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European Heart Journal Advance Access originally published online on February 19, 2007
European Heart Journal 2007 28(6):733-740; doi:10.1093/eurheartj/ehl525
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© The European Society of Cardiology 2007. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Myocarditis in hypertrophic cardiomyopathy patients presenting acute clinical deterioration

Andrea Frustaci1,2,*, Romina Verardo2, Marina Caldarulo2, Maria Cristina Acconcia1, Matteo A. Russo3,4 and Cristina Chimenti1,2,4

1 Heart and Great Vessels ‘Attilio Reale’ Department, La Sapienza University, viale del Policlinico 155, 00100 Rome, Italy
2 ‘Molecular and Cellular Cardiology’ Laboratory, National Institute for Infectious Disease ‘L. Spallanzani’, Rome, Italy
3 Pathology and Experimental Medicine Department, La Sapienza University, Rome, Italy
4 IRCCS San Raffaele Pisana, Rome, Italy

Received 8 September 2006; revised 5 January 2007; accepted 18 January 2007; online publish-ahead-of-print 19 February 2007.

* Corresponding author. Tel: +39 06 55170575; fax: +39 06 55170577. E-mail address: biocard{at}inmi.it

See page 661 for the editorial comment on this article (doi:10.1093/eurheartj/ehm008)


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 Conclusions
 Acknowledgements
 References
 
Aim We sought to determine whether myocarditis can be a major cause of acute electrical instability or clinical deterioration in HCM patients.

Methods and results A total of 119 HCM patients (69 M/50F, mean age 41 ± 8), 42 with acute clinical deterioration and 77 clinically stable, underwent cardiac catheterization with left ventricular endomyocardial biopsy and gene analysis of major sarcomeric proteins. Endomyocardial tissue was processed for histology, immunohistochemistry, and polymerase chain reaction for the most common cardiotropic viruses. Controls were surgical samples from 50 patients with mitral stenosis. All 119 patients showed histological findings suggestive of HCM. In addition, CD45RO+ lymphocytes (≥14/mm2) with focal necrosis of the adjacent severely hypertrophied and often disorganized myocytes, consistent with an overlapping active myocarditis, were observed in 28 of 42 unstable and none of 77 stable HCM patients. A viral genome was detected in 14 of 28 patients with myocarditis and in none of HCM patients without and in none of controls. No correlation between sarcomeric protein gene mutations and HCM clinical profile was observed.

Conclusion Myocarditis, often viral, represents a common cause of acute clinical deterioration in HCM. Its recognition can potentially affect disease prognosis and treatment.

Key Words: Hypertrophic cardiomyopathy • Myocarditis • Viruses • Arrhythmia • Heart failure


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 Conclusions
 Acknowledgements
 References
 
Progression to dilated phase has been reported in up to 10% of HCM patients observed in a 10-year follow-up.1 However, the mechanisms of progression remain largely unclear although clinical indications as the severity of LV wall thickness, histological findings as extension of myocardial disarray and fibrosis,2 or an ischaemic damage from a coexistent small vessels disease,3 as well as specific mutations of sarcomeric proteins,4 have been advocated. The occurrence of life-threatening arrhythmias appears to be even more unpredictable and unexplainable as sudden death is reported as first manifestation of the disease in otherwise asymptomatic subjects.5

The potential destabilizing role of myocardial viral infection has been raised in occasional reports6 of patients with systemic hepatitis C virus infection. In the present study, we report the results of a systematic histological and molecular biology evaluation of LV endomyocardial tissue from a large HCM population exhibiting either a stable clinical profile or a sudden electrical and/or mechanical instability.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 Conclusions
 Acknowledgements
 References
 
Patient population
From January 1989 to December 2004, 140 consecutive patients with HCM were submitted to cardiac catheterization, coronary angiography, LV angiography, and LV endomyocardial biopsy. The procedures followed were in accordance with institutional guidelines. Our institution is a tertiary referral centre dedicated to the study of different types of cardiac muscle diseases, including HCM, in adults.7 HCM was diagnosed in the presence of a hypertrophic non-dilated LV, in the absence of another cardiac or systemic disease capable of producing the magnitude of hypertrophy evident.8 Twenty patients with Anderson Fabry disease and one patient with glycogen storage disease due to LAMP2 gene mutation, diagnosed on the basis of pathology and genetic findings, were excluded from the present study.

