Hyperbaric air mobilizes stem cells in humans; a new perspective on the hormetic dose curve.

Introduction: Hyperbaric air (HBA) was first used pharmaceutically in 1662 to treat lung disease. Extensive use in Europe and North America followed throughout the 19th century to treat pulmonary and neurological disorders. HBA reached its zenith in the early 20th century when cyanotic, moribund "Spanish flu pandemic" patients turned normal color and regained consciousness within minutes after HBA treatment. Since that time the 78% Nitrogen fraction in HBA has been completely displaced by 100% oxygen to create the modern pharmaceutical hyperbaric oxygen therapy (HBOT), a powerful treatment that is FDA approved for multiple indications. Current belief purports oxygen as the active element mobilizing stem progenitor cells (SPCs) in HBOT, but hyperbaric air, which increases tensions of both oxygen and nitrogen, has been untested until now. In this study we test HBA for SPC mobilization, cytokine and chemokine expression, and complete blood count. Methods: Ten 34-35-year-old healthy volunteers were exposed to 1.27ATA (4 psig/965 mmHg) room air for 90 min, M-F, for 10 exposures over 2-weeks. Venous blood samples were taken: (1) prior to the first exposure (served as the control for each subject), (2) directly after the first exposure (to measure the acute effect), (3) immediately prior to the ninth exposure (to measure the chronic effect), and (4) 3 days after the completion of tenth/final exposure (to assess durability). SPCs were gated by blinded scientists using Flow Cytometry. Results: SPCs (CD45dim/CD34+/CD133-) were mobilized by nearly two-fold following 9 exposures (p = 0.02) increasing to three-fold 72-h post completion of the final (10th) exposure (p = 0.008) confirming durability. Discussion: This research demonstrates that SPCs are mobilized, and cytokines are modulated by hyperbaric air. HBA likely is a therapeutic treatment. Previously published research using HBA placebos should be re-evaluated to reflect a dose treatment finding rather than finding a placebo effect. Our findings of SPC mobilization by HBA support further investigation into hyperbaric air as a pharmaceutical/therapy.

Functional xenon-129 magnetic resonance imaging response to antifibrotic treatment in idiopathic pulmonary fibrosis.

A measure of regional gas exchange on HP 129Xe MRI was able to detect apparent improvements in IPF patients treated with antifibrotic medication after 1 year, while no such improvements were found in patients treated with conventional therapies https://bit.ly/3ZXipzD.

Diffuse Myocardial Fibrosis at Cardiac MRI in Young Adults Born Prematurely: A Cross-sectional Cohort Study.

Purpose: To measure native T1 values, a marker of diffuse fibrosis, by using cardiac MRI (CMR) in young adults born prematurely. Materials and Methods: This 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. Results: Of 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 (ß = 2.1, standard error = 0.7 and ß = 3.8, standard error = 1.2, respectively), the RV end-diastolic volume index (ß = 1.3, standard error = 0.6), and the LV mass index (ß = 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. Conclusion: Young 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.

Hyperpolarized 129Xe MR Spectroscopy in the Lung Shows 1-year Reduced Function in Idiopathic Pulmonary Fibrosis.

