Guenther Kundt

Endovascular Repair of Type B Aortic Dissection Long-term Results of the Randomized Investigation of Stent Grafts in Aortic Dissection Trial

Background—Thoracic endovascular aortic repair (TEVAR) represents a therapeutic concept for type B aortic dissection. Long-term outcomes and morphology after TEVAR for uncomplicated dissection are unknown. Methods and Results—A total of 140 patients with stable type B aortic dissection previously randomized to optimal medical treatment and TEVAR (n=72) versus optimal medical treatment alone (n=68) were analyzed retrospectively for aorta-specific, all-cause outcomes, and disease progression using landmark statistical analysis of years 2 to 5 after index procedure. Cox regression was used to compare outcomes between groups; all analyses are based on intention to treat. The risk of all-cause mortality (11.1% versus 19.3%; P=0.13), aorta-specific mortality (6.9% versus 19.3%; P=0.04), and progression (27.0% versus 46.1%; P=0.04) after 5 years was lower with TEVAR than with optimal medical treatment alone. Landmark analysis suggested a benefit of TEVAR for all end points between 2 and 5 years; for example, for all-cause mortality (0% versus 16.9%; P=0.0003), aorta-specific mortality (0% versus 16.9%; P=0.0005), and for progression (4.1% versus 28.1%; P=0.004); Landmarking at 1 year and 1 month revealed consistent findings. Both improved survival and less progression of disease at 5 years after elective TEVAR were associated with stent graft induced false lumen thrombosis in 90.6% of cases (P<0.0001). Conclusions—In this study of survivors of type B aortic dissection, TEVAR in addition to optimal medical treatment is associated with improved 5-year aorta-specific survival and delayed disease progression. In stable type B dissection with suitable anatomy, preemptive TEVAR should be considered to improve late outcome. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT01415804.

Intracardiac injection of erythropoietin induces stem cell recruitment and improves cardiac functions in a rat myocardial infarction model

Erythropoietin (EPO) protects the myocardium from ischaemic injury and promotes beneficial remodelling. We assessed the therapeutic efficacy of intracardiac EPO injection and EPO‐mediated stem cell homing in a rat myocardial infarction (MI) model. Following MI, EPO (3000 U/kg) or saline was delivered by intracardiac injection. Compared to myocardial infarction control group (MIC), EPO significantly improved left ventricular function (n= 11–14, P< 0.05) and decreased right ventricular wall stress (n= 8, P< 0.05) assessed by pressure‐volume loops after 6 weeks. MI‐EPO hearts exhibited smaller infarction size (20.1 ± 1.1%versus 27.8 ± 1.2%; n= 6–8, P< 0.001) and greater capillary density (338.5 ± 14.7 versus 259.8 ± 9.2 vessels per mm; n= 6–8, P< 0.001) than MIC hearts. Direct EPO injection reduced post‐MI myocardial apoptosis by approximately 41% (0.27 ± 0.03%versus 0.42 ± 0.03%; n= 6, P= 0.005). The chemoattractant SDF‐1 was up‐regulated significantly assessed by quantitative realtime PCR and immunohistology. c‐Kit+ and CD34+ stem cells were significantly more numerous in MI‐EPO than in MIC at 24 hrs in peripheral blood (n= 7, P< 0.05) and 48 hrs in the infarcted hearts (n= 6, P< 0.001). Further, the mRNAs of Akt, eNOS and EPO receptor were significantly enhanced in MI‐EPO hearts (n= 7, P< 0.05). Intracardiac EPO injection restores myocardial functions following MI, which may attribute to the improved early recruitment of c‐Kit+ and CD34+ stem cells via the enhanced expression of chemoattractant SDF‐1.

Strategies for subacute/chronic type B aortic dissection: the Investigation Of Stent Grafts in Patients with type B Aortic Dissection (INSTEAD) trial 1-year outcome.

