A 32-year-old woman with a history of an undifferentiated connective tissue disease (CTD) was admitted with arthralgias and severe hypotension.
History of the present illness.
The patient had been in her usual state of health until 6 days earlier, when she developed acute bilateral wrist and hand arthralgias, left-sided pleuritic chest pain, and dyspnea on exertion. She noted stiffness of approximately 30 minutes' duration. Her dyspnea had worsened progressively and she presented to an outside hospital. She denied fever, rash, night sweats, Raynaud's phenomenon, hair loss, sores in the mouth and nose, nasal congestion, epistaxis, cough, hemoptysis, palpitations, myalgia, muscle weakness, and paresthesia.
Evaluation in the emergency department showed a blood pressure of 90/60 mm Hg and tachycardia, with a regular heart rate of approximately 130 beats/minute. The patient was tachypneic, with a respiratory rate of 28 breaths/minute, and had 93% O2 saturation on room air. She was afebrile. Diagnostic study results included a normal chest radiograph and a computed tomography angiogram that was negative for pulmonary emboli. An electrocardiogram (EKG) revealed a sinus tachycardia with mild ST-segment depression in leads V4, V5, and V6. The patient's troponin 1 and creatine kinase (CK) concentrations were elevated, as was the myocardial fraction of CK: troponin 1 level 10.6 ng/ml (normal value <0.10), CK level 263 units/liter (normal value <165), and MB fraction 44.3 ng/ml (normal value <5). A transthoracic echocardiogram (TTE) revealed normal left ventricular cavity size, a left ventricular ejection fraction (LVEF) of 20% with severe global hypokinesis, increased left ventricular wall thickness (septal thickness 16 mm), and severely reduced right ventricular function.
Over the course of the first hospital day, the patient developed worsening hypotension that required the placement of an intraaortic balloon pump and the use of inotropic pressor support. An emergent cardiac catheterization revealed normal coronary arteries. On the day following admission, she was transferred to our institution for further evaluation and treatment of cardiogenic shock.
Past medical history.
A diagnosis of undifferentiated CTD had been made 2 years before presentation, when the patient presented with pleuritic chest pain and arthralgias of the proximal interphalangeal joints. Diagnostic studies showed a small right pleural effusion and an erythrocyte sedimentation rate of 85 mm/hour, a slightly elevated rheumatoid factor (RF) of 17 IU (normal value <15), and a positive antinuclear antibody (ANA) assay at a titer of 1:320 (homogeneous pattern). Antibodies to double-stranded DNA (dsDNA) and to the Sm, SSA, SSB, and RNP antigens were negative. Urinalysis with microscopic examination of the sediment was unremarkable. The patient was treated with prednisone for 2 months. Her symptoms improved and the prednisone was discontinued. Intermittent joint pain affecting the proximal interphalangeal joints occurred over the next 2 years. Hydroxychloroquine was recommended, but the patient declined this therapy.
The patient also had a history of attention deficit hyperactivity disorder, diagnosed as a child, for which she had taken dextroamphetamine (20 mg/day) for 1 year. Her only pregnancy had ended in a miscarriage in the tenth week of gestation.
Family and social histories.
At age 18 years, she underwent rehabilitation for alcohol and cocaine abuse, but had been sober and drug-free since that time. She had no family history of autoimmune diseases or coronary artery disease.
The patient appeared ill, with a respiratory rate of 30 breaths/minute, a pulse that was 154 beats/minute and regular, a temperature of 36.6°C, and a blood pressure of 80/50 mm Hg. Her O2 saturation was 99% while breathing and 100% via a facemask. The jugular veins were distended 8 cm above the sternomanubrial junction. The heart sounds were faint. She had crackles at both lung bases and mild pitting edema in her hands and feet. The peripheral pulses were thready and her extremities cool. There were no abnormalities of the nailbed capillaries and no other cutaneous lesions. There was no swelling or tenderness of joints, and the neurologic examination was non-focal.
