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Short-term electrocardiographic and echocardiographic effects of levothyroxine replacement in adults with newly diagnosed hypothyroidism

 Department of Medicine, INHS Asvini, Mumbai, Maharashtra, India

Date of Submission14-Jun-2022
Date of Acceptance04-Jul-2022
Date of Web Publication13-Oct-2022

Correspondence Address:
Jnanaprakash B Karanth,
Shripad Hegde Kadave Institute of Medical Sciences, College Road, Uttara Kannada, Sirsi - 581 402, Karnataka
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jmms.jmms_95_22


Background and Aims: Thyroid hormones play a key role in modulating the cardiac function and structure. Expectedly, thyroid hormone deficiency in primary hypothyroidism has a profound and clinically relevant effect on the cardiac structure and function manifesting in characteristic electrocardiographic and echocardiographic (ECHO) abnormalities. The aim is to evaluate the effects of levothyroxine replacement therapy on the electrocardiographic (ECG) and ECHO changes in patients with primary hypothyroidism by assessing the changes in ECG and ECHO before and after 6 weeks of optimal levothyroxine (LT4) treatment in adults with newly diagnosed primary hypothyroidism. Methodology: Prospective, observational study conducted in the department of medicine in an armed forces tertiary care teaching hospital from October 2018 to April 2021. We studied newly diagnosed adults with primary hypothyroidism who were treated with optimal LT4 replacement. Descriptive statistics along with Student's t-test and Chi-square test were used to determine the statistical significance. Results: In 152 participants, the mean age was 41.0 ± 13.2 years and 79% were female. After 6 weeks of LT4 treatment, the proportion of participants with abnormal ECG findings reduced significantly (from 77% to 14.5%, P < 0.0001) with a significant reduction in those having sinus bradycardia (P < 0.0001) and low-voltage complexes (P < 0.0001). On ECHO, there was a significant improvement in left ventricular ejection fraction (P < 0.001), fractional shortening (P < 0.001), and a significant reduction in myocardial thickness parameters. The systolic and diastolic function improved significantly after 6 weeks of treatment. The proportion of patients without pericardial effusion increased from 34.9% to 79.6%. Conclusion: Replacement therapy with LT4 in newly diagnosed primary hypothyroid patients substantially improves cardiac structure, systolic and diastolic function and has a positive impact on underlying pericardial effusion. A large, prospective, trial is necessary to determine the long-term effects after thyroid hormone replacement.

Keywords: Diastolic dysfunction, ejection fraction, levothyroxine, pericardial effusion, Primary hypothyroidism, sinus bradycardia

How to cite this URL:
Vikram S, Mohanty S, Behera V, Ananthakrishnan R, Karanth JB, Mahadev N. Short-term electrocardiographic and echocardiographic effects of levothyroxine replacement in adults with newly diagnosed hypothyroidism. J Mar Med Soc [Epub ahead of print] [cited 2022 Dec 7]. Available from: https://www.marinemedicalsociety.in/preprintarticle.asp?id=358469

  Introduction Top

Hypothyroidism is a common endocrine disorder defined as clinical and biochemical manifestations of thyroid hormone deficiency. Virtually every organ system in the body is affected by hypothyroidism as thyroid hormone receptors are expressed on almost all cells and tissues in the body. The clinical spectrum of hypothyroidism ranges from an asymptomatic or subclinical state to an overt state of myxedema, end-organ effects, and multisystem failure.[1],[2] In the developed world, the prevalence of hypothyroidism varies from 4% to 15%.[3],[4],[5] In India, the reported prevalence is 11% with a female preponderance.[6] The link between thyroid dysfunction and CVS was established more than a century ago.[7] Hypothyroidism is a multisystem disorder that affects the cardiovascular system (CVS) as well.[8],[9] Hypothyroidism is associated with alterations in lipids, chronic low-grade inflammatory state, higher oxidative stress, and increased insulin resistance, all adding to the increased cardiovascular disease risk.[10],[11] Electrocardiographic (ECG) alterations in hypothyroidism include sinus bradycardia, prolongation of QTc, the reduced amplitude of P-wave, low-voltage complexes, and varying degrees of heart block.[12] Echocardiography (ECHO) can reveal the presence of pericardial effusion, wall motion abnormalities, and diastolic and systolic dysfunction.[13] With the progression of the disease to overt hypothyroidism (OH) and further, reduced ventricular filling and cardiac contractility lead to dilated cardiomyopathy with reduced cardiac output (CO).[14],[15] Compared to euthyroid individuals, all hypothyroid patients are at increased risk of CV events and mortality.[16] It is essential to diagnose CV dysfunction in hypothyroidism to improve morbidity and mortality. It has been observed that levothyroxine (LT4) supplementation has a positive impact on both myocardial structure and contractility improving cardiac function.[17] However, some reports identified no effect of LT4 treatment on systolic and diastolic heart function in older adults.[18] Therefore, we conducted this study to evaluate the ECG and ECHO changes after 6-week treatment with LT4 in newly diagnosed patients with primary hypothyroidism.

