Abstract
Hutchinson-Gilford progeria syndrome (HGPS) is an ultra-rare disorder with devastating sequelae resulting in early death, presently thought to stem primarily from cardiovascular events. We analyse novel longitudinal cardiovascular data from a mouse model of HGPS (LmnaG609G/G609G) using allometric scaling, biomechanical phenotyping, and advanced computational modelling and show that late-stage diastolic dysfunction, with preserved systolic function, emerges with an increase in the pulse wave velocity and an associated loss of aortic function, independent of sex. Specifically, there is a dramatic late-stage loss of smooth muscle function and cells and an excessive accumulation of proteoglycans along the aorta, which result in a loss of biomechanical function (contractility and elastic energy storage) and a marked structural stiffening despite a distinctly low intrinsic material stiffness that is consistent with the lack of functional lamin A. Importantly, the vascular function appears to arise normally from the low-stress environment of development, only to succumb progressively to pressure-related effects of the lamin A mutation and become extreme in the peri-morbid period. Because the dramatic life-threatening aortic phenotype manifests during the last third of life there may be a therapeutic window in maturity that could alleviate concerns with therapies administered during early periods of arterial development.
Highlights
Hutchinson‐Gilford Progeria Syndrome (HGPS) is a genetic disorder characterized by premature ageing with devastating consequences to cardiovascular and musculoskeletal tissues
All control (Lmna+/+ or Wt) and progeria (LmnaG609G/G609G or G609G) mice survived to the intended 140 days (d) of age, though progeria mice were significantly smaller after ~42d (Fig. 1A): for example, body mass at 140d was 12.1±0.8 g in female and 13.8±0.9 g in male G609G mice compared with 25.0±1.1 g in female and 30.4±2.2 g in male Wt mice (p < 0.01)
Though tail‐cuff blood pressure was lower in progeria (Fig. 1G), ejection fraction and fractional shortening were similar between progeria and controls (Fig. 1H), suggesting a preserved systolic function even in the peri‐morbid period (G609G mice died by ~150d)
Summary
Hutchinson‐Gilford Progeria Syndrome (HGPS) is a genetic disorder characterized by premature ageing with devastating consequences to cardiovascular and musculoskeletal tissues. Accelerated atherosclerosis in muscular arteries (Olive et al, 2010), which can lead to myocardial infarction or stroke, was thought to cause death in the early teens, but statins and lipid‐lowering agents did not improve lifespan. Increased central artery stiffness is an initiator and indicator of diverse cardiovascular diseases in the general population and a predictor of all‐cause mortality (Vlachopoulos et al, 2010), due to myocardial infarction, stroke, and heart failure (Mitchell et al, 2010). A recent study revealed that left ventricular diastolic dysfunction was the most prevalent abnormality in HGPS (Prakash et al, 2018), and a clinical trial identified heart failure as the primary cause of death (Gordon et al, 2018). Given the scarcity of human data, mouse models enable more detailed study of both the underlying mechanisms and resulting clinical phenotypes
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