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  • 1
    Online Resource
    Online Resource
    Theory of Optimal Experiments. (1972)
    Saint Louis :Elsevier Science & Technology,
    Details
    Keywords: Experimental design. ; Regression analysis. ; Mathematical optimization. ; Electronic books.
    Description / Table of Contents: Theory Of Optimal Experiments.
    Type of Medium: Online Resource
    Pages: 1 online resource (307 pages)
    Edition: 1st ed.
    ISBN: 9780323162463
    URL: https://ebookcentral.proquest.com/lib/geomar/detail.action?docID=1178434
    DDC: 501
    Language: English
    Note: Front Cover -- Theory of Optimal Experiments -- Copyright Page -- Table of Contents -- Foreword -- Preface -- Introduction -- Chapter 1. Regression Analysis and Optimality Criteria for Regression Experiments -- 1.1 Basic Elements of Matrix Algebra -- 1.2 General Requirements Satisfied by Estimates -- 1.3 Best Linear Estimates -- 1.4 The Search for Estimates for Nonlinear Parametrization. Best Quasi-Linear Estimates -- 1.5 Estimation of the Dispersion of the Resulting Observations. The Efficiency of an Experiment -- 1.6 Regression Analysis in the Presence of Errors in the Determination of the Control Variables -- 1.7 Analysis of Experimental Data in the Case of Simultaneous Observations of Several Variables -- 1.8 Methods of Comparing Results of Experiments -- 1.9 The Loss Function for Regression Experiments -- 1.10 The Concept of Experimental Design. Continuous Normalized Designs -- Chapter 2. Continuous Optimal Designs (Statistical Methods) -- 2.1 Basic Properties of the Information Matrix -- 2.2 Equivalence of D-Optimal and Minimax Designs. Basic Properties of These Designs -- 2.3 One-Dimensional Polynomial Regression -- 2.4 Trigonometric Regression on an Interval -- 2.5 Computational Methods for Construction of D-Optimal Designs -- 2.6 Some Particular Iterative Procedures for Constructing D-Optimal Designs -- 2.7 Truncated D-Optimal Designs -- 2.8 Nonlinear Parametrization of a Response Surface. Local D-Optimal Designs -- 2.9 Linear Criteria of Optimality -- 2.10 Iterative Methods for Constructing Linear-Optimal Designs -- 2.11 Designs Minimizing Tr D(ε) -- 2.12 Designs Minimizing the Mean Dispersion of the Estimate of the Response Surface over the Domain of Values -- 2.13 Extrapolation at a Point -- 2.14 Quadratic Loss -- Chapter 3. Properties and Methods of Construction for Optimal Discrete Designs -- 3.1 Discrete Designs. , 3.2 Properties and Methods of Constructing D-Optimal Designs -- 3.3 Construction of Discrete Linear Optimal Designs -- Chapter 4. Sequential Methods of Designing Experiments for Refining and Determining Estimates of the Parameters -- 4.1 Some Generalities of Contemporary Experimental Investigations -- 4.2 Sequential D-Optimal Design (Linear Parametrization and Time Constant Efficiency of the Experiment) -- 4.3 Sequential Linear-Optimal Designs (Linear Parametrization and Time Constant Efficiency of the Experiment) -- 4.4 Sequential Designs for Nonlinear Parametrization -- 4.5 Designs When the Efficiency Function of the Experiment Is Unknown -- 4.6 Design in the Presence of Errors in the Determination of the Control Variables -- 4.7 Construction of Optimal Designs When the Experimental Conditions Vary in Time -- Chapter 5. Design of Experiments in the Case of Simultaneous Observation of Several Random Quantities -- 5.1 Basic Properties of the Information Matrix -- 5.2 D-Optimal Designs -- 5.3 Linear-Optimal Designs -- 5.4 Sequential Design -- Chapter 6. Discriminating Experiments -- 6.1 Statement of the Problem -- 6.2 Criteria Depending on the Difference of Sums of Weighted Squares of Residuals -- 6.3 The Method of Likelihood Ratio -- 6.4 Discriminating Hypotheses Based on the Entropy Measure of Information -- Chapter 7. Generalized Criteria of Optimality -- 7.1 Experiments Minimizing Generalized Loss -- 7.2 The Information Approach to the General Problem of Seeking the True Mathematical Model -- References -- Subject Index.
