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| ORIGINAL ARTICLE |
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| Year : 2015 | Volume
: 1
| Issue : 3 | Page : 247-251 |
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Endocrine abnormalities in dilated cardiomyopathy
Ankit Jain1, S Ramakrishanan1, Rajesh Khadgawat2
1 Department of Cardiology, All India Institute of Medical Sciences, New Delhi, India
2 Department of Endocrinology and Metabolism, All India Institute of Medical Sciences, New Delhi, India
| Date of Web Publication | 23-Feb-2016 |
Correspondence Address:
Ankit Jain
Department of Cardiology, All India Institute of Medical Sciences, New Delhi
India
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/2395-5414.177235
Background: Progress has been made in the understanding of cellular and molecular mechanisms of hormone action and its effects on the cardiac tissue. There is evidence from observational studies that patients with postpartum cardiomyopathy improve after inhibition of release of prolactin from the pituitary by bromocriptine. This has renewed interest in the role of hormones in the pathogenesis of cardiomyopathy, especially in women. We intended to assess the hormonal changes in female patients with dilated cardiomyopathy (DCM). Methods: Twenty female patients aged 20-40 years old (mean age 29 5.6 years) with a diagnosis of idiopathic DCMP with left ventricular ejection fraction [EF] <35% and a stable clinical course in the last 3 months were included in the study. All the patients were in New York Heart Association (NYHA) Class II or III. All the patients underwent clinical evaluation followed by blood sampling for hormonal analysis. Blood was taken after overnight fasting and analyzed for thyroid stimulating hormone (TSH), T3, T4, insulin-like growth factor I (IGF-I), prolactin, insulin, parathyroid hormone (PTH), and 25 (OH) Vitamin D. The results were compared with twenty age and sex matched controls. Results: The mean EF of the twenty patients was 24.4 5.3% and duration of symptoms was 29.1 24 months. Insulin growth factor 1 levels were significantly lower than normal. Fifty percent of the patients had levels lower than normal, but there was no correlation of IGF-I with NYHA class and EF. Testing of the thyroid hormones revealed that TSH levels were similar between patient and controls though 40% of the patients had elevated TSH levels. Of these patients, 5% (1) had hypothyroid. In addition to this, 10% (2) had isolated low T3, suggestive of the low T3 syndrome. None of the thyroid abnormalities showed a correlation with NYHA class or EF. All other hormone concentrations were comparable in both groups. Conclusion: In this cohort of female patients with DCM, circulating concentrations of IGF-I was significantly lower than in healthy controls, most likely as a result of chronic disease. Some patients had serum evidence of hypothyroidism and some with isolated low T3 levels. Other hormone levels were normal including blood glucose, insulin, and prolactin. Keywords: DCM, dilated cardiomyopathy, growth, endocrine changes
How to cite this article:
Jain A, Ramakrishanan S, Khadgawat R. Endocrine abnormalities in dilated cardiomyopathy. J Pract Cardiovasc Sci 2015;1:247-51 |
| Introduction | |  |
The pathophysiology of congestive heart failure (CHF) is closely linked to the neuroendocrine axis, and these changes act as a prognostic marker. Modifying the Neuroendocrine axis plays a major role in the management of heart failure (HF) today. While overt hypothyroidism and hyperthyroidism need to be treated in DCM and so does growth hormone (GH) deficiency, recent evidence points out to the possibility of hyperprolactinemia in postpartum DCM and a therapeutic role for bromocriptine.
The current study was planned to find out the various hormonal changes in patients with dilated cardiomyopathy especially the roles of hormones in the pathogenesis of cardiomyopathy in females. The correction of the detected hormonal abnormalities may favorably influence the outcome of this disorder.
| Methods | | |
This was a cross-sectional observational study, twenty female patients with dilated cardiomyopathy with systolic HF ejection fraction ([EF] <40%) were selected. They were Class II or III, age <40, evidence of normal coronaries (coronary angiogram or a normal stress thallium), and stable for the past 3 months. Twenty age-matched controls were chosen. We excluded patients with known endocrinopathies, diabetes, or any acute illness.
After taking a written informed consent, detailed clinical history of symptoms of dilated cardiomyopathy was taken. Relevant history taking and clinical examination was done to rule out known causes of dilated cardiomyopathy. Patients were New York Heart Association (NYHA) Class II-III disease and had a stable clinical course in the last 3 months fulfilling criteria for the study. These twenty patients underwent detailed hormonal testing.
All blood samples were collected from cases and control subjects in the fasting state and ambulatory setting, at around 9:00 am and after 10 min of bed rest. Blood sample for hormonal analysis was taken in fasting state from twenty patients to twenty healthy age- and sex-matched healthy controls. The hormonal analysis was conducted in the in the Department of Endocrinology and the Cardiac Biochemistry laboratory at our institute. The serum was analyzed for levels of T3, T4, thyroid stimulating hormone (TSH), insulin-like growth factor I (IGF-I), prolactin, 25 (OH) Vitamin D, parathyroid hormone (PTH), and insulin by electrochemilumniscent assay technique.
