Publications by authors named "Kendall S Hunter"

59 Publications

The Right Ventricular-Pulmonary Arterial Coupling and Diastolic Function Response to Therapy in Pulmonary Arterial Hypertension.

Chest 2021 Oct 9. Epub 2021 Oct 9.

Department of Medicine, University of Arizona, Tucson, AZ; Division of Pulmonary, Critical Care, Sleep, and Allergy Medicine, University of Arizona, Tucson, AZ. Electronic address:

Background: Multiparametric risk assessment is used in pulmonary arterial hypertension (PAH) to target therapy. However, this strategy is imperfect as most patients remain in intermediate or high risk after initial treatment with low risk being the goal. Metrics of right ventricular (RV) adaptation are promising tools that may help refine our therapeutic strategy.

Research Question: Does RV adaptation predict therapeutic response over time?

Study Design And Methods: We evaluated 52 incident treatment naïve patients with advanced PAH by catheterization and cardiac imaging longitudinally at baseline, follow-up 1 (∼3 mo.) and follow-up 2 (∼18 mo.). All patients were placed on goal-directed therapy with parenteral treprostinil and/or combination therapy with treatment escalation if functional class I-II was not achieved. Therapeutic response was evaluated at follow-up 1 as non-responders (died) or responders and again at follow-up 2 as super-responders (low risk) or partial-responders (high/intermediate risk). Multiparametric risk was based on a simplified ERS/ESC guideline score. RV adaptation was evaluated with the single-beat coupling ratio (Ees/Ea) and diastolic function with diastolic elastance (Eed). Data are expressed as mean±SD or odds ratio [95%CI].

Results: Nine patients (17%) were non-responders. PAH-directed therapy improved ERS low risk from 1 (2%) at baseline to 23 (55%) at follow-up 2. Ees/Ea at presentation was non-significantly higher in responders (0.9±0.4) versus non-responders (0.6±0.4, p=0.09) but was unable to predict super-responder status at follow-up 2 (odds ratio 1.40 [0.28-7.0], p=0.84). Baseline RVEF and change in Eed successfully predicted super-responder status at follow-up 2 (odds ratio 1.15 [1.0-1.27], p=0.009 and 0.29 [0.86-0.96], p=0.04, respectively).

Interpretation: In patients with advanced PAH, RV-PA coupling could not discriminate irreversible RV failure (non-responders) at presentation but showed a late trend to improvement by follow-up 2. Early change in Eed and baseline RVEF were the best predictors of therapeutic response.
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http://dx.doi.org/10.1016/j.chest.2021.09.040DOI Listing
October 2021

Pulmonary arterial banding in mice may be a suitable model for studies on ventricular mechanics in pediatric pulmonary arterial hypertension.

J Cardiovasc Magn Reson 2021 06 3;23(1):66. Epub 2021 Jun 3.

Department of Bioengineering, University of Colorado Denver, Denver, CO, USA.

Background: The role of interventricular mechanics in pediatric pulmonary arterial hypertension (PAH) and its relation to right ventricular (RV) dysfunction has been largely overlooked. Here, we characterize the impact of maintained pressure overload in the RV-pulmonary artery (PA) axis on myocardial strain and left ventricular (LV) mechanics in pediatric PAH patients in comparison to a preclinical PA-banding (PAB) mouse model. We hypothesize that the PAB mouse model mimics important aspects of interventricular mechanics of pediatric PAH and may be beneficial as a surrogate model for some longitudinal and interventional studies not possible in children.

Methods: Balanced steady-state free precession (bSSFP) cardiovascular magnetic resonance (CMR) images of 18 PAH and 17 healthy (control) pediatric subjects were retrospectively analyzed using CMR feature-tracking (FT) software to compute measurements of myocardial strain. Furthermore, myocardial tagged-CMR images were also analyzed for each subject using harmonic phase flow analysis to derive LV torsion rate. Within 48 h of CMR, PAH patients underwent right heart catheterization (RHC) for measurement of PA/RV pressures, and to compute RV end-systolic elastance (RV_E, a measure of load-independent contractility). Surgical PAB was performed on mice to induce RV pressure overload and myocardial remodeling. bSSFP-CMR, tagged CMR, and intra-cardiac catheterization were performed on 12 PAB and 9 control mice (Sham) 7 weeks after surgery with identical post-processing as in the aforementioned patient studies. RV_E was assessed via the single beat method.

Results: LV torsion rate was significantly reduced under hypertensive conditions in both PAB mice (p = 0.004) and pediatric PAH patients (p < 0.001). This decrease in LV torsion rate correlated significantly with a decrease in RV_E in PAB (r = 0.91, p = 0.05) and PAH subjects (r = 0.51, p = 0.04). In order to compare combined metrics of LV torsion rate and strain parameters principal component analysis (PCA) was used. PCA revealed grouping of PAH patients with PAB mice and control subjects with Sham mice. Similar to LV torsion rate, LV global peak circumferential, radial, and longitudinal strain were significantly (p < 0.05) reduced under hypertensive conditions in both PAB mice and children with PAH.

Conclusions: The PAB mouse model resembles PAH-associated myocardial mechanics and may provide a potential model to study mechanisms of RV/LV interdependency.
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http://dx.doi.org/10.1186/s12968-021-00759-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8173855PMC
June 2021

Abnormal pulmonary flow is associated with impaired right ventricular coupling in patients with COPD.

Int J Cardiovasc Imaging 2021 Oct 21;37(10):3039-3048. Epub 2021 May 21.

Division of Cardiology, Heart Institute, Children's Hospital Colorado, University of Colorado Denver, Anschutz Medical Campus, 13123 E 16th Ave, Aurora, CO, 80045-2560, USA.

