Transcriptional Regulation of Cardiac Remodeling in a Porcine Model with Validation in Human Subjects

Introduction: The majority of new atrial fibrillation (AF) cases occur in elderly patients with cardiac remodeling (CR) in the setting of structural heart disease and heart failure (HF). We leveraged a unique animal model to identify cardiac microRNAs (miRNAs) and gene regulatory mechanisms that drive this process. Methods: We prospectively quantified atrial expression of 48 miRNAs by high-throughput qRT-PCR in 15 pigs with right-atrial pacing-induced heart disease (5 pigs with AF/severe HF, 5 pigs with AF/mild HF, and 5 control pigs) as well as in 21 patients (11 with AF and CR and 10 controls) undergoing cardiac surgery. CR and HF were defined through a metric of left atrial volume index, BNP and ejection fraction. MiRNA levels were normalized to global mean and expression compared across pig subtypes and between the two human groups. Results: In the porcine model, miR-208b was upregulated at week 1 (ΔCT= -3.9, pT = -5.5, pT = -1.5, pT = -1.5, pT = -1.5, pT = -1.5, p\u3c0.05). Conclusions: Dysregulation of miR-208b is confirmed in our porcine model and is validated in humans. Prior studies have identified miR-208b in both myosin isoform switching and conduction disease. We theorize that dysregulation of miR-208b may play a critical role in atrial structural remodeling and vulnerability to AF

The Dust and Molecular Gas in the Brightest Cluster Galaxy in MACS 1931.8-2635

We present new ALMA observations of the molecular gas and far-infrared continuum around the brightest cluster galaxy (BCG) in the cool-core cluster MACS 1931.8-2635. Our observations reveal $1.9 \pm 0.3 \times 10^{10}$ M$_{\odot}$ of molecular gas, on par with the largest known reservoirs of cold gas in a cluster core. We detect CO(1-0), CO(3-2), and CO(4-3) emission from both diffuse and compact molecular gas components that extend from the BCG center out to $\sim30$ kpc to the northwest, tracing the UV knots and H$\alpha$ filaments observed by HST. Due to the lack of morphological symmetry, we hypothesize that the $\sim300$ km s$^{-1}$ velocity of the CO in the tail is not due to concurrent uplift by AGN jets, rather we may be observing the aftermath of a recent AGN outburst. The CO spectral line energy distribution suggests that molecular gas excitation is influenced by processes related to both star formation and recent AGN feedback. Continuum emission in Bands 6 and 7 arises from dust and is spatially coincident with young stars and nebular emission observed in the UV and optical. We constrain the temperature of several dust clumps to be $\lesssim 10$ K, which is too cold to be directly interacting with the surrounding $\sim 4.8$ keV intracluster medium (ICM). The cold dust population extends beyond the observed CO emission and must either be protected from interacting with the ICM or be surrounded by local volumes of ICM that are several keV colder than observed by Chandra.Comment: Accepted for Publication in ApJ, 19 pages, 11 figures. Minor revisions to the discussion and accompanying figur

Dust and Molecular Gas in the Brightest Cluster Galaxy in MACS 1931.8-2635

We present new Atacama Large Millimeter Array observations of the molecular gas and far-infrared continuum around the brightest cluster galaxy (BCG) in the cool-core cluster MACS 1931.8-2635. Our observations reveal (1.9 ± 0.3) × 10^(10) M⊙ of molecular gas, on par with the largest known reservoirs of cold gas in a cluster core. We detect CO(1−0), CO(3−2), and CO(4−3) emission from both diffuse and compact molecular gas components that extend from the BCG center out to ~30 kpc to the northwest, tracing the UV knots and Hα filaments observed by the Hubble Space Telescope. Due to the lack of morphological symmetry, we hypothesize that the ~300 km s−1 velocity of the CO in the tail is not due to concurrent uplift by active galactic nucleus (AGN) jets; rather, we may be observing the aftermath of a recent AGN outburst. The CO spectral line energy distribution suggests that molecular gas excitation is influenced by processes related to both star formation and recent AGN feedback. Continuum emission in Bands 6 and 7 arises from dust and is spatially coincident with young stars and nebular emission observed in the UV and optical. We constrain the temperature of several dust clumps to be ≾10 K, which is too cold to be directly interacting with the surrounding ~4.8 keV intracluster medium (ICM). The cold dust population extends beyond the observed CO emission and must either be protected from interacting with the ICM or be surrounded by local volumes of ICM that are several keV colder than observed by Chandra

Burden of Psychosocial and Cognitive Impairment in Patients With Atrial Fibrillation

BACKGROUND: Impairments in psychosocial status and cognition relate to poor clinical outcomes in patients with atrial fibrillation (AF). However, how often these conditions co-occur and associations between burden of psychosocial and cognitive impairment and quality of life (QoL) have not been systematically examined in patients with AF. METHODS: A total of 218 patients with symptomatic AF were enrolled in a prospective study of AF and psychosocial factors between May 2013 and October 2014 at the University of Massachusetts Medical Center. Cognitive function, depression, and anxiety were assessed at baseline and AF-specific QoL was assessed 6 months after enrollment using validated instruments. Demographic and clinical information were obtained from a structured interview and medical record review. RESULTS: The mean age of the study participants was 63.5 +/- 10.2 years, 35% were male, and 81% had paroxysmal AF. Prevalences of impairment in 1, 2, and 3 psychosocial/cognitive domains (eg, depression, anxiety, or cognition) were 75 (34.4%), 51 (23.4%), and 16 (7.3%), respectively. Patients with co-occurring psychosocial/cognitive impairments (eg, \u3e 1 domain) were older, more likely to smoke, had less education, and were more likely to have heart failure (all P \u3c 0.05). Compared with participants with no psychosocial/cognitive impairments, AF-specific QoL at 6 months was significantly poorer among participants with baseline impairment in 2 (B = -13.6, 95% CI: -21.7 to -5.4) or 3 (B = -15.1, 95% CI: -28.0 to -2.2) psychosocial/cognitive domains. CONCLUSION: Depression, anxiety, and impaired cognition were common in our cohort of patients with symptomatic AF and often co-occurred. Higher burden of psychosocial/cognitive impairment was associated with poorer AF-specific QoL

