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.

Impact of Percutaneous Mitral Valve Repair Using the MitraClipTM System on Ventricular Arrhythmias and ICD Therapies.

Transcatheter edge-to-edge repair (TEER) using the MitraClip™ device has been established as a suitable alternative to mitral valve surgery in patients with severe mitral regurgitation (MR) and high or prohibitive surgical risk. Only limited information regarding the impact of TEER on ventricular arrhythmias (VA) has been reported. The aim of the present study was to assess the impact of TEER using the MitraClipTM device on the burden of VA and ICD (Implantable Cardioverter Defibrillator) therapies. Among 600 MitraClipTM implantations performed in our clinic between September 2009 and October 2018, we identified 86 patients with successful TEER and an active implantable cardiac device (pacemaker, ICD, CRT-P/D (Cardiac Resynchronization Therapy-Pacemaker/Defibrillator)) eligible for retrospective VA analyses. These patients presented with mainly functional MR (81.4%) and severely reduced left ventricular ejection fraction (mean LVEF 22.1% ± 10.3%). The observation period comprised 456 ± 313 days before and 424 ± 287 days after TEER. The burden of ventricular arrhythmias (sustained ventricular tachycardia (sVT) and ventricular fibrillation (VF)) was significantly reduced after TEER (0.85 ± 3.47 vs. 0.43 ± 2.03 events per patient per month, p = 0.01). Furthermore, the rate of ICD therapies (anti-tachycardia pacing (ATP) and ICD shock) decreased significantly after MitraClipTM implantation (1.0 ± 3.87 vs. 0.32 ± 1.41, p = 0.014). However, reduction of VA burden did not result in improved two-year survival in this patient cohort with severely reduced LVEF. Mitral valve TEER using the MitraClip™ device was associated with a significant reduction of ventricular arrhythmias and ICD therapies.

One-year results following PASCAL-based or MitraClip-based mitral valve transcatheter edge-to-edge repair.

AIMS: Mitral valve transcatheter edge-to-edge repair (TEER) has been established as a suitable alternative to mitral valve surgery in patients with severe mitral regurgitation (MR) and high surgical risk. The PASCAL system represents a novel device, potentially augmenting the toolkit for TEER. The aim of this study was to assess and compare short and 1 year safety and efficacy of the PASCAL and MitraClip systems for TEER. METHODS AND RESULTS: Procedural, short, and 1 year outcomes of a 1:2 propensity-matched cohort including 41 PASCAL and 82 MitraClip cases were investigated. Matching was based on clinical, laboratory, echocardiographic, and functional characteristics. The primary endpoints assessed were procedural success [as defined by the Mitral Valve Academy Research Consortium (MVARC)], residual MR, functional class, and a composite endpoint comprising death, heart failure hospitalization, and mitral valve re-intervention. We found for the PASCAL and the matched MitraClip cohort no significant differences in MVARC defined technical (90.2% vs. 95.1%, P = 0.44), device (90.2% vs. 89.0%, P = 1.0), or procedural (87.8% vs. 80.5%, P = 0.45) success rates. Accordingly, the overall MR reduction and improvement in New York Heart Association (NYHA) class were comparable (1 year follow-up: MR ≤ 2 95% vs. 93.6%, P = 1.0; NYHA ≤ 2 57.1% vs. 66.7%, P = 0.59). The composite outcome revealed no statistically significant difference between both devices (1 year follow-up: 31.7% vs. 37.8%, P = 0.55). Interestingly, we found at both short and 1 year follow-up a significantly higher rate of patients with none or trace MR in the PASCAL-treated cohort (short follow-up: 17.9% vs. 0%, P = 0.0081; 1 year follow-up: 25% vs. 0%, P = 0.0016). Conversely, the rate of aborted device implantations due to an elevated transmitral gradient was higher in PASCAL interventions (9.8% vs. 1.2%, P = 0.04). CONCLUSIONS: Transcatheter edge-to-edge repair using the PASCAL or MitraClip device results in favourable and comparable outcomes regarding safety, efficacy, and clinical improvement after 1 year.

