Determinants of global cardiac implantable electrical device remote monitoring utilization - Results from an international survey.

Background: Despite near-global availability of remote monitoring (RM) in patients with cardiac implantable electronic devices (CIED), there is a high geographical variability in the uptake and use of RM. The underlying reasons for this geographic disparity remain largely unknown. Objectives: To study the determinants of worldwide RM utilization and identify locoregional barriers of RM uptake. Methods: An international survey was administered to all CIED clinic personnel using the Heart Rhythm Society global network collecting demographic information, as well as information on the use of RM, the organization of the CIED clinic, and details on local reimbursement and clinic funding. The most complete response from each center was included in the current analysis. Stepwise forward multivariate linear regression was performed to identify determinants of the percentage of patients with a CIED on RM. Results: A total of 302 responses from 47 different countries were included, 61.3% by physicians and 62.3% from hospital-based CIED clinics. The median percentage of CIED patients on RM was 80% (interquartile range, 40-90). Predictors of RM use were gross national income per capita (0.76% per US$1000, 95% CI 0.72-1.00, P < .001), office-based clinics (7.48%, 95% CI 1.53-13.44, P = .014), and presence of clinic funding (per-patient payment model 7.90% [95% CI 0.63-15.17, P = .033); global budget 3.56% (95% CI -6.14 to 13.25, P = .471]). Conclusion: The high variability in RM utilization can partly be explained by economic and structural barriers that may warrant specific efforts by all stakeholders to increase RM utilization.

Utilization of the remote monitoring of cardiac implantable electronic devices in a diverse demographic cohort: Insights from a single-center observation.

BACKGROUND: Despite its clinical benefits, patient compliance to remote monitoring (RM) of cardiac implantable electronic devices (CIEDs) varies and remains under-studied in diverse populations. OBJECTIVE: We sought to evaluate RM compliance, clinical outcomes, and identify demographic and socioeconomic factors affecting RM in a diverse urban population in New York. METHODS: This retrospective cohort study included patients enrolled in CIED RM at Montefiore Medical Center between December 2017 and May 2022. RM compliance was defined as the percentage of days compliant to RM transmission divided by the total prescribed days of RM. Patients were censored when they were lost to follow-up or at the time of death. The cohorts were categorized into low (≤30%), intermediate (31-69%), and high (≥70%) RM compliance groups. Statistical analyses were conducted accordingly. RESULTS: Among 853 patients, median RM compliance was 55%. Age inversely affected compliance (p < .001), and high compliance was associated with guideline-directed medical therapy (GDMT) usage and implantable cardioverter defibrillator (ICD)/cardiac resynchronization defibrillator (CRTD) devices. The low-compliance group had a higher mortality rate and fewer regular clinic visits (p < .001) than high-compliance group. Socioeconomic factors did not significantly impact compliance, while Asians showed higher compliance compared with Whites (OR 3.67; 95% CI 1.08-12.43; p = .04). Technical issues were the main reason for non-compliance. CONCLUSION: We observed suboptimal compliance to RM, which occurred most frequently in older patients. Clinic visit compliance, optimal medical therapy, and lower mortality were associated with higher compliance, whereas insufficient understanding of RM usage was the chief barrier to compliance.

Low Utility of Short-Term Rhythm Assessment Before Long-Term Rhythm Monitoring in Patients With Cryptogenic Stroke.

Implantable cardiac monitors are routinely placed for long-term monitoring (LTM) after a period of negative short-term monitoring (STM) to increase atrial fibrillation (AF) detection after a cryptogenic stroke or transient ischemic attack (TIA). Optimizing AF monitoring after a cryptogenic stroke is critical to improve outcomes and reduce costs. We sought to compare the diagnostic yield of STM versus LTM, assess the impact of routine STM on hospitalization length of stay, and perform a financial analysis comparing the current model to a theoretical model wherein patients can proceed directly to LTM. Our retrospective observational cohort study analyzed patients admitted to Montefiore Medical Center between May 2017 and June 2022 with a primary diagnosis of cryptogenic stroke or TIA who underwent Holter device monitoring. Of 396 subjects, STM detected AF in 10 (2.5%) compared with a diagnostic yield of 14.6% for LTM (median time to diagnosis of 76 days). Of the 386 patients with negative STM, 130 (33.7%) received an implantable cardiac monitor while an inpatient, and 256 (66.3%) did not. We calculated a point estimate of 1.67 days delay of discharge attributable to the requirement for STM to precede LTM. Our model showed that the expected cost per patient in the STM-first paradigm is $28,615.33 versus $27,111.24 in the LTM-or-STM paradigm. Considering the relatively lower diagnostic yield of STM and its association with a longer length of stay and higher costs, it may be reasonable to proceed directly to LTM to optimize AF detection after a cryptogenic stroke or TIA.

