Table of Contents
ORIGINAL ARTICLE
Year : 2021  |  Volume : 6  |  Issue : 3  |  Page : 174-180

Low tri-iodothyronine syndrome improves the risk prediction for mortality in patients with acute heart failure: A prospective observational cohort study


Department of Cardiology, Jiangsu Province Hospital, the First Affiliated Hospital of Nanjing Medical University, Jiangsu, Nanjing 210029, China

Date of Submission11-Aug-2021
Date of Acceptance09-Sep-2021
Date of Web Publication30-Sep-2021

Correspondence Address:
Xin-Li Li
Department of Cardiology, the First Affiliated Hospital of Nanjing Medical University, Guangzhou Road 300, Jiangsu, Nanjing 210029
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2470-7511.327243

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  Abstract 


Background and Objective: Clinical studies have suggested that low tri-iodothyronine (T3) syndrome negatively affects the clinical outcomes of patients with acute heart failure (AHF). The aim of this prospective cohort study was to evaluate the effect of low T3 syndrome in terms of prognosis and risk-predictive potential in AHF. Methods: A prospective observational cohort study was conducted from April 2012 to August 2016 in Nanjing, China. All clinical baseline characteristics were retrieved from electronic medical records. Low T3 syndrome was defined by a low free T3 level (<3.1 pM) accompanied by a normal thyroid-stimulating hormone level. The association between the free T3 level and mortality and the incremental risk prediction were estimated in Cox regression adjusted models. Results: In total, 312 patients with AHF for whom detailed thyroid hormone profiles were available were prospectively enrolled. Seventy-two patients exhibited low T3 syndrome. Over a median follow-up period of 35 months, 121 cumulative deaths occurred. Cardiovascular death was observed in 94 patients. After extensive adjustment for confounders, the low T3 syndrome-associated hazard ratios (95% confidence intervals) were 1.74 (1.16–2.61, P = 0.007) for all-cause mortality and 1.90 (1.21–2.98, P = 0.005) for cardiovascular mortality. The restricted cubic splines suggested a negative linear relationship between the free T3 level and mortality risk. Considering reclassification, adding low T3 syndrome to the fully adjusted model improved the risk prediction for all-cause mortality (integrated discrimination improvement [IDI]: 2.0%, P = 0.030; net reclassification improvement [NRI]: 8.9%, P = 0.232) and cardiovascular mortality (IDI: 2.5%, P = 0.030; NRI: 21.3%, P = 0.013). Conclusions: Low T3 syndrome reclassified risk prediction for mortality beyond traditional risk factors for patients with AHF.

Keywords: Acute heart failure; Linear relationship; Low T3 syndrome; Mortality; Risk prediction


How to cite this article:
Liao SG, Gao RR, Cheang I, Lu XY, Zhou YL, Zhang HF, Yao WM, Li XL. Low tri-iodothyronine syndrome improves the risk prediction for mortality in patients with acute heart failure: A prospective observational cohort study. Cardiol Plus 2021;6:174-80

How to cite this URL:
Liao SG, Gao RR, Cheang I, Lu XY, Zhou YL, Zhang HF, Yao WM, Li XL. Low tri-iodothyronine syndrome improves the risk prediction for mortality in patients with acute heart failure: A prospective observational cohort study. Cardiol Plus [serial online] 2021 [cited 2021 Nov 27];6:174-80. Available from: https://www.cardiologyplus.org/text.asp?2021/6/3/174/327243




  Introduction Top


Heart failure is associated with high-level morbidity and mortality.[1] The cardiovascular system, particularly the heart, is a key target of thyroid hormones,[2] and changes in circulating hormone levels modulate cardiovascular metabolism. Low tri-iodothyronine (T3) syndrome is commonly considered to be an adaptive response to severe functional impairment[3] and has been reported in patients with heart failure. Clinical and experimental studies[4],[5] have shown that T3 plays fundamental roles in the modulation of cardiac contractility, ventricular remodeling, and peripheral vascular resistance, and reduction in the activity of 5-monodeiodinase (which converts thyroid hormone [T4] to T3) is proportional to the clinical severity of heart disease. Changes in T4 levels are associated with significant alterations in heart function.[5]

