Transcatheter Aortic Valve Replacement for Isolated Aortic Regurgitation Using a New Self-Expanding TAVR System.

BACKGROUND: Patients with severe aortic regurgitation (AR) are often not considered for surgery because of increased surgical risk. Because of unique anatomical characteristics among patients with AR, interventional treatment options are limited, and implantation results are inconsistent compared with those among patients with aortic stenosis. OBJECTIVES: The authors describe the initial commercial experience of the first Conformité Européenne-marked transfemoral transcatheter aortic valve replacement system (JenaValve Trilogy [JV]) for the treatment of patients with AR. METHODS: This multicenter registry included 58 consecutive patients from 6 centers across Germany. Transcatheter aortic valve replacement was performed with the JV system for isolated severe and symptomatic AR. Patient characteristics, primary implantation outcomes, and valve performance up to 30 days were analyzed using Valve Academic Research Consortium 3 definitions. RESULTS: The mean patient age was 76.5 ± 9 years, with a mean Society of Thoracic Surgeons score of 4.2% ± 4.3%. Device success was achieved in 98% of patients. The mean gradient was 4.3 ± 1.6 mm Hg, and no moderate or severe paravalvular regurgitation occurred. No conversion to open heart surgery or valve embolization was reported. There were no major vascular complications or bleeding events. The rate of new permanent pacemaker implantation was 19.6%. At 30 days, 92% of the patients were in NYHA functional class I or II, and the 30-day mortality rate was 1.7%. CONCLUSIONS: Treatment of patients with severe symptomatic AR using the transfemoral JV system is safe and effective. Given its favorable hemodynamic performance and low complication rates, this system may offer a new treatment option for patients with AR not suitable for surgery.

Suture-based vs. pure plug-based vascular closure devices for VA-ECMO decannulation-A retrospective observational study.

Background: Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) is a valuable treatment option for patients in cardiogenic shock, but complications during decannulation may worsen the overall outcome. Therefore, the aim of this study was to compare the efficacy and safety of suture-based to pure plug-based vascular closure devices for VA-ECMO decannulation. Methods: In this retrospective study, the procedural outcome of 33 patients with suture-based Perclose ProGlide closure devices was compared to 38 patients with MANTA plug-based closure devices. Results: Rate of technically correct placement of closure devices was 88% in the suture-based group and 97% in the plug-based group (p = 0.27). There was a significant reduction of severe bleeding events during VA-ECMO decannulation in plug-based versus suture-based systems (3% vs. 21%, p = 0.04). Ischemic complications occurred in 6% with suture-based and 5% with plug-based device (p = 1.00). Pseudoaneurysm formation was detected in 3% in both groups (p = 1.00). No switch to vascular surgery due to bleeding after decannulation was necessary in both groups. Conclusion: Based on our retrospective analysis, we propose that plug-based vascular closure should be the preferred option for VA-ECMO decannulation. This hypothesis should be further tested in a randomized trial.

Quantification of physical activity with prospective activity tracking after transfemoral aortic valve replacement.

BACKGROUND: Transcatheter aortic valve replacement (TAVR) is a well-established, safe and effective therapy for severe symptomatic aortic stenosis (AS). The aim of this study was to objectively quantify improvement of physical activity after TAVR, with consideration of different low-gradient AS subtypes. METHODS AND RESULTS: All patients undergoing TAVR for severe AS were screened. Participants received a wearable activity tracker (Fitbit®) at hospital discharge following TAVR and 6 months thereafter. The difference of median daily steps was defined as surrogate outcome for physical activity. For analysis, patients were grouped into high-gradient (HG) AS (dPmean ≥40 mmHg), classical low-flow low-gradient (LFLG) AS (dPmean <40 mmHg, EF <50%), paradoxical LFLG-AS (dPmean <40 mmHg, EF ≥50%, SVi ≤35 ml/m2) and normal-flow low-gradient (NFLG) AS (dPmean <40 mmHg, EF ≥50%, SVi >35 ml/m2) according to mean transvalvular pressure gradient (dPmean), stroke volume index (SVi) and left-ventricular ejection fraction (LVEF). RESULTS AND CONCLUSIONS: The analysis is based on 230 patients. The median daily step count was 4409 [IQR 2581-7487] after hospital discharge and 5326 [IQR 3045-8668] 6 months thereafter. Median difference of daily steps was ∆529 [IQR -702-2152]). Patients with HG-AS and paradoxical LFLG-AS showed a significant improvement of daily steps (∆951 [IQR -378-2323], p <0.001 and (∆1392 [IQR -609-4444], p = 0.02, respectively). Patients with classical LFLG-AS showed no statistically relevant improvement of daily steps (∆192 [IQR -687-770], p = 0.79). Patients with NFLG-AS showed a numerical decline in daily steps without statistical significance (∆-300 [IQR -1334-1406], p = 0.67). This first prospective study of this sample size shows significant improvement of physical activity after TAVR with an objective and reproducible method. This was mainly driven by an improvement in patients with HG-AS and paradoxical LFLG-AS.

