Translating proof-of-concept for platelet slip into improved antithrombotic therapeutic regimens.

Platelets are central to thrombosis. Research at the intersection of biological and physical sciences provides proof-of-concept for shear rate-dependent platelet slip at vascular stenosis and near device surfaces. Platelet slip extends the observed biological "slip-bonds" to the boundary of functional gliding without contact. As a result, there is diminished engagement of the coagulation cascade by platelets at these surfaces. Comprehending platelet slip would more precisely direct antithrombotic regimens for different shear environments, including for percutaneous coronary intervention (PCI). In this brief report we promote translation of the proof-of-concept for platelet slip into improved antithrombotic regimens by: (1) reviewing new supporting basic biological science and clinical research for platelet slip; (2) hypothesizing the principal variables that affect platelet slip; (3) applying the consequent construct model in support of-and in some cases to challenge-relevant contemporary guidelines and their foundations (including for urgent, higher-risk PCI); and (4) suggesting future research pathways (both basic and clinical). Should future research demonstrate, explain and control platelet slip, then a paradigm shift for choosing and recommending antithrombotic regimens based on predicted shear rate should follow. Improved clinical outcomes with decreased complications accompanying this paradigm shift for higher-risk PCI would also result in substantive cost savings.

Progression of left ventricular diastolic function in the neonate and early childhood from transmitral color M-mode filling analysis.

BACKGROUND: We implemented sophisticated color M-mode analysis to assess age-dependent progression of left ventricular (LV) diastolic function. METHODS: Normal infants were prospectively enrolled for serial echocardiograms at 1 week, 1 month, 6 months, 1 year, and 2 years. From color M-mode scans, propagation velocity (VP), strength of filling (VS), and intraventricular pressure difference (IVPD) in 3 segments along apex-to-mitral valve scan line were measured. RESULTS: Age-wise comparisons of diastolic filling from 121 echocardiograms in 31 infants showed VP (cm/s), VS (cm2/s), and E-wave IVPD (mmHg) at 1 week to be 66.2 ± 11.9, 75.3 ± 19.9, and 1.5 ± 0.4, respectively, while VP, VS, and E-wave IVPD at 1 month were 80.3 ± 14.4, 101.2 ± 28.3, and 2.42 ± 1.1, respectively. There were significant differences in VP and segmental IVPD between first week and first month (p < 0.005) and IVPD between the age groups (p < 0.001). CONCLUSIONS: Comprehensive analysis of transmitral color M-mode data is feasible in infants, enabling calculation of pressure drop between the LV base and apex and strength of propagation from two distinct slopes. Profound changes very early followed by relatively constant filling mechanics in later infancy indicate significant LV maturation occurring during the first month of life. IMPACT: We implemented sophisticated analytic methods for color M-mode echocardiography in infants to assess age- and dimension-dependent changes in left ventricular diastolic function. Comprehensive characterization of transmitral color M-mode flow was feasible, enabling calculation of pressure drop between left ventricular base and apex and strength of propagation. Left ventricular diastolic filling function has predictable maturational progression, with significant differences in the intraventricular pressure between infants from birth to 2 years. This study forms the basis for future studies to examine alteration of early diastolic filling in congenital heart disease.

Computational Fluid Dynamics of Vascular Disease in Animal Models.

