Increased systolic load causes adverse remodeling of fetal aortic and mitral valves.
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-β2, Wnt-2b, BMP-1, and versican were suppressed in aortic and mitral valve leaflets; elastin and α1 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.
Knight Cardiovascular Institute, Oregon Health & Science University, Portland, Oregon; Department of Surgery, Oregon Health & Science University, Portland, Oregon; and tibayan@ohsu.edu.
Frederick A
FA
Tibayan
Knight Cardiovascular Institute, Oregon Health & Science University, Portland, Oregon;
Samantha
S
Louey
Knight Cardiovascular Institute, Oregon Health & Science University, Portland, Oregon;
Sonnet
http://orcid.org/0000-0002-1097-2562
S
Jonker
Knight Cardiovascular Institute, Oregon Health & Science University, Portland, Oregon;
Herbert
H
Espinoza
Knight Cardiovascular Institute, Oregon Health & Science University, Portland, Oregon;
Natasha
N
Chattergoon
Knight Cardiovascular Institute, Oregon Health & Science University, Portland, Oregon;
Fanglei
F
You
Knight Cardiovascular Institute, Oregon Health & Science University, Portland, Oregon;
Kent L
KL
Thornburg
Knight Cardiovascular Institute, Oregon Health & Science University, Portland, Oregon; VA Portland Health Care System, Portland, Oregon.
George
G
Giraud
D000818:Animals; D001021:Aortic Valve / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D062186:Arterial Pressure; D004195:Disease Models, Animal; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism; D005260:Female; D005318:Fetal Heart / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D020567:Fetal Weight; D018507:Gene Expression Regulation, Developmental; D005865:Gestational Age; D006439:Hemodynamics; D006801:Humans; D006973:Hypertension / Q000150:complications* / Q000473:pathology / Q000503:physiopathology; D008297:Male; D008943:Mitral Valve / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D009929:Organ Size; D011247:Pregnancy; D059285:Pregnancy, Twin; D012333:RNA, Messenger / Q000378:metabolism; D012756:Sheep; D015398:Signal Transduction / Q000235:genetics; D013599:Systole; D013997:Time Factors
D016326:Extracellular Matrix Proteins; D012333:RNA, Messenger
animal model; fetus; heart development; heart valve; mechanical load