Publications by authors named "Gregory P Barton"

25 Publications

  • Page 1 of 1

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

Early Hum Dev 2021 Sep 24;160:105426. Epub 2021 Jul 24.

Department of Pediatrics, Orthopedics and Rehabilitation, University of Wisconsin-Madison, Madison, WI, United States of America.

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 ± 8.6 v 47.5 ± 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.
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http://dx.doi.org/10.1016/j.earlhumdev.2021.105426DOI Listing
September 2021

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

Radiol Cardiothorac Imaging 2021 Jun 3;3(3):e200618. Epub 2021 Jun 3.

Departments of Medical Physics, Radiology, Pediatrics, and Medicine, University of Wisconsin-Madison, Madison, Wis (P.A.C., M.W.E., O.W.); Department of Internal Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390-8558 (G.P.B., K.N.G.); Department of Radiology, University of Michigan, Ann Arbor, Mich (J.A.M.); and Department of Radiology, Mayo Clinic, Rochester, Minn (C.J.F.).

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; <.01) and lower E/A peak filling rate ratios (computed from RV volume-time curves; 2.3 ± 1.3 vs 3.5 ± 2.5; = .03). Additionally, viscous energy dissipation was increased during systole (5.7 µW/mL ± 3.0 vs 4.2 µW/mL ± 1.6; = .03), increased during late diastole (3.9 µW/mL ± 4.0 vs 2.2 µW/mL ± 1.6; = .03), and summed over the cardiac cycle (2.4 µJ/mL ± 1.0 vs 1.9 µJ/mL ± 0.6; = .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. Adults, Cardiac, Comparative Studies, MR-Imaging, Right Ventricle © RSNA, 2021.
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http://dx.doi.org/10.1148/ryct.2021200618DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8259661PMC
June 2021

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

Metabolites 2021 Apr 27;11(5). Epub 2021 Apr 27.

Department of Medical Physics, University of Wisconsin-Madison, 1111 Highland Ave., Madison, WI 53705, USA.

This study uses dynamic hyperpolarized [1-C]pyruvate magnetic resonance spectroscopic imaging (MRSI) to estimate differences in glycolytic metabolism between highly metastatic (4T1, = 7) and metastatically dormant (4T07, = 7) murine breast cancer models. The apparent conversion rate of pyruvate-to-lactate (k) and lactate-to-pyruvate area-under-the-curve ratio (AUC) were estimated from the metabolite images and compared with biochemical metabolic measures and immunohistochemistry (IHC). A non-significant trend of increasing k ( = 0.17) and AUC ( = 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, AUC was significantly correlated with tumor LDH activity ( = 0.621, = 0.027) and blood glucose levels ( = -0.474, = 0.042). k displayed a similar, non-significant trend for LDH activity ( = 0.480, = 0.114) and blood glucose levels ( = -0.414, = 0.088). Neither k nor AUC were significantly correlated with blood lactate levels or tumor LDHA or MCT1. The significant positive correlation between AUC and tumor LDH activity indicates the potential of AUC 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.
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http://dx.doi.org/10.3390/metabo11050274DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8145849PMC
April 2021

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

Am J Physiol Heart Circ Physiol 2021 06 16;320(6):H2295-H2304. Epub 2021 Apr 16.

Department of Medicine, University of Texas Southwestern, Dallas, Texas.

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 β 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 / wave kinetic energy ratio. Sildenafil resulted in a median CI increase of 0.24 L/min/m ( = 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 ( = 0.04), consistent with hemodynamic improvement. Metoprolol administration resulted in a 5-beats/min median decrease in HR ( = 0.01), a 0.37 L/min/m median decrease in CI ( = 0.04), and a reduction in time-averaged kinetic energy (KE) in both ventricles ( < 0.01), despite increased RV diastolic / KE ratio ( = 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. 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.
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http://dx.doi.org/10.1152/ajpheart.00824.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8289359PMC
June 2021

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

J Clin Med 2021 Mar 22;10(6). Epub 2021 Mar 22.

Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.

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% O; 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 ( = 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.
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http://dx.doi.org/10.3390/jcm10061301DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8004130PMC
March 2021

Exaggerated Cardiac Contractile Response to Hypoxia in Adults Born Preterm.

J Clin Med 2021 Mar 10;10(6). Epub 2021 Mar 10.