OBJECTIVE Endovascular stent grafting represents a novel concept for type B aortic dissection both in the acute and subacute/chronic setting, with an unknown effect on outcomes. METHODS In a prospective trial 140 patients with stable type B dissection were randomly subjected to elective stent-graft placement in addition to optimal medical therapy (n = 72) or to optimal medical therapy (n = 68) with surveillance (arterial pressure according to World Health Organization guidelines ≤ 120/80 mm Hg). The primary end point was 1-year all-cause mortality, whereas aorta-related mortality, progression (with need for conversion or additional endovascular or open surgical intervention), and aortic remodeling were secondary end points. RESULTS There was no difference in all-cause mortality: cumulative survival was 97.0% ± 3.4% with optimal medical therapy versus 91.3% ± 2.1% with thoracic endovascular aortic repair (P = .16). Moreover, aorta-related mortality was not different (P = .42), and the risk for the combined end point of aorta-related death (rupture) and progression (including conversion or additional endovascular or open surgical intervention) was similar (P = .86). Three neurologic adverse events occurred in the thoracic endovascular aortic repair group (1 paraplegia, 1 stroke, and 1 transient paraparesis) versus 1 episode of paraparesis with medical treatment. Finally, aortic remodeling (with true-lumen recovery and thoracic false-lumen thrombosis) occurred in 91.3% with thoracic endovascular aortic repair versus 19.4% with medical treatment (P < .001), which is suggestive of continued remodeling. CONCLUSIONS In survivors of uncomplicated type B aortic dissection, elective stent-graft placement does not improve 1-year survival and adverse events, despite favorable aortic remodeling.

Intramyocardial bone marrow stem cell transplantation during coronary artery bypass surgery: a meta-analysis.

OBJECTIVE Experimental and clinical studies have suggested that intramyocardial bone marrow stem cell transplantation combined with coronary artery bypass grafting might improve left ventricular function in the setting of chronic ischemic heart disease. We therefore conducted a systematic review and meta-analysis of available publications regarding the efficacy and safety of intramyocardial bone marrow stem cell transplantation during coronary artery bypass grafting. METHODS The databases PUBMED, MEDLINE, Cochrane Controlled Trials Register, and ClinicalTrials.gov (all from their inception to May 2009) were searched for randomized controlled trials and cohort studies of intramyocardial bone marrow stem cell transplantation during coronary artery bypass grafting to treat ischemic heart disease. Six studies were included. RESULTS Compared with control groups, the bone marrow stem cell transplantation group showed a significant improvement of left ventricular ejection fraction from baseline to follow-up (5.40%; 95% confidence interval, 1.36-9.44; P = .009). Moreover, the overall change of left ventricular end-diastolic volume from baseline to follow-up favored the bone marrow stem cell therapy group (9.55 mL; 95% confidence interval, -2.82 to 21.92; P = .13). Major adverse cardiovascular events, including ventricular arrhythmia and the composite of other cardiovascular events, were not significantly different between the bone marrow stem cell therapy group and controls (relative risk for ventricular arrhythmia = 0.951; 95% confidence interval, 0.389-2.325; P = .913; relative risk for cardiovascular event = 1.134; 95% confidence interval, 0.28-4.6; P = .86). CONCLUSIONS Clinical evidence suggests that intramyocardial bone marrow stem cell transplantation in combination with coronary artery bypass grafting is associated with improvements of functional parameters in patients with chronic ischemic heart disease. Furthermore, surgical intramyocardial bone marrow stem cell transplantation seems to be safe.

Imaging and Quantification of Subbasal Nerve Plexus in Healthy Volunteers and Diabetic Patients with or without Retinopathy

