Protective Effects of Thyroid Hormone Deprivation on Progression of Maladaptive Cardiac Hypertrophy and Heart Failure.

Kristina Lorenz,Janina Gassen,Elen Tolstik,Helena Kerp,Dagmar Führer,Lars Christian Moeller,Judith Hönes-Wendland,Georg Sebastian Hönes

doi:10.3389/fcvm.2021.683522

Abstract

Purpose: Thyroid hormones (TH) play a central role for cardiac function. TH influence heart rate and cardiac contractility, and altered thyroid function is associated with increased cardiovascular morbidity and mortality. The precise role of TH in onset and progression of heart failure still requires clarification.Methods: Chronic left ventricular pressure overload was induced in mouse hearts by transverse aortic constriction (TAC). One week after TAC, alteration of TH status was induced and the impact on cardiac disease progression was studied longitudinally over 4 weeks in mice with hypo- or hyperthyroidism and was compared to euthyroid TAC controls. Serial assessment was performed for heart function (2D M-mode echocardiography), heart morphology (weight, fibrosis, and cardiomyocyte cross-sectional area), and molecular changes in heart tissues (TH target gene expression, apoptosis, and mTOR activation) at 2 and 4 weeks.Results: In diseased heart, subsequent TH restriction stopped progression of maladaptive cardiac hypertrophy and improved cardiac function. In contrast and compared to euthyroid TAC controls, increased TH availability after TAC propelled maladaptive cardiac growth and development of heart failure. This was accompanied by a rise in cardiomyocyte apoptosis and mTOR pathway activation.Conclusion: This study shows, for the first time, a protective effect of TH deprivation against progression of pathological cardiac hypertrophy and development of congestive heart failure in mice with left ventricular pressure overload. Whether this also applies to the human situation needs to be determined in clinical studies and would infer a critical re-thinking of management of TH status in patients with hypertensive heart disease.

Highlights

Despite great therapeutic advances, cardiovascular diseases remain the most common cause of death, globally [1]
Modulation of thyroid status commenced 1 week after transverse aortic constriction (TAC), when first signs of cardiac hypertrophy and impaired cardiac function have evolved [21]. In this heart disease model, we show that reducing thyroid hormones (TH) availability effectively slows down pathological cardiac growth and improves cardiac function even under continued left ventricular pressure overload, while opposite effects occur with increased TH availability
To investigate how TH status impacts progression of pathological cardiac hypertrophy and development of heart failure, we used a heart disease mouse model with chronic left ventricular pressure overload induced by ligation of the transverse aorta

Summary

Introduction

Cardiovascular diseases remain the most common cause of death, globally [1]. Treatment with TH has been shown to improve cardiac output, reduce afterload, and lead to a compensated, so-called physiological or “athletic,” cardiac hypertrophy [3, 12,13,14,15,16,17,18] These effects could even be shown in relation to cardiac diseases in a small patient cohort with advanced heart failure [19] and in patients with dilated cardiomyopathy [20]. Modulation of thyroid status commenced 1 week after TAC, when first signs of cardiac hypertrophy and impaired cardiac function have evolved [21] In this heart disease model, we show that reducing TH availability effectively slows down pathological cardiac growth and improves cardiac function even under continued left ventricular pressure overload, while opposite effects occur with increased TH availability

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