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2.  Evaluation of calcium loss after transcatheter aortic valve implantation 
OBJECTIVES
Aortic valve calcification and changes after transcatheter aortic valve implantation (TAVI) were specifically assessed by computed tomography (CT). The main difference between TAVI and the conventional technique is the compression of the cusps of the calcified native valve against the aortic wall before implantation. The objective of this study was to quantify the segmented calcification in the area of the basal annular plane before and after TAVI.
METHODS
The CT scans of 20 patients (13 male and 7 female; mean age: 82.9 ± 8.1 years) were assessed. The aortic valve calcification was segmented; derived from this segmentation volume, mass and Hounsfield units (HU)/density of the calcifications on the annulus and cusps before and after TAVI were evaluated. Pre- and postoperative data were compared regarding potential calcification loss and calcification distances to the left and right coronary ostia.
RESULTS
Significantly lower postprocedural mean volumes and masses for all cusps (P < 0.001) were found. The mean differences in the volume for the non-coronary, right-coronary and left-coronary cusp were −156.8 ± 53.73, −155.5 ± 62.54 and −115 ± 57.53 mm3, respectively, and differences in mass were −88.78 ± 29.48, −95.2 ± 39.27 and −71.56 ± 35.62 mg, respectively. Over all cusps, mean HU increased after intervention [784.41 ± 92.5 HU (pre) and 818.63 ± 78.71 HU (post); P < 0.004]. In 80.03% of all cusps, calcification loss was found; all patients were affected. Significantly lower (P < 0.047) postprocedural mean distances were found from the left and right coronary ostia to the next calcification point.
CONCLUSIONS
Our results show a significant loss of calcification in all patients after TAVI, with a reduction in the calcification distances to the coronary ostia and the compression of calcification in the area of the device landing zone. The clinical implications of this finding need to be investigated further.
doi:10.1093/icvts/ivt432
PMCID: PMC3867042  PMID: 24105864
Aortic root; Aortic valve repair; Aortic valve replacement; Valve calcification
3.  Comparison of NOGA Endocardial Mapping and Cardiac Magnetic Resonance Imaging for Determining Infarct Size and Infarct Transmurality for Intramyocardial Injection Therapy Using Experimental Data 
PLoS ONE  2014;9(11):e113245.
Objectives
We compared the accuracy of NOGA endocardial mapping for delineating transmural and non-transmural infarction to the results of cardiac magnetic resonance imaging (cMRI) with late gadolinium enhancement (LE) for guiding intramyocardial reparative substance delivery using data from experimental myocardial infarction studies.
Methods
Sixty domestic pigs underwent diagnostic NOGA endocardial mapping and cMRI-LE 60 days after induction of closed-chest reperfused myocardial infarction. The infarct size was determined by LE of cMRI and by delineation of the infarct core on the unipolar voltage polar map. The sizes of the transmural and non-transmural infarctions were calculated from the cMRI transmurality map using signal intensity (SI) cut-offs of>75% and>25% and from NOGA bipolar maps using bipolar voltage cut-off values of <0.8 mV and <1.9 mV. Linear regression analysis and Bland-Altman plots were used to determine correlations and systematic differences between the two images. The overlapping ratios of the transmural and non-transmural infarcted areas were calculated.
Results
Infarct size as determined by 2D NOGA unipolar voltage polar mapping correlated with the 3D cMRI-LE findings (r = 0.504, p<0.001) with a mean difference of 2.82% in the left ventricular (LV) surface between the two images. Polar maps of transmural cMRI and bipolar maps of NOGA showed significant association for determining of the extent of transmural infarction (r = 0.727, p<0.001, overlap ratio of 81.6±11.1%) and non-transmural infarction (r = 0.555, p<0.001, overlap ratio of 70.6±18.5%). NOGA overestimated the transmural scar size (6.81% of the LV surface) but slightly underestimated the size of the non-transmural infarction (−3.04% of the LV surface).
