Published online before print August 18, 2003, doi: 10.1161/01.CIR.0000085168.02782.2C
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(Circulation. 2003;108:945.)
© 2003 American Heart Association, Inc.
Clinical Investigation and Reports |
Parvovirus B19 Infection Mimicking Acute Myocardial Infarction
From the Medical Clinic II (U.K., M.P., C.P.L.S., B.S., L.K., W.P., H.-P.S.), Department of Cardiology, University Hospital Benjamin Franklin, Berlin, Germany; Institute for Pathology (T.B., K.K., R.K.), University Hospital of Tübingen, Tübingen, Germany.
Correspondence to Uwe Kühl, PhD, Department of Internal Medicine, Cardiology and Pneumonology, Benjamin Franklin Hospital, Free University of Berlin, Hindenburgdamm 30, D-12200 Berlin, Germany. E-mail dcmkuehl{at}zedat.fu-berlin.de
Received February 19, 2003; revision received June 2, 2003; accepted June 3, 2003.
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Abstract |
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Background— Enteroviruses (EVs) and adenoviruses (ADVs) have been considered common causes of myocarditis and dilated cardiomyopathy. In the present study, we report on the association of parvovirus B19 (PVB19) genomes in the clinical setting of acute myocarditis.
Methods and Results— This study included 24 consecutive patients admitted to our hospital within 24 hours after onset of chest pain. Acute myocardial infarction had been excluded in all patients by coronary angiography. Endomyocardial biopsies were analyzed by nested polymerase chain reaction/reverse transcriptase-polymerase chain reaction for EV, ADV, PVB19, human cytomegalovirus, Epstein-Barr virus, Chlamydia pneumoniae, influenza virus A and B, and Borrelia burgdorferi genomes, respectively, followed by direct sequencing of the amplification products. All patients presented with acute onset of angina pectoris and ST-segment elevations or T-wave inversion mimicking acute myocardial infarction. Mean baseline peak creatinine kinase and creatine kinase-isoenzyme fraction were 342±241 U/L and 32±20 U/L, respectively. Mean troponin T was increased to 7.5±15.0 ng/mL and C-reactive protein to 91±98 mg/mL. Eighteen patients had global or regional wall motion abnormalities (ejection fraction 62.5±15.5%). Histological analysis excluded the presence of active or borderline myocarditis in all but one patient. PVB19, EV, and ADV genomes were detected in the myocardium of 12, 3, and 2 patients, respectively (71%). Follow-up biopsies of virus-positive patients (11 of 17) demonstrated persistence of PVB19 genomes in 6 of 6 patients, EV genomes in 2 of 3 patients, and ADV genomes in 1 of 2 patients, respectively.
Conclusions— Virus genomes can be demonstrated in 71% of patients with normal coronary anatomy, clinically mimicking acute myocardial infarction. In addition to EVs and ADVs, PVB19 was the most frequent pathogen.
Key Words: myocarditis • viruses • pericarditis • biopsy • polymerase chain reaction
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Introduction |
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Myocarditis is the term used to indicate infectious, toxic, or autoimmune processes causing inflammation of the heart. The clinical spectrum of myocarditis includes asymptomatic patients who may have electrocardiographic abnormalities, patients with signs of clinical heart failure and ventricular dilatation, and patients with symptoms of fulminant heart failure and severe left ventricular dysfunction without cardiac dilatation.1 Myocarditis can also mimic acute myocardial infarction, with acute onset of chest pain, ECG abnormalities, serum creatinine kinase elevation, arrhythmias, or hemodynamic instability.2–6
Patients with myocarditis may present with or without a history of a recent flu-like syndrome accompanied by fever, arthralgias, and malaise. Most cases with acute onset in otherwise healthy people are considered to have an infectious origin. Unfortunately, the clinical diagnosis of myocarditis remains a challenge because of the nonspecific pattern of clinical presentation and the lack of universally accepted and standardized diagnostic criteria. The discordance between clinical and histological features of acute myocarditis and the inherent limitation of histological diagnosis necessitates further diagnostic procedures to establish the infectious origin of the acute disease. Recent studies suggest that assessment of viral genomes in endomyocardial biopsies may provide further diagnostic and prognostic information, as well as discriminate between autoimmune and viral myocarditis.