Among the 119 patients with HCM (74M, 45F, mean age 42.4 ± 14.3 years), 42 (35%, 28M, 14F, mean age 40 ± 13 years), defined as Group A, were admitted for a recent acute clinical deterioration. Twenty of them (Group A1) experienced a progressive worsening of heart failure symptoms (increase of at least one NYHA Class) with impairment of systolic function, while 22 (Group A2) manifested multiple episodes of sustained ventricular arrhythmias (Lown class grade 4b). The remaining 77 patients (Group B) (65%, 46M, 31F, 44 ± 14) showed a stable clinical picture and were referred to our Institution for clinical management [28 (36%)], diagnostic clarification of non-familial cases [14 (18%)], genetic counselling or referral for a second opinion [14 (18%)], risk stratification [13 (17%)], and family screening [8 (10%)].

Echocardiography
Left ventricular septal, posterior, and maximal wall thicknesses; end-diastolic and end-systolic dimensions; ejection fraction; fractional shortening, and left atrial volumes were determined. Maximal wall thickness was defined as the greatest thickness measured at any segment of LV wall and patterns of hypertrophy were defined in accordance with previously published methods.9 An LV outflow gradient >30 mmHg was considered significant.

Cardiac catheterization and endomyocardial biopsy
All invasive studies were performed after patient written informed consent and approved by the Ethical Committee of our Institution. All patients were submitted to cardiac catheterization, coronary and LV angiography, LV endomyocardial biopsy according with institutional guidelines.

Endomyocardial biopsies were performed in the septal–apical region of the LV (6–8 samples/patient). Myocardial specimens were either fixed in 10% buffered formalin and embedded in paraffin for histology or frozen in liquid nitrogen for molecular biology studies. Controls were histological sections and frozen samples from papillary muscles of 50 patients undergoing mitral valve replacement because of mitral stenosis, with normal LV dimension and function. Blood samples drawn at the time of cardiac catheterization were used for genetic, immunologic, and molecular biology studies, and serological tests for the most common cardiotropic viruses.10

Histology and immunohistochemistry studies
Five-micron-thick sections were stained with haematoxylin–eosin, Miller's elastic Van Gieson, Masson's trichrome and examined by light microscopy. Immunohistochemistry for the characterization of inflammatory infiltrates was carried out as previously described.10 The diagnosis of myocarditis was established in the presence of inflammatory infiltrates associated with necrosis of adjacent myocytes, according to Dallas criteria.11 Extent of fibrous tissue was evaluated by means of a computer-assisted image analyser, utilizing the Lucia G software (version 4.82, Nikon, Japan) directly on acquired images of histological sections, under direct visual control.

Screening of myocardial specimens for viral genome
Two frozen myocardial specimens from each patient were used for PCR and reverse transcriptase PCR analysis, as previously described.12 Endomyocardial biopsies from patients recruited from 2000 to 2004 were processed at the same time of the patient admission while samples stored from 1989 to 1999 were analysed retrospectively. The old vs. fresh frozen samples were homogeneously distributed among patient groups.

Ten primer pairs were used to detect cardiotropic viruses DNA and RNA (adenovirus, enterovirus, cytomegalovirus, parvovirus B19, influenza A and B viruses, herpes simplex viruses, Epstein-Barr virus, hepatitis C virus). Each assay included negative controls and known positive controls (infected viral cells). The purified PCR products were sequenced directly on an automated ABI Model 310 A sequencer. Blood samples of patients whose myocardium was infected by a viral agent were analysed by PCR for the presence of the same virus.

Genetic studies
Genomic DNA was isolated from peripheral blood lymphocytes using the QIAmp DNA Blood Mini kit from Qiagen. In all patients, we analysed the coding regions and the exon–intron boundaries of MYH7, MYBPC3, TNNT2, and TPM1 genes as previously described.13

Follow-up
To assess clinical, morphological, and functional evolution of cardiomyopathy, patients were followed at our institution through serial (at least two times/year in the absence of major clinical events) echocardiographic and clinical assessment. In patients who received an ICD, serial ICD interrogation was part of the follow-up.

Statistical analysis
Categorical data were presented as absolute frequencies and percent values. Quantitative measurements were expressed as mean ± SD. The length of follow-up was expressed as median and interquartile range.

The data were checked for testing the normality of distribution either in the overall patients as well as in the three groups of patients separately. In addition, Levene's test for variances was used for testing the homogeneity of variance among groups.

Owing to non-normality and/or dishomogeneity of variance for some variables, the three Groups of patient (A1, A2, B) were compared with Kruskal–Wallis analysis of variance for the quantitative variables. The categorical variables among groups were compared with {chi}2 test.