Cor Pulmonale or right ventricular (RV) dysfunction due to pulmonary disease is an expected complication of COPD resulting primarily from increased afterload mediated by chronic alveolar hypoxemia and resulting hypoxic pulmonary vasoconstriction. Early detection of elevated RV afterload has been previously demonstrated by visualization of abnormal flow patterns in the proximal pulmonary arteries. Prior analysis of helicity in the pulmonary arteries in pulmonary hypertension patients has demonstrated a strong association between helicity and increased RV afterload. However, these flow hemodynamics have yet to be fully explored in patients with COPD. We hypothesized that patients with COPD will have abnormal pulmonary flow as evaluated by 4D-Flow MRI and associated with RV function and pulmonary arterial stiffness. Patients with COPD (n = 15) (65 years ± 6) and controls (n = 10) (58 years ± 9) underwent 4D-Flow MRI to calculate helicity. The helicity was calculated in the main pulmonary artery (MPA) and along the RV outflow tract (RVOT)-MPA axis. Main pulmonary arterial stiffness was measured using the relative area change (RAC). We found COPD patients had decreased helicity relative to healthy controls in the MPA (19.4 ± 7.8vs 32.8 ± 15.9, P = 0.007) and reduced helicity along the RVOT-MPA axis (33.2 ± 9.0 vs 43.5 ± 8.3, P = 0.010). Our investigation indicates a strong association between helicity along the MPA-RV outflow tract axis and RV function and suggests that 4D-Flow MRI might be a sensitive tool in evaluating RV-pulmonary arterial coupling in COPD.
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http://dx.doi.org/10.1007/s10554-021-02285-1DOI Listing
October 2021

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.

J Am Heart Assoc 2021 04 6;10(8):e020548. Epub 2021 Apr 6.

Division of Cardiology Heart Institute Children's Hospital ColoradoUniversity of Colorado DenverAnschutz Medical Campus Aurora CO USA.

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 , , , and . 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 (<0.001) and increase in residual volume (<0.001). Similarly, the left ventricular analysis revealed decreased direct flow in patients with PAH when compared with controls (=0.004) and increased proportion of the residual volume (=0.014). There was an increase in the RV direct flow during iNO delivery (=0.009), with parallel decrease in the residual volume (=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.
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http://dx.doi.org/10.1161/JAHA.120.020548DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8174179PMC
April 2021

Serum copeptin and NT-proBNP is associated with central aortic stiffness and flow hemodynamics in adolescents with type 1 diabetes: A pilot study.

J Diabetes Complications 2021 05 6;35(5):107883. Epub 2021 Feb 6.

Department of Pediatric Endocrinology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA. Electronic address:

Aims: Cardiovascular disease (CVD) is the major cause of mortality in type 1 diabetes (T1D). Biomarkers, N-terminal pro-brain natriuretic peptide (NT-proBNP) and copeptin have been linked with measures of CVD, but their relationship in adolescents with T1D remains incompletely understood. Accordingly, we examined the associations between NT-proBNP and copeptin and hemodynamic markers of central aortic stiffness in adolescents with T1D.

Methods: In this pilot study, forty-nine pubertal adolescents with T1D (mean age 17 ± 2 years, median [Q1-Q3] Tanner Stage 5 [5, 5] and HbA1c 8.5 ± 1.5%), from the EMERALD study, were assessed for copeptin and NT-proBNP, and indices of central aortic stiffness non-invasively assessed by MRI. Pearson correlations and generalized linear regression models, adjusting for confounders, were applied to examine the relationships between biomarkers and vascular measures.

Results: Copeptin correlated independently with both ascending aortic (AA) (β ± SE: -4.28 ± 1.87, p = 0.03) and descending aortic (DA) relative area change (RAC) (-3.41 ± 1.55, p = 0.04). NT-proBNP was independently associated with DA time-averaged wall shear stress (WSS) (0.87 ± 0.25, p = 0.001) and DA maximum wall shear stress (WSS) (2.45 ± 1.00, p = 0.02).

Conclusions: Serum copeptin and NT-proBNP may be associated with central aortic stiffness and elevated WSS in youth with T1D, potentially offering a non-invasive way to identify and monitor the development of early CVD in an at-risk population.
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http://dx.doi.org/10.1016/j.jdiacomp.2021.107883DOI Listing
May 2021

Patients with Fontan circulation have abnormal aortic wave propagation patterns: A wave intensity analysis study.

Int J Cardiol 2021 01 25;322:158-167. Epub 2020 Aug 25.

Heart Institute, Children's Hospital Colorado, University of Colorado - Denver, Anschutz Medical Campus, USA.

Background: Elevated systemic afterload in patients with Fontan circulation may lead to impaired single ventricular function. Wave intensity analysis (WIA) enables evaluation of compression and expansion waves traveling through vasculature. We aimed to investigate the unfavorable wave propagation causing excessive afterload may be an important contributor to the overall single ventricle function and to the limited functional capacity in this patient population.

Methods: Patients with hypoplastic left heart syndrome (HLHS) (n = 25), single left ventricle (SLV) (n = 24), and normal controls (n = 10) underwent phase-contrast MRI based WIA analysis evaluated in the ascending aorta. Forward compression wave (FCW) representing dP/dt, backward compression wave (BCW) reflecting vascular stiffness, and forward decompression wave (FDW) representing LV relaxation were recorded and indexed to each other.

Results: FCW was lowest in HLHS patients (1098 mm/s), and higher in the SLV group (1457 mm5/s), and controls (6457 mm5/s) (P < 0.001). BCW/FCW was increased in HLHS (0.22) and SLV (0.14) groups compared to controls (0.08) (P = 0.003). Peak VO2 correlated with FCW (R = 0.50, P = 0.015), stroke volume (R = 0.72, P < 0.001), and cardiac output (R = 0.44, P = 0.034).

Conclusions: Patients with HLHS and SLV have unfavorable aortic WIA patterns with increased BCW/FCW ratio indicating increased systemic afterload due to retrograde compression waves. Reduced FCW and systolic MRI indices correlated with peak VO2 suggesting that abnormal systolic wave propagation may play a role in exercise intolerance for Fontan patients.
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http://dx.doi.org/10.1016/j.ijcard.2020.08.063DOI Listing
January 2021

Flow profile characteristics in Fontan circulation are associated with the single ventricle dilation and function: principal component analysis study.

Am J Physiol Heart Circ Physiol 2020 05 13;318(5):H1032-H1040. Epub 2020 Mar 13.

Division of Cardiology, Heart Institute, Children's Hospital Colorado, University of Colorado Denver, Anschutz Medical Campus, Denver, Colorado.

