Hierarchical Modeling of Activation Mechanisms in the ABL and EGFR Kinase Domains: Thermodynamic and Mechanistic Catalysts of Kinase Activation by Cancer Mutations

Structural and functional studies of the ABL and EGFR kinase domains have recently suggested a common mechanism of activation by cancer-causing mutations. However, dynamics and mechanistic aspects of kinase activation by cancer mutations that stimulate conformational transitions and thermodynamic stabilization of the constitutively active kinase form remain elusive. We present a large-scale computational investigation of activation mechanisms in the ABL and EGFR kinase domains by a panel of clinically important cancer mutants ABL-T315I, ABL-L387M, EGFR-T790M, and EGFR-L858R. We have also simulated the activating effect of the gatekeeper mutation on conformational dynamics and allosteric interactions in functional states of the ABL-SH2-SH3 regulatory complexes. A comprehensive analysis was conducted using a hierarchy of computational approaches that included homology modeling, molecular dynamics simulations, protein stability analysis, targeted molecular dynamics, and molecular docking. Collectively, the results of this study have revealed thermodynamic and mechanistic catalysts of kinase activation by major cancer-causing mutations in the ABL and EGFR kinase domains. By using multiple crystallographic states of ABL and EGFR, computer simulations have allowed one to map dynamics of conformational fluctuations and transitions in the normal (wild-type) and oncogenic kinase forms. A proposed multi-stage mechanistic model of activation involves a series of cooperative transitions between different conformational states, including assembly of the hydrophobic spine, the formation of the Src-like intermediate structure, and a cooperative breakage and formation of characteristic salt bridges, which signify transition to the active kinase form. We suggest that molecular mechanisms of activation by cancer mutations could mimic the activation process of the normal kinase, yet exploiting conserved structural catalysts to accelerate a conformational transition and the enhanced stabilization of the active kinase form. The results of this study reconcile current experimental data with insights from theoretical approaches, pointing to general mechanistic aspects of activating transitions in protein kinases

Comparison of Rate Control versus Rhythm Control for Management of Atrial Fibrillation in Patients with Coexisting Heart Failure: A Cost-Effectiveness Analysis

STUDY OBJECTIVE: To compare lifetime costs and health outcomes of rate control versus rhythm control for management of atrial fibrillation in patients with coexisting heart failure from the third-party payer perspective. DESIGN: A Markov decision analysis model constructed from costs, utility, and transition probability inputs obtained from randomized clinical trials and publically available databases. PATIENTS: A simulated cohort aged 65 years or older with persistent or paroxysmal atrial fibrillation and heart failure. MEASUREMENTS AND MAIN RESULTS: Markov states for rhythm control were cardioversion plus amiodarone and maintenance amiodarone, and those for rate control were β-blocker, digoxin, and calcium channel blocker. Transition states included treatment success, hospitalizations for atrial fibrillation and/or heart failure, and severe adverse effects. Economic inputs included cost for drugs, cost of hospitalizations for atrial fibrillation and/or heart failure, and cost of management of severe adverse effects. Costs were measured in 2009 U.S. dollars, and clinical outcomes in quality-adjusted life-years (QALYs). One-way and multivariable sensitivity analyses were conducted. Uncertainty intervals (UIs) were obtained from probabilistic sensitivity analyses. Rate control was found to be less costly and more effective than rhythm control. Base case and probabilistic sensitivity analyses cost and effectiveness values for rate control were $7231 (95$5517-9016) and 2.395 QALYs (95% UI 2.366-2.424 QALYs); whereas those for rhythm control were $16,291 (95$11,033-21,434) and 2.197 QALYs (95% UI 2.155-2.237 QALYs). No critical values were found for any model parameters in the one-way sensitivity analyses. The cost-effectiveness acceptability curves showed that rate control was considered cost-effective in 100% of cases at willingness-to-pay ratios between $0 and$200,000/QALY. CONCLUSION: Rate control is less costly and more effective than rhythm control and should be the initial treatment for atrial fibrillation among patients with coexisting heart failure

Left Ventricular global longitudinal strain predicts heart failure readmission in acute decompensated heart failure

Background: The goal of this study was to determine if left ventricular (LV) global longitudinal strain (GLS) predicts heart failure (HF) readmission in patients with acute decompensated heart failure. Methods and results: Two hundred ninety one patients were enrolled at the time of admission for acute decompensated heart failure between January 2011 and September 2013. Left ventricle global longitudinal strain (LV GLS) by velocity vector imaging averaged from 2, 3 and 4-chamber views could be assessed in 204 out of 291 (70%) patients. Mean age was 63.8 ± 15.2 years, 42% of the patients were males and 78% were African American or Hispanic. Patients were followed until the first HF hospital readmission up to 44 months. Patients were grouped into quartiles on the basis of LV GLS. Kaplan-Meier curves showed significantly higher readmission rates in patients with worse LV GLS (log-rank p < 0.001). After adjusting for age, sex, history of ischemic heart disease, dementia, New York Heart Association class, LV ejection fraction, use of angiotensin converting enzyme inhibitors or angiotensin receptor blockers, systolic and diastolic blood pressure on admission and sodium level on admission, worse LV GLS was the strongest predictor of recurrent HF readmission (p < 0.001). The ejection fraction was predictive of readmission in univariate, but not in multivariate analysis. Conclusion: LV GLS is an independent predictor of HF readmission after acute decompensated heart failure with a higher risk of readmission in case of progressive worsening of LV GLS, independent of the ejection fraction

