Safety and Hemodynamic Effects of Intravenous Triiodothyronine in Advanced Congestive Heart Failure

doi:10.1016/S0002-9149(97)00950-8

The American Journal of Cardiology

Volume 81, Issue 4, 15 February 1998, Pages 443-447

https://doi.org/10.1016/S0002-9149(97)00950-8 Get rights and content

Abstract

Most patients with advanced congestive heart failure have altered thyroid hormone metabolism. A low triiodothyronine level is associated with impaired hemodynamics and is an independent predictor of poor survival. This study sought to evaluate safety and hemodynamic effects of short-term intravenous administration of triiodothyronine in patients with advanced heart failure. An intravenous bolus dose of triiodothyronine, with or without a 6- to 12-hour infusion (cumulative dose 0.15 to 2.7 μg/kg), was administered to 23 patients with advanced heart failure (mean left ventricular ejection fraction 0.22 ± 0.01). Cardiac rhythm and hemodynamic status were monitored for 12 hours, and basal metabolic rate by indirect calorimetry, echocardiographic parameters of systolic function and valvular regurgitation, thyroid hormone, and catecholamine levels were measured at baseline and at 4 to 6 hours. Triiodothyronine was well tolerated without episodes of ischemia or clinical arrhythmia. There was no significant change in heart rate or metabolic rate and there was minimal increase in core temperature. Cardiac output increased with a reduction in systemic vascular resistance in patients receiving the largest dose, consistent with a peripheral vasodilatory effect. Acute intravenous administration of triiodothyronine is well tolerated in patients with advanced heart failure, establishing the basis for further investigation into the safety and potential hemodynamic benefits of longer infusions, combined infusion with inotropic agents, oral triiodothyronine replacement therapy, and new triiodothyronine analogs.

Section snippets

Study Population:

Twenty-three patients with class III or IV advanced congestive heart failure due to ischemic or idiopathic cardiomyopathy admitted to the University of California, Los Angeles Medical Center for transplant evaluation were enrolled in accordance with the Human Subjects Protection Committee provisions. All patients were in sinus rhythm and had therapy with oral vasodilators and diuretics withdrawn 24 hours before the study. The exclusion criteria included intravenous inotropic drug infusion,

Patient Group and Hormone Levels:

There were 17 men and 6 women (mean age 50 years) enrolled in the study, 11 with ischemic and 12 idiopathic cardiomyopathy. At baseline, the free triiodothyronine levels were low, with elevated reverse triiodothyronine and normal free thyroxine and TSH (Table II). Patients receiving an intravenous bolus without infusion had a transient increase in free triiodothyronine levels to supranormal values, returning to baseline within 2 hours (Fig. 1). Patients receiving a continuous infusion after a

Discussion

This study demonstrates that a short-term intravenous infusion of triiodothyronine is well tolerated in patients with advanced heart failure. There was no evidence of ischemia or clinical arrhythmia, and despite doses sufficient to raise free triiodothyronine levels transiently above the normal range, there was no significant increase in heart rate or ambient ectopy. Although the metabolic rate has been presumed to be elevated in heart failure because of increased work of breathing and

Acknowledgements

Acknowledgment:

We are grateful for the extensive nursing assistance of Kimberly Scheibly, RN, Susan Kaiser, RN, and Julie Walden, RN, MN, and the administrative assistance of Leila Terada.

References (23)

MA Hamilton et al.
Altered thyroid hormone metabolism in advanced heart failure
J Am Coll Cardiol
(1990)
MA Hamilton
Prevalence and clinical implications of abnormal thyroid hormone metabolism in advanced heart failure
Ann Thorac Surg
(1993)
JD Klemperer et al.
Triiodothyronine improves left ventricular function without oxygen wasting effects after global hypothermic ischemia
J Thorac Cardiovasc Surg
(1995)
JD Walker et al.
The direct effects of 3,5,3′-triiodothyronine (T3) on myocyte contractile processes
J Thorac Cardiovasc Surg
(1995)
PW Ladenson et al.
Modulation of myocardial L-triiodothyronine receptors in normal, hypothyroid, and hyperthyroid rats
Metabolism
(1986)
WH Dillmann
Biochemical basis of thyroid hormone action in the heart
Am J Med
(1990)
D Novitsky et al.
Triiodothyronine as an inotropic agent after open-heart surgery
J Thorac Cardiovasc Surg
(1989)
RD Hesch et al.
Treatment of dopamine-dependent shock with triiodothyronine
Endoc Res Commun
(1981)
JG Pittman et al.
The pathogenesis of cardiac cachexia
N Engl J Med
(1964)
JD Klemperer et al.
Thyroid hormone treatment after coronary artery bypass surgery
N Engl J Med
(1995)

E Bennett-Guerrero et al.

