Wagoner, David R. Van

There has been sustained focus on the secondary prevention of coronary heart disease and heart failure; yet, apart from stroke prevention, the evidence base for the secondary prevention of atrial fibrillation (AF) recurrence, AF progression, and AF‐related complications is modest. Although there are multiple observational studies, there are few large, robust, randomized trials providing definitive effective approaches for the secondary prevention of AF. Given the increasing incidence and prevalence of AF nationally and internationally, the AF field needs transformative research and a commitment to evidenced‐based secondary prevention strategies. We report on a National Heart, Lung, and Blood Institute virtual workshop directed at identifying knowledge gaps and research opportunities in the secondary prevention of AF. Once AF has been detected, lifestyle changes and novel models of care delivery may contribute to the prevention of AF recurrence, AF progression, and AF‐related complications. Although benefits seen in small subgroups, cohort studies, and selected randomized trials are impressive, the widespread effectiveness of AF secondary prevention strategies remains unknown, calling for development of scalable interventions suitable for diverse populations and for identification of subpopulations who may particularly benefit from intensive management. We identified critical research questions for 6 topics relevant to the secondary prevention of AF: (1) weight loss; (2) alcohol intake, smoking cessation, and diet; (3) cardiac rehabilitation; (4) approaches to sleep disorders; (5) integrated, team‐based care; and (6) nonanticoagulant pharmacotherapy. Our goal is to stimulate innovative research that will accelerate the generation of the evidence to effectively pursue the secondary prevention of AF.

Background: While NKX2-5 plays pivotal roles in human cardiac development and disease, no ChIP-Seq studies of NKX2-5 in human cardiac tissues currently exist, resulting in an incomplete understanding of its direct gene targets. Modern computational methods which identify binding sites using transcription factor motif and tissue-specific experimental data can help to fill this knowledge gap. Objective: To use computational methods to identify likely NKX2-5 binding sites and downstream gene targets using human heart-specific experimental data. Methods: Human cardiomyocyte DNAse hypersensitivity data (2 replicates) were downloaded from the Encyclopedia of DNA Elements (ENCODE) database. The position weight matrix (PWM) representing the transcription factor motif of NKX2-5 was obtained from JASPAR. We applied the Protein Interaction Quantification (PIQ) algorithm to detect NKX2-5 binding sites using the PWM and DNAse hypersensitivity data as inputs. RNA-Seq data from 108 human heart-specific samples (atrial appendages and left ventricles) were downloaded from the Genotype-Tissue Expression (GTEx) database. Protein-coding genes significantly expressed in the heart (RPKM <= 1 based on the GTEx RNA-Seq data) that were within 100kb of the predicted binding sites were then identified. Pathway analysis of these genes was performed using Ingenuity Pathway Analysis (IPA). Results: 1283 binding sites for NKX2-5 were discovered by PIQ. Of 12698 protein-coding, heart-expressed genes, 625 were within 100kb of these binding sites. The identified genes were highly enriched in physiologic categories like “Vasculogenesis” and “Development of Cardiovascular Tissue” (p = 2.36x10-9 and 2.31x10-8 respectively). Notable genes included: cardiac transcription factors (MEF2A, TBX20); growth factors (TGFB2, BMP2); muscle and ion channel function (ACTA2, BIN1), and; calcium signaling (CALM2, CAMK2D). Conclusion: By using computational analyses of transcription factor motif and human heart-specific experimental data, we have identified candidate downstream targets of NKX2-5. Future work will include validation studies in an external cohort and analysis of associations between these candidate genes and cardiac disease.

Genetic College Many genomic elements in humans are associated with behavior, including educational attainment. In a genome-wide association study including more than 100,000 samples, Rietveld et al. (p. 1467 , published online 30 May; see the Perspective by Flint and Munafò ) looked for genes related to educational attainment in Caucasians. Small genetic effects at three loci appeared to impact educational attainment.

The National Heart, Lung, and Blood Institute (NHLBI) convened a workshop of cardiologists, cardiac electrophysiologists, cell biophysicists, and computational modelers on August 20 and 21, 2007, in Washington, DC, to advise the NHLBI on new research directions needed to develop integrative approaches to elucidate human cardiac function. The workshop strove to identify limitations in the use of data from nonhuman animal species for elucidation of human electromechanical function/activity and to identify what specific information on ion channel kinetics, calcium handling, and dynamic changes in the intracellular/extracellular milieu is needed from human cardiac tissues to develop more robust computational models of human cardiac electromechanical activity. This article summarizes the workshop discussions and recommendations on the following topics: (1) limitations of animal models and differences from human electrophysiology, (2) modeling ion channel structure/function in the context of whole-cell electrophysiology, (3) excitation–contraction coupling and regulatory pathways, (4) whole-heart simulations of human electromechanical activity, and (5) what human data are currently needed and how to obtain them. The recommendations can be found on the NHLBI Web site at http://www.nhlbi.nih.gov/meetings/workshops/electro.htm.