Publications by authors named "Leonid Shmuylovich"

27 Publications

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Research Techniques Made Simple: Scientific Communication using Twitter.

J Invest Dermatol 2021 Jul;141(7):1615-1621.e1

Department of Molecular, Cellular, and Developmental Biology, Yale University, New Haven, Connecticut, USA; Department of Dermatology, Yale School of Medicine, New Haven, Connecticut, USA.

The scientific process depends on social interactions: communication and dissemination of research findings, evaluation and discussion of scientific work, and collaboration with other scientists. Social media, and specifically, Twitter has accelerated the ability to accomplish these goals. We discuss the ways that Twitter is used by scientists and provide guidance on navigating the academic Twitter community.
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http://dx.doi.org/10.1016/j.jid.2021.03.026DOI Listing
July 2021

Signet-ring cutaneous metastasis presenting with massive anasarca.

JAAD Case Rep 2021 Apr 17;10:123-125. Epub 2021 Feb 17.

Division of Dermatology, Washington University School of Medicine, St. Louis, Missouri.

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http://dx.doi.org/10.1016/j.jdcr.2021.02.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8042238PMC
April 2021

Body site distribution of pediatric-onset morphea and association with extracutaneous manifestations.

J Am Acad Dermatol 2021 Jul 6;85(1):38-45. Epub 2021 Mar 6.

Departments of Dermatology and Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, Illinois.

Background: The distribution of pediatric-onset morphea and site-based likelihood for extracutaneous complications has not been well characterized.

Objective: To characterize the lesional distribution of pediatric-onset morphea and to determine the sites with the highest association of extracutaneous manifestations.

Methods: A retrospective cross-sectional study was performed. Using clinical photographs, morphea lesions were mapped onto body diagrams using customized software.

Results: A total of 823 patients with 2522 lesions were included. Lesions were more frequent on the superior (vs inferior) anterior aspect of the head and extensor (vs flexor) extremities. Linear morphea lesions were more likely on the head and neck, whereas plaque and generalized morphea lesions were more likely on the trunk. Musculoskeletal complications were more likely with lesions on the extensor (vs flexor) extremity (odds ratio [OR], 2.0; 95% confidence interval [CI], 1.2-3.4), whereas neurologic manifestations were more likely with lesions on the anterior (vs posterior) (OR, 2.8; 95% CI, 1.7-4.6) and superior (vs inferior) aspect of the head (OR, 2.3; 95% CI, 1.6-3.4).

Limitations: Retrospective nature and the inclusion of only patients with clinical photographs.

Conclusion: The distribution of pediatric-onset morphea is not random and varies with body site and within individual body sites. The risk stratification of extracutaneous manifestations by body site may inform decisions about screening for extracutaneous manifestations, although prospective studies are needed.
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http://dx.doi.org/10.1016/j.jaad.2021.03.017DOI Listing
July 2021

Social Media: A New Tool for Scientific Engagement.

J Invest Dermatol 2020 10;140(10):1884-1885

Department of Dermatology, Stanford University School of Medicine, Redwood City, California, USA. Electronic address:

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http://dx.doi.org/10.1016/j.jid.2020.08.005DOI Listing
October 2020

Focal dynamic thermal imaging for label-free high-resolution characterization of materials and tissue heterogeneity.

Sci Rep 2020 07 28;10(1):12549. Epub 2020 Jul 28.

Department of Radiology, Washington University School of Medicine, 4515 McKinley Ave., Couch Biomedical Research Building, St. Louis, MO, 63110, USA.

Evolution from static to dynamic label-free thermal imaging has improved bulk tissue characterization, but fails to capture subtle thermal properties in heterogeneous systems. Here, we report a label-free, high speed, and high-resolution platform technology, focal dynamic thermal imaging (FDTI), for delineating material patterns and tissue heterogeneity. Stimulation of focal regions of thermally responsive systems with a narrow beam, low power, and low cost 405 nm laser perturbs the thermal equilibrium. Capturing the dynamic response of 3D printed phantoms, ex vivo biological tissue, and in vivo mouse and rat models of cancer with a thermal camera reveals material heterogeneity and delineates diseased from healthy tissue. The intuitive and non-contact FDTI method allows for rapid interrogation of suspicious lesions and longitudinal changes in tissue heterogeneity with high-resolution and large field of view. Portable FDTI holds promise as a clinical tool for capturing subtle differences in heterogeneity between malignant, benign, and inflamed tissue.
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http://dx.doi.org/10.1038/s41598-020-69362-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7387563PMC
July 2020

Hyperspectral imaging and characterization of allergic contact dermatitis in the short-wave infrared.

J Biophotonics 2020 09 18;13(9):e202000040. Epub 2020 Jun 18.

Department of Radiology, Washington University School of Medicine, St. Louis, Missouri, USA.

