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Deep phenotyping of pulmonary hypertension (PH) with multimodal diagnostic exercise interventions can lead to early focused therapeutic interventions. Herein, we report methods to simultaneously assess pulmonary impedance, differential biventricular myocardial strain, and right ventricular:pulmonary arterial (RV:PA) uncoupling during exercise, which we pilot in subjects with suspected PH. As proof-of-concept, we show that four subjects with different diagnoses [pulmonary arterial hypertension (PAH); chronic thromboembolic disease (CTEPH); PH due to heart failure with preserved ejection fraction (PH-HFpEF); and noncardiac dyspnea (NCD)] have distinct patterns of response to exercise. RV:PA coupling assessment with exercise was highest-to-lowest in this order: PAH > CTEPH > PH-HFpEF > NCD. Input impedance (Z0) with exercise was highest in precapillary PH (PAH, CTEPH), followed by PH-HFpEF and NCD. Characteristic impedance (ZC) tended to decline with exercise, except for the PH-HFpEF subject (initial Zc increase at moderate workload with subsequent decrease at higher workload with augmentation in cardiac output). Differential myocardial strain was normal in PAH, CTEPH, and NCD subjects and lower in the PH-HFpEF subject in the interventricular septum. The combination of these metrics allowed novel insights into mechanisms of RV:PA uncoupling. For example, while the PH-HFpEF subject had hemodynamics comparable to the NCD subject at rest, with exercise coupling dropped precipitously, which can be attributed (by decreased myocardial strain of interventricular septum) to poor support from the left ventricle (LV). We conclude that this deep phenotyping approach may distinguish afterload sensitive vs. LV-dependent mechanisms of RV:PA uncoupling in PH, which may lead to novel therapeutically relevant insights.

PurposeTo measure native T1 values, a marker of diffuse fibrosis, by using cardiac MRI (CMR) in young adults born prematurely.Materials and methodsThis secondary analysis of a prospective cohort study included young adults born moderately to extremely preterm and age-matched, term-born participants. CMR was performed with a 3.0-T imager that included cine imaging for the quantification of left ventricular (LV) and right ventricular (RV) volumes and function and native saturation recovery T1 mapping for the assessment of diffuse myocardial fibrosis. Values between preterm and term were compared by using the Student t test. Associations between T1 values and other variables were analyzed by using linear regression and multivariate regression.ResultsOf the 50 young-adult participants, 32 were born preterm (mean age, 25.8 years ± 4.2 [SD]; 23 women) and 18 were born at term (mean age, 26.2 years ± 5.4; 10 women). Native T1 values were significantly higher in participants born preterm than in participants born at term (1477 msec ± 77 vs 1423 msec ± 71, respectively; unadjusted P = .0019). Native T1 values appeared to be positively associated with indexed LV end-diastolic and end-systolic volumes (β = 2.1, standard error = 0.7 and β = 3.8, standard error = 1.2, respectively), the RV end-diastolic volume index (β = 1.3, standard error = 0.6), and the LV mass index (β = 2.5, standard error = 0.9). Higher T1 values may be associated with reduced cardiac systolic strain measures and diastolic strain measures. Five-minute Apgar scores were inversely associated with native T1 values.ConclusionYoung adults born moderately to extremely preterm exhibited significantly higher native T1 values than age-matched, term-born young adults.Keywords: MRI, Cardiac, Heart, Left Ventricle, CardiomyopathiesClinical trial registration no. NCT03245723Published under a CC BY 4.0 license Supplemental material is available for this article.

Individuals born prematurely have smaller hearts, cardiac limitations to exercise, and increased overall cardiometabolic risk. The cardiac effects of acute hypoxia exposure as another physiologic stressor remain under explored. The purpose of this study was to determine the effects of hypoxia on ventricular function in adults born preterm. Adults born moderately to extremely preterm (≤32 weeks gestation or

