605 Assessment of intracardiac flow dynamics for the evaluation of patients with cardiac resynchronization therapy

Aims Cardiac resynchronization therapy (CRT) is an established treatment for patients with heart failure (HF), reduced left ventricular ejection fraction (EF ≤ 35%) and high-grade intraventricular conduction delays. CRT improves cardiac function, symptoms and well-being, and reduces morbidity and mortality in this setting. However, there are patients unresponsive to CRT. Responders show reverse ventricular remodelling, volumes and diameters reduction, and EF improvement. Noninvasive cardiovascular imaging for visualization and quantitation of intracardiac flows and turbulences has not been assessed thoroughly in CRT. This study seeks to evaluate if the quantitative analysis of intracardiac flow dynamics in HF patients treated by CRT might provide additional information for device optimization and clinical response. Methods and results Fifteen HF patients (five females, age 69.6 ± 9.4 years, NYHA class II/III, EF 29.3 ± 4.6%) were enrolled in the study. Eleven had primitive dilated cardiomyopathy and four had post-ischaemic etiology with completed revascularization. Pacemaker-dependent cases were excluded. MyLab™ X8 platform was used for echocardiographic assessment of intracardiac flow dynamics performed on apical three chamber views. All examinations were realized in baseline (active CRT) and after 5 min of biventricular pacing switch off. The hyperDoppler software was used to assess intracardiac vortexes properties. The analyzed parameters were: vortex area, vortex length, vortex depth, and kinetic of energy dissipation (ΔKE). Categorical variables are expressed as numbers and percentages. Quantitative variables are expressed as mean and standard deviation (SD). Shapiro–Wilk test, D’Agostino Pearson test, and visual inspection of Q–Q-plots were executed to evaluate if variables were normally distributed. Quantitative variables were evaluated with paired sample T-test or Wilcoxon test when appropriate. Clinical features, biochemical parameters, electrocardiograms with and without cardiac pacing, and EF before and after CRT implantation were collected. Although no difference was observed in vortex area/depth/length, a significant increase in KE dissipation after switching OFF the CRT devices (from 1.2 ± 0.9 to 3.5 ± 2.3 J, P < 0.03) was remarkably observed. According to EF improvement after CRT, the patients were divided in responders (5% increase in EF, N = 10) and non-responders (N = 5). Moreover, by analysing the extent of QRS dispersion and the variation of KE dissipation in spontaneous rhythm and after silencing the biventricular pacing, a positive ventricular remodelling (QRS 141.3 ± 29.3 vs. 154.4 ± 24.4ms, P = 0.02; KE dissipation 0.92 ± 0.87 J in responders and 1.53 ± 1.76 J in non-responders, P = 0.006) was detected in responders. Conclusions Noninvasive intracardiac flow dynamics in HF patients represents a complementary tool to standard echocardiography, and provides additional parameters for assessing prognosis and outcomes in CRT recipients. The impact of maladaptation in intracardiac flow dynamic on progressive LV remodelling could be useful to evaluate the prognostic meaning of implanted CRT device and to predict the response to device implantation, based on cardiac flow analysis.

746 Assessment of intracardiac fluid-dynamics of patients with aortic stenosis

Aims Recent technological developments enabled visualization of intracardiac flow patterns. This study aims to evaluate intracardiac flow dynamics of patients with aortic stenosis (AS). Methods and results Sixty-one patients with severe AS and 38 healthy sex- and BSA-matched controls (CTRL) were prospectively included. Standard echocardiographic assessment was performed in all patients. Fluid dynamics were evaluated using the HyperDoppler software to measure vortex area (VA), vortex length (VL), and vortex depth (VD). The assessment of VA, VL, and VD was feasible and reliable, as the inter-rater variability (ICCs) were very good for VA (0.878, P = 0.033), VL (0.960, P = 0.004), and VD (0.905, P = 0.021). Mean VA, VL, and VD (P = 0.033, P = 0.026, and P > 0.001, respectively) were significantly larger in AS patients compared with CTRL. A significant difference in the delta values of VA and VL, reflecting their change from before to after TAVI, was observed in patients with and without significant paravalvular leak. Conclusions The newly developed quantitative indices of flow dynamics, namely VA, VL, and VD, were significantly increased in the LV of patients with severe AS compared to controls and their measurement was feasible and reliable in a clinical setting.