The Fontan circulation is characterized as a nonpulsatile flow propagation without a pressure-generating ventricle. However, flow through the Fontan circulation still exhibits oscillatory waves as a result of pressure changes generated by the systemic single ventricle. Identification of discrete flow patterns through the Fontan circuit may be important to understand single ventricle performance. Ninety-seven patients with Fontan circulation underwent phase-contrast MRI of the right pulmonary artery, yielding subject-specific flow waveforms. Principal component (PC) analysis was performed on preprocessed flow waveforms. Principal components were then correlated with standard MRI indices of function, volume, and aortopulmonary collateral flow. The first principal component (PC) described systolic versus diastolic-dominant flow through the Fontan circulation, accounting for 31.3% of the variance in all waveforms. The first PC correlated with end-diastolic volume ( = 0.34, = 0.001), and end-systolic volume ( = 0.30, = 0.003), cardiac index ( = 0.51, < 0.001), and the amount of aortopulmonary collateral flow ( = 0.25, = 0.027)-lower ventricular volumes and a smaller volume of collateral flow-were associated with diastolic-dominant cavopulmonary flow. The second PC accounted for 19.5% of variance and described late diastolic acceleration versus deceleration and correlated with ejection fraction-diastolic deceleration was associated with higher ejection fraction. Principal components describing the diastolic flow variations in pulmonary arteries are related to the single ventricle function and volumes. Particularly, diastolic-dominant flow without late acceleration appears to be related to preserved ventricular volume and function, respectively. The exact physiological significance of flow oscillations of phasic and temporal flow variations in Fontan circulation is unknown. With the use of principal component analysis, we discovered that flow variations in the right pulmonary artery of Fontan patients are related to the single ventricle function and volumes. Particularly, diastolic-dominant flow without late acceleration appears to be related to more ideal ventricular volume and systolic function, respectively.
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http://dx.doi.org/10.1152/ajpheart.00686.2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8302236PMC
May 2020

Relation between right ventricular wall stress, fibrosis, and function in right ventricular pressure loading.

Am J Physiol Heart Circ Physiol 2020 02 30;318(2):H366-H377. Epub 2019 Dec 30.

The Labatt Family Heart Centre and Department of Pediatrics, University of Toronto, Toronto, Ontario, Canada.

Right ventricle (RV) pressure loading can lead to RV fibrosis and dysfunction. We previously found increased RV, septal hinge-point and left ventricle (LV) fibrosis in experimental RV pressure loading. However, the relation of RV wall stress to biventricular fibrosis and dysfunction is incompletely defined. Rabbits underwent progressive pulmonary artery banding (PAB) over 3 wk with hemodynamics, echocardiography, and myocardial samples obtained at a terminal experiment at 6 wk. An additional group received PAB and treatment with an endothelin receptor antagonist. The endocardial and epicardial borders of short-axis echo images were traced and analyzed with invasive pressures to yield regional end-diastolic (ED) and end-systolic (ES) wall stress. To increase clinical translation, computer model-derived wall stress was compared with Laplace wall stress. The relation of wall stress with fibrosis (picrosirius red staining) and ventricular function was analyzed. ED wall stress in all regions and RV and LV free-wall ES wall stress were increased in PAB rabbits versus sham animals. Laplace wall stress correlated well with computational models. In PAB, fibrosis was highest in the RV free wall, then septal hinge regions, and lowest in the septum and LV free wall. Fibrosis was moderately related to ED ( = 0.47, = 0.0011), but not ES wall stress. RV ED wall stress was strongly related to echo indexes of function (strain rate:  = 0.71, = 0.048; ',  = -0.75, = 0.0077; tricuspid annular plane systolic excursion:  = 0.85, = 0.0038) and RV fractional area change ( = 0.77, = 0.027). ED, more than ES, wall stress is related moderately to fibrosis and strongly to function in experimental RV pressure loading, especially at the septal hinge-point regions, where fibrosis is prominent. This suggests that wall stress partially links RV pressure loading, fibrosis, and dysfunction and may be useful to follow clinically. Biventricular fibrosis and dysfunction impact outcomes in RV pressure loading, but their relation to wall stress is poorly defined. Using a pulmonary artery band rabbit model, we entered echocardiography and catheter data into a computer model to yield regional end-diastolic (EDWS) and end-systolic (ESWS) wall stress. EDWS, more than ESWS, correlated with fibrosis and dysfunction, especially at the fibrosis-intense septal hinge-point regions. Thus, wall stress may be clinically useful in linking RV pressure loading to regional fibrosis and dysfunction.
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http://dx.doi.org/10.1152/ajpheart.00343.2019DOI Listing
February 2020

Parameters of Right Ventricular Function Reveal Ventricular-Vascular Mismatch as Determined by Right Ventricular Stroke Work versus Pulmonary Vascular Resistance in Children with Pulmonary Hypertension.

J Am Soc Echocardiogr 2020 02 10;33(2):218-225. Epub 2019 Dec 10.

Division of Cardiology, The Labatt Family Heart Center, Hospital for Sick Children and University of Toronto, Toronto, Ontario, Canada.

Background: Right ventricular (RV) failure, a determinant of outcomes in pulmonary hypertension (PH), occurs when the right ventricle cannot compensate for increased afterload. The authors showed that RV stroke work (RVSW) can be estimated in children with PH as the product of stroke volume and RV pressure and is related to adverse outcomes. The aim of this study was to test the hypothesis that ventricular-vascular (VV) mismatch (high afterload and low RVSW) is associated with echocardiographic measures of RV performance and adverse outcomes.

Methods: Invasive hemodynamic data and concurrent echocardiograms were reviewed. Fifty subjects with PH were included. Four groups were created by dividing the patients using median RVSW and median pulmonary vascular resistance. For each group, tricuspid annular plane systolic excursion, fractional area change, myocardial performance index, and anterior RV wall thickness were determined. Both major (i.e., death) and minor (i.e., worsening World Health Organization class) clinical outcomes were tabulated. Groups were compared using the Kruskal-Wallis or Fisher exact test.

Results: Patients in the high pulmonary vascular resistance/low RVSW cohort (VV mismatch) had the worst RV dysfunction: median tricuspid annular plane systolic excursion, 0.8 cm (interquartile range, 0.7-0.8 cm; P = .0002); median fractional area change, 0.29% (interquartile range, 0.27%-0.30%; P = .004); median myocardial performance index, 0.622 (interquartile range, 0.548-0.789; P = .0004). This group had the highest incidence of adverse outcomes: major events in 40%, minor events in 80%, and syncope in 60%.

Conclusion: VV mismatch in pediatric PH can be assessed using RVSW and pulmonary vascular resistance and is associated with RV performance and adverse events. RVSW increases in compensated high-afterload states and falls as the right ventricle fails to meet increased load; thus, VV matching status may be a sensitive predictor of outcomes in pediatric PH.
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http://dx.doi.org/10.1016/j.echo.2019.09.013DOI Listing
February 2020

Differences in pulmonary arterial flow hemodynamics between children and adults with pulmonary arterial hypertension as assessed by 4D-flow CMR studies.

