Adam S. Barnett

Calcium influx through L-type CaV1.2 Ca2+ channels regulates mandibular development.

The identification of a gain-of-function mutation in CACNA1C as the cause of Timothy Syndrome (TS), a rare disorder characterized by cardiac arrhythmias and syndactyly, highlighted unexpected roles for the L-type voltage-gated Ca2+ channel CaV1.2 in nonexcitable cells. How abnormal Ca2+ influx through CaV1.2 underlies phenotypes such as the accompanying syndactyly or craniofacial abnormalities in the majority of affected individuals is not readily explained by established CaV1.2 roles. Here, we show that CaV1.2 is expressed in the first and second pharyngeal arches within the subset of cells that give rise to jaw primordia. Gain-of-function and loss-of-function studies in mouse, in concert with knockdown/rescue and pharmacological approaches in zebrafish, demonstrated that Ca2+ influx through CaV1.2 regulates jaw development. Cranial neural crest migration was unaffected by CaV1.2 knockdown, suggesting a role for CaV1.2 later in development. Focusing on the mandible, we observed that cellular hypertrophy and hyperplasia depended upon Ca2+ signals through CaV1.2, including those that activated the calcineurin signaling pathway. Together, these results provide new insights into the role of voltage-gated Ca2+ channels in nonexcitable cells during development.

Quality of evidence underlying the American Heart Association/American College of Cardiology/Heart Rhythm Society guidelines on the management of atrial fibrillation

Importance The joint American College of Cardiology (ACC), American Heart Association (AHA), and Heart Rhythm Society (HRS) guidelines on the management of atrial fibrillation (AF) are used extensively to guide patient care. Objective To describe the evidence base and changes over time in the AHA/ACC/HRS guidelines on AF with respect to the distribution of recommendations across classes of recommendations and levels of evidence. Data Sources Data from the AHA/ACC/HRS guidelines on AF from 2001, 2006, 2011, and 2014 were abstracted. A total of 437 recommendations were included. Data Extraction and Synthesis The number of recommendations and distribution of classes of recommendation (I, II, and III) and levels of evidence (A, B, and C) were determined for each guideline edition. Changes in recommendation class and level of evidence were analyzed using the 2001 and 2014 guidelines. Results From 2001 to 2014, the total number of AF recommendations increased from 95 to 113. Numerically, there was a nonsignificant increase in the use of level of evidence B (30.5% to 39.8%; P = .17) and a nonsignificant decrease in the use of level of evidence C (60.0% to 51.3%; P = .21), with limited changes in the use of level A evidence (8.4% to 8.8%; P = .92). In the 2014 guideline document, 10 of 113 (8.8%) recommendations were supported by level of evidence A, whereas 58 of 113 (51.3%) were supported by level of evidence C. Most recommendations were equally split among class I (49/113; 43.4%) and class IIa/IIb (49/113; 43.4%), with the minority (15/113; 13.3%) assigned as class III. Most class I recommendations were supported by level of evidence C (29/49; 59.2%), whereas only 6 of 49 (12.2%) were supported by level of evidence A. No rate control category recommendations were supported by level of evidence A. Conclusions and Relevance Some aspects of the quality of evidence underlying AHA/ACC/HRS AF guidelines have improved over time. However, the use of level of evidence A remains low and has not increased since 2001. These findings highlight the need for focused and pragmatic randomized studies on the clinical management of AF.

Fibroblast Growth Factor Homologous Factors in the Heart: A Potential Locus for Cardiac Arrhythmias

The four fibroblast growth factor homologous factors (FHFs; FGF11-FGF14) are intracellular proteins that bind and modulate voltage-gated sodium channels (VGSCs). Although FHFs have been well studied in neurons and implicated in neurologic disease, their role in cardiomyocytes was unclear until recently. This review discusses the expression profile and function of FHFs in mouse and rat ventricular cardiomyocytes. Recent data show that FGF13 is the predominant FHF in the murine heart, directly binds the cardiac VGSC α subunit, and is essential for normal cardiac conduction. FHF loss-of-function mutations may be unrecognized causes of cardiac arrhythmias, such as long QT and Brugada syndromes.

The impact of a failing right heart in patients supported by intra-aortic balloon counterpulsation.

Background: Intra-aortic balloon pumps (IABPs) provide primarily left ventricular support, yet few data detail the efficacy of this temporary mechanical circulatory support device in patients with concomitant right ventricular failure. We compared the efficacy of IABPs in cardiogenic shock patients with isolated left ventricular versus biventricular failure. Methods: IABP-treated cardiogenic shock patients were identified from our center between 2006 and 2012, with patients stratified by either isolated left ventricular failure or biventricular failure. We compared baseline characteristics and 72-hour and 30-day outcomes between groups. Outcomes of interest included escalation of mechanical circulatory support, a clinical definition of IABP failure, and death. Results: Among 107 patients, 60 patients (56%) had isolated left ventricular failure compared with 47 patients (44%) having biventricular failure. Patients with isolated left ventricular failure were older and more likely to have coronary artery disease (p<0.05, both). Patients with biventricular failure more often required escalation of mechanical circulatory support at both 72 hours (21% vs. 2%, p<0.001) and 30 days (36% vs. 30%). However, there was no significant difference between groups for failure of IABP therapy at 72 hours (p=0.27) or at 30 days (p=0.62) and death at 30 days (p=0.98). In adjusted analysis, there was no significant difference between groups with regard to risk for a clinical definition of IABP failure at 30 days (odds ratio=0.85, 95% confidence interval (0.27, 2.69)). Conclusions: IABP-treated cardiogenic shock patients with biventricular failure more often required early escalation of mechanical circulatory support. However, there were no significant differences by type of ventricular failure with regard to 30-day outcomes.

