Leadless pacemakers at 5-year follow-up: the Micra transcatheter pacing system post-approval registry.

BACKGROUND AND AIMS: Prior reports have demonstrated a favourable safety and efficacy profile of the Micra leadless pacemaker over mid-term follow-up; however, long-term outcomes in real-world clinical practice remain unknown. Updated performance of the Micra VR leadless pacemaker through five years from the worldwide post-approval registry (PAR) was assessed. METHODS: All Micra PAR patients undergoing implant attempts were included. Endpoints included system- or procedure-related major complications and system revision rate for any cause through 60 months post-implant. Rates were compared through 36 months post-implant to a reference dataset of 2667 transvenous pacemaker patients using Fine-Gray competing risk models. RESULTS: 1809 patients were enrolled between July 2015 and March 2018 and underwent implant attempts from 179 centres in 23 countries with a median follow-up period of 51.1 months (IQR: 21.6-64.2). The major complication rate at 60 months was 4.5% [95% confidence interval (CI): 3.6%-5.5%] and was 4.1% at 36 months, which was significantly lower than the 8.5% rate observed for transvenous systems (HR: .47, 95% CI: .36-.61; P < .001). The all-cause system revision rate at 60 months was 4.9% (95% CI: 3.9%-6.1%). System revisions among Micra patients were mostly for device upgrades (41.2%) or elevated thresholds (30.6%). There were no Micra removals due to infection noted over the duration of follow-up. At 36 months, the system revision rate was significantly lower with Micra vs. transvenous systems (3.2% vs. 6.6%, P < .001). CONCLUSIONS: Long-term outcomes with the Micra leadless pacemaker continue to demonstrate low rates of major complications and system revisions and an extremely low incidence of infection.

Impact of initiation of SGLT2 inhibitor treatment on the development of arrhythmias in patients with implantable cardiac devices.

INTRODUCTION AND OBJECTIVES: Sodium-glucose cotransporter type 2 inhibitors (SGLT2i) have been associated with improved prognosis in patients with heart failure, but their impact on atrial arrhythmic (AA) and ventricular arrhythmic (VA) events is not fully understood. METHODS: This multicenter retrospective study included patients with implantable cardioverter-defibrillators who initiated treatment with SGLT2i. AA and VA events were compared in 2 time periods for each patient: 1 year before and 1 year after starting SGLT2i. RESULTS: The study included 195 patients (66.8 [61.3-73.1] years, 18.5% women). In the post-SGLT2i period, there was a reduction in the percentage of patients with any VA (pre: 52.3% vs post: 30.3%; P<.001) and clinically relevant VA (excluding nonsustained ventricular tachycardia) (pre: 21.5% vs post: 8.7%; P<.001). There was also a decrease in the number of episodes per patient/y of nonsustained ventricular tachycardia (pre: 2 (1-5) vs post: 1 (0-2); P<.001) and sustained ventricular tachycardia (pre: 1 (1-3) vs post: 0 (0-2); P=0.046). However, no differences were observed in the prevalence of AA (24.7% vs 18.8%; P=.117) or the burden of atrial fibrillation (pre: 0% (0-0.1) vs post: 0% (0-0); P=.097). CONCLUSIONS: Initiation of SGLT2i treatment was associated with a decrease in the percentage of patients with relevant VA but this effect was not observed for AA.

Plasma miR-486-5p Expression Is Upregulated in Atrial Fibrillation Patients with Broader Low-Voltage Areas.

Atrial fibrillation (AF) is the most common arrhythmia worldwide, affecting 1% of the population over 60 years old. The incidence and prevalence of AF are increasing globally, representing a relevant health problem, suggesting that more advanced strategies for predicting risk stage are highly needed. miRNAs mediate several processes involved in AF. Our aim was to identify miRNAs with a prognostic value as biomarkers in patients referred for AF ablation and its association with LVA extent, based on low-voltage area (LVA) maps. In this study, we recruited 44 AF patients referred for catheter ablation. We measured the expression of 84 miRNAs in plasma from peripheral blood in 3 different groups based on LVA extent. Expression analysis showed that miR-486-5p was significantly increased in patients with broader LVA (4-fold, p = 0.0002; 5-fold, p = 0.0001). Receiver operating characteristic curve analysis showed that miR-486-5p expression could predict atrium LVA (AUC, 0.8958; p = 0.0015). Also, miR-486-5p plasma levels were associated with AF-type (AUC, 0.7137; p = 0.0453). In addition, miR-486-5p expression was positively correlated with LVA percentage, left atrial (LA) area, and LA volume (r = 0.322, p = 0.037; r = 0.372, p = 0.015; r = 0.319, p = 0.045, respectively). These findings suggest that miR-486-5p expression might have prognostic significance in LVA extent in patients with AF.

