Hemodynamic-guided management with a pulmonary artery pressure sensor (CardioMEMS) is effective in reducing heart failure hospitalization in patients with chronic heart failure. This study aims to ...determine the feasibility and clinical utility of the CardioMEMS heart failure system to manage patients supported with left ventricular assist devices (LVADs).
In this multicenter prospective study, we followed patients with HeartMate II (n=52) or HeartMate 3 (n=49) LVADs and with CardioMEMS PA Sensors and measured pulmonary artery pressure, 6-minute walk distance, quality of life (EQ-5D-5 L scores), and heart failure hospitalization rates through 6 months. Patients were stratified as responders (R) and nonresponders to reductions in pulmonary artery diastolic pressure (PAD).
There were significant reductions in PAD from baseline to 6 months in R (21.5-16.5 mm Hg;
<0.001), compared with an increase in NR (18.0-20.3;
=0.002), and there was a significant increase in 6-minute walk distance among R (266 versus 322 meters;
=0.025) compared with no change in nonresponder. Patients who maintained PAD <20 compared with PAD ≥20 mm Hg for more than half the time throughout the study (averaging 15.6 versus 23.3 mm Hg) had a statistically significant lower rate of heart failure hospitalization (12.0% versus 38.9%;
=0.005).
Patients with LVAD managed with CardioMEMS with a significant reduction in PAD at 6 months showed improvements in 6-minute walk distance. Maintaining PAD <20 mm Hg was associated with fewer heart failure hospitalizations. Hemodynamic-guided management of patients with LVAD with CardioMEMS is feasible and may result in functional and clinical benefits. Prospective evaluation of ambulatory hemodynamic management in patients with LVAD is warranted.
URL: https://www.
gov; Unique identifier: NCT03247829.
To maintain genome integrity and epigenetic information, mammalian cells must carefully coordinate the supply and deposition of histones during DNA replication. Here we report that the CUL4 E3 ...ubiquitin ligase complex CRL4WDR23 directly regulates the stem-loop binding protein (SLBP), which orchestrates the life cycle of histone transcripts including their stability, maturation, and translation. Lack of CRL4WDR23 activity is characterized by depletion of histones resulting in inhibited DNA replication and a severe slowdown of growth in human cells. Detailed analysis revealed that CRL4WDR23 is required for efficient histone mRNA 3′ end processing to produce mature histone mRNAs for translation. CRL4WDR23 binds and ubiquitylates SLBP in vitro and in vivo, and this modification activates SLBP function in histone mRNA 3′ end processing without affecting its protein levels. Together, these results establish a mechanism by which CUL4 regulates DNA replication and possible additional chromatin transactions by controlling the concerted expression of core histones.
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•CRL4WDR23 binds and ubiquitylates SLBP in vitro and in vivo in human cells•CRL4WDR23-mediated SLBP ubiquitylation promotes histone mRNA processing•Expression of histones in S phase requires CRL4WDR23•Lack of CRL4WDR23 activity leads to DNA replication block and impaired growth
CUL4 is essential for maintaining chromatin integrity. Brodersen et al. identify histone expression regulator SLBP as a ubiquitylation target of CRL4WDR23 E3 ubiquitin ligase. CRL4WDR23 functionally ubiquitylates SLBP to activate histone mRNA processing during S phase and ensures unperturbed histone supply during DNA replication.
To maintain genome integrity and epigenetic information, mammalian cells must carefully coordinate the supply and deposition of histones during DNA replication. Here we report that the CUL4 E3 ...ubiquitin ligase complex CRL4 super(WDR23) directly regulates the stem-loop binding protein (SLBP), which orchestrates the life cycle of histone transcripts including their stability, maturation, and translation. Lack of CRL4 super(WDR23) activity is characterized by depletion of histones resulting in inhibited DNA replication and a severe slowdown of growth in human cells. Detailed analysis revealed that CRL4 super(WDR23) is required for efficient histone mRNA 3' end processing to produce mature histone mRNAs for translation. CRL4 super(WDR23) binds and ubiquitylates SLBP in vitro and in vivo, and this modification activates SLBP function in histone mRNA 3' end processing without affecting its protein levels. Together, these results establish a mechanism by which CUL4 regulates DNA replication and possible additional chromatin transactions by controlling the concerted expression of core histones.
IntroductionThe safety of vigorous exercise for individuals with appropriately-treated LQTS remains unproven, and physical activity practices in this population have not been ...described.MethodsLIVE-LQTS prospectively enrolled individuals age 8-60 years with overt LQTS or gene mutation carriers. Participants (or parents, for children) answered surveys describing activity patterns. Vigorous exercise was defined as > 6 METS for > 60 hours per year. Clinical and demographic data were derived from medical record review.ResultsAmong 1554 participants, 804 (52%) reported exercising vigorously, 473 of these competitively, 577 (37%) exercising at moderate, and 173 (11%) at low levels. Seven percent of those working describe jobs more active than walking, including 10 in protective services and 19 in sports/coaching. Over 90% are genotype positive, 57% are phenotype positive at rest and an additional 16% have exercise-induced QT prolongation. Forty four percent have had documented ventricular arrhythmias or syncope. Eighty-four percent are appropriately treated with either beta-blockers, ICD, and/or sympathectomy, although among beta-blocked patients, only 60% are on the most effective agents. Among adults, BMI was significantly lower among the vigorous exercisers.ConclusionWhile the high percentage of vigorous exercisers seen in this study may not represent all patients with LQTS due to self-selection for study participation, many patients with LQTS are engaged in vigorous exercise or competitive athletics. Prospective follow up of this cohort is ongoing and will determine safety of vigorous exercise through comparison of arrhythmic outcomes in vigorous exercisers vs moderate/low level exercisers.
