American Journal of Cardiovascular Drugs

https://doi.org/10.1007/s40256-022-00548-3

SYSTEMATIC REVIEW

Effectiveness and Safety of Thyroid Hormone Therapy in Patients

with Dilated Cardiomyopathy: A Systematic Review and Meta‑analysis
of RCTs
Xiaoai Chen1,2,3 · Yun Bao3,4 · Chunxia Shi1,2,3 · Limin Tian2,3 

Accepted: 11 August 2022

© The Author(s), under exclusive licence to Springer Nature Switzerland AG 2022

Abstract
Background  Previous research demonstrated that short-term treatment of dilated cardiomyopathy with thyroid hormones
exerted beneficial hemodynamic effects when added to standard anti-heart failure therapy, but it remains debatable whether
thyroid hormones can be used to treat dilated cardiomyopathy. Therefore, we conducted a meta-analysis to evaluate the
effectiveness and safety of thyroid hormone treatment in patients with dilated cardiomyopathy.
Methods  The Cochrane Clinical Trials Registry database, PubMed, Embase, Chinese Biomedical Literature Database, China
Academic Journals full-text database, Wanfang Database, China Science and Technology Journal Database, and Clinical
Trials.gov were screened through 15 October, 2021. Randomized controlled clinical trials were selected based on study
inclusion criteria. Two independent reviewers extracted the data and assessed study bias using the Cochrane risk of bias tool.
For the data synthesis, the weighted mean difference was calculated using baseline and post-thyroid hormone treatment data.
Random-effects models were used for the meta-analysis. The primary outcomes were left ventricular ejection fraction after
a minimum follow-up of 1 week and adverse events.
Results  Ten of the 1149 published reports met the inclusion criteria (N = 608 randomized individuals). After reasonable use
of thyroid hormone therapy, left ventricular ejection fraction increased (weighted mean difference, 3.94; 95% confidence
interval 3.06–4.81; I2 = 0.00%), cardiac output increased, and left ventricular end-diastolic diameter decreased, but left
ventricular mass index and thyroid function were unaffected. Adverse events were reported in the intervention group of two
studies. The ten studies demonstrated a low risk of bias.
Conclusions  Adding thyroid hormones to conventional anti-heart failure treatment in patients with DCM appears to be an
effective and well tolerated therapeutic option.
Clinical Trial Registration  The protocol was registered in the International Prospective Register of Systematic Reviews
(PROSPERO) database (CRD42021286043).

Key Points 

The add-on use of thyroid hormones with conventional

Xiaoai Chen and Yun Bao contributed equally to this work. anti-heart failure drugs led to significant improvements
of heart structure and function in patients with dilated
* Limin Tian
tlm7066@sina.com cardiomyopathy (DCM) without thyroid diseases com-
pared with non-use of thyroid hormones.
1
School of Medicine, Jiangsu University, Zhenjiang, Jiangsu,
China Our systematic review supports the efficacy and safety
2 of thyroid hormones in patients with DCM and provides
Department of Endocrinology, Gansu Provincial Hospital,
Lanzhou, Gansu, China a basis for prospective evaluation of this therapy in the
3 treatment of DCM.
Clinical Research Center for Metabolic Diseases, Gansu,
China
4
Institute of Clinical Research and Evidence Based Medicine,
Gansu Provincial Hospital, Lanzhou, Gansu, China

Vol.:(0123456789)