The hematology and chemistry tests obtained upon admission are shown in Table 1. The findings upon serologic testing included a positive ANA assay at a titer of 1:640 (speckled pattern) and a positive RF (93.5 IU; normal value <20). In addition, assays for antibodies directed against dsDNA (73 IU; normal value <25) and the SSA (>200 IU; normal value <20), SSB (94.2 IU; normal value <20), and RNP antigens (22.2 IU; normal value <20) were also positive. Tests for antibodies to the Sm antigen and to topoisomerase III were negative. The serum complement levels were within normal limits or elevated: C3 level 235 mg/dl (normal range 71.3–185), C4 level 30 mg/dl (normal range 9.4–51), and CH50 level 251 complement activation enzyme-linked immunosorbent assay/ml (normal range 63–145).
Table 1. Hematology and chemistry test results upon admission
Mean corpuscular volume, μm3
White blood cell count, per μl
Differential count, %
Platelet count, per μl
Erythrocyte sedimentation rate, mm/hour
Blood urea nitrogen, mg/dl
Lactate dehydrogenase, units/liter
Creatine kinase, units/liter
Creatine kinase, MB fraction, ng/ml
Troponin 1, ng/ml
Brain natriuretic peptide, pg/ml
A diagnostic procedure was performed.
The patient is a 32-year-old woman with a history of an undifferentiated CTD who now presents with arthralgias, cardiac decompensation with hypotension, and serologies consistent with systemic lupus erythematosus (SLE).
Does the patient have a rheumatic disease?.
Although her underlying diagnosis was unclear at the time she presented 2 years earlier with features of an undifferentiated CTD, the evolution of the patient's serologies in the setting of her previous symptoms resolves any uncertainty about whether or not her previous manifestations of a CTD were real. Rheumatic diseases, particularly those of the CTD variety, commonly unfold over a period of months to years.
In this case, based on the patient's arthralgias and pleuritis prior to the current presentation and her antibodies to dsDNA and the Ro, La, and RNP antigens, it is reasonable to consider her disease to be within the spectrum of SLE or an overlap CTD. However, the potential relationship (if any) between her cardiac decompensation and her underlying rheumatic disease is less clear.
The acute onset of progressive dyspnea and the physical examination findings suggest fluid overload from decompensated heart failure. The patient's clinical symptoms, abnormal EKG results, and elevated cardiac enzymes suggest the possibility of acute coronary syndrome (ACS). The TTE confirmed a cardiomyopathy, with global hypokinesis and an LVEF of only 20%. In addition, increased left ventricular wall thickness was detected, potentially indicative of myocardial hypertrophy, an infiltrative process, or myocardial edema.
The categories of cardiopulmonary disease to consider as explanations for cardiac decompensation include an ACS, cardiac tamponade, stress-induced cardiomyopathy, myocarditis, and pulmonary embolism (PE). As discussed below, each of these could have been triggered by a direct or indirect complication of her underlying rheumatic illness.
Acute coronary syndrome.
An ACS resulting from an unstable thrombus could explain her clinical presentation as well as the resulting cardiomyopathy and elevated cardiac enzymes. However, the EKG was notable only for anterolateral ST-segment depression, without Q waves to indicate a previous transmural myocardial infarction. In addition, the global nature of the left ventricular dysfunction seen on the TTE suggests a non-ischemic process. Furthermore, as a 32-year-old woman, the patient did not have traditional risk factors for atherosclerosis. In this case, cardiac catheterization revealed normal-appearing coronary arteries, excluding ACS as a cause of her profound left ventricular dysfunction.
Acute PE may result in significant elevations in cardiac enzymes in situations that cause significant right ventricular strain. The TTE sample revealed that there was significant right ventricular dysfunction. A prior medical history of CTD (1), clinical symptoms of pleuritic chest pain, and the acute onset of shortness of breath all suggest a high level of concern for PE. However, a negative chest computed tomography angiogram performed on the day of presentation excludes a PE of any significant size with a high degree of certainty. In addition, a PE would also not fully explain her severe left ventricular dysfunction.