Cardiovascular effects of intravenous triiodothyronine in patients undergoing coronary artery bypass graft surgery

JAMA

(1996)

Cited by (200)

Effects of levothyroxine in subclinical hypothyroidism and heart failure with reduced ejection fraction: An open-label randomized trial
2024, Cell Reports Medicine
We report a randomized, multicenter, open-label trial (ClinicalTrials.gov: NCT03096613) to investigate the clinical benefits of levothyroxine (L-T4) administration in subclinical hypothyroidism (SCH) patients with heart failure with reduced ejection fraction (HFrEF). Overall, 117 patients were enrolled and received L-T4 plus standard HFrEF treatment (experimental group, N = 57) or standard HFrEF therapy alone (control group, N = 60). The change of 6-min walk test distance in the experimental group was significantly higher than that in the control group at 24 weeks (70.08 ± 85.76 m vs. 27.73 ± 82.00 m, mean difference [95% confidence interval (CI)] 46.90 [12.90, 80.90], p < 0.001). Improvements in New York Heart Association (NYHA) classification (p = 0.033) and thyroid function were significant. Adverse event incidence was similar between groups (risk ratio [95% CI]: 0.942 1.053 (0.424, 2.616); p = 0.628). L-T4 addition to HFrEF treatment improved activity tolerance, NYHA class, and thyroid function within 6 months, suggesting its potential for combined therapy in HFrEF patients with SCH. Future double-blind, placebo-controlled trials should be performed to confirm these results.
Triiodothyronine maintains cardiac transverse-tubule structure and function
2021, Journal of Molecular and Cellular Cardiology
Citation Excerpt :
While correction of overt thyroid dysfunction in HF patients is recommended, treatment recommendations of subclinical hypothyroidism or low-T3 syndrome have not been made. However, clinical trials restoring TH function in patients with HF or after myocardial infarction (MI) have shown significant improvements in ventricular remodeling and contractile function [11–15]. Thyroid hormones, specifically bioactive T3, function primarily by regulating transcription of cardiac genes encoding ion channels, contractile and structural proteins [16,17].
Subclinical hypothyroidism and low T3 syndrome are commonly associated with an increased risk of cardiovascular disease (CVD) and mortality. We examined effects of T3 on T-tubule (TT) structures, Ca²⁺ mobilization and contractility, and clustering of dyadic proteins.
Thyroid hormone (TH) deficiency was induced in adult female rats by propyl-thiouracil (PTU; 0.025%) treatment for 8 weeks. Rats were then randomized to continued PTU or triiodo-L-thyronine (T3; 10 μg/kg/d) treatment for 2 weeks (PTU + T3). After in vivo echocardiographic and hemodynamic recordings, cardiomyocytes (CM) were isolated to record Ca²⁺ transients and contractility. TT organization was assessed by confocal microscopy, and STORM images were captured to measure ryanodine receptor (RyR2) cluster number and size, and L-type Ca²⁺ channel (LTCC, Ca_v1.2) co-localization. Expressed genes including two integral TT proteins, junctophilin-2 (Jph-2) and bridging integrator-1 (BIN1), were analyzed in left ventricular (LV) tissues and cultured CM using qPCR and RNA sequencing.
The T3 dosage used normalized serum T3, and reversed adverse effects of TH deficiency on in vivo measures of cardiac function. Recordings of isolated CM indicated that T3 increased rates of Ca²⁺ release and re-uptake, resulting in increased velocities of sarcomere shortening and re-lengthening. TT periodicity was significantly decreased, with reduced transverse tubules but increased longitudinal tubules in TH-deficient CMs and LV tissue, and these structures were normalized by T3 treatment. Analysis of STORM data of PTU myocytes showed decreased RyR2 cluster numbers and RyR localizations within each cluster without significant changes in Ca_v1.2 localizations within RyR clusters. T3 treatment normalized RyR2 cluster size and number. qPCR and RNAseq analyses of LV and cultured CM showed that Jph2 expression was T3-responsive, and its increase with treatment may explain improved TT organization and RyR-LTCC coupling.
