Rheumatology 2006 45(Supplement 4):iv32-iv38; doi:10.1093/rheumatology/kel307
© The Author 2006. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
Invasive techniques—from diagnosis to treatment
B. Maisch,
S. Pankuweit,
K. Karatolios and
A. D. Risti
1
Department of Internal Medicine and Cardiology, University Hospital of Gießen and Marburg, Philipps-University Marburg, Germany and 1Department of Cardiology, Institute for Cardiovascular Diseases of the Clinical Centre of Serbia and Belgrade University School of Medicine, Belgrade, Serbia
Correspondence to: Prof. Bernhard Maisch, MD, FESC, FACC, Director of the Department of Internal Medicine and Cardiology, Dean of the Medical Faculty, University Hospital of Gießen and Marburg, Baldingerstr, 35043 Marburg, Germany. E-mail: Bernhard.Maisch{at}med.uni-marburg.de; BerMaisch{at}aol.com
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Abstract
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Invasive diagnostic and therapeutic techniques are indispensable
for the diagnosis and interventional treatment of coronary artery
disease, valvular involvement and, in particular, if the specific
components of the inflammatory or degenerative processes in
rheumatic disease are to be identified in the different components
of the heart. Although impairment of cardiac function and ischaemia
can be suspected also by non-invasive techniques, coronary involvement
needs the final proof by angiography. Endomyocardial or epicardial
biopsy identifies the key players of autoreactivity: the infiltrating
cells and the bound and circulating antibodies. Before corticoid
treatment is started, a viral or microbial aetiology has to
be excluded at the site of cardiac inflammation. This again
can only be done by the analysis of cardiac tissue samples.
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Introduction and definition of terms
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Autoimmune rheumatic or connective tissue diseases comprise
a number of diseases, in which the heart with its components
can be involved in the systemic process, but is not necessarily
the most obvious target of the pathogenetic mechanism.
Table 1delineates
the systemic disorders, and the estimated incidence of the involvement
of pericardium, myocardium, the valves, and the coronary macro-
and microvasculature [
1–6]. The underlying immunopathology
is either a manifestation of the systemic disease or a secondary
immunopathogenesis following a primary assault from infection
or trauma, in which all effector organs of the immune system
can participate [
1,
7,
8].
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TABLE 1. Rheumatic diseases and collagen disorders—incidence of cardiac involvement (%) as assessed clinically, by necropsy or by endomyocardial biopsy
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For the cardiac involvement in systemic collagen disorders,
the specific term ‘rheumatoid heart disease’ is
used in English-speaking countries. Carditis in rheumatic fever
is referred to as ‘rheumatic heart disease’. The
different terms underline the clinical observation that the
clinical manifestations, pathogenetic and aetiological features
and the time course of both forms of ‘rheumatic disorders’
are different. This also holds for their cardiac involvement,
which will in turn be reflected by the methodological armamentarium
the cardiologist uses for diagnosis and tailored treatment [
3].
Major clinical symptoms are those of heart failure as assessed by the New York Heart Association Classification of breathlessness (dyspnoea), when structural heart disease is present: class I being no, class II slight and class III being marked limitation of physical activity. In class IV, discomfort is present even at rest. If angina is the major symptom, the classification of the Canadian Cardiac Society (CCS) is used, in which precordial discomfort is classified 1–4 in a similar manner [8].
In general, non-invasive methods precede the application of invasive techniques. They include electrocardiogram (EKG), exercise tests, or stress tests in which either the EKG and/or the perfusion (scintigraphy), wall motion (echocardiography, MRI) at rest and at exercise are compared. Cardiac function and imaging are, evaluated together, the best by non-invasive imaging (echocardiography, MRI, CT) or invasive techniques such as left and right heart catheterization, coronary angiography, left ventricular and/or right ventricular angiography and endomyocardial biopsy [3–12]. For pericardial disorders, the best and most complete approach is pericardiocentesis, and, if the amount of effusion permits, pericardioscopy and epi- and pericardial biopsy [6–12].
