ORCID Profile
0000-0002-5561-4785
Current Organisation
Oregon Health & Science University
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Publisher: Elsevier BV
Date: 07-2011
Publisher: Bentham Science Publishers Ltd.
Date: 31-08-2013
Publisher: American Physiological Society
Date: 23-10-2023
Publisher: Wiley
Date: 15-12-2009
Publisher: BMJ
Date: 07-2005
Publisher: American Physiological Society
Date: 15-12-2015
DOI: 10.1152/AJPREGU.00040.2015
Abstract: While abnormal hemodynamic forces alter fetal myocardial growth, little is known about whether such insults affect fetal cardiac valve development. We hypothesized that chronically elevated systolic load would detrimentally alter fetal valve growth. Chronically instrumented fetal sheep received either a continuous infusion of adult sheep plasma to increase fetal blood pressure, or a lactated Ringer's infusion as a volume control beginning on day 126 ± 4 of gestation. After 8 days, mean arterial pressure was higher in the plasma infusion group (63.0 mmHg vs. 41.8 mmHg, P 0.05). Mitral annular septal-lateral diameter (11.9 mm vs. 9.1 mm, P 0.05), anterior leaflet length (7.7 mm vs. 6.4 mm, P 0.05), and posterior leaflet length (P2 4.0 mm vs. 3.0 mm, P 0.05) were greater in the elevated load group. mRNA levels of Notch-1, TGF-β 2 , Wnt-2b, BMP-1, and versican were suppressed in aortic and mitral valve leaflets elastin and α 1 type I collagen mRNA levels were suppressed in the aortic valves only. We conclude that sustained elevated arterial pressure load on the fetal heart valve leads to anatomic remodeling and, surprisingly, suppression of signaling and extracellular matrix genes that are important to valve development. These novel findings have important implications on the developmental origins of valve disease and may have long-term consequences on valve function and durability.
Publisher: Cambridge University Press
Date: 16-12-2010
Publisher: Wiley
Date: 13-12-2021
DOI: 10.1113/JP281415
Abstract: At birth, the mammalian myocardium switches from using carbohydrates as the primary energy substrate to free fatty acids as the primary fuel. Thus, a compromised switch could jeopardize normal heart function in the neonate. Placental embolization in sheep is a reliable model of intrauterine growth restriction (IUGR). It leads to suppression of both proliferation and terminal differentiation of cardiomyocytes. We hypothesized that the expression of genes regulating cardiac fatty acid metabolism would be similarly suppressed in IUGR, leading to compromised processing of lipids. Following 10 days of umbilicoplacental embolization in fetal sheep, IUGR fetuses had elevated circulating long‐chain fatty acylcarnitines compared with controls (C14: CTRL 0.012 ± 0.005 nmol/ml vs . IUGR 0.018 ± 0.005 nmol/ml, P 0.05 C18: CTRL 0.027 ± 0.009 nmol/mol vs . IUGR 0.043 ± 0.024 nmol/mol, P 0.05, n = 12 control, n = 12 IUGR) indicative of impaired fatty acid metabolism. Uptake studies using fluorescently tagged BODIPY‐C12‐saturated free fatty acid in live, isolated cardiomyocytes showed lipid droplet area and number were not different between control and IUGR cells. mRNA levels of sarcolemmal fatty acid transporters (CD36, FATP6), acylation enzymes (ACSL1, ACSL3), mitochondrial transporter (CPT1), β‐oxidation enzymes (LCAD, HADH, ACAT1), tricarboxylic acid cycle enzyme (IDH), esterification enzymes (PAP, DGAT) and regulator of the lipid droplet formation (BSCL2) gene were all suppressed in IUGR myocardium ( P 0.05). However, protein levels for these regulatory genes were not different between groups. This discordance between mRNA and protein levels in the stressed myocardium suggests an adaptive protection of key myocardial enzymes under conditions of placental insufficiency. image The fetal heart relies on carbohydrates in utero and must be prepared to metabolize fatty acids after birth but the effects of compromised fetal growth on the maturation of this metabolic system are unknown. Plasma fatty acylcarnitines are elevated in intrauterine growth‐restricted (IUGR) fetuses compared with control fetuses, indicative of impaired fatty acid metabolism in fetal organs. Fatty acid uptake and storage are not different in IUGR cardiomyocytes compared with controls. mRNA levels of genes regulating fatty acid transporter and metabolic enzymes are suppressed in the IUGR myocardium compared with controls, while protein levels remain unchanged. Mismatches in gene and protein expression, and increased circulating fatty acylcarnitines may have long‐term implications for offspring heart metabolism and adult health in IUGR in iduals. This requires further investigation.