Role of Soluble ST2 Biomarker in Predicting Recurrence of Atrial Fibrillation after Electrical Cardioversion or Pulmonary Vein Isolation.

This study aims to determine the predictive value of the soluble suppression of tumorigenicity 2 (sST2) biomarker in atrial fibrillation (AF) recurrence. This prospective, observational study included patients with AF referred for electrical cardioversion (ECV) or pulmonary vein isolation (PVI) procedures. Baseline characteristics were collected, and sST2 was determined at baseline and at 3 and 6 months of follow-up. sST2 was determined at baseline in a matched control group. Left atrial voltage mapping was performed in patients undergoing PVI. The sST2 maximal predictive capacity of AF recurrence was at the 3-month FU in the cohort of patients undergoing ECV with respect to 6-month AF recurrence with an AUC of 0.669, a cut-off point of 15,511 pg/mL, a sensitivity of 60.97%, and a specificity of 69.81%. The ROC curve of the sST2 biomarker at baseline and 3 months in the cohort of patients undergoing PVI showed AUCs of 0.539 and 0.490, respectively. The logistic regression model identified the rhythm (AF) and the sST2 biomarker at 3 months as independent factors for recurrence at 6 months in the ECV cohort. In the logistic regression model, sST2 was not an independent factor for recurrence at 6 months of follow-up in the PVI cohort. In patients who underwent ECV, sST2 values at 3 months may provide utility to predict AF recurrence at 6 months of follow-up. In patients who underwent PVI, sST2 had no value in predicting AF recurrence at 6 months of follow-up.

Atrial fibrillation ablation in patients with arrhythmia-induced cardiomyopathy: a prospective multicentre study.

AIMS: This study aims to investigate the clinical and biochemical characteristics of patients with atrial fibrillation (AF) referred for ablation who develop arrhythmia-induced cardiomyopathy (AiCM) as well as their long-term outcomes after catheter ablation (CA). METHODS AND RESULTS: A prospective multicentre study was conducted on consecutive AF patients who underwent CA. AiCM was defined as the development of heart failure in the presence of AF and an improvement of left ventricular fraction by at least 10% at 6 months after ablation. A subgroup of patients underwent peripheral and left atrial blood samples [galectin-3, fatty acid-binding protein 4 (FABP4), and soluble receptor for advanced glycation end products (sRAGE)] at the time of the procedure. Of the 769 patients who underwent AF ablation, 135 (17.56%) met the criteria for AiCM. Independent predictors of AiCM included persistent AF, male gender, left atrial volume, QRS width, active smoking, and chronic kidney disease (CKD). Biomarker analysis revealed that sRAGE, FABP4, and galectin-3 levels were not predictive of AiCM development nor did they differ between groups or predict recurrence. There were no differences in AF recurrence between patients with and without AiCM (30.83% vs. 27.77%; P = 0.392) during a median follow-up of 23.83 months (inter-quartile range 9-36). CONCLUSIONS: In the subset of patients referred for AF ablation, the development of AiCM was associated with persistent AF and CKD. Biomarker analysis was not different between groups nor predicted recurrence. Patients with AiCM benefited from ablation, with a significant improvement in left ventricular ejection fraction and similar AF recurrence rates to those without AiCM.

Gender-Related Differences in Atrial Substrate in Patients with Atrial Fibrillation.

