Cardio-hepatic syndrome in patients undergoing transcatheter aortic valve replacement.

BACKGROUND: Cardiohepatic syndrome (CHS) has been identified as an important but underrecognized survival predictor in multiple cardiovascular disease entities. The objectives of this study were to evaluate the prevalence and prognostic value of CHS in patients undergoing TAVR for severe aortic stenosis (AS). METHODS: The study included patients with available laboratory parameters of hepatic function who underwent TAVR from July 2013 until December 2019 at our center. CHS was defined as an elevation of at least two of three laboratory cholestasis parameters above the upper limit of normal (bilirubin, alkaline phosphatase, and gamma glutamyl transferase). Study endpoints were three-year survival, technical and device failure (VARC 3), as well as New York Heart Association (NYHA) functional class at follow-up. RESULTS: Among a total of 953 analyzed patients (47.6% females, median age 80.0 [76.0-85.0] years) CHS was present in 212 patients (22.4%). In patients with vs. without CHS, rates of technical (6.1% vs. 8.4%, p = 0.29) and device failure (18.9% vs. 17.3%, p = 0.59) were comparable. NYHA functional class at baseline and follow-up was more severe in patients with CHS. Nevertheless, heart failure symptoms improved from baseline to follow-up irrespective of hepatic function. Three-year survival rates were significantly lower in patients with CHS (49.4 vs. 65.4%, p < 0.001). The predictive value of CHS persisted after adjustment in a multivariable analysis (hazard ratio 1.58, p < 0.01). CONCLUSION: In patients undergoing TAVR, CHS is prevalent in 22% of patients and is associated with increased postinterventional mortality. Thus, CHS should be included in the decision-making process within the TAVR heart team. Cardiohepatic syndrome (CHS) as defined by an elevation of at least two of three laboratory cholestasis parameters above the upper limit of normal was prevalent in 22% of patients undergoing TAVR for severe AS. The presence of CHS was associated with more severe heart failure symptoms and worse three-year survival.

Systolic or diastolic CT image acquisition for transcatheter aortic valve replacement - An outcome analysis.

BACKGROUND: Computed tomography (CT) imaging is the standard of care before transcatheter aortic valve replacement (TAVR). The aortic annulus undergoes conformational changes during the heart cycle. Therefore, the image acquisition time point can impact prosthesis sizing and fit. Clinical outcome data are lacking. The aim of this study was to compare systolic and diastolic cardiac CT data acquisition with regard to procedural and clinical outcomes in patients undergoing TAVR for severe aortic stenosis (AS). METHODS: Preprocedural high-pitch helical CT datasets were analyzed in 1954 patients undergoing TAVR between 2013 and 2018 â€‹at our center. Patients were stratified into two groups according to the acquisition heart phase (979 systolic and 975 diastolic). The study was approved by the local ethics committee. RESULTS: Median age was 81.6 [interquartile range 77.5-85.8] years and 964 (49.3%) patients were male. No significant difference was found for the Valve Academic Research Consortium-3 (VARC-3) endpoints of technical failure (systolic, 5.1% vs. diastolic, 5.2%, p â€‹= â€‹0.94) or device failure (systolic, 13.7% vs. diastolic, 13.5%, p â€‹= â€‹0.92). There was no difference in paravalvular regurgitation. All-cause 30-day mortality was comparable (systolic, 3.6% [95% confidence interval, 2.4-4.7%] vs. diastolic, 3.6% [2.4-4.8%], p â€‹= â€‹1.00), while 3-year mortality rates were higher in the diastolic group (Society of Thoracic Surgeons score adjusted hazard ratio, 1.25 [1.07-1.46], p â€‹< â€‹0.01). CONCLUSIONS: While the 30-day technical and clinical outcomes after TAVR are comparable between systolic and diastolic CT imaging, diastolic imaging was associated with higher long-term mortality. Therefore, the data support the guideline recommendation of systolic imaging.

Outcome of patients treated with extracorporeal life support in cardiogenic shock complicating acute myocardial infarction: 1-year result from the ECLS-Shock study.