1 Introduction
Dilated cardiomyopathy (DCM), the most common form
of cardiomyopathy, is characterized by structural and func-
tional myocardial alteration. Dysfunctional left ventricular
dilatation and contractility are typically observed in DCM
[1]. The prevalence of DCM ranges from 1/2500 to 1/250
people [2]. In most cases, DCM is progressive and can
lead to heart failure (HF) and arrhythmia, with a high rate
of sudden death and a 5-year fatality rate of 15–50% [3].
Survival rates without transplantation are low [4, 5].
The standard strategy for preventing and treating HF
is first-line therapy in patients with DCM as it ultimately
leads to systolic impairment [2]. However, first-line medi-
cations for HF can only control symptoms [6]. Therefore,
patients with DCM require more effective medications.
Zawadzka et al. reported that short-term oral levothyroxine
or intravenous liothyronine can improve hemodynamics in
patients with DCM by interpreting cardiac-related path-
ways. However, the long-term safety and efficacy of thy-
roid hormone (TH) therapy are unknown [1]. Despite sev-
eral clinical trials, no systematic review or meta-analysis
has estimated whether TH effectively treated patients with
DCM, and TH safety remains unknown. This systematic
review and meta-analysis aimed to synthesize the evidence
of the efficacy and safety of TH therapy in patients with
DCM.
2 Methods
This systematic review and meta-analysis followed the
Preferred Reporting Items for Systematic Reviews and
Meta-Analyses (PRISMA) statement [7] and was regis-
tered in the International Prospective Register of System-
atic Reviews (PROSPERO) database (CRD42021286043).
2.1 Data Sources and Study Selection
A systematic literature search was conducted of the
Cochrane Central Register of Controlled Trials, PubMed,
Embase, Chinese Biological Medical Literature, Chi-
nese National Knowledge Infrastructure, Wanfang, China
Science and Technology Journal Database, and Clinical
Trials.gov databases from inception to 15 October, 2021
without language restrictions. The search terms used were
“thyroid hormone” and “dilated cardiomyopathy”.
2.1.1 Inclusion Criteria
(1) Diagnosis of DCM [8];
X. Chen et al.
(2) Intervention group was treated with TH (triiodothyro-
nine, thyroxine, levothyroxine therapy, or any combina-
tion therein) with a minimum follow-up of 1 week plus
conventional anti-HF therapy [9];
(3) Control group received conventional anti-HF therapy
(or placebo);
(4) Study reported at least one primary (left ventricu-
lar ejection fraction [LVEF] and adverse events)
and secondary (left ventricular end-diastolic diam-
eter [LVEDD], left ventricular end-systolic diameter
[LVESD], left ventricular mass index [LVMI], cardiac
output [CO], triiodothyronine [T3], free T3 [FT3],
thyroxine [T4], free T4 [FT4], and thyroid-stimulating
hormone [TSH]) outcomes; and
(5) Randomized controlled clinical trial design.
2.1.2 Exclusion Criteria
(1) Participants had a history of thyroid disease, had used
TH-interfering drugs in the previous 2 weeks, or had
received cardiac resynchronization therapy;
(2) Studies in which conventional anti-HF intervention
did not meet the prescribed standards of anti-HF treat-
ment were excluded. Studies that added other drugs
(alpha-blockers) to the standard HF treatment were also
excluded;
(3) The study provided a result of interest but did not pro-
vide available data on mean differences and standard
deviations.
2.2 Data Extraction and Risk of Bias Assessment
The extracted information included eligibility criteria, infor-
mation about the study population (number, country, age, sex
ratio), study design, risk of bias, intervention drugs and pla-
cebos, follow-up time, and outcomes. The data were indepen-
dently extracted by two researchers (Xiaoai Chen, Chunxia
Shi). Discrepancies were resolved by a third researcher (Yun
Bao). If studies reported an outcome at multiple timepoints
during the intervention, only the most recent result was
used in the statistical analyses. The study’s risk of bias was
assessed using the Cochrane risk of bias tool.
2.3 Data Synthesis and Analysis
The weighted mean difference (WMD) and 95% confidence
interval (CI) were used to estimate the changes in cardiac
function (LVEF, LVEDD, LVESD, LVMI, and CO) in the
treatment of DCM. Estimates of changes in thyroid function
(T3, FT3, T4, FT4, and TSH) were translated into stand-
ardized mean differences (SMDs) when measured in dif-
ferent units. The data were pooled using a random-effects
Effectiveness and Safety of Thyroid Hormone Therapy in Patients with Dilated Cardiomyopathy
meta-analysis. Heterogeneity was assessed visually using
forest plots and quantified using I 2 (no: 0–25%; low:
25–50%; moderate: 50–75%; and high: 75–100%). The
subgroup analysis was performed by country and length of
intervention time. A sensitivity analysis was used to deter-
mine the individual impact of each study on the combined
results by omitting each study in turn. Publication bias was
assessed using Egger’s test. All statistical analyses were per-
formed using Stata/SE16.0. Two-sided values of p ≤ 0.05
were considered statistically significant.
3 Results
The flow diagram is shown in Fig. 1. A total of 1149 studies
were identified in a systematic literature search; of them, 258
were deleted because of duplication. Following the removal
of 868 publications after the title and abstract screening, 23
reports were subjected to full-text screening. Three studies
were excluded because they were observational. Four stud-
ies had no or unavailable data, and six failed to meet the
inclusion criteria.
A total of ten randomized controlled clinical trials [10–19]
with a total of 608 adults were included (Table 1). The partic-
ipants were recruited from China, Italy, and Egypt. Except for
one study [13], the mean age of the studies ranged from 37.1
to 66.5 years. The male-to-female sex ratio in seven studies
was 1.3:1 [10, 11, 14–17, 19]. The patients of five studies
Fig. 1  Flow diagram of the study selection process. ICM idiopathic
dilated cardiomyopathy
were diagnosed with idiopathic dilated cardiomyopathy by
echocardiogram and coronary angiography [11, 13, 16, 18,
19], but the type of cardiomyopathy was not mentioned in
the other five studies [10, 12, 14, 15, 17]. In five studies [10,
12, 17–19], the cardiac function classes of patients were New
York Heart Association II–IV and were not mentioned in
three studies [11, 13, 14]. All patients in the remaining two
studies [15, 16] had cardiac function classes of New York
Heart Association II and IV, respectively [15, 16]. Only one
study showed that enrolled patients had arrhythmias [12], and
the remaining studies except for two studies that excluded
complex arrhythmias were not presented [16, 18]. Six stud-
ies [12, 13, 15, 17–19] showed patients’ exercise capacity, of
which three showed an increase in walking distance after TH
treatment through a 6-minute walk test [13, 15, 17], and two
showed cardiopulmonary exercise in patients after TH treat-
ment using specific cardiopulmonary exercise test values [18,
19]. Only one study showed no change in exercise capacity
after TH treatment [12]. All cardiac function indicators were
measured by a conventional echocardiogram. The baseline
LVEF ranged from 22.5 to 34.9%. The baseline LVEDD val-
ues ranged from 64 to 76.82 mm. The baseline mean value
of TSH ranged from 1.1 to 6.05 MIU/L [10–15, 17–19]. The
baseline mean value of FT3, FT4, T3, and T4 ranged from
1.87 to 4.44 pmol/L, from 8.03 to 18.91 pmol/L, from 0.95
to 1.82 nmol/L, and from 72.16 to 126.56 nmol/L, respec-
tively. The intervention group received TH (T4 and TH) and
conventional anti-HF drugs. All patients received oral T4
except for one study in which the type of TH was unclear
[12]. The patients of one study received titration for 8 weeks
after 4 weeks of oral T4 [16]. The five studies [10, 11, 15–17]
had a dose range of 12.5–100 μg/day and all varied over time.
The remaining studies [12–14, 18, 19] were fixed-dose stud-
ies, with a maximum dose of 10 mg/day and a minimum
dose of 12.5 μg/day. Three of the control groups received
a placebo in addition to conventional anti-HF therapy [16,
18, 19], while the other seven groups received conventional
anti-HF therapy [10–15, 17]. Conventional anti-HF drugs
include angiotensin-converting enzyme inhibitors, diuretics,
β-blockers, nitrates, digitalis, and warfarin in patients with
DCM [10–19]. Some patients received non-digitalis cardiac
drugs (dopamine and dobutamine). The intervention time and
follow-up time varied from 1 week to 2 years. There were
two studies [15, 17] of long-term treatment (> 12 weeks)
and eight studies [10–14, 16, 18, 19] of short-term treatment
(≤ 12 weeks).
3.1 Quality Assessment
The ten included studies were generally of good quality;
three of them had a low risk of bias for all criteria, while six
studies (including the largest) had an unclear risk of bias
in three of seven domains [10–12]. Only one study had a


