Multi-modal and multiscale imaging approaches reveal novel cardiovascular pathophysiology in Drosophila melanogaster

Research output: Contribution to journalArticle

Abstract

Establishing connections between changes in linear DNA sequences and complex downstream mesoscopic pathology remains a major challenge in biology. Herein, we report a novel, multi-modal and multiscale imaging approach for comprehensive assessment of cardiovascular physiology in Drosophila melanogaster. We employed high-speed angiography, optical coherence tomography (OCT) and confocal microscopy to reveal functional and structural abnormalities in the hdp2 mutant, pre-pupal heart tube and aorta relative to controls. hdp2 harbor a mutation in wupA, which encodes an ortholog of human troponin I (TNNI3). TNNI3 variants frequently engender cardiomyopathy. We demonstrate that the hdp2 aortic and cardiac musclewalls are disrupted and that shorter sarcomeres are associated with smaller, stiffer aortas, which consequently result in increased flow and pulse wave velocities. The mutant hearts also displayed diastolic and latent systolic dysfunction.We conclude that hdp2 pre-pupal hearts are exposed to increased afterload due to aortic hypoplasia. This may in turn contribute to diastolic and subtle systolic dysfunction via vascular-heart tube interaction, which describes the effect of the arterial loading system on cardiac function. Ultimately, the cardiovascular pathophysiology caused by a point mutation in a sarcomeric protein demonstrates that complex and dynamic micro-and mesoscopic phenotypes can be mechanistically explained in a gene sequence-and molecular-specific manner.

Details

Authors
  • Constance G. Weismann
  • Anna Blice-Baum
  • Tangji Tong
  • Joyce Li
  • Brendan K. Huang
  • Stephan M. Jonas
  • Anthony Cammarato
  • Michael A. Choma
Organisations
External organisations
  • Yale University
  • Skåne University Hospital
  • Johns Hopkins University School of Medicine
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Medical Genetics

Keywords

  • Aortic stiffness, Cardiovascular physiology, Drosophila melanogaster, hdp, OCT, Troponin
Original languageEnglish
Article numberbio044339
JournalBiology Open
Volume8
Issue number8
Publication statusPublished - 2019
Publication categoryResearch
Peer-reviewedYes