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BACKGROUND Tricuspid regurgitation (TR) has a poor prognosis and limited treatment options and is frequently accompanied by right ventricular (RV) dysfunction. Transcatheter tricuspid valve interventions (TTVI) to reduce TR have been shown to be safe and feasible with encouraging early results. Patient selection for TTVI remains challenging, with the role of right ventricular (RV) function being unknown. AIMS The aims of this study were 1) to investigate survival in a TTVI-treated patient population and a conservatively treated TR population, and 2) to evaluate the outcome of TTVI as compared to conservative treatment stratified according to the degree of RV function. METHODS We studied 684 patients from the multicentre TriValve cohort (TTVI cohort) and compared them to 914 conservatively treated patients from two tertiary care centres. Propensity matching identified 213 pairs of patients with severe TR. As we observed a non-linear relationship of RV function and TTVI outcome, we stratified patients according to tricuspid annular plane systolic excursion (TAPSE) to preserved (TAPSE >17 mm), mid-range (TAPSE 13-17 mm) and reduced (TAPSE

Objectives The aim of this study was to investigate age-related outcomes of patients undergoing transcatheter aortic valve replacement (TAVR) as assessed in a nationwide, prospective, multicenter cohort study. Background TAVR is the preferred treatment for elderly patients with severe aortic stenosis and is expanding into lower age groups. Methods Data from the SwissTAVI Registry were analyzed. Clinical outcomes were compared between patients 70 years of age or younger (n = 324), 70 to 79 years of age (n = 1,913), 80 to 89 years of age (n = 4,353), and older than 90 years of age (n = 507). Observed deaths were correlated with expected deaths in the general Swiss population using standardized mortality ratios. Results Between February 2011 and June 2018, 7,097 patients (mean age 82.0 ± 6.4 years, 49.6% women) underwent TAVR at 15 hospitals in Switzerland. Procedural characteristics were similar; however, older patients more often had discharge to the referring hospital or a rehabilitation facility after TAVR. Using adjusted analyses, a linear trend for mortality (30-day adjusted hazard ratio [HRadj]: 1.45; 95% confidence interval [CI]: 1.18 to 1.77; 1-year HRadj: 1.12; 95% CI: 1.01 to 1.24), cerebrovascular accidents (30-day HRadj: 1.35; 95% CI: 1.09 to 1.66; 1-year HRadj: 1.21; 95% CI: 1.02 to 1.45), and pacemaker implantation (30-day HRadj: 1.23; 95% CI: 1.12 to 1.34; 1-year HRadj: 1.19; 95% CI: 1.09 to 1.30) was observed with increasing age. Furthermore, standardized mortality ratios were 12.63 (95% CI: 9.06 to 17.58), 4.09 (95% CI: 3.56 to 4.74), 1.63 (95% CI: 1.50 to 1.78), and 0.93 (95% CI: 0.76 to 1.14) for TAVR patients in relation to the Swiss population Conclusions Increasing age is associated with a linear trend for mortality, stroke, and pacemaker implantation during early and longer-term follow-up after TAVR. Standardized mortality ratios were higher for TAVR patients younger than 90 years of age compared with expected rates of mortality in an age- and sex-matched Swiss population. (SWISS TAVI Registry; NCT01368250 )

BackgroundGiant coronary artery aneurysms (CAAs) are rare and treatment strategies various, especially in the setting of a concomitant abdominal aortic aneurysm (AAA) which needs urgent repair.Case summaryA 78-year-old Caucasian male was admitted for evaluation of a rapidly expanding AAA. In addition, computed tomography angiography revealed a 5 x 4 cm giant aneurysm of the right coronary artery. After interdisciplinary discussion, the patient underwent aorto-bi-iliac bypass grafting first. In a second step, CAA was successfully excluded and coronary artery bypass grafting of the right coronary artery was performed.DiscussionTreatment strategy of CAA and timing of non-cardiac surgery is challenging. In order to minimize the overall risk of rupture interdisciplinary discussion is crucial. In our case, aorto-bi-iliac bypass grafting was safely performed, and the patient underwent successful CAA excision in a second step.

Objectives The interference of a transtricuspid cardiac implantable electronic device (CIED) lead with tricuspid valve function may contribute to the mechanism of tricuspid regurgitation (TR) and poses specific therapeutic challenges during transcatheter tricuspid valve intervention (TTVI). Feasibility and efficacy of TTVI in presence of a CIED is unclear. Background Feasibility of TTVI in presence of a CIED lead has never been proven on a large basis. Methods The study population consisted of 470 patients with severe symptomatic TR from the TriValve (Transcatheter Tricuspid Valve Therapies) registry who underwent TTVI at 21 centers between 2015 and 2018. The association of CIED and outcomes were assessed. Results Pre-procedural CIED was present in 121 of 470 (25.7%) patients. The most frequent location of the CIED lead was the posteroseptal commissure (44.0%). As compared with patients without a transvalvular lead (no-CIED group), patients having a tricuspid lead (CIED group) were more symptomatic (New York Heart Association functional class III to IV in 95.9% vs. 92.3%; p = 0.02) and more frequently had previous episodes of right heart failure (87.8% vs. 69.0%; p = 0.002). No-CIED patients had more severe TR (effective regurgitant orifice area 0.7 ± 0.6 cm2 vs. 0.6 ± 0.3 cm2; p = 0.02), but significantly better right ventricular function (tricuspid annular plane systolic excursion = 16.7 ± 5.0 mm vs. 15.9 ± 4.0 mm; p = 0.04). Overall, 373 patients (79%) were treated with the MitraClip (Abbott Vascular, Santa Clara, California) (106 [87.0%] in the CIED group). Among them, 154 (33%) patients had concomitant transcatheter mitral repair (55 [46.0%] in the CIED group, all MitraClip). Procedural success was achieved in 80.0% of no-CIED patients and in 78.6% of CIED patients (p = 0.74), with an in-hospital mortality of 2.9% and 3.7%, respectively (p = 0.70). At 30 days, residual TR ≤2+ was observed in 70.8% of no-CIED and in 73.7% of CIED patients (p = 0.6). Symptomatic improvement was observed in both groups (NYHA functional class I to II at 30 days: 66.0% vs. 65.0%; p = 0.30). Survival at 12 months was 80.7 ± 3.0% in the no-CIED patients and 73.6 ± 5.0% in the CIED patients (p = 0.30). Conclusions TTVI is feasible in selected patients with CIED leads and acute procedural success and short-term clinical outcomes are comparable to those observed in patients without a transtricuspid lead.

Background The percutaneously implanted hemodynamic mechanical support devices Impella are commonly used in patients at risk for or with cardiogenic shock (CS). Impella removal after hemodynamic stabilization on the intensive care unit (ICU) remains a major challenge and is prone to high rates of bleeding and vascular complications. Purpose It is unknown if the use of the novel large-bore access closure device MANTA® is safe and facilitates access management compared to manual compression. Methods Between January 2017 and December 2020, 172 CS patients were treated with an Impella® device at our centre. Of those, in 89 patients the Impella® was removed on the ICU and access site management occurred with either MANTA® device or manual compression. The criteria for MANTA® 14 french device deployment included: (i) femoral artery Diameter >6mm and (ii) absence of significant peripheral arterial disease (PAD). Bleeding and vascular access site complications were assessed and adjudicated according to the Valve Academic Research Consortium-2 (VARC-2) criteria. Results Among the 89 included patients, Impella® removal was performed using the MANTA® device in 31 cases and manual compression in 58 cases. Mean age was 66±11 years, and 50 (56.2%) patients had a CS classified as Society for Cardiovascular Angiography and Interventions (SCAI) D or higher due to myocardial infarction. Median support time was 40 (IQR 24; 69) hours. Baseline characteristics are displayed in Table 1. Immediate haemostasis was more frequently achieved by MANTA® device compared to manual compression (p=0.034). Moreover, we observed significantly less overall (2 (6.5%) vs. 22 (37.9%), p=0.001) and minor bleedings (1 (3.2%) vs. 15 (25.9%), p=0.006) with the MANTA® device when compared to manual compression. Of note, there were no significant differences in vascular complications between the two groups (Table 2). Conclusions In patients requiring Impella® support and residing on ICU, the MANTA® device, compared to standard of care manual compression, seems to be a safe and effective option for access site management, especially with regards to the reduction of bleeding events. However, physicians should carefully assess the vascular anatomy and degree of calcification prior to deployment of the MANTA® device. Nevertheless, more prospective data is necessary for evaluating the optimal access closure among CS patients treated with a percutaneously implanted Impella® device. Funding Acknowledgement Type of funding sources: None. Table 1. Baseline demographicsTable 2. Outcomes

