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

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 (n = 10) and children (n = 10) with PAH matched by pulmonary vascular resistance index (PVRi) and healthy adult (n = 10) and pediatric (n = 10) subjects underwent comprehensive 4D-flow MRI to assess peak systolic wall shear stress (WSSmax) measured in the main (MPA), right (RPA), and left pulmonary arteries (LPA), viscous energy loss (EL) along the MPA-RPA and MPA-LPA tract, and qualitative analysis of secondary flow hemodynamics. WSSmax was decreased in all pulmonary vessels in children with PAH when compared with the same age group (all P < 0.05). Similarly, WSSmax was decreased in all pulmonary vessels in adult PAH patients when compared with healthy adult subjects (all P < 0.01). Average EL was increased in adult patients with PAH when compared with the same age group along both MPA-RPA (P = 0.020) and MPA-LPA (P = 0.025) tracts. There were no differences in EL 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. NEW & NOTEWORTHY 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.

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

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/m2; 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.

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

PURPOSE: 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). MATERIALS AND METHODS: In all, 17 patients with pulmonary hypertension (PH) and five controls underwent right heart catheterization (RHC), 4D and 2D Cine MRI (1.5T) within 24 hours. MRI was used to compute maximum spatial peak systolic vorticity in the main pulmonary artery (MPA) and right pulmonary artery (RPA), cardiac output, and relative area change in the MPA. These parameters were combined in a four-parameter multivariate linear regression model to arrive at an estimate of PVR. Agreement between model predicted and measured PVR was also evaluated using Bland-Altman plots. Finally, model accuracy was tested by randomly withholding a patient from regression analysis and using them to validate the multivariate equation. RESULTS: A decrease in vorticity in the MPA and RPA were correlated with an increase in PVR (MPA: R(2) = 0.54, P < 0.05; RPA: R(2) = 0.75, P < 0.05). Expanding on this finding, we identified a multivariate regression equation that accurately estimates PVR (R(2) = 0.94, P < 0.05) across severe PH and normotensive populations. Bland-Altman plots showed 95% of the differences between predicted and measured PVR to lie within 1.49 Wood units. Model accuracy testing revealed a prediction error of ∼20%. CONCLUSION: A multivariate model that includes MPA relative area change and flow characteristics, measured using 4D and 2D Cine MRI, offers a promising technique for noninvasively estimating PVR in PH patients. J. MAGN. RESON. IMAGING 2016;44:914-922.

Galectin-3 levels are associated with right ventricular functional and morphologic changes in pulmonary arterial hypertension.

The response of the right ventricle (RV) to pulmonary arterial hypertension (PAH) involves changes in contractile function, chamber size, hypertrophy, and extracellular matrix (ECM). Galectin-3 (Gal-3) is a mediator of myocardial ECM metabolism and biomarker for left heart remodeling, yet its ability to reflect RV remodeling is unknown. We hypothesized that serum Gal-3 levels correlate with RV morphology and function in PAH, and that Gal-3 is associated with circulating markers of ECM. Fifteen subjects with PAH and 10 age-matched controls underwent same-day echocardiography, cardiac magnetic resonance (CMR) imaging, and phlebotomy for Gal-3 and ECM biomarkers including N-terminal propeptide of type III collagen type (PIIINP), tissue inhibitor of metalloproteinase-1 (TIMP-1), and hyaluronic acid (HA). RV ejection fraction, end diastolic volume index, end systolic volume index, and mass index were calculated using CMR. Echocardiography was used to estimate RV systolic pressure and measure RV strain. Serum Gal-3, TIMP-1, and HA levels were all significantly increased in PAH subjects when compared to controls. Gal-3 correlated with RV ejection fraction (ρ -0.44, p 0.03), end diastolic volume index (ρ 0.42, p 0.03), end systolic volume index (ρ 0.44, p 0.027), mass index (ρ 0.47, p 0.016), systolic pressure (ρ 0.55, p < 0.001), and strain (ρ 0.43, p 0.03). Gal-3 levels positively correlated with the ECM markers TIMP-1 and HA but not with PIIINP. In conclusion, Gal-3 levels are associated with multiple indices of RV function and morphology. Gal-3 may represent a novel biomarker for RV remodeling and associated ECM turnover in PAH.

Vorticity is a marker of right ventricular diastolic dysfunction.

