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Thyroid dysfunction and cardiovascular risk

Thyroid dysfunction and cardiovascular risk

A. Effects of thyroid hormone on the cardiovascular system

Triiodothyronine (T3) is essential to preserve cardiac morphology and function in adult life. The heart is particularly vulnerable to a reduction in T3 levels because T3 controls the inotropic and lusitropic properties of the myocardium, cardiac growth, myocardial contractility and vascular function.1,2 Thyroid hormones influence cardiac performance by genomic and non-genomic effects and increase cardiac output by affecting stroke volume and heart rate.1,2 Many of the physiological effects of thyroid hormone are mediated by its genomic nuclear effects.1,2 Several important cardiac structural and functional proteins are transcriptionally regulated by T3, namely, sarcoplasmic reticulum calcium adenosine triphosphatase (ATP-ase), α myosin heavy chain (α MHC), β1 adrenergic receptors, sodium / potassium ATP-ase, voltage-gated potassium channels, malic enzyme and atrial and brain natriuretic hormone. Furthermore, thyroid hormone regulates the transcription of pacemaker-related genes and hyperpolarization-activated cyclic nucleotide-gated channels 3 and 4, and guanine nucleotide regulatory proteins. In addition, T3 modulates the expression of angiotensin receptors in vascular smooth muscle cells. Other cardiac genes are negatively regulated by T3, i.e., β-myosin heavy chain (β MHC), phospholamban, sodium / calcium exchanger, TRa1 and adenylyl cyclase types V and VI.

The non-genomic effects exerted by thyroid hormones on cardiac myocytes and peripheral vascular resistance are the effects that do not require binding to nuclear receptors.1,2 These effects involve the transport of ions (calcium, sodium and potassium) across the plasma membrane, glucose and amino acid transport, mitochondrial function and a variety of intracellular signalling pathways.1,2

B. Cardiovascular effects of hyperthyroidism

Short-term hyperthyroidism is characterized by a high cardiac output state with a remarkable increase in heart rate and cardiac preload and a reduction in peripheral vascular resistance, resulting in a hyper dynamic circulation.1,2 The hyperthyroid heart increases its performance through the modulation of haemodynamic loads. This positive effect on energy metabolism and oxygen consumption improves mechanical efficiency of the left ventricle of the hyperthyroid heart by optimising its cardiac mechanical energy use.3-5

Long-term overt and subclinical hyperthyroidism (SH) may have unfavourable effects on cardiac morphology and function.6 In fact, prolonged untreated thyroid hormone excess may increase left ventricular mass, arterial stiffness and left atrial size, and may induce diastolic dysfunction thereby impairing left ventricle performance.6-14However, these alterations may be reversible or may improve when euthyroidism is restored because thyroid hormone excess does not induce cardiac fibrosis.

Clinical studies indicate that overt hyperthyroidism is associated with severe cardiac symptoms (Table 1). Patients with overt and subclinical hyperthyroidism are at increased risk of cardiac death. The increased risk of cardiac mortality may be a consequence of the increased risk of atrial arrhythmias and heart failure.6-11 Patients with severe hyperthyroidism may develop a high-output heart failure, which is due to tachycardia-mediated cardiomyopathy. In young hyperthyroid patients, this condition is not associated with underlying heart disease and the heart is intrinsically normal with increased cardiac output, although congestive circulation is present.11,15 About 7-8% of middle-aged hyperthyroid patients develop atrial fibrillation or flutter; this risk may further increase to 10-20% in elderly patients and up to 20-35% in hyperthyroid patients with coexistent ischaemic heart disease or heart valve disease.11,15 Thyrotoxic atrial fibrillation has been associated with an increased risk of cerebrovascular and pulmonary embolism.11,15 Moreover, atrial fibrillation at presentation is an independent predictor of congestive heart failure in thyrotoxic patients.11 Elderly hyperthyroid patients may develop heart failure accompanied by a low ejection fraction. In this condition, cardiac output is low, systemic vascular resistance is increased, left ventricular contractility is reduced and left ventricular filling is impaired, whereas blood volume is increased.11,15 The risk of cardiac failure and low ejection fraction is increased in hyperthyroid patients with coexistent ischaemic, hypertensive or valvular disease and/or atrial fibrillation.11