Multiple comparisons were performed by Mann–Whitney test for quantitative variables and by {chi}2 test or Fisher's exact probability test (in case of two-by-two contingency tables) for the categorical variables. In case of multiple comparison, Bonferroni's correction was applied to control the experimentwise Type I error probability. H1 was postulated bidirectional for all the analysis. A P-value of ≤0.05 was considered statistically significant.

Statistical analysis was performed using a BMDP package.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 Conclusions
 Acknowledgements
 References
 
Clinical and echocardiographic data of HCM patients are listed in Table 1.


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  		Table 1 Comparison among data of different HCM Groups

 
At the time of the present study, most of the patients were in treatment with beta-blockers or verapamil and some of them were assuming amiodarone for prevention of paroxysmal atrial fibrillation or treatment of ventricular arrhythmias. In addition, patients with recent deterioration of LV function were assuming ACE-inhibitors and diuretics (Table 2).


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  		Table 2 P-values* of the multiple comparisons with Bonferroni's correction

 
Cardiac catheterization and endomyocardial biopsy
Cardiac catheterization showed normal coronary arteries in all patients. Systolic function was normal or hyperkinetic in Group B and in Group A2 patients, while it was slightly to moderately impaired in Group A1. Left ventricular angiography showed the presence of apical enlargement with aneurysm formation in seven Group A1 cases and in three Group A2 patients (Table 3), but in none of Group B.


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  		Table 3 Clinical and virological profile of HCM patients with myocarditis

 
Histology and immunohistochemistry
Histology, showing marked hypertrophy and disarray of myocardiocytes, in some cases associated with wall thickening of intramural arterioles, was suggestive of HCM in all cases. Inflammatory infiltrates associated with focal necrosis of adjacent myocytes, consistent with a diagnosis of active myocarditis according to Dallas criteria, were observed in 28 of the 42 Group A patients (67%; 13 of Group A1;15 of Group A2) (Figure 1A) and in none of Group B patients. Immunohistochemistry showed the inflammatory infiltrates (≥14 leucocytes/mm2) to be mainly represented by activated CD45RO+ T lymphocytes (Figure 1B) with a moderate amount of cytotoxic lymphocytes (CD8+). In the remaining 14 patients with clinical instability, a larger interstitial and replacement fibrosis was observed (16 ± 4.4 vs. 4.5 ± 1.8% in stable patients, and vs. 8 ± 2.5% in myocarditis group, control values in normal surgical biopsies = 2.7 ± 0.8%) while no significant differences in terms of myocyte hypertrophy and severity of small vessel disease could be ascertained with the other patients of Group A and Group B.


Figure 1
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  		Figure 1 Left ventricular endomyocardial biopsy showing at histology (A) severely hypertrophied myocardiocytes with a central area of disarray associated with multiple inflammatory infiltrates and focal necrosis of the adjacent myocytes (arrows) suggesting an active lymphocytic myocarditis overlapping HCM (Haematoxylin and eosin 250x). At immunohistochemistry (B), the inflammatory infiltrates are mainly represented by activated T lymphocytes (arrows) (Anti-CD45RO monoclonal antibodies 400x). At reverse transcriptase–PCR analysis (C), detection of an influenza A virus using primers designed to amplify a 190-bp sequence, is shown in the myocardium. Products were detected by ethidium bromide staining of 3% agarose gel. M indicates molecular weight marker; lane 1, influenza A virus positive control (infected cells); lane 2, myocardium from patient 1; lane 3, negative control (no template).

 
Screening of myocardial specimens for viral genome
The presence of sufficient target nucleic acid for PCR analysis was confirmed by amplification of ß-globin for DNA and 3GPDH for RNA in all cases. No differences were detected between samples stored at –80°C for several years or for few days either in terms of nucleic acid amplification and of viral detection. Viral genome were found in 14 out of 119 patients (12%) all pertaining to Group A and all with the histologic evidence of myocarditis (14 out of 28, 50%) (Figure 1C). Both positive and negative strands of enterovirus and HCV genome were present in positive patients. No viral genome was detectable in Group B patients or in surgical control samples.

Sequencing analysis of enterovirus and adenovirus PCR amplimers showed a high homology with coxsackievirus B3 (accession number U57056 [GenBank] ) and adenovirus 5 (accession number S74067 [GenBank] ). Comparison of influenza virus A and Epstein-Barr virus showed high homology with human viral sequences (accession numbers V01104 [GenBank] for influenza A and V015555 for Epstein-Barr virus). Hepatitis C virus-positive case showed high homology for genotype 1.

