Six recurrences of myocarditis in 3 years: A case report

Abstract

A recent study revealed that recurrence of myocarditis occurs in a significant proportion of patients, but multiple recurrences of myocarditis have rarely been reported. The pathophysiology and best treatments for multiple recurrences of myocarditis remain unclear.

A 60-year-old man presented to our emergency department with fever and chest pain. Physical examination, imaging, and laboratory findings were consistent with fulminant myocarditis. Paired titers confirmed adenovirus infection. The patient was treated with intra-aortic balloon pump and percutaneous cardiopulmonary support for 7 days and was discharged with near-normal electrocardiographic and echocardiographic findings on day 26. Over the subsequent 3 years, the patient experienced six episodes of recurrence of myocarditis with a progressive decrease in his ability to perform activities of daily living. At the time of his sixth recurrence, he died of ventricular fibrillation. Autopsy revealed mild enlargement of the left ventricle, extensive inflammatory cell infiltration, and mild interstitial fibrosis, suggesting left ventricle remodeling because of repetitive myocarditis. We have presented a case of multiple recurrences of myocarditis. This is the largest number of recurrences in a single patient reported to date. Further studies are needed to elucidate the underlying pathogenesis and best treatment of this condition.

<Learning objective: Although few cases of multiple recurrent myocarditis have been reported, we recently experienced a case of multiple recurrences of myocarditis over a 3-year period. However, we did not definitively diagnose the etiology of myocarditis or perform etiologically based medical therapy, so we could not rescue our patient. In cases of multiple recurrent myocarditis, more aggressive and accurate investigation are required to elucidate the etiology and pathophysiology of this condition.>

Introduction

Recurrence of myocarditis is known to occur in a significant proportion of patients [1], [2], [3]. However, multiple recurrences of myocarditis have rarely been reported. The underlying pathophysiology and best treatment for multiple recurrent myocarditis remain unclear. The following case report describes a patient who had six recurrences of myocarditis over a period of 3 years, leading to death.

Case report

A 60-year-old man was admitted as an emergency with fever and chest pain. At the time of presentation, the patient’s body temperature was 37.5 °C, his pulse rate (PR) was 109 beats/min, and his blood pressure (BP) was 91/66 mmHg. Electrocardiography (ECG) revealed ventricular tachycardia and convex ST-segment elevations in the precordial lead. Chest radiography showed pulmonary congestion. Laboratory examination revealed increased serum aspartate aminotransferase (AST; 235 IU/L), lactic dehydrogenase (LDH; 697 IU/L), creatine kinase [CK; 632 IU/L with 10.9% CK-myocardial band (MB)], and cardiac troponin I (23.8 ng/mL). Echocardiography showed reduced left ventricular ejection fraction (LVEF; 20%) and a diffusely thickened left ventricular wall. Mild pericardial effusion was seen. Because fulminant myocarditis was strongly suspected, cardiac catheterization was planned. Upon transfer of the patient to the cardiac catheterization room, he developed ventricular fibrillation, which did not resolve with electrical defibrillation. An intra-aortic balloon pump (IABP) was therefore inserted immediately and percutaneous cardiopulmonary support begun. Coronary angiography revealed normal coronary arteries. IgG antibody titers for adenovirus (1, 2, 3, 4), influenza (A, B), coxsackievirus (A9, B1, B2, B3, B4), and echovirus (3, 7, 11, 12) were requested, adenovirus infection being confirmed by paired titers (initial titer, 1:16; titer 2 weeks later, >1:128). Intravenous cardiotonic drugs, diuretics, and intravenous immunoglobulin 20 g for 2 days were administered. CK and CK-MB levels peaked on the second hospital day at 989 IU/L and 81 IU/L, respectively. Cardiac function showed signs of recovery beginning on the fourth hospital day; mechanical support systems were discontinued on the seventh day. Before discharge, the patient’s ECG returned to sinus rhythm with no significant ST-T change. On echocardiogram, neither LV wall motion abnormalities nor LV dilatation were detected. LVEF had improved to 58%. The patient was discharged in an ambulatory state on the 26th day.