Gender-related differences have been reported in patients who underwent pulmonary vein isolation (PVI). Atrial substrate plays a role in the outcomes after ablation but gender-related differences in atrial substrate have never been described in detail. We sought to analyze gender-related differences in atrial remodeling (spontaneous low-voltage zones [LVZs]) and their clinical relevance after PVI. We conducted a prospective multicenter study, including consecutive patients who underwent first PVI-only atrial fibrillation (AF) ablation. LVZs were analyzed on high-density electroanatomical maps collected with multipolar catheter, before PVI. In total, 262 patients (61 ± 11 years, 31% female, 50% persistent AF) were followed for 28 months. In women, LVZs were larger (10% vs 4% of left atrial surface [p <0.001]) and female gender was independently associated with fourfold higher risk of having advanced (LVZ > 15%) atrial remodeling (odds ratio 4.56, p <0.001). AF recurrence-free survival was not different between men and women (log-rank p = 0.2). Although LVZs were independently associated higher AF recurrences at multivariate analysis (hazard ratio [HR] 1.2, p = 0.038), female gender was not (HR 1.4, p = 0.211). Specifically, the LVZ cutoff to predict outcomes was different in men and women: >5% in men (HR 3.0, p <0.001), >15% in women (HR 2.7, p = 0.02). In conclusion, women have more widespread LVZ in all left atrial regions. Despite more extensive atrial remodeling, the AF recurrence rate is similar in men and women, and LVZs become prognostic in women only at high burden (>15%). LVZs seem to have a different prognostic role in men and women.

Circulating miR-451a Expression May Predict Recurrence in Atrial Fibrillation Patients after Catheter Pulmonary Vein Ablation.

Atrial fibrillation is the most prevalent tachyarrhythmia in clinical practice, with very high cardiovascular morbidity and mortality with a high-cost impact in health systems. Currently, it is one of the main causes of stroke and subsequent heart failure and sudden death. miRNAs mediate in several processes involved in cardiovascular disease, including fibrosis and electrical and structural remodeling. Several studies suggest a key role of miRNAs in the course and maintenance of atrial fibrillation. In our study, we aimed to identify the differential expression of circulating miRNAs and their predictive value as biomarkers of recurrence in atrial fibrillation patients undergoing catheter pulmonary vein ablation. To this effect, 42 atrial fibrillation patients were recruited for catheter ablation. We measured the expression of 84 miRNAs in non-recurrent and recurrent groups (45.2%), both in plasma from peripheral and left atrium blood. Expression analysis showed that miRNA-451a is downregulated in recurrent patients. Receiver operating characteristic curve analysis showed that miR-451a in left atrium plasma could predict atrial fibrillation recurrence after pulmonary vein isolation. In addition, atrial fibrillation recurrence is positively associated with the increment of scar percentage. Our data suggest that miRNA-451a expression plays an important role in AF recurrence by controlling fibrosis and progression.

Characterization of Atrial Substrate to Predict the Success of Pulmonary Vein Isolation: The Prospective, Multicenter MASH-AF II (Multipolar Atrial Substrate High Density Mapping in Atrial Fibrillation) Study.

Background Left atrial substrate may have mechanistic relevance for ablation of atrial fibrillation (AF). We sought to analyze the relationship between low-voltage zones (LVZs), transition zones, and AF recurrence in patients undergoing pulmonary vein isolation. Methods and Results We conducted a prospective multicenter study on consecutive patients undergoing pulmonary vein isolation-only approach. LVZs and transition zones (0.5-1 mV) were analyzed offline on high-density electroanatomical maps collected before pulmonary vein isolation. Overall, 262 patients (61±11 years, 31% female) with paroxysmal (130 pts) or persistent (132 pts) AF were included. After 28 months of follow-up, 73 (28%) patients experienced recurrence. An extension of more than 5% LVZ in paroxysmal AF and more than 15% in persistent AF was associated with recurrence (hazard ratio [HR], 4.4 [95% CI, 2.0-9.8], P<0.001 and HR, 1.9 [95% CI, 1.1-3.7], P=0.04, respectively). Significant association was found between LVZs and transition zones and between LVZs and left atrial volume index (LAVI) (both P<0.001). Thirty percent of patients had significantly increased LAVI without LVZs. Eight percent of patients had LVZs despite normal LAVI. Older age, female sex, oncological history, and increased AF recurrence characterized the latter subgroup. Conclusions In patients undergoing first pulmonary vein isolation, the impact of LVZs on outcomes occurs with lower burden in paroxysmal than persistent AF, suggesting that not all LVZs have equal prognostic implications. A proportional area of moderately decreased voltages accompanies LVZs, suggesting a continuous substrate instead of the dichotomous division of healthy or diseased tissue. LAVI generally correlates with LVZs, but a small subgroup of patients may present with disproportionate atrial remodeling, despite normal LAVI.