Accumulation of fluid in the pericardial space can cause the clinical symptoms of chest pain and dyspnea. If the pericardial pressure equals or exceeds intracardiac pressures, the life-threatening complication of cardiac tamponade can occur. The physical examination in patients with cardiac tamponade may show an accentuated pulsus paradoxus (a fall in systolic blood pressure >10 mm Hg during inspiration), an elevated jugular venous pulse, or occasionally, a pericardial rub. The diagnosis of tamponade is made by observing a pericardial effusion causing either cardiac chamber collapse during diastolic filling on echocardiography or significant respiratory flow variation during filling of the right or left ventricle. In this case, no pericardial effusion was observed on TTE. Although pericarditis or pleuritis is a potential cause of the patient's chest pain, the elevated cardiac enzymes and decreased left ventricular function suggest myocyte damage and cannot be explained by pericarditis or pleuritis alone.
Stress-induced cardiomyopathy, referred to as the “broken heart” syndrome or Takotsubo syndrome (2), can result in a constellation of symptoms that resembles an ACS, including chest pain, dyspnea, and abnormal cardiac biomarkers. Symptoms of chest pain and dyspnea typically occur in postmenopausal women who have experienced recent emotional stress. EKG abnormalities and elevated cardiac enzymes are also evident in this syndrome, but cardiac catheterization yields normal coronary arteries. Stress-induced cardiomyopathy usually demonstrates characteristic findings on TTE, including apical akinesis with hyperkinetic basal segments (apical ballooning). However, variations involving other segments also exist. The wall motion abnormalities typically do not correspond to a single coronary vascular territory. If the patient survives the initial acute episode, stress-induced cardiomyopathy is usually transient and resolves fully within weeks to months with few or no sequelae. An argument against stress-induced cardiomyopathy is that, in contrast to this case, the disorder seldom affects the ventricles in a global fashion.
Patients with myocarditis typically present with nonspecific reports of malaise, fatigue, myalgias, or fevers that can progress to chest pain and significant dyspnea indicative of worsening heart failure (3). The acute onset as well as the severity of symptoms in this case indicates an aggressive, fulminant myocarditis.
The majority of myocarditis cases caused by infections are caused by viral organisms, but bacterial, fungal, parasitic, and protozoan etiologies have also been reported. Drug-induced myocarditis may result from either allergic mechanisms or direct toxic effects (e.g., anthracyclines). Myocarditis may also be a manifestation of various autoimmune diseases, including CTDs, vasculitis, and sarcoidosis (see below). Giant cell myocarditis (GCM) is a particularly aggressive form of myocarditis that should be considered, particularly in cases of severe cardiovascular compromise or malignant arrhythmias. Its prevalence is rare in comparison with other etiologies of myocarditis, but it is frequently fatal because of extensive myocardial necrosis. Patients can present with symptoms of acutely decompensated heart failure, life-threatening arrhythmias, or symptoms that resemble ACS (4).
Autoimmune diseases associated with myocarditis.
The rheumatic diseases with which myocarditis is most often associated are SLE, systemic sclerosis (SSc; scleroderma), polymyositis, dermatomyositis, and overlap CTD syndromes, including mixed CTD. Other rheumatic diagnoses to consider include vasculitis, sarcoidosis, and rheumatoid arthritis.
The most commonly found cardiac abnormalities in SSc are pericarditis and myocardial fibrosis, the latter of which appears to be due to microvascular ischemia that may be subclinical. Myocarditis, an uncommon manifestation of SSc, is more likely to develop in patients who also have myositis of skeletal muscle. Myocarditis can lead to congestive heart failure or sudden death (5). However, this patient did not have Raynaud's phenomenon, nailbed capillary abnormalities, or the typical skin changes, essentially ruling out scleroderma. Patients with polymyositis, dermatomyositis, and the overlap CTDs can have similar myocardial changes, but this patient lacked clinical evidence of those diagnoses.
