Plasma N-terminal pro-B-type natriuretic peptide (BNP) in mesalazine-induced myopericarditis

Abstract

Mesalazine (5-aminosalicylic acid)-based products are a widely used treatment for inflammatory bowel disease in children and adults. Associated myopericarditis is an uncommon but recorded phenomenon related to drug hypersensitivity. Unless recognised, this important complication may culminate in the development of dilated cardiomyopathy and severe heart failure. We report the case of a boy with Crohn’s disease who developed myopericarditis 14 days after starting treatment with mesalazine. Discontinuation of the drug rapidly led to normalisation of left ventricular structure and function, and a parallel improvement in the levels of plasma N-terminal pro-B-type natriuretic peptide and other markers of myocardial damage. Clinicians should be aware of this potentially life-threatening adverse effect of mesalazine therapy, which is quickly and fully reversible on cessation of the agent.

Background

Mesalazine (5-aminosalicylic acid)-based products are a widely used treatment for inflammatory bowel disease in children and adults. Mesalazine-associated myopericarditis is an uncommon but recorded phenomenon that can result in the development of dilated cardiomyopathy and severe heart failure. It is important that clinicians are aware of this potentially life-threatening adverse effect of mesalazine, as it is fully reversible on cessation of the agent. We have demonstrated that measurement of cardiac peptide plasma B-type natriuretic peptide (BNP) is an important marker, both in the initial diagnosis and in the follow-up recovery of left ventricular (LV) structure and function.

Case presentation

A 16-year-old Caucasian boy was first diagnosed with Crohn’s disease at the age of 9 years, affecting predominantly the terminal ileum and caecum. He had remained in stable remission for 7 years on increasing doses of azathioprine according to weight, reaching a maximum dose of 150 mg daily. During this period, he occasionally received antibiotic treatment with metronidazole and ciprofloxacin for recurrent perianal abscesses and fistulae formation.

He presented to the emergency department with a 3-day history of dull central chest pain that intensified with inspiration and on lying flat, accompanied by shortness of breath, fever, lethargy and malaise. Two weeks earlier, he had been treated with mesalazine 3 g add-on therapy, after experiencing abdominal pain and watery diarrhoea up to five times a day.

On clinical examination the body temperature was 38.3°C. Chest auscultation revealed a pericardial rub. There were no overt features of heart failure or dynamic instability. Resting 12-lead ECG revealed sinus tachycardia, without ischaemic changes. Transthoracic echocardiography demonstrated mild global LV systolic dysfunction, with an estimated ejection fraction of 40%–45% and a small posterior pericardial effusion (4 mm). Laboratory investigations were notable for troponin T of 610 pg/mL (normal values <14 pg/mL), C reactive protein of 240 mg/L (normal values <5.6 mg/mL) and plasma BNP level at 2231 pg/mL (normal values <88 pg/mL).

A diagnosis of myopericarditis and inflammatory cardiomyopathy was made and attributed to the recent introduction of mesalazine for a flare-up of Crohn’s disease. He continued to feel unwell with fever for several days after admission. Repeated blood cultures were unyielding. Serological tests including IgG and IgM antibodies for cytomegalovirus were all negative. Mesalazine was withdrawn on admission to the hospital, and treatment with carvedilol 3.125 mg twice daily was initiated on day 3 and ramipril 1.25 mg daily on day 4. There was a dramatic clinical improvement over the next 24 hours, and he was discharged on day 5 in good condition with outpatient follow-up. The biochemical markers of inflammation, myocardial damage and plasma BNP also normalised within 11 days of the event (figure 1). Repeat echocardiography performed on day 11 confirmed normalisation of the cardiac structure and function, with an improved ejection fraction of 55%. At the same time, a cardiac MRI with gadolinium revealed delayed pericardial enhancement in the basal and posterolateral wall, with a small effusion of less than 11 mm most prominent in the posterolateral and lateral walls and apex. The LV function was now preserved with an ejection fraction of 58%; there was, however, a non-ischaemic pattern of delayed enhancement in the subepicardial basal and posterolateral LV walls, in keeping with the diagnosis of myocarditis and arrested (non-ischaemic) inflammatory cardiomyopathy. At follow-up 3 months after the event, he remained asymptomatic on treatment with azathioprine 100 mg daily, carvedilol 3.125 mg twice daily and ramipril 1.25 mg once daily. Echocardiography now demonstrated normal structure, with improved LV wall mobility and a further improved ejection fraction of 63%. We suggest cardioprotective therapy should be continued for 6 months if echocardiography and BNP remain within normal limits at 3 and 6 months.

Figure 1.

Plasma BNP, troponin T level and CRP following admission to hospital (day 0) and following withdrawal of mesalazine in a patient with myopericarditis. CRP, C reactive protein; pro-BNP NT, N-terminal pro-B-type natriuretic peptide.

Discussion

Mesalazine is well established as a first-line treatment for inflammatory bowel disease, both in adults and children. It combines both immunosuppressive and anti-inflammatory properties, largely due to its mechanism of action through the lipoxygenase and cyclo-oxygenase pathways.

Mesalazine is usually well tolerated. Recognised side effects include headaches, skin rash and gastrointestinal upset, including diarrhoea and abdominal pain. Our case report clearly demonstrates that treatment with mesalazine is an important and reversible cause of acute dilated cardiomyopathy and pericarditis in patients with inflammatory bowel disease. This is supported by a handful of published reports describing the onset of symptoms within 2–4 weeks after starting treatment with mesalazine and with resolution of symptoms occurring within a week of drug withdrawal.^{1 2} The precise mechanism leading to the above is poorly understood. It has been suggested that a humoral-mediated hypersensitivity occurs, in which antibodies formed against mesalazine cross-react with the myocardium, causing inflammation with a predominance of eosinophilic infiltration.^{3 4} The temporal relation between starting mesalazine and the onset of symptoms makes the diagnosis of a drug-induced reaction likely. A lack of improvement in LV structure and function after stopping the above drug would support an unrelated diagnosis of viral myocarditis.

Non-invasive imaging modalities employed to diagnose the above condition include transthoracic echocardiography and cardiac MRI. Our case demonstrates that plasma BNP, secreted by the atria in normal physiology and by the ventricles in cardiac disease, is an important biochemical marker in the initial diagnosis of acute mesalazine-induced cardiomyopathy, for response to treatment. Normalisation of the plasma BNP confirms resolution of the myopathic process. Indeed, in clinical practice plasma BNP may be a more sensitive and easier index than transthoracic echocardiography for monitoring changes in cardiac structure and function.⁵ It is evident in our case that early introduction of cardioactive/protective pharmacotherapy (carvedilol and ramipril) has accelerated the improvement of markers of inflammation and myocardial damage.

Conclusion

We propose that patients with inflammatory bowel disease who are on treatment with mesalazine and who present with chest pain or breathlessness should be evaluated for the potential diagnosis of myopericarditis and that the culprit drug be withdrawn immediately. Furthermore, timely initiation of cardioprotective pharmacotherapy may hasten the recovery process. In these patients, measurement of cardiac peptide plasma BNP is an important marker, both in the initial diagnosis and in the follow-up recovery of LV structure and function. The condition is fully reversible.

Learning points.

• Patients on treatment with mesalazine who present with chest pain or breathlessness should be evaluated for myopericarditis.

• The culprit drug should be withdrawn immediately.

• Timely initiation of cardioprotective pharmacotherapy may hasten the recovery process.

• Measurement of cardiac peptide plasma B-type natriuretic peptide is an important marker both in the initial diagnosis and in the follow-up recovery of left ventricular structure and function.

• The condition is fully reversible.