BMP Signaling Determines Body Size via Transcriptional Regulation of Collagen Genes in Caenorhabditis elegans.

Body size is a tightly regulated phenotype in metazoans that depends on both intrinsic and extrinsic factors. While signaling pathways are known to control organ and body size, the downstream effectors that mediate their effects remain poorly understood. In the nematode Caenorhabditis elegans, a Bone Morphogenetic Protein (BMP)-related signaling pathway is the major regulator of growth and body size. We investigated the transcriptional network through which the BMP pathway regulates body size and identified cuticle collagen genes as major effectors of growth control. We demonstrate that cuticle collagens can act as positive regulators (col-41), negative regulators (col-141), or dose-sensitive regulators (rol-6) of body size. Moreover, we find a requirement of BMP signaling for stage-specific expression of cuticle collagen genes. We show that the Smad signal transducers directly bind conserved Smad-binding elements in regulatory regions of col-141 and col-142, but not of col-41 Hence, cuticle collagen genes may be directly and indirectly regulated via the BMP pathway. Our work thus connects a conserved signaling pathway with its critical downstream effectors, advancing insight into how body size is specified. Since collagen mutations and misregulation are implicated in numerous human genetic disorders and injury sequelae, understanding how collagen gene expression is regulated has broad implications.

Repeat ablation or medical management alone for recurrent arrhythmias after ablation of persistent atrial fibrillation.

INTRODUCTION: Management of persistent atrial fibrillation (PersAF) remains challenging, and many patients are left on medical therapy after a failed first ablation. In patients with recurrent symptomatic arrhythmias after PersAF ablation, we aimed to compare outcomes of repeat ablation and medical therapy versus medical therapy alone. METHODS AND RESULTS: All 682 consecutive patients with recurrent symptomatic arrhythmia after a first ablation for PersAF at our institution (2005-2012) were included. Repeat ablation with continuation of medical therapy was performed in 364 patients (Group 1) and 318 were only medically managed (Group 2). The outcome of interest was freedom from arrhythmia recurrence beyond a 3-month blanking period. Separate analyses were performed to assess this endpoint totally off antiarrhythmics (primary endpoint) or alternatively with/without use of antiarrhythmics (secondary endpoint). Over a median follow-up of 26 months, 41.5% of Group 1 patients met the primary endpoint and remained free from arrhythmia recurrence off antiarrhythmics (vs. 14.5% in Group 2, P < 0.0001). At last follow-up, antiarrhythmics continued to be required for rhythm control in 40.1% and 46.2% of patients in Groups 1 and 2, respectively (P < 0.0001). The secondary endpoint was met in 60.2% versus 32.1% of patients in Groups 1 and 2, respectively (P < 0.0001). In multivariable Cox analyses, repeat ablation was associated with significant reduction in arrhythmia recurrences compared to medical therapy alone (HR 0.48, 95% CI 0.35-0.65, P < 0.0001). CONCLUSION: In patients with recurrent symptomatic arrhythmia after ablation of PersAF, repeat ablation was associated with significant reduction in arrhythmia recurrences compared to routine medical therapy alone.

Quantitative assessment of pericardial delayed hyperenhancement helps identify patients with ongoing recurrences of pericarditis.

Objectives: Recurrences of pericarditis (RP) are often difficult to diagnose due to lack of clinical signs and symptoms during subsequent episodes. We aimed to investigate the value of quantitative assessment of pericardial delayed hyperenhancement (DHE) in diagnosing ongoing recurrences of pericarditis. Methods: Quantitative DHE was measured in 200 patients with established diagnosis of RP using cardiac MRI. Conventional clinical criteria for diagnosis of pericarditis were ≥2 of the following: chest pain, pericardial rub, ECG changes and new or worsening pericardial effusion. Results: A total of 67 (34%) patients were identified as having ongoing episode of recurrence at the time of DHE measurements. In multivariable analysis, chest pain (OR: 10.9, p<0.001) and higher DHE (OR: 1.32, p<0.001) were associated with ongoing recurrence of RP. Addition of DHE to conventional clinical criteria significantly increased the ability to diagnose ongoing recurrence (net reclassification improvement (NRI): 0.80, p<0.001; integrated discrimination improvement (IDI): 0.12, p<0.001). Among 150 patients with history of RP who presented with chest pain, higher DHE was still independently associated with ongoing recurrence (OR: 1.28, p<0.001), showed incremental value over clinical criteria (NRI: 0.76, p<0.001; IDI: 0.13, p<0.001) and demonstrated a sensitivity of 70% and specificity of 74%. Conclusion: Among patients with RP, quantitative DHE provided incremental information to diagnose ongoing recurrences over conventional clinical criteria of pericarditis. Quantitative DHE demonstrated acceptable test characteristics to diagnose ongoing recurrence even in RP patients presenting with chest pain.