BACKGROUND: Treatment with extracorporeal life support (ECLS) in acute myocardial infarction (AMI) complicated by cardiogenic shock (CS) fell short of improving myocardial recovery measured by 30 day ejection fraction in the ECLS-SHOCK trial. However, to date, no data regarding impact of ECLS on long-term outcomes exist. METHODS: In this randomized, controlled, prospective, open-label trial, 42 patients with CS complicating AMI were randomly assigned to ECLS (ECLS group, n = 21) or no ECLS (control group, n = 21). The primary endpoint was left ventricular ejection fraction (LVEF) after 30 days. Secondary endpoints included mortality and neurological outcome after 12 months. Evaluation of neurological outcome used the modified Rankin Scale. RESULTS: The 12-month all-cause mortality was 19% in the ECLS group versus 38% in the control group (p = 0.31). Only one patient (control group) died after the initial 30 days. Three patients underwent elective percutaneous coronary intervention (PCI) during follow-up (one in the control and two in the ECLS group). Favorable neurological outcome (modified Rankin Score ≤ 2) was seen in 61.9% of patients in the ECLS group versus 57.1% in the control group (p = 1). CONCLUSION: This pilot study showed that randomized studies with ECLS in CS patients are feasible and safe. Small numbers of included patients impede meaningful conclusions about mortality and neurological outcome. Our findings of numerical differences in mortality and survival with severe neurological impairment give an urgent call for larger multi-centric randomized trials assessing the endpoint of all-cause mortality but also considering the effects on neurological outcome measures.

CT-Determined Tricuspid Annular Dilatation Is Associated With Increased 2-Year Mortality in TAVR Patients.

OBJECTIVES: The aim of this study was to investigate the prevalence and prognostic impact of tricuspid annular dilatation (TAD) measured in multislice computed tomography datasets in patients undergoing transfemoral transcatheter aortic valve replacement for severe aortic stenosis. BACKGROUND: TAD is an increasingly recognized entity associated with poor outcomes in patients with valvular heart disease. METHODS: The maximal septolateral diameter of the tricuspid annulus was measured in consecutive patients with 3-dimensional multidetector row computed tomographic datasets undergoing transfemoral transcatheter aortic valve replacement. Receiver-operating curve characteristic analysis was performed to obtain an ideal, body surface area-normalized cutoff for TAD. Ethical approval was obtained from the institutional ethics board. RESULTS: The study included 1,137 patients, of whom 299 died within a mean follow-up period of 1.8 ± 1.0 years. TAD was identified in 446 patients (39.2%) on the basis of a receiver-operating characteristic cutoff of 23 mm/m2. TAD had no impact on procedural outcomes, including device failure defined according to Valve Academic Research Consortium-2 criteria. Patients with TAD experienced significantly greater mortality (hazard ratio: 1.99; 95% confidence interval: 1.59 to 2.51; p < 0.001). Multivariate analysis including clinical and echocardiographic parameters confirmed the predictive value of TAD (hazard ratio: 1.78; 95% confidence interval: 1.33 to 2.38; p < 0.001), while echocardiographic variables, including estimated pulmonary artery pressure and the severity of tricuspid regurgitation, did not reach statistical significance. The predictive value of TAD was incremental to a baseline model of clinical and echocardiographic parameters (continuous net reclassification improvement 0.204; p < 0.01) and incremental to the Society of Thoracic Surgeons score (continuous net reclassification improvement 0.209; p < 0.001). CONCLUSIONS: TAD is an independent predictor of all-cause mortality in patients with severe aortic stenosis undergoing transcatheter aortic valve replacement.

Sex and long-term outcomes after implantation of the Absorb bioresorbable vascular scaffold for treatment of coronary artery disease.

AIMS: Women and men suffering from coronary artery disease differ in their risk profiles. We sought to investigate the impact of sex on two-year outcomes after BVS implantation in routine clinical practice. METHODS AND RESULTS: Sex-based analysis of clinical outcomes was carried out by pooling the individual patient data of the ISAR-ABSORB and KUM-ABSORB registries performed in four high-volume tertiary centres in Munich. Of the total of 1,032 patients, 259 (25.1%) were women. The primary composite endpoint of death, target vessel myocardial infarction (TV-MI) and target lesion revascularisation (TLR) up to two years occurred in 13.2% of women and 17.9% of men (p=0.12). Compared to men, women experienced numerically lower rates of TLR and definite or probable BVS thrombosis - 7.5% vs 12.4% (p=0.051) and 1.2% and 2.7% (p=0.20), respectively. Independent predictors of increased risk for TLR were use of smaller size BVS (HR 1.28, 95% CI: 1.02-1.62), while being a woman was a protective factor (HR 0.59, 95% CI: 0.35-1.00). CONCLUSIONS: BVS used in a routine setting tend to perform better among women compared to men, which might be partially related to the lower complexity of their coronary artery disease.