Table 1.  Characteristics of the included randomized controlled clinical trials

Study Country Type of DCM Cardiac Number of Age, Male-to- Intervention Control Intervention time Follow-up ­timeb of Outcomesc
function participants mean ± SD female measured data
­classa ratio

Moruzzi Italy Idiopathic II, III 20 53 ± 8 11/9 Levothy- Placebo 1 week 1 week LVEDD,
et al., 1994 dilated car- roxine LVEF,
[19] diomyopathy (100 μg/ LVMI, TSH,
day, T3, T4
1 week)
Moruzzi Italy Idiopathic II, III, IV 20 66 ± 4.75 N/A Levothy- Placebo 1 week 2 weeks CO, LVEDD,
et al., 1996 dilated car- roxine LVMI,
[18] diomyopathy (100 μg/ LVEF, TSH,
day, T3, T4
1 week)
Zhang et al., China N/A II, III, IV 27 42.4 ± 11.25 N/A Thyroid Metoprolol 2 weeks 6 weeks LVEF, TSH,
1997 [12] hormone T3, T4
(10 mg/day,
2 weeks)
Fu et al., China N/A N/A 19 48.6 ± 12.7 13/6 L-T4 CWM 4 weeks 4 weeks CO, LVEF, LV
2000 [14] (100 μg/
day,
4 weeks)
Li et al., 2008 China Idiopathic N/A 52 37.1 ± 9.9 38/14 Levothyrox- CWM 8 weeks 8 weeks LVEF, LVD,
[11] dilated car- ine (12.5– TSH, FT3,
diomyopathy 25 μg/day, FT4
8 weeks)
Cheng et al., China N/A IV 142 66.5 ± 16.0 70/72 Euthyrox® CWM 165 ± 14/163 ± 17 days 165 ± 14/163 ± 17 days CO, LVEF,
2009 [15] (L-T50) LVDS,
(25– LVDD, TSH,
100 μg/day, T3, T4
> 120 days)
Wu et al., China N/A II, III, IV 62 56 ± 15.3 30/32 Euthyrox® CWM 4 weeks 4 weeks LVEF, LVDD,
2010 [10] (L-T50) LVDS, TSH,
(25–50 μg/ FT3, FT4
day,
4 weeks)
Gao et al., China Idiopathic N/A 110 N/A N/A Euthyrox® CWM 12 weeks 12 weeks LV, LVEF,
2011 [13] dilated car- (L-T4) TSH, FT3,
diomyopathy (12.5 μg/ FT4
day,
12 weeks)
X. Chen et al.
 Effectiveness and Safety of Thyroid Hormone Therapy in Patients with Dilated Cardiomyopathy

high risk of bias in two of seven domains [13]. The detailed

CO cardiac output, CWM conventional Western medicine, DCM dilated cardiomyopathy, E/A Peak E peak of rapid filling in early left ventricular diastole, Peak A filling peak of late diastolic

EDD end-diastolic dimension, ESD end-systolic dimension, Euthyrox® levothyroxine (L-thyroxine) sodium and the main component is T4, LV left ventricular diameter, LVEDD left ventricular
(atrial contraction) filling (E/A ratio is often used to measure the spectrum of mitral orifice flow velocity in clinical practice and can be used to evaluate the diastolic function of the ventricle),
T3, FT3, T4,

ESD, LVMI,
LVEF, TSH,

LVEF, EDD,
E/A, LVDD,
results are summarized in eFig. 1 in the Electronic Supple-

TSH, FT3,
Outcomesc
mentary Material (ESM).

