Philip F. Binkley

The Ohio State University, Columbus, Ohio, United States

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Publications (181)1116.73 Total impact

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    ABSTRACT: Our objective was to evaluate the associations of genetic variants affecting simvastatin (SV) and simvastatin acid (SVA) metabolism [the gene encoding cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4)*22 and the gene encoding cytochrome P450, family 3, subfamily A, polypeptide 5 (CYP3A5)*3] and transport [the gene encoding solute carrier organic anion transporter family member 1B1 (SLCO1B1) T521C] with 12-hour plasma SV and SVA concentrations. The variants were genotyped, and the concentrations were quantified by high performance liquid chromatography-tandem mass spectrometry in 646 participants of the Cholesterol and Pharmacogenetics clinical trial of 40 mg/d SV for 6 weeks. The genetic variants were tested for association with 12-hour plasma SV, SVA, or the SVA/SV ratio using general linear models. CYP3A5*3 was not significantly associated with 12-hour plasma SV or SVA concentration. CYP3A4*1/*22 participants had 58% higher 12-hour plasma SV concentration compared with CYP3A4*1/*1 participants (P = 0.006). SLCO1B1 521T/C and 521C/C participants had 71% (P < 0.001) and 248% (P < 0.001) higher 12-hour plasma SVA compared with SLCO1B1 521T/T participants, respectively. CYP3A4 and SLCO1B1 genotypes combined categorized participants into low (<1), intermediate (≈1), and high (>1) SVA/SV ratio groups (P = 0.001). In conclusion, CYP3A4*22 and SLCO1B1 521C were significantly associated with increased 12-hour plasma SV and SVA concentrations, respectively. CYP3A5*3 was not significantly associated with 12-hour plasma SV or SVA concentrations. The combination of CYP3A4*22 and SLCO1B1 521C was significantly associated with SVA/SV ratio, which may translate into different clinical SV risk/benefit profiles.
    Journal of cardiovascular pharmacology 07/2015; 66(1):80-85. DOI:10.1097/FJC.0000000000000246 · 2.11 Impact Factor
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    ABSTRACT: Identified genetic variants are insufficient to explain all cases of inherited arrhythmia. We tested whether the integration of whole exome sequencing with well-established clinical, translational, and basic science platforms could provide rapid and novel insight into human arrhythmia pathophysiology and disease treatment. We report a proband with recurrent ventricular fibrillation, resistant to standard therapeutic interventions. Using whole-exome sequencing, we identified a variant in a previously unidentified exon of the dipeptidyl aminopeptidase-like protein-6 (DPP6) gene. This variant is the first identified coding mutation in DPP6 and augments cardiac repolarizing current (Ito) causing pathological changes in Ito and action potential morphology. We designed a therapeutic regimen incorporating dalfampridine to target Ito. Dalfampridine, approved for multiple sclerosis, normalized the ECG and reduced arrhythmia burden in the proband by >90-fold. This was combined with cilostazol to accelerate the heart rate to minimize the reverse-rate dependence of augmented Ito. We describe a novel arrhythmia mechanism and therapeutic approach to ameliorate the disease. Specifically, we identify the first coding variant of DPP6 in human ventricular fibrillation. These findings illustrate the power of genetic approaches for the elucidation and treatment of disease when carefully integrated with clinical and basic/translational research teams. © 2015 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.