Department of Pediatrics, University of Wisconsin-Madison School of Medicine and Public Health, Madison, WI 53792, USA.

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, = 32) and born at term ( = 18) underwent cardiac magnetic resonance imaging under normoxic (21% O) and hypoxic (12% O) 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) ( = 0.002), ventricular-vascular coupling (VVC) ( = 0.004), and strain ( < 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.
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http://dx.doi.org/10.3390/jcm10061166DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7999333PMC
March 2021

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

J Cardiovasc Magn Reson 2021 02 25;23(1):13. Epub 2021 Feb 25.

Biomedical Engineering, University of Wisconsin-Madison, Madison, WI, USA.

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.
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http://dx.doi.org/10.1186/s12968-021-00709-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7905680PMC
February 2021

Increased mitochondrial oxygen consumption in adult survivors of preterm birth.

Pediatr Res 2021 Feb 22. Epub 2021 Feb 22.

Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.

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.
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http://dx.doi.org/10.1038/s41390-021-01387-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8380256PMC
February 2021

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

Radiol Cardiothorac Imaging 2020 Jun 18;2(3):e190033. Epub 2020 Jun 18.

Departments of Medical Physics (J.A.M., P.A.C., O.W.), Pediatrics (A.G.B., G.P.B., K.N.G., M.W.E.), Medicine (K.N.G.), Biomedical Engineering (M.W.E., O.W.), and Radiology (C.J.F., O.W.), University of Wisconsin, 1111 Highland Ave, Room 1005, Madison, WI 53705.

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 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. © RSNA, 2020See also the commentary by Markl and Lee in this issue.
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http://dx.doi.org/10.1148/ryct.2020190033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7373355PMC
June 2020

Sex Differences in Cardiac Flow Dynamics of Healthy Volunteers.

Radiol Cardiothorac Imaging 2020 Feb 27;2(1). Epub 2020 Feb 27.

Departments of Mechanical Engineering (D.R.R., A.R.A.), Radiology (D.R.R., G.P.B., C.J.F., A.R.A.), Medical Physics (G.P.B.), Cardiovascular Medicine (N.A.), and Biomedical Engineering (A.R.A.), University of Wisconsin-Madison, 1111 Highland Ave, Madison, WI 53705.

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-m/ml-s; female: 0.014 ± 0.007 rad-m/ml-s; p=0.007), peak diastolic vorticity index (male: 0.007 ± 0.006 rad-m/ml-s; female: 0.014 ± 0.010 rad-m/ml-s; p=0.015), and cycle-average vorticity (male: 0.006 ± 0.001 rad-m/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.
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http://dx.doi.org/10.1148/ryct.2020190058DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7053179PMC
February 2020

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

JAMA Cardiol 2020 Aug;5(8):910-919

Department of Pediatrics, School of Medicine and Public Health, University of Wisconsin-Madison.

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.
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http://dx.doi.org/10.1001/jamacardio.2020.1511DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7240643PMC
August 2020

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

Quant Imaging Med Surg 2020 Feb;10(2):485-495

Diagnostic Imaging Center, Shanghai Children's Medical Center Affiliated with Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China.

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 -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 -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 -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 -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 1.07±0.36, P=0.044; 7.36±3.41 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 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.
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http://dx.doi.org/10.21037/qims.2020.01.07DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7063280PMC
February 2020

Measuring the link between cardiac mechanical function and metabolism during hyperpolarized C-pyruvate magnetic resonance experiments.

Magn Reson Imaging 2020 05 21;68:9-17. Epub 2020 Jan 21.

Medical Physics, University of Wisconsin, Madison, WI, USA; Biomedical Engineering, University of Wisconsin, Madison, WI, USA; Radiology, University of Wisconsin, Madison, WI, USA. Electronic address:

Purpose: The goal of this study was to develop a methodology to investigate the relationship between contractile function and hyperpolarized (HP) [1-C]pyruvate metabolism in a small animal model. To achieve sufficient signal from HP C compounds, HP C MRS/MRSI has required relatively large infusion volumes relative to the total blood volume in small animal models, which may affect cardiac function.

