Section structure
1. Highlights
2. Why this topic matters: disease burden and clinical relevance
3. Pathophysiology: how thyroid hormones influence the cardiovascular system
4. Epidemiology and cardiovascular phenotypes across the spectrum of thyroid dysfunction
5. What recent omics and Mendelian randomization studies add
6. Evidence for treatment, with emphasis on subclinical hypothyroidism and levothyroxine
7. Hyperthyroidism, arrhythmia, and vascular risk: implications for practice
8. Practical clinical approach to testing, risk stratification, and treatment decisions
9. Expert commentary: where evidence is strong, weak, or frequently misapplied
10. Conclusion, research gaps, funding, and trial registration
Highlights
Thyroid hormones are integral regulators of cardiovascular biology, influencing heart rate, myocardial contractility, diastolic relaxation, systemic vascular resistance, endothelial function, lipid handling, coagulation, and electrical stability. As a result, both hypothyroidism and hyperthyroidism can produce clinically meaningful cardiovascular phenotypes.
The most consistent cardiovascular associations are seen at the biochemical extremes: overt hypothyroidism is linked to atherogenic dyslipidaemia, diastolic hypertension, endothelial dysfunction, and impaired cardiac performance, whereas overt hyperthyroidism strongly increases the risk of atrial fibrillation, high-output states, and adverse hemodynamic remodeling.
Subclinical thyroid disease is common, but therapeutic decisions remain nuanced. In subclinical hypothyroidism, randomized trial evidence has not conclusively demonstrated reduction in hard cardiovascular endpoints with levothyroxine, although signal direction in some datasets is potentially favorable and risk may differ by thyroid-stimulating hormone level, age, symptoms, and baseline cardiovascular status.
Emerging omics and Mendelian randomization studies support biological plausibility and causal inference for selected pathways, especially rhythm disturbance and metabolic risk, but these methods do not yet replace careful phenotype-based clinical management.
Why this topic matters: disease burden and clinical relevance
Thyroid dysfunction is among the most common endocrine disorders worldwide. Because cardiovascular disease remains the leading global cause of mortality, even modest cardiovascular effects of altered thyroid status can have substantial population-level consequences. This is particularly relevant for subclinical thyroid dysfunction, which is far more prevalent than overt disease and frequently detected through routine biochemical testing.
The review by Alwan and colleagues in the European Heart Journal addresses a question of enduring clinical importance: when does altered thyroid function merely correlate with cardiovascular risk, and when does it causally contribute to cardiovascular disease in a way that should change treatment? This distinction matters because thyroid tests are often abnormal in older adults, in women, and in people with multimorbidity, yet the benefits of treatment are uneven across patient groups.
The unmet need is straightforward. Clinicians already recognize severe thyroid disease as medically consequential. The difficult cases are the common ones: mildly elevated thyroid-stimulating hormone, low-normal free thyroxine, suppressed thyroid-stimulating hormone without obvious symptoms, or thyroid dysfunction coexisting with atrial fibrillation, heart failure, ischemic heart disease, frailty, or polypharmacy. In these scenarios, over-treatment can be harmful, but under-recognition can also miss a modifiable contributor to cardiovascular events.
Pathophysiology: how thyroid hormones influence the cardiovascular system
Thyroid hormones, especially triiodothyronine, regulate cardiovascular physiology through genomic and non-genomic mechanisms. At the myocardial level, they influence expression of ion channels, sarcoplasmic reticulum calcium ATPase, phospholamban, myosin heavy chain isoforms, and beta-adrenergic signaling pathways. The net effect in euthyroid physiology is optimized chronotropy, inotropy, lusitropy, and vascular responsiveness.
In hypothyroidism, reduced thyroid hormone signaling lowers heart rate, impairs diastolic relaxation, reduces cardiac output, and raises systemic vascular resistance. These changes can contribute to exercise intolerance, widened arterial stiffness, and diastolic hypertension. Hypothyroidism also promotes an atherogenic lipid profile, typically with increased low-density lipoprotein cholesterol and apolipoprotein B-containing particles, partly through reduced hepatic LDL receptor activity and altered cholesterol synthesis and clearance. Endothelial dysfunction, oxidative stress, low-grade inflammation, and potential changes in coagulation and homocysteine metabolism may further connect hypothyroidism to vascular risk.
In hyperthyroidism, the physiology runs in the opposite direction but is no less hazardous. Increased thyroid hormone action enhances sympathetic sensitivity, accelerates sinus rate, shortens atrial refractory periods, increases myocardial oxygen demand, and reduces systemic vascular resistance while expanding plasma volume. This creates a substrate for atrial arrhythmias, especially atrial fibrillation, and can precipitate angina, worsen pre-existing heart failure, or induce tachycardia-mediated cardiomyopathy. Systolic hypertension and widened pulse pressure are common hemodynamic signatures.