  Subjects and Methods Top

Design, setting, and ethics

This prospective, observational, study was conducted in the department of internal medicine of a tertiary care center in armed forces teaching college. The study was conducted as per the ethical principles of the Declaration of Helsinki, good clinical practices, and applicable local regulatory guidelines. The study was approved by the institute's ethical committee. Informed consent was obtained from all the participants before enrolment in the study.


We included participants aged 18 years or above visiting either the internal medicine or endocrine department of our hospital who were newly diagnosed with primary hypothyroidism including subclinical hypothyroidism (SCH) those required levothyroxine for the disease treatment. We excluded participants with secondary hypothyroidism, known cardiac disease, chronic obstructive pulmonary disease, severe anemia, and diabetes mellitus and those who were receiving medication that could alter thyroid function (e.g., beta-blockers, lithium, oral contraceptive pills, alcohol, and amiodarone).


We recorded the demographics and clinical symptoms in a structured case record form. All eligible participants underwent routine clinical and biochemical evaluation followed by thyroid profile, ECG, and ECHO recording. Each case was specifically screened for cardiovascular manifestations. Participants were screened for thyroid abnormalities based on clinical examination. To test for thyroid function, a 2 ml venous blood sample was collected in a sterile tube. Free T3 (FT3) and free T4 (FT4) were estimated using a specific radioimmunoassay (RIA) technique and thyroid-stimulating hormone (TSH) was estimated using a specific immunoradiometric assay technique in the central laboratory of our hospital using kits manufactured by Beckman Coulter, Czech Republic. The normal range of FT3, FT4, and TSH is 2.3–4.1 pg/dl, 0.9–1.7 ng/dl, and 0.4–4.5 mIU/ml, respectively. The coefficients of variation were 3.3% or less (intraassay) and 7% or less (interassay). Participants were categorized based on their thyroid hormones profiles as SCH if TSH was increased and T4 was normal whereas they were classified as OH if TSH was increased and T4 was low.

ECG was recorded using 12 leads standard ECG. At normal standardization, PR interval of >0.2 s was taken as prolonged; QRS complexes of <5 mm in limb leads and <10 mm in chest leads were taken as low-voltage complexes. Other changes in the QT segment and ST changes were also recorded. After ECG, an ECHO examination was performed. ECHO was done on Siemens Acuson SC2000 four-dimensional (4D) system. Cardiac 2D-Mode, M-mode, and Doppler examinations were performed. Left ventricular ejection fraction (LVEF) was measured using Teich formula in M-Mode and Simpsons formula. LV function was quantified as normal, mild dysfunction, moderate dysfunction, and severe LV dysfunction if LVEF was >50%, 41%–50%, 31%–40%, and <30%, respectively. Diastolic functions were measured as per standard guidelines. E/A, E/e', deceleration time (DT), and isovolumetric relaxation time (IVRT) were measured. Diastolic dysfunction was graded as mild (Grade 1) (E/A < 0.8, DT >200 msonds, E/e′ ≤8), moderate (Grade 2) (E/A 0.8–1.5, DT 160–200 msonds, E/e′ 9–12), and severe (Grade 3) (E/A ≥2, DT <160 msonds, E/e′ ≥13).

Pericardial effusion was considered mild, moderate, and large if the pericardial separation in diastole was 5–10 mm (fluid volume ~100–250 mL), 10–20 mm (fluid volume ~250–500 mL), and >20 mm (fluid volume >500 mL), respectively.

Outcome assessment

The primary outcome of our study was changes in the ECG and ECHO parameters after 6 weeks of LT therapy.

Statistical analysis

At 5% alpha level and 7.5% allowable error a sample size of 143 was calculated considering a 30% prevalence of cardiac dysfunction in hypothyroidism. With a 10% drop-out rate consideration, the final sample was estimated to be 160 patients. Out of these, 152 patients were followed till 6 weeks of starting LT4 therapy and therefore included in the analysis. The quantitative data were represented as their mean ± standard deviation categorical and nominal data were expressed in percentage. The t-test was used for analyzing quantitative data, or else nonparametric data were analyzed by Mann–Whitney test and categorical data were analyzed using the Chi-square test. The significance threshold of the P value was set at < 0.05. All analysis was carried out using IBM SPSS Statistics for Windows, Version 21.0. Armonk, NY: IBM Corp.