Short-wave infrared hyperspectral imaging is applied to diagnose and monitor a case of allergic contact dermatitis (ACD) due to poison ivy exposure in one subject. This approach directly demonstrates increased tissue fluid content in ACD lesional skin with a spectral signature that matches the spectral signature of intradermally injected normal saline. The best contrast between the affected and unaffected skin is achieved through a selection of specific wavelengths at 1070, 1340 and 1605 nm and combining them in a pseudo-red-green-blue color space. An image derived from these wavelengths normalized to unaffected skin defines a "tissue fluid index" that may aid in the quantitative diagnosis and monitoring of ACD. Further clinical testing of this promising approach towards disease detection and monitoring with tissue fluid content quantification is warranted.
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http://dx.doi.org/10.1002/jbio.202000040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7549435PMC
September 2020

Label-free high-throughput photoacoustic tomography of suspected circulating melanoma tumor cells in patients in vivo.

J Biomed Opt 2020 03;25(3):1-17

California Institute of Technology, Caltech Optical Imaging Laboratory, Andrew and Peggy Cherng Depa, United States.

Significance: Detection and characterization of circulating tumor cells (CTCs), a key determinant of metastasis, are critical for determining risk of disease progression, understanding metastatic pathways, and facilitating early clinical intervention.

Aim: We aim to demonstrate label-free imaging of suspected melanoma CTCs.

Approach: We use a linear-array-based photoacoustic tomography system (LA-PAT) to detect melanoma CTCs, quantify their contrast-to-noise ratios (CNRs), and measure their flow velocities in most of the superficial veins in humans.

Results: With LA-PAT, we successfully imaged suspected melanoma CTCs in patients in vivo, with a CNR >9. CTCs were detected in 3 of 16 patients with stage III or IV melanoma. Among the three CTC-positive patients, two had disease progression; among the 13 CTC-negative patients, 4 showed disease progression.

Conclusions: We suggest that LA-PAT can detect suspected melanoma CTCs in patients in vivo and has potential clinical applications for disease monitoring in melanoma.
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http://dx.doi.org/10.1117/1.JBO.25.3.036002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7069252PMC
March 2020

Quantifying Diastolic Function: From E-Waves as Triangles to Physiologic Contours via the 'Geometric Method'.

Cardiovasc Eng Technol 2018 03 16;9(1):105-119. Epub 2018 Jan 16.

Cardiovascular Biophysics Laboratory, Cardiovascular Division, Washington University School of Medicine, 660 South Euclid Ave, Box 8086, St. Louis, MO, 63110, USA.

Conventional echocardiographic diastolic function (DF) assessment approximates transmitral flow velocity contours (Doppler E-waves) as triangles, with peak (E), acceleration time (AT), and deceleration time (DT) as indexes. These metrics have limited value because they are unable to characterize the underlying physiology. The parametrized diastolic filling (PDF) formalism provides a physiologic, kinematic mechanism based characterization of DF by extracting chamber stiffness (k), relaxation (c), and load (x ) from E-wave contours. We derive the mathematical relationship between the PDF parameters and E, AT, DT and thereby introduce the geometric method (GM) that computes the PDF parameters using E, AT, and DT as input. Numerical experiments validated GM by analysis of 208 E-waves from 31 datasets spanning the full range of clinical diastolic function. GM yielded indistinguishable average parameter values per subject vs. the gold-standard PDF method (k: R = 0.94, c: R = 0.95, x : R = 0.95, p < 0.01 all parameters). Additionally, inter-rater reliability for GM-determined parameters was excellent (k: ICC = 0.956 c: ICC = 0.944, x : ICC = 0.993). Results indicate that E-wave symmetry (AT/DT) may comprise a new index of DF. By employing indexes (E, AT, DT) that are already in standard clinical use the GM capitalizes on the power of the PDF method to quantify DF in terms of physiologic chamber properties.
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http://dx.doi.org/10.1007/s13239-017-0339-5DOI Listing
March 2018

What global diastolic function is, what it is not, and how to measure it.

Am J Physiol Heart Circ Physiol 2015 Nov 28;309(9):H1392-406. Epub 2015 Aug 28.

Cardiovascular Biophysics Laboratory, Cardiovascular Division, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri

Despite Leonardo da Vinci's observation (circa 1511) that "the atria or filling chambers contract together while the pumping chambers or ventricles are relaxing and vice versa," the dynamics of four-chamber heart function, and of diastolic function (DF) in particular, are not generally appreciated. We view DF from a global perspective, while characterizing it in terms of causality and clinical relevance. Our models derive from the insight that global DF is ultimately a result of forces generated by elastic recoil, modulated by cross-bridge relaxation, and load. The interaction between recoil and relaxation results in physical wall motion that generates pressure gradients that drive fluid flow, while epicardial wall motion is constrained by the pericardial sac. Traditional DF indexes (τ, E/E', etc.) are not derived from causal mechanisms and are interpreted as approximating either stiffness or relaxation, but not both, thereby limiting the accuracy of DF quantification. Our derived kinematic models of isovolumic relaxation and suction-initiated filling are extensively validated, quantify the balance between stiffness and relaxation, and provide novel mechanistic physiological insight. For example, causality-based modeling provides load-independent indexes of DF and reveals that both stiffness and relaxation modify traditional DF indexes. The method has revealed that the in vivo left ventricular equilibrium volume occurs at diastasis, predicted novel relationships between filling and wall motion, and quantified causal relationships between ventricular and atrial function. In summary, by using governing physiological principles as a guide, we define what global DF is, what it is not, and how to measure it.
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http://dx.doi.org/10.1152/ajpheart.00436.2015DOI Listing
November 2015

Early detection of abnormal left ventricular relaxation in acute myocardial ischemia with a quadratic model. Med Eng Phys 2014;36(September (9)):1101-5 by Morimont et al.

Med Eng Phys 2015 Aug 3;37(8):826. Epub 2015 Jun 3.

Cardiovascular Biophysics Laboratory, Departments of Physics, Biomedical Engineering, Physiology, and Medicine, Washington University in St Louis, St Louis, MO, USA.

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http://dx.doi.org/10.1016/j.medengphy.2015.05.002DOI Listing
August 2015

Quantification of global diastolic function by kinematic modeling-based analysis of transmitral flow via the parametrized diastolic filling formalism.

J Vis Exp 2014 Sep 1(91):e51471. Epub 2014 Sep 1.

Department of Medicine, Cardiovascular Division, Washington University in St. Louis; Cardiovascular Biophysics Lab, Washington University in St. Louis;

Quantitative cardiac function assessment remains a challenge for physiologists and clinicians. Although historically invasive methods have comprised the only means available, the development of noninvasive imaging modalities (echocardiography, MRI, CT) having high temporal and spatial resolution provide a new window for quantitative diastolic function assessment. Echocardiography is the agreed upon standard for diastolic function assessment, but indexes in current clinical use merely utilize selected features of chamber dimension (M-mode) or blood/tissue motion (Doppler) waveforms without incorporating the physiologic causal determinants of the motion itself. The recognition that all left ventricles (LV) initiate filling by serving as mechanical suction pumps allows global diastolic function to be assessed based on laws of motion that apply to all chambers. What differentiates one heart from another are the parameters of the equation of motion that governs filling. Accordingly, development of the Parametrized Diastolic Filling (PDF) formalism has shown that the entire range of clinically observed early transmitral flow (Doppler E-wave) patterns are extremely well fit by the laws of damped oscillatory motion. This permits analysis of individual E-waves in accordance with a causal mechanism (recoil-initiated suction) that yields three (numerically) unique lumped parameters whose physiologic analogues are chamber stiffness (k), viscoelasticity/relaxation (c), and load (xo). The recording of transmitral flow (Doppler E-waves) is standard practice in clinical cardiology and, therefore, the echocardiographic recording method is only briefly reviewed. Our focus is on determination of the PDF parameters from routinely recorded E-wave data. As the highlighted results indicate, once the PDF parameters have been obtained from a suitable number of load varying E-waves, the investigator is free to use the parameters or construct indexes from the parameters (such as stored energy 1/2kxo(2), maximum A-V pressure gradient kxo, load independent index of diastolic function, etc.) and select the aspect of physiology or pathophysiology to be quantified.
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http://dx.doi.org/10.3791/51471DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4828027PMC
September 2014

The Challenge of Chamber Stiffness Determination in Chronic Atrial Fibrillation vs. Normal Sinus Rhythm: Echocardiographic Prediction with Simultaneous Hemodynamic Validation.

J Atr Fibrillation 2013 Oct-Nov;6(3):878. Epub 2013 Oct 31.

Cardiovascular Biophysics Laboratory, Cardiovascular DivisionWashington University School of Medicine, St. Louis, MO, USA.

Echocardiographic diastolic function (DF) assessment remains a challenge in atrial fibrillation (AF), because indexes such as E/A cannot be used and because chronic, rate controlled AF causes chamber remodeling. To determine if echocardiography can accurately characterize diastolic chamber properties we compared 15 chronic AF subjects to 15, age matched normal sinus rhythm (NSR) subjects using simultaneous echocardiography-cardiac catheterization (391 beats analyzed). Conventional DF parameters (DT, Epeak, AT, Edur, E-VTI, E/E') and validated, E-wave derived, kinematic modeling based chamber stiffness parameter (k), were compared. For validation, chamber stiffness (dP/dV) was independently determined from simultaneous, multi-beat P-V loop data. Results show that neither AT, Epeak nor E-VTI differentiated between groups. Although DT, Edur and E/E' did differentiate between groups (DTNSR vs. DTAF p < 0.001, EdurNSR vs. EdurAF p < 0.001, E/E'NSR vs. E/E'AF p < 0.05), the model derived chamber stiffness parameter k was the only parameter specific for chamber stiffness, (kNSR vs. kAF p <0.005). The invasive gold standard determined end-diastolic stiffness in NSR was indistinguishable from end-diastolic (i.e. diastatic) stiffness in AF (p = 0.84). Importantly, the analysis provided mechanistic insight by showing that diastatic stiffness in AF was significantly greater than diastatic stiffness in NSR (p < 0.05). We conclude that passive (diastatic) chamber stiffness is increased in normal LVEF chronic, rate controlled AF hearts relative to normal LVEF NSR controls and that in addition to DT, the E-wave derived, chamber stiffness specific index k, differentiates between AF vs. NSR groups, even when invasively determined end-diastolic chamber stiffness fails to do so.
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http://dx.doi.org/10.4022/jafib.878DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5153031PMC
October 2013