Am J Physiol Heart Circ Physiol 2019 05 1;316(5):H1091-H1104. Epub 2019 Mar 1.

Division of Pediatric Cardiology, Heart Institute, Children's Hospital Colorado, University of Colorado Denver, Anschutz Medical Campus, Aurora, Colorado.

Despite different developmental and pathological processes affecting lung vascular remodeling in both patient populations, differences in 4D MRI findings between children and adults with PAH have not been studied. The purpose of this study was to compare flow hemodynamic state, including flow-mediated shear forces, between pediatric and adult patients with PAH matched by severity of pulmonary vascular resistance index (PVRi). Adults ( = 10) and children ( = 10) with PAH matched by pulmonary vascular resistance index (PVRi) and healthy adult ( = 10) and pediatric ( = 10) subjects underwent comprehensive 4D-flow MRI to assess peak systolic wall shear stress (WSS) measured in the main (MPA), right (RPA), and left pulmonary arteries (LPA), viscous energy loss (E) along the MPA-RPA and MPA-LPA tract, and qualitative analysis of secondary flow hemodynamics. WSS was decreased in all pulmonary vessels in children with PAH when compared with the same age group (all < 0.05). Similarly, WSS was decreased in all pulmonary vessels in adult PAH patients when compared with healthy adult subjects (all < 0.01). Average E was increased in adult patients with PAH when compared with the same age group along both MPA-RPA ( = 0.020) and MPA-LPA ( = 0.025) tracts. There were no differences in E indices between adults and pediatric patients. Children and adult patients with PAH have decreased shear hemodynamic forces. However, pathological flow hemodynamic formations appear to be more consistent in adult patients, whereas flow hemodynamic abnormalities appear to be more variable in children with PAH for comparable severity of PVRi. Both children and adult patients with PAH have decreased shear hemodynamic forces inside the pulmonary arteries associated with the degree of vessel dilation and stiffness. These differences also exist between healthy normotensive children and adults. However, pathological flow hemodynamic formations appear to more uniform in adult patients, whereas in children with PAH flow, hemodynamic abnormalities appear to be more variable. Pathological flow formations appear not to have a major effect on viscous energy loss associated with the flow conduction through proximal pulmonary arteries.
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http://dx.doi.org/10.1152/ajpheart.00802.2018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7327229PMC
May 2019

Influence of aortic stiffness on ventricular function in patients with Fontan circulation.

J Thorac Cardiovasc Surg 2019 02 5;157(2):699-707. Epub 2018 Oct 5.

Division of Cardiology, Heart Institute, Children's Hospital Colorado, University of Colorado Denver Anschutz Medical Campus, Denver, Colo.

Objective: Elastic properties of the thoracic aorta are responsible for buffering systemic afterload, and may be particularly important in patients with Fontan circulation, in whom heart failure is a major source of attrition. The purpose of this study was to characterize regional stiffness in the ascending and descending aorta in patients with hypoplastic left heart syndrome and single left ventricle morphology after Fontan operation by cardiac magnetic resonance imaging, and to assess whether changes in aortic stiffness are associated with the ventricular function.

Methods: Phase-contrast-derived pulse-wave velocity (PWV) and relative-area change (RAC) were measured in the ascending and descending aorta of patients with hypoplastic left heart syndrome (n = 9), patients with single left ventricle circulation (n = 18), and normal controls (n = 8) by magnetic resonance imaging. Stiffness metrics were then correlated with the ventricular volumetric and functional indices.

Results: Patients with hypoplastic left heart syndrome had elevated ascending aortic PWV along with reduced RAC when compared with controls (both P values < .001). Patients with a single left ventricle presented no change in PWV but had reduced RAC in comparison to controls (P < .01). There were no differences in PWV and RAC between all considered groups in the descending aorta. PWV and RAC measured in the ascending aorta correlated with end-systolic and end-diastolic volume indices, ventricular ejection fraction, and ventricular-vascular coupling ratio.

Conclusions: Aortic stiffness is most elevated in patients with hypoplastic left heart syndrome, yet patients with single left ventricle morphology show signs of abnormal stiffness as well in the form of reduced aortic strain. Stiffness indices measured in the ascending aorta were associated with overall ventricular function and measures of aortoventricular coupling in both patient populations.
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http://dx.doi.org/10.1016/j.jtcvs.2018.09.039DOI Listing
February 2019

Noninvasive wave intensity analysis predicts functional worsening in children with pulmonary arterial hypertension.

Am J Physiol Heart Circ Physiol 2018 10 13;315(4):H968-H977. Epub 2018 Jul 13.

Division of Cardiology, Heart Institute, Children's Hospital Colorado, University of Colorado Anschutz Medical Campus , Aurora, Colorado.

The purpose of the present study was to characterize pulmonary vascular stiffness using wave intensity analysis (WIA) in children with pulmonary arterial hypertension (PAH), compare the WIA indexes with catheterization- and MRI-derived hemodynamics, and assess the prognostic ability of WIA-derived biomarkers to predict the functional worsening. WIA was performed in children with PAH ( n = 40) and healthy control subjects ( n = 15) from phase-contrast MRI-derived flow and area waveforms in the main pulmonary artery (MPA). From comprehensive WIA spectra, we collected and compared with healthy control subjects forward compression waves (FCW), backward compression waves (BCW), forward decompression waves (FDW), and wave propagation speed ( c-MPA). There was no difference in the magnitude of FCW between PAH and control groups (88 vs. 108 mm·s·ml, P = 0.239). The magnitude of BCW was increased in patients with PAH (32 vs. 5 mm·s·ml, P < 0.001). There was no difference in magnitude of indexed FDW (32 vs. 28 mm·s·ml, P = 0.856). c-MPA was increased in patients with PAH (3.2 vs. 1.6 m/s, P < 0.001). BCW and FCW correlated with mean pulmonary arterial pressure, right ventricular volumes, and ejection fraction. Elevated indexed BCW [heart rate (HR) = 2.91, confidence interval (CI): 1.18-7.55, P = 0.019], reduced indexed FDW (HR = 0.34, CI: 0.11-0.90, P = 0.030), and increased c-MPA (HR = 3.67, CI: 1.47-10.20, P = 0.004) were strongly associated with functional worsening of disease severity. Our results suggest that noninvasively derived biomarkers of pulmonary vascular resistance and stiffness may be helpful for determining prognosis and monitoring disease progression in children with PAH. NEW & NOTEWORTHY Wave intensity analysis (WIA) studies are lacking in children with pulmonary arterial hypertension (PAH) partially because WIA, which is necessary to assess vascular stiffness, requires an invasive pressure-derived waveform along with simultaneous flow measurements. We analyzed vascular stiffness using WIA in children with PAH who underwent phase-contrast MRI and observed significant differences in WIA indexes between patients with PAH and control subjects. Furthermore, WIA indexes were predictive of functional worsening and were associated with standard catheterization measures.
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http://dx.doi.org/10.1152/ajpheart.00227.2018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6737454PMC
October 2018

Lung and airway shape in neuroendocrine cell hyperplasia of infancy.

