Relationship between thyroid status and survival rates in patients presenting with acute coronary syndrome

Thyroid dysfunction is relatively common, readily diagnosed and treatable. Most thyroid dysfunction is subclinical and is only diagnosed with the appropriate blood test.

There are long term effects associated with thyroid dysfunction.  Overt hypothyroidism and hyperthyroidism are linked to adverse cardiovascular (CV) outcomes.^1-2 Various studies have also shown that even in subclinical hypothyroidism and subclinical hyperthyroidism there is an increase in CV morbidity and mortality.^3-7

The reason for this association is that thyroid hormone receptors are found both in the heart and vasculature. Therefore, any changes in thyroid hormone levels will affect end organ function in these areas. The relationship of thyroid hormone with the CV system is complex and the effects are modulated in several different ways. Excess thyroid hormone effects on the heart include increased heart rate, contractility and overall risk of coronary heart disease. On the other hand thyroid hormone effects on vasculature include variation in smooth muscle tone and hence blood pressure.^8-9

Hyperthyroidism and therefore thyroid hormone excess, is associated with a hyperdynamic circulation, an increased cardiac output, subsequent development of systolic hypertension¹⁰ and an increased risk of coronary heart disease. Hypothyroidism and hence thyroid hormone deficiency, is associated with diastolic hypertension and impaired vascular function.¹¹ Thyroid hormones increase endothelial production of nitric oxide and other changes which lead to changes in endothelial function due to smooth muscle relaxation.¹² Consequently, in hypothyroidism this impaired endothelial function improves with replacement of thyroid hormone.^13-14 In addition thyroid hormones have a direct effect on lipid metabolism with hyperthyroidism associated with decreased levels of cholesterol (TC)¹⁵ and hypothyroidism with higher low density lipoprotein cholesterol (LDL-C) levels.¹⁶ Once thyroid hormone levels normalized, lipid profiles return to normal in both hyper- and hypothyroidism. Thyroid hormones also modulate inflammatory and coagulation pathways. An overall increased hypercoagulability has been documented in hyperthyroidism,¹⁷ while conflicting results have been reported in hypothyroidism.¹⁸

Overt and subclinical hyperthyroidism

Hyperthyroidism and thyroid hormone excess cause increased cardiac output by increasing stroke volume and heart rate.¹⁹ However despite a high output state, hyperthyroid patients have reduced cardiopulmonary function during exercise due to decreased CV reserve²⁰. Overt hyperthyroidism is associated with increased CV morbidity and mortality mainly due to an increased incidence of heart failure.^21-22 Untreated hyperthyroidism may cause high output heart failure even in those with a previously healthy heart. ²²

Furthermore, hyperthyroidism is associated with increased risk of atrial ectopics and atrial fibrillation. The onset of atrial fibrillation is associated with increased CV morbidity and mortality.²³ Subclinical hyperthyroidism was also shown to be associated with the development of atrial fibrillation.⁷ On the other hand, studies regarding the association of CV morbidity and mortality with subclinical hyperthyroidism provide conflicting data due to major differences in study design, methods and cut-offs used. Despite this, treatment of subclinical hyperthyroidism is advocated internationally especially if the patient has other CV risk factors and a Thyroid Stimulating Hormone (TSH) suppressed to less than 0.1mIU/L. In particular the European Thyroid Association guidelines recommend treatment in those with CV risk factors and a TSH <0.1mIU/L at any age. It is also suggested that if the patient is over 65 years and has underlying CV disease or history of fractures, treatment should be considered even if TSH is only mildly suppressed (0.1-0.39 mIU/L) in an attempt to decrease risk.²⁴

A well-known long term effect of both subclinical and clinical hyperthyroidism is increased bone turnover causing osteoporosis and increased risk of fractures.^1,25 As described above, treatment is recommended to improve outcomes.