Methods: Eight female Sprague Dawley rats were imaged on a 4.7T scanner with a dual tuned H/C volume coil. ECG and respiratory gated k-t spiral MRSI and an IDEAL based reconstruction to determine [1-C]pyruvate metabolism in the myocardium. This was coupled with H cine MRI to determine ventricular volumes and mechanical function pre- and post-infusion of [1-C]pyruvate. For comparison to the [1-C]pyruvate experiments, three female Sprague Dawley rats were imaged with H cine MRI to determine myocardial function pre- and post-saline infusion.

Results: We demonstrated significant changes in cardiac contractile function between pre- and post-infusion of [1-C]pyruvate. Specifically, there was an increase in end-diastolic volume (EDV), stroke volume (SV), and ejection fraction (EF). Additionally, the ventricular vascular coupling ratio (VVCR) showed an improvement after [1-C]pyruvate infusion, indicating increased systolic performance due to an increased arterial load. There was a moderate to strong relationship between the downstream metabolic conversion of pyruvate to bicarbonate and a strong relationship between the conversion of pyruvate to lactate and the cardiac mechanical function response.

Conclusion: The infusion of [1-C]pyruvate resulted in demonstrable increases in contractile function which was related to pyruvate conversion to bicarbonate and lactate. The combined effects of the infusion volume and inotropic effects of pyruvate metabolism likely explains the augmentation in myocardial mechanical function seen in these experiments. Given the relationship between pyruvate metabolism and contractile function observed in this study, this methodological approach may be utilized to better understand cardiac metabolic and functional remodeling in heart disease.
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http://dx.doi.org/10.1016/j.mri.2020.01.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7131884PMC
May 2020

Improved reconstruction stability for chemical shift encoded hyperpolarized C magnetic resonance spectroscopic imaging using k-t spiral acquisitions.

Magn Reson Med 2020 07 9;84(1):25-38. Epub 2019 Dec 9.

Department of Medical Physics, University of Wisconsin-Madison, Madison, Wisconsin.

Purpose: A multiecho, field of view (FOV)-oversampled k-t spiral acquisition and direct iterative decomposition of water and fat with echo asymmetry and least-squares estimation reconstruction is demonstrated to improve the stability of hyperpolarized C magnetic resonance spectroscopic imaging (MRSI) in the presence of signal ambiguities attributed to low-SNR (signal-to-noise-ratio) species, local uncertainties in metabolite peaks, and echo-to-echo signal inconsistencies.

Theory: k-t spiral acquisitions redistribute readout points to be more densely spaced radially in k-space by acquiring an FOV and matrix that are oversampled by η. These more densely spaced spiral turns constitute effective intraspiral echoes and can supplement conventional interspiral echoes to improve spectral separation and reduce spectral cross-talk to better resolve C-labeled species for spectroscopic imaging.

Methods: Digital simulations and imaging phantom experiments were performed for a range of interspiral echo spacings and η using multiecho, k-t spiral acquisitions. Image spectral cross-talk artifacts were evaluated both qualitatively and quantitatively as the percent error in measured metabolite ratios. In vivo murine experiments evaluated the feasibility of multiecho, k-t spiral [1- C]pyruvate MRSI to reduce spectral cross-talk for 3 scenarios of different expected reconstruction stability.

Results: Digital simulations and imaging phantom experiments both demonstrated reduced or comparable image spectral cross-talk and percent errors in measured metabolite ratios with increasing η and better choices of echo spacings. In vivo images displayed markedly reduced spectral cross-talk in lactate images acquired with η = 7 versus η = 1.

Conclusion: The precision of hyperpolarized C metabolic imaging and quantification in the presence of low-SNR species, local uncertainties in metabolite resonances, and echo-to-echo signal inconsistencies can be improved with the use of FOV-oversampled k-t spiral acquisitions.
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http://dx.doi.org/10.1002/mrm.28122DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7083691PMC
July 2020

Bimodal right ventricular dysfunction after postnatal hyperoxia exposure: implications for the preterm heart.

Am J Physiol Heart Circ Physiol 2019 12 8;317(6):H1272-H1281. Epub 2019 Nov 8.

Department of Medicine, School of Medicine and Public Health, University of Madison-Wisconsin, Madison, Wisconsin.

