Progress in Inflammation Research

(1)

(2)

(3)

Series Editor

Prof. Michael J. Parnham, PhD Director of Science

MediMlijeko d.o.o. 10000 Zagreb Croatia

Progress in Inflammation Research

Forthcoming titles:

Endothelial Dysfunction and Inflammation, A. Karsan, S. Dauphinee (Editors), 2010

Muscle, Fat and Inflammation: Sustaining a Healthy Body Composition, S.A. Stimpson, B. Han, A.N. Billin (Editors), 2011

The Inflammasomes, I. Couillin, V. Petrilli, F. Martinon (Editors), 2011 (Already published titles see last page.)

Advisory Board

G. Z. Feuerstein (Wyeth Research, Collegeville, PA, USA)

M. Pairet (Boehringer Ingelheim Pharma KG, Biberach a. d. Riss, Germany) W. van Eden (Universiteit Utrecht, Utrecht, The Netherlands)

(4)

Birkhäuser

Inflammatory Cardiomyopathy (DCMi)

Pathogenesis and Therapy

Heinz-Peter Schultheiss

Michel Noutsias

(5)

ISBN 978-3-7643-8351-0

The publisher and editor can give no guarantee for the information on drug dosage and administration contained in this publication. The respective user must check its accuracy by consulting other sources of reference in each individual case. The use of registered names, trademarks etc. in this publication, even if not identified as such, does not imply that they are exempt from the relevant protective laws and regulations or free for general use.

This work is subject to copyright. All rights are reserved, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, re-use of illustrations, recitation, broadcasting, reproduction on micro-films or in other ways, and storage in data banks. For any kind of use, permission of the copyright owner must be obtained.

P.O. Box 133, CH-4010 Basel, Switzerland Part of Springer Science+Business Media

Printed on acid-free paper produced from chlorine-free pulp. TCF d Cover design: Markus Etterich, Basel

Cover illustration: see p. 207, with friendly permission by Michel Noutsias Printed in Germany

ISBN 978-3-7643-8351-0 e-ISBN 978-3-7643-8352-7

9 8 7 6 5 4 3 2 1 www.birkhauser.ch

Library of Congress Control Number: 2010923938

Bibliographic information published by Die Deutsche Bibliothek

Die Deutsche Bibliothek lists this publication in the Deutsche Nationalbibliografie; detailed bibliographic data is available in the internet at http://dnb.ddb.de Editors

Heinz-Peter Schultheiss Michel Noutsias

Department of Cardiology and Pneumology Charité – Universitätsmedizin Berlin Campus Benjamin Franklin Hindenburgdamm 30 12200 Berlin Germany

(6)

List of contributors . . . vii

Preface . . . xi

Myocarditis and inflammatory cardiomyopathy – clinical management, epidemiology and prognosis

Bernhard Maisch, Konstantinos Karatolios, Sabine Pankuweit and Arsen Ristic

Pathogenesis, diagnosis and treatment of pericarditis . . . 3

G. William Dec

Epidemiology and prognosis of myocarditis and dilated cardiomyopathy:

Predictive value of clinical parameters and biopsy findings . . . 25

Animal models of myocarditis – autoimmunity and viral infection; therapeutic interventions

Christoph Berger und Urs Eriksson

Autoimmune murine myocarditis and immunomodulatory interventions . . . 37

Michel Noutsias and Peter Liu

Coxsackievirus-induced murine myocarditis and

immunomodulatory interventions . . . 51

Susanne Rutschow, Michel Noutsias and Matthias Pauschinger Myocardial proteases and matrix remodeling in acute myocarditis

and inflammatory cardiomyopathy . . . 71

Alterations of the immune system in human viral and inflammatory cardiomyopathy

Jeffrey A. Towbin and Matteo Vatta

Molecular genetics of cardiomyopathies and myocarditis . . . 91

(7)

Dalip J.S. Sirinathsinghji and Ray G. Hill

vi

Roland Jahns, Valérie Boivin, Georg Ertl and Martin J. Lohse

Pathogenic relevance of autoantibodies in dilated cardiomyopathy . . . 157

Jesus G. Vallejo and Douglas L. Mann

The role of cytokines in inflammation-induced cardiomyopathy:

Pathogenesis and therapeutic implications . . . 171

Diagnosis of inflammatory and viral cardiomyopathy

Annalisa Angelini, Fiorella Calabrese and Gaetano Thiene

Histology and immunohistology of myocarditis . . . 185

Michel Noutsias, Heinz-Peter Schultheiss and Uwe Kühl

Immunohistological diagnosis of inflammatory cardiomyopathy and

diagnosis of cardiotropic viral infections . . . 201

Matthias Gutberlet

Cardiac magnetic resonance imaging: A non-invasive approach for the

detection of myocardial inflammation – Potentials and limitations. . . 227

Treatment strategies in inflammatory cardiomyopathy patients

Kenneth L. Baughman†

Clinical management of acute myocarditis and cardiomyopathy . . . 239

Andrea Frustaci and Cristina Chimenti

Immunosuppressive treatment of inflammatory cardiomyopathy patients . . . 257

Heinz-Peter Schultheiss, Michel Noutsias and Uwe Kühl Antiviral interferon-B treatment in patients with chronic

viral cardiomyopathy . . . 265

Stephan B. Felix and Alexander Staudt

Immunoadsorption in dilated cardiomyopathy patients . . . 279

Index . . . 291 Contents

(8)

vii

Annalisa Angelini, Department of Medico-diagnostic Sciences and Special Thera-pies, Special Pathological Anatomy, University of Padua Medical School, Via A. Gabelli, 61, 35121 Padova, Italy; e-mail: [email protected]

Christoph Berger, Departments of Internal Medicine and Research, University Hos-pital, Petersgraben 4, 4031 Basel, Switzerland

Valérie Boivin, Institute of Pharmacology and Toxicology, University of Würzburg, Versbacher Str. 9, 97078 Würzburg, Germany; e-mail: [email protected]

Fiorella Calabrese, Department of Medico-diagnostic Sciences and Special Thera-pies, Special Pathological Anatomy, University of Padua Medical School, Via A. Gabelli, 61, 35121 Padova, Italy; e-mail: [email protected]

Cristina Chimenti, Department of Cardiovascular and Respiratory Sciences, La Sapienza University, Viale del Policlinico 155, 00161 Rome, Italy; e-mail: [email protected]

G. William Dec, Cardiology Division, Massachusetts General Hospital, Heart Fail-ure and Transplantation Unit, Boston, MA 02114, USA; e-mail: [email protected] Urs Eriksson, GZO AG Spital Wetzikon, Spitalstr. 66, 8620 Wetzikon, Switzerland; and Universitätsspital Zürich, Rämistr. 100, 8091 Zürich, Switzerland; e-mail: urs. [email protected]

Georg Ertl, Department of Internal Medicine, Medizinische Klinik und Poliklinik I, Cardiology, University Hospital of Würzburg, Oberdürrbacher Str. 6, 97080 Würz-burg, Germany; e-mail: [email protected]

Stephan B. Felix, Klinik für Innere Medizin B, Ernst-Moritz-Arndt-Universität, Friedrich-Loefflerstr. 23a, 17475 Greifswald, Germany; e-mail: felix@uni-greifswald. de

(9)

viii

Andrea Frustaci, Department of Cardiovascular and Respiratory Sciences, La Sapien-za University, Viale del Policlinico 155, 00161 Rome, Italy; e-mail: [email protected] Matthias Gutberlet, University Leipzig/ Leipzig Heart Center, Department of Diag-nostic and Interventional Radiology, Strümpellstrasse 39, 04289 Leipzig, Germany; e-mail: [email protected]

Roland Jahns, Department of Internal Medicine, Medizinische Klinik und Poliklinik I, Cardiology, University Hospital of Würzburg, Oberdürrbacher Str. 6, 97080 Würzburg, and Institute of Pharmacology and Toxicology, University of Würzburg, Versbacher Str. 9, 97078 Würzburg, Germany; e-mail: [email protected]

Konstantinos Karatolios, Department of Internal Medicine-Cardiology, University Hospital of Giessen and Marburg, Baldingerstrasse 1, 35033 Marburg, Germany; e-mail: [email protected]

Uwe Kühl, Department of Cardiology and Pneumonology, Charité – Universitäts-medizin Berlin, Campus Benjamin Franklin, Hindenburgdamm 30, 12200 Berlin, Germany; e-mail: [email protected]

Peter Liu, Heart & Stroke Medicine and Physiology, Institute of Circulatory and Respiratory Health, Canadian Institutes of Health Research, Toronto General Hos-pital, University of Toronto, Canada; e-mail: [email protected]

Martin J. Lohse, Institute of Pharmacology and Toxicology, University of Würzburg, Versbacher Str. 9, 97078 Würzburg, Germany; e-mail: [email protected] Bernhard Maisch, Department of Internal Medicine – Cardiology, University Hos-pital of Giessen and Marburg, Philipps-Universität Marburg, Baldingerstrasse 1, 35033 Marburg, Germany; e-mail: [email protected]

