Proceedings of The Physiological Society

Europhysiology 2018 (London, UK) (2018) Proc Physiol Soc 41, C007

Oral Communications

Nuclear envelope disruption drives myocardial ‘Inflammageing' in cardiomyopathies

D. Brayson1, A. Frustaci2,3, R. Verardo3, C. Chimenti2,3, M. A. Russo4, E. Ehler1,5, C. dos Remedios6, A. M. Shah1, C. M. Shanahan1

1. School of Cardiovascular Science and Medicine, King's College London BHF centre, London, United Kingdom. 2. Department of Cardiovascular, Nefrologic, Anestesiologic and Geriatric Sciences, La Sapienza University of Rome, Rome, Italy. 3. National Institute for Infectious Diseases IRCCS ‘L. Spallanzani', Riome, Italy. 4. Laboratory of Molecular and Cellular Pathology, MEBIC Open University San Raffaele and IRCCS San Raffaele Pisana, Rome, Italy. 5. Randall Centre for Cell and Molecular Biophysics, King's College London, London, United Kingdom. 6. Department of Anatomy, Bosch Institute, University of Sydney, Sydney, United Kingdom.


Accumulation of prelamin A, the precursor to the nuclear intermediate filament protein lamin A, is known to initiate the onset of premature senescence in various tissue types. In addition, mutations in the LMNA gene, encoding the lamins A & C, are known to cause a specific subset of cardiomyopathies known as LMNA cardiomyopathy. An unresolved question is whether prelamin A accumulation is relevant to primary heart disease. That there are mutations known to abolish prelamin A processing suggests there is a potential role for prelamin A amongst familial cardiomyopathy cases. Additionally, there is an active debate as to whether highly active anti-retroviral therapy (HAART), employed in the treatment of HIV patients, contributes to the presentation of HIV cardiomyopathy. Evidence suggests that certain HAART regimes impair prelamin A processing. We hypothesised that prelamin A may be a mediator of cardiac pathology in both of these settings and sought to investigate mechanisms. To confirm the presence of prelamin A in diseased tissue we performed Western blotting and immunostaining on Human heart tissue samples. To investigate potential cause and effect we generated a novel line of cardiomyocyte specific prelamin A (csPLA) transgenic mice and performed in vivo physiology, ex vivo histology and investigated changes on the molecular level. We discovered that prelamin A accumulated in a subset of human dilated cardiomyopathy samples. csPLA mice died of heart failure at 5 weeks post-natal. At 4 weeks, echocardiography was performed with a fast induction of 5% isofluorane inhalation anaesthesia followed by maintenance of 1-1.5%, which was vaporized in 100% oxygen delivered at 1.5-2 liters/min. A marked decline in cardiac function in vivo was observed, e.g. ejection fraction was substantially depressed in transgenic mice (20.9 ± 3.6%) compared with wildtype (56.7 ± 11.2%, P = 0.01, n=6/group). Cardiac histology showed marked cardiomyocyte disarray, profound fibrosis and necrosis. CD45 and CD68 expressing cells were evident in the myocardium and genes for pro-inflammatory cytokines were upregulated. DNA damage accumulation and expression of senescence markers suggested that prelamin A accumulation initiated an immuno-senescence or ‘Inflammageing' response within the myocardial milieu that was regulated by activation of nuclear factor kappa-light-chain-enhancer of activated B cells signaling, instigated by persistent DNA damage. Identifying a link between the csPLA model and HIV associated cardiomyopathy phenotypes, we confirmed that prelamin A accumulated in heart tissue of patients presenting with HIV cardiomyopathy. In conclusion, prelamin A accumulation in cardiomyocytes resulted in myocardial inflammageing. These results provide novel insights for a subset of cardiomyopathies in which prelamin A processing is affected, in particular HIV cardiomyopathy, and may also have translational potential in this setting via the modulation of HAART regimes.

Where applicable, experiments conform with Society ethical requirements