Vitaly O. Kheyfets

Patient-specific computational modeling of blood flow in the pulmonary arterial circulation

Computational fluid dynamics (CFD) modeling of the pulmonary vasculature has the potential to reveal continuum metrics associated with the hemodynamic stress acting on the vascular endothelium. It is widely accepted that the endothelium responds to flow-induced stress by releasing vasoactive substances that can dilate and constrict blood vessels locally. The objectives of this study are to examine the extent of patient specificity required to obtain a significant association of CFD output metrics and clinical measures in models of the pulmonary arterial circulation, and to evaluate the potential correlation of wall shear stress (WSS) with established metrics indicative of right ventricular (RV) afterload in pulmonary hypertension (PH). Right Heart Catheterization (RHC) hemodynamic data and contrast-enhanced computed tomography (CT) imaging were retrospectively acquired for 10 PH patients and processed to simulate blood flow in the pulmonary arteries. While conducting CFD modeling of the reconstructed patient-specific vasculatures, we experimented with three different outflow boundary conditions to investigate the potential for using computationally derived spatially averaged wall shear stress (SAWSS) as a metric of RV afterload. SAWSS was correlated with both pulmonary vascular resistance (PVR) (R(2)=0.77, P<0.05) and arterial compliance (C) (R(2)=0.63, P<0.05), but the extent of the correlation was affected by the degree of patient specificity incorporated in the fluid flow boundary conditions. We found that decreasing the distal PVR alters the flow distribution and changes the local velocity profile in the distal vessels, thereby increasing the local WSS. Nevertheless, implementing generic outflow boundary conditions still resulted in statistically significant SAWSS correlations with respect to both metrics of RV afterload, suggesting that the CFD model could be executed without the need for complex outflow boundary conditions that require invasively obtained patient-specific data. A preliminary study investigating the relationship between outlet diameter and flow distribution in the pulmonary tree offers a potential computationally inexpensive alternative to pressure based outflow boundary conditions.

Characterization of CMR-derived haemodynamic data in children with pulmonary arterial hypertension

Aims Paediatric pulmonary arterial hypertension (PAH) is manifested as increased arterial pressure and vascular resistive changes followed by progressive arterial stiffening. The aim of this study was to characterize regional flow haemodynamic patterns and markers of vascular stiffness in the proximal pulmonary arteries of paediatric PAH patients, and to explore the association with right ventricular (RV) function. Methods and results Forty paediatric PAH patients and 26 age- and size-matched controls underwent cardiac magnetic resonance studies in order to compute time-resolved wall shear stress metrics, oscillatory shear index (OSI), and vascular strain as measured by relative area change (RAC), and RV volumetric and functional parameters. Phase-contrast imaging planes were positioned perpendicular to the mid-main and right pulmonary arteries (MPA and RPA, respectively). Compared with controls, the PAH group had decreased systolic wall shear stress (dyne cm-2) and RAC (%) in both MPA (WSSsys: 6.5 vs. 4.3, P < 0.0001; RAC: 36 vs. 25, P < 0.0001) and RPA (WSSsys: 11.2 vs. 7.3, P < 0.0001; strain: 37 vs. 30, P < 0.05). The OSI was significantly higher in the MPA of PAH subjects (0.46 vs. 0.17, P < 0.05). WSS measured in the MPA correlated positively with RAC (r = 0.63, P < 0.0001) and RV ejection fraction (%) (r = 0.63, P < 0.0001). Conclusion Wall shear stress, the principal haemodynamic force driving endothelial functional changes, is severely decreased in paediatric PAH patients and correlates with increased stiffness in the proximal pulmonary vasculature and reduced RV function.

