 activity, and mitochondrial depolarization. CONCLUSIONS: Therefore Gremlin-1 can modulate MIF dependent monocyte adhesion, migration, differentiation and survival.

Impact of counterbalance between macrophage migration inhibitory factor and its inhibitor Gremlin-1 in patients with coronary artery disease.

OBJECTIVE: Monocyte infiltration is a critical step in the pathophysiology of plaque instability in coronary artery disease (CAD). Macrophage migration inhibitory factor (MIF) is involved in atherosclerotic plaque progression and instability leading to intracoronary thrombosis. Gremlin-1 (Grem1) has been recently identified as endogenous inhibitor of MIF. To date there are no data on the clinical impact of this interaction in cardiovascular patients. METHODS AND RESULTS: Plasma levels of MIF and Grem1 were determined by enzyme-linked immunoassay in patients with acute coronary syndromes (ACS, n = 120; stable CAD, n = 166 and healthy control subjects, n = 25). MIF levels were significantly increased in ACS compared to stable CAD and healthy control (ACS: median 2.85; IQR 3.52 ng/ml; versus SAP: median 1.22; IQR 2.99 ng/ml; versus healthy control: median 0.10; IQR 0.09 ng/ml, p < 0.001). Grem1 levels were significantly higher in ACS and stable CAD patients compared to healthy control (ACS: median 211.00; IQR 130.47 ng/ml; SAP: median 220.20; IQR 120.93 ng/ml, versus healthy control: median 90.57; IQR 97.68 ng/ml, p < 0.001). Grem1/MIF ratio was independently associated with ACS, whereas the single parameters were not associated with the presence of ACS. Furthermore, Grem1/MIF ratio was associated with angiographic signs of intracoronary thrombi and severity of thrombus burden. CONCLUSION: These novel findings suggest a potential role of Grem1/MIF ratio to indicate acuity of CAD and the grade of plaque stability. Prospective angiographic cohort studies involving plaque imaging techniques are warranted to further characterize the prognostic role of this novel risk marker in CAD patients.

Prognostic value of contrast-enhanced cardiac magnetic resonance imaging in patients with newly diagnosed non-ischemic cardiomyopathy: cohort study.

BACKGROUND: Owing to its variable course from asymptomatic cases to sudden death risk stratification is of paramount importance in newly diagnosed non-ischemic cardiomyopathy. We tested whether late gadolinium enhancement (LGE) assessed by cardiac magnetic resonance (CMR) imaging is a prognostic marker in consecutive patients with newly diagnosed non-ischemic cardiomyopathy. METHODS: We enrolled 185 patients who presented for evaluation of newly diagnosed non-ischemic cardiomyopathy. Coronary artery disease was excluded by coronary angiography. Following risk markers were additionally assessed: NYHA functional class (≥II), brain natriuretic peptide (>100 ng/l), troponin I (TnI, ≥0.03 µg/l), left ventricular ejection fraction (LVEF, ≤40%), left ventricular enddiastolic diameter (>55 mm) and QRS duration (>98 ms). Endpoint of the study was the composite of all-cause mortality, heart transplantation, aborted sudden death, sustained ventricular tachycardia or hospitalization due to decompensated heart failure within three years of follow-up. RESULTS: During median follow-up of 21 months, 54 patients (29.2%) reached the composite endpoint. Ninety-four of the 185 patients (50.8%) were judged LGE-positive. Prognosis of LGE-positive patients was significantly worse than that of LGE-negative patients (cumulative 3-year event rates of 67.4% in LGE-positive and 27.2% in LGE-negative patients, respectively; p = 0.021). However, in multivariable analysis, presence of LGE was not an independent predictor of outcome. Only LVEF ≤40% and TnI ≥0.03 µg/l were independent risk predictors of the composite endpoint yielding relative risks of 3.9 (95% CI 1.9-8.1; p<0.0001) and 2.2 (95% CI 1.2-4.0; p = 0.014), respectively. CONCLUSIONS: In consecutive patients presenting with newly diagnosed non-ischemic cardiomyopathy, LGE-positive patients had worse prognosis. However, only traditional risk parameters like left ventricular performance and cardiac biomarkers but not presence of LGE were independent risk predictors.

Cyclophilin A predicts clinical outcome in patients with congestive heart failure undergoing endomyocardial biopsy.

