Summary

Patients with acute myocarditis may present with non-specific symptoms and signs. The disease is underdiagnosed because a high index of suspicion is required for diagnosing the condition in its early stage. The gold standard for diagnosis is by performing an endomyocardial biopsy, which is not widely performed because of inherent risks and limitations. We report on two cases of suspected myocarditis, which were diagnosed early using cardiovascular magnetic resonance and subsequently confirmed on endomyocardial biopsy. Early diagnosis of myocarditis has important implications for management of this potentially fatal illness.

摘要

急性心肌炎病人的病徵可能並不明確。此病的診斷率偏低，要對它有很高的警覺性才能在早期作出確診。確診的必然標準是作心肌內膜組織化驗。但因其內在的危險性及局限性而未能廣泛施行。本文報告兩個懷疑患上心肌炎的病例，利用心臟磁力共振在疾病早期作出診斷，及後再以心肌內膜組織化驗證實。能為早期心肌炎作出診斷，對醫治這個有生命危險的疾病有重大含義。

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Introduction

Myocarditis may be caused by a wide variety of infectious organisms, autoimmune disorders and exogenous agents. Damage to the myocardium occurs through the direct cytotoxic effect of the causative agent followed by a secondary immune response. Histopathologically, there is a diffuse or focal inflammatory process of the myocardium, the commonest cell type being lymphocytic myocarditis. Other inflammatory infiltrates may be classified as eosinophilic, giant cell, neutrophilic, granulomatous or mixed, according to the WHO Marburg Classification.¹ Acute myocarditis may present with non-specific symptoms such as general malaise, palpitations, shortness of breath, chest discomfort etc and may or may not be preceded by viral or flu-like illness. Although many cases of myocarditis may be subclinical with eventual full recovery, some cases of myocarditis may become fulminant, leading to cardiogenic shock, multi-organ failure and rapid demise. Undiagnosed and untreated cases of myocarditis may also lead to dilated cardiomyopathy. The gold standard for diagnosis of myocarditis is endomyocardial biopsy (EMB), which is not routinely performed in many cardiac centres for evaluation of suspected cases of myocarditis. Therefore early and reliable diagnosis of acute myocarditis is challenging and requires a high index of suspicion. We report on two cases of acute myocarditis, which were diagnosed early in the course of the disease by cardiovascular magnetic resonance and subsequently confirmed histologically to be lymphocytic myocarditis. Recommendations on management of suspected cases of myocarditis are discussed.

Case reports

Case 1

A 47-year-old Chinese male presented to his family doctor with subacute onset of dyspnoea, palpitations and mild chest discomfort. He gave a history of diarrhoea five days prior to admission. Resting ECG showed mild ST elevation in the anterior leads. Blood tests showed elevated creatinine phosphokinase (CPK) of 1507 U/L (normal <180 U/L) with MB-fraction of 313 mcg/L (normal <3.8 mcg/L) and raised Tropinin-I of 35 mcg/L (normal <0.4 mcg/L). Echocardiogram showed mildly impaired left ventricular function with an ejection fraction (EF) of 43%. Myocarditis was suspected and cardiovascular magnetic resonance (CMR) was performed. No perfusion abnormality was detected at rest. After stress with adenosine infusion, there was concentric hypoperfusion in the subendocardial and middle layer of the left ventricle at basal, mid-ventricular and apex levels, suggestive of small vessels or triple vessels disease. Viability study using gadolinium showed patchy delayed enhancement at different levels of the left ventricular walls (Figure 1). Urgent computer tomography (CT) coronary angiogram showed no stenosis in the coronary arteries. The patient was then transferred to the cardiac catheterization laboratory for coronary angiogram and EMB from the right ventricle. Normal coronary anatomy was confirmed and EMB subsequently showed focal, moderate lymphocytic myocarditis with mild interstitial fibrosis. The patient was treated with intravenous diuretics. He had palpitations associated with frequent episodes of non-sustained ventricular tachycardia and was treated with intravenous pulsed methylprednisolone at 10mg/kg/day for 3 days. The ventricular arrhythmia settled after about 1 week. Once he was haemodynamically stable, he was started on oral angiotensin converting enzyme inhibitor and beta-blocker. There was a rise in the influenza virus type A antibodies titre during the admission, compatible with a recent influenza viral illness. His left ventricular EF improved and he was fit for discharge on day 13 after admission.