    Journal of the American Heart Association 05/2015; 4(5):pii: e001762. DOI:10.1161/JAHA.114.001762 · 2.88 Impact Factor
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    ABSTRACT: Hypothesis 1 of the Surgical Treatment for Ischemic Heart Failure (STICH) trial enrolled 1212 patients with an LVEF of ≤35% and CAD amenable to coronary artery bypass grafting (CABG). Patients were randomized to CABG and optimal medical therapy (MED) or MED alone. The objective was to assess whether or not patients with diabetes mellitus (DM) enrolled in the STICH trial would have greater benefit from CABG than patients without DM. The characteristics and clinical outcomes of patients with and without DM randomized to CABG and MED or MED alone were compared. DM was present in 40%. At baseline, patients with DM had more triple vessel CAD, higher LVEF, and smaller left ventricular volumes. In patients with DM, the primary outcome of all-cause mortality occurred in 39% of patients in the MED group and 39% in the CABG group [hazard ratio (HR) with CABG 0.96, 95% confidence interval (CI) 0.73-1.26]. In patients without DM, the primary outcome occurred in 41% of patients in the MED group and 32% in the CABG group (HR with CABG 0.80, 95% CI 0.63-1.02). While numerically it would appear that the treatment effect of CABG is blunted in patients with DM, there was no significant interaction between DM and treatment group on formal statistical testing. Patients with DM enrolled in the STICH trial had more triple vessel disease, smaller hearts, and higher LVEF than those without DM. CABG did not exert greater benefit in patients with DM. © 2015 The Authors European Journal of Heart Failure © 2015 European Society of Cardiology.
    European Journal of Heart Failure 05/2015; 17(7). DOI:10.1002/ejhf.288 · 6.58 Impact Factor
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    ABSTRACT: A significant proportion of patients admitted for acute decompensated heart failure (ADHF) that undergo volume reduction therapy are discharged with unchanged or increased bodyweight suggesting that the endpoints for these therapies are not optimally defined. We aimed to identify vectors that can help monitor changes in intravascular fluid volume, that in turn may more accurately guide volume reduction therapy.
    05/2015; 8. DOI:10.1016/j.ijcha.2015.05.003
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    ABSTRACT: -The cardiac cytoskeleton plays key roles in maintaining myocyte structural integrity in health and disease. In fact, human mutations in cardiac cytoskeletal elements are tightly linked with cardiac pathologies including myopathies, aortopathies, and dystrophies. Conversely, the link between cytoskeletal protein dysfunction in cardiac electrical activity is not well understood, and often overlooked in the cardiac arrhythmia field. -Here, we uncover a new mechanism for the regulation of cardiac membrane excitability. We report that βII spectrin, an actin-associated molecule, is essential for the post-translational targeting and localization of critical membrane proteins in heart. βII spectrin recruits ankyrin-B to the cardiac dyad, and a novel human mutation in the ankyrin-B gene disrupts the ankyrin-B/βII spectrin interaction leading to severe human arrhythmia phenotypes. Mice lacking cardiac βII spectrin display lethal arrhythmias, aberrant electrical and calcium handling phenotypes, and abnormal expression/localization of cardiac membrane proteins. Mechanistically, βII spectrin regulates the localization of cytoskeletal and plasma membrane/sarcoplasmic reticulum protein complexes that include the Na/Ca exchanger, RyR2, ankyrin-B, actin, and αII spectrin. Finally, we observe accelerated heart failure phenotypes in βII spectrin-deficient mice. -Our findings identify βII spectrin as critical for normal myocyte electrical activity, link this molecule to human disease, and provide new insight into the mechanisms underlying cardiac myocyte biology.
    Circulation 01/2015; 131(8). DOI:10.1161/CIRCULATIONAHA.114.013708 · 14.95 Impact Factor
  • Kathleen Dungan · Philip Binkley · Kwame Osei
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    ABSTRACT: GlycA is a nuclear magnetic resonance-derived signal that originates from oligosaccharide chains of acute phase proteins. The objective of this study is to characterize GlycA levels in hospitalized non-critically ill patients with type 2 diabetes. This study evaluated traditional and novel (GlycA) inflammatory markers among 121 patients who were stratified by admission diagnoses: congestive heart failure (CHF), cardiac non-CHF (CARD), infection (INF), and other (OTH). HbA1c was similar across groups (8.0-9.2 %, p = 0.20). Inflammatory markers were elevated but varied significantly across disease categories, with the highest values of interleukin-6 (IL-6), c-reactive protein (CRP), and GlycA in the INF group and the highest tumor necrosis factor-α and intracellular adhesion molecule-1 levels in CHF group. GlycA was associated with higher IL-6 and CRP, lower hemoglobin, and lower glomerular filtration rate. GlycA and other inflammatory markers were not significantly associated with admission glucose or HbA1c. Among hospitalized non-critically ill patients with type 2 diabetes, GlycA was highest in INF patients and was associated with IL-6 and CRP. None of the markers were significant predictors of glucose control.