Relaxin-2 plasma levels in atrial fibrillation are linked to inflammation and oxidative stress markers.

Relaxin-2 exerts many favourable cardiovascular effects in pathological circumstances such as atrial fibrillation (AF) and heart failure, but the mechanisms underlying its actions are not completely understood. Since inflammation and fibrosis are pivotal processes in the pathogenesis of AF, our aim was to study the relationship between relaxin-2 plasma levels in left atrium (LA) and peripheral vein with molecules implicated in fibrosis, inflammation and oxidative stress in AF patients, and to evaluate the anti-fibrotic ability of relaxin-2 in normal human atrial cardiac fibroblasts (NHCF-A). Peripheral vein relaxin-2 plasma levels were higher than LA relaxin-2 plasma levels in men while, in women, peripheral vein relaxin-2 levels were increased compared to men. AF patients with higher levels of relaxin-2 exhibited a reduction in H2O2 plasma levels and in mRNA levels of alpha-defensin 3 (DEFA3) and IL-6 in leucocytes from LA plasma. Relaxin-2-in-vitro treatment inhibited NHCF-A migration and decreased mRNA and protein levels of the pro-fibrotic molecule transforming growth factor-ß1 (TGF-ß1). Our results support an association between relaxin-2 and molecules involved in fibrosis, inflammation and oxidative stress in AF patients, and reinforce an anti-fibrotic protective role of this hormone in NHCF-A; strengthening the relevance of relaxin-2 in AF physiopathology, diagnosis and treatment.

The Role of Fatty Acid-Binding Protein 4 in the Characterization of Atrial Fibrillation and the Prediction of Outcomes after Catheter Ablation.

Aims: The utility of biomarkers in characterizing atrial cardiomyopathy is unclear. We aim to test the ability of biomarkers of fibrosis (galectin-3 (Gal-3)) and adiposity (fatty acid-binding protein 4 (FABP4) and leptin) to predict: (1) the presence of low-voltage areas (LVA) in the electroanatomic voltage mapping; and (2) the recurrence of atrial fibrillation (AF) after pulmonary vein isolation (PVI). Methods: Patients referred for PVI were enrolled. Areas of bipolar voltage < 0.5 mV were considered as LVA. An aggregate score incorporating AF pattern (paroxysmal, persistent and long-standing persistent) and peripheral levels of FABP4 (>20 ng/mL) was developed. Results: 299 patients were included. AF was paroxysmal in 100 (33%), persistent in 130 (43%) and long-standing persistent in 69 (23%). Multivariable analysis revealed age, left atrium area, and the proposed score as independent predictors of LVA. During a mean follow-up period of 972 ± 451 days, freedom from AF recurrence was 63%. The score incorporating AF pattern and FABP4 levels accurately predicted freedom from AF recurrence, stratifying risk into ranges from 28% (score of 1) to 68% (score of 3). Cox regression models identified the score including AF pattern + FABP4 as the best model for AF recurrence (hazard ratio 2.32; 95% CI, 1.19 to 4.5; p = 0.014). Conclusions: Traditional clinical classification of atrial cardiomyopathy may be improved by markers of adiposity (FABP4). The combination allows better prediction of the presence of LVA and AF recurrence post-PVI. Gal-3 provided no added predictive value.

Outcomes of leadless pacemaker implantation in patients with mechanical heart valves.

