Genetic Risk Stratification in Arrhythmogenic Left Ventricular Cardiomyopathy.

Arrhythmogenic left ventricular cardiomyopathy is characterized by early malignant ventricular arrhythmia associated with varying degrees and times of onset of left ventricular dysfunction. Variants in numerous genes have been associated with this phenotype. Here, the authors review the literature on recent cohort studies of patients with variants in desmoplakin, lamin A/C, filamin-C, phospholamban, RBM20, TMEM43, and selected channelopathy genes also associated with structural disease. Unlike traditional sudden cardiac death risk assessment in nonischemic cardiomyopathy, left ventricular systolic function is an insensitive predictor of risk in patients with these genetic diagnoses.

Association of Longitudinal Change in High-Sensitivity Troponin with All-Cause Mortality in Coronary Artery Disease: The Heart and Soul Study.

BACKGROUND: Serial increases in high-sensitivity cardiac troponin (hs-cTnT) have been associated with death in community-dwelling adults, but the association remains uninvestigated in those with coronary artery disease (CAD). METHODS: We measured hs-cTnT at baseline and after 5 years in 635 ambulatory Heart and Soul Study patients with CAD. We also performed echocardiography at rest and after treadmill exercise at baseline and after 5 years. Participants were subsequently followed for the outcome of death. We used a multivariable-adjusted Cox proportional hazards model to evaluate the association between 5-year change in hs-cTnT and subsequent all-cause mortality. RESULTS: Of the 635 subjects, there were 386 participants (61%) who had an increase in hs-cTnT levels between baseline and year 5 measurements (median increase 5.6 pg/mL, IQR 3.2-9.9 pg/mL). There were 182 deaths after a mean 4.2-year follow-up after the year 5 visit. After adjusting for clinical variables, a >50% increase in hs-cTnT between baseline and year 5 was associated with a nearly 2-fold increased risk of death from any cause (hazard ratio 1.7, 95% confidence interval 1.1-2.7). When addition of year 5 hs-cTnT was compared to a model including clinical variables and baseline hs-cTnT, there was a modest but statistically significant increase in C-statistic from 0.82 to 0.83 (p = 0.04). CONCLUSION: In ambulatory patients with CAD, serial increases in hs-cTnT over time are associated with an increased risk of death.

Implantable Cardioverter-Defibrillator Placement for Primary Prevention in 2,346 Patients: Predictors of One-Year Survival.

Guidelines suggest that patients who receive implantable cardioverter-defibrillators (ICDs) for primary prevention should be expected to live more than one year after placement. However, tools for validating this prognosis are not sufficiently predictive. We sought to identify definitive predictors of one-year survival after ICD placement. By reviewing medical records and the Social Security Death Index, we analyzed baseline characteristics and survival outcomes of 3,164 patients who underwent ICD placement at our institution from January 2006 through March 2014. Survival outcome could be confirmed for 2,346 patients (74%). Of these, 184 (7.8%) died within one year of ICD placement. We noted significant differences in numerous variables between those who lived and died. However, multivariable analysis revealed only 5 independent predictors of earlier death: worse New York Heart Association functional class (hazard ratio [HR]=1.87 per class [95% CI, 1.22-2.87]; P <0.01); lower serum sodium level (HR=0.93 per 1 mEq/L increase [95% CI, 0.88-0.99]; P=0.04); atrial fibrillation (HR=1.81 [95% CI, 1.03-3.21]; P=0.04); chronic lung disease (HR=2.05 [95% CI, 1.20-3.51]; P <0.01), and amiodarone use (HR=10.1 [95% CI, 4.51-22.5]; P <0.01). Using receiver operating characteristic curves, we developed a model with an area under the curve of 0.718 that predicted death at one year after ICD implantation. Despite significant univariate differences between the ICD recipients who did and did not live beyond one year, we found only moderate predictors of survival. Better tools are needed to predict outcomes when considering ICD placement for primary prevention.

Procedural outcomes and long-term survival associated with lead extraction in patients with abandoned leads.