Recent applications of computational fluid dynamics (CFD) applied to the cardiovascular system have demonstrated its power in investigating the impact of hemodynamics on disease initiation, progression, and treatment outcomes. Flow metrics such as pressure distributions, wall shear stresses (WSS), and blood velocity profiles can be quantified to provide insight into observed pathologies, assist with surgical planning, or even predict disease progression. While numerous studies have performed simulations on clinical human patient data, it often lacks prediagnosis information and can be subject to large intersubject variability, limiting the generalizability of findings. Thus, animal models are often used to identify and manipulate specific factors contributing to vascular disease because they provide a more controlled environment. In this review, we explore the use of CFD in animal models in recent studies to investigate the initiating mechanisms, progression, and intervention effects of various vascular diseases. The first section provides a brief overview of the CFD theory and tools that are commonly used to study blood flow. The following sections are separated by anatomical region, with the abdominal, thoracic, and cerebral areas specifically highlighted. We discuss the associated benefits and obstacles to performing CFD modeling in each location. Finally, we highlight animal CFD studies focusing on common surgical treatments, including arteriovenous fistulas (AVF) and pulmonary artery grafts. The studies included in this review demonstrate the value of combining CFD with animal imaging and should encourage further research to optimize and expand upon these techniques for the study of vascular disease.

Novel interpretable Feature set extraction and classification for accurate atrial fibrillation detection from ECGs.

OBJECTIVE: We present a novel method for detecting atrial fibrillation (AFib) by analyzing Lead II electrocardiograms (ECGs) using a unique set of features. METHODS: For this purpose, we used specific signal processing techniques, such as proper orthogonal decomposition, continuous wavelet transforms, discrete cosine transform, and standard cross-correlation, to extract 48 features from the ECGs. Thus, our approach aims to more effectively capture AFib signatures, such as beat-to-beat variability and fibrillatory waves, than traditional metrics. Moreover, our features were designed to be physiologically interpretable. Subsequently, we incorporated an XGBoost-based ECG classifier to train and evaluate it using the publicly available 'Training' dataset of the 2017 PhysioNet Challenge, which includes 'Normal,' 'AFib,' 'Other,' and 'Noisy' ECG categories. RESULTS: Our method achieved an accuracy of 96 % and an F1-score of 0.83 for 'AFib' detection and 80 % accuracy and 0.85 F1-score for 'Normal' ECGs. Finally, we compared our method's performance with the top-classifiers from the 2017 PhysioNet Challenge, namely ENCASE, Random Forest, and Cascaded Binary. As reported by Clifford et al., 2017, these three best performing models scored 0.80, 0.83, 0.82, in terms of F1-score for 'AFib' detection, respectively. CONCLUSION: Despite using significantly fewer features than the competition's state-of-the-art ECG detection algorithms (48 vs. 150-622), our model achieved a comparable F1-score of 0.83 for successful 'AFib' detection. SIGNIFICANCE: The interpretable features specifically designed for 'AFib' detection results in our method's adaptability in clinical settings for real-time arrhythmia detection and is even effective with short ECGs (<10 heartbeats).

Evolution of cardiac tissue and flow mechanics in developing Japanese Medaka.

The effects of pressure drop across cardiac valve cushion regions and endocardial wall strain in the early developmental stages of a teleost species heart are poorly understood. In the presented work, we utilize microscale particle image velocimetry (µPIV) flow measurements of developing medaka hearts from 3 to 14 dpf (n = 5 at each dpf) to quantify the pressure field and endocardial wall strain. Peak pressure drop at the atrioventricular canal (ΔPAVC) and outflow tract (ΔPOFT) show a steady increase with fish age progression. Pressure drops when non-dimensionalized with blood viscosity and heart rate at each dpf are comparable with measurements in zebrafish hearts. Retrograde flows captured at these regions display a negative pressure drop. A novel metric, Endocardial Work (EW), is introduced by analyzing the ΔPAVC-strain curves, which is a non-invasive measure of work required for ventricle filling. EW is a metric that can differentiate between the linear heart stage (< 100 Pa-%), cardiac looped chamber stage (< 300 Pa-%), and the fully formed chamber stage (> 300 Pa-%).

Enhanced echocardiographic assessment of intracardiac flow in congenital heart disease.