A recent meta-analysis assessed the association between SH and heart failure events. Among the 648 participants with SH from six prospective cohort studies, the hazard ratio (HR) for heart failure events in age- and gender-adjusted analyses was 1.46 compared with euthyroid subjects during a median follow-up of 10.4 years. These data suggest that the risk of cardiac failure is significantly increased in patients with undetectable serum thyroid stimulating hormone (TSH; HR 1.94, CI 1.01–3.72).11,16 Interestingly, autoimmune hyperthyroidism has been frequently linked to autoimmune cardiovascular involvement; therefore, pulmonary arterial hypertension, myxomatous cardiac valve disease and autoimmune reversible and irreversible dilated cardiomyopathy have been reported in patients with Graves’ disease.15

C. Cardiovascular effects of hypothyroidism

Hypothyroidism is characterized by a low cardiac output due to a decreased heart rate and stroke volume.1,2 Systolic and diastolic functions are reduced at rest and during exercise.6,7,17–22 Cardiac preload is decreased due to impaired diastolic function and decreased blood volume. Vascular function may also be deranged in overt and mild thyroid hormone deficiency due to the increase in systemic vascular resistance and arterial stiffness and impaired endothelial function.6,7–17,20,22 The cardiac energy efficiency of the hypothyroid human heart is impaired, despite its reduced cardiac oxygen consumption.1 Experimental and clinical studies have demonstrated that hypothyroidism causes cardiac atrophy, due to both decreased α MHC expression and increased β MHC expression.11 Moreover, hypothyroidism leads to chamber dilatation and impaired myocardial blood flow.11 Clinical studies indicate that overt hypothyroidism is associated with severe cardiac symptoms (Table 2).

Subclinical hypothyroidism with TSH >10 mU/L is an important risk factor for heart failure in older adults.11,23–24 A recent meta-analysis of six prospective cohort studies reported that the risk of heart failure events was significantly increased in patients with TSH levels >10 mU/L (HR 1.86; CI 1.27–2.72) compared with euthyroid controls.23 Moreover, some studies suggest that subclinical hypothyroidism is a risk factor for cardiac death in patients with chronic heart failure.25

Important metabolic effects may develop in long-term, untreated hypothyroidism. Hypothyroidism is associated with lipid abnormalities, especially increased total and LDL cholesterol, triglycerides and lipoprotein a. The lipid pattern is particularly altered in overt hypothyroidism, and in subclinical hypothyroidism patients with a serum TSH >10 mU/L, in smokers and in insulin-resistant subjects.6–7,18 Vascular dysfunction and dyslipidaemia may increase the risk of atherosclerosis in patients with subclinical hypothyroidism.22 Data on a potential link between subclinical hypothyroidism and homocysteine high-sensitive C-reactive protein coagulation parameters are conflicting and require additional studies to clarify the potential role of these non-traditional cardiovascular risk factors in increasing the cardiovascular risk in subclinical hypothyroidism.6–7,26

An increased risk of coronary heart disease events and mortality has been reported in young patients affected by mild or subclinical hypothyroidism.27 A recent meta-analysis analyzed the individual data of 55,287 participants from 11 prospective cohorts. This analysis showed that the risk of both coronary heart disease and mortality due to coronary disease were significantly increased in participants with TSH levels of 10 mU/L or greater.27

D. Levothyroxine improves the cardiovascular risk in hypothyroidism

Administration of replacement doses of levothyroxine (L-T4) reduces myocyte apoptosis and improves cardiovascular performance and ventricular remodelling in experimental hypothyroidism.11 Clinical studies have demonstrated that replacement doses of L-T4 may improve cardiovascular remodelling and function in patients with hypothyroidism6–7,11 (Table 3). Replacement doses of L-T4 should be considered in patients with subclinical hypothyroidism and TSH >10 mU/L to prevent the risk of heart failure and coronary disease.6,7

