Potential mechanisms of endothelialisation in individuals implanted with a leadless pacemaker systems: An experimental in vitro study.

BACKGROUND: Leadless pacemaker technology is a promising upcoming field in clinical rhythmology. Today, the most commonly used system in the clinical setting is the Micra™ leadless pacemaker system (Medtronic). In autopsies of patients who witnessed non-pacemaker associated death, unexpected ingrowth/encapsulation within the wall of the right ventricle was reported. The occurrence of a complete encapsulation was not expected and the process of endothelialisation remains unclear. We hypothesized, that a local inflammatory response might be the cause of these findings. The aim of our experimental in-vitro study was to investigate the effect of the Micra™ system and its single components on inflammatory processes. METHODS: For this purpose, whole Micra™ pacemakers were incubated in heparin plasma from 25 healthy volunteers for 48 h at 37 °C. Furthermore, 1 g gold, steel, titanium, tungsten and nitinol wires were incubated in heparin plasma for 48 h at 37 °C as well (n = 10). To detect eventual inflammatory processes, interleukin- (IL) 1ß, IL-6, and tumor necrosis factor alpha (TNF-α), the chemokine IL-8 were measured using enzyme-linked immunosorbent assay (ELISA). Additionally, the level of transforming growth factor beta 1 (TGF-ß1) and vascular endothelial growth factor (VEGF) were analysed. RESULTS: ELISA analyses showed that the whole Micra system leads to a significant increase in the inflammatory cytokine IL-6 which correlates with the data gained by the incubation of whole blood with the different wires. In particular, 0.5 g of tungsten showed a significant rise of IL-6 which could also be found for IL-1ß and IL-8. CONCLUSIONS: The in vitro study of the Micra system showed that the material composition led to an onset of inflammatory processes in whole blood. Consequently, one may speculate that the composition of Micra pacemaker may have a local inflammatory, though subclinical, effects in patients implanted with a Micra™ pacemakers.

Monocenter Investigation Micra® MRI study (MIMICRY): feasibility study of the magnetic resonance imaging compatibility of a leadless pacemaker system.

AIMS: As in vivo real-life data are still scarce, we conducted a study to assess the safety and feasibility of cardiac magnetic resonance imaging (MRI) in patients with a leadless pacemaker system. METHODS AND RESULTS: In this prospective non-randomized interventional trial, we enrolled 15 patients with an MRI conditional Micra® leadless pacemaker system to undergo either a 1.5 T or 3.0 T cardiac MRI scan. Clinical adverse events as well as device parameters such as pacing threshold, sensing, impedance, and battery life were assessed at baseline as well as 1 and 3 months after the scan. Device parameter changes between different time points were tested for statistical significance and compared with pre-set cut-off values. Fourteen patients underwent the cardiac MRI scan according to the protocol as well as the scheduled follow-up visits. One participant was excluded from analysis, as the MRI scan was not possible because of severe claustrophobia. Other clinical events did not occur during the scan and the follow-up period. Device parameters stayed stable and changes during the observational period were statistically not significant (changes vs. baseline: pacing threshold: 0.01 ± 0.05 V, P = 0.308, 0.01 ± 0.07 V, P = 0.419, sensing: -0.15 ± 1.11 mV, P = 0.658, -0.19 ± 1.17 mV, P = 0.800, impedance: -7.86 ± 30.7 Ohm, P = 0.447, -7.86 ± 25.77 Ohm, P = 0.183, at 1 and 3 months follow-up, respectively). Parameter changes were not statistically different between patients who underwent imaging at 1.5 T (n = 7) or 3.0 T (n = 7). CONCLUSION: In our set of patients with a Micra® leadless pacemaker, cardiac magnetic resonance imaging at either 1.5 T or 3.0 T proved feasible and safe with no relevant changes in device parameters within 3 months of follow-up.

Visualization and appearance of artifacts of leadless pacemaker systems in cardiac MRI : An experimental ex vivo study.

