Diseases of the heart

As described above, vascular endothelial cells contain the HHV-6 receptor CD46 and may carry HHV-6 antigens and DNA. This includes the blood vessels in the heart (Fig. 1). CD46 is weakly expressed only in striated muscle cells (Loveland, 2003). The distribution of viral receptors in the myocardium for well-documented cardiotropic viruses (coxsackie virus, adenovirus) is highly variable with a frequent increase in patients with dilated cardiomyopathy (Poller et al., 2002). No systematic studies to this effect are available yet for the HHV-6. However, it is possible that increased expression of the HHV-6 receptor CD46 in cardiomyocytes may occur in myopathic conditions (Poller et al., 2002).

Active myocarditis has been diagnosed in endomyocardial biopsies from a substantial percentage of patients with various kinds of heart failure, with a variable prevalence of less than 20% to over 50% (Nippoldt et al., 1982; Feldman and McNamara, 2000). Viral infection has been implicated as a leading cause of myocarditis. In a large series, viral genome was amplified by PCR from 239 (38%) of 624 patients with clinical myocarditis, and 30 (20%) of 149 patients with dilated cardiomyopathy (Bowles et al., 2003). Most frequently detected viruses were adenovirus and enterovirus. However, reports of HHV-6-associated myocarditis are rather scarce. Fukae and coworkers (2000) describe a case of fulminant myocarditis in which HHV-6 DNA was demonstrated by PCR in the myocardium and serum IgG antibodies increased to fourfold levels. One year later, Yoshikawa and collaborators (2001) reported on a 5-month-old girl with acute myocarditis, HHV-6B isolation from the blood and positive HHV-6 DNA by PCR in various tissues including the heart. Other viral infections were excluded in both cases. We have observed a similar, although focal, myocarditis at autopsy of sporadic cases of AIDS with HHV-6 reactivation (Fig. 2), yet HHV-6 DNA was demonstrable by in situ hybridization only in vascular endothelial cells (as shown in Fig. 1). Except for HIV-1, no other cardiotropic virus was identified in our cases. Rohayem et al. (2001) reported a fatal case of fulminant myocarditis due to acute coinfection with parvovirus B19 and HHV-6 in the absence of an antiviral immune response. By nested PCR, parvovirus B19 and HHV-6 DNA were detected in multiple tissues, but only parvovirus B19 DNA was found in the myocardium. The authors suggested that immunosuppression induced by HHV-6 enhanced the dissemination of parvovirus B19, which led to fatal myocarditis.

In a case series of patients, Mahrholdt and colleagues (2004) reported that myocarditis as diagnosed by magnetic resonance imaging and endomyocardial biopsy was linked to HHV-6 in six, and parvovirus B19 in 12 of the 32 patients. All but one diagnostic biopsies was taken from regions of contrast enhancement.

Fig. 2 Various forms of myocarditis accompanying HHV-6 reactivation in AIDS patients (hematoxylin and eosin stain of autopsy specimens). Lower right shows an interstitial cardiac arteriole from such cases containing HHV-6 DNA (in situ hybridization with pZVH14 probe). (for colour version: see colour section on page 358).

Fig. 2 Various forms of myocarditis accompanying HHV-6 reactivation in AIDS patients (hematoxylin and eosin stain of autopsy specimens). Lower right shows an interstitial cardiac arteriole from such cases containing HHV-6 DNA (in situ hybridization with pZVH14 probe). (for colour version: see colour section on page 358).

Myocarditis occurred predominantly in the lateral free wall. The left ventricular ejection fraction was reduced in these patients to 47+19%.

Although HHV-6 may reside latently in cardiac vessels, cardiac transplantation followed by immunosuppression appears not associated with a higher risk of HHV-6 myocarditis. Adenovirus and other viruses have been implicated in coronary vasculopathy, chronic graft failure, and acute rejection (Bowles et al., 2001; Shirali et al., 2001). To date, we know of only two reports of reactivated HHV-6 causing disease after cardiac transplantation (Randhawa et al., 1997; Nash et al., 2004). In both cases, the heart alone was not affected, but rather gastroduodenitis, pancreatitis, and encephalitis were described by these authors.