Cardiac manifestations are seen in approximately 5% of patients with sarcoidosis. This may precede, follow, or occur concurrently with involvement of the lungs or other organs (6). The diagnosis is made by finding evidence of this disease in more typical locations or by direct biopsy.
Rheumatoid myocarditis is perhaps underappreciated but usually remains asymptomatic (7). This patient had a moderately elevated RF and arthralgias, but in the absence of frank arthritis or joint deformity, this diagnosis is unlikely.
Finally, myocarditis can be a complication of some forms of systemic vasculitis. Heart involvement of the valves, myocardium, and pericardium is known to be a major cause of morbidity and mortality in Churg-Strauss vasculitis (8). Endomyocardial biopsy performed in Churg-Strauss myocarditis may show a prominent eosinophil component to the inflammatory infiltrate. The absence of peripheral eosinophilia and other typical clinical features such as asthma and sinusitis readily excludes Churg-Strauss syndrome in this case.
The presence of 4 criteria among the 1997 American College of Rheumatology modified criteria (9) is required for the classification of a patient with the diagnosis of SLE. Our patient met 4 criteria: the positive ANA assay, antibodies against both dsDNA and the Sm antigen (additional immunologic abnormality), lymphopenia, and serositis. The patient had arthralgias but never documented arthritis, the finding of which would have fulfilled a fifth classification criterion.
Myocarditis has been reported to occur in up to 9% of patients with SLE (10). The diagnosis of lupus myocarditis is based primarily on clinical suspicion. It is often clinically mild if not subclinical, but occasionally presents with congestive heart failure.
A biopsy is not required in many cases of lupus myocarditis, but can be useful in some patients to confirm the clinical diagnosis, determine the severity of myocardial involvement, and distinguish this disorder from other causes of myocardial disease (10). The pathologic findings vary in severity and consist mainly of foci of interstitial plasma cell and lymphocyte infiltrates and patchy fibrosis. In rare cases, the infiltrate is diffuse. Lupus myocarditis usually responds to immunosuppressive medications. Additional cardiac manifestations that can be seen in SLE, none of which were clinically thought to be significant considerations in this patient's acute presentation, include valvular thickening and decompensation, pericarditis, small-vessel vasculopathy, and thromboses associated with antiphospholipid-antibody syndrome.
Should a biopsy be performed?.
Because most cases of myocarditis in developed countries are presumably caused by viral pathogens, the course of this disease is usually self-limited, and pinpointing a precise etiology is often challenging. However, in cases in which the clinical picture is not clear or there is a persistent or fulminant myocarditis, performing right heart catheterization with endomyocardial biopsy may guide management, exclude important treatable causes, and yield a tissue diagnosis. Performing a biopsy may be useful for confirming diagnoses such as sarcoidosis, amyloidosis, hemochromatosis, GCM, and metastatic neoplasm. The scenario of new-onset heart failure of less than 6 days' duration associated with hemodynamic compromise is an American Heart Association/American College of Cardiology/European Society of Cardiology class I indication for endomyocardial biopsy (11). However, the sensitivity of endomyocardial biopsy may be limited by the focal and patchy nature of myocarditis (12). Owing to the severity of cardiac dysfunction in this patient and her fulminant clinical course, an endomyocardial biopsy was performed.
The diagnostic procedure performed was an endomyocardial biopsy. This revealed extensive myocyte necrosis in association with a mixed dense lymphoplasmacytic infiltrate (13) (Figure 1). There were also numerous multinucleated giant cells and degranulated eosinophils. These findings were consistent with GCM, which is a pathologic diagnosis characterized by myocardial necrosis and chronic inflammation. The inflammatory infiltrate consists of lymphocytes, plasma cells, macrophages, eosinophils, and multinucleated giant cells. Well-formed granulomas are typically absent.