BACKGROUND: Leadless pacemaker systems are an important upcoming device in clinical rhythmology. Currently two different products are available with the Micra system (Medtronic) being the most used in the clinical setting to date. The possibility to perform magnetic resonance imaging (MRI) is an important feature of modern pacemaker devices. Even though the Micra system is suitable for MRI, little is yet known about its impact on artifacts within the images. OBJECTIVE: The aim of our ex vivo study was to perform cardiac MRI to quantify the artifacts and to evaluate if artifacts limit or inhibit the assessment of the surrounding myocardium. METHODS: After ex vivo implantation of the leadless pacemaker (LP) in a porcine model, hearts were filled with saline solution and fixed on wooden sticks on a plastic container. The model was examined at 1.5 T and at 3 T using conventional sequences and T2 mapping sequences. In addition, conventional X­rays and computed tomography (CT) scans were performed. RESULTS: Correct implantation of the LP could be performed in all hearts. In almost all MRI sequences the right ventricle and the septal region surrounding the (LP) were altered by an artifact and therefore would sustain limited assessment; however, the rest of the myocardium remained free of artifacts and evaluable for common radiologic diagnoses. A characteristic shamrock-shaped artifact was generated which appeared to be even more intense in magnitude and brightness when using 3 T compared to 1.5 T. CONCLUSION: The use of the Micra system in cardiac MRI appeared to be feasible. In our opinion, it will still be possible to make important clinical cardiac MRI diagnoses (the detection of major ischemic areas or inflammatory processes) in patients using the Micra system. We suggest the use of 1.5 T as the preferred method in clinical practice.

Economic assessment of traditional surgical intervention versus use of a new innovative radiofrequency based surgical system in device replacements.

INTRODUCTION: Intra-operative complications like mechanical damages to the leads, infections and hematomas during generator replacements of implantable pacemakers and defibrillators contribute to additional costs for hospitals. The aim of this study was to evaluate operation room use, costs and budget impact of generator replacements using either a traditional surgical intervention (TSI) with scissors, scalpel and electrocautery vs. a new radiofrequency energy based surgical system, called PEAK PlasmaBladeTM (PPB). MATERIALS AND METHODS: We conducted a retrospective analysis of a population including 508 patients with TSI and 254 patients with PPB who underwent generator replacement at the Kepler University Hospital in Linz or the St. Josef Hospital in Braunau, Austria. The economic analysis included costs of resources used for intra-operative complications (lead damages) and of procedure time for TSI vs. PPB. RESULTS: Proportion of males, mean age and type of generator replaced were similar between the two groups. Lead damages occurred significantly more frequent with TSI than with PPB (5.3% and 0.4%; p< 0.001) and the procedure time was significantly longer with TSI than with PPB (47.9±24.9 and 34.1±18.1 minutes; p<0.001). Shorter procedure time and a lower rate of lead damages with PPB resulted in per patient cost savings of €81. Based on estimated 2,700 patients annually undergoing generator replacement in Austria, the use of PPB may translate into cost savings of €219,600 and 621 saved operating facility hours. CONCLUSION: PPB has the potential to minimize the risk of lead damage with more efficient utilization of the operating room. Along with cost savings and improved quality of care, hospitals may use the saved operating room hours to increase the number of daily surgeries.

Impact of operator experience and training strategy on procedural outcomes with leadless pacing: Insights from the Micra Transcatheter Pacing Study.

BACKGROUND: Leadless pacemaker systems have been designed to avoid the need for a pocket and transvenous lead. However, delivery of this therapy requires a new catheter-based procedure. This study evaluates the role of operator experience and different training strategies on procedural outcomes. METHODS: A total of 726 patients underwent implant attempt with the Micra transcatheter pacing system (TPS; Medtronic, Minneapolis, MN, USA) by 94 operators trained in a teaching laboratory using a simulator, cadaver, and large animal models (lab training) or locally at the hospital with simulator/demo model and proctorship (hospital training). Procedure success, procedure duration, fluoroscopy time, and safety outcomes were compared between training methods and experience (implant case number). RESULTS: The Micra TPS procedure was successful in 99.2% of attempts and did not differ between the 55 operators trained in the lab setting and the 39 operators trained locally at the hospital (P = 0.189). Implant case number was also not a determinant of procedural success (P = 0.456). Each operator performed between one and 55 procedures. Procedure time and fluoroscopy duration decreased by 2.0% (P = 0.002) and 3.2% (P < 0.001) compared to the previous case. Major complication rate and pericardial effusion rate were not associated with case number (P = 0.755 and P = 0.620, respectively). There were no differences in the safety outcomes by training method. CONCLUSIONS: Among a large group of operators, implantation success was high regardless of experience. While procedure duration and fluoroscopy times decreased with implant number, complications were low and not associated with case number. Procedure and safety outcomes were similar between distinct training methodologies.