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  • 2
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    Synchronization of Ca2+ waves in CPVT [Physiology] (2013)
    National Academy of Sciences
    Details
    Publication Date: 2013-06-19
    Description: Dysregulated intracellular Ca2+ signaling is implicated in a variety of cardiac arrhythmias, including catecholaminergic polymorphic ventricular tachycardia. Spontaneous diastolic Ca2+ release (DCR) can induce arrhythmogenic plasma membrane depolarizations, although the mechanism responsible for DCR synchronization among adjacent myocytes required for ectopic activity remains unclear. We investigated the synchronization mechanism(s) of...
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
    Published by National Academy of Sciences
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  • 3
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    Right ventricular arrhythmogenesis in failing human heart: the role of conduction and repolarization remodeling (2012)
    The American Physiological Society (APS)
    Details
    Publication Date: 2012-12-16
    Description: Increased dispersion of repolarization has been suggested to underlie increased arrhythmogenesis in human heart failure (HF). However, no detailed repolarization mapping data were available to support the presence of increased dispersion of repolarization in failing human heart. In the present study, we aimed to determine the existence of enhanced repolarization dispersion in the right ventricular (RV) endocardium from failing human heart and examine its association with arrhythmia inducibility. RV free wall preparations were dissected from five failing and five nonfailing human hearts, cannulated and coronary perfused. RV endocardium was optically mapped from an ~6.3 x 6.3 cm 2 field of view. Action potential duration (APD), dispersion of APD, and conduction velocity (CV) were quantified for basic cycle lengths (BCL) ranging from 2,000 ms to the functional refractory period. We found that RV APD was significantly prolonged within the failing group compared with the nonfailing group (560 ± 44 vs. 448 ± 39 ms, at BCL = 2,000 ms, P 〈 0.05). Dispersion of APD was increased in three failing hearts (161 ± 5 vs. 86 ± 19 ms, at BCL = 2,000 ms). APD alternans were induced by rapid pacing in these same three failing hearts. CV was significantly reduced in the failing group compared with the nonfailing group (81 ± 11 vs. 98 ± 8 cm/s, at BCL = 2,000 ms). Arrhythmias could be induced in two failing hearts exhibiting an abnormally steep CV restitution and increased dispersion of repolarization due to APD alternans. Dispersion of repolarization is enhanced across the RV endocardium in the failing human heart. This dispersion, together with APD alternans and abnormal CV restitution, could be responsible for the arrhythmia susceptibility in human HF.
    Print ISSN: 0363-6135
    Electronic ISSN: 1522-1539
    Topics: Medicine
    Published by The American Physiological Society (APS)
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  • 4
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    Nav1.5 H1849R and arrhythmia [Physiology] (2015)
    National Academy of Sciences
    Details
    Publication Date: 2015-10-07
    Description: Nav channels are essential for metazoan membrane depolarization, and Nav channel dysfunction is directly linked with epilepsy, ataxia, pain, arrhythmia, myotonia, and irritable bowel syndrome. Human Nav channelopathies are primarily caused by variants that directly affect Nav channel permeability or gating. However, a new class of human Nav channelopathies has...
