PPP1R12C Promotes Atrial Hypocontractility in Atrial Fibrillation.

BACKGROUND: Atrial fibrillation (AF)-the most common sustained cardiac arrhythmia-increases thromboembolic stroke risk 5-fold. Although atrial hypocontractility contributes to stroke risk in AF, the molecular mechanisms reducing myofilament contractile function remain unknown. We tested the hypothesis that increased expression of PPP1R12C (protein phosphatase 1 regulatory subunit 12C)-the PP1 (protein phosphatase 1) regulatory subunit targeting MLC2a (atrial myosin light chain 2)-causes hypophosphorylation of MLC2a and results in atrial hypocontractility. METHODS: Right atrial appendage tissues were isolated from human patients with AF versus sinus rhythm controls. Western blots, coimmunoprecipitation, and phosphorylation studies were performed to examine how the PP1c (PP1 catalytic subunit)-PPP1R12C interaction causes MLC2a dephosphorylation. In vitro studies of pharmacological MRCK (myotonic dystrophy kinase-related Cdc42-binding kinase) inhibitor (BDP5290) in atrial HL-1 cells were performed to evaluate PP1 holoenzyme activity on MLC2a. Cardiac-specific lentiviral PPP1R12C overexpression was performed in mice to evaluate atrial remodeling with atrial cell shortening assays, echocardiography, and AF inducibility with electrophysiology studies. RESULTS: In human patients with AF, PPP1R12C expression was increased 2-fold versus sinus rhythm controls (P=2.0×10-2; n=12 and 12 in each group) with >40% reduction in MLC2a phosphorylation (P=1.4×10-6; n=12 and 12 in each group). PPP1R12C-PP1c binding and PPP1R12C-MLC2a binding were significantly increased in AF (P=2.9×10-2 and 6.7×10-3, respectively; n=8 and 8 in each group). In vitro studies utilizing drug BDP5290, which inhibits T560-PPP1R12C phosphorylation, demonstrated increased PPP1R12C binding with both PP1c and MLC2a and dephosphorylation of MLC2a. Mice treated with lentiviral PPP1R12C vector demonstrated a 150% increase in left atrial size versus controls (P=5.0×10-6; n=12, 8, and 12), with reduced atrial strain and atrial ejection fraction. Pacing-induced AF in mice treated with lentiviral PPP1R12C vector was significantly higher than in controls (P=1.8×10-2 and 4.1×10-2, respectively; n=6, 6, and 5). CONCLUSIONS: Patients with AF exhibit increased levels of PPP1R12C protein compared with controls. PPP1R12C overexpression in mice increases PP1c targeting to MLC2a and causes MLC2a dephosphorylation, which reduces atrial contractility and increases AF inducibility. These findings suggest that PP1 regulation of sarcomere function at MLC2a is a key determinant of atrial contractility in AF.

Myosin Light Chain Dephosphorylation by PPP1R12C Promotes Atrial Hypocontractility in Atrial Fibrillation.

Background: Atrial fibrillation (AF), the most common sustained cardiac arrhythmia, increases thromboembolic stroke risk five-fold. Although atrial hypocontractility contributes to stroke risk in AF, the molecular mechanisms reducing myofilament contractile function remain unknown. We tested the hypothesis that increased expression of PPP1R12C, the PP1 regulatory subunit targeting atrial myosin light chain 2 (MLC2a), causes hypophosphorylation of MLC2a and results in atrial hypocontractility. Methods: Right atrial appendage tissues were isolated from human AF patients versus sinus rhythm (SR) controls. Western blots, co-immunoprecipitation, and phosphorylation studies were performed to examine how the PP1c-PPP1R12C interaction causes MLC2a de-phosphorylation. In vitro studies of pharmacologic MRCK inhibitor (BDP5290) in atrial HL-1 cells were performed to evaluate PP1 holoenzyme activity on MLC2a. Cardiac-specific lentiviral PPP1R12C overexpression was performed in mice to evaluate atrial remodeling with atrial cell shortening assays, echocardiography, and AF inducibility with EP studies. Results: In human patients with AF, PPP1R12C expression was increased two-fold versus SR controls ( P =2.0×10 -2 , n=12,12 in each group) with > 40% reduction in MLC2a phosphorylation ( P =1.4×10 -6 , n=12,12 in each group). PPP1R12C-PP1c binding and PPP1R12C-MLC2a binding were significantly increased in AF ( P =2.9×10 -2 and 6.7×10 -3 respectively, n=8,8 in each group). In vitro studies utilizing drug BDP5290, which inhibits T560-PPP1R12C phosphorylation, demonstrated increased PPP1R12C binding with both PP1c and MLC2a, and dephosphorylation of MLC2a. Lenti-12C mice demonstrated a 150% increase in LA size versus controls ( P =5.0×10 -6 , n=12,8,12), with reduced atrial strain and atrial ejection fraction. Pacing-induced AF in Lenti-12C mice was significantly higher than controls ( P =1.8×10 -2 and 4.1×10 -2 respectively, n= 6,6,5). Conclusions: AF patients exhibit increased levels of PPP1R12C protein compared to controls. PPP1R12C overexpression in mice increases PP1c targeting to MLC2a and causes MLC2a dephosphorylation, which reduces atrial contractility and increases AF inducibility. These findings suggest that PP1 regulation of sarcomere function at MLC2a is a key determinant of atrial contractility in AF.