Publisher: Elsevier BV
Date: 09-2005
DOI: 10.1016/J.EARLHUMDEV.2005.07.001
Abstract: Exposure of an embryo or fetus to a sub-optimal environment increases its risk of acquiring coronary disease and heart failure in adult life through a process known as programming. For ex le, stress experienced in utero and during early postnatal life imparts an increased vulnerability for adult onset cardiovascular disease. Programming is a change in gene expression pattern that occurs in response to a stressor and leads to altered growth of specific organs during their most critical times of development. Known stressors include improper nourishment, hypoxia and excess glucocorticoids. Programming becomes evident through a number of risk factors that are only now becoming understood, including growth patterns in childhood, structural and cellular changes to the heart and coronary vessels, impaired endothelial function, and altered lipid metabolism. Thus, adults most vulnerable for coronary artery disease may have experienced rapid weight gain in childhood and now have dyslipidemias and depressed endothelial function.
Publisher: Wiley
Date: 21-05-2023
DOI: 10.1113/JP284538
Abstract: Contraction of cardiomyocytes is initiated at subcellular elements called dyads, where L‐type Ca 2+ channels in t‐tubules are located within close proximity to ryanodine receptors in the sarcoplasmic reticulum. While evidence from small rodents indicates that dyads are assembled gradually in the developing heart, it is unclear how this process occurs in large mammals. We presently examined dyadic formation in fetal and newborn sheep ( Ovis aries ), and the regulation of this process by fetal cardiac workload. By employing advanced imaging methods, we demonstrated that t‐tubule growth and dyadic assembly proceed gradually during fetal sheep development, from 93 days of gestational age until birth (147 days). This process parallels progressive increases in fetal systolic blood pressure, and includes step‐wise colocalization of L‐type Ca 2+ channels and the Na + /Ca 2+ exchanger with ryanodine receptors. These proteins are upregulated together with the dyadic anchor junctophilin‐2 during development, alongside changes in the expression of hiphysin‐2 (BIN1) and its partner proteins myotubularin and dynamin‐2. Increasing fetal systolic load by infusing plasma or occluding the post‐ductal aorta accelerated t‐tubule growth. Conversely, reducing fetal systolic load with infusion of enalaprilat, an angiotensin converting enzyme inhibitor, blunted t‐tubule formation. Interestingly, altered t‐tubule densities did not relate to changes in dyadic junctions, or marked changes in the expression of dyadic regulatory proteins, indicating that distinct signals are responsible for maturation of the sarcoplasmic reticulum. In conclusion, augmenting blood pressure and workload during normal fetal development critically promotes t‐tubule growth, while additional signals contribute to dyadic assembly. image T‐tubule growth and dyadic assembly proceed gradually in cardiomyocytes during fetal sheep development, from 93 days of gestational age until the post‐natal stage. Increasing fetal systolic load by infusing plasma or occluding the post‐ductal aorta accelerated t‐tubule growth and hypertrophy. In contrast, reducing fetal systolic load by enalaprilat infusion slowed t‐tubule development and decreased cardiomyocyte size. Load‐dependent modulation of t‐tubule maturation was linked to altered expression patterns of the t‐tubule regulatory proteins junctophilin‐2 and hiphysin‐2 (BIN1) and its protein partners. Altered t‐tubule densities did not influence dyadic formation, indicating that distinct signals are responsible for maturation of the sarcoplasmic reticulum.
Publisher: KARGER
Date: 2008
DOI: 10.1159/000113169
Abstract: While it is established that the quality of the perinatal environment is critical in sculpting the developing in idual, the mechanisms by which this occurs remain poorly defined. The growing fetus is dependent on the nutrients (including oxygen) it receives from the mother via the placenta. When this supply line is compromised, heart growth patterns are altered. In addition, hormones, other circulating factors, and the hemodynamic environment in which the fetus develops are important in determining outcomes for organ structure and function. Numerous studies in sheep have demonstrated that heart development can be modified in a number of ways, and the nature of the change differs between types and gestational timings of insults. Embolization of the placenta leads to the cessation of proliferation and maturation of cardiomyocytes this may be due in part to changes in circulating insulin-like growth factor-1 levels. Such insults may be the underlying cause of cardiovascular disease in adults. Insults that modify the maturational timeline, final myocyte number, vascularity and endothelial responsiveness in the heart can have effects that persist long after the insult has been ameliorated.
Publisher: Elsevier BV
Date: 03-2010
Publisher: Wiley
Date: 29-10-2012
Publisher: Wiley
Date: 10-04-2007
Location: United States of America
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Kent Thornburg.