Background Idiopathic pulmonary fibrosis (IPF) is a temporally and spatially heterogeneous lung disease. Identifying whether IPF in a patient is progressive or stable is crucial for treatment regimens. Purpose To assess the role of hyperpolarized (HP) xenon 129 (129Xe) MRI measures of ventilation and gas transfer in IPF generally and as an early signature of future IPF progression. Materials and Methods In a prospective study, healthy volunteers and participants with IPF were consecutively recruited between December 2015 and August 2019 and underwent baseline HP 129Xe MRI and chest CT. Participants with IPF were followed up with forced vital capacity percent predicted (FVC%p), diffusing capacity of the lungs for carbon monoxide percent predicted (DLco%p), and clinical outcome at 1 year. IPF progression was defined as reduction in FVC%p by at least 10%, reduction in DLco%p by at least 15%, or admission to hospice care. CT and MRI were spatially coregistered and a measure of pulmonary gas transfer (red blood cell [RBC]-to-barrier ratio) and high-ventilation percentage of lung volume were compared across groups and across fibrotic versus normal-appearing regions at CT by using Wilcoxon signed rank tests. Results Sixteen healthy volunteers (mean age, 57 years ± 14 [SD]; 10 women) and 22 participants with IPF (mean age, 71 years ± 9; 15 men) were evaluated, as follows: nine IPF progressors (mean age, 72 years ± 7; five women) and 13 nonprogressors (mean age, 70 years ± 10; 11 men). Reduction of high-ventilation percent (13% ± 6.1 vs 8.2% ± 5.9; P = .03) and RBC-to-barrier ratio (0.26 ± 0.06 vs 0.20 ± 0.06; P = .03) at baseline were associated with progression of IPF. Participants with progressive disease had reduced RBC-to-barrier ratio in structurally normal-appearing lung at CT (0.21 ± 0.07 vs 0.28 ± 0.05; P = .01) but not in fibrotic regions of the lung (0.15 ± 0.09 vs 0.14 ± 0.04; P = .62) relative to the nonprogressive group. Conclusion In this preliminary study, functional measures of gas transfer and ventilation measured with xenon 129 MRI and the extent of fibrotic structure at CT were associated with idiopathic pulmonary fibrosis disease progression. Differences in gas transfer were found in regions of nonfibrotic lung. © RSNA, 2022 Online supplemental material is available for this article. See also the editorial by Gleeson and Fraser in this issue.

Dynamic contrast enhanced MRI for the evaluation of lung perfusion in idiopathic pulmonary fibrosis.

BACKGROUND: The objective of this work was to apply quantitative and semiquantitative dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) methods to evaluate lung perfusion in idiopathic pulmonary fibrosis (IPF). METHODS: In this prospective trial 41 subjects, including healthy control and IPF subjects, were studied using DCE-MRI at baseline. IPF subjects were then followed for 1 year; progressive IPF (IPFprog) subjects were distinguished from stable IPF (IPFstable) subjects based on a decline in percent predicted forced vital capacity (FVC % pred) or diffusing capacity of the lung for carbon monoxide (D LCO % pred) measured during follow-up visits. 35 out of 41 subjects were retained for final baseline analysis (control: n=15; IPFstable: n=14; IPFprog: n=6). Seven measures and their coefficients of variation (CV) were derived using temporally resolved DCE-MRI. Two sets of global and regional comparisons were made: control versus IPF groups and control versus IPFstable versus IPFprog groups, using linear regression analysis. Each measure was compared with FVC % pred, D LCO % pred and the lung clearance index (LCI % pred) using a Spearman rank correlation. RESULTS: DCE-MRI identified regional perfusion differences between control and IPF subjects using first moment transit time (FMTT), contrast uptake slope and pulmonary blood flow (PBF) (p≤0.05), while global averages did not. FMTT was shorter for IPFprog compared with both IPFstable (p=0.004) and control groups (p=0.023). Correlations were observed between PBF CV and D LCO % pred (rs= -0.48, p=0.022) and LCI % pred (rs= +0.47, p=0.015). Significant group differences were detected in age (p<0.001), D LCO % pred (p<0.001), FVC % pred (p=0.001) and LCI % pred (p=0.007). CONCLUSIONS: Global analysis obscures regional changes in pulmonary haemodynamics in IPF using DCE-MRI in IPF. Decreased FMTT may be a candidate marker for IPF progression.

Exercise-induced irregular right heart flow dynamics in adolescents and young adults born preterm.