FT4

FT4
3.2 Cardiac Function

end-diastolic diameter, LVEF left ventricular ejection fraction, LVM left ventricular mass, LVMI left ventricular mass index, N/A, SD standard deviation, TH thyroid hormone
For LVEF (ten studies; 608 participants), the WMD was
Follow-up ­timeb of

3.94 (95% CI 3.06–4.81; I2 = 0.00%) (Fig. 2). For LVEDD

measured data

12 weeks (nine studies; 581 participants), the WMD was − 3.35 (95%
CI − 4.02 to − 2.67; I2 = 0.00%) (Fig. 3). For LVESD (three
2 years

studies; 264 participants), the WMD was − 3.49 (95% CI

− 8.44 to 1.47; I2 = 91.35%). For CO (two studies; 161 par-
ticipants), the WMD was 0.37 (95% CI 0.19–0.55; I2 = 0.00).
For LVMI (three studies; 100 participants), the WMD was
Intervention time

− 16.15 (95% CI − 41.41 to 9.12; I2 = 0.00%) (Table 2).

12 weeks

3.3 Thyroid Function
2 years

For TSH (nine studies, 589 participants), the SMD was

− 0.14 (95% CI − 0.30 to 0.03; I2 = 0.00%). For FT3 (five
(sugar)

studies; 380 participants), the SMD was 1.21 (95% CI − 0.05

Placebo
Control

CWM

to 2.46; I2 = 96.64%). For T3 (five studies; 305 participants),

the SMD was 1.05 (95% CI − 0.39 to 2.49; I2 = 96.01%).
(25–50 μg/

(25–50 μg/

For FT4 (five studies; 380 participants), the SMD was 0.00
Intervention

l-Thyroxine

12 weeks)
2 years)

(95% CI − 0.20 to 0.21; I2 = 0.00%). For T4 (5 studies; 305

Levothy-
roxine

 Follow-up time refers to the time at which echocardiography and thyroid function were measured again
day,

day,

participants), the SMD was 0.20 (95% CI − 0.05 to 0.45;

I2 = 12.08%) (Table 2).
Male-to-
female

46/50

44/16
ratio

3.4 Adverse Events

There were no adverse events in seven studies [10, 14–19];

41.15 ± 3.5

41.8 ± 10.9
participants mean ± SD

one study [11]. Zhang et al. reported transient hypotension in

a patient treated with TH in addition to conventional anti-HF
 Cardiac function class assessed according to New York Heart Association
Number of Age,

therapy in the intervention group [12]. Gao et al. reported

a case of sudden cardiac death due to refractory HF in an
intervention group that was treated with TH in addition to
conventional anti-HF therapy [13]. No cases of drug-induced
96

60

 Included only outcomes relevant to this systematic review

hyperthyroidism or thyrotoxicosis occurred in nine studies,

while the tenth study did not specify this information [11].
function
Cardiac

III, IV
­classa

II

3.5 Subgroup Analysis by Country

diomyopathy
Country Type of DCM

dilated car-

As shown in Table 3, the WMD of LVEF in studies con-

Idiopathic

ducted in China was 4.03 (95% CI 2.74–5.32; I2 = 36.84%),

N/A

while that in other countries was 7.25 (95% CI 3.82–10.67;

I2 = 0.00%). This result was not statistically significant
China

Badran et al., Egypt

between the subgroups (p = 0.08). The SMD of FT3 in

Table 1.  (continued)

studies in China was 1.61 (95% CI 0.33–2.89; I2 = 95.93%),

while that in other countries was − 0.06 (95% CI − 0.59 to
Zhong et al.,
2015 [17]

2020 [16]

0.47). This result was significantly different between the

subgroups (p = 0.02), whereas the others were not (p > 0.05).
Study

b
a

c
 X. Chen et al.

