Best Cardiovascular Basic Science of the Decade Award Nominations

Nomination 1

Dick, S. A., Macklin, J. A., Nejat, S., Clemente-Casares, X., Momen, A., Kantores, C., Hosseinzadeh, S., Barbu, I., Chen, J., Althagafi, M. G., Besla, R., Wong, A., Aronoff, L., Zaman, R., Lavine, K. J., Razani, B., Ginhoux, F., Husain, M., Cybulsky, M. I., … Epelman, S. (2019). Self-renewing resident cardiac macrophages limit adverse remodeling following myocardial infarction. Nature Immunology, 20, 29–39. https://doi.org/10.5281/zenodo.1407166

Bibliometrics (Citations per Year)* – 103.167

Bibliometrics (Field-Weighted Citation Impact)* – 20.39

Dr. Epelman’s influential study, published in the prestigious journal, Nature Immunology (2019) has been cited over 750 times, reflecting its major impact on cardiac immunology. This pioneering work identified a distinct population of self-renewing, embryonically-derived tissue resident macrophages that persist independently of circulating monocytes and play a critical role in promoting reparative remodeling after myocardial infarction. The study’s rigorous use of fate mapping, bioinformatics and genetic models demonstrates the protective function of these macrophages in limiting adverse ventricular remodeling and preserving cardiac function. By shifting the paradigm from monocyte driven inflammation to highlighting resident macrophages’ reparative capacity, this research offers novel insights with high translational potential. This work lays the foundation for new therapeutic strategies aimed at enhancing resident macrophage function to improve recovery and prevent heart failure progression after myocardial injury.

Nomination 2

Veitch S, Njock MS, Chandy M, Siraj MA, Chi L, Chen Z, Alibhai FJ, Gustafson D, Raju S, Wu R, Rathnakumar K, Khat DZ, Caballero A, Meagher P, Lau E, Pepic L, Cheng HS, Galant NJ, Howe KL, Li RK, Connelly KA, Delgado-Olguin P, Husain M, Fish JE. MiR-30 promotes fatty acid beta-oxidation and endothelial cell dysfunction in diabetic cardiomyopathy. Cardiovascular Diabetology. 2022; 21(1):31. Impact Factor: 10.6. Citations:61. http://doi.org/10.1186/s12933-022-01458-z

Bibliometrics (Citations per Year)* – 18.67

Bibliometrics (Field-Weighted Citation Impact)* – 5.91

This project was directly funded by the TRCHR and Shawn Veitch received trainee funding. This manuscript revealed that the miR-30 family is induced in the endothelium of the coronary microvasculature in the setting of diabetes to alter fatty acid metabolism. This in turn induces oxidative stress and may be responsible for coronary microvascular rarefaction, which contributes to diastolic dysfunction and heart failure with preserved ejection fraction. This study also revealed that miR-30 levels increase in circulation prior to the development of diastolic dysfunction and that miR-30 inhibitors can improve microvascular density. This paper has been cited 61 times in only 3 years, demonstrating its impact. The study provides a new paradigm for how microvascular dysfunction occurs in diabetes-induced heart failure with preserved ejection fraction and reveals a potential biomarker and therapeutic target for this disease.

Nomination 3

Ensan, S., Li, A., Besla, R., Degousee, N., Cosme, J., Roufaiel, M., Shikatani, E. A., El-Maklizi, M., Williams, J. W., Robins, L., Li, C., Lewis, B., Yun, T. J., Lee, J. S., Wieghofer, P., Khattar, R., Farrokhi, K., Byrne, J., Ouzounian, M., … & Robbins, C. S. (2016). Self-renewing resident arterial macrophages arise from embryonic CX3CR1⁺ precursors and circulating monocytes immediately after birth. Nature immunology, 17(2), 159–168. https://doi.org/10.1038/ni.3343

Bibliometrics (Citations per Year)* – 33.22

Bibliometrics (Field-Weighted Citation Impact)* – 9.09

We discovered two distinct aortic macrophage (Mφ) populations with divergent origins and functions under homeostatic and inflammatory conditions. Using Lyve-1 as a defining surface marker, we showed that tissue-resident Mφ arise prenatally and contribute to vascular homeostasis, while inflammation triggers the recruitment of a transient, functionally distinct Lyve-1⁻ bone marrow–derived Mφ population. This study provided one of the first demonstrations of ontogenically distinct macrophage lineages in the vasculature and introduced Lyve-1 as a marker of homeostatic arterial Mφ. Cited over 400 times, this work has significantly shaped current understanding of vascular immunity, influencing both basic macrophage biology and translational research into atherosclerosis and aneurysm.