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Left and right heart catheterization and angiography
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In the failing heart, blood pressure can be lowered, and the
wall tension according to the Laplace formula is increased with
the radius and the end-diastolic pressure:
T =
K(
P x R):
h, whereby
T = tension,
K = constant factor,
P = pressure,
R = radius and
h = wall thickness. Wall tension itself correlates with the
oxygen demand of the heart. As measured by a thermodilution
Swan–Ganz catheter, the cardiac index [stroke volume (l)
heart
x rate]: body surface (m
2) can fall below its normal range
of 3.0 l/m
2 (body surface). In dilated hearts, the left ventricular
and end-diastolic volume indexes, assessed from angiocardiography
and normalized per body surface (in m
2), are pathologically
increased (>100 ml/m
2). The stroke volume index may still
stay the same at the beginning or already decrease. The cardiac
output can be reduced or often be maintained only by an increase
in beating frequency. The contractile state will be assessed
best by the ejection fraction (EF): EF(%) = [(stroke volume
index): (end-diastolic volume index)]
x 100. Its normal range
is >55%.
Stenoses of cardiac valves are assessed by the pressure difference in mmHg on both sides of the impaired opening and normalized by the cardiac index, thus allowing: measurement of the opening surface area. In aortic stenosis, opening areas <0.8 cm2 have to be operated, and areas between 0.8 and 1.2 cm2 can be considered for surgery, when the patient is symptomatic. Mitral valve stenoses should be operated when the opening area is below 1.5 cm2. In valvular regurgitations, it is the angiographic reflux of contrast media (degrees 1–4), the symptoms of the patient, which determines the indication for repair or valve replacement.
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Coronary angiography
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Coronary angiography is justified in patients with collagen
and rheumatic diseases, when angina pectoris and/or dyspnoea
are present, and non-invasive methods point to ischaemia. This
applies particularly to patients suffering from rheumatic fever,
panarteritis nodosa, systemic lupus erythematosus (SLE), systemic
sclerosis or transplant vasculopathy. In the latter, an infection
with cytomegalo virus (CMV) or
chlamydia pneumoniae have been
suggested to play a role, but also a vascular form of rejection
has been advocated. In rheumatic fever, granuloma and fibrinoid
degeneration may also affect the cardiac vessels. In SLE, panarteritis,
systemic sclerosis and dermatomyositis, the involvement of the
microvasculature has also to be taken into account and compared
with the affection of the major coronary arteries (macroangiopathy).
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Endomyocardial biopsy
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Endomyocardial biopsy is, apart from necropsy, the only tool
to demonstrate inflammation of the myocardium, the fixation
of immunoglobulins and complement to cardiovascular structures
and to assess or exclude a microbial aetiology by PCR and/or
in situ hybridization of cardiotropic agents. [
9–12].
The step-like approach that our institution uses before an endomyocardial
biopsy is carried out, and the treatment course we offer our
patients, depending on the result of the histological, immunohistological
and viral evaluations of the specimens and the peripheral blood,
are shown in
Fig. 1. For each procedure, written consent was
obtained according to the Declaration of Helsinki. The performance
of myocardial biopsies conforms to the standards currently applied
in our country and was initially approved by the local ethics
committee. Since we regularly examine the presence (qualitative
analysis) and load (quantitative analysis) by polymerase chain
reaction (PCR) for RNA or DNA of entero-, adeno-, echo-, herpes,
cytomegalo-, influenza-hepatitis C- and HI viruses as well as
and for
Borrelia burgdorferi, Mycobacterium tuberculosis and
Chlamydia pneumonia in biopsies, peripheral blood and effusions
in autoreactive myocarditis is defined as non-viral, non-bacterial
inflammation with lymphocytic infiltrates (
Fig. 2A) adjacent
to the myocytes (
Fig. 2B). Increased major histocompatibility
complex (MHC) expression can be found at the endothelium of
small vessels and at the sarcolemma (
Fig. 2C). Immunoglobulin
binding to the sarcolemma and contractile proteins (myosin)
in the biopsy (
Fig. 2D left) reflects the presence of identical
circulating antibodies in the peripheral blood (
Fig. 2D right)
of a representative 43-yr-old woman with rheumatoid arthritis
and cardiac involvement. The methodology for quantitative PCR
and results of viral and bacterial assessments from endomyocardial
biopsies of patients who underwent the procedure for suspected
myocarditis or inflammatory cardiomyopathy and were enrolled
in the Marburg Registry, are given in
Fig. 3 [
9]; the results
from the patients in the registry with the respective collagen
disorders are shown in
Table 2. Hereby we follow the algorithm
for the quantification of an infiltrate as defined by the World
Heart Federation task force on cardiomyopathies, 1999 [
4], which
extends the historic Dallas classification [
10], which was designed
for H & E staining to 14 infiltrating cells/mm
2 or for a
focal infiltrate to be named myocarditis or inflammatory cardiomyopathy.