Background The alterations of subbasal nerve plexus (SBP) innervation and corneal sensation were estimated non-invasively and compared with the values in healthy volunteers. Additionally, this study addressed the relation of SBP changes to the retinal status, glycemic control and diabetes duration. Methodology/Principal Findings Eighteen eyes of diabetic patients with peripheral diabetic neuropathy aged 68.8±8.8 years and twenty eyes of healthy volunteers aged 66.3±13.3 yrs. were investigated with in vivo confocal laser-scanning microscopy (CLSM). An adapted algorithm for image analysis was used to quantify the morphological and topological properties of SBP. These properties were correlated to incidence of diabetic retinopathy (DR) and corneal sensation (Cochet-Bonnet esthesiometer). The developed algorithm allows a fully automated analysis of pre-segmented SBP structures. Altogether, 10 parameters were analysed, and all of them revealed significant differences between diabetic patients and healthy volunteers. The nerve fibre density, total fibre length and nerve branches were found to be significantly lower in patients with diabetes than those of control subjects (nerve fibre density 0.006±0.002 vs. 0.020±0.007 mm/mm2; total fibre length 6223±2419 vs. 19961±6553 µm; nerve branches 25.3±28.6 vs. 141.9±85.7 in healthy volunteers). Also the corneal sensation was significantly lower in diabetic group when compared to controls (43±11 vs. 59±18 mm). There was found no difference in SBP morphology or corneal sensation in the subgroups with (DR) or without (NDR) diabetic retinopathy. Conclusions/Significance SBP parameters were significantly reduced in diabetic patients, compared to control group. Interestingly, the SBP impairment could be shown even in the diabetic patients without DR. Although automatic adapted image analysis simplifies the evaluation of in vivo CLSM data, image acquisition and quantitative analysis should be optimised for the everyday clinical practice.

Demographic, clinical and treatment related predictors for event-free probability following low-dose radiotherapy for painful heel spurs – a retrospective multicenter study of 502 patients

A total of 502 patients treated between 1990 and 2002 with low-dose radiotherapy (RT) for painful heel spurs were analysed for prognostic factors for long-term treatment success. The median follow-up was 26 months, ranging from 1 to 103 months. Events were defined as (1) slightly improved or unchanged pain after therapy, or (2) recurrent pain sensations during the follow-up period. Overall 8-year event-free probability was 60.9%. Event-free probabilities of patients with one/two series (414/88) were 69.7%/32.2% (p <0.001); >58/ ≤58 years (236/266), 81.3%/47.9% (p =0.001); high voltage/orthovoltage (341/161), 67.9%/60.6% (p =0.019); pain anamnesis ≤6 months/ >6 months (308/194), 76.3%/43.9% (p =0.001); single dose 0.5/1.0 Gy (100/401), 86.2%/55.1% (p =0.009); without/with prior treatment (121/381), 83.1%/54.9% (p =0.023); men/women (165/337), 61.2%/61.5% (p =0.059). The multivariate Cox regression analysis with inclusion of the number of treatment series, age, photon energy, pain history, single-dose and prior treatments revealed patients with only one treatment series (p <0.001), an age >58 years (p =0.011) and therapy with high voltage photons (p =0.050) to be significant prognostic factors for pain relief. Overall low-dose RT is a very effective treatment in painful heel spurs.

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

BackgroundFor 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/DesignThe 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.DiscussionPatients 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 registrationClinicalTrials.gov Identifier: NCT00950274

Comparison of several approaches of therapeutic drug monitoring of cyclosporin A based on individual pharmacokinetics

AbstractObjective: The clinical outcome of patients after organ transplantation is correlated with cyclosporin A (CyA) exposure. It is generally accepted that the area under the concentration–time curve (AUC) provides a reliable means for drug exposure. However, in routine therapeutic drug monitoring (TDM) of CyA, trough levels are mostly used. Currently, a number of different new concepts of CyA-TDM, including approaches such as single, double or triple time-point and abbreviated AUC determinations, have been introduced. The purpose of this study was to compare the predictive value of the different strategies of TDM. Methods: Calculations were based on 40 individual concentration–time profiles after oral administration of CyA to patients who had been included into an ongoing prospective clinical trial. Non-compartmental analysis was used to calculate the AUC0–12h. Multiple linear regression was performed to describe the relationship between the different sets of blood concentrations and the respective AUC0–12h as well as to evaluate their predictive value regarding AUC. Predictive performance was assessed by prediction bias and prediction precision, which were estimated as the mean prediction error and root mean squared error, respectively. Results: When comparing the various combinations of time points, it was found that one-point approaches showed the strongest differences with regard to the predictive value; the associated r2 values differed from 0.203 to 0.792. The two and three time-point approaches showed lower differences – r2 0.802–0.972. The four-point and five-point approaches (r2 0.942–0.982) were the strongest predictors for CyA AUC0–12h. Relative bias ranged from −27.7% to 63.8% and changed significantly when multiple-point predictors were used. In those cases, the predictive performance improved. Considering the predictive performance as well as the smallest bias and highest prediction precision, C3, C1 + C3, C1 + C3 + C6 and C1 + C2 + C3 + C6 were the best predictors. Conclusion: The results of this study indicate that in kidney transplant patients a clinically sufficient precise estimation of the CyA AUC is possible using two or three concentration–time points.

