What Contributes to a Spongy, Thick Heart Muscle: Understanding Non-compaction of the Heart

by Amanda Chase, PhD
August 2, 2021

As we all know, the heart muscle (myocardium) is critical for blood flow. The myocardium is a smooth, firm muscle that can contract and relax in a coordinated manner to facilitate the pumping of blood.  Heart failure is when the heart muscle is unable to pump enough blood to meet the body’s needs, usually because the heart cannot pump or fill correctly. Left ventricular non-compaction (LVNC) is a rare cardiovascular disease in which the lower part of the heart that helps pump blood does not develop correctly. The myocardium is thick and spongy instead of being smooth and firm, meaning that the heart is unable to fully relax or fully contract and thus there is decreased blood flow. LVNC is the third most common form of congenital cardiomyopathy in the US, and two-thirds of patients develop heart failure. There remains no therapeutic cure to reverse the non-compact phenotype, primarily because the genetic basis of LVNC is both complex and not well understood.

Better understanding the mechanisms underlying LVNC, and the cell types involved, would eventually enable clinical strategies to treat LVNC instead of the symptoms. Stanford University researchers, led by first authors Siyeon Rhee, PhD, and David Paik, PhD, and senior authors Ashby Morrison, PhD, Joseph Wu, MD, PhD, and Kristy Red-Horse, PhD, recently published a proposed model of how the non-compact phenotype may occur in European Heart Journal.  

Figure. Analysis of a mouse model of ventricular non-compaction, coupled with in vitro analysis of cardiomyocyte growth, found that endothelial factors expressed during development can contribute to non-compaction.

While not much is understood about what causes LVNC, it is believed to occur during development, when the cardiac muscle is forming. Small animal models available to date had suggested that the cause of LVNC is largely due to insufficient growth and premature maturation of cardiomyocytes. In this manuscript, the team explored a novel idea that non-cardiomyocyte cell types may also be the culprit. Specifically, the team found that endothelial cells, which compose the innermost lining of blood vessels, and endocardial cells, which give rise to valves, together secrete a number of paracrine factors (also known as “angiocrine” factors) that dynamically regulate the growth (proliferation) and maturation of the cardiomyocytes during heart development. These critical cellular processes of developing cardiomyocytes are naturally linked to the structural formation and maturation of the ventricular wall, notably in the reduction of trabeculae and generation of compact myocardium. The team identified that dysfunction in secretion of specific angiocrine factors by these endothelial and endocardial cells lead to LVNC in both mouse and human stem cell models.

Specifically, the authors used a mouse model with a chromatin remodeler gene lno80 deleted in endothelial cells to study how certain factors could be important for normal heart wall growth. Using a technique called single cell RNA sequencing, they were able to show that lno80 mutant hearts had a cell state that was specific to non-compact myocardium. Further, using iPSCs they found that cardiomyocytes and other stromal cells are the cell types that express genes associated with human LVNC. Importantly, this suggested a potential site of origin for the human LVNC disease. They identified that in the case of LVNC, endothelial cells and endocardial cells excessively secreted angiocrine factors that promote cardiomyocyte maturation such as Tgfbi, Igfbp3, Isg15, and Adm. Conversely, the same cells lacked proper secretion of Col15a1, which was shown to promote cardiomyocyte proliferation. Consequently, identification of the specific factors that impact cardiomyocyte proliferation and maturation during development  renders the potential to lead to the development of effective, patient-specific therapeutics to treat and correct LVNC.

Other authors affiliated with the Stanford Cardiovascular Institute include Johnson Yang, Ian Williams, Lei Tian, Mark Chandy, Nadjet Belbachir, and Hao Zhang. Other members of the collaborative team include Danielle Nagelberg, Robert Roth, Jiyeon Ban, Seokho Kim, Ragini Phansalkar, Ka Man Wong, Devin King, Caroline Valdez, and Virginia Winn, all affiliated with Stanford University.

Siyeon Rhee, PhD

David Paik, PhD

Kristy Red-Horse, PhD