Conclusions
By combining unipolar and bipolar voltage maps, NOGA endocardial mapping is useful for accurate delineation of the targeted zone for intramyocardial therapy and is comparable to cMRI-LE. This may be useful in patients with contraindications for cMRI who require targeted intramyocardial regenerative therapy.
doi:10.1371/journal.pone.0113245
PMCID: PMC4237404  PMID: 25409528
4.  The endovascular occlusion system for safe and immediate peripheral vessel occlusion during vascular interventions 
Endovascular occlusion of blood vessels is an important part of interventional therapy concepts. Here, we evaluate the feasibility, procedural safety and efficacy of the novel endovascular occlusion system (EOS) in the arterial system in a porcine model. Thirteen devices were deployed in the iliac and femoral arteries (diameter: 4–5 mm) of five adult swine. Post-deployment angiography was performed at 1, 5 and 10 min and 6 h. All devices (n = 13) could be successfully delivered without any complications, such as dissection, perforation or rupture. The devices could be easily advanced to the target vessel segment, deployed at the intended target location and produced immediate and complete vessel occlusion which was confirmed to be maintained after 6 h. No leaks, recanalization or device migration was observed. In this pilot study, we demonstrate the feasibility, safety and efficacy of immediate vessel occlusion with the EOS device in the peripheral arterial system in a porcine animal model. Our data indicate that this novel device allows precise delivery without the occurrence of cardiovascular complications. Owing to its long-term safety and efficacy the EOS may represent a promising and effective alternative to currently available devices for vessel occlusion during vascular interventions.
doi:10.1093/icvts/ivt318
PMCID: PMC3805205  PMID: 23868605
Vessel occlusion; Endovascular; Occlusion device; Embolization
5.  HEARTSTRING enabled no-touch proximal anastomosis for off-pump coronary artery bypass grafting: current evidence and technique 
Surgical revascularization remains the standard of care for many patients. Off-pump coronary artery bypass grafting (OPCAB) without cardiopulmonary bypass (CPB) has evolved during the past 20 years, and as such can significantly reduce the occurrence of neurological complications. While avoiding the aortic cross-clamping required in conventional on-pump techniques, OPCAB results in a lower incidence of stroke. However, clamp-related risk of stroke remains if partial or side-biting clamps are applied for proximal anastomoses. Others and we have demonstrated that no-touch ‘anaortic’ approaches avoiding any clamping during off-pump procedures via complete in situ grafting result in significantly reduced stroke rates when compared with partial clamping. Therefore, OPCAB in situ grafting has been proposed as the ‘standard of care’ to reduce neurological complications. However, this technique may not be applicable to for every patient as the use of free grafts (arterial or venous) requiring proximal anastomosis is often still necessary to achieve complete revascularization. In these situations, proximal anastomosis can be performed without a partial clamp by using the HEARTSTRING device, and over the last few years, considerable evidence has arisen supporting the impact of HEARTSTRING-enabled anastomosis to significantly minimize atheroembolism and neurological complications when compared with partial- or side-bite clamping. This paper provides a systematic overview and technical information about the combination of OPCAB and clampless strategies using the HEARTSTRING for proximal anastomosis to reduce stroke to levels reported for percutaneous coronary intervention.
doi:10.1093/icvts/ivt237
PMCID: PMC3745146  PMID: 23732260
Coronary artery bypass grafting; Coronary artery disease; Off-pump; Clampless; HEARTSTRING; No-touch; Stroke; Neurological complication
6.  Laser-Supported CD133+ Cell Therapy in Patients with Ischemic Cardiomyopathy: Initial Results from a Prospective Phase I Multicenter Trial 
PLoS ONE  2014;9(7):e101449.
Objectives
This study evaluates the safety, principal feasibility and restoration potential of laser-supported CD133+ intramyocardial cell transplantation in patients with ischemic cardiomyopathy.