TAVI for patients with normal-flow low-gradient compared to high-gradient aortic stenosis.

BACKGROUND: Normal-flow (stroke volume index, SVi >35 ml/m2) low-gradient (dPmean <40 mmHg) aortic stenosis (NFLG-AS) is subject of scientific debate. Guidelines fail to give conclusive treatment recommendations. We hypothesized that NFLG patients are heterogenous, containing a subgroup similar to high-gradient aortic stenosis patients (dPmean ≥40 mmHg, HG-AS) concerning characteristics and outcomes. METHODS: 2326 patients undergoing transcatheter aortic valve replacement (TAVI) at our centre between 2013 and 2019 were analysed. 386 patients fulfilled criteria of NFLG-AS. Their median dPmean was 33 mmHg, which was used for grouping (204 patients with higher gradient NFLG-AS, 186 patients with lower gradient NFLG-AS). They were compared to 956 HG-AS patients. RESULTS: Characteristics of lower gradient NFLG-AS patients differed from HG-AS patients in many aspects while higher gradient NFLG-AS and HG-AS patients were mostly similar, underscored by higher Society of Thoracic Surgeons scores in lower gradient NFLG-AS (lower gradient NFLG-AS, 3.9, HG-AS, 3.0, p = 0.03, higher gradient NFLG-AS, 3.0, p = 0.04). Procedural complications were comparable. Estimated 3-year all-cause mortality was higher in lower gradient NFLG-AS compared to HG-AS patients (hazard ratio 1.7, p < 0.01), whereas mortality of higher gradient NFLG-AS was similar to HG-AS patients (hazard ratio 1.2, p = 0.31). Cardiovascular mortality was highest among lower gradient NFLG-AS patients (21.6% vs. higher gradient NFLG-AS, 15.4%, vs. HG-AS, 11.1%, p < 0.01). CONCLUSIONS: NFLG-AS patients are indeed heterogenous. NFLG-AS patients with higher gradients resemble HG-AS patients in clinical characteristics and outcomes and should not be treated differently. Lower gradient NFLG-AS patients have increased long-term mortality and the use of TAVI requires careful consideration.

Dual ProGlide versus ProGlide and FemoSeal for vascular access haemostasis after transcatheter aortic valve implantation.

BACKGROUND: Large-bore arteriotomy for transcatheter aortic valve implantation (TAVI) requires percutaneous vascular closure devices, but real-world data comparing different closure strategies are limited. AIMS: We sought to compare a dual ProGlide strategy vs a combination of one ProGlide and one FemoSeal for vascular closure after TAVI. METHODS: We retrospectively analysed 874 propensity score-matched patients undergoing TAVI at the Munich University Hospital from August 2018 to October 2020. From August 2018 to August 2019, a dual ProGlide strategy was used for vascular closure. From October 2019 to October 2020, a combination of one ProGlide and one FemoSeal was used. The primary endpoint was defined as access-related major vascular complications or bleeding ≥Type 2 according to Valve Academic Research Consortium 3 criteria. RESULTS: Patients in the dual ProGlide group (n=437) had a higher incidence of the primary endpoint than patients treated with one ProGlide and one FemoSeal (n=437; 11.4% vs 3.0%; p<0.001). Furthermore, they had a higher rate of closure device failure (2.7% vs 0.9%; p=0.044) and more often required unplanned surgery or endovascular treatment (3.9% vs 0.9%; p=0.004). The incidence of death did not differ significantly between groups (3.4% vs 1.6%; p=0.08). CONCLUSIONS: A combined ProGlide and FemoSeal strategy might have the potential to reduce access-related vascular complications following TAVI.