Pediatr Radiol 2018 11 28;48(12):1745-1754. Epub 2018 Jun 28.

Department of Pediatrics and Breathing Institute, Children's Hospital Colorado, University of Colorado Anschutz Medical Campus, 13123 E. 16th Ave. B-395, Aurora, CO, 80045, USA.

Background: Neuroendocrine cell hyperplasia of infancy (NEHI) is a rare lung disease associated with significant air trapping. Although chest CT is crucial in establishing a diagnosis, CT and biopsy findings do not reveal airway abnormalities to explain the air trapping.

Objective: We compared lung and airway morphology obtained from chest CT scans in children with NEHI and control children. In the children with NEHI, we explored relationships between lung and airway shape and lung function.

Materials And Methods: We performed a retrospective review of children with NEHI who underwent clinical chest CT. We identified control children of similar size and age. We created lung masks and airway skeletons using semi-automated software and compared them using statistical shape modeling methods. Then we calculated a logistic regression model using lung and airway shape to differentiate NEHI from controls, and we compared shape model parameters to lung function measurements.

Results: Airway and lung shapes were statistically different between children with NEHI and controls. We noted a broad lung apex in the children with NEHI and a significantly increased apical anterior-posterior lung diameter. A logistic regression model including lung shape was 90% accurate in differentiating children with NEHI from controls. Correlation coefficients were significant between lung function values and lung and airway shape.

Conclusion: Lung and airway shapes were different between children with NEHI and control children in this cohort. Children with NEHI had an increased anteroposterior diameter of their lungs that might be useful in the diagnostic criteria.
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http://dx.doi.org/10.1007/s00247-018-4189-6DOI Listing
November 2018

Proximal pulmonary vascular stiffness as a prognostic factor in children with pulmonary arterial hypertension.

Eur Heart J Cardiovasc Imaging 2019 02;20(2):209-217

Division of Cardiology, Heart Institute, Children's Hospital Colorado, University of Colorado Denver, Anschutz Medical Campus, 13123 E 16th Avenue, Aurora, CO, USA.

Aims: Main pulmonary artery (MPA) stiffness and abnormal flow haemodynamics in pulmonary arterial hypertension (PAH) are strongly associated with elevated right ventricular (RV) afterload and associated with disease severity and poor clinical outcomes in adults with PAH. However, the long-term effects of MPA stiffness on RV function in children with PAH remain poorly understood. This study is the first comprehensive evaluation of MPA stiffness in children with PAH, delineating the mechanistic relationship between flow haemodynamics and MPA stiffness as well as the prognostic ability of these measures regarding clinical outcomes.

Methods And Results: Fifty-six children diagnosed with PAH underwent baseline cardiac magnetic resonance (CMR) acquisition and were compared with 23 control subjects. MPA stiffness and wall shear stress (WSS) were evaluated using phase contrast CMR and were evaluated for prognostic potential along with standard RV volumetric and functional indices. Pulse wave velocity (PWV) was significantly increased (2.8 m/s vs. 1.4 m/s, P < 0.0001) and relative area change (RAC) was decreased (25% vs. 37%, P < 0.0001) in the PAH group, correlating with metrics of RV performance. Decreased WSS was associated with a decrease in RAC over time (r = 0.679, P < 0.001). For each unit increase in PWV, there was approximately a 3.2-fold increase in having a moderate clinical event.

Conclusion: MPA stiffness assessed by non-invasive CMR was increased in children with PAH and correlated with RV performance, suggesting that MPA stiffness is a major contribution to RV dysfunction. PWV is predictive of moderate clinical outcomes, and may be a useful prognostic marker of disease activity in children with PAH.
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http://dx.doi.org/10.1093/ehjci/jey069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6343079PMC
February 2019

Children with kawasaki disease present elevated stiffness of great arteries: Phase-contrast MRI study.

J Magn Reson Imaging 2018 11 29;48(5):1228-1236. Epub 2018 Apr 29.

Department of Radiology, Children's Hospital Colorado, University of Colorado Denver, Anschutz Medical Campus, Denver, Colorado, USA.

Background: Patients with diagnosed Kawasaki disease (KD) are known to develop extracardiac vascular lesions and are prone to accelerated stiffening of medium-size arteries.

Purpose: To noninvasively evaluate great vessel (central aorta and main pulmonary artery (MPA)) stiffness using phase-contrast MRI (PC-MRI).

Study Type: Retrospective review.

Subjects: Thirty-three patients with previously diagnosed KD and 15 control subjects underwent PC-MRI evaluation.

Field Strength/sequence: A free-breathing PC-MRI sequence was applied with Cartesian encoding and retrospective sorting using a 1.5 or 3.0T system.

Assessment: We evaluated regionally specific vessel stiffness using pulse-wave velocity (PWV) and relative area change (RAC) at the ascending aorta, descending aorta, and MPA.

Statistical Tests: Hemodynamics among patients with KD and controls were compared using Student's t-test, Wilcoxon Rank-sum, and χ . Additional group-specific comparisons were performed using Kruskal-Wallis or one-way analysis of variance (ANOVA).

Results: Patients with KD showed elevated PWV in both ascending (5.0 ± 1.2 vs. 2.4 ± 0.5, P < 0.001) and descending aorta (4.4 ± 2.1 vs. 2.8 ± 0.8, P < 0.001). RAC was correspondingly reduced in both segments (both P < 0.01). PWV measured in MPA was increased in KD patients (2.2 ± 0.5 vs. 1.5 ± 0.6, P = 0.045) while the RAC was reduced (34 ± 6 vs. 47 ± 3, P = 0.045). There were no associations between considered vessel stiffness indices and respective ventricular size and function, functional indices, and no correlations were observed with KD severity markers.

Data Conclusion: Patients with KD have elevated great vessel stiffness measured at the chronic stage of the disease. Accelerated stiffness process does not appear to affect biventricular function in youth Level of Evidence: 1 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018;47:1228-1236.
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http://dx.doi.org/10.1002/jmri.26167DOI Listing
November 2018

Aortic stiffness in adolescent Turner and Marfan syndrome patients.