Methods
Forty-two patients with severe ischemic cardiomyopathy (left ventricular ejection fraction (LVEF) >15% and <35%) were included in this prospective multicenter phase I trial. They underwent coronary artery bypass grafting (CABG) with subsequent transepicardial low-energy laser treatment and autologous CD133+ cell transplantation, and were followed up for 12 months. To evaluate segmental myocardial contractility as well as perfusion and to identify the areas of scar tissue, cardiac MRI was performed at 6 months and compared to the preoperative baseline. In addition, clinical assessment comprising of CCS scoring, blood and physical examination was performed at 3, 6 and 12 months, respectively.
Results
Intraoperative cell isolation resulted in a mean cell count of 9.7±1.2×106. Laser treatment and subsequent CD133+ cell therapy were successfully and safely carried out in all patients and no procedure-related complications occurred. At 6 months, the LVEF was significantly increased (29.7±1.9% versus 24.6±1.5% with p = 0.004). In addition, freedom from angina was achieved, and quality of life significantly improved after therapy (p<0.0001). Interestingly, an extended area of transmural delayed enhancement (>3 myocardial segments) determined in the preoperative MRI was inversely correlated with a LVEF increase after laser-supported cell therapy (p = 0.024).
Conclusions
This multicenter trial demonstrates that laser-supported CD133+ cell transplantation is safe and feasible in patients with ischemic cardiomyopathy undergoing CABG, and in most cases, it appears to significantly improve the myocardial function. Importantly, our data show that the beneficial effect was significantly related to the extent of transmural delayed enhancement, suggesting that MRI-guided selection of patients is mandatory to ensure the effectiveness of the therapy.
Trial Registration:
EudraCT 2005-004051-35) Controlled-Trials.com ISRCTN49998633
doi:10.1371/journal.pone.0101449
PMCID: PMC4084817  PMID: 25000346
7.  A Three-Dimensional Engineered Artery Model for In Vitro Atherosclerosis Research 
PLoS ONE  2013;8(11):e79821.
The pathogenesis of atherosclerosis involves dysfunctions of vascular endothelial cells and smooth muscle cells as well as blood borne inflammatory cells such as monocyte-derived macrophages. In vitro experiments towards a better understanding of these dysfunctions are typically performed in two-dimensional cell culture systems. However, these models lack both the three-dimensional structure and the physiological pulsatile flow conditions of native arteries. We here describe the development and initial characterization of a tissue engineered artery equivalent, which is composed of human primary endothelial and smooth muscle cells and is exposed to flow in vitro. Histological analyses showed formation of a dense tissue composed of a tight monolayer of endothelial cells supported by a basement membrane and multiple smooth muscle cell layers. Both low (LDL) and high density lipoproteins (HDL) perfused through the artery equivalent were recovered both within endothelial cells and in the sub-endothelial intima. After activation of the endothelium with either tumour necrosis factor alpha (TNFα) or LDL, monocytes circulated through the model were found to adhere to the activated endothelium and to transmigrate into the intima. In conclusion, the described tissue engineered human artery equivalent model represents a significant step towards a relevant in vitro platform for the systematic assessment of pathogenic processes in atherosclerosis independently of any systemic factors.
doi:10.1371/journal.pone.0079821
PMCID: PMC3828234  PMID: 24244566
8.  Epicardial left atrial appendage clip occlusion also provides the electrical isolation of the left atrial appendage 
OBJECTIVES
The exclusion of the left atrial appendage (LAA) has been used to reduce the risk of stroke associated with atrial fibrillation (AF). While LAA exclusion has been associated with a reduced risk of stroke, the effect on the electrical activity of the LAA (a potential source of AF) remains unknown. As such, we sought to demonstrate whether surgical epicardial clip occlusion leads to the electrical isolation of the LAA.
METHODS
From December 2010 until August 2011, 10 patients with paroxysmal AF underwent off-pump coronary artery bypass surgery with bilateral pulmonary vein isolation and an LAA clip occlusion with a new epicardial clip. Before and after the clip was placed, pacing manoeuvres were performed to assess the electrical exit and entry blocks from the LAA.
