Effects of Triiodothyronine Treatment in an Animal Model of Heart Failure with Preserved Ejection Fraction

Data de publicação: 30/05/2023 Data Ahead of Print: 01/05/2023

Autores da FMUP

• João Sérgio De Lima Soares Neves

  Autor

• Glória De Fátima Almeida Conceição

  Autor

• Marta Borges Canha

  Autor

• Catarina Afonso Couto E Vale

  Autor

• Madalena Pereira De Sousa Von Hafe Pérez

  Autor

• Sara Vanessa Amorim Leite

  Autor

• Cláudia Cristiana Sousa Mendes

  Autor

• Isabel Alexandra Marcos Miranda

  Autor

• Davide Maurício Costa Carvalho

  Autor

• Inês Maria Falcão Sousa Pires Marques

  Autor

• Joaquim Adelino Correia Ferreira Leite Moreira

  Autor

Participantes de fora da FMUP

• Leite, AR
• Gonçalves, A
• Martins, D
• Miranda-Silva, D
• Rocha-Oliveira, E
• Chaves, J
• Lourenço, IM
• Grijota-Martinez, C
• Barez-Lopez, S
• Almeida-Coelho, J
• Vasques N?voa, F.
• Lourento, A

Unidades de investigação

• Cirurgia e Fisiologia

• Laboratório Associado RISE- Rede de Investigação em Saúde

  

  Investigador

  Fernando Carlos De Landér Schmitt

• Medicina

• RISE-Health

  

  Investigador

  Fernando Carlos De Landér Schmitt

Abstract

Background: Low levels of triiodothyronine (T3) are common in patients with heart failure (HF). Our aim was to evaluate the effects of supplementation with low and replacement doses of T3 in an animal model of HF with preserved ejection fraction (HFpEF).Methods: We evaluated four groups: ZSF1 Lean (n = 8, Lean-Ctrl), ZSF1 Obese (rat model of metabolic-induced HFpEF, n = 13, HFpEF), ZSF1 Obese treated with a replacement dose of T3 (n = 8, HFpEF-T3high), and ZSF1 Obese treated with a low-dose of T3 (n = 8, HFpEF-T3low). T3 was administered in drinking water from weeks 13 to 24. The animals underwent anthropometric and metabolic assessments, echocardiography, and peak effort testing with maximum O-2 consumption (VO(2)max) determination at 22 weeks, and a terminal hemodynamic evaluation at 24 weeks. Afterwhile myocardial samples were collected for single cardiomyocyte evaluation and molecular studies.Results: HFpEF animals showed lower serum and myocardial thyroid hormone levels than Lean-Ctrl. Treatment with T3 did not normalize serum T3 levels, but increased myocardial T3 levels to normal levels in the HFpEF-T3high group. Body weight was significantly decreased in both the T3-treated groups, comparing with HFpEF. An improvement in glucose metabolism was observed only in HFpEF-T3high. Both the treated groups had improved diastolic and systolic function in vivo, as well as improved Ca2+ transients and sarcomere shortening and relaxation in vitro. Comparing with HFpEF animals, HFpEF-T3high had increased heart rate and a higher rate of premature ventricular contractions. Animals treated with T3 had higher myocardial expression of calcium transporter ryanodine receptor 2 (RYR2) and alpha-myosin heavy chain (MHC), with a lower expression of beta-MHC. VO(2)max was not influenced by treatment with T3. Myocardial fibrosis was reduced in both the treated groups. Three animals died in the HFpEF-T3high group.Conclusions: Treatment with T3 was shown to improve metabolic profile, myocardial calcium handling, and cardiac function. While the low dose was well-tolerated and safe, the replacement dose was associated with increased heart rate, and increased risk of arrhythmias and sudden death. Modulation of thyroid hormones may be a potential therapeutic target in HFpEF; however, it is important to take into account the narrow therapeutic window of T3 in this condition.

Keywords

• heart failure; heart failure with preserved ejection fraction; triiodothyronine; thyroid hormones; metabolic syndrome; diastolic function