Governance of advanced materials: Shaping a safe and sustainable future.

The past few decades of managing the uncertain risks associated with nanomaterials have provided valuable insights (knowledge gaps, tools, methods, etc.) that are equally important to promote safe and sustainable development and use of advanced materials. Based on these insights, the current paper proposes several actions to optimize the risk and sustainability governance of advanced materials. We emphasise the importance of establishing a European approach for risk and sustainability governance of advanced materials as soon as possible to keep up with the pace of innovation and to manage uncertainty among regulators, industry, SMEs and the public, regarding potential risks and impacts of advanced materials. Coordination of safe and sustainable advanced material research efforts, and data management according to the Findable, Accessible, Interoperable and Reusable (FAIR) principles will enhance the generation of regulatory-relevant knowledge. This knowledge is crucial to identify whether current regulatory standardised and harmonised test methods are adequate to assess advanced materials. At the same time, there is urgent need for responsible innovation beyond regulatory compliance which can be promoted through the Safe and Sustainable Innovation Approach. that combines the Safe and Sustainable by Design concept with Regulatory Preparedness, supported by a trusted environment. We further recommend consolidating all efforts and networks related to the risk and sustainability governance of advanced materials in a single, easy-to-use digital portal. Given the anticipated complexity and tremendous efforts required, we identified the need of establishing an organisational structure dedicated to aligning the fast technological developments in advanced materials with proper risk and sustainability governance. Involvement of multiple stakeholders in a trusted environment ensures a coordinated effort towards the safe and sustainable development, production, and use of advanced materials. The existing infrastructures and network of experts involved in the governance of nanomaterials would form a solid foundation for such an organisational structure.

Long-term durability of posterior wall isolation using the cryoballoon in patients with persistent atrial fibrillation: a multicenter analysis of repeat catheter ablations.

PURPOSE: There is a growing interest in performing pulmonary vein isolation (PVI) with concomitant posterior wall isolation (PWI) using the cryoballoon for the treatment of patients with persistent atrial fibrillation (AF). However, there is little known about the long-term durability of PWI using this approach. METHODS: In this multicenter study, we retrospectively examined the durability of PVI + PWI using the 28-mm cryoballoon by investigating the outcomes from consecutive patients referred for repeat catheter ablation. RESULTS: Altogether, 81/519 patients (15.6%) were referred for repeat catheter ablation. Repeat ablation was associated with a longer AF duration, hypertension, heart failure, multiple cardioversions, and antiarrhythmic therapy as well as larger left atrial (LA) diameters (49 ± 4 mm versus 43 ± 5 mm; P < 0.001) and greater need for "touch-up" (adjunct) radiofrequency ablation (44.4% versus 18.3%; P < 0.001). LA diameter also emerged as a significant predictor for adjunct radiofrequency ablation (P < 0.001). Durable PVI was observed in 66/81 patients (81.5%) and PWI in 67/81 patients (82.7%). Those with incomplete PWI exhibited larger LA diameters, particularly > 48 mm (negative predictive value = 89.7%). Lastly, an atypical LA posterior wall/roof flutter represented the third most common cause of arrhythmia recurrence and essentially every patient with incomplete PWI exhibited such an arrhythmia. CONCLUSION: PWI performed using a 28-mm cryoballoon in conjunction with PVI exhibits long-term durability in the vast majority of patients with persistent AF. While LA diameter (particularly > 48 mm) is a significant predictor for the need for adjunct radiofrequency ablation when performing this technique, those with incomplete PWI invariably present with an atypical flutter using this substrate.

Left atrial posterior wall isolation in conjunction with pulmonary vein isolation using cryoballoon for treatment of persistent atrial fibrillation (PIVoTAL): study rationale and design.