Defining the impact of continuous positive airway pressure therapy on diastolic function in adults with moderate-to-severe obstructive sleep apnea.

Although studies have shown that continuous positive airway pressure (CPAP) therapy to treat obstructive sleep apnea improves left ventricular diastolic function, modifiers of improvement are unknown. We explored race and pre-treatment 24-h non-dipping blood pressure status as modifiers of improved diastolic function. Participants (N = 220) with obstructive sleep apnea (apnea-hypopnea index ≥15 events/h) and hypertension were recruited to a cohort study that examined effects of 3-month CPAP therapy on 24-h blood pressure. Those who completed echocardiogram at baseline and follow-up were included in this analysis. Diastolic function parameters (E, A, e', E/A, E/e') were assessed. Race was categorised to African American versus others. Participants were categorised as nocturnal dippers (night-time blood pressure decrease by ≥10%) versus non-dippers. We compared changes in parameters of diastolic function by race and nocturnal dipping status. A total of 92 participants were included. They were men (86%), African American (67.4%), and current smoker (29.5%). Mean apnea-hypopnea index was 32.9 events/h. Mean CPAP usage was 3.15 h/day. After 3 months of CPAP treatment, there were significant improvements in measures of diastolic function: a median (interquartile range [IQR]) increase in E velocity by 4.00 (-5.75 to 13.75) cm/s, an increase in e' by 2.00 (0-4.00) cm/s, and a decrease in the E/e' ratio by 1.74 (-4.27 to 0.00) at follow-up (p < 0.05). These changes did not differ by race or nocturnal dipping status. Improvements in diastolic function after CPAP therapy did not differ by race or nocturnal dipping status. Further studies are needed to understand predictors of CPAP effects on diastolic function.

Comparing individual differences in inconsistency and plasticity as predictors of cognitive function in older adults.

INTRODUCTION: Recent theorizing differentiates key constraints on cognition, including one's current range of processing efficiency (i.e., flexibility or inconsistency) as well as the capacity to expand flexibility over time (i.e., plasticity). The present study uses intensive assessment of response time data to examine the interplay between markers of intraindividual variability (inconsistency) and gains across biweekly retest sessions (plasticity) in relation to age-related cognitive function. METHOD: Participants included 304 adults (aged 64 to 92 years: M = 74.02, SD = 5.95) from Project MIND, a longitudinal burst design study assessing performance across micro and macro intervals (response latency trials, weekly bursts, annual retests). For two reaction time (RT) measures (choice RT and one-back choice RT), baseline measures of RT inconsistency (intraindividual standard deviation, ISD, across trials at the first testing session) and plasticity (within-person performance gains in average RT across the 5 biweekly burst sessions) were computed and were then employed in linear mixed models as predictors of individual differences in cognitive function and longitudinal (6-year) rates of cognitive change. RESULTS: Independent of chronological age and years of education, higher RT inconsistency was associated uniformly with poorer cognitive function at baseline and with increased cognitive decline for measures of episodic memory and crystallized verbal ability. In contrast, predictive associations for plasticity were more modest for baseline cognitive function and were absent for 6-year cognitive change. CONCLUSIONS: These findings underscore the potential utility of response times for articulating inconsistency and plasticity as dynamic predictors of cognitive function in older adults.

Clinical features and multidisciplinary approaches to dementia care.

Dementia is a clinical syndrome of widespread progressive deterioration of cognitive abilities and normal daily functioning. These cognitive and behavioral impairments pose considerable challenges to individuals with dementia, along with their family members and caregivers. Four primary dementia classifications have been defined according to clinical and research criteria: 1) Alzheimer's disease; 2) vascular dementias; 3) frontotemporal dementias; and 4) dementia with Lewy bodies/Parkinson's disease dementia. The cumulative efforts of multidisciplinary healthcare teams have advanced our understanding of dementia beyond basic descriptions, towards a more complete elucidation of risk factors, clinical symptoms, and neuropathological correlates. The characterization of disease subtypes has facilitated targeted management strategies, advanced treatments, and symptomatic care for individuals affected by dementia. This review briefly summarizes the current state of knowledge and directions of dementia research and clinical practice. We provide a description of the risk factors, clinical presentation, and differential diagnosis of dementia. A summary of multidisciplinary team approaches to dementia care is outlined, including management strategies for the treatment of cognitive impairments, functional deficits, and behavioral and psychological symptoms of dementia. The needs of individuals with dementia are extensive, often requiring care beyond traditional bounds of medical practice, including pharmacologic and non-pharmacologic management interventions. Finally, advanced research on the early prodromal phase of dementia is reviewed, with a focus on change-point models, trajectories of cognitive change, and threshold models of pathological burden. Future research goals are outlined, with a call to action for social policy initiatives that promote preventive lifestyle behaviors, and healthcare programs that will support the growing number of individuals affected by dementia.

