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Genetically predicted hypothyroidism, thyroid hormone treatment, and the risk of cardiovascular diseases: a mendelian
Shuaidan Zhang1, Hangtian Yu1, Yan Zhao1
1Department of Cardiology, The Second Hospital of Hebei Medical University, Shijiazhuang, 050000, People's Republic of China.
Insights
Hypothyroidism increases myocardial infarction risk. Levothyroxine treatment, used for thyroid hormone replacement, may also elevate risks for myocardial infarction and heart failure.
Area of Science:
- Cardiovascular Disease Epidemiology
- Endocrinology
- Genetic Epidemiology
Background:
- Hypothyroidism and its treatment with levothyroxine are common.
- Cardiovascular diseases (CVDs) are a major health concern.
- The causal relationship between hypothyroidism, levothyroxine treatment, and CVD risk requires further investigation.
Purpose of the Study:
- To investigate the causal effect of hypothyroidism and levothyroxine treatment on the risk of myocardial infarction, heart failure, and cardiac death.
- To utilize Mendelian randomization to assess these associations, accounting for potential confounding factors.
Main Methods:
- Two-sample Mendelian randomization analysis using genetic variants associated with hypothyroidism, levothyroxine treatment, and cardiovascular outcomes.
- Inverse-variance weighting as the primary analysis method.
- MR-Egger regression, Cochran's Q test, and leave-one-out analyses for robustness; multivariable MR and mediation analysis to address confounding and mediating pathways.
Main Results:
- Genetically predicted hypothyroidism showed a strong association with increased myocardial infarction risk (OR: 15.11).
- Levothyroxine treatment was significantly associated with higher risks of myocardial infarction (OR: 3.75) and heart failure (OR: 2.16).
- No significant association was found between hypothyroidism and heart failure risk, or between either condition and cardiac death risk. Atrial fibrillation and stroke were identified as potential mediators for levothyroxine treatment effects.
Conclusions:
- Hypothyroidism is associated with an increased risk of myocardial infarction.
- Levothyroxine treatment may increase the risk of myocardial infarction and heart failure.
- Further research is warranted to elucidate the mechanisms and clinical implications of these findings.
Background:
In this study, we explored the impact of hypothyroidism and thyroid hormone replacement therapy on the risk of developing cardiovascular diseases, including myocardial infarction, heart failure, and cardiac death, via Mendelian randomization analysis.
Methods:
Genetic instrumental variables related to hypothyroidism, levothyroxine treatment (refer to Participants were taking the medication levothyroxine sodium) and adverse cardiovascular events were obtained from a large publicly available genome-wide association study. Two-sample Mendelian randomization analysis was performed via inverse-variance weighting as the primary method. To ensure the reliability of our findings, we performed MR‒Egger regression, Cochran's Q statistic, and leave-one-out analysis. Additionally, multivariable Mendelian randomization was employed to regulate confounding factors, including systolic blood pressure (SBP), diastolic blood pressure (DBP), body mass index (BMI), diabetes, cholesterol, low-density lipoprotein (LDL), triglycerides and metformin. A mediation analysis was conducted to assess the mediating effects on the association between exposure and outcome by treating atrial fibrillation and stroke as mediator variables of levothyroxine treatment and bradycardia as mediator variables of hypothyroidism.
Results:
Genetically predicted hypothyroidism and levothyroxine treatment were significantly associated with the risk of experiencing myocardial infarction [levothyroxine: odds ratio (OR) 3.75, 95% confidence interval (CI): 1.80-7.80; hypothyroidism: OR: 15.11, 95% CI: 2.93-77.88]. Levothyroxine treatment was also significantly related to the risk of experiencing heart failure (OR: 2.16, 95% CI: 1.21-3.88). However, no associations were detected between hypothyroidism and the risk of experiencing heart failure or between hypothyroidism or levothyroxine treatment and the risk of experiencing cardiac death. After adjusting for confounding factors, the results remained stable. Additionally, mediation analysis indicated that atrial fibrillation and stroke may serve as potential mediators in the relationships between levothyroxine treatment and the risk of experiencing heart failure or myocardial infarction.
Conclusion:
The results of our study suggest a positive association between hypothyroidism and myocardial infarction and highlight the potential effects of levothyroxine treatment, the main thyroid hormone replacement therapy approach, on increasing the risk of experiencing myocardial infarction and heart failure.
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