Individuals born very premature have an increased cardiometabolic and heart failure risk. While the structural differences of the preterm heart are now well-described, metabolic insights into the physiologic mechanisms underpinning this risk are needed. Here, we used dynamic fluorodeoxyglucose (FDG) positron emission tomography/magnetic resonance imaging (PET-MRI) in young adults born term and preterm during normoxic (N = 28 preterm; 18 term) and hypoxic exposure (12% O2; N = 26 preterm; 17 term) to measure the myocardial metabolic rate of glucose (MMRglc) in young adults born term (N = 18) and preterm (N = 32), hypothesizing that young adults born preterm would have higher rates of MMRglc under normoxic conditions and a reduced ability to augment glucose metabolism under hypoxic conditions. MMRglc was calculated from the myocardial and blood pool time-activity curves by fitting the measured activities to the 3-compartment model of FDG kinetics. MMRglc was similar at rest between term and preterm subjects, and decreased during hypoxia exposure in both groups (p = 0.02 for MMRglc hypoxia effect). There were no differences observed between groups in the metabolic response to hypoxia, either globally (serum glucose and lactate measures) or within the myocardium. Thus, we did not find evidence of altered myocardial metabolism in the otherwise healthy preterm-born adult. However, whether subtle changes in myocardial metabolism may preceed or predict heart failure in this population remains to be determined.

BackgroundWhile primarily a right heart disease, pulmonary arterial hypertension (PAH) can impact left heart function and aortic flow through a shifted interventricular septum from right ventricular pressure overload and reduced left ventricular preload, among other mechanisms. In this study, we used phase contrast (PC) MRI and a modest exercise challenge to examine the effects of PAH on systemic circulation. While exercise challenges are typically performed with ultrasound in the clinic, MRI exercise studies allow for more reproducible image alignment, more accurate flow quantification, and improved tissue contrast.MethodsSix PAH patients and fifteen healthy controls (8 older age-matched, 7 younger) exercised in the magnet bore with an MRI-compatible exercise device that allowed for scanning immediately following cessation of exercise. PC scans were performed in the ascending aorta during a breath hold immediately after modest exercise to non-invasively measure stroke volume (SV), cardiac output (CO), aortic peak systolic flow (PSF), and aortic wall stiffness via relative area change (RAC).ResultsImages following exercise showed mild blurring, but were high enough quality to allow for segmentation of the aorta. While SV was approximately 30% lower in PAH patients (SVPAH,rest = 67 ± 16 mL; SVPAH,stress = 90 ± 42 mL) than age-matched controls (SV,older,rest = 93 ± 16 mL; SVolder,stress = 133 ± 40 mL) at both rest and following exercise, CO was similar for both groups following exercise (COPAH,stress = 10.8 ± 5.7 L/min; COolder,stress = 11.8 ± 5.0 L/min). This was achieved through a compensatory increase in heart rate in the PAH subjects (74% increase as compared to 29% in age-matched controls). The PAH subjects also demonstrated reduced aortic peak systolic flow relative to the healthy controls (PSFPAH,rest = 309 ± 52 mL/s; PSFolder,rest = 416 ± 114 mL/s; PSFPAH,stress = 388 ± 113 mL/s; PSFolder,stress = 462 ± 176 mL/s). PAH patients and older controls demonstrated stiffer aortic walls when compared to younger controls (RACPAH,rest = 0.15 ± 0.05; RAColder,rest = 0.17 ± 0.05; RACyoung,rest = 0.28 ± 0.08).ConclusionsPC MRI following a modest exercise challenge was capable of detecting differences in left heart dynamics likely induced from PAH. These results demonstrated that PAH can have a significant influence on systemic flow, even when the patient has no prior left heart disease. Image quantification following exercise could likely be improved in future studies through the implementation of free-breathing or real-time MRI acquisitions.Trial registrationRetrospectively registered on 02/26/2018 (TRN: NCT03523910 ).