Right ventricular diastolic dysfunction (RVDD) is an important prognostic indicator in pulmonary arterial hypertension (PAH). RV vortex rings have been observed in healthy subjects, but their significance in RVDD is unknown. Vorticity, the local spinning motion of an element of fluid, may be a sensitive measure of RV vortex dynamics. Using four-dimensional (4D) flow cardiac magnetic resonance imaging (CMR), we investigated the relationship between right heart vorticity with echocardiographic indexes of RVDD. Thirteen (13) PAH subjects and 10 controls underwent same-day 4D flow CMR and echocardiography. RV diastolic function was assessed using trans-tricuspid valve (TV) early (E) and late (A) velocities, E/A ratio, and e' and a' tissue Doppler velocities. RV and right atrial (RA) integrated mean vorticity was calculated for E and A-wave filling periods using 4D datasets. Compared with controls, A-wave vorticity was significantly increased in RVDD subjects in both the RV [2343 (1,559-3,295) vs. 492 (267-2,649) 1/s, P = 0.028] and RA [30 (27-44) vs. 9 (5-27) 1/s, P = 0.005]. RA E vorticity was significantly decreased [13 (7-22) vs. 28 (15-31) 1/s, P = 0.038] in RVDD. E-wave vorticity correlated TV e', E-,and TV E/A (P < 0.05), and A-wave vorticity associated with both TV A and E/A (P < 0.02). RVDD is associated with alterations in E- and A-wave vorticity, and vorticity correlates with multiple echocardiographic markers of RVDD. Vorticity may be a robust noninvasive research tool for the investigation of RV fluid and tissue mechanical interactions in PAH.

Cystatin C: a potential biomarker for pulmonary arterial hypertension.

BACKGROUND AND OBJECTIVE: Cystatin C (CysC), a novel marker of renal function, predicts left heart failure and cardiovascular mortality. The hypothesis that serum CysC levels correlate with right ventricular (RV) morphology, function and pressure in pulmonary arterial hypertension (PAH) was tested. METHODS: As part of a prospective study, 14 PAH subjects and 10 matched controls underwent same-day echocardiography, cardiac magnetic resonance imaging (CMR), and phlebotomy for CysC, brain natriuretic peptide (BNP), and N-terminal BNP (NT-ProBNP). RV ejection fraction (RVEF), end-diastolic volume, end-systolic volume and mass were calculated using CMR. RV systolic pressure (RVSP), strain and diastolic function (including tricuspid valve (TV) E velocity, A velocity, e' velocity, E/A ratio and E/e' ratio) were assessed using echocardiography. RESULTS: RVSP was significantly elevated in PAH subjects versus controls (57 ± 17 vs. 28 ± 8 mm Hg, P < 0.0001). CysC was abnormally elevated in the PAH cohort when compared with controls (1.00 ± 0.23 vs 0.78 ± 0.05 mg/L, P = 0.001). CysC positively correlated with RVSP (rho 0.61, P = 0.002), RV end-diastolic volume (rho 0.50, P = 0.01), RV end-systolic volume (rho 0.58, P = 0.003), mass index (rho 0.66, P = 0.0004), strain (rho 0.51, P = 0.01) and strain rate (rho 0.51, P = 0.01) and negatively correlated with RVEF (rho -0.58, P = 0.003) and TV e' (rho -0.75, P < 0.0001). The same correlations with BNP and NT-ProBNP were comparable with CysC. CONCLUSIONS: In a small cohort, CysC accurately correlates with RV pressure, function and morphology. CysC may represent a novel PAH biomarker.

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.

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/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.

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.

Exercise treadmill saline contrast echocardiography for the detection of patent foramen ovale in hypoxia.

Percutaneous patent foramen ovale (PFO) occluder placement improves dyspnea and oxygen requirement in hypoxic patients with PFO-mediated right-to-left shunt (RTLS). Although saline contrast echocardiography (SCE) in the resting state can identify PFO RTLS, SCE performed with exercise stress testing may provide incremental diagnostic yield compared to rest SCE. We evaluated the ability of exercise SCE to predict PFO presence and size using intracardiac echocardiography (ICE) as a gold standard in a hypoxic cohort. Thirty-three hypoxic patients with suspected PFO RTLS who underwent rest, Valsalva, and exercise stress SCE prior to ICE were evaluated retrospectively. PFO RTLS was defined by ICE findings including PFO anatomy, RTLS by saline contrast and color Doppler, and probe patency. SCE shunt severity was compared to the presence of ICE-defined PFO RTLS and PFO size. Exercise SCE for the detection of PFO RTLS performed with an area under the curve of 0.77, sensitivity of 73%, and specificity of 86%. Among 26 patients with PFO RTLS, exercise SCE identified four additional patients with PFO that had negative rest SCE and two patients with negative Valsalva SCE. Exercise SCE had a stronger correlation with PFO size than resting or Valsalva SCE. Exercise SCE detects PFO RTLS and predicts PFO size in a hypoxic cohort. In addition, exercise SCE can identify PFO RTLS that is otherwise undetected with rest or Valsalva SCE. Exercise SCE may be appropriate when a clinical suspicion for PFO RTLS persists despite negative rest and Valsalva SCE.