RESULTS
All clips were applied successfully. The mean procedure time for the clip application was 4 ± 1 min. No complications occurred related to clip application. Prior to the pericardial closure, 18 ± 3 min after the clip placement, the LAA stimulation and pacing manoeuvres demonstrated complete electrical isolation of the LAA in all cases.
CONCLUSIONS
Epicardial LAA clip occlusion leads to the acute electrical isolation of the LAA and may not only provide stroke prevention but also reduce the recurrence of AF.
doi:10.1093/icvts/ivs136
PMCID: PMC3422917  PMID: 22647971
Atrial fibrillation; Left atrial appendage; Clip; Electrical isolation; Stroke; Occlusion; Maze; Ablation; Surgery
9.  Intramyocardial Transplantation and Tracking of Human Mesenchymal Stem Cells in a Novel Intra-Uterine Pre-Immune Fetal Sheep Myocardial Infarction Model: A Proof of Concept Study 
PLoS ONE  2013;8(3):e57759.
Although stem-cell therapies have been suggested for cardiac-regeneration after myocardial-infarction (MI), key-questions regarding the in-vivo cell-fate remain unknown. While most available animal-models require immunosuppressive-therapy when applying human cells, the fetal-sheep being pre-immune until day 75 of gestation has been proposed for the in-vivo tracking of human cells after intra-peritoneal transplantation. We introduce a novel intra-uterine myocardial-infarction model to track human mesenchymal stem cells after direct intra-myocardial transplantation into the pre-immune fetal-sheep. Thirteen fetal-sheep (gestation age: 70–75 days) were included. Ten animals either received an intra-uterine induction of MI only (n = 4) or MI+intra-myocardial injection (IMI;n = 6) using micron-sized, iron-oxide (MPIO) labeled human mesenchymal stem cells either derived from the adipose-tissue (ATMSCs;n = 3) or the bone-marrow (BMMSCs;n = 3). Three animals received an intra-peritoneal injection (IPI;n = 3; ATMSCs;n = 2/BMMSCs;n = 1). All procedures were performed successfully and follow-up was 7–9 days. To assess human cell-fate, multimodal cell-tracking was performed via MRI and/or Micro-CT, Flow-Cytometry, PCR and immunohistochemistry. After IMI, MRI displayed an estimated amount of 1×105–5×105 human cells within ventricular-wall corresponding to the injection-sites which was further confirmed on Micro-CT. PCR and IHC verified intra-myocardial presence via detection of human-specific β-2-microglobulin, MHC-1, ALU-Sequence and anti-FITC targeting the fluorochrome-labeled part of the MPIOs. The cells appeared viable, integrated and were found in clusters or in the interstitial-spaces. Flow-Cytometry confirmed intra-myocardial presence, and showed further distribution within the spleen, lungs, kidneys and brain. Following IPI, MRI indicated the cells within the intra-peritoneal-cavity involving the liver and kidneys. Flow-Cytometry detected the cells within spleen, lungs, kidneys, thymus, bone-marrow and intra-peritoneal lavage, but not within the heart. For the first time we demonstrate the feasibility of intra-uterine, intra-myocardial stem-cell transplantation into the pre-immune fetal-sheep after MI. Utilizing cell-tracking strategies comprising advanced imaging-technologies and in-vitro tracking-tools, this novel model may serve as a unique platform to assess human cell-fate after intra-myocardial transplantation without the necessity of immunosuppressive-therapy.
doi:10.1371/journal.pone.0057759
PMCID: PMC3606388  PMID: 23533575
10.  Tissue-engineered vascular graft remodeling in a growing lamb model: expression of matrix metalloproteinases 
OBJECTIVES
We have previously demonstrated the functionality and growth of autologous, living, tissue-engineered vascular grafts (TEVGs) in long-term animal studies. These grafts showed substantial in vivo tissue remodeling and approximation to native arterial wall characteristics. Based on this, in vitro and in vivo matrix metalloproteinase (MMP) activity of TEVGs is investigated as a key marker of matrix remodeling.