Soluble ST2 predicts 1-year outcome in patients undergoing transcatheter aortic valve implantation.

BACKGROUND: Soluble ST2 (sST2) has been introduced as a novel biomarker in patients suffering from heart failure for risk stratification. In this study, we sought to investigate whether sST2 is useful for risk stratification and prediction of mortality in patients undergoing transcatheter aortic valve implantation (TAVI). MATERIALS AND METHODS: A total of 274 patients undergoing TAVI were included in this study (149 female; age 81 ± 1 years; EUROSCORE 25 ± 1; STS score 3·8 ± 0·2). Plasma samples were obtained preinterventional and analysed for sST2. Patients were followed up 1 month and 1 year after TAVI. RESULTS: In a Cox regression analysis, sST2 plasma concentration was associated with increased mortality (changes per pg/mL sST2 concentration; HR 1·00006 95% (1·00004-1·00009); P < 0·001). A cut-off by means of the Youden Index was calculated (10 070·27 pg/mL), and patients were retrospectively divided into two cohorts, in those above (31·3%) and those below (68·7%) this value. These two groups were then compared regarding mortality both after 30 days and 1 year: whereas 1-month mortality did not differ (7·0% vs. 10·3%, OR 1·50 95% CI (0·60-3·79; P = 0·46)), patients with a sST2 concentration above the cut-off of 10 070·27 pg/mL showed a significantly worse outcome after 1 year (49·2% vs. 23·2%; OR 3·21 95% CI (1·70-6·04); P < 0·001). After correction for confounders in a multivariate Cox regression analysis, sST2 (1·0002 95% CI (1·0001-1·0003); P = 0·001) concentration remained associated with mortality. CONCLUSIONS: sST2 levels were associated with 1-year mortality after TAVI. Based on these results, we assume that sST2 might help to identify patients at high risk for death in whom conservative treatment should be considered.

Analysis of Ambient Influences Affecting Interleukin-6 Secretion in the Context of Clinical Trials of Stem Cell Therapy for Myocardial Infarction.

BACKGROUND: Contradictory results of large clinical trials of stem cell therapy in acute myocardial infarction (AMI) have impeded a wider clinical use. As signalling via paracrine factors in AMI has received more and more attention recently, we sought to compare processing protocols with special emphasis on interleukin-6 (IL-6), a factor of major relevance for triggering cardioprotective signals via STAT3 and PI3K. METHODS: Bone marrow and peripheral blood mononuclear cells were processed according to protocols used in the REPAIR-AMI and ASTAMI study. RESULTS: Keeping cells at higher temperatures significantly boosted secretion of IL-6. Moreover, the use of autologous serum and X-Vivo medium was superior over reagents used in the protocol of the ASTAMI study. CONCLUSIONS: External influencing factors (higher temperature, use of a modern cell culture medium supplemented with serum) led to higher concentrations of IL-6. These results could provide an explanation for the superior results found in the REPAIR-AMI study.

Endpoint design for future renal denervation trials - Novel implications for a new definition of treatment response to renal denervation.

