Werkgroep: Schildklier en hart- en vaatziekten

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Werkgroep: Schildklier en hart- en vaatziekten

Bericht door ineke » 15 jun 2019, 20:26

Werkgroep: Schildklier en hart- en vaatziekten met onderaan conclusies en aanbevelingen.

Hierin ook vertegenwoordiging van Dr. Marco Medici van het Erasmus MC Thyroid Center



Free Access
THYROID Volume 29, Number 6, 2019
ª 2019 American Thyroid Association, Mary Ann Liebert, Inc., and American Heart Association, Inc.
DOI: 10.1089/thy.2018.0416

Anne R. Cappola,1 Akshay S. Desai,2 Marco Medici,3 Lawton S. Cooper,4 Debra Egan,5 George Sopko,4 Glenn I. Fishman,6 Steven Goldman,7 David S. Cooper,8 Samia Mora,9 Peter J. Kudenchuk,10
Anthony N. Hollenberg,11 Cheryl L. McDonald,4 and Paul W. Ladenson8

1 Division of Endocrinology, Diabetes, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.
2 Cardiovascular Division; 9 Divisions of Preventive and Cardiovascular Medicine; Brigham and Women’s Hospital, Boston, Massachusetts.
3 Department of Internal Medicine and Erasmus MC Academic Center for Thyroid Diseases, Erasmus MC, Rotterdam, The Netherlands.
4 Division of Cardiovascular Sciences, National Heart, Lung, and Blood Institute, Bethesda, Maryland.
5 Office of Clinical and Regulatory Affairs, National Center for Complementary and Integrative Health, Bethesda, Maryland.
6 Division of Cardiology, NYU School of Medicine, New York, New York.
7 Sarver Heart Center, University of Arizona, Tucson, Arizona.
8 Division of Endocrinology, Diabetes and Metabolism, Johns Hopkins University School of Medicine, Baltimore, Maryland.
10 Division of Cardiology, Arrhythmia Services, University of Washington, Seattle, Washington.
11 Department of Medicine, Weill Cornell Medicine, New York, New York.
This article has been co-published in Circulation
Thyroid and Cardiovascular Disease:
Research Agenda for Enhancing Knowledge, Prevention, and Treatment
Schildklier en hart- en vaatziekten:
Onderzoeksagenda voor het verbeteren van kennis, preventie en behandeling
Thyroid hormones have long been known to have a range of effects on the cardiovascular system. However, significant knowledge gaps exist concerning the precise molecular and biochemical mechanisms governing these effects and the optimal strategies for management of abnormalities in thyroid function in patients with and without preexisting cardiovascular disease.

In September 2017, The National Heart, Lung, and Blood Institute convened a Working Group with the goal of developing priorities for future scientific research relating thyroid dysfunction to
the progression of cardiovascular disease.

The Working Group reviewed and discussed the roles of normal thyroid physiology, the consequences of thyroid dysfunction, and the effects of therapy in three cardiovascular areas:
cardiac electrophysiology and arrhythmias, the vasculature and atherosclerosis, and the myocardium and heart failure.

This report describes the current state of the field, outlines barriers and challenges to progress, and proposes research opportunities to advance the field, including strategies for leveraging novel approaches using omics and big data.

The Working Group recommended research in three broad areas:
1) 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;
2) studies that define subgroups of patients with thyroid dysfunction amenable to specific preventive strategies and interventional therapies related to cardiovascular disease;
and
3) clinical trials focused on improvement in cardiovascular performance and cardiovascular
outcomes through treatment with thyroid hormone or thyromimetic drugs.
Het is al lang bekend dat schildklierhormonen een scala aan effecten hebben op het cardiovasculaire systeem. Er bestaan echter aanzienlijke kennislacunes met betrekking tot de precieze moleculaire en biochemische mechanismen die deze effecten regelen en de optimale strategieën voor het beheer van abnormaliteiten in de schildklierfunctie bij patiënten met en zonder reeds bestaande cardiovasculaire aandoeningen.

In september 2017 hebben The National Heart, Lung en Blood Institute een werkgroep bijeengeroepen met als doel prioriteiten te ontwikkelen voor toekomstig wetenschappelijk onderzoek met betrekking tot schildklierdisfunctie. de progressie van hart- en vaatziekten.

De werkgroep beoordeelde en besprak de rollen van normale schildklierfysiologie, de gevolgen van schildklierdisfunctie en de effecten van therapie op drie cardiovasculaire gebieden:
hartelektrofysiologie en aritmieën, de vasculatuur en atherosclerose, en het myocardium en hartfalen.

Dit rapport beschrijft de huidige stand van zaken, schetst hindernissen en uitdagingen voor vooruitgang en biedt onderzoeksmogelijkheden om het veld te verbeteren, inclusief strategieën om nieuwe benaderingen te gebruiken met behulp van omics en big data.