    Inflammation 01/2015; 38(3). DOI:10.1007/s10753-014-0107-8 · 2.21 Impact Factor
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    ABSTRACT: Background The study aims to determine whether the route of insulin administration influences glycaemic variability and inflammatory or neurohormonal markers in patients with type 2 diabetes and congestive heart failure (CHF) exacerbation. Methods Patients (n=65) were randomized to intravenous (IV) insulin (duration 48h) or subcutaneous (SQ) insulin. Inflammatory cytokines and markers of lipid oxidation, high-frequency heart rate variability (n=27) and cardiac impedance (pre-ejection period, n=28) were used to estimate parasympathetic and sympathetic tone in patients with valid cardiac data. Glycaemic variability was measured using a continuous glucose monitor. ResultsMean glucose was lower (7.71.2 vs 9.4 +/- 2.7mmol/L, p=0.004), coefficient of variation was higher (p=0.03) and glycaemic lability index was similar on day 1 in the IV group compared with the SQ group, but groups were similar by day 2. The IV group had more confirmed hypoglycaemia (p=0.005). There were no differences in hospital readmission or hospital length of stay between groups. There were no differences in CHF biomarkers, heart rate variability or pre-ejection period between groups. Increasing log glycaemic lability index was associated with lower on-treatment pre-ejection period (p=0.03) while increasing coefficient of variation was associated with increasing brain natriuretic peptide (p=0.004) and paroxonase-1 (p=0.02). Other univariable analyses were not significant. Conclusions There were modest, transient differences in glucose control between IV and SQ insulin in hospitalized CHF patients. However, the analyses do not support a link between insulin route and inflammatory markers or autonomic tone. Further study is needed to assess outcomes in hospitalized CHF patients. Copyright (c) 2014 John Wiley & Sons, Ltd.
    Diabetes/Metabolism Research and Reviews 01/2015; 31(1). DOI:10.1002/dmrr.2569 · 3.59 Impact Factor
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    ABSTRACT: The role of IKCa 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 IKCa 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 IKCa 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 IKCa blockade in all of the groups studied. IKCa blockade did not affect ventricular myocyte repolarization in controls. HF caused prolongation of ventricular myocyte action potential repolarization. IKCa 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, IKCa blockade in ventricular myocytes results in cellular arrhythmias. Furthermore, our data suggest an important role for IKCa 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.
    PLoS ONE 10/2014; 9(10):e108824. DOI:10.1371/journal.pone.0108824 · 3.23 Impact Factor
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    ABSTRACT: DEFEAT-PE is a prospective, multi-center study of multiple intrathoracic impedance vectors to detect pulmonary congestion (PC) events. Changes in intrathoracic impedance between the right ventricular (RV) coil and device can (RVcoil→Can) of implantable cardioverter defibrillators (ICDs) and cardiac resynchronization therapy ICDs (CRT-Ds) are used clinically for detection of PC events, but other impedance vectors and algorithms have not been studied prospectively. An initial 75 patient study was used to derive optimal impedance vectors to detect PC events, with 2 vector combinations selected for prospective analysis in DEFEAT-PE: (ICD vectors: RVring→Can + RVcoil→Can, detection threshold 13 days; CRT-D vectors: LVring→Can + RVcoil→Can, detection threshold 14 days). Impedance changes were considered true positive if detected within 30 days prior to an adjudicated PC event. 162 patients were enrolled (80 ICDs and 82 CRT-Ds), all with > 1 prior PC event. 144 patients provided study data, with 214 patient years of follow-up and 139 PC events. Sensitivity for PC events of the pre-specified algorithms was: ICD: sensitivity 32.3%, False Positive Rate (FPR) 1.28/pt-year; CRT-D: sensitivity 32.4%, FPR 1.66/pt-year. An alternative algorithm, ultimately FDA approved (RVring→Can + RVcoil→Can detection threshold 14 days), resulted in (all patients): sensitivity 21.6%, FPR 0.9/pt-year. The CRT-D thoracic impedance vector algorithm selected in the derivation study was not superior to the ICD algorithm RVring→Can + RVcoil→Can when studied prospectively. In conclusion, to achieve an acceptably low false positive rate, the intra-thoracic impedance algorithms studied in DEFEAT-PE resulted in low sensitivity for prediction of heart failure events.