Main pulmonary arterial wall shear stress correlates with invasive hemodynamics and stiffness in pulmonary hypertension

Pulmonary hypertension (PH) is associated with proximal pulmonary arterial remodeling characterized by increased vessel diameter, wall thickening, and stiffness. In vivo assessment of wall shear stress (WSS) may provide insights into the relationships between pulmonary hemodynamics and vascular remodeling. We investigated the relationship between main pulmonary artery (MPA) WSS and pulmonary hemodynamics as well as markers of stiffness. As part of a prospective study, 17 PH patients and 5 controls underwent same-day four-dimensional flow cardiac magnetic resonance imaging (4-D CMR) and right heart catheterization. Streamwise velocity profiles were generated in the cross-sectional MPA in 45° increments from velocity vector fields determined by 4-D CMR. WSS was calculated as the product of hematocrit-dependent viscosity and shear rate generated from the spatial gradient of the velocity profiles. In-plane average MPA WSS was significantly decreased in the PH cohort compared with that in controls (0.18 ± 0.07 vs. 0.32 ± 0.08 N/m2; P = 0.01). In-plane MPA WSS showed strong inverse correlations with multiple hemodynamic indices, including pulmonary resistance (ρ = –0.74, P < 0.001), mean pulmonary pressure (ρ = –0.64, P = 0.006), and elastance (ρ = –0.70, P < 0.001). In addition, MPA WSS had significant associations with markers of stiffness, including capacitance (ρ = 0.67, P < 0.001), distensibility (ρ = 0.52, P = 0.013), and elastic modulus (ρ = –0.54, P = 0.01). In conclusion, MPA WSS is decreased in PH and is significantly associated with invasive hemodynamic indices and markers of stiffness. 4-D CMR-based assessment of WSS may represent a novel methodology to study blood-vessel wall interactions in PH.

4D magnetic resonance flow imaging for estimating pulmonary vascular resistance in pulmonary hypertension

To develop an estimate of pulmonary vascular resistance (PVR) using blood flow measurements from 3D velocity‐encoded phase contract magnetic resonance imaging (here termed 4D MRI).

Vorticity is a marker of diastolic ventricular interdependency in pulmonary hypertension.

Our objective was to determine whether left ventricular (LV) vorticity (ω), the local spinning motion of a fluid element, correlated with markers of ventricular interdependency in pulmonary hypertension (PH). Maladaptive ventricular interdependency is associated with interventricular septal shift, impaired LV performance, and poor outcomes in PH patients, yet the pathophysiologic mechanisms underlying fluid-structure interactions in ventricular interdependency are incompletely understood. Because conformational changes in chamber geometry affect blood flow formations and dynamics, LV ω may be a marker of LV-RV (right ventricular) interactions in PH. Echocardiography was performed for 13 PH patients and 10 controls for assessment of interdependency markers, including eccentricity index (EI), and biventricular diastolic dysfunction, including mitral valve (MV) and tricuspid valve (TV) early and late velocities (E and A, respectively) as well as MV septal and lateral early tissue Doppler velocities (e′). Same-day 4-dimensional cardiac magnetic resonance was performed for LV E (early)-wave ω measurement. LV E-wave ω was significantly decreased in PH patients (P = 0.008) and correlated with diastolic EI (Rho = −0.53, P = 0.009) as well as with markers of LV diastolic dysfunction, including MV E(Rho = 0.53, P = 0.011), E/A (Rho = 0.56, P = 0.007), septal e′ (Rho = 0.63, P = 0.001), and lateral e′ (Rho = 0.57, P = 0.007). Furthermore, LV E-wave ω was associated with indices of RV diastolic dysfunction, including TV e′ (Rho = 0.52, P = 0.012) and TV E/A (Rho = 0.53, P = 0.009). LV E-wave ω is decreased in PH and correlated with multiple echocardiographic markers of ventricular interdependency. LV ω may be a novel marker for fluid-tissue biomechanical interactions in LV-RV interdependency.