METHODS
TEVGs fabricated from biodegradable scaffolds (polyglycolic-acid/poly-4-hydroxybutyrate, PGA/P4HB) seeded with autologous vascular cells were cultured in static and dynamic in vitro conditions. Thereafter, TEVGs were implanted as pulmonary artery replacements in lambs and followed up for 2 years. Gelatin gel zymography to detect MMP-2 and -9 was performed and collagen content quantified (n = 5). Latent (pro) and active MMP-2 and -9 were detected.
RESULTS
Comparable levels of active MMP-9 and pro-MMP-2 were detected in static and dynamic culture. Higher levels of active MMP-2 were detected in dynamic cultures. Expression of MMP-2 and -9 was minimal in native grafts but was increased in implanted TEVG. Pro-MMP-9 was expressed 20 weeks post implantation and persisted up to 80 weeks post implantation. Collagen content in vitro was increased in dynamically conditioned TEVG as compared with static constructs and was increased in vivo compared with the corresponding native pulmonary artery.
CONCLUSIONS
MMPs are up-regulated in vitro by dynamic culture conditions and could contribute to increased matrix remodeling, native analogous tissue formation and functional growth of TEVGs in vivo. Monitoring of MMP activity, for example, by molecular imaging techniques, may enable the non-invasive assessment of functional tissue quality in future clinical tissue-engineering applications.
doi:10.1016/j.ejcts.2011.02.077
PMCID: PMC3241092  PMID: 21530291
Matrix metalloproteinases; Tissue engineering; Vascular graft; Autologous; Growth; Cells
11.  Antibody Phage Display Assisted Identification of Junction Plakoglobin as a Potential Biomarker for Atherosclerosis 
PLoS ONE  2012;7(10):e47985.
To date, no plaque-derived blood biomarker is available to allow diagnosis, prognosis or monitoring of atherosclerotic vascular diseases. In this study, specimens of thrombendarterectomy material from carotid and iliac arteries were incubated in protein-free medium to obtain plaque and control secretomes for subsequent subtractive phage display. The selection of nine plaque secretome-specific antibodies and the analysis of their immunopurified antigens by mass spectrometry led to the identification of 22 proteins. One of them, junction plakoglobin (JUP-81) and its smaller isoforms (referred to as JUP-63, JUP-55 and JUP-30 by molecular weight) were confirmed by immunohistochemistry and immunoblotting with independent antibodies to be present in atherosclerotic plaques and their secretomes, coronary thrombi of patients with acute coronary syndrome (ACS) and macrophages differentiated from peripheral blood monocytes as well as macrophage-like cells differentiated from THP1 cells. Plasma of patients with stable coronary artery disease (CAD) (n = 15) and ACS (n = 11) contained JUP-81 at more than 2- and 14-fold higher median concentrations, respectively, than plasma of CAD-free individuals (n = 13). In conclusion, this proof of principle study identified and verified JUP isoforms as potential plasma biomarkers for atherosclerosis. Clinical validation studies are needed to determine its diagnostic efficacy and clinical utility as a biomarker for diagnosis, prognosis or monitoring of atherosclerotic vascular diseases.
doi:10.1371/journal.pone.0047985
PMCID: PMC3480477  PMID: 23110151
12.  Fibroblast activation protein is induced by inflammation and degrades type I collagen in thin-cap fibroatheromata 
European Heart Journal  2011;32(21):2713-2722.
Aims
Collagen degradation in atherosclerotic plaques with thin fibrous caps renders them more prone to rupture. Fibroblast activation protein (FAP) plays a role in arthritis and tumour formation through its collagenase activity. However, the significance of FAP in thin-cap human fibroatheromata remains unknown.
