Anticoagulant Use in High Stroke-Risk Patients With Nonvalvular Atrial Fibrillation.

Background Oral anticoagulants (OACs) are recommended for nonvalvular atrial fibrillation (NVAF) patients with moderate-to high-stroke risk. Objective To examine nationally reflective OAC usage in incident NVAF patients longitudinally. Design Three-year retrospective cohort analysis. Setting Medicare Part D recipients in the contiguous United States. PARTICIPANTS: 52,465 Medicare beneficiaries with incident NVAF in 2010 with two or more atrial fibrillation diagnoses seven or more days apart. Main outcome measure Stroke risk via congestive heart failure, hypertension, age greater than or equal to 75, diabetes, stroke, vascular disease, age 65-74, sex category (CHA2DS2-VASc) score. Primary outcome was proportion of patients receiving one or more OACs post-NVAF diagnoses. Results Of 48,980 high-risk patients, 32.7% received one or more OAC within 60 days of diagnosis. By close of 2011, 48% had one or more OAC. OAC use increased to 52.9% by close of 2012. Conclusions Fewer than 33% of high-risk NVAF patients received OACs within 60 days of diagnosis in 2010. Despite increased use over time, oral anticoagulation was below 53% at study end. Use of OACs declined with CHA2DS2-VASc greater than 6. Expanded efforts are warranted to augment OAC use in high stroke-risk patients.

Chromatin reader L(3)mbt requires the Myb-MuvB/DREAM transcriptional regulatory complex for chromosomal recruitment.

Lethal malignant brain tumors (lmbt) result from the loss of the conserved transcriptional repressor l(3)mbt, in Drosophila melanogaster. Similar mutations in the human homolog L3MBTL1 correlate with some cancers. The protein's C-terminal MBT repeats bind mono and dimethylated histones in vitro, which could influence recruitment of L3MBTL1 to its target sites. The L(3)mbt chromatin targeting mechanism, however, is controversial and several studies suggest insufficiency or a minor role for histone methylation in determining the site specificity for recruitment. We report that L(3)mbt colocalizes with core members of the Myb-MuvB/DREAM (MMB/DREAM) transcriptional regulatory complex genome-wide, and that L(3)mbt-mediated repression requires this complex in salivary glands and larval brains. Loss of l(3)mbt or of MMB components through mutation cause similar spurious expression of genes, including the transposon regulatory gene piwi, in terminally differentiated cells. The DNA-binding MMB core component Mip120 (Lin54) is required for L(3)mbt recruitment to chromosomes, whereas Mip130 (Lin9) (an MMB core protein) and E2f2 (an MMB transcriptional repressor) are not, but are essential for repression. Cytolocalization experiments suggest the presence of site-specific differential composition of MMB in polytene chromosomes where some loci were bound by a Myb-containing or alternatively, an E2f2 and L(3)mbt form of the complex.

Tricuspid annular plane systolic excursion in chronic thromboembolic pulmonary hypertension before and after pulmonary thromboendarterectomy.

BACKGROUND: Right ventricular function is impaired in chronic thromboembolic pulmonary hypertension (CTEPH). Tricuspid annular plane systolic excursion (TAPSE) and right ventricular fractional area change (RVFAC) have been shown to help assess right ventricular function in pulmonary hypertension. Our goal was to (1) assess TAPSE and RVFAC before and after PTE, and (2) assess correlation of these variables with right heart catheterization data and PVR. METHODS: We evaluated 67 consecutive patients with CTEPH for pulmonary thromboendarterectomy (PTE). Of these 67 patients, 48 were deemed surgical candidates. Preoperative right heart catheterization was performed within 1.3±1.2 days of the preoperative echocardiogram. All postoperative right heart catheterizations were performed on the first postoperative day. RESULTS: TAPSE dropped from 18±6 to 10±3 mm after PTE (P<.0001). RVFAC remained the same (25%±10% vs 30%±12%). Mean pulmonary artery (mPAP) pressure dropped from 45±12 to 28±6 mm Hg after PTE, and pulmonary vascular resistance (PVR) decreased from 757±406 to 306±147 dyne-s/cm5 (P<.0001 for both). Before PTE, TAPSE correlated inversely with PVR (r=-.57, P<.0001, TAPSE=-5.904×ln[PVR]+56.318). RVFAC did not correlate well with PVR or mean pulmonary artery pressure. After PTE, both TAPSE and RVFAC correlated poorly with PVR (r=-.12 and .01, respectively). CONCLUSION: In patients with CTEPH, TAPSE paradoxically decreased by 50% early after PTE. TAPSE correlated inversely with PVR prior to PTE, but this correlation was lost completely after PTE. Thus, despite the immediate and marked decrease in afterload postoperatively, TAPSE did not improve; thus, TAPSE cannot be used as an early marker for surgical success.