BACKGROUND: The decision to abandon or extract superfluous sterile leads is controversial. OBJECTIVE: The purpose of this study was to compare procedural outcomes and long-term survival of patients with and those without abandoned leads undergoing lead extraction (LE). METHODS: Retrospective review of all patients who had undergone transvenous LE at our institution from January 2007 to May 2016 was performed. Patients were stratified into 2 groups based on the presence (group 1) or absence (group 2) of abandoned leads. RESULTS: Among 774 patients who had undergone LE procedures, 38 (4.9%) had abandoned leads (group 1). Dwell time of the oldest extracted lead was longer in group 1 vs group 2 (7.6 ± 4.9 years vs 5.6 ± 4.4 years; P = .017), as was infection as an indication for LE (76% vs 33%; P <.001). A bailout femoral approach was more commonly required in group 1 than in group 2 (18.4% vs 6%; P = .007). Complete procedural success rates were similar (92.1% in group 1 vs 95.0% in group 2; P = .439), but there was a trend toward lower clinical success in group 1 (92.1% vs 97.4%; P = .088), primarily due to failure to remove all hardware in the setting of infection. Major procedural complication rates were similar (2.6% in group 1 vs 1.2% in group 2; P = .397), as was long-term survival (mean follow-up 2.3 ± 2.2 years). CONCLUSION: Abandoned leads at the time of LE were associated with increased procedural complexity, including a higher rate of bailout femoral extraction, and may be associated with lower clinical success. Among appropriately selected patients, consideration should be given to LE instead of abandonment.

Clinical and anatomic predictors of need for repeat atrial fibrillation ablation.

AIM: To identify predictors of need for repeat procedures after initial atrial fibrillation (AF) ablation. METHODS: We identified a cohort undergoing first time AF ablation at our institution from January 2004 to February 2014 who had cardiac magnetic resonance (CMR) imaging performed prior to ablation. Clinical variables and anatomic characteristics (determined from CMR) were assessed as predictors of need for repeat ablation. The decision regarding need for and timing of repeat ablation was at the discretion of the treating physician. RESULTS: From a cohort of 331 patients, 142 patients (43%) underwent repeat ablation at a mean of 13.6 ± 18.4 mo after the index procedure. Both male gender (81% vs 71%, P = 0.05) and lower ejection fraction (57.4% ± 10.3% vs 59.8% ± 9.4%, P = 0.04) were associated with need for repeat ablation. On pre-ablation CMR, mean pulmonary vein (PV) diameters were significantly larger in all four PVs among patients requiring repeat procedures. In multivariate analysis, increased right superior PV diameter significantly predicted need for repeat ablation (odds ratio 1.08 per millimeter increase in diameter, 95%CI: 1.00-1.16, P = 0.05). There were also trends toward significance for increased left and right inferior PV sizes among those requiring repeat procedures. CONCLUSION: Increased PV size predicts the need for repeat AF ablation, with each millimeter increase in PV diameter associated with an approximately 5%-10% increased risk of requiring repeat procedures.

Encouraging Student Interest in Teaching Through a Medical Student Teaching Competition.

PROBLEM: Clinician educators have realized the value not only of assigning teaching roles to medical students but also of offering explicit training in how to teach effectively. Despite this interest in the development of medical students' teaching skills, formal teaching instruction and opportunities for practice are lacking. APPROACH: To encourage medical student interest in teaching, the authors developed and implemented a medical student teaching competition (MSTC) at Emory University School of Medicine during the summers of 2014, 2015, and 2016. Each year, eight student finalists were each paired with a physician "teaching coach" and given one month to prepare for the MSTC. During the competition, each finalist delivered an eight-minute presentation to a panel of seven physician and resident judges. The authors describe the development, implementation, and assessment of the MSTC. OUTCOMES: Approximately 150 medical students and faculty members attended the MSTC each year. The students in attendance felt that the MSTC made them more likely to seek out opportunities to learn how to teach effectively and to practice teaching. Additionally, some students are now more interested in learning about a career in academic medicine than they were before the MSTC. NEXT STEPS: Given the need for more formal initiatives dedicated to improving the teaching skills of doctors-in-training, including medical students, innovative solutions such as the MSTC may enhance a medical school's existing curriculum and encourage student interest in teaching. The MSTC model may be generalizable to other medical schools.

Procedural outcomes and long-term survival following lead extraction in octogenarians.