Eur J Cardiothorac Surg 2018 11;54(5):926-932

Division of Congenital Heart Surgery, Department of Surgery, Heart Institute, Children's Hospital Colorado, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA.

Objectives: Turner syndrome (TS) and Marfan syndrome (MFS) are partially characterized by aortopathies with a risk of developing severe aortic dilation, stiffness and consequent dissection and aneurysm formation. The incidence of a bicuspid aortic valve (BAV) is also increased in TS. We investigated aortic stiffness in teenage TS and MFS patients and evaluated to what degree stiffness in TS patients is augmented by the presence of a BAV.

Methods: Fifty-seven patients with TS (n = 37) and MFS (n = 20), as well as 22 controls with similar age and size distribution underwent evaluation of thoracic aortic stiffness using phase-contrast magnetic resonance imaging. Calculated stiffness indices including pulse wave velocity (PWV), distensibility and relative area change (RAC) were collected to characterize the ascending aorta and descending aorta. PWV was also determined to evaluate global aortic arch stiffness.

Results: Patients with TS had reduced distensibility (0.43 vs 0.58%/mmHg, P < 0.05) and RAC (21 vs 29%, P < 0.01) in the ascending aorta when compared with normal controls. Similarly, patients with MFS had reduced ascending aortic distensibility (0.39 vs 0.58%/mmHg, P < 0.05) and RAC (22 vs 29%, P < 0.05). There were no differences in measured PWV in the ascending aorta. Patients with TS had significantly elevated PWV measured in the aortic arch when compared with controls (2.7 vs 1.9 m/s, P < 0.05). Patients with MFS had more prominent elevation in aortic arch PWV (4.2 vs 1.9 m/s, P < 0.01). The descending aortas had decreased distensibility (0.36 vs 0.55%/mmHg, P < 0.05) and RAC (18 vs 25%, P < 0.01) only in MFS patients. Additionally, 18 TS patients with a BAV were compared with 19 TS patients with a trileaflet aortic valve, without significant differences observed in any of the considered stiffness indices.

Conclusions: TS and MFS teenage patients display evidence of increased aortic stiffness. In TS patients, this is focused in the ascending aorta and is independent of the presence of a BAV. MFS patients display a generalized reduction in compliance of the entire aorta.
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http://dx.doi.org/10.1093/ejcts/ezy168DOI Listing
November 2018

Impact of different coarctation therapies on aortic stiffness: phase-contrast MRI study.

Int J Cardiovasc Imaging 2018 Sep 17;34(9):1459-1469. Epub 2018 Apr 17.

Department of Radiology, Children's Hospital Colorado, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA.

Coarctation of the aorta has been associated with increased thoracic aortic stiffness in adolescents and young adults. However, the effects of different therapeutic strategies on aortic stiffness in a young population is unknown. This study aimed to non-invasively assess aortic stiffness between different repair or intervention strategies in patients with coarctation of the aorta. Forty-nine coarctation patients who underwent either surgery (n = 26), balloon angioplasty (n = 14), or stent implantation (n = 12), and 26 age- and size-matched normotensive healthy controls underwent evaluation of thoracic aortic stiffness and flow hemodynamics via phase-contrast cardiac magnetic resonance. In children who had undergone surgical repair or balloon angioplasty, ascending aortic stiffness was increased when measured via pulse wave velocity (PWV) when compared to normal controls (all P < 0.05). Furthermore, ascending aortic distensibility and relative area change (RAC) was significantly lower in surgically and balloon treated groups (both P < 0.01). Stiffness (PWV), distensibility, and RAC in the ascending aorta were not statistically different between stented patients and controls. The ascending aorta of children following surgical repair or balloon angioplasty demonstrated signs of elevated stiffness, whereas those treated by stent implantation showed no difference in stiffness markers when compared to normal controls.
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http://dx.doi.org/10.1007/s10554-018-1357-6DOI Listing
September 2018

Effect of electrical dyssynchrony on left and right ventricular mechanics in children with pulmonary arterial hypertension.

J Heart Lung Transplant 2018 07 6;37(7):870-878. Epub 2018 Feb 6.

Division of Cardiology, Heart Institute, Children's Hospital Colorado, Anschutz Medical Campus, University of Colorado Denver, Aurora, Colorado.

Background: Electrical and right ventricular (RV) mechanical dyssynchrony has been previously described in pediatric pulmonary arterial hypertension (PAH), but less is known about the relationship between electrical dyssynchrony and biventricular function. In this study we applied cardiac magnetic resonance (CMR) imaging to evaluate biventricular size and function with a focus on left ventricular (LV) strain mechanics in pediatric PAH patients with and without electrical dyssynchrony.

Methods: Fifty-six children with PAH and comprehensive CMR evaluation were stratified based on QRS duration z-score, with electrical dyssynchrony defined as z-score ≥2. Comprehensive biventricular volumetric, dyssynchrony, and strain analysis was performed.

Results: Nineteen PAH patients had or developed electrical dyssynchrony. Patients with electrical dyssynchrony had significantly reduced RV ejection fraction (35% vs 50%, p = 0.003) and greater end-diastolic (168 vs 112 ml/m, p = 0.041) and end-systolic (119 vs 57, ml/m, p = 0.026) volumes. Patients with electrical dyssynchrony had reduced RV longitudinal strain (-14% vs -19%, p = 0.007), LV circumferential strain measured at the free wall (-19% vs -22%, p = 0.047), and the LV longitudinal strain in the septal region (-10% vs -15%, p = 0.0268). LV mechanical intraventricular dyssynchrony was reduced in patients with electrical dyssynchrony at the LV free wall (43 vs 19 ms, p = 0.019).

Conclusions: The electrical dyssynchrony is associated with the reduced LV strain, enlarged RV volumes, and reduced biventricular function in children with PAH. CMR assessment of biventricular mechanical function with respect to QRS duration may help to detect pathophysiologic processes associated with progressed PAH.
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http://dx.doi.org/10.1016/j.healun.2018.01.1308DOI Listing
July 2018

Helicity and Vorticity of Pulmonary Arterial Flow in Patients With Pulmonary Hypertension: Quantitative Analysis of Flow Formations.

J Am Heart Assoc 2017 Dec 20;6(12). Epub 2017 Dec 20.

Division of Cardiology, National Jewish Health, Denver, CO.

