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(Circulation. 1995;92:2519-2525.)
© 1995 American Heart Association, Inc.

Articles

Dilated Cardiomyopathy Associated With Hepatitis C Virus Infection

Akira Matsumori, MD; Yoshiki Matoba, MD; Shigetake Sasayama, MD

From the Third Division, Department of Internal Medicine, Faculty of Medicine, Kyoto (Japan) University.

Correspondence to Akira Matsumori, MD, Third Division, Department of Internal Medicine, Faculty of Medicine, Kyoto University, 54 Kawaracho, Shogoin, Sakyo-ku, Kyoto 606, Japan.

	Abstract

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Background Myocarditis is thought to be commonly caused by various viruses, and accumulating evidence links viral myocarditis with the eventual development of dilated cardiomyopathy. In many cases, however, the evidence is only circumstantial, and direct conclusive proof is not available. Polymerase chain reaction (PCR) has been used to detect enterovirus RNA in myocardial tissue, but the wide discrepancy in results emphasizes the need for further study.

Methods and Results We investigated hepatitis C virus infection in patients with dilated cardiomyopathy. The presence, type, and quantity of hepatitis C virus RNA were evaluated in the sera, and the presence of positive and negative strands of hepatitis C virus RNA in the heart was investigated with the PCR technique. Anti–hepatitis C virus antibody was present in the sera of 6 of 36 patients (16.7%) with dilated cardiomyopathy and in 1 of 40 patients (2.5%) with ischemic heart disease, showing a statistically significant (P<.05) difference. At an earlier time, acute myocarditis was suspected in 3 patients who had developed acute onset of heart failure, and the diagnosis was confirmed by endomyocardial biopsy in 1 patient. Hepatitis C virus RNA was present in the sera of 4 of the 6 patients, and all 4 had hepatitis C virus type II. The copy number of hepatitis C virus RNA in the serum was 8x10² to 2x10³ genomes per 1 mL serum. Positive strands of hepatitis C virus were found in the hearts of 3 patients, and negative strands of hepatitis C virus were detected in the heart of 1 patient.

Conclusions The results suggest that hepatitis C virus infection is frequently found in patients with dilated cardiomyopathy and that hepatitis C virus is an important causal agent in the pathogenesis of the disease. Antiviral therapy against hepatitis C virus may be indicated in these patients.

Key Words: viruses • heart failure • myocarditis • polymerase chain reaction • cardiomyopathy

	Introduction

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The myocardium is affected in a wide range of virus infections. In some cases, myocarditis may be the primary problem; in others, myocarditis may occur as part of the general disease. Myocarditis is thought to be most commonly caused by enteroviruses, particularly coxsackievirus B. However, in many cases when myocarditis has been assumed on clinical grounds, no definite evidence of viral origin is obtained, despite extensive laboratory investigation. The evidence often is only circumstantial, and direct conclusive proof of cardiac involvement is not available.^{1 2 3} Now that endomyocardial biopsy has become available,⁴ more data are accumulating from direct examination of the myocardial tissue of patients during episodes of myocarditis. The use of nucleic acid technology may help to overcome some of these diagnostic difficulties.^{5 6 7} In addition to direct damage to the cardiac muscle by virus infection, an immunologically mediated process may be taking place over a longer time period, continuing after clinical evidence of the triggering infection has been resolved.

Accumulating evidence links viral myocarditis with the eventual development of dilated cardiomyopathy.^{8 9 10} The development of molecular biological techniques made detecting viral nucleic acid in small endomyocardial tissue samples possible. This has not only strengthened the pathogenetic link between myocarditis and dilated cardiomyopathy but also provided some evidence that the presence of virus may have prognostic implications.¹¹ The polymerase chain reaction (PCR) gene amplification technique, which is sensitive and specific, has been applied in the diagnosis of viral disease in small tissue samples in which low copy numbers of the viral genome may be present. Although the PCR technique might appear to be a sensitive means of detecting enterovirus in myocardial biopsy tissue, other centers have reported somewhat conflicting results. The wide discrepancy in reported results is probably due to the different detection procedures adopted by the various investigators, thereby emphasizing the need for a detection assay that is reliable, sensitive, and specific. Furthermore, recent study has shown that enterovirus RNA is not a major cause of dilated cardiomyopathy.¹²

We found a relation between hepatitis C virus infection and the occurrence of dilated cardiomyopathy. The results suggest that hepatitis C virus infection is important in the pathogenesis of myocarditis and cardiomyopathy and that antiviral therapy against hepatitis C virus might be considered in such patients.

