Association between Sub-Clinical Hypothyroidism and Heart Failure with Preserved Ejection Fraction
Heart failure with preserved ejection fraction (HFpEF) is a growing concern worldwide, particularly as global populations age. It is anticipated that the prevalence of HFpEF will increase significantly over the next decade. Thyroid hormones play a crucial role in regulating cardiovascular physiology, and thyroid dysfunction has been observed in approximately 22% of patients with HFpEF. Sub-clinical hypothyroidism (SCH), characterized by elevated thyroid-stimulating hormone (TSH) levels but normal free tri-iodothyronine (FT3) and free thyroxine (FT4) levels, has been linked to an increased risk of cardiovascular diseases. This association is thought to be mediated by factors such as elevated low-density lipoprotein, increased homocysteine levels, and a hyper-coagulative state. Animal studies have further suggested that SCH may lead to the accumulation of mucopolysaccharides in the myocardium, potentially contributing to heart failure. Despite these findings, clinical studies investigating the relationship between thyroid hormones and HFpEF remain limited. This study aims to explore the association between SCH and HFpEF and to evaluate its clinical significance.
Study Design and Methodology
This study was conducted at the Department of Cardiology of Lanzhou University Second Hospital between January 1, 2016, and January 1, 2018. The diagnostic criteria for HFpEF were based on the 2016 ESC Guidelines for the Diagnosis and Treatment of Acute and Chronic Heart Failure. The study protocol was approved by the Ethics Committee of Lanzhou University Second Hospital, and all participants provided informed consent before enrollment.
Patients were included if they met the following criteria: (1) a confirmed diagnosis of HFpEF; (2) typical symptoms or signs of heart failure; (3) a left ventricular ejection fraction (LVEF) of 50% or higher; (4) cardiac function classified as II to III according to the New York Heart Association (NYHA) heart failure classification; (5) baseline thyroid function test results; and (6) no recent use of medications that could affect thyroid function. Exclusion criteria included: (1) clinical hypothyroidism, hyperthyroidism, or a history of thyroid disease; (2) systolic heart failure; (3) valvular disease; (4) acute myocardial infarction; (5) any arrhythmia; and (6) pericardial effusion.
A total of 73 HFpEF patients with SCH were included in the observation group, while 73 HFpEF patients with normal thyroid function were selected as the control group. The two groups were matched by age, gender, and index year. Baseline data, including gender, age, medical history, concomitant diseases, medications, and other general information, were collected at admission. Blood samples were drawn after an overnight fast, and biochemical indices such as TSH, FT3, FT4, brain natriuretic peptide (BNP), and C-reactive protein (CRP) were measured using an automatic biochemical analyzer. Echocardiographic examinations were performed on the same day as blood testing using an HP Sonos 5500 Color Doppler Ultrasound Machine. LVEF was measured via trans-thoracic two-dimensional echocardiography, and the peak velocities of blood flow across the mitral valve in early diastole (E) and late diastole (A) were measured using trans-thoracic-pulsed Doppler echocardiography. The E/A ratio was calculated, and the mitral annular velocity in early diastole (E0) was measured using tissue Doppler imaging to calculate the E/E0 ratio.
Results
The baseline characteristics of the patients, including age, gender, body mass index, systolic and diastolic blood pressure, comorbidities (hypertension, coronary heart disease, and diabetes), and primary medications (angiotensin-converting enzyme inhibitors, calcium channel blockers, and statins), were well-matched between the two groups. However, significant differences were observed in biochemical and echocardiographic parameters.
Patients with SCH had significantly higher levels of BNP (210.45 ± 52.42 pg/mL vs. 188.75 ± 49.08 pg/mL, P < 0.05) and CRP (2.32 ± 0.89 mg/L vs. 1.26 ± 0.33 mg/L, P < 0.05) compared to those with normal thyroid function. Echocardiographic results revealed that the E/A ratio was significantly lower, and the E/E0 ratio was significantly higher in the SCH group compared to the euthyroidism group (P < 0.05). No significant differences were observed in LVEF, E velocity, or E’ velocity between the two groups.
Pearson correlation analysis demonstrated that circulating TSH levels were positively correlated with BNP (r = 0.335, P < 0.05), CRP (r = 0.256, P < 0.05), and the E/E0 ratio (r = 0.266, P < 0.05). However, no significant correlation was found between TSH and the E/A ratio. These findings suggest that SCH may adversely affect cardiac diastolic function in patients with HFpEF.
Discussion
The cardiovascular system is a specific target of thyroid hormones. Triiodothyronine (T3) binds to nuclear receptors in cells and regulates the transcription of genes involved in cardiac myocyte and vascular smooth muscle cell activity. SCH, which represents early or mild hypothyroidism, has been associated with an increased risk of cardiovascular events and mortality, particularly when TSH levels exceed 10 mU/L. The findings of this study support the hypothesis that SCH may contribute to molecular and structural disorders in the myocardium, leading to impaired cardiac function in patients with HFpEF.
CRP, an independent risk factor for cardiovascular events, and BNP, a marker of cardiac dysfunction severity, were both elevated in patients with SCH. The increased E/E0 ratio and decreased E/A ratio observed in the SCH group further indicate impaired diastolic function. These results align with previous studies suggesting that SCH may negatively impact cardiac diastolic function through mechanisms involving calcium handling in the myocardium.
One potential mechanism involves the sarco/endoplasmic reticulum Ca2+-ATPase isoform 2 (SERCA2), a calcium transporter critical for the reuptake of calcium from the plasma into the sarco/endoplasmic reticulum during cardiac diastole. Thyroid hormones are known to activate genes encoding α-myosin heavy chain and SERCA2, promoting calcium reuptake and improving ventricular diastolic function. In SCH, the relative deficiency of thyroid hormones may lead to decreased SERCA2 expression, resulting in impaired calcium uptake and compromised ventricular relaxation. However, further research is needed to fully elucidate the impact of SCH on the SERCA2 system and its role in HFpEF development.
Clinical Implications
The American College of Cardiology/American Heart Association (ACC/AHA) guidelines recommend evaluating thyroid function in all newly diagnosed heart failure patients. The findings of this study suggest that correcting SCH in patients with HFpEF may improve diastolic cardiac function and overall prognosis. However, this study is limited by its observational design and relatively small sample size. Future studies with larger cohorts are needed to confirm these findings and further explore the role of SCH in HFpEF pathogenesis.
Conclusion
This study highlights the association between SCH and HFpEF, demonstrating that SCH is linked to increased levels of BNP and CRP, as well as impaired diastolic function as indicated by echocardiographic parameters. These findings suggest that SCH may play a role in the development and progression of HFpEF, potentially through mechanisms involving calcium handling in the myocardium. Further research is warranted to validate these results and to investigate the therapeutic potential of correcting SCH in patients with HFpEF.
doi.org/10.1097/CM9.0000000000000631
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