Fig. 2  Effect of thyroid hor-

mone therapy on left ventricular
ejection fraction. CI confidence
interval, SD standard deviation,
WMD weighted mean difference

Fig. 3  Effect of thyroid hor-

mone therapy on left ventricular
end-diastolic diameter. CI
confidence interval, SD standard
deviation, WMD weighted mean
difference

3.6 Subgroup Analysis by Intervention Time

As shown in Fig. 4, the WMD of LVEDD in studies with

Table 2  Presentation of outcome indicators
an intervention time of less than 12 weeks was − 2.43
Indicator SMD/WMD 95% CI I2 (%) P-value (95% CI − 3.43 to − 1.42; I 2 = 0.00%) and more than
12 weeks − 4.32 (95% CI − 5.80 to − 2.84; I2 = 46.73%).
TSH − 0.14 − 0.30 to 0.03 0.00 0.28
This result was significantly different between the sub-
T3 1.05 − 0.39 to 2.49 96.01 0.15
groups (p = 0.04). However, the other outcomes were not
T4 0.2 − 0.05 to 0.45 12.08 0.11
statistically different between the subgroups (p > 0.05)
FT3 1.21 − 0.05 to 2.46 96.64 0.06
(Table 3).
FT4 0 − 0.20 to 0.21 0.00 0.96
LVEF 3.94 3.06 to 4.81 0.00 0.00
LVEDD –3.35 − 4.02 to − 2.67 0.00 0.00 3.7 Sensitivity Analysis and Publication Bias
LVESD − 3.49 − 8.44 to 1.47 91.35 0.17
CO 0.37 0.19 to 0.55 0.00 0.00 After excluding the Gao et al. study [13], the WMD of
LVMI − 16.15 − 41.41 to 9.12 0.00% 0.21 LVEF was 5.30 (95% CI 4.25–6.36; I2 = 0.00%). The sen-
sitivity analysis of the other outcomes did not change the
CI confidence interval, CO cardiac output, FT3 free T3, FT4 free T4,
LVEDD left ventricular end-diastolic diameter, LVEF left ventricular results (eTable 1 in the ESM). Publication bias for each
ejection fraction, LVESD left ventricular end-systolic diameter, LVMI outcome was evaluated using Egger’s test, and the results
left ventricular mass index, SMD standard mean difference, T3 trii- showed that each outcome measure had no publication
odothyronine, T4 thyroxine, TSH thyroid-stimulating hormone, WMD bias.
weighted mean difference
Effectiveness and Safety of Thyroid Hormone Therapy in Patients with Dilated Cardiomyopathy

Table 3  Subgroup analysis of all outcomes

TSH T3 T4 FT4 FT3 LVEF LVEDD
N; SMD (95% N; SMD (95% N; SMD (95% N; SMD (95% N; SMD (95% N; WMD (95% N; WMD (95%
CI) CI) CI) CI) CI) CI) CI)

Country
 China 6; − 0.10 3; 1.78 (− 0.24 3; 0.12 (− 0.12 4; − 0.13 4; 1.61 (0.33 to 7; 4.03 (2.74 to 6; − 3.11 (− 4.34
(− 0.27 to to 3.81) to 0.36) (− 0.10 to 2.89) 5.32) to − 1.88)
0.08) 0.36)
 Other coun- 3; − 0.35 2; − 0.07 2; 0.33 (− 0.26 1; − 0.05 1; − 0.06 3; 7.25 (3.82 to 3; − 4.64 (− 8.30
tries (− 0.75 to (− 0.77 to to 0.93) (− 0.58 to (− 0.59 to 10.67) to − 0.97)
0.05) 0.62) 0.48) 0.47)
 Group dif- 0.26 0.09 0.51 0.55 0.02 0.08 0.44
ference
(p-value)
Intervention length
 1–24 weeks
  ≤ 1 week 2; − 0.43 2; − 0.07 (0.77 2; 0.33 (− 0.26 N/A N/A 2; 5.35 (0.41 to 4; − 3.37 (− 4.73
(− 1.03 to to 0.62) to 0.93) 10.29) to − 2.00)
0.17)
  1–24 weeks 4; − 0.11 1; 0.74 (− 0.02 1; 0.18 (− 0.55 4; 0.04 (− 0.19 4; 0.99 (− 0.53 6; 4.62 (2.23 to 3; − 2.36 (− 5.59
(− 0.34 to to 1.50) to 0.92) to 0.28) to 2.52) 7.01) to 0.87)
0.11)
  > 24 weeks 2; 0.01 (− 0.25 2; 2.30 (− 0.73 2; 0.11 (− 0.14 1; − 0.11 1; 2.06 (1.57 to 2; 4.93 (3.56 to 2; − 4.32 (− 5.80
to 0.26) to 5.32) to 0.36) (− 0.51 to 2.55) 6.30) to − 2.84)
0.29)
  Group dif- 0.4 0.13 0.79 0.27 0.19 0.96 0.46
ference
(p-value)
 12 weeks
  ≤ 12 weeks 7; − 0.15 3; 0.22 (− 0.45 3; 0.45 (− 0.02 4; 0.04 (− 0.19 1; 2.06 (1.57 to 8; 3.26 (2.13 to 7; − 2.43 (− 3.43
(− 0.36 to to 0.88) to 0.92) to 0.28) 2.55) 4.39) to − 1.42)
0.06)
  > 12 weeks 2; 0.01 (− 0.25 2; 2.30 (− 0.73 2; 0.11 (− 0.14 1; − 0.11 4; 0.99 (− 0.53 2; 4.93 (3.56 to 2; − 4.32 (− 5.80
to 0.26) to 5.32) to 0.36) (− 0.51 to to 2.52) 6.30) to − 2.84)
0.29)
  Group dif- 0.34 0.19 0.21 0.51 0.19 0.07 0.04
ference
(p-value)