BACKGROUND: 4D flow magnetic resonance imaging (4D flow MRI) can assess and measure the complex flow patterns of the right ventricle (RV) in congenital heart diseases, but its limited availability makes the broad application of intracardiac flow assessment challenging. Color Doppler imaging velocity reconstruction from conventional echocardiography is an emerging alternative, but its validity against 4D flow MRI needs to be established. OBJECTIVE: To compare intracardiac flow parameters measured by color Doppler velocity reconstruction (DoVeR) against parameters measured from 4D flow MRI. METHODS: We analyzed 20 subjects, including 7 normal RVs and 13 abnormal RVs (10 with repaired Tetralogy of Fallot, and 3 with atrial-level shunts). Intracardiac flow parameters such as relative pressure difference, vortex strength, total kinetic energy, and viscous energy loss were quantified using DoVeR and 4D flow MRI. The agreement between the two methods was determined by comparing the spatial fields and quantifying the cross-correlation and normalized difference between time-series measurements. RESULTS: The hemodynamic parameters obtained from DoVeR and 4D flow MRI showed similar flow characteristics and spatial distributions. The time evolutions of the parameters were also in good agreement between the two methods. The median correlation coefficient between the time-series of any parameter was between 0.87 and 0.92, and the median L2-norm deviation was between 10% to 14%. CONCLUSIONS: Our study shows that DoVeR is a reliable alternative to 4D flow MRI for quantifying intracardiac hemodynamic parameters in the RV.

NOVEL ECHOCARDIOGRAM ANALYSIS OF CARDIAC DYSFUNCTION IS ASSOCIATED WITH MORTALITY IN PEDIATRIC SEPSIS.

ABSTRACT: Objectives: The objective of our study was to semiautomatically generate echocardiogram indices in pediatric sepsis using novel algorithms and determine which indices were associated with mortality. We hypothesized that strain and diastolic indices would be most associated with mortality. Design: Retrospective cohort study of children with sepsis from 2017 to 2022. Survivors and nonsurvivors were compared for echocardiogram indices. Multivariate Cox proportional hazard models were constructed for our primary outcome of in-hospital mortality. Linear regression was performed for secondary outcomes, which included multiple composite 28-day outcomes. Results: Of the 54 patients in the study, 9 (17%) died. Multiple echocardiogram indices of both right (RV) and left ventricles (LV) were associated with in-hospital mortality [RV GLS adjusted hazard ratio (aHR): 1.16 (1.03-1.29), P = 0.011; RV global longitudinal early diastolic strain rate (GLSre) aHR: 0.24 (0.07 to 0.75), P = 0.014; LV GLSre aHR: 0.33 (0.11-0.97), P = 0.044]. Impairment in GLS was associated with fewer ventilator-free days [RV GLS ß-coefficient: -0.47 (-0.84 to -0.10), P = 0.013; LV GLS ß-coefficient -0.62 (-1.07 to -0.17), P = 0.008], organ-support free days [RV GLS ß-coefficient: -0.49 (-0.87 to -0.11), P = 0.013; LV GLS ß-coefficient: -0.64 (-1.10 to -0.17), P = 0.008], and days free from ICU [RV GLS ß-coefficient: -0.42 (-0.79 to -0.05), P = 0.026; LV GLS ß-coefficient: -0.58 (-1.03 to -0.13), P = 0.012]. Systolic indices were not associated with mortality in this cohort. Conclusion: Our study demonstrates the feasibility of obtaining echocardiogram indices in a semiautomatic method using our algorithms. We showed that abnormal strain is associated with worse outcomes in a cohort of children with sepsis.

Intracardiac Flow Analysis of the Right Ventricle in Pediatric Patients With Repaired Tetralogy of Fallot Using a Novel Color Doppler Velocity Reconstruction.

