Subclinical hypothyroidism: a new risk factor for prediction of heart failure with improved ejection fraction

doi:10.21203/rs.3.rs-4904289/v1

BACKGROUND

Heart failure (HF) with improved ejection fraction (HFimpEF) has gradually attracted widespread attention in recent years for its better clinical prognosis. In this study, we attempted to investigate the relationship between subclinical hypothyroidism (SCH) and HFimpEF.

METHODS

This study retrospectively collected clinical data on patients with HF with reduced ejection fraction (HFrEF) hospitalized at the First Affiliated Hospital of USTC from March 2015 to September 2023, and divided into two groups as euthyroidism or SCH according to the baseline thyroid function. Then patients were further categorized into HFimpEF (follow-up LVEF > 40% and absolute increase ≥ 10%) and persistent HFrEF based on their LVEF on the echocardiograms during the follow-up period. Afterwards, logistic regression was used to estimate the effect of SCH on HFimpEF.

RESULTS

A total of 916 patients with HFrEF met the inclusion and exclusion criteria, and 396 patients (43.2%) progressed to HFimpEF status during the follow-up period. Compared with HFrEF patients, the prevalence of SCH is lower in HFimpEF patients (9.3% vs. 14.4%, P = 0.020). Univariate logistic regression analysis indicates that SCH was a potential risk factor for HFimpEF (OR: 0.612 [95% CI 0.403–0.928], P = 0.021). After adjusting for multiple factors in logistic regression, the odds ratios of HFrEF patients with SCH progressing to HFimpEF decreased by 37.8% (OR: 0.622 [95%CI 0.397–0.974], P = 0.038) compared with patients with euthyroidism.

CONCLUSIONS

This study demonstrated that thyroid function affects the improvement of cardiac function in patients with HFrEF and SCH is an independent risk factor for HFimpEF.

HFimpEF

HFrEF

Subclinical hypothyroidism

Thyroid function

Currently, heart failure (HF) affects more than 64 million people worldwide, the prevalence is expected to increase by 34% in the next few decades[1–2]. Approximately 40% of HF is HF with reduced ejection fraction (HFrEF) in China, which is often associated with progressive ventricular remodeling and dilatation that underlie adverse cardiovascular outcomes [3]. With the rapid development of drug and device therapy for HF, approximately 20%-50% of HFrEF patients can significantly improve their left ventricular ejection fraction (LVEF) [4], those with a baseline LVEF ≤ 40%, a ≥ 10 point increase from baseline LVEF, and a second measurement of LVEF > 40% are defined as HF with improved ejection fraction (HFimpEF) [5].Studies have shown significant reductions in HF readmission rates, cardiovascular mortality and all-cause mortality in patients with HFimpEF [6]. Consequently, identifying the factors that influence the improvement of LVEF at an early stage is of significant clinical importance for improving the prognosis of HFrEF patients.

Thyroid hormones play an important role in the regulation of the cardiovascular system, and the most common type of thyroid dysfunction is subclinical hypothyroidism (SCH), with an estimated prevalence of 3%- 15% in the general population [7]. Previous studies have shown that SCH can result in left ventricular dysfunction, atherosclerosis, and is significantly associated with the occurrence and progression of HF [8–9]. However, there is a lack of clinical evidence regarding the impact of SCH on the improvement of LVEF among HFrEF patients. This study aims to evaluate the impact of SCH on HFimpEF by retrospectively analyzing the baseline characteristics, thyroid function, and LVEF outcomes of patients with HFrEF.

Study Population

This is a single-center, retrospective study, and the study population selected from patients with HFrEF who were first hospitalized for HF at the First Affiliated Hospital of USTC from March 2015 to September 2023, then the follow-up echocardiographic parameters were collected until March 2024. The inclusion criteria were as follows: 1) age ≥ 18 years; 2) HF diagnostic criteria in accordance with “Chinese guidelines for the diagnosis and treatment of heart failure 2024” [10], baseline LVEF ≤ 40%, N-terminal pro-B-type (NT-pro BNP) ≥ 300 pg/mL; 3) at least 2 comparable echocardiograms (If a patient undergone two more echocardiograms during the follow-up period, the highest LVEF value was included in the analysis). The exclusion criteria were as follows: 1) the interval between two echocardiograms < 3 months; 2) patients with missing or unclassifiable thyroid function data; 3) patients with hyperthyroidism, subclinical hyperthyroidism or hypothyroidism; 4) patients who have undergone thyroid surgery and received amiodarone or thyroid hormone treatment before. This study finally consisted of 916 patients with HFrEF, the flow chart is shown in Fig. 1. The study protocol was in accordance with the tenets of the Declaration of Helsinki and approved by the Hospital Ethics Committee (Approved No. of ethics committee: 2024-RE-268).