Background Severe mitral regurgitation (MR) conveys significant morbidity and mortality, and surgical repair or replacement may not be a desirable option. Objectives The purpose of this study was to evaluate the feasibility of a percutaneous transseptal transcatheter mitral valve replacement (TMVR) system. Methods This first-in-human study was conducted between August 2017 and August 2018. The system comprises a nitinol dock, which encircles the chordae tendineae, and a balloon-expandable transcatheter heart valve. The dock and transcatheter heart valve form an ensemble, with the native mitral valve leaflets secured in between, thereby abolishing MR. Key inclusion criteria were severe symptomatic MR and high surgical risk; exclusion criteria included left ventricular ejection fraction 1, mitral gradient >6 mm Hg, left ventricular outflow tract gradient >20 mm Hg) at 30 days. Results Ten patients with severe MR of various etiologies (4 degenerative, 4 functional, and 2 mixed) were treated. The device was successfully implanted and the primary endpoint was achieved in 9 of 10 patients (90%). By transesophageal echocardiography, total MR was reduced to ≤ trivial in all implanted patients, and mean transmitral gradient was 2.3 ± 1.4 mm Hg. A pericardial effusion occurred in 1 patient: pericardiocentesis was performed, and the device was not implanted. Median length of hospital stay was 1.5 days. At 30 days, there was no stroke, myocardial infarction, rehospitalization, left ventricular outflow tract obstruction, device migration, embolization, or conversion to mitral surgery. One patient had recurrent regurgitation due to a paravalvular leak, treated with a closure device. All other treated patients had ≤1+ MR. No patients died. Conclusions Percutaneous transvenous transseptal TMVR is feasible and safe in patients with severe MR who are at high risk for mitral valve surgery. Further evaluation is warranted.

BACKGROUND: Inflammation plays a pivotal role in coronary artery disease (CAD). The anti- inflammatory drug colchicine seems to reduce ischemic events in patients with CAD. So far there is equipoise about its safety and impact on mortality METHODS AND RESULTS: To evaluate the utility of colchicine in patients with acute and chronic CAD, we performed a systematic review and meta- analysis. MEDLINE, EMBASE, Cochrane CENTRAL and conference abstracts were searched from January 1975 to October 2020. Randomized trials assessing colchicine compared with placebo/standard therapy in patients with CAD were included. Data were combined using random- effects models. The reliability of the available data was tested using trial sequential analyses. Of 3108 citations, 13 randomized trials (n=13 125) were included. Colchicine versus placebo/standard therapy in patients withCAD reduced risk of myocardial infarction (odds ratio [OR] 0.64; 95% CI, 0.46 ��� 0.90; P= 0.01; I 41%) and stroke/transient ischemic attack (OR 0.50; 95% CI, 0.31��� 0.81; P=0.005; I 0%). But treatment with colchicine compared with placebo/standard therapy had no influence on all- cause and cardiovascular mortality (OR 0.96; 95% CI, 0.65��� 1.41; P=0.83; I 24%; and OR 0.82; 95% CI, 0.55��� 1.22; P=0.45; I 0%, respectively). Colchicine increased the risk for gastrointestinal side effects (P, + ID der Publikation: unilu_54969 + Sprache: Englisch + Letzte Aktualisierung: 2021-10-27 16:06:46

OBJECTIVES Report MANTA-associated vascular complications after implementation of key insights on failure mechanisms. BACKGROUND The MANTA vascular closure device is utilized to close large-bore arterial access sites. We have previously identified and published the mechanisms and predictors of MANTA-associated vascular complications. We identified three distinct mechanisms leading to MANTA-associated vascular complications, predictors were a common femoral artery (CFA) diameter

BACKGROUND Scarce data exist on patients with previous left valve surgery (PLVS) undergoing transcatheter tricuspid valve intervention (TTVI). This study sought to investigate the procedural and early outcomes in patients with PLVS undergoing TTVI. METHODS This was a subanalysis of the multicenter TriValve registry including 462 patients, 82 (18%) with PLVS. Data were analyzed according to the presence of PLVS in the overall cohort and in a propensity score-matched population including 51 and 115 patients with and without PLVS, respectively. RESULTS Patients with PLVS were younger (72 �� 10 vs 78 �� 9 years; p < 0.01) and more frequently female (67.1% vs 53.2%; P��= 0.02). Similar rates of procedural success (PLVS 80.5%; no-PLVS 82.1%; P��= 0.73), and 30-day mortality (PLVS 2.4%, no-PLVS 3.4%; P��= 0.99) were observed. After matching, there were no significant differences in both all-cause rehospitalisation (PLVS 21.1%, no-PLVS 26.5%; P��= 0.60) and all-cause mortality (PLVS 9.8%, no-PLVS 6.7%; P��= 0.58). At last follow-up (median 6 [interquartile range 1-12] months after the procedure), most patients (81.8%) in the PLVS group were in NYHA functional class I-II (P��= 0.12 vs no-PLVS group), and TR grade was ��� 2 in 82.6% of patients (P��= 0.096 vs no-PVLS group). A poorer right ventricular function and previous heart failure hospitalization determined increased risks of procedural failure and poorer outcomes at follow-up, respectively. CONCLUSIONS In patients with PLVS, TTVI was associated with high rates of procedural success and low early mortality. However, about one-third of patients required rehospitalisation or died at midterm follow-up. These results would support TTVI as a reasonable alternative to redo surgery in patients with PLVS and suggest the importance of earlier treatment to improve clinical outcomes.

Background: Scarce data exist on patients with right ventricular dysfunction (RVD) or pulmonary hypertension (PH) undergoing transcatheter tricuspid valve intervention. This study aimed to determine the early and midterm outcomes and the factors associated with mortality in this group of patients. Methods: This subanalysis of the multicenter TriValve (Transcatheter Tricuspid Valve Therapies) registry included 300 patients with severe tricuspid regurgitation with RVD (n=244), PH (n=127), or both (n=71) undergoing transcatheter tricuspid valve intervention. RVD was defined as a tricuspid annular plane systolic excursion Results: Mean age of the patients was 77±9 years (54% women). Procedural success was 80.7%, and 9 patients (3%) died during the hospitalization. At a median follow-up of 6 (interquartile range, 2–12) months, 54 patients (18%) died, and the independent associated factors were higher gamma-glutamyl transferase values at baseline (hazard ratio, 1.02 for each increase of 10 u/L [95% CI, 1.002–1.04]), poorer renal function defined as an estimated glomerular filtration rate P Conclusions: In patients with severe tricuspid regurgitation and RVD/PH, transcatheter tricuspid valve intervention was associated with high procedural success and a relatively low in-hospital mortality, along with significant improvements in functional status. However, about 1 out of 5 patients died after a median follow-up of 6 months, with hepatic congestion, renal dysfunction, and the lack of procedural success determining an increased risk. These results may improve the clinical evaluation of transcatheter tricuspid valve intervention candidates and would suggest a closer follow-up in those at increased risk. Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT03416166.

