A randomized controlled trial demonstrating sustained benefit of autologous matrix-induced chondrogenesis (AMIC®) over microfracture: 10-year follow-up.

PURPOSE: Autologous matrix-induced chondrogenesis (AMIC®) and microfracture are established treatments for focal chondral defects in the knee, but there are little clinical data concerning these procedures over the long term. This study evaluates the outcomes of AMIC® compared to microfracture over 10-year follow-up. METHODS: Forty-seven patients were randomized and treated either with MFx (n = 13), sutured AMIC® (n = 17) or glued AMIC® (n = 17) in a prospective, randomized, controlled multicentre trial. The Modified Cincinnati Knee Score, a visual analogue scale for pain and MOCART score were used to assess outcomes over 10 years post-operatively. RESULTS: All treatment arms improved in the first 2 years, but a progressive and significant deterioration in scores was observed in the MFx group, while both AMIC® groups remained stable. MOCART scores were comparable between groups. CONCLUSION: The AMIC® procedure results in improved patient outcomes in comparison with microfracture up to 10 years following surgery for the repair of focal chondral defects in the knee. CLINICALTRIALS: gov Identifier: NCT02993510.

Empfehlungen der AG Klinische Geweberegeneration zur Behandlung von Knorpelschäden am Kniegelenk. / Empfehlungen der AG Klinische Geweberegeneration zur Behandlung von Knorpelschäden am Kniegelenk.

The Working Group of the German Orthopedic and Trauma Society (DGOU) on Tissue Regeneration has published recommendations on the indication of different surgical approaches for treatment of full-thickness cartilage defects in the knee joint in 2004, 2013 and 2016. Based upon new scientific knowledge and new developments, this recommendation is an update based upon the best clinical evidence available. In addition to prospective randomised controlled clinical trials, this also includes studies with a lower level of evidence. In the absence of evidence, the decision is based on a consensus process within the members of the working group.The principle of making decision dependent on defect size has not been changed in the new recommendation either. The indication for arthroscopic microfracturing has been reduced up to a defect size of 2 cm2 maximum, while autologous chondrocyte implantation is the method of choice for larger cartilage defects. Additionally, matrix-augmented bone marrow stimulation (mBMS) has been included in the recommendation for defects ranging from 1 to 4.5 cm2. For the treatment of smaller osteochondral defects, in addition to osteochondral transplantation (OCT), mBMS is also recommended. For larger defects, matrix-augmented autologous chondrocyte implantation (mACI/mACT) in combination with augmentation of the subchondral bone is recommended.

Initial experience with transcatheter tricuspid valve repair in patients with cardiac amyloidosis.

AIMS: Wildtype transthyretin amyloid cardiomyopathy is an under-recognized cause of heart failure in elderly patients. Transcatheter tricuspid valve repair is a newly emerging therapeutic option for severe tricuspid regurgitation (TR). We present first insights into safety and possible benefits of this procedure in patients with cardiac amyloidosis. METHODS AND RESULTS: Eight patients with cardiac non-hereditary (wildtype) transthyretin (ATTRwt) amyloidosis and severe to torrential TR, undergoing successful transcatheter tricuspid valve repair, were included in the analysis and compared to a control group of 21 patients without cardiac amyloidosis. All patients presented with an advanced stage of amyloid cardiomyopathy. Primary endpoint was reduction in TR at 3 months follow-up. Secondary endpoints were feasibility, safety, hospitalization or death, clinical improvement, cardiac biomarkers, and structural and functional right heart parameter obtained by echocardiography. Transcatheter tricuspid valve repair resulted in a significant reduction of TR (IV to II, P = 0.008) in all eight patients with cardiac amyloidosis (100%). Device success (amyloidosis 75% vs. control group 86%, P = 0.597) and overall probability of hospitalization or death (amyloidosis 13% vs. control group 25%, P = 0.646) were similar compared with those in the control group at 3 months follow-up. Transcatheter tricuspid valve repair led to an improvement of New York Heart Association functional class (P = 0.031) and 6 min walking distance (from 313 ± 118 to 337 ± 106, P = 0.012). TR reduction in amyloidosis patients was less extensive compared with that in control group (TR-reduction 1.6 ± 0.3, P = 0.008 vs. control group 2.3 ± 0.3, P < 0.0001). Furthermore, these patients showed no significant improvement of structural right heart parameters. CONCLUSIONS: Transcatheter tricuspid valve repair is a safe and feasible new treatment option in patients with amyloid cardiomyopathy and has the potential to improve TR-grade and clinical status. However, the benefit appears to be less pronounced compared with patients without cardiac amyloidosis.