Douglas L. Mann, Division of Cardiology, Washington University School of Medi-cine, St. Louis, MO, USA; e-mail: [email protected]

Michel Noutsias, Department of Internal Medicine – Cardiology, University Hos-pital of Marburg and Giessen, Philipps-Universität Marburg, Baldinger Strasse 1, 35033 Marburg, Germany; e-mail: [email protected]

Sabine Pankuweit, Department of Internal Medicine-Cardiology, University Hospi-tal of Giessen and Marburg, Baldingerstrasse 1, 35033 Marburg, Germany; e-mail: [email protected]

(10)

ix

Matthias Pauschinger, Department of Cardiology, Medizinische Klinik 8, Klinikum Nürnberg Süd, Breslauer Straße 201, 90471 Nürnberg, Germany; e-mail: matthias. [email protected]

Arsen Ristic, Department of Cardiology II, Belgrade University, Belgrade, Serbia; e-mail: [email protected]

Susanne Rutschow, Department of Cardiology and Pneumonology, CharitéCen-trum 11 for Cardiovascular Medicine, Charité – Universitätsmedizin Berlin, Cam-pus Benjamin Franklin, Hindenburgdamm 30, 12200 Berlin, Germany; e-mail: [email protected]

Heinz-Peter Schultheiss, Department of Cardiology and Pneumonology, Charité – Universitätsmedizin Berlin, Campus Benjamin Franklin, Hindenburgdamm 30, 12200 Berlin, Germany; e-mail: [email protected]

Alexander Staudt, Klinik für Innere Medizin B, Ernst-Moritz-Arndt-Universität, Friedrich-Loefflerstr. 23a, 17475 Greifswald, Germany; e-mail: staudt@uni-greifs wald. de

Gaetano Thiene, Department of Medico-diagnostic Sciences and Special Therapies, Special Pathological Anatomy, University of Padua Medical School, Via A. Gabelli, 61, 35121 Padova, Italy; e-mail: [email protected]

Jeffrey A. Towbin, The Heart Institute, Division of Pediatric Cardiology, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229, USA; e-mail: [email protected]

Jesus G. Vallejo, Section of Infectious Diseases, Department of Pediatrics and Win-ters Center for Heart Failure Research, Baylor College of Medicine and Texas Chil-dren’s Hospital, 6621 Fannin Street, Houston, TX 77030, USA; e-mail: jvallejo@ bcm.tmc.edu

Matteo Vatta, Baylor College of Medicine, Texas Children’s Hospital, 6621 Fannin Street, MC 19345-C, Houston, TX 77030, USA

(11)

Acute myocarditis (AMC) and its sequelae, inflammatory cardiomyopathy (DCMi), are leading entities of heart failure and of cardiac transplantation. AMC is mostly caused by various cardiotropic viruses in the Western World. The long-anticipated association of dilated cardiomyopathy with chronic inflammation and viral persis-tence in terms of DCMi has been substantiated by more sensitive and specific diag-nostic methods for analyzing material from endomyocardial biopsies (EMBs) during the last 15 years. This development has led to the broadly acknowledged “death of the Dallas criteria” as the single conditio sine qua non for the histological diagnosis of myocarditis. Moreover, these refined diagnostic techniques have been pertinent for successful randomized immunomodulatory trials. As such, immunosuppression, antiviral interferon treatment and immunoadsorption have shown significant ben-eficial results in selected DCMi patients. These compelling insights will likely lead to a renunciation of the limited usage of EMBs, seen as a consequence after the first immunosuppressive trial based on the Dallas criteria. In addition, cardiac magnetic resonance (CMR) has evolved to a powerful non-invasive diagnostic approach.

“Cardiac inflammation is difficult to diagnose and, even if diagnosed, can we then treat it more effectively?” This was written 1772 by Jean Baptiste Sénag, physi-cian to Louis XV. Are we yet able to answer this simple, but decisive question? In fact, DCMi is still an enigmatic disease, with highly diverging clinical courses, and potentially fatal outcomes. More robust prognostic variables and selection criteria for appropriate DCMi candidates and the corresponding immunomodulatory treat-ment strategies are needed. Almost yearly new key players of the immune system and of viral entry/persistence mechanisms are unraveled as relevant pathogenic and therapeutic targets in experimental myocarditis. “It is better to know some of the questions than all of the answers.” (James Thurber; 1894–1961).