CI confidence interval, FT3 free T3, FT4 free T4, LVEDD left ventricular end-diastolic diameter, LVEF left ventricular ejection fraction, N/A,
SMD standard mean difference, T3 triiodothyronine, T4 thyroxine, TSH thyroid-stimulating hormone, WMD weighted mean difference

4 Discussion DCM. Current guideline recommendations for the treatment

In this systematic review and meta-analysis of the efficacy
and safety of TH therapy in patients with DCM without a
history of thyroid diseases, LVEF and CO were increased,
LVEDD was decreased, and LVMI did not change versus the
control group. The TSH, T4, and FT4 levels did not change
versus those in the control group. The systematic review and
meta-analysis demonstrated that the cardiac function and
cardiac structure were improved and thyroid function (TSH,
T4, FT4) was not influenced by treatment with TH based on
conventional anti-HF drug treatment.
To our knowledge, this is the first study to synthesize
evidence on the efficacy and safety of TH in patients with
of DCM are primarily based on the treatment of HF [9].
This systematic review and meta-analysis provided evidence
about TH therapy for DCM, which confirmed the effective-
ness of TH, and additionally reported the safety of TH. This
study demonstrated that TH may improve heart structure
and function in patients with DCM. The results of this meta-
analysis were similar to those of previous studies. Previ-
ous reviews demonstrated that the short-term treatment of
DCM with TH based on standard anti-HF therapy is associ-
ated with beneficial hemodynamic effects without relevant
adverse effects [1]. Other studies demonstrated that LVEF
increases and LVEDD decreases after low-dose TH ther-
apy in patients with DCM [20, 21]. This study also showed