    The American Journal of Cardiology 10/2014; 114(8). DOI:10.1016/j.amjcard.2014.07.048 · 3.43 Impact Factor
  • Sakima A Smith · Ayesha K Hasan · Philip F Binkley · Randi E Foraker
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    ABSTRACT: Background: There has been a steady increase of patients living in the community with Left Ventricular Assist Devices (LVADs). There is a significant gap in our fund of knowledge with respect to the impact that insurance and socioeconomic status has on outcomes for LVAD patients. We thus hypothesize that low neighborhood socioeconomic status and receipt of Medicaid, respectively, lead to earlier readmissions, earlier death, as well as longer time to transplantation among LVAD patients. Methods: This was a retrospective review of 101 patients using existing data in the medical information warehouse database at The Ohio State University Medical Center. Primary outcomes measured included time to first event (first readmission or death), death, and time to rehospitalization. Our secondary outcome of interest included time from LVAD implantation to cardiac transplantation. Results: Recipients of Medicaid did not have an increased risk of adverse events compared with patients without Medicaid coverage. Low Median Household Income (MHI) was associated with an increased risk of readmission (log-rank P = 0.0069) and time to first event (log-rank P = 0.0088). Bridge to transplantation was the only independent predictor of time to death (Hazard Ratio 2.1, [95% confidence interval = 1.03-4.37]). Low MHI and a history of atherosclerosis were both significant predictors for readmission and time to first event. Aldosterone antagonist use decreased the risk of readmission or time to first event by 46%. Conclusions: LVAD recipients with a low MHI were more likely to be readmitted to the hospital after LVAD implantation. Whether these patients are adequately monitored on an outpatient basis remains unclear.
    Journal of Surgical Research 05/2014; 191(2). DOI:10.1016/j.jss.2014.05.004 · 2.12 Impact Factor
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    ABSTRACT: Cardiac function depends on the highly regulated and coordinate activity of a large ensemble of potassium channels that control myocyte repolarization. While voltage-gated K(+) channels have been well-characterized in heart, much less is known about regulation and/or targeting of two-pore K(+) channel (K2P) family members, despite their potential importance in modulation of heart function.Methods and ResultsHere we report a novel molecular pathway for membrane targeting of TREK-1, a mechano-sensitive K2P channel regulated by environmental and physical factors including membrane stretch, pH, and polyunsaturated fatty acids (e.g. arachidonic acid). We demonstrate that βIV-spectrin, an actin-associated protein, is co-localized with TREK-1 at the myocyte intercalated disc, associates with TREK-1 in heart, and is required for TREK-1 membrane targeting. Mice expressing βIV-spectrin lacking TREK-1 binding (qv(4 J)) display aberrant TREK-1 membrane localization, decreased TREK-1 activity, delayed action potential repolarization, and arrhythmia without apparent defects in localization/function of other cardiac potassium channel subunits. Finally, we report abnormal βIV-spectrin levels in human heart failure. These data provide new insight into membrane targeting of TREK-1 in heart and establish a broader role for βIV-spectrin in organizing functional membrane domains critical for normal heart function.