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
    Published by National Academy of Sciences
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  • 5
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    The Frank-Starling mechanism involves deceleration of cross-bridge kinetics and is preserved in failing human right ventricular myocardium (2015)
    The American Physiological Society (APS)
    Details
    Publication Date: 2015-12-17
    Description: Cross-bridge cycling rate is an important determinant of cardiac output, and its alteration can potentially contribute to reduced output in heart failure patients. Additionally, animal studies suggest that this rate can be regulated by muscle length. The purpose of this study was to investigate cross-bridge cycling rate and its regulation by muscle length under near-physiological conditions in intact right ventricular muscles of nonfailing and failing human hearts. We acquired freshly explanted nonfailing ( n = 9) and failing ( n = 10) human hearts. All experiments were performed on intact right ventricular cardiac trabeculae ( n = 40) at physiological temperature and near the normal heart rate range. The failing myocardium showed the typical heart failure phenotype: a negative force-frequency relationship and β-adrenergic desensitization ( P 〈 0.05), indicating the expected pathological myocardium in the right ventricles. We found that there exists a length-dependent regulation of cross-bridge cycling kinetics in human myocardium. Decreasing muscle length accelerated the rate of cross-bridge reattachment ( k tr ) in both nonfailing and failing myocardium ( P 〈 0.05) equally; there were no major differences between nonfailing and failing myocardium at each respective length ( P 〉 0.05), indicating that this regulatory mechanism is preserved in heart failure. Length-dependent assessment of twitch kinetics mirrored these findings; normalized dF/d t slowed down with increasing length of the muscle and was virtually identical in diseased tissue. This study shows for the first time that muscle length regulates cross-bridge kinetics in human myocardium under near-physiological conditions and that those kinetics are preserved in the right ventricular tissues of heart failure patients.
    Print ISSN: 0363-6135
    Electronic ISSN: 1522-1539
    Topics: Medicine
    Published by The American Physiological Society (APS)
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  • 6
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    Common Coding Variants in SCN10A Are Associated With the Nav1.8 Late Current and Cardiac Conduction [Original Articles] (2018)
    American Heart Association (AHA)
    Details
    Publication Date: 2018-05-16
    Description: Background: Genetic variants at the SCN5A / SCN10A locus are strongly associated with electrocardiographic PR and QRS intervals. While SCN5A is the canonical cardiac sodium channel gene, the role of SCN10A in cardiac conduction is less well characterized. Methods: We sequenced the SCN10A locus in 3699 European-ancestry individuals to identify variants associated with cardiac conduction, and replicated our findings in 21,000 individuals of European ancestry. We examined association with expression in human atrial tissue. We explored the biophysical effect of variation on channel function using cellular electrophysiology. Results: We identified 2 intronic single nucleotide polymorphisms in high linkage disequilibrium ( r 2 =0.86) with each other to be the strongest signals for PR (rs10428132, β=–4.74, P =1.52 x 10 –14 ) and QRS intervals (rs6599251, QRS β=–0.73; P =1.2 x 10 –4 ), respectively. Although these variants were not associated with SCN5A or SCN10A expression in human atrial tissue (n=490), they were in high linkage disequilibrium ( r 2 ≥0.72) with a common SCN10A missense variant, rs6795970 (V1073A). In total, we identified 7 missense variants, 4 of which (I962V, P1045T, V1073A, and L1092P) were associated with cardiac conduction. These 4 missense variants cluster in the cytoplasmic linker of the second and third domains of the SCN10A protein and together form 6 common haplotypes. Using cellular electrophysiology, we found that haplotypes associated with shorter PR intervals had a significantly larger percentage of late current compared with wild-type (I962V+V1073A+L1092P, 20.2±3.3%, P =0.03, and I962V+V1073A, 22.4±0.8%, P =0.0004 versus wild-type 11.7±1.6%), and the haplotype associated with the longest PR interval had a significantly smaller late current percentage (P1045T, 6.4±1.2%, P =0.03). Conclusions: Our findings suggest an association between genetic variation in SCN10A , the late sodium current, and alterations in cardiac conduction.