Three months later, the patient returned to our hospital because of chest pain. On admission, his PR was 90 beats/min and his BP was 78/43 mmHg. ECG showed bigeminy and convex ST-segment elevations in the precordial lead. Echocardiography showed reduced LV function. Serum AST (74 IU/L), LDH (321 IU/L), CK (445 IU/L), CK-MB (66 IU/L), and cardiac troponin I (14.1 ng/mL) were again elevated. Because the patient had experienced a previous episode of fulminant myocarditis, recurrence was suspected. An IABP was therefore inserted and an endomyocardial biopsy obtained from the right ventricle. Histological examination revealed interstitial fibrosis with mild inflammatory cell infiltration without eosinophils or giant cells (Fig. 1). Paired titers again revealed adenovirus (initial titer, 1:32; titer 2 weeks later, >1:128). Intravenous cardiotonic drugs, diuretics, and intravenous immunoglobulin 20 g for 2 days were again administered. CK and CK-MB peaked on the second hospital day at 480 IU/L and 73 IU/L, respectively. Cardiac function recovered beginning on the third hospital day and IABP was discontinued on the fourth day. Before discharge, the patient’s ECG findings were the same as at the time of his previous discharge and his LVEF on echocardiogram was 48%. He was discharged on the 20th hospital day.

Fig. 1.

Endomyocardial biopsy from the right ventricle showing interstitial fibrosis and slight inflammatory cell infiltration (hematoxylin and eosin; original magnification ×200).

Five months later, the patient was readmitted to our hospital with chest pain. ECG changes and elevated serum levels of cardiac enzymes (CPK, 359 IU/L; CK-MB, 48 IU/L; cardiac troponin I, 8.68 ng/mL) were documented. It was hypothesized that the patient was experiencing a second recurrence of myocarditis. However, unlike the previous episodes of fulminant myocarditis, his vital signs remained within normal range and echocardiography showed preserved LV function. His cardiac function did not worsen after admission and he was discharged on the 12th hospital day.

The patient experienced repeated recurrence of myocarditis thereafter. Over the course of the next 2 years, three recurrences of myocarditis were documented. In each case, the patient’s cardiac function was not impaired during hospitalization (Fig. 2). However, his ability to perform activities of daily living gradually declined.

Fig. 2.

Clinical course following the patient’s third admission. White triangle indicates LVEF; white circle CK; black circle CK-MB; white block TnI; black block TnT. LVEF, left ventricular ejection fraction; CK, creatine kinase; CKMB, creatine kinase myocardial band; TnI, troponin I; TnT, troponin T.

Three years after the patient’s first admission with fulminant myocarditis, a sixth recurrence of myocarditis occurred. At the time of presentation, the patient’s PR was 100 beats/min and his BP was 81/57 mmHg. Serum levels of AST (131 IU/L), LDH (493 IU/L), CK (880 IU/L), CK-MB (118 IU/L), and cardiac troponin T (6.46 ng/mL) were elevated. Echocardiography showed reduced LV function. LVEF on echocardiogram was 15%. Because these findings indicated a recurrence of fulminant myocarditis, the use of mechanical circulatory-assist devices was planned. However, both the patient and his family refused mechanical circulatory assistance. Therefore, intravenous cardiotonic drugs and diuretics and oxygen supplementation were administered. However, the patient’s cardiac function did not recover and congestive heart failure progressively worsened. On the eighth hospital day, the patient died of ventricular fibrillation. An autopsy was immediately performed. Postmortem autopsy findings included a heart weight of 475 g with mild left ventricle enlargement. Mild patchy fibrosis and edema of the bilateral ventricles were noted (Fig. 3A), as was degeneration of myocardial cells and extensive inflammatory cell infiltration (Fig. 3B). Immunohistochemistry revealed that inflammatory cells in the myocardium were mainly macrophages and a few CD4⁺T-cells; very few CD8⁺T-cells were detected (Fig. 3B). Slight interstitial fibrosis was also present (Fig. 3C).

Fig. 3.

