Heart failure in thyrotoxicosis, an approach to management

Case history

An 80-year-old female was admitted in extremis. Her respiratory rate was 50 min⁻¹; she was sweaty and pale, with a pulse rate of 155 beats min⁻¹. There was a history of increasing shortness of breath and orthopnoea in the preceding days, but none of chest pain. She was taking nifedipine 20 mg twice daily for hypertension. Her bowel habit was normal and her weight was said to be stable. The electrocardiogram showed sinus tachycardia with absence of ‘R’ waves in the septal leads. A chest radiograph demonstrated pulmonary oedema. The biochemical investigations were normal.

There was an initial symptomatic response to frusemide 100 mg i.v., but atrial fibrillation, with a ventricular rate of 170 beats min⁻¹ developed subsequently. Digoxin 500 μg i.v. was administered and intravenous heparin was commenced. The heart rate remained uncontrolled and the patient was unwell. Chemical cardioversion was attempted with amiodarone 300 mg i.v. over 1 h and subsequent infusion. By the following morning the rhythm had reverted to sinus and the symptoms of cardiac failure had resolved. However, by the third hospital day fast atrial fibrillation had returned, with recurrence of pulmonary oedema. At this time thyroid function tests from the time of admission became available and revealed thyrotoxicosis: TSH < 0.08 mU l⁻¹; T₄ 47.8 pmol l⁻¹. A cardiac enzyme series was normal over 3 days. In light of the recurrent atrial dysrhythmia in the context of proven thyrotoxicosis, propranolol 20 mg orally three times daily was commenced. The rate and rhythm were controlled and heart failure did not recur. The echocardiogram in sinus rhythm showed good left ventricular function with septal hypokinesis. Carbimazole 20 mg once daily was added and the patient was anticoagulated with warfarin. She was discharged, well, on the seventh hospital day. On outpatient review, at 2 weeks, there had been no recurrence of heart failure.

Discussion

Pathophysiology

The haemodynamic features of hyperthyroidism are due to functional alterations in both the peripheral circulation and the myocardium. There is an increase in total blood volume and a decrease in systemic vascular resistance [1]. These effects increase preload and decrease afterload and are accompanied by an increase in heart rate and myocardial contractility [2]. The result is a high output cardiac state.

Overt heart failure in hyperthyroidism occurs in 6–19% of unselected patients [3, 4], the incidence increasing with age. However, on systematic enquiry Sandler & Wilson elicited cardiac symptoms in 33% of patients treated for hyperthyroidism [3]. Of these 57% had pre-existing ischaemic, hypertensive or valvular heart disease.

There are reports of patients with thyrotoxic heart failure associated with a cardiomyopathy, in whom no additional cause could be found [5, 6]. Some authors have proposed that there is a specific thyrotoxic cardiomyopathy, with reduced myocardial function in the hyperthyroid state, reversible after treatment [7, 8]. However, this is not supported by data from invasive monitoring studies which have demonstrated increased myocardial contractility and cardiac index at rest in patients with hyperthyroidism whether symptoms of cardiac failure were present or not [2, 8]. There is an inability to increase cardiac output further in response to exercise, but this is due primarily to the high output state rather than myocardial depression. Moreover changes at the molecular level suggest adaptations to enhance myocardial performance in hyperthyroidism. There is an increase in mRNA coding for contractile elements [9] and for the sarcoplasmic reticulum Ca²⁺ ATPase [10]. Left ventricular mass increases [11] and diastolic function, assessed by trans-mitral Doppler echocardiography is enhanced [12]. Furthermore, cardiac failure in hyperthyroidism is not associated with any histopathological change [13]. For all of these reasons hyperthyroid cardiomyopathy has not been demonstrated convincingly.

Role of the sympathetic nervous system

The role of the sympathetic nervous system in the pathophysiolology of hyperthyroidism is unclear. This uncertainty complicates both our understanding of the disease and, as will be discussed, the formulation of a targeted approach to treatment. The clinical spectrum of symptoms (including tachycardia, tremor and anxiety) suggests that, in addition to any effect of thyroid hormone itself, there is also a hyperadrenergic state. This impression is reinforced by the dramatic reversal of these symptoms after the administration of β-adrenoceptor antagonists [14]. Despite this, the concentrations of catecholamines in both plasma [15] and urine [16] are normal or low in hyperthyroidism. An alternative explanation is that sensitivity to catecholamines is enhanced. Increased numbers of β-adrenoceptors have been reported in rat heart [17] and human muscle and adipose tissue in hyperthyroidism [18]. There is also a greater increase in plasma cAMP concentration in response to insulin induced hypoglycaemia in hyperthyroid patients than in normal controls [19], suggestive of enhanced β-adrenergic responsiveness. By contrast, there is no increase in the metabolic or haemodynamic sensitivity to infused adrenaline [18, 20].

Atrial tachyarrhythmias

Atrial premature depolarizations, paroxysmal atrial tachycardia, atrial flutter and, most significantly, atrial fibrillation all occur in hyperthyroidism. The incidence of atrial fibrillation ranges from about 10–21% in unselected patients [21, 22], compared with 0.4% in the overall adult population [23]. These rhythm disturbances may arise from a reduction in the electrical threshold for atrial depolarization [24] and are frequently a precipitant of cardiac failure [3].

Thromboembolism

Table 1 shows the incidence of arterial thromboembolic events (10–40%) in three retrospective series of thyrotoxicosis-related atrial fibrillation compared with unselected patients with nonrheumatic atrial fibrillation. It is not possible to compare these data directly, but the incidence of thromboembolism in thyrotoxicosis is considerable. This may be due to a procoaguable state [28] or other factors such as the increased incidence of mitral valve prolapse [29].

Table 1.