[Drop in oxygen saturation and blood pressure as well as increase in central venous pressure during mitral valve clipping in an 81-year-old female patient]. / Abfall von Sauerstoffsättigung und Blutdruck sowie Anstieg des zentralen Venendrucks im Rahmen eines Mitralklappenclippings bei einer 81-Jährigen.

BACKGROUND: Atrial septal defects (ASD) following endovascular mitral valve clipping are potentially hemodynamically relevant complications. Immediate closure with an occluder can represent a safe and effective treatment. An 81-year-old female patient suffering from severe dyspnea due to previously known severe mitral valve regurgitation was scheduled for elective mitral valve clipping. The clip was successfully implanted. Removal of the transseptal cannula resulted in a sudden drop in oxygen saturation and systolic blood pressure as well as an immediate increase in central venous pressure. An iatrogenic left-right shunt was observed at the atrial level with a relevant shunt volume. Immediate closure using an atrial septal occluder successfully restored the oxygen saturation and hemodynamic parameters. CONCLUSION: An increase in central venous pressure, reduction of systolic blood pressure or oxygen saturation after withdrawal of the transseptal cannula during mitral valve clipping should always be further investigated regarding a possible ASD.

Functional improvement following direct interventional leaflet repair of severe tricuspid regurgitation.

AIMS: Several new percutaneous tricuspid repair systems have recently been introduced as new treatment options for severe tricuspid regurgitation (TR). Clinical improvement following percutaneous tricuspid valve leaflet repair has been demonstrated by recent studies. A possible impact on exercise capacity has not yet been reported. METHODS AND RESULTS: Eleven patients with at least severe TR and successful tricuspid leaflet repair using the PASCAL Ace implant at our cardiology department were included in this analysis. All patients suffered from symptomatic right-sided heart failure with compromised exercise capacity. Cardiopulmonary exercise testing (CPET), clinical, laboratory, and echocardiographic parameters were assessed at baseline and 3 months follow-up. The primary endpoint was the change in maximal oxygen consumption [VO2 max (mL/(min*kg))] at 3 months follow-up. Secondary endpoints included improvement in TR, cardiac biomarkers, and other clinical outcomes. TR severity at 3 months follow-up post-PASCAL Ace implantation was significantly lower than at baseline (P = 0.004). Cardiac biomarkers including high-sensitivity troponin T and N-terminal pro-brain natriuretic peptide as well as right ventricular diameter improved slightly without reaching statistical significance (P = 0.89, P = 0.32, and P = 0.06, respectively). PASCAL Ace implantation resulted in a significant improvement in cardiopulmonary exercise capacity at 3 months follow-up compared with baseline. Mean VO2 max improved from 9.5 ± 2.8 to 11.4 ± 3.4 mL/(min*kg) (P = 0.006), VO2 max per cent predicted from 42 ± 12% to 50 ± 15% (P = 0.004), peak oxygen uptake from 703 ± 175 to 826 ± 198 mL/min (P = 0.004), and O2 pulse per cent predicted from 67 ± 21% to 81 ± 25% (P = 0.011). Other CPET-related outcomes did not show any significant change over time. CONCLUSIONS: In this single-centre retrospective analysis, direct tricuspid valve leaflet repair using the transcatheter PASCAL Ace implant system was associated with a reduced TR severity and improved cardiopulmonary exercise capacity.

Re-do MitraClip in patients with functional mitral valve regurgitation and advanced heart failure.