Clinical and Biochemical Assessments

By searching the medical record system of the First Affiliated Hospital of USTC, collected the patients' initial vital signs, medical history, medication and the results of the first laboratory measurements during hospitalization (including thyroid function, hemoglobin, serum creatinine, blood lipids and NT-pro BNP), features with missing data for < 10% of the patients were subjected to multiple imputation. BMI was calculated as weight/height² (kg/m²). The serum levels of thyroid hormones and TSH were measured using chemiluminescence, euthyroidism was defined as normal TSH (0.45–4.5 mIU/L), and subclinical hypothyroidism was defined as TSH > 4.5 and < 20 mIU/L with normal FT3 (2.1–5.4 pmol/L) and FT4 (9–25 pmol/L) [11].

Echocardiographic Examination

The echocardiographic parameters investigated included left atrial diameter (LAD), left ventricular end-diastolic diameter (LVEDD), LVESD, left ventricular end-systolic diameter (LVESD), systolic pulmonary artery pressure (SPAP) and LVEF. To assess the relationship between thyroid function and LVEF outcomes, the enrolled HFrEF patients were categorized into 2 groups based on the LVEF values obtained from echocardiography during the follow-up period: those with a baseline LVEF ≤ 40%, a second measurement of LVEF > 40% and 10% increase from baseline LVEF are defined as HFimpEF [5], then the remaining patients were classified as having persistent HFrEF.

Statistical Analysis

Continuous variables were presented as median (interquartile range) and were compared using the Mann-Whitney U test. Categorical variables were described as frequency and ratio and were compared using the chi-square test, and the Mann-Whitney U test was used for the comparison of ranked data (NYHA class). Univariable logistic regression analysis was performed to screen potential influencing factors for HFimpEF. Afterwards, multivariable logistic regression models were constructed to validate the independent effect of SCH on HFimpEF. In Model 1, age and gender were adjusted. In Model 2, additional adjustment for LVEF baseline, BMI, LAD, LVEDD, SPAP and NT-pro BNP; medical history and medication use. In Model 3, additional adjustment for coronary heart disease, PCI and diabetes, medication use of ARNI/ACEI/ARB, SGLT2 inhibitors. All analyses were performed using SPSS version 24.0 (IBM Corp., Armonk, NY, USA). A P-value < 0.05 was considered statistically significant.

Baseline Characteristics of the Study Population

A total of 916 patients with HFrEF with data on thyroid function and echocardiography during the follow-up period were included in this study, with a median age of 64 years and 629 patients (68.7%) were male. Of whom 357 patients (39.0%) had coronary heart disease, 313 patients (34.2%) had hypertension, and 177 patients (19.3%) had diabetes. Additionally, 677 individuals (73.9%) were treated with ARNI/ACEI/ARB drugs, 685 (74.8%) with beta-blockers, 146 (15.9%) with SGLT2 inhibitors, and 813 (88.8%) with Antisterone.

Patients were classified into the euthyroid group with 804 cases (87.8%) and the SCH group with 112 cases (12.2%) according to their thyroid function. The baseline characteristics of the two groups are shown in Table 1, compared with those with euthyroidism, patients in the SCH group had a higher proportion of women (P=0.01), higher NT-pro BNP values (P=0.046), and higher SPAP (P=0.003), a lower median LVEF (P=0.033) during follow-up, and a lower proportion of patients on ARNI/ACEI/ARB analogs (P=0.044). No significant differences were observed in baseline LVEF values, other clinical characteristics, or medication treatment status (Table 1).