Rats exposed to postnatal hyperoxia develop right ventricular (RV) dysfunction, mild pulmonary hypertension, and dysregulated cardiac mitochondrial biogenesis when aged to one year, with the degree of cardiac dysfunction and pulmonary hypertension similar to that previously described in young adults born preterm. Here, we sought to understand the impact of postnatal hyperoxia exposure on RV hemodynamic and mitochondrial function across the life span. In Methods, pups from timed-pregnant Sprague-Dawley rats were randomized to normoxia or hyperoxia [fraction of inspired oxygen (), 0.85] exposure for the first 14 days of life, a commonly used model of chronic lung disease of prematurity. RV hemodynamic and mitochondrial function were assessed by invasive measurement of RV pressure-volume loops and by high-resolution respirometry at (P21), P90, and P365. In Results, at P21, hyperoxia-exposed rats demonstrated severe pulmonary hypertension and RV dysfunction, accompanied by depressed mitochondrial oxidative capacity. However, significant upregulation of mitochondrial biogenesis at P21 as well as improved afterload led to complete RV hemodynamic and mitochondrial recovery at P90. Mitochondrial DNA mutations were significantly higher by P90 and associated with significant late RV mitochondrial and hemodynamic dysfunction at P365. In conclusion, there appears to be a "honeymoon period" where cardiac hemodynamic and mitochondrial function normalizes following postnatal hyperoxia exposure, only to decline again with ongoing aging. This finding may have significant implications if a long-term pulmonary vascular screening program were to be developed for children or adults with a history of severe prematurity. Further investigation into the mechanisms of recovery are warranted. Premature birth is associated with increased risk for cardiac dysfunction and failure throughout life. Here, we identify bimodal right ventricular dysfunction after postnatal hyperoxia exposure. Mitochondrial biogenesis serves as an early adaptive feature promoting recovery of cardiac hemodynamic and mitochondrial function. However, the accumulation of mitochondrial DNA mutations results in late mitochondrial and right ventricular dysfunction. This bimodal right ventricular dysfunction may have important implications for the development of screening programs in the preterm population.
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http://dx.doi.org/10.1152/ajpheart.00383.2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6962619PMC
December 2019

Effect of intermittent hyperoxia on stem cell mobilization and cytokine expression.

Med Gas Res 2019 Jul-Sep;9(3):139-144

Department of Pediatrics; John Rankin Laboratory of Pulmonary Medicine, University of Wisconsin, Madison, WI, USA.

The best known form of oxygen therapy is hyperbaric oxygen (HBO) therapy, which increases both concentration and atmospheric pressure. HBO supports tissue regeneration and is indicated in an increasing number of pathologies. Less known but still showing some promising effects is normobaric oxygen (NBO) therapy, which provides some advantages over HBO including eliminating barotrauma risk, increased ease of administration and a significant cost reduction. However, still little is known about differences and similarities in treatment effects between HBO and NBO. Therefore we tested whether NBO induces a biological response comparable to HBO with a focus on stem progenitor cell mobilization and changes in serum cytokine concentration. We randomly assigned Sprague-Dawley rats into an NBO treatment group (n = 6), and a room air control group (n = 6). The NBO treatment group was exposed to 42% oxygen for 2 hours a day for 10 days. The room air group was concurrently kept at 20.9% oxygen. The frequency and number of stem progenitor cells in peripheral blood were analyzed by flow cytometry. Plasma cytokine expression was analyzed by cytokine array enzyme linked immunosorbent assay. All analyses were performed 24 hours after the final exposure to control for transient post treatment effects. The NBO treatment group showed an increase in circulating CD133/CD45 stem progenitor cell frequency and number compared to the room air control group. This rise was largely caused by CD34 stem progenitor cells (CD133/CD34/CD45) without changes in the CD34 population. The plasma cytokine levels tested were mostly unchanged with the exception of tumor necrosis factor-α which showed a decrease 24 hours after the last NBO exposure. These findings support our hypothesis that NBO induces a biological response similar to HBO, affecting serum stem progenitor cell populations and tumor necrosis factor-α concentration. The study was approved by Institutional Animal Care and Use Committee (IACUC) of the University of Wisconsin, Madison, WI, USA (approval No. M005439) on June 28, 2016.
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http://dx.doi.org/10.4103/2045-9912.266989DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6779002PMC
May 2020

Early Pulmonary Vascular Disease in Young Adults Born Preterm.

Am J Respir Crit Care Med 2018 12;198(12):1549-1558

Department of Pediatrics.