Purpose: Tricuspid valve flow velocities are challenging to measure with cardiovascular MR, as the rapidly moving valvular plane prohibits direct flow evaluation, but they are vitally important to diastolic function evaluation. We developed an automated valve‐tracking 2D method for measuring flow through the dynamic tricuspid valve. Methods: Nine healthy subjects and 2 patients were imaged. The approach uses a previously trained deep learning network, TVnet, to automatically track the tricuspid valve plane from long‐axis cine images. Subsequently, the tracking information is used to acquire 2D phase contrast (PC) with a dynamic (moving) acquisition plane that tracks the valve. Direct diastolic net flows evaluated from the dynamic PC sequence were compared with flows from 2D‐PC scans acquired in a static slice localized at the end‐systolic valve position, and also ventricular stroke volumes (SVs) using both planimetry and 2D PC of the great vessels. Results: The mean tricuspid valve systolic excursion was 17.8 ± 2.5 mm. The 2D valve‐tracking PC net diastolic flow showed excellent correlation with SV by right‐ventricle planimetry (bias ± 1.96 SD = −0.2 ± 10.4 mL, intraclass correlation coefficient [ICC] = 0.92) and aortic PC (−1.0 ± 13.8 mL, ICC = 0.87). In comparison, static tricuspid valve 2D PC also showed a strong correlation but had greater bias (p = 0.01) versus the right‐ventricle SV (10.6 ± 16.1 mL, ICC = 0.61). In most (8 of 9) healthy subjects, trace regurgitation was measured at begin‐systole. In one patient, valve‐tracking PC displayed a high‐velocity jet (380 cm/s) with maximal velocity agreeing with echocardiography. Conclusion: Automated valve‐tracking 2D PC is a feasible route toward evaluation of tricuspid regurgitant velocities, potentially solving a major clinical challenge. [ABSTRACT FROM AUTHOR]

Cerebrovascular and neurological diseases exhibit sex-specific patterns in prevalence, severity, and regional specificity, some of which are associated with altered cerebral blood flow (CBF). Females often exhibit higher resting CBF, but understanding the impact of sex per se on CBF is hampered by study variability in age, comorbidities, medications, and control for menstrual cycle or hormone therapies. A majority of studies report whole brain CBF without differentiating between gray and white matter or without assessing regional CBF. Thus fundamental sex differences in regional or whole brain CBF remain unclarified. While controlling for the above confounders, we tested the hypothesis that females will exhibit higher total gray and white matter perfusion as well as regional gray matter perfusion. Adults 18–30 yr old (females = 22 and males = 26) were studied using arterial spin labeling (ASL) magnetic resonance imaging (MRI) scans followed by computational anatomy toolbox (CAT12) analysis in statistical parametric mapping (SPM12) to quantify CBF relative to brain volume. Females displayed 40% higher perfusion globally (females = 62 ± 9 and males = 45 ± 10 mL/100 g/min, P < 0.001), gray matter (females = 75 ± 11 and males = 54 ± 12 mL/100 g/min, P < 0.001), and white matter (females = 44 ± 6 and males = 32 ± 7 mL/100 g/min, P < 0.001). Females exhibited greater perfusion than males in 67 of the 68 regions tested, ranging from 14% to 66% higher. A second MRI approach (4-dimensional flow) focused on large arteries confirmed the sex difference in global CBF. These data indicate strikingly higher basal CBF in females at global, gray, and white matter levels and across dozens of brain regions and offer new clarity into fundamental sex differences in global and regional CBF regulation before aging or pathology. NEW & NOTEWORTHY: MRI used to measure cerebral blood flow (CBF) in gray matter, white matter, and 68 regions in healthy men and women. This study demonstrated that CBF is 40% higher in women, the highest sex difference reported, when controlling for numerous important clinical confounders like age, smoking, menstrual cycle, comorbidities, and medications. [ABSTRACT FROM AUTHOR]

Infection with Zika virus (ZIKV) is associated with human congenital fetal anomalies. To model fetal outcomes in nonhuman primates, we administered Asian-lineage ZIKV subcutaneously to four pregnant rhesus macaques. While non-pregnant animals in a previous study contemporary with the current report clear viremia within 10-12 days, maternal viremia was prolonged in 3 of 4 pregnancies. Fetal head growth velocity in the last month of gestation determined by ultrasound assessment of head circumference was decreased in comparison with biparietal diameter and femur length within each fetus, both within normal range. ZIKV RNA was detected in tissues from all four fetuses at term cesarean section. In all pregnancies, neutrophilic infiltration was present at the maternal-fetal interface (decidua, placenta, fetal membranes), in various fetal tissues, and in fetal retina, choroid, and optic nerve (first trimester infection only). Consistent vertical transmission in this primate model may provide a platform to assess risk factors and test therapeutic interventions for interruption of fetal infection. The results may also suggest that maternal-fetal ZIKV transmission in human pregnancy may be more frequent than currently appreciated.

