The Role of Alterations in Thyroid Function in Cardiovascular Disease and the Identification of Early Pathways to Prevention

Executive Summary

The National Heart, Lung, and Blood Institute (NHLBI) convened a Working Group (WG) in Bethesda, MD on September 8, 2017 to discuss current knowledge and future directions for research in thyroid function and cardiovascular disease. Pathophysiologic mechanisms relating these conditions and potential clinical benefits of concurrent management of thyroid and cardiovascular conditions have not been adequately explored using contemporary research methods. The WG brought together scientists with expertise in basic, clinical, and epidemiologic aspects of both thyroid dysfunction and cardiovascular disease. The principal goal was to define key knowledge gaps, in order to outline priorities for future scientific research that might benefit from NHLBI leadership, facilitation, and support.

Discussion

Thyroid hormone has known genomic and non-genomic effects on the conduction system, vasculature, and myocardium. Clinically, both thyroid hormone excess and deficiency can induce or exacerbate cardiovascular comorbidities, including atrial and ventricular arrhythmias, atherosclerotic vascular disease, and heart failure, and in doing so, contribute to higher risk of premature death. Despite a clear linkage between thyroid function and cardiovascular disease, uncertainties remain, particularly about appropriate management of common subclinical abnormalities in thyroid function in patients with and without pre-existing cardiovascular disease. The WG discussed the roles of normal thyroid physiology and the consequences of thyroid function abnormalities in three cardiovascular areas: the conduction system, the vasculature, and the myocardium.

Key topics addressed included the current understanding of fundamental molecular and cellular mechanisms underlying the pathophysiology of cardiovascular disease in patients with thyroid dysfunction, observational and epidemiologic data exploring the associations of thyroid dysfunction with incident cardiovascular disease and prognosis, clinical trials of thyroid hormone supplementation to prevent and treat cardiovascular disease, and strategies for harnessing ‘big data’ to develop insights into subgroups that may be at particular risk and novel therapeutic targets.

WG Recommendations: Based on discussion at the meeting, the WG defined three broad recommendations for the NHLBI:

1. Support investigation into the fundamental biology relating thyroid dysfunction to the development of cardiovascular disease and into the identification of novel biomarkers of thyroid hormone action in cardiovascular tissues.

Areas of particular interest for further research include:

• Defining the cellular signaling processes and gene expression variations by which thyroid hormone regulates electrical conduction, contractility, and peripheral vascular function;
• Defining the cellular and molecular mechanisms relating thyroid hormone action to incident atrial and ventricular arrhythmias;
• Examining the role of thyroid hormone and its receptors in modulating myocardial systolic and diastolic functions;
• Exploring the role of thyroid hormone in the setting of ischemia and its responsiveness to thyroid modulating agents;
• Exploring the role of thyroid hormone in modulation of endothelial function;
• Examining the mechanisms by which cardiac medications affect thyroid hormone production or action;
• Developing novel serum and imaging biomarkers reflecting tissue thyroid hormone actions.

2. Support studies that define patient subgroups of patients with thyroid dysfunction amenable to specific preventive strategies and interventional therapies related to cardiovascular disease.

Areas of particular interest include:

• Identifying subgroups of persons with pre-existing cardiovascular disease or at high risk for cardiovascular disease, who may benefit from manipulation of thyroid hormone status, including persons in the “euthyroid state.” These studies would potentially support thresholds for treatment (based on specific levels of thyroid function tests) that vary by subgroup characteristics;
• Utilizing modern genetic approaches including GWAS, whole exome/genome sequencing, epigenetics, mRNA expression, metabolomics, and other Omics data to generate a HPT(hypothalamic–pituitary–thyroid) axis set-point prediction model to prevent cardiovascular complications by personalizing treatment of thyroid dysfunction;
• Recognizing the developmental and mechanistic differences among the newborn, pediatric, and adult populations; potential variations in key demographic subgroups including age, sex, and race; and issues of health disparities and global health;
• Leveraging the infrastructure from the two existing large consortia in this field (Thyroid Studies Collaboration, Thyroidomics Consortium) to integrate data from existing large-scale cohorts or use existing registries.

3. Support clinical trials focused on improvement in cardiovascular performance and cardiovascular outcomes through treatment with thyroid hormone or drugs exploiting known thyroid hormone actions.

Areas of particular interest for further research include:

• Designing studies, including small clinical trials designed to evaluate the feasibility and rationale for large intervention studies and test optimal strategies for management of subclinical hyperthyroidism, subclinical hypothyroidism, and low T3 syndrome in patients with and without pre-existing cardiovascular disease. These studies might test the treatment thresholds suggested by subgroup analyses of observational data;
• Designing studies, including small clinical trials, designed to justify large intervention studies of targeted thyromimetic analogs to treat dyslipidemia, heart failure, and peripheral vascular dysfunction;
• Incorporating appropriate examination of the HPT axis for new cardiovascular therapies for which preclinical data suggest an effect on the thyroid;
• Identifying appropriate surrogate (intermediate) endpoints for small clinical trials to help plan large intervention studies;
• Establishing consortia to identify priority areas for therapeutic pharmacology studies and provide centralized protocol coordination, data management and endpoint assessment for multi-center studies.

Publication Plans

A full report summarizing the detailed deliberations of the working group is planned for publication in a peer-reviewed journal.