Paediatric reference values for the C-terminal fragment of fibroblast-growth factor-23, sclerostin, bone-specific alkaline phosphatase and isoform 5b of tartrate-resistant acid phosphatase

Background Paediatric reference values for novel markers of phosphate homeostasis, bone formation and resorption and their putative relationship to growth are lacking. Methods A total of 424 healthy children, adolescents and young adults (221 males) aged 0.1–21 y, were enrolled in this cross-sectional study. Height, weight and height velocity were assessed. Plasma/serum samples for determination of C-terminal fragment of fibroblast growth factor-23 (cFGF-23), sclerostin, bone alkaline phosphatase (BAP) and tartrate-resistant acid phosphatase 5b (TRAP5b) were available from 222, 264, 352 and 338 individuals, respectively. Calculation of cross-sectional centiles and z-scores was based on median (M), standard coefficient of variation (S) and the Box-Cox power (L) of transformation (LMS method) per age cohort. Correlations between variables as well as with growth were assessed. Results cFGF-23, BAP and TRAP5b were significantly correlated with age (each P < 0.01), with highest values during infancy and adolescence. Serum levels of BAP and TRAP5b were significantly higher in adolescent boys compared with girls (each P < 0.01). In contrast, sclerostin levels were independent of age and gender. BAP and TRAP5b were strongly correlated and both were significantly associated with cFGF-23 and sclerostin as well (each P < 0.01). cFGF-23 was positively correlated with serum phosphate and renal phosphate threshold concentration (each P < 0.01). Height, weight, body mass index and height velocity were weakly correlated with BAP and TRAP5b (each P < 0.05). Conclusions This study provides age- and gender-related centile charts and z-scores for cFGF-23, BAP, TRAP5b and sclerostin and highlights the link between phosphate homeostasis and markers of bone metabolism during growth.

Ceramic Femoral Components in Total Knee Arthroplasty - Two Year Follow-Up Results of an International Prospective Multi-Centre Study

Background: Total knee arthroplasty can be considered as a reliable surgical procedure with a good long-term clinical result. However, implant failure due to particle induced aseptic loosening as well as the aspect of hypersensitivity to metal ions still remains an emerging issue. Methods: The purpose of this prospective international multi-centre study was to evaluate the clinical and radiological outcomes and the reliability of the unconstrained Multigen Plus Total Knee System with a new BIOLOX® delta ceramic femoral component. Cemented total knee arthroplasty was performed on 108 patients (110 knees) at seven hospitals in three countries. Clinical and radiological evaluations were performed preoperatively, and after 3, 12 and 24 months postoperatively using the HSS-, WOMAC-, SF-36-score and standardised X-rays. Results: The mean preoperative HSS-Score amounted to 55.5 ± 11.5 points and improved significantly in all postoperative evaluations (85.7 ± 11.7 points at 24 months). Furthermore, improvements in WOMAC- and SF-36-score were evaluated as significant at all points of evaluation. Radiolucent lines around the femoral ceramic component at 24 months were found in four cases. Progression of radiolucent lines was not seen and no implant loosening was observed. During the 24 month follow-up eight patients underwent subsequent surgery due to reasons unrelated to the implant material. Conclusions: The observed clinical and radiological results are encouraging for a long-term survival of the ceramic femoral component. Therefore, ceramic implants could be a promising solution not only for patients with allergies against metallic implant materials, but also for the osteoarthritic knee joint. Long-term follow-up is necessary to draw conclusions regarding the superiority of the ceramic knee implants concerning in vivo wear and long-term survivorship.