Paradoxical Aortic Stiffening and Subsequent Cardiac Dysfunction in Hutchinson-Gilford Progeria Syndrome

Abstract

Normal ageing progressively and differentially affects the aorta along its length (Rogers et al., 2001;, thus effects of HGPS should be quantified as a function of age and aortic location. Our aim was to biomechanically phenotype the entire aorta in adult male and female Lmna G609G/G609G mice and to evaluate associated effects on the heart. We thus quantified cardiac function and central hemodynamics in vivo as well as SMC contractility and biaxial passive aortic properties ex vivo; we also used a novel computational model to associate changes in biomechanical behavior with observed microstructural features. The implications of these findings are interpreted, in part, via direct comparisons to similar data for mice that have aged normally, have germline mutations that compromise elastic fibre integrity, a feature common in central artery ageing, or have induced hypertension, which also arises in ageing. RESULTS Systolic Cardiac Function is Normal, but PWV and Diastolic Function Become Aberrant.All control (Lmna +/+ or Wt) and progeria (Lmna G609G/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). The heart was similarly smaller in progeria, yet myocardial microstructure appeared normal (Fig. 1B). In vivo measurements at 140d revealed that left ventricular mass and diameter, cardiac output, and stroke volume were all significantly less in progeria (Table S1), but these metrics followed allometric scaling with body mass ( , with mass and and allometric parameters), indicative of normal function for a smaller mouse (Fig. 1C-F). 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). In contrast, diastolic function was compromised near the end of life. E (peak filling velocity in early diastole) and A (atrial contraction induced filling velocity in late diastole) were lower in progeria mice at 140d, with E/A higher suggestive of diastolic dysfunction (Table S1). Moreover, E' was lower but E/E' was elevated significantly (Fig. 1I), confirming late-stage diastolic dysfunction.Proximal aortic diameters were less in progeria mice, as expected of a smaller mouse, but this metric again followed allometric scaling with body mass (Fig. 1J). Aortic lengths were less in progeria (Fig. 1K,L), but the transit time for the pulse pressure wave to travel from the aortic root to the aortic bifurcation was considerably less (Fig. 1M). Consequently, PWV was dramatically higher in late-stage progeria (Fig. 1N), trending toward significance (6.16 m/s vs. 3.68 m/s; p < 0.062) and suggesting increased central artery stiffness consistent with diastolic dysfunction.

Smooth Muscle Cell Death Drives an Osteochondrogenic Phenotype and Severe Proximal Vascular Disease in Progeria

“…The present histo-mechanical results significantly extend vascular findings reported in prior studies on mouse models of progeria that did not contrast findings in elastic versus muscular arteries or quantify the disease progression (e.g., Varga et al, 2006; Capell et al, 2008; Osorio et al, 2011; Kreienkamp et al, 2018; del Campo et al, 2019; Murtada et al, 2020). Our temporal data reveal complex, differential changes in key geometric and mechanical metrics across five arterial segments.…”

“…To understand better the reasons for distinctive changes in aortic composition in progeria, we first performed bulk RNA-sequencing on the abdominal aorta, which exhibits a phenotype similar to the thoracic aorta in progeria (Murtada et al, 2020). Contrasting results for naturally aged WT and progeria aortas well prior to end-of-life (P300 and P120, respectively) revealed dramatic differences in many transcripts (Fig.…”

“…We previously showed that the elastic lamellar structures of the medial layer appear normal at P100 in the thoracic and abdominal aorta of Lmna G609G/G609G progeria mice (Murtada et al, 2020), suggesting that the primary effects of this Lmna mutation on aortic extracellular matrix deposition and organization emerge after P21 (when elastic layers normally mature), a period normally characterized by stresses having values increasingly >80 kPa. For this reason, and because these progeria mice begin to show marked losses in body mass ~P42 (Murtada et al, 2020), we selected P42 as a late developmental age of interest, just prior to the aorta reaching biomechanical maturity. The original report of these progeria mice showed 50% survival at P103 despite an absence of cardiac dysfunction (Osorio et al, 2011).…”

“…These metrics include intramural biaxial stress and stretch, material stiffness, and elastic energy storage as well calculated local pulse wave velocity (PWV=√𝐸ℎ/2𝜚𝑎 where 𝐸 is a linearized material stiffness, ℎ wall thickness, 𝑎 inner radius, and 𝜚 the mass density of the fluid). We used an independently validated (Schroder et al, 2018) four-fiber family constitutive relation to quantify the passive behavior (Ferruzzi et al, 2018;Murtada et al, 2020), which can be written in terms of the stored energy 𝑊 as,…”

Progerin mislocalizes myocardin-related transcription factor in Hutchinson–Guilford Progeria syndrome

“…In addition to displaying decreased expression of Myh11 and other smooth muscle differentiation markers, arteries and SMCs from HGPS mice show reduced contractility and an increased production and remodeling of the ECM 38,[45][46][47][48][49] . Our analysis of DEGs in HGPS also revealed an increased gene expression of "synthetic" SMC markers in HGPS aortas.…”