AIM: Percutaneous mitral valve repair (PMVR) via MitraClip implantation is a therapeutic option for severe mitral regurgitation (MR) in advanced stages of heart failure (HF). However, progressive left ventricular dilation in these patients may lead to recurrent MR after PMVR and consequent re-do MitraClip implantation. Here, we describe the characteristics and outcomes of this clinical scenario. METHODS AND RESULTS: Patients with systolic HF and functional MR undergoing a re-do MitraClip procedure were retrospectively analysed. Inclusion criteria were age ≥18 years, technical, device and procedural success at first MitraClip procedure, functional MR and systolic HF with an ejection fraction (EF) of <45%. Seventeen out of 684 patients undergoing PMVR with the MitraClip device at our institution between September 2009 and July 2019 were included. All patients displayed advanced HF with an EF of 20% (±9.9) and highly elevated N-terminal pro-brain natriuretic peptide. Technical success of the re-do MitraClip procedure was 100%, whereas procedural and device success were only achieved in 11 patients (65%). Unsuccessful re-do procedures were related to lower EF and implantation of more than one clip at initial procedure. However, despite reduction in MR grade and no occurrence of significant mitral stenosis after the procedure, the mortality during 12 months follow-up remained high (8 of 17; 47%). CONCLUSIONS: In a cohort of patients with advanced HF undergoing PMVR, re-do MitraClip procedure was feasible, but procedural success was unsatisfactory and morbidity and mortality remained high, possibly reflecting the advanced stage of HF in these patients.

Initial Experience With the PASCAL Ace Implant System for Treatment of Severe Tricuspid Regurgitation.

[Figure: see text].

Initial experience with percutaneous mitral valve repair in patients with cardiac amyloidosis.

BACKGROUND: Percutaneous mitral valve repair (PMVR) is a therapeutic option for severe mitral regurgitation (MR) in patients with heart failure due to differential aetiologies. However, only little is known about the safety and efficacy of this procedure in patients with amyloid cardiomyopathy. METHODS: Five patients with cardiac amyloidosis and moderate to severe or severe MR undergoing PMVR were analysed retrospectively and compared to seven patients with cardiac amyloidosis and severe MR without intervention. Clinical and functional data, renal function and cardiac biomarkers as well as established risk scores for cardiac amyloidosis were assessed. Primary endpoint was the reduction in MR one year after PMVR. Secondary endpoints were safety, overall mortality after 12 months compared with the control group, as well as changes in clinical and functional parameters. RESULTS: Amyloidosis risk assessment documented amyloid cardiomyopathy at an advanced stage in all patients. Procedural, technical and device success of PMVR were all 100% and residual MR remained mild to moderate at 12 months follow-up (P = .038 vs before PMVR). Differences in survival compared with the control (no PMVR) group pointed to a possible survival benefit in the PMVR group (P = .02). CONCLUSION: PMVR is a feasible and safe procedure in patients with cardiac amyloidosis and might carry a possible survival benefit in this patient group.

Systematic Review and Meta-Analysis of the Clinical Evidence on the Use of Autologous Matrix-Induced Chondrogenesis in the Knee.

OBJECTIVE: A systematic review and meta-analysis of Autologous Matrix-Induced Chondrogenesis (AMIC®) outcomes for grade III/IV chondral and osteochondral lesions of the knee treated with Chondro-Gide®. DESIGN: Studies with a minimum follow-up of 1 year providing clinical results of AMIC repair in the knee were included based on PRISMA guidelines (Preferred Reporting Items for Systematic Reviews and Meta-Analyses). Methodological quality was assessed by the modified Coleman Methodology Score (mCMS). The meta-analysis was comparing pain VAS (Visual Analog Scale), Lysholm score, and IKDC score (International Knee Documentation Committee) between baseline and follow-up after 1 or 2 years and after >3 years. RESULTS: Twelve studies (375 patients) were included. The mCMS demonstrated a suboptimal study design (ranking between 52 and 80). The mean age was 36.2 years (14-70 years). The mean defect size was 4.24 cm2 (0.8-22 cm2). The results from the random effects model indicated a clinically significant (P < 0.05) improvement of pain VAS from baseline to follow-up at year 1 to 2 of -4.02(confidence interval -4.37; -3.67), still significant after 3 years. Lysholm score at year 1 or 2 improved significantly and remained highly significant after 3 years. IKDC score showed highly significant improvement of 32.61 between 1 and 2 years versus baseline values maintained after 3 years. CONCLUSIONS: The AMIC procedure significantly improved the clinical status and functional scoring versus preoperative values. Evidence was obtained in a non-selected patient population, corresponding to real-life treatment of knee chondral and osteochondral defects. The evidence is sufficient to recommend AMIC in this indication.

MitraClip implantation followed by insertion of a left ventricular assist device in patients with advanced heart failure.