INTRODUCTION: Device infections constitute a major complication of transvenous pacemakers. Mechanical heart valves (MHV) increase the risk of infective endocarditis (IE) and pacemaker infection, requiring lifelong vitamin K-antagonists (VKA), which may affect patient management. Leadless pacemakers (LP) are associated with low infection rates, posing an attractive option in MHV patients requiring permanent pacing. This study describes outcomes following LP implantation in patients with MHV. METHODS: This is a multicenter, observational, retrospective study including consecutive patients implanted with an LP at 5 centers between June 2015 and January 2020. Procedural outcomes, antithrombotic management, complications, performance during follow-up and episodes of bacteremia and IE were compared between patients with and without an MHV (MHV and non-MHV groups). RESULTS: Four hundred fifty-nine patients were included (74 in the MHV group, 16.1%, and 385 in the non-MHV group, 83.9%). Procedural outcomes and acute electrical performance were comparable between groups. Vascular complications and cardiac perforation occurred in 2.7 versus 2.3% (p = 1) and 0% versus 0.8% (p = 1) in the MHV group and non-MHV group. One case of IE occurred in the MHV group and 2 in the non-MHV group. In MHV patients, uninterrupted VKA was used in 83.8%, whereas 16.2% were heparin-bridged. Vascular complication or tamponade occurred in 1 (8.3%) MHV heparin-bridged patient versus 1 (1.6%) MHV uninterrupted VKA patient (p = .3). CONCLUSION: LP implantation outcomes in MHV patients are comparable to the general LP population. Device-related infections are rare following LP implantation, including in patients with MHV. In the MHV group, periprocedural anticoagulation management was not associated with significantly different rates of tamponade or vascular complication.

Circulating miR-499a and miR-125b as Potential Predictors of Left Ventricular Ejection Fraction Improvement after Cardiac Resynchronization Therapy.

Cardiac resynchronization therapy represents a therapeutic option for heart failure drug-refractory patients. However, due to the lack of success in 30% of the cases, there is a demand for an in-depth analysis of individual heterogeneity. In this study, we aimed to evaluate the prognostic value of circulating miRNA differences. Responder patients were defined by a composite endpoint of the presence of left ventricular reverse remodelling (a reduction ≥15% in telesystolic volume and an increment ≥10% in left ventricular ejection fraction). Circulating miRNAs signature was analysed at the time of the procedure and at a 6-month follow-up. An expression analysis showed, both at baseline and at follow-up, differences between responders and non-responders. Responders presented lower baseline expressions of miR-499, and at follow-up, downregulation of miR-125b-5p, both associated with a significant improvement in left ventricular ejection fraction. The miRNA profile differences showed a marked sensitivity to distinguish between responders and non-responders. Our data suggest that miRNA differences might contribute to prognostic stratification of patients undergoing cardiac resynchronization therapy and suggest that preimplant cardiac context as well as remodelling response are key to therapeutic success.

Leadless pacemaker implant, anticoagulation status, and outcomes: Results from the Micra Transcatheter Pacing System Post-Approval Registry.

BACKGROUND: Early results from the Micra investigational trial and Micra Post-Approval Registry (PAR) demonstrated excellent safety and device performance; however, outcomes based on anticoagulation (AC) status at implant have not been evaluated. OBJECTIVE: The purpose of this study was to report implant characteristics, perforation rate, and vascular-related events based on perioperative oral AC strategy in patients undergoing Micra implant. METHODS: We compared procedure characteristics, major complications, and vascular events, including pericardial effusion, stratified by any adverse event (including major complications, minor complications, and observations) or major complication only according to AC status in the Micra PAR. RESULTS: Among 1795 patients with AC status available, 585 were not on AC, 795 had AC interrupted, and 415 had AC continued during Micra implant. Non-AC patients tended to be younger, with less history of atrial fibrillation and chronic obstructive pulmonary disease, and more history of dialysis than interrupted and continued patients. The implant success rate was similar for all groups (99.1%-99.8%). Through 30 days postimplant, the overall major complication rate was 3.1% for the non-AC group, 2.6% for the interrupted group, and 1.5% for the continued group. The combined rate for any vascular or pericardial effusion adverse event did not differ significantly among AC strategies (6.5%, 4.8%, and 3.6%, respectively). CONCLUSION: Implant of Micra seems to be safe and feasible regardless of an interrupted or continued periprocedural oral AC strategy, with no increased risk of perforation or vascular complications.