BACKGROUND: Defining an adequate endpoint for renal denervation trials represents a major challenge. A high inter-individual and intra-individual variability of blood pressure levels as well as a partial or total non-adherence on antihypertensive drugs hamper treatment evaluations after renal denervation. Blood pressure measurements at a single point in time as used as primary endpoint in most clinical trials on renal denervation, might not be sufficient to discriminate between patients who do or do not respond to renal denervation. METHODS: We compared the traditional responder classification (defined as systolic 24-hour blood pressure reduction of -5mmHg six months after renal denervation) with a novel definition of an ideal respondership (based on a 24h blood pressure reduction at no point in time, one, or all follow-up timepoints). RESULTS: We were able to re-classify almost a quarter of patients. Blood pressure variability was substantial in patients traditionally defined as responders. On the other hand, our novel classification of an ideal respondership seems to be clinically superior in discriminating sustained from pseudo-response to renal denervation. CONCLUSION: Based on our observations, we recommend that the traditional response classification should be reconsidered and possibly strengthened by using a composite endpoint of 24h-BP reductions at different follow-up-visits.

Anti-Inflammatory Effects and Prediction of Blood Pressure Response by Baseline Inflammatory State in Catheter-Based Renal Denervation.

This retrospective analysis aimed to examine off-target effects on inflammatory and renal function parameters in n=78 subsequent patients treated with renal denervation (RDN) for resistant hypertension. Ambulatory and office blood pressure (ABP/OBP), serum creatinine, glomerular filtration rate (GFR), cystatin C, C-reactive protein (CRP), interleukin-6 (IL-6), and white blood cell count (WBC) were assessed before, 6 and 12 months after RDN. ABP was significantly reduced by -8.2/-3.8 mm Hg (P=.002/.021) at 1 year after RDN, while an initial OBP reduction was not sustained during follow-up. IL-6 levels significantly decreased by -0.5 pg/mL (P=.042) and by -1.7 pg/mL (P<.001) at 6 and 12 months, baseline IL-6 levels possibly predicting ABP response to RDN (r=-0.295; P=.020). Concurrently, leukocyte count was reduced by -0.5 × 103 /µL (P=.017) and -0.8 × 103 /µL (P<.001), respectively. Serum creatinine and GFR remained unchanged, but we observed a significant increase in cystatin C by 0.04 mg/L (P=.026) and 0.14 mg/L (P<.001) at 6 and 12 months after the intervention.

Leadless Cardiac Pacemaker Implantation After Lead Extraction in Patients With Severe Device Infection.

BACKGROUND: Conventional pacemaker therapy is limited by short- and long-term complications, most notably device infection. Transcatheter pacing systems (TPS) may be beneficial in this kind of patients as they eliminate the need for a device pocket and leads and thus may reduce the risk of re-infection. METHODS: We assessed a novel procedure in 6 patients with severe device infection who were pacemaker dependent. After lead extraction a single chamber TPS was implanted into the right ventricle. RESULTS: Of the 6 patients who underwent lead extraction due to severe device infection at our institution, 3 were diagnosed with a pocket infection only, whereas the other 3 showed symptoms of both pocket and lead infection. Successful lead extraction and TPS implantation was accomplished in all patients. Four patients were bridged with a temporary pacemaker between 2 hours and 2 days after lead extraction, whereas 2 patients had the TPS implanted during the same procedure just before traditional pacemaker system removal. All patients stayed free of infection during the follow-up period of 12 weeks. An additional positron emission tomography scan was performed in each patient and indicated no signs of an infection around the TPS. CONCLUSION: Transcather pacemaker implantation was safe and feasible in 6 patients and did not result in re-infection even if implanted before removal of the infected pacemaker system within the same procedure. Therefore, implantation of a TPS may be an option for patients with severe device infection, especially in those with blocked venous access or who are pacemaker dependent.

Temporary leadless pacing in a patient with severe device infection.

A 64-year-old patient underwent implantation of a transcatheter pacing systems (TPS) for severe lead endocarditis. The patient experienced fever after a dental procedure. On the transoesophageal echocardiogram (TEE), vegetations were attached to the leads. Because the patient was pacemaker dependent, a temporary pacing lead had to be placed. After removal, however, he did not improve. A second TEE showed new vegetations. Ventricular fibrillation occurred spontaneously; so isoprenalin had to be stopped and a new lead was implanted. Vegetations appeared soon after the new temporary lead was placed. We used a TPS as a bridging device, followed by implantation of a resynchronisation system, and explantation of the TPS. After the Micra TPS was implanted, the patient recovered noticeably. All inflammation parameters were negative and an additional (18)F-fluorodeoxyglucose-positron emission tomography/CT imaging also proved to be negative. So a CRT-D device was then implanted, and the TCP was removed.