Case 2

A 49-year-old Caucasian lady presented to the Accident & Emergency Department with a few days' history of chest discomfort and dyspnoea, preceded by symptoms of an upper respiratory tract infection. She had arrived from the United States 2 months earlier and had had excision of a sebaceous cyst at the neck and two treated episodes of urinary tract infections since her arrival in Hong Kong. She had a strong family history of coronary artery disease. ECG showed normal sinus rhythm with T-wave flattening in leads V2-V3. However, her blood tests revealed elevated CPK of 218 U/L with MB-fraction of 8.3 mcg/L and Tropinin-I of 0.45 mcg/L. Echocardiogram showed a mildly impaired left ventricular function (with EF of 50%) and a small rim (0.2cm) of pericardial effusion. CT coronary angiogram showed normal coronary arteries. Urgent CMR was performed and showed no perfusion abnormality at rest or during stress with intravenous adenosine infusion. Viability study with gadolinium showed patchy enhancement in the septum and lateral wall at mid-ventricular level and in the pericardium from basal to mid-ventricular level. Subsequent endomyocardial biopsy on the following day showed focal moderate lymphocytic myocarditis with endocardial fibrosis. She continued to complain of chest discomfort and dyspnoea and was treated with intravenous pulsed methylprednisolone for 3 days. Over the following few days her symptoms of chest discomfort and dyspnoea resolved. She was discharged on oral angiotensin converting enzyme inhibitor. Her viral serology showed a rise in the titre of coxsackie B type 4 antibodies. At 2 weeks after her presentation, her left ventricular EF had returned to normal.

Discussion

These two cases of viral myocarditis showed that myocarditis should be suspected when cardiac enzyme levels are elevated in the presence of normal coronary anatomy. The diagnosis of myocarditis was made rapidly and non-invasively by CMR in these two cases and preceded the histological confirmation by EMB by about 2 days. Although the mainstay of treatment for myocarditis is supportive, early diagnosis of the disease calls for intensive monitoring of complications and prompt treatment of heart failure and arrhythmias. Further characterization of the histological type of myocarditis by EMB is indicated because certain types of myocarditis, such as eosinophilic and giant cell myocarditis, may require specific treatment with immunosuppressive therapy.

EMB has long been considered the gold standard for the diagnosis of myocarditis but its usefulness has been questioned because of the limitations including poor sensitivity and potential sampling errors due to the focal nature of the inflammation in its early phase. The incidence of positive right ventricular biopsy findings in patients with suspected myocarditis is highly variable. The false negative rates of endomyocardial biopsy in myocarditis has been reported to range from 2% to 58%.^2,3 Although a negative endomyocardial biopsy does not exclude myocarditis, a positive biopsy is useful to define the type of myocarditis, to guide therapy and assess the response to treatment and to predict the long-term prognosis.

Several clinical studies have demonstrated the usefulness of magnetic resonance imaging as a powerful non-invasive diagnostic tool in acute myocarditis.^4-6 In patients presenting with acute myocardial injury (with raised CPK-MB or troponin), differentiation between coronary artery disease and acute myocarditis is important.⁷ In coronary artery disease, ischaemic myocardial segments corresponding to the diseased artery can be identified as subendocardial hypo-perfused defects on first-pass MRI perfusion. Stress with intravenous adenosine or dipyridamole is commonly used in first-pass perfusion imaging to detect myocardial perfusion reserve. Gadolinium contrast enhanced imaging is used to differentiate between infarcted or viable myocardium, with the former appearing bright or hyperenhanced compared with the latter. In contrast, patients with acute myocarditis will most likely have normal first-pass perfusion imaging. On gadolinium contrast enhanced imaging, there may be diffuse or nodular delayed enhancement in a nonvascular patchy distribution.⁷ MRI techniques using a combination of T2-weighted triple inversion recovery, early and late gadolinium enhancement can provide high degrees of sensitivity (76%), specificity (95.5%) and diagnostic accuracy (85%) in cases of suspected myocarditis.⁶ Furthermore, MRI visualizes the localization, activity and extent of inflammation in the myocardium and can guide biopsy of the area with the most marked contrast enhancement, thereby increasing the sensitivity of EMB.⁸ Serial MRI studies can also assess the natural history of the disease and the myocardial response to treatment.