Studies regarding the effect of replacement therapy on lipid profile and specific symptoms of hypothyroidism have yielded conflicting results in patients with mild subclinical hypothyroidism (TSH between 5–10 mU/L).6,7 On the contrary, randomized and placebo-controlled studies have demonstrated an improvement of cardiovascular function in patients with mild or subclinical hypothyroidism after replacement doses of L-T4, suggesting that L-T4 should be considered in patients with subclinical hypothyroidism and cardiovascular risk factors.6,7 All of the available trials concur that replacement therapy may improve systolic, diastolic and vascular function, and therefore cardiovascular haemodynamics in patients with mild hypothyroidism.6,7,21 These results should be verified in larger randomized trials and longitudinal studies, assessing cardiac morbidity and mortality; however, the available data suggest that L-T4 treatment should be administered to patients with subclinical hypothyroidism and a high cardiovascular risk.6,7,21 Replacement therapy may improve cardiovascular function and/or the associated cardiovascular risk factors. The aim of treatment with L-T4 should be to normalize serum TSH levels to a range between 1 and 2.5 mU/L in young and middle-aged patients.6,7,21 This treatment does not have any adverse effects in healthy young subjects, especially when the same L-T4 product is used and thyroid function is regularly monitored.6,7,21

 E. Summary and conclusions

Thyroid hormones influence cardiac performance by genomic and non-genomic effects and increase cardiac output by affecting stroke volume and heart rate. Short-term hyperthyroidism is characterized by a high cardiac output state with a remarkable increase in heart rate and cardiac preload and a reduction in peripheral vascular resistance, resulting in a hyper dynamic circulation. However, patients with untreated overt and subclinical hyperthyroidism are at increased risk of cardiac death due to the increased risk of atrial arrhythmias and heart failure. Moreover, autoimmune hyperthyroidism has been linked to autoimmune cardiovascular involvement. Pulmonary arterial hypertension, myxomatous cardiac valve disease and autoimmune reversible and irreversible dilated cardiomyopathy have been reported in patients with Graves’ disease. Short-term hypothyroidism is characterized by a low cardiac output due to decreased heart rate and stroke volume. Subclinical hypothyroidism with TSH >10 mU/L is an important risk factor for heart failure and coronary heart disease events and mortality in adults. Replacement doses of L-T4  may improve cardiovascular remodelling and function in patients with overt and subclinical hypothyroidism, and may improve the cardiovascular risk factors associated with mild hypothyroidism. 

In conclusion, early detection and effective treatment of patients affected by thyroid dysfunction is essential to improve their cardiovascular prognosis. Close cooperation between endocrinologists and cardiologists is necessary. Randomized, controlled clinical trials are needed to assess the benefits of treatment to improve the cardiovascular mortality and morbidity of thyroid hormone excess and deficiency.

