Angiotensin-Converting Enzyme Inhibitor-Induced Oropharyngeal edema with Subsequent Stress-Cardiomyopathy.

Intramuscular adrenaline is a standard treatment approach for the symptomatic patient presenting with distress and oropharyngeal edema, requiring subsequent doses if oedema persists. This case demonstrates a delayed side-effect of stress-induced cardiomyopathy after adrenaline administration. A 62-year-old suffered acute oropharyngeal angioedema secondary to angiotensin-converting-enzyme inhibitor use. Two standard doses of intramuscular adrenaline 2 hours apart were administered, and she was monitored for 2 days. On day three post discharge, she represented with acute hypervolaemia. Transthoracic echocardiogram showed a globally dilated, poorly functioning left ventricle. Cardiac magnetic resonance imaging described takotsubo cardiomyopathy. One month later, left ventricular function had normalised with optimal medical treatment. Cardiomyopathy with a temporal relationship to a hypersensitivity reaction is thought to occur due to one of three mechanisms: Stress (takotsubo) cardiomyopathy, allergic acute coronary (Kounis) Syndrome, and hypersensitive myocarditis. If a clinical presentation of hypersensitivity is such that it requires treatment with epinephrine, it is particularly challenging to determine the exact cause of cardiomyopathy. Copyright:

INTRODUCTION

Takotsubo cardiomyopathy, also known as stress-induced cardiomyopathy, results in transient systolic dysfunction of the left ventricle in the absence of angiographic evidence of obstruction.[1] While the exact pathogenesis of this disease is not fully understood, the etiology is thought to be related to excess levels of catecholamines released during times of high stress.[1] We report a rare case of delayed takotsubo cardiomyopathy post administration of epinephrine in response to angiotensin-converting-enzyme (ACE) inhibitor-induced angioedema. If a clinical presentation of hypersensitivity is such that it requires treatment with epinephrine, it is particularly challenging to determine the exact cause of resultant cardiomyopathy.

CASE REPORT

A 62-year-old female presented to the emergency department at 13:30 with a 6 h history of oropharyngeal edema and dyspnea. She had a medical history of essential hypertension, chronic obstructive pulmonary disease, and gastroesophageal reflux disease. In 2019, she had undergone an invasive coronary angiogram performed for angina-type symptoms. This demonstrated no obstructive coronary atheroma [Videos 1 and 2]. Regular medications were esomeprazole 40 mg, perindopril/indapamide 5 mg/1.25 mg, and aclidinium bromide 322 mcg all once daily, and had not changed for 2 years. She was a retired teacher, an active smoker with a 40 pack-year history, and consumed 14 units of alcohol per week. She denied significant family history and was unaware of any known allergies.

Airway obstruction was observed secondary to oropharyngeal oedema. No skin changes were observed and she remained normotensive. Her bloodwork revealed a general blood count within the normal limits and a biochemical profile with no major abnormality. Eosinophils were normal at 0.29 × 109/L. Tryptase on the day of admission was 7.5ug/L (<13.5). The patient was administered intravenous hydrocortisone 200 mg, chlorphenamine 10 mg, and subcutaneous adrenaline (0.5 mg of 1:1000). Following interval resolution, several hours later oropharyngeal edema re-occurred necessitating subcutaneous adrenaline (0.5 mg 1:1000). Advanced airway was not deemed necessary, and the patient was monitored in the high dependency unit. The differential diagnosis considered at this stage was bradykinin-induced angioedema secondary to ACE-inhibitor, acute hereditary angioedema, idiopathic angioedema, or atypical allergic reaction secondary to mast cell activation. Given the subsequent good clinical response to glucocorticoids and epinephrine hereditary oedema was later felt to be less likely. Similarly, when it was known that the tryptase level was normal, atypical allergic reaction was no longer felt to be a strong differential diagnosis. After 48 h she was discharged from the hospital with a diagnosis of angioedema secondary to ACE inhibitor use. Perindopril/indapamide was replaced with the calcium channel blocker amlodipine 5 mg once daily.

Three days after discharge, she re-presented with nonpleuritic chest pain and intermittent dyspnea. 12-lead electrocardiogram showed t-wave inversion in leads I, II, aVl and V2-V6 [Figure 1]. Septal Q-waves were present, however, these were previously noted in 2016. Troponin level was 0.04ug/L (<0.01), and 0.04 after six hours. A chest X-ray showed bilateral pleural effusions. The d-dimer was elevated at 668 ng/ml FEU. Clinical concern at this point was a healthcare-acquired lower respiratory tract infection or pulmonary embolus. A computed tomography pulmonary angiogram did not demonstrate a pulmonary embolus, but again showed bilateral pleural effusions. To investigate her hypervolemia a transthoracic echocardiogram was filmed: it revealed a dilated, generally, hypokinetic left ventricle with the poor overall function was demonstrated [Figure 2]. Sigmoid septal hypertrophy was also noted, and ejection fraction was estimated to be at 15%–20% via the Simpsons method.