Baseline characteristics

The participant flow in the study is shown in [Figure 1]. A total of 180 new cases of primary hypothyroidism were screened for recruitment. Subsequently, 160 cases were selected for the study after exclusion based on the study criteria and taking informed consent. In excluded 20 cases, seven had diabetes mellitus, five had existing coronary artery disease, four had chronic obstructive pulmonary disease, and four denied consents for the study. Of 160 cases recruited, eight were lost to follow-up with no follow-up data on ECO and ECHO available. Thus, the data of 152 participants were included in the final analysis.
Figure 1: Study participant flow

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The demographic parameters of participants analyzed are shown in [Table 1]. The mean age was 41.0 ± 13.2 years with one-third being in the age group of 41–50 years. Female (79%) predominance was seen with a female-to-male ratio of 3.75:1. The clinical signs and symptoms of the patients at presentation and after 6 weeks of LT4 are depicted in [Table 2]. The most common presenting symptom was generalized weakness (86%) followed by facial puffiness (63%), decreased appetite (56%), hoarseness of voice (50%), skin changes (49%), cold intolerance (33%), limb swelling (31%), and weight gain (30.0%). At the end of 6 weeks of treatment, there was a significant reduction in the proportion of patients reporting all these symptoms (P < 0.0001 for all mentioned symptoms). The most common cardiovascular symptom was breathlessness (36%) followed by effort intolerance (13%), chest pain (6%), and palpitation (3%). After treatment, we observed a significant reduction in the proportion of patients experiencing breathlessness (P < 0.0001) and effort intolerance (P = 0.003). There was a significant increase in heart rate after 6 weeks of LT4 therapy, whereas systolic and diastolic BP reduced significantly.
Table 1: Age and gender distribution of the study participants

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Table 2: Clinical signs and symptoms at presentation and after 6 weeks of levothyroxine therapy

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The ECG findings at baseline and after 6 weeks of LT4 therapy in the study participants are depicted in [Table 3]. At baseline, 77% had abnormal ECG findings which reduced significantly to 14.5% after 6 weeks of LT4 therapy (P < 0.0001). The most common ECG findings were sinus bradycardia (37%) and low-voltage complexes (20%). Other ECG findings observed were T-wave inversion (10%), right bundle branch block (7%), and QTc prolongation (3%). The proportion of patients with these ECG abnormalities reduced with treatment and significant reduction was seen in sinus bradycardia (P < 0.0001), low-voltage complexes (P < 0.0001), and T-wave inversion (P = 0.0003).
Table 3: Electrocardiographic changes in the study participants at presentation and after 6 weeks of levothyroxine therapy

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The cardiac function and ECHO changes at baseline and after 6 weeks of LT4 therapy in the study participants are depicted in [Table 4]. After 6 weeks of LT4 therapy, the mean heart rate increased significantly whereas systolic and diastolic blood pressure reduced (P < 0.001 for all three parameters). There was a significant reduction in the interventricular septum thickness from 1.4 ± 0.14 mm to 1.2 ± 0.11 mm (P < 0.001) in diastole and from 1.8 ± 0.32 mm to 1.7 ± 0.31 mm (P = 0.006) in systole. Similarly, the left ventricle posterior wall thickness decreased significantly in both diastole (P = 0.003) and systole (P < 0.001). In the cardiac chamber dimensions, there was a nonsignificant reduction Left Atrium (LA), LV size in systole, and diastole. Significant improvements in the systolic functions such as LVEF (54.2 ± 5.6% to 57 ± 6.5%, P < 0.001) and fractional shortening (27.5 ± 2.4% to 29.6 ± 3.9%, P < 0.001) were also noted. Mean CO also increased significantly (3237.2 ± 69.8 ml/min to 3546.3 ± 75.6, P < 0.01). We observed improvement in systolic and diastolic dysfunction as well [Figure 2]. At baseline, 99 participants had pericardial effusion. It was trivial, mild, moderate, and large in 9.9%, 29.6%, 19.7%, and 5.9% participants, respectively. After treatment, the proportion of participants without pericardial effusion increased from 34.9% to 79.6% with a reduction in a substantial number of all severities of pericardial effusion [Figure 3].
Figure 2: Changes in the proportion of participants with systolic (a) and diastolic (b) dysfunction before and after 6 weeks of levothyroxine therapy

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Figure 3: Changes in the proportion of patients with various grades of pericardial effusion before and after levothyroxine therapy

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Table 4: Changes in cardiac function and echocardiographic changes in the study participants at presentation and after 6 weeks of levothyroxine therapy

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  Discussion Top

Thyroid hormone deficiency in hypothyroidism produces a profound impact on the cardiac structures, function, as well as cardiovascular hemodynamic. The foremost changes in cardiovascular dynamics include an increased peripheral vascular resistance and decreased CO. Increased vascular resistance results from impaired relaxation of the vascular smooth muscle and endothelial dysfunction. Decreased CO is a manifestation of reduced stroke volume and heart rate. Hypothyroidism is associated with bradycardia, weakened myocardial contraction and relaxation, reduction in systolic and diastolic function, an increased risk of coronary artery disease and cardiovascular mortality especially in those who have TSH levels >10 mIU/L.[19],[20] The characteristic electrocardiogram changes include bradycardia, conduction abnormalities, and nonspecific ST-T changes. The severity of these cardiac effects is directly proportional to the degree and duration of thyroid hormone deficiency. These cardiovascular dynamics respond positively to treatment with levothyroxine. It is essential to evaluate all newly diagnosed hypothyroid patients for CV abnormalities using non-invasive techniques such as ECG and ECHO.

