Low‐Dose Triiodo‐L‐Thyronine Treatment Prevents Decline in Cardiac Function And Arrhythmia Inducibility Resulting from Severe Calorie Restriction
Authors: Costello Clifford , Rajagopalan Viswanathan , Zhang Youhua , Schultz Emily , Thawani Angeli , Gerdes Anthony M 
Published: November 2023

Background

Starvation/severe calorie restriction induces a low thyroid hormone (TH) condition, apparently to extend life by reducing metabolic needs. Consequently, it is reasonable to propose that when the heart senses hypoxia it is evolutionarily programmed to lower TH signaling. However, a persistent decrease in TH function may compromise heart function. We hypothesized that supplementation of low dose Triiodo‐L‐Thyronine (T3) will prevent deterioration of cardiac performance following acute fasting.

Methods

Adult 5‐month old mice (n=7–11 per group) underwent 48 hr fasting based on institutional animal protocol with ad libitum access to water. The following groups were studied: (1) Control (C), ad libitum access to food; (2) Fasting (F), no food for 48‐hr; (3) Fasting, no food for 48‐hr +T3 treatment (5 μg/kg i.p. once daily × 48‐hr). Vehicle (V), the T3 diluent was administered in C and F groups.

Results

Following 48‐hr fasting, body weights and heart weights were significantly decreased (21% p<0.01 and 15% respectively). Heart weight to body weight ratio and left ventricle (LV) weight to body weight ratio were not significantly altered. Low‐dose T3 treatment prevented reduction in heart weight (mg; C+V:108±5.9; F+V:92±4.9, p<0.05 vs. C+V; F+T3:105±6.1, p=0.067 vs. F+V) and LV weight (mg; C+V:67±3.4; F+V:62±2; F+T3:68±2.5, p=0.089 vs. F+V).

LV hemodynamics showed a significant decrease in dPmax/dt (62%) and dPmin/dt (56%) (indices of cardiac contractility and relaxation respectively) following fasting. Both improved following T3 treatment compared to fasting (dPmax/dt: 87%, p< 0.05; dPmin/dt: 100% p< 0.01). Correspondingly, the increases in end‐diastolic pressure (mmHg: C+V:4.2±2; F+V:7.5±0.3, p<0.05 vs. C+V; F+T3:3.9±1; p<0.05 vs. F+V) and Tau (msec; C+V:7.1±0.8; F+V:14.9±1.3, p<0.05 vs. C+V; F+T3:8.4±0.6, p<0.01 vs. F+V) were significantly attenuated following T3 treatment.

In electrophysiology studies, 20% of controls and 64% of fasting mice developed atrial tachyarrhythmias upon induction. This was reverted back to control levels (22%) following T3. There was a significant increase in atrioventricular conduction time (p<0.05) and significant decrease in sinus cycle length (p<0.001) following fasting. Both these changes were attenuated following T3 treatment (p<0.05). Heart rate fell following fasting and this was significantly improved by T3 treatment (C+V:382±19; F+V:253±16, p<0.001 vs. C+V; F+T3:321±12; p<0.05 vs. F+V).

Compared to controls, fasting animals showed an increase in real time PCR‐based hypoxia inducible factor 1‐a and thyroid hormone receptor beta (p<0.05) gene expression, which partially decreased with T3 treatment.

Conclusions

T3 supplementation largely prevented cardiac atrophy without adverse cardiovascular effects following acute fasting. T3 also improved cardiac performance via improvements in LV systolic function, diastolic function, heart rate and cardiac rhythm. These changes were associated with partial restoration of hypoxia and thyroid genes.

Support or Funding Information

NIH Grant R01HL103671 for Dr. Anthony Martin Gerdes