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.

Fully automated intracardiac 4D flow MRI post-processing using deep learning for biventricular segmentation.

OBJECTIVES: 4D flow MRI allows for a comprehensive assessment of intracardiac blood flow, useful for assessing cardiovascular diseases, but post-processing requires time-consuming ventricular segmentation throughout the cardiac cycle and is prone to subjective errors. Here, we evaluate the use of automatic left and right ventricular (LV and RV) segmentation based on deep learning (DL) network that operates on short-axis cine bSSFP images. METHODS: A previously published DL network was fine-tuned via retraining on a local database of 106 subjects scanned at our institution. In 26 test subjects, the ventricles were segmented automatically by the network and manually by 3 human observers on bSSFP MRI. The bSSFP images were then registered to the corresponding 4D flow images to apply the segmentation to 4D flow velocity data. Dice coefficients and the relative deviation between measurements (automatic vs. manual and interobserver manual) of various hemodynamic parameters were assessed. RESULTS: The automated segmentation resulted in similar Dice scores (LV: 0.92, RV: 0.86) and lower relative deviations from manual segmentation in left ventricular (LV) average kinetic energy (KE) (8%) and RV KE (15%) than the Dice scores (LV: 0.91, RV: 0.87) and relative deviations between manual segmentation observers (LV KE: 11%, p = 0.01; RV KE: 19%, p = 0.03). CONCLUSIONS: The automated post-processing method using deep learning resulted in hemodynamic measurements that differ from a manual observer's measurements equally or less than the variation between manual observers. This approach can be used to decrease post-processing time on intraventricular 4D flow data and mitigate interobserver variability. KEY POINTS: • Our proposed method allows for fully automated post-processing of intraventricular 4D flow MRI data. • Our method resulted in hemodynamic measurements that matched those derived from manual segmentation equally as well as interobserver variability. • Our method can be used to greatly accelerate intraventricular 4D flow post-processing and improve interobserver repeatability.

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.

Interferon-ß-Induced Pulmonary Arterial Hypertension: Approach to Diagnosis and Clinical Monitoring.

A 48-year-old woman who had been receiving long-term interferon-ß for 8 years for multiple sclerosis developed drug-induced World Health Organization group I pulmonary arterial hypertension. Triple therapy for pulmonary arterial hypertension and suspension of interferon-ß led to improvement from a high-risk to low-risk state and improvement in exercise hemodynamics, including vascular distensibility, and right ventricle-pulmonary artery coupling. (Level of Difficulty: Advanced.).

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.

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.

Cardiovascular impact and sequelae of bronchopulmonary dysplasia.

The development, growth, and function of the cardiac, pulmonary, and vascular systems are closely intertwined during both fetal and postnatal life. In utero, placental, environmental, and genetic insults may contribute to abnormal pulmonary alveolarization and vascularization that increase susceptibility to the development of bronchopulmonary dysplasia (BPD) in preterm infants. However, the shared milieu of stressors may also contribute to abnormal cardiac or vascular development in the fetus and neonate, leading to the potential for cardiovascular dysfunction. Further, cardiac or pulmonary maladaptation can potentiate dysfunction in the other organ, amplify the risk for BPD in the neonate, and increase the trajectory for overall neonatal morbidity. Beyond infancy, there is an increased risk for systemic and pulmonary vascular disease including hypertension, as well as potential cardiac dysfunction, particularly within the right ventricle. This review will focus on the cardiovascular antecedents of BPD in the fetus, cardiovascular consequences of preterm birth in the neonate including associations with BPD, and cardiovascular impact of prematurity and BPD throughout the lifespan.

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.

Long-term Outcomes and Survival in Moderate-severe Portopulmonary Hypertension After Liver Transplant.