Statistical analysis
Results of quantitative variables are given as mean ± standard deviation. A Student's t-test for independent samples was used to compare means between groups. The Mann-Whitney U-test was used where ever the samples showed a non-normal distribution. Statistical data processing was performed using software SPSS 14.0 for Windows, (SPSS Inc, Chicago, IL). P ≤ 0. 05 was considered statistically significant.
| Results | | |
There were twenty female patients with a diagnosis of dilated cardiomyopathy and twenty age-matched female controls (mean age 30 ± 4.9 years) and their hormonal profiles were analyzed and compared. [Table 1] shows the baseline demographic and clinical profile. The majority were young (mean age 29 years) with systolic dysfunction (EF 24.4 ± 5.3%) and symptoms for <3 years. Body mass index of the patients was 19.6 ± 3.6 and controls were 20.3 ± 3.2. No patient was pregnant.
Hormonal analysis
Blood glucose, insulin levels, thyroid hormones, prolactin levels, Vitamin D, IGF-I, insulin, PTH, thyroid hormones, and prolactin levels were compared between controls and cases [Table 2]. | Table 2: Comparison of hormones analyzed between cases and controls and significance of difference
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Insulin-like growth factor I and growth hormones
In this population of female patients with dilated cardiomyopathy, IGF-I concentrations were significantly lower than in healthy individuals (normal reference range 112-300 μg/L). Ten patients (50%) had reduced IGF-I levels (mean: 71.7 ± 22.7, range 45-110 μg/L) but their NYHA class (mean 2.5 ± 0.5) and EF (24.9 ± 0.5%) was similar to those with normal IGF-I (NYHA: 2.6 ± 5.1; EF: 24 ± 5.2). We did not test for GH levels [Figure 1] and [Figure 2].
Thyroid hormones
Though the mean TSH value was similar between patients and controls, detailed review of the individual values showed that eight of twenty (40%) had TSH levels above normal (0.5-5 mU/L normal range, AP). Within this group with raised TSH levels, 3 (15%) patients had associated low T3 levels (75-200 ng/dL normal range). One patient (5%) was hypothyroid, having T4 below normal levels (4.5-11.5 ug/dL normal range).
In addition, two (10%) patients had low T3 with a normal TSH and normal T4 suggestive of a low T3 syndrome.
The EF in patients with elevated TSH (23 ± 5.9%) was similar to those with a normal TSH (25.4 ± 5.2). There was also no difference in the functional class between those with normal and elevated TSH; in the group with elevated TSH, 50% patient were Class II and 50% Class III while in the group with normal TSH, 42% were Class II and 58% Class III [Figure 3].
Other hormones
Fasting blood glucose and insulin levels (<25 mIU/L normal range) were in the normal range in all the patients.
PTH and Vitamin D levels were similar in patients and controls. Prolactin levels were also similar to controls.
| Discussion | | |
The clinical picture of HF is influenced by cytokine, hormonal and musculoskeletal changes. [1],[2] Studies on GH levels have had mixed findings with some studies suggesting higher levels in cachexic patients while recent studies suggest low levels in CHF. GH stimulates the secretion of IGF-I, and, therefore, IGF-I levels reflect GH activity in the body. The lower levels of GH/IGF-I in HF have also led to trials with GH supplementation with mixed results. Thyroid hormone alterations are also related to both progression of heart disease and the development of HF. Both hyper- and hypothyroidism have been associated with HF. In our study, we found that in female patients of DCM, IGF-I levels were lower than normal, but there was no correlation with their NYHA class or ventricular function. Average TSH levels were similar to controls, but 40% had high TSH, half of them had reduced thyroid hormones. Ten percent had isolated T3 syndrome. There was no correlation of thyroid hormone alterations with either EF or functional class. Blood glucose, insulin levels, PTH and Vitamin D levels were normal.
DCM and growth hormones
GH stimulates the production of IGF-I in the liver, kidney and other peripheral tissues and acts directly via an endocrine mechanism as well as autocrine and paracrine mechanisms mediated by IGF-I. [3],[4],[5],[6],[7],[8],[9],[10],[11],[12],[13],[14],[15],[16],[17],[18],[19],[20],[21],[22],[23],[24],[25],[26],[27],[28],[29],[30],[31] The initial studies of DCM and cachexia had reported elevated levels of GH in cachectic patients but similar levels of GH in noncachectic patients. It was suggested that this was due to the presence of GH-resistance in CHF because an increase in GH in the cachectic patients was not accompanied by an increase in IGF-I. [3],[4] another study of nine patients in Class III-IV found low levels of IGF-I, but data on GH was not available. [5] Giustina et al. showed an impaired GH secretion in severe HF, but Anand et al. found GH to be elevated in untreated patients with severe CHF. [6],[7]
Early studies showed that GH supplementation in patients with HF enhanced cardiac function; however, subsequent studies did not demonstrate significant improvements in cardiac function. Most studies were also small, and the role of GH-resistance was not explored also in these studies. A meta-analysis in 2007 suggested that while benefit may be there with GH therapy, larger trials are needed.