References

  1. Fazio S, et al. Effects of thyroid hormone on the cardiovascular system. Recent Progress in Horm Res 2004;59:31-50.
  2. Kahaly GJ and Dillmann WH. Thyroid hormone action in the heart. Endocrine  Reviews 2005;26:704-728
  3. Palmieri EA, et al. Myocardial contractility and total arterial stiffness in patients with overt hyperthyroidism: acute effects of beta1-adrenergic blockade. Eur J Endocrinol 2004;150:757-762.
  4. Biondi B, et al. Effects of thyroid hormone on cardiac function: the relative importance of heart rate, loading conditions, and myocardial contractility in the regulation of cardiac performance in human hyperthyroidism. J Clin Endocrinol Metab 2002;87:968-974.
  5. Napoli R, et al. Impact of hyperthyroidism and its correction on vascular reactivity in humans. Circulation 2001;104:3076-3080.
  6. Biondi B and Cooper DS. Subclinical thyroid disease. Lancet 2012;379:1142-1154.
  7. Biondi B and Cooper DS. The clinical significance of subclinical thyroid dysfunction. Endocrine Rev 2008;29:76-131.
  8. Biondi B et al. Endogenous subclinical hyperthyroidism affects quality of life and cardiac morphology and function in young and middle-aged patients. J Clin Endocrinol Metab 2000;85:4702-4705.
  9. Biondi B. Cardiovascular mortality in subclinical hyperthyroidism: an ongoing dilemma. Eur J Endocrinol 2010;162:587-589.
  10. Biondi B. How could we improve the increased cardiovascular mortality in patients with overt and subclinical hyperthyroidism? Eur J Endocrinol 2012; 167:295-259.
  11. Biondi B. Mechanisms in endocrinology: Heart failure and thyroid dysfunction.  Eur J Endocrinol 2012;167:609-618.
  12. Kahaly GJ et al. Stress echocardiography in hyperthyroidism. J Clin Endocrinol Metab 1999;84:2308-2313.
  13. Kahaly GJ et al. Cardiac risks of hyperthyroidism in the elderly. Thyroid 1998; 8:1165-1169.
  14. Kahaly GJ et al. Cardiovascular hemodynamics and exercise tolerance in thyroid disease. Thyroid 2002;12:473-481.
  15. Biondi B and Kahaly GJ. Cardiovascular involvement in patients with different causes of hyperthyroidism. Nature Reviews Endocrinol 2010;6:431-443.
  16. Collet TH et al. Subclinical hyperthyroidism and the risk of coronary heart disease and mortality. Arch Intern Med 2012;172:799-809.
  17. Biondi B and Klein I. Hypothyroidism as a risk factor for cardiovascular disease. Endocrine 2004;24:1-13.
  18. Kahaly GJ. Cardiovascular and atherogenic aspects of subclinical hypothyroidism. Thyroid 2000;10:665-679.
  19. Biondi B et al. Left ventricular diastolic dysfunction in patients with subclinical hypothyroidism. J Clin Endocrinol Metab 1999;84:2064-2067.
  20. Biondi B et al. Subclinical hypothyroidism and cardiac function. Thyroid 2002;  12:505-510.
  21. Biondi B. Natural history, diagnosis and management of subclinical thyroid dysfunction. Best Pract Res Clin Endocrinol Metab 2012;26:431-436.
  22. Biondi B et al. Endothelial-mediated coronary flow reserve in patients with mild thyroid hormone deficiency. Eur J Endocrinol 2009;161:323-329.
  23. Ladenson PW et al. Reversible alterations in myocardial gene expression in a young man with dilated cardiomyopathy and hypothyroidism. PNAS 1992;89: 5251-5255.
  24. Gencer B et al. Subclinical thyroid dysfunction and the risk of heart failure events: An individual participant data analysis from six prospective cohorts. Circulation 2012;126:1040-1049.
  25. Iervasi G et al. Association between increased mortality and mild thyroid dysfunction in cardiac patients. Arch Intern Med 2007;167:1526-1532.
  26. Duntas LH et al. New insights into subclinical hypothyroidism and cardiovascular risk. Semin Thromb Hemost 2011;37:27-34.
  27. Rodondi N et al. Subclinical hypothyroidism and the risk of coronary heart disease and mortality. J Am Med Assoc 2010;304:1365-374.

Table 1

Cardiac features in untreated hyperthyroid patients
  • Tachycardia
  • Heart failure 
  • Atrial fibrillation
  • Atrial arrhythmias
  • Systolic hypertension
  • Reduced exercise tolerance
  • Impaired left ventricular filling
  • Increased left ventricular mass

Table 2

Cardiac features in untreated hypothyroid patients
  • Bradycardia
  • Heart failure
  • Hypertension
  • Dyspnoea on effort
  • Coronary heart disease
  • Reduced exercise tolerance
  • Pericardial and pleural effusion

Table 3

Levothyroxine effects on cardiovascular parameters in hypothyroidism
  • Improved systolic function
  • Improved cardiac preload
  • Improved arterial stiffness
  • Improved endothelial function
  • Improved diastolic blood pressure 
  • Reduction in systemic vascular resistance
  • Improved diastolic function at rest and during exercise

 

 

George J. Kahaly

Professor of Medicine and Endocrinology / Metabolism, Chief of the endocrine outpatient clinic
Dept of Medicine
Gutenberg University Medical Center
Mainz, Germany
hyperthyroidism
hypothyroidism
Cardiovascular risk
levothyroxine