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/s; <0.001), the right pulmonary artery (24 versus 50 m/s; <0.001), and the RV outflow tract-MPA unit (15 versus 42 m/s; <0.001). Vorticity was significantly decreased in patients with PH only in the right pulmonary artery (26 versus 45 1/s; <0.001). Total helicity computed correlated with the cardiac magnetic resonance imaging-derived ventricular-vascular coupling (-0.927; <0.000), the RV ejection fraction (0.865; <0.0001), cardiac output (0.581; <0.0001), mean pulmonary arterial pressure (-0.581; =0.0008), and relative area change measured at the MPA (0.789; <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.
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http://dx.doi.org/10.1161/JAHA.117.007010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5779020PMC
December 2017

Measuring Flow Hemodynamic Indices and Oxygen Consumption in Children with Pulmonary Hypertension: A Comparison of Catheterization and Phase-Contrast MRI.

Pediatr Cardiol 2018 Feb 17;39(2):268-274. Epub 2017 Oct 17.

Division of Cardiology, Children's Hospital Colorado, Anschutz Medical Campus, 13123 E 16th Avenue, Aurora, CO, 80045-2560, USA.

We sought to compare pulmonary flow hemodynamic indices obtained by Fick and thermodilution catheterization techniques with phase-contrast MRI (PC-MRI) in children with diverse etiologies of pulmonary arterial hypertension (PAH). Calculation of pulmonary flow ([Formula: see text]) using the Fick principle in most catheter laboratories relies on an estimate of oxygen consumption which may limit its reliability. Flow hemodynamic indices acquired from thirty patients with PAH who underwent successful same-day PC-MRI and catheterization were evaluated for absolute and percent bias. Comparison of [Formula: see text] between PC-MRI and Fick revealed poor agreement with an absolute bias of 0.96 ± 0.53 L/min/m and percent bias of 27.7 ± 19.6%. Same analysis between PC-MRI and thermodilution revealed better agreement as demonstrated by absolute bias 0.64 ± 0.47 L/min/m and percent bias 16.8 ± 12.3%. Retrospectively calculated [Formula: see text] from PC-MRI and LaFarge equations revealed poor agreement, with an absolute bias of 33.4 ± 21.6 mL/min/m and percent bias of 25.8 ± 12.6%. We found that Fick-derived flow hemodynamics dramatically differs from PC-MRI computed metrics in children with PAH. The non-invasive nature of PC-MRI and short acquisition time is ideal for pediatric flow evaluation and may offer a novel route of absolute flow and resistance assessment when combined with cardiac catheterization.
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http://dx.doi.org/10.1007/s00246-017-1751-1DOI Listing
February 2018

Reduced shear stress and associated aortic deformation in the thoracic aorta of patients with chronic obstructive pulmonary disease.

J Vasc Surg 2018 07 3;68(1):246-253. Epub 2017 Oct 3.

Department of Cardiology, National Jewish Health, Denver, Colo.

Objective: Central aortic stiffness and chronic obstructive pulmonary disease (COPD) are associated with increased incidence of devastating aortopathies. However, the exact mechanism leading to elevated aortic stiffness in patients with COPD is unknown. The purpose of this study was to quantify flow and shear hemodynamic indices, known markers of vascular remodeling, in the thoracic aorta of patients with mild to moderate COPD (n = 16) and to compare these results with an age-matched control group (n = 10).

Methods: Four-dimensional flow magnetic resonance imaging has been applied to measure hemodynamic wall shear stress (WSS) at four specific planes along the ascending aorta, aortic arch, and proximal descending aorta for all subjects. Peak systolic WSS and time-averaged WSS, which respectively reflect magnitude and temporal shear variability, were calculated at standardized planes. Aortic deformation was measured by means of relative area change (RAC) at the midlevel of the ascending and descending aorta.

Results: Compared with controls, patients with COPD had significantly reduced RAC in the mid ascending aorta (9% vs 18%; P < .0001) and descending aorta (15% vs 19%; P = .0206). Peak systolic WSS in COPD patients was significantly reduced in all considered planes, with the most dramatic difference occurring in the descending aorta (0.46 vs 0.86 N/m; P < .0001). Peak systolic WSS and time-averaged WSS were both significantly correlated with aortic RAC at each evaluated plane.

Conclusions: Reduced flow shear metrics assessed at specific aortic regions correlated with RAC, a marker of aortic stiffness. Reduced hemodynamic WSS may then contribute to central aortic stiffening and perpetuate the risk for development of severe aortopathy.
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http://dx.doi.org/10.1016/j.jvs.2017.06.110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6639049PMC
July 2018

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.

Eur Heart J Cardiovasc Imaging 2018 04;19(4):415-424

Department of Cardiology, National Jewish Health, 1400 Jackson St, Denver, CO 80206, USA.

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.
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http://dx.doi.org/10.1093/ehjci/jex069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6279084PMC
April 2018

Dynamic Changes in Aortic Vascular Stiffness in Patients Bridged to Transplant With Continuous-Flow Left Ventricular Assist Devices.

JACC Heart Fail 2017 06 8;5(6):449-459. Epub 2017 Mar 8.

Division of Cardiology, University of Colorado, Aurora, Colorado. Electronic address:

Objectives: The aim of this study was to measure aortic vascular stiffness from orthotopic heart transplant (OHT) patients exposed to varying types of flow as a result of the presence or absence of left ventricular assist device (LVAD) support pre-OHT.

Background: The effects of continuous-flow LVADs (CF-LVADs) on vascular properties are unknown, but may contribute to the pathophysiology of CF-LVAD complications such as stroke, hypertension, and bleeding.

Methods: Echocardiograms were reviewed from 172 OHT patients immediately before LVAD and at 3 time points post-OHT: baseline, 6 months, and 1 year. For each study, pulse pressure and aortic end-systolic and end-diastolic dimensions were used to calculate aortic strain, distensibility, and stiffness index. Patients were categorized into 3 groups based on the presence or absence of a LVAD and a pulse pre-OHT: No LVAD (n = 111), LVAD No Pulse (n = 30), and LVAD With Pulse (n = 31).

Results: The aortic stiffness index among LVAD No Pulse patients increased from 2.8 ± 1.1 pre-CF-LVAD to 10.9 ± 4.7 immediately post-OHT (p < 0.001). This aortic stiffness index was also significantly higher compared with No LVAD (3.4 ± 1.1; p < 0.001) and LVAD With Pulse (3.7 ± 1.4; p < 0.001) immediately post-OHT with attenuation of these differences by 1 year post-OHT. Similar findings were noted for the other indices of aortic stiffness.