Among others, enteroviruses (EVs) and adenoviruses (ADVs) have been demonstrated in patients with myocarditis and dilated cardiomyopathy.7–9 In patients in whom myocarditis presented clinically as acute myocardial infarction, active or borderline myocarditis were diagnosed in various percentages, depending on the time interval of biopsy after acute onset of the disease, whereas virus analysis was either not performed or resulted in low evidence of virus genomes.2–6
The aim of the present study was to define the role of early endomyocardial biopsy in detecting virus genomes in patients with the clinical setting of acute myocardial infarction despite a normal coronary angiogram.
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Methods |
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Patients and Clinical Classification
Between April 1999 and February 2001, endomyocardial biopsies of 346 patients with clinically suspected myocarditis (n=242) or dilated cardiomyopathy (n=104) were investigated in our hospital. Among these patients, 24 patients with clinical signs and symptoms consistent with acute myocardial infarction underwent right ventricular endomyocardial biopsy within 6.7 days (95% confidence interval, 1.8 to 11.5 days) after onset of symptoms, after angiographic identification of normal coronary anatomy and exclusion of other possible causes of clinical symptoms (ie, valvular and hypertensive heart disease or systemic diseases). The initial diagnosis of clinically suspected acute myocarditis was based on abrupt onset of complaints, such as angina, together with newly developed ECG changes (ST-segment elevation or T inversion) and simultaneous detection of a serum marker of myocardial injury (creatine kinase/creatine kinase-MB or troponin T). Serum markers of myocardial injury were an elevated creatine kinase with an activity >80 U/L, an elevated creatine kinase-MB >8%, and/or a troponin T serum level of
0.2 ng/mL.
Endomyocardial Biopsy and Right-Heart Catheterization
After written informed consent, 8 endomyocardial biopsies were obtained from the right side of the ventricular septum of each patient with a flexible bioptome (Westmed, Germany) via the femoral vein approach. Two biopsies were used for the histological evaluation according to the Dallas criteria and immunohistochemistry,10 respectively, whereas the remaining 4 biopsies were subjected to DNA and RNA extraction for the amplification of viral genomes.
After the biopsy specimens were obtained, the patients underwent right heart catheterization. Right atrial, right ventricular, pulmonary arterial, pulmonary-capillary wedge pressures, and cardiac index calculated by thermodilution technique were recorded. Standard 2-dimensional and M-mode echocardiography were performed at the time of biopsy in all patients.
Etiologic Investigations: Detection of Viral Genomes and Direct DNA-Sequencing of PVB19 Genomes
DNA and RNA were extracted simultaneously from frozen heart muscle tissue probes. Polymerase chain reaction (PCR)/reverse transcriptase (RT)-PCR was performed for the detection of EVs (including coxsackieviruses and echoviruses), ADVs, parvovirus B19 (PVB19), human cytomegalovirus, Epstein-Barr-virus, Chlamydia pneumoniae, influenza virus A and B, and Borrelia burgdorferi, as described.8,11 As a control for successful extraction of nucleic acids, primer sequences were chosen from the sequence of the glyceraldehyde-3-phosphate dehydrogenase gene.
Sequence analysis of PVB19 PCR fragments were performed by automatic ABI Prism 310 Genetic Analyzer and BigDye Cycle Sequencing Kit according to manufacturer instructions (Applied Biosystems).12 The PVB3-primer (5'-GCTAACTCTGTAACTTG-TAC-3') was used for cycle sequencing. The sequences obtained were matched with the National Center for Biotechnology Information GenBank and compared with a recently described PVB19 genome (accession No. U3850913).
