The use of intravenous gamma-globulin in acute dilated cardiomyopathy

Introduction
Myocarditis involves inflammation and injury of the myocardium in the absence of ischemia, and it may result in cardiac dysfunction. Idiopathic, autoimmune, and infectious forms have been recognized,[1] with Coxsackievirus B3 infection being the most commonly identified cause of myocarditis in an immunocompetent person.[2] Only a minority of patients with acute viral myocarditis progress to chronic myocardial disease[3] such as dilated cardiomyopathy. The incidence of dilated cardiomyopathy has been reported as 5 to 8 cases per 100,000 population per year,[4] but the frequency of myocarditis as the direct cause is not known.[5] This is partially due to difficulty in diagnosing myocarditis accurately (even with endomyocardial biopsy), since myocarditis is frequently focal or patchy, with consequent sampling error.[6]

The definition and classification of cardiomyopathies were revised in 1995 by the World Health Organization/International Society and Federation of Cardiology Task Force.[1] Cardiomyopathies are defined as heart muscle diseases of unknown cause and are divided into four distinct groups: dilated, hypertrophic, restrictive, and arrhythmogenic right ventricular cardiomyopathies. These cardiomyopathies are distinguished from specific cardiomyopathies in which myocardial ventricular dysfunction is part of a cardiac or systemic disorder. Types of specific cardiomyopathies are listed in Table 1.

Acute dilated cardiomyopathy is defined as the onset of cardiac symptoms within 6 months of presentation with dilated cardiomyopathy.[7] In a recent abstract by McNamara et al,[7] the frequency of inflammation on endomyocardial biopsy of patients with acute dilated cardiomyopathy in the IMAC study was 16%. The most common pathologic findings were mild fibrosis and hypertrophy.

The conventional treatment of myocarditis is composed largely of supportive measures such as bed rest and treatment of heart failure symptoms with salt and fluid restriction, diuretics, digoxin, and angiotensin-converting enzyme inhibitors. Recent articles supporting the use of beta-blockers have been published.[8-11] Antiarrhythmic agents[5] and anticoagulation[12] therapy may be required.

Alternative methods of therapy have received much attention, including the use of immunosuppressants, immuno-modulators, and antiviral agents. However, the Myocarditis Treatment Trial,[13] the only double-blinded randomized trial of immunosuppressive therapy utilizing prednisone and cyclophosphamide, showed no significant difference in survival or ejection fraction between the treatment and placebo groups. Therefore, immunosuppressive drugs should not routinely be used to treat myocarditis. Exceptions are patients who deteriorate despite maximal conventional therapy for congestive heart failure and have ongoing myocarditis on biopsy, or patients with underlying immune-mediated myocarditis.[5]

The use of high-dose intravenous gamma-globulin in the treatment of myocarditis and idiopathic dilated cardiomyopathy have been evaluated recently.[14,15] Possible beneficial results have been suggested, but current experience is still deficient and no randomized data is available yet to support widespread use of intravenous gamma-globulin for this indication. In Vancouver, six patients were given intravenous gamma-globulin for treatment of acute dilated cardiomyopathy. The 6 cases we present here add to the limited data available for this non-conventional therapy.

Case reports
We report six patients with acute dilated cardiomyopathy who had been administered intravenous gamma-globulin in Vancouver, British Columbia, between 1998 and 1999. The dose of intravenous gamma-globulin given was 1g/kg over 12 hours intravenously for 2 consecutive days. Average age at presentation was 41.2 years (range 31 to 54 years).

Five of the six patients had endomyocardial biopsy performed. All patients had normal coronary arteries. Two patients died, one in hospital and the other 7 months after presentation. Four of six patients had symptomatic improvement. Clinical characteristics and baseline and post-intravenous gamma-globulin transthoracic echocardiogram results are summarized in Table 2.

Patient 1
A 31-year-old male who consumed 4 to 5 beer per day presented with a 2-week history of dyspnea, myalgia, fatigue, fever, sweats, and rigors. He was admitted to hospital with NYHA (New York Heart Association) class IV heart failure symptoms. Admission transthoracic echocardiogram showed a left ventricular ejection fraction of 20% and a left ventricular end-diastolic dimension of 65 mm. Cardiac catheterization and endomyocardial biopsy showed normal coronary arteries and no evidence of myocarditis. Intravenous gamma-globulin was administered 6 days after admission.

He was also treated with digoxin, quinapril, carvedilol, furosemide, and warfarin. A transthoracic echocardiogram repeated 5 months after showed left ventricular ejection fraction of 25% and a left ventricular end-diastolic dimension of 63 mm. At follow-up 11 months after intravenous gamma-globulin therapy, his symptoms had improved to NYHA class I, and a repeat transthoracic echocardiogram showed a left ventricular ejection fraction of 30% and a left ventricular end-diastolic dimension of 61 mm.

Patient 2
A 38-year-old female presented 6 weeks post-partum (after an uncomplicated pregnancy) with dyspnea and cough for 4 weeks. She was admitted to hospital with pulmonary edema, with admission transthoracic echocardiogram showing a left ventricular ejection fraction of 30% and a left ventricular end-diastolic dimension of 60 mm. Endomyocardial biopsy showed a slightly fibrotic heart, with no myocarditis or active necrotic process. She had normal coronary arteries on cardiac catheterization.