Diagnosis and Treatment of Atrial Fibrillation.

Atrial fibrillation is a supraventricular arrhythmia that adversely affects cardiac function and increases the risk of stroke. It is the most common arrhythmia and a major source of morbidity and mortality; its prevalence increases with age. Pulse rate is sensitive, but not specific, for diagnosis, and suspected atrial fibrillation should be confirmed with 12-lead electrocardiography. Because normal electrocardiographic findings do not rule out atrial fibrillation, home monitoring is recommended if there is clinical suspicion of arrhythmia despite normal test results. Treatment is based on decisions made regarding when to convert to normal sinus rhythm vs. when to treat with rate control, and, in either case, how to best reduce the risk of stroke. For most patients, rate control is preferred to rhythm control. Ablation therapy is used to destroy abnormal foci responsible for atrial fibrillation. Anticoagulation reduces the risk of stroke while increasing the risk of bleeding. The CHA2DS2-VASc scoring system assesses the risk of stroke, with a score of 2 or greater indicating a need for anticoagulation. The HAS-BLED score estimates the risk of bleeding. Scores of 3 or greater indicate high risk. Warfarin, dabigatran, factor Xa inhibitors (e.g., rivaroxaban, apixaban, edoxaban), and aspirin are options for stroke prevention. Selection of therapy should be individualized based on risks and potential benefits, cost, and patient preference. Left atrial appendage obliteration is an option for reducing stroke risk. Two implantable devices used to occlude the appendage, the Watchman and the Amplatzer Cardiac Plug, appear to be as effective as warfarin in preventing stroke, but they are invasive. Another percutaneous approach to occlusion, wherein the left atrium is closed off using the Lariat, is also available, but data on its long-term effectiveness and safety are still limited. Surgical treatments for atrial fibrillation are reserved for patients who are undergoing cardiac surgery for other reasons.

Right ventricular strain before and after pulmonary thromboendarterectomy in patients with chronic thromboembolic pulmonary hypertension.

BACKGROUND: Right ventricular (RV) function is significantly impaired in patients with chronic thromboembolic pulmonary hypertension (CTEPH). Two-dimensional speckle tracking RV strain and strain rate are novel methods to assess regional RV systolic function in CTEPH patients before and after pulmonary thromboendarterectomy (PTE). Our goal was to (1) assess baseline longitudinal strain and strain rate of the basal RV free wall in CTEPH and (2) measure early changes in RV strain and strain rate after PTE. METHODS: We performed echocardiography on 30 consecutive patients with CTEPH referred for PTE with adequate pre- and post-PTE strain imaging. Strain and strain rate were assessed 6.4 ± 4.5 days before and 9.1 ± 3.9 after PTE. RESULTS: Basal RV free wall strain and time to peak strain-but not basal RV strain rate and time to peak strain rate-changed significantly after PTE. Unexpectedly, basal RV strain became less negative, from -24.3% to -18.9% after PTE (P = 0.005). Time to peak strain decreased from 356 to 287 msec after PTE (P < 0.001). Preoperatively, RV strain correlated with pulmonary vascular resistance (PVR) and mean pulmonary artery pressure (mPAP) but this relationship was not evident postoperatively. Furthermore, the change in RV strain did not correlate with the change in mPAP or PVR. CONCLUSIONS: In patients with CTEPH, RV basal strain paradoxically became less negative (i.e., relative systolic shortening decreased) following PTE. This change in RV strain could be due to intraoperative RV ischemia and/or postoperative stunning. Thus, RV basal strain cannot be used as a surrogate marker for surgical success early after PTE.