BACKGROUND: Preterm birth has been linked to an elevated risk of heart failure and cardiopulmonary disease later in life. With improved neonatal care and survival, most infants born preterm are now reaching adulthood. In this study, we used 4D flow cardiovascular magnetic resonance (CMR) coupled with an exercise challenge to assess the impact of preterm birth on right heart flow dynamics in otherwise healthy adolescents and young adults who were born preterm. METHODS: Eleven young adults and 17 adolescents born preterm (< 32 weeks of gestation and < 1500 g birth weight) were compared to 11 young adult and 18 adolescent age-matched controls born at term. Stroke volume, cardiac output, and flow in the main pulmonary artery were quantified with 4D flow CMR. Kinetic energy and vorticity were measured in the right ventricle. All parameters were measured at rest and during exercise at a power corresponding to 70% VO2max for each subject. Multivariate linear regression was used to perform age-adjusted term-preterm comparisons. RESULTS: With exercise, stroke volume increased 10 ± 21% in term controls and decreased 4 ± 18% in preterm born subjects (p = 0.007). This resulted in significantly reduced capacity to increase cardiac output in response to exercise stress for the preterm group (58 ± 26% increase in controls, 36 ± 27% increase in preterm, p = 0.004). Elevated kinetic energy (KEterm = 71 ± 22 nJ, KEpreterm = 87 ± 38 nJ, p = 0.03) and vorticity (ωterm = 79 ± 16 s-1, ωpreterm = 94 ± 32 s-1, p = 0.01) during diastole in the right ventricle (RV) suggested altered RV flow dynamics in the preterm subjects. Streamline visualizations showed altered structure to the diastolic filling vortices in those born preterm. CONCLUSIONS: For the participants examined here, preterm birth appeared to result in altered right-heart flow dynamics as early as adolescence, especially during diastole. Future studies should evaluate whether the altered dynamics identified here evolves into cardiopulmonary disease later in life. Trial registration None.

Altered Right Ventricular Filling at Four-dimensional Flow MRI in Young Adults Born Prematurely.

PURPOSE: To use four-dimensional (4D) flow MRI to measure intraventricular flow in young adults who were born prematurely to investigate mechanisms that may account for increased heart failure risk in this population. MATERIALS AND METHODS: In this secondary analysis of a prospective study, a total of 56 young adults participated in an observational cardiac 4D flow MRI study from 2016 to 2020. There were 35 participants who had been born moderately to extremely prematurely (birth weight <1500 g or gestational age ≤32 weeks; 23 women; mean age, 26 years ± 4) and 21 term-born participants (11 women; mean age, 25 years ± 3). Participants underwent cardiac MRI, including cine cardiac structure and function assessment, as well as 4D flow MRI. In each ventricle, normalized kinetic energy (KE/end diastolic volume) and flow through the atrioventricular valve were computed and compared between term-born and preterm participants at systolic and diastolic (early diastolic filling rate [E wave] and late diastolic filling [atrial contraction] rate [A wave]) time points by using Wilcoxon rank-sum tests. RESULTS: Preterm-born participants had lower right ventricular (RV) E wave/A wave (E/A) KE ratios (2.4 ± 1.7 vs 3.5 ± 1.4; P <.01) and lower E/A peak filling rate ratios (computed from RV volume-time curves; 2.3 ± 1.3 vs 3.5 ± 2.5; P = .03). Additionally, viscous energy dissipation was increased during systole (5.7 µW/mL ± 3.0 vs 4.2 µW/mL ± 1.6; P = .03), increased during late diastole (3.9 µW/mL ± 4.0 vs 2.2 µW/mL ± 1.6; P = .03), and summed over the cardiac cycle (2.4 µJ/mL ± 1.0 vs 1.9 µJ/mL ± 0.6; P = .02) in preterm relative to term participants. CONCLUSION: These results suggest that RV diastolic filling is altered in young adults who were born moderately to severely prematurely.Supplemental material is available for this article. Keywords: Adults, Cardiac, Comparative Studies, MR-Imaging, Right Ventricle © RSNA, 2021.

Decreased ventricular size and mass mediate the reduced exercise capacity in adolescents and adults born premature.