Impact of the bioresorbable vascular scaffold surface area on on-treatment platelet reactivity.

While promising data with the novel bioresorbable vascular scaffold (BVS) are accumulating, signals of scaffold thrombosis (ST) were noted in recent reports. We aimed to assess the relationship between the total surface area (TSA) of implanted everolimus-eluting BVSs and the on-treatment adenosine diphosphate (ADP)-induced platelet reactivity in patients undergoing percutaneous coronary intervention (PCI). 202 consecutive patients undergoing BVS implantation and platelet function testing were included. For investigating the impact of the scaffold surface on platelet reactivity, patients were stratified into two groups regarding the median BVS TSA. The on-treatment ADP-induced platelet reactivity was determined with the Multiplate analyzer and 30-day follow-up was available in 98% of patients. ADP-induced platelet aggregation values (median, [IQR]) did not differ between the two study groups (12.0 [9.0-19.0] U for patients with TSA > 1.39 cm(2) and 13.0 [9.0-19.5] U for patients with TSA ≤ 1.39 cm(2); p = 0.69). No correlation was observed between the BVS TSA and levels of platelet reactivity (Spearman rank correlation = -0.10, p = 0.16). At 30 days after PCI, two early STs (1%) were documented. Thus, in patients on a dual antiplatelet treatment regimen following BVS implantation, the extent of blood-to-BVS contact surface does not negatively affect levels of on-treatment platelet reactivity.

The role of 1.5 tesla MRI and anesthetic regimen concerning cardiac analysis in mice with cardiomyopathy.

Accurate assessment of left ventricular function in rodent models is essential for the evaluation of new therapeutic approaches for cardiac diseases. In our study, we provide new insights regarding the role of a 1.5 Tesla (T) magnetic resonance imaging (MRI) device and different anesthetic regimens on data validity. As dedicated small animal MRI and echocardiographic devices are not broadly available, we evaluated whether monitoring cardiac function in small rodents with a clinical 1.5 T MRI device is feasible. On a clinical electrocardiogram (ECG) synchronized 1.5 T MRI scanner we therefore studied cardiac function parameters of mice with chronic virus-induced cardiomyopathy. Thus, reduced left ventricular ejection fraction (LVEF) could be verified compared to healthy controls. However, our results showed a high variability. First, anesthesia with medetomidine, midazolam and fentanyl (MMF) led to depressed cardiac function parameters and more variability than isoflurane gas inhalation anesthesia, especially at high concentrations. Furthermore, calculation of an average ejection fraction value from sequenced scans significantly reduced the variance of the results. To sum up, we introduce the clinical 1.5 T MRI device as a new tool for effective analysis of left ventricular function in mice with cardiomyopathy. Besides, we suggest isoflurane gas inhalation anesthesia at high concentrations for variance reduction and recommend calculation of an average ejection fraction value from multiple sequenced MRI scans to provide valid data and a solid basis for further clinical testing.

Percutaneous extracorporeal life support for patients in therapy refractory cardiogenic shock: initial results of an interdisciplinary team.