Cardiac Limited Ultrasound Examination Techniques to Augment the Bedside Cardiac Physical Examination.

The current practice of physical diagnosis is dependent on physician skills and biases, inductive reasoning, and time efficiency. Although the clinical utility of echocardiography is well known, few data exist on how to integrate 2-dimensional screening "quick-look" ultrasound applications into a novel, modernized cardiac physical examination. We discuss the evidence basis behind ultrasound "signs" pertinent to the cardiovascular system and elemental in synthesis of bedside diagnoses and propose the application of a brief cardiac limited ultrasound examination based on these signs. An ultrasound-augmented cardiac physical examination can be taught in traditional medical education and has the potential to improve bedside diagnosis and patient care.

Assessment of left atrial volume before and after pulmonary thromboendarterectomy in chronic thromboembolic pulmonary hypertension.

BACKGROUND: Impaired left ventricular diastolic filling is common in chronic thromboembolic pulmonary hypertension (CTEPH), and recent studies support left ventricular underfilling as a cause. To investigate this further, we assessed left atrial volume index (LAVI) in patients with CTEPH before and after pulmonary thromboendarterectomy (PTE). METHODS: Forty-eight consecutive CTEPH patients had pre- & post-PTE echocardiograms and right heart catheterizations. Parameters included mean pulmonary artery pressure (mPAP), pulmonary vascular resistance (PVR), cardiac index, LAVI, & mitral E/A ratio. Echocardiograms were performed 6 ± 3 days pre-PTE and 10 ± 4 days post-PTE. Regression analyses compared pre- and post-PTE LAVI with other parameters. RESULTS: Pre-op LAVI (mean 19.0 ± 7 mL/m2) correlated significantly with pre-op PVR (R = -0.45, p = 0.001), mPAP (R = -0.28, p = 0.05) and cardiac index (R = 0.38, p = 0.006). Post-PTE, LAVI increased by 18% to 22.4 ± 7 mL/m2 (p = 0.003). This change correlated with change in PVR (765 to 311 dyne-s/cm5, p = 0.01), cardiac index (2.6 to 3.2 L/min/m2, p = 0.02), and E/A (.95 to 1.44, p = 0.002). CONCLUSION: In CTEPH, smaller LAVI is associated with lower cardiac output, higher mPAP, and higher PVR. LAVI increases by ~20% after PTE, and this change correlates with changes in PVR and mitral E/A. The rapid increase in LAVI supports the concept that left ventricular diastolic impairment and low E/A pre-PTE are due to left heart underfilling rather than inherent left ventricular diastolic dysfunction.

Echocardiographic estimation of pulmonary vascular resistance in chronic thromboembolic pulmonary hypertension: utility of right heart Doppler measurements.