The patient with myocardial infection by hepatitis C had also detectable viral infection in the blood. Conversely, no viral genomes were detected in the blood samples of any other patient with viral myocarditis. Serological tests for cardiotropic viruses were positive in two patients, one for anti-hepatitis C IgG antibodies and one for anti-influenza A virus IgG antibodies (title 1:128). In the other 12 patients with myocardial viral infection, in the remaining 14 patients with myocarditis, and in the Group B patients no positive serology for cardiotropic viral agents was detected. Positivity for antinuclear antibodies (titer ≥ 1/80) was found in the single patient with HCV infection. The low frequency of positive viral serology in HCM patient with viral myocarditis is in agreement with previous studies12,14 showing that serology cannot be used as an alternative to endomyocardial tissue PCR for the diagnosis of viral myocarditis.

Genetic studies
Gene mutations known to be associated with HCM, including five new genetic defects previously reported by the authors,13 were identified in 84 patients (71%) and, in particular, in 14 Group A1, in 16 Group A2, and in 54 Group B patients. We identified mutations in MYH7 gene in 36 patients, in MYBPC3 gene in 29 cases, in TNNT2 gene in 14 subjects, and in TPM1 gene in 5 patients. No significant prevalence of mutations previously associated with higher susceptibility to sudden cardiac death or progression to end-stage heart failure was observed in the different groups and no correlation between sarcomeric protein gene mutations and HCM clinical profile was observed. In three Group A patients with evidence of viral myocarditis, family members carrying the disease-causing mutation were mildly (five patients) or non (four patients)-symptomatic.

Follow-up
During a mean follow-up of 77 ± 46 months (range 12–176 months) all Group B patients remained clinically stable with no major clinical event (ventricular tachycardia, sudden death, admission for heart failure, heart transplantation). With regard to the 13 Group A1 patients with myocarditis (Table 3), six of them (46%) showed a progressive recovery of contractility few weeks after the detection of cardiac dysfunction (LVEF from 38 ± 4 to 62 ± 5%) while the remaining seven (54%) showed a progression to end-stage heart failure (LVEF from 42 ± 5 to 28 ± 6%). The other seven Group A1 patients with no evidence of myocarditis remained clinically unchanged on anti-heart failure drugs over the follow-up period. Among the 15 Group A2 patients with myocarditis, eight (53%) showed a reduction of ventricular arrhythmias (Table 3) even when antiarrhythmic drugs were withdrawn. Conversely, in the remaining seven cases (47%), arrhythmias persisted and a contractile dysfunction ensued in the following months (LVEF from 62 ± 4 to 36 ± 8): all these patients received an ICD and were included in a heart-transplant list. In the other seven Group A2 patients with no evidence of myocarditis, arrhythmias persisted and an ICD was implanted. Interestingly, Group A patients with myocarditis recovering from LV dysfunction or improving from their arrhythmic profile had no viral genome detectable at PCR of cardiac biopsies (Table 3).


   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
Conclusions
 Acknowledgements
 References
 
The extreme variability in the phenotype and progression of HCM, particularly in family members carrying an identical gene mutation, appears still largely unexplained. Changes in the synthesis of wild sarcomeric protein because of an alternative splicing or a concurrent abnormality of modifier genes have been advocated but still unproved. Actually, only gross indicators of adverse outcome are available, as the severity of LV wall thickness (≥30 mm), extension of myocardial disarray, and fibrosis or a prominent small vessel disease at histology. Nevertheless, acute electrical instability can occur unpredictably at any evolutive phase of the disease and can even be the first manifestation of the disorder in otherwise asymptomatic subjects.5 The potential destabilizing role of viral myocardial infection has been raised in occasional reports from patients with systemic infection by HCV.6 Our report is the first systematic study on a large HCM population correlating signs of clinical instability with the histological evidence of active myocarditis and myocardial viral infection. The high prevalence of acute clinical events (35%) accounted in our patient population is at variance with long-term follow-up of major HCM studies reporting between 3.515 and 15%16,17 of clinical deterioration. This may derive from patient selection biases, as our hospital is a tertiary referral centre for heart muscle diseases, thus receiving preferentially unstable and complicated cardiomyopathies. However, this is not in contrast with the principal aim of our study directed to investigate the possible role of myocarditis in HCM destabilization.