BACKGROUND: Portopulmonary hypertension is present in an estimated 5.3% to 8.5% of liver transplant candidates. Untreated, 5-year survival is estimated between 14% and 28%. Moderate-severe disease is a contraindication to liver transplant due to the high perioperative mortality, but patients optimized with pulmonary vasodilator therapy can become eligible for transplant. There is minimal data regarding posttransplant outcomes and ability to discontinue pulmonary vasodilator therapy posttransplant. METHODS: We performed a single-center retrospective analysis to evaluate long-term outcomes of patients with moderate-severe portopulmonary hypertension who were optimized with pulmonary vasodilator therapy, became eligible for liver transplant, and subsequently underwent transplant. We identified 24 patients optimized with pulmonary vasodilator therapy who underwent subsequent liver transplantation and 25 patients who were treated with pulmonary vasodilator therapy alone. RESULTS: In the transplanted cohort, 1-year survival from portopulmonary hypertension diagnosis date: 95.8%, 3-year survival: 90.9%, and 5-year survival: 90.9%. Posttransplant; 1-, 3-, and 5-year survival was 86.9%. Among transplanted patients, 41.6% (10/24) were optimized with nonparenteral therapy. Following transplantation, 100% (14/14) of the surviving patients were able to discontinue parenteral therapy; median time: 7.2 months (interquartile range: 5.1-8.9 mo), while 61.9% (13/21) were able to discontinue pulmonary vasodilator therapy altogether; median time: 13.9 months (interquartile range: 5.1-17.6 mo). CONCLUSIONS: Patients who are optimized with pulmonary vasodilator therapy before liver transplant can have excellent long-term outcomes posttransplant. Oral pulmonary vasodilator therapy can be effective treatment to qualify a patient for transplant, and the majority are able to wean from pulmonary vasodilator therapy entirely posttransplant.

Estrogen receptor-α prevents right ventricular diastolic dysfunction and fibrosis in female rats.

Although women are more susceptible to pulmonary arterial hypertension (PAH) than men, their right ventricular (RV) function is better preserved. Estrogen receptor-α (ERα) has been identified as a likely mediator for estrogen protection in the RV. However, the role of ERα in preserving RV function and remodeling during pressure overload remains poorly understood. We hypothesized that loss of functional ERα removes female protection from adverse remodeling and is permissive for the development of a maladapted RV phenotype. Male and female rats with a loss-of-function mutation in ERα (ERαMut) and wild-type (WT) littermates underwent RV pressure overload by pulmonary artery banding (PAB). At 10 wk post-PAB, WT and ERαMut demonstrated RV hypertrophy. Analysis of RV pressure waveforms demonstrated RV-pulmonary vascular uncoupling and diastolic dysfunction in female, but not male, ERαMut PAB rats. Similarly, female, but not male, ERαMut exhibited increased RV fibrosis, comprised primarily of thick collagen fibers. There was an increased protein expression ratio of TIMP metallopeptidase inhibitor 1 (Timp1) to matrix metalloproteinase 9 (Mmp9) in female ERαMut compared with WT PAB rats, suggesting less collagen degradation. RNA-sequencing in female WT and ERαMut RV revealed kallikrein-related peptidase 10 (Klk10) and Jun Proto-Oncogene (Jun) as possible mediators of female RV protection during PAB. In summary, ERα in females is protective against RV-pulmonary vascular uncoupling, diastolic dysfunction, and fibrosis in response to pressure overload. ERα appears to be dispensable for RV adaptation in males. ERα may be a mediator of superior RV adaptation in female patients with PAH.NEW & NOTEWORTHY Using a novel loss-of-function mutation in estrogen receptor-α (ERα), we demonstrate that female, but not male, ERα mutant rats display right ventricular (RV)-vascular uncoupling, diastolic dysfunction, and fibrosis following pressure overload, indicating a sex-dependent role of ERα in protecting against adverse RV remodeling. TIMP metallopeptidase inhibitor 1 (Timp1), matrix metalloproteinase 9 (Mmp9), kallikrein-related peptidase 10 (Klk10), and Jun Proto-Oncogene (Jun) were identified as potential mediators in ERα-regulated pathways in RV pressure overload.