BACKGROUND: Octogenarians account for a significant percentage of patients with indwelling pacemakers or defibrillators. OBJECTIVES: To determine procedural outcomes and long-term survival after lead extraction (LE) in octogenarians. METHODS: We retrospectively identified all patients who underwent defibrillator or pacemaker LE at our institution between January 1, 2007 and May 31, 2016. Patients were stratified based on age into two groups: <80 years old (Group 1, n = 674) or ≥80 (Group 2, n = 100). Outcomes were determined by medical records review and query of the Social Security Death Index. RESULTS: Patients in Group 2 were more likely to be hypertensive (77% vs 61%, P = 0.02), more like to have coronary artery disease (50% vs 39%, P = 0.049), and more likely to be extracted for infectious indications (47% vs 33%, P = .009). The number of leads extracted per procedure was 2.0 ± 0.8 and the mean dwell time of the oldest extracted lead was 5.6 ± 4.3 years, without significant differences between groups. Extraction procedure success (Group 1: 94.7%, Group 2: 96%, P = 0.808) and procedural deaths (Group 1: 0.9% vs Group 2: 0%, P = 1.0) were similar. There was no significant difference in survival up to 3 years following LE between groups. CONCLUSION: At experienced centers, LE can be performed safely in octogenarians with procedural success rates and long-term survival comparable to younger individuals.

Outcomes of lead extraction in young adults.

BACKGROUND: Extraction of pacemaker and defibrillator leads in young adults may be technically challenging because of more extensive fibrosis and calcification in this patient population. OBJECTIVE: The purpose of this study was to examine outcomes of lead extraction (LE) in young adults at our institution. METHODS: We retrospectively identified all patients who underwent LE at our institution between January 1, 2007, and May 31, 2016. Patients were divided by age into 2 groups: <40 years (group 1, n = 84) or ≥40 years (group 2, n = 690). Outcomes were determined by medical records review. RESULTS: Patients in group 2 had a higher overall average number of leads extracted per procedure compared to group 1 (1.64 ± 0.80 vs 1.45 ± 0.64; P <.001). Lead dwell time was similar in the 2 groups (5.7 ± 5 years vs 5.6 ± 4.3 years; P = .95). The younger cohort tended to require femoral extraction techniques more frequently (9.5% vs 4.4%; P = .055). Extraction procedural success (group 1: 94.1%, group 2: 94.9%; P = .792), major complications (group 1: 0%, group 2: 1.3%; P = 1), and periprocedural mortality (group 1: 0%, group 2: 0.86%; P = 1) were similar in the 2 groups. CONCLUSION: LE can be performed safely and effectively in young adults. Despite the lower number of leads extracted per procedure and the similar lead dwell time, younger adults more frequently required the use of femoral extraction tools, thus highlighting the importance of performing these procedures in centers with advanced expertise in extraction techniques.

Predictors and outcomes of lead extraction requiring a bailout femoral approach: Data from 2 high-volume centers.

BACKGROUND: Lead extraction (LE) infrequently requires the use of the "bailout" femoral approach. Predictors and outcomes of femoral extraction are not well characterized. OBJECTIVE: The aim of this study was to determine the predictors of need for femoral LE and its outcomes. METHODS: Consecutive patients who underwent LE at our centers were identified. Baseline demographic characteristics, procedural outcomes, and clinical outcomes were ascertained by medical record review. Patients were stratified into 2 groups on the basis of the need for femoral extraction. RESULTS: A total of 1080 patients underwent LE, of whom 50 (4.63%) required femoral extraction. Patients requiring femoral extraction were more likely to have leads with longer dwell time (9.5 ± 6.0 years vs 5.7 ± 4.3 years; P < .001), to have more leads extracted per procedure (2.0 ± 1.0 vs 1.7 ± 0.9; P = .003), and to have infection as an indication for extraction (72% vs 37.2%; P < .001). Procedural and clinical success was lower in the femoral extraction group than in the nonfemoral group (58% and 76% vs 94.7% and 97.9 %, respectively; P < .001). Major periprocedural complications (0% vs 1.3%; P = 1.0) and periprocedural mortality (0% vs 0.8%; P = 1.0) were similar between the 2 groups. CONCLUSION: In this study, femoral extraction was needed in ~5% of LEs. Longer lead dwell time, higher number of leads extracted per procedure, and the presence of infection predicted the need for femoral extraction. Procedural success of femoral extraction was low, highlighting the fact that this approach is mostly used as a bailout strategy and thus selects for more challenging cases.

