Mechanical regulation of cardiac development

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Abstract

Mechanical forces are essential contributors to and unavoidable components of cardiac formation, both inducing and orchestrating local and global molecular and cellular changes. Experimental animal studies have contributed substantially to understanding the mechanobiology of heart development. More recent integration of high-resolution imaging modalities with computational modeling has greatly improved our quantitative understanding of hemodynamic flow in heart development. Merging these latest experimental technologies with molecular and genetic signaling analysis will accelerate our understanding of the relationships integrating mechanical and biological signaling for proper cardiac formation. These advances will likely be essential for clinically translatable guidance for targeted interventions to rescue malforming hearts and/or reconfigure malformed circulations for optimal performance. This review summarizes our current understanding on the levels of mechanical signaling in the heart and their roles in orchestrating cardiac development.

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Most cited references 135

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Genetics of congenital heart disease: the glass half empty.

Akl Fahed, Bruce Gelb, J G Seidman … (2013)

Congenital heart disease (CHD) is the most common congenital anomaly in newborn babies. Cardiac malformations have been produced in multiple experimental animal models, by perturbing selected molecules that function in the developmental pathways involved in myocyte specification, differentiation, or cardiac morphogenesis. In contrast, the precise genetic, epigenetic, or environmental basis for these perturbations in humans remains poorly understood. Over the past few decades, researchers have tried to bridge this knowledge gap through conventional genome-wide analyses of rare Mendelian CHD families, and by sequencing candidate genes in CHD cohorts. Although yielding few, usually highly penetrant, disease gene mutations, these discoveries provided 3 notable insights. First, human CHD mutations impact a heterogeneous set of molecules that orchestrate cardiac development. Second, CHD mutations often alter gene/protein dosage. Third, identical pathogenic CHD mutations cause a variety of distinct malformations, implying that higher order interactions account for particular CHD phenotypes. The advent of contemporary genomic technologies including single nucleotide polymorphism arrays, next-generation sequencing, and copy number variant platforms are accelerating the discovery of genetic causes of CHD. Importantly, these approaches enable study of sporadic cases, the most common presentation of CHD. Emerging results from ongoing genomic efforts have validated earlier observations learned from the monogenic CHD families. In this review, we explore how continued use of these technologies and integration of systems biology is expected to expand our understanding of the genetic architecture of CHD.

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Cardiac chamber formation: development, genes, and evolution.

Mark Moorman, Vincent Christoffels (2003)

Concepts of cardiac development have greatly influenced the description of the formation of the four-chambered vertebrate heart. Traditionally, the embryonic tubular heart is considered to be a composite of serially arranged segments representing adult cardiac compartments. Conversion of such a serial arrangement into the parallel arrangement of the mammalian heart is difficult to understand. Logical integration of the development of the cardiac conduction system into the serial concept has remained puzzling as well. Therefore, the current description needed reconsideration, and we decided to evaluate the essentialities of cardiac design, its evolutionary and embryonic development, and the molecular pathways recruited to make the four-chambered mammalian heart. The three principal notions taken into consideration are as follows. 1) Both the ancestor chordate heart and the embryonic tubular heart of higher vertebrates consist of poorly developed and poorly coupled "pacemaker-like" cardiac muscle cells with the highest pacemaker activity at the venous pole, causing unidirectional peristaltic contraction waves. 2) From this heart tube, ventricular chambers differentiate ventrally and atrial chambers dorsally. The developing chambers display high proliferative activity and consist of structurally well-developed and well-coupled muscle cells with low pacemaker activity, which permits fast conduction of the impulse and efficacious contraction. The forming chambers remain flanked by slowly proliferating pacemaker-like myocardium that is temporally prevented from differentiating into chamber myocardium. 3) The trabecular myocardium proliferates slowly, consists of structurally poorly developed, but well-coupled, cells and contributes to the ventricular conduction system. The atrial and ventricular chambers of the formed heart are activated and interconnected by derivatives of embryonic myocardium. The topographical arrangement of the distinct cardiac muscle cells in the forming heart explains the embryonic electrocardiogram (ECG), does not require the invention of nodes, and allows a logical transition from a peristaltic tubular heart to a synchronously contracting four-chambered heart. This view on the development of cardiac design unfolds fascinating possibilities for future research.

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Aortic dilation in bicuspid aortic valve disease: flow pattern is a major contributor and differs with valve fusion type.