Treatment of Atrial Fibrillation and Concordance With the American Heart Association/American College of Cardiology/Heart Rhythm Society Guidelines: Findings From ORBIT-AF (Outcomes Registry for Better Informed Treatment of Atrial Fibrillation)

Background: It is unclear how frequently patients with atrial fibrillation receive guideline-concordant (GC) care and whether guideline concordance is associated with improved outcomes. Methods and Results: Using data from ORBIT-AF (Outcomes Registry for Better Informed Treatment of Atrial Fibrillation), we determined how frequently patients received care that was concordant with 11 recommendations from the 2014 American Heart Association/American College of Cardiology/Heart Rhythm Society atrial fibrillation guidelines pertaining to antithrombotic therapy, rate control, and antiarrhythmic medications. We also analyzed the association between GC care and clinical outcomes at both the patient level and center level. A total of 9570 patients were included. The median age was 75 years (interquartile range, 67–82), and the median CHA2DS2-VASc score was 4 (interquartile range, 3–5). A total of 5977 patients (62.5%) received care that was concordant with all guideline recommendations for which they were eligible. Rates of GC care were higher in patients treated by providers with greater specialization in arrhythmias (60.0%, 62.4%, and 67.0% for primary care physicians, cardiologists, and electrophysiologists, respectively; P<0.001). During a median of 30 months of follow-up, patients treated with GC care had a higher risk of bleeding hospitalization (hazard ratio=1.21; P=0.021) but a similar risk of death, stroke, major bleeding, and all-cause hospitalization. Conclusions: Over a third of patients with atrial fibrillation in this large outpatient registry received care that differed in some respect from guideline recommendations. There was no apparent association between GC care and improved risk-adjusted outcomes.

Recent Advances in Lesion Formation for Catheter Ablation of Atrial Fibrillation.

Despite advances in ablation technology, many patients experience recurrent atrial fibrillation (AF) after radiofrequency ablation. Although estimates vary, the overall 1-year drug-free success for AF ablation is estimated at 40% to 60% for a single procedure and 70% for multiple procedures.1 The cornerstone of conventional AF ablation is pulmonary vein isolation (PVI), and in clinical practice, the most common PVI technique involves creating circular radiofrequency lesions in a point-by-point fashion around the PV ostia/antra.2 However, conventional radiofrequency ablation can be difficult and time-consuming, has less than outstanding efficacy, and can be associated with potentially serious complications, such as steam pops, perforation, tamponade, and thrombus formation, which can lead to thromboembolic events. Given the limitations of conventional radiofrequency ablation, there has been ongoing development of new technologies to facilitate the safety and efficacy of lesion formation and durability. This review will summarize several recent advancements in catheter technology for AF ablation aimed at improving lesion formation (Figure 1). Figure 1. Summary of recent innovations in lesion formation. In radiofrequency ablation, the contact force (CF) between the ablation electrode and the atrial wall is a major determinant of lesion size and durability.3,4 Insufficient CF can result in inadequate lesion formation and higher rates of PV reconnection.5 However, excessive CF can result in complications, such as perforation.6 Therefore, monitoring CF would be expected to maximize ablation efficacy and improve safety. Until recent years, CF has been monitored indirectly using a combination of visual observation of catheter tip motion, tactile feedback, local electrogram attenuation, impedance monitoring, and in some laboratories, intracardiac echocardiogaphy. Although widely used, these methods are a poor surrogate for CF.4,7,8 Recently, ablation catheters that can directly measure CF have become available in the United States. A spring-coupled catheter (SmartTouch) was …

Net clinical benefit of rivaroxaban compared with warfarin in atrial fibrillation: Results from ROCKET AF