Prevalence and association of the Wellens' sign with coronary artery disease in an ethnically diverse urban population.

BACKGROUND: Wellens' sign is considered to be an ominous sign indicative of underlying significant proximal left anterior descending artery stenosis. We sought to identify the prevalence of the Wellens' pattern in a large ethnically diverse urban population and assess its association with the presence and extent of coronary artery disease. METHODS: We utilized the MUSE ECG database of Montefiore Medical Center, an academic tertiary health care system, to identify ECGs from 2012 to 2019 exhibiting a Wellens' pattern. From a dataset of 1.76 million tracings, six screening diagnosis codes were selected to approximate the Wellens' pattern. These codes were used to generate a cohort of ECGs for manual review by a board certified cardiologist to determine if a Wellens' pattern was present. RESULTS: Of 1,756,742 ECGs performed on 433,218 patients from 2012 to 2019; after initial screening 2186 ECGs were identified for manual review. Of these, 448 (0.1%) patients were confirmed to have a Wellens' pattern. 229 patients underwent cardiac catheterization, while 219 patients were managed medically. No statistical difference was seen in the occurrence of Wellens' Type A and B pattern across the ethnic groups after multivariate analysis. Women were more likely to have Type B Wellens' compared to men (OR 2.40 (1.58, 3.62) P < 0.0001). 80 (35%) patients had single vessel LAD disease of which 22 (10%) had proximal, 40 (17%) had mid, 4 (1%) had distal stenosis, while diffuse LAD disease was seen in 14 (6%) patients. Two vessel disease was seen in 46 (20%) patients with a Wellens' pattern, and triple vessel disease was seen in 23 (10%) patients. Of note, 71 (31%) patients had either normal or nonobstructive coronary disease despite exhibiting a Wellens' pattern ECG. CONCLUSION: Wellens' sign is a rare electrocardiographic pattern which when seen in a patient with an appropriate clinical presentation, suggests but is not definitive for the presence of significant coronary disease, often but not exclusively in an LAD distribution. We found no statistical difference in the occurrence of Wellens' sign among different racial/ethnic groups. Patients with a Wellens' pattern may have critical lesions at a variety of LAD sites as well as in multiple vessels. As such, the interventionalist needs to be prepared for these uncertainties at the time of cardiac catheterization.

Wearable Cardioverter Defibrillators.

The use of implantable cardioverter defibrillators (ICD) has favorably impacted the prevention and treatment of sudden cardiac death (SCD) associated with ventricular arrhythmias. However, there are situations where an ICD cannot be immediately implanted, even though the patient is at high risk for SCD. The wearable cardioverter defibrillator (WCD) is a unique technology that can bridge this gap for patients. The WCD has been demonstrated to terminate ventricular tachycardia/fibrillation if worn and used correctly. With proper training, it is relatively easy to put on, maintain, and use. Most patients are compliant and are able to consistently wear the device. The WCD negates the infection risk or procedural complications associated with insertion and possible extraction of leads, as with an ICD. In terms of primary prevention of ventricular tachycardia/fibrillation in patients with a left ventricular ejection fraction ≤35%, prospective, randomized studies evaluating the survival of patients utilizing the WCD will need to be performed before evidenced-based criteria for its use can be established. On the basis of current data, WCD use for those awaiting heart transplant, for those with ICD indications status post-ICD explant, and for high-risk SCD patients with possible reversible cardiomyopathy appears to be a reasonable approach on the basis of current data.