UNLABELLED: The ratio of tricuspid regurgitation velocity divided by the velocity-time integral of right ventricular outflow tract pulsed-wave Doppler tracing (TRV/VTI(RVOT) ) has been used to estimate pulmonary vascular resistance (PVR). However, this method has not been validated in chronic thromboembolic pulmonary hypertension (CTEPH). We assessed the utility of TRV/VTI(RVOT) in patients with CTEPH and PVR from 2 to 20 WU. All had right heart catheterization (RHC) within 2 days of echocardiography. TRV/VTI(RVOT) was calculated and RHC-derived pressures, PVR, and cardiac outputs were recorded. Mean pulmonary artery pressure was 47 ± 12 mmHg, cardiac output: 4.2 ± 1.1 L/min, PVR: 9 ± 4 WU, right atrial pressure: 12 ± 6 mmHg. Mean VTI(RVOT) was 13 ± 5 cm; mean TRV was 4.2 ± 0.8 m/s, mean tricuspid regurgitation severity was 2.5 ± 0.8 (1 = trace, 2 = mild, 3 = moderate, 4 = severe). Regression analysis demonstrated a correlation between RHC PVR and TRV/VTI(RVOT) : PVR = 19.4 × (TRV/VTI(RVOT) ) + 2.4 (r = 0.74, P < 0.001). However, Bland-Altman analysis found a poor degree of agreement between echo-derived PVR and RHC PVR. We also studied 28 patients with non-CTEPH pulmonary hypertension. Similar analysis revealed a regression equation of PVR = 20.1 × (TRV/VTIR(RVOT) ) + 0.3 (r = 0.57, P < 0.01). CONCLUSION: TRV/VTI(RVOT) is only marginally useful for estimating PVR in CTEPH (r = 0.74). Moreover, the regression equation in CTEPH differs significantly from previous studies in pulmonary hypertension. Reasons for this may include the markedly elevated PVR levels in this population and specific effects on VTI(RVOT) from CTEPH.

Diminished aortic excursion in chronic thromboembolic pulmonary hypertension.

BACKGROUND: Although studies have found diminished aortic root motion in left ventricular systolic dysfunction, few data exist on aortic root excursion in isolated right ventricular dysfunction due to chronic thromboembolic pulmonary hypertension (CTEPH). OBJECTIVE: We conducted this study to evaluate aortic root excursion in CTEPH. METHODS: We studied 20 consecutive patients with CTEPH, normal left ventricular ejection fraction and pulmonary capillary wedge pressures, and 10 normal control subjects. Anterior excursion of the aortic root was measured using M-mode echocardiography as the difference between the maximal and minimal anterior distance of the posterior wall of the aortic root at the level of the aortic valve. RESULTS: Mean aortic excursion for CTEPH patients was approximately half that of normal controls (0.66 ± 0.25 cm vs. 1.16 ± 0.15 cm, P < 0.0001). There was a significant inverse linear correlation between mean pulmonary artery pressure and aortic excursion in the CTEPH group (r = 0.66, P = 0.001). CONCLUSION: Aortic excursion is diminished in the right ventricular pressure overload of CTEPH. This impaired motion of the aortic root may influence systolic expansion of the left atrium, and may contribute to the impaired left atrial diastolic filling patterns often seen in patients with CTEPH.

On the nature of in vivo requirements for rde-4 in RNAi and developmental pathways in C. elegans.

C. elegans RDE-4 is a double-stranded RNA binding protein that has been shown to play a key role in response to foreign double-stranded RNA (dsRNA). We have used diverse tools for analysis of gene function to characterize the domain and organismal foci of RDE-4 action in C. elegans. First, we examined the focus of activity within the RDE-4 protein, by testing a series of RDE-4 deletion constructs for their ability to support dsRNA-triggered gene silencing. These assays indicated a molecular requirement for a linker region and the second dsRNA-binding domain of RDE-4, with ancillary contributions to function from the C and N terminal domains. Second, we used mosaic analysis to explore the cellular focus of action of RDE-4. These experiments indicated an ability of RDE-4 to function non-autonomously in foreign RNA responses. Third, we used growth under stressful conditions to search for evidence of an organismal focus of action for RDE-4 distinct from its role in response to foreign dsRNA. Propagation at high temperatures exposed a conditional requirement for RDE-4 for optimal growth and fertility, indicating at least under these conditions that RDE-4 can serve an essential role in C. elegans.

Elongated eustachian valve dividing the right atrium.

A 64-year-old man underwent transthoracic echocardiography after a syncopal event. Two-dimensional imaging demonstrated a linear density that appeared to divide the right atrium. Color doppler imaging demonstrated that inflow from the inferior vena cava, but not from the superior vena cava, was obstructed by this density. Injection of agitated saline through an upper extremity vein demonstrated that the linear density did create a functional separation of the right atrium. The contrast material also crossed the interatrial septum within two cardiac cycles. This constellation of findings is consistent with an elongated eustachian valve and a patent foramen ovale.