	Methods

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Patients and Clinical Assessment
The patient population studied comprised 36 consecutive patients, 25 men and 11 women 46.5±15.8 years of age (mean±SD; range, 17 to 66 years), admitted to Kyoto (Japan) University Hospital between 1987 and October 1994 for the investigation and treatment of heart muscle disease. A full history was obtained from each patient before investigation, and the following details were recorded: duration of symptoms before presentation, history of preceding viral illness, history of alcohol abuse (defined as >80 g alcohol daily for >5 years), history of chest pain, arrhythmia, and symptoms of cardiac failure. Routine ECGs, chest radiographs, echocardiograms, and Holter monitoring were performed on all patients. The presence of cardiomegaly on chest radiographs and any ECG abnormalities, including left bundle-branch block and ventricular arrhythmia, were recorded.

Cardiac catheterization, including coronary angiography, was performed by the Judkins technique in all patients. Endomyocardial biopsy from the right ventricle was performed on all patients at the time of catheterization using a Stanford bioptome by the internal jugular approach.¹³ Five samples usually were taken from each patient; three samples were fixed in 10% formalin, embedded in paraffin, and cut into 6-µm sections; the other two samples were instantly frozen in liquid nitrogen for molecular diagnosis. Multiple sections of the biopsy were stained with hematoxylin and eosin and examined by light microscopy. Samples from 3 patients were obtained at the time of autopsy. The pathological changes in dilated cardiomyopathy were nonspecific but consisted of hypertrophic myocardial fibers, thickening of the endocardium, evidence of myocardial dilatation, and a variable degree of interstitial fibrous replacement.¹⁴

Endomyocardial biopsy samples for viral evaluation were quick-frozen in liquid nitrogen and stored at -80°C until analysis.

Hepatitis C Virus Antibody
Blood was collected at the time of diagnostic catheterization, and the separated serum was stored at -80°C until the time of assay. The incidence of antibody against hepatitis C virus was compared with that of 40 consecutive patients, 24 men and 16 women 57.7±8.2 years of age (range, 38 to 70 years), who underwent cardiac catheterization during July through December 1993. These patients did not differ demographically or socioeconomically from those with dilated cardiomyopathy. Antibodies against hepatitis C virus were detected by a second-generation immunoradiometric assay (Ortho Diagnostics).

Hepatitis C Virus RNA and Typing
The frozen tissue was homogenized in 200 µL of 4 mol/L guanidium thiocyanate, 25 mmol/L sodium citrate (pH 7.0), 5% sarcosyl, and 0.1 mol/L mercaptoethanol. RNA was extracted by a previously described method.¹⁵

The positive and negative strands of viral RNA were detected by reverse transcription (RT) of RNA samples in the presence of only one oligonucleotide primer (either the sense or the antisense primer) followed by heart inactivation of the reverse transcriptase. The DNA produced in this RT reaction was therefore complementary to one of the two RNA strands and could then be amplified by PCR in the presence of both oligonucleotide primers.

The oligonucleotide primers used were chosen from the highly conserved 5' noncoding region nucleotide sequence of the hepatitis C virus genome.¹⁶ For the external primers, the following sequences were used: sense, nucleotides 29 through 53, 5'-CACTCCCCTGTGAGGAACTACTGTC-3'; antisense, nucleotides 310 through 334, 5'-ATGGTGCAGGGTCTACGAGACCTCC-3'. The internal primers were as follows: sense, nucleotides 54 through 73, 5'-TTCACGCAGAAAGCGTCTAG-3'; antisense, nucleotides 179 through 198, 5'GTTGATCCAAGAAAGGACCC-3'.

RT was performed as described in a 20-µL reaction volume containing 1 µL serum RNA, 0.4 µmol/L sense or antisense primer, 250 µmol/L of the four dNTPs (Perkin Elmer Cetus), 15 U RNasin (Wako Chemical Co, Ltd), 1x RT buffer, and 100 U murine leukemia reverse transcriptase (GIBCO BRL). The mixture was overlaid with mineral oil and incubated at 37°C for 1 hour. The reverse transcriptase was then inactivated by heating at 95°C for 5 minutes, and the mixture was quickly chilled on ice.

