Stents versus bypass surgery: 3-year mortality risk of patients with coronary interventions aged 50+ in Germany.

OBJECTIVES: Due to demographic aging, the prevalence of coronary artery disease (CAD) is expected to increase in the future, resulting in a growing demand for stent and bypass interventions. This study aims to investigate the mortality risk of patients following conventional coronary artery bypass grafting (CABG) or endovascular procedure by the implantation of bare-metal stents (BMS) or drug-eluting stents (DES). METHODS: Based on a random sample of 250,000 members of Germany's largest health insurance 'Allgemeine Ortskrankenkassen' (AOK) from 2004 to 2015, incident CAD patients were analyzed by Cox Proportional-Hazard models. Risk adjustment was made for sex, age, other cardiac diseases, non-cardiovascular comorbidities and years since intervention. Due to later admission of DES and thus a shorter observation time, mortality was examined for 3 years since the intervention. RESULTS: BMS represented the most frequent procedure (48%). We found similar proportions of CABG (19%) and DES interventions (23%). After risk adjustment, the models showed a 21% (p = 0.004) lower mortality risk of patients with DES and also a 21% (p = 0.002) lower mortality risk of CABG patients compared to persons with BMS. CONCLUSION: Based on a large-scale dataset, our study demonstrated survival advantages of CABG and DES interventions over BMS, with no differences between the DES and CABG groups. The results help to assess the risks of coronary interventions. Aspects of quality of life, severity of postoperative physical limitations, duration of rehabilitation, patients' preferences, and aspects of cost-effectiveness for hospitals and society should be further considered.

Gender-Dependent Clinical Outcome and Other Predictors of In-Hospital Mortality Following Out-Of-Center Extracorporeal Membrane Oxygenation and Extracorporeal Life Support: A Single Center Experience.

BACKGROUND: Out-of-center extracorporeal membrane oxygenation (ECMO) and extracorporeal life support (ECLS) implantation for the treatment of acute cardiorespiratory failure with subsequent transport to a tertiary care center has been introduced successfully into the medical practice. However, due to the very specific and resource intensive nature of this therapeutic concept, it seems important to generate algorithms for adequate patient selection. The aim of our study was to analyze the impact of patients' gender on early clinical outcome in this specific therapeutic scenario. METHODS: Ninety-seven consecutive patients treated by out-of-center ECMO/ECLS implantation and subsequent transport and treatment in our tertiary care cardiovascular center within the Hallesche Extracorporeal Life Support Program (HELP) retrospectively were analyzed, regarding the impact of patients' gender on early clinical outcome. RESULTS: Mechanical circulatory support successfully was weaned in two-thirds of the male patients. This result was achieved in only one-third of the female patients (59.4% in male vs. 33.3% in female, P = .0267). Overall survival significantly was higher in the male group (62.5% in male versus 30.3% in female, P = .0052). In uni- and multivariate logistic regression analysis, female gender was an independent predictor of in-hospital mortality (uni: OR:3.833, CI:1.597-9.745, P = .0034; multi: OR:3.477, CI:1.146-11.494, P = .0322). Worse outcome also was associated with following independent predictors, age, SOFA score, lactate and ventilation time pre-ECMO/ECLS implantation. CONCLUSION: The current study demonstrates a worse early survival for women, following emergent out-of- center ECMO/ECLS implantation and subsequent transport and treatment in our tertiary care cardiovascular center. Gender should be included in patient selection algorithms while basic research approaches are needed to better understand the mechanisms underlying these gender- specific outcome disparities.

Stem cell registry programme for patients with ischemic cardiomyopathy undergoing coronary artery bypass grafting: what benefits does it derive?

