Researchers at the Victor Chang Cardiac Research Institute in Australia have now confirmed the world’s first holistic mapping of heart cells. This tremendous breakthrough explains cardiac fibrosis, one of the main causes of heart failure, and might give birth to new and effective medicines that can prevent scarring after heart attack.
Cardiac fibrosis is scarring in heart muscles that occurs due to their damage during and after a heart attack. This scarring, unlike healthy heart muscles, does not have the requisite elasticity and contractility and hence constitutes permanent damage, thus giving way to a complication in the heart’s pumping function and the consequence of heart failure.
The study, led by Professor Richard Harvey, Dr. Ralph Patrick, and Dr. Vaibhao Janbandhu, is a quantum leap towards the understanding of cardiac fibrosis, which in many cases is omnipresent in all forms of heart diseases, even those brought on by hypertension. “Despite significant investments in discovering drugs to manage cardiac fibrosis, success has been limited,” says Professor Harvey. “There is a dire need for the discovery of new treatments that help in stopping and, hence, reversing cardiac fibrosis” to benefit millions of people.
Although these fibrotic processes constitute a normal process of wound healing, mistimed or excessive reparative response—caused by unresolved disease triggers—results in severe, excessive scarring in the heart and impairs the proper functioning of essential viscera like the heart, leading to heart failure. The researchers have used, for the first time, revolutionary single-cell gene expression analysis technology to map progressive cell states involved in cardiac fibrosis and their evolution over time.
The researchers analyzed RNA signals from 100,000 single cells, focusing on those responsible for fibrosis development, and this information was combined with data published in several seminal studies that explored different conditions leading to heart disease. This achieved an integrated cellular map of the mouse model of a heart and defined cells and pathways implicated in fibrosis.
These key cell types provided by the study include resting cells, activated cells, an inflammatory population, a progenitor pool of cells, cell types committed to division, and other cell types that become specialized into myofibroblasts and known fibrocytes. The myofibroblasts—considered main drivers of scarring—begin to develop in a mouse model three days post–heart attack, peak at day five, and then change into the so-called matrifibrocytes, which prevent the resolution of the scar. This research offers an unparalleled view of the cellular dynamics underlying cardiac fibrosis by providing exhaustive mapping of cell states and their transitions.
The findings, published in Science Advances, concerned other heart failure models that result from high internal blood pressure caused by aortic stenosis or hypertension. Dr Vaibhao Janbandhu: “We were quite surprised to find a very similar time-course for the development of fibrosis across all these types of heart disease. Myofibroblasts dominated at an early stage of hypertension and then converted into matrifibrocytes as they did following heart attack.”
This discovery raises the possibility for potential future therapies to target specific cell types or processes across a wide range of heart diseases at early timepoints, preventing permanent damage to healthy cells. The study used data from both mouse models and human patients. Since heart failure can take several decades to manifest, it will need additional careful studies in human patients to confirm specific cell types and timing of processes.
Dr. Janbandhu added, “Persistent high blood pressure can have serious implications, but to a great extent, it is controllable, therefore monitoring and early control of high blood pressure are crucial.”
The researchers also developed a web tool called the “CardiacFibroAtlas” for use by the international research community, which allows access for visualization and observation in respect to cardiac conduct after heart attacks and other associated ailments.
The work offers not only critical insights into the mechanisms of cardiac fibrosis but also opens the way to the development of new innovative therapies. A comprehensive cellular map and the CardiacFibroAtlas resource could be translated into a useful printed reference and online browser tool for the scientific community worldwide; this will make it easy to discover novel treatments that can help in fighting heart failure.
The authors have mapped the natural progression of fibrosis at cellular resolution and further traced back the molecular pathways involved to identify specific gene expressions with different cell states, thereby marking new potential targets for therapeutic intervention. Such fine understanding of the genetic and cellular machinery driving fibrosis can therefore lead to drugs that hit exactly the pathways and hence might stop or even reverse the progression of fibrosis.
It is further carried out by the combination of data from multiple heart disease models in this study, emphasizing both similarities and differences in mechanisms for fibrosis driven by various conditions. Comparative modality ensured that the results are more solid and widely applicable. By showing treatment of generic cellular processes occurring across different forms of heart disease, the study underlines potential therapies with universal benefits to large numbers of patients.
One of the most encouraging lines emerging from this research is in the potential for tackling the paradigm shift in current treatment of heart disease. To this point, therapies aimed at reducing fibrosis in the setting of heart disease have focused on ameliorating symptoms and preventing further cardiac damage. The insights brought to light by this study could give real meaning to a more proactive approach aimed at the causes of fibrosis. Cellular and molecular level interventions can prevent, if not reverse, the progression of fibrosis and drive regeneration of healthy heart tissue.
The publication of the online tool called CardiacFibroAtlas—I would say it’s really a milestone in research into cardiovascular studies. This online resource makes available to researchers huge data pertaining to cardiac gene expression and cellular behavior in disease. By facilitating visualization and analysis of this information, the CardiacFibroAtlas accelerates banded research efforts, leading to accelerated rates of new discoveries. The user interface is friendly, with a very complete dataset that makes it easy for researchers to use in their quest to better understand the complexities of cardiac fibrosis and develop new therapeutic strategies.
This breakthrough in creating a comprehensive map of heart cells by scientists at the Victor Chang Cardiac Research Institute marks a milestone in cardiac research—real realization of new insights at the cellular and molecular levels regarding cardiac fibrosis and potential institution of targeted therapies that will revolutionize the treatment of heart disease. Identifying key cell types and pathways involved in fibrosis, this study provides a roadmap of sorts to develop drugs that would have the potential to halt or reverse this process, opening options for millions of patients across the world. The CardiacFibroAtlas tool increases the impact of this study by providing a truly valuable resource for collaborative study by the global scientific community toward the discovery of new treatments at an accelerated pace. It is therefore a landmark study that has led to great strides in the fight against heart failure and improvement of cardiovascular health as comprehension of cardiac fibrosis continues to unfold.