Effect of Left Atrial Function Index on Late Atrial Fibrillation Recurrence after Pulmonary Vein Isolation

Background: Although the rates of catheter ablation (CA) for atrial fibrillation (AF) are rapidly increasing, there are few predictors of outcome to help inform appropriate patient selection for this procedure. Traditional echocardiographic measures of atrial structure do not significantly reclassify risk of AF recurrence over and above the clinical risk factors. Left Atrial Function Index (LAFI) is a rhythm-independent measure of atrial function. We hypothesized that baseline LAFI would relate to AF recurrence after CA. Methods: Pre-procedural echocardiograms from 170 participants, who underwent CA for AF and were enrolled in the UMMC AF Treatment Registry, were analyzed. LAFI was calculated by a previously validated formula. Primary outcome was late or clinically significant AF recurrence 3-12 months after CA. Baseline clinical, laboratory and echocardiographic variables were compared between the recurrence and non-recurrence groups. Results: Study participants were middle aged (60+/10 years) and had a moderate-to-severe burden of cardiovascular comorbidities. 78 participants (46%) experienced late AF recurrence. Mean LAFI was 0.26+/-0.18. In multivariate analysis, lower LAFI was independently associated with the risk of recurrence (0.23 in recurrence group vs 0.29 in non-recurrence group, p \u3c 0.01). Predictive value of LAFI for AF recurrence was similar to CHADS2 score (c-statistic 0.60 vs 0.58, p 0.76). In subgroup of patients with persistent AF, LAFI predicted AF recurrence more strongly than CHADS2 score (c-statistic: 0.79 vs 0.58, p 0.02). Conclusions: In our cohort of 170 participants with AF undergoing index CA ablation, we observed that LAFI related to late AF recurrence after CA, independent of the traditional risk factors. Since LAFI can be calculated from almost any traditional echocardiographic recording, our findings suggest that LAFI may help guide therapeutic decision-making regarding application of CA, particularly among challenging patients with symptomatic persistent AF

Relations between plasma microRNAs, echocardiographic markers of atrial remodeling, and atrial fibrillation: Data from the Framingham Offspring study

BACKGROUND: Circulating microRNAs may reflect or influence pathological cardiac remodeling and contribute to atrial fibrillation (AF). OBJECTIVE: The purpose of this study was to identify candidate plasma microRNAs that are associated with echocardiographic phenotypes of atrial remodeling, and incident and prevalent AF in a community-based cohort. METHODS: We analyzed left atrial function index (LAFI) of 1788 Framingham Offspring 8 participants. We quantified expression of 339 plasma microRNAs. We examined associations between microRNA levels with LAFI and prevalent and incident AF. We constructed pathway analysis of microRNAs\u27 predicted gene targets to identify molecular processes involved in adverse atrial remodeling in AF. RESULTS: The mean age of the participants was 66 +/- 9 years, and 54% were women. Five percent of participants had prevalent AF at the initial examination and 9% (n = 157) developed AF over a median 8.6 years of follow-up (IQR 8.1-9.2 years). Plasma microRNAs were associated with LAFI (N = 73, p \u3c 0.0001). Six of these plasma microRNAs were significantly associated with incident AF, including 4 also associated with prevalent AF (microRNAs 106b, 26a-5p, 484, 20a-5p). These microRNAs are predicted to regulate genes involved in cardiac hypertrophy, inflammation, and myocardial fibrosis. CONCLUSIONS: Circulating microRNAs 106b, 26a-5p, 484, 20a-5p are associated with atrial remodeling and AF

Dust and Molecular Gas in the Brightest Cluster Galaxy in MACS 1931.8-2635

We present new Atacama Large Millimeter Array observations of the molecular gas and far-infrared continuum around the brightest cluster galaxy (BCG) in the cool-core cluster MACS 1931.8-2635. Our observations reveal (1.9 ± 0.3) × 10^(10) M⊙ of molecular gas, on par with the largest known reservoirs of cold gas in a cluster core. We detect CO(1−0), CO(3−2), and CO(4−3) emission from both diffuse and compact molecular gas components that extend from the BCG center out to ~30 kpc to the northwest, tracing the UV knots and Hα filaments observed by the Hubble Space Telescope. Due to the lack of morphological symmetry, we hypothesize that the ~300 km s−1 velocity of the CO in the tail is not due to concurrent uplift by active galactic nucleus (AGN) jets; rather, we may be observing the aftermath of a recent AGN outburst. The CO spectral line energy distribution suggests that molecular gas excitation is influenced by processes related to both star formation and recent AGN feedback. Continuum emission in Bands 6 and 7 arises from dust and is spatially coincident with young stars and nebular emission observed in the UV and optical. We constrain the temperature of several dust clumps to be ≾10 K, which is too cold to be directly interacting with the surrounding ~4.8 keV intracluster medium (ICM). The cold dust population extends beyond the observed CO emission and must either be protected from interacting with the ICM or be surrounded by local volumes of ICM that are several keV colder than observed by Chandra