BACKGROUND: Repaired tetralogy of Fallot (RTOF) patients will develop right ventricular (RV) dysfunction from chronic pulmonary regurgitation (PR). Cardiac magnetic resonance sequences such as four-dimensional flow can demonstrate altered vorticity and flow energy loss (FEL); however, they are not as available as conventional echocardiography (echo). The study determined whether a novel, vendor-independent Doppler velocity reconstruction (DoVeR) could measure RV intracardiac flow in conventional echo of RTOF patients. The primary hypothesis was that DoVeR could detect increased vorticity and diastolic FEL in RTOF patients. METHODS: Repaired tetralogy of Fallot patients with echo were retrospectively paired with age-/size-matched controls. Doppler velocity reconstruction employed the stream function-vorticity equation to approximate intracardiac flow fields from color Doppler. A velocity field of the right ventricle was reconstructed from the apical 4-chamber view. Vortex strength (VS, area integral of vorticity) and FEL were derived from DoVeR. Cardiac magnetic resonance and exercise stress parameters (performed within 1 year of echo) were collected for analysis. RESULTS: Twenty RTOF patients and age-matched controls were included in the study. Mean regurgitant fraction was 40.5% ± 7.6%, and indexed RV end-diastolic volume was 158 ± 36 mL/m2. Repaired tetralogy of Fallot patients had higher total, mean diastolic, and peak diastolic VS (P = .0013, P = .0012, P = .0032, respectively) and higher total, mean diastolic, and peak diastolic body surface area-indexed FEL (P = .0016, P = .0022, P < .001, respectively). Peak diastolic indexed FEL and peak diastolic VS had weak-to-moderate negative correlation with RV ejection fraction (r = -0.52 [P = .019] and r = -0.49 [P = .030], respectively) and left ventricular ejection fraction (r = -0.47 [P = .034] and r = -0.64 [P = .002], respectively). Mean diastolic indexed FEL and VS had moderate-to-strong negative correlation with percent predicted maximal oxygen consumption (r = -0.69 [P = .012] and r = -0.75 [P = .006], respectively). CONCLUSIONS: DoVeR can detect alterations to intracardiac flow in RTOF patients from conventional color Doppler imaging. Echo-based measures of diastolic VS and FEL correlated with ventricular function. DoVeR has the potential to provide serial evaluation of abnormal flow dynamics in RTOF patients.

Determinants of exercise capacity in patients with heart failure without left ventricular hypertrophy.

BACKGROUND: Determinants of exercise intolerance in a phenotype of heart failure with preserved ejection fraction (HFpEF) with normal left ventricular (LV) structure have not been fully elucidated. METHODS: Cardiopulmonary exercise testing and exercise-stress echocardiography were performed in 44 HFpEF patients without LV hypertrophy. Exercise capacity was determined by peak oxygen consumption (peak VO2). Doppler-derived cardiac output (CO), transmitral E velocity, systolic (LV-s') and early diastolic mitral annular velocities (e'), systolic pulmonary artery (PA) pressure (SPAP), tricuspid annular plane systolic excursion (TAPSE), and peak systolic right ventricular (RV) free wall velocity (RV-s') were measured at rest and exercise. E/e' and TAPSE/SPAP were used as an LV filling pressure parameter and RV-PA coupling, respectively. RESULTS: During exercise, CO, LV-s', RV-s', e', and SPAP were significantly increased (p < 0.05 for all), whereas E/e' remained unchanged and TAPSE/SPAP was significantly reduced (p < 0.001). SPAP was higher and TAPSE/SPAP was lower at peak exercise in patients showing lower-half peak VO2. In univariable analyses, LV-s' (R = 0.35, p = 0.022), SPAP (R = -0.40, p = 0.008), RV-s' (R = 0.47, p = 0.002), and TAPSE/SPAP (R = 0.42, p = 0.005) were significantly correlated with peak VO2. In multivariable analyses, not only SPAP, but also TAPSE/SPAP independently determined peak VO2 even after the adjustment for clinically relevant parameters. CONCLUSIONS: In HFpEF patients without LV hypertrophy, altered RV-PA coupling by exercise could be associated with exercise intolerance, which might not be caused by elevated LV filling pressure.