    Keywords: Electrophysiology, Atrial Fibrillation, Ion Channels/Membrane Transport, Functional Genomics
    Print ISSN: 1942-325X
    Electronic ISSN: 1942-3268
    Topics: Medicine
    Published by American Heart Association (AHA)
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  • 7
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    Two-Pore K+ Channel TREK-1 Regulates Sinoatrial Node Membrane Excitability [Arrhythmia and Electrophysiology] (2016)
    American Heart Association (AHA)
    Details
    Publication Date: 2016-04-27
    Description: Background Two-pore K + channels have emerged as potential targets to selectively regulate cardiac cell membrane excitability; however, lack of specific inhibitors and relevant animal models has impeded the effort to understand the role of 2-pore K + channels in the heart and their potential as a therapeutic target. The objective of this study was to determine the role of mechanosensitive 2-pore K + channel family member TREK-1 in control of cardiac excitability. Methods and Results Cardiac-specific TREK-1–deficient mice (αMHC- Kcnk f/f ) were generated and found to have a prevalent sinoatrial phenotype characterized by bradycardia with frequent episodes of sinus pause following stress. Action potential measurements from isolated αMHC- Kcnk2 f/f sinoatrial node cells demonstrated decreased background K + current and abnormal sinoatrial cell membrane excitability. To identify novel pathways for regulating TREK-1 activity and sinoatrial node excitability, mice expressing a truncated allele of the TREK-1–associated cytoskeletal protein β IV -spectrin ( qv 4J mice) were analyzed and found to display defects in cell electrophysiology as well as loss of normal TREK-1 membrane localization. Finally, the β IV -spectrin/TREK-1 complex was found to be downregulated in the right atrium from a canine model of sinoatrial node dysfunction and in human cardiac disease. Conclusions These findings identify a TREK-1–dependent pathway essential for normal sinoatrial node cell excitability that serves as a potential target for selectively regulating sinoatrial node cell function.
    Keywords: Arrhythmias, Pacemaker
    Electronic ISSN: 2047-9980
    Topics: Medicine
    Published by American Heart Association (AHA)
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  • 8
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    Atrial fibrillation driven by micro-anatomic intramural re-entry revealed by simultaneous sub-epicardial and sub-endocardial optical mapping in explanted human hearts (2015)
    Oxford University Press
    Details
    Publication Date: 2015-09-15
    Description: Aims The complex architecture of the human atria may create physical substrates for sustained re-entry to drive atrial fibrillation (AF). The existence of sustained, anatomically defined AF drivers in humans has been challenged partly due to the lack of simultaneous endocardial–epicardial (Endo–Epi) mapping coupled with high-resolution 3D structural imaging. Methods and results Coronary-perfused human right atria from explanted diseased hearts ( n = 8, 43–72 years old) were optically mapped simultaneously by three high-resolution CMOS cameras (two aligned Endo–Epi views (330 µm 2 resolution) and one panoramic view). 3D gadolinium-enhanced magnetic resonance imaging (GE-MRI, 80 µm 3 resolution) revealed the atrial wall structure varied in thickness (1.0 ± 0.7–6.8 ± 2.4 mm), transmural fiber angle differences, and interstitial fibrosis causing transmural activation delay from 23 ± 11 to 43 ± 22 ms at increased pacing rates. Sustained AF (〉90 min) was induced by burst pacing during pinacidil (30–100 µM) perfusion. Dual-sided sub-Endo–sub-Epi optical mapping revealed that AF was driven by spatially and temporally stable intramural re-entry with 107 ± 50 ms cycle length and transmural activation delay of 67 ± 31 ms. Intramural re-entrant drivers were captured primarily by sub-Endo mapping, while sub-Epi mapping visualized re-entry or ‘breakthrough’ patterns. Re-entrant drivers were anchored on 3D micro-anatomic tracks (15.4 ± 2.2 x 6.0 ± 2.3 mm 2 , 2.9 ± 0.9 mm depth) formed by atrial musculature characterized by increased transmural fiber angle differences and interstitial fibrosis. Targeted radiofrequency ablation of the tracks verified these re-entries as drivers of AF. Conclusions Integrated 3D structural–functional mapping of diseased human right atria ex vivo revealed that the complex atrial microstructure caused significant differences between Endo vs. Epi activation during pacing and sustained AF driven by intramural re-entry anchored to fibrosis-insulated atrial bundles.
