The use of ivabradine in a patient with inappropriate sinus tachycardia and cardiomyopathy due to limb girdle muscular dystrophy type 2I

Abstract

Muscular dystrophies are a heterogeneous group of disorders that commonly involve cardiac and skeletal muscle. Comprehensive guidelines for the management of cardiac failure and arrhythmias are available. However, the studies from which their recommendations are derived did not include any patients with muscular dystrophy. Some medications (eg, betablockers) may have significant side effects in this cohort. In some situations the use of agents with unique mechanisms of action such as ivabradine (a ‘funny’ channel inhibitor) may be more appropriate. Use of ivabradine has not previously been reported in limb girdle muscular dystrophy (LGMD). We describe the course of a patient with LGMD type 2I, cardiomyopathy and inappropriate sinus tachycardia treated with ivabradine. As advances in respiratory support have improved the outcomes of patients with muscular dystrophy; the prognostic significance of cardiac disease has increased. Ivabradine is tolerated and may reduce symptoms, morbidity and mortality in this cohort.

Background

Muscular dystrophies are a heterogeneous group of disorders that commonly involve cardiac and skeletal muscle. Comprehensive guidelines for the management of cardiac failure and arrhythmias are available^{1 2}; but the studies which underpin their recommendations did not include patients with muscular dystrophy. Such guidelines can still inform physicians managing this cohort. However it must be recognised that some medications (eg, betablockers, calcium channel blockers and magnesium) may cause significant adverse effects in patients with muscular dystrophy. The use of novel agents with unique mechanisms of action such as the ‘funny’ channel inhibitor, ivabradine, may be more appropriate in some cases.

Ivabradine may improve cardiac function in Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD).^{3 4} However, use of ivabradine has not previously been reported in limb girdle muscular dystrophy (LGMD). We therefore describe the course of a patient with LGMD type 2I, cardiomyopathy and inappropriate sinus tachycardia (IST) treated with ivabradine.

Case presentation

A 20-year-old woman with autosomal recessive muscular dystrophy-dystroglycanopathy (LGMD type 2I) presented to hospital with a 3-day history of cough, fever and breathlessness due to pneumonia. The patient also reported intermittent, disabling, fast, regular palpitations.

Two years prior to this presentation she had become dependent on oxygen and intermittent non-invasive ventilation (NIV; inspiratory positive airway pressure 14 cmH₂o; expiratory positive airway pressure 5 cmH₂o) as a result of progressive chronic, type 2 respiratory failure.

The patient first experienced symptomatic palpitations 2 years prior to this presentation with pneumonia. At that time, the diagnosis of IST had been made after extensive investigation (see section on investigations) and the patient had been started on metoprolol tartrate 50 mg two times per day. Metoprolol reduced the frequency of the palpitations but had unfortunately resulted in increased fatigue and weakness.

The severity of the symptoms associated with the IST had increased since the onset of the pneumonia. The now crippling palpitations resulted in severe dizziness, breathlessness at rest and fatigue. The palpitations usually occurred several times every day with gradual onset and offset. The palpitations were highly variable in duration and had occasionally lasted for several days. There was no obvious precipitant. The patient denied consumption of caffeine, alcohol and nicotine. The patient was prescribed guaifenesin 100 mg two times per day and inhaled bronchodilators (salbutamol 100 μg and ipratropium 20 μg) for use as required. However, the patient denied any association between use of the bronchodilators and the palpitations.

While the respiratory failure and pneumonia improved with increased NIV support, physiotherapy, antibiotics and mucolytic therapy; the disabling intermittent palpitations persisted.

Investigations

At 16 years of age genetic testing revealed a homozygous missense pathogenic variant in the gene encoding fukutin-related protein (FKRP); FKRP Exon 1 c941C>T NM_024301.4 pThr314Met NP_077277.1 Homozygous Chr 19:47259648 Reference Genome Reference Consortium Human build 37 (GRCh37). At the time of the patient’s diagnosis with type 2I LGMD echocardiography demonstrated only mild septal hypokinesia. Left ventricular (LV) size and function were otherwise normal.

Two years later echocardiography revealed mild to moderate global hypokinesis with mildly reduced LV systolic function (ejection fraction 45%–50%). Although the right ventricle (RV) was not dilated; RV systolic function was also mildly impaired. Electrocardiographs (ECGs) performed during outpatient visits demonstrated sinus tachycardia on several occasions. The sinus tachycardia was associated with the patient’s symptomatic palpitations. Laboratory blood tests including full blood count, serum creatinine and electrolytes and thyroid function tests were unremarkable. IST was diagnosed at 18 years of age.

On presentation to hospital with pneumonia the patient had acute on chronic type 2 respiratory failure (pH 7.29, PCO₂ 97 mm Hg, PO₂ 79 mm Hg (FiO₂ 0.35), bicarbonate 45 mmol/L, base excess (BE) +15.6 mmol/L) and sinus tachycardia; resting heart rate (HR) 140/min. Blood pressure was maintained around 110/50 mm Hg. The ECG performed on admission (figure 1) demonstrated sinus tachycardia.

