The assessment of myocardial viability has been used to identify patients with coronary artery disease and left ventricular dysfunction in whom coronary-artery bypass grafting (CABG) will provide a ...survival benefit. However, the efficacy of this approach is uncertain.
In a substudy of patients with coronary artery disease and left ventricular dysfunction who were enrolled in a randomized trial of medical therapy with or without CABG, we used single-photon-emission computed tomography (SPECT), dobutamine echocardiography, or both to assess myocardial viability on the basis of prespecified thresholds.
Among the 1212 patients enrolled in the randomized trial, 601 underwent assessment of myocardial viability. Of these patients, we randomly assigned 298 to receive medical therapy plus CABG and 303 to receive medical therapy alone. A total of 178 of 487 patients with viable myocardium (37%) and 58 of 114 patients without viable myocardium (51%) died (hazard ratio for death among patients with viable myocardium, 0.64; 95% confidence interval CI, 0.48 to 0.86; P=0.003). However, after adjustment for other baseline variables, this association with mortality was not significant (P=0.21). There was no significant interaction between viability status and treatment assignment with respect to mortality (P=0.53).
The presence of viable myocardium was associated with a greater likelihood of survival in patients with coronary artery disease and left ventricular dysfunction, but this relationship was not significant after adjustment for other baseline variables. The assessment of myocardial viability did not identify patients with a differential survival benefit from CABG, as compared with medical therapy alone. (Funded by the National Heart, Lung, and Blood Institute; STICH ClinicalTrials.gov number, NCT00023595.).
The role of I(KCa) in cardiac repolarization remains controversial and varies across species. The relevance of the current as a therapeutic target is therefore undefined. We examined the cellular ...electrophysiologic effects of I(KCa) blockade in controls, chronic heart failure (HF) and HF with sustained atrial fibrillation. We used perforated patch action potential recordings to maintain intrinsic calcium cycling. The I(KCa) blocker (apamin 100 nM) was used to examine the role of the current in atrial and ventricular myocytes. A canine tachypacing induced model of HF (1 and 4 months, n = 5 per group) was used, and compared to a group of 4 month HF with 6 weeks of superimposed atrial fibrillation (n = 7). A group of age-matched canine controls were used (n = 8). Human atrial and ventricular myocytes were isolated from explanted end-stage failing hearts which were obtained from transplant recipients, and studied in parallel. Atrial myocyte action potentials were unchanged by I(KCa) blockade in all of the groups studied. I(KCa) blockade did not affect ventricular myocyte repolarization in controls. HF caused prolongation of ventricular myocyte action potential repolarization. I(KCa) blockade caused further prolongation of ventricular repolarization in HF and also caused repolarization instability and early afterdepolarizations. SK2 and SK3 expression in the atria and SK3 in the ventricle were increased in canine heart failure. We conclude that during HF, I(KCa) blockade in ventricular myocytes results in cellular arrhythmias. Furthermore, our data suggest an important role for I(KCa) in the maintenance of ventricular repolarization stability during chronic heart failure. Our findings suggest that novel antiarrhythmic therapies should have safety and efficacy evaluated in both atria and ventricles.
There is conflicting evidence as to the impact of mental health treatment on outcomes in patients with heart disease. The aim of this study was to examine whether individuals who received mental ...health treatment for anxiety or depression after being hospitalized for ischemic disorders or heart failure had a reduced frequency of rehospitalizations, emergency department visits, or mortality compared with those who did not receive treatment.
A population-based, retrospective, cohort design was used to examine the association between psychotherapy or antidepressant medication prescription and health service utilization and mortality in patients with coronary artery disease or heart failure and comorbid anxiety or depression. Those receiving versus not receiving mental health treatment were compared based on the frequency of rehospitalization, emergency department visits, and mortality. The study sample included 1563 patients who had a mean age of 50.1 years. Individuals who received both forms of mental health treatment for anxiety or depression were 75% less likely to be rehospitalized, 74% less likely to have an emergency department visit, and 66% less likely to die from any cause.
Mental health treatment for anxiety or depression has a significant impact on outcomes in patients with cardiovascular disease consisting of reduced hospitalizations, emergency department visits, and in some conditions improved survival.