Table 1. Main baseline characteristics of patients according to thyroid functional status

Variables	Euthyroidism (N =804)	SCH (N =112)	P value
Age (years)	64 (52, 71)	63 (53, 72)	0.546
Females n, (%)	240 (29.9)	47 (42.0)	0.010
BMI (kg/m²)	24.03 (21.61, 26.73)	23.84 (21.61, 26.50)	0.781
Heart rate (beats/min)	81 (71, 96)	80 (68, 90)	0.134
SBP (mmHg)	121 (109, 134)	120 (110, 134)	0.669
DBP (mmHg)	78 (69, 87)	78 (69, 86)	0.668
*NYHA class*
NYHA class III n, (%)	464 (57.7)	63 (56.3)	0.711
NYHA class IV n, (%)	265 (33.0)	39 (34.8)	0.711
Baseline EF (%)	31 (27, 36)	31 (25, 37)	0.833
Change in EF (%)	10 (3, 20)	8 (3, 18)	0.054
EF MAX (%)	42 (33, 52)	40 (28, 50)	0.033
HFimpEF n, (%)	359 (44.7)	37 (33.0)	0.020
LAD (mm)	48 (43, 53)	50 (44, 55)	0.136
LVEDD (mm)	69 (63, 76)	69 (61, 78)	0.506
LVESD (mm)	59 (53, 65)	58 (51, 68)	0.726
SPAP (mmHg)	43 (32, 54)	46 (37, 60)	0.003
*Medical history*
Coronary heart disease n, (%)	321 (39.9)	36 (32.1)	0.114
Hypertension n, (%)	277 (34.5)	36 (32.1)	0.629
Atrial fibrillation n, (%)	144 (17.9)	27 (24.1)	0.115
PCI n, (%)	55 (6.8)	10 (8.9)	0.420
Diabetes n, (%)	157 (19.5)	20 (17.9)	0.675
*Laboratory measurements*
NT-pro BNP (pg/mL)	2983 (1494, 5803)	3566 (1909, 6968)	0.046
Hemoglobin (g/L)	132 (122, 143)	130 (121, 142)	0.364
Serum creatinine (μmol/mL)	85 (71, 105)	92 (76, 105)	0.099
LDL cholesterol (mmol/L)	2.34 (1.81, 2.83)	2.13 (1.78, 2.86)	0.177
FT3 (pmol/L)	4.37 (3.90, 5.00)	4.26 (3.47, 4.61)	< 0.001
FT4 (pmol/L)	14.89 (12.97, 17.15)	14.22 (12.60, 16.68)	0.049
TSH (mIU/L)	1.99 (1.25, 2.81)	5.90 (5.18, 7.48)	< 0.001
*Medication*
ARNI /ACEI/ARB n, (%)	603 (75.0)	74 (66.1)	0.044
SGLT2 inhibitors n, (%)	126 (15.7)	20 (17.9)	0.554
Beta-blockers n, (%)	609 (75.7)	76 (67.9)	0.072
Antisterone n, (%)	715 (88.9)	98 (87.5)	0.653
Loop diuretic n, (%)	723 (89.9)	99 (88.4)	0.617

Abbreviations: SCH, subclinical hypothyroidism; BMI, body mass index; SBP, systolic blood pressure; DBP, diastolic blood pressure; NYHA, New York Heart Association; EF, ejection fraction; HFimpEF, heart failure with improved ejection fraction; LAD, left atrial diameter; LVEDD, left ventricular end-diastolic diameter; LVESD, left ventricular end-systolic diameter; SPAP, systolic pulmonary artery pressure; PCI, percutaneous coronary intervention; NT-pro BNP, N-terminal pro-B-type; LDL, low-density lipoprotein; FT3, free triiodothyronine; FT4, free thyroxine; TSH, thyroid-stimulating hormone; ARNI, angiotensin-receptor neprilysin inhibitors; ACEI, angiotensin-converting enzyme inhibitors; ARB, angiotensin receptor blockers; SGLT2, sodium-glucose cotransporter 2.

P-values were obtained by using the Mann-Whitney U test for continuous variables and the chi-square test for categorical variables.

Potential influencing factor of HFimpEF

By collecting the LVEF values during the follow-up period of the enrolled HFrEF patients, a total of 396 (43.2%) patients improved their LVEF to HFimpEF. In comparison with patients with persistent HFrEF, HFimpEF patients had slightly higher baseline LVEF values (P=0.005), with an improvement in median LVEF values from 32% to 54.0%, whereas the median LVEF only increased by 4% in patients with persistent HFrEF. Table S1 showed that compared with persistent HFrEF patients, HFimpEF patients had a lower prevalence of SCH (9.3% Vs. 14.4%, P=0.020), and were relatively younger (P=0.026) with higher heart rate (P=0.023) SBP (P＜0.001) and DBP (P= 0.006) (Table S1).