She was given intravenous gamma-globulin, nitroglycerin patch, digoxin, quinapril, carvedilol, and warfarin. Four months later her symptoms improved to NYHA class II, and a repeat transthoracic echocardiogram showed a left ventricular ejection fraction of 50% and a left ventricular end-diastolic dimension of 51 mm. At 8 months follow-up, she had sustained improvement in her ejection fraction at 50%, and a left ventricular end-diastolic dimension of 49 mm.

Patient 3
A 40-year-old female with a 4-year history of fatigue after a flu-like illness was admitted to hospital with an acute onset of chest pain with severe dyspnea. Admission ECG was suggestive of inferior myocardial infarction, and she was treated with streptokinase. Cardiac catheterization showed normal coronary arteries with a normal ergotamine test. Admission transthoracic echocardiogram showed a left ventricular ejection fraction of 35% with inferior wall hypokinesis and dilated left ventricle.

The diagnosis of myocarditis was entertained, and she underwent an endomyocardial biopsy, which showed chronic fibrosis suggestive of previous myocarditis or chronic cardiomyopathy. She was given intravenous gamma-globulin 2 weeks after admission. Other medications included aspirin, digoxin, quinapril, and carvedilol. At 3 months follow-up her transthoracic echocardiogram showed a left ventricular ejection fraction of 20% and a left ventricular end-diastolic dimension of 62 mm. During follow-up at 6 months she was well, with NYHA class I symptoms. However, she died in her sleep 7 months after presentation.

Patient 4
A 54-year-old male with a 2-month prior history of orthopnea and paroxysmal nocturnal dyspnea was admitted to hospital with NYHA class IV heart failure. Admission cardiac catheterization showed normal coronary arteries, but severe left ventrical dysfunction with a left ventricular ejection fraction estimated between 15% and 25%. Endomyocardial biopsy was not performed. He was treated with digoxin, furosemide, ramipril, and intravenous gamma-globulin in hospital.

At 2 months follow-up, transthoracic echocardiogram showed a left ventricular ejection fraction of 25% to 40% and a left ventricular end-diastolic dimension of 59 mm. At follow-up 7 months after admission, his symptoms improved to NYHA class I, and transthoracic echocardiogram showed a left ventricular ejection fraction of 40% to 50% and a left ventricular end-diastolic dimension of 65 mm.

Patient 5
A 44-year-old male with 10 days history of dyspnea, dizziness, and diaphoresis presented to hospital with NYHA class IV heart failure. Cardiac catheterization showed normal coronary arteries but a left ventricular ejection fraction of 20%. He underwent endomyocardial biopsy showing giant cell myocarditis with considerable necrosis and drop-out of cells. He was promptly started on immunosuppressive therapy consisting of intravenous gamma-globulin, cyclosporin, imuran, and solumedrol followed by prednisone. His other heart failure medications included furosemide, ramipril, and carvedilol. He initially improved to NYHA class I symptoms over the next 2 months with intensive medical therapy. However, he subsequently deteriorated with repeat transthoracic echocardiogram over the following 3 to 6 months, showing no significant change from baseline. He underwent cardiac transplantation 8 months after initial presentation.

Patient 6
A 40-year-old female was admitted to hospital with NYHA class IV heart failure symptoms. Her symptoms dated back 7 months with progressive dyspnea and fatigue. Five months prior to this admission, she was seen in an emergency department for congestive heart failure, with a transthoracic echocardiogram showing a left ventricular ejection fraction of 20%, a left ventricular end-diastolic dimension of 60 mm, and severe mitral regurgitation.

She was treated with furosemide, digoxin, and ramipril at that time without further investigations. During this admission, she was given aggressive medical therapy including inotropic support. Coronary angiogram showed normal coronary arteries, and endomyocardial biopsy showed non-specific focal interstitial fibrosis, with no active inflammation. Transthoracic echocardiogram on this admission showed a left ventricular ejection fraction of 20%, a left ventricular end-diastolic dimension of 65 mm, and a structurally normal mitral valve with severe mitral regurgitation.

Intravenous gamma-globulin was given 4 days after admission for probable myocarditis. Symptoms failed to improve despite these therapies and she was listed for heart transplant as status 4. Intractable ectopic atrial tachycardia developed in-hospital, requiring atrioventricular nodal ablation after an unsuccessful attempt to ablate the arrhythmia. She died 24 days after admission with a cardiac arrest.