A method for direct estimation of left ventricular global longitudinal strain rate from echocardiograms.

We present a new method for measuring global longitudinal strain and global longitudinal strain rate from 2D echocardiograms using a logarithmic-transform correlation (LTC) method. Traditional echocardiography strain analysis depends on user inputs and chamber segmentation, which yield increased measurement variability. In contrast, our approach is automated and does not require cardiac chamber segmentation and regularization, thus eliminating these issues. The algorithm was benchmarked against two conventional strain analysis methods using synthetic left ventricle ultrasound images. Measurement error was assessed as a function of contrast-to-noise ratio (CNR) using mean absolute error and root-mean-square error. LTC showed better agreement to the ground truth strain [Formula: see text] and ground truth strain rate [Formula: see text] compared with agreement to ground truth for two block-matching speckle tracking algorithms (one based on sum of square difference and the other on Fourier transform correlation; strain [Formula: see text], strain rate [Formula: see text]). A 200% increase in strain measurement accuracy was observed compared to the conventional algorithms. Subsequently, we tested the method using a 53-subject clinical cohort (20 subjects diseased with cardiomyopathy, 33 healthy controls). Our method distinguished between normal and abnormal left ventricular function with an AUC = 0.89, a 5% improvement over the conventional GLS algorithms.

Automated Peak Prominence-Based Iterative Dijkstra's Algorithm for Segmentation of B-Mode Echocardiograms.

We present a user-initialized, automated left ventricle (LV) segmentation method for use with echocardiograms (echo). The method uses an iterative Dijkstra's algorithm, strategic node selection, and novel cost matrix formulation based on intensity peak prominence and is termed the "Prominence Iterative Dijkstra's" algorithm, or ProID. ProID is initialized with three user-input clicks per time-series scan. ProID was tested using artificial echos representing five different systems. Results showed accurate LV contours and volume estimations as compared to the ground-truth for all systems. Using the CAMUS dataset, we demonstrate ProID maintained similar Dice similarity scores (DSS) to other automated methods. ProID was then used to analyze a clinical cohort of 66 pediatric patients, including normal and diseased hearts. Output segmentations, LV volume, and ejection fraction were compared against manual segmentations from two expert readers. ProID maintained an average DSS of 0.93 when comparing against manual segmentation. Comparing the two expert readers, the manual segmentations maintained a DSS of 0.93 which increased to 0.95 when they used ProID. Thus, ProID reduced inter-operator variability across the expert readers. Overall, this work demonstrates ProID yields accurate boundaries across age groups, disease states, and echo platforms with low computational cost and no need for training data.

Determinants of altered left ventricular suction in pre-capillary pulmonary hypertension.

AIMS: Although the left ventricular (LV) dysfunction in pre-capillary pulmonary hypertension (PH) has been recently recognized, the mechanism of LV dysfunction in this entity is not completely understood. We thus aimed to elucidate the determinants of intraventricular pressure difference (IVPD), a measure of LV suction, in pre-capillary PH. METHODS AND RESULTS: Right heart catheterization and echocardiography were performed in 86 consecutive patients with pre-capillary PH (57 ± 18 years, 85% female). IVPD was determined using colour M-mode Doppler to integrate the Euler equation. In overall, IVPD was reduced compared to previously reported value in normal subjects. In univariable analyses, QRS duration (P = 0.028), LV ejection fraction (P = 0.006), right ventricular (RV) end-diastolic area (P < 0.001), tricuspid annular plane systolic excursion (P = 0.004), and LV early-diastolic eccentricity index (P = 0.009) were associated with IVPD. In the multivariable analyses, RV end-diastolic area and LV eccentricity index independently determined the IVPD. CONCLUSION: Aberrant ventricular interdependence caused by RV enlargement could impair the LV suction. This study first applied echocardiographic IVPD, a reliable marker of LV diastolic suction, to investigate the mechanism of LV diastolic dysfunction in pre-capillary PH.