Overt and subclinical hypothyroidism

Overt hypothyroidism is associated with a reduction in cardiac output, decreased heart rate and increase in peripheral vascular resistance and diastolic dysfunction.²⁶ There is an association of hypercholesterolemia, diastolic hypertension and reduced endothelial nitric oxide with overt hypothyroidism. Normalization of thyroid hormone levels causes reversal of these features.²⁷

Subclinical hypothyroidism is known to be associated with diastolic dysfunction due to impaired ventricular relaxation.²⁸ Subclinical hypothyroidism was shown to be linked to an increased risk of congestive heart failure among adults with a TSH level of 7.0 mIU/L or greater.²⁹ The Whickam Survey cohort showed that subclinical hypothyroidism is associated with dyslipidaemia namely higher TC levels, LDL-C levels, and triglycerides (TG).^5,30 Higher TSH levels were associated with higher systolic and diastolic blood pressure.^5,31-32

Various studies have been published showing an association between CV outcomes and subclinical hypothyroidism. The EPIC- Norfolk study found a worse cardiovascular risk factor profile.³³ However, this increased CV risk was not confirmed in all studies. Specifically subclinical hypothyroidism was not associated with increased risk for coronary heart disease,^34-35 stroke,³⁶ peripheral arterial disease,²⁹ or CV-related or total mortality.²⁹

Current data on mortality is not conclusive. Subclinical hypothyroidism was shown to be associated with an increased risk of coronary heart disease and mortality in those with higher TSH levels,²⁹ especially in those with a TSH concentration of 10 mIU/L or greater.³⁴ Subclinical hypothyroidism was also shown to be linked with an increased risk for all-cause mortality and CV death.³⁷ On the other hand, another study has shown that subclinical hypothyroidism might be associated with a lower risk in all cause mortality.³⁸ More recent studies showed no association with subclinical hypothyroidism and overall death in the elderly.^39-40 However, treatment of subclinical hypothyroidism was shown not to improve either all cause mortality,⁴¹ or CV mortality.⁴²

Aim

The aims of the study included investigating the frequency of thyroid dysfunction in patients presenting with acute coronary syndrome (ACS) to the Coronary Care Unit at St Luke's Hospital, Malta between 1^st February 2002 and 30^th June 2003, follow-up of these patients at St. Luke's and Mater Dei hospitals until December 2010 and assessing the impact of thyroid dysfunction on patient outcomes.

Method

This was a prospective, case controlled study.  Patients presenting with Acute Coronary Syndrome (ACS) at St Luke's Hospital, Malta between February 2002 and June 2003 were included in the study. 

Exclusion criteria included ongoing treatment for thyroid dysfunction and ongoing treatment with beta-blockers and/or amiodarone. All patients who were admitted to CCU and did not fit in the exclusion criteria were included in this study.

Data collected included anthropometric parameters at presentation; serum and plasma samples were taken within 24 hours of presentation for thyroid function tests, renal profiles, creatinine kinase, lipid profile, random blood glucose (RBG) and glycosylated haemoglobin.

Additional data captured at presentation with ACS included diabetes subtype, current glucose lowering regime at presentation and cardiovascular risk factors, namely smoking, hypertension, dyslipidaemia, and family history.

Subsequently, follow-up data was collected until December 2010. Cardiovascular complications were recorded together with readmission rates with coronary and other events, duration of hospital stay and mortality data. Information was collected both from hospital notes and death certificates.

SPSS® 22.0 was used for data analysis. Mann-Whitney U and Kruskal-Wallis tests were used to compare differences in continuous variables between thyroid categories. Chi Square test and Kruskal-Wallis tests were used to compare frequencies across thyroid categories. Spearman's correlation was used to correlate continuous variables. Kaplan Meier survival curve was used to compare survival rates across thyroid categories. Significance was defined by a two-tailed p value of < 0.05.

Classification

The classification of thyroid status was defined in Table 1 as follows:

Results

There were a total of 201 patients admitted to the coronary care unit from February 2002 to June 2003 as shown in Figure 1. Out of these, 88 patients admitted with ACS fitted the inclusion criteria. Another 6 were admitted with ACS but were already known to have thyroid dysfunction.