Management of Atrial Fibrillation in Elderly Adults.

Driven in large part by the aging of the population and the increasing prevalence of cardiovascular comorbidities associated with atrial fibrillation (AF), there is a burgeoning epidemic of AF in elderly adults. Although there is a large body of literature to guide management of people with AF, elderly adults with AF are frequently underrepresented in clinical trials. This review provides a contemporary update on management of elderly adults with AF with a particular focus on the two main clinical challenges that AF poses: stroke risk reduction and control of symptoms. The evidence to support novel AF treatment strategies in elderly adults is reviewed, including novel oral anticoagulants and left atrial appendage closure for stroke risk reduction and catheter ablation for control of symptoms.

A multifunctional nanoplatform for imaging, radiotherapy, and the prediction of therapeutic response.

Gold nanoparticles have garnered interest as both radiosensitzers and computed tomography (CT) contrast agents. However, the extremely high concentrations of gold required to generate CT contrast is far beyond that needed for meaningful radiosensitization, which limits their use as combined therapeutic-diagnostic (theranostic) agents. To establish a theranostic nanoplatform with well-aligned radiotherapeutic and diagnostic properties for better integration into standard radiation therapy practice, a gold- and superparamagnetic iron oxide nanoparticle (SPION)-loaded micelle (GSM) is developed. Intravenous injection of GSMs into tumor-bearing mice led to selective tumoral accumulation, enabling magnetic resonance (MR) imaging of tumor margins. Subsequent irradiation leads to a 90-day survival of 71% in GSM-treated mice, compared with 25% for irradiation-only mice. Furthermore, measurements of the GSM-enhanced MR contrast are highly predictive of tumor response. Therefore, GSMs may not only guide and enhance the efficacy of radiation therapy, but may allow patients to be managed more effectively.

Global analysis of RNA secondary structure in two metazoans.

The secondary structure of RNA is necessary for its maturation, regulation, processing, and function. However, the global influence of RNA folding in eukaryotes is still unclear. Here, we use a high-throughput, sequencing-based, structure-mapping approach to identify the paired (double-stranded RNA [dsRNA]) and unpaired (single-stranded RNA [ssRNA]) components of the Drosophila melanogaster and Caenorhabditis elegans transcriptomes, which allows us to identify conserved features of RNA secondary structure in metazoans. From this analysis, we find that ssRNAs and dsRNAs are significantly correlated with specific epigenetic modifications. Additionally, we find key structural patterns across protein-coding transcripts that indicate that RNA folding demarcates regions of protein translation and likely affects microRNA-mediated regulation of mRNAs in animals. Finally, we identify and characterize 546 mRNAs whose folding pattern is significantly correlated between these metazoans, suggesting that their structure has some function. Overall, our findings provide a global assessment of RNA folding in animals.

Spo0A~P imposes a temporal gate for the bimodal expression of competence in Bacillus subtilis.

ComK transcriptionally controls competence for the uptake of transforming DNA in Bacillus subtilis. Only 10%-20% of the cells in a clonal population are randomly selected for competence. Because ComK activates its own promoter, cells exceeding a threshold amount of ComK trigger a positive feedback loop, transitioning to the competence ON state. The transition rate increases to a maximum during the approach to stationary phase and then decreases, with most cells remaining OFF. The average basal rate of comK transcription increases transiently, defining a window of opportunity for transitions and accounting for the heterogeneity of competent populations. We show that as the concentration of the response regulator Spo0A∼P increases during the entry to stationary phase it first induces comK promoter activity and then represses it by direct binding. Spo0A∼P activates by antagonizing the repressor, Rok. This amplifies an inherent increase in basal level comK promoter activity that takes place during the approach to stationary phase and is a general feature of core promoters, serving to couple the probability of competence transitions to growth rate. Competence transitions are thus regulated by growth rate and temporally controlled by the complex mechanisms that govern the formation of Spo0A∼P. On the level of individual cells, the fate-determining noise for competence is intrinsic to the comK promoter. This overall mechanism has been stochastically simulated and shown to be plausible. Thus, a deterministic mechanism modulates an inherently stochastic process.