A Wavelet Approach to the Estimation of Left Ventricular Early Filling Wave Propagation Velocity from Color M-Mode Echocardiograms.

A new approach to calculating left ventricular (LV) early filling propagation velocity (VP) from color M-mode echocardiograms using wavelet analysis is described. Current methods for measuring VP do not account for the spatiotemporal variation in VP. They are confined by empirical assumptions and user inputs that hinder the accuracy of VP, limiting its clinical utility. We evaluated three methods for measuring LV early filling: conventional VP, the strength of propagation (VS) and wavelet propagation velocity (VW) determined from the most energetically significant wave (peak VW). Group A comprised 125 patients (n = 50 normal filling, n = 25 impaired relaxation, n = 25 pseudonormal filling and n = 25 restrictive filling), and group B comprised 69 patients (n = 32 normal, n = 15 dilated and n = 22 hypertrophic). Peak VW most accurately distinguished normal from diseased patients. For group A, the area under the receiver operating characteristic curve was 0.92 for peak VW versus 0.62 for VP, 0.63 for VS and 0.58 for intraventricular pressure difference. These correspond to a 50%-70% improvement in classification ability. Similar improvements were measured in group B. Peak VW may provide a more accurate evaluation of diastolic function than standard methods and enable better diagnostic classification of patients with diastolic dysfunction.

Universality of vortex ring decay in the left ventricle.

We present clinical measurements and a theoretical model for the decay of the left ventricular (LV) vortex ring. Previous works have postulated that the formation of the vortex ring downstream of the mitral annulus is affected by LV diastolic impairment. However, no previous works have considered how the strength of the vortex ring will decay inside the ventricle after its formation. Although the vortex ring formation relates to the very initial stage of the filling, the decay process is governed by a large portion of the diastolic time and will be affected by the interaction of the ventricle walls and the vortex ring. Here we used in-vivo measurements and presented a mechanistic model to calculate the evolution of the vortex ring strength and predict the rate of vortex ring decay within the left ventricle. The results demonstrated the actual circulation decay rate was universal, remaining nearly unchanged across all subjects of varying LV geometry or diastolic function. Furthermore, using the model-predicted circulation decay rate, differentiation between normal and abnormal filling was observed.

Colour-Doppler echocardiography flow field velocity reconstruction using a streamfunction-vorticity formulation.

We introduce a new method (Doppler Velocity Reconstruction or DoVeR), for reconstructing two-component velocity fields from colour Doppler scans. DoVeR employs the streamfunction-vorticity equation, which satisfies mass conservation while accurately approximating the flow rate of rotation. We validated DoVeR using artificial colour Doppler images generated from computational fluid dynamics models of left ventricle (LV) flow. We compare DoVeR against the conventional intraventricular vector flow mapping (iVFM1D) and reformulated iVFM (iVFM2D). LV model error analysis showed that DoVeR is more robust to noise and probe placement, with noise RMS errors (nRMSE) between 3.81% and 6.67%, while the iVFM methods delivered 4.16-24.17% for iVFM1D and 4.06-400.21% for iVFM2D. We test the DoVeR and iVFM methods using in vivo mouse LV ultrasound scans. DoVeR yielded more haemodynamically accurate reconstructions, suggesting that it can provide a more reliable approach for robust quantification of cardiac flow.

Development and Validation of a Phase-Filtered Moving Ensemble Correlation for Echocardiographic Particle Image Velocimetry.