Assessment of intracardiac flow dynamics for the evaluation of patients with different ventricular geometry

Background Over the last decades growing evidence have demonstrated the promising role of intracardiac flow dynamic analysis in evaluating cardiac performance. Diastolic forces contribute to the formation of vortices, complex structures capable of kinetic energy storage and responsible of a smoother transition of blood from left ventricular (LV) inlet to outlet. Change in shape and location of these structures has been related with cardiovascular disease and prognosis. Purpose To investigate quantitative changes in vortices parameters in patients with different ventricular geometry. Methods We enrolled 72 consecutive patients (age 66±11 years, 49 male, 68%) with LV concentric hypertrophy (CH, n=15), eccentric hypertrophy (EH, n=13), concentric remodeling (CR, n=15) and normal LV geometry (CTRL, n=29). Each patient underwent a complete echocardiographic examination and a non-invasive intracardiac fluid dynamic analysis by Color Vector Flow Mapping. A 3-chamber apical view with a frame rate between 22 and 25 Hz has been acquired and subsequently analyzed offline by a semi-automatic software obtaining the following parameters: vortex area (VA) (the ratio between the total vortex area and the left ventricular (LV) area); vortex length (VL) (the longitudinal length of the vortex relative to the total LV length; vortex depth (VD) (the distance of the vortex center from the LV base relative to the total LV long axis). Bland Altman Plot has been used to assess intra and inter-observer variability. Results Mean VD was higher in CR, CH and EH compared to CTRL (p=0.013, p=0.001 and p=0.022, respectively). Moreover, CH showed higher VL (p=0.006) and larger VA (p=0.012) compared to CTRL. A similar trend was noticed in EH patients, despite did not reach statistical significance (p=0.21 and p=0.07 for VA and VL respectively). No significative differences in vortices parameters have been observed between CH and EH. Conclusion(s) This is the first study providing quantitative echocardiographic parameters of vortex location and morphology in different LV geometries. Higher values of VD were found in CR, CH and EG. Quantitative intra dynamic fluid assessment was feasible and reliable in the whole population and could provide additional information to the standard echocardiographic examination. FUNDunding Acknowledgement Type of funding sources: None.

Assessment of intracardiac flow dynamics for the evaluation of patients with aortic stenosis

Background Assessment of intracardiac flows and turbulence has acquired rising significance in the past few years, due to the development and introduction of technologies for non-invasive cardiovascular imaging. Recent studies have shown that alterations in intracardiac fluid dynamics can be helpful to identify abnormalities in cardiac function. Purpose This study investigates the additional information provided by the quantitative assessment of intracardiac flow dynamics for the evaluation of patients with aortic stenosis (AS), by using an advanced echocardiography vortex-based approach. Methods Sixty-one patients with severe AS (33 females) and 38 healthy sex- and BSA-matched controls (CTRL) (15 females) were prospectively included and underwent echocardiographic assessment of intracardiac flow dynamics. Echocardiographic measurements were performed on apical three chamber views. The HyperDoppler software adapted to the echo-scanner without contrast injection was used to assess intracardiac vortex properties. The following parameters were obtained: vortex area (VA) (the ratio between the total vortex area and the left ventricular (LV) area); vortex length (VL) (the longitudinal length of the vortex relative to the total LV length; vortex depth (VD) (the distance of the vortex center from the LV base relative to the total LV long axis). Inter-rater variability was measured using intraclass correlation coefficients (ICCs) between two independent operators. Results Patients with severe AS (mean gradient: 47,5±13,9 mmHg; aortic valve area: 0.7±0.2 cm2; ejection fraction: 53±7%) had increased LV wall thickness (p<0.001) and mass index (p<0.001) compared with controls. Greater indexed left atrial volume (p<0.001), E/e' (p<0.001) and trans-tricuspid gradient (p<0.001) were also observed in the AS group. The assessment of VA, VL and VD was feasible in the whole population. Their calculation was reliable, as ICCs were very good for VA (0.878, p=0.033), VL (0.960, p=0.004) and VD (0,905, p=0.021). Mean VA was significantly larger in patients with severe aortic stenosis compared with CTRL (p=0.033). VL and VD (p=0.026 and p>0.001, respectively) were significantly higher in AS patients compared with CTRL. Among those who underwent TAVR, we observed a significant difference in the delta values of VA and VL pre-postTAVR in patients with and without significant paravalvular leak (p<0.05). Conclusions The newly defined VA, VL and VD, quantitative indices of vortical flow, were significantly increased in the LV cavity of patients with severe AS compared to normal subjects. These indices, whose measurement was feasible and reliable, might provide complementary information to standard echocardiography, useful for the further diagnostic and prognostic characterization of the heterogeneous population of patients with severe AS. FUNDunding Acknowledgement Type of funding sources: None.