Premature birth affects 10% of live births in the United States and is associated with alveolar simplification and altered pulmonary microvascular development. However, little is known about the long-term impact prematurity has on the pulmonary vasculature. Determine the long-term effects of prematurity on right ventricular and pulmonary vascular hemodynamics. Preterm subjects ( = 11) were recruited from the Newborn Lung Project, a prospectively followed cohort at the University of Wisconsin-Madison, born preterm with very low birth weight (≤1,500 g; average gestational age, 28 wk) between 1988 and 1991. Control subjects ( = 10) from the same birth years were recruited from the general population. All subjects had no known adult cardiopulmonary disease. Right heart catheterization was performed to assess right ventricular and pulmonary vascular hemodynamics at rest and during hypoxic and exercise stress. Preterm subjects had higher mean pulmonary arterial pressures (mPAPs), with 27% (3 of 11) meeting criteria for borderline pulmonary hypertension (mPAP, 19-24 mm Hg) and 18% (2 of 11) meeting criteria for overt pulmonary hypertension (mPAP ≥ 25 mm Hg). Pulmonary vascular resistance and elastance were higher at rest and during exercise, suggesting a stiffer vascular bed. Preterm subjects were significantly less able to augment cardiac index or right ventricular stroke work during exercise. Among neonatal characteristics, total ventilatory support days was the strongest predictor of adult pulmonary pressure. Young adults born preterm demonstrate early pulmonary vascular disease, characterized by elevated pulmonary pressures, a stiffer pulmonary vascular bed, and right ventricular dysfunction, consistent with an increased risk of developing pulmonary hypertension.
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http://dx.doi.org/10.1164/rccm.201710-2016OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6298636PMC
December 2018

Simultaneous determination of dynamic cardiac metabolism and function using PET/MRI.

J Nucl Cardiol 2019 12 1;26(6):1946-1957. Epub 2018 May 1.

Department of Radiology, University of Wisconsin-Madison, Madison, USA.

Background: Cardiac metabolic changes in heart disease precede overt contractile dysfunction. However, metabolism and function are not typically assessed together in clinical practice. The purpose of this study was to develop a cardiac positron emission tomography/magnetic resonance (PET/MR) stress test to assess the dynamic relationship between contractile function and metabolism in a preclinical model.

Methods: Following an overnight fast, healthy pigs (45-50 kg) were anesthetized and mechanically ventilated. F-fluorodeoxyglucose (F-FDG) solution was administered intravenously at a constant rate of 0.01 mL/s for 60 minutes. A cardiac PET/MR stress test was performed using normoxic gas (FO = .209) and hypoxic gas (FO = .12). Simultaneous cardiac imaging was performed on an integrated 3T PET/MR scanner.

Results: Hypoxic stress induced a significant increase in heart rate, cardiac output, left ventricular (LV) ejection fraction (EF), and peak torsion. There was a significant decline in arterial SpO, LV end-diastolic and end-systolic volumes in hypoxia. Increased LV systolic function was coupled with an increase in myocardial FDG uptake (Ki) during hypoxic stress.

Conclusion: PET/MR with continuous FDG infusion captures dynamic changes in both cardiac metabolism and contractile function. This technique warrants evaluation in human cardiac disease for assessment of subtle functional and metabolic abnormalities.
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http://dx.doi.org/10.1007/s12350-018-1287-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7851880PMC
December 2019

Sex-Specific Skeletal Muscle Fatigability and Decreased Mitochondrial Oxidative Capacity in Adult Rats Exposed to Postnatal Hyperoxia.

Front Physiol 2018 29;9:326. Epub 2018 Mar 29.

Department of Pediatrics, University of Wisconsin, Madison, WI, United States.