Malenka M Bissell, Aaron T Hess, Luca Biasiolli … (2013)

Ascending aortic dilation is important in bicuspid aortic valve (BAV) disease, with increased risk of aortic dissection. We used cardiovascular MR to understand the pathophysiology better by examining the links between 3-dimensional flow abnormalities, aortic function, and aortic dilation. A total of 142 subjects underwent cardiovascular MR (mean age, 40 years; 95 with BAV, 47 healthy volunteers). Patients with BAV had predominantly abnormal right-handed helical flow in the ascending aorta, larger ascending aortas (18.3±3.3 versus 15.2±2.2 mm/m²; P<0.001), and higher rotational (helical) flow (31.7±15.8 versus 2.9±3.9 mm²/s; P<0.001), systolic flow angle (23.1°±12.5° versus 7.0°±4.6°; P<0.001), and systolic wall shear stress (0.85±0.28 versus 0.59±0.17 N/m²; P<0.001) compared with healthy volunteers. BAV with right-handed flow and right-non coronary cusp fusion (n=31) showed more severe flow abnormalities (rotational flow, 38.5±16.5 versus 27.8±12.4 mm²/s; P<0.001; systolic flow angle, 29.4°±10.9° versus 19.4°±11.4°; P<0.001; in-plane wall shear stress, 0.64±0.23 versus 0.47±0.22 N/m²; P<0.001) and larger aortas (19.5±3.4 versus 17.5±3.1 mm/m²; P<0.05) than right-left cusp fusion (n=55). Patients with BAV with normal flow patterns had similar aortic dimensions and wall shear stress to healthy volunteers and younger patients with BAV showed abnormal flow patterns but no aortic dilation, both further supporting the importance of flow pattern in the pathogenesis of aortic dilation. Aortic function measures (distensibility, aortic strain, and pulse wave velocity) were similar across all groups. Flow abnormalities may be a major contributor to aortic dilation in BAV. Fusion type affects the severity of flow abnormalities and may allow better risk prediction and selection of patients for earlier surgical intervention.

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Author and article information

Contributors

Stephanie E. Lindsey: URI : http://community.frontiersin.org/people/u/169121

Jonathan T. Butcher: URI : http://community.frontiersin.org/people/u/177312

Huseyin C. Yalcin: URI : http://community.frontiersin.org/people/u/120099

Journal

Journal ID (nlm-ta): Front Physiol

Journal ID (iso-abbrev): Front Physiol

Journal ID (publisher-id): Front. Physiol.

Title: Frontiers in Physiology

Publisher: Frontiers Media S.A.

ISSN (Electronic): 1664-042X

Publication date (Electronic): 21 August 2014

Publication date Collection: 2014

Volume: 5

Electronic Location Identifier: 318

Affiliations

[1] ¹Department of Biomedical Engineering, Cornell University Ithaca, NY, USA

[2] ²Department of Mechanical Engineering, Dogus University Istanbul, Turkey

Author notes

Edited by: Michiko Watanabe, Case Western Reserve University School of Medicine, USA

Reviewed by: Indika Rajapakse, University of Michigan, USA; Jennifer Lynn Ross, University of Massachusetts Amherst, USA; Russell Norris, Medical University of South Carolina, USA

*Correspondence: Huseyin C. Yalcin, Department of Mechanical Engineering, Dogus University, G Blok 508B, Acibadem Zeamet Sokak, Kadikoy 34722, Istanbul, Turkey e-mail: yalcincagatay@ 123456gmail.com

This article was submitted to Biophysics, a section of the journal Frontiers in Physiology.

Article

DOI: 10.3389/fphys.2014.00318

PMC ID: 4140306

PubMed ID: 25191277

SO-VID: 159a0ed3-2dd0-4817-b2e8-f413d1e20c91

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

History

Date received : 15 May 2014

Date accepted : 03 August 2014

Page count

Figures: 4, Tables: 3, Equations: 0, References: 148, Pages: 15, Words: 13468

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Mechanical regulation of cardiac development

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The Journal of Physiology

Most cited references 135

Genetics of congenital heart disease: the glass half empty.

Cardiac chamber formation: development, genes, and evolution.

Aortic dilation in bicuspid aortic valve disease: flow pattern is a major contributor and differs with valve fusion type.

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