Age-Related Changes in Left Ventricular Vortex Formation and Flow Energetics

Analysis of the cardiac vortex has been used for a deeper understanding of the pathophysiology in heart diseases. However, physiological changes of the cardiac vortex with normal aging are incompletely defined. Vector flow mapping (VFM) is a novel echocardiographic technique based on Doppler and speckle tracking for analysis of the cardiac vortex. Transthoracic echocardiography and VFM analysis were performed in 100 healthy adults (33 men; age = 18–67 years). The intracardiac flow was assessed throughout the cardiac cycle. The size (cross-sectional area) and circulation (equivalent to the integral of normal component of vorticity) of the largest vortices in systole (S-vortex), early diastole (E-vortex), and late diastole (A-vortex) were measured. Peak energy loss (EL) was calculated from information of the velocity vector of intracardiac flow in systole and diastole. With normal aging, the circulation (p = 0.049) of the E-vortex decreased, while that of the A-vortex increased (both p < 0.001). E-vortex circulation correlated directly to e’ (p = 0.003), A-vortex circulation correlated directly to A and a’ (both p < 0.001), and S-vortex circulation correlated directly to s’ (p = 0.032). Despite changes in vortex patterns, energy loss was not significantly different in older individuals. Normal aging is associated with altered intracardiac vortex patterns throughout the cardiac cycle, with the late-diastolic A-vortex becoming physiologically more dominant. Maintained energy efficiency accompanies changes in vortex patterns in aging hearts.

Short‐Term Effects of Inhaled Nitric Oxide on Right Ventricular Flow Hemodynamics by 4‐Dimensional–Flow Magnetic Resonance Imaging in Children With Pulmonary Arterial Hypertension

Background Pulmonary arterial hypertension (PAH) manifests with progressive right ventricular (RV) dysfunction, which eventually impairs the left ventricular function. We hypothesized that 4‐dimensional–flow magnetic resonance imaging can detect flow hemodynamic changes associated with efficient intracardiac flow during noninvasive inhaled nitric oxide (iNO) challenge in children with PAH. Methods and Results Children with PAH (n=10) underwent 2 same‐day separate iNO challenge tests using: (1) 4‐dimensional–flow magnetic resonance imaging and (2) standard catheterization hemodynamics. Intracardiac flow was evaluated using the particle tracking 4‐flow component analysis technique evaluating the direct flow , retained inflow , delayed ejection flow , and residual volume . Respective flow hemodynamic changes were compared with the corresponding catheterization iNO challenge results. The RV analysis revealed decreased direct flow in patients with PAH when compared with controls ( P <0.001) and increase in residual volume ( P <0.001). Similarly, the left ventricular analysis revealed decreased direct flow in patients with PAH when compared with controls ( P =0.004) and increased proportion of the residual volume ( P =0.014). There was an increase in the RV direct flow during iNO delivery ( P =0.009), with parallel decrease in the residual volume ( P =0.008). Conclusions Children with PAH have abnormal biventricular flow associated with impaired diastolic filling. The flow efficiency is significantly improved in the RV on iNO administration with no change in the left ventricle. The changes in the RV flow have occurred despite the minimal change in catheterization hemodynamics, suggesting that flow hemodynamic evaluation might provide more quantitative insights into vasoreactivity testing in PAH.

A zebrafish forward genetic screen identifies an indispensable threonine residue in the kinase domain of PRKD2

ABSTRACT Protein kinase D2 belongs to a family of evolutionarily conserved enzymes regulating several biological processes. In a forward genetic screen for zebrafish cardiovascular mutants, we identified a mutation in the prkd2 gene. Homozygous mutant embryos develop as wild type up to 36 h post-fertilization and initiate blood flow, but fail to maintain it, resulting in a complete outflow tract stenosis. We identified a mutation in the prkd2 gene that results in a T757A substitution at a conserved residue in the kinase domain activation loop (T714A in human PRKD2) that disrupts catalytic activity and drives this phenotype. Homozygous mutants survive without circulation for several days, allowing us to study the extreme phenotype of no intracardiac flow, in the background of a functional heart. We show dysregulation of atrioventricular and outflow tract markers in the mutants and higher sensitivity to the Calcineurin inhibitor, Cyclosporin A. Finally we identify TBX5 as a potential regulator of PRKD2. Our results implicate PRKD2 catalytic activity in outflow tract development in zebrafish. This article has an associated First Person interview with the first author of the paper.