Physician burnout has a negative impact on patient care, productivity and job retention, whereas the cost of recruiting and replacing burned-out physicians can be steep (1). The current health care ...environment places strong emphasis on accomplishing the triple aim: improving population health and enhancing patient experience while reducing overall costs; however, absence of clinician well-being has a negative impact on achievement of these aims. Accordingly, many have called for modification of health care goals to include clinician well-being, thereby expanding to a “quadruple aim”(2). To date, there has been highly variable uptake of the quadruple aim's call to action with inconsistent efforts to address well-being across institutions.
Background: Although β-blockers (BB) could increase the risk of hypoglycemia, the difference between subtypes on hypoglycemia and mortality have not been studied.
Aim: To determine the relationship ...between type of BB and incidence of hypoglycemia and mortality in hospitalized patients.
Methods: We retrospectively identified non-critically ill hospitalized patients who were undergoing bedside glucose monitoring over a 2 year period. Admission BB was categorized as carvedilol (C) or selective BB (SBB). Other nonselective BB were excluded. Hypoglycemia was defined as any glucose < 70 mg/dl within 24 hours of admission (Hypo24) or throughout hospitalization (HypoT) and any glucose <40 mg/dl throughout hospitalization (Hypo40).
Results: There were 1022 patients on C, 886 on SBB, and 10,217 on no BB. After controlling for other variables, the odds of Hypo24 HypoT and Hypo40 were higher for BB recipients, and the odds were greater for SBB vs. carvedilol for HypoT (Table). Findings were not observed in heart failure patients. Hypo24, HypoT, and Hypo40 were all associated with increased mortality in adjusted models among non-BB and C recipients, but not among SBB recipients.
Conclusions: BB use is associated with hypoglycemia, except in heart failure. C is associated with lower odds of hypoglycemia compared to SSB. Moreover, hypoglycemia associated mortality was attenuated with C. The findings warrant further study among patients with diabetes.
Disclosure
C. Long: None. P.F. Binkley: None. K.M. Dungan: Advisory Panel; Self; Eli Lilly and Company, Elsevier, Sanofi-Aventis. Research Support; Self; Eli Lilly and Company, GlaxoSmithKline plc., Novo Nordisk Inc., Sanofi-Aventis, Viacyte. Other Relationship; Self; DKBmed, UpToDate.
Human gene variants affecting ion channel biophysical activity and/or membrane localization are linked to potentially fatal cardiac arrhythmias. However, the mechanism for many human arrhythmia ...variants remains undefined despite more than a decade of investigation. Posttranslational modulation of membrane proteins is essential for normal cardiac function. Importantly, aberrant myocyte signaling has been linked to defects in cardiac ion channel posttranslational modifications and disease. We recently identified a novel pathway for posttranslational regulation of the primary cardiac voltage-gated Na(+) channel (Na(v)1.5) by Ca(2+)/calmodulin-dependent protein kinase II (CaMKII). However, a role for this pathway in cardiac disease has not been evaluated.
We evaluated the role of CaMKII-dependent phosphorylation in human genetic and acquired disease. We report an unexpected link between a short motif in the Na(v)1.5 DI-DII loop, recently shown to be critical for CaMKII-dependent phosphorylation, and Na(v)1.5 function in monogenic arrhythmia and common heart disease. Experiments in heterologous cells and primary ventricular cardiomyocytes demonstrate that the human arrhythmia susceptibility variants (A572D and Q573E) alter CaMKII-dependent regulation of Na(v)1.5, resulting in abnormal channel activity and cell excitability. In silico analysis reveals that these variants functionally mimic the phosphorylated channel, resulting in increased susceptibility to arrhythmia-triggering afterdepolarizations. Finally, we report that this same motif is aberrantly regulated in a large-animal model of acquired heart disease and in failing human myocardium.
We identify the mechanism for 2 human arrhythmia variants that affect Na(v)1.5 channel activity through direct effects on channel posttranslational modification. We propose that the CaMKII phosphorylation motif in the Na(v)1.5 DI-DII cytoplasmic loop is a critical nodal point for proarrhythmic changes to Na(v)1.5 in congenital and acquired cardiac disease.
Purpose
Protein kinase C α (PRKCA) is involved in multiple functions and has been implicated in heart failure risks and treatment outcomes. This study aims to identify regulatory variants affecting
...PRKCA
expression in human heart, and evaluate attributable risk of heart disease.