Low T3 syndrome is common in patients with heart failure (10.6%–34.5% of such patients).[6],[7],[8] Increasing evidence suggests that low T3 syndrome is independently associated with an increased risk of adverse clinical outcomes in patients with acute heart failure (AHF)[6],[8],[9] and chronic heart failure.[10] Although previous studies[8],[9],[10] have demonstrated the independent prognostic impact of low T3 syndrome on AHF, there is a lack of studies adjust for baseline N-terminal pro-B-type natriuretic peptide (NT-proBNP) concentrations in AHF. Therefore, it remains uncertain whether low T3 syndrome is associated with long-term prognosis in patients with AHF, independently of renal function, NT-proBNP levels, and other comorbid conditions.[11] Herein, we evaluated the effect of low T3 syndrome in terms of prognosis and risk-predictive potential in patients with AHF.


  Subjects and Methods Top


Study design and population

From April 2012 and August 2016, 482 consecutive patients were hospitalized for AHF in the First Affiliated Hospital of Nanjing Medical University. The inclusion criteria were age ≥18 years and hospitalization because of AHF. Patients with malignant tumors, those exhibiting cognitive dysfunction or dementia, and those with uncontrolled systemic disease or severe mental illness were excluded. Patients who were taking amiodarone or antithyroid drugs or exhibited clinical hyperthyroidism, hypothyroidism, subclinical hyperthyroidism, and hypothyroidism were also excluded. In total, 131 patients were excluded because they were taking amiodarone or antithyroid drugs (n = 12) or exhibited clinical hyperthyroidism (n = 9), hypothyroidism (n = 30), subclinical hyperthyroidism (n = 2), or subclinical hypothyroidism (n = 78). Furthermore, a total of 39 patients were lost to follow-up. The study cohort flow diagram is shown in [Figure 1].
Figure 1: Study flow chart.
AHF: Acute heart failure


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Data collection

Baseline demographic and clinical data (medical history, physical examination findings, laboratory data, and etiology and complications of AHF) were collected within 24 h of admission. The estimated glomerular filtration rate (eGFR) was calculated using the Modification of Diet in Renal Disease equation.[12] The left ventricular ejection fraction (LVEF) was measured by transthoracic echocardiography using the Simpson method.[13] Chronic kidney disease was defined as an eGFR <60 mL/min/1.73 m2. Hyponatremia was defined as a serum sodium level ≤135 mM. Anemia was defined as a hemoglobin level <130 g/L in male patients and <120 g/L in female patients. Hypoalbuminemia was defined as a serum albumin level <34 g/L. All patients were treated in a standard manner including angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, beta-blockers, antisterone, etc. The thyroid function profile was evaluated on admission or the following morning using an automated chemiluminescence immunoassay system (AutoBio 12 Co., Ltd., Zhengzhou, China). The reference intervals used were 3.10–6.80 pmol/L for serum-free T3, 12.00–22.00 pM for serum-free T4, and 0.27–4.20 mIU/L for thyroid-stimulating hormone (TSH). Low T3 syndrome was diagnosed when the level of free T3 was <3.1 pM, but the TSH level was normal.[4]

The primary endpoint was all-cause mortality, and the secondary endpoint was cardiovascular mortality. Prospective follow-up commenced after the measurement of thyroid function. Mortality was ascertained every 6 months by examination of hospital records or patient contact (directly or by telephone) and verified by viewing death certificates held in the local disease control center or by contact with family members.

Ethics statements

Our study was approved by the Ethics Committee of the First Affiliated Hospital of Nanjing Medical University (number: 2011-SR-012, date: 02/14/2012), and all patients gave written informed consent. Our study also complied with the Declaration of Helsinki for investigation in human patients, and the study was registered with the Chinese Clinical Trial registry (ChiCTR-ONC-12001944, date: 02/05/2012).