    Cardiovascular Research 01/2014; 102(1). DOI:10.1093/cvr/cvu008 · 5.81 Impact Factor
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    ABSTRACT: We describe the development and implementation of a randomized controlled trial to investigate the impact of genomic counseling on a cohort of patients with heart failure (HF) or hypertension (HTN), managed at a large academic medical center, the Ohio State University Wexner Medical Center (OSUWMC). Our study is built upon the existing Coriell Personalized Medicine Collaborative (CPMC®). OSUWMC patient participants with chronic disease (CD) receive eight actionable complex disease and one pharmacogenomic test report through the CPMC® web portal. Participants are randomized to either the in-person post-test genomic counseling—active arm, versus web-based only return of results—control arm. Study-specific surveys measure: (1) change in risk perception; (2) knowledge retention; (3) perceived personal control; (4) health behavior change; and, for the active arm (5), overall satisfaction with genomic counseling. This ongoing partnership has spurred creation of both infrastructure and procedures necessary for the implementation of genomics and genomic counseling in clinical care and clinical research. This included creation of a comprehensive informed consent document and processes for prospective return of actionable results for multiple complex diseases and pharmacogenomics (PGx) through a web portal, and integration of genomic data files and clinical decision support into an EPIC-based electronic medical record. We present this partnership, the infrastructure, genomic counseling approach, and the challenges that arose in the design and conduct of this ongoing trial to inform subsequent collaborative efforts and best genomic counseling practices.
    01/2014; 4(1):1-19. DOI:10.3390/jpm4010001
  • Philip F Binkley · Heather C Brod
    The American journal of medicine 09/2013; 126(11). DOI:10.1016/j.amjmed.2013.07.016 · 5.30 Impact Factor
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    ABSTRACT: The role of viral infections in the pathogenesis of atherosclerosis remains controversial largely due to inconsistent detection of the virus in atherosclerotic lesions. However, viral infections elicit a pro-inflammatory cascade known to be atherogenic and to precipitate acute ischemic events. We have published in vitro data that provide the foundation for a mechanism that reconciles these conflicting observations. To determine the relation between an early viral protein, deoxyuridine triphosphate nucleotidohydrolase (dUTPase), produced following reactivation of Epstein Barr Virus (EBV) to circulating pro-inflammatory cytokines, intercellular adhesion molecule-1 (ICAM-1) and acute coronary events. Blood samples were obtained from 299 patients undergoing percutaneous coronary intervention for stable angina (SA), unstable angina (UA), or acute myocardial infarction (AMI). Plasma concentrations of pro-inflammatory cytokines and neutralizing antibody against EBV-encoded dUTPase were compared in the three patient groups. AMI was associated with the highest measures of interleukin-6 (ANOVA p<0.05; 4.6±2.6 pg/mL in patients with AMI vs. 3.2±2.3 pg/mL in SA). ICAM-1 was significantly higher in patients with AMI (ANOVA p<0.05; 304±116 pg/mL in AMI vs. 265±86 pg/mL SA). The highest values of ICAM-1 were found in patients having an AMI and who were antibody positive for dUTPase (ANOVA p = 0.008; 369±183 pg/mL in AMI and positive for dUTPase vs. 249±70 pg/mL in SA negative for dUTPase antibody). These clinical data support a model, based on in vitro studies, by which EBV may precipitate AMI even under conditions of low viral load through the pro-inflammatory action of the early protein dUTPase that is produced even during incomplete viral replication. They further support the putative role of viral infections in the pathogenesis of atherosclerosis and coronary artery events.
    PLoS ONE 08/2013; 8(1):e54008. DOI:10.1371/journal.pone.0054008 · 3.23 Impact Factor
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    ABSTRACT: Indicated for treating hyperlipidemias and for the prevention of cardiovascular disease (CVD), statins rank among the most commonly prescribed drug classes. While statins are considered to be highly effective in preventing atherosclerotic events, a substantial portion of treated patients still progress to overt CVD. Genetic factors are thought to contribute substantially to treatment outcome. Several candidate genes have been associated with statin dose requirements and treatment outcomes, but a clinically relevant pharmacogenomics test to guide statin therapy has not yet emerged. Here we define basic pharmacogenomics terminology, present strong candidate genes (CETP, HMGCR, SLCO1B1, ABCB1, and CYP3A4/5), and discuss the challenges in developing much-needed statin pharmacogenomics biomarkers for predicting treatment outcomes.