Figure 1

Flow Chart of inclusion of patients

Thirty-six patients (25 males, 11 females) had abnormal thyroid function tests at presentation with ACS. Thyroid dysfunction is common among patients presenting with ACS in Malta- 41% of our cohort were newly diagnosed with thyroid dysfunction on admission. Fifty nine percent of the cohort was euthyroid at presentation. The most common thyroid dysfunction was subclinical hypothyroidism which represented 17% of the cohort followed by subclinical hyperthyroidism in 12.5% of the cohort. 9% were overtly hypothyroid and 2.2% were overtly hyperthyroid. There were no patients who met the criteria for sick euthyroid syndrome given the available thyroid hormone parameters.

The mean age of all patients was 62.3 years and there was no difference in baseline characteristics between males and females, as shown in table 2 below.

There was no definitive correlation between age and TSH and age and T4 as shown in Figure 2. Nonetheless, available data suggests a trend towards a weak correlation between TSH and age with a p value of 0.055.

Figure 2

Correlation between age and TSH and age and T4

Normal thyroid and different abnormal thyroid cohorts were compared as shown in Table 3. TSH and fT4 levels were significantly different, as expected. There were no differences in age, RBG, and cholesterol across different thyroid categories.

Figure 3 shows thyroid status at presentation: 52 patients were euthyroid, 8 were hypothyroid, 15 were subclinically hypothyroid, 2 were hyperthyroid and 11 were subclinically hyperthyroid.

Figure 3

Thyroid status at presentation with acute coronary syndrome

There was no difference in counts of thyroid categories across the genders although one can say there is a trend towards some difference with a p value of 0.051 (Chi squared). There was also no difference in age across patients with different thyroid categories (p=0.175- Independent Samples Kruskall Wallis test).

Numbers were very small. In order to perform further survival statistics, patients were divided in 2 different groups as normal thyroid function and abnormal thyroid function on admission. There was no difference in survival status between the 2 groups- p=0.262 (Chi squared). As shown in Table 4.

Figure 4

Kaplan-Meier curves comparing time to death for euthyroid patients and those with thyroid dysfunction at presentation with an acute coronary syndrome

Discussion

As discussed previously, the most common thyroid dysfunction was subclinical hypothyroidism (15% of the cohort) followed by 12% who were subclinical hyperthyroid. Of note, no patients were noticed to have thyroid function tests showing the sick euthyroid pattern which would be expected in a hospital cohort. Low T3 levels post myocardial infarction due to sick euthyroid syndrome have been associated with molecular changes which cause depressed myocardial function and have been implicated in the potential development of heart failure post infarction.⁴³ Our patients had their blood tests taken on admission, potentially prior to the occurrence of a sick euthyroid state although the lack of routine FT3 and rT3 estimations at the laboratory poses a limitation. However, T4 and TSH data did not show isolated hypothyroxinaemia.

A significant number of patients (42.05%) died during follow-up. Analysis of biochemistry results of the whole cohort on admission, revealed that twenty one percent of the cohort had been diagnosed with diabetes and a significant number had additional co-morbidities apart from coronary artery disease.

We report shorter survival times for patients who are euthyroid at presentation with an ACS, a finding that was unexpected. Most studies in the field have shown the opposite.^44-45 An explanation for this result could be the small numbers involved. Another reason could be the methodology in having grouped all thyroid dysfunction (hypothyroid and hyperthyroid) patients together in one cohort. In our cohort the euthyroid group had more diabetics than the dysthyroid group. This may have masked any opposing effects of these conditions.

In our study, there were 27 euthyroid males and 25 euthyroid females and a total of 25 male patients with thyroid dysfunction and 11 female patients with thyroid dysfunction. This is unusual as thyroid dysfunction is generally more common in females than males. In addition, women with IHD have higher rates of death compared to men after myocardial infarction⁴⁶. It is possible that females in this cohort had more comorbidities eg higher RBG in women. Therefore, it could be that our results show a reverse mortality trend due to the gender bias, i.e. more males and hence less mortality.

A possible explanation may be that patients who have thyroid dysfunction are inevitably followed up because of the thyroid dysfunction itself and hence other issues may be picked up earlier and treated accordingly improving their survival compared to euthyroid patients.

Another explanation for our results could be that having thyroid dysfunction itself might have been the reason for the patients’ ACS and hence this was easily treatable, thus decreasing mortality. On the other hand, patients who were euthyroid and had ACS, probably had non-reversible or difficult to treat causes for their IHD like hereditary causes, smoking or significant co-morbidities.