ObjectivesReport predictors and the natural course of paravalvular leak (PVL) following implantation of the ACURATE neo transcatheter heart valve (THV).BackgroundUnderstanding the mechanisms of PVL may help to improve patient selection, patient outcomes and the design of next-generation THVs.MethodsA total of 30 patients (mean age 81±5 years, 47% women) undergoing transcatheter aortic valve replacement with the ACURATE neo were enrolled in the PREDICT PVL study. The effective regurgitant orifice area (EROA, in mm2) of PVL was assessed by transthoracic and transoesophageal echocardiography before discharge and at 6 months follow-up.ResultsPVL was none/trace in 10 (33%), mild in 18 (60%) and moderate in 2 (7%) patients and occurred in distinct locations with largest EROAs in the area of the left coronary cusp and its adjacent commissures. Independent predictors for EROA were implantation depth (r coefficient −1.9 mm2 per mm implantation depth, p=0.01), leaflet calcification (6.2 mm2 per calcification grade, p=0.03) and THV size L (7.6 mm2 more than size S or M, p=0.01). At 6 months follow-up, EROA decreased by 29% from 13.7±9.7 mm2 to 9.5±7.9 mm2 (pConclusionsPVL occurred predominantly in the region of the left coronary cusp and decreased by 29% during 6 months of follow-up. Our results underscore the importance of adequate patient selection and optimal implantation depth.

Introduction CT measurement of supra-annular area (SA) has been proposed as an alternative to annular area (AA) for sizing of trancatheter valves in biscuspid aortic valves (BAV). This study examines the reproducibility of SA and AA measurements and their potential impact on downstream transcatheter heart valve sizing and clinical outcomes. Methods 44 consecutive patients (mean age: 73±15 years, 57% male) undergoing CTA with subsequent SAPIEN 3 valve insertion for severe bicuspid aortic stenosis (AS) were included. AA was measured at the basal ring. SA was measured by generating a circle defined by the intercommisural distance. AA and SA were measured by 2 independent observers. Baseline characteristics, TAVR procedural data, and discharge echocardiography data were collected. Results The SA was significantly larger than the AA (562±146 mm2 vs. 518±112 mm2,p=0.013). Interobserver agreement was high using both techniques (ICC AA=0.98,p Conclusion Supra-annular sizing is less reproducible than annular sizing, with no difference in procedural complication rates in patients in whom supra-annular sizing would have altered the device size used. These results suggest no role for supra-annular sizing in current clinical practice.

Chronic kidney disease (CKD) has a negative impact on outcomes after transcatheter aortic valve replacement (TAVR). Data on outcomes in renal transplant recipients (RTRs) undergoing TAVR are scarce. We compared the outcomes in RTRs undergoing TAVR with matched patients who have native kidneys and similar kidney function.This retrospective cohort study used data from 16 TAVR centres (13,941 patients). The study cohort included 216 patients (72 RTRs and 144 matched controls).The mean estimated glomerular filtration rate (eGFR) was 39.2 ± 23.6 vs 44.5 ± 23.6 mL/min for RTRs and control patients (P = 0.149), with a similar CKD stage distribution. After TAVR, the eGFR declined among RTRs but remained stable for up to 1 year in controls (P = 0.021). Long-term hemodialysis was required in 19 (26.4%) RTRs and 20 (13.8%) controls (hazard ratio [HR] = 2.09 95% confidence interval [CI], 1.03-3.86; P = 0.039) and was most often initiated during the periprocedural period (14 RTRs vs 16 controls; P = 0.039). After a median follow-up of 2.3 years, risk of death (29.2% vs 31.9%) and death/hemodialysis (40.3% vs 36.8%) was similar between the groups. The contrast volume/eGFR ratio was the strongest predictor of hemodialysis initiation (odds ratio [OR] = 1.64; 95% CI, 1.36-1.97 per 1 unit increase; P0.001), with a greater effect among RTRs than controls (P for interaction = 0.022).s: TAVR appears safe in RTRs with mortality rates similar to matched patients with native kidneys. However, RTRs carry an increased risk of progressive renal impairment and need for hemodialysis initiation after TAVR. Our data highlight the importance of minimizing contrast load during TAVR, particularly in RTRs.

Objectives A large, prospective international registry was developed to evaluate the initial clinical applications of transcatheter tricuspid valve intervention (TTVI) with different devices. Background TTVI for native tricuspid valve dysfunction has been emerging during the last few years as an alternative therapeutic option to serve a large high-risk population of patients with severe symptomatic tricuspid regurgitation (TR). Methods The TriValve Registry included 312 high-risk patients with severe TR (76.4 ± 8.5 years of age; 57% female; EuroSCORE II 9 ± 8%) at 18 centers. Interventions included repair at the level of the leaflets (MitraClip, Abbott Vascular, Santa Clara, California; PASCAL Edwards Lifesciences, Irvine, California), annulus (Cardioband, Edwards Lifesciences; TriCinch, 4tech, Galway, Ireland; Trialign, Mitraling, Tewksbury, Massachusetts), or coaptation (FORMA, Edwards Lifesciences) and replacement (Caval Implants, NaviGate, NaviGate Cardiac Structures, Lake Forest, California). Clinical outcomes were prospectively determined during mid-term follow-up. Results A total of 108 patients (34.6%) had prior left heart valve intervention (84 surgical and 24 transcatheter, respectively). TR etiology was functional in 93%, and mean annular diameter was 46.9 ± 9 mm. In 75% of patients the regurgitant jet was central (vena contracta 1.1 ± 0.5; effective regurgitant orifice area 0.78 ± 0.6 cm2). Pre-procedural systolic pulmonary artery pressure was 41 ± 14.8 mm Hg. Implanted devices included: MitraClip in 210 cases, Trialign in 18 cases, TriCinch first generation in 14 cases, caval valve implantation in 30 cases, FORMA in 24 cases, Cardioband in 13 cases, NaviGate in 6 cases, and PASCAL in 1. In 64% of the cases, TTVI was performed as a stand-alone procedure. Procedural success (defined as the device successfully implanted and residual TR ≤2+) was 72.8%. Greater coaptation depth (odds ratio: 24.1; p = 0.002) was an independent predictor of reduced device success. Thirty-day mortality was 3.6% and was significantly lower among patients with procedural success (1.9% vs. 6.9%; p = 0.04); Actuarial survival at 1.5 years was 82.8 ± 4% and was significantly higher among patients who had procedural success achieved. Conclusions TTVI is feasible with different technologies, has a reasonable overall procedural success rate, and is associated with low mortality and significant clinical improvement. Mid-term survival is favorable in this high-risk population. Greater coaptation depth is associated with reduced procedural success, which is an independent predictor of mortality.

BACKGROUND Tricuspid regurgitation is associated with increased rates of heart failure (HF) and mortality. Transcatheter tricuspid valve interventions (TTVI) are promising, but the clinical benefit is unknown. OBJECTIVES The purpose of this study was to investigate the potential benefit of TTVI over medical therapy in a propensity score matched population. METHODS The TriValve (Transcatheter Tricuspid Valve Therapies) registry collected 472 patients from 22 European and North American centers who underwent TTVI from 2016 to 2018. A control cohort formed by 2 large retrospective registries enrolling medically managed patients with >= moderate tricuspid regurgitation in Europe and North America (n = 1,179) were propensity score 1:1 matched (distance +/- 0.2 SD) using age, EuroSCORE II, and systolic pulmonary artery pressure. Survival was tested with Cox regression analysis. Primary endpoint was 1-year mortality or HF rehospitalization or the composite. RESULTS After matching, 268 adequately matched pairs of patients were identified. Compared with control subjects, TTVI patients had lower 1-year mortality (23 +/- 3% vs. 36 +/- 3%; p = 0.001), rehospitalization (26 +/- 3% vs. 47 +/- 3%; p < 0.0001), and composite endpoint (32 +/- 4% vs. 49 +/- 3%; p = 0.0003). TTVI was associated with greater survival and freedom from HF rehospitalization (hazard ratio [HR]: 0.60; 95% confidence interval [CI]: 0.46 to 0.79; p = 0.003 unadjusted), which remained significant after adjusting for sex, New York Heart Association functional class, right ventricular dysfunction, and atrial fibrillation (HR: 0.39; 95% CI: 0.26 to 0.59; p < 0.0001) and after further adjustment for mitral regurgitation and pacemaker/defibrillator (HR: 0.35; 95% CI: 0.23 to 0.54; p < 0.0001). CONCLUSIONS In this propensity-matched case-control study, TTVI is associated with greater survival and reduced HF rehospitalization compared with medical therapy alone. Randomized trials should be performed to confirm these results. (C) 2019 by the American College of Cardiology Foundation.