Fazio et al. were the first to assess GH therapy in patients with idiopathic dilated cardiomyopathy with moderatetosevere HF. This was an open trial study that included seven patients. These patients received 4 IU of recombinant GH subcutaneously every alternate day over a 3month treatment period. The authors observed an increase in left ventricular (LV) wall mass from 275 ± 11 g to 326 ± 12 g (P < 0.05), a change in EF from 34 ± 1.5 to 47 ± 1.9% (P < 0.05), and a change in exercise duration from 6.5 ± 0.5 to 8.9 ± 0.9 min (P < 0.05), which resulted in an improvement in hemodynamics, exercise capacity and myocardial energy metabolism. The patients reported symptomatic improvements and improved quality of life. Subsequent studies also showed similar results of increased LV mass and hypertrophy with improvement in clinical symptoms.
In contrast, subsequent randomized placebo-controlled studies did not observe significant beneficial effects of GH administration. These findings might be explained by the presence of partial resistance to GH in patients with chronic HF and other chronic illnesses. Other studies have also shown that patients with advanced HF had decreased sensitivity to GH.
A meta-analysis evaluated data from 14 trials regarding the efficacy and safety of GH therapy in patients with HF. Significant treatment effects between GH-treated patients versus placebo-treated patients were found in several clinical endpoints, including increased exercise duration, a decrease in NYHA classes, and increased maximum oxygen consumption, besides a significant increase in LV mass and wall thickness. There was also a significant association between an increase in serum IGF-1 levels and a decrease in NYHA class. A positive association was detected between increased IGF-1 levels and EF and LV mass.
A recent trial has suggested a way out and used a new approach. Fifty-six patients with DCM, who were shown to have GH deficiency on testing, were given GH for 6 months and showed benefit in EF, quality of life, and fall in BNP. [8]
The various studies [9],[10],[11],[12],[13],[14],[15],[16],[17],[18],[19],[20],[21],[22],[23],[24],[25],[26],[27],[28],[29],[30],[31] of supplementation have suggested a potential role for GH supplementation, but there is as yet not sufficient data to clearly state when to give GH in patients with HF.
DCM and thyroid hormones
Patients with HF often have a sick euthyroid state with normal TSH levels, low T4, and increased rT3 (reverse T3) due to reduced deiodination of T4 to T3. Sometimes, patients can have reduced the peripheral conversion of T4 to T3. In some of the reports as many as one-third of patients with HF were found to have low T3 levels while TSH levels were normal. Low T3 levels have also been suggested as a poor prognostic marker.
Hypothyroidism promotes myocardial fibrosis by stimulating fibroblasts. [25] Chronic hypothyroidism leads to loss of coronary arterioles, impaired blood flow, raised peripheral vascular resistance, decreased ionotropy, maladaptive change in myocyte shape, and development of HF. Independent from the presence of primary thyroid hypofunction and different from other organs, the heart is particularly vulnerable to reductions in biologically active T3 in plasma because cardiomyocytes have a negligible capability to generate T3 from locally converted precursor T4. Consequently, when circulating T3 is low, the myocardium may become relatively hypothyroid.
Our study showed a trend toward lower T3 and T4 levels in the patients, although levels are not significantly different between groups except for T4 levels. The relatively normal levels in our study may be because of the small size of the study. Almost 7-10% of older women have subclinical hypothyroidism. [32] The benefits of treating subclinical hypothyroidism have been controversial though a recent paper suggests that there may be a benefit. [33] The low T3 syndrome (low T3, with normal T3 and TSH) is another condition which is a poor prognostic marker and where again it has been suggested that T3 therapy might be beneficial. [34] All these reasons suggest that thyroid hormones should repeatedly be checked in patients with HF, especially in women with dilated cardiomyopathy not only for their prognostic importance but perhaps also from their therapeutic importance.
DCM and other hormones
Insulin resistance
Insulin is an anabolic hormone and insulin resistance is common in severe HF and characterized by high circulating insulin levels and normal blood sugar. Insulin resistance is associated with cachexia or HF, and since we had no cachexic Class IV patients, we probably picked up no patients with insulin resistance. We also found no alteration in prolactin levels.
| Conclusion | | |
In this population of patients suffering from chronic HF due to dilated cardiomyopathy, circulating concentrations of IGF-I was significantly lower than in healthy controls, most likely as a result of chronic disease. Some patients had serum evidence of hypothyroidism and some with isolated low T3 levels. Other hormone levels were normal including blood sugar, insulin, and prolactin. The presence of hormone abnormalities in patients with DCM and evidence in literature of some benefit of treatment with GH, IGF-I and with T4 and T3 supplementation and some of the trials with bromocriptine have renewed interest in the role of hormones in the pathophysiology of HF and potential of interventions in the endocrine axis.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2]
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