AIMS The aim of this study was to determine the net clinical benefit (NCB) of rivaroxaban compared with warfarin in patients with atrial fibrillation. METHODS This was a retrospective analysis of 14,236 patients included in ROCKET AF who received at least one dose of study drug. We analyzed NCB using four different methods: (1) composite of death, stroke, systemic embolism, myocardial infarction, and major bleeding; (2) method 1 with fatal or critical organ bleeding substituted for major bleeding; (3) difference between the rate of ischemic stroke or systemic embolism minus 1.5 times the difference between the rate of intracranial hemorrhage; and (4) weighted sum of differences between rates of death, ischemic stroke or systemic embolism, intracranial hemorrhage, and major bleeding. RESULTS Rivaroxaban was associated with a lower risk of the composite outcome of death, myocardial infarction, stroke, or systemic embolism (rate difference per 10,000 patient-years [RD]=-86.8 [95% CI -143.6 to -30.0]) and fatal or critical organ bleeding (-41.3 [-68 to -14.7]). However, rivaroxaban was associated with a higher risk of major bleeding other than fatal or critical organ bleeding (55.9 [14.7 to 97.2]). Method 1 showed no difference between treatments (-35.5 [-108.4 to 37.3]). Methods 2-4 favored treatment with rivaroxaban (2: -96.8 [-157.0 to -36.8]; 3: -65.2 [-112.3 to -17.8]; 4: -54.8 [-96.0 to -10.2]). CONCLUSIONS Rivaroxaban was associated with favorable NCB compared with warfarin. The NCB was attributable to lower rates of ischemic events and fatal or critical organ bleeding.

Ranolazine reduces atrial fibrillatory wave frequency.

Aims Antiarrhythmic medications for the treatment of atrial fibrillation (AF) have limited efficacy and rare but potentially life-threatening side effects. Ranolazine is an antianginal agent that may have antiarrhythmic activity in AF. Methods and results Using the Duke Enterprise Data Unified Content Explorer database, we analysed a cohort of AF patients on ranolazine. Patients served as their own historic control. Electrocardiograms (ECGs) were analysed before and after ranolazine initiation to determine the effect of ranolazine on dominant frequency (DF), f-wave amplitude, and organizational index (OI). We identified 15 patients with ECGs in AF before and after ranolazine. Ranolazine was associated with lower DF by an average of 10% (5.10 ± 0.74 vs. 5.79 ± 0.96 Hz, P = 0.04) but not with changes in OI (0.47 ± 0.11 vs. 0.50 ± 0.12, P = 0.71) or amplitude (0.47 ± 0.43 vs. 0.41 ± 0.40 mV, P = 0.82). Ranolazine was also associated with lower DF in patients (n = 10) not on concomitant antiarrhythmic therapy (5.25 ± 0.78 vs. 6.03 ± 0.79 Hz, P = 0.04). Conclusion Ranolazine is associated with lower AF DF but no change in OI or fibrillatory wave amplitude. Prospective trials are needed to evaluate ranolazines potential as a novel antiarrhythmic drug for AF.

Adiponectin: an accurate biomarker for patients at risk for atrial fibrillation?

Despite the rising prevalence of atrial fibrillation (AF) throughout the world, the prevention of AF has received relatively little attention. The first step in effective prevention is the accurate identification of persons at risk.1 Biomarkers have been shown to have an important role in risk prediction in other cardiovascular diseases (CVDs), yet few biomarkers, if any, have shown promise in identifying patients at risk for AF. In addition to the challenges of risk prediction, the development of therapeutic interventions to prevent AF is limited by our poor understanding of the factors that promote atrial fibrosis and maladaptive remodelling. Adiponectin is a peptide hormone that has gained attention as a risk marker for CVD and, potentially, AF. Although produced by adipocytes, adiponectin levels fall with increasing adiposity due to obesity-related changes in adipocyte function. Adiponectin is found abundantly in the circulation and has insulin-sensitising, anti-inflammatory and anti-atherosclerotic effects.2 Despite its beneficial metabolic properties, higher adiponectin levels have been associated with worse cardiovascular outcomes, including coronary heart disease,3 heart failure4 and all-cause mortality.5 To date, there is conflicting evidence regarding adiponectin and the risk of AF.6 ,7 In their Heart publication, Macheret et al 8 provide further support for a link between adiponectin and AF. The authors examined the association between adiponectin levels and incident AF in 3190 patients aged over 65 years from the Cardiovascular Health Study. Patients with prevalent CVD and AF were excluded. Total and …

Increased Ca2+ signaling through CaV1.2 promotes bone formation and prevents estrogen deficiency–induced bone loss

While the prevalence of osteoporosis is growing rapidly with population aging, therapeutic options remain limited. Here, we identify potentially novel roles for CaV1.2 L-type voltage-gated Ca2+ channels in osteogenesis and exploit a transgenic gain-of-function mutant CaV1.2 to stem bone loss in ovariectomized female mice. We show that endogenous CaV1.2 is expressed in developing bone within proliferating chondrocytes and osteoblasts. Using primary BM stromal cell (BMSC) cultures, we found that Ca2+ influx through CaV1.2 activates osteogenic transcriptional programs and promotes mineralization. We used Prx1-, Col2a1-, or Col1a1-Cre drivers to express an inactivation-deficient CaV1.2 mutant in chondrogenic and/or osteogenic precursors in vivo and found that the resulting increased Ca2+ influx markedly thickened bone not only by promoting osteogenesis, but also by inhibiting osteoclast activity through increased osteoprotegerin secretion from osteoblasts. Activating the CaV1.2 mutant in osteoblasts at the time of ovariectomy stemmed bone loss. Together, these data highlight roles for CaV1.2 in bone and demonstrate the potential dual anabolic and anticatabolic therapeutic actions of tissue-specific CaV1.2 activation in osteoblasts.