Burden, Type, and Associated Factors of Thyroid Dysfunction in Patients with Heart Failure in Sub-Saharan Africa: A Cross-Sectional Study

Background: Various thyroid abnormalities have been reported during heart failure (HF). The present study aimed to evaluate the burden, type, and associated factors of thyroid disorders in Cameroonian patients with heart failure. Materials and Methods: We conducted a cross-sectional study from January to May 2020, involving volunteer adults followed for heart failure at the Yaoundé Central Hospital. Those receiving treatment that could cause thyroid dysfunction were excluded. Thyroid hormone levels (TSH, free T3, and free T4) were measured by enzyme-linked immunosorbent assay. Results: A total of 63 patients (30 women; 47.6%) were included. The median age was 65 (IQR: 56 - 70) years. The main etiology of heart failure was hypertension (52.4%) fraction (OR: 3.5, [95% CI: 1.2 - 9.9], p = 0.016). Also, patients with more than one hospital admission in the past 12 months were more likely to have hypothyroidism (OR: 5.3, [95% CI: 1.3 - 21.5], p = 0.013). Conclusion: The burden of thyroid dysfunction was high in this group of patients with HF. These were mainly low T3 syndrome and sub-clinical hypothyroidism. These were associated with heart failure with reduced ejection fraction and those with more than one hospitalization within the past 12-months.


Introduction
Thyroid hormones play an important role in the homeostasis of the cardiovascular system in health and disease [1]. They influence the heart rate, myocardial contractility, diastolic function, and peripheral vascular resistance [1]. The positive inotropic and chronotropic effect of thyroid hormones can result in high output heart failure in the case of hyperthyroidism, while hypothyroidism is associated with atherogenicity thereby increasing the risk of ischemic heart disease and heart failure [2] [3]. Many studies in Caucasians have shown high rates of low T3 Syndrome characterized by low blood levels of free triiodothyronine (FT3) with normal levels of free thyroxine (FT4) and Thyroid Stimulating Hormone (TSH) [4] [5] [6]. This syndrome, initially considered to be an adaptive phenomenon, has deleterious effects in patients with heart failure (HF). It contributes to the worsening of cardiac function and is a strong predictor of mortality [1] [3] [4] [7]. Besides the low T3 Syndrome, other thyroid dysfunctions such as hyperthyroidism (clinical and sub-clinical) and hypothyroidism (clinical and sub-clinical) have been described in patients with chronic HF and are associated with poor prognosis [6] [7]. Due to the high burden and prognostic impact of thyroid dysfunction in patients with HF, the American Heart Association recommends the systematic assay of TSH [8].
Data on the burden of thyroid dysfunction and associated factors in patients with chronic HF are scarce in sub-Saharan Africa. This study aimed at describing the burden, type, and associated factors of thyroid dysfunction in patients with chronic heart HF in Cameroon, central Africa.

Methods
Study design and setting: We carried out a cross-sectional study between January and May 2020 in the Cardiology Unit of the Yaounde Central Hospital (YCH) of Cameroon. The YCH is a tertiary health institution that serves as one of the University teaching hospitals. The YCH has a catchment population of over 2 million inhabitants.

Study participants
We included consenting patients of both sexes aged ≥ 21 years with an established diagnosis of chronic HF (clinical and echocardiography) by a Cardiologist. We excluded those with a previous diagnosis of thyroid dysfunction, and those on medications that can alter the thyroid function such as; synthetic anti-thyroid, thyroid hormone supplements, amiodarone, corticosteroids, and nonsteroidal anti-inflammatory medications.

Sample size
We used the Cochran formula to estimate the sample size [9]. With a 10% precision and an estimated prevalence of 17.5% [10]. The minimal sample size was 56 participants.

Data collection
Data were collected using pre-established questionnaires. The following variables were collected in a face-to-face interview and complete physical examination: age, sex, duration of HF, number of hospitalizations within the past 12 months, NYHA functional class, the actual treatment of HF, resting blood pressure (using standard procedure), weight and height (to calculate the body mass index). We then collected venous blood after strict asepsis from a peripheral vein for the assay of thyroid hormones. TSH was measured using the ELISA Sandwich method and FT3 and FT4 were measured using the ELISA competition method. We also studied the patients' medical records to collect ECG and Echocardiographic data, as well as the type (preserved versus reduced ejection fraction) and the etiologic diagnosis of HF.

Statistical analyses
Data were analyzed using Epi-Info version 7. Continuous variables are presented as medians (IQR) and discrete variables as proportions (95% confidence intervals). We calculated the Odds ratios (OR) to assess the association between clinical and heart failure variables with thyroid dysfunction (Hyperthyroidism and hypothyroidism). A p-value < 0.05 was considered statistically significant.

Characteristics of the study population
We approached 96 patients with chronic HF of which 63-33 (52.4%) males Factors associated with thyroid dysfunction: The factors associated with thyroid dysfunction are shown in Table 3

Discussion
Thyroid dysfunction is frequent in patients with chronic disease conditions including heart failure [14]. Amongst these functional disorders, low T3 syndrome is the most frequent in Caucasians [1] [7]. The pathophysiologic role is not well known, even though studies suggest an adaptive mechanism to minimize energy expenditure in patients with chronic diseases [15]. Nevertheless, based on the fundamental action of FT3 on the heart and vessels, a direct relationship between FT3 and poor prognosis in patients with chronic HF represents an interesting research pathway. It is postulated that the state of low FT3 can result in a hypothyroid-like syndrome which can contribute to or worsen intrinsic heart disease [15]. This work aimed at studying the burden and type of thyroid dysfunction in patients with chronic HF in an African context, as well as the associated factors. We found a high burden of thyroid dysfunction, especially low T3   [7]. These anomalies can occur before the occurrence of HF, and could even be the cause of HF. Also, they can occur concomitantly after the occurrence of HF [7]. The high rate of these anomalies poses the problem of systematic evaluation of thyroid function in these patients. This systematic evaluation could be pertinent if correcting them will improve the prognosis. This is highly debatable in our setting where there is a lack of social security and the high costs of these tests and the  [13].

Limitations and strength
The cross-sectional design did not permit us to have an insight into the short and medium-term consequences of thyroid dysfunction on HF outcomes. Also, we were unable to tell the time at which thyroid dysfunction occurred as the median duration of evolution was 36 months. However, to the best of our knowledge, this is the first study of its kind in our setting. Further studies are needed with a cohort design to evaluate the prognostic significance of thyroid dysfunction in HF.

Conclusion
The burden of thyroid dysfunction was high in this group of patients with chronic HF in sub-Saharan Africa. These were mainly low T3 syndrome and sub-clinical hypothyroidism. These were associated with heart failure with reduced ejection fraction and those with more than one hospitalization within the past 12-months.
Further studies are needed to assess the therapeutic implications of short-term and long-term supplementation of thyroid hormones in patients with chronic HF in a sub-Saharan setting.