Multiple Drug Treatments That Increase cAMP Signaling Restore Long-Term Memory and Aberrant Signaling in Fragile X Syndrome Models.

Fragile X is the most common monogenic disorder associated with intellectual disability (ID) and autism spectrum disorders (ASD). Additionally, many patients are afflicted with executive dysfunction, ADHD, seizure disorder and sleep disturbances. Fragile X is caused by loss of FMRP expression, which is encoded by the FMR1 gene. Both the fly and mouse models of fragile X are also based on having no functional protein expression of their respective FMR1 homologs. The fly model displays well defined cognitive impairments and structural brain defects and the mouse model, although having subtle behavioral defects, has robust electrophysiological phenotypes and provides a tool to do extensive biochemical analysis of select brain regions. Decreased cAMP signaling has been observed in samples from the fly and mouse models of fragile X as well as in samples derived from human patients. Indeed, we have previously demonstrated that strategies that increase cAMP signaling can rescue short term memory in the fly model and restore DHPG induced mGluR mediated long term depression (LTD) in the hippocampus to proper levels in the mouse model (McBride et al., 2005; Choi et al., 2011, 2015). Here, we demonstrate that the same three strategies used previously with the potential to be used clinically, lithium treatment, PDE-4 inhibitor treatment or mGluR antagonist treatment can rescue long term memory in the fly model and alter the cAMP signaling pathway in the hippocampus of the mouse model.

PDE-4 inhibition rescues aberrant synaptic plasticity in Drosophila and mouse models of fragile X syndrome.

Fragile X syndrome (FXS) is the leading cause of both intellectual disability and autism resulting from a single gene mutation. Previously, we characterized cognitive impairments and brain structural defects in a Drosophila model of FXS and demonstrated that these impairments were rescued by treatment with metabotropic glutamate receptor (mGluR) antagonists or lithium. A well-documented biochemical defect observed in fly and mouse FXS models and FXS patients is low cAMP levels. cAMP levels can be regulated by mGluR signaling. Herein, we demonstrate PDE-4 inhibition as a therapeutic strategy to ameliorate memory impairments and brain structural defects in the Drosophila model of fragile X. Furthermore, we examine the effects of PDE-4 inhibition by pharmacologic treatment in the fragile X mouse model. We demonstrate that acute inhibition of PDE-4 by pharmacologic treatment in hippocampal slices rescues the enhanced mGluR-dependent LTD phenotype observed in FXS mice. Additionally, we find that chronic treatment of FXS model mice, in adulthood, also restores the level of mGluR-dependent LTD to that observed in wild-type animals. Translating the findings of successful pharmacologic intervention from the Drosophila model into the mouse model of FXS is an important advance, in that this identifies and validates PDE-4 inhibition as potential therapeutic intervention for the treatment of individuals afflicted with FXS.

The Drosophila DmGluRA is required for social interaction and memory.

Metabotropic glutamate receptors (mGluRs) have well-established roles in cognition and social behavior in mammals. Whether or not these roles have been conserved throughout evolution from invertebrate species is less clear. Mammals have eight mGluRs whereas Drosophila has a single DmGluRA, which has both Gi and Gq coupled signaling activity. We have utilized Drosophila to examine the role of DmGluRA in social behavior and various phases of memory. We have found that flies that are homozygous or heterozygous for loss of function mutations of DmGluRA have impaired social behavior in male Drosophila. Futhermore, flies that are heterozygous for loss of function mutations of DmGluRA have impaired learning during training, immediate-recall memory, short-term memory, and long-term memory as young adults. This work demonstrates a role for mGluR activity in both social behavior and memory in Drosophila.

Apoptosis inhibitor ARC promotes breast tumorigenesis, metastasis, and chemoresistance.