Limiting Factors

The whole cohort was a convenience sample and therefore it may not represent a normal distribution. As discussed already we had very small numbers and in addition many more male patients than female patients which may have skewed the results. Follow up data collection was retrospective and 68 case notes were unavailable (Figure 1). Hence these patients were lost to follow-up and not included in the study. This amounted to almost a third of the cohort.

Diabetes has a huge impact in the outcome of ACS treatment. Twenty percent of our cohort had diabetes at presentation and this may have influenced their outcomes (n=20 of which 13 where euthyroid and 7 were dysthyroid). Management of patients of ACS varies starting from PCI to conservative management. We did not collect any data about the management of the ACS since this was beyond the scope of our study. However, the outcomes of these patients definitely may have been influenced by the type of treatment for their ACS.

Another problem was the methodology used for the Kaplan Meier analysis in grouping normal thyroid function group and abnormal thyroid function group. In grouping the different thyroid categories the analysis may have been skewed. Given the findings reported here, there is clearly a need for a larger prospective, case controlled study with prospective data collection and analysis.

Conclusions

Thyroid dysfunction is common among patients presenting with ACS in Malta, the most common being subclinical hypothyroidism. We report and discuss the observed shorter survival times for patients who are euthyroid at presentation with an acute coronary syndrome.

Summary Box

What is already known about this subject:

• Current data on mortality is not conclusive.
• Overt hypothyroidism and hyperthyroidism are linked to adverse CV outcomes.
• Various studies have also shown that even in subclinical hypothyroidism and subclinical hyperthyroidism there is an increase in CV morbidity and mortality.

What are the new findings:

• Thyroid dysfunction is common among patients presenting with ACS in Malta. Diabetes was also very common in the above cohort which may be a confounding factor.
• The most common dysfunction being subclinical hypothyroidism.
• We report shorter survival times for patients who are euthyroid at presentation with an acute coronary syndrome which is in contrast to other studies.