Subclinical disease sits in an intermediate zone. Although biochemical abnormalities are milder, persistent exposure over time may still affect lipids, vascular reactivity, arterial stiffness, and atrial electrophysiology. Importantly, the magnitude of these effects likely depends on age, sex, baseline cardiovascular risk, degree of thyroid-stimulating hormone abnormality, and whether the disturbance is transient or sustained.
Epidemiology and cardiovascular phenotypes across the spectrum of thyroid dysfunction
Overt hypothyroidism and overt hyperthyroidism are both associated with clinically important cardiovascular manifestations, but their risk profiles differ. Overt hypothyroidism has been linked to dyslipidaemia, coronary artery disease risk, impaired ventricular function, and in severe cases pericardial effusion. Overt hyperthyroidism is most clearly associated with atrial fibrillation, supraventricular arrhythmias, embolic risk mediated through atrial fibrillation, and high-output heart failure.
Subclinical hypothyroidism is common, especially in older adults and women. Epidemiologic studies have suggested associations with coronary heart disease events, heart failure, and cardiovascular mortality, but results have varied, in part because risk is concentrated in those with higher thyroid-stimulating hormone levels, usually at or above 10 mIU/L, and in younger or middle-aged populations. In very old adults, mildly elevated thyroid-stimulating hormone may have weaker associations with adverse outcomes, making uniform treatment strategies inappropriate.
Subclinical hyperthyroidism is less prevalent but clinically important because of its consistent association with atrial fibrillation and possibly heart failure, especially when thyroid-stimulating hormone is persistently suppressed below 0.1 mIU/L. Bone risk often dominates treatment discussions, yet cardiovascular risk is equally central in older adults.
A key clinical lesson is that thyroid dysfunction is not a single exposure. Cardiovascular implications differ by overt versus subclinical status, endogenous versus exogenous cause, degree and duration of abnormality, and patient context. For example, iatrogenic subclinical hyperthyroidism from excessive levothyroxine dosing may be especially relevant in older adults, where even modest over-replacement can increase arrhythmia risk.
What recent omics and Mendelian randomization studies add
One of the strengths of the 2026 review is its integration of newer mechanistic evidence. Omics studies, including transcriptomic, proteomic, metabolomic, and lipidomic approaches, are helping map how thyroid status reshapes cardiovascular biology. These methods have reinforced known pathways, such as lipid metabolism and myocardial energy handling, but also suggest effects on inflammatory mediators, extracellular matrix remodeling, endothelial signaling, and thrombosis-related proteins.
Mendelian randomization studies are useful because they leverage genetic variants associated with thyroid function to estimate whether lifelong differences in thyroid-related traits may causally influence cardiovascular outcomes. Across studies, genetically predicted variation in thyroid function has shown stronger support for effects on atrial fibrillation risk than for a broad range of atherosclerotic endpoints. This is biologically plausible, given the direct electrophysiologic sensitivity of the atria to thyroid hormone action.
However, clinicians should interpret these data carefully. Mendelian randomization estimates reflect lifelong genetic exposure, not necessarily the effect of short- or medium-term pharmacologic treatment. They can be distorted by pleiotropy, phenotype definition, and ancestry limitations. Similarly, omics findings are rich in mechanistic signal but do not by themselves prove clinical benefit from intervention. These tools sharpen causal reasoning; they do not replace randomized evidence.
Evidence for treatment, with emphasis on subclinical hypothyroidism and levothyroxine
The major treatment controversy remains subclinical hypothyroidism. Levothyroxine clearly corrects biochemical hypothyroidism and is standard therapy for overt disease. The challenge is whether treating milder thyroid-stimulating hormone elevations improves cardiovascular outcomes enough to justify long-term therapy in broad populations.
The TRUST trial, the largest randomized placebo-controlled trial in older adults with subclinical hypothyroidism, showed no clear symptomatic benefit on its primary endpoints and was not powered for cardiovascular outcomes. As noted by Alwan and colleagues, the cardiovascular signal did not exclude benefit and may have trended in a favorable direction, but the trial cannot be taken as proof of cardiovascular protection. This is a crucial methodological point: absence of definitive benefit in an underpowered trial is not equivalent to evidence of no benefit.
Meta-analyses of randomized trials suggest that levothyroxine can improve surrogate markers such as total cholesterol and LDL cholesterol in some patients with subclinical hypothyroidism, though the average effect is modest and heterogeneous. Improvements in endothelial function or carotid intima-media thickness have been reported in smaller studies, but these surrogate endpoints have not translated into robust evidence for reduced myocardial infarction, stroke, heart failure hospitalization, or cardiovascular death.