Incidence of arterial thromboembolic event in thyrotoxic related atrial fibrillation and unselected non-rheumatic atrial fibrillation.

Management

The difficulty with the management of heart failure in the presence of hyperthyroidism is that it represents a heterogeneous entity. The majority of patients are old, often with underlying cardiovascular disease and perhaps an associated tachyarrhythmia. Correction of the underlying hyperthyroidism is the primary consideration of management. However, this can take many days, and rapid control of symptoms is important.

As with patients who do not have thyrotoxicosis, the initial management of congestive cardiac failure is by reduction of the volume overload with loop diuretics. Hyperthyroidism is associated with vasodilatation and decreased systemic vascular resistance [8] and, where this is apparent on clinical examination or on invasive monitoring, vasodilators such as nitrates should not be given.

Digoxin

If the hyperthyroid patient has atrial fibrillation, digoxin can slow the ventricular response rate. However, larger than usual doses may be required. A relative resistance to digoxin may be present, due both to increased renal clearance [30] and to the increased number of Na/K ATPase units in cardiac muscle [31].

β-adrenoceptor blockers

β-adrenoceptor antagonists are used for the alleviation of thyrotoxic symptoms [32] and in thyroid storm [33]. Their mechanism of action is not clear. As discussed, there is little evidence for sympathetic overactivity in hyperthyroidism. The reported effects of β-adrenoceptor blockers on thyroid hormone levels are variable and not of a magnitude which could explain the therapeutic effect [32].

Although there are no trial data to support their use in thyrotoxic cardiac failure, β-adrenoceptor blockers, and propranolol in particular, are effective in alleviating the attendant symptoms of hyperthyroidism and also control heart rate. However, invasive monitoring in hyperthyroid patients with cardiac failure [34] has demonstrated depressed myocardial function in response to β-adrenoceptor blockade, as evidenced by decreased stroke volume and increased pulmonary artery diastolic pressure.

The key issue in thyrotoxic cardiac failure is the relative contribution of accelerated heart rate. If the tachycardia is judged to be a critical feature, as in the case presented above, then the cautious trial of β-adrenoceptor blockade is warranted, despite the possibility of depressing myocardial contractility.

Where the cardiac failure is truly congestive, due to intravascular expansion and subsequent decompensation, possibly with underlying ischaemic, hypertensive or valvular heart disease, then the negative inotropic β-adrenoceptor blockers is probably best avoided.

In practice, the clinical situation is unlikely to be so clear-cut. The ultra-short acting β-adrenoceptor blocker esmolol has been used successfully in the treatment of hyperthyroid-related cardiac failure [35, 36]. Its half-life of 9 min facilitates rapid titration of β-adrenoceptor blockade and if there is a detrimental effect on myocardial function, evidenced by worsening features of congestive failure or by hypotension, the drug can be withdrawn promptly. If propranolol is used, a low intravenous dose (0.5 mg) should be given in the first instance.

If β-adrenoceptor blockade is well tolerated, an oral β-adrenoceptor blocker can be introduced. Propranolol is widely favoured for its nonselective β-adrenoceptor blockade, although the plasma concentrations are highly variable in thyrotoxicosis [37]. Greater doses than usual may be required because of accelerated hepatic metabolism [38]. Atenolol is an effective, once daily, alternative and may be used, particularly when the symptoms are predominantly cardiac [39].

Amiodarone

Amiodarone is used widely in the treatment of atrial fibrillation [40, 41]. It is a safe and effective agent for chemical cardioversion of atrial fibrillation, even when the dysrhythmia is refractory to other drugs [42, 43].

Amiodarone is an iodine-rich benzofuran. In patients taking amiodarone, the plasma and urinary levels of inorganic iodide can increase 40-fold [44]. As a consequence, thyroid dynamics change in many patients [45]. Changes to thyroid function tests in patients taking amiodarone are complex and are not necessarily physiologically relevant [46].

There are theoretical benefits in thyrotoxicosis from the use of amiodarone, which has been demonstrated to reduce the concentration of T₃ induced -adrenoceptors in cardiac myocytes [47]. Some authors have suggested a role for amiodarone in combination with propylthiouracil for accelerating the reduction of serum concentrations of T₃ and T₄ [48, 49]. However, the potential confounding effects of amiodarone in thyroid disease dictate that this drug should not be used as a first line agent.

Carbimazole

The mainstay of management is prompt alleviation of thyrotoxicosis. Both β-adrenoceptor blockade and rendering the patient euthyroid are associated with decreased stroke volume, but this is achieved in different ways. Propranolol decreases end systolic volume whereas thyroid correction with carbimazole reduces end diastolic volume [2]. In other words, while β-adrenoceptor blockade depresses myocardial contractility, corrective therapy reverses the primary haemodynamic disturbance responsible for the increase in stroke volume.

Anticoagulation

Anticoagulation is indicated in atrial fibrillation. Intravenous heparinization should be instituted in the first instance, followed by warfarin. Reduced levels of vitamin K-dependent clotting factors mean that lower doses of warfarin than usual may be required [50].

Key points

• Heart failure in thyrotoxicosis is well recognized.

• Thyrotoxicosis is associated with a high cardiac output state and heart failure in this context is usually associated with underlying cardiac disease.

• There is a high incidence of atrial dysrhythmia, particularly atrial fibrillation, in thyrotoxicosis. Patients who have atrial fibrillation should be anticoagulated to reduce thromboembolic risk.

• β-adrenoceptor blockade can be a useful treatment for hyperthyroid related heart failure, but should be introduced cautiously since it occasionally exacerbates symptoms.

• The pharmacokinetic and pharmacodynamic properties of many drugs used in the treatment of heart failure are altered in the thyrotoxic state.