Intercalated discs of mammalian heart: A review of structure and function

Propagation of action potentials through the heart coordinates the heartbeat. Thus, intercalated discs, specialized cell–cell contact sites that provide electrical and mechanical coupling between cardiomyocytes, are an important target for study. Impaired propagation leads to arrhythmias in many pathologies, where intercalated disc remodeling is a common finding, hence the importance and urgency of understanding propagation dependence on intercalated disc structure. Conventional modeling approaches cannot predict changes in propagation elicited by perturbations that alter intercalated disc ultrastructure or molecular organization, because of lack of quantitative structural data at subcellular through nano scales.

This study sought to quantify intercalated disc structure at these spatial scales in the healthy adult mouse heart and relate them to chamber-specific properties of propagation as a precursor to understanding the effects of pathological intercalated disc remodeling.

Using super-resolution light microscopy, electron microscopy, and computational image analysis, we provide here the first ever systematic, multiscale quantification of intercalated disc ultrastructure and molecular organization.

By incorporating these data into a rule-based model of cardiac tissue with realistic intercalated disc structure, and comparing model predictions of electrical propagation with experimental measures of conduction velocity, we reveal that atrial intercalated discs can support faster conduction than their ventricular counterparts, which is normally masked by interchamber differences in myocyte geometry. Further, we identify key ultrastructural and molecular organization features underpinning the ability of atrial intercalated discs to support faster conduction.

These data provide the first stepping stone to elucidating chamber-specific effects of pathological intercalated disc remodeling, as occurs in many arrhythmic diseases.

The atrium of the juvenile teleost, smallmouth bass, Micropterus dolomieu Lacépède showed a pigmented endocardium. Our goal was to use fine structure to survey this fish heart tissues and verify the content responsible for this shrouding and discuss mammalian, translational conjectures about this cardiac structure.

Using electron microscopy, heart pericardium, myocardium, and endocardium were analyzed, including atrial peptide immunolabeling.

The endocardium endothelial cells of the atrium revealed pinocytosis and endocytosis activities that resulted in accumulated electron-contrasted secondary lysosomes and lipofuscin bodies not found in the ventricle endocardium. This endothelium contacted subjacent atrial and ventricular myocardial cells producing immunolabeled atrial peptide-containing vesicles. Other migrating cells, including melano-macrophages, were noticed in the atrial sub endocardium.

The endocardium functioned as a potent blood-heart barrier where transcytosis and dispatching of numerous materials, including those atrial peptides, between myocardium and the circulation occur. Peculiarly, this juvenile endothelium revealed abundant lysosomal processing of scavenged circulation materials like in a reticuloendothelial tissue. These juvenile cell's accumulated ‘aging’ lipofuscin bodies as organized deposits into a network with other organelles, especially mitochondria without evident disposal. Additionally, other cells, including melano-macrophages roamed both sub endocardium and ventricle; those also can influence the viewed pigmentation. Some of these data comforted the endocardial mesodermal lineage, still sketchy for all vertebrates while fish heart development is still used. These observations could raise questions: Does turnover of lipofuscin and associated captures make endocardial cells to model other mammalian pathologies, including those associated with heart failure?

Cardiac pacemaker cells (CPCs) rhythmically initiate the electrical impulses that drive heart contraction. CPCs display the highest rate of spontaneous depolarization in the heart despite being subjected to inhibitory electrochemical conditions that should theoretically suppress their activity. While several models have been proposed to explain this apparent paradox, the actual molecular mechanisms that allow CPCs to overcome electrogenic barriers to their function remain poorly understood. Here, we have traced CPC development at single-cell resolution and uncovered a series of cytoarchitectural patterning events that are critical for proper pacemaking. Specifically, our data reveal that CPCs dynamically modulate adherens junction (AJ) engagement to control characteristics including surface area, volume, and gap junctional coupling. This allows CPCs to adopt a structural configuration that supports their overall excitability. Thus, our data have identified a direct role for local cellular mechanics in patterning critical morphological features that are necessary for CPC electrical activity.

The purpose of this chapter is to indicate those areas of cardiovascular research in which the rat has been particularly useful in recapitulating human cardiovascular disease as a model organism. Rat cardiovascular anatomy and electrophysiology is reviewed, highlighting similarities and differences to humans and other mammalian species. Prominent genetic, spontaneous, and experimentally induced rat models of cardiovascular diseases or associated risk factors, such as hypertension, are described and compared. A review of current in vivo phenotyping modalities as well as in vitro culture and benchtop techniques is provided.

Heart disease is the leading cause of death worldwide, and cardiotoxicity is one of the most common reasons for drug withdrawal. Both statistics are in part because conventional in vitro and in vivo models of the heart are ineffective at modeling human diseases and predicting drug responses due to limited relevance and/or scalability. In this chapter, we first define the structure and function of myocardial tissue, the minimum functional unit of the heart. Next, we describe approaches for acquiring human cardiac myocytes, the key functional cells in the myocardium. We then present innovative techniques for engineering cardiac tissues in two and three dimensions that more closely replicate native myocardium. We also describe assays for quantitatively interrogating the mechanical and electric function of engineered cardiac tissues. Next, we provide examples of applications of cardiac tissue models in human cardiotoxicity screening and disease modeling. Finally, we summarize ongoing biological and technical challenges.

Gap Junction (GJ) channels, including the most common Connexin 43 (Cx43), have fundamental roles in excitable tissues by facilitating rapid transmission of action potentials between adjacent cells. For instance, synchronization during each heartbeat is regulated by these ion channels at the cardiomyocyte cell-cell border. Cx43 protein has a short half-life, and rapid synthesis and timely delivery of those proteins to particular subdomains are crucial for the cellular organization of gap junctions and maintenance of intracellular coupling. Impairment in gap junction trafficking contributes to dangerous complications in diseased hearts such as the arrhythmias of sudden cardiac death. Of recent interest are the protein-protein interactions with the Cx43 carboxy-terminus. These interactions have significant impact on the full length Cx43 lifecycle and also contribute to trafficking of Cx43 as well as possibly other functions. We are learning that many of the known non-canonical roles of Cx43 can be attributed to the recently identified six endogenous Cx43 truncated isoforms which are produced by internal translation. In general, alternative translation is a new leading edge for proteome expansion and therapeutic drug development. This review highlights recent mechanisms identified in the trafficking of gap junction channels, involvement of other proteins contributing to the delivery of channels to the cell-cell border, and understanding of possible roles of the newly discovered alternatively translated isoforms in Cx43 biology. This article is part of a Special Issue entitled: Gap Junction Proteins edited by Jean Claude Herve.