IntroductionCaregivers (CGs) of heart failure (HF) patients (PTs) who undergo heart transplantation (HT) or Destination Therapy Mechanical Circulatory Support (DT MCS) provide support to PTs before ...and after surgery, which may affect their own health-related quality of life (HRQOL). In SUSTAIN-IT, we previously reported that CG HRQOL was good at baseline (i.e., before HT and DT MCS surgery) and was impacted by CG comorbidities and CG anxiety. This report explores change in CG overall HRQOL, depression, and anxiety from baseline to 12 months after HT or DT MCS surgery.MethodsFrom 10/1/15-12/31/18, 13 U.S. centers enrolled 301 CGs of HF PTs193 awaiting HT (92 HT with MCS as a bridge to transplant HT BTT and 101 HT without MCS HT non-BTT), and 108 awaiting DT MCS. At baseline, 3, 6, and 12 months post HT or DT MCS surgery, CGs completed the following instrumentsEQ-5D-3L (Visual Analog Scale VAS0 worst to 100 best imaginable health state), PHQ-8 (range=0-24; score ≥10=depressive symptoms requiring evaluation), and STAI-State (range=20-80, higher score=more anxiety). Analyses included unadjusted and baseline-adjusted linear regression models.ResultsCGs were age 61.0±10.3 years; the majority were Caucasian (86%), female (86%), spouses (85%) of enrolled HF PTs. At baseline, CG EQ-5D-3L VAS and PHQ-8 average scores were 83.8 ± 13.99 (high) and 2.6 ± 2.85 (low), respectively, for the entire cohort. No significant interval changes in CG HRQOL and depressive symptoms were found within or between groups. DT MCS and HT non-BTT CG anxiety significantly decreased over time (baseline to 12 months) (Figure). Levels of CG anxiety were similar among all groups at 12 months after HT or DT MCS surgery.ConclusionsThe demonstrated reduction in anxiety among CGs in the post-operative period provides clinicians with important information to share with CGs when PTs are considering surgical treatment options for HF.
PurposeCaregivers (CGs) for patients with advanced heart failure (HF) assist in HF-specific disease management. In the SUSTAIN-IT study, we reported CG perception of difficulty and time needed to ...perform tasks for patients awaiting surgery in 3 groupsHF patients awaiting heart transplant (HT) without mechanical support (HT-non-MCS), HF patients awaiting HT bridged with mechanical support (HT-MCS), and HF patient awaiting left ventricular device implantation as destination therapy (DT-MCS). In this report, we compare CG perceived burden from baseline to 1 year after surgery.MethodsWe enrolled 301 CGs of HF patients between 10/1/15-12/31/18 from 12 U.S. hospitals193 awaiting HT (92 with and 101 without MCS), and 108 scheduled for DT-MCS. Prior to surgery and 3, 6, and 12 months after surgery, CGs completed the Oberst Caregiver Burden Scale (OCBS) which has 15 items with 2 subscales(1) time and (2) difficultyrange=1-5, higher score=more time required for tasks and more task difficulty. Analyses included t-tests, chi-square tests, and baseline-adjusted linear regression models.ResultsCGs were age 61.0±10.3 years, the majority were spouses (85%), female (86%), and white (86%). Average time spent on caregiving was moderate and decreased significantly from baseline to 12 months after surgery for all groups (Figure). DT-MCS CGs spent significantly more time than HT CGs on tasks 12 months after surgery. There were no significant differences in perceived difficulty (which was low) in performing CG tasks in all groups from baseline to 12 months. DT-MCS CGs did perceive tasks to be more difficult than HT CGs at 12 months.ConclusionCGs of advanced HF patients adapted well to assisting with care, without increased burden, 1 year after HT and DT-MCS surgery. CGs of DT-MCS patients required more time and reported CG tasks to be more difficult than HT CGs. Understanding differences in CG burden will aid in pre surgical risk discussions and post-surgical follow-up.
A positive family history (FH) raises the risk for late-onset Alzheimer's disease though, other than the known risk conferred by apolipoprotein ε4 (ApoE4), much of the genetic variance remains ...unexplained. We examined the effect of family history on longitudinal regional brain atrophy rates in 184 subjects (42% FH+, mean age 79.9) with mild cognitive impairment (MCI) enrolled in a national biomarker study. An automated image analysis method was applied to T1-weighted MR images to measure atrophy rates for 20 cortical and subcortical regions. Mixed-effects linear regression models incorporating repeated-measures to control for within-subject variation over multiple time points tested the effect of FH over a follow-up of up to 48 months. Most of the 20 regions showed significant atrophy over time. Adjusting for age and gender, subjects with a positive FH had greater atrophy of the amygdala (p < 0.01), entorhinal cortex (p < 0.01), hippocampus (p < 0.053) and cortical gray matter (p < 0.009). However, when E4 genotype was added as a covariate, none of the FH effects remained significant. Analyses by ApoE genotype showed that the effect of FH on amygdala atrophy rates was numerically greater in ε3 homozygotes than in E4 carriers, but this difference was not significant. FH+ subjects had numerically greater 4-year cognitive decline and conversion rates than FH- subjects but the difference was not statistically significant after adjusting for ApoE and other variables. We conclude that a positive family history of AD may influence cortical and temporal lobe atrophy in subjects with mild cognitive impairment, but it does not have a significant additional effect beyond the known effect of the E4 genotype.
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