The diastolic function to cyclic variation of myocardial ultrasonic backscatter relation: the influence of parameterized diastolic filling (PDF) formalism determined chamber properties.

Ultrasound Med Biol 2011 Aug 16;37(8):1185-95. Epub 2011 Jun 16.

Department of Physics, Washington University in Saint Louis, Saint Louis, MO, USA.

Myocardial tissue characterization represents an extension of currently available echocardiographic imaging. The systematic variation of backscattered energy during the cardiac cycle (the "cyclic variation" of backscatter) has been employed to characterize cardiac function in a wide range of investigations. However, the mechanisms responsible for observed cyclic variation remain incompletely understood. As a step toward determining the features of cardiac structure and function that are responsible for the observed cyclic variation, the present study makes use of a kinematic approach of diastolic function quantitation to identify diastolic function determinants that influence the magnitude and timing of cyclic variation. Echocardiographic measurements of 32 subjects provided data for determination of the cyclic variation of backscatter to diastolic function relation characterized in terms of E-wave determined, kinematic model-based parameters of chamber stiffness, viscosity/relaxation and load. The normalized time delay of cyclic variation appears to be related to the relative viscoelasticity of the chamber and predictive of the kinematic filling dynamics as determined using the parameterized diastolic filling formalism (with r-values ranging from .44 to .59). The magnitude of cyclic variation does not appear to be strongly related to the kinematic parameters.
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http://dx.doi.org/10.1016/j.ultrasmedbio.2011.05.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3129365PMC
August 2011

The thermodynamics of diastole: kinematic modeling-based derivation of the P-V loop to transmitral flow energy relation with in vivo validation.

Am J Physiol Heart Circ Physiol 2011 Feb 12;300(2):H514-21. Epub 2010 Nov 12.

Cardiovascular Biophysics Laboratory, School of Medicine, Department of Physics, College of Arts and Sciences, Washington University Medical Center, 660 S. Euclid Ave., Box 8086, St. Louis, MO. 63110, USA.

Pressure-volume (P-V) loop-based analysis facilitates thermodynamic assessment of left ventricular function in terms of work and energy. Typically these quantities are calculated for a cardiac cycle using the entire P-V loop, although thermodynamic analysis may be applied to a selected phase of the cardiac cycle, specifically, diastole. Diastolic function is routinely quantified by analysis of transmitral Doppler E-wave contours. The first law of thermodynamics requires that energy (ε) computed from the Doppler E-wave (εE-wave) and the same portion of the P-V loop (εP-V E-wave) be equivalent. These energies have not been previously derived nor have their predicted equivalence been experimentally validated. To test the hypothesis that εP-V E-wave and εE-wave are equivalent, we used a validated kinematic model of filling to derive εE-wave in terms of chamber stiffness, relaxation/viscoelasticity, and load. For validation, simultaneous (conductance catheter) P-V and echocadiographic data from 12 subjects (205 total cardiac cycles) having a range of diastolic function were analyzed. For each E-wave, εE-wave was compared with εP-V E-wave calculated from simultaneous P-V data. Linear regression yielded the following: εP-V E-wave=αεE-wave+b (R2=0.67), where α=0.95 and b=6e(-5). We conclude that E-wave-derived energy for suction-initiated early rapid filling εE-wave, quantitated via kinematic modeling, is equivalent to invasive P-V-defined filling energy. Hence, the thermodynamics of diastole via εE-wave generate a novel mechanism-based index of diastolic function suitable for in vivo phenotypic characterization.
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http://dx.doi.org/10.1152/ajpheart.00814.2010DOI Listing
February 2011

Vortex formation time-to-left ventricular early rapid filling relation: model-based prediction with echocardiographic validation.

J Appl Physiol (1985) 2010 Dec 23;109(6):1812-9. Epub 2010 Sep 23.

Department of Biomedical Engineering, School of Engineering and Applied Science, Washington University, St. Louis, Missouri, USA.