In our study, we observed sinus bradycardia, low-voltage complexes, T-wave inversion, and QTc prolongation as the most common ECG findings in patients with primary hypothyroidism. We also observed significant improvement in sinus bradycardia and low-voltage complexes with LT4 treatment. Satpathy et al., have reported T-wave inversion (34%) and sinus bradycardia (23%) as the most common ECG findings in patients with hypothyroidism.[21] In a study from Korea, LT4 replacement therapy resulted in improvement of ECG abnormalities such as T-wave inversion, QTc prolongation, and QTc dispersion.[22] Other studies have also documented improvement in ECG abnormalities with thyroxine replacement.[23],[24]

On ECHO, we observed a significant improvement in cardiac systolic, and diastolic function as well as a reduction in myocardial thickness. In evaluating 3 months' treatment effects of LT4 in patients with idiopathic cardiomyopathy, Badran et al. reported significant improvements in functional status and ECHO parameters such as end-systolic and end-diastolic diameter, reduction in the severity of mitral regurgitation, and a significant increase in LVEF.[25] A randomized trial done by Monzani et al., observed that treatment with LT4 significantly reduced pre-ejection/ejection time ratio and cyclic variation index. However, these changes were not evident in the placebo group.[17] In patients with SCH, Yacizi et al. reported that after 1-year therapy, there was a significant reduction of myocardial performance index, IVRT and there was normalization of the E/A ratio. These changes were not evident in the placebo group.[26] The hypothyroid state is associated with depressed myocardial contractility. Improvement in fractional shortening was seen in our study. Multiple other studies also report improvements in FS with LT4 therapy.[17],[27] Thus, LT4 supplementation has a substantial effect on cardiac function and morphology. It is advised that appropriate adjusted LT4 maintenance therapy be instituted in patients with hypothyroidism for optimal cardiac function.[28]

Pericardial effusion in hypothyroidism has been reported in various reports.[29],[30] It occurs probably because of increased permeability of the epicardial vessels and reduced lymphatic drainage of albumin. As the fluid accumulation is slow, the disease remains asymptomatic.[31] We observed a substantial reduction in the number of patients with pericardial effusion after 6 weeks of treatment. Rawat and Styal reported reduction or disappearance of pericardial effusion alongside other ECHO changes after the initiation of thyroid hormone replacement. These findings suggest that hypothyroidism may be an underlying cause of the unexplained pericardial effusion. The changes in ECG and ECHO parameters were also accompanied by significant changes in baseline clinical symptoms. In cardiac symptoms, we observed a significant reduction in breathlessness and effort intolerance.


Our study has certain limitations. First, we did not assess the abnormalities in ECG and ECHO by TSH levels. Severe hypothyroidism may have more severe abnormalities. Second, we did not assess the LT4 effect on TSH levels and its correlation with the changes in cardiac structure and function. Third, the duration of the assessment was short. The long-term cardiac effects of thyroid replacement therapy remain unclear. Finally, we did not evaluate the impact on CV outcomes which would have highlighted the prognostic importance of LT4 therapy in reversing the cardiac remodeling.


We recommend that every newly diagnosed patient to be evaluated with ECG and ECHO examination to identify underlying cardiac structure and function abnormalities. There is a need to conduct a large-scale, prospective, randomized study to establish the role of screening with ECG and ECHO to prevent cardiac complications in hypothyroid patients.

  Conclusion Top

Cardiovascular effects of the thyroid hormones are quite dramatic, and the cardiac abnormalities associated with thyroid dysfunction have attracted a great deal of investigative effort. Alteration in thyroid status can lead to changes in both systolic and diastolic function of the left ventricle. Such changes may have clinical relevance when they affect target organs over several years. Our study has also substantiated the effects of thyroid hormones on cardiac structure and function. The hypothyroid state, which has a significant impact on cardiac structure/function, is reversible with thyroid hormone treatment. The treatment also impacts pericardial effusions effectively. The changes in the CVS are thus directly proportional to the returning of the euthyroid state, demonstrating the importance of early diagnosis and treatment of the disease.

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Conflicts of interest

There are no conflicts of interest.

  References Top

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  [Table 1], [Table 2], [Table 3], [Table 4]


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