Quantitative Pericardial Delayed Hyperenhancement Informs Clinical Course in Recurrent Pericarditis.

OBJECTIVES: The aim of this study was to evaluate the prognostic value of quantitative assessment of pericardial delayed hyperenhancement (DHE) among patients with recurrent pericarditis (RP). BACKGROUND: Pericardial DHE on cardiac magnetic resonance may persist beyond the acute phase of pericarditis, suggesting continued pericardial inflammation. METHODS: This is a retrospective cohort study of 159 patients with RP who underwent DHE imaging and had a follow-up period of more than 6 months. Pericardial inflammation was quantified on short-axis DHE sequences by contouring the pericardium, selecting normal septal myocardium as a reference region, and then quantifying the pericardial signal that was >6 SD above the reference. Our primary outcome was clinical remission; secondary outcomes were time to recurrence and recurrence rate. RESULTS: The mean age of our patients was 46 ± 14 years, and 52% were women. During a median follow-up period of 23 months (interquartile range: 15 to 34 months), 32 (20%) patients achieved clinical remission. In the multivariable Cox proportional hazards model, lower quantitative pericardial DHE (hazard ratio: 0.77; 95% confidence interval: 0.64 to 0.93; p = 0.008) was independently associated with clinical remission. When added to background clinical and laboratory variables, quantitative pericardial DHE had incremental prognostic value over baseline clinical and laboratory variables (integrated discrimination improvement: 8%; net reclassification improvement: 36%). Furthermore, patients with a higher quantitative DHE had shorter time to subsequent recurrence (p = 0.012) and had a higher recurrence rate at 6 months (p = 0.026). CONCLUSIONS: Quantitative assessment of pericardial DHE was associated with clinical outcomes among patients with RP and provided incremental information regarding the clinical course of patients with RP.

Management of Cognitive Impairment in Heart Failure.

OPINION STATEMENT: Cognitive impairment (CI) is an inclusive term to describe trouble with memory, learning, concentration, or decision-making. CI is highly prevalent in patients with heart failure (HF) and is known to be associated with a variety of poor outcomes. While published HF guidelines recommend screening for CI, they do not indicate how, due to a lack of consensus in the literature about which instrument to use. Our recommendation is to use the Mini-Cog for this purpose because of its brevity and utility in identifying patients with HF at high risk for hospitalization or mortality. At this time, there is minimal published clinical trial evidence about how to manage CI in patients with HF. Reasonable approaches to management may include following guideline-directed medical therapy for HF, treatment of hypertension and atrial fibrillation, management of depression, proactive diagnosis and treatment of sleep apnea, and encouragement of aerobic exercise and weight loss. Left ventricular assist device (LVAD) therapy in patients with Stage D HF may improve CI in the short term after implantation, though there is a risk of worsening CI in the intermediate and long term. Clinicians who care for patients with HF should routinely screen for CI and when identified should encourage interventions to support self-care, increase family involvement, and arrange for more frequent follow-up.

C. elegans ADAMTS ADT-2 regulates body size by modulating TGFß signaling and cuticle collagen organization.

Organismal growth and body size are influenced by both genetic and environmental factors. We have utilized the strong molecular genetic techniques available in the nematode Caenorhabditis elegans to identify genetic determinants of body size. In C. elegans, DBL-1, a member of the conserved family of secreted growth factors known as the Transforming Growth Factor ß superfamily, is known to play a major role in growth control. The mechanisms by which other determinants of body size function, however, is less well understood. To identify additional genes involved in body size regulation, a genetic screen for small mutants was previously performed. One of the genes identified in that screen was sma-21. We now demonstrate that sma-21 encodes ADT-2, a member of the ADAMTS (a disintegrin and metalloprotease with thrombospondin motifs) family of secreted metalloproteases. ADAMTS proteins are believed to remodel the extracellular matrix and may modulate the activity of extracellular signals. Genetic interactions suggest that ADT-2 acts in parallel with or in multiple size regulatory pathways. We demonstrate that ADT-2 is required for normal levels of expression of a DBL-1-responsive transcriptional reporter. We further demonstrate that adt-2 regulatory sequences drive expression in glial-like and vulval cells, and that ADT-2 activity is required for normal cuticle collagen fibril organization. We therefore propose that ADT-2 regulates body size both by modulating TGFß signaling activity and by maintaining normal cuticle structure.