TAVI in patients with low-flow low-gradient aortic stenosis-short-term and long-term outcomes.

OBJECTIVES: The study objective was to characterize different groups of low-flow low-gradient (LFLG) aortic stenosis (AS) and determine short-term outcomes and long-term mortality according to Valve Academic Research Consortium-3 (VARC-3) endpoint definitions. BACKGROUND: Characteristics and outcomes of patients with LFLG AS undergoing transcatheter aortic valve implantation (TAVI) are poorly understood. METHODS: All patients undergoing TAVI at our center between 2013 and 2019 were screened. Patients were divided into three groups according to mean pressure gradient (dPmean), ejection fraction (LVEF), and stroke volume index (SVi): high gradient (HG) AS (dPmean ≥ 40 mmHg), classical LFLG (cLFLG) AS (dPmean < 40 mmHg, LVEF < 50%), and paradoxical LFLG (pLFLG) AS (dPmean < 40 mmHg, LVEF ≥ 50%, SVi ≤ 35 ml/m2). RESULTS: We included 1776 patients (956 HG, 447 cLFLG, and 373 pLFLG patients). Most baseline characteristics differed significantly. Median Society of Thoracic Surgeons (STS) score was highest in cLFLG, followed by pLFLG and HG patients (5.0, 3.9 and 3.0, respectively, p < 0.01). Compared to HG patients, odds ratios for the short-term VARC-3 composite endpoints, technical failure (cLFLG, 0.76 [95% confidence interval, 0.40-1.36], pLFLG, 1.37 [0.79-2.31]) and device failure (cLFLG, 1.06 [0.74-1.49], pLFLG, 0.97 [0.66-1.41]) were similar, without relevant differences within LFLG patients. NYHA classes improved equally in all groups. Compared to HG, LFLG patients had a higher 3-year all-cause mortality (STS score-adjusted hazard ratios, cLFLG 2.16 [1.77-2.64], pLFLG 1.53 [1.22-193]), as well as cardiovascular mortality (cLFLG, 2.88 [2.15-3.84], pLFLG, 2.08 [1.50-2.87]). CONCLUSIONS: While 3-year mortality remains high after TAVI in LFLG compared to HG patients, symptoms improve in all subsets after TAVI.

Age-dependent impact of the SYNTAX-score on longer-term mortality after percutaneous coronary intervention in an all-comer population.

BACKGROUND: The Synergy between Percutaneous Coronary Intervention with TAXUS and Cardiac Surgery (SYNTAX)-score is a validated tool for risk stratification and revascularization strategy selection in patients with complex coronary artery disease. The aim of this study was to analyse its age-related prognostic value. METHODS: SYNTAX-score was calculated in 1331 all-comer patients undergoing percutaneous coronary intervention (PCI): 463 patients ≥ 75 years and 868 patients < 75 years. Outcomes of interest were all-cause mortality at one and two years. RESULTS: A significant interaction of age and SYNTAX-score for mortality was observed at two-year (P interaction = 0.019) but not at one-year follow-up (P interaction = 0.594). In multivariable analysis, SYNTAX-score independently predicted 1-year mortality in both age groups (< 75 years, hazard ratio (HR): 1.43, 95% confidence intervals (CI): 1.03-2.00, P = 0.034; and ≥ 75 years, HR: 1.37, 95% CI: 1.01-1.85, P = 0.042), but only two-year mortality among younger patients (< 75 years, HR: 1.33, 95% CI: 1.01-1.76, P = 0.041; and ≥ 75 years, HR: 1.11, 95% CI: 0.87-1.41, P = 0.394). SYNTAX-score tertiles were useful to stratify 1-year mortality in both, patients < 75 years (SYNTAX-score < 9, 3.8%; 9-20, 5.3%; ≥ 20, 10.3%; P = 0.004) and ≥ 75 years (SYNTAX-score < 11, 5.7%; 11-22.5, 16.1%; ≥ 22.5, 18.7%; P = 0.003), but two-year mortality only among patients < 75 years (SYNTAX-score < 9, 6.5%; 9-20, 7.6%; ≥ 20, 15%; P < 0.001) and not among ≥ 75 years old patients (SYNTAX-score < 11, 19.4%; 11-22.5, 26.3%; ≥ 22.5, 27.9%; P = 0.138). CONCLUSIONS: Age modifies the impact of the SYNTAX-score on longer-term mortality after PCI. Among patients < 75 years, the SYNTAX-score independently predicts the risk of death at one and two years after PCI, while among patients ≥ 75 years its predictive role is limited to the first year after PCI. Further studies are needed to evaluate the value of SYNTAX-score for selecting the most appropriate revascularization strategy among elderly patients.