Established criteria for the pathological diagnosis of myocarditis requires the presence of inflammatory cellular infiltrates in association with degeneration and necrosis of cardiomyocytes, the Dallas criteria (Aretz, 1987). The pathogenesis of viral myocarditis involves a variable interaction of direct viral damage to cells, virus-induced immune-mediated cellular damage, and viral persistence (Feldman and McNamara, 2000; Esfandiarei et al., 2004). Viral myocarditis is considered to be an important precursor in the pathogenesis of acquired cardiomyopathy, which is recognized as established or chronic heart muscle disease, often manifested as hypertrophy and dilatation of the heart (Feldman and McNamara, 2000; Poller et al., 2005). However, there is mounting evidence that viral infection can produce myocardial disease in the absence of the classic features of myocarditis (Feldman and McNamara, 2000; Poller et al., 2005). This may involve more subtle forms of cellular injury and inflammation. Adenovirus infection of the myocardium has been found to be associated with significantly less inflammation than enterovirus infection of the myocardium (Bowles et al., 2003). Recent studies discussed below indicate that HHV-6 infection may produce myocardial disease without classical features of myocarditis.

In 245 patients with dilated cardiomyopathy characterized by unexplained left ventricular dysfunction, viral genomes were amplified by PCR in endomyocardial biopsy samples from 165 (67.4%) of the 245 patients (Kuhl et al., 2005). HHV-6 was detected in 53 (21.6%), and this was second in frequency to parvovirus B19, which occurred in 126 patients (51.4%). Other viruses, including adenovirus and enterovirus, occurred at lower frequency. Multiple infections occurred in 45 samples (27.3%) with 26 (15.8%) showing coinfection with parvovirus B19 and HHV-6. Active or borderline myocarditis according to the Dallas criteria was not present in any case. Also, lymphocyte and macrophage infiltrates were not significantly different in virus-positive and virus-negative patients. Similar recovery of virus has not been reported in normal hearts of multiorgan donors or patients with valvular heart disease. The findings in the patients with idiopathic left ventricular dysfunction suggest that viral persistence, often presenting as multiple infection, may play a role in the pathogenesis of dilated cardiomyopathy (Kuhl et al., 2005).

In another study, 37 of 70 patients presenting with exertional dyspnea and/or reduced exercise tolerance were confirmed to have isolated diastolic left ventricular dysfunction by echocardiography and cardiac catheterization, and 35 (95%) of these patients had cardiotropic viral genomes, which were detected in endomyo-cardial biopsies (Tschope et al., 2005). Of these 37 patients, 24 (65%) had a parvovirus B19 monoinfection, and 6 of 37 (16%) had a coinfection with HHV-6. Of the 37 patients, 24 (65%) had atypical angina pectoris, and 13 of these 24 patients (54%) had evidence of coronary endothelial dysfunction on the basis of abnormal response to provocative testing with acetylcholine. Ten of these 13 patients (77%) also had diastolic dysfunction, and were all positive for parvovirus B19 genomes with 73% having a monoinfection and 27% coinfection with HHV-6.

A group of 71 patients with nonischemic cardiomyopathy were evaluated for coronary microcirculatory dysfunction in relationship to viral persistence and myocardial inflammation with endothelial activation (Vallbracht et al., 2005). Coronary endothelial microcirculatory function was measured by vasoreactive response to acetylcholine challenge, with a positive finding characterized by abnormal vasoconstriction or impaired vasodilation in response to acetylcholine. Myocardial inflammation was measured by increased numbers of lymphocytes and expression of endothelial adhesion molecules (HLA-1, HLA-DR, ICAM-1). PCR showed evidence of viral persistence in 43 patients, with parvovirus B19 in 33 and HHV-6 in 12. Endothelial dysfunction occurred in patients with viral persistence independently of myocardial inflammation and endothelial activation but was more pronounced in patients with concurrent inflammation. These findings indicate that viral-induced microcirculatory dysfunction with impaired coronary blood flow can be important in the pathogenesis of cardiomyopathy. This and other viral-induced abnormalities can occur in the absence of classical myocarditis.

HHV-6 may directly damage cells, particularly endothelial cells, or induce immune or autoimmune reactions. HHV-6 is able to activate other viral infections, including Epstein-Barr virus and parvovirus B19, and the coinfection may enhance the pathogenicity of other viruses (Krueger and Ablashi, 2003). Transient viral infection may be sufficient to trigger enough insult to lead to chronic disease. Conversely, viral persistence may lead to progressive disease. Potential mechanisms include direct cytopathic effects of the viruses and indirect effects, including low-grade inflammation, release of cytokines, alterations of cell signaling pathways, alterations in cytoskeletal proteins of myocytes, and alterations of the extracellular matrix (Kuhl et al., 2005; Vallbracht et al., 2005). These mechanisms may be particularly important in HHV-6-induced myocardial disease.

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