Endomyocardial biopsy (EMB) is an invasive procedure and a diagnostic tool used mainly on the follow-up of post-heart transplant rejection in the past years. Currently, it has an important role in the diagnosis of non-ischemic cardiomyopathies. EMB is frequently performed through a venous access to enter the right ventricle. Diagnostic performance has improved with advances in pathology analysis. Its complications risk, close to 1% in high-volume interventional centers, can be justified considering the potential benefit of an accurate diagnosis and prognosis.

UNASSIGNED: The elaborate patterning of coronary arteries critically supports the high metabolic activity of the beating heart. How coronary endothelial cells coordinate hierarchical vascular remodeling and achieve arteriovenous specification remains largely unknown. Understanding the molecular and cellular cues that pattern coronary arteries is crucial to develop innovative therapeutic strategies that restore functional perfusion within the ischemic heart.
UNASSIGNED: Single-cell transcriptomics and histological validation were used to delineate heterogeneous transcriptional states of the developing and mature coronary endothelium with a focus on sprouting endothelium and arterial cell specification. Genetic lineage tracing and high-resolution 3-dimensional imaging were used to characterize the origin and mechanisms of coronary angiogenic sprouting, as well as to fate-map selective endothelial lineages. Integration of single-cell transcriptomic data from ischemic adult mouse hearts and human embryonic data served to assess the conservation of transcriptional states across development, disease, and species.
UNASSIGNED: We discover that coronary arteries originate from cells that have previously transitioned through a specific tip cell phenotype. We identify nonoverlapping intramyocardial and subepicardial tip cell populations with differential gene expression profiles and regulatory pathways. Esm1-lineage tracing confirmed that intramyocardial tip cells selectively contribute to coronary arteries and endocardial tunnels, but not veins. Notably, prearterial cells are detected from development stages to adulthood, increasingly in response to ischemic injury, and in human embryos, suggesting that tip cell-to-artery specification is a conserved mechanism.
UNASSIGNED: A tip cell-to-artery specification mechanism drives arterialization of the intramyocardial plexus and endocardial tunnels throughout life and is reactivated upon ischemic injury. Differential sprouting programs govern the formation and specification of the venous and arterial coronary plexus.

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Tricuspid atresia (TA) is a rare congenital heart condition that presents with a complete absence of the right atrioventricular valve. Because of the rarity of familial and/or isolated cases of TA, little is known about the potential genetic abnormalities contributing to this condition. Potential responsible chromosomal abnormalities were identified in exploratory studies and include deletions in 22q11, 4q31, 8p23, and 3p as well as trisomies 13 and 18. In parallel, potential culprit genes include the ZFPM2, HEY2, NFATC1, NKX2-5, MYH6, and KLF13 genes. The aim of this chapter is to expose the genetic components that are potentially involved in the pathogenesis of TA in humans. The large variability in phenotypes and genotypes among cases of TA suggests a genetic network that involves many components yet to be unraveled.

The relative simplicity of the clinical presentation and management of an atrial septal defect belies the complexity of the developmental pathogenesis. Here, we describe the anatomic development of the atrial septum and the venous return to the atrial chambers. Experimental models suggest how mutations and naturally occurring genetic variation could affect developmental steps to cause a defect within the oval fossa, the so-called secundum defect, or other interatrial communications, such as the sinus venosus defect or ostium primum defect.

This chapter will describe basic structural and functional features of the contractile apparatus of muscle cells of the heart, namely, cardiomyocytes and smooth muscle cells. Cardiomyocytes form the contractile myocardium of the heart, while smooth muscle cells form the contractile coronary vessels. Both muscle types have distinct properties and will be considered with respect to their cellular appearance (brick-like cross-striated versus spindle-like smooth), arrangement of contractile proteins (sarcomeric versus non-sarcomeric organization), calcium activation mechanisms (thin-filament versus thick-filament regulation), contractile features (fast and phasic versus slow and tonic), energy metabolism (high oxygen versus low oxygen demand), molecular motors (type II myosin isoenzymes with high adenosine diphosphate [ADP]-release rate versus myosin isoenzymes with low ADP-release rates), chemomechanical energy conversion (high adenosine triphosphate [ATP] consumption and short duty ratio versus low ATP consumption and high duty ratio of myosin II cross-bridges [XBs]), and excitation-contraction coupling (calcium-induced calcium release versus pharmacomechanical coupling). Part of the work has been published (Neuroscience - From Molecules to Behavior\", Chap. 22, Galizia and Lledo eds 2013, Springer-Verlag; with kind permission from Springer Science + Business Media).

The major events of cardiac development, including early heart formation, chamber morphogenesis and septation, and conduction system and coronary artery development, are briefly reviewed together with a short introduction to the animal species commonly used to study heart development and model congenital heart defects (CHDs).

BACKGROUND: Although the epicardial predominance of substrate abnormalities has been well demonstrated in early stages of arrhythmogenic right ventricular cardiomyopathy (ARVC), endocardial (ENDO) ablation may suffice to eliminate ventricular tachycardia (VT) in some patients.
OBJECTIVE: This study aimed to report the long-term outcomes of ENDO-only ablation in ARVC patients and factors that predict VT-free survival.
METHODS: We included consecutive patients with Task Force Criteria diagnosis of ARVC undergoing a first ENDO-only VT ablation between 1998 and 2020. Ablation was predominantly guided by activation/entrainment mapping for mappable VTs and pace mapping/targeting abnormal electrograms for unmappable VTs. The primary endpoint was freedom from any recurrent sustained VT after the last ENDO-only ablation.
RESULTS: Seventy-four ARVC patients underwent ENDO-only VT ablation. VT noninducibility was achieved in 49 (66%) patients. During median follow-up of 6.6 years (Q1-Q3: 3.4-11.2 years), 40 (54.1%) patients remained free from any VT recurrence with rare VT ≤2 episodes in additional 12.2%. Among patients with noninducibility, VT-free survival was 75.5% during long-term follow-up. In multivariable analysis, >45 y of age at diagnosis (HR: 0.41; 95% CI: 0.17-0.98) and VT noninducibility (HR: 0.36; 95% CI: 0.16-0.80) were predictors of VT-free survival.
CONCLUSIONS: Long-term VT-free survival can be achieved in over half of ARVC patients following ENDO-only VT ablation, increasing to over 75% if VT noninducibility is achieved. Our results support consideration of a stepwise ENDO-only approach before proceeding to epicardial ablation if VT noninducibility can be achieved particularly in older patients.

Failure of proper ventricular trabeculation is often associated with congenital heart disease. Support from endocardial cells, including the secretion of extracellular matrix and growth factors is critical for trabeculation. However, it is poorly understood how the secretion of extracellular matrix and growth factors is initiated and regulated by endocardial cells. We find that genetic knockout of histone deacetylase 3 in the endocardium in mice results in early embryo lethality and ventricular hypotrabeculation. Single cell RNA sequencing identifies significant downregulation of extracellular matrix components in histone deacetylase 3 knockout endocardial cells. Secretome from cultured histone deacetylase 3 knockout mouse cardiac endothelial cells lacks transforming growth factor ß3 and shows significantly reduced capacity in stimulating cultured cardiomyocyte proliferation, which is remarkably rescued by transforming growth factor ß3 supplementation. Mechanistically, we identify that histone deacetylase 3 knockout induces transforming growth factor ß3 expression through repressing microRNA-129-5p. Our findings provide insights into the pathogenesis of congenital heart disease and conceptual strategies to promote myocardial regeneration.