This volume focuses on major advances in DCMi over the last 10 years, encom-passing:

(1) Epidemiology and prognosis; (2) insights from experimental myocarditis; (3) alterations of the immune system in human DCMi; (4) diagnostic concepts of DCMi

xi

(12)

xii

Dalip J.S. Sirinathsinghji and Ray G. Hill Preface

in EMBs and by CMR; and (5) conventional and immunomodulatory treatment strategies in DCMi.

We thank the international group of leading authors who have contributed to this book. This volume serves as a valuable source for cardiologists, cardiovascular pathologists and related researchers to update their knowledge on DCMi. DCMi is specific cardiomyopathy entity, defined in 1996 by the WHO/International Society and Federation of Cardiology Task Force on the Definition and Classification of cardiomyopathies, and since then research into this entity has made major steps from bench to bedside.

January 2010 H.-P. Schultheiss

(13)

Myocarditis and inflammatory cardiomyopathy –

clinical management, epidemiology and prognosis

(14)

3 Inflammatory Cardiomyopathy (DCMi) – Pathogenesis and Therapy,

Abstract

The spectrum of inflammatory pericardial syndromes includes acute, chronic and recurrent (relaps-ing) pericarditis, pericardial effusion and cardiac tamponade as well as constrictive pericarditis. The etiology of pericardial diseases is extensive, including infectious, non-infectious, systemic and autoimmune causes. A substantial proportion of idiopathic pericarditis represents viral infections or autoreactive pericarditis. The diagnosis of pericardial diseases is based on clinical presentation, electrocardiogram changes and echocardiographic findings. Pericardiocentesis, pericardioscopy with pericardial biopsy and contemporary pathology, immunohistochemistry and molecular biol-ogy techniques have extended the diagnostic armamentarium and contributed to etiopathogenetic understanding and treatment in pericardial diseases. Nevertheless, in uncomplicated cases, resolv-ing to conventional anti-inflammatory treatment such a comprehensive approach is clinically not justified. On the other side, in chronic, recurrent or resistant forms an etiological diagnosis enables specific treatment. Furthermore, intrapericardial treatment after pericardiocentesis with cytostatic agents (cisplatin or thiotepa) in malignant pericardial effusions or sclerosing agents (triamcinolone, gentamycin) in chronic recurrent autoreactive effusions may prevent recurrences. Pericardiocente-sis is life saving in cardiac tamponade and indicated in large effusions (> 20 mm in echocardiogra-phy in diastole), and suspected purulent, tuberculous and neoplastic pericarditis. Pericardiectomy is the only treatment for permanent constriction.

Classification and etiology of pericardial disease

Inflammatory pericardial syndromes include acute, chronic and recurrent (relaps-ing) pericarditis, pericardial effusion and cardiac tamponade as well as constrictive pericarditis. Their etiology comprises infectious, systemic autoimmune, metabolic, toxic, neoplastic, postmyocardial infarction syndrome, postcardiotomy syndrome and autoreactive disorders (Tab. 1) [1–4].

Pathogenesis, diagnosis and treatment of pericarditis

Bernhard Maisch1, Konstantinos Karatolios1, Sabine Pankuweit 1 and Arsen Ristic 2

1_{Department of Internal Medicine-Cardiology, University Hospital of Giessen and Marburg,} Marburg, Germany

(15)

4

Bernhard Maisch et al.

Table 1. Etiology, incidence and pathogenesis of pericarditis

Etiology Incidence (%) Pathogenesis

Infectious pericarditis

- Viral (Coxsackie A9, B1-4, Echo 8, mumps, EBV, CMV, Varicella, Rubella, HIV, Parvo B19...) - Bacterial (pneumo-, meningo-,

gonococcosis, hemophilus,

Treponema pallidum, borreliosis, chlamydia, tuberculosis...) - Fungal (candida, histoplasma...) - Parasitary (Entameba histolytica,

Echinococcus, toxoplasma...)

30–50a

5–10a

Rare Rare

Multiplication and spread of the causative agent and release of toxic substances in pericardial tissue cause serous, serofibrinous or hemorrhagic (bacterial, viral, tuberculous, fungal) or purulent inflammation (bacterial)

Pericarditis in systemic autoimmune disease - Systemic lupus erythematosus

- Rheumatoid arthritis - Spondylitis ankylosans - Systemic sclerosis - Dermatomyositis - Periarteritis nodosa - Reiter’s syndrome