BackgroundExercise stress tests are commonly used in clinical settings to monitor the functional state of the heart and vasculature. Large artery stiffness is one measure of arterial function that can be quantified noninvasively during exercise stress. Changes in proximal pulmonary artery stiffness are especially relevant to the progression of pulmonary hypertension (PH), since pulmonary artery (PA) stiffness is the best current predictor of mortality from right ventricular failure.MethodsCardiovascular magnetic resonance (CMR) was used to investigate the effect of exercise stress on PA pulse wave velocity (PWV) and relative area change (RAC), which are both non-invasive measures of PA stiffness, in healthy subjects. All 21 subjects (average age 26 ± 4 years; 13 female and 8 male) used a custom-made MR-compatible stepping device to exercise (two stages of mild-to-moderate exercise of 3-4 min duration each) in a supine position within the confines of the scanner. To measure the cross-sectional area and blood flow velocity in the main PA (MPA), two-dimensional phase-contrast (2D-PC) CMR images were acquired. To measure the reproducibility of metrics, CMR images were analyzed by two independent observers. Inter-observer agreements were calculated using the intraclass correlation and Bland-Altman analysis.ResultsFrom rest to the highest level of exercise, cardiac output increased from 5.9 ± 1.4 L/min to 8.2 ± 1.9 L/min (p

Pulsatile blood flow through the cavities of the heart and great vessels is time-varying and multidirectional. Access to all regions, phases and directions of cardiovascular flows has formerly been limited. Four-dimensional (4D) flow cardiovascular magnetic resonance (CMR) has enabled more comprehensive access to such flows, with typical spatial resolution of 1.5×1.5×1.5 - 3×3×3 mm(3), typical temporal resolution of 30-40 ms, and acquisition times in the order of 5 to 25 min. This consensus paper is the work of physicists, physicians and biomedical engineers, active in the development and implementation of 4D Flow CMR, who have repeatedly met to share experience and ideas. The paper aims to assist understanding of acquisition and analysis methods, and their potential clinical applications with a focus on the heart and greater vessels. We describe that 4D Flow CMR can be clinically advantageous because placement of a single acquisition volume is straightforward and enables flow through any plane across it to be calculated retrospectively and with good accuracy. We also specify research and development goals that have yet to be satisfactorily achieved. Derived flow parameters, generally needing further development or validation for clinical use, include measurements of wall shear stress, pressure difference, turbulent kinetic energy, and intracardiac flow components. The dependence of measurement accuracy on acquisition parameters is considered, as are the uses of different visualization strategies for appropriate representation of time-varying multidirectional flow fields. Finally, we offer suggestions for more consistent, user-friendly implementation of 4D Flow CMR acquisition and data handling with a view to multicenter studies and more widespread adoption of the approach in routine clinical investigations.

PurposeTo compare pulmonary artery flow using Cartesian and radially sampled four-dimensional flow-sensitive (4D flow) MRI at two institutions.MethodsNineteen healthy subjects and 17 pulmonary arterial hypertension (PAH) subjects underwent a Cartesian 4D flow acquisition (institution 1) or a three-dimensional radial acquisition (institution 2). The diameter, peak systolic velocity (Vmax), peak flow (Qmax), stroke volume (SV), and wall shear stress (WSS) were computed in two-dimensional analysis planes at the main, right, and left pulmonary artery. Interobserver variability, interinstitutional differences, flow continuity, and the hemodynamic measurements in healthy and PAH subjects were assessed.ResultsVmax, Qmax, SV, and WSS at all locations were significantly lower (P