Fig. 4  Subgroup analysis of
left ventricular end-diastolic
diameter by study intervention
time. CI confidence interval,
SD standard deviation, WMD
weighted mean difference
that TH treatment is safe for patients with DCM. Only two
adverse events in the ten included studies occurred in this
range of TH therapy. However, the safety of TH in patients
with DCM is closely related to intervention dose and dura-
tion. Some reports in humans, but not in animals, suggested
that excessive TH can lead to undesirable side effects [22].
Cardiac function and susceptibility to arrhythmias are influ-
enced by TH through long-term or rapid regulation of the
sarcolemma ion channels, C ­ a2+ circulating proteins, and
intercellular communication channels [23]. The safety of
TH in patients with DCM is closely related to intervention
dose and duration. The TH dosage was 12.5–10,000 μg/
day and the time range of intervention in this meta-analysis
was 1 week to 2 years. Only a few studies have attempted
to investigate the dose of TH in DCM [24], and concluded
that different doses have different effects and adverse events.
Therefore, the safe range of dosage and intervention duration
should be verified in future studies.
The standard strategy for preventing and treating HF is
first-line therapy in patients with DCM, which is primarily
based on the treatment of HF. Our results show that add-
ing TH to conventional anti-HF treatment is an effective
tolerated therapeutic option without adverse effects. We
noticed that the increase of LVEF was the least in the Gao
et al. study [13]. It was also the group with the lowest TH
dose of any study. We performed a sensitivity analysis after
omitting this study, which led to an increase in LVEF. This
may indicate that LVEF increases more significantly when
the TH maintenance dose is greater than 12.5 μg/day in the
treatment of DCM. For LVEDD, there was a statistically
significant difference between subgroups with different
intervention times (≤ 12 weeks and > 12 weeks). This may
indicate that different intervention times could influence
TH treatment and the LVEDD decreases more significantly
X. Chen et al.
when the intervention time is greater than 12 weeks in the
treatment of DCM [13].
This study has five limitations. First, the limited number
of included studies and patients made it impossible to further
analyze the high heterogeneity of some outcome indicators
(LVESD, T3, and FT3). Second, conventional anti-HF drugs
were administered in a range. Some studies did not specify
which drug was used. In one study [12], only one traditional
HF drug, metoprolol, was used. Therefore, it is possible that
other drugs may have also contributed to the results of this
meta-analysis. Third, the intervention time and dosage range
in this meta-analysis varied across the studies, and only two
studies focused on long-term intervention times. Although
dose-dependent effects of TH may exist, we were not able
to explore this effect because the dosage was not specific.
In addition, some studies explored the length of the follow-
up, and concluded that TH has greater influence on cardiac
structure after a longer follow-up time [13]. However, the
length of the intervention and follow-up were basically the
same in this study. Thus, it is difficult to explore and prove.
Fourth, some studies reported that the FT3/FT4 ratio in
patients with DCM is significantly associated with LVEF
and other indicators [25]. Thyroid hormones are likely to
change cardiac function by altering the FT3/FT4 values and
this ratio may be a new indicator to ensure the safety of TH
use by adjusting the dose and intervention time. We were not
able to prove it because of no effective FT3/FT4 data in ten
studies. It should be verified in future studies. Fifth, the type
of cardiomyopathy, function status, and exercise capacity of
the patients, which were only reported in some studies, may
also influence the treatment effects.
Effectiveness and Safety of Thyroid Hormone Therapy in Patients with Dilated Cardiomyopathy
5 Conclusions
Among patients with DCM but no history of thyroid dis-
eases, adding TH to conventional anti-HF treatment is an
effective tolerated therapeutic option without adverse effects.
Supplementary Information  The online version contains supplemen-
tary material available at https://d​ oi.o​ rg/1​ 0.1​ 007/s​ 40256-0​ 22-0​ 0548-3.
Declarations  8. Echocardiography Group CSoUM, Echocardiography Committee
Funding  This work was supported by grant from the National Natural
Science Foundation of China (No. 82060152), and Gansu Province Sci-
ence and Technique Special Program, Clinical Research Center for
Metabolic Diseases, Gansu (No. 18JR2FA006).
Conflict of interest  Xiaoai Chen, Yun Bao, Chunxia Shi, and Limin
Tian declare that they have no known competing financial interests or
personal relationships that could have appeared to influence the work
reported in this paper.
Ethics approval  Not applicable.
Consent to participate  Not applicable.
Consent for publication  Not applicable.
Data availability  All data generated or analyzed during this study are
included in this published article (and its supplementary information
files).
Code availability  Not applicable.
Author contributions  XC had full access to all of the data in the study
and takes responsibility for the integrity of the data and the accuracy of
the data analysis. Concept and design: XC, LT. Acquisition, analysis, or
interpretation of data: XC, CS. Drafting of the manuscript: XC. Critical
revision of the manuscript for important intellectual content: XC, YB.
Statistical analysis: XC. Obtained funding: LT. Administrative, techni-
cal, or material support: LT, YB. Supervision: LT, YB.
References
1. Zawadzka K, Dziedzic R, Surdacki A, Chyrchel B. Thyroid hor-
mones: an underestimated player in dilated cardiomyopathy? J
Clin Med. 2021;10(16):3618. https://​doi.​org/​10.​3390/​jcm10​
163618.
2. Schultheiss H-P, Fairweather D, Caforio AL, Escher F, Her-
shberger RE, Lipshultz SE, et al. Dilated cardiomyopathy. Nat
Rev Dis Primers. 2019;5(1):1–19. https:// ​ d oi. ​ o rg/ ​ 1 0. ​ 1 038/​
s41572-​019-​0084-1.
3. Hershberger RE, Hedges DJ, Morales A. Dilated cardiomyopathy:
the complexity of a diverse genetic architecture. Nat Rev Cardiol.
2013;10(9):531–47. https://​doi.​org/​10.​1038/​nrcar​dio.​2013.​105.
4. Mahmaljy H, Yelamanchili VS, Singhal M. Dilated Cardiomyo-
pathy. [Updated 2021 Aug 11]. In: StatPearls [Internet]. Treasure
Island (FL): StatPearls Publishing; 2022 Jan-. Available from:
https://​www.​ncbi.​nlm.​nih.​gov/​books/​NBK44​1911/
5. Komajda M, Jais J, Reeves F, Goldfarb B, Bouhour J, Juillieres Y,
et al. Factors predicting mortality in idiopathic dilated cardiomyo-
pathy. Eur Heart J. 1990;11(9):824–31. https://​doi.​org/​10.​1093/​
oxfor​djour​nals.​eurhe​artj.​a0598​03.
6. UK NA-A, Atherton JJ, Bauersachs J, UK AJC, Carerj S, Ceconi
C, et al. 2016 ESC guidelines for the diagnosis and treatment of
acute and chronic heart failure. Eur Heart J. 2016;37:2129–200.
https://​doi.​org/​10.​1093/​eurhe​artj/​ehw128.
7. Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann
TC, Mulrow CD, et  al. The PRISMA 2020 statement: an
updated guideline for reporting systematic reviews. Syst Rev.
2021;10(1):1–11. https://​doi.​org/​10.​1186/​s13643-​021-​01626-4.
BoCM, Chinese Medical Doctor Association. Clinical guidelines
for echocardiography in the diagnosis of cardiomyopathy. Chin
J Ultrasound Imaging. 2020;29(10):17. https://​doi.​org/​10.​3389/​
fmicb.​2015.​00927
9. Cardiology CSo, Disease EBoCJoC, Cardiomyopathy CwgodaTo.
Diagnosis and Treatment of Cardiomyopathy. Chin J Cardio-
vasc Dis. 2007;1:5–16. https://​doi.​org/​10.​1016/​S1473-​3099(13)​
70318-9.
10. Dichun W. Effect of low dose levothyroxine on heart failure in
dilated cardiomyopathy. Chin J Misdiagn. 2010;10(06):1309–10.
11. Feng L, Yong W, Yumin Z. Effects of levothyroxine on cardiac
function and cytokines in patients with dilated cardiomyopathy
with severe heart failure. J Hunan Normal Univ. 2008;3:23–5.
https://​doi.​org/​10.​3969/j.​issn.​1673-​016X.​2008.​03.​008.
12. Guisheng Z, Deshan J, Chunhua W, Xiuli L, Weixia G, Liran W,
et al. Metoprolol combined with low dose thyroid hormone in
the treatment of heart failure in dilated cardiomyopathy. Beijing
Military Area Med. 1997;03:165–7.
13. Hongmei G, Dalong X, Julong T, Jianjun L, Juan Z, Changming Q,
et al. Effect of low dose levothyroxine on dilated cardiomyopathy
with normal thyroid syndrome. Sichuan Med. 2011;32(07):1078–
80. https://​doi.​org/​10.​16252/j.​cnki.​issn1​004-​0501-​2011.​07.​015.
14. Lu F, Jinxia W, Jingxia S, Nan W. A preliminary study of thyroid
hormone therapy for heart failure in dilated cardiomyopathy. J
Clin Cardiovas Dis. 2000;03:100–2. https://d​ oi.o​ rg/1​ 0.3​ 969/j.i​ ssn.​
1001-​1439.​2000.​03.​002.
15. Xufeng C, Xuebin L. Application of thyroxine in heart failure in
dilated cardiomyopathy. Modern Pract Med. 2009;21(02):134–5.
https://​doi.​org/​10.​3969/j.​issn.​1671-​0800.​2009.​02.​024.
16. Badran HM, Faheem N, Zidan A, Yacoub MH, Soltan G. Effect
of short-term l-thyroxine therapy on left ventricular mechanics
in idiopathic dilated cardiomyopathy. J Am Soc Echocardiogr.
2020;33(10):1234–44. https://​doi.​org/​10.​1016/j.​echo.​2020.​05.​
009.
17. Zhiying Z, Zhanqing M, Tugang C, Weiling T, Weiguo S, Yuxin
Z, et al. Clinical effect of long-term treatment of dilated cardio-
myopathy heart failure with low T3 syndrome with levothyroxine.
J Clin Rational Drug Use. 2015;8(13):32–3. https://​doi.​org/​10.​
15887/j.​cnki.​13-​1389/r.​2015.​13.​023.
18. Moruzzi P, Doria E, Agostoni PG. Medium-term effectiveness of
l-thyroxine treatment in idiopathic dilated cardiomyopathy. Am J
Med. 1996;101(5):461–7. https://d​ oi.o​ rg/1​ 0.1​ 016/S
​ 0002-9​ 343(96)​
00281-1.
19. Moruzzi P, Doria E, Agostoni PG, Capacchione V, Sganzerla
P. Usefulness of l-thyroxine to improve cardiac and exercise
performance in idiopathic dilated cardiomyopathy. Am J Car-
diol. 1994;73(5):374–8. https://​doi.​org/​10.​1016/​0002-​9149(94)​
90011-6.
20. Luhua H. Effect of low dose thyroxine on heart failure in dilated
cardiomyopathy. Jiangxi Med. 2014;49(7):602. https://d​ oi.o​ rg/1​ 0.​
3969/j.​issn.​1006-​2238.​2014.​07.​018.