PCR amplification was performed by adding 77.5 µL of 1x PCR buffer containing 400 µmol/L of the opposite sense primer and 2.5 U of Taq polymerase (Perkin Elmer Cetus). The mixture was overlaid with mineral oil. The thermocycler was programmed to incubate samples at 1 cycle at 92°C for 5 minutes, 55°C for 2 minutes, and 72°C for 3 minutes and then 35 cycles at 90°C for 1 minute, 55°C for 1 minute, and 72°C for 2 minutes, followed by a 10-minute final extension at 72°C.

For the second amplification, 5 µL removed from the first reaction was added to a reaction mixture similar to the first mixture but with 1 µmol/L of the inner primers instead of the outer primers. PCR was carried out for 35 cycles as described for the first amplification. Then 10 µL of the second amplification was analyzed by electrophoresis in a 3% agarose gel containing 1 µg/mL ethidium bromide and visualized under UV light. The size of the expected amplification product was 145 bp.

Hepatitis C virus types were determined on the basis of variations in nucleotide sequence within restricted regions in the putative C (core) gene of the hepatitis C virus.¹⁷ Amplification of a C gene sequence by PCR with a universal primer (sense) and a mixture of four type-specific primers (antisense) produced the products specific for types I through IV.¹⁷ The amplification products of the PCR of each type were 49, 144, 174, and 123 bp for types I through IV, respectively.

To quantify hepatitis C virus RNA in serum, the method used was a competitive assay based on coamplification of the target RNA with known amounts of synthetic mutated RNA.¹⁸

Statistical Analysis
The incidence of antibody against hepatitis C virus was compared by Fisher's exact test.

	Results

Top Abstract Introduction Methods Results Discussion References

 
We identified 6 patients (16.7%) with dilated cardiomyopathy during a 7-year period who had evidence of hepatitis C virus infection on the basis of a positive immunoradiometric assay, whereas only 1 patient (2.5%) of those with ischemic heart disease was positive for the hepatitis C antibody. The difference was statistically significant by Fisher's exact test (P=.039, Table 1). Of the 6 patients, 3 were men and 3 were women; their average age was 45.7±20.9 years (range, 17 to 66 years). Although the patients with dilated cardiomyopathy were younger on average than those with ischemic heart disease, the age difference could not cause a change of statistical significance because prevalence of hepatitis C virus infection increases with increasing age. Prevalence of positive hepatitis C antibody in voluntary blood donors in Japan was 1.65% in subjects 45 to 49 years of age and 2.41% in subjects 55 to 59 years of age (data from the Japan Red Cross Blood Center, 1990). None of the patients with hepatitis C virus antibody in this study had known risk factors for hepatitis C virus infection, such as a history of intravenous drug use, previous blood transfusions, acute hepatitis, or abnormal liver function. Mildly elevated levels of serum transaminase were found in patients 2, 4, and 5. The primary findings at presentation were congestive heart failure and cardiac arrhythmias (Table 2).

View this table: [in this window] [in a new window]   Table 1. Incidence of Antibodies Against Hepatitis C Virus

View this table: [in this window] [in a new window]   Table 2. Clinical Profiles of Patients With Dilated Cardiomyopathy With Positive Anti-HCV Antibody

Sudden onset of congestive heart failure and a previous history of flulike illness were found in 3 patients (patients 2, 5, and 6). In patients 5 and 6, cardiac function improved gradually and became normal within 6 months after the onset of the disease in patient 5 and within 8 months in patient 6. These findings may suggest that these 2 patients had acute myocarditis, but the diagnosis of acute myocarditis was not confirmed by endomyocardial biopsy. Patient 2 exhibited congestive heart failure after flulike symptoms. The diagnosis of acute myocarditis was confirmed by endomyocardial biopsy.

Of the 6 patients in this study with positive hepatitis C virus antibody, none had purpura, arthralgia, or other symptoms suggesting cryoglobulinemia or renal disease (proteinuria and/or abnormal renal function). Three patients had mildly elevated serum transaminase on admission (Table 2). Of these 3 patients, 2 had continued elevation of transaminases, but the elevation was mild; maximal values of SGOT and SGPT were 53 and 43 U/L, respectively, in patient 4 and 49 and 64 U/L, respectively, in patient 5. Liver function test values became normal within 1 week after admission in patient 2.

Of the 6 patients with hepatitis C virus antibodies, 4 patients had hepatitis C virus RNA in the serum, and all 4 patients had type II hepatitis C virus (Fig 1). Quantitative analysis of the hepatitis C virus RNA by competitive nested PCR showed that the copy number in serum was 8x10² to 2x10³ (Table 2). Hepatitis C virus RNA was found in the autopsied heart of patient 1 and in the biopsy specimens of patients 2 and 5 (Fig 2). Negative strands of hepatitis C virus RNA were detected in the heart of patient 1 (Fig 3).