BACKGROUND: There is growing evidence in support of pulmonary vein isolation (PVI) with concomitant posterior wall isolation (PWI) for the treatment of patients with symptomatic persistent atrial fibrillation (persAF). However, there is limited data on the safety and efficacy of this approach using the cryoballoon. OBJECTIVE: The aim of this multicenter, investigational device exemption trial (G190171) is to prospectively evaluate the acute and long-term outcomes of PVI versus PVI+PWI using the cryoballoon in patients with symptomatic persAF. METHODS: The PIVoTAL is a prospective, randomized controlled study ( ClinicalTrials.gov : NCT04505163) in which patients with symptomatic persAF refractory/intolerant to ≥ 1 class I-IV antiarrhythmic drug, undergoing first-time catheter ablation, will be randomized to PVI (n = 183) versus PVI+PWI (n = 183) using the cryoballoon in a 1:1 fashion. The design will be double-blind until randomization immediately after PVI, beyond which the design will transform into a single-blind. PVI using cryoballoon will be standardized using a pre-specified dosing algorithm. Other empiric ablations aside from documented arrhythmias/arrhythmias spontaneously induced during the procedure will not be permitted. The primary efficacy endpoint is defined as AF recurrence at 12 months, after a single procedure and a 90-day blanking period. Arrhythmia outcomes will be assessed by routine electrocardiograms and 7-14 day ambulatory electrocardiographic monitoring at 3, 6, and 12 months post-ablation. CONCLUSION: The PIVoTAL is a prospective, randomized controlled trial designed to evaluate the outcomes of PVI alone versus PVI+PWI using the cryoballoon, in patients with symptomatic persAF. We hypothesize that PVI+PWI will prove to be superior to PVI alone for prevention of AF recurrence.

Posterior wall isolation using the cryoballoon in conjunction with pulmonary vein ablation is superior to pulmonary vein isolation alone in patients with persistent atrial fibrillation: A multicenter experience.

BACKGROUND: Pulmonary vein isolation (PVI) in conjunction with isolation of the posterior left atrial wall (PVI+PWI) is associated with improved clinical outcomes in certain patients with atrial fibrillation (AF). OBJECTIVE: The purpose of this multicenter study was to evaluate the acute and long-term outcomes of PVI+PWI vs PVI alone performed using cryoballoon ablation in patients with persistent AF (persAF). METHODS: We examined the procedural safety and efficacy and short- and long-term outcomes in 390 consecutive patients with persAF who underwent a first-time cryoballoon ablation procedure using PVI+PWI (n = 222 [56.9%]) vs PVI alone (n = 168 [43.1%]). RESULTS: Acute isolation was achieved in 99.7% of all pulmonary veins (PVI+PWI = 99.8% vs PVI alone = 99.3%; P = .23) using 6.3 ± 1.4 applications and 17 ± 2 minutes of cryoablation. PWI was achieved using 13.7 ± 3.2 applications and 34 ± 10 minutes of cryoablation. Adjunct radiofrequency ablation was required in 1.8% of patients to complete PVI (4 ± 2 minutes) and in 32.4% to complete PWI (5 ± 2 minutes). PVI+PWI yielded significantly greater posterior wall (77.2% ± 6.4% vs 40.6% ± 4.9%; P < .001) and total left atrial (53.3% ± 4.2% vs 36.3% ± 3.8%; P < .001) isolation. In addition, PVI+PWI was associated with greater AF termination (19.8% vs 8.9%; P = .003) and conversion to atrial flutters (12.2% vs 5.4%; P = .02). Adverse events were similar in both groups, whereas recurrence of AF and all atrial arrhythmias was lower with PVI+PWI at 12 months of follow-up. Moreover, in a Cox regression analysis, PVI+PWI emerged as a significant predictor of freedom from recurrent atrial arrhythmias (hazard ratio: 2.04; 95% confidence interval: 1.15-3.61; P = .015). CONCLUSION: PVI+PWI can be achieved safely and effectively using the cryoballoon. This approach appears superior to PVI alone in patients with persAF.

The ABCD (Alternans Before Cardioverter Defibrillator) Trial: strategies using T-wave alternans to improve efficiency of sudden cardiac death prevention.