Methods
mRNA expression quantitative trait loci (eQTLs) were extracted from the Genotype and Tissue Expression Project (GTEx). Allelic mRNA ratios were measured in 51 human heart tissues to identify
cis-
acting regulatory variants. Potential regulatory regions were tested with luciferase reporter gene assays and further evaluated in GTEx and genome-wide association studies.
Results
Located in a region with robust enhancer activity in luciferase reporter assays, rs9909004 (
T > C
, minor allele frequency =0.47) resides in a haplotype displaying strong eQTLs for
PRKCA
in heart (
p
= 1.2 × 10
−23
). The minor
C
allele is associated with both decreased
PRKCA
mRNA expression and decreased risk of phenotypes characteristic of heart failure in GWAS analyses (QT interval
p
= 3.0 × 10
−14
). While rs9909004 is the likely regulatory variant, other variants in high linkage disequilibrium cannot be excluded. Distinct regulatory variants appear to affect expression in other tissues.
Conclusions
The haplotype carrying rs9909004 influences
PRKCA
expression in the heart and is associated with traits linked to heart failure, potentially affecting therapy of heart failure.
Kinase/phosphatase balance governs cardiac excitability in health and disease. Although detailed mechanisms for cardiac kinase regulation are established, far less is known regarding cardiac protein ...phosphatase 2A (PP2A) regulation. This is largely due to the complexity of the PP2A holoenzyme structure (combinatorial assembly of three subunit enzyme from >17 subunit genes) and the inability to segregate “global” PP2A function from the activities of multiple “local” holoenzyme populations. Here we report that PP2A catalytic, regulatory, and scaffolding subunits are tightly regulated at transcriptional, translational, and post-translational levels to tune myocyte function at base line and in disease. We show that past global read-outs of cellular PP2A activity more appropriately represent the collective activity of numerous individual PP2A holoenzymes, each displaying a specific subcellular localization (dictated by select PP2A regulatory subunits) as well as local specific post-translational catalytic subunit methylation and phosphorylation events that regulate local and rapid holoenzyme assembly/disassembly (via leucine carboxymethyltransferase 1/phosphatase methylesterase 1 (LCMT-1/PME-1). We report that PP2A subunits are selectively regulated between human and animal models, across cardiac chambers, and even within specific cardiac cell types. Moreover, this regulation can be rapidly tuned in response to cellular activation. Finally, we report that global PP2A is altered in human and experimental models of heart disease, yet each pathology displays its own distinct molecular signature though specific PP2A subunit modulatory events. These new data provide an initial view into the signaling pathways that govern PP2A function in heart but also establish the first step in defining specific PP2A regulatory targets in health and disease.
Background: PP2A regulates cardiac excitability and physiology.
Results: PP2A regulation in heart occurs through integrative transcriptional, translational, and post-translational control of three classes of subunits (17 genes) to control holoenzyme synthesis, localization, and maintenance; pathways are mechanistically altered in heart disease.
Conclusion: Multiple mechanisms are present for acute and chronic regulation of specific PP2A populations.
Significance: Results provide molecular insight into cardiac PP2A regulation.
Abstract Background Our aim was to describe the relationship between risk factors, such as stress, depression, and anxiety, and potentially protective factors against pediatric headache-related ...disability, such as mindfulness, resilience, and self-compassion, and to determine teens' interest in mind-body skills training to help reduce headache-related disability. Methods This was a cross-sectional survey among adolescents seen in an academic neurology clinic reporting four or more headaches monthly using standardized instruments to determine the relationship between putative risk and protective factors as well as physiologic markers of inflammation and vagal tone and headache-related disability. Results Among the 29 participants, 31% were male, the average age was 14.8 years, average headache frequency was 11.6 per month, and the most commonly reported trigger was stress (86%). The only risk or protective factor significantly associated with headache-related disability was depression (r = 0.52, P = 0.004). Depression was negatively correlated with mindfulness, resilience, and self-compassion ( P < 0.01 each) and positively correlated with stress, sleep disturbance, and anxiety ( P < 0.01 each). Biomarkers of vagal tone and inflammation were correlated with each other but not with headache-related disability or depression. There was strong interest in learning skills like slow, deep breathing practices supported by a smart phone application to reduce stress and the negative impact of headaches on daily life. Discussion Among teens with frequent migraine headaches, depression is the strongest risk factor for headache-related disability. Stress is viewed as a headache trigger, and teens reported wanting to learn simple stress management strategies supported by a smart phone application to help reduce headache-related disability.
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