Nomination 4

Hamidzada, H., Pascual-Gil, S., Wu, Q., Kent, G. M., Massé, S., Kantores, C., … & Epelman, S. (2024). Primitive macrophages induce sarcomeric maturation and functional enhancement of developing human cardiac microtissues via efferocytic pathways. Nature cardiovascular research, 3(5), 567-593.

Bibliometrics (Citations per Year) – 15

Bibliometrics (Field-Weighted Citation Impact) – 5.6

This paper received two nominations. Below are both nomination blurbs:

1. A major barrier in cardiac regeneration has persisted for decades: hESC-derived cardiomyocytes fail to mature or functionally integrate, limiting their therapeutic potential. This study introduces a novel solution: the incorporation of human primitive macrophages into developing cardiac tissues. It is the first to demonstrate that hESC-derived macrophages, long overlooked in cardiac engineering, can drive functional maturation of hESC-cardiomyocytes through efferocytic clearance of apoptotic cells, enhancing sarcomeric structure, contractile force, and relaxation kinetics. Beyond biological discovery, this work establishes the first immunoengineered human cardiac tissue. By introducing an immune lineage never before included in cardiac modeling, the platform captures key aspects of fetal heart development that existing models miss. This breakthrough challenges the cardiomyocyte-centric paradigm that has defined the field for over a decade, introducing macrophages as a powerful and necessary cellular component for building functional human heart tissue – transforming both in vitro modeling and future regenerative therapies.

2. In a groundbreaking recent study, published in Nature Cardiovascular Research (2024) Dr. Epelman et al. demonstrate the first-ever incorporation of stem-cell made macrophages into engineered heart tissue. This research introduces a novel concept: primitive yolk sac macrophages, generated from human embryonic stem cells (hESCs), directly enhance cardiac tissue maturation and function. These findings challenge existing models and open new possibilities for regenerative medicine. In recognition of this research, Dr. Slava Epelman was awarded the 2024 Till & McCulloch Award. This study highlights the crucial role of macrophage-engineered human cardiac microtissues for therapeutic strategies in heart repair, offering a revolutionary approach to heart regeneration.

Nomination 5

Lee, J. H., Protze, S. I., Laksman, Z., Backx, P. H., & Keller, G. M. (2017). Human pluripotent stem cell-derived atrial and ventricular cardiomyocytes develop from distinct mesoderm populations. Cell Stem Cell, 21(2), 179–194.e4. https://doi.org/10.1016/j.stem.2017.07.003

Bibliometrics (Citations per Year) – 38.375

Bibliometrics (Field-Weighted Citation Impact) – 7.84

Using human pluripotent stem cells, this work showed, for the first time, that human ventricular and atrial cardiomyocytes derive from different mesoderm progenitors. We identified CD235a and RALDH2 as markers for the distinct atrial and ventricular mesoderm progenitors that give rise to atrial and ventricular cardiomyocytes respectively. Importantly molecular and electrophysiological characterization of the cardiomyocytes revealed that the optimal differentiation of functional ventricular and atrial cells is dependent on the generation of the appropriate mesoderm progenitor. This has important implications for disease modelling applications where the correct cardiomyocyte subtype is essential to recapitulate disease phenotypes and identify novel treatment options in the petri dish. This finding is highly relevant for cell therapy applications especially of ventricular cardiomyocytes to replace cardiomyocytes lost during a myocardial infarction. Pure and functional ventricular cardiomyocyte populations that do not cause unwanted arrhythmias will be important for successful remuscularization and improved heart function in MI patients.

* Bibliometrics were collected from Scopus.