Serological Investigations
Serum titers of IgM antibodies for coxsackievirus B1 were increased in only one patient (1:128), whereas all other patients had low IgG titers for various virus species (eg, EVs, ADVs, cytomegalovirus, influenza virus, Epstein-Barr virus). Because PVB19 myocarditis had not been expected in the beginning of the study, PVB19 viral antibody titers had not been serially evaluated at the initial presentation of the patients. At follow-up, serological analyses (remcomBlot Parvovirus-B19-IgG, Mikrogen), however, revealed positive PVB19 IgG titers for 9 of 12 PVB19-positive and for 2 PVB19-negative patients. Two PVB19-negative patients and 2 EV-positive patients had a negative PVB19 serology (Table 4).
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Statistical Analysis
Statistical analysis was performed using JMP Statistical Discovery Software 3.1.6 (SAS Institute). Results are expressed as mean±SD, unless stated otherwise. Nonparametric tests were used for non-normally distributed variables. Qualitative data were compared by 
2 test. A 2-sided value of P<0.05 was considered statistically significant.
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Results |
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Clinical Presentation
The study group comprised 21 men and 3 women (mean age, 39.5±15.4 years; range, 18 to 70 years). Seven patients (29%) were febrile at the time of admission, 14 patients had an antecedent upper respiratory tract infection 18 days (median) (95% confidence interval, 5.1 to 31 days) preceding the onset of cardiac symptoms, 8 patients had coronary risk factors (smoking), and 2 patients had a family history of cardiomyopathy. All patients admitted to our hospital presented with acute onset of nonpleuritic precordial chest pain within 24 hours of presentation, suggestive of acute myocardial infarction. Baseline clinical characteristics of all patients are given in Table 1.
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At the time of presentation, observed electrocardiographic changes included ST-segment elevation in 20 patients (anterior precordial leads, 8 patients; inferior, 12 patients) and T-wave inversion in 4 patients (anterior, 2; inferior, 2) but no ST-segment depression or pathological Q waves. None of the patients had supraventricular or ventricular extra beats or tachycardia or electrocardiographic conductance abnormalities at presentation or during hospitalization.
Baseline peak creatine kinase and MB isoenzyme fraction were increased to 342±241 U/mL (range, 104 to 962) and 32±20 U/mL (range, 10 to 86) (n=22) and normalized within 60 hours in all but one patient. Mean troponin T (normal <0.05 ng/mL) was increased to 7.5±15.0 ng/mL and C-reactive protein (normal <6 mg/dL) to 91±98 mg/mL (n=16), respectively.
Biplane left ventricular angiography revealed normal wall motion in 6 patients, global left ventricular hypokinesia in 14, and segmental hypokinesia in 4. The mean ejection fraction (EF) was 62.3±15.9%, and it was below 45% in only 3 of the patients. Cardiac index was normal in 18 patients and below 2.6 l per min/m2 in 3 (mean 3.4±1.3 l per min/m2, range 1.7 to 6.9 l per min/m2). Mean pulmonary artery pressure and pulmonary wedge pressure were increased >14 mm Hg and 12 mm Hg in 3 patients, respectively. Wall motion abnormalities persisted during time of hospitalization in all 18 patients initially presenting with regional and global hypokinesia of the left ventricle in angiography and was associated with persisting ventricular dilatation in only one patient. Three patients had a pericardial effusion. Hemodynamic and echocardiographic data are summarized in Table 1.
After admission, the initial episode of chest pain ceased within 1 to 24 hours in 12 patients, but 12 patients continued to have recurrent episodes of chest pain despite therapy directed at reversing ischemia. Episodes of chest pain persisted on discharge in these patients. Although all patients had normal coronary arteries on angiography, coronary artery spasms could be induced in 6 of 9 patients who underwent a challenge test with the vasoconstrictor ergonovine. Four of the 6 patients in whom coronary artery spasm could be induced and who complained of recurrent episodes of angina were PVB19 positive in the PCR analysis.