BackgroundEarly studies evaluating the performance of bioresorbable scaffold (BRS) Absorb in in-stent restenosis (ISR) lesions indicated promising short-term to mid-term outcomes.AimsTo evaluate long-term outcomes (up to 5 years) of patients with ISR treated with the Absorb BRS.MethodsWe did an observational analysis of long-term outcomes of patients treated for ISR using the Absorb BRS (Abbott Vascular, Santa Clara, California, USA) between 2013 and 2016 at the Heart Centre Luzern. The main outcomes included a device-oriented composite endpoint (DOCE), defined as composite of cardiac death, target vessel (TV) myocardial infarction and TV revascularisation, target lesion revascularisation and scaffold thrombosis (ScT).ResultsOverall, 118 ISR lesions were treated using totally 131 BRS among 89 patients and 31 (35%) presented with an acute coronary syndrome. The median follow-up time was 66.3 (IQR 52.3–77) months. A DOCE had occurred in 17% at 1 year, 27% at 2 years and 40% at 5 years of all patients treated for ISR using Absorb. ScTs were observed in six (8.4%) of the cohort at 5 years.ConclusionsTreatment of ISR using the everolimus-eluting BRS Absorb resulted in high rates of DOCE at 5 years. Interestingly, while event rates were low in the first year, there was a massive increase of DOCE between 1 and 5 years after scaffold implantation. With respect to its complexity, involving also a more unpredictable vascular healing process, current and future BRS should be used very restrictively for the treatment of ISR.

Objectives This study sought to develop a large, international registry to evaluate the diffusion of these approaches and investigate patient characteristics and initial clinical results. Background Several transcatheter tricuspid valve therapies are emerging as therapeutic options for patients with severe symptomatic tricuspid regurgitation (TR), generally a high-risk surgical population. Methods The TriValve (Transcatheter Tricuspid Valve Therapies) registry included 106 high-risk patients (76 ± 9 years of age; 60.4% women; European System for Cardiac Operative Risk Evaluation II 7.6 ± 5.7%) from 11 cardiac centers, with severe TR. Results A total of 35% of the patients had prior left heart valve intervention (surgical in 29 of 106 and transcatheter in 8 of 106 patients). Right ventricular (RV) dysfunction (tricuspid annular plane systolic excursion Conclusions Patients currently undergoing transcatheter tricuspid valve therapy are mostly high risk, with a functional etiology and very severe central regurgitation, and do not have severely impaired RV function. Initial results suggest that transcatheter tricuspid valve therapy is feasible with different techniques, but clinical efficacy requires further investigation.

Background Smartphone manufacturers offer mobile health monitoring technology to their customers, including apps using the built-in camera for heart rate assessment. This study aimed to test the diagnostic accuracy of such heart rate measuring apps in clinical practice. Methods The feasibility and accuracy of measuring heart rate was tested on four commercially available apps using both iPhone 4 and iPhone 5. 'Instant Heart Rate' (IHR) and 'Heart Fitness' (HF) work with contact photoplethysmography (contact of fingertip to built-in camera), while 'Whats My Heart Rate' (WMH) and 'Cardiio Version' (CAR) work with non-contact photoplethysmography. The measurements were compared to electrocardiogram and pulse oximetry-derived heart rate. Results Heart rate measurement using app-based photoplethysmography was performed on 108 randomly selected patients. The electrocardiogram-derived heart rate correlated well with pulse oximetry ( r = 0.92), IHR ( r = 0.83) and HF ( r = 0.96), but somewhat less with WMH ( r = 0.62) and CAR ( r = 0.60). The accuracy of app-measured heart rate as compared to electrocardiogram, reported as mean absolute error (in bpm ± standard error) was 2 ± 0.35 (pulse oximetry), 4.5 ± 1.1 (IHR), 2 ± 0.5 (HF), 7.1 ± 1.4 (WMH) and 8.1 ± 1.4 (CAR). Conclusions We found substantial performance differences between the four studied heart rate measuring apps. The two contact photoplethysmography-based apps had higher feasibility and better accuracy for heart rate measurement than the two non-contact photoplethysmography-based apps.

Background: There has been a renewed interest in balloon aortic valvuloplasty (BAV) since the inception of transcatheter aortic valve replacement (TAVR) in treating aortic stenosis (AS). This study...

Spontaneous recanalized coronary thrombi (SRCT), a rare and under-diagnosed entity, are old thrombus formations characterized by multiple communicating channels. We report the case of a 72-year-old female patient who presented with SRCT in the context of polycythemia vera. Optical coherence tomography (OCT) is the diagnostic method of choice. (Level of Difficulty: Intermediate.), Graphical abstract, Spontaneous recanalized coronary thrombi (SRCT), a rare and under-diagnosed entity, are old thrombus formations characterized by multiple…

Objectives The aim of this study was to assess the clinical outcome of baseline massive or torrential tricuspid regurgitation (TR) after transcatheter tricuspid valve intervention (TTVI). Background The use of TTVI to treat symptomatic severe TR has been increasing rapidly, but little is known regarding the impact of massive or torrential TR beyond severe TR. Methods The study population comprised 333 patients with significant symptomatic TR from the TriValve Registry who underwent TTVI. Mid-term outcomes after TTVI were assessed according to the presence of massive or torrential TR, defined as vena contracta width ≥14 mm. Procedural success was defined as patient survival after successful device implantation and delivery system retrieval, with residual TR ≤2+. The primary endpoint comprised survival rate and freedom from rehospitalization for heart failure, survival rate, and rehospitalization at 1 year. Results Baseline massive or torrential TR and severe TR were observed in 154 patients (46.2%) and 179 patients (53.8%), respectively. Patients with massive or torrential TR had a higher prevalence of ascites than those with severe TR (27.3% vs. 20.4%, respectively; p = 0.15) and demonstrated a similar procedural success rate (83.2% vs. 77.3%, respectively; p = 0.21). The incidence of peri-procedural adverse events was low, with no significant between-group differences. Freedom from the composite endpoint was significantly lower in patients with massive or torrential TR than in those with severe TR, which was significantly associated with an increased risk for 1-year death of any cause or rehospitalization for heart failure (adjusted hazard ratio: 1.91; 95% confidence interval: 1.10 to 3.34; p = 0.022). Freedom from the composite endpoint was significantly higher in patients with massive or torrential TR when procedural success was achieved (69.9% vs. 54.2%, p = 0.048). Conclusions Baseline massive or torrential TR is associated with an increased risk for all-cause mortality and rehospitalization for heart failure 1 year after TTVI. Procedural success is related to better outcomes, even in the presence of baseline massive or torrential TR. (International Multisite Transcatheter Tricuspid Valve Therapies Registry [TriValve]; NCT03416166)

Introduction: Transcatheter aortic valve implantation (TAVI) is the preferred treatment for elderly patients with severe aortic stenosis and is expanding into lower age groups. We investigated age-related outcomes of patients undergoing TAVI as assessed in a nationwide, prospective, multicenter cohort study. Methods: We analyzed data from the SwissTAVI Registry. Clinical outcomes were compared between patients aged 70years or younger (n=324), 70-79years (n=1913), 80-89years (n=4353) and older than 90years (n=507). Observed deaths were correlated with expected deaths in the general Swiss population using standardized mortality ratios (SMR). Results: Between 02/2011 and 06/2018, 7097 patients (age 82·0±6.4years, 49·6%females) underwent TAVI at 15 hospitals in Switzerland. Procedural characteristics were similar; however, older patients more often had discharge to the referring hospital or a rehabilitation facility after TAVI. Using adjusted analyses, a linear trend for mortality (30-day HRadj 1·45; 95%CI 1·18-1·77; 1-year HRadj 1·12; 95%CI 1·01-1·24), cerebrovascular accidents (30-day HRadj 1·35; 95%CI 1·09-1·66; 1-year HRadj 1·21; 95%CI 1·02-1·45) and pacemaker implantation (30-day HRadj 1·23; 95%CI 1·12-1·34; 1-year HRadj 1·19; 95%CI 1·09-1·30) was observed with increasing age. Furthermore, SMRs were 12·63(95%CI 9·06-17·58), 4·09(3·56-4·74), 1·63(1·50-1·78) and 0·93(0·76-1·14) for TAVI patients in relation to the Swiss population