Figure 1.

Electrocardiograph demonstrating sinus tachycardia.

Several subsequent ECGs performed when the patient reported symptomatic palpitations also demonstrated sinus tachycardia. Echocardiography confirmed mildly reduced left and right ventricular systolic function. Two weeks after presentation, the chronic type 2 respiratory failure was controlled with oxygen and NIV at the preadmission settings (pH 7.40, PCO₂ 92 mm Hg, PO₂ 106 mm Hg (FiO₂ 0.28), bicarbonate 55 mmol/L, BE +26 mmol/L). Laboratory blood tests including full blood count, serum creatinine and electrolytes and thyroid function tests were unremarkable.

Differential diagnosis

This patient had a symptomatic narrow complex tachycardia. Serial ECGs, recorded on several occasions when the patient reported symptoms, demonstrated sinus tachycardia (figure 1). However, the broader differential diagnosis of supraventricular tachycardia and mimics of sinus tachycardia were carefully considered.

Atrial tachycardia originating from the superior aspect of the crista terminalis and sinus node re-entrant tachycardia can mimic sinus tachycardia. However atrial tachycardia and sinus node re-entrant tachycardia usually start and end abruptly. In the present case the tachycardia was persistent and gradually increased and decreased. This is consistent with sinus tachycardia.

The patient’s palpitations and sinus tachycardia were initially thought to be secondary to pneumonia. However, the symptoms and tachycardia persisted after resolution of the pneumonia. The patient denied anxiety and pain. The patient was euvolaemic, thyroid function tests were normal and the patient’s mild anaemia (haemoglobin 110 g/L) was not sufficient to explain the degree of sinus tachycardia. The symptoms and tachycardia were independent of posture; excluding postural orthostatic tachycardia syndrome. Echocardiography was performed and while the patient had mildly impaired LV systolic function this was not sufficient to explain the severity of the tachycardia. CT pulmonary angiography excluded pulmonary embolism. So IST was diagnosed after exclusion of other possible causes of tachycardia.

Treatment

Respiratory failure was controlled by increasing NIV support and pneumonia was treated with chest physiotherapy, mucolytics and antibiotics. However, 7 days after presentation the disabling palpitations and IST persisted despite increasing metoprolol tartrate to 75 mg two times per day. Despite improvement of the patient’s productive cough and breathlessness, the patient described significant fatigue and weakness which were exacerbated by metoprolol and IST. Ivabradine was therefore introduced and titrated up to 7.5 mg two times per day over 2 weeks while metoprolol tartrate was reduced to 25 mg two times per day.

Outcome and follow-up

On discharge home chronic type 2 respiratory failure was controlled with oxygen and NIV at the preadmission settings (pH 7.40, PCO₂ 92 mm Hg, PO₂ 106 mm Hg (FiO₂ 0.28), bicarbonate 55 mmol/L, BE +26 mmol/L). Resting HR was controlled (70–90 beats/min; figure 2) by ivabradine 7.5 mg two times per day and metoprolol tartrate 25 mg two times per day. Blood pressure was maintained over 90/40 mm Hg. The frequency of the palpitations and the symptoms of fatigue and weakness had improved significantly with the improved control of IST.

Figure 2.

Electrocardiograph demonstrating control of sinus rhythm. This was performed after treatment of inappropriate sinus tachycardia with ivabradine and metoprolol.

Discussion

Autosomal recessive type 2 LGMD (LGMD2) can be caused by mutations in at least 15 genes.^{5 6} To date 12 subgroups of LGMD2 have been described (LGMD2A–L). The proteins affected by these mutations are located in the sarcomere, the dystrophin-associated glycoprotein complex or are involved in the homeostasis of these complexes. Type 2I LGMD is associated with a mutation in FKRP. The normal protein (FKRP) catalyses the transfer of ribitol 5-phosphate to the phosphorylated O-mannosyl trisaccharide structure present in alpha-dystroglycan (α-DG).⁷ This glycosylation is disrupted in patients with LGMD2I. Dystroglycan is a highly glycosylated basement membrane receptor.⁷ It organises the basement membrane by binding ligands in the extracellular matrix. It is involved in several physiological processes including maintenance of the integrity of muscle cell membranes. Correct glycosylation of α-DG is essential; disruption causes muscular dystrophy.⁷

Hereditary myopathies such as LGMD often involve the heart. A Danish case series reported that the prevalence of cardiac involvement in all patients with LGMD2 was 24%.⁸ However, cardiac involvement varies significantly between subtypes.⁸ It is most common in LGMD2I and LGMD2E; while LGMD2A, LGMD2D and unclassified LGMD2 are generally spared.⁸ Sveen et al ⁸ reported that 29% (men 38%, women 18%) of patients with LGMD2I had cardiac involvement. Cardiac involvement has previously been reported to be 10%,⁹ and 55%,¹⁰ in this population. However, each series used different definitions and investigations to detect cardiac involvement.