OBJECTIVES: Therapy refractory cardiogenic shock is associated with dismal outcome. Percutaneous implantation of an extracorporeal life support (ECLS) system achieves immediate cardiopulmonary stabilization, sufficient end-organ perfusion and reduction of subsequent multiorgan failure (MOF). METHODS: Forty-one patients undergoing percutaneous ECLS implantation for cardiogenic shock from February 2012 until August 2013 were retrospectively analysed. Mean age was 52 ± 13 years, 6 (15%) were female. Mean pH values obtained before ECLS implantation were 7.15 ± 0.24, mean lactate concentration was 11.7 ± 6.4 mmol/l. Levels obtained 6 h after ECLS implantation were 7.30 ± 0.14 and 8.7 ± 5.0 mmol/l, respectively. In 23 patients (56%) cardiogenic shock resulted from an acute coronary syndrome in 13 (32%) from cardiomyopathy, in 5 (12%) from other causes. Twenty-seven (66%) had been resuscitated, in 14 (34%) implantation was performed under ongoing cardiopulmonary resuscitation (CPR). Of note, 97% of the acute coronary syndrome patients underwent percutaneous coronary intervention (PCI) either before ECLS implantation or under ECLS support. Extracorporeal life support implantation was performed on scene (Emergency Department, Cath Lab, Intensive Care Unit) by a senior cardiac surgeon and a trained perfusionist, in 8 cases (20%) in the referring hospital. RESULTS: Thirty-day mortality was 51% [21 patients, due to MOF (n = 14), cerebral complications (n = 6) and heart failure (n = 1)]. Logistic regression analysis identified 6-h pH values as an independent risk factor of 30-day mortality (P < 0.001, OR = 0.000, 95% CI 0.000-0.042). Neither CPR nor implantation under ongoing CPR resulted in significant differences. In 26 cases (63%), the ECLS system could be explanted, after mean support of 169 ± 67 h. Seven of these patients received cardiac surgery [ventricular assist device implantation (n = 4), heart transplantation (n = 1), other procedures (n = 2)]. CONCLUSIONS: Due to the evolution of transportable ECLS systems and percutaneous techniques implantation on scene is feasible. Extracorporeal life support may serve as a bridge-to-decision and bridge-to-treatment device. Neurological evaluation before ventricular assist device implantation and PCI under stable conditions are possible. Despite substantial mortality, ECLS implantation in selected patients by an experienced team offers additional support to conventional therapy as well as CPR and allows survival in patients that otherwise most likely would have died. This concept has to be implemented in cardiac survival networks in the future.

Preconditioning with levosimendan before implantation of left ventricular assist devices.

In this retrospective study, we investigated the impact of preconditioning of the right ventricle with the calcium sensitizer levosimendan immediately before left ventricular assist device (LVAD) implantation on outcome and survival. Nine consecutive LVAD patients (seven suffering from dilative cardiomyopathy and two from ischemic cardiomyopathy) with echocardiographic and invasive evidence of right heart insufficiency received levosimendan with 0.1 µg/kg body weight/min for 24 h before implantation of the assist device (seven HeartWare and two Jarvik 2000). Administration of levosimendan was safe and had not to be discontinued in any patient. We observed no relevant side effects. Twelve-month survival after implantation of the LVAD was 89% representing a superior outcome compared with the fifth INTERMACS registry data with 75% survival. Two temporary extracorporeal membrane-oxygenation implantations were necessary due to intraoperative right ventricular dysfunction. Only one patient died 5 weeks after LVAD implantation of multiorgan failure, five patients were successfully transplanted, and three patients underwent LVAD implantation for destination therapy. Levosimendan might improve clinical outcome and survival when used as pretreatment in patients with right heart insufficiency prior to LVAD implantation. However, we recommend a larger controlled trial in the future to confirm our preliminary results.

Enhanced stem cell migration mediated by VCAM-1/VLA-4 interaction improves cardiac function in virus-induced dilated cardiomyopathy.

Endogenous circulation of bone marrow-derived cells (BMCs) was observed in patients with dilated cardiomyopathy (DCM) who showed cardiac upregulation of Vascular Cell Adhesion Protein-1 (VCAM-1). However, the underlying pathophysiology is currently unknown. Thus, we aimed to analyze circulation, migration and G-CSF-based mobilization of BMCs in a murine model of virus-induced DCM. Mice with coxsackievirus B3 (CVB3) induced DCM and healthy controls were analyzed regarding their myocardial homing factors by PCR. To determine cardiac VCAM-1 expression ELISA and immunohistochemistry were applied. Flow cytometry was performed to analyze BMCs. Cardiac diameters and function were evaluated by echocardiography before and 4 weeks after G-CSF treatment. In murine CVB3-induced DCM an increase of BMCs in peripheral blood and a decrease of BMCs in bone marrow was observed. We found an enhanced migration of Very Late Antigen-4 (VLA-4⁺) BMCs to the diseased heart overexpressing VCAM-1 and higher numbers of CD45⁻CD34⁻Sca-1⁺ and CD45⁻CD34⁻c-kit⁺ cells. Mobilization of BMCs by G-CSF boosted migration along the VCAM-1/VLA-4 axis and reduced apoptosis of cardiomyocytes. Significant improvement of cardiac function was detected by echocardiography in G-CSF-treated mice. Blocking VCAM-1 by a neutralizing antibody reduced the G-CSF-dependent effects on stem cell migration and cardiac function. This is the first study showing that in virus-induced DCM VCAM-1/VLA-4 interaction is crucial for recruitment of circulating BMCs leading to beneficial anti-apoptotic effects resulting in improved cardiac function after G-CSF-induced mobilization.

