Department of Internal Medicine and Hepatitis Research
Center,
National Taiwan University College of Medicine and National Taiwan
University Hospital,
Taipei, Taiwan
To the Editor:
Okabe et al1 studied the association of hepatitis
C virus (HCV) infection with chronic active myocarditis, a variant form
of chronic myocarditis characterized by numerous lymphocytic clusters
and myocardial cell damage, in 3 patients. Using the so-called genomic
analysis to detect positive (genomic) and negative
(replicative) strands of HCV RNA, the authors found that all 3 patients
had both positive- and negative-strand HCV RNA in their myocardial
tissue. They therefore concluded that HCV can replicate in inflamed
myocardial tissue and may contribute to the development of chronic
active myocarditis. Although their findings are interesting and the
association of HCV infection with chronic active myocarditis may be
true, controversial issues still exist that should be carefully
addressed before drawing a final conclusion.
First, the strand-specific polymerase chain reaction (PCR) used by the
authors to detect positive- and negative-strand HCV RNA may not be
stringent enough, and possible false positivity cannot be excluded.
Previous studies2 3 have questioned the strand
specificity of HCV sequences detected in cell samples by heat
inactivation of reverse transcriptase alone. Because cDNA can still be
synthesized in the presence of Taq polymerase (reverse transcription
activity in vitro), this may lead to false-positive results.
Accordingly, we and other investigators have treated samples with RNase
after heat inactivation to eliminate both positive and negative strands
of RNA to further minimize the possible false
positivity.2 4 Second, HCV infection of
lymphocytic cells in patients with chronic hepatitis C has been
documented.4 5 Thus, the HCV sequences detected
in the myocardial tissue of patients with chronic active myocarditis
could be derived from the infiltrating lymphocytes actively infected by
HCV and not from the myocardial cells themselves.
Accordingly, the suggestion by Okabe and colleagues that HCV not only
has a tropism to myocardial cells but also can replicate in them and
may play a role in the development of an unusual form of myocarditis
should be interpreted cautiously because of the limited case numbers
studied and the possible false positivity in detecting negative strands
of HCV RNA. Further larger studies that include adequate tissue samples
and more convincing methods, such as localization of HCV antigens
and/or HCV genome, are needed to confirm whether HCV is one of the
responsible agents.
References
Department of Internal Medicine
Department of Pathology School of Medicine,
Fukuoka University,
Fukuoka, Japan
We appreciate the comments of Drs Kao and Hwang regarding the
reverse-transcription polymerase chain reaction (RT-PCR) we used for
genomic analysis of hepatitis C virus
(HCV)1 in 3 patients with chronic active
myocarditis.2
We agree that heat denaturation after RT incubation is insufficient to
prevent self-transcription of both the positive and negative strands of
HCV RNA.3 To minimize the possibility of
self-annealing of HCV sequences, we adopted a relatively high
temperature (60°C) during the RT reaction. This procedure validates
the RT-PCR results regarding the positive and negative strands of HCV
RNA as well as RNAse digestion after cDNA synthesis. In each of our 3
patients, the copy number of HCV RNA was estimated to be
102 or 103 by a competitive
RT-PCR assay. Even if we falsely detected HCV sequences in our study,
why was negative-strand RNA repeatedly undetectable in the kidney of 1
patient (case 3)1 who had approximately the same
amount of positive strand RNA as the other 2 patients? This was a key
finding of our study.
In our study,1 HCV sequences may have been
derived from lymphocytes infiltrating the myocardium, as
mentioned by Drs Kao and Hwang. However, this possibility does not deny
a relationship between HCV infection and chronic active myocarditis,
because these lymphocytes appear to play a major role in triggering
and/or maintaining myocarditic activity. As discussed in our
article,1 further evidence must be obtained by a
more convincing technique, such as in situ hybridization.
We believe that HCV infection contributes to the eventual development
of a failing dilated heart but assume that this situation may be rare.
We recently reviewed the clinical charts of patients who were admitted
to Fukuoka University Hospital for invasive cardiac evaluation. In 31
consecutive patients (including 21 men, mean age 45.1±13.9 years) with
dilated cardiomyopathy (DCM) who were admitted from
January 1993 to September 1997, HCV antibody was detected in 3 cases
(9.7%). In 246 consecutive patients (including 150 men, mean age
63.4±12.9 years) with ischemic heart disease (IHD) who were
admitted from May 1996 to September 1997, HCV antibody was present
in 13 cases (5.5%). These IHD patients had no previous major surgery,
including a cardiac operation, and none of them was on
maintenance hemodialysis. The incidence of HCV antibody did not
differ significantly between the DCM and IHD patients (Fisher's exact
test). This is inconsistent with a recent report by Matsumori
et al.4
We agree that a large-scale study is needed to confirm the relationship
between HCV infection and a failing heart (ie, DCM).
References
© 1998 American Heart Association, Inc.
Correspondence
Hepatitis C Virus Infection and Chronic Active Myocarditis
Response
This article has been cited by other articles:
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  A. M. Feldman and D. McNamara Myocarditis N. Engl. J. Med., November 9, 2000; 343(19): 1388 - 1398. [Full Text] [PDF]
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