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.

The extent of aortic annulus calcification is a predictor of postprocedural eccentricity and paravalvular regurgitation: a pre- and postinterventional cardiac computed tomography angiography study.

PURPOSE: To investigate if the extent of aortic valve calcification is associated with postprocedural prosthesis eccentricity and paravalvular regurgitation (PAR) in patients undergoing transcatheter aortic valve implantation (TAVI). METHODS: Cardiac computed tomography angiography (CCTA) was performed before and 3 months after TAVI in 46 patients who received the self-expanding CoreValve and in 22 patients who underwent balloon-expandable Edwards Sapien XT implantation. Aortic annulus calcification was measured with CCTA prior to TAVI and prosthesis eccentricity was assessed with post-TAVI CCTA. Standard echocardiography was also performed in all patients at 3-month follow-up exam. RESULTS: Annulus eccentricity was reduced during TAVI using both implantation systems (from 0.23 ± 0.06 to 0.18 ± 0.07 using CoreValve and from 0.20 ± 0.07 to 0.05 ± 0.03 using Edwards Sapien XT; P<.001 for both). With Edwards Sapien XT, eccentricity reduction at the level of the aortic annulus was significantly higher compared with CoreValve (P<.001). Annulus eccentricity after CoreValve use was significantly related to absolute valve calcification and to valve calcification indexed to body surface area (BSA) (r = 0.48 and 0.50, respectively; P<.001 for both). Furthermore, a significant association was observed between aortic valve calcification and PAR (P<.01 by ANOVA) in patients who received CoreValve. Using ROC analysis, a cut-off value over 913 mm² aortic valve calcification predicted the occurrence of moderate or severe PAR with a sensitivity of 92% and a specificity of 63% (area under the curve = 0.75). Furthermore, multivariable analysis showed that aortic valve calcification was a robust predictor of postprocedural eccentricity and PAR, independent of the aortic annulus size and native valve eccentricity and of CoreValve prosthesis size (adjusted r = 0.46 and 0.50, respectively; P<.01 for both). Such associations were not present with the Edwards Sapien XT system. CONCLUSION: The extent of native aortic annulus calcification is predictive for postprocedural prosthesis eccentricity and PAR, which is an important marker for long-term mortality in patients undergoing TAVI. This observation applies for the CoreValve, but not for the Edwards Sapien XT valve.

Feasibility and clinical benefit of a suture-mediated closure device for femoral vein access after percutaneous edge-to-edge mitral valve repair.

AIMS: We assessed feasibility, efficacy and safety of a suture-mediated closure device, Perclose Proglide (Abbott Vascular Devices, Santa Clara, CA, USA), for closure of the femoral vein access after percutaneous MitraClip (Abbott Vascular Devices) implantation. METHODS AND RESULTS: Venous access of 80 consecutive patients undergoing percutaneous mitral valve repair using the MitraClip device was managed either by manual compression, "figure eight" suture and compression bandage for 12 hours, or by applying the Proglide device for haemostasis after the procedure (40 patients each group). Patients with Proglide closure showed complete immediate haemostasis in 92.5% (37/40) and were immobilised with a compression bandage for only four hours. In the Proglide group, one arteriovenous fistula was observed and had to be treated by vascular surgery. The overall duration of stay on an intensive care unit was significantly reduced in the Proglide group (59.4±48.9 hours vs. 84.6±59.5 hours, p<0.005). CONCLUSIONS: Using a suture-mediated closure device for the femoral vein after percutaneous MitraClip implantation is feasible and safe. This allows earlier patient mobilisation and may reduce post-interventional duration of stay on an intensive care unit.

Microbubbles as a vehicle for gene and drug delivery: current clinical implications and future perspectives.