OBJECTIVES: Because risk stratification with electrophysiological study (EPS) improves efficiency but is invasive, we sought to determine whether noninvasive microvolt T-wave alternans (MTWA) testing could identify patients who benefit from implantable cardioverter-defibrillators (ICDs) as well as EPS. BACKGROUND: Prevention of sudden cardiac death on the basis of left ventricular ejection fraction (LVEF) alone is inefficient, because most ICDs never deliver therapy. METHODS: The ABCD (Alternans Before Cardioverter Defibrillator) trial is a multicenter prospective study that enrolled patients with ischemic cardiomyopathy (LVEF < or =0.40) and nonsustained ventricular tachycardia. All patients underwent MTWA and EPS. ICDs were mandated if either test was positive. RESULTS: Of 566 patients followed for a median of 1.9 years, 39 (7.5%) met the primary end point of appropriate ICD discharge or sudden death at 1 year. As hypothesized, primary analysis showed that MTWA achieved 1-year positive (9%) and negative (95%) predictive values that were comparable to EPS (11% and 95%, respectively). In addition, secondary analysis showed that at the pre-specified 1-year end point, event rates were significantly higher in patients with both a positive MTWA-directed strategy (hazard ratio: 2.1, p = 0.03) and a positive EPS-directed strategy (hazard ratio: 2.4, p = 0.007). Moreover, the event rate in patients with both negative MTWA test and EPS was lower than in those with 2 positive tests (2% vs. 12%; p = 0.017). CONCLUSIONS: The ABCD study is the first trial to use MTWA to guide prophylactic ICD insertion. Risk stratification strategies using noninvasive MTWA versus invasive EPS are comparable at 1 year and complementary when applied in combination. Strategies employing MTWA, EPS, or both might identify subsets of patients least likely to benefit from ICD insertion. (Study to Compare TWA Test and EPS Test for Predicting Patients at Risk for Life-Threatening Heart Rhythms [ABCD Study]; NCT00187291).

Performance of the St. Jude Medical Riata leads.

BACKGROUND: Recent attention has been focused on the performance of high-voltage implantable cardioverter-defibrillator (ICD) leads. Lead-related adverse events can be caused by several factors, including patient characteristics, concomitant therapies, implantation technique, access site, and lead design. Few studies have included the number of patients and the follow-up duration necessary to characterize accurately the lead performance and the incidence of lead-related adverse events. OBJECTIVE: This study sought to define the incidence of lead-related adverse events including conductor fracture, insulation damage, perforation, and dislodgement of St. Jude Medical Riata ICD leads. METHODS: Data from the Advancements in ICD Therapy, OPTIM Lead InsUlation Material (OPTIMUM), Resynchronization HemodYnamic Treatment for Heart Failure Management (RHYTHM), and Post Approval Study (PAS) registries provided data from 7,497 patients with Riata leads. Patients were followed up for a median of 22 months. Adverse events, defined as those that required lead revision, extraction, or replacement, were recorded. RESULTS: Conductor fracture occurred in 0.09%, insulation damage in 0.13%, dislodgement in 0.88%, and perforation in 0.31% of patients, respectively. CONCLUSION: During more than 22 months of follow-up of over 7,000 Riata leads in 4 prospective registries and clinical trials, the incidence of lead-related adverse events including conductor fracture, insulation damage, dislodgement, and perforation necessitating lead revision, extraction, or replacement is rare.

Cardiac-resynchronization therapy in heart failure with narrow QRS complexes.