TRB3 function in cardiac endoplasmic reticulum stress.

RATIONALE: Tribbles (TRB)3 is an intracellular pseudokinase that modulates the activity of several signal transduction cascades. TRB3 has been reported to inhibit the activity of Akt protein kinases. TRB3 gene expression is highly regulated in many cell types, and amino acid starvation, hypoxia, or endoplasmic reticulum (ER) stress promotes TRB3 expression in noncardiac cells. OBJECTIVE: The objective of this work was to examine TRB3 expression and function in cultured cardiac myocytes and in mouse heart. METHODS AND RESULTS: Agents that induced ER stress increased TRB3 expression in cultured cardiac myocytes while blocking insulin-stimulated Akt activation in these cells. Knockdown of TRB3 in cultured cardiac myocytes reversed the effects of ER stress on insulin signaling. Experimental myocardial infarction led to increased TRB3 expression in murine heart tissue in the infarct border zone suggesting that ER stress may play a role in pathological cardiac remodeling. Transgenic mice with cardiac-specific overexpression of TRB3 were generated and they exhibited normal contractile function but altered cardiac signal transduction and metabolism with reduced cardiac glucose oxidation rates. Transgenic TRB3 mice were also sensitized to infarct expansion and cardiac myocyte apoptosis in the infarct border zone after myocardial infarction. CONCLUSIONS: These results demonstrate that TRB3 induction is a significant aspect of the ER stress response in cardiac myocytes and that TRB3 antagonizes cardiac glucose metabolism and cardiac myocyte survival.

Transition from cognitively impaired not demented to Alzheimer's disease: an analysis of changes in functional abilities in a dementia clinic cohort.

BACKGROUND: Patients with cognitive impairment no dementia (CIND) are at an increased risk of progression to Alzheimer's disease (AD). Whether subtle impairments in functional or social abilities at the CIND stage can predict progression to AD is not yet fully determined. We evaluated whether impairments on the Disability Assessment for Dementia (DAD) and Functional Rating Scale (FRS) can predict progression to AD. METHODS: We examined 70 patients with CIND from the ACCORD cohort having complete DAD and FRS baseline and 2-year follow-up data. MANCOVA adjusted for age, sex, education and baseline MMSE score compared the baseline and 2-year change in DAD and FRS scores in CIND patients who progressed to AD versus non-progressors. RESULTS: There were no significant differences between CIND progressors and non-progressors in baseline total DAD or FRS scores. FRS domain analysis revealed that greater impairment in social/occupational functioning significantly predicted progression, while there were no predictive DAD domains. In progressors, both DAD and FRS scores significantly declined over time with the largest changes in instrumental activities of daily living (IADL). CONCLUSION: While changes in IADL characterize the progression from CIND to AD, impairment in complex social-cognitive competency significantly predicts risk of progression and may mark early AD.

Outcomes of cognitively impaired not demented at 2 years in the Canadian Cohort Study of Cognitive Impairment and Related Dementias.

BACKGROUND: People who are cognitively impaired not demented (CIND) can be at an increased risk for developing dementia, but little is known about the natural history of CIND in clinical settings. METHOD: We examined the 2-year outcome of CIND subjects in the Canadian Cohort Study of Cognitive Impairment and Related Dementias.CIND was diagnosed when at least one positive item was endorsed on the DSM-III-R dementia criteria, but not all criteria were met. CIND was further subclassified as: pre-Alzheimer's disease (pre-AD), vascular cognitive impairment (VCI-ND), non-AD degenerative, psychiatric, other neurologic, other medical conditions, mixed disorders and no etiology identified (not otherwise specified [NOS]). RESULT: Of 146 CIND patients with 2-year follow-up data available, 49 (34%) progressed to dementia, while 20 (14%) recovered to not cognitively impaired (NCI). Progressors were significantly older than stable CIND and reverters (p < 0.0001; mean age = 71.1, 64.3, and 59.1, respectively), and there were significantly (p = 0.001) more ApoE epsilon4 carriers among progressors (67%) than stable CIND (29%) and reverters (12%). Pre-AD CIND and VCI-ND had the highest rate of conversion to dementia (41.0 and 40.0%, respectively), while psychiatric CIND and CIND NOS had highest rate of recovery to NCI (20.0 and 30.0%, respectively). All conversions in pre-AD CIND were to 'probable AD'. CONCLUSION: CIND consists of a heterogeneous group of disorders that can be classified syndromically. Many subclassess - not just those with pre-AD CIND - are at high risk of progression to dementia, usually to Alzheimer's disease.