Observational studies have sometimes suggested lower cardiovascular risk with treatment in selected subgroups, especially younger patients or those with thyroid-stimulating hormone levels above 10 mIU/L. Yet confounding by indication, healthy user bias, and variable treatment targets limit inference. The most defensible current position is individualized treatment: strong consideration of levothyroxine for overt hypothyroidism and for subclinical hypothyroidism with thyroid-stimulating hormone at or above 10 mIU/L, with more selective treatment below that threshold based on symptoms, age, pregnancy status, anti-thyroid peroxidase antibody positivity, progressive thyroid failure, dyslipidaemia, or established cardiovascular disease.
Importantly, treatment quality matters. Over-replacement is not benign. Suppressed thyroid-stimulating hormone during levothyroxine therapy may increase the risk of atrial fibrillation, reduced bone density, and possibly adverse cardiovascular outcomes, particularly in older adults. Therefore, any potential benefit from replacement depends on achieving and maintaining an appropriate biochemical target rather than simply prescribing thyroid hormone.
Hyperthyroidism, arrhythmia, and vascular risk: implications for practice
If subclinical hypothyroidism occupies the gray zone, hyperthyroidism offers a clearer message. Overt hyperthyroidism should be recognized as a cardiovascular condition as much as an endocrine one. Palpitations, exertional dyspnea, new atrial fibrillation, unexplained systolic hypertension, worsening angina, or unexplained heart failure should prompt thyroid testing, particularly in older adults where classic hyperadrenergic symptoms may be muted.
The association between hyperthyroidism and atrial fibrillation is one of the most robust links in endocrine cardiology. Thyroid excess promotes atrial ectopy, electrical remodeling, and faster conduction. Restoring euthyroidism reduces arrhythmia burden, although established atrial fibrillation may persist, especially when structural atrial disease is present. Beta-blockers provide immediate symptomatic and hemodynamic control, while definitive therapy depends on the cause, including antithyroid drugs, radioiodine, or surgery.
Subclinical hyperthyroidism also warrants careful management in patients at cardiovascular risk. Professional society guidance generally supports treatment in those with persistent thyroid-stimulating hormone suppression below 0.1 mIU/L who are older than 65 years or who have heart disease, osteoporosis, or symptoms. This threshold-based approach aligns with the stronger evidence for harm at lower thyroid-stimulating hormone levels.
Another practical issue is anticoagulation in atrial fibrillation associated with thyrotoxicosis. Current management generally follows standard stroke-risk assessment frameworks rather than assuming thyroid-mediated atrial fibrillation is transient and therefore low risk. This is clinically sensible, as embolic risk is determined by the overall substrate, not solely by the trigger.
Practical clinical approach to testing, risk stratification, and treatment decisions
A pragmatic cardiovascular approach begins with phenotype recognition. Thyroid testing is appropriate in atrial fibrillation, unexplained dyslipidaemia, resistant blood pressure abnormalities, new or worsening heart failure without clear cause, bradycardia, pericardial effusion, or unexpected changes in body weight and exercise tolerance. Initial evaluation generally includes thyroid-stimulating hormone, with reflex free thyroxine when abnormal; free triiodothyronine may help in selected hyperthyroid presentations.
Risk stratification should incorporate four variables: degree of biochemical abnormality, persistence over time, age, and cardiovascular context. A single mildly abnormal thyroid-stimulating hormone value does not define long-term risk, especially during acute illness or medication changes. Repeat testing is essential before labeling persistent subclinical disease.
For overt hypothyroidism, levothyroxine remains standard of care, initiated cautiously in patients with ischemic heart disease or frailty. For subclinical hypothyroidism, treatment is more compelling when thyroid-stimulating hormone is at or above 10 mIU/L, symptoms are present, thyroid autoimmunity suggests progression, or dyslipidaemia and cardiovascular risk are substantial. For older adults with mild thyroid-stimulating hormone elevation and no clear symptoms, watchful monitoring is often appropriate.
For hyperthyroidism, the cardiovascular urgency is higher when tachyarrhythmia, heart failure, or ischemia is present. Beta-blockade, rhythm evaluation, and definitive endocrine management should proceed in parallel. In both hypo- and hyperthyroid states, interdisciplinary care between cardiology, endocrinology, and primary care improves medication safety and follow-up.
Expert commentary: where evidence is strong, weak, or frequently misapplied
The strongest element of the current evidence base is biological coherence. Few endocrine disorders affect the cardiovascular system as broadly and predictably as thyroid dysfunction. The mechanistic links between thyroid hormone signaling and rhythm control, vascular resistance, and lipid metabolism are unusually well established.
The weakest element is outcome-trial evidence for treating subclinical hypothyroidism to prevent cardiovascular events. This gap has sometimes led to overconfident clinical claims at both extremes: one side assumes treatment must help because the biology is convincing; the other concludes treatment does not help because randomized data are inconclusive. Neither position is fully justified. The correct interpretation is narrower: routine levothyroxine for all subclinical hypothyroidism cannot be recommended on current cardiovascular outcome evidence, but selected patients may still benefit, especially those with higher thyroid-stimulating hormone levels or specific risk profiles.