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.

FDG-PET reveals improved cardiac regeneration and attenuated adverse remodelling following Sitagliptin + G-CSF therapy after acute myocardial infarction.

AIMS: Dual therapy comprising G-CSF for mobilization of bone marrow-derived progenitor cells (BMPCs), with simultaneous pharmacological inhibition of dipeptidylpeptidase-IV for enhanced myocardial recruitment of circulating BMPC via the SDF-1α/CXCR4-axis, has been shown to improve survival after acute myocardial infarction (AMI). Using an innovative method to provide non-invasive serial in vivo measurements and information on metabolic processes, we aimed to substantiate the possible effects of this therapeutic concept on cardiac remodelling after AMI using 2-deoxy-2-[18F]fluoro-d-glucose positron emission tomography (FDG-PET). METHODS AND RESULTS: AMI was induced in C57BL/6 mice by performing surgical ligation of the left anterior descending artery in these mice. Animals were then treated with granulocyte-colony stimulating factor + Sitagliptin (GS) or placebo for a duration of 5 days following AMI. From serial PET scans, we verified that the infarct size in GS-treated mice (n = 13) was significantly reduced at Day 30 after AMI when compared with the mice receiving placebo (n = 10). Analyses showed a normalized FDG uptake on Day 6 in GS-treated mice, indicating an attenuation of the cardiac inflammatory response to AMI in treated animals. Furthermore, flow cytometry showed a significant increase in the anti-inflammatory M2-macrophages subpopulation in GS-treated animals. In comparing GS treated with placebo animals, those receiving GS-therapy showed a reduction in myocardial hypertrophy and left ventricular dilatation, which indicates the beneficial effect of GS treatment on cardiac remodelling. Remarkably, flow cytometry and immunohistochemistry showed an increase of myocardial c-kit positive cells in treated mice (n = 12 in both groups). CONCLUSION: Using the innovative method of micro-PET for non-invasive serial in vivo measurements of metabolic myocardial processes in mice, we were able to provide mechanistic evidence that GS therapy improves cardiac regeneration and reduces adverse remodelling after AMI.

Sitagliptin plus granulocyte colony-stimulating factor in patients suffering from acute myocardial infarction: A double-blind, randomized placebo-controlled trial of efficacy and safety (SITAGRAMI trial).

OBJECTIVE: In animal models, G-CSF based progenitor cell mobilization combined with a DPP4 inhibitor leads to increased homing of bone marrow derived progenitor cells to the injured myocardium via the SDF1/CXCR4 axis resulting in improved ejection fraction and survival after acute myocardial infarction (AMI). RESEARCH DESIGN AND METHODS: After successful revascularization in AMI, 174 patients were randomized 1:1 in a multi-centre, prospective, placebo-controlled, parallel group, double blind, phase III efficacy and safety trial to treatment with G-CSF and Sitagliptin (GS) or placebo. Diabetic and non-diabetic patients were included in our trial. The primary efficacy endpoint hierarchically combined global left and right ventricular ejection fraction changes from baseline to 6 months of follow-up (ΔLVEF, ΔRVEF), as determined by cardiac MRI. RESULTS: At follow-up ΔLVEF as well as ΔRVEF did not differ between the GS and placebo group. Patients in the placebo group had a similar risk for a major adverse cardiac event within 12 months of follow-up as compared to patients under GS. CONCLUSION: Progenitor cell therapy comprising the use of G-CSF and Sitagliptin after successfully revascularized acute myocardial infarction fails to show a beneficial effect on cardiac function and clinical events after 12 months. (EudraCT: 2007-003,941-34; ClinicalTrials.gov: NCT00650143, funding: Heinz-Nixdorf foundation).