During early rapid filling, blood aspirated by the left ventricle (LV) generates an asymmetric toroidal vortex whose development has been quantified using vortex formation time (VFT), a dimensionless index defined by the length-to-diameter ratio of the aspirated (equivalent cylindrical) fluid column. Since LV wall motion generates the atrioventricular pressure gradient resulting in the early transmitral flow (Doppler E-wave) and associated vortex formation, we hypothesized that the causal relation between VFT and diastolic function (DF), parametrized by stiffness, relaxation, and load, can be elucidated via kinematic modeling. Gharib et al. (Gharib M, Rambod E, Kheradvar A, Sahn DJ, Dabiri JO. Proc Natl Acad Sci USA 103: 6305-6308, 2006) approximated E-wave shape as a triangle and calculated VFT(Gharib) as triangle (E-wave) area (cm) divided by peak (Doppler M-mode derived) mitral orifice diameter (cm). We used a validated kinematic model of filling for the E-wave as a function of time, parametrized by stiffness, viscoelasticity, and load. To calculate VFT(kinematic), we computed the curvilinear E-wave area (using the kinematic model) and divided it by peak effective orifice diameter. The derived VFT-to-LV early rapid filling relation predicts VFT to be a function of peak E-wave-to-peak mitral annular tissue velocity (Doppler E'-wave) ratio as (E/E')(3/2). Validation utilized 262 cardiac cycles of simultaneous echocardiographic high-fidelity hemodynamic data from 12 subjects. VFT(Gharib) and VFT(kinematic) were calculated for each subject and were well-correlated (R(2) = 0.66). In accordance with prediction, VFT(kinematic) to (E/E')(3/2) relationship was validated (R(2) = 0.63). We conclude that VFT(kinematic) is a DF index computable in terms of global kinematic filling parameters of stiffness, viscoelasticity, and load. Validation of the fluid mechanics-to-chamber kinematics relation unites previously unassociated DF assessment methods and elucidates the mechanistic basis of the strong correlation between VFT and (E/E')(3/2).
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http://dx.doi.org/10.1152/japplphysiol.00645.2010DOI Listing
December 2010

The E-wave delayed relaxation pattern to LV pressure contour relation: model-based prediction with in vivo validation.

Ultrasound Med Biol 2010 Mar;36(3):497-511

Cardiovascular Biophysics Laboratory, Department of Physics, College of Arts and Sciences, St. Louis, MO, USA.

The transmitral Doppler E-wave "delayed relaxation" (DR) pattern is an established sign of diastolic dysfunction (DD). Furthermore, chambers exhibiting a DR filling pattern are also expected to have a prolonged time-constant of isovolumic relaxation (tau). The simultaneous observation of a DR pattern and normal tau in the same heart is not uncommon, however. The simultaneous hemodynamic equivalent of the DR pattern has not been proposed. To determine the feature of the left ventricular (LV) pressure contour during the E-wave that is causally related to its DR pattern we applied kinematic and fluid mechanics based arguments to derive the pressure recovery ratio (PRR). The PRR is dimensionless and is defined by the left ventricular pressure difference between diastasis and minimum pressure, normalized to the pressure difference between a fiducial diastolic filling pressure and minimum pressure [PRR=(P(Diastasis)-P(Min))/(P(Fiducial)-P(Min))]. We analyzed 354 cardiac cycles from 40 normal sinus rhythm (NSR) subjects and 113 beats from nine atrial fibrillation (AF) subjects from our database of simultaneous transmitral flow-micromanometric LV pressure recordings. The fiducial pressure is defined by the end diastolic pressure in NSR and by the pressure at dP/dt(MIN) in the setting of AF. Consistent with derivation, PRR was linearly related to a DR pattern related, model-based relaxation parameter (R(2) = 0.77, 0.83 in NSR and AF, respectively). Furthermore, the PRR successfully differentiated subjects with a DR pattern from subjects with partial DR or normal E-wave pattern (p < 0.05). We conclude that the PRR may differentiate between subjects having a DR pattern and subjects with normal E-waves, even when tau cannot.
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http://dx.doi.org/10.1016/j.ultrasmedbio.2009.10.012DOI Listing
March 2010

Automated method for calculation of a load-independent index of isovolumic pressure decay from left ventricular pressure data.

Annu Int Conf IEEE Eng Med Biol Soc 2009 ;2009:3031-4

Cardiovascular Biophysics Laboratory, Cardiovascular Division, Department of Internal Medicine, Washington University School of Medicine, Washington University Department of Physics, College of Arts and Sciences. 660 Euclid Avenue Box 8086, Saint Louis, MO 63110, USA.