BACKGROUND: Premature birth is associated with lower levels of cardiorespiratory fitness (CRF) but the underlying mechanisms responsible remain unclear. This study assessed whether differences in cardiac morphology or function mediate differences in CRF among adolescents and young adults born preterm. METHODS: Adolescents and young adults born moderately to extremely premature (gestational age ≤ 32 weeks or birth weight < 1500 g) and age-matched term born participants underwent resting cardiac MRI and maximal exercise testing. Mediation analysis assessed whether individual cardiovascular variables accounted for a significant proportion of the difference in maximal aerobic capacity between groups. RESULTS: Individuals born preterm had lower VO2max than those born term (41.7 ±â€¯8.6 v 47.5 ±â€¯8.7, p < 0.01). Several variables differed between term and preterm born subjects, including systolic and diastolic blood pressure, mean pulmonary artery pressure, indexed left ventricular end-diastolic volume (LVEDVi), right ventricular end-diastolic volume (RVEDVi), LV mass (LVMi), LV stroke volume index (LVSVi), and LV strain (p < 0.05 for all). Of these variables, LVEDVi, RVEDVi, LVSVi, LVMi, and LV longitudinal strain were significantly related to VO2max (p < 0.05 for all). Significant portions of the difference in VO2max between term and preterm born subjects were mediated by LVEDVi (74.3%, p = 0.010), RVEDVi (50.6%, p = 0.016), and LVMi (43.0%, p = 0.036). CONCLUSIONS: Lower levels of CRF in adolescents and young adults born preterm are mediated by differences in LVEDVi, RVEDVi, and LVMi. This may represent greater risk for long-term cardiac morbidity and mortality in preterm born individuals.

Sildenafil administration improves right ventricular function on 4D flow MRI in young adults born premature.

Extreme preterm birth conveys an elevated risk of heart failure by young adulthood. Smaller biventricular chamber size, diastolic dysfunction, and pulmonary hypertension may contribute to reduced ventricular-vascular coupling. However, how hemodynamic manipulations may affect right ventricular (RV) function and coupling remains unknown. As a pilot study, 4D flow MRI was used to assess the effect of afterload reduction and heart rate reduction on cardiac hemodynamics and function. Young adults born premature were administered sildenafil (a pulmonary vasodilator) and metoprolol (a ß blocker) on separate days, and MRI with 4D flow completed before and after each drug administration. Endpoints include cardiac index (CI), direct flow fractions, and ventricular kinetic energy including E/A wave kinetic energy ratio. Sildenafil resulted in a median CI increase of 0.24 L/min/m2 (P = 0.02), mediated through both an increase in heart rate (HR) and stroke volume. Although RV ejection fraction improved only modestly, there was a significant increase (4% of end diastolic volume) in RV direct flow fraction (P = 0.04), consistent with hemodynamic improvement. Metoprolol administration resulted in a 5-beats/min median decrease in HR (P = 0.01), a 0.37 L/min/m2 median decrease in CI (P = 0.04), and a reduction in time-averaged kinetic energy (KE) in both ventricles (P < 0.01), despite increased RV diastolic E/A KE ratio (P = 0.04). Despite reduced right atrial workload, metoprolol significantly depressed overall cardiac systolic function. Sildenafil, however, increased CI and improved RV function, as quantified by the direct flow fraction. The preterm heart appears dependent on HR but sensitive to RV afterload manipulations.NEW & NOTEWORTHY We assessed the effect of right ventricular afterload reduction with sildenafil and heart rate reduction with metoprolol on cardiac hemodynamics and function in young adults born premature using 4D flow MRI. Metoprolol depressed cardiac function, whereas sildenafil improved cardiac function including right ventricular direct flow fraction by 4D flow, consistent with hemodynamic improvement. This suggests that the preterm heart is dependent on heart rate and sensitive to right ventricular afterload changes.

Hyperpolarized 13C Magnetic Resonance Spectroscopic Imaging of Pyruvate Metabolism in Murine Breast Cancer Models of Different Metastatic Potential.

