title: Blood flow patterns underlie developmental heart defects.
abstract: Although cardiac malformations at birth are typically associated with genetic anomalies, blood flow dynamics also play a crucial role in heart formation. However, the relationship between blood flow patterns in the early embryo and later cardiovascular malformation has not been determined. We used the chicken embryo model to quantify the extent to which anomalous blood flow patterns predict cardiac defects that resemble those in humans and found that restricting either the inflow to the heart or the outflow led to reproducible abnormalities with a dose-response type relationship between blood flow stimuli and the expression of cardiac phenotypes. Constricting the outflow tract by 10-35% led predominantly to ventricular septal defects, whereas constricting by 35-60% most often led to double outlet right ventricle. Ligation of the vitelline vein caused mostly pharyngeal arch artery malformations. We show that both cardiac inflow reduction and graded outflow constriction strongly influence the development of specific and persistent abnormal cardiac structure and function. Moreover, the hemodynamic-associated cardiac defects recapitulate those caused by genetic disorders. Thus our data demonstrate the importance of investigating embryonic blood flow conditions to understand the root causes of congenital heart disease as a prerequisite to future prevention and treatment.NEW & NOTEWORTHYCongenital heart defects result from genetic anomalies, teratogen exposure, and altered blood flow during embryonic development. We show here a novel "dose-response" type relationship between the level of blood flow alteration and manifestation of specific cardiac phenotypes. We speculate that abnormal blood flow may frequently underlie congenital heart defects.
authors.affiliation: Biomedical Engineering, Knight Cardiovascular Institute, Oregon Health & Science University, Portland, Oregon; and.
authors.forename: Madeline
authors.initials: M
authors.lastname: Midgett
authors.affiliation: Center for Developmental Health, Knight Cardiovascular Institute, Oregon Health & Science University, Portland, Oregon.
authors.forename: Kent
authors.initials: K
authors.lastname: Thornburg
authors.affiliation: Biomedical Engineering, Knight Cardiovascular Institute, Oregon Health & Science University, Portland, Oregon; and rugonyis@ohsu.edu.|Center for Developmental Health, Knight Cardiovascular Institute, Oregon Health & Science University, Portland, Oregon.
authors.forename: Sandra
authors.initials: S
authors.lastname: Rugonyi
mesh_terms: D000818:Animals; D001158:Arteries / Q000002:abnormalities / Q000000981:diagnostic imaging; D001783:Blood Flow Velocity; D001934:Branchial Region / Q000098:blood supply / Q000000981:diagnostic imaging; D002642:Chick Embryo; D002645:Chickens; D003326:Coronary Circulation; D005333:Fetus / Q000098:blood supply; D006330:Heart Defects, Congenital / Q000000981:diagnostic imaging / Q000503:physiopathology*; D006345:Heart Septal Defects, Ventricular / Q000000981:diagnostic imaging / Q000503:physiopathology; D006352:Heart Ventricles / Q000002:abnormalities / Q000000981:diagnostic imaging; D006439:Hemodynamics; D010641:Phenotype; D012039:Regional Blood Flow / Q000502:physiology; D014057:Tomography, X-Ray Computed
keywords: chick embryo; congenital heart defects; hemodynamics; outflow tract banding; vitelline vein ligation