Discussion
Intravenous gamma-globulin has been used for more than two decades to treat a variety of immunopathologic disorders despite its unknown mechanism of action.[16] Diseases that have been reported to benefit from intravenous gamma-globulin include idiopathic thrombocytopenic purpura, Guillain-Barre syndrome, myasthenia gravis, Lambert-Eaton syndrome, chronic inflammatory demyelinating polyneuropathy, and Kawasaki’s syndrome.[16] Postulated mechanisms of action include:

• Blockade of Fc receptors on reticuloendothelial cells by intravenous IgG[16,17]
• Antiidiotypic antibodies in intravenous gamma-globulin binding to idiotypic region of specific disease-associated autoantibodies[15-19]
• Modulation of immune response by down-regulation of proinflammatory cytokines[14,16]
• Intravenous gamma-globulin providing specific antibodies against viruses[14,20]
• Concentration-dependent elimination of IgG from plasma[17]

Intravenous gamma-globulin is not a standard therapy for myocarditis, and has only recently been evaluated in animal and human models. In experimental animal studies, polyclonal immunoglobulin has been demonstrated to protect against development of Coxsackievirus myocarditis in mice when given before virus inoculation.[21] In another study, immunoglobulin given to Coxsackievirus-infected mice lead to decreased inflammatory infiltrate, myocardial necrosis, and mortality.[22] 

With respect to human studies, Drucker and colleagues[14] retrospectively evaluated a group of 21 consecutive children with presumed active myocarditis given intravenous gamma-globulin. This group was compared to historical control patients who did not receive intravenous gamma-globulin. The intravenous gamma-globulin group had statistically significant smaller mean adjusted left ventricular end-diastolic dimension and higher fractional shortening.

There was also a trend towards higher survival with intravenous gamma-globulin at 1 year follow-up. Following this study, McNamara and colleagues[15] evaluated the use of intravenous gamma-globulin in adults with myocarditis or idiopathic dilated cardiomyopathy. They studied 10 patients with new-onset idiopathic dilated cardiomyopathy referred to the University of Pittsburgh for consideration of cardiac transplantation. All patients received conventional treatment for congestive heart failure as well as intravenous gamma-globulin (2g/kg). Left ventricular ejection fraction assessed 12 months after intravenous gamma-globulin showed significant improvement by 17%. Unfortunately, there was no placebo group in this study. 

Intravenous gamma-globulin is much better tolerated than other immunosuppressive agents. The most common side effects are flu-like symptoms or headache in 5% to 10% of patients. Rare cases of worsening renal function have been reported.[15]

In our six case reports of acute dilated cardiomyopathy, two patients died and one required cardiac transplantation despite intensive medical therapy and intravenous gamma-globulin. Only three of six patients had improvement in their NYHA class, ejection fraction, fractional shortening, and left ventricular end-diastolic dimension.

The improvement seen cannot be entirely attributed to intravenous gamma-globulin since spontaneous improvement of systolic function has been reported frequently in such patients. In a study by Steimle et al,[23] of 49 patients with recent onset dilated cardiomyopathy (symptoms of heart failure <6 months), 27% showed mean improvement of left ventricular ejection fraction from 0.22 to 0.49 on standard supportive therapy.

The potential benefit of intravenous gamma-globulin in the setting of myocarditis and idiopathic dilated cardiomyopathy should be validated in prospective randomized controlled studies. The ongoing ESETCID trial (European Study of Epidemiology and Treatment of Cardiac Inflammatory Disease),[24] a multicenter double-blind placebo-controlled randomized trial, attempts to divide patients with myocarditis into those with autoimmune, enteroviral, or cytomegalovirus-induced disease.

Patients with cytomegalovirus-induced myocarditis will be treated with hyperimmunoglobulin; Enterovirus-positive patients with alpha-interferon; and autoimmune patients with immunosuppression. However, with respect to the use of intravenous gamma-globulin, this study will only evaluate its effect in cytomegalovirus myocarditis.

The unpublished IMAC study[7] was recently presented by McNamara and colleagues from the University of Pittsburgh. They found no difference in outcomes in patients with acute dilated cardiomyopathy treated with either intravenous gamma-globulin or placebo. There is another ongoing randomized controlled study evaluating intravenous gamma-globulin versus placebo in women with post-partum cardiomyopathy. We hope that the completion of these three studies over the next few years will help clarify the role of intravenous gamma-globulin in acute dilated cardiomyopathy.

Conclusion
Acute dilated cardiomyopathy is a peculiar cardiac disease of less than 6 months duration, where spontaneous resolution is possible. Despite aggressive supportive therapy, the majority of patients with idiopathic dilated cardiomyopathy end up with markedly decreased left ventricular systolic function.

Currently, there is no definitive treatment other than heart transplant for patients who fail medical therapy. Intravenous gamma-globulin is an experimental treatment with uncertain effectiveness and should not be routinely administered to patients with acute dilated cardiomyopathy. Our small series of six patients adds to the limited data available for intravenous gamma-globulin usage. Randomized controlled trials should be published in the near future to clarify the role of intravenous gamma-globulin in acute dilated cardiomyopathy.

Dr Saw is a cardiology fellow in the Department of Cardiology at UBC. Dr Pamboukian is a cardiology fellow training at Rush-Presbyterian Hospital in Chicago. Dr Naiman is a clinical professor in the Department of Pathology at UBC, and staff hematopathologist at St Paul’s Hospital. Dr Ignaszewski is a clinical professor in the Department of Cardiology at UBC, and staff cardiologist at St Paul’s Hospital.