This study uses dynamic hyperpolarized [1-13C]pyruvate magnetic resonance spectroscopic imaging (MRSI) to estimate differences in glycolytic metabolism between highly metastatic (4T1, n = 7) and metastatically dormant (4T07, n = 7) murine breast cancer models. The apparent conversion rate of pyruvate-to-lactate (kPL) and lactate-to-pyruvate area-under-the-curve ratio (AUCL/P) were estimated from the metabolite images and compared with biochemical metabolic measures and immunohistochemistry (IHC). A non-significant trend of increasing kPL (p = 0.17) and AUCL/P (p = 0.11) from 4T07 to 4T1 tumors was observed. No significant differences in tumor IHC lactate dehydrogenase-A (LDHA), monocarboxylate transporter-1 (MCT1), cluster of differentiation 31 (CD31), and hypoxia inducible factor-α (HIF-1α), tumor lactate-dehydrogenase (LDH) activity, or blood lactate or glucose levels were found between the two tumor lines. However, AUCL/P was significantly correlated with tumor LDH activity (ρspearman = 0.621, p = 0.027) and blood glucose levels (ρspearman = -0.474, p = 0.042). kPL displayed a similar, non-significant trend for LDH activity (ρspearman = 0.480, p = 0.114) and blood glucose levels (ρspearman = -0.414, p = 0.088). Neither kPL nor AUCL/P were significantly correlated with blood lactate levels or tumor LDHA or MCT1. The significant positive correlation between AUCL/P and tumor LDH activity indicates the potential of AUCL/P as a biomarker of glycolytic metabolism in breast cancer models. However, the lack of a significant difference between in vivo tumor metabolism for the two models suggest similar pyruvate-to-lactate conversion despite differing metastatic potential.

Dynamic FDG PET Imaging to Probe for Cardiac Metabolic Remodeling in Adults Born Premature.

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.

Exaggerated Cardiac Contractile Response to Hypoxia in Adults Born Preterm.

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 <1500 g, N = 32) and born at term (N = 18) underwent cardiac magnetic resonance imaging under normoxic (21% O2) and hypoxic (12% O2) conditions to assess cardiovascular function. In normoxia, cardiac function parameters were similar between groups. During hypoxia, the right ventricular (RV) contractile response was significantly greater in participants born premature, demonstrated by greater increases in RV ejection fraction (EF) (p = 0.002), ventricular-vascular coupling (VVC) (p = 0.004), and strain (p < 0.0001) measures compared to term-born participants, respectively. Left ventricular contractile reserve was similar to term-born participants. Adults born preterm exhibit an exaggerated contractile response to acute hypoxia, particularly in the RV. This suggests that adults born preterm may have contractile reserve, despite the lack of volume reserve identified in previous exercise studies. However, this exaggerated and hyper-adapted response may also increase their risk for late RV failure.

Increased mitochondrial oxygen consumption in adult survivors of preterm birth.

BACKGROUND: Premature birth affects roughly 10% of live births and is associated with long-term increased risk for multiple comorbidities. Although many comorbidities are associated with increased oxidative stress, the potential late impact of extreme premature birth on mitochondrial function has not previously been assessed. We hypothesized that mitochondrial function would be impaired in adult survivors of premature birth. METHODS: Mitochondrial function in peripheral blood mononuclear cells from young adults born moderately to extremely preterm was measured using a Seahorse XF Analyzer at baseline and in response to acute oxidative stress, and compared to age-matched term-born adults. Adult pulmonary function was also obtained. RESULTS: Young adults born preterm (average gestational age 29 weeks) had increased mitochondrial oxygen consumption at baseline, particularly with respect to basal and non-ATP-linked respiration. Maximal and spare capacities were also higher, even in response to acute oxidative stress. Lung function was lower in adults born preterm, and the degree of airflow obstruction correlated only modestly with mitochondrial function. CONCLUSIONS: In conclusion, adults born preterm have higher basal and non-ATP-linked mitochondrial respiration. Similar mitochondrial profiles have previously been documented in diabetics, and may support the increased risk for cardiometabolic disease in adults born preterm. IMPACT: Adults born preterm have higher maximal but also higher basal and non-ATP-linked mitochondrial respiration. Similar mitochondrial profiles have previously been documented in diabetics, and may support the increased risk for cardiometabolic disease in adults born preterm. Prior studies demonstrate a link between perinatal mitochondrial function and risk for development of bronchopulmonary dysplasia. Here, maximal mitochondrial respiration correlates modestly with adult lung function. Peripheral blood mononuclear cell mitochondrial function may be a biomarker of both early lung function and late cardiometabolic risk after preterm birth.