The quantitative assessment is of particular value in chronic
forms of virus-negative (autoreactive) forms of chronic myocarditis.
This type of inflammatory involvement is seen most frequently
in patients with autoimmune rheumatic disease also [
3].
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FIG. 1. Diagnostic and treatment algorithm in myocarditis and inflammatory dilated cardiomyopathy. VT, ventricular tachycardia; Vfib, ventricular fibrillation; VES, ventricular premature contraction; CAD, coronary artery disease; ly, lymphocyte; Mo, monocyte; PCR, polymerase chain reaction.
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FIG. 2. Biopsy findings in a 43-yr-old woman with rheumatoid arthritis and severe cardiac involvement (left ventricular dilatation, small pericardial effusion). (A) Haematoxilin–eosin staining, 400x, (B) CD45RO, EN4, 400x, (C) HLA-ABC (MHC Class I), 400x, (D, left) IgG-binding to sarcolemma and myosin, (D, right) double sandwich (rhyanodin) circulating antisarcolemmal and antimyosin antibodies, 400x. HE, haematoxylin-eosin stain; CD, cluster of differentiation; MHC, major histocompatibility complex; HLA, human leukocyte antigen.
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The complication rate of endomyocardial biopsy is extremely
low when it is carried out in an experienced centre: from 1989
to 2005, we carried out left ventricular endomyocardial biopsies
in 5123 patients, acquiring 38 782 biopsy samples. We experienced
no lethal complication. Perforation with need for pericardial
puncture was observed in 1/1000 patients or 1/10 000 biopsies.
Incidence of cerebral emboli was negligible (<1:10 000 patients),
as were valvular lesions (mitral valve lesion: 1/5000).
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Current definitions of cardiomyopathies
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The 1995 World Health Organisation/International Society and
Federation of Cardiology (WHO/ISFC) classification [
11] divided
cardiomyopathies according to their clinical and haemodynamic
phenotype as dilated, hypertrophic, restrictive, right ventricular
and unclassifiable. It attributed these phenotypes, in cases
of known aetiopathogenesis, to specific cardiomyopathies. Among
the latter were inflammatory cardiomyopathy and hypersensitivity
and toxic reactions. Inflammation seen in systemic collagen
disorders or rheumatic disease could be attributed to this cohort,
particularly when making use of the World Health Federation
(WHF) task force definition on inflammatory cardiomyopathy of
1999 [
4].
Recently, Maron et al. [13] reported for the American Heart Association (AHA) on contemporary definitions and classification of cardiomyopathies with the recommendation that cardiomyopathies can be most effectively classified as primary when the heart was involved primarily. These cases were subdivided as genetic, mixed and acquired forms. Secondary cardiomyopathies were those forms in which the heart was not the dominating organ to be involved. When using this new AHA classification, cardiac involvement in rheumatic diseases would have to be searched for only among the secondary forms.