PURPOSE: To examine the prognostic implication of fractional flow reserve (FFR) derived from coronary CT (FFR(CT)) in routine clinical practice. MATERIALS AND METHODS: Patients referred for FFR(CT) analysis at a single center between October 2015 and June 2017 were retrospectively included and followed up for rates of invasive angiography and clinical events. Two hundred seven patients underwent successful FFR(CT) analysis with seven lost to follow-up, leaving 200 (mean age ± standard deviation, 62.4 years ± 10.0; 49 [24.5%] women) patients for analysis. At coronary CT angiography, patients were categorized as having significant stenosis (SS) in the presence of a diameter stenosis greater than or equal to 50% (hereafter, SS positive) and flow limitation in the presence of a postlesion (that is, FFR(CT) measured 2 cm to the distal aspect of the lesion) FFR(CT) less than 0.80 (hereafter, FFR(CT) positive). Vessel-oriented clinical events (VOCEs) were defined as vessel-related late revascularization (>90 days), myocardial infarction, and cardiac mortality. RESULTS: At CT angiography, 130 (65%) studies were SS positive and 63 (31.5%) were FFR(CT) positive. At median follow-up of 477 days (range, 252–859 days), there were 26 VOCE end points in 22 patients: 22 revascularizations and four nonfatal myocardial infarctions. VOCE end points occurred in zero of 58 (0%) of SS-negative and FFR(CT) negative patients, in eight of 79 (10.1%) of SS-positive and FFR(CT)-negative patients, in zero of 12 (0%) of SS-negative and FFR(CT)-positive patients, and in 18 of 51 (35.3%) of SS-positive and FFR(CT)-positive patients (log-rank χ(2) = 30.1; P < .001). At multivariable Cox regression, both FFR(CT) (hazard ratio per 0.1 decrease, 1.54 [95% confidence interval: 1.1, 2.2] P = .013) and stenosis (hazard ratio per unit increase, 2.16 [95% confidence interval: 1.25, 3.72] P = .006) were independently associated with VOCE. CONCLUSION: Stenosis and FFR(CT) are independent predictors of intermediate-term outcomes. In the absence of a stenosis greater than 50%, a positive FFR(CT) result is not associated with an increased intermediate risk. © RSNA, 2019 Supplemental material is available for this article. See also commentary by Fairbairn and Bull in this issue.

Objectives: To perform clinical and echocardiographic follow-up beyond 1 year in consecutive patients with severe bicuspid aortic stenosis (AS) undergoing transcatheter aortic valve replacement (TAVR) with a current generation balloon-expandable valve. Background: Treatment of bicuspid aortic valve disease with TAVR remains controversial and late follow-up data is still scarce. Methods: We collected baseline characteristics, procedural data, 30-day and mid-term clinical follow-up findings from six centers in Europe and Canada from patients with bicuspid AS treated with TAVR using the SAPIEN 3 valve. Results: Seventy-nine patients underwent TAVR. Mean age was 76 ± 9 years; median STS risk score for mortality was 3.8% (interquartile range 2.3–5.5%). Median follow-up was 390 days (interquartile range 138–739 days). Device success was achieved in 95% of patients. Postimplantation mean aortic gradient decreased from 50.2 ± 16.2 to 8.8 ± 4.4 mmHg and no patient had more than mild aortic regurgitation. At last follow-up, there was persistent good valve performance. At 30 days and 1 year, the rates of all-cause mortality were 3.8 and 7.7%, stroke 1.2 and 1.2%, and the rate of new pacemakers 18 and 18%. Conclusions: Our data confirm that treating patients with stenotic bicuspid aortic valves is safe, effective, and has favorable valve performance over time.

Araris' site-specific conjugation technology is improving the safety and efficacy of ADCs without antibody engineering. Our technology is using transglutaminase for site-specific enzymatic payload conjugation to ‘off-the-shelf' antibodies, i.e., without the need to reduce or engineer the antibody. The functionalization takes place site-specifically and stoichiometrically (drug-to-antibody ratio, DAR = 2) at the glutamine residue Q295 in the Fc-part of antibodies. The resulting ADCs show favorable biophysical properties such as high solubility and stability. Additionally, initial data show that linker conjugation does not interfere with Fc-gamma receptor and FcRn binding. Using native polatuzumab (non-engineered, same antibody sequence as present in approved polatuzumab-vedotin) as the targeting antibody and monomethyl auristatin E (MMAE) as payload, we generated within 24 hours highly homogeneous and pure ADCs with a well-defined DAR of 1.9 (LC-MS). Size exclusion chromatography analysis showed a highly monomeric ADC product (> 96% monomer content) that remained stable under stressed conditions at elevated temperatures. In in-vitro assays our ADCs demonstrated potent cytotoxicity in four tested cell-lines, similar to the approved polatuzumab-vedotin (Polivy®). Moreover, our anti-CD79b ADC (termed ARC-01) is highly stable in mouse, cynomolgus and human sera and is resistant to mouse Ces1c cleavage but is cleaved by the lysosomal human Cathepsin B. Most importantly, the resulting ADC is extremely stable as shown in pharmacokinetic studies in mice demonstrating a very long exposure comparable to the unmodified polatuzumab antibody and twice as long as the approved polatuzumab-vedotin (half-life 10d vs 5d). Most importantly, the in vivo efficacy of our ARC-01 (DAR 1.9) as compared with approved polatuzumab-vedotin (DAR 3.5) was assessed in the Granta-519 tumor model. Animals received a single injection of 0.53 or 2.1 mg/kg polatuzumab-vedotin (Polivy®) and either 0.53, 1 or 2.1 mg/kg of ARC-01. ARC-01 provided equal tumor growth inhibition and survival at about half the payload dose relative to polatuzumab-vedotin (comparison of the 2mg/kg doses and 0.53 mg/kg doses). At an approximately equal payload dose, ARC-01 treatment led to a greater antitumor efficacy and a considerable survival advantage with 6/8 complete tumor remissions over polatuzumab-vedotin with 0/8 complete tumor remission (comparison of the 0.53mg/kg dose of polatuzumab-vedotin and 1mg/kg dose of ARC-01). These encouraging results obtained so far indicate that our linker technology a) allows for fast (< 24 hours) and straightforward manufacturing of ADCs without protein engineering efforts, b) results in ADCs with favorable biophysical properties and a clear defined drug-to-antibody ratio, and c) enables the generation of highly potent and stable, thus safer, next-generation ADCs. Citation Format: Philipp René Spycher, Philipp Probst, Romain Bertrand, Ramona Stark, Roger Santimaria, Dragan Grabulovski, Isabella Attinger-Toller. CD79b targeting ADC with superior pharmacokinetic profile and anti-tumor activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1842.

OBJECTIVE The study in patients with percutaneous left atrial appendage (LAA) occlusion investigates clinical outcomes according to the position of the Amplatzer Cardiac Plug (ACP) disc. BACKGROUND The ACP consists of a disc and an anchoring lobe. The disc is meant to cover the ostium of the LAA, but frequently retracts partially or completely into the neck of the LAA. It is not known whether a retracted disc affects outcome. METHODS Outcomes of 169 consecutive patients (age 73.1 ± 10.4 years; 76% male) with successful LAA closure were analyzed according to the position of the ACP disc: group A had complete coverage of the LAA ostium; in group B the disc prolapsed partially or completely into the LAA-neck. Transesophageal echocardiography was performed 1-6 months after ACP implantation. The safety endpoint was the composite of clinically significant pericardial effusion, device embolization, procedure-related stroke/transient ischemic attack (TIA), major bleeding, or device thrombus. The efficacy endpoint was the composite of death, neurological events (ischemic and hemorrhagic stroke, TIA), or systemic embolism during follow-up. RESULTS Group A comprised 76 patients (age 73.0 ± 9.9 years; 74% male) and group B 93 patients (age 73.3 ± 10.9 years; 79% male). Mean CHA2 DS2 -Vasc score and HASBLED score were 4.2 ± 1.7 (group A 4.3 ± 1.6; group B 4.2 ± 1.8) and 2.9 ± 1.1 (group A 2.9 ± 1.0; group B 3.0 ± 1.2), respectively. Mean follow-up of the study population was 13.0 ± 10.4 months. Overall, the composite safety and efficacy endpoints occurred in 20 (12%) and 6 patients (4%), respectively. There was no significant difference between groups A and B in the occurrence of the safety endpoint (13% vs. 11%, P = 0.64), or the efficacy endpoint (4% vs. 3%, P = 1.0). CONCLUSIONS No evidence for a difference in the occurrence of the safety and efficacy endpoint was found between patients with complete vs. incomplete ACP disc coverage of the LAA ostium. The risk of repositioning attempts in case of incomplete coverage does not seem to be warranted. Current findings need further confirmation in a larger scale clinical trial.