A new processing method for echocardiographic particle image velocimetry (EchoPIV) using moving ensemble (ME) correlation with dynamic phase correlation filtering was developed to improve velocity measurement accuracy for routine clinical evaluation of cardiac function. The proposed method was tested using computationally generated echocardiogram images. Error analysis indicated that ME EchoPIV yields a twofold improvement in bias and random error over the current standard correlation method (ßPairwise = -0.15 vs. ßME = -0.06; σPairwise = 1.00 vs. σME = 0.49). Subsequently a cohort of eight patients with impaired diastolic filling underwent similar evaluation. Comparison of patient EchoPIV velocity time series with corresponding color M-mode velocity time series revealed better agreement for ME EchoPIV compared with standard PIV processing (RME = 0.90 vs. RPairwise = 0.70). Further time series analysis was performed to measure filling propagation velocity and 1-D intraventricular pressure gradients. Comparison against CMM values indicated that both measurements are completely decorrelated for pairwise processing (R2Vp = 0.15, R2IVPD = 0.07), whereas ME processing correlates decently (R2Vp = 0.69, R2IVPD = 0.69). This new approach enables more robust processing of routine clinical scans and can increase the utility of EchoPIV for the assessment of left ventricular function.

Assessment of methodologies to calculate intraventricular pressure differences in computational models and patients.

Intraventricular pressure differences (IVPDs) govern left ventricular (LV) efficient filling and are a significant determinant of LV diastolic function. Our primary aim is to assess the performance of available methods (color M-mode (CMM) and 1D/2D MRI-based methods) to determine IVPDs from intracardiac flow measurements. Performance of three methods to calculate IVPDs was first investigated via an LV computational fluid dynamics (CFD) model. CFD velocity data were derived along a modifiable scan line, mimicking ultrasound/MRI acquisition of 1D (IVPDCMM/IVPD1D MRI) and 2D (IVPD2D MRI) velocity-based IVPD information. CFD pressure data (IVPDCFD) was used as a ground truth. Methods were also compared in a small cohort (n = 13) of patients with heart failure with preserved ejection fraction (HFpEF). In silico data showed a better performance of the IVPD2D MRI approach: RMSE values for a well-aligned scan line were 0.2550 mmHg (IVPD1D MRI), 0.0798 mmHg (IVPD2D MRI), and 0.2633 mmHg (IVPDCMM). In vivo data exhibited moderate correlation between techniques. Considerable differences found may be attributable to different timing of measurements and/or integration path. CFD modeling demonstrated an advantage using 2D velocity information to compute IVPDs, and therefore, a 2D MRI-based method should be favored. However, further studies are needed to support the clinical significance of MRI-based computation of IVPDs over CMM.

Delay of left ventricular longitudinal expansion with diastolic dysfunction: impact on load dependence of e' and longitudinal strain rate.

The effect of diastolic dysfunction (DD) on the timing of left ventricular (LV) diastolic longitudinal and circumferential expansion and their load dependence is not known. This study evaluated the timing of the peak early diastolic LV inflow velocity (E), mitral annular velocity (e'), and longitudinal and circumferential global strain rates (SRE) in 161 patients in sinus rhythm. The intraventricular pressure difference (IVPD) from the left atrium to the LV apex was obtained using color M-mode Doppler data to integrate the Euler equation. The diastolic function was graded according to the guidelines. In normals (N = 57), E, e', longitudinal SRE, and circumferential SRE occurred nearly simultaneously during the IVPD. With DD (N = 104), e' and longitudinal SRE were delayed occurring after the IVPD (e': 18 ± 23 msec, longitudinal SRE: 13 ± 21 msec from the IVPD), whereas circumferential SRE (-8 ± 28 msec) and E (-2 ± 13 msec) were not delayed. The normal dependence of e' and longitudinal SRE on IVPD was reduced in DD; while the relation of circumferential SRE and E to IVPD were unchanged in DD. Thus, normally, the LV expands symmetrically during early diastole and both longitudinal and circumferential expansions are related to the IVPD. With DD, early diastolic longitudinal LV expansion is delayed, occurring after the IVPD and LV filling, resulting in their relative independence from the IVPD. In contrast, with DD, circumferential SRE and mitral inflow are not delayed and their normal relation to the IVPD is unchanged.