Premature birth affects more than 10% of live births, and is characterized by relative hyperoxia exposure in an immature host. Long-term consequences of preterm birth include decreased aerobic capacity, decreased muscular strength and endurance, and increased prevalence of metabolic diseases such as type 2 diabetes mellitus. Postnatal hyperoxia exposure in rodents is a well-established model of chronic lung disease of prematurity, and also recapitulates the pulmonary vascular, cardiovascular, and renal phenotype of premature birth. The objective of this study was to evaluate whether postnatal hyperoxia exposure in rats could recapitulate the skeletal and metabolic phenotype of premature birth, and to characterize the subcellular metabolic changes associated with postnatal hyperoxia exposure, with a secondary aim to evaluate sex differences in this model. Compared to control rats, male rats exposed to 14 days of postnatal hyperoxia then aged to 1 year demonstrated higher skeletal muscle fatigability, lower muscle mitochondrial oxidative capacity, more mitochondrial damage, and higher glycolytic enzyme expression. These differences were not present in female rats with the same postnatal hyperoxia exposure. This study demonstrates detrimental mitochondrial and muscular outcomes in the adult male rat exposed to postnatal hyperoxia. Given that young adults born premature also demonstrate skeletal muscle dysfunction, future studies are merited to determine whether this dysfunction as well as reduced aerobic capacity is due to reduced mitochondrial oxidative capacity and metabolic dysfunction.
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http://dx.doi.org/10.3389/fphys.2018.00326DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5884929PMC
March 2018

Impaired autonomic function in adolescents born preterm.

Physiol Rep 2018 03;6(6):e13620

Department of Pediatrics, University of Wisconsin, Madison, Wisconsin.

Preterm birth temporarily disrupts autonomic nervous system (ANS) development, and the long-term impacts of disrupted fetal development are unclear in children. Abnormal cardiac ANS function is associated with worse health outcomes, and has been identified as a risk factor for cardiovascular disease. We used heart rate variability (HRV) in the time domain (standard deviation of RR intervals, SDRR; and root means squared of successive differences, RMSSD) and frequency domain (high frequency, HF; and low frequency, LF) at rest, as well as heart rate recovery (HRR) following maximal exercise, to assess autonomic function in adolescent children born preterm. Adolescents born preterm (less than 36 weeks gestation at birth) in 2003 and 2004 and healthy age-matched full-term controls participated. Wilcoxon Rank Sum tests were used to compare variables between control and preterm groups. Twenty-one adolescents born preterm and 20 term-born controls enrolled in the study. Preterm-born subjects had lower time-domain HRV, including SDRR (69.1 ± 33.8 vs. 110.1 ± 33.0 msec, respectively, P = 0.008) and RMSSD (58.8 ± 38.2 vs. 101.5 ± 36.2 msec, respectively, P = 0.012), with higher LF variability in preterm subjects. HRR after maximal exercise was slower in preterm-born subjects at 1 min (30 ± 12 vs. 39 ± 9 bpm, respectively, P = 0.013) and 2 min (52 ± 10 vs. 60 ± 10 bpm, respectively, P = 0.016). This study is the first report of autonomic dysfunction in adolescents born premature. Given prior association of impaired HRV with adult cardiovascular disease, additional investigations into the mechanisms of autonomic dysfunction in this population are warranted.
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http://dx.doi.org/10.14814/phy2.13620DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5875539PMC
March 2018

Altered Right Ventricular Mechanical Properties Are Afterload Dependent in a Rodent Model of Bronchopulmonary Dysplasia.

Front Physiol 2017 25;8:840. Epub 2017 Oct 25.

Department of Pediatrics, University of Wisconsin-Madison, Madison, WI, United States.

Infants born premature are at increased risk for development of bronchopulmonary dysplasia (BPD), pulmonary hypertension (PH), and ultimately right ventricular (RV) dysfunction, which together carry a high risk of neonatal mortality. However, the role alveolar simplification and abnormal pulmonary microvascular development in BPD affects RV contractile properties is unknown. We used a rat model of BPD to examine the effect of hyperoxia-induced PH on RV contractile properties. We measured RV pressure as well as passive force, maximum Ca activated force, calcium sensitivity of force (pCa) and rate of force redevelopment () in RV skinned trabeculae isolated from hearts of 21-and 35-day old rats pre-exposed to 21% oxygen (normoxia) or 85% oxygen (hyperoxia) for 14 days after birth. Systolic and diastolic RV pressure were significantly higher at day 21 in hyperoxia exposed rats compared to normoxia control rats, but normalized by 35 days of age. Passive force, maximum Ca activated force, and calcium sensitivity of force were elevated and cross-bridge cycling kinetics depressed in 21-day old hyperoxic trabeculae, whereas no differences between normoxic and hyperoxic trabeculae were seen at 35 days. Myofibrillar protein analysis revealed that 21-day old hyperoxic trabeculae had increased levels of beta-myosin heavy chain (β-MHC), atrial myosin light chain 1 (aMLC1; often referred to as essential light chain), and slow skeletal troponin I (ssTnI) compared to age matched normoxic trabeculae. On the other hand, 35-day old normoxic and hyperoxic trabeculae expressed similar level of α- and β-MHC, ventricular MLC1 and predominantly cTnI. These results suggest that neonatal exposure to hyperoxia increases RV afterload and affect both the steady state and dynamic contractile properties of the RV, likely as a result of hyperoxia-induced expression of β-MHC, delayed transition of slow skeletal TnI to cardiac TnI, and expression of atrial MLC1. These hyperoxia-induced changes in contractile properties are reversible and accompany the resolution of PH with further developmental age, underscoring the importance of reducing RV afterload to allow for normalization of RV function in both animal models and humans with BPD.
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http://dx.doi.org/10.3389/fphys.2017.00840DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5660986PMC
October 2017