Autopsy findings. (A) The left ventricle is mildly enlarged. Mild patchy fibrosis and edema of the bilateral ventricles are seen. (B) Degeneration of myocardial cells and extensive inflammatory cell infiltration are noted (hematoxylin and eosin; original magnification left upper panel ×200). On immunohistochemistry, most of the infiltrating cells are positive for CD68 (right upper panel ×200), only a few are positive for CD4 (left lower panel ×200), and very few are positive for CD8 (right lower panel ×200). (C) Slight interstitial fibrosis is evident (Masson trichrome stain; original magnification ×40).

Discussion

Recurrence of myocarditis has been reported and is not thought to be rare [1], [2], [3]. However, multiple recurrences of myocarditis have rarely been reported. We recently encountered a patient with myocarditis who experienced six recurrences over a period of 3 years. In the present case, there were thought to be two types of repetitive myocarditis: on the first and second admission, he demonstrated repeated fulminant myocarditis during a short period. In contrast, on the third to sixth admissions, he experienced relative stable episodes of recurrent myocarditis. On the first and second admissions, the condition of myocarditis was fulminant, which required the use of mechanical circulatory-assist devices. The pathophysiology for recurrence of acute myocarditis remain unclear. Development of autoimmunity is considered the major mechanism of recurrence in acute pericarditis [4]. In most patients with acute myocarditis, viral infection is cleared after the acute phase and myocarditis resolves [5]. However, in some patients, viral infection triggers autoimmune myocarditis, as demonstrated by the development of autoreactive T-cells [6] and heart-specific antibodies [7]. These findings suggest that mechanisms similar to those of pericarditis are likely to contribute to recurrence of myocarditis. Reactivation of persistent viral infection is also recognized as a potential mechanism of recurrence [8]. In the present case, we did not perform specific immunohistochemistry to investigate development of autoimmunity such as autoreactive T-cells or heart-specific antibodies. Moreover, we did not perform confirmatory studies such as polymerase chain reaction testing and therefore could not definitively determine whether he had persistent viral infection nor could we be certain of the cause of his condition. The above-described mechanisms may have facilitated the recurrence of fulminant myocarditis; however, we cannot be sure of that in this case. During third to sixth admissions, the condition of myocarditis was relatively stable, and the patient’s cardiac function was not impaired during hospitalization.

Postmortem autopsy findings of disappearance or necrosis of cardiomyocytes and interstitial fibrosis were made in the present case, which may suggest chronic myocarditis with incomplete healing, leading to left ventricle remodeling. We speculate that there are two possible explanations: repetitive acute myocarditis due to viral infection, which progressed to chronic myocarditis, with recurrent episodes; or multiple recurrences of chronic myocarditis of varying severity. Hiramitsu et al. demonstrated the transition from acute to chronic myocarditis in an autopsy case [9]. Moreover, long-term follow-up studies with acute myocarditis have documented myocardial remodeling and the development of dilated cardiomyopathy in about 20% of patients [10]. Thus, these mechanisms may have been involved in the present case. Immunohistochemistry revealed that inflammatory cells in the myocardium were mainly macrophages. No non-caseating granulomas were seen; however, the histiocyte infiltration suggests that the underlying disease may have been cardiac sarcoidosis, which we failed to consider at the time. Indeed, the recurrence of chronic myocarditis is not uncommon in cardiac sarcoidosis [3]. We should have performed positron emission tomography or cardiac magnetic resonance imaging to assess myocardial properties and inflammation.

In the present case, it was difficult to determine the pathophysiology underlying the multiple repeated myocarditis. We did not perform comprehensive testing or imaging, so we could not definitively diagnose the etiology of myocarditis or perform etiologically based medical therapy. Accurate diagnosis and treatment might have prevented fulminant and multiple recurrences of myocarditis in our patient.

In conclusion, we have described a patient with six recurrences of myocarditis over a period of 3 years. In cases of multiple recurrent myocarditis, more aggressive and accurate investigations are required to elucidate the etiology and pathophysiology of this condition.

Conflict of interest

The authors declare no conflicts of interest associated with this manuscript.