Univariable logistic regression analysis indicated that elevated LAD, LVEDD, LVESD and SPAP (P all< 0.001), serum creatinine (OR: 0.996, P=0.012), and NT-pro BNP (OR: 0.956, P=0.001) may served as potential risk factors for HFimpEF. In contrast, the use of SGLT2 inhibitors (OR: 1.478, P=0.031) were potential protective factors for HFimpEF (Table S2).

Association between SCH and HFimpEF

Univariable logistic regression analysis showed that SCH (OR: 0.612 [95% CI 0.403-0.928]) was negatively associated with the progress of HFimpEF (Table S1). After adjusting for age and gender (Model 1), baseline LVEF, BMI, laboratory measurements and echocardiographic parameters (Model 2), medical history and medication (Model 3), SCH was persistently associated with HFimpEF. As shown in Model 3, the probability of HFrEF patients with SCH progressing to HFimpEF decreased by 37.8% (OR: 0.622 [95%CI 0.397-0.974]) compared with patients with euthyroidism (Table 2). Subgroup analysis showed that there was no significant difference in the effect of SCH on HFimpEF among subgroups defined by gender, age, BMI and cardiovascular risk factors (Figure 2).

Table 2. Multivariate analysis for SCH and development of HFimpEF

Models	OR (95%CI)	P value
Model 1	0.600 (0.394- 0.915)	0.018
Model 2	0.616 (0.394- 0.962)	0.033
Model 3	0.622 (0.397- 0.974)	0.038

Model 1, adjustment for age and gender;

Model 2, additional adjustment for LVEF baseline, BMI, LAD, LVEDD, SPAP, NT-pro BNP;

Model 3, additional adjustment for coronary heart disease, PCI and diabetes, medication use of ARNI/ACEI/ARB, SGLT2 inhibitors;

Abbreviations: HFimpEF, heart failure with improved ejection fraction; SCH, subclinical hypothyroidism; BMI, body mass index; EF, ejection fraction; LAD, left atrial diameter; LVEDD, left ventricular end-diastolic diameter; SPAP, systolic pulmonary artery pressure; NT-pro BNP, N-terminal pro-B-type; PCI, percutaneous coronary intervention; ARNI, angiotensin-receptor neprilysin inhibitors; ACEI, angiotensin-converting enzyme inhibitors; ARB, angiotensin receptor blockers; SGLT2, sodium-glucose cotransporter 2.

The results of this study suggested that SCH is an independent risk factor for the development of HFimpEF. What' s more, the odds ratios of HFrEF patients with SCH progressing to HFimpEF decreased by 37.8% after further adjusting for multiple factors in logistic regression potential confounding factors. Subgroup analysis showed that there was no significant difference in the effect of SCH on HFimpEF among subgroups defined by gender, age, BMI and cardiovascular risk factors.

In recent years, there have been significant advancements in the treatment of HFrEF. Some patients may demonstrate an improvement in LVEF due to the pharmacological and device-based therapies, which may lead to improve clinical outcomes [12–13]. This study indicated that after a minimum interval of 3 months, 43.2% of HFrEF patients showed an improvement in their LVEF values. Bermejo et al. demonstrated that compared to HFrEF patients, HFimpEF patients had significantly reduced rates of all-cause mortality (HFrEF: HFimpEF HR = 2.22, 95% CI 1.189–4.186) and hospitalization (HFrEF: HFimpEF HR = 1.388, 95% CI 1.002–1.924) at the 1-year follow-up [14]. Even compared with HFpEF and HFmrEF patients, HFimpEF can still show better outcomes in adverse HF-related outcomes such as left ventricular assist device implantation, heart transplantation and all-cause mortality [15–16].

Given the favorable clinical prognosis, the clinical and biochemical factors associated with HFimpEF have received increasing attention in recent years. Available data suggested that younger age, female gender, non-ischemic cardiomyopathy, and fewer cardiac comorbidities may be protective factors for LVEF improvements [17–19]. Similarly, our univariate analysis showed that younger age, no history of PCI treatment, smaller cardiac structural changes and SPAP, lower NT-pro BNP and serum creatinine levels, and the use of SGLT2i inhibitors may be associated with improved LVEF, further exploration of HFimpEF-related influencing factors is beneficial for determining prognosis and adjusting treatment plans.

