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BS31 The senescence-associated secretory phenotype as a biomarker for age-related myocardial remodelling and cardiovascular disease
  1. Laura Booth1,
  2. Rachael Redgrave2,
  3. Maria Camacho Encina3,
  4. Simon Tual-Chalot4,
  5. Omowumi Folaranmi3,
  6. Carmen Martin-Ruiz5,
  7. Ioakim Spyridopoulos1,
  8. Jason Gill1,
  9. Gavin Richardson4
  1. 1Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK, Institute of Genetic Medicine Centre for Life, Central Pkway Newcastle Upon Tyne, TWR NE1 3BZ United Kingdom, UK
  2. 2Bioscience Institute, Vascular Biology and Medicine Theme, Newcastle University, UK
  3. 3Biosciences Institute, Newcastle University, UK
  4. 4Biosciences Institute, Newcastle University, Newcastle upon Tyne, UK
  5. 5Bio Screening Core Facility, Newcastle University, UK


Introduction Preclinical models have demonstrated that the accumulation of senescent myocardial cells is casual to age-related myocardial dysfunction. In vitro and in vivo studies point to the pro-inflammatory senescence-associated secretory phenotype (SASP) being a key driver of cardiac remodelling, but this is decidedly more well-studied in the murine context. The role of SASP in myocardial remodelling clinically, and the capacity of the human myocardial SASP to serve as a biomarker for age-related cardiac remodelling and associated CVD, is still unclear. We aimed to evaluate this by marrying in vitro studies with clinical data from a large, older (> 85 years-old) patient cohort, and clinical data from small cohort of human donor hearts spanning a range of normality.

Methods and Results In human donor hearts, left ventricular p16 protein expression correlated with donor age (Pearson’s correlation=0.631, p<0.1), indicating that senescence is associated with increased donor age. To identify the mechanisms by which myocardial senescence may drive age-related dysfunction, we employed an in vitro model. AC16 cardiomyocytes were induced to senescence using doxorubicin (shown by transcript- and protein-level induction of classical senescence markers p16 (figure 1A) and p21), demonstrating the utility of this in vitro model for recapitulating cardiac senescence. Suggesting that cardiomyocyte senescence contributes to clinical age-related cardiac dysfunction through paracrine mechanisms, senescent human cardiomyocytes expressed a functional SASP which induced phenotypic changes in cardiac fibroblasts (formation of smooth muscle actin-positive stress fibres). Subsequent molecular analysis identified that this SASP contained emergent biomarkers of clinical CVD including GDF15 (figure 1B) and fractalkine. Fractalkine has previously been associated with poorer outcomes in clinical CVD but GDF15 is currently not well-understood. Therefore, GDF15 was analysed in clinical data from a large, older patient cohort (Newcastle 85+ study, n = 774) and was found to significantly elevated in patients with cardiac dysfunction (figure 2A, p<0.005), alongside the gold-standard clinical biomarker of cardiac dysfunction, NT-proBNP (figure 2B).

Conclusions Cardiomyocyte senescence is associated with a functional SASP which is capable of inducing remodelling phenotypes in non-cardiomyocyte cell types. Selected SASP factors such as GDF15 appear to show utility as clinical biomarkers of an aged, diseased cardiac phenotype. These may be useful additions to current biomarkers to form a signature which may aid prognosis and monitoring of CVD, even outside an ageing context.

Conflict of Interest None to declare

  • Senescence
  • Biomarker
  • Ageing

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