AIMS: Standardization of stem cell therapy requires application of appropriate methods to evaluate safety and efficacy, including long-term pharmacovigilance. To accomplish this objective, a long-term registry programme was installed. METHODS AND RESULTS: We analysed 150 patients with ischemic cardiomyopathy, who received intramyocardial CD133+ bone marrow mononuclear stem cell treatment combined with coronary artery bypass grafting (CABG) or CABG alone. The mortality rate, major adverse cerebral and cardiac events, and functional outcome parameters were evaluated for the time period up to 14 years follow-up. As a result, we have stratified the patient population (96 patients) into responders and non-responders. Furthermore, the analysis of relevant predictors of good response to CD133+ bone marrow mononuclear stem cell treatment was performed. Several positive tendencies related to stem cells transplantation were demonstrated. First, no significant difference in major adverse cardiovascular and cerebral events was observed between stem cell and control group up to 14 years follow-up. Second, an improvement of left ventricle ejection fraction (LVEF) in stem cell group retained for 5 years in contrast with CABG-only group, where no significant changes in LVEF after 2 years were observed. In addition, LVEF under 30% and left ventricle end diastolic diameter above 60 mm were independent predictors of functional response to CD133+ cell therapy. CONCLUSIONS: Participants with overt heart failure benefit most from CABG combined with intramyocardial injection of CD133+ bone marrow mononuclear cell within the group. An improvement LVEF in stem cell group remained for 5 years in contrast with the CABG-only group. The patients, in whom the improvement of both LVEF and LVED was observed, have benefited by increased life expectancy.

Therapeutic progenitor cell application for tissue regeneration: Analyzing the impact of toll-like receptor signaling on c-kit+ cell migration following ischemia-reperfusion injury in vivo.

OBJECTIVES: Toll-like-receptor (TLR) mediated immune response has been shown to regulate myocardial damage following cardiac ischemia-reperfusion (IR). It has not been described conclusively so far whether migration of therapeutically applied progenitor cells following an IR event depends on TLR-signaling. METHODS: In vivo migratory capacity murine c-kit+ cells following IR injury was quantified by intravital fluorescence microscopy, utilizing the mouse cremaster muscle model and analyzing early (rolling) and late (adhesion) c-kit+ cell interaction with the local endothelium. The role of TLR-2 and TLR-4, as well as MyD88 and TRIF was analyzed by applying specific knock-out models. RESULTS: A sequence of 15min ischemia followed by 15min of reperfusion induced firm endothelial c-kit+ cell adhesion (5.6±1.3cells/mm2 in Control vs. 30.2±10.1cells/mm2 in IR, p<0.05). Knock-out of TLR-2 and TLR-4 diminished both IR induced early c-kit+ cell-endothelial cell interactions (67.6±2.3% c-kit+ cell rolling in IR vs. 46.3±4.8% c-kit+ cell rolling in IR-TLR-2-ko vs. 45.3±4.8% c-kit+ cell rolling in IR-TLR-4-ko, p<0.05) as well as firm endothelial c-kit+ cell adhesion (30.2±10.1cells/mm2 in IR vs. 16.3±3.9cells/mm2 in IR-TLR-2-ko vs. 14.5±4.4cells/mm2 in IR-TLR-4-ko, p<0.05). Adaptor protein knock-out resulted in a significantly decreased firm endothelial c-kit+ cell adhesion only in MyD88 knock-out but not in TRIF knock-out (9.2±2.2cells/mm2 in IR-MyD88-ko vs. 30.1±9.9cells/mm2 in IR-WT, p<0.05). CONCLUSION: Artificially applied c-kit+ cells interact with the target organ endothelium following IR injury. This interaction seems to depend on TLR-MyD88 signaling. Therapeutic blockade of TLR signaling for anti-inflammatory purposes might interfere with regenerative cell-based therapy protocols.

Mobilization of Bone Marrow-Derived Endothelial Progenitor Cells following Finnish Sauna: A Pilot Study.