Ultrasound targeted microbubble destruction (UTMD) has evolved as a novel system for non-invasive, organ- and tissue-specific drug and gene delivery. Initially developed as ultrasound contrast agents, microbubbles (MBs) have increasingly gained attention for their ability to directly deliver different classes of bioactive substances (e.g. genes, drugs, proteins, gene silencing constructs) to various organ systems and tumors. Bioactive substances can be attached to or incorporated in the microbubble shells. Applying ultrasound at their resonance frequency, microbubbles oscillate. When using higher ultrasound energies, oscillation amplitudes increase, finally resulting in microbubble destruction. This leads to increased capillary and cell membrane permeability in the immediate vicinity of the ruptured MBs, thus facilitating tissue and cell penetration of co-administered or loaded bioactive substances. Numerous proof of principle studies have been performed, demonstrating the broad potential of UTMD as a site-specific, non-invasive therapeutic tool, delivering microbubble payload to various target tissues and organ systems or facilitating uptake of bioactive substances into tissues or cells. This review focuses on current in vivo studies and therapeutic approaches of UTMD. Promising results give hope for future clinical applications of this novel non-viral vector system. Nevertheless, several limitations remain, which will also be discussed in this review article.

New doxorubicin-loaded phospholipid microbubbles for targeted tumor therapy: in-vivo characterization.

Doxorubicin(DOX) is a potent chemotherapy drug that is often limited by severe adverse effects such as cardiac toxicity and myelosupression. Drug targeting with non invasive techniques would be desirable, aiming at increased local drug concentration and reduced systemic side effects. Ultrasound(US) targeted destruction of drug loaded microbubbles(MBs) has evolved as a promising strategy for non invasive local gene and drug delivery. A recently developed novel DOX-loaded microbubble (DOX-MB) formulation was previously tested in-vitro, with optimal DOX loading capacity, ideal physical characteristics and preserved antiproliferative efficacy. The aim of this study was to evaluate applicability and efficacy of DOX-loaded MBs in a pancreas carcinoma model of the rat. First, immediate toxicity was tested in rats ruling out in-vivo MB agglomeration/capillary adhesion with subsequent embolisation/occlusion of the pulmonary vasculature. In a second set of experiments, tumors derived from pancreas carcinomas were implanted in both flanks of Lewis rats. After establishing the tumors, DOX-MBs were administered intravenously while one of the two tumors was exposed to US (1.3 MHz; mechanical index 1.6). DOX tissue concentration was measured in tumors and control organs after the experiment. Finally, efficacy of US targeted destruction of DOX-MBs in tumors was studied, looking at tumor growth after two therapeutic applications. All rats survived the DOX-MB administration without any sign of embolisation/occlusion of the pulmonary vasculature. US targeted destruction of DOX-MBs leads to a 12-fold higher tissue concentration of DOX and a significantly lower tumor growth in the target tumor compared to the contralateral control tumor. In conclusion, novel DOX-loaded MBs can be safely administered to rats, leading to a relevant increase in local drug concentration and reduction in tumor growth.

Ultrasound targeted microbubble destruction for drug and gene delivery.

BACKGROUND: Gas-filled microbubbles have been used as ultrasound contrast agents for some decades. More recently, such microbubbles have evolved as experimental tools for organ- and tissue-specific drug and gene delivery. When sonified with ultrasound near their resonance frequency, microbubbles oscillate. With higher ultrasound energies, oscillation amplitudes increase, leading to microbubble destruction. This phenomenon can be used to deliver a substance into a target organ, if microbubbles are co-administered loaded with drugs or gene therapy vectors before i.v. injection. OBJECTIVE: This review focuses on different experimental applications of microbubbles as tools for drug and gene delivery. Different organ systems and different classes of bioactive substances that have been used in previous studies will be discussed. METHODS: All the available literature was reviewed to highlight the potential of this non-invasive, organ-specific delivery system. CONCLUSION: Ultrasound targeted microbubble destruction has been used in various organ systems and in tumours to successfully deliver drugs, proteins, gene therapy vectors and gene silencing constructs. Many proof of principle studies have demonstrated its potential as a non-invasive delivery tool. However, too few large animal studies and studies with therapeutic aims have been performed to see a clinical application of this technique in the near future. Nevertheless, there is great hope that preclinical large animal studies will confirm the successful results already obtained in small animals.