Diastolic heart failure (DHF) is present in over 50% of hospitalized heart failure patients, and diastolic dysfunction is known to play a critical pathophysiologic role. Measurement of left-ventricular pressure (LVP) via catheterization is the gold standard for diastolic function (DF) evaluation, but current methods fail to fully capitalize on the complete information content of the pressure contour. We have previously demonstrated that a kinematic model of isovolumic pressure decay (IVPD), which accounts for restoring force (stiffness) and resistance (viscoelasticity/relaxation), provides mechanistic insight into IVPD physiology and provides an accurate fit to the recorded contour. Recently we derived a novel load-independent index of isovolumic pressure decay (LIIIVPD) involving IVPD kinematic model stiffness and resistance parameters. In this work we detail methods and provide guidelines by which LIIIVPD computation may be achieved in real-time from the pressure contour recorded during cardiac catheterization.
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http://dx.doi.org/10.1109/IEMBS.2009.5333753DOI Listing
March 2010

Determination of early diastolic LV vortex formation time (T*) via the PDF formalism: a kinematic model of filling.

Annu Int Conf IEEE Eng Med Biol Soc 2009 ;2009:2883-6

Department of Biomedical Engineering, School of Engineering and Applied Sciences, Washington University, St. Louis, MO 63130, USA.

The filling (diastolic) function of the human left ventricle is most commonly assessed by echocardiography, a non-invasive imaging modality. To quantify diastolic function (DF) empiric indices are obtained from the features (height, duration, area) of transmitral flow velocity contour, obtained by echocardiography. The parameterized diastolic filling (PDF) formalism is a kinematic model developed by Kovács et. al. which incorporates the suction pump attribute of the left ventricle and facilitates DF quantitation by analysis of echocardiographic transmitral flow velocity contours in terms of stiffness (k), relaxation (c) and load (x(0)). A complementary approach developed by Gharib et. al., uses fluid mechanics and characterizes DF in terms of vortex formation time (T*) derived from streamline features formed by the jet of blood aspirated into the ventricle. Both of these methods characterize DF using a causality-based approach. In this paper, we derive T*'s kinematic analogue T*(kinematic) in terms of k, c and x(0). A comparison between T*(kinematic) and T*(fluid) (mechanic) obtained from averaged transmitral velocity and mitral annulus diameter, is presented. We found that T* calculated by the two methods were comparable and T*(kinematic) correlated with the peak LV recoil driving force kx(0).
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http://dx.doi.org/10.1109/IEMBS.2009.5333111DOI Listing
March 2010

The pressure recovery ratio: The invasive index of LV relaxation during filling. Model-based prediction with in-vivo validation.

Annu Int Conf IEEE Eng Med Biol Soc 2009 ;2009:3940-3

Department of Physics, Washington University, USA.

Using a simple harmonic oscillator model (PDF formalism), every early filling E-wave can be uniquely described by a set of parameters, (x(0), c, and k). Parameter c in the PDF formalism is a damping or relaxation parameter that measures the energy loss during the filling process. Based on Bernoulli's equation and kinematic modeling, we derived a causal correlation between the relaxation parameter c in the PDF formalism and a feature of the pressure contour during filling - the pressure recovery ratio defined by the left ventricular pressure difference between diastasis and minimum pressure, normalized to the pressure difference between a fiducial pressure and minimum pressure [PRR = (P(Diastasis)-P(Min))/(P(Fiducial)-P(Min))]. We analyzed multiple heart beats from one human subject to validate the correlation. Further validation among more patients is warranted. PRR is the invasive causal analogue of the noninvasive E-wave relaxation parameter c. PRR has the potential to be calculated using automated methodology in the catheterization lab in real time.
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http://dx.doi.org/10.1109/IEMBS.2009.5333092DOI Listing
April 2010

Stiffness and relaxation components of the exponential and logistic time constants may be used to derive a load-independent index of isovolumic pressure decay.

Am J Physiol Heart Circ Physiol 2008 Dec 24;295(6):H2551-9. Epub 2008 Oct 24.

Cardiovascular Biophysics Laboratory, Department of Internal Medicine, College of Arts and Sciences, Washington University School of Medicine, 660 S. Euclid Ave., Box 8086, St. Louis, MO 63110, USA.