Stent interventions for pulmonary artery stenosis improve bi-ventricular flow efficiency in a swine model.

BACKGROUND: Branch pulmonary artery (PA) stenosis (PAS) commonly occurs in patients with congenital heart disease (CHD). Prior studies have documented technical success and clinical outcomes of PA stent interventions for PAS but the impact of PA stent interventions on ventricular function is unknown. The objective of this study was to utilize 4D flow cardiovascular magnetic resonance (CMR) to better understand the impact of PAS and PA stenting on ventricular contraction and ventricular flow in a swine model of unilateral branch PA stenosis. METHODS: 18 swine (4 sham, 4 untreated left PAS, 10 PAS stent intervention) underwent right heart catheterization and CMR at 20 weeks age (55 kg). CMR included ventricular strain analysis and 4D flow CMR. RESULTS: 4D flow CMR measured inefficient right ventricular (RV) and left ventricular (LV) flow patterns in the PAS group (RV non-dimensional (n.d.) vorticity: sham 82 ± 47, PAS 120 ± 47; LV n.d. vorticity: sham 57 ± 5, PAS 78 ± 15 p < 0.01) despite the PAS group having normal heart rate, ejection fraction and end-diastolic volume. The intervention group demonstrated increased ejection fraction that resulted in more efficient ventricular flow compared to untreated PAS (RV n.d. vorticity: 59 ± 12 p < 0.01; LV n.d. vorticity: 41 ± 7 p < 0.001). CONCLUSION: These results describe previously unknown consequences of PAS on ventricular function in an animal model of unilateral PA stenosis and show that PA stent interventions improve ventricular flow efficiency. This study also highlights the sensitivity of 4D flow CMR biomarkers to detect earlier ventricular dysfunction assisting in identification of patients who may benefit from PAS interventions.

Feasibility of Cardiovascular Four-dimensional Flow MRI during Exercise in Healthy Participants.

PURPOSE: To explore the feasibility of using four-dimensional (4D) flow MRI to quantify blood flow and kinetic energy (KE) in the heart during strenuous exercise. MATERIALS AND METHODS: For this prospective study, cardiac 4D flow MRI was performed in 11 healthy young adult participants (eight men, three women; mean age, 26 years ± 1 [standard deviation]) at rest and during exercise with an MRI-compatible exercise stepper between March 2016 and July 2017. Flow was measured in the ascending aorta (AAo) and main pulmonary artery (MPA). KE was quantified in the left and right ventricle. Significant changes in flow and KE during exercise were identified by using t tests. Repeatability was assessed with inter- and intraobserver comparisons and an analysis of internal flow consistency. RESULTS: Nine participants successfully completed both rest and exercise imaging. Internal flow consistency analysis in systemic and pulmonary circulation showed average relative differences of 10% at rest and 16% during exercise. For flow measurements in the AAo and MPA, relative differences between observers never exceeded 6% in any vessel and showed excellent correlation, even during exercise. Relative differences were increased for KE, typically on the order of 30%, with poor interobserver correlation between measurements. CONCLUSION: Four-dimensional flow MRI can quantify increases in flow in the AAo and MPA during strenuous exercise and is highly repeatable. KE had reduced repeatability because of suboptimal segmentation methods and requires further development before clinical implementation. Supplemental material is available for this article. © RSNA, 2020See also the commentary by Markl and Lee in this issue.