The dilated coronary sinus: utility of coronary sinus cross-sectional area and eccentricity index in differentiating right atrial pressure overload from persistent left superior vena cava.

BACKGROUND: Pulmonary hypertension and right atrial pressure overload (RAPO) cause dilation of the coronary sinus (CS). Persistent connection of the left superior vena cava (LSVC) to the CS is another cause of CS dilation. The purpose of this study was to evaluate the usefulness of coronary sinus cross-sectional area (CSA) and eccentricity index (EI) in differentiating persistent LSVC from right heart overload and RAPO in patients with dilated CS. METHODS: We identified 15 patients with a dilated CS by echocardiography. Offline analysis was used to measure CS-CSA and CS-EI at end-diastole in the parasternal long axis plane. EI was defined as B/A, where A is the widest diameter and major axis of the CS, and B is the diameter of the minor axis (perpendicular to and bisecting A at its midpoint). Persistent LSVC was confirmed by either computed tomography or injection of agitated saline in the left antecubital vein. RESULTS: CS-CSA was significantly larger in PLSVC group than in group with RAPO. Also, CS-EI was lower in PLSVC than in RAPO group (P = 0.0003). EI was the most sensitive and specific discriminator between patients with persistent LSVC vs. RAPO. CS-EI was <0.8 in all PLSVC patients and >0.8 in all RAPO patients (sensitivity and specificity = 100%). CONCLUSION: Patients with persistent LSVC have a significantly higher CS-CSA than those with elevated RA pressure. When dilated CS is present, a CS-EI <0.8 is 100% sensitive and specific for persistent LSVC. Thus, the CS-EI can be used in cases of dilated CS to diagnose the presence of persistent LSVC with a very high degree of certainty, and can help differentiate this congenital anomaly from RAPO.

Optimal Quantification of Functional Mitral Regurgitation: Comparison of Volumetric and Proximal Isovelocity Surface Area Methods to Predict Outcome.

Background Effective orifice area (EOA) ≥0.2 cm2 or regurgitant volume (Rvol) ≥30 mL predicts prognostic significance in functional mitral regurgitation (FMR). Both volumetric and proximal isovelocity surface area (PISA) methods enable calculation of these metrics. To determine their clinical value, we compared EOA and Rvol derived by volumetric and PISA quantitation upon outcome of patients with FMR. Methods and Results We examined the outcome of patients with left ventricular ejection fraction <35% and moderate to severe FMR. All had a complete echocardiogram including EOA and Rvol by both standard PISA and volumetric quantitation using total stroke volume calculated by left ventricular end-diastolic volume×left ventricular ejection fraction and forward flow by Doppler method: EOA=Rvol/mitral regurgitation velocity time integral. Primary outcome was all-cause mortality or heart transplantation. We examined 177 patients: mean left ventricular ejection fraction 25.2% and 34.5% with ischemic cardiomyopathy. Echo measurements were greater by PISA than volumetric quantitation: EOA (0.18 versus 0.11 cm2), Rvol (24.7 versus 16.9 mL), and regurgitant fraction (61 versus 37 %) respectively (all P value <0.001). During 3.6±2.3 years' follow-up, patients with EOA ≥0.2 cm2 or Rvol ≥30 mL had a worse outcome than those with EOA <0.2 cm2 or Rvol <30 mL only by volumetric (log rank P=0.003 and 0.004) but not PISA quantitation (log rank P=0.984 and 0.544), respectively. Conclusions Volumetric and PISA methods yield different measurements of EOA and Rvol in FMR; volumetric values exhibit greater prognostic significance. The echo method of quantifying FMR may affect the management of this disorder.

Clinical and Echocardiographic Predictors of Reduced Survival in Patient with Functional Mitral Regurgitation.

