Long-term Outcome of Cryoballoon Ablation in Korean Patients With Atrial Fibrillation: Real-world Experience From the Cryo Global Registry.

BACKGROUND AND OBJECTIVES: Atrial fibrillation (AF), the most common atrial arrhythmia (AA), is an increasing healthcare burden in Korea. The objective of this sub-analysis of the Cryo Global Registry was to evaluate long-term efficacy, symptom burden, quality of life (QoL), and healthcare utilization outcomes and factors associated with AA recurrence in Korean patients treated with cryoballoon ablation (CBA). METHODS: Patients were treated and followed up according to local standard-of-care in 3 Korean hospitals. Kaplan-Meier estimates were used in analyzing (1) efficacy defined as freedom from ≥30 second recurrence of AA at 24 months, (2) healthcare utilization, and (3) predictors of 24-month AA recurrence. Patient-reported QoL (using European Quality of Life-5 Dimensions-3 Levels) and predefined AF-related symptoms were assessed at baseline and 24-month follow-up. RESULTS: Efficacy was 71.9% in paroxysmal AF (PAF) and 49.3% in persistent AF (PsAF) patients (p<0.01). A larger left atrial diameter (LAD), an increased time from AF diagnosis to CBA, and PsAF were independent predictors of AA recurrence. The percentage of patients with no AF symptoms significantly increased from baseline (24.5%) to 24-month (89.5%) follow-up (p<0.01). Improvement in QoL from baseline to 24 months was not statistically different between AF cohorts. PAF patients experienced greater freedom from repeat ablations (93.9% vs. 81.4%) and cardiovascular hospitalizations (91.3% vs. 72.5%, p<0.001 for both). CONCLUSIONS: In alignment with global outcomes, CBA is an effective treatment for AF in the Korean population, with patients possessing a large LAD and not receiving ablation soon after diagnosis being the most at risk for AA recurrence. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02752737.

Cryoballoon ablation of atrial fibrillation in octogenarians: one year outcomes from the cryo global registry.

BACKGROUND: Limited information is available on the safety and efficacy of cryoballoon ablation (CBA) in elderly patients with atrial fibrillation (AF). Moreover, global utilization of CBA in this population (≥ 80 years old) has not been reported. This study's objectives were to determine the use, efficacy, and safety of CBA to treat octogenarians suffering from AF. METHODS: In this sub-analysis of the Cryo Global Registry, 12-month outcomes of treating AF via CBA in octogenarians were compared to patients < 80 years old. Efficacy was evaluated as time to a ≥ 30 s atrial arrhythmia (AA) recurrence. Healthcare utilization was determined via repeat ablations and hospitalizations. Improvement upon disease burden was evaluated through patient reporting of symptoms and the EQ-5D-3L quality of life (QoL) survey. RESULTS: The octogenarian cohort (n = 101) had a higher prevalence of females (51.5% vs 35.7%) and CHA2DS2-VASc scores (4.2 ± 1.3 vs 2.0 ± 1.5) compared to the control cohort (n = 1573, both p < 0.01). Even when adjusting for baseline characteristics and antiarrhythmic drug usage, freedom from AA recurrence at 12 months (80.6% vs 78.9%, HRadj:0.97 [95% CI:0.59-1.58], p = 0.90) was comparable between octogenarians and control, respectively. Similar serious adverse event rates were observed between octogenarians (5.0%) and control (3.2%, p = 0.38). The groups did not differ in healthcare utilization nor reduction of AF-related symptoms from baseline to follow-up, but both experienced an improvement in QoL at 12 months. CONCLUSIONS: Despite more age-related comorbidities, CBA is a safe and effective treatment for AF in octogenarians, with efficacy and adverse events rates akin to ablations performed in younger patients. CLINICAL TRIAL REGISTRATION: https://clinicaltrials.gov/ct2/show/NCT02752737.

Influence of monitoring and atrial arrhythmia burden on quality of life and health care utilization in patients undergoing pulsed field ablation: A secondary analysis of the PULSED AF trial.

BACKGROUND: Freedom from atrial arrhythmia (AA) recurrence ≥30 seconds after pulsed field ablation (PFA) in patients with atrial fibrillation (AF) was reported in PULSED AF (Pulsed Field Ablation to Irreversibly Electroporate Tissue and Treat AF; ClinialTrials.gov Identifier: NCT04198701). AA burden may be a more clinically meaningful endpoint. OBJECTIVE: The purpose of this study was to determine the influence of monitoring strategies on AA detection and AA burden association with quality of life (QoL) and health care utilization (HCU) after PFA. METHODS: Patients underwent 24-hour Holter monitoring at 6 and 12 months and weekly, and symptomatic transtelephonic monitoring (TTM). AA burden post-blanking was calculated as the greater of (1) percentage of AA on total Holter time; or (2) percentage of weeks with ≥1 TTM with AA out of all weeks with ≥1 TTM. RESULTS: Freedom from all AAs varied by >20% when differing monitoring strategies were used. PFA resulted in zero burden in 69.4% of paroxysmal atrial fibrillation (PAF) and 62.2% of persistent atrial fibrillation (PsAF) patients. Median burden was low (<9%). Most PAF and PsAF patients had ≤1 week of AA detection on TTM (82.6% and 75.4%) and <30 minutes of AA per day of Holter monitoring (96.5% and 89.6%), respectively. Only PAF patients with <10% AA burden averaged a clinically meaningful (>19 point) QoL improvement. PsAF patients experienced clinically meaningful QoL improvements irrespective of burden. Repeat ablations and cardioversions significantly increased with higher AA burden (P <.01). CONCLUSION: The ≥30-second AA endpoint is dependent on the monitoring protocol used. PFA resulted in low AA burden for most patients, which was associated with clinically relevant improvement in QoL and reduced AA-related HCU.

