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Research Needed to Unravel Pieces of Thyroid-CVD Jigsaw

Acknowledging significant knowledge gaps regarding the complex relationship between thyroid function — and dysfunction — and cardiovascular disease, an international working group has identified key research priorities that need to be addressed.

These include a focus on mechanisms; vulnerabilities in key patient subgroups; and the role of thyroid-related treatment in influencing cardiovascular outcomes, according to new recommendations from the group, published simultaneously in Thyroid, the journal of the American Thyroid Association (ATA), and Circulation, the journal of the American Heart Association.

“The connection between thyroid and cardiac function has been intriguing physicians for more than a century,” said Peter A. Kopp, MD, professor and chief of the Division of Endocrinology, Diabetology and Metabolism at the University of Lausanne, Switzerland, in a press statement from the ATA.

“This multidisciplinary international working group…has identified key areas where further research may provide fundamental new insights into this connection, and these recommendations will be stimulating for numerous investigators interested in this field,” added Kopp, who is also editor-in-chief of Thyroid.

The working group, led by Anne Cappola, MD, of the Perelman School of Medicine at the University of Pennsylvania, in Philadelphia, was convened by the US National Heart, Lung, and Blood Institute to identify existing challenges and set forth a research agenda.

The guidelines recommend three broad areas of research interest: the fundamental biology behind the relationship between thyroid dysfunction and cardiovascular disease and the pursuit of novel biomarkers linking thyroid hormone action in cardiovascular tissues; the definition of subgroups of patients with thyroid dysfunction who may respond to preventive strategies; and the design of clinical trials to investigate how thyroid hormone therapy or thyromimetic drugs can improve cardiovascular outcomes.

Although the focus on fundamental biology is of ongoing relevance, “the second and third recommendations, with their focus on refining thresholds and testing treatment strategies in clinical trials, have more immediate translational potential,” the authors note.

Patient Subgroups Could Provide Insights for Treatment Thresholds

The focus on patient subgroups is particularly important in light of the fact that there is some evidence that cardiovascular disorders may be exacerbated by thyroid excess and deficiency even at subclinical levels. Other subgroups, such as older patients, may also have a greater risk, the authors explain.

“A growing body of observational data suggests that cardiovascular risk may also be increased in subgroups of patients with subclinical thyrotoxicosis or subclinical hypothyroidism,” they write.

Furthermore, “the heightened risk for both incident heart failure and thyroid disease in the aging population threatens a growing burden of both diseases in the coming decades, underscoring the need for greater attention to their intersection.”

The working group recommends the utilization of data from genome-wide association studies and other sources, which could lead to more precise medicine, such as an “HPT (hypothalamic–pituitary–thyroid) axis set-point prediction model to personalize treatment of thyroid dysfunction.”

Such a model could also be beneficial by including HPT axis set points that are indicative of increasing cardiovascular risk levels, the working group notes.

In addition to age categories, research into subgroups should investigate developmental and mechanistic differences according to sex, as well as demographic differences, such as regards race/ethnicity, with respect to health disparities, it recommends.

Data from two large consortia — the Thyroid Studies Collaboration and the ThyroidOmics Consortium, with existing registries and large-scale cohorts — could be further leveraged to pursue such research endeavors in important ways, the authors emphasize.

Trials on Treatment Thresholds, Effects on CVD Outcomes Needed

Regarding clinical trials to explore how thyroid treatment or management could influence cardiovascular outcomes, the authors suggest designing research that could lay the groundwork for large intervention studies of subclinical hypo- and hyperthyroidism, as well as low T3 syndrome, in patients with and those without preexisting cardiovascular disease.

“These studies might test the treatment thresholds suggested by subgroup analyses of observational data,” they indicate.

The need for such trials was underscored in a separate recommendation, published last week, as reported by Medscape Medical News, that concluded that thyroid hormone treatment provided no benefit to patients with subclinical hypothyroidism.

The basis for that recommendation was a systematic review and meta-analysis of 21 trials with 2192 participants that was published in JAMA in November 2018. Importantly, that trial found that the harms of thyroid hormones with respect to cardiovascular events or mortality were measured in only one of the 21 trials. In that trial, there were few events during 2 years of follow-up.

Although that guideline panel concluded that “thyroid hormones may have little or no effect on cardiovascular events or mortality,” it noted that the evidence was “low quality.”

Targeted Thyroid Medications as Cardiovascular Therapies?

The current working group recommends further studies to pave the way for large intervention studies of how targeted thyromimetic analogues might be of benefit in treating conditions such as heart failure, peripheral vascular dysfunction, and dyslipidemia.

In one example, they note that low T3 levels are common in patients with established heart failure, as a result of impaired T4 to T3 conversion, and the decline in serum T3 is in fact proportional to the severity of left ventricular dysfunction.

“Reduced T3 in the presence of normal thyroid stimulating hormone (TSH) and free T4 concentrations — the low T3 syndrome — is a powerful predictor of all-cause mortality in heart failure, even after adjustment for conventional predictors, including ejection fraction and natriuretic peptide levels,” the working group explains.

Although T3 is routinely administered to heart transplant donors and recipients to improve function, the authors note that no randomized studies support this practice and that more research is needed.

The working group says that studies should also examine the HPT axis in relation to new cardiovascular therapies and effects on the thyroid.

For all of the research efforts, the authors underscore the need for large-scale coordination and to “establish consortia to further identify areas of priority for therapeutic pharmacology studies and to provide centralized protocol coordination, data management, and end point assessment for multicentre studies.”

Coauthor Akshay S. Desai, MD, MPH, has received a research grant from Novartis and consulting fees from Novartis, Abbott, AstraZeneca, Boston Scientific, Bohringer-Ingelheim, Corvidia Therapeutics, Dalcor Pharma, Regeneron, Relypsa, and Signature Medical. Coauthor Samia Mora, MD, has received a research grant from Atherotech Diagnostics.

Thyroid. Published online May 13, 2019. Full text

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