Conclusions: Aortic stiffness is markedly increased immediately post-OHT among patients bridged with CF-LVADs, with attenuation of this increased stiffness over the first year after transplant. These results suggest that aortic vascular properties are dynamic and may be influenced by alterations in flow pulsatility. As more patients are supported with CF-LVADs and as newer pump technology attempts to modulate pulsatility, further research examining the role of alterations in flow patterns on vascular function and the potential resultant systemic sequelae are needed.
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http://dx.doi.org/10.1016/j.jchf.2016.12.009DOI Listing
June 2017

Apparent Aortic Stiffness in Children With Pulmonary Arterial Hypertension: Existence of Vascular Interdependency?

Circ Cardiovasc Imaging 2017 02;10(2)

From the Division of Cardiology, Heart Institute, Children's Hospital Colorado (M.S., D.D.I., B.F., K.S.H., U.T.), Department of Bioengineering, College of Engineering and Applied Sciences (M.S., D.D.I., V.K., K.S.H., U.T.), Division of Pulmonology, Breathing Institute, Children's Hospital Colorado (S.H.A.), and Department of Radiology, Children's Hospital Colorado (L.P.B.), University of Colorado Denver/Anschutz Medical Campus; and Department of Radiology, Feinberg School of Medicine, Northwestern University, Chicago, IL (A.J.B.).

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; =0.001) and reduced aortic strain (23% versus 29%; <0.0001) and distensibility (0.47 versus 0.64%/mm Hg; =0.02). Indexed MPA diameter correlated with pulse wave velocity (=0.04) and with aortic strain (=0.02). The ratio of MPA to aortic size correlated with pulse wave velocity (=0.0098), strain (=0.0099), and distensibility (=0.015). Furthermore, aortic relative area change was associated with left ventricular ejection fraction (=0.045) and ventricular-vascular coupling ratio (=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.
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http://dx.doi.org/10.1161/CIRCIMAGING.116.005817DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5314208PMC
February 2017

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

Eur Heart J Cardiovasc Imaging 2017 Apr;18(4):424-431

Department of Pediatrics, Section of Cardiology, Children's Hospital Colorado, Denver-Aurora, CO, USA.

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.
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http://dx.doi.org/10.1093/ehjci/jew152DOI Listing
April 2017

The endothelial glycocalyx promotes homogenous blood flow distribution within the microvasculature.

Am J Physiol Heart Circ Physiol 2016 07 6;311(1):H168-76. Epub 2016 May 6.

Division of Endocrinology, University of Colorado Anschutz Medical Campus, Aurora, Colorado; Department of Medicine, Denver Veterans Affairs Medical Center, Denver, Colorado; Department of Bioengineering, University of Colorado Anschutz Medical Campus, Aurora, Colorado; Center for Women's Health Research, University of Colorado School of Medicine, Aurora, Colorado

Many common diseases involve impaired tissue perfusion, and heterogeneous distribution of blood flow in the microvasculature contributes to this pathology. The physiological mechanisms regulating homogeneity/heterogeneity of microvascular perfusion are presently unknown. Using established empirical formulations for blood viscosity modeling in vivo (blood vessels) and in vitro (glass tubes), we showed that the in vivo formulation predicts more homogenous perfusion of microvascular networks at the arteriolar and capillary levels. Next, we showed that the more homogeneous blood flow under simulated in vivo conditions can be explained by changes in red blood cell interactions with the vessel wall. Finally, we demonstrated that the presence of a space-filling, semipermeable layer (such as the endothelial glycocalyx) at the vessel wall can account for the changes of red blood cell interactions with the vessel wall that promote homogenous microvascular perfusion. Collectively, our results indicate that the mechanical properties of the endothelial glycocalyx promote homogeneous microvascular perfusion. Preservation or restoration of normal glycocalyx properties may be a viable strategy for improving tissue perfusion in a variety of diseases.
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http://dx.doi.org/10.1152/ajpheart.00132.2016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6189750PMC
July 2016

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

Pulm Circ 2016 Mar;6(1):46-54

Department of Cardiology, National Jewish Health, University of Colorado, Denver, Colorado, USA.

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.
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http://dx.doi.org/10.1086/685052DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4860542PMC
March 2016

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

Pulm Circ 2016 Mar;6(1):37-45

Division of Cardiology, National Jewish Health, Denver, Colorado, USA; BEF and KSH are co-senior authors.

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/m(2); 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.
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http://dx.doi.org/10.1086/685024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4809665PMC
March 2016

Erratum to: Analysis of pediatric airway morphology using statistical shape modeling.

Med Biol Eng Comput 2016 06;54(6):913

Department of Pediatrics, University of Colorado Denver, Aurora, CO, USA.

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http://dx.doi.org/10.1007/s11517-016-1451-7DOI Listing
June 2016

Analysis of pediatric airway morphology using statistical shape modeling.

Med Biol Eng Comput 2016 Jun 31;54(6):899-911. Epub 2015 Dec 31.

Department of Pediatrics, University of Colorado Denver, Aurora, CO, USA.

Traditional studies of airway morphology typically focus on individual measurements or relatively simple lumped summary statistics. The purpose of this work was to use statistical shape modeling (SSM) to synthesize a skeleton model of the large bronchi of the pediatric airway tree and to test for overall airway shape differences between two populations. Airway tree anatomy was segmented from volumetric chest computed tomography of 20 control subjects and 20 subjects with cystic fibrosis (CF). Airway centerlines, particularly bifurcation points, provide landmarks for SSM. Multivariate linear and logistic regression was used to examine the relationships between airway shape variation, subject size, and disease state. Leave-one-out cross-validation was performed to test the ability to detect shape differences between control and CF groups. Simulation experiments, using tree shapes with known size and shape variations, were performed as a technical validation. Models were successfully created using SSM methods. Simulations demonstrated that the analysis process can detect shape differences between groups. In clinical data, CF status was discriminated with good accuracy (precision = 0.7, recall = 0.7) in leave-one-out cross-validation. Logistic regression modeling using all subjects showed a good fit (ROC AUC = 0.85) and revealed significant differences in SSM parameters between control and CF groups. The largest mode of shape variation was highly correlated with subject size (R = 0.95, p < 0.001). SSM methodology can be applied to identify shape differences in the airway between two populations. This method suggests that subtle shape differences exist between the CF airway and disease control.
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http://dx.doi.org/10.1007/s11517-015-1445-xDOI Listing
June 2016
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