Non-thyroidal illness syndrome, the hidden player in the septic shock induced myocardial contractile depression
2020, Medical Hypotheses
Septic shock causes high mortality in hospitalized patients, especially in those that develop myocardial dysfunction as an early complication. The myocardial dysfunction of septic shock is characterized by a decrease in ventricular relaxation (diastolic dysfunction) and reduced ventricular ejection fraction (systolic dysfunction). Most patients with septic shock have low serum thyroid hormone levels, a condition known as non-thyroidal illness syndrome. Thyroid hormones sustain myocardial contractility and energy metabolism. Septic shock non-thyroidal illness syndrome causes myocardial hypothyroidism, and hypothyroidism causes myocardial dysfunction that resembles the myocardial depression of septic shock.
We hypothesize that the myocardial hypothyroidism that occurs during septic shock has a causal role in the pathogenesis of septic shock-induced myocardial dysfunction. Thyroid hormones regulate the calcium cycle, the phenotype of contractile proteins, adrenergic response, and fatty acid transport and oxidation in the cardiomyocytes. Therefore, the administration of levothyroxine and liothyronine to normalize thyroid hormones level within the myocardium will improve the myocardial function.
The hypothesis will be tested in humans with septic shock by performing a prospective, randomized, placebo-controlled study to compare the effect of thyroid hormone administration with placebo on myocardial function.
The proposed hypothesis challenges the idea that non-thyroidal illness syndrome is a beneficial response of the thyroid hormone axis to illness and that thyroid hormone replacement is detrimental. The administration of thyroid hormone in order to prevent and reverse myocardial hypothyroidism during septic shock is a new theoretical concept on thyroid hormone metabolism and action at the tissue level during non-thyroidal illness syndrome. If the hypothesis is correct, clinicians should consider cardiac hypothyroidism as a central player in myocardial dysfunction caused by sepsis. Thyroid hormone replacement should be incorporated into the armamentarium of septic shock treatment.
The Management of Thyroid Abnormalities in Chronic Heart Failure
2019, Heart Failure Clinics
Citation Excerpt :
The first study that used LT3 was performed by Hamilton and colleagues.45 In a small nonrandomized trial, these investigators used an intravenous bolus of liothyronine (LT3) followed by LT3 infusion in patients with advanced HF and low T3 syndrome.45 CO improved significantly 2 hours after T3 administration.
Synergistic effects of hormones on structural and functional maturation of cardiomyocytes and implications for heart regeneration
2023, Cellular and Molecular Life Sciences
Thyroid Hormone and Heart Failure: Charting Known Pathways for Cardiac Repair/Regeneration
2023, Biomedicines

View all citing articles on Scopus

^☆: This study was supported by a grant from SmithKline Beecham Pharmaceuticals, Philadelphia, Pennsylvania.

View full text

Congestive Heart FailureSafety and Hemodynamic Effects of Intravenous Triiodothyronine in Advanced Congestive Heart Failure☆

Abstract

Section snippets

Study Population:

Patient Group and Hormone Levels:

Discussion

Acknowledgements

J Am Coll Cardiol

Ann Thorac Surg

J Thorac Cardiovasc Surg

J Thorac Cardiovasc Surg

Metabolism

Am J Med

Triiodothyronine as an inotropic agent after open-heart surgery

J Thorac Cardiovasc Surg

Treatment of dopamine-dependent shock with triiodothyronine

Endoc Res Commun

The pathogenesis of cardiac cachexia

N Engl J Med

Thyroid hormone treatment after coronary artery bypass surgery

N Engl J Med

Cardiovascular effects of intravenous triiodothyronine in patients undergoing coronary artery bypass graft surgery

JAMA

Congestive Heart Failure
Safety and Hemodynamic Effects of Intravenous Triiodothyronine in Advanced Congestive Heart Failure☆