Sickle cell disease promotes sex-dependent pathological bone loss through enhanced cathepsin proteolytic activity in mice.

Sickle cell disease (SCD) is the most common hereditary blood disorder in the United States. SCD is frequently associated with osteonecrosis, osteoporosis, osteopenia, and other bone-related complications such as vaso-occlusive pain, ischemic damage, osteomyelitis, and bone marrow hyperplasia known as sickle bone disease (SBD). Previous SBD models have failed to distinguish the age- and sex-specific characteristics of bone morphometry. In this study, we use the Townes mouse model of SCD to assess the pathophysiological complications of SBD in both SCD and sickle cell trait. Changes in bone microarchitecture and bone development were assessed by using high-resolution quantitative micro-computed tomography and the three-dimensional reconstruction of femurs from male and female mice. Our results indicate that SCD causes bone loss and sex-dependent anatomical changes in bone. SCD female mice in particular are prone to trabecular bone loss, whereas cortical bone degradation occurs in both sexes. We also describe the impact of genetic knockdown of cathepsin K- and E-64-mediated cathepsin inhibition on SBD.

Sickle Cell Anemia Mediates Carotid Artery Expansive Remodeling That Can Be Prevented by Inhibition of JNK (c-Jun N-Terminal Kinase).

OBJECTIVE: Sickle cell anemia (SCA) causes chronic inflammation and multiorgan damage. Less understood are the arterial complications, most evident by increased strokes among children. Proteolytic mechanisms, biomechanical consequences, and pharmaceutical inhibitory strategies were studied in a mouse model to provide a platform for mechanistic and intervention studies of large artery damage due to sickle cell disease. Approach and Results: Townes humanized transgenic mouse model of SCA was used to test the hypothesis that elastic lamina and structural damage in carotid arteries increased with age and was accelerated in mice homozygous for SCA (sickle cell anemia homozygous genotype [SS]) due to inflammatory signaling pathways activating proteolytic enzymes. Elastic lamina fragmentation observed by 1 month in SS mice compared with heterozygous littermate controls (sickle cell trait heterozygous genotype [AS]). Positive immunostaining for cathepsin K, a powerful collagenase and elastase, confirmed accelerated proteolytic activity in SS carotids. Larger cross-sectional areas were quantified by magnetic resonance angiography and increased arterial compliance in SS carotids were also measured. Inhibiting JNK (c-jun N-terminal kinase) signaling with SP600125 significantly reduced cathepsin K expression, elastin fragmentation, and carotid artery perimeters in SS mice. By 5 months of age, continued medial thinning and collagen degradation was mitigated by treatment of SS mice with JNK inhibitor. CONCLUSIONS: Arterial remodeling due to SCA is mediated by JNK signaling, cathepsin proteolytic upregulation, and degradation of elastin and collagen. Demonstration in Townes mice establishes their utility for mechanistic studies of arterial vasculopathy, related complications, and therapeutic interventions for large artery damage due to SCA.

Novel Lipid Signaling Mediators for Mesenchymal Stem Cell Mobilization during Bone Repair.

INTRODUCTION: Mesenchymal stem and progenitor cells (MSCs), which normally reside in the bone marrow, are critical to bone health and can be recruited to sites of traumatic bone injury, contributing to new bone formation. The ability to control the trafficking of MSCs provides therapeutic potential for improving traumatic bone healing and therapy for genetic bone diseases such as hypophosphatasia. METHODS: In this study, we explored the sphingosine-1-phosphate (S1P) signaling axis as a means to control the mobilization of MSCs into blood and possibly to recruit MSCs enhancing bone growth. RESULTS: Loss of S1P receptor 3 (S1PR3) leads to an increase in circulating CD45-/CD29+/CD90+/Sca1 putative mesenchymal progenitor cells, suggesting that blocking S1PR3 may stimulate MSCs to leave the bone marrow. Antagonism of S1PR3 with the small molecule VPC01091 stimulated acute migration of CD45-/CD29+/CD90+/Sca1+ MSCs into the blood as early as 1.5 hours after treatment. VPC01091 administration also increased ectopic bone formation induced by BMP-2 and significantly increased new bone formation in critically sized rat cranial defects, suggesting that mobilized MSCs may home to injuries to contribute to healing. We also explored the possibility of combining S1P manipulation of endogenous host cell occupancy with exogenous MSC transplantation for potential use in combination therapies. Importantly, reducing niche occupancy of host MSCs with VPC01091 does not impede engraftment of exogenous MSCs. CONCLUSIONS: Our studies suggest that MSC mobilization through S1PR3 antagonism is a promising strategy for endogenous tissue engineering and improving MSC delivery to treat bone diseases.