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07. Syncope and Bradycardia
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Thyroid hormone as a therapy for Heart Failure with Preserved Ejection Fraction in a rat model
Session:
Prémio Jovem Investigador
Speaker:
Alexandre Gonçalves
Congress:
CPC 2020
Topic:
O. Basic Science
Theme:
36. Basic Science
Subtheme:
36.3 Basic Science - Cardiac Diseases
Session Type:
Prémios
FP Number:
---
Authors:
Alexandre Gonçalves; João Sérgio Neves; Catarina Vale; Madalena von Haffe; Glória Conceição; Daniela Miranda-Silva; Dulce Fontoura; João Almeida-Coelho; Sara Leite; André Lourenço; Inês Falcão-Pires; Adelino Leite-Moreira
Abstract
<p><strong>Background:</strong> Heart failure with preserved ejection fraction (HFpEF) now represents over 50% of heart failure patients, while being the leading cause of morbimortality and remaining elusive to effective therapeutic intervention. Approximately 22% of HFpEF patients present reduced triiodothyronine (T3) levels and these lower levels are inversely correlated to HFpEF severity, symptomatology and prognosis. The present study aims to evaluate the impact of T3 supplementation in the cardiac function of an HFpEF animal model as a possible therapy for this disease.</p> <p><strong>Methods:</strong> Starting at 14 weeks of age, ZSF1 Obese rats (HFpEF, n=8) were randomly allocated to either receive an oral administration of T3 (0.04 - 0.06 µg/mL, n=5) or vehicle. ZSF1 Lean rats (CT, n=8) were used as control throughout the experiments. Thyroid function was systematically assessed every two weeks via serum T3, T4 and TSH levels to fine-tune the administered T3 dosage. Echocardiographic evaluation was conducted at 22<sup>nd</sup> week followed by terminal hemodynamic, tissue collection and morphometric assessment by the 24<sup>th</sup> week. Single isolated cardiomyocyte function was studied using a combination of field fluorescent recordings through the FURA-2 probe (cytosolic Ca<sup>2+</sup> kinetics) and optical edge detection (sarcomere shortening) at 37<sup>o</sup>C.</p> <p><strong>Results:</strong> We confirmed that HFpEF rats had lower T3 levels in the serum and left ventricle when compared to CT. Oral T3 supplementation was found to be effective at normalizing the left ventricular levels without variation in serum levels. Echocardiographic and hemodynamic evaluations revealed impaired diastolic (IVRT, E/e’, LAA, ?exp and systolic (S’, Ea) function in the HFpEF model. In this regard, T3 treated rats shown significant functional improvements in all parameters. Lastly, functional studies at the isolated cardiomyocyte level found substantial Ca<sup>2+</sup> kinetics (time to peak Ca<sup>2+ </sup>and Ca<sup>2+ </sup>decay half-time), contractile amplitude and relaxation impairments (?exp), in the HFpEF model corroborating the <em>in vivo</em> results. Cardiomyocytes isolated from the treated group displayed a complete normalization of Ca<sup>2+</sup> handling and contractile capacity.</p> <p><strong>Conclusion:</strong> T­ogether our results shown T3 to improve and even normalize several functional parameters associated to HFpEF, specifically diastolic disfunction, thus supporting it as a promising therapy for HFpEF when a disruption in thyroid function is found.</p>
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