AIMS: Mitral valve regurgitation (MR) is common in patients with advanced heart failure (HF). Percutaneous mitral valve repair (PMVR) via MitraClip (MC) has emerged as a feasible treatment strategy for these high-risk patients. However, as HF often further progresses, there is a frequent need for left ventricular assist device (LVAD) implantation in these patients. We aimed to investigate whether prior MC implantation affects the subsequent LVAD implantation and outcome. METHODS AND RESULTS: Thirty-seven patients with advanced HF and significant MR who underwent LVAD implantation were retrospectively analysed. Follow-up data were collected at 1 year after LVAD implantation. Primary endpoint was all-cause mortality. Secondary endpoint included peri-operative parameters and clinical development depicted as New York Heart Association (NYHA) class and Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) level. Seventeen patients initially received a MC device (MC group), resulting in a significant reduction in MR grade. After MC, NYHA class and INTERMACS level further worsened, leading to subsequent LVAD implantation after a median time of 475 days in the MC group. At LVAD implantation, overall characteristics were comparable with those of the patients undergoing LVAD implantation without prior MC placement (no-MC group). Procedural data revealed a higher incidence of right ventricular (RV) failure needing mechanical RV assistance and a longer need for nitric oxide ventilation in the MC group after LVAD implantation. One-year survival was slightly better in the no-MC group compared with the MC group [41% (n = 7/17) vs. 65% (n = 13/20); P = 0.15], albeit event-free survival was comparable between both groups, MC and no-MC. CONCLUSIONS: LVAD implantation after MC is feasible and safe. However, in patients with advanced HF and severe MR, PMVR may only delay a needed LVAD implantation and thereby lead to poorer peri-operative RV function and impaired outcome. Arguably, these patients might benefit from the timely management of advanced HF by the means of early LVAD implantation or heart transplantation.

A novel risk score to predict survival in advanced heart failure due to cardiac amyloidosis.

BACKGROUND: Cardiac amyloidosis, caused by deposition of immunoglobulin light chains (AL) or transthyretin (ATTR), carries a poor prognosis. Established risk scores for amyloidosis may not predict outcomes in those patients who develop advanced heart failure and who are potential candidates for heart transplantation. Here, we aimed to identify predictive parameters for patients with severe heart failure due to amyloidosis. METHODS: Out of > 1000 patients with cardiac amyloidosis (AL or ATTR) admitted to our centre between September 1998 and January 2016, a cohort of 120 patients with a complete cardiac assessment at diagnosis, including right heart catheterization, echocardiography and biomarkers, was analysed retrospectively in this study. Primary endpoint was all-cause mortality. We performed univariate and multivariate Cox regression analysis, generated risk scores to predict outcomes in AL and ATTR amyloidosis and compared those to established risk models for amyloidosis. RESULTS: In the Cox multivariate model, high-sensitivity troponin T (hsTnT; hazard ratio (HR) 1.003; confidence interval (CI) 1.001-1.005; p = 0.009) and mean pulmonary artery pressure (HR 1.061; CI 1.024-1.100; p = 0.001) were found to significantly and independently predict outcomes for AL amyloidosis, whereas QRS duration (HR 1.021; CI 1.004-1.039; p = 0.013), hsTnT (HR 1.021; CI 1.006-1.036; p = 0.006) and N-terminal pro-brain natriuretic peptide (HR 1.0003; CI 1.0001-1.0004; p = 0.002) were the best predictors for ATTR amyloidosis. A simple risk score ("HeiRisk") including these parameters for AL and ATTR allowed a more precise risk stratification in our patient population compared to established risk models. CONCLUSIONS: Risk stratification for cardiac amyloidosis with the newly developed "HeiRisk" score may be superior to other staging systems for patients with advanced heart failure due to amyloid cardiomyopathy.

[Significance of Matrix-augmented Bone Marrow Stimulation for Treatment of Cartilage Defects of the Knee: A Consensus Statement of the DGOU Working Group on Tissue Regeneration]. / Stellenwert der matrixaugmentierten Knochenmarkstimulation in der Behandlung von Knorpelschäden des Kniegelenks: Konsensusempfehlungen der AG Klinische Geweberegeneration der DGOU.