BACKGROUND: Sauna bathing is claimed to provide benefits for patients suffering from cardiovascular diseases. The current study aims at analyzing the induction of potential regenerative processes by quantifying the mobilization of bone marrow-derived stem cells into the peripheral blood of healthy adults following Finnish sauna. MATERIALS AND METHODS: Twenty healthy unbiased male volunteers (20-30 years old) were exposed to a Finnish sauna bath (3 × 10 min, 90°C). Venous blood samples were drawn before (baseline), immediately, and 6 h as well as 24 h after the sauna bath. Blood analysis included isolation of mononuclear cells, cell staining with mononuclear antibodies, and fluorescence-activated cell sorting (FACS). For baseline and 24 h post-sauna samples colony-forming unit-Hill assays were applied to quantify endothelial progenitor cells (EPC). RESULTS: Flow cytometry revealed an upregulation of circulating CD45+/CD309+ progenitor cells immediately after the sauna bath, however without reaching statistical significance. Circulating cell numbers of the CD45+CD34+, CD45+CD34+CD133+, and CD45+CD34+CD117+ populations did not show clear enhancements following sauna. EPC colony formation tended to be enhanced after sauna as compared to baseline values. CONCLUSION: Peripheral EPC numbers exhibited a moderate increase following Finnish sauna in a cohort of healthy young men. Furthermore, sauna bathing tended to increase EPC colony-forming capacity. These rather weak responses to thermotherapy might indicate a ceiling effect. In individuals exhibiting cardiovascular risk factors the effects may be more pronounced.

Impact of closed minimal extracorporeal circulation on microvascular tissue perfusion during surgical aortic valve replacement: intravital imaging in a prospective randomized study.

OBJECTIVES: Closed minimal extracorporeal circulation (MECC) systems currently do not represent the standard of surgical care for open-heart surgery. Yet, considering the beneficial results reported for coronary artery bypass graft (CABG) surgery, we used an MECC system in aortic valve replacement (AVR) and analysed the effects on intraoperative microvascular perfusion in comparison with conventional open extracorporeal circulation (CECC). METHODS: In the current study, we analysed alterations in microvascular perfusion at 4 predefined time points (T1-T4) during surgical AVR utilizing orthogonal polarization spectral (OPS) imaging. Twenty patients were randomized for being operated on utilizing either MECC or CECC. Changes in functional capillary density (FCD, cm/cm(2)), mircovascular blood flow velocity (mm/s) and vessel diameter (µm) were analysed by a blinded investigator. RESULTS: After the start of extracorporeal circulation and aortic cross-clamping (T2), both groups showed a significant drop in FCD, but with a significantly higher FCD in the MECC group (153.1 ± 15.0 cm/cm² in the CECC group vs 160.8 ± 12.2 cm/cm² in the MECC group, P = 0.034). During the late phase of the cardiopulmonary bypass (CPB) (T3), the FCD was still significantly depressed in both treatment groups (153.5 ± 14.6 cm/cm² in the CECC group, P <0.05 vs 'T1'; 159.5 ± 12.4 cm/cm² in the MECC group, P <0.05 versus 'T1'). After termination of CPB (T4), the FCD recovered in both groups to baseline values. Microvascular blood flow velocity tended to remain at a higher level in the MECC group, whereas haemodilution during CPB was significantly reduced in the MECC group. CONCLUSIONS: The use of MECC in AVR did not affect procedural safety and, resulted in beneficial preservation of microvascular blood flow velocity and significantly reduced haemodilution during CPB. In contrast to CABG surgery, the use of MECC did not improve FCD during surgical AVR. Clinical advantages possibly resulting from attenuated haemodilution and preservation of microvascular blood flow velocity require further validation in larger patient cohorts.

Intravital microscopy of the microcirculation in the mouse cremaster muscle for the analysis of peripheral stem cell migration.

In the era of intravascular cell application protocols in the context of regenerative cell therapy, the underlying mechanisms of stem cell migration to nonmarrow tissue have not been completely clarified. We describe here the technique of intravital microscopy applied to the mouse cremaster microcirculation for analysis of peripheral bone marrow stem cell migration in vivo. Intravital microscopy of the M. cremaster has been previously introduced in the field of inflammatory research for direct observation of leucocyte interaction with the vascular endothelium. Since sufficient peripheral stem and progenitor cell migration includes similar initial steps of rolling along and firm adhesion at the endothelial lining it is conceivable to apply the M. cremaster model for the observation and quantification of the interaction of intravasculary administered stem cells with the endothelium. As various chemical components can be selectively applied to the target tissue by simple superfusion techniques, it is possible to establish essential microenvironmental preconditions, for initial stem cell recruitment to take place in a living organism outside the bone marrow.