OBJECTIVES The aim of this study was to assess predictors of adverse 1-week outcomes and determine the effect of left atrial appendage (LAA) morphology following LAA closure (LAAC) with Amplatzer devices. BACKGROUND Percutaneous LAAC is a valuable treatment option for stroke prevention in patients with atrial fibrillation. Determinants of procedural safety events with Amplatzer occluders are not well established, and the possibly interrelating effect of LAA anatomy is unknown. METHODS Between 2009 and 2014, 500 consecutive patients with atrial fibrillation ineligible or at high risk for oral anticoagulation underwent LAAC using Amplatzer devices. Procedure- and device-related major adverse events (MAEs) were defined as the composite of death, stroke, major or life-threatening bleeding, serious pericardial effusion, device embolization, major access-site vascular complication, or need for cardiovascular surgery within 7 days following the intervention. RESULTS Patients (mean age 73.9 ± 10.1 years) were treated with Amplatzer Cardiac Plug (n = 408 [82%]) or Amulet (n = 92 [18%]) devices. Early procedural success was 97.8%, and MAEs occurred in 29 patients (5.8%). Independent predictors of MAEs included device repositioning (odds ratio: 9.13; 95% confidence interval: 2.85 to 33.54; p < 0.001) and left ventricular ejection fraction

OBJECTIVES: The aim of this study was to investigate the safety and efficacy of combining transcatheter valve replacement (TAVR) and left atrial appendage occlusion (LAAO) versus TAVR alone. BACKGROUND: Patients with severe aortic stenosis and atrial fibrillation undergoing TAVR are at increased risk for stroke and bleeding complications. METHODS: A cohort of 52 patients undergoing concomitant TAVR and LAAO were compared with 52 patients undergoing isolated TAVR. A primary safety endpoint at 30 days, a clinical efficacy endpoint from day 30 to last follow-up, and an LAAO efficacy endpoint from the first post-interventional day to the last follow-up were chosen. RESULTS: The mean age of the study population was 85 ± 5 years. The mean CHA2DS2-VASc score and HAS-BLED score were 3.9 ± 1.1 and 2.6 ± 0.9, respectively. The mean Society of Thoracic Surgeons score was 7.8 ± 5.5. The median follow-up duration of the study population was 9.4 months (range 0 to 48 months). The primary safety endpoint occurred in 10 patients in the concomitant group and in 7 patients in the isolated TAVR group (19% vs. 14%; 95% confidence interval: 0.59 to 4.06). The clinical and LAAO efficacy endpoints were achieved in 81 (79%) (75% vs. 82%; 95% confidence interval: 0.49 to 2.92) and 75 (73%) patients (69% vs. 76%; 95% confidence interval: 0.54 to 2.51), respectively. CONCLUSIONS: This pilot study shows that concomitant TAVR and LAAO is feasible and seems to be safe among patients with severe aortic stenosis and atrial fibrillation. Larger trials and longer follow-up are needed to confirm the safety and efficacy of such an approach.

Objectives: To demonstrate safety, feasibility and short-term clinical outcomes after transcatheter aortic valve-in-valve (ViV) implantation under local anesthesia without contrast aortography or echocardiographic guidance. Background: Transcatheter ViV implantation is an emerging treatment modality for patients with degenerative surgical bioprostheses. Given the radiopaque properties of the surgical aortic valve (SAV) frame, ViV procedures can often be performed with fluoroscopic guidance alone. Methods: ViV implantation was performed in 37 patients with SAV failure under local anesthesia without contrast aortography. Clinical and echocardiographic data were obtained at baseline, discharge, and 30 days. Results: Mean age was 74 ± 10 years and STS predicted risk of mortality was 5.6 ± 2.4%. Mean transaortic gradient decreased from 39.4 ± 15.5 mmHg to 13 ± 6.3 mmHg at discharge (p

Biologic treatment options such as tumor necrosis factor (TNF) inhibitors have revolutionized the treatment of inflammatory diseases, including rheumatoid arthritis. Recent data suggest, however, that full and long-lasting responses to TNF inhibitors are limited because of the activation of the pro-inflammatory TH17/interleukin (IL)-17 pathway in patients. Therefore, dual TNF/IL-17A inhibition is an attractive avenue to achieve superior efficacy levels in such diseases. Based on the marketed anti-TNF antibody adalimumab, we generated the bispecific TNF/IL-17A-binding FynomAb COVA322. FynomAbs are fusion proteins of an antibody and a Fyn SH3-derived binding protein. COVA322 was characterized in detail and showed a remarkable ability to inhibit TNF and IL-17A in vitro and in vivo. Through its unique mode-of-action of inhibiting simultaneously TNF and the IL-17A homodimer, COVA322 represents a promising drug candidate for the treatment of inflammatory diseases. COVA322 is currently being tested in a Phase 1b/2a study in psoriasis ( ClinicalTrials.gov Identifier: NCT02243787).

Objectives The aim of this study was to determine factors affecting paravalvular leak (PVL) in transcatheter aortic valve replacement (TAVR) with the Edwards SAPIEN 3 (S3) valve in extremely large annuli. Background The largest recommended annular area for the 29-mm S3 is 683 mm2. However, experience with S3 TAVR in annuli >683 mm2 has not been widely reported. Methods From December 2013 to July 2017, 74 patients across 16 centers with mean area 721 ± 38 mm2 (range: 684 to 852 mm2) underwent S3 TAVR. The transfemoral approach was used in 95%, and 39% were under conscious sedation. Patient, anatomic, and procedural characteristics were retrospectively analyzed. Valve Academic Research Consortium–2 outcomes were reported. Results Procedural success was 100%, with 2 deaths, 1 stroke, and 2 major vascular complications at 30 days. Post-dilatation occurred in 32%, with final balloon overfilling (1 to 5 ml extra) in 70% of patients. Implantation depth averaged 22.3 ± 12.4% at the noncoronary cusp and 20.7 ± 9.9% at the left coronary cusp. New left bundle branch block occurred in 17%, and 6.3% required new permanent pacemakers. Thirty-day echocardiography showed mild PVL in 22.3%, 6.9% moderate, and none severe. There was no annular rupture or coronary obstruction. Mild or greater PVL was associated with larger maximum annular and left ventricular outflow tract (LVOT) diameters, larger LVOT area and perimeter, LVOT area greater than annular area, and higher annular eccentricity. Conclusions TAVR with the 29-mm S3 valve beyond the recommended range by overexpansion is safe, with acceptable PVL and pacemaker rates. Larger LVOTs and more eccentric annuli were associated with more PVL. Longer term follow-up will be needed to determine durability of S3 TAVR in this population.