Sex Differences in Cardiac Flow Dynamics of Healthy Volunteers.

PURPOSE: The purpose of this study was to further understand the relationship between cardiac function and flow, on the basis of sex, by quantifying cardiac flow characteristics and relating them to cardiac muscle performance in young adults. MATERIALS AND METHODS: In this cross-sectional study, cardiac four-dimensional flow (4D flow) magnetic resonance imaging (MRI) and two-dimensional cine MRI were performed on 20 male and 19 female volunteers aged 20-35. Velocity-based metrics of flow, kinetic energy, vorticity, and efficiency indices were quantified, as well as cardiac strain metrics. RESULTS*: Peak systolic blood kinetic energy (male: 4.76 ± 2.66 mJ; female: 3.36 ± 1.43 mJ; p=0.047) was significantly higher in the male left ventricle (LV) than in the female LV. Peak systolic vorticity index (male: 0.008 ± 0.005 rad-m2/ml-s; female: 0.014 ± 0.007 rad-m2/ml-s; p=0.007), peak diastolic vorticity index (male: 0.007 ± 0.006 rad-m2/ml-s; female: 0.014 ± 0.010 rad-m2/ml-s; p=0.015), and cycle-average vorticity (male: 0.006 ± 0.001 rad-m2/ml-s; female: 0.011 ± 0.002 rad/s; p=0.001) were all significantly higher in the LV of women than they were in the LV of men. Radial, circumferential, and long-axis strain metrics were significantly higher in the female LV than in the male LV (p<0.05). Circumferential systolic and diastolic strain rates displayed moderate correlation to peak systolic (r=-0.38, p=0.022) and diastolic vorticity (r=0.40, p=0.015) values, respectively. *Results are reported as mean ± standard deviation. CONCLUSION: Left ventricular vorticity metrics were observed to be higher in women than in men and displayed moderate correlation to cardiac strain metrics. The methods and results of this study may be used to further understand the sex-based cardiac efficiency relationship between cardiac function and flow.

Association Between Preterm Birth and Arrested Cardiac Growth in Adolescents and Young Adults.

Importance: Premature birth is associated with substantially higher lifetime risk for cardiovascular disease, including arrhythmia, ischemic disease, and heart failure, although the underlying mechanisms are poorly understood. Objective: To characterize cardiac structure and function in adolescents and young adults born preterm using cardiac magnetic resonance imaging (MRI). Design, Setting, and Participants: This cross-sectional cohort study at an academic medical center included adolescents and young adults born moderately to extremely premature (20 in the adolescent cohort born from 2003 to 2004 and 38 in the young adult cohort born in the 1980s and 1990s) and 52 age-matched participants who were born at term and underwent cardiac MRI. The dates of analysis were February 2016 to October 2019. Exposures: Premature birth (gestational age ≤32 weeks) or birth weight less than 1500 g. Main Outcomes and Measures: Main study outcomes included MRI measures of biventricular volume, mass, and strain. Results: Of 40 adolescents (24 [60%] girls), the mean (SD) age of participants in the term and preterm groups was 13.3 (0.7) years and 13.0 (0.7) years, respectively. Of 70 adults (43 [61%] women), the mean (SD) age of participants in the term and preterm groups was 25.4 (2.9) years and 26.5 (3.5) years, respectively. Participants from both age cohorts who were born prematurely had statistically significantly smaller biventricular cardiac chamber size compared with participants in the term group: the mean (SD) left ventricular end-diastolic volume index was 72 (7) vs 80 (9) and 80 (10) vs 92 (15) mL/m2 for adolescents and adults in the preterm group compared with age-matched participants in the term group, respectively (P < .001), and the mean (SD) left ventricular end-systolic volume index was 30 (4) vs 34 (6) and 32 (7) vs 38 (8) mL/m2, respectively (P < .001). Stroke volume index was also reduced in adolescent vs adult participants in the preterm group vs age-matched participants in the term group, with a mean (SD) of 42 (7) vs 46 (7) and 48 (7) vs 54 (9) mL/m2, respectively (P < .001), although biventricular ejection fractions were preserved. Biventricular mass was statistically significantly lower in adolescents and adults born preterm: the mean (SD) left ventricular mass index was 39.6 (5.9) vs 44.4 (7.5) and 40.7 (7.3) vs 49.8 (14.0), respectively (P < .001). Cardiac strain analyses demonstrated a hypercontractile heart, primarily in the right ventricle, in adults born prematurely. Conclusions and Relevance: In this cross-sectional study, adolescents and young adults born prematurely had statistically significantly smaller biventricular cardiac chamber size and decreased cardiac mass. Although function was preserved in both age groups, these morphologic differences may be associated with elevated lifetime cardiovascular disease risk after premature birth.