Functional mitral regurgitation (FMR) is associated with a poor outcome in patients with reduced left ventricular ejection fraction (LVEF). Two recent studies of percutaneous mitral valvular repair therapy reported disparate results, likely due in part to variable risk among FMR patients. The aim of this study is to define echocardiographic factors of prognostic significance in FMR patients, and particularly to compare ischemic and nonischemic FMR. We followed three hundred sixteen consecutive patients (age 60 ± 14 years, men 70%) with FMR and LVEF ≤ 35% between January 2010 and December 2015 (mean follow-up 3.7 years). Patients were categorized into ischemic (39.6%) and nonischemic (60.4%). MR was graded according to the American Society of Echocardiography guidelines. Although echo findings were similar between ischemic and nonischemic patient, the incidence of death, heart transplantation (HT), or LVAD implantation was higher in ischemic than in nonischemic patients (Log rank p = 0.001). In age and gender adjusted multivariate (11 variables) Cox regression analysis, left atrium volume index (LAVI) was associated with death, HT, or LVAD with hazard ratio of 2.1 for patients with FMR (p = 0.003). LAVI greater than 48.7 mL/m2 predicts adverse outcome in both nonischemic and ischemic FMR (AUC 0.62, p < 0.001). Combined ischemic FMR with LAVI ≥ 48.7 mL/m2 had the highest incident rate of all groups. In conclusion, despite similar LV function and MR severity, ischemic FMR patients had higher mortality than nonischemic patients. Of all echocardiographic parameters, an LAVI ≥ 48.7 mL/m2 predicted adverse clinical outcome.

Evaluation of Routine Coronary Angiography Before Pulmonary Thromboendarterectomy.

BACKGROUND: At the University of California, San Diego, routine coronary angiography has generally been performed in men 40 years of age and older and women 45 years of age and older before pulmonary thromboendarterectomy for chronic thromboembolic pulmonary hypertension (CTEPH). The prevalence of significant coronary artery disease (CAD) in this population has not been evaluated, however, and the optimal screening strategy has not been established. This study sought to evaluate whether the current approach may be better optimized on the basis of cardiac risk factors. METHODS: This study included 462 consecutive patients with CTEPH who were undergoing preoperative coronary angiography for pulmonary thromboendarterectomy. Baseline demographic and medical information was recorded. Major cardiac risk factors included: diabetes, hypertension, hyperlipidemia, body mass index 25 kg/m2 or greater, tobacco use, and family history of CAD. Charts were then reviewed for presence of significant CAD and revascularization. RESULTS: Significant CAD was found in 13.4% of patients who underwent routine preoperative coronary angiography; it was present in only 5% of patients younger than 50 years of age, compared with 16% of patients 50 years old and older. No patient younger than 50 years of age without cardiac risk factors was found to have significant CAD. Furthermore, in patients younger than 50 years of age, significant CAD was found only among those with 3 or more major risk factors. CONCLUSIONS: In patients younger than 50 years of age with CTEPH, the prevalence of significant CAD was low. Omitting preoperative coronary angiography in this subset of patients is reasonable when no coronary risk factors are present. Preoperative coronary angiography is warranted in individuals 50 years of age and older, as well as in those younger than 50 years who have significant risk factors for CAD.

Distributed probing of chromatin structure in vivo reveals pervasive chromatin accessibility for expressed and non-expressed genes during tissue differentiation in C. elegans.

