SFEBES2021 Oral Communications Reproductive and Neuroendocrinology (6 abstracts)
Acromegalic cardiomyopathy in pituitary-specific aryl hydrocarbon receptor interacting protein (Aip) gene knockout animals
Anisha Mistry 1 , Gregory Funge 1 , Sonia Sebastian 1 , Qadeer Aziz 1 , Antonia Solomou 2 , Maria Lillina Vignola 2 , Chung Thong Lim 1 , Maria Herincs 1 , Francisca Caimari 1 , Carles Gaston-Massuet 1 , Andrew Tinker 1 & Marta Korbonits 1
1Queen Mary University, London, United Kingdom; 2Kings College London, London, United Kingdom
Introduction: Patients with a germline loss-of-function mutation in AIP are predisposed to young-onset GH excess resulting in gigantism or acromegaly. Acromegaly leads to disease-specific cardiomyopathy with biventricular hypertrophy and diastolic dysfunction progressing to fulminant cardiac failure if left untreated, therefore it is vital to have a tractable animal model to investigate the disease
Findings: Our AipFlox/Flox;Hesx1Cre/+ model abrogates Aip in cells expressing the early pituitary transcription factor Hesx1, specifically targeting cells of the anterior pituitary from embryonic day (e)8.5. These animals develop functional pituitary adenomas with 85% penetrance by the age of 15 months. Our data on these mice suggest that the excess GH from these tumours recapitulate the phenotype similar to human acromegaly. This includes an increase in weight and body size of mutant animals, increased IGF-1 circulating levels and enlargement of the pituitary gland and other organs, particularly the heart. The hearts of these mice are significantly larger (mean (base to apex) ±SD: 10.8±1.0mm,n = 7) than wild-type controls (9.2±0.4mm,n = 7), p-value <0.0001. We observe hypertrophy of the left ventricular wall, apex and nodes of the heart as well as areas with increased fibrosis compared to controls. Cardiac ultrasound on the hearts of these animals has revealed a significant reduction in stroke volume in knockout animals (mean±SEM: 31±0.07µl) compared to controls (51±1.36µl, P < 0.005) observed at 9 months of age. At this age, we also observed a trend towards reduced cardiac output and ejection fraction and are currently increasing our replicates for these experiments.
Conclusions: Data from our AipFlox/Flox;Hesx1Cre/+ model shows development of pituitary tumours and consequently cardiac abnormalities. These data support the clinical observations and overall provides an effective model to study cardiac disease in acromegaly.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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