Methods and results
We detected enhanced FAP expression in type IV–V human aortic atheromata (n = 12), compared with type II–III lesions (n = 9; P < 0.01) and healthy aortae (n = 8; P < 0.01) by immunostaining and western blot analyses. Fibroblast activation protein was also increased in thin-cap (<65 µm) vs. thick-cap (≥65 µm) human coronary fibroatheromata (n = 12; P < 0.01). Fibroblast activation protein was expressed by human aortic smooth muscle cells (HASMC) as shown by colocalization on immunofluorescent aortic plaque stainings (n = 10; P < 0.01) and by flow cytometry in cell culture. Although macrophages did not express FAP, macrophage burden in human aortic plaques correlated with FAP expression (n = 12; R2= 0.763; P < 0.05). Enzyme-linked immunosorbent assays showed a time- and dose-dependent up-regulation of FAP in response to human tumour necrosis factor α (TNFα) in HASMC (n = 6; P < 0.01). Moreover, supernatants from peripheral blood-derived macrophages induced FAP expression in cultured HASMC (n = 6; P < 0.01), an effect abolished by blocking TNFα (n = 6; P < 0.01). Fibroblast activation protein associated with collagen-poor regions in human coronary fibrous caps and digested type I collagen and gelatin in vitro (n = 6; P < 0.01). Zymography revealed that FAP-mediated collagenase activity was neutralized by an antibody directed against the FAP catalytic domain both in HASMC (n = 6; P < 0.01) and in fibrous caps of atherosclerotic plaques (n = 10; P < 0.01).
Conclusion
Fibroblast activation protein expression in HASMC is induced by macrophage-derived TNFα. Fibroblast activation protein associates with thin-cap human coronary fibroatheromata and contributes to type I collagen breakdown in fibrous caps.
doi:10.1093/eurheartj/ehq519
PMCID: PMC3205479  PMID: 21292680
Atherosclerosis; Antibodies; Collagen; Inflammation; Smooth muscle cells
13.  EH-myomesin splice isoform is a novel marker for dilated cardiomyopathy 
Basic Research in Cardiology  2010;106(2):233-247.
The M-band is the prominent cytoskeletal structure that cross-links the myosin and titin filaments in the middle of the sarcomere. To investigate M-band alterations in heart disease, we analyzed the expression of its main components, proteins of the myomesin family, in mouse and human cardiomyopathy. Cardiac function was assessed by echocardiography and compared to the expression pattern of myomesins evaluated with RT-PCR, Western blot, and immunofluorescent analysis. Disease progression in transgenic mouse models for dilated cardiomyopathy (DCM) was accompanied by specific M-band alterations. The dominant splice isoform in the embryonic heart, EH-myomesin, was strongly up-regulated in the failing heart and correlated with a decrease in cardiac function (R = −0.86). In addition, we have analyzed the expressions of myomesins in human myocardial biopsies (N = 40) obtained from DCM patients, DCM patients supported by a left ventricular assist device (LVAD), hypertrophic cardiomyopathy (HCM) patients and controls. Quantitative RT-PCR revealed that the EH-myomesin isoform was up-regulated 41-fold (P < 0.001) in the DCM patients compared to control patients. In DCM hearts supported by a LVAD and HCM hearts, the EH-myomesin expression was comparable to controls. Immunofluorescent analyses indicate that EH-myomesin was enhanced in a cell-specific manner, leading to a higher heterogeneity of the myocytes’ cytoskeleton through the myocardial wall. We suggest that the up-regulation of EH-myomesin denotes an adaptive remodeling of the sarcomere cytoskeleton in the dilated heart and might serve as a marker for DCM in mouse and human myocardium.
Electronic supplementary material
The online version of this article (doi:10.1007/s00395-010-0131-2) contains supplementary material, which is available to authorized users.
doi:10.1007/s00395-010-0131-2
PMCID: PMC3032906  PMID: 21069531
Dilated cardiomyopathy; Heart failure; Sarcomere cytoskeleton; M-band; Myomesin

Results 1-13 (13)