The relationship between metabolic disorders and improvement in LVEF has recently attracted increased attention these years. Ye et al. observed that higher BMI was associated with the recovery of LVEF among HFrEF patients (OR 1.75, [95% CI 1.12–2.72]) at the six-months follow-up [20]. In addition, Yang et al. demonstrated that in a 12-months follow-up, insulin resistance was negatively associated with LVEF recovery in patients without diabetes (OR 0.572, [95% CI 0.385–0.827]), they also observed that higher HbA1c levels were independently and negatively associated with HFimpEF in diabetic patients (HbA1c > 7.1% Vs. ≤6.2%: OR 0.48, [95% CI 0.28–0.81]) [21–22]. In this study, we investigated the effect of thyroid function on LVEF improvement and revealed that the rate of HFimpEF was lower among HFrEF patients with SCH, and the probability decreased by 37.8% after adjusting for multiple factors, moreover the prevalence of SCH was higher in patients with persistent HFrEF. All of the evidence above suggested an adverse effect of SCH on HFimpEF.

The association between SCH and HF has been widely documented, with several studies demonstrating a significant increase in the prevalence of HF, cardiac events and all-cause mortality in patients with SCH [23–24]. The underlying mechanism may be attributed to the impact of hypothyroidism on the structure and function of the heart, as well as cardiac load and lipid metabolism [25–26]. In this study, compared with patients with euthyroidism, patients with SCH had higher baseline values of SPAP and NT-pro BNP, which may be related to the poor improvement of LVEF.

Whether to initiate thyroid hormone replacement therapy in patients with SCH combined with HF remains controversial. Some studies have shown that thyroid hormone replacement therapy has no significant effect on cardiovascular outcomes [27–28]. However, a recent multicenter RCT study confirmed that after 24 weeks of treatment with low-dose levothyroxine (L-T4) in patients with SCH and HFrEF, both the 6-min walk test distance (P < 0.001) and the NYHA classification (P = 0.033) were significantly improved [29]. Combined with the confirmation of SCH as an independent risk factor for LVEF improvement in HFrEF patients in this study, suggesting that further studies are needed in the future to implement more precise and stratified management measures for HFrEF patients with SCH with the aim of further improving cardiac function.

To the best of our knowledge, this is the first study to demonstrate the association between SCH and HFimpEF. However, as a single-center, retrospective study, there are inherent limitations. Firstly, baseline information were missing in some patients, and secondly, the time to improvement of LVEF varied considerably among different patients, with a relatively long lag in follow-up. However, considering that this article aims to examine the relationship between SCH and HFimpEF, no specific time frame was set for HFimpEF. Thirdly, the patients' enrollment time span varies considerably, and with the updates of HF guidelines, the recommended medication regimens for patients have changed. Accordingly, we adjusted the use of HF-related medications in the multivariate analysis. Finally, only the baseline thyroid function was available for analysis, which may changed during the follow-up period.

In conclusion, this study reveals that SCH is an independent risk factor for the development of HFimpEF. Therapies targeted at improving SCH might provide favorable effects on patients with HFrEF.

Acknowledgements

None.

Author contributions

Chen K, Wang Q and Zhou H contributed to the study conception and design. Data collection was performed by Zhou H, Liu Z, Wu G, Zhou W and Yang D. Zhou H analyzed the data and wrote the first draft of the manuscript, Chen K and Wang Q revised the manuscript. All authors read and approved the final manuscript.

Funding

None.

Data availability

The data analyzed during the presented study are available upon reasonable request from the corresponding author.

Conflicts of interest

The authors have no conflicts of interest to disclose.

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onlinesupplementSCHandHFimpEF.docx

Subclinical hypothyroidism: a new risk factor for prediction of heart failure with improved ejection fraction

Status:

Version 1

Abstract

BACKGROUND

METHODS

RESULTS

CONCLUSIONS

Figures

INTRODUCTION

METHODS

Study Population

Clinical and Biochemical Assessments

Echocardiographic Examination

Statistical Analysis

RESULTS

DISCUSSION

CONCLUSIONS

Declarations

References

Supplementary Files

Status:

Version 1