Background Percutaneous mitral valve repair (PMVR) using the MitraClip™ system has become a valuable alternative in patients with severe mitral regurgitation (MR) and high surgical risk. We sought to evaluate the prognostic value of the SYNTAX II score (SSII) in patients with concomitant coronary artery disease (CAD) undergoing a Mitraclip procedure. Methods In seventy-five consecutive patients who underwent PMVR at the University Heart Center Zurich and the Cardiocentro Ticino, the SSSII was calculated at baseline. Clinical endpoints comprised of all-cause mortality, mitral valve surgery due to failure of PMVR or reoperation, hospitalization for congestive heart failure, heart transplantation and the composite of all four endpoints. Results Patients were followed for a median of 271days. And were divided in tertiles of SSII: SSII low ≤46.5 ( n =25), SSII mid 46.6–54.4 ( n =25) and SSII high ≥54.5 ( n =25). Patients in the highest SSII tertile had a lower left ventricular ejection fraction (33% vs. 40% vs. 53%) with a higher log-BNP (3.6 vs. 3.45 vs. 3.16) when compared to SSII mid and SSII low, respectively. However, the anatomical syntax score (SS) did not differ significantly within the tertiles (9.1±6.3 (SSII Low) vs 9.5±7.6 (SSII Mid) vs 10.2±6.7(SSII High), p =0.837). The primary endpoint occurred in 33% of patients ( n =25). By multivariate analysis patients in the high SSII tertile (OR=6.12, 95% confidence interval, [CI] 1.45–25.86, p =0.014) and patients with a history of MI (OR=3.57, 95% confidence interval, [CI] 1.17–10.88, p =0.025) were at significantly higher risk of experiencing adverse events. Furthermore, in a combined outcome ROC curve analysis, the SSII showed good discrimination with an AUC of 0.73, p =0.001. A cutoff SSII >49 has been identified to have a sensitivity of 83% and specificity of 53% with approximately 45% of the patients experiencing an event during follow-up. Conclusion Using SSII in CAD patients undergoing PMVR is feasible and of prognostic significance hence widening its clinical utility in valvular heart disease.

AIMS: The aim of our study is to report our single-centre experience with concomitant MitraClip (MC) and left atrial appendage occlusion (LAAO) and further to assess the feasibility, safety and short-term outcome of such an approach. METHODS AND RESULTS: Twenty-five consecutive patients underwent MC with concomitant LAAO at our hospital (combined group). As a control group, 25 consecutive patients with atrial fibrillation (AF) undergoing standalone MC were selected. Baseline parameters were equal between the two groups. Patients in the combined group had longer procedural time (90.0 min vs. 66.0 min, p=0.02) and radiation time (32.0 min vs. 18.0 min, p=0.01). There were no procedural deaths. At 30 days, one patient died due to cerebral haemorrhage (combined vs. CONTROL: 4% vs. 0%, p=0.32) and two had acute kidney injury (combined vs. CONTROL: 4% vs. 4%, p=1.00). In multivariate analysis, the association of LAAO with device or procedural success was not significant. CONCLUSIONS: LAAO along with MC in a single stage procedure is feasible. These preliminary results have to be validated in a large randomised study, in order to assess the efficacy of combined LAAO that can be expected to become evident only after longer follow-up.

Upregulation of HER2 is a hallmark of 20% to 30% of invasive breast cancers, rendering this receptor an attractive target for cancer therapy. Although HER2-targeting agents have provided substantial clinical benefit as cancer therapeutics, there is a need for the development of new agents aiming at circumventing anti-HER2 resistance. On the basis of the approved antibody pertuzumab, we have created a panel of bispecific FynomAbs, which target two epitopes on HER2. FynomAbs are fusion proteins of an antibody and a Fyn SH3–derived binding protein. One bispecific FynomAb, COVA208, was characterized in detail and showed a remarkable ability to induce rapid HER2 internalization and apoptosis in vitro. Moreover, it elicited a strong inhibition of downstream HER2 signaling by reducing HER2, HER3, and EGFR levels in vitro and in vivo. Importantly, COVA208 demonstrated superior activity in four different xenograft models as compared with the approved antibodies trastuzumab and pertuzumab. The bispecific FynomAb COVA208 has the potential to enhance the clinical efficacy and expand the scope of HER2-directed therapies, and delineates a paradigm for designing a new class of antibody-based therapeutics for other receptor targets. Mol Cancer Ther; 13(8); 2030–9. ©2014 AACR.

We introduce a novel and versatile ADC-linker technology that is based on site-specific enzymatic payload conjugation to ‘off-the-shelf’ antibodies, i.e., without the need to reduce or engineer the antibody. The functionalization takes place site-specifically and stoichiometrically (drug-to-antibody ratio, DAR = 2.0) at the Fc-part of antibodies. The resulting ADCs show favorable biophysical properties such as high solubility and stability using different payloads. Additionally, initial ELISA findings show that our modification does not interfere with Fc-gamma receptor and FcRn binding. Importantly, our ADCs showed superior efficacy in different tumor animal models as compared to control Thiomab™ ADCs. Using native trastuzumab (non-engineered) as the targeting antibody and amanitin as payload, we generated within 36 hours highly homogeneous and pure ADCs with a well-defined DAR of 2.0 as confirmed by LC-MS. In in-vitro assays our ADCs demonstrated potent cytotoxicity in all tested cell-lines (SKBR-3, BT-474, JIMT-1, and NCI-N87) as compared to the control Thiomab™ ADCs, most strikingly for the JIMT-1 cell-line: EC50 of 0.15nM vs 2.5nM. In the mouse JIMT-1 tumor model, our anti-HER2 ADC was highly potent and resulted in complete tumor remission in all mice (10/10 mice) at a single dose of 2mg/kg. In contrast, the control Thiomab™-functionalized ADC showed tumor regrowth in 4 out of 10 animals, starting on day 50. The same high potency was observed for the NCI-N87 xenograft model at a dose of 3mg/kg in which tumor growth inhibition was significantly delayed versus the reference ADC (8/10 vs 4/10 animals alive on day 110). These encouraging results obtained so far indicate that our linker technology a) allows for fast (< 36 hours) and straightforward manufacturing of ADCs using different payloads without protein engineering efforts, b) results in ADCs with favorable biophysical properties and a clear defined drug-to-antibody ratio, and c) enables the generation of highly potent and stable, thus safer, next-generation ADCs. Citation Format: Philipp Rene Spycher, Julia Carina Frei, Jöri Elias Wehrmüller, Isabella Attinger-toller, Dragan Grabulovski, Torsten Hechler, Michael Kulke, Andreas Pahl, Martin Behe, Roger Schibli. Overcoming limitations of current Antibody-Drug Conjugates (ADCs) by a novel linker technology [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-106.

Background: Mitral regurgitation (MR) is one of the most common valvular diseases. Percu­taneous mitral valve repair with the MitraClip TM system is a novel percutaneous mitral valve repair (PMVR) technique for high-surgical-risk patients. However, the effect of PMVR on cir­culating cardiac or inflammatory biomarkers and their association with individual functional, echocardiographic and clinical outcomes is poorly investigated. Methods: A group of 144 patients with functional or degenerative MR (age, 75 ± 11 years; 41% females) underwent PMVR with the MitraClip system at the University Heart Center Zu­rich. Serum biomarkers as N-terminal pro-B-type natriuretic peptide (NT-proBNP), C-reactive protein (CRP) and creatinine were obtained from venous sampling at baseline and follow-up of 3–6 months. Results: Median NT-proBNP decreased insignificantly from 2,942 (IQR 1,596–5,722) to 2,739 (IQR 1,440–4,296) ng/L, p = 0.21. NT-proBNP changes did not correlate with baseline left ventricular (LV) ejection fraction or LV dimensions, with New York Heart Association class on follow-up, or with clinical events on follow-up. CRP levels reached a peak on the third postoperative day at 34.0 mg/L with a subsequent slow decrease over the ensuing days. Conclusions: Despite successful PMVR, NT-proBNP remain fairly unchanged on follow-up and changes in NT-proBNP levels are poor predictors of functional improvement or clinical outcome after MitraClip treatment.