Antidiabetic gliptins in combination with G-CSF enhances myocardial function and survival after acute myocardial infarction.

BACKGROUND: Medical stimulation of endogenous progenitor cell circulation may serve as a new therapeutic tool for treatment of acute myocardial infarction. We analyzed the effects of antidiabetic gliptins plus GCSF (granulocyte colony stimulating factor) on myocardial regeneration after myocardial infarction in a mouse model. METHODS AND RESULTS: After surgical LAD-ligation (left anterior descending artery), Sitagliptin/Vildagliptin was applied yielding sufficient blood levels verified by mass spectrometry and significantly reducing activity of dipeptidyl peptidase (DPP) IV. GCSF or saline was administered intraperitoneally for 6 days. We assessed stem cell mobilization and homing (flow cytometry), infarct size (histology), neovascularization and cellular proliferation (immunohistology), heart function (Millar tip catheterization) and survival (Kaplan-Meier-curves). Gliptins±GCSF administration increased mobilization and cardiac homing of bone-marrow derived stem cells by stabilization of cardiac SDF1 (stromal cell-derived factor). For Sitagliptin, it could be shown that resident cardiac stem cells were stimulated, neovascularization was enhanced and cardiac remodeling was reduced. These effects finally improved myocardial function and increased survival for both gliptins. Although gliptins as a mono therapy lead to remarkable effects in a dose dependent manner and were superior to G-CSF mono-therapy, dual application of GCSF and gliptins revealed the best results. Since both gliptins yielded comparable effects concerning stem cell homing, cardiac function and survival, we suggest a class-effect of DPP-IV-inhibitors. CONCLUSIONS: Thus, gliptins+GCSF and in high concentrations even as mono therapy have beneficial effects on cardiac regeneration after myocardial infarction beyond its anti-diabetic potential.

The cardioprotective effects of parathyroid hormone are independent of endogenous granulocyte-colony stimulating factor release.

AIMS: Parathyroid hormone (PTH) administration after myocardial infarction (MI) is known to attenuate ischaemic cardiomyopathy. This effect mainly resulted from an increase in mobilization and homing of CD34+/CD45+ cells into the ischaemic myocardium. PTH-related stem cell mobilization was shown to be related to endogenous granulocyte-colony stimulating factor (G-CSF) release. The aim of our study is to determine the role of G-CSF on the cardioprotective effects of PTH. METHODS AND RESULTS: G-CSF +/+ (C57BL/6) and G-CSF -/- mice were treated with PTH for 6 days after inducing a MI. The myocardial homing factor stromal cell-derived factor-1 (SDF-1) was analysed on day 2 with enzyme-linked immunosorbent assay. Stem cell populations in peripheral blood and hearts were examined by FACS on days 6 and 2, respectively. Cardiac function and immunohistochemistry were investigated on day 6 and day 30. PTH treatment resulted in a significant increase in CD45+/CD34+ cells in peripheral blood in G-CSF +/+ but not in G-CSF -/- mice. However, a significant increase in SDF-1 and enhanced migration of CD45+/CD34+ cells into the ischaemic myocardium was revealed after PTH administration in both G-CSF +/+ and G-CSF -/- mice. Enhanced stem cell homing was associated with improved cardiac function and post-MI survival after PTH treatment. Furthermore, infarct size, wall thickness, and neovascularization showed a significant improvement in both groups 30 days after MI. CONCLUSION: The cardioprotective effects of PTH were shown to be independent of endogenous G-CSF release and therefore from stem cell mobilization. This puts more emphasis on the role of stem cell homing into ischaemic myocardium.

Dual stem cell therapy after myocardial infarction acts specifically by enhanced homing via the SDF-1/CXCR4 axis.