    Discovery medicine 08/2013; 16(86):45-51. · 3.50 Impact Factor
  • Kathleen Dungan · Kwame Osei · Colleen Sagrilla · Philip Binkley
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    ABSTRACT: AIMS: Glycemic variability (GV) is associated with mortality in acutely ill patients, but the mechanism is unknown. The objective of this study is to determine whether common approaches to insulin therapy have distinct effects on GV and autonomic tone. MATERIALS & METHODS: Hospitalized patients with diabetes were randomized to short-term intravenous (IV) or physiologic subcutaneous (SQ) insulin. Heart rate variability (HRV) and cardiac impedance (pre-ejection period, PEP) were used to estimate parasympathetic and sympathetic tone respectively. GV was measured using a continuous glucose monitor. RESULTS: Mean glucose tended to be lower initially in the SQ group (N=16) compared to the IV group (N=17) on day 1 (10.5 vs. 8.6mmol/l, p=0.05), but became nonsignificant during the transition off of the infusion. There was no difference in glycemic lability index (GLI), continuous overlapping net glycemic action (CONGA) or coefficient of variation (CV) on day 1, but by day 2, these measures were higher in the IV group (p<0.05 for all). PEP was higher in the SQ group during (110 vs. 123 ms, p=0.02) and after the intervention (104 vs. 126 ms, p=0.004). Hypoglycemia was similar in both groups. There were only small differences in HRV. Post-treatment PEP was inversely correlated with log GLI (r= -0.41, p=0.03) but not other measures. CONCLUSIONS: Short-term IV insulin is associated with an increase in multiple GV measures compared to optimal SQ insulin. However, GLI was the only predictor of PEP. Further research is needed to determine if interventions that minimize GV improve outcomes in the hospital.
    Diabetes Obesity and Metabolism 01/2013; 15(6). DOI:10.1111/dom.12069 · 5.46 Impact Factor
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    ABSTRACT: ABSTRACT This phase I study was conducted to determine the maximum tolerated dose (MTD) and dose limiting toxicities (DLT) of the heat shock protein 90 (HSP90) inhibitor 17-allyamino-17-demethoxygeldanamycin (17-AAG) in combination with bortezomib, and to provide pharmacokinetic data in relapsed or refractory acute myeloid leukemia (AML). Eleven patients were enrolled. The MTD was 17-AAG 150mg/m(2) and bortezomib 0.7mg/m(2). Hepatic toxicity and cardiac toxicity were dose limiting. Co-administration on day 4 led to a decrease in clearance (p=0.005) and increase in AUC (p=.032) of 17-amino-17-demethoxygeldanamycin (17-AG) not observed when 17-AAG was administered alone. Pharmacokinetic parameters of patients who developed toxicities and those who did not were not different. The combination of 17-AAG and bortezomib led to toxicity without measurable response in patients with relapsed or refractory AML. Pharmacokinetic data provide insight for studies of related agents in AML; next generation HSP90 inhibitors are appealing for further development in this area.
    Leukemia & lymphoma 12/2012; 54(9). DOI:10.3109/10428194.2012.760733 · 2.89 Impact Factor
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    ABSTRACT: Kinase/phosphatase balance governs cardiac excitability in health and disease. While 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 >seventeen 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 baseline 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 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.
    Journal of Biological Chemistry 11/2012; 288(2). DOI:10.1074/jbc.M112.426957 · 4.57 Impact Factor
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    ABSTRACT: 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.
    Circulation 09/2012; 126(17):2084-94. DOI:10.1161/CIRCULATIONAHA.112.105320 · 14.95 Impact Factor

Publication Stats

4k Citations
1,116.73 Total Impact Points

Institutions

  • 1982–2015
    • The Ohio State University
      • • Division of Cardiovascular Medicine
      • • Division of Cardiology
      • • Division of Hospital Medicine
      • • Department of Internal Medicine
      Columbus, Ohio, United States
  • 2005
    • National Heart, Lung, and Blood Institute
      Maryland, United States
  • 1986–1991
    • Columbus State University
      Columbus, Georgia, United States