BackgroundThe purpose of this study was to quantify right (RV) and left (LV) ventricular function, pulmonary artery flow (QP), tricuspid valve regurgitation velocity (TRV), and aorta flow (QS) from a single 4D flow cardiovascular magnetic resonance (CMR) (time-resolved three-directionally motion encoded CMR) sequence in a canine model of acute thromboembolic pulmonary hypertension (PH).MethodsAcute PH was induced in six female beagles by microbead injection into the right atrium. Pulmonary arterial (PAP) and pulmonary capillary wedge (PCWP) pressures and cardiac output (CO) were measured by right heart catheterization (RHC) at baseline and following induction of acute PH. Pulmonary vascular resistance (PVRRHC) was calculated from RHC values of PAP, PCWP and CO (PVRRHC = (PAP-PCWP)/CO). Cardiac magnetic resonance (CMR) was performed on a 3 T scanner at baseline and following induction of acute PH. RV and LV end-diastolic (EDV) and end-systolic (ESV) volumes were determined from both CINE balanced steady-state free precession (bSSFP) and 4D flow CMR magnitude images. QP, TRV, and QS were determined from manually placed cutplanes in the 4D flow CMR flow-sensitive images in the main (MPA), right (RPA), and left (LPA) pulmonary arteries, the tricuspid valve (TRV), and aorta respectively. MPA, RPA, and LPA flow was also measured using two-dimensional flow-sensitive (2D flow) CMR.ResultsBiases between 4D flow CMR and bSSFP were 0.8 mL and 1.6 mL for RV EDV and RV ESV, respectively, and 0.8 mL and 4 mL for LV EDV and LV ESV, respectively. Flow in the MPA, RPA, and LPA did not change after induction of acute PAH (p = 0.42-0.81). MPA, RPA, and LPA flow determined with 4D flow CMR was significantly lower than with 2D flow (p

Cardiovascular disease is the leading cause of death worldwide. Many cardiovascular diseases are better diagnosed during a cardiac stress test. Current approaches include either exercise or pharmacological stress echocardiography and pharmacological stress magnetic resonance imaging (MRI). MRI is the most accurate noninvasive method of assessing cardiac function. Currently there are very few exercise devices that allow collection of cardiovascular MRI data during exercise. We developed a low-cost exercise device that utilizes adjustable weight resistance and is compatible with magnetic resonance (MR) imaging. It is equipped with electronics that measure power output. Our device allows subjects to exercise with a leg-stepping motion while their torso is in the MR imager. The device is easy to mount on the MRI table and can be adjusted for different body sizes. Pilot tests were conducted with 5 healthy subjects (3 male and 2 female, 29.2 ± 3.9 yr old) showing significant exercise-induced changes in heart rate (+42%), cardiac output (+40%) and mean pulmonary artery (PA) flow (+%49) post exercise. These data demonstrate that our MR compatible stepper exercise device successfully generated a hemodynamically stressed state while allowing for high quality imaging. The adjustable weight resistance allows exercise stress testing of subjects with variable exercise capacities. This low-cost device has the potential to be used in a variety of pathologies that require a cardiac stress test for diagnosis and assessment of disease progression.

Purpose: Depicting the stiffness of biological soft tissues, MR elastography (MRE) has a wide range of diagnostic applications. The purpose of this study was to improve the temporal resolution of 2D hepatic MRE in order to provide more rapid feedback on the quality of the wavefield and ensure better temporal sampling of respiration‐induced stiffness changes. Methods: We developed a rapid MRE sequence that uses 2D segmented gradient‐echo spiral readout to encode 40 Hz harmonic vibrations and generate stiffness maps within 625 ms. We demonstrate the use of this technique as a rapid test for shear wave amplitudes and overall MRE image quality and as a method for monitoring respiration‐induced stiffness changes in the liver in comparison to 3D MRE and ultrasound‐based time‐harmonic elastography. Results: Subsecond MRE allowed monitoring of increasing shear wave amplitudes in the liver with increasing levels of external stimulation within a single breath‐hold. Furthermore, the technique detected respiration‐induced changes in liver stiffness with peak values (1.83 ± 0.22 m/s) at end‐inspiration, followed by softer values during forced abdominal pressure (1.60 ± 0.22 m/s) and end‐expiration (1.49 ± 0.22 m/s). The effects of inspiration and expiration were confirmed by time‐harmonic elastography. Conclusion: Our results suggest that subsecond MRE of the liver is useful for checking MRE driver settings and monitoring breathing‐induced changes in liver stiffness in near real time. [ABSTRACT FROM AUTHOR]