Apparent Aortic Stiffness in Children with Pulmonary Arterial Hypertension

Background— Left ventricular dysfunction, mediated by ventricular interdependence, has been associated with negative outcomes in children with pulmonary arterial hypertension (PAH). Considering the dilation of the pulmonary arteries as a paramount sign of PAH, we hypothesized that the ascending aorta will present signs of apparent stiffness in children with PAH and that this effect may be because of mechanical interaction with the dilated main pulmonary artery (MPA). Methods and Results— Forty-two children with PAH and 26 age- and size-matched controls underwent comprehensive cardiac magnetic resonance evaluation. Assessment of aortic stiffness was evaluated by measuring pulse wave velocity, aortic strain, and distensibility. Children with PAH had significantly increased pulse wave velocity in the ascending aorta (3.4 versus 2.3 m/s for PAH and controls, respectively; P=0.001) and reduced aortic strain (23% versus 29%; P<0.0001) and distensibility (0.47 versus 0.64%/mm Hg; P=0.02). Indexed MPA diameter correlated with pulse wave velocity (P=0.04) and with aortic strain (P=0.02). The ratio of MPA to aortic size correlated with pulse wave velocity (P=0.0098), strain (P=0.0099), and distensibility (P=0.015). Furthermore, aortic relative area change was associated with left ventricular ejection fraction (P=0.045) and ventricular–vascular coupling ratio (P=0.042). Conclusions— Pediatric PAH patients have increased apparent ascending aortic stiffness, which was strongly associated with the degree of MPA distension. We speculate that distension of the MPA may play a major role in limiting full aortic expansion during systole, which modulates left ventricular performance and impacts systemic hemodynamics in pediatric PAH.

Assessment of N-terminal prohormone B-type natriuretic peptide as a measure of vascular and ventricular function in pediatric pulmonary arterial hypertension

Pulmonary arterial hypertension (PAH) is a progressive disease that puts excessive mechanical loads on the ventricle due to a gradual increase in pulmonary vascular impedance. We hypothesize that the increase in right ventricular (RV) afterload is reflected in the concentration of circulating biochemical markers of ventricular strain and stress (B-type natriuretic peptide [BNP] and N-terminal prohormone BNP [NT-proBNP]). We retrospectively analyzed right heart catheterization (RHC) and serum biochemical analysis data (n = 56) for a pediatric PAH cohort with no sign of left ventricular dysfunction. Using RHC data, we computed an estimate of pulmonary vascular resistance (PVR), compliance, and ventricular-vascular coupling. We also compared how the early onset of interventricular decoupling (characterized as septal flattening) impacts serum NT-proBNP concentrations. Our data revealed correlated NT-proBNP expression with both the resistive and reactive components of RV afterload, an estimate of ventricular-vascular coupling, and a significant increase in biomarker expression in patients with a flattened interventricular septum. Furthermore, the strong correlation between PVR and NT-proBNP appears to break down under flat septum morphology. Over 80% of resistive RV afterload variance is reflected in serum NT-proBNP concentration in pediatric patients with PAH with no sign of left ventricular dysfunction. Reactive afterload appears to contribute to myocardial NT-proBNP release at advanced stages of PAH. Therefore, in mild-to-moderate PAH, resistive afterload is likely the greatest contributor to RV wall stress. These findings could also be used to estimate invasive RHC measurements from serum biochemical analysis, but more work is needed to improve correlations and overcome the issue of interventricular decoupling.

4D-flow cardiac magnetic resonance-derived vorticity is sensitive marker of left ventricular diastolic dysfunction in patients with mild-to-moderate chronic obstructive pulmonary disease

Aims To investigate the possibility that vorticity assessed by four-dimensional flow cardiac magnetic resonance (4D-Flow CMR) in the left ventricle of patients with mild-to-moderate chronic obstructive pulmonary disease (COPD) is a potential marker of early LV diastolic dysfunction (LVDD) and more sensitive than standard echocardiography, and whether changes in vorticity are associated with quantitative computed tomography (CT) and clinical markers of COPD, and right ventricular (RV) echocardiographic markers indicative of ventricular interdependency. Methods and results Sixteen COPD patients with presumptive LVDD and 10 controls underwent same-day 4D-Flow CMR and Doppler echocardiography to quantify early and late diastolic vorticity as well as standard evaluation for LVDD. Furthermore, all patients underwent detailed CT analysis for COPD markers including percent emphysema and air trapping. The 4D-Flow CMR derived diastolic vorticity measures were correlated with CT measures, standard clinical and CMR markers, and echocardiographic diastolic RV metrics. Early diastolic vorticity was significantly reduced in COPD patients (P < 0.0001) with normal left ventricular (LV) mass, geometry, systolic function, and no or mild signs of Doppler LVDD when compared with controls. Vorticity significantly differentiated COPD patients without echocardiographic signs of LVDD (n = 11) from controls (P < 0.0001), and from COPD patients with stage I LVDD (n = 5) (P < 0.0180). Vorticity markers significantly correlated with CT computed measures, CMR-derived RV ejection fraction, echocardiographic RV diastolic metrics, and 6-minute walk test. Conclusion 4D-Flow CMR derived diastolic vorticity is reduced in patients with mild-to-moderate COPD and no or mild signs of LVDD, implying early perturbations in the LV flow domain preceding more obvious mechanical changes (i.e. stiffening and dilation). Furthermore, reduced LV vorticity appears to be driven by COPD induced changes in lung tissue and parallel RV dysfunction.