Subcutaneous Double "Purse String Suture"-A Safe Method for Femoral Vein Access Site Closure after Leadless Pacemaker Implantation.

BACKGROUND: Leadless cardiac pacemaker (LCP) requires large-caliber venous sheaths for device placement. Sheath sizes for these procedures vary from 18- to 23-French (F). The most common complications are hematomas, pseudoaneurysms, and arteriovenous fistulas. Complete and secure closure of the venous access is an important step at the end of such a procedure. METHODS: We performed a retrospective analysis of all patients who had undergone LCP implantation at our institution. Patients and procedural characteristics as well as groin complications at 30 days and 3 months were evaluated. After sheath removal venous access sites were closed performing a so-called "purse-string" suture (PSS). RESULTS: Seventy-seven patients received an LCP at our institution. In 27 (35%) of these patients a heparin bolus was given at the beginning of the procedure. Anticoagulation therapy with phenprocoumon was present in 32 (40%) of patients. In 76 (98.7%) patients, the LCP was implanted without complications. In one (1.3%) patient a perforation occurred during implantation, which required surgical intervention. Access site complications occurred in three (3.9%) patients, two (2.6%) groin hematomas, and one (1.3%) arteriovenous fistula. The hematomas disappeared completely after 3 weeks, and the fistula was not detectable by ultrasound anymore after 4 weeks. CONCLUSION: Use of subcutaneous absorbable double PSS closure after removal of large-caliber venous sheaths is a safe technique to achieve immediate postprocedural hemostasis. Especially for sheath sizes with an inner diameter of 23F, this technique creates a very secure and also cosmetically appealing closure.

Dawn of a new era: the completely interventionally treated patient.

A frail 75-year-old woman with permanent atrial fibrillation and angina pectoris was admitted to our department for further evaluation. Echocardiography revealed concurrent severe aortic valve stenosis. Furthermore, significant coronary artery stenoses were identified on the coronary angiogram. We chose the following treatment strategy: first, two drug eluting stents were implanted successfully in the left anterior descending and circumflex artery, respectively. Second, a 23 mm Core Valve bioprosthesis (Medtronic Inc, Minneapolis, Minnesota, USA) was implanted without complications within the same session. Two weeks after hospital discharge, the patient showed up at our outpatient department, with a symptomatic complete atrioventricular-block with an escape rhythm of 35 bpm. Thus, finally, a leadless pacemaker Micra (Medtronic Inc) was implanted via a transvenous transfemoral access without any complications.

Implantation depth measured by 64-slice computed tomography is associated with permanent pacemaker requirement following transcatheter aortic valve implantation with the Core Valve(®) system.

BACKGROUND: Patients undergoing transcatheter aortic valve implantation (TAVI) are at increased risk for post-interventional conduction disturbances leading to pacemaker (PM) implantation. We analyzed the association between implantation depth within the left ventricular outflow tract (LVOT), measured by 64-slice computed tomography (CT), and 'index electrocardiographic (ECG) changes' (new onset atrioventricular-block grade II or III or left bundle branch block with PR interval prolongation >200ms). METHODS: We evaluated patients who underwent TAVI with the Core Valve(®) revalving system (Medtronic, Minneapolis, MN, USA) for treatment of severe aortic stenosis at our department. Patients with a prior PM implantation and patients for whom no CT scan was available after 3 months were excluded from analysis. We assessed implantation depth of the prosthesis within the LVOT as possible risk factors for the development of post-interventional 'index ECG changes' resulting in PM implantation and compared it with individual patient data as well as echocardiographic and electrocardiographic parameters. RESULTS: The final study cohort comprised 53 patients for whom a 64-slice CT scan was available (mean age 81.7±5.1 years, 36% male). Twenty-eight of these finally underwent PM implantation due to 'index ECG changes' within the first 48hours after TAVI. Univariate logistic regression analysis could identify implantation depth of the prosthesis as the only significantly correlated risk factor for PM need in our cohort (OR 1.27, 95% CI: 1.08-1.51, p=0.004). A cut-off value of 6mm predicted this need with a sensitivity of 89% and specificity of 40%. CONCLUSION: Implantation depth of the Core Valve(®) into the LVOT was associated with post-procedural PM requirement. Thereby, a cut-off value of 6mm, as measured by 64-slice CT, proved useful to define patients at risk for PM requirement.