View larger version (62K): [in this window] [in a new window]   Figure 1. Blot showing a representative result of the detection of subtypes of hepatitis C virus by polymerase chain reaction (PCR) with mixed type-specific primers. The amplification of a C gene sequence by PCR with a universal primer (sense) and a mixture of four type-specific primers (antisense) produced the products specific for types I through IV. The amplification products of the PCR of each types were 49, 144, 174, and 123 bp for types I through IV, respectively. Hepatitis C virus type II was detected by 144 bps. Lanes 1 and 2, patient 1; lane 3, positive control; and lane 4, DNA size marker (pUC19/Msp1).

View larger version (68K): [in this window] [in a new window]   Figure 2. Blot showing ethidium bromide–stained agarose gels demonstrating detection of positive stands of hepatitis C virus RNA in the heart by use of strand-specific polymerase chain reaction (PCR) with primers from the hepatitis C virus genomes. RNA was extracted from an endomyocardial biopsy sample, reverse transcribed to cDNA, and amplified by nested PCR. The size of the expected amplification product was 145 bp. Lane 1, DNA size marker; lanes 4 and 5, patient 5; and lane 6, positive control.

View larger version (73K): [in this window] [in a new window]   Figure 3. Blot showing ethidium bromide–stained agarose gels demonstrating detection of negative stands of hepatitis C virus RNA in the heart by use of strand-specific polymerase chain reaction (PCR) with primers from the hepatitis C virus genomes. RNA was extracted from an autopsy sample, reverse transcribed to cDNA, and amplified by nested PCR. The size of the expected amplification product was 145 bp. Lane 1, DNA size marker; lanes 4 and 5, patient 1; lane 6, positive control.

Brief histories of three patients in whom hepatitis virus RNA was detected in the heart are presented here. Patient 1 suffered from chronic congestive heart failure for 3 years. The diagnosis of dilated cardiomyopathy was confirmed at the age of 56 years. The patient died of heart failure 6 years later, and autopsy findings showed an enlarged heart with the diffuse interstitial fibrosis typical of dilated cardiomyopathy. Because only the heart was obtained at autopsy, hepatic histology was not examined.

Patient 2 presented with congestive heart failure after flulike symptoms. The diagnosis of acute myocarditis was confirmed by endomyocardial biopsy, which revealed myocyte necrosis and mild infiltration of inflammatory cells. A favorable response to ß-adrenergic receptor blockade was observed, and the patient was discharged without symptoms. Congestive heart failure recurred 5 months later, however, and the patient died 10 months after the onset of the disease. Postmortem examination revealed left ventricular dilatation with slight interstitial fibrosis, and the diagnosis was dilated cardiomyopathy. Hepatitis C virus RNA was found in the myocardial biopsy specimen but was not detected in the autopsied heart. At autopsy, severe centrilobular necrosis and fibrosis of the liver were observed with systemic congestion, suggesting that liver damage had been induced by congestive heart failure. Renal congestion also was noted.

Patient 5 had a flulike illness for 1 month. Nocturnal dyspnea, orthopnea, and palpitation developed suddenly. The patient was admitted to a local hospital and was referred to our hospital 2 weeks later. ECG showed left ventricular hypertrophy, and chest radiograph showed cardiomegaly on admission. Echocardiography showed dilatation of left ventricular end-diastolic diameter (59 mm) and decreased ejection fraction (31%). The patient improved gradually and 3 months later was in New York Heart Association class II with normal left ventricular dimension and slightly decreased ejection fraction (49%).

	Discussion

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It has been shown that encephalomyocarditis virus and coxsackievirus in experimental animals induce myocarditis, which can evolve into cardiomyopathy, with the associated virus persisting for several months after the primary infection.^{19 20} Molecular hybridization studies have documented the presence of enteroviral nucleic acids in the myocardium of patients with dilated cardiomyopathy. By use of a slot-blot hybridization assay, enteroviral genomic sequences have been detected in 52% of total nucleic acid extracts from myocardial biopsy samples from patients with myocarditis and dilated cardiomyopathy, 28.5% of hearts removed at cardiac transplantation from patients with dilated cardiomyopathy, and 5% of control subjects.⁷ However, dilated cardiomyopathy hearts or control hearts removed at cardiac transplantation failed to demonstrate any viral genomic sequences when a Northern blot assay was used.²¹ The PCR allows rapid amplification of specific DNA sequences. The high specificity and sensitivity of this technique make it uniquely suitable for studying viral diseases when few copies of the viral genome may be present. However, the wide discrepancy in results reported^{22 23} is probably due to the different detection procedures adopted by the various investigators. This discrepancy emphasizes the need for a detection assay that is reliable, sensitive, and specific. More recently, it has been shown that enterovirus is not a primary cause of dilated cardiomyopathy.¹²

