Safety of Pill-in-the-Pocket Class 1C Antiarrhythmic Drugs for Atrial Fibrillation.

BACKGROUND: Guidelines recommend that initial trial of a "pill-in-the-pocket" (PIP) Class 1C antiarrhythmic drug (AAD) for cardioversion of atrial fibrillation (AF) be performed in a monitored setting because of the potential for adverse reactions. OBJECTIVES: This study sought to characterize real-world, contemporary use of the PIP approach, including the setting of initiation and incidence of adverse events. METHODS: This retrospective cohort study included all patients at the Hospital of the University of Pennsylvania treated with a PIP approach for AF between 2007 and 2020. RESULTS: A total of 273 patients (age 56 ± 13 years; 182 [67%] male; CHA2DS2VASc score 1.1 ± 1.2) took a first dose of PIP AAD. Flecainide was used in 151 (55%) and propafenone in 122 (45%). The first dose of PIP AAD was taken in a monitored setting in 167 (62%). Significant adverse events occurred in 7 patients (3%), 2 of whom had taken the dose in a monitored setting. Significant adverse events included unexplained syncope (1 of 7), symptomatic bradycardia/hypotension (4 of 7), and 1:1 atrial flutter (2 of 7). All occurred in patients taking 300 mg of flecainide (n = 4) or 600 mg of propafenone (n = 3). Electrical cardioversion was performed in 29 (11%) patients because of failure of the AAD to terminate AF. One patient required intravenous fluids and vasopressors for 2 hours because of persistent hypotension and bradycardia. Two patients required permanent pacemakers for bradycardia. The remaining patients required no intervention. CONCLUSIONS: Our data support the current recommendation to initiate PIP AAD in a monitored setting because of rare significant adverse reactions that can require urgent intervention.

CXCR4 Cardiac Specific Knockout Mice Develop a Progressive Cardiomyopathy.

Activation of multiple pathways is associated with cardiac hypertrophy and heart failure. We previously published that CXCR4 negatively regulates ß-adrenergic receptor (ß-AR) signaling and ultimately limits ß-adrenergic diastolic (Ca2+) accumulation in cardiac myocytes. In isolated adult rat cardiac myocytes; CXCL12 treatment prevented isoproterenol-induced hypertrophy and interrupted the calcineurin/NFAT pathway. Moreover; cardiac specific CXCR4 knockout mice show significant hypertrophy and develop cardiac dysfunction in response to chronic catecholamine exposure in an isoproterenol-induced (ISO) heart failure model. We set this study to determine the structural and functional consequences of CXCR4 myocardial knockout in the absence of exogenous stress. Cardiac phenotype and function were examined using (1) gated cardiac magnetic resonance imaging (MRI); (2) terminal cardiac catheterization with in vivo hemodynamics; (3) histological analysis of left ventricular (LV) cardiomyocyte dimension; fibrosis; and; (4) transition electron microscopy at 2-; 6- and 12-months of age to determine the regulatory role of CXCR4 in cardiomyopathy. Cardiomyocyte specific-CXCR4 knockout (CXCR4 cKO) mice demonstrate a progressive cardiac dysfunction leading to cardiac failure by 12-months of age. Histological assessments of CXCR4 cKO at 6-months of age revealed significant tissue fibrosis in knockout mice versus wild-type. The expression of atrial naturietic factor (ANF); a marker of cardiac hypertrophy; was also increased with a subsequent increase in gross heart weights. Furthermore, there were derangements in both the number and the size of the mitochondria within CXCR4 cKO hearts. Moreover, CXCR4 cKO mice were more sensitive to catocholamines, their response to ß-AR agonist challenge via acute isoproterenol (ISO) infusion demonstrated a greater increase in ejection fraction, dp/dtmax, and contractility index. Interestingly, prior to ISO infusion, there were significant differences in baseline hemodynamics between the CXCR4 cKO compared to littermate controls. However, upon administering ISO, the CXCR4 cKO responded in a robust manner overcoming the baseline hemodynamic deficits reaching WT values supporting our previous data that CXCR4 negatively regulates ß-AR signaling. This further supports that, in the absence of the physiologic negative modulation, there is an overactivation of down-stream pathways, which contribute to the development and progression of contractile dysfunction. Our results demonstrated that CXCR4 plays a non-developmental role in regulating cardiac function and that CXCR4 cKO mice develop a progressive cardiomyopathy leading to clinical heart failure.