Once the diagnosis of acute myocarditis is made, the patient should be monitored closely for development of congestive heart failure, arrhythmias and haemodynamic instability. The first line of treatment in acute myocarditis is supportive care with appropriate treatment of heart failure, heart block or ventricular arrhythmias. Those patients with cardiogenic shock due to fulminant myocarditis often require aggressive short-term haemodynamic support with intravenous positive inotropic agents with or without mechanical circulatory support (such as intra-aortic balloon pump, extra-corporeal membrane oxygenator or ventricular assist device) until recovery of the ventricular function, which may take 2 to 3 weeks.⁹

Since myocarditis is related to the activation of autoimmunity, a variety of immunosuppressive agents have been used to treat this disease. Numerous anecdotal and small case series suggested that patients with viral myocarditis may benefit from early steroid or immunosuppressive therapy shown by rapid resolution of inflammation in the myocardium and improvement in left ventricular function. However, the Myocarditis Treatment Trial, which was a randomized and double-blind immunosuppression treatment trial for biopsy-proven myocarditis, showed no significant benefit of a 24-week immunosuppressive therapy (prednisone plus cyclosporine or prednisone plus azathioprine) over conventional therapy in mortality or ventricular function.¹⁰ The study included an aetiologically heterogeneous patient population such as patients with symptom duration as long as 2 years. It is debatable whether the results can be extrapolated to patients with acute myocarditis of short duration. Intravenous gammaglobulins (IVIG) have been reported to be beneficial in the treatment of acute myocarditis in children¹¹ and in small series of adults.¹² The mechanism is thought to be suppression of inflammatory cytokines and a reduction of oxidative stress.¹² Thus, the use of immunosuppression remains controversial in the treatment of lymphocytic myocarditis. The current recommendation is that although immunosuppressive therapy is not indicated for routine treatment of myocarditis, it may have an important role in selected patients, such as those with myocarditis due to systemic autoimmune diseases,^11-13 those with fulminant biopsy-proven myocarditis^15,16 and those with idiopathic giant-cell myocarditis.¹⁷ The theoretical risk of giving steroid therapy in the very early phase of viral myocarditis is that it may increase viral replication. In our institution, we adopt the policy of giving 3 days of intravenous methylprednisolone at 10 mg/kg/day to biopsy-proven cases of acute myocarditis provided there are no contraindications such as fever or sepsis. Intravenous immunoglobulins (1-2 g/kg) are given if the patient becomes haemodynamically unstable despite conventional treatment and intravenous steroid. In our experience with cases of biopsy-proven myocarditis, most of our patients survived after treatment with the above regimen of immunosuppression and, if necessary, mechanical circulatory support. Recovery of myocardial function may take two to three weeks from the onset of illness.⁹

Conclusion

A patient with suspected myocarditis may have the diagnosis confirmed quickly using cardiovascular magnetic resonance imaging. This non-invasive technique can demonstrate the site and extent of myocardial damage, identify those who may benefit from endomyocardial biopsy and enhance the sensitivity of endomyocardial biopsy by guiding to the appropriate site of maximum inflammation. Early diagnosis of myocarditis will hopefully identify those at risk from cardiac complications and lead to appropriate treatment and good recovery.

Key messages

1. Acute myocarditis may present with non-specific symptoms and may recover spontaneously or lead to serious consequences such as congestive heart failure and death.
2. In patients presenting with evidence of myocardial injury, differentiation between acute coronary syndrome and acute myocarditis is important and can be done using non-invasive cardiac MR imaging.
3. Patients diagnosed with acute myocarditis must be monitored closely for development of congestive heart failure, arrhythmia and haemodynbamic instability.
4. Early referral to specialist cardiac centres for endomyocardial biopsy to confirm and characterize the myocarditis and for mechanical circulatory support in fulminant myocarditis should be considered.

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References