Statistical analysis

Continuous variables are expressed as means ± standard deviations or as medians with 25th and 75th percentiles and were compared using the unpaired Student's t-test or Mann–Whitney U-test, depending on whether they were normally distributed, as revealed by the Kolmogorov–Smirnov test. Categorical variables are presented as numbers (%) and were compared using Pearson's Chi-square test. The levels of NT-proBNP were transformed logarithmically to normalize the distribution. Multiple imputation (with five imputed data sets in R version 3.6.0 [R Foundation for Statistical Computing, Vienna, Austria]) was used to impute data for patients who were missing covariate data. The sample size for our study was based on a previous study using similar methodology that evaluated 270 hospitalized AHF patients with thyroid hormone levels measured at admission with the sample size of 270.[9] Our study evaluated 312 hospitalized AHF patients, and the sample size is larger than previous study. Survival curves were drawn using the Kaplan–Meier method, and survival differences were compared using the log-rank test. Associations of low T3 syndrome with all-cause and cardiovascular mortalities during follow-up were assessed using cox proportional hazard regression analyses with adjustment sets as follows: (i) unadjusted, (ii) adjusted for age and sex, and (iii) adjusted for age, sex, hypertension, diabetes, body mass index, New York Heart Association (NYHA) functional class, atrial fibrillation, log-transformed NT-proBNP (Ln NT-proBNP), eGFR, and anemia. Furthermore, to clarify the improvement in risk prediction by low T3 syndrome over established risk factors, integrated discrimination improvement (IDI) and net reclassification improvement (NRI) were calculated. The linearity of risk was evaluated through restricted cubic spline[14] regression modeling of the association between the free T3 level (a continuous variable) and the risk of all-cause mortality. P < 0.05 was considered to be statistically significant. All statistical analyses were performed with the aid of R version 3.6.0 (R Foundation for Statistical Computing, Vienna, Austria) and Stata version 14 (StataCorp LP, College Station, TX, USA).


  Results Top


Baseline characteristics

Of the 351 patients, 39 (11.1%) were lost to follow-up; we finally analyzed 312 AHF patients with an average age of 60.4 ± 16.2 years, of whom 69.6% were male. Seventy-two (23.1%) patients exhibited low T3 syndrome, whereas the other 240 (76.9%) were euthyroid. The patients with low T3 syndrome were older, female, smokers, and had more heart failure symptoms and poorer nutritional status compared to those without low T3 syndrome. They also exhibited a higher NT-proBNP level, more elevated eGFR, higher ejection fraction, and greater prevalence of electrolyte disturbance than patients without low T3 syndrome. The free T3 level was significantly increased in patients with low T3 syndrome compared to those without low T3 syndrome [P < 0.001; [Table 1].
Table 1: Clinical characteristics of acute heart failure patients with or without low tri-iodothyronine syndrome

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Prognostic value of low T3 syndrome in acute heart failure

During a median follow-up period of 35 (18–46) months, the numbers of all-cause deaths were 41 for patients with low T3 syndrome and 80 for euthyroid patients (56.9% vs. 33.3%, P < 0.0001). Cardiovascular death was observed in 34 patients with low T3 syndrome and 61 with euthyroidism (47.2% vs. 25.4, P < 0.0001). Kaplan–Meier analysis revealed that low T3 syndrome was associated with a significantly increased risk of all-cause mortality and cardiovascular mortality [Figure 2]A and [Figure 2]B. In further analyses of multivariable-adjusted Cox models, we accounted for risk factors at baseline, including age, sex, hypertension, diabetes, atrial fibrillation, body mass index, NYHA functional class, LnNT-proBNP, eGFR, and anemia; low T3 syndrome was related to all-cause mortality (hazard ratio [HR]: 1.74, 95% confidence interval [CI]: 1.16–2.61, P = 0.007) and cardiovascular mortality (HR: 1.90, 95% CI: 1.21–2.98, P = 0.005) [Table 2].
Figure 2: Kaplan–Meier survival curve for all-cause A and cardiovascular B, mortalities in patients with euthyroidism and low T3 syndrome