Myocarditis in HCM
Interstitial inflammatory infiltrates, often entrapped in areas of fibrous replacement, are a common histological finding in the myocardium of patients with HCM and are usually interpreted as part of the healing process of myocytes necrosis.18,19 In our patients, the diagnosis of myocarditis has been obtained by a pathologist blind to the clinical data, through the application of Dallas criteria and the identification of clusters (≥14/mm2) of CD45RO+ activated T lymphocytes adherent to cell membrane and focally associated with necrosis of adjacent myocytes. Myocardiocyte morphology was inherent to the characteristics of HCM including severe cell hypertrophy with disarray, perinuclear halo, and various degree of myocardial fibrosis.

The presence of inflammatory infiltration of the myocardium with areas of intense myocytolysis in addition to an elevated intraventricular pressure are the most likely mechanism of LV aneurysm formation, that occured in 36% of patients with HCM and myocarditis and could have contributed either to worsening of cardiac function and to the induction of ventricular arrhythmias.10

Virus detection and destabilizing role in HCM
A myocardial viral genome was detected in 12% of 119 patients with HCM screened in this study. Although the presence of viral genomes in the myocardium does not itself indicate the cause of cardiac deterioration, the coexistence of a clinical profile of electrical instability and/or impairment of contractile function and the histological findings of active lymphocytic myocarditis makes very likely a pathogenetic role for the detected viral agents. In the remaining 12% of patients with myocardial inflammation and negative PCR, an analogous viral cause cannot be excluded since the eventual agent could not be included in the screening panel of PCR or cleared from the myocardium by the host immune response.

It is noteworthy relieving a worse outcome in virus-positive vs. virus-negative patients in the HCM-myocarditis group. This is in agreement with what reported in patients with dilated cardiomyopathy20 and myocarditis12 and confirms the attribution of adverse prognosis to the myocardial viral persistence.

Anyway our data providing a high prevalence of viral agents in HCM myocardium suggest a susceptibility of the disease to viral infection. Predisposition of congenital heart disease to infectious disorders is, on the other hand, well known and may attain to valve abnormalities as bicuspid aortic valve and mitral valve prolapse21 as well as to myocardial diseases as arrhythmogenic right ventricular dysplasia.22 The spectrum of viral agents detected in our study is not different from that reported in other forms of myocarditis, while a flu-like syndrome could be often ascertained in the patients' clinical history few weeks to few months before HCM deterioration. Viral destabilization of HCM can be explained by cytoskeletal proteins disruption of myocytes due to viral release of protease 2A23 causing alteration of cell structure and function as well as by the strong histological evidence of cell death.24

Histology of unstable HCM without myocarditis
No distinctive histological finding was documented in this patient category except a larger myocardial fibrosis. This feature is aspecific and can be the result of various mechanisms of damage. In this context, however, even a healed myocarditis can be included and expand the possible contribution of myocardial inflammation towards HCM deterioration. In addition, due to the sampling limitations of endomyocardial biopsy, foci of active myocarditis could have been missed.

Clinical implications
Patients with HCM manifesting electrical instability and/or functional deterioration are usually considered for ICD implantation or cardiac transplantation. If a viral myocarditis is the cause of clinical destabilization, prognostic and therapeutic considerations may be different. Indeed in 50% of acute viral myocarditis, a spontaneous resolution of the disease occurs because of viral clearance and the clinical impairment is usually transient. On the other hand, if the evolution towards a chronic myocarditis is the case, several therapeutic options can be eventually available including antiviral agents as interferon,20 immunosuppression,12 and immunoadsorption procedures25 with potential impact on recovery of cardiac function. However, due to the present uncertainty of these therapeutic approaches, a prospective randomized trial, including immunosuppression for virus-negative and antiviral agents for virus-positive HCM myocarditis patients, is suggested.


   Conclusions
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusions
Acknowledgements
 References
 
Myocarditis, often viral, is a common cause of electrical instability and/or functional deterioration in HCM. Its recognition can affect both prognosis and treatment of the disease.


   Acknowledgements
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusions
 Acknowledgements
References
 
This study was partially supported by the Italian Ministry of Health grant ‘Inflammatory cardiomyopathies: etiopathogenesis and treatments for the recovery of cardiac contractility’.

Conflict of interest: none declared.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusions
 Acknowledgements
 References
 

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Myocarditis in hypertrophic cardiomyopathy: reply
Eur. Heart J., July 1, 2007; 28(13): 1664 - 1664.
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