Surgical double valve replacement after transcatheter aortic valve implantation and interventional mitral valve repair.

Transcatheter aortic valve implantation, as well as interventional mitral valve repair, offer reasonable therapeutic options for high-risk surgical patients. We report a rare case of early post-interventional aortic valve prosthesis migration to the left ventricular outflow tract, with paravalvular leakage and causing severe mitral valve regurgitation. Initial successful interventional mitral valve repair using a clipped edge-to-edge technique revealed, in a subsequent procedure, the recurrence of mitral valve regurgitation leading to progressive heart failure and necessitating subsequent surgical aortic and mitral valve replacement.

Analyzing migratory properties of human CD133(+) stem cells in vivo after intraoperative sternal bone marrow isolation.

Human bone marrow stem cell populations have been applied for cardiac regeneration purposes within different clinical settings in the recent past. The migratory capacity of applied stem cell populations towards injured tissue, after undergoing specific peri-interventional harvesting and isolation procedures, represents a key factor limiting therapeutic efficacy. We therefore aimed at analyzing the migratory capacity of human cluster of differentiation (CD) 133(+) bone marrow stem cells in vivo after intraoperative harvesting from the sternal bone marrow. Human CD133(+) bone marrow stem cells were isolated from the sternal bone marrow of patients undergoing cardiac surgery at our institution. Migratory capacity towards stromal cell-derived factor-1α (SDF-1α) gradients was tested in vitro and in vivo by intravital fluoresecence microscopy, utilizing the cremaster muscle model in severe combined immunodeficient (SCID) mice and analyzing CD133(+) cell interaction with the local endothelium. Furthermore, the role of a local inflammatory stimulus for CD133(+) cell interaction with the endothelium was studied. In order to describe endothelial response upon chemokine stimulation laser scanning microscopy of histological cremaster muscle samples was performed. SDF-1α alone was capable to induce relevant early CD133(+) cell interaction with the endothelium, indicated by the percentage of rolling CD133(+) cells (45.9±1.8% in "SDF-1" vs. 17.7±2.7% in "control," p<0.001) and the significantly reduced rolling velocity after SDF-1α treatment. Furthermore, SDF-1α induced firm endothelial adhesion of CD133(+) cells in vivo. Firm endothelial adhesion, however, was significantly enhanced by additional inflammatory stimulation with tumor necrosis factor-α (TNF-α) (27.9±4.3 cells/mm(2)in "SDF-1 + TNF" vs. 2.2±1.1 cells/mm(2) in "control," p<0.001). CD133(+) bone marrow stem cells exhibit sufficient in vivo homing towards SDF-1α gradients in an inflammatory microenvironment after undergoing standardized intraoperative harvesting and isolation from the sternal bone marrow.

Stem cell therapy for the treatment of acute myocardial infarction and chronic ischemic heart disease.

Chronic ischemic heart disease remains a major cause of morbidity and mortality worldwide. Although revascularisation strategies and pharmaceutical therapy are able to delay ventricular remodelling, until today no therapeutic strategy is available that might prevent or even reverse this process of remodelling and consequent ventricular failure. In the recent past, experimental and clinical studies have demonstrated the capacity of bone marrow stem cells in cardiac repair and regeneration of compromised heart muscle. Several clinical trials showed the safety and efficacy of autologous bone marrow stem cell transplantation in the patients with acute myocardial infarction or chronic ischemic heart disease. Today the therapeutic strategy of cell administration during cardiac surgery or coronary artery intervention is entering the clinical practice. In the following Review we will highlight biological as well as methodological backgrounds, indications and clinical results of cardiac stem cell therapy for the treatment of acute myocardial infarction and chronic ischemic heart disease.

Asymptomatic blood cyst of the papillary muscle in an adult undergoing coronary bypass surgery.