21. Lizhi W, Xiangquan K, Yingli W, Xiaohua W, Yun Z, Qing-
hua Z, et al. Clinical study on long-term treatment of conges-
tive heart failure with low-dose thyroxine. Clin Med China.
2003;19(11):987–8. https://d​ oi.o​ rg/1​ 0.3​ 760/c​ ma.j.i​ ssn.1​ 008-6​ 315.​
2003.​11.​015.
22. Kuzman JA, Thomas TA, Vogelsang KA, Said S, Ander-
son BE, Gerdes AM. Effects of induced hyperthyroidism
in normal and cardiomyopathic hamsters. J Appl Physiol.
2005;99(4):1428–33.
23. Tribulova N, Knezl V, Shainberg A, Seki S, Soukup T. Thyroid
hormones and cardiac arrhythmias. Vasc Pharmacol. 2010;52(3–
4):102–12. https://​doi.​org/​10.​1016/j.​vph.​2009.​10.​001.
24. Shengyou M, Erzhou H, Qisheng Y, Yangchun L. Clinical effect
of different doses of thyroid hormone on heart failure in dilated
X. Chen et al.
cardiomyopathy. Guangxi Med. 2002;10:1551–2. https://​doi.​org/​
10.​3969/j.​issn.​0253-​4304.​2002.​10.​015.
25. Kozdag G, Ural D, Vural A, et al. Relation between free trii-
odothyronine/free thyroxine ratio, echocardiographic parameters
and mortality in dilated cardiomyopathy. Eur J Heart Fail. 2005.
https://​doi.​org/​10.​1016/j.​ejhea​rt.​2004.​04.​016.
Springer Nature or its licensor holds exclusive rights to this article under
a publishing agreement with the author(s) or other rightsholder(s);
author self-archiving of the accepted manuscript version of this article
is solely governed by the terms of such publishing agreement and
applicable law.