Effectiveness of percutaneous closure of patent foramen ovale for hypoxemia.

The aim of this study was to evaluate the ability of percutaneous patent foramen ovale (PFO) closure to improve systemic hypoxemia. Although PFO-mediated right-to-left shunt (RTLS) is associated with hypoxemia, the ability of percutaneous closure to ameliorate hypoxemia is unknown. Between 2004 and 2009, 97 patients who underwent PFO closure for systemic hypoxemia and dyspnea that was disproportionate to underlying lung disease were included for evaluation. All patients exhibited PFO-mediated RTLS as determined by agitated saline echocardiography. Procedural success was defined as implantation of a device without major complications and mild or no residual shunt at 6 months. Clinical success was defined as a composite of an improvement in New York Heart Association (NYHA) functional class, reduction of dyspnea symptoms, or decreased oxygen requirement. Procedural success was achieved in 96 of 97 (99%), and clinical success was achieved in 68 of 97 (70%). The presence of any moderate or severe interatrial shunt by agitated saline study (odds ratio [OR] = 4.7; p <0.024), NYHA class at referral (OR = 2.9; p <0.0087), and 10-year increase in age (OR = 1.8; p <0.0017) increased likelihood of clinical success. In contrast, a pulmonary comorbidity (OR = 0.18; p <0.005) and male gender (OR = 0.30; p <0.017) decreased the likelihood of success. In conclusion, based on the largest single-center experience of patients referred for PFO closure for systemic hypoxemia, PFO closure was a mechanically effective procedure with an associated improvement in echocardiographic evidence of RTLS, NYHA functional class, and oxygen requirement.

Predictors of cardiac sarcoidosis using commonly available cardiac studies.

Cardiac involvement affects ≤40% of patients with sarcoidosis and accounts for ≤25% of deaths. The diagnosis of cardiac sarcoidosis is challenging using the existing screening tests and often relies on expensive cardiac magnetic resonance imaging (cMRI) and cardiac 18-fluorodeoxuyglucose positron emission tomography (FDG-cPET). We developed a scoring system using common clinical tests to predict positive imaging findings using cMRI or FDG-cPET. A retrospective chart review of subjects undergoing cMRI or FDG-cPET was performed. The data were extracted and scored using a predetermined system. Our cohort was predominantly white, with a mean age of 55 years, and 60% were women. The scoring system was compared with the findings from cMRI and FDG-cPET to determine the ability to predict the imaging results that define cardiac sarcoidosis. The scoring system for the patients who had undergone both FDG-cPET and cMRI suggested predictability, but the differences were not statistically significant. However, the positive results from just 1 study were as predictive as having positive findings from both studies. A 1-point increase in the total score increased the probability of positive findings from cMRI or FDG-cPET by 14% (95% confidence interval 3% to 25% increase; p = 0.01). The scoring system seemed to be driven more by the findings from cMRI than by those from FDG-cPET. In patients who had undergone cMRI alone, for each 1-point increase in the total score, the probability of positive cMRI findings increased 11% (95% confidence interval 1% decrease to 25% increase, p = 0.08). All screening modalities were analyzed. No modality was sensitive or specific, although major findings (defined in our scoring system) were most predictive of positive imaging findings. In conclusion, commonly available cardiac screening tools used together in a composite score provide reasonable results to predict positive cardiac sarcoidosis findings on imaging, but the system needs refinement. Our data suggest that major findings from screening studies are more likely to correlate with cMRI findings than with findings from FDG-cPET.

Hypoxia caused by persistent left superior vena cava connecting to the left atrium a rare clinical entity.

We relate the case of a 40-year-old man with a history of premature birth and dextroposition of the heart who presented for an evaluation of persistent hypoxia. An unrevealing pulmonary evaluation and agitated-saline echocardiogram led to cardiac magnetic resonance imaging. This revealed a very unusual finding: a persistent left superior vena cava with insertion into the left atrium and a small connecting vein between the right and left superior venae cavae. The implications, embryology, and pathogenesis of this rare condition are discussed.