Myocardial infarction is a leading cause of morbidity and mortality. While reperfusion is now standard therapy, pathological remodelling leading to heart failure remains a clinical problem. Cellular senescence has been shown to contribute to disease pathophysiology and treatment with the senolytic navitoclax attenuates inflammation, reduces adverse myocardial remodelling and results in improved functional recovery. However, it remains unclear which senescent cell populations contribute to these processes. To identify whether senescent cardiomyocytes contribute to disease pathophysiology post-myocardial infarction, we established a transgenic model in which p16 (CDKN2A) expression was specifically knocked-out in the cardiomyocyte population. Following myocardial infarction, mice lacking cardiomyocyte p16 expression demonstrated no difference in cardiomyocyte hypertrophy but exhibited improved cardiac function and significantly reduced scar size in comparison to control animals. This data demonstrates that senescent cardiomyocytes participate in pathological myocardial remodelling. Importantly, inhibition of cardiomyocyte senescence led to reduced senescence-associated inflammation and decreased senescence-associated markers within other myocardial lineages, consistent with the hypothesis that cardiomyocytes promote pathological remodelling by spreading senescence to other cell-types. Collectively this study presents the demonstration that senescent cardiomyocytes are major contributors to myocardial remodelling and dysfunction following a myocardial infarction. Therefore, to maximise the potential for clinical translation, it is important to further understand the mechanisms underlying cardiomyocyte senescence and how to optimise senolytic strategies to target this cell lineage.

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Cancer continues to place a heavy burden on healthcare systems around the world. Although cancer survivorship continues to improve, cardiotoxicity leading to cardiomyopathy and heart failure as a consequence of cancer therapy is rising, and yesterday’s cancer survivors are fast becoming today’s heart failure patients. Although the mechanisms driving cardiotoxicity are complex, cellular senescence is gaining attention as a major contributor to chemotherapy-induced cardiotoxicity and, therefore, may also represent a novel therapeutic target to prevent this disease. Cellular senescence is a well-recognized response to clinical doses of chemotherapies, including anthracyclines, and is defined by cell cycle exit, phenotypic alterations which include mitochondrial dysfunction, and the expression of the pro-senescent, pro-fibrotic, and pro-inflammatory senescence-associated phenotype. Senescence has an established involvement in promoting myocardial remodeling during aging, and studies have demonstrated that the elimination of senescence can attenuate the pathophysiology of several cardiovascular diseases. Most recently, pharmacology-mediated elimination of senescence, using a class of drugs termed senolytics, has been demonstrated to prevent myocardial dysfunction in preclinical models of chemotherapy-induced cardiotoxicity. In this review, we will discuss the evidence that anthracycline-induced senescence causes the long-term cardiotoxicity of anticancer chemotherapies, consider how the senescent phenotype may promote myocardial dysfunction, and examine the exciting possibility that targeting senescence may prove a therapeutic strategy to prevent or even reverse chemotherapy-induced cardiac dysfunction.

Atherosclerotic plaques progress towards instability and rupture, triggering myocardial infarction or stroke. Plaque instability is characterised by several features including reduced collagen content and increased inflammation. Disturbed blood flow influences plaque instability by altering endothelial cell (EC) physiology via pathways that are incompletely understood. TWIST1, a transcription factor, has been linked to coronary artery disease and stroke in human genetic studies. Additionally, TWIST1 expression is induced in atheroprone areas exposed to disturbed flow. Although endothelial Twist1 promotes early atherogenesis, the role of Twist1 in atheroprogression and plaque stability is unknown, and is a focus of the current study.ApoE-/-mice with an inducible EC-specific Twist1 knockout (Twist1fl/fl ApoE-/-Cdh5CreERT2/+; called Twist1EC-KO) and control mice (Twist1fl/fl ApoE-/-Cdh5+/+; called Twist1EC-WT) were generated. 8-10 weeks old mice were exposed to a Western diet for 8 weeks to generate plaques, then given tamoxifen to activate Cre, and fed a Western diet for a further 6 weeks to drive atheroprogression. Aortic EC (CD31+ CD45-) were isolated by FACS and analysed by single-cell RNA sequencing (scRNAseq), to assess the influence of Twist1 on downstream targets and EC phenotype. Additionally, plaque histological studies were performed in brachiocephalic arteries.Twist1 deletion in aortic EC was validated by qRT-PCR, revealing a >90% reduction in Twist1EC-KO mice. scRNAseq identified 10 EC subtypes in mouse aortas. Twist1 deletion had a major effect on EC heterogeneity by suppressing clusters 2, 7 and 8. Gene ontology analysis revealed that these clusters are associated with endothelial-to-mesenchymal-transition (cluster 8), development (cluster 7) and extracellular matrix organisation (cluster 2, 8). Ongoing studies of brachiocephalic plaques show that Twist1 EC deletion reduces plaque size, reduces collagen content (feature of stability), and increases macrophage content (feature of instability).In conclusion, Twist1 controls EC heterogeneity in atherosclerosis to increase plaque growth and concomitantly enhance features of plaque stability.