Martin et al²⁴ recently reported that adenovirus was more prevalent (68%) than enterovirus in pediatric patients with acute myocarditis by PCR. In a different series of studies, we evaluated 36 patients with cardiomyopathy and myocarditis by PCR for the presence of RNA viruses such as enterovirus, cardiovirus, hepatitis A virus, human immunodeficiency viruses 1 and 2, human T lymphocytic leukemia virus I, influenza A and B viruses, and reovirus. We also evaluated 25 patients with cardiomyopathy and myocarditis for DNA viruses such as adenovirus, cytomegalovirus, Epstein-Barr virus, hepatitis B virus, human herpesvirus 6, varicella-zoster virus, and herpes simplex virus types 1 and 2. However, enterovirus RNA was detected in only 1 patient with dilated cardiomyopathy, and no other virus genomes were found (A.M., unpublished observation, 1995).

We report a relation between hepatitis C virus infection and dilated cardiomyopathy. We found high incidence (16.7%) of hepatitis C virus infection in patients with dilated cardiomyopathy. This incidence was significantly more frequent than in patients with ischemic heart disease in our institution or in the general population because hepatitis C virus infection involves (1% of the general population worldwide.²⁵ Different hepatitis C virus types have been reported in different populations, and hepatitis C virus type II is the most common in both healthy blood donors and patients with liver diseases in Japan.¹⁷ We found hepatitis C virus type II in 4 patients. The amount of hepatitis C virus RNA in the sera in patients with hepatitis by competitive RT-PCR assay ranged from 10⁴ to 10^9.5 genomes per 1 mL serum.¹⁸ The copy numbers of hepatitis C virus in the serum in this study were <10⁴ genomes per 1 mL serum in 3 patients with dilated cardiomyopathy, which was lower than in patients with chronic liver diseases.

Although the sample size was not large enough for a firm conclusion to be drawn, the data suggest that hepatitis C virus infections are important in the pathogenesis of dilated cardiomyopathy. Enterovirus RNA was detected in only 1 patient with dilated cardiomyopathy in our study. These results suggest that hepatitis C virus infection is found more frequently than enterovirus infection and that hepatitis C virus is an important causal agent in the pathogenesis of dilated cardiomyopathy.

In this study, hepatitis C virus infection was associated with the occurrence of dilated cardiomyopathy. Three patients developed acute onset of heart failure, and acute myocarditis was suspected. Two patients recovered well, but 1 patient developed a lesion similar to changes seen in dilated cardiomyopathy. Three other patients had insidious onset and progressively deteriorated in the long-term follow-up study.

Hepatitis C virus, an RNA virus first identified in 1989,^{26 27} is a primary cause of both transfusion-associated and sporadic non-A, non-B hepatitis.²⁷ The most striking feature of hepatitis C is the risk of persistent infection and progression to chronic liver disease. Persistent infection occurs in >50% of patients with hepatitis C virus infection and may result in chronic active hepatitis, cirrhosis, and possibly hepatocellular carcinoma.²⁸ Patients with hepatitis C may have persistent viremia, even after resolution of the clinical signs of hepatitis.²⁹ The disease is often overlooked because it can remain remarkably indolent for years, producing few symptoms and only modest alterations in liver function test values. In fact, at many centers, cirrhosis resulting from chronic hepatitis C virus infection is now the most frequent indication for liver transplantation. The chronically progressive clinical course of patients with myocarditis or dilated cardiomyopathy may be compatible with chronic persistent hepatitis C virus infection.

Chronic hepatitis C virus infection has been associated with several other syndromes, including mixed cryoglobulinemia, polyarteritis nodosa, a siccalike syndrome that resembles Sjögren's syndrome,^{30 31 32 33} and membranous proliferative glomerulonephritis.³⁴ However, none of patients with hepatitis C virus infection in this study was associated with these diseases.