Figure 1

Electrocardiography on presentation of the second admission

Figure 2

Transthoracic echocardiogram– three-chamber view– showing a dilated, generally hypokinetic left ventricle with the poor overall function was demonstrated

Due to the global nature of the myocardial dilation and nondynamic cardiac enzymes, the clinical suspicion of both a symptomatic dilated cardiomyopathy and stress-induced cardiomyopathy arose. A cardiac magnetic resonance imaging (MRI) without stress perfusion demonstrated a normal indexed left ventricular volume with moderately impaired ventricular function. There was moderate circumferential hypokinesis from mid-ventricle through to the apex, with appearances in keeping with a resolving takotsubo cardiomyopathy [Videos 3 and 4].

The patient was commenced on intravenous diuresis with the loop diuretic furosemide and once euvolemic, was discharged home. During her admission, the angiotensin-blocking receptor agent valsartan 80 mg, along with bisoprolol 2.5 mg were both introduced once daily and continued on discharge. A maintenance oral diuretic of frusemide 40 mg once daily also continued during recovery. Follow-up echocardiogram 1 month later revealed resolution of left ventricular systolic function to 50%–55%. Clinical follow up at 3 months postevent demonstrated euvolemia and symptomatic recovery. A full timeline of events is available [Table 1].

Table 1

Timeline of events

First hospital admission October 26, 2020

First adrenaline administration October 26, 2020 14:10

Secondary adrenaline administration October 26, 2020 15:53

Discharge from first admission October 28, 2020

Second hospital admission October 31, 2020

Echocardiography November 02, 2020

CT pulmonary angiogram November 03, 2020

Cardiac MRI November 04, 2020

Discharge from second admission December 07, 2020

Follow up echocardiography November 07, 2020

Follow up clinical review February 15, 2021

CT=Computed tomography, MRI=Magnetic resonance imaging

DISCUSSION

This case raises two predominant issues: firstly that of isolated angioedema, and secondly resultant cardiomyopathy. Historically, the incidence of ACE-inhibitor-induced oropharyngeal edema is 0.1%–0.7%,[2] with risk factors including age >65, female sex, seasonal allergies, concomitant use of aspirin and previous history of angioedema.[3] Typically, it is seen within 30 days of ACE-inhibitor initiation,[4] and treatment mainly includes the withdrawal of the precipitant and observation in the case of airway concern with consideration of intubation.[45] Convincing data regarding the use of treatments designed for other causes of angioedema, namely bradykinin-receptor antagonists and C1 concentrate, is lacking for angioedema secondary to ACE-inhibitor.[4]

Acute cardiomyopathy was also demonstrated in this patient. Cardiomyopathy with a temporal relationship to a hypersensitivity reaction is thought to occur due to one of three mechanisms: Stress (takotsubo) cardiomyopathy, allergic acute coronary (Kounis) Syndrome, and hypersensitivity myocarditis.[6] If a clinical presentation of hypersensitivity is such that it requires treatment with epinephrine, it is particularly challenging to determine the exact cause of cardiomyopathy. The true cause of cardiomyopathy could be extrinsic catecholamines from administered epinephrine as previously reported,[7] or intrinsic catecholamines released secondary to anaphylaxis. There remains a limitation within this report, in that no preliminary echocardiogram was performed during the initial admission, leaving the possibility that the wall motion abnormalities described may have been already present before the second re-admission.

Takotsubo cardiomyopathy results in transient systolic dysfunction of the left ventricle mimicking myocardial infarction in the absence of angiographic evidence of obstruction, thought to be related to excess levels of catecholamines released during times of high stress.[1] Kounis syndrome is defined as an allergic-mediated acute coronary syndrome causing mast cell activation.[8] It involves the release of inflammatory cytokines in response to an allergen through mast cell activation, associated with both coronary vasospasm and atheromatous plaque rupture.[8] Differing from stress cardiomyopathy it is associated with regional contraction defects.[9] Hypersensitivity myocarditis is characterized by the presence of peripheral eosinophils, high signal intensities within the left ventricle on cardiac MRI, and histological evidence of lymphohistiocytic infiltrate.[10] Hypersensitivity myocarditis occurs as a reaction to certain classes of drugs, including methyldopa, sulphonamides, and penicillins.[10]

The higher incidence of takotsubo cardiomyopathy, along with the patients' age, gender and MRI findings make this a likely diagnosis. As cardiac enzymes remained stable, and without pericardial effusion, Kounis syndrome is felt to be an unlikely cause. Endomyocardial biopsy ideally would provide histological evidence of eosinophils and lymphohistiocytes to yield a definitive diagnosis of hypersensitivity myocarditis, but with a normal peripheral eosinophil count, the likelihood of this remains low.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.