Histology, Immunohistology, and PCR Analysis
The data on endomyocardial biopsy specimens are summarized in Table 2. One EV-positive patient had active myocarditis according to the Dallas Criteria. In the remaining 23 patients, neither active nor borderline myocarditis was present. Immunohistochemically, numbers of infiltrating CD3-positive T lymphocytes and macrophages (median) were 5.0 and 3.0 cells/mm2, respectively. Numbers of CD3-positive lymphocytes were not statistically different between virus-positive (n=17) and virus-negative (n=7) patients (1.4 versus 5.0 cells/mm2; P=0.19), whereas macrophages were increased in the virus-positive cohort of patients (2.1 versus 3.9 cells/mm2; P=0.04).
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PCR amplification of parvoviral genomes occurred in cardiac tissue specimen from 12 patients (50%). Enteroviral RNA and adenoviral DNA were detected in 3 and 2 patients, respectively. Seven patients (30%) were negative in the PCR analysis. Representative gel electrophoresis results of PVB19 detection are summarized in the Figure (A). All PCR fragments were sequenced and confirmed the positive PVB19 nested-PCR results (Figure, B). Sequence analysis of PVB19 revealed randomly distributed point mutations in the VP1/2 region of the PVB19 isolates. In view of quality control, it is noteworthy that the PVB19 isolates showed sequence differences when compared with each other. Therefore, contaminations with PVB19 of the patient’s samples that may especially occur during nested PCR methods could be excluded. Interestingly, mutational hot spot-like regions that appeared in the analyzed sequences may be due to different PVB19 genotypes described previously14 (Figure, B). However, the presence of different genotype has to be elucidated in more detail. These sequence variations may be due to different PVB19 genotypes as discussed previously.14,15
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Follow-Up
Control biopsies were available from 11 of 17 initially virus-positive patients (EV 3, ADV 2, PVB19 6). Although PVB19 persisted in all 6 patients, enteroviral and adenoviral genomes were cleared from the myocardium in one patient.
During a mean echocardiographic follow-up period of 7.4 months, regional and global wall motion abnormalities persisted in patients who developed virus persistence (n=9), despite medication with ACE inhibitors and diuretics. Left ventricular end-diastolic diameters of these patients increased in tendency, whereas the increase of end-systolic diameters was statistically significant (P<0.02) (Table 3). In the subgroup of patients with PVB19 persistence (n=6), EF decreased from 70.4±9.6% to 60.8±13.5% (P<0.02). EF improved in one patient who cleared enteroviral RNA from the myocardium. In the 2 patients developing EV persistence, EF decreased from 81% to 69% and from 80% to 65%, respectively (Table 4). One of the 2 ADV-positive patients developed virus persistence, whereas the other cleared adenoviral DNA from the myocardium (Table 4). In virus-negative patients, global hypokinesia persisted in one patient and resolved in another. Wall motion remained unaffected in the other 5 patients (data not shown).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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All 24 patients presented with abrupt onset of angina and variable degrees of wall motion abnormalities, mimicking acute myocardial infarction. Clinical symptoms, ECG abnormalities, and creatine kinase or troponin T elevations, suggestive of myocardial injury, were the reason for immediate coronary angiography that demonstrated normal coronary anatomy in all patients. One important differential diagnosis to be taken into consideration in this clinical setting is acute myocarditis, which neither exclusively afflicts younger people nor has to be associated with a typical history of antecedent viral illness. Thus, after exclusion of coronary artery disease, clinical presentation of the patients led to the consideration of an acute infectious myocardial process, which is the characteristic indication for endomyocardial biopsy in the search for active myocarditis.2–6
Recently, the application of molecular technology to the clinical diagnosis of infectious disease has confirmed viral genomic persistence in myocardial tissues in a variable percentage of patients with myocarditis.7–9,16,17–20 However, reported frequencies of cardiotropic viruses in patients with acute myocarditis and histological or clinical signs of myocardial injury appear to be low.3,6,21 Spontaneous clearance of the viral infection during this early stage of the disease may be one explanation for the low virus frequency detected in these patients. On the other hand, other viruses that have not been taken into consideration in the diagnostic concepts in the past might be responsible for the acute myocardial injury of the early disease.