BACKGROUND: Indications for cardiac-resynchronization therapy (CRT) in patients with heart failure include a prolonged QRS interval (> or =120 msec), in addition to other functional criteria. Some patients with narrow QRS complexes have echocardiographic evidence of left ventricular mechanical dyssynchrony and may also benefit from CRT. METHODS: We enrolled 172 patients who had a standard indication for an implantable cardioverter-defibrillator. Patients received the CRT device and were randomly assigned to the CRT group or to a control group (no CRT) for 6 months. The primary end point was the proportion of patients with an increase in peak oxygen consumption of at least 1.0 ml per kilogram of body weight per minute during cardiopulmonary exercise testing at 6 months. RESULTS: At 6 months, the CRT group and the control group did not differ significantly in the proportion of patients with the primary end point (46% and 41%, respectively). In a prespecified subgroup with a QRS interval of 120 msec or more, the peak oxygen consumption increased in the CRT group (P=0.02), but it was unchanged in a subgroup with a QRS interval of less than 120 msec (P=0.45). There were 24 heart-failure events requiring intravenous therapy in 14 patients in the CRT group (16.1%) and 41 events in 19 patients in the control group (22.3%), but the difference was not significant. CONCLUSIONS: CRT did not improve peak oxygen consumption in patients with moderate-to-severe heart failure, providing evidence that patients with heart failure and narrow QRS intervals may not benefit from CRT. (ClinicalTrials.gov number, NCT00132977 [ClinicalTrials.gov].).

Acute evaluation of programmer-guided AV/PV and VV delay optimization comparing an IEGM method and echocardiogram for cardiac resynchronization therapy in heart failure patients and dual-chamber ICD implants.

INTRODUCTION: Intracardiac delay optimization of biventricular and dual-chamber pacing devices currently relies on time-consuming echocardiographic measurements. A novel intracardiac electrogram (IEGM) method for atrioventricular (AV/PV) and interventricular (VV) delay optimization was developed, which can be performed during routine device follow-up. METHODS AND RESULTS: In this prospective, nonrandomized, multi-center trial, patients previously implanted with St. Jude Medical cardiac resynchronization therapy defibrillator (CRT-D) devices or dual-chamber implantable cardioverter defibrillators (ICDs) underwent standard AV/PV and/or VV delay optimization guided by Doppler echocardiogram measurements of the maximum aortic velocity time integral (aortic VTI). Aortic VTI measurements applying the IEGM method recommended delays were then obtained in all patients. Fifty-eight patients (age: 68 +/- 11 years; 81% male; 74% ischemic) and 57 patients (age: 71 +/- 10 years; 74% male; 71% ischemic) were enrolled for AV/PV and VV delay evaluation, respectively. An independent core lab determined the maximum aortic VTIs. Data analysis of the AV, PV, and VV delays demonstrated the concordance correlation coefficient (CCC) between the standard method aortic VTI values and the IEGM method aortic VTI values was 97.5%, 96.1%, and 96.6%, respectively. All analyses demonstrated that the CCC > 90% (P < 0.05). CONCLUSION: The automated programmer-based IEGM method provides a reliable and simpler alternative to standard techniques for the optimization of AV/PV and VV delay settings in patients with CRT-D devices and dual-chamber ICDs.

Estimation of the optimal VV delay by an IEGM-based method in cardiac resynchronization therapy.

Determination of the optimal interventricular (VV) delay in cardiac resynchronization therapy currently relies on costly, time-consuming echocardiographic (ECHO) methods. This study evaluated the performance of a new intracardiac electrogram (IEGM)-based VV method compared to the aortic velocity time integral (AVTI) method of VV delay optimization. The study included two patient groups. Eleven patients enrolled by a single center in the Rhythm II ICD trial underwent prospective comparisons of the AVTI at the VV interval determined by the IEGM VV method versus the maximum AVTI at the echocardiographically determined optimal VV delay. In 61 patients enrolled in the RHYTHM VV trial, the same testing methods were compared retrospectively. In the prospective study, the maximum AVTI by the ECHO-based method (24.3 +/- 7.9 cm), was closely correlated with maximum AVTI by the IEGM-based method (23.9 +/- 7.9 cm; concordance correlation coefficient = 0.99; 95% confidence, lower limit of 98%. Likewise, in the retrospective analysis, the ECHO-determined maximum AVTI (22.1 +/- 8.2 cm) was similar to that determined by the IEGM-based method (20.9 +/- 8.3 cm; concordance correlation coefficient = 0.98; 95% confidence, lower limit of 97%).