Short-term inhibition of DPP-4 enhances endothelial regeneration after acute arterial injury via enhanced recruitment of circulating progenitor cells.

BACKGROUND: Endothelial injuries regularly occur in atherosclerosis and during interventional therapies of the arterial occlusive disease. Disturbances in the endothelial integrity can lead to insufficient blood supply and bear the risk of thrombus formation and acute vascular occlusion. At present, effective therapeutics to restore endothelial integrity are barely available. We analyzed the effect of pharmacological DPP-4-inhibition by Sitagliptin on endogenous progenitor cell-based endothelial regeneration via the SDF-1α/CXCR4-axis after acute endothelial damage in a mouse model of carotid injury. METHODS AND RESULTS: Induction of a defined endothelial injury was performed in the carotid artery of C57Bl/6 mice which led to a local upregulation of SDF-1α expression. Animals were treated with placebo, Sitagliptin or Sitagliptin+AMD3100. Using mass spectrometry we could prove that Sitagliptin prevented cleavage of the chemokine SDF-1α. Accordingly, increased SDF-1α concentrations enhanced recruitment of systemically applied and endogenous circulating CXCR4+ progenitor cells to the site of vascular injury followed by a significantly accelerated reendothelialization as compared to placebo-treated animals. Improved endothelial recovery, as well as recruitment of circulating CXCR4+ progenitor cells (CD133+, Flk1+), was reversed by CXCR4-antagonization through AMD3100. In addition, short-term Sitagliptin treatment did not significantly promote neointimal or medial hyperplasia. CONCLUSION: Sitagliptin can accelerate endothelial regeneration after acute endothelial injury. DPP-4 inhibitors prevent degradation of the chemokine SDF-1α and thus improve the recruitment of regenerative circulating CXCR4+ progenitor cells which mediate local endothelial cell proliferation without adversely affecting vessel wall architecture.

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.

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.

Endobronchial lipomatous hamartoma: an incidental finding in a patient with atrial fibrillation-a case report.

Introduction. Lung hamartomas are the most common benign tumors of the lung. Typically, they are located in the peripheral lung, while an endobronchial localisation is rare. Case Presentation. We present a case with the rare diagnosis of an endobronchial hamartoma as incidental finding in a 69-year-old male, caucasian patient with atrial fibrillation. At first admission, the patient's exertional dyspnea was caused by atrial fibrillation. Relapse of exertional dyspnea in the absence of arrhythmia was due to postobstructive pneumonia caused by an endobronchial hamartoma. Conclusion. Endobronchial tumors such as endobronchial lipoma or hamartoma should be considered as potential causes of exertional dyspnea and thus as differential diagnosis of atrial fibrillation. Although endobronchial hamartomas are benign, resection is recommended to prevent postobstructive lung damage.

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.

Synergy between CD26/DPP-IV inhibition and G-CSF improves cardiac function after acute myocardial infarction.

Ischemic cardiomyopathy is one of the main causes of death, which may be prevented by stem cell-based therapies. SDF-1alpha is the major chemokine attracting stem cells to the heart. Since SDF-1alpha is cleaved and inactivated by CD26/dipeptidylpeptidase IV (DPP-IV), we established a therapeutic concept--applicable to ischemic disorders in general--by combining genetic and pharmacologic inhibition of DPP-IV with G-CSF-mediated stem cell mobilization after myocardial infarction in mice. This approach leads to (1) decreased myocardial DPP-IV activity, (2) increased myocardial homing of circulating CXCR-4+ stem cells, (3) reduced cardiac remodeling, and (4) improved heart function and survival. Indeed, CD26 depletion promoted posttranslational stabilization of active SDF-1alpha in heart lysates and preserved the cardiac SDF-1-CXCR4 homing axis. Therefore, we propose pharmacological DPP-IV inhibition and G-CSF-based stem cell mobilization as a therapeutic concept for future stem cell trials after myocardial infarction.