In current practice, empirical parameters such as the monoexponential time constant tau or the logistic model time constant tauL are used to quantitate isovolumic relaxation. Previous work indicates that tau and tauL are load dependent. A load-independent index of isovolumic pressure decline (LIIIVPD) does not exist. In this study, we derive and validate a LIIIVPD. Recently, we have derived and validated a kinematic model of isovolumic pressure decay (IVPD), where IVPD is accurately predicted by the solution to an equation of motion parameterized by stiffness (Ek), relaxation (tauc), and pressure asymptote (Pinfinity) parameters. In this study, we use this kinematic model to predict, derive, and validate the load-independent index MLIIIVPD. We predict that the plot of lumped recoil effects [Ek.(P*max-Pinfinity)] versus resistance effects [tauc.(dP/dtmin)], defined by a set of load-varying IVPD contours, where P*max is maximum pressure and dP/dtmin is the minimum first derivative of pressure, yields a linear relation with a constant (i.e., load independent) slope MLIIIVPD. To validate the load independence, we analyzed an average of 107 IVPD contours in 25 subjects (2,669 beats total) undergoing diagnostic catheterization. For the group as a whole, we found the Ek.(P*max-Pinfinity) versus tauc.(dP/dtmin) relation to be highly linear, with the average slope MLIIIVPD=1.107+/-0.044 and the average r2=0.993+/-0.006. For all subjects, MLIIIVPD was found to be linearly correlated to the subject averaged tau (r2=0.65), tauL(r2=0.50), and dP/dtmin (r2=0.63), as well as to ejection fraction (r2=0.52). We conclude that MLIIIVPD is a LIIIVPD because it is load independent and correlates with conventional IVPD parameters. Further validation of MLIIIVPD in selected pathophysiological settings is warranted.
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http://dx.doi.org/10.1152/ajpheart.00780.2008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2614548PMC
December 2008

Transmitral flow velocity-contour variation after premature ventricular contractions: a novel test of the load-independent index of diastolic filling.

Ultrasound Med Biol 2008 Dec 9;34(12):1901-8. Epub 2008 Aug 9.

Department of Physics, Washington University School of Arts and Sciences, St. Louis, MO, USA.

The new echocardiography-based, load-independent index of diastolic filling (LIIDF) M was assessed using load-/shape-varying E-waves after premature ventricular contractions (PVCs). Twenty-six PVCs in 15 subjects from a preexisting simultaneous echocardiography-catheterization database were selected. Perturbed load-state beats, defined as the first two post-PVC E-waves, and steady-state E-waves, were subjected to conventional and model-based analysis. M, a dimensionless index, defined by the slope of the peak driving-force vs. peak (filling-opposing) resistive-force regression, was determined from steady-state E-waves alone, and from load-perturbed E-waves combined with a matched number of subsequent beats. Despite high degrees of E-wave shape variation, M derived from load-varying, perturbed beats and M derived from steady-state beats alone were indistinguishable. Because the peak driving-force vs. peak resistive-force relation determining M remains highly linear in the extended E-wave shape and load variation regime observed, we conclude that M is a robust LIIDF.
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http://dx.doi.org/10.1016/j.ultrasmedbio.2008.05.002DOI Listing
December 2008

Is left ventricular volume during diastasis the real equilibrium volume, and what is its relationship to diastolic suction?

J Appl Physiol (1985) 2008 Sep 27;105(3):1012-4. Epub 2007 Sep 27.

Washington Univ. Medical Center, St. Louis, MO 63110, USA.

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http://dx.doi.org/10.1152/japplphysiol.00799.2007DOI Listing
September 2008

The kinematic filling efficiency index of the left ventricle: contrasting normal vs. diabetic physiology.

Ultrasound Med Biol 2007 Jun 3;33(6):842-50. Epub 2007 May 3.

Cardiovascular Biophysics Laboratory, Cardiovascular Division, Washington University School of Medicine, St. Louis, MO 63110, USA.

An index of filling efficiency incorporating stiffness and relaxation (S&R) parameters has not been derived or validated, although numerous studies have focused on the effects of altered relaxation or stiffness on early rapid filling and diastolic function. Previous studies show that S&R parameters can be obtained from early rapid filling (Doppler E-wave) via kinematic modeling. E-wave contours are governed by harmonic oscillatory motion modeled via the parameterized diastolic filling (PDF) formalism. The previously validated model determines three (unique) oscillator parameters from each E-wave having established physiological analogues: x(o) (load), c (relaxation/viscoelasticity) and k (chamber stiffness). We define the dimensionless, filling-volume-based kinematic filling efficiency index (KFEI) as the ratio of the velocity-time integral (VTI) of the actual clinical E-wave contour fit via PDF to the VTI of the PDF model-predicted ideal E-wave contour having the same x(o) and k, but with no resistance to filling (c = 0). To validate the new index, Doppler E-waves from 36 patients with normal ventricular function, 17 diabetic and 19 well-matched non-diabetic controls, were analyzed. E-wave parameters x(o), c and k and KFEI were computed for each patient and compared. In concordance with prior human and animal studies in which c differentiated between normal and diabetic hearts, KFEI differentiated (p < 0.001) between nondiabetics (55.8% +/- 3.3%) and diabetics (49.1% +/- 3.3%). Thus, the new index introduces and validates the concept of filling efficiency, and, using diabetes as a working example, provides quantitative and mechanistic insight into how S&R affect ventricular filling efficiency.
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http://dx.doi.org/10.1016/j.ultrasmedbio.2006.11.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1995600PMC
June 2007

E-wave deceleration time may not provide an accurate determination of LV chamber stiffness if LV relaxation/viscoelasticity is unknown.