BACKGROUND: Tissue differentiation is accompanied by genome-wide changes in the underlying chromatin structure and dynamics, or epigenome. By controlling when, where, and what regulatory factors have access to the underlying genomic DNA, the epigenome influences the cell's transcriptome and ultimately its function. Existing genomic methods for analyzing cell-type-specific changes in chromatin generally involve two elements: (i) a source for purified cells (or nuclei) of distinct types, and (ii) a specific treatment that partitions or degrades chromatin by activity or structural features. For many cell types of great interest, such assays are limited by our inability to isolate the relevant cell populations in an organism or complex tissue containing an intertwined mixture of other cells. This limitation has confined available knowledge of chromatin dynamics to a narrow range of biological systems (cell types that can be sorted/separated/dissected in large numbers and tissue culture models) or to amalgamations of diverse cell types (tissue chunks, whole organisms). RESULTS: Transgene-driven expression of DNA/chromatin modifying enzymes provides one opportunity to query chromatin structures in expression-defined cell subsets. In this work we combine in vivo expression of a bacterial DNA adenine methyltransferase (DAM) with high throughput sequencing to sample tissue-specific chromatin accessibility on a genome-wide scale. We have applied the method (DALEC: Direct Asymmetric Ligation End Capture) towards mapping a cell-type-specific view of genome accessibility as a function of differentiated state. Taking advantage of C. elegans strains expressing the DAM enzyme in diverse tissues (body wall muscle, gut, and hypodermis), our efforts yield a genome-wide dataset measuring chromatin accessibility at each of 538,000 DAM target sites in the C. elegans (diploid) genome. CONCLUSIONS: Validating the DALEC mapping results, we observe a strong association between observed coverage by nucleosomes and low DAM accessibility. Strikingly, we observed no extended regions of inaccessible chromatin for any of the tissues examined. These results are consistent with "local choreography" models in which differential gene expression is driven by intricate local rearrangements of chromatin structure rather than gross impenetrability of large chromosomal regions.

An AMPK-FOXO pathway mediates longevity induced by a novel method of dietary restriction in C. elegans.

BACKGROUND: Dietary restriction (DR) is the most effective environmental intervention to extend lifespan in a wide range of species. However, the molecular mechanisms underlying the benefits of DR on longevity are still poorly characterized. AMP-activated protein kinase (AMPK) is activated by a decrease in energy levels, raising the possibility that AMPK might mediate lifespan extension by DR. RESULTS: By using a novel DR assay that we developed and validated in C. elegans, we find that AMPK is required for this DR method to extend lifespan and delay age-dependent decline. We find that AMPK exerts its effects in part via the FOXO transcription factor DAF-16. FOXO/DAF-16 is necessary for the beneficial effects of this DR method on lifespan. Expression of an active version of AMPK in worms increases stress resistance and extends longevity in a FOXO/DAF-16-dependent manner. Lastly, we find that AMPK activates FOXO/DAF-16-dependent transcription and phosphorylates FOXO/DAF-16 at previously unidentified sites, suggesting a possible direct mechanism of regulation of FOXO/DAF-16 by AMPK. CONCLUSIONS: Our study shows that an energy-sensing AMPK-FOXO pathway mediates the lifespan extension induced by a novel method of dietary restriction in C. elegans.

Left ventricular underfilling and not septal bulging dominates abnormal left ventricular filling hemodynamics in chronic thromboembolic pulmonary hypertension.

Chronic thromboembolic pulmonary hypertension (CTEPH) is associated with abnormal left ventricular (LV) filling hemodynamics [mitral early passive filling wave velocity/late active filling wave velocity (E/A) < 1]. Pulmonary endarterectomy (PEA) acutely reduces pulmonary vascular resistance, resulting in an increase of mitral E/A. The abolishment of leftward septal bulging and an increase in right ventricular (RV) output are thought to be responsible for the increase of mitral E/A. In this study, we quantified the separate effects of leftward septal bulging and RV output on LV hemodynamics. In 39 CTEPH patients who underwent PEA, transmitral flow velocities and RV hemodynamic data were obtained pre- and postoperatively. A mathematical model describing the mechanics of ventricular interaction was fitted to the preoperative average values of cardiac output (CO; 4.4 l/min), mean pulmonary artery pressure (mPAP; 50 mmHg), mitral E/A (0.74), and mean left atrial pressure (mLAP; 9.8 mmHg). Starting from this preoperative reference state with leftward septal bulging, PEA was simulated by changing mPAP and CO to average postoperative values (28 mmHg and 5.7 l/min, respectively). Simulated and postoperatively measured data on E/A (1.27 vs. 1.48), mLAP (12.6 vs. 11.5 mmHg), and septal curvature (both rightward) were consistent. When an exclusive decrease of mPAP was simulated, mitral E/A increased 26%, mLAP decreased 16%, and septal curvature became rightward. When an exclusive increase of CO was simulated, mitral E/A increased 53% and mLAP increased 62%, whereas leftward septal bulging persisted. Thus, our simulations suggest that the increase of mitral E/A with PEA is caused two-thirds by an increase of RV output and one-third by the abolishment of leftward septal bulging.