De werkgroep adviseerde onderzoek op drie brede gebieden:
1) onderzoek naar de fundamentele biologie met betrekking tot schildklierstoornissen voor de ontwikkeling van hart- en vaatziekten en naar de identificatie van nieuwe biomarkers voor de werking van schildklierhormonen in cardiovasculaire weefsels;
2) onderzoeken die subgroepen van patiënten met schildklierstoornissen definiëren die vatbaar zijn voor specifieke preventieve strategieën en interventionele therapieën gerelateerd aan hart- en vaatziekten;
en
3) klinische onderzoeken gericht op verbetering van cardiovasculaire prestaties en cardiovasculaire
resultaten door behandeling met schildklierhormoon of thyromimetische geneesmiddelen

Table 1. Guidelines with Recommendations for Management of Thyroid Dysfunction Coexistent
with Cardiovascular Disease Condition Recommendation

Subclinical hyperthyroidism /
If cardiac risk factors or cardiac disease, treat if TSH persistently
<0.1 mIU/L (8,9) If cardiac disease, consider treatment if TSH persistently 0.1–0.4 mIU/L (8,9)

Overt hypothyroidism /
With known coronary artery disease, start low-dose levothyroxine and
increase dose slowly If unable to tolerate full dose, additional measures to treat CVD are indicated (11)

Subclinical hypothyroidism /
Treat all patients (12) or consider treatment (13) with TSH level persistently >10 mIU/L
Consider treatment:
_ For patients with TSH levels 4.5–10 mIU/L with ASCVD, heart failure, or associated risk factors for these diseases (13)
_ For patients with TSH levels 4.5–10 mIU/L, for those patients younger than 65 years with increased cardiovascular risk (e.g., previous cardiovascular disease, diabetes, dyslipidemia, hypertension,
metabolic syndrome), particularly with TSH level persistently >7 mIU/L (12)

FIG. 1.
Commonly defined categories of thyroid status. FT4, free T4; TSH, thyroid-stimulating hormone; TT3, total T3


FIG. 2.
Role of big data in identifying novel genetic determinants of thyroid (dys)function.
The identification of these markers is essential to perform reliable Mendelian randomization studies, which will clarify causality in the observed associations between thyroid (dys)function and cardiovascular complications.
Furthermore, these genetic markers could play a role in hypothalamus–pituitary–thyroid (HPT) axis setpoint prediction, which is essential to start personalizing the treatment of patients with thyroid diseases.


FIG. 3.
Effect of thyroid hormones on the cardiomyocyte via genomic and nongenomic actions from Reference (2).
Reproduced with permission from Jabbar et al. (2). Copyright ª 2017, Springer Nature Publishing AG. DIO2, type 2 iodothyronine deiodinase; DIO3, type 3 iodothyronine deiodinase; MAPK, mitogen-activated protein kinase; MYH6, myosin heavy chaina; MYH7, myosin heavy chainb; PI3K, phosphoinositide 3 kinase; PLN, phospholamban; rT3, reverse T3; SERCA, sarco/endoplasmic reticulum Ca2+-ATPase; T2, diiodothyronine; T3, triiodothyronine; T4, thyroxine; TR, thyroid receptor; TRE, thyroid hormone response element.


Table 2.
Research Opportunities in Thyroid Hormones and Cardiac Electrophysiology


Table 3.
Research Opportunities in Thyroid Hormones and the Vasculature


FIG. 4.
Cardiovascular effects of T3, from Reference (95). Reproduced
with permission from Danzi and Klein (95). Copyright ª 2014, Elsevier. HR, heart rate;
hyper, hyperthyroidism; hypo, hypothyroidism; T3, triiodothyronine; T4, thyroxine.


Table 4.
Research Opportunities in Thyroid Hormones and the Myocardium



Conclusions and Recommendations
Based on discussion at the meeting, the Working Group defined three broad recommendations for research activity.
The first set of recommendations focuses on basic biology.
The second and third recommendations, with their focus on refining thresholds and testing treatment strategies in clinical trials, have more immediate translational potential.

1.
Investigation into the fundamental biology relating thyroid dysfunction to the development of CVD and
into the identification of novel biomarkers of thyroid hormone action in cardiovascular tissues.
Areas of particular interest for further research include the following:
_ Defining the cellular signaling processes and gene expression variations by which thyroid hormone
regulates electric 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, its receptors, and cofactors in modulating myocardial systolic
and diastolic function;
_ 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;
and
_ Developing novel serum and imaging biomarkers reflecting tissue thyroid hormone actions.


2.
Studies that define subgroups of patients with thyroid dysfunction amenable to specific preventive
strategies and interventional therapies related to cardiovascular disease.
Areas of particular interest include the following:
_ Identifying subgroups of individuals with preexisting CVD or at high risk for CVD who may benefit from
manipulation of thyroid hormone status, including individuals 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
_ Using modern approaches including genome-wide association studies, whole-exome/genome sequencing,
epigenetics, mRNA expression, metabolomics, and other omics data to generate an HPT (hypothalamic–
pituitary–thyroid) axis set-point prediction model to personalize treatment of thyroid dysfunction and test to what extent a deviation from the HPT axis set point is also important in determining a patient’s cardiovascular risk;
_ Recognizing the developmental and mechanistic differences among the newborn, pediatric, and adult
populations; potential variations in key demographic subgroups, including age, sex, and race/ethnicity;
and issues of health disparities and global health;
and
_ Leveraging the infrastructure from the two existing large consortia in this field (Thyroid Studies Collaboration and ThyroidOmics Consortium) to integrate data from existing large-scale cohorts or use existing registries


3.
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 the following:
_ 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 preexisting CVD;
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) end points for small clinical trials to help plan large intervention studies;
and
_ Establishing consortia to identify priority areas for therapeutic pharmacology studies and provide
centralized protocol coordination, data management, and end point assessment for multicenter
studies.


Volledig artikel
https://www.liebertpub.com/doi/pdfplus/ ... .2018.0416


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