PVB19 is typically linked with the clinically presentation of erythema infectiosum (Fifth disease), hydrops fetalis, and fetal death, or transient aplastic crisis in patients with various forms of anemia. Besides the well-established enteroviral and adenoviral origin of myocarditis, a growing number of case reports show the association between PVB19 infection and myocarditis,11,22–25 various vasculitis syndromes in children,26 and fulminant hepatitis or meningoencephalitis.27,28 In addition, a role of PVB19 in cardiac allograft rejection has been suggested at the onset of acute rejection after heart transplantation.29,30 As of now, the frequency and clinical course of PVB19 in adults has not been investigated systematically.
In the present study, we analyzed the potential role of PVB19 in the clinical setting of acute myocarditis, in addition to EV and ADV infections. PCR analysis demonstrated the presence of virus genomes in 71% of the patients. PVB19 was the most frequent pathogen, whereas enteroviral and adenoviral genomes were detected in 3 and 2 of 24 consecutive patients, respectively. Histological and immunohistological analysis excluded lymphocytic infiltration in the majority of patients. These findings indicate that, in the absence of myocardial lymphocytic infiltration, PVB19 may represent a frequent and hitherto not considered pathogen in addition to enteroviral and adenoviral infections of the myocardium in patients in the clinical setting of acute viral-induced heart disease.
Most previous studies in patients with acute myocarditis have analyzed endomyocardial biopsy specimens according to the histological Dallas classification. Active or borderline myocarditis was diagnosed in various percentages depending on the time interval of biopsy after acute onset of the disease.4,6,31 In PVB19-positive patients, the situation appears to be different to that of EV-induced myocarditis. All biopsies but one were negative in the histological analysis, revealing no histological signs of myocarditis in 23 of 24 patients. In the immunohistochemical analysis, the majority of patients (21 of 24) presented with low-grade lymphocytic inflammation. Lymphocyte numbers, which were <10 cells/mm2, did not discriminate between different viruses or virus-positive and virus-negative patients, respectively. Macrophages, on the other hand, were increased in virus-positive biopsies. Thus, acute onset of symptoms and myocardial damage may be caused by different mechanisms, depending on the involved virus species. The lack of substantial lymphocytic inflammation in our patients with virally induced heart disease may indicate an inefficient immune response against the viral infections, preventing effective virus clearance. Alternatively, it may point to macrophage-dependent pathomechanisms different from those of lymphocytic myocarditis. It cannot be ruled out, however, that the timing of the biopsy was too early or too late to detect possible transient infiltration of the myocardium.
At least for ADVs and EVs, serology does not correlate with local virus infection of the myocardium, and therefore, absence or presence of serum antibodies does not allow any conclusion about infection of the heart by those viruses. On the other hand, it cannot be excluded that latent persistence of PVB19 genomes may last for years without causing damage to the host, until hitherto-unknown factors induce transcriptional activity of the PVB19 genomes, resulting in an acute symptomatic disease as described in this study.
Twelve patients experienced prolonged or recurrent episodes of chest pain during their hospital course and after dismissal despite antiischemic treatment. Coronary spasms could be induced in a challenge test in a subset of these patients.
In addition to proliferating erythroid precursor cells, endothelial cells have been recognized as targets for PVB19 infection if they express blood group P antigen, which serves as a cellular receptor for this virus.32 Because endothelial cells but not cardiac myocytes represent the PVB19-specific target cells in PVB19-associated myocarditis,11 initial PVB19 infection of endothelial cells of small coronary arteries and venules may cause endothelial dysfunction, which might explain the persistence of anginal symptoms as well as electrocardiographic and laboratory findings consistent with myocardial injury.
Follow-up of a subgroup of PVB19-positive patients revealed that persistence of virus genomes may be associated with progression of left ventricular dysfunction. This observation is in accordance with data from a treatment study of EV-caused left ventricular dysfunction, where interferon-ß was found to be effective with regard to virus clearance and improvement of ventricular function, whereas ventricular dysfunction did not improve in patients with enteroviral persistence.33
The small series of PVB19-positive patients seems to confirm that PVB19 infection of the myocardium is a hitherto infrequently considered pathogen in adults, which may masquerade as acute myocardial infarction. Because PVB19 infection may persist and be associated with progression of left ventricular dysfunction clinically diagnosed as dilated cardiomyopathy, routine molecular biological methods should be extended to this virus in the virological diagnosis of patients with myocarditis and particularly idiopathic left ventricular dysfunction. Endothelial dysfunction may be caused by early PVB19 infection of vascular endothelial cells, thus being a reason for unexplained angina pectoris in patients in the absence of coronary heart disease.