Left ventricular strain and strain rate by 2D speckle tracking in chronic thromboembolic pulmonary hypertension before and after pulmonary thromboendarterectomy.

BACKGROUND: Echocardiographic evaluation of left ventricular (LV) strain and strain rate (SR) by 2D speckle tracking may be useful tools to assess chronic thromboembolic pulmonary hypertension (CTEPH) severity as well as response to successful pulmonary thromboendarterectomy (PTE). METHODS: We evaluated 30 patients with CTEPH before and after PTE using 2D speckle tracking measurements of LV radial and circumferential strain and SR in the short axis, and correlated the data with right heart catheterization (RHC). RESULTS: PTE resulted in a decrease in mean PA pressure (44 ± 15 to 29 ± 9 mmHg), decrease in PVR (950 ± 550 to 31 ± 160 [dyne-sec]/cm5), and an increase in cardiac output (3.9 ± 1.0 to 5.0 ± 1.0 L/min, p < 0.001 for all). Circumferential and posterior wall radial strain changed by -11% and +15% respectively (p < 0.001 for both). Circumferential SR and posterior wall radial SR changed by -7% and 6% after PTE. While the increase in posterior wall SR with PTE reached statistical significance (p = 0.04) circumferential SR did not (p = 0.07). In addition, septal radial strain and SR did not change significantly after PTE (p = 0.1 and 0.8 respectively). Linear regression analyses of circumferential and posterior wall radial strain and SR revealed little correlation between strain/SR measurements and PVR, mean PA pressure, or cardiac output. However, change in circumferential strain and change in posterior wall radial strain correlated moderately well with changes in PVR, mean PA pressure and cardiac output (r = 0.69, 0.76, and 0.51 for circumferential strain [p < 0.001 for all] and r = 0.7, 0.7, 0.45 for posterior wall radial strain [p = 0.001, 0.001, and 0.02, respectively]). CONCLUSIONS: LV circumferential and posterior wall radial strain change after relief of pulmonary arterial obstruction in patients with CTEPH, and these improvements occur rapidly. These changes in LV strain may reflect effects from improved LV diastolic filling, and may be useful non-invasive markers of successful PTE.

Modeling the contribution of phonotactic cues to the problem of word segmentation.

How do infants find the words in the speech stream? Computational models help us understand this feat by revealing the advantages and disadvantages of different strategies that infants might use. Here, we outline a computational model of word segmentation that aims both to incorporate cues proposed by language acquisition researchers and to establish the contributions different cues can make to word segmentation. We present experimental results from modified versions of Venkataraman's (2001) segmentation model that examine the utility of: (1) language-universal phonotactic cues; (2) language-specific phonotactic cues which must be learned while segmenting utterances; and (3) their combination. We show that the language-specific cue improves segmentation performance overall, but the language-universal phonotactic cue does not, and that their combination results in the most improvement. Not only does this suggest that language-specific constraints can be learned simultaneously with speech segmentation, but it is also consistent with experimental research that shows that there are multiple phonotactic cues helpful to segmentation (e.g. Mattys, Jusczyk, Luce & Morgan, 1999; Mattys & Jusczyk, 2001). This result also compares favorably to other segmentation models (e.g. Brent, 1999; Fleck, 2008; Goldwater, 2007; Johnson & Goldwater, 2009; Venkataraman, 2001) and has implications for how infants learn to segment.