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Table 2: Predictive value of low tri-iodothyronine syndrome in acute heart failure using multivariable-adjusted Cox models

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Restricted cubic spline regression analysis was used to model continuous associations. A significant dose-dependent association was observed between the free T3 level and the risk of all-cause and cardiovascular mortalities. The free T3 level exhibited a negative linear relationship with the mortality risk [Figure 3]A and [Figure 3]B.
Figure 3: Restricted cubic spline regression analysis (knots located at 10th, 50th, and 90th percentiles with 3.1 pM as the reference value) of the association between free T3 levels and risk of all-cause A and cardiovascular B, mortalities. A significant dose-dependent association is observed between the free T3 level and the risk of all-cause and cardiovascular mortalities. Solid lines mean adjusted HR, and dashed lines are 95% confidence intervals. HRs are estimated using Cox regression modeling, adjusted for age, sex, hypertension, diabetes, body mass index, New York Heart Association functional class, atrial fibrillation, log-transformed NT-proBNP, estimated glomerular filtration rate, and anemia

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Reclassification

Reclassification of patients with AHF by adding low T3 syndrome to the fully adjusted model according to the occurrence of death during follow-up is summarized in [Table 3]. The IDI after the individual inclusion of low T3 syndrome in the fully adjusted model for all-cause mortality was 2.0% (95% CI: 0.1–7.2; P = 0.030), and the NRI was 8.9% (95% CI: 0.5–16.2; P = 0.232). For prediction of cardiovascular mortality, adding low T3 syndrome to the fully adjusted model increased the IDI by 2.5% (95% CI: 0.1–7.7, P = 0.030) and the NRI by 21.3% (95% CI: 7.6–50.2, P = 0.013).
Table 3: Integrated discrimination improvement and net reclassification improvement by adding low tri-iodothyronine syndrome to the fully adjusted model

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  Discussion Top


We found that low T3 syndrome was common in patients with AHF and was associated with increased all-cause mortality and cardiovascular mortality. A high free T3 level was associated with a lower risk of mortality. We also showed that low T3 syndrome improved risk prediction over clinical risk factors for mortality.

Several studies have shown that low T3 syndrome is associated independently with adverse clinical outcomes in patients with heart failure.[6],[7],[8],[10] However, definitions of low T3 syndrome and the measurement of thyroid function among different studies varied. Kannan et al.[7] found that an isolated low T3 level was associated with poor clinical outcomes in 1,365 patients with preexisting heart failure. An isolated low T3 level was also associated with a composite endpoint including death, ventricular assistive device placement, and heart transplantation (HR: 2.12, 95% CI: 1.65–2.72, P < 0.001). In the cited work, low T3 syndrome was diagnosed when the TSH and free T4 levels were within the reference ranges and the total T3 level was below the reference range. In the cohort study of Sato et al.,[8] low T3 syndrome (free T3 <2.3 pg/mL) was associated significantly with higher all cause-mortality in patients with heart failure (unadjusted HR: 1.926, 95% CI: 1.268–2.927, P = 0.002). However, no Cox regression model in previous studies has adjusted for brain natriuretic peptide or NT-proBNP levels, usually considered to be the most powerful prognostic factors in patients with heart failure.[11] Our finding that low T3 syndrome is indicative of a poor prognosis is consistent with those of previous studies exploring the effects of free T3 levels. Associations of low T3 syndrome with all-cause mortality were generally homogeneous across multiple clinically relevant subgroups, including patients divided by age, sex, ischemic heart failure, hypertension, diabetes, chronic kidney disease status, LVEF, NT-proBNP level, anemia and hyponatremia status, NYHA functional class, and hypoalbuminemia status. The differences between our study findings and those of previous works are attributable to the way in which we assessed thyroid function, our definition of low T3 syndrome, and the confounders for which we adjusted in regression analyses. However, the evaluation of tissue thyroid hormone status by reference to blood data alone may be unreliable; how thyroid hormones act in target tissues such as the heart is not clear.