BACKGROUND: G-CSF based stem cell mobilization and stabilization of cardiac SDF-1 by DPP-IV-inhibition (dual stem cell therapy) improve heart function and survival after myocardial infarction. However, it is barely understood whether this new approach acts specifically through the SDF-1/CXCR4 axis, stimulation of resident cardiac stem cells and improved myocardial perfusion. Therefore, we aimed to clarify the role of the SDF1/CXCR4 axis with respect to the benefits of a dual stem cell based therapy. METHODOLOGY/PRINCIPAL FINDINGS: After surgically induced ligation of the LAD, SDF-1/CXCR4 interactions were specifically blocked by the CXCR4 receptor antagonist AMD3100 in G-CSF and Diprotin A treated C57BL/6 mice. G-CSF+DipA treated and non-treated animals served as controls. Because AMD3100 is known to mobilize bone marrow derived stem cells (BMCs) in high concentrations, the optimal dosage (1.25mg per kg body weight) sufficient to block CXCR4 without stimulating mobilization was established. AMD3100 treatment of G-CSF and Diprotin A stimulated mice significantly decreased myocardial homing of circulating stem cells (FACS analysis) and inverted the beneficial effects of (i) cardiac remodeling (histological analyses), (ii) heart function (Millar tip catheterization) and (iii) survival (Kaplan-Meier curves). G-CSF treatment in combination with DPP-IV inhibition enhanced neovascularization at the infarct border zone which was related to an improved myocardial blood flow as measured by SPECT. Moreover, dual stem cell treatment effectively stimulated the pool of resident cardiac stem cells (FACS) which was reversed by AMD3100 treatment. CONCLUSIONS/SIGNIFICANCE: Our data give final proof that homing through the SDF-1/CXCR-4 axis is essential for the success of dual stem cell therapy.

Parathyroid hormone is a DPP-IV inhibitor and increases SDF-1-driven homing of CXCR4(+) stem cells into the ischaemic heart.

AIMS: Parathyroid hormone (PTH) has been shown to promote stem cell mobilization into peripheral blood. Moreover, PTH treatment after myocardial infarction (MI) improved survival and myocardial function associated with enhanced homing of bone marrow-derived stem cells (BMCs). To unravel the molecular mechanisms of PTH-mediated stem cell trafficking, we analysed wild-type (wt) and green fluorescent protein (GFP)-transgenic mice after MI with respect to the pivotal stromal cell-derived factor-1 (SDF-1)/chemokine receptor type 4 (CXCR4) axis. METHODS AND RESULTS: WT and GFP-transgenic mice (C57BL/6J) were infarcted by coronary artery ligation and PTH (80 µg/kg/day) was injected for 6 days afterwards. Number of BMCs was analysed by flow cytometry. SDF-1 protein levels and activity of dipeptidyl peptidase-IV (DPP-IV) were investigated by ELISA and activity assay. Functional analyses were performed at day 30 after MI. PTH-treated animals revealed an enhanced homing of CXCR4(+) BMCs associated with an increased protein level of the corresponding homing factor SDF-1 in the ischaemic heart. In vitro and in vivo, PTH inhibited the activity of DPP-IV, which cleaves and inactivates SDF-1. Functionally, PTH significantly improved myocardial function after MI. Both stem cell homing as well as functional recovery were reversed by the CXCR4 antagonist AMD3100. CONCLUSION: In summary, PTH is a DPP-IV inhibitor leading to an increased cardiac SDF-1 level, which enhances recruitment of CXCR4(+) BMCs into the ischaemic heart associated with attenuated ischaemic cardiomyopathy. Since PTH is already clinically used our findings may have direct impact on the initiation of studies in patients with ischaemic disorders.

Safety and efficacy of SITAgliptin plus GRanulocyte-colony-stimulating factor in patients suffering from Acute Myocardial Infarction (SITAGRAMI-Trial)--rationale, design and first interim analysis.