Apoptosis repressor with caspase recruitment domain (ARC) inhibits both death receptor- and mitochondrial/ER-mediated pathways of apoptosis. Although expressed mainly in terminally differentiated cells, ARC is markedly upregulated in a variety of human cancers, where its potential contributions have not yet been defined. In this study, we provide evidence of multiple critical pathophysiologic functions for ARC in breast carcinogenesis. In the polyoma middle T-antigen (PyMT) transgenic mouse model of breast cancer, in which endogenous ARC is strongly upregulated, deletion of the ARC-encoding gene nol3 decreased primary tumor burden without affecting tumor onset or multiplicity. More notably, ARC deficiency also limited tumor cell invasion and the number of circulating cancer cells, markedly reducing the number of lung metastases. Conversely, ectopic overexpression of ARC in a PyMT-derived metastatic breast cancer cell line increased invasion in vitro and lung metastasis in vivo. We confirmed these results in a humanized orthotopic model based on MDA-MB-231-derived LM2 metastatic breast cancer cells, in which RNAi-mediated knockdown of ARC levels was shown to reduce tumor volume, local invasion, and lung metastases. Lastly, we found that endogenous levels of ARC conferred chemoresistance in primary tumors and invading cell populations. Our results establish that ARC promotes breast carcinogenesis by driving primary tumor growth, invasion, and metastasis as well as by promoting chemoresistance in invasive cells.

Pharmacological and genetic reversal of age-dependent cognitive deficits attributable to decreased presenilin function.

Alzheimer's disease (AD) is the leading cause of cognitive loss and neurodegeneration in the developed world. Although its genetic and environmental causes are not generally known, familial forms of the disease (FAD) are attributable to mutations in a single copy of the Presenilin (PS) and amyloid precursor protein genes. The dominant inheritance pattern of FAD indicates that it may be attributable to gain or change of function mutations. Studies of FAD-linked forms of presenilin (psn) in model organisms, however, indicate that they are loss of function, leading to the possibility that a reduction in PS activity might contribute to FAD and that proper psn levels are important for maintaining normal cognition throughout life. To explore this issue further, we have tested the effect of reducing psn activity during aging in Drosophila melanogaster males. We have found that flies in which the dosage of psn function is reduced by 50% display age-onset impairments in learning and memory. Treatment with metabotropic glutamate receptor (mGluR) antagonists or lithium during the aging process prevented the onset of these deficits, and treatment of aged flies reversed the age-dependent deficits. Genetic reduction of Drosophila metabotropic glutamate receptor (DmGluRA), the inositol trisphosphate receptor (InsP(3)R), or inositol polyphosphate 1-phosphatase also prevented these age-onset cognitive deficits. These findings suggest that reduced psn activity may contribute to the age-onset cognitive loss observed with FAD. They also indicate that enhanced mGluR signaling and calcium release regulated by InsP(3)R as underlying causes of the age-dependent cognitive phenotypes observed when psn activity is reduced.

Age-dependent cognitive impairment in a Drosophila fragile X model and its pharmacological rescue.

Fragile X syndrome afflicts 1 in 2,500 individuals and is the leading heritable cause of mental retardation worldwide. The overriding clinical manifestation of this disease is mild to severe cognitive impairment. Age-dependent cognitive decline has been identified in Fragile X patients, although it has not been fully characterized nor examined in animal models. A Drosophila model of this disease has been shown to display phenotypes bearing similarity to Fragile X symptoms. Most notably, we previously identified naive courtship and memory deficits in young adults with this model that appear to be due to enhanced metabotropic glutamate receptor (mGluR) signaling. Herein we have examined age-related cognitive decline in the Drosophila Fragile X model and found an age-dependent loss of learning during training. We demonstrate that treatment with mGluR antagonists or lithium can prevent this age-dependent cognitive impairment. We also show that treatment with mGluR antagonists or lithium during development alone displays differential efficacy in its ability to rescue naive courtship, learning during training and memory in aged flies. Furthermore, we show that continuous treatment during aging effectively rescues all of these phenotypes. These results indicate that the Drosophila model recapitulates the age-dependent cognitive decline observed in humans. This places Fragile X in a category with several other diseases that result in age-dependent cognitive decline. This demonstrates a role for the Drosophila Fragile X Mental Retardation Protein (dFMR1) in neuronal physiology with regard to cognition during the aging process. Our results indicate that misregulation of mGluR activity may be causative of this age onset decline and strengthens the possibility that mGluR antagonists and lithium may be potential pharmacologic compounds for counteracting several Fragile X symptoms.