Extraction of a trapped pacemaker lead in a pacemaker-dependent patient.

A 47-year-old female with a dual chamber pacemaker was referred to our institution for transvenous lead removal because of suspected pocket infection. The history of this patient started in 2002 with a tricuspid valve endocarditis. Therefore, the patient had tricuspid valve repair that yielded a poor outcome. The patient received biological tricuspid valve in 2006. Due to postoperative total atrioventricular-block a DDDR device was implanted. The biological valve degenerated and thus was replaced by a mechanical one in 2014. During this valve implantation the atrial lead was removed and the ventricular lead was trapped by the mechanical valve between the native tricuspid valve annulus of the right ventricle and the outer ring of the mechanical valve. Three months after the last revision the patient developed signs of inflammation. The pocket was opened and a swab test proved positive for Staphylococcus epidermidis. After disinfection with iodine solution the pacemaker was placed under the pectoralis muscle. However, during the following 3 months the patient suffered from swelling over the pacemaker pocket and severe pain. In awareness of the previous history and the clinical symptoms we decided to implant a new pacemaker system on the left side and explant the infected system on the right side. .

Clinical safety of an MRI conditional implantable cardioverter defibrillator system: A prospective Monocenter ICD-Magnetic resonance Imaging feasibility study (MIMI).

BACKGROUND: The aim of this study was to evaluate the safety and efficacy of the Lumax 740(®) Implantable Cardioverter Defibrillator (ICD) system in patients undergoing a defined 1.5 Tesla (T) MRI. MATERIALS AND METHODS: Between November 2013 and April 2014, eighteen patients (age range, 41-78 years; mean age, 64 years) implanted with a Lumax 740(®) ICD system for at least 6 weeks before an MRI were enrolled into this single-center feasibility study. The local ethics committee approved the study before patients gave written informed consent. Patients underwent defined MRI 1.5T of the brain and lower lumbar spine with three safety follow-up evaluations obtained during the 3-month study period. Data were analyzed descriptively. Study endpoints were the absence of either MRI and pacing system related serious adverse device effects (SADE), or of a ventricular pacing threshold increase >0.5V, or of an R-wave amplitude attenuation < 50%, or of an R-wave amplitude < 5.0 mV at 1-month follow-up. The assessment of safety and efficacy was supported by recording of all adverse events, changes in pacing threshold, R-wave sensing, pacing impedances and in battery status. RESULTS: Sixteen patients completed the MRI and the follow-up period. As no SADE occurred, the SADE free rate was 100%. Freedom from ventricular pacing threshold increase was 100% (16/16; 95%CI: 82.9%; 100.0%). There were no significant differences between baseline and follow-up measurements of sensing amplitudes (-0.58 ± 2.07 mV, P = 0.239, -0.41 ± 1.04 mV, P = 0.133, and -0.25 ± 1.36 mV, P = 0.724, for immediately after, 1 month and 3 months after MRI scan, respectively) and pacing thresholds (-0.047 ± 0.18 V, P = 0.317, -0.019 ± 0.11 V, P = 0.490, and 0.075 ± 0.19 V, P = 0.070, for immediately after, 1 month and 3 months after MRI scan, respectively). Lead impedances after the MRI scan were significantly lower as compared with baseline values (-22.8 ± 21.69 Ω, P = 0.001, -21.62 ± 39.71 Ω, P = 0.040, and -33.68 ± 57.73 Ω, P = 0.018, for immediately after, 1 month and 3 months after MRI scan, respectively). CONCLUSION: MRI scans in patients with MRI conditional ICD system (Lumax 740(®) ) are feasible and can be performed safely under defined conditions in a hospital setting.