Linking metabolic and contractile dysfunction in aged cardiac myocytes.

Physiol Rep 2017 Nov 29;5(20). Epub 2017 Oct 29.

Balke Biodynamics Laboratory, Department of Kinesiology, University of Wisconsin-Madison, Madison, Wisconsin.

Aging is associated with declining cardiac contractile function as well as changes in metabolism and mitochondrial function. The relationship between age-related changes in cardiac metabolism and declining cardiac contractile function has not been determined. In order to define the role energetics play in changes in contractile function, we measured mitochondrial NADH, [NADH], during continuous contractions of isolated left ventricular myocytes from young (Y) and old (O) FBN rats. Second, we explored the role of metabolic disruption with rotenone and increased workload with isoproterenol (ISO) had on age-related changes in myocytes shortening. Single, intact myocytes were stimulated for 10 min of continuous contraction at either 2 Hz or 4 Hz while being perfused with Ringer's solution. Properties of shortening (peak shortening and rate of shortening) were measured at the onset (T0) and after 10 min (T10) of continuous contraction, and the decline in shortening over time (T10/T0) was determined. Although young and old myocytes had similar contractile function under resting conditions, old myocytes demonstrated decrements in [NADH] during continuous stimulation, while young myocytes maintained constant [NADH]m over this time. In addition, old myocytes exhibited impaired contractile function to a workload (ISO) and metabolic (rotenone) stress compared to young myocytes. Taken together, these results demonstrated that old myocytes are susceptible to stress-induced contractile dysfunction which may be related to altered cellular energetics.
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http://dx.doi.org/10.14814/phy2.13485DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5661240PMC
November 2017

Mitochondrial and Metabolic Gene Expression in the Aged Rat Heart.

Front Physiol 2016 23;7:352. Epub 2016 Aug 23.

Balke Biodynamics Laboratory, Department of Kinesiology, University of Wisconsin-Madison Madison, WI, USA.

Aging is associated with a decline in cardiac function. Exercise intervention has been suggested as a way to improve this decrement. Age-related decline in cardiac function is associated with decreases in fatty acid oxidation, mitochondrial function, and AMP-activated protein kinase (AMPK) activity. The molecular mechanisms involved with age-related changes in mitochondrial function and substrate metabolism are poorly understood. We determined gene expression differences in hearts of Young (6 mo), Old (33 mo), and old exercise trained (Old + EXE) (34 mo) FBN rats, using Qiagen PCR arrays for Glucose, Fatty acid, and Mitochondrial metabolism. Old rats demonstrated decreased (p < 0.05) expression for key genes in fatty acid oxidation, mitochondrial function, and AMPK signaling. There were no differences in the expression of genes involved in glucose metabolism with age. These gene expression changes occurred prior to altered protein translation as we found no differences in the protein content of peroxisome proliferator activated receptor gamma, coactivators 1 alpha (PGC-1α), peroxisome proliferator activated receptor alpha (PPARα), and AMPKα2 between young and old hearts. Four months of exercise training did not attenuate the decline in the gene expression in aged hearts. Despite this lack of change in gene expression, exercise-trained rats demonstrated increased exercise capacity compared to their sedentary counterparts. Taken together, our results show that differential expression of genes associated with fatty acid metabolism, AMPK signaling and mitochondrial function decrease in the aging heart which may play a role in age-related declines in fatty acid oxidation, AMPK activity, and mitochondrial function in the heart.
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http://dx.doi.org/10.3389/fphys.2016.00352DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4993773PMC
September 2016
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