SDF-1 induces TNF-mediated apoptosis in cardiac myocytes.

Chemokines are small secreted proteins with chemoattractant properties that play a key role in inflammation. One such chemokine, Stromal cell-derived factor-1 (SDF-1) also known as CXCL12, and its receptor, CXCR4, are expressed and functional in cardiac myocytes. SDF-1 both stimulates and enhances the cellular signal which attracts potentially beneficial stem cells for tissue repair within the ischemic heart. Paradoxically however, this chemokine is known to act in concert with the inflammatory cytokines of the innate immune response which contributes to cellular injury through the recruitment of inflammatory cells during ischemia. In the present study, we have demonstrated that SDF-1 has dose dependent effects on freshly isolated cardiomyocytes. Using Tunnel and caspase 3-activation assays, we have demonstrated that the treatment of isolated adult rat cardiac myocyte with SDF-1 at higher concentrations (pathological concentrations) induced apoptosis. Furthermore, ELISA data demonstrated that the treatment of isolated adult rat cardiac myocyte with SDF-1 at higher concentrations upregulated TNF-α protein expression which directly correlated with subsequent apoptosis. There was a significant reduction in SDF-1 mediated apoptosis when TNF-α expression was neutralized which suggests that SDF-1 mediated apoptosis is TNF-α-dependent. The fact that certain stimuli are capable of driving cardiomyocytes into apoptosis indicates that these cells are susceptible to clinically relevant apoptotic triggers. Our findings suggest that the elevated SDF-1 levels seen in a variety of clinical conditions, including ischemic myocardial infarction, may either directly or indirectly contribute to cardiac cell death via a TNF-α mediated pathway. This highlights the importance of this receptor/ligand in regulating the cardiomyocyte response to stress conditions.

CXCR4 and CXCR7 play distinct roles in cardiac lineage specification and pharmacologic ß-adrenergic response.

CXCR4 and CXCR7 are prominent G protein-coupled receptors (GPCRs) for chemokine stromal cell-derived factor-1 (SDF-1/CXCL12). This study demonstrates that CXCR4 and CXCR7 induce differential effects during cardiac lineage differentiation and ß-adrenergic response in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). Using lentiviral vectors to ablate CXCR4 and/or CXCR7 expression, hiPSC-CMs were tested for phenotypic and functional properties due to gene knockdown. Gene expression and flow cytometry confirmed the pluripotent and cardiomyocyte phenotype of undifferentiated and differentiated hiPSCs, respectively. Although reduction of CXCR4 and CXCR7 expression resulted in a delayed cardiac phenotype, only knockdown of CXCR4 delayed the spontaneous beating of hiPSC-CMs. Knockdown of CXCR4 and CXCR7 differentially altered calcium transients and ß-adrenergic response in hiPSC-CMs. In engineered cardiac tissues, depletion of CXCR4 or CXCR7 had opposing effects on developed force and chronotropic response to ß-agonists. This work demonstrates distinct roles for the SDF-1/CXCR4 or CXCR7 network in hiPSC-derived ventricular cardiomyocyte specification, maturation and function.

The duality of chemokines in heart failure.

The failing human heart is a bustling network of intra- and inter-cellular signals and related processes attempting to coordinate a repair mechanism for the injured or diseased myocardium. While our understanding of signaling by mode of cytokines is well understood on a systemic level, we are only now coming to elucidate the role of cytokines in cardiac self-regulation. An increasing number of studies are showing now that cardiomyocytes themselves have not only the ability but also the mandate to produce signals, and play direct roles in how these signals are interpreted. One of the families of cytokines employed by distressed cardiac tissue are chemokines. By regulating the movement of pro-inflammatory cell types to sites of injury, we see now how the myocardium responds to stress. Herein we review the participation of these inflammatory mediators and explore the delicate balance between their protective roles and damaging functions.