Another recurring problem is failure to account for age. Thyroid physiology, reference ranges, comorbidity burden, and treatment tolerance shift with aging. Applying the same thyroid-stimulating hormone threshold to a 45-year-old with dyslipidaemia and a 90-year-old with frailty is poor medicine. Age-stratified management is more consistent with both physiology and trial evidence.
The review by Alwan et al. is particularly valuable because it bridges classical physiology with modern causal-inference tools. That said, clinicians should resist the temptation to let omics and genetic epidemiology outrun bedside evidence. The future likely lies in precision treatment: identifying which biochemical pattern, molecular signature, or clinical phenotype predicts cardiovascular benefit from correcting mild thyroid dysfunction.
Conclusion
Thyroid dysfunction is best understood not as a laboratory abnormality in isolation, but as a systemic cardiovascular modifier. Overt hypothyroidism and hyperthyroidism clearly merit treatment because they produce adverse hemodynamic, metabolic, and electrophysiologic effects. Subclinical disease requires greater discrimination. Cardiovascular risk appears graded rather than binary, shaped by severity, duration, age, and baseline disease burden.
The central clinical message is therefore practical: test thoughtfully, confirm persistence, treat overt disease promptly, avoid levothyroxine over-replacement, and individualize management of subclinical hypothyroidism rather than defaulting to either universal treatment or universal nihilism. For subclinical hyperthyroidism, the case for intervention is strongest in patients with persistent thyroid-stimulating hormone suppression and elevated arrhythmic risk.
Future research should prioritize adequately powered randomized trials for cardiovascular endpoints, better age-specific thresholds, and biomarker-guided strategies that distinguish patients likely to benefit from treatment from those better served by surveillance. Until then, the most evidence-based approach is targeted, phenotype-aware care.
Funding and ClinicalTrials.gov
The cited review article is: Alwan H, Hysaj O, Gencer B, Duntas L, Rodondi N. Thyroid dysfunction and cardiovascular disease. European Heart Journal. 2026-Jun-02;47(21):2606-2623. PMID: 41996368. Specific funding details for the review are not provided in the source summary above and should be verified in the full publication. As a narrative review, ClinicalTrials.gov registration is not applicable.
For the TRUST randomized trial discussed in this article, the trial is registered at ClinicalTrials.gov: NCT01660126.
References
1. Alwan H, Hysaj O, Gencer B, Duntas L, Rodondi N. Thyroid dysfunction and cardiovascular disease. European Heart Journal. 2026;47(21):2606-2623. PMID: 41996368.
2. Stott DJ, Rodondi N, Kearney PM, et al. Thyroid Hormone Therapy for Older Adults with Subclinical Hypothyroidism. New England Journal of Medicine. 2017;376(26):2534-2544. PMID: 28402245.
3. Biondi B, Cooper DS. The Clinical Significance of Subclinical Thyroid Dysfunction. Endocrine Reviews. 2008;29(1):76-131. PMID: 17991805.
4. Collet TH, Gussekloo J, Bauer DC, et al. Subclinical Hyperthyroidism and the Risk of Coronary Heart Disease and Mortality. Archives of Internal Medicine. 2012;172(10):799-809. PMID: 22529182.
5. Rodondi N, den Elzen WPJ, Bauer DC, et al. Subclinical Hypothyroidism and the Risk of Coronary Heart Disease and Mortality. JAMA. 2010;304(12):1365-1374. PMID: 20858880.
6. Gencer B, Collet TH, Virgini V, et al. Subclinical Thyroid Dysfunction and Cardiovascular Outcomes among Prospective Cohorts. Endocrine and Metabolic Clinics of North America. 2014;43(2):577-596. PMID: 24891178.
7. Kahapola-Arachchige KM, Hadlow N, Walsh JP, et al. Age-specific TSH reference ranges have minimal impact on the diagnosis of thyroid dysfunction. Clinical Endocrinology. 2012;77(5):773-779. PMID: 22339604.
8. Ross DS, Burch HB, Cooper DS, et al. 2016 American Thyroid Association Guidelines for Diagnosis and Management of Hyperthyroidism and Other Causes of Thyrotoxicosis. Thyroid. 2016;26(10):1343-1421. PMID: 27521067.
9. Garber JR, Cobin RH, Gharib H, et al. Clinical Practice Guidelines for Hypothyroidism in Adults. Thyroid. 2012;22(12):1200-1235. PMID: 22954017.
10. Baumgartner C, da Costa BR, Collet TH, et al. Thyroid function within the normal range, subclinical hypothyroidism, and the risk of atrial fibrillation. Circulation. 2017;136(22):2100-2116. PMID: 29038123.