Systemic ventricular strain and torsion are predictive of elevated serum NT-proBNP in Fontan patients: a magnetic resonance study.

BACKGROUND: This study aimed to investigate the associations between cardiac strain, cardiac torsion, ventricular volumes, and ventricular ejection fraction, with N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels in Fontan patients who were age- and gender-matched with healthy control subjects. METHODS: Cardiovascular magnetic resonance (CMR) studies performed in 22 (15 male, 7 female) patients with single-ventricle physiology (all morphological left ventricles) palliated with Fontan and 17 (10 male, 7 female) age- and gender-matched healthy children volunteers were retrospectively analyzed. Serum NT-proBNP levels were obtained in Fontan subjects. Standard post-processing of CMR images included systemic ventricular end-diastolic and end-systolic volumes, stroke volume, cardiac mass, atrioventricular regurgitation, and ejection fraction. CMR tissue tracking (TT) software was used to quantify global longitudinal strain (GLS), global radial strain (GRS), and global circumferential strain (GCS) and torsion of the systemic ventricle. Pearson and Spearman correlation coefficients were used in comparisons of correlations between NT-proBNP and functional parameters in repair Fontan patients. Intra-observer and inter-observer variability of CMR strain and torsion values were determined from 10 randomly selected Fontan subjects and 10 randomly selected control subjects. RESULTS: GLS was significantly lower in Fontan patients than in control subjects (-15.19±2.94 vs. -19.97±1.70; P<0.001). GLS was not significantly different between normal NT-proBNP levels and high NT-proBNP levels in Fontan patients (-15.59±2.72 vs. -14.62±3.32; P=0.462). The GCS of repair Fontan patients was not significantly lower than that of the control group (-16.76±3.27 vs. -17.88±2.26; P=0.235). GCS was significantly different between normal and high NT-proBNP levels group in Fontan patients (-17.95±2.43 vs. -15.04±3.67; P=0.036). The peak systolic torsion and peak systolic torsion rates were significantly lower in Fontan patients than in control subjects (0.81±0.41 vs. 1.07±0.36, P=0.044; 7.36±3.41 vs. 9.85±2.61, P=0.017). Peak systolic torsion was significantly lower in Fontan patients with normal NT-proBNP levels than in high NT-proBNP subjects (0.67±0.43 vs. 1.01±0.29; P=0.036). GCS and torsion were more strongly correlated with NT-proBNP in the patient group (r=0.541 for GCS; r=0.588 for torsion, P<0.01). The parameters of strain and torsion could be reproduced with sufficient accuracy by intra-observer agreement(biases =0.04 for GLS; biases =0.66 for GCS; biases =1.03 for GRS; biases =0.04 for torsion) and inter-observer agreement (biases =0.32 for GLS; biases =0.85 for GCS; biases =1.52 for GRS; biases =0.18 for torsion). CONCLUSIONS: GLS is an earlier marker of contractile dysfunction in repair Fontan patients. Peak systolic torsion may be a biomarker for determining subclinical dysfunction, as it is more strongly correlated with serum biomarkers of ventricular function than ventricular size or ejection fraction.