- Familial Mediterranean fever

30b 30b 1b > 50b Rare Rare ~2b 0.7b

Cardiac manifestations of the basic disease, often clinically mild or silent

Type 2 (auto)immune process Secondary, after infection/surgery - Rheumatic fever

- Postcardiotomy syndrome - Postmyocardial infarction

syndrome

- Autoreactive (chronic) pericarditis

20–50b ~ 20b

1–5b 23.1a

Mostly in acute phase 10–14 days after surgery DDg P. epistenocardica Common form Pericarditis and pericardial effusion in diseases of surrounding organs - Acute MI (P. epistenocardica) - Myocarditis - Aortic aneurysm - Lung infarction - Pneumonia - Esophageal diseases - Hydropericardium in CHF - Paraneoplastic pericarditis 5–20b 30b Rare Rare Rare Rare Rare Frequent

1–5 days after transmural MI Accompanying epimyocarditis Dissection: hemorrhagic PE

(16)

5 Pathogenesis, diagnosis and treatment of pericarditis

Etiology Incidence (%) Pathogenesis

Pericarditis in metabolic disorders - Renal insufficiency (uremia) - Myxedema - Addison’s disease - Diabetic ketoacidosis - Cholesterol pericarditis - Pregnancy Frequent 30b Rare Rare Very rare Rare - Viral/toxic/autoimmune - Serous, cholesterol rich PE - Membranous leak? - Transudation of cholesterol

(sterile serofibrinous PE) Traumatic pericarditis

- Direct injury (penetrating thoracic injury, esophageal perforation, foreign bodies)

- Indirect injury (Non-penetrating thoracic injury, mediastinal irradiation)

Rare

Rare Less frequent after introduction of topical convergent irradiation

Neoplastic pericardial disease 35a - Primary tumors

- Secondary metastatic tumors: Lung carcinoma

Breast carcinoma Gastric and colon Other carcinoma Leukemia and lymphoma Melanoma Sarcoma Other tumors Rare Frequent 40c 22c 3c 6c 15c 3c 4c 7c

Serous or fibrinous, frequently hemorrhagic effusion

Accompanying disease during the infiltration of malignant cells

Idiopathic 3.5a_,

in other series > 50a

Serous, fibrinous, sometimes hemorrhagic PE with suspect viral or autoimmune secondary immunopathogenesis

CHF, congestive heart failure; DDg, differential diagnosis; MI, myocardial infarction; P., peri-carditis; PE, pericardial effusion

a_{Percentage related to the population of 260 subsequent patients undergoing}

pericardiocen-tesis, pericardioscopy and epicardial biopsy (Marburg pericarditis registry 1988–2001) [1]

b_{Percentage related to the incidence of pericarditis in the specific population of patients}

(e.g., with systemic lupus erythematosus)

c_{Percentage related to the population of patients with neoplastic pericarditis}

With permission from the ESC-Textbook on the Management of Pericardial Disease (Maisch et al. [12])

(17)

6

Pericardial syndromes Acute pericarditis

The acute inflammation of the pericardium can be dry, fibrinous or effusive. Their etiology is extensive (Tab. 1).

Clinical presentation

Retrosternal or left precordial chest pain is usually pleuritic or pericarditic in nature. It varies with posture, being worse in the supine position and relieved by sitting and leaning forward. Typical pericardial pain radiates to the trapezius ridge due to irrita-tion of the phrenic nerves, which traverse the anterior pericardium and innervate the trapezius ridge [3, 5, 6]. Pericardial pain can also simulate ischemic pain, leading to a false diagnosis of myocardial infarction. Pericardial friction rub is diagnostic of pericarditis and is present in about 85% of patients with pericarditis. This requires a careful and frequent auscultation of the left sternal edge and the cardiac borders at expiration, with the patient sitting and leaning forward, since the pericardial rub can be transient [5, 6].

Electrocardiogram

An electrocardiogram (ECG) often displays a rapid heart rhythm and, classically, diffuse concave ST elevations with PR segment depressions (Fig. 1). In approxi-mately 40% of cases, the ECG is atypical [7].

Laboratory results

They may include leukocytosis, elevated C-reactive protein and erythrocyte sedi-mentation rate [8, 9]. Elevated troponin levels are detectable in 1/3 of cases indicat-ing epicardial and myocardial involvement [9, 10].

Echocardiography

Echocardiography detects effusion and determines the extent of the effusion, its physiological significance, signs of constriction, concomitant myocardial disease or paracardial pathology.

Acute pericarditis may be a transient, often benign disease, but also the first manifestation of an underlying neoplastic, purulent or tuberculous disorder that requires prompt specific therapy. A systematic, step-wise approach to the etio-logical diagnosis is essential to select the patients that can be effectively treated (Tab. 2, Figs 2