AIMS: Cyclophilin A (CyPA) represents a ubiquitous intracellular protein, which is secreted by inflammatory and by dying/necrotic cells. The aim of this study was to evaluate the prognostic relevance of CyPA expression in endomyocardial biopsies of consecutive patients with congestive heart failure. METHODS AND RESULTS: A total of 227 unselected patients (age 53.9 ± 15 years) with congestive heart failure undergoing endomyocardial biopsy for diagnostic reasons were enrolled. Biopsies were analysed using established histopathological and immunohistological criteria together with CyPA staining. Virus genome was studied by polymerase chain reaction. CyPA was significantly enhanced in patients with inflammatory cardiomyopathy (n = 127) as compared with patients with non-inflammatory cardiomyopathy (n = 100, P < 0.0001). During a mean follow-up of 16.3 months, 60 patients (26.4%) reached the primary endpoint, a composite of all-cause death, heart transplantation, malignant arrhythmia, and heart failure-related rehospitalization. Of all clinical (ejection fraction, New York Heart Association functional class), laboratory (brain natriuretic peptide), and immunohistological parameters (CyPA, extracellular matrix metalloproteinase inducer, CD68, CD3, major hisocompatibility complex II, and virus genome) tested, only CyPA was identified as an independent predictor for the composite endpoint [hazard ratio (HR) 2.4; 95% confidence interval (CI) 1.2-5.2; P = 0.019] as well as for all-cause death and heart transplantation alone (HR 4.7; 95% CI 1.1-19.8; P = 0.036). Subgroup analysis revealed CyPA as a predictor in patients with non-inflammatory cardiomyopathy for the composite endpoint (HR 3.0; 95% CI 1.3-6.6; P = 0.007) as well as all-cause death or heart transplantation alone (HR 6.4; 95% CI 1.4-28.1; P = 0.014). CONCLUSIONS: CyPA is an independent predictor of clinical outcome in patients with congestive heart failure undergoing endomyocardial biopsy.

Novel antiplatelet therapy in acute coronary syndromes: what is new in the pipeline?

Acute coronary syndromes (ACS) are triggered by enhanced platelet activation and aggregation. Hence, a cornerstone of successful secondary prevention in ACS is an effective platelet inhibition. Additionally, coronary interventions (PCI) lead to even increased artherothrombotic risks, another challenge in preventing recurrent events including stent thrombosis. Promising platelet targets were characterized and novel molecules were developed that are currently under investigation. Intensified antiplatelet therapy includes the risk of major bleeding which itself increases the mortality rate. Previous strategies of antiplatelet therapy were based on an "one-size fits all" concept. However, there has been evidence that variability of drug response exists and represents a clinically relevant issue. This observation is in line with results of randomized clinical trials that standard-of-care antiplatelet therapy is not sufficient to reduce cardiovascular (CV) risk in certain subgroups of ACS patients. In the last years, novel antiplatelet substances have entered the clinical arena and others are currently under investigation in phase II and III clinical trials. These include 3rd generation thienopyridine (prasugrel, elinogrel), ATP analogs (Ticagrelor, cangrelor), and non-ADP-receptor blocking antiplatelet substances like thrombin receptor antagonists. These agents have shown promising results in pilot studies and recent randomized trials. As the prevention of atherothrombotic risk is at the expense of bleeding risk, it will be a future task to clearly define patients' groups and subsets of ACS for the best net clinical benefit. This article focuses on the role of novel antiplatelet substances to reduce CV risk in ACS, discuss clinical implications and their potential future role.

Severe autonomic failure in moderate to severe aortic stenosis: prevalence and association with hemodynamics and biomarkers.

BACKGROUND: Severe autonomic failure (SAF) refers to combined abnormalities in reflex and tonic autonomic function. SAF indicates increased risk of death in post-infarction and heart failure patients, but has not been studied in aortic stenosis (AS). Here, we investigated SAF in patients with AS and tested its correlation with hemodynamic and biochemical markers. METHODS: We prospectively enrolled 174 patients with moderate to severe AS in sinus rhythm (age 76 ± 9 years; mean aortic valve area 0.9 ± 0.3 cm(2)). Heart rate turbulence (as marker of autonomic reflex activity) and deceleration capacity (as marker of autonomic tonic activity) were calculated from 24-h Holter recordings. According to the previously published technology, SAF was considered present if both factors were abnormal. RESULTS: 44 (25.3%) of the 174 patients had signs of SAF. Patients with SAF had lower left ventricular ejection fraction (LVEF: 48.1 vs. 54.8%; p = 0.002), lower mean aortic gradients (28 vs. 34 mmHg, p = 0.019), higher systolic pulmonary artery pressures (46.8 vs. 40.9 mmHg, p = 0.028), higher levels of brain natriuretic peptide (905 vs. 407 ng/l; p = 0.003) and higher levels of high sensitive troponin I (0.65 vs. 0.24 µg/l; p = 0.013). Impaired LVEF (≤50%) was the only independent factor associated with SAF, but only explained autonomic abnormalities in less than half of the patients. CONCLUSIONS: In patients with moderate to severe AS prevalence of SAF is high. SAF correlates with hemodynamic and biochemical markers indicating increased risk. Future studies should evaluate the prognostic value of SAF in patients with AS.