Our findings provide further evidence of a consistent, dose-dependent association between the free T3 level and mortality of patients with AHF. Low T3 syndrome improved risk prediction, especially for cardiovascular mortality, beyond traditional clinical risk factors in AHF.

The mechanism by which low T3 levels cause adverse clinical outcomes may include effects on cardiac contractility, pathological cardiac remodeling, and the development of peripheral vascular resistance.[4],[15] Thyroid hormones critically regulate cardiac contractility by upregulating the expression of genes encoding sodium/potassium-transporting ATPases, thereby increasing expression of the myosin heavy chain (MHC) α gene and decreasing that of the MHC β gene, resulting in faster contraction.[16],[17] Thyroid hormones also reduce cardiac fibrosis by downregulating the expression of collagen-encoding genes and inducing metalloproteinase expression; the hormones act in an inotropic manner to upregulate the expression of β1-adrenergic receptors and modulate the activities of ionic channels.[18],[19] Cardiac remodeling is a critical step during the progression of heart failure. Accumulating experimental evidence indicates that matrix metalloproteinases play important roles in the pathogenesis and progression of left ventricular dysfunction.[20] Thyroid hormones seem to significantly regulate metalloproteinase expression[21],[22] and to reduce peripheral arterial resistance by acting directly on vascular smooth muscle cells to lower the mean arterial pressure. When this reduction is sensed by the kidney, the renin–angiotensin–aldosterone system is activated to increase renal sodium absorption.[23]

Given the roles played by thyroid hormones in cardiovascular regulation, might such hormones be useful in the treatment of heart failure? Such treatment (possibly using hormonal analogs) poses certain challenges; the available data are limited. Morkin et al.[24] demonstrated that 3,5-diiodothyropropionic acid (a T4 analog) was tolerated well and improved cardiac performance. In patients with heart failure who received 4 weeks of therapy, the cardiac index and exercise capacity increased and the systemic vascular resistance index decreased. However, in a subsequent phase II multicenter randomized placebo-controlled study, the agent afforded no symptomatic benefit in patients with congestive heart failure.[25] In another randomized placebo-controlled study of patients with ischemic and nonischemic dilated cardiomyopathy, T3 replacement therapy significantly improved ventricular performance; the heart rate and NT-proBNP level decreased significantly.[26] However, none of the cited works[24],[25],[26] assessed mortality or hospital re-admission; the assumption that increases in the cardiac index and exercise capacity reflect a clinical benefit needs to be proven.

Limitations

Our study has certain limitations. First, it had a single-center observational design, and residual or unmeasured factors may have confounded the association between low T3 syndrome and mortality. Further research is warranted in the future to validate the association between low T3 syndrome and mortality in another cohort of patients with AHF. Second, thyroid hormone function was measured only once; we did not measure changes in T3 levels over time. Future studies should explore whether dynamic changes in the free T3 level correlate with adverse clinical outcomes.


  Conclusions Top


Low T3 syndrome is an independent prognostic factor predicting higher all-cause and cardiovascular mortality in patients with AHF. The free T3 level is linearly, and negatively, associated with such risk. Low T3 syndrome is a clinically significant risk stratification factor in patients with AHF.

Institutional review board statement

The study was approved by the Ethics Committee of the First Affiliated Hospital of Nanjing Medical University (number: 2011-SR-012, date: 02/14/2012).

Declaration of patient consent

The authors certify that they have obtained all appropriate consent from patients. In the forms, the patients have given their consent for their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity forms.

Financial support and sponsorship

The study was supported by the Twelve-Fifth National Key Technology R and D Program (2011BAI11B08).

Conflicts of interest

There are no conflicts of interest.



 
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    Figures

  [Figure 1], [Figure 2], [Figure 3]
 
 
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