Cardiac phenotypes are mainly dilated and hypokinetic in patients with LGMD.⁸ The pathogenesis involves replacement of myocardium by connective tissue.⁸ The pathogenesis of the associated myopathies affecting skeletal muscle is similar. However, the relative involvement of the various subtypes of muscle differs between patients.⁸ So management of hereditary myopathies must be individualised.

Several international societies have produced comprehensive guidelines for the management of cardiac failure and arrhythmias.^{1 2} However, the studies from which their recommendations are derived did not include any patients with muscular dystrophy. Such guidelines can still inform physicians managing cardiomyopathy or IST in patients with muscular dystrophy. However, it is important to recognise that some interventions and medications (eg, betablockers, calcium channel blockers, magnesium, gentamicin) may have significant side effects in this cohort. The use of novel agents with unique mechanisms of action such as ivabradine may be more appropriate in some situations.

Ivabradine selectively inhibits cardiac potassium/sodium hyperpolarisation-activated cyclic nucleotide-gated channel 2 (‘funny’ channels).¹¹ This unique channel is responsible for the automaticity of the sinus node. These channels in the sinoatrial node open during repolarisation and close during depolarisation.¹¹ Ivabradine prolongs diastolic depolarisation, reducing pacemaker firing, HR and myocardial oxygen demand.¹¹ This improves oxygen supply; prevents ischaemia and increases exercise capacity.¹¹ Ivabradine is approved for use in patients with systolic heart failure.

In patients with impaired LV function ivabradine has been shown to reduce HR by 6–8 bpm.^{12 13} Ivabradine activity depends on the rate of opening and closing of If channels (ie, HR).¹¹ So ivabradine is more active at higher HR. The effect of ivabradine is dose-dependent but plateaus at higher doses. So the risk of ivabradine causing sinus bradycardia is low.¹¹ Thus, ivabradine is safe in comparison to placebo and in combination with betablockade.^{12 13}

IST is generally benign so treatment is rarely necessary. However, management of symptomatic IST can be extremely challenging. Ivabradine is a particularly effective treatment for IST as it has no haemodynamic effects besides reducing HR.^{2 13–16} In one small randomised, placebo controlled trial; ivabradine significantly reduced daytime HR in patients with IST.¹⁴ This improved exercise tolerance and symptoms. Similar findings have been described in several observational studies.^{2 15 16} Many patients in these studies reported complete resolution of symptoms.

Betablockers can control HR and improve symptoms of IST. In observational studies, metoprolol succinate (target 95 mg daily) reduced HR over 4 weeks.^{15 16} In a comparison of metoprolol with ivabradine, both reduced HR and increased exercise tolerance.¹⁵ The efficacy of betablockers may be limited by hypotension. So ivabradine may provide better control of both HR and symptoms.¹⁵

Patients with IST may be refractory to treatment with a single agent. Combination therapy with ivabradine (7.5 mg two times per day) and metoprolol succinate (95 mg daily) controls HR and symptoms better than metoprolol alone.¹⁶ Combination therapy is well tolerated but close monitoring for bradycardia is required.

While data on the role of ivabradine in the treatment of IST and other arrhythmias are emerging; ivabradine is already well recognised as a second line agent for the treatment of cardiac failure and angina. In these settings it is usually considered if doses of betablockers have been maximised or betablockers are contraindicated.⁹

Ivabradine does not affect any other ion channels in cardiac or skeletal muscle. So it reduces HR and improves systolic function without causing arterial hypotension or impairing muscle function. It is theoretically the drug of choice for cardiac disease in myopathic patients.

As advances in respiratory support have improved the prognosis of hereditary myopathy the significance of cardiac disease has increased. The use of ivabradine has not previously been described in LGMD. However, ivabradine has been reported to improve cardiac function in the dystrophinopathies DMD and BMD.^{3 4 7}

In the present case of LGMD2I ivabradine clearly controlled IST; but metoprolol 25 mg two times per day was also required to maintain HR under 90/min. Fatigue and weakness were significantly improved by this optimisation of medical therapy. Further data are clearly required in this unique cohort but will be nearly impossible to obtain. The authors strongly recommend avoidance of any intervention that may exacerbate weakness (eg, betablockade, calcium channel blockers, magnesium). For the specific treatment of cardiomyopathy or symptomatic IST the authors pragmatically advocate use of medications such as ivabradine that do not affect skeletal muscle function.

Learning points.

• Advances in respiratory support have improved the prognosis of hereditary myopathy. So the significance of cardiac involvement in this cohort has increased.

• Medications that may exacerbate weakness (eg betablockers, calcium channel blockers, magnesium, gentamicin) should be avoided by patients with muscular dystrophy.

• In patients with muscular dystrophy the use of novel agents with unique mechanisms of action such as ivabradine may be more appropriate than the standard therapeutic approach.

• Ivabradine was tolerated by a patient with limb girdle muscular dystrophy and cardiomyopathy and controlled inappropriate sinus tachycardia in combination with a low dose of metoprolol.