title: Model of Human Fetal Growth in Hypoplastic Left Heart Syndrome: Reduced Ventricular Growth Due to Decreased Ventricular Filling and Altered Shape.
abstract: BACKGROUND
  Hypoplastic left heart syndrome (HLHS) is a congenital condition with an underdeveloped left ventricle (LV) that provides inadequate systemic blood flow postnatally. The development of HLHS is postulated to be due to altered biomechanical stimuli during gestation. Predicting LV size at birth using mid-gestation fetal echocardiography is a clinical challenge critical to prognostic counseling.
  
  
  OBJECTIVE
  We hypothesized that decreased ventricular fillingin uterodue to mitral stenosis may reduce LV growth in the fetal heart via mechanical growth signaling.
  
  
  METHODS
  We developed a novel finite element model of the human fetal heart in which cardiac myocyte growth rates are a function of fiber and cross-fiber strains, which is affected by altered ventricular filling, to simulate alterations in LV growth and remodeling. Model results were tested with echocardiogram measurements from normal and HLHS fetal hearts.
  
  
  RESULTS
  A strain-based fetal growth model with a normal 22-week ventricular filling (1.04 mL) was able to replicate published measurements of changes between mid-gestation to birth of mean LV end-diastolic volume (EDV) (1.1-8.3 mL) and dimensions (long-axis, 18-35 mm; short-axis, 9-18 mm) within 15% root mean squared deviation error. By decreasing volumetric load (-25%) at mid-gestation in the model, which emulates mitral stenosisin utero, a 65% reduction in LV EDV and a 46% reduction in LV wall volume were predicted at birth, similar to observations in HLHS patients. In retrospective blinded case studies for HLHS, using mid-gestation echocardiographic data, the model predicted a borderline and severe hypoplastic LV, consistent with the patients' late-gestation data in both cases. Notably, the model prediction was validated by testing for changes in LV shape in the model against clinical data for each HLHS case study.
  
  
  CONCLUSIONS
  Reduced ventricular filling and altered shape may lead to reduced LV growth and a hypoplastic phenotype by reducing myocardial strains that serve as a myocyte growth stimulus. The human fetal growth model presented here may lead to a clinical tool that can help predict LV size and shape at birth based on mid-gestation LV echocardiographic measurements.
authors.affiliation: Department of Bioengineering, University of California at San Diego , La Jolla, CA , USA.
authors.forename: Sukriti
authors.initials: S
authors.lastname: Dewan
authors.affiliation: Department of Bioengineering, University of California at San Diego, La Jolla, CA, USA; Department of Mechanical Engineering, Iowa State University, Ames, IA, USA.
authors.forename: Adarsh
authors.initials: A
authors.lastname: Krishnamurthy
authors.affiliation: Department of Bioengineering, University of California at San Diego , La Jolla, CA , USA.
authors.forename: Devleena
authors.initials: D
authors.lastname: Kole
authors.affiliation: Department of Bioengineering, University of California at San Diego , La Jolla, CA , USA.
authors.forename: Giulia
authors.initials: G
authors.lastname: Conca
authors.affiliation: Department of Bioengineering, University of California at San Diego , La Jolla, CA , USA.
authors.forename: Roy
authors.initials: R
authors.lastname: Kerckhoffs
authors.affiliation: Pediatric Cardiology, Primary Children's Hospital, University of Utah , Salt Lake City, UT , USA.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Puchalski
authors.affiliation: Department of Bioengineering, University of California at San Diego, La Jolla, CA, USA; Department of Medicine, University of California at San Diego, La Jolla, CA, USA.
authors.forename: Jeffrey H
authors.initials: JH
authors.lastname: Omens
authors.affiliation: Pediatric Cardiology, Rady Children's Hospital, University of California at San Diego , San Diego, CA , USA.
authors.forename: Heather
authors.initials: H
authors.lastname: Sun
authors.affiliation: Pediatric Cardiology, Rady Children's Hospital, University of California at San Diego , San Diego, CA , USA.
authors.forename: Vishal
authors.initials: V
authors.lastname: Nigam
authors.affiliation: Department of Bioengineering, University of California at San Diego, La Jolla, CA, USA; Department of Medicine, University of California at San Diego, La Jolla, CA, USA.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: McCulloch
keywords: HLHS; biomechanics; computational model; growth hormone; mechanobiology; patient-specific modeling; sarcomeres