There are a number of valid reasons to reject this AHA classification:
- It reverses the use of primary, of the 1996 classification, from idiopathic (unknown aetiology) to predominating affection of the heart, and the use of secondary from known aetiology and pathogenesis to only minor involvement of the heart.
- It includes in the primary cardiomyopathy group, among the genetically determined group, the channelopathies, many of which do not show the phenotype of any previously described cardiomyopathy but only rhythm disturbances.
- The classification is totally impracticable for the clinician because he will never start his examination of a patient by a complicated analysis of the genotype or a single channel. The patient will always consult because of symptoms and he will be transferred to him because of abnormalities in the phenotype assessed by imaging.
- A satisfying definition of inflammation has not at all been given.
- The interplay between microbial infection, inflammation and dilatation has been largely discarded.
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Pericardiocentesis and pericardioscopy
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The diagnostic and treatment algorithms, which should be followed
according to the guidelines of the European Society of Cardiology
(ESC) 2004 [
7], can be derived from
Fig. 4. In
Fig. 5, the two
approaches for pericardiocentesis, i.e. the subxyphoidal approach,
which we predominantly use, or the lateral approach, which uses
the smallest distance between effusion and thoracic wall, were
guided most often by echocardiography. The macroscopic inspection
of the epi- and pericardial layers are examined for the classic
criteria of fibrinous autoreactive pericardial effusion: fibrin
deposits (upper lane), petechiae (middle lane) and increased
pericardial vascularization [
14–17].
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FIG. 5. The two modes of access for pericardiocentesis (left side) and the pericardioscopic findings in fibrinous pericardial effusion: fibrin deposits, petechiae, increased vascularization of peri- and epicardial layer.
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Epicardial and pericardial biopsy
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The specific findings (
Fig. 6) from a 59-yr-old patient with
a large pericardial effusion in lupus erythematodes are the
following: pericardioscopy with epicardial rubeosis (upper left),
pericardial cytology with lymphocytes and macrophages in the
exudates (lower left), the epicardial infiltrate with a semigranulomatous
conformation (upper right) and the epi- and myocardial IgG fixation.
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FIG. 6. Findings in a 59-yr-woman with lupus erythematodes and large pericardial effusion: pericardioscopy with epicardial rubeosis (upper left), pericardial cytology with lymphocytes and macrophages in the exudate (lower left), the epicardial infiltrate with granuloma-like conformation (upper right) and the epi- and myocardial IgG fixation to sarcolemma, interstitial tissue and epicardium.
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Specific treatment in inflammatory autoreactive (virus-negative) heart muscle disease
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Treatment in rheumatic and collagen disease with myocardial
inflammation is directed by the therapy of the underlying systemic
disorder. The repertoire can include corticoids, antimetabolites
and antiphlogistics. For autoreactive myocarditis independent
of an underlying systemic rheumatic disorder, the American Myocarditis
Trial has shown neither benefit nor detriment, but it was underpowered
and did not exclude viral aetiology, which would, according
to our present knowledge, make up in between 30 and 60%. The
only double-blind randomized trial to re-examine the effect
of a combined treatment with azathioprin and corticosteroids
is the European Study of Epidemiology and Treatment of Cardiac
Inflammatory Disease (ESETCID) trial, which is still ongoing
[
18].
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Treatment in pericarditis and pericardial effusion
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The recommended treatment in pericarditis and pericardial effusion,
including intrapericardial gentamycin and crystalloid triamcinolone
instillation, can be appreciated from
Fig. 7. Recurrence of
pericardial effusion can be prevented by the combination of
intrapericardial triamcinolone and oral colchicine in about
90% of cases [
16].
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FIG. 7. Options for intrapericardial treatment in patients with pericardial effusion based on the aetiology. Data from the Marburg Registry. For intrapericardial treatment in all patients, 80 mg gentamycin is given as sclerosing therapy. Intrapericardial triamcinolone is given only in autoreactive (virus-negative forms) pericardial effusion. Malignant effusion is treated with intrapericardial cis-platin.