Surgical principles for treatment of full-thickness cartilage defects of the knee include bone marrow stimulation techniques (i.e. arthroscopic microfracturing) and transplantation techniques (i.e. autologous chondrocyte implantation and osteochondral transplantation). On the basis of increasing scientific evidence, indications for these established therapeutical concepts have been specified and clear recommendations for practical use have been given. Within recent years, matrix-augmented bone marrow stimulation has been established as a new treatment concept for chondral lesions. To date, scientific evidence is limited and specific indications are still unclear. The present paper gives an overview of available products as well as preclinical and clinical scientific evidence. On the basis of the present evidence and an expert consensus from the "Working Group on Tissue Regeneration" of the German Orthopaedic and Trauma Society (DGOU), indications are specified and recommendations for the use of matrix-augmented bone marrow stimulation are given. In principle, it can be stated that the various products offered in this field differ considerably in terms of the number and quality of related studies (evidence level). Against the background of the current data situation, their application is currently seen in the border area between cell transplantation and bone marrow stimulation techniques, but also as an improvement on traditional bone marrow stimulation within the indication range of microfracturing. The recommendations of the Working Group have preliminary character and require re-evaluation after improvement of the study situation.

A randomized controlled trial demonstrating sustained benefit of Autologous Matrix-Induced Chondrogenesis over microfracture at five years.

PURPOSE: Autologous Matrix-Induced Chondrogenesis (AMIC®) utilizing a type I/III collagen membrane was compared with microfracture (MFx) alone in focal cartilage lesions of the knee at one, two and five years. METHODS: Forty-seven patients (aged 37 ± 10 years, mean defect size 3.6 ± 1.6 cm2) were randomized and treated either with MFx, with sutured or glued AMIC® in a prospective multicentre clinical trial. RESULTS: After improvement for the first two years in all subgroups, a progressive and significant score degradation was observed in the MFx group, while all functional parameters remained stable for least five years in the AMIC® groups. At two and five years, MRI defect filling was more complete in the AMIC® groups. No treatment-related adverse events were reported. CONCLUSIONS: AMIC® is an effective cartilage repair procedure in the knee resulting in stable clinical results significantly better than the MFx group at five years.

A Randomized, Controlled Trial Comparing Autologous Matrix-Induced Chondrogenesis (AMIC®) to Microfracture: Analysis of 1- and 2-Year Follow-Up Data of 2 Centers.

Microfracture (MFx) is currently the recommended option for the treatment of small cartilage defects but is not regarded as suitable for the treatment of defects larger than 2.5 cm(2). To extent its applicability to medium-sized defects MFx has been combined with a collagen type I/III matrix (Chondro-Gide(®)). This technique is called Autologous Matrix-Induced Chondrogenesis (AMIC(®)) and meanwhile a clinically established treatment option for localized full-thickness small- to medium-sized cartilage defects. Despite its more spreading clinical use, clinical data published so far are limited to mainly case report series. In this study, we report the first results of a randomized, controlled trial assessing the efficacy and safety of AMIC(®) versus MFx. Patients enrolled in 2 centers were included in this analysis. 38 patients (aged 21-50 years, mean defect size 3.4 cm(2)) were randomized and treated either with MFx, with sutured AMIC(®) or glued AMIC(®). Clinical outcomes (modified Cincinnati and ICRS score) could be assessed in 30 patients at 1-year and 27 patients at 2-years post-operation. Improvements in both scores were seen at 1-and 2-years post-operation, irrespective of the technique used. MRI assessment revealed a satisfactory and homogenous defect filling in the majority of patients. No treatment-related adverse events were reported. This interim analysis confirms the mid-term results for AMIC(®) reported in literature. It demonstrates clearly that clinical outcomes at 1-year post-operation are maintained at 2-years. Therefore we consider enhancing MFx with Chondro-Gide (®) is a valid and safe cartilage repair option for small- to medium-sized cartilage defects of the knee.

Temporal course of emotional startle modulation in schizophrenia patients.

The temporal course of startle reflex modulation to emotional pictures was investigated in 49 relatively asymptomatic schizophrenia outpatients and 46 normal controls. Participants viewed pleasant, neutral and unpleasant pictures, which were presented for 6 s and acoustic startle probes were delivered at five different times after picture onset. Replicating previous findings schizophrenia patients showed the same affective modulation of the startle reflex as healthy controls when probes were presented later during the picture-viewing period (3800 ms). For the early probe times (300 and 800 ms), affective pictures proved to be the effective prepulse stimuli resulting in a clear Prepulse inhibition (PPI) effect in both groups. In contrast to previous findings, the PPI of startle response was not stronger during processing emotional stimuli relative to neutral stimuli. For control subjects, blink reflexes were larger for unpleasant pictures compared with neutral and pleasant pictures, representing an early activation of motivational systems. Schizophrenia patients on the other hand, did not show this early affective modulation of the acoustic startle reflex.