Am J Physiol Heart Circ Physiol 2007 Jun 12;292(6):H2712-20. Epub 2007 Jan 12.

Cardiovascular Biophysics Laboratory, Washington University, School of Medicine, St. Louis, MO, USA.

Average left ventricular (LV) chamber stiffness (Delta P(avg)/Delta V(avg)) is an important diastolic function index. An E-wave-based determination of Delta P(avg)/Delta V(avg) (Little WC, Ohno M, Kitzman DW, Thomas JD, Cheng CP. Circulation 92: 1933-1939, 1995) predicted that deceleration time (DT) determines stiffness as follows: Delta P(avg)/Delta V(avg) = N(pi/DT)(2) (where N is constant), which implies that if the DTs of two LVs are indistinguishable, their stiffness is indistinguishable as well. We observed that LVs with indistinguishable DTs may have markedly different Delta P(avg)/Delta V(avg) values determined by simultaneous echocardiography-catheterization. To elucidate the mechanism by which LVs with indistinguishable DTs manifest distinguishable chamber stiffness, we use a validated, kinematic E-wave model (Kovács SJ, Barzilai B, Perez JE. Am J Physiol Heart Circ Physiol 252: H178-H187, 1987) with stiffness (k) and relaxation/viscoelasticity (c) parameters. Because the predicted linear relation between k and Delta P(avg)/Delta V(avg) has been validated, we reexpress the DT-stiffness (Delta P(avg)/Delta V(avg)) relation of Little et al. as follows: DT(k) approximately pi/(2k). Using the kinematic model, we derive the general DT-chamber stiffness/viscoelasticity relation as follows: DT(k,c) = pi/(2skrt[k])+c/(2k)(where c and k are determined directly from the E-wave), which reduces to DT(k) when c << k. Validation involved analysis of 400 E-waves by determination of five-beat averaged k and c from 80 subjects undergoing simultaneous echocardiography-catheterization. Clinical E-wave DTs were compared with model-predicted DT(k) and DT(k,c). Clinical DT was better predicted by stiffness and relaxation/viscoelasticity (r(2) = 0.84, DT vs. DT(k,c)) jointly rather than by stiffness alone (r(2) = 0.60, DT vs. DT(k)). Thus LVs can have indistinguishable DTs but significantly different Delta P(avg)/Delta V(avg) if chamber relaxation/viscoelasticity differs. We conclude that DT is a function of both chamber stiffness and chamber relaxation viscoelasticity. Quantitative diastolic function assessment warrants consideration of simultaneous stiffness and relaxation/viscoelastic effects.
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http://dx.doi.org/10.1152/ajpheart.01068.2006DOI Listing
June 2007

Load-independent index of diastolic filling: model-based derivation with in vivo validation in control and diastolic dysfunction subjects.

J Appl Physiol (1985) 2006 Jul 30;101(1):92-101. Epub 2006 Mar 30.

Cardiovascular Biophysics Laboratory, Washington University School of Medicine, St. Louis, Missouri, USA.

Maximum elastance is an experimentally validated, load-independent systolic function index stemming from the time-varying elastance paradigm that decoupled extrinsic load from (intrinsic) contractility. Although Doppler echocardiography is the preferred method of diastolic function (DF) assessment, all echo-derived indexes are load dependent, and no invasive or noninvasive load-independent index of filling (LIIF) exists. In this study, we derived and experimentally validated a LIIF. We used a kinematic filling paradigm (the parameterized diastolic filling formalism) to predict and derive the (dimensionless) dynamic diastolic efficiency M, defined by the slope of the peak driving force [maximum driving force (kx(o)) proportional, variant peak atrioventricular (AV) gradient] to maximum viscoelastic resistive force [peak resistive force (cE(peak))] relation. To validate load independence, we analyzed E-waves recorded while load was varied via tilt table (head up, horizontal, and head down) in 16 healthy volunteers. For the group, linear regression of E-wave derived kx(o) vs. cE(peak) yielded kx(o) = M (cE(peak)) + B, r2 = 0.98; where M = 1.27 +/- 0.09 and B = 5.69 +/- 1.70. Effects of diastolic dysfunction (DD) on M were assessed by analysis of preexisting simultaneous cath-echo data in six DD vs. five control subjects. Average M for the DD group (M = 0.98 +/- 0.07) was significantly lower than controls (M = 1.17 +/- 0.05, P < 0.001). We conclude that M is a LIIF because it uncouples intrinsic DF (i.e., the pressure-flow relation) from extrinsic load (left ventricular end-diastolic pressure). Larger M values imply better DF in that increasing AV pressure gradient results in relatively smaller increases in peak resistive losses (cE(peak)). Conversely, lower M implies that increasing AV gradient leads to larger increases in resistive losses. Further prospective validation characterizing M in well-defined pathological states is warranted.
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http://dx.doi.org/10.1152/japplphysiol.01305.2005DOI Listing
July 2006
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