The pathologic differential diagnosis of this case focused primarily on the question of idiopathic GCM versus GCM associated with disorders of immune dysregulation, including autoimmune disease (14, 15). Fulminant sarcoidosis and infectious etiologies such as tuberculosis also warranted consideration. Fulminant sarcoidosis is characterized by the presence of well-formed granulomas, in contrast to this case, and few or no eosinophils (16). In addition, sarcoidosis also usually reveals itself with involvement clinically or pathologically at other typical locations, for which there was no evidence here. Special stains for acid-fast bacilli and fungi were negative, making the diagnosis of tuberculosis or fungal myocarditis unlikely. In summary, the histologic appearance was most consistent with GCM.
GCM is a rare and aggressive form of myocarditis. Its etiology is unknown. Patients with GCM develop rapidly progressive congestive heart failure, ventricular arrhythmias, and frequently have a poor prognosis. The median survival from the onset of symptoms is only 5.5 months (4). Responses to immunosuppressive therapy in GCM are often not sustained and patients may deteriorate rapidly to death or cardiac transplantation. Nonetheless, Cooper et al (4) reported that patients who were treated aggressively with combination immunosuppressive therapy fared better in comparison with untreated patients or patients treated with glucocorticoids alone. Those same investigators reported the occurrence of an autoimmune disease in association with GCM in 19% of their cohort. Other reported associations of GCM and CTD are few, although some case reports exist (15, 17). It is not known whether the GCM in this case was associated with or triggered by the CTD; however, the unusually rapid and durable response to immunosuppressive treatment may hint at a relationship with her underlying autoimmune state. One can speculate whether compliance with the recommendation to start hydroxychloroquine when the patient had presented with CTD may have blocked the triggering of GCM. However, additional studies and observations are required before the true nature of the association, if there is any, between GCM and CTDs can be clarified.
SUBSEQUENT CLINICAL COURSE
Due to a high clinical suspicion for myocarditis related to her autoimmune disease, the patient was treated empirically with high-dose glucocorticoids until the endomyocardial biopsy results were available. Once the histologic diagnosis of GCM had been established, an aggressive regimen of glucocorticoids, cyclosporine, and muromonab-CD3 (OKT3) was started. This therapeutic regimen was chosen based on data showing that combination therapy of multiple immunosuppressive agents appears to be associated with improved survival in patients with GCM compared with corticosteroids alone (4). However, survival remains poor and heart transplantation is often required. Capillary leak syndrome developed after 7 days of OKT3 and this treatment was discontinued. Despite this, her clinical status improved, the intraaortic balloon pump was removed, and inotropic support was discontinued. She was eventually discharged to home on hospital day 14, receiving prednisone (60 mg/day), cyclosporine, carvedilol, and lisinopril.
A repeat endomyocardial biopsy performed 1 week after discharge revealed ongoing myocyte necrosis and giant cells in spite of a stable clinical picture; however, the associated inflammatory infiltrates were less. Mycophenolate mofetil (MMF) was added to her regimen. Right heart catheterization demonstrated normal left and right filling pressures. Two weeks after initiation of MMF, repeat right heart catheterization remained normal and endomyocardial biopsy samples showed that the inflammatory infiltrates had diminished further. Myocyte necrosis was more focal, consistent with resolving myocarditis (Figure 2). TTE performed at this time revealed normal left and right ventricular function (LVEF 60%) and normalized thickness of the left ventricular wall. Two weeks later, a repeat biopsy showed only a single small focus of lymphoplasmacytic infiltrate with only a few giant cells remaining. Fifteen weeks after the initial biopsy, the endomyocardium appeared essentially normal, with no further myocyte necrosis or giant cells and a few minute clusters of mature quiescent lymphocytes (Figure 3). Five months after discharge from her initial hospitalization, the prednisone was discontinued entirely. At 1 year of followup she continues to do well on MMF and cyclosporine with New York Heart Association class I symptoms.
Dr. Kalish had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study design. Martorell, Kalish.
Acquisition of data. Martorell, Rust, Salomon, Krishnamani, Kalish.
Analysis and interpretation of data. Martorell, Rust, Patel, Kalish.