AIMS: Our pre-clinical studies demonstrated that G-CSF based stem cell mobilization in combination with genetic or pharmaceutical CD26/DPP-IV inhibition after acute myocardial infarction leads to improved cardiac homing of stem cells, enhanced heart function and increased survival. Thereupon, we initiated a phase III, multi-centre, randomised, placebo-controlled efficacy and safety study (n=100) analyzing the effect of combined application of G-CSF and Sitagliptin, which is a clinically admitted, anti-diabetic DPP-IV-inhibitor, after acute myocardial infarction ("SITAGRAMI-Trial"; EudraCT Number: 2007-003941-34). METHODS: The primary objective of the study is to assess myocardial regeneration by improved myocardial homing of mobilized stem cells, as measured by cardiac function using MRI analysis. In this paper, we report on the study design and a planned first interim-analysis on safety issues without unblinding. RESULTS: During the first 6 weeks of follow-up, only two major adverse cardiac events occurred (one de novo stenosis and one instent-restenosis) in the first 36 patients. Presumably, they were not related to any study medication. No other side effects like headache, bone pain, hypoglycaemias etc. were observed. Furthermore, no myocardial infarction or death occurred in any patient. Thus, the rate of serious adverse events lay within the expected range. CONCLUSIONS: Our data demonstrate that the combined application of Sitagliptin and G-CSF seems to be safe on the short term and feasible after acute myocardial infarction and may represent a new therapeutic option in future.

G-CSF in patients suffering from late revascularised ST elevation myocardial infarction: final 1-year-results of the G-CSF-STEMI Trial.

AIMS: The aims of this trial were to investigate the effect of granulocyte colony-stimulating factor (G-CSF) on left-ventricular ejection fraction and event-free survival in patients suffering from sub-acute myocardial infarction (STEMI). METHODS: We enrolled 44 patients suffering from sub-acute STEMI with late revascularization achieved by percutaneous coronary intervention (PCI). Patients were randomized to receive either G-CSF (Filgrastim) at a dose of 10 µg/kg body weight/day subcutaneously or placebo. Changes of global and regional cardiac function from baseline (1 week after PCI) over 1 and 3 months to 12 months of follow-up were analyzed by magnetic resonance imaging. RESULTS: Ejection fraction improved in G-CSF treated patients from 41.1±11.9% to 47.1±11.9% (3 months) and decreased slightly to 45.7±15.1% after 1 year. Ejection fraction also improved in the placebo group from 43.8±9.0% to 49.5±11.8% (3 months) and decreased slightly to 42.9±15.4% after 1 year (1 year MRI follow-up was performed in 23 out initial 44 patients). There was no significant difference between the two groups at any time point. Other parameters such as infarct size, myocardial perfusion, left ventricular end-diastolic and end-systolic volumes were not different between the two groups. Event-free survival of such as death, (re) myocardial infarction or acute coronary syndromes, coronary artery bypass grafting and target lesion revascularization was not significantly different between both groups. CONCLUSIONS: G-CSF administration after sub-acute STEMI is feasible and safe but does not improve myocardial function or survival when used as a single substance.

G-CSF in patients suffering from late revascularized ST elevation myocardial infarction: analysis on the timing of G-CSF administration.

OBJECTIVE: Granulocyte colony-stimulating factor (G-CSF) improves myocardial function after infarction in vivo. Placebo-controlled clinical studies failed to show beneficial effects on myocardial function. Recent data demonstrate that the time point of treatment initiation may be crucial for the efficacy of G-CSF. We investigated the influence of the timing of G-CSF treatment on myocardial function and perfusion in a subgroup study of the G-CSF-ST Elevation Myocardial Infarction trial. MATERIALS AND METHODS: Patients with late revascularized myocardial infarction (n = 44) were treated with either G-CSF or placebo over 5 days after successful percutaneous coronary intervention (PCI). Of the G-CSF group, 13 patients had received G-CSF early treatment started within 24 hours after PCI (mean: 16 +/- 6 hours). In 10 patients, G-CSF was initiated late (>24 hours after PCI, mean: 49 +/- 26 hours). Global and regional myocardial function and perfusion were assessed from baseline to 3 months after PCI using magnetic resonance imaging in 37 patients who completed magnetic resonance follow-up. RESULTS: G-CSF was safe when used early or late after PCI. Early G-CSF administration resulted in significantly improved perfusion at rest 1 month after PCI when compared to placebo (Up-slope, signal intensity 1.2 [0.4-1.8] vs 0.6 [0.1-1.3], p = 0.03). Timing of G-CSF had no influence on global and regional function. CONCLUSION: This post-hoc analysis indicates that timing of G-CSF after myocardial infarction does not improve myocardial function but myocardial perfusion if the cytokine is given early. This urges the need to investigate alternative dosage regimens or combination with novel therapeutics promoting mobilization and homing.