The presence of hepatitis C virus genome was demonstrated in hepatocytes, mononuclear cells, bile duct epithelial cells, and sinusoidal cells within the liver tissue by use of nonisotopic in situ hybridization.³⁵ Further studies using sense and antisense probes confirmed these findings, except for the presence of the replicative intermediary strand of hepatitis C virus RNA, which was detectable in all cell populations within the liver other than the bile duct epithelium. These findings suggest that hepatitis C virus may infect cells other than hepatocytes. The observation of positive and especially negative strands of hepatitis C virus RNA located in the nuclei and perinuclei of hepatocytes may suggest that hepatitis C virus uses the host genome or nuclear apparatus for replication.³⁵ Negative strands of hepatitis C virus RNA were also detected in peripheral blood mononuclear cells from patients with chronic active hepatitis.³⁶ Because negative RNA molecules are considered to be intermediates in the replication of the hepatitis C virus genome, it was supposed that hepatitis C virus replicates in peripheral blood mononuclear cells. In this study, we found negative strands of hepatitis C virus RNA in 1 patient with dilated cardiomyopathy and positive strands in 3 patients. Although these findings support the hypothesis and indicate replication of hepatitis C virus in myocardial tissues, they do not necessarily prove that replication occurs in these tissues and may simply represent the uptake of viral material from the neighboring infected cells or plasma. In situ hybridization, using sense and antisense probes, may confirm the presence of hepatitis C virus genome in myocytes, inflammatory cells, or other cell populations. Further study is necessary to confirm the localization of hepatitis C virus in myocardial tissue.

In this study, serum transaminase was only slightly elevated in 3 patients, and liver function tests were normal in 3 patients. Active hepatitic infection was not shown in an autopsied liver. It was reported that a significant percentage of patients with active hepatitis C virus infections lacked biochemical evidence of hepatitis³⁷ and that hepatitis C virus replication did not parallel the necrosis of hepatocytes or an inflammatory response.³⁸ Hepatitis C virus genome has been observed in some patients with no significant histological abnormality. Although the cytopathic effect of the virus may be important, the damage seen in chronic hepatitis C virus infection may be mediated by an immune mechanism.³⁵

Clinical cardiac involvement has been reported in hepatitis B, and an occasional patient may develop fulminant myocarditis with congestive heart failure, hypotension, and death.^{39 40} Symptomatic myocarditis is generally observed in the first to third week of illness. Patients may have dyspnea, palpitations, and anginal pain, and fatalities have occurred.³⁹ Cardiac abnormalities are usually transient and asymptomatic, although congestive heart failure, cardiomegaly, and sudden death have been reported.³⁹ Acute pericarditis associated with hepatitis B infection also has been reported.⁴¹ However, no acute myocarditis or dilated cardiomyopathy associated with hepatitis C virus infection has been reported.

Interferon has immunomodulating, antiproliferative, and antiviral effects⁴² and has been used to successfully treat patients with chronic hepatitis C virus infection.^{43 44} Interferon- therapy also has been reported to benefit patients with hepatitis C virus infection and cryoglobulinemia,^{31 45} hepatitis C virus– and hepatitis B virus–associated membranous nephropathy,⁴⁶ and essential mixed cryoglobulinemia.⁴⁷ However, a wide spectrum of toxicities affecting virtually every organ system can be produced by interferon administration.^{48 49 50} The cardiovascular complications of interferon administration range from tachycardia to myocardial infarction and congestive heart failure. Sinus tachycardia occurs in most patients and is related to the febrile response. These arrhythmias and cardiovascular ischemia are generally seen in older individuals who have preexisting heart disease.

Current therapy for myocarditis is controversial.¹⁹ Antiviral therapy has been shown to be beneficial for picornavirus myocarditis in animal models.¹⁹ Our results emphasize the need for studies to determine whether interferon therapy is effective in treating patients with myocarditis and cardiomyopathy who have hepatitis C virus.

	Acknowledgments

 
This work was supported in part by a grant-in-aid for general scientific research and for developmental scientific research from the Japanese Ministry of Education, Science and Culture and by a research grant from the Japanese Ministry of Health and Welfare. We thank Drs N. Tomioka, I. Okada, M. Tominaga, H. Suzuki, A. Tanaka, T. Hirozane, T. Yamada, Y. Sato, S. Morishima, S. Maruyama, B. Kyu, T. Shioi, S. Matsui, Y. Furukawa, T. Nakamura, W. Wang, K. Ono, and M. Kawanami for helping with this work. We also thank Y. Ohmoto and H. Toriyama for valuable discussion.

Received February 13, 1995; revision received April 6, 1995; accepted May 25, 1995.

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