References

1. De Leo S, Lee SY, Braverman LE. Hyperthyroidism. Lancet 2016; 388(10047):906-18.
2. Chaker L, Bianco AC, Jonklaas J, Peeters RP. Hypothyroidism. Lancet 2017; 390(10101): 1550-62.
3. Hak AE, Pols HA, Visser TJ, Drexhage HA, Hofman A, Witteman JC. Subclinical hypothyroidism is an independent risk factor for atherosclerosis and myocardial infarction in elderly women: the Rotterdam Study. Ann Intern Med 2000; 132(4): 270–8.
4. Walsh JP, Bremner AP, Bulsara MK, O'Leary P, Leedman PJ, Feddema P, et al. Subclinical thyroid dysfunction as a risk factor for cardiovascular disease. Arch Intern Med 2005; 165: 2467–72.
5. Razvi S, Weaver JU, Vanderpump MP, Pearce SH. The incidence of ischemic heart disease and mortality in people with subclinical hypothyroidism: reanalysis of the Whickham Survey cohort. J Clin Endocrinol Metab 2010; 95: 1734–40.
6. Parle JV, Maisonneuve P, Sheppard MC, Boyle P, Franklyn JA. Prediction of all-cause and cardiovascular mortality in elderly people from one low serum thyrotropin result: a 10 year cohort study. Lancet 2001; 358: 861–5.
7. Cappola AR, Fried LP, Arnold AM, Danese MD, Kuller LH, Burke GL, et al. Thyroid Status, Cardiovascular Risk, and Mortality in Older Adults. JAMA 2006; 295: 1033-41.
8. Razvi S, Jabbar A, Pingitore A, Danzi S, Biondi B, Klein I, et al. Thyroid Hormones and Cardiovascular Function and Diseases. J Am Coll Cardiol 2018; 71: 1781-96. doi: 10.1016/j.jacc.2018.02.045.
9. Jabbar A, Pingitore A, Pearce SH, Zaman A, Iervasi G, Razvi S. Thyroid hormones and cardiovascular disease. Nat Rev Cardiol 2017; 14(1): 39-55.
10. Danzi S, Klein I. Thyroid hormone and blood pressure regulation. Curr Hypertens Rep. 2003; 5: 513–20.
11. Klein I, Ojamaa K. Thyroid hormone and the cardiovascular system. N Engl J Med. 2001; 344: 501–9.
12. Park KW, Dai HB, Ojamaa K, Lowenstein E, Klein I, Sellke FW. The direct vasomotor effect of thyroid hormones on rat skeletal muscle resistance arteries. Anesth Analg 1997; 85: 734–8.
13. Papaioannou GI, Lagasse M, Mather JF, Thompson PD. Treating hypothyroidism improves endothelial function. Metabolism 2004; 53: 278-9.
14. Taddei S, Caraccio N, Virdis A, Dardano A, Versari D, Ghiadoni L et al. Impaired endothelium-dependent vasodilatation in subclinical hypothyroidism; beneficial effect of levothyroxine therapy. J Clin Endocrinol Metab 2003; 88: 3731-7.
15. Canaris GJ, Manowitz NR, Mayor G, Ridgway EC. The Colorado thyroid disease prevalence study. Arch Intern Med 2000; 160: 526–34.
16. Duntas LH. Thyroid disease and lipids. Thyroid 2002; 12: 287–93.
17. Franchini M, Lippi G, Targher G. Hyperthyroidism and venous thrombosis: a casual or causal association? A systematic literature review. Clin Appl Thromb Hemost 2011; 17: 387–92.
18. Erem C, Kavgaci H, Ersöz HO, Hacihasanoglu A, Ukinç K, Karti SS et al. Blood coagulation and fibrinolytic activity in hypothyroidism. Int J Clin Pract 2003; 57: 78–81.
19. Jabbar A, Pingitore A, Pearce SH, Zaman A, Iervasi G, Razvi S. Thyroid hormones and cardiovascular disease. Nat Rev Cardiol 2017; 14:39–55.
20. Biondi B, Kahaly GJ. Cardiovascular involvement in patients with different causes of hyperthyroidism. Nat Rev Endocrinol 2010; 6: 431–43.
21. Brandt F, Green A, Hegedüs L, Brix TH. A critical review and meta-analysis of the association between overt hyperthyroidism and mortality. Eur J Endocrinol 2011; 165: 491–7.
22. Biondi B. Mechanisms in endocrinology: heart failure and thyroid dysfunction. Eur J Endocrinol 2012; 167: 609–18.
23. Bielecka-Dabrowa A, Mikhailidis DP, Rysz J, Banach M. The mechanisms of atrial fibrillation in hyperthyroidism. Thyroid Res 2009; 2:4.
24. Biondi B, Bartalena L, Cooper DS, Hegedüs L, Laurberg P, Kahaly GL, The 2015 European Thyroid Association guidelines on diagnosis and treatment of endogenous subclinical hyperthyroidism. Eur Thyroid J. 2015; 4(3): 149–163.
25. Blum MR, Bauer DC, Collet TH, Fink HA, Cappola AR, da Costa BR et al, Subclinical thyroid dysfunction and fracture risk: a meta-analysis. JAMA 2015; 313: 2055-65.
26. Klein I, Danzi S, Thyroid disease and the heart. Circulation 2007; 116: 1725–35.
27. Cappola AR, Ladenson PW, Hypothyroidism and atherosclerosis. J Clin Endocrinol Metab 2003; 88: 2438–44.