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That oral colchicine is an effective treatment for recurrent
[
19] and acute [
20] pericarditis has been recently shown. The
colchicine for acute pericarditis (COPE) study demonstrated
this in a head to head comparison with aspirin [
20]. Our finding,
that high-dose intrapericardial corticoid treatment together
with oral colchicine effectively prevents recurrences in almost
90% of cases [
16], contrasts somewhat with the report by Adler
et al. [
19] that a previous treatment with oral cortisone may
reduce the effect of colchicine given later on to reduce the
recurrence of pericardial effusion. Further details on recommended
treatment regimens can also be derived from the ESC guidelines
on management of pericardial diseases [
7] and from
Fig. 7.
The authors have declared no conflicts of interest.
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FIG. 3. Assessment of viral aetiology by PCR in patients with myocarditis, pericarditis and inflammatory dilated cardiomyopathy. A positive PCR for different viruses is found in up to one-third of patients, Parvo B19 virus being the most important one. In order to diagnose an autoreactive myo- or pericarditis, microbial aetiology has to be excluded. CMV, cytomegalo virus; ADV, adeno virus; PB19, Parvo B19; Myoc./DCMi, myocarditis/inflammatory dilated cardiomyopathy; DCM, dilated cardiomyopathy; PCR, polymerase chain reaction.
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References
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- Hort W (Hrsg.). (1999) Pathologische Anatomie des Herzens und seiner Hülle II: Pathologie des Endokard, der Kranzarterien und des Myokard(Springer, Berlin).
- Maisch B. (1992) The heart in rheumatic disease. Rheumatic diseases and sport. In Baenkler HW (Ed.). Rheumatology(Basel, Karger) 16: pp. 81–117.
- Maisch B, Bültmann B, Factor S, et al. (1999) World Heart Federation consensus conferences' definition of inflammatory cardiomyopathy (myocarditis): report from 2 expert committees on histology and viral cardiomyopathy. Heart Beat 4:3–6.
- Maisch B, Ristic AD, Pankuweit S, Seferovic PM, Spodick DH. (2000) Intrapericardial treatment of autoreactive myopericarditis with triamcinolone: successful administration in patients with minimal pericardial effusion. Herz 25:781–6.[CrossRef][Web of Science][Medline]
- In Seferovi PM, Spodick DH, Maisch B (Eds.). Pericardiology: contemporary answers to continuing challenges (2000) (Science, Belgrade) Maksimovi R, Risti AD, assoc. eds.
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- Aretz HAT, Billingham ME, Edwards WD, et al. (1987) Myocarditis: a histopathologic definition and classification. Am J Cardiovasc Path 1:3–14.
- Richardson P, McKenna W, Bristow M, et al. (1996) Report of the 1995 World Health Organization/International Society and Federation of Cardiology task force on the definition and classification of cardiomyopathies. Circulation 93:841–2.[Free Full Text]
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- Maisch B, Ristic AD, Rupp H, Spodick DH. (2001) Pericardial access using the PerDUCER® and flexible percutaneous pericardioscopy. Am J Cardiol 88:1323–6.[CrossRef][Web of Science][Medline]
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- Adler Y, Finkelstein Y, Guindo J, et al. (1998) Colchicine treatment for recurrent pericarditis: a decade of experience. Circulation 97:2183–5.[Abstract/Free Full Text]
- Imazio M, Bobbio M, Cecchi E, et al. (2005) Colchicine in addition to conventional therapy for acute pericarditis. Results of the COlchicine for acute PEricarditis (COPE) Trial. Circulation 112:2012–6.[Abstract/Free Full Text]
- Special Writing Group of the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease of the Council of Cardiovascular Disease in the Young of the American Heart Association. (1992) Guidelines for the diagnosis of rheumatic fever. Jones Criteria. JAMA 268:152069–73 1992 update.[Abstract/Free Full Text]
Submitted 10 July 2006;
revised version accepted 16 July 2006.
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Abstract
Introduction and definition of...