Helicity and vorticity of pulmonary arterial flow in patients with pulmonary hypertension: Quantitative analysis of flow formations

Background Qualitative and quantitative flow hemodynamic indexes have been shown to reflect right ventricular (RV) afterload and function in pulmonary hypertension (PH). We aimed to quantify flow hemodynamic formations in pulmonary arteries using 4‐dimensional flow cardiac magnetic resonance imaging and the spatial velocity derivatives helicity and vorticity in a heterogeneous PH population. Methods and Results Patients with PH (n=35) and controls (n=10) underwent 4‐dimensional flow magnetic resonance imaging study for computation of helicity and vorticity in the main pulmonary artery (MPA), the right pulmonary artery, and the RV outflow tract. Helicity and vorticity were correlated with standard RV volumetric and functional indexes along with MPA stiffness assessed by measuring relative area change. Patients with PH had a significantly decreased helicity in the MPA (8 versus 32 m/s2; P<0.001), the right pulmonary artery (24 versus 50 m/s2; P<0.001), and the RV outflow tract–MPA unit (15 versus 42 m/s2; P<0.001). Vorticity was significantly decreased in patients with PH only in the right pulmonary artery (26 versus 45 1/s; P<0.001). Total helicity computed correlated with the cardiac magnetic resonance imaging–derived ventricular‐vascular coupling (−0.927; P<0.000), the RV ejection fraction (0.865; P<0.0001), cardiac output (0.581; P<0.0001), mean pulmonary arterial pressure (−0.581; P=0.0008), and relative area change measured at the MPA (0.789; P<0.0001). Conclusions The flow hemodynamic character in patients with PH assessed via quantitative analysis is considerably different when compared with healthy and normotensive controls. A strong association between helicity in pulmonary arteries and ventricular‐vascular coupling suggests a relationship between the mechanical and flow hemodynamic domains.

A Zero-Dimensional Model and Protocol for Simulating Patient-Specific Pulmonary Hemodynamics From Limited Clinical Data

In pulmonary hypertension (PH) diagnosis and management, many useful functional markers have been proposed that are unfeasible for clinical implementation. For example, assessing right ventricular (RV) contractile response to a gradual increase in pulmonary arterial (PA) impedance requires simultaneously recording RV pressure and volume, and under different afterload/preload conditions. In addition to clinical applications, many research projects are hampered by limited retrospective clinical data and could greatly benefit from simulations that extrapolate unavailable hemodynamics. The objective of this study was to develop and validate a 0D computational model, along with a numerical implementation protocol, of the RV-PA axis. Model results are qualitatively compared with published clinical data and quantitatively validated against right heart catheterization (RHC) for 115 pediatric PH patients. The RV-PA circuit is represented using a general elastance function for the RV and a three-element Windkessel initial value problem for the PA. The circuit mathematically sits between two reservoirs of constant pressure, which represent the right and left atriums. We compared Pmax, Pmin, mPAP, cardiac output (CO), and stroke volume (SV) between the model and RHC. The model predicted between 96% and 98% of the variability in pressure and 98-99% in volumetric characteristics (CO and SV). However, Bland Altman plots showed the model to have a consistent bias for most pressure and volumetric parameters, and differences between model and RHC to have considerable error. Future studies will address this issue and compare specific waveforms, but these initial results are extremely promising as preliminary proof of concept of the modeling approach.