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P.-Y. Levy, P.-E. Fournier, R. Charrel, D. Metras, G. Habib, and D. Raoult Molecular analysis of pericardial fluid: a 7-year experience Eur. Heart J., August 2, 2006; 27(16): 1942 - 1946. [Abstract] [Full Text] [PDF]
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U. Sechtem and M. Vohringer The clinical role of 'non-invasive' coronary angiography by multidetector spiral computed tomography: yet to be defined Eur. Heart J., October 1, 2005; 26(19): 1942 - 1944. [Full Text] [PDF]
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U. Kuhl, M. Pauschinger, B. Seeberg, D. Lassner, M. Noutsias, W. Poller, and H.-P. Schultheiss Viral Persistence in the Myocardium Is Associated With Progressive Cardiac Dysfunction Circulation, September 27, 2005; 112(13): 1965 - 1970. [Abstract] [Full Text] [PDF]
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H. Abdel-Aty, P. Boye, A. Zagrosek, R. Wassmuth, A. Kumar, D. Messroghli, P. Bock, R. Dietz, M. G. Friedrich, and J. Schulz-Menger Diagnostic Performance of Cardiovascular Magnetic Resonance in Patients With Suspected Acute Myocarditis: Comparison of Different Approaches J. Am. Coll. Cardiol., June 7, 2005; 45(11): 1815 - 1822. [Abstract] [Full Text] [PDF]
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K. B. Vallbracht, P. L. Schwimmbeck, U. Kuhl, U. Rauch, B. Seeberg, and H.-P. Schultheiss Differential Aspects of Endothelial Function of the Coronary Microcirculation Considering Myocardial Virus Persistence, Endothelial Activation, and Myocardial Leukocyte Infiltrates Circulation, April 12, 2005; 111(14): 1784 - 1791. [Abstract] [Full Text] [PDF]
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U. Kuhl, M. Pauschinger, M. Noutsias, B. Seeberg, T. Bock, D. Lassner, W. Poller, R. Kandolf, and H.-P. Schultheiss High Prevalence of Viral Genomes and Multiple Viral Infections in the Myocardium of Adults With "Idiopathic" Left Ventricular Dysfunction Circulation, February 22, 2005; 111(7): 887 - 893. [Abstract] [Full Text] [PDF]
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C. Tschope, C.-T. Bock, M. Kasner, M. Noutsias, D. Westermann, P.-L. Schwimmbeck, M. Pauschinger, W.-C. Poller, U. Kuhl, R. Kandolf, et al. High Prevalence of Cardiac Parvovirus B19 Infection in Patients With Isolated Left Ventricular Diastolic Dysfunction Circulation, February 22, 2005; 111(7): 879 - 886. [Abstract] [Full Text] [PDF]
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K. B. Vallbracht, P. L. Schwimmbeck, U. Kuhl, B. Seeberg, and H.-P. Schultheiss Endothelium-Dependent Flow-Mediated Vasodilation of Systemic Arteries Is Impaired in Patients With Myocardial Virus Persistence Circulation, November 2, 2004; 110(18): 2938 - 2945. [Abstract] [Full Text] [PDF]
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 B. D. Bultmann, K. Sotlar, K. Klingel, P. H. Pronovost, N. S. Young, and K. E. Brown Parvovirus B19 N. Engl. J. Med., May 6, 2004; 350(19): 2006 - 2007. [Full Text] [PDF]
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S. Pankuweit, S. Lamparter, M. Schoppet, and B. Maisch Parvovirus B19 Genome in Endomyocardial Biopsy Specimen Circulation, April 13, 2004; 109(14): e179 - e179. [Full Text] [PDF]
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