AIMS: Tricuspid regurgitation (TR) severity and right ventricular (RV) dysfunction have been identified as significant predictors of outcome after mitral valve surgery. The aim of the present study was to investigate the impact of percutaneous mitral valve repair (PMVR) with the MitraClip system on functional TR severity and RV function. METHODS AND RESULTS: Among 119 consecutive patients with severe mitral regurgitation who underwent PMVR, 67 had complete baseline and follow-up transthoracic echocardiography after 3-12 months (6.8±2.9 months). TR severity was graded as mild, moderate, and severe. RV systolic function was assessed by fractional area change (FAC) and tricuspid annular plane systolic excursion (TAPSE). Clinical endpoints at follow-up included mortality, reoperation of the mitral valve, hospitalisation for congestive heart failure and New York Heart Association (NYHA) functional class. After PMVR, a significant decrease in TR severity (by at least one grade) was observed in 22 (33%) patients, while an increase occurred in only seven (10%) patients (p=0.02). Overall, systolic RV function (FAC and TAPSE), RV dimensions, and tricuspid annular diameter did not change significantly. Baseline SPAP was significantly higher (57±15 vs. 43±14 mmHg, p=0.002) and SPAP reduction significantly larger (-14±13 versus 1±15 mmHg, p=0.012) in patients who improved their TR. Multivariate logistic regression analysis identified the change in SPAP as the only significant predictor of changes in TR (odds ratio [OR] [for every change in SPAP by 10 mmHg] 1.90, 95% CI: 1.02±3.54; p=0.044). Patients with mild/moderate TR at follow-up after PMVR had lower event rates compared to those with severe TR (35% vs. 78%, respectively, p=0.025). CONCLUSIONS: PMVR using the MitraClip device improves functional TR severity in approximately one third of patients, particularly in those who experience a significant SPAP reduction after the procedure.

Acute myeloid leukemia (AML) is an aggressive blood cancer with neoplastic infiltration of leukemic blasts in blood, bone marrow and viscera. Current treatment options have limited efficacy, and the 5-year survival rate is only 27%. CD3 bispecific antibodies that re-direct T cells towards the tumor have shown promising efficacy in hematological malignancies. The CD3/CD19 bispecific antibody blinatumomab has recently been approved by the FDA for the treatment of B-cell acute lymphocytic leukemia (ALL) (Kantarjian H et al (2017) NEJM). We evaluated COVA4231, a CD3/CD33 bispecific FynomAb, preclinically as therapeutic candidate for AML. CD33 is a cell surface receptor expressed on blasts of the majority of AML patients (Walter RB (2014) Expert Opin Ther Targets). COVA4231 was constructed by fusing the CD33-specific Fynomer D5 - a small (7 kDa) globular protein derived from the human Fyn SH3 domain with engineered affinity for CD33 - to a CD3-specific antibody with a novel silent IgG1 Fc. COVA4231 induced T cell activation and cytokine release in a CD33-dependent manner, and elicited potent T cell mediated cytotoxicity of CD33-expressing target cells in vitro with EC50 in the range of 4 - 29 pM (E:T cell ratio of 2:1, KG-1 or MOLM-13 as target cells). COVA4231 showed potent activity against 13 out of 15 primary AML blast samples ex vivo at E:T cell ratio of 1:1. The in vivo efficacy of COVA4231 was investigated in a subcutaneous HL-60 leukemia xenograft model in NSG mice in the presence of human T cells. COVA4231 was highly active across a wide dose range (0.05 - 5 mg/kg) and prevented tumor outgrowth in all treated mice. COVA4231 demonstrated an IgG1-like pharmacokinetic profile in mice with a terminal half-life 15.8 days (total drug), providing the opportunity to avoid continuous intravenous infusion protocols required for established CD3 bispecific formats (e.g. (scFv)2). In conclusion, COVA4231 is a highly active therapeutic candidate in vitro, in vivo and ex vivo, has IgG-like pharmacokinetics and is a promising therapeutic candidate for further preclinical and clinical development. Citation Format: Kristina Klupsch, Vanessa Baeriswyl, Roland Scholz, Joana Dannenberg, Roger Santimaria, David Senn, Elena Kage, Adrian Zumsteg, Isabella Attinger-Toller, Ulrike von der Bey, Susann König-Friedrich, Fanny Dupuy, Wibke Lembke, Clara Albani, Severin Wendelspiess, Lucijana Dinkel, Chelsea J. Gudgeon, Roland B. Walter, Julian Bertschinger, Simon Brack. COVA4231, a potent CD3/CD33 bispecific FynomAb with IgG-like pharmacokinetics for the treatment of acute myeloid leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1787.

CD3 bispecific therapies retargeting T cells to tumors have recently demonstrated striking activity in patients. Several CD3 bispecific antibodies directed against various tumor targets are currently being investigated in the clinic across different tumors. One limitation of these therapies is the risk of target-related toxicity due to low-level expression of tumor antigen in normal tissue. In this study we have engineered a bispecific CD3/HER2 FynomAb, COVA420, which redirects T cells with high potency and selectivity to tumor cells with high HER2 expression in vitro and in vivo. COVA420 activity depends on high HER2 density as no activity was observed on cells with lower HER2 levels as found in human normal tissue. These results suggest that COVA420 may spare normal tissue expressing low levels of HER2 while still having uncompromised efficacy on tumor cells with high HER2 expression. This concept may be applied to other cancer antigens that otherwise cannot be targeted by T cell redirecting approaches, and may therefore expand the applicability of CD3 bispecific FynomAbs to a larger number of solid tumors.

Patients suffering from severe aortic stenosis and atrial fibrillation (AF) who undergo transcatheter valve replacement (TAVR) are at high risk for stroke and major bleeding. Left atrial appendage occlusion (LAAO), obviates the need for oral anticoagulation. Therefore, combining TAVR and LAAO makes

QUESTIONS UNDER STUDY: The study objective was to evaluate the impact of the amount of contrast medium used for transcatheter aortic valve implantation (TAVI) on short-term outcome. Patients undergoing TAVI are exposed to repeat contrast medium application both for preprocedural screening and during the TAVI procedure itself. Whether the amount of contrast media is associated with worse outcome is unclear. METHODS: A total of 257 patients were included (median age 82.7 years) and divided into two groups with preserved and reduced kidney function (glomerular filtration rate

Upregulation of HER2 is a hallmark of 20% to 30% of invasive breast cancers, rendering this receptor an attractive target for cancer therapy. Although HER2 targeting agents have provided substantial clinical benefit as cancer therapeutics, there is a need for the development of new agents aiming at circumventing anti-HER2 resistance. Fynomers are small 7 kDa globular proteins derived from the SH3 domain of the human Fyn kinase (Fyn SH3) that can be engineered to bind with antibody-like affinity and specificity to virtually any target of choice. Fynomers can be fused to N-terminal and/or C-terminal ends of antibodies to generate multispecific therapeutics (FynomAbs) with tailored architectures. FynomAbs can be produced using standard antibody technology (GMP production yield of 3.3 g/L at 1000 L scale achieved), and show IgG-like biophysical properties and pharmacokinetic profiles. Based on the approved antibody pertuzumab we have created a panel of bispecific FynomAbs which target two epitopes on HER2. The activity of the HER2 targeting FynomAbs was found to depend on the FynomAb architecture, i.e. the spatial arrangement of the binding sites of antibody and the Fynomer. The most potent of these FynomAbs, termed COVA208, demonstrated superior tumor cell growth inhibition in vitro compared to pertuzumab and trastuzumab. COVA208 was characterized in detail and showed an increased ability to induce rapid HER2-internalization and apoptosis in vitro. Moreover, it elicited a stronger inhibition of downstream HER2 signaling which was accompanied by a reduction of HER2, HER3 and EGFR levels in vitro and in vivo. The therapeutic potential of COVA208 has been demonstrated in vivo in four different HER2 mouse models, where COVA208 exhibited excellent anti-tumor activity. Importantly, COVA208 demonstrated superior activity in vivo compared to trastuzumab and pertuzumab. The bispecific FynomAb COVA208 has the potential to enhance the clinical efficacy and expand the scope of HER2-directed therapies, and delineates a paradigm for designing a new class of antibody-based therapeutics for other receptor targets. Citation Format: Babette Schade, Simon Brack, Isabella Attinger-Toller, Kristina Klupsch, Richard Woods, Helen Hachemi, Ulrike von der Bey, Susann Koönig-Friedrich, Julian Bertschinger, Dragan Grabulovski. A bispecific HER2 targeting FynomAb with superior anti-tumor activity and novel mode of action. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 658. doi:10.1158/1538-7445.AM2014-658