28. Biondi, Fazio S, Palmieri EA, Carella C, Panza N, Cittadini A et al, Left ventricular diastolic dysfunction in patients with subclinical hypothyroidism. J Clin Endocrinol Metab 1999; 84(6): 2064-7.
29. Rodondi N, Newman AB, Vittinghoff E, de Rekeneire N, Satterfield S, Harris TB et al, Subclinical Hypothyroidism and the Risk of Heart Failure, Other Cardiovascular Events, and Death. Arch Intern Med 2005; 165: 2460-66.
30. Asvold BO, Bjoro T, Nilsen TI, Vatten LJ, Association between blood pressure and serum thyroid stimulating hormone concentration within the reference range: a population based study. J Clin Endocrinol Metab 2007; 92: 841-5.
31. Ye Y, Xie H, Zeng Y, Zhao X, Tian Z, Zhang S, Association between subclinical hypothyroidism and blood pressure: a meta-analysis of observational studies. Endocr Pract 2014; 20: 150-8.
32. Liu XL, He S, Zhang SF, Wang J, Sun XF, Gong CM et al, Alteration of lipid profile in subclinical hypothyroidism: a meta-analysis. Med Sci Monit 2014; 20: 1432-41.
33. Boekholdt SM, Titan SM, Wiersinga WM, Chatterjee K, Basart DC, Luben R et al, Initial thyroid status and cardiovascular risk factors: the EPIC-Norfolk prospective population study. Clin Endocrinol (Oxf) 2010; 72(3): 404-10.
34. Rodondi N, den Elzen WP, Bauer DC, Cappola AR, Razvi S, Walsh JP et al, Subclinical hypothyroidism and the risk of coronary heart disease and mortality. JAMA 2010; 304(12): 1365-74.
35. [Singh S, Duggal J, Molnar J, Maldonado F, Barsano CP, Arora R, Impact of subclinical thyroid disorders on coronary heart disease, cardiovascular and all-cause mortality: a meta-analysis. Int J Cardiol 2008; 125(1): 41–8.
36. Chaker L, Baumgartner C, den Elzen WP, Ikram MA, Blum MR, Collet TH et al. Subclinical Hypothyroidism and the Risk of Stroke Events and Fatal Stroke: An Individual Participant Data Analysis. J Clin Endocrinol Metab 2015; 100(6): 2181-91.
37. Tseng FY, Lin WY, Lin CC, Lee LT, Li TC, Sung PK et al. Subclinical hypothyroidism is associated with increased risk for all-cause and cardiovascular mortality in adults. J Am Coll Cardiol 2012; 60(8): 730-7.
38. Selmer C, Olesen JB, Hansen ML, von Kappelgaard LM, Madsen JC, Hansen PR et al. Subclinical and overt thyroid dysfunction and risk of all-cause mortality and cardiovascular events: a large population study. J Clin Endocrinol Metab 2014; 99(7): 2372-82.
39. Waring AC, Arnold AM, Newman AB, Buzkova P, Hirsch C, Cappola AR. Longitudinal changes in thyroid function in the oldest old and survival: the cardiovascular health study all-stars study. J Clin Endocrinol Metab 2012; 97(11): 3944-50.
40. Gussekloo J, van Exel E, de Craen AJ, Meinders AE, Frolich M, Westendorp RG. Thyroid status, disability and cognitive function, and survival in old age. JAMA 2004; 292(21): 2591-9.
41. Andersen M, Olsen A, Madsen J, Faber J, Torp-Pedersen C, Gislason G, et al. Levothyroxine Substitution in Patients with Subclinical Hypothyroidism and the Risk of Myocardial Infarction and Mortality. PLoS One 2015; 10(6): e0129793.
42. Villar HC, Saconato H, Valente O, Atallah AN. Thyroid hormone replacement for subclinical hypothyroidism. Cochrane Database Syst Rev 2007; (3): CD003419.
43. Lymvaios I, Mourouzis I, Cokkinos DV, Dimopoulos MA, Toumanidis ST, Pantos C. Thyroid hormone and recovery of cardiac function in patients with acute myocardial infarction: a strong association? Eur J Endocrinol 2011; 165(1): 107-14.
44. Collet TH, Gussekloo J, Bauer DC, den Elzen WP, Cappola AR, Balmer P et al. Subclinical hyperthyroidism and the risk of coronary heart disease and mortality. Arch Intern Med. 2012; 172(10): 799-809.
45. Ning Y, Cheng YJ, Liu LJ, Sara JD, Cao ZY, Zheng WP et al. What is the association of hypothyroidism with risks of cardiovascular events and mortality? A meta-analysis of 55 cohort studies involving 1,898,314 participants. BMC Med. 2017; 15(1): 21.
46. Vaccarino V, Parsons L, Every NR, Barron HV, Krumholz HM. Sex-based differences in early mortality after myocardial infarction. National Registry of Myocardial Infarction 2 participants. N Engl J Med. 1999; 341(4): 217-25.

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