    Print ISSN: 0195-668X
    Electronic ISSN: 1522-9645
    Topics: Medicine
    Published by Oxford University Press
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  • 9
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    Conduction barriers and pathways of the sinoatrial pacemaker complex: their role in normal rhythm and atrial arrhythmias (2012)
    The American Physiological Society (APS)
    Details
    Publication Date: 2012-05-03
    Description: Since Keith and Flack's anatomical discovery of the sinoatrial node (SAN), the primary pacemaker of the heart, the question of how such a small SAN structure can pace the entire heart has remained for a large part unanswered. Recent advances in optical mapping technology have made it possible to unambiguously resolve the origin of excitation and conduction within the animal and human SAN. The combination of high-resolution optical mapping and histological structural analysis reveals that the canine and human SANs are functionally insulated from the surrounding atrial myocardium, except for several critical conduction pathways. Indeed, the SAN as a leading pacemaker requires anatomical (fibrosis, fat, and blood vessels) and/or functional barriers (paucity of connexins) to protect it from the hyperpolarizing influence of the surrounding atrium. The presence of conduction barriers and pathways may help explain how a small cluster of pacemaker cells in the SAN pacemaker complex manages to depolarize different, widely distributed areas of the right atria as evidenced functionally by exit points and breakthroughs. The autonomic nervous system and humoral factors can further regulate conduction through these pathways, affecting pacemaker automaticity and ultimately heart rate. Moreover, the conduction barriers and multiple pathways can form substrates for reentrant activity and thus lead to atrial flutter and fibrillation. This review aims to provide new insight into the function of the SAN pacemaker complex and the interaction between the atrial pacemakers and the surrounding atrial myocardium not only in animal models but also human hearts.
    Print ISSN: 0363-6135
    Electronic ISSN: 1522-1539
    Topics: Medicine
    Published by The American Physiological Society (APS)
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  • 10
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    Ryanodine receptor phosphorylation by oxidized CaMKII contributes to the cardiotoxic effects of cardiac glycosides (2013)
    Oxford University Press
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    Publication Date: 2013-12-20
    Description: Aims Recent studies suggest that proarrhythmic effects of cardiac glycosides (CGs) on cardiomyocyte Ca 2+ handling involve generation of reactive oxygen species (ROS). However, the specific pathway(s) of ROS production and the subsequent downstream molecular events that mediate CG-dependent arrhythmogenesis remain to be defined. Methods and results We examined the effects of digitoxin (DGT) on Ca 2+ handling and ROS production in cardiomyocytes using a combination of pharmacological approaches and genetic mouse models. Myocytes isolated from mice deficient in NADPH oxidase type 2 (NOX2KO) and mice transgenically overexpressing mitochondrial superoxide dismutase displayed markedly increased tolerance to the proarrhythmic action of DGT as manifested by the inhibition of DGT-dependent ROS and spontaneous Ca 2+ waves (SCW). Additionally, DGT-induced mitochondrial membrane potential depolarization was abolished in NOX2KO cells. DGT-dependent ROS was suppressed by the inhibition of PI3K, PKC, and the mitochondrial K ATP channel, suggesting roles for these proteins, respectively, in activation of NOX2 and in mitochondrial ROS generation. Western blot analysis revealed increased levels of oxidized CaMKII in WT but not in NOX2KO hearts treated with DGT. The DGT-induced increase in SCW frequency was abolished in myocytes isolated from mice in which the Ser 2814 CaMKII phosphorylation site on RyR2 is constitutively inactivated. Conclusion These results suggest that the arrhythmogenic adverse effects of CGs on Ca 2+ handling involve PI3K- and PKC-mediated stimulation of NOX2 and subsequent NOX2-dependent ROS release from the mitochondria; mitochondria-derived ROS then activate CaMKII with consequent phosphorylation of RyR2 at Ser 2814.
    Print ISSN: 0008-6363
    Electronic ISSN: 1755-3245
    Topics: Medicine
    Published by Oxford University Press
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