Endothelial nitric oxide synthase genotype is associated with pulmonary hypertension severity in left heart failure patients

The biological mechanisms behind the development of pulmonary hypertension in the setting of left heart failure (HF-PH), including combined pre- and post-capillary pulmonary hypertension (Cpc-PH), remains unclear. This study aimed to use candidate polymorphisms in nitric oxide synthase (NOS) genes to explore the role of NOS in HF-PH. DNA samples from 118 patients with HF-PH were genotyped for the NOS3 rs1799983 and NOS2 rs3730017 polymorphisms. A multiple regression model was used to compare hemodynamic measurements between genotype groups. Patients with the T/T genotype at rs1799983 possessed a nearly 10 mmHg increased transpulmonary gradient (TPG) compared to those with other genotypes (P = 0.006). This finding was replicated in an independent cohort of 94 HF-PH patients (P = 0.005). However, when tested in a cohort of 162 pre-capillary pulmonary arterial hypertension patients, no association was observed. In a combined analysis of both HF-PH cohorts, mean pulmonary artery pressure (mPAP), diastolic pulmonary gradient (DPG), and CpcPH status were also associated with rs1799983 genotype (P = 0.005, P = 0.03, and P= 0.02, respectively). In patients with HF-PH, the NOS3 rs1799983 polymorphism is associated with TPG, and potentially mPAP and DPG as well. These findings suggest that endothelial NOS (encoded by NOS3) may be involved in the pulmonary vascular remodeling observed in Cpc-PH and warrants further study.NIH/NIGMS [K23 GM112014]; NIH/NHLBI [R01 HL141281, R01 HL111656, R01 HL127342, R01 HL133951]12 month embargo; published online: 2 May 2018This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Enhancing Participation in Cardiac Rehabilitation: A Question of Proximity and Integration of Outpatient Services

Numerous investigations have established the strong clinical utility of cardiac rehabilitation, while clinical guidelines continually call for a high level of referral and participation. Historically, medical facilities have faced challenges referring eligible patients to cardiac rehabilitation, enrolling only a small portion of those receiving referral. Consequently, less than ~10% of qualifying patients receive any amount of cardiac rehabilitation. This sobering figure has prompted many efforts to identify barriers to referral as well as enrollment and accordingly propose strategies to bolster participation rates. Although reports have highlighted improvements through focused approaches, enrollment rates still lag behind the goal of reaching 70% by 2022, proposed by the Million Hearts Cardiac Rehabilitation Collaborative. An area of inquiry that has received little to no attention in this effort has been the influence of proximity between physician-driven outpatient clinics and cardiac rehabilitation facilities. In this primer we outline the development and design of a clinical faculty practice aimed to maintain close geographical proximity between our physician clinic and the cardiac rehabilitation area. We also propose that our impressive enrollment rates of 57% within our facility and 73% when including patients that started alternative exercise programs were likely due to establishing a close proximity between the respective practices

Association of Aldosterone Synthase Polymorphism (<i>CYP11B2</i> -344T>C) and Genetic Ancestry with Atrial Fibrillation and Serum Aldosterone in African Americans with Heart Failure

<div><p>The objective of this study was to examine the extent to which aldosterone synthase genotype (<i>CYP11B2</i>) and genetic ancestry correlate with atrial fibrillation (AF) and serum aldosterone in African Americans with heart failure. Clinical data, echocardiographic measurements, and a genetic sample for determination of <i>CYP11B2</i> -344T>C (rs1799998) genotype and genetic ancestry were collected from 194 self-reported African Americans with chronic, ambulatory heart failure. Genetic ancestry was determined using 105 autosomal ancestry informative markers. In a sub-set of patients (n = 126), serum was also collected for determination of circulating aldosterone. The <i>CYP11B2</i> −344C allele frequency was 18% among the study population, and 19% of patients had AF. Multiple logistic regression revealed that the <i>CYP11B2</i> −344CC genotype was a significant independent predictor of AF (OR 12.7, 95% CI 1.60–98.4, p = 0.0150, empirical p = 0.011) while holding multiple clinical factors, left atrial size, and percent European ancestry constant. Serum aldosterone was significantly higher among patients with AF (p = 0.036), whereas increased West African ancestry was inversely correlated with serum aldosterone (r = −0.19, p = 0.037). The <i>CYP11B2</i> −344CC genotype was also overrepresented among patients with extreme aldosterone elevation (≥90th percentile, p = 0.0145). In this cohort of African Americans with chronic ambulatory heart failure, the <i>CYP11B2</i> −344T>C genotype was a significant independent predictor of AF while holding clinical, echocardiographic predictors, and genetic ancestry constant. In addition, increased West African ancestry was associated with decreased serum aldosterone levels, potentially providing an explanation for the lower risk for AF observed among African Americans.</p></div

Predictors of atrial fibrillation in multiple logistic regression analysis.

<p>LA, left atrial; CrCl, creatinine clearance.</p><p>Adjusted for age, sex, body size (BMI), mitral regurgitation, systemic hypertension, coronary artery disease, diabetes mellitus, left atrial size, creatinine clearance, and percent European ancestry.</p>*<p>Empirical p value generated by permuting the CC genotype term in the logistic model (10,000 reps). The p values represents the proportion of permutations that led to a coefficient on the CC term at least as large as the one observed in the actual sample.</p