Blood-filled cysts of larger size attached to the heart valves represent a very rare finding in adults. We report here a case of a blood-filled cyst attached to the papillary muscle, demonstrating the importance of multimodal preoperative diagnostic imaging combining both echocardiography and magnetic resonance imaging.

CD133-Positive Cells for Cardiac Stem Cell Therapy: Current Status and Outlook.

Ischemic heart disease represents one major cause of death in developed countries. Ten years ago, cardiac application of bone marrow-derived progenitor cells was introduced as a new therapeutic strategy with the aim of restoring the function of ischemic myocardium. Among other cell populations, CD133(+) bone marrow stem cells form a major subpopulation of progenitor cells studied in this context. Following promising preclinical evidence, both cardiac surgeons and interventional cardiologists have applied CD133(+) cells in setting of chronic ischemic heart failure as well as acute myocardial infarction within phase I and II clinical trials. This chapter summarizes the rationale for the use of this stem cell subpopulation in the field of regenerative cardiac therapy strategies and gives an overview on the current clinical evidence as well as upcoming phase III trials.

Validating intramyocardial bone marrow stem cell therapy in combination with coronary artery bypass grafting, the PERFECT Phase III randomized multicenter trial: study protocol for a randomized controlled trial.

BACKGROUND: For the last decade continuous efforts have been made to translate regenerative cell therapy protocols in the cardiovascular field from 'bench to bedside'. Successful clinical introduction, supporting safety, and feasibility of this new therapeutic approach, led to the initiation of the German, Phase III, multicenter trial - termed the PERFECT trial (ClinicalTrials.gov Identifier: NCT00950274), in order to evaluate the efficacy of surgical cardiac cell therapy on left ventricular function. METHODS/DESIGN: The PERFECT trial has been designed as a prospective, randomized, double-blind, placebo controlled, multicenter trial, analyzing the effect of intramyocardial CD 133(+) bone marrow stem cell injection in combination with coronary artery bypass grafting on postoperative left ventricular function. The trial includes patients aged between 18 and 79 years presenting with a coronary disease with indication for surgical revascularization and reduced global left ventricular ejection fraction as assessed by cardiac magnet resonance imaging. The included patients are treated in the chronic phase of ischemic cardiomyopathy after previous myocardial infarction. DISCUSSION: Patients undergoing coronary artery bypass grafting in combination with intramyocardial CD133+ cell injection will have a higher LV ejection fraction than patient who undergo CABG alone, measured 6 months after the operation. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00950274.

Comparing microvascular alterations during minimal extracorporeal circulation and conventional cardiopulmonary bypass in coronary artery bypass graft surgery: a prospective, randomized study.

OBJECTIVES: Minimal extracorporeal circulation (MECC) has been introduced in coronary artery bypass graft (CABG) surgery, offering clinical benefits owing to reduced hemodilution and no blood-air interface. Yet, the effects of MECC on the intraoperative microvascular perfusion in comparison with conventional extracorporeal circulation (CECC) have not been studied so far. METHODS: The current study aimed to analyze alterations in microvascular perfusion at 4 predefined time points (T1-T4) during on-pump CABG using orthogonal polarization spectral imaging. Forty patients were randomized for being operated on with either MECC or CECC. Changes in functional capillary density (FCD), blood flow velocity, and vessel diameter were analyzed by a blinded investigator. RESULTS: After start of extracorporeal circulation (ECC) and aortic crossclamping (T2), both groups showed a significant drop of FCD, with a significantly higher FCD in the MECC group (206.8 ± 33.6 cm/cm² in CECC group versus 217.8 ± 35.3 cm/cm² in MECC group; P = .034). In the late phase of the ECC (T3), FCD in the MECC group was already recovered, whereas FCD in the CECC group was still significantly depressed (223.1 ± 35.6 cm/cm² in MECC group; P = .100 vs T1; 211.1 ± 36.9 cm/cm² in CECC group; P = .017 vs T1). After termination of ECC (T4), FCD recovered in both groups to baseline. Blood flow velocity tended to be higher in the MECC group, with a significant intergroup difference after aortic crossclamping (T2). CONCLUSIONS: Orthogonal polarization spectral imaging data reveal an impairment of microvascular perfusion during on-pump CABG. Changes in FCD indicate a faster recovery of the microvascular perfusion in MECC during the reperfusion period. Beneficial recovery of microvascular organ perfusion could partly explain the perioperative advantages reported for MECC.

Update on cardiac stem cell therapy in heart failure.

PURPOSE OF REVIEW: Presentation of the current status of cardiac stem cell therapy for the treatment of ischaemic heart failure by highlighting recent clinical results and introducing ongoing trials. Furthermore, necessary upcoming procedural adjustments are discussed. RECENT FINDINGS: During the last decade, stem cell application in the setting of ischaemic heart failure has been evaluated in phase I and II clinical trials, proving safety and feasibility of this approach. Functional results gained so far indicate moderate benefits. However, conclusive evaluation of cell therapy will not be possible before completion of ongoing phase III multicentre trials. Moreover, questions regarding the optimal cell population for treatment in a chronic setting and the favourable time-point of cell delivery have not been ultimately answered. SUMMARY: Cell therapy for the treatment of ischaemic heart failure needs to be evaluated separately from the setting of acute myocardial infarction. In parallel with upcoming clinical evaluation in large-scale trials, further optimization of the 'cell product' regarding the favourable cell type and periprocedural processing, as well as route and time-point of application, is mandatory.

HMGB-1 induces c-kit+ cell microvascular rolling and adhesion via both toll-like receptor-2 and toll-like receptor-4 of endothelial cells.

High-mobility group box 1 (HMGB-1) is a strong chemo-attractive signal for both inflammatory and stem cells. The aim of this study is to evaluate the mechanisms regulating HMGB-1-mediated adhesion and rolling of c-kit(+) cells and assess whether toll-like receptor-2 (TLR-2) and toll-like receptor-4 (TLR-4) of endothelial cells or c-kit(+) cells are implicated in the activation of downstream migration signals to peripheral c-kit(+) cells. Effects of HMGB-1 on the c-kit(+) cells/endothelial interaction were evaluated by a cremaster muscle model in wild-type (WT), TLR-2 (-/-) and Tlr4 (LPS-del) mice. The mRNA and protein expression levels of endothelial nitric oxide synthase were determined by quantitative real-time PCR and immunofluorescence staining. Induction of crucial adhesion molecules for rolling and adhesion of stem cells and leukocytes were monitored in vivo and in vitro. Following local HMGB-1 administration, a significant increase in cell rolling was detected (32.4 ± 7.1% in 'WT' versus 9.9 ± 3.2% in 'control', P < 0.05). The number of firmly adherent c-kit(+) cells was more than 13-fold higher than that of the control group (14.6 ± 5.1 cells/mm(2) in 'WT' versus 1.1 ± 1.0 cells/mm(2) in 'control', P < 0.05). In knockout animals, the fraction of rolling cells did not differ significantly from control levels. Firm endothelial adhesion was significantly reduced in TLR-2 (-/-) and Tlr4 (LPS-del) mice compared to WT mice (1.5 ± 1.4 cells/mm(2) in 'TLR-2 (-/-)' and 2.4 ± 1.4 cells/mm(2) in 'Tlr4 (LPS-del)' versus 14.6 ± 5.1 cells/mm(2) in 'WT', P < 0.05). TLR-2 (-/-) and Tlr4 (LPS-del) stem cells in WT mice did not show significant reduction in rolling and adhesion compared to WT cells. HMGB-1 mediates c-kit(+) cell recruitment via endothelial TLR-2 and TLR-4.

Early stenotic prosthesis failure after implantation of a stentless porcine aortic valve prosthesis.

Stentless biological aortic prostheses are used routinely in aortic valve replacement surgery, offering beneficial hemodynamics compared to stented biological valves of similar size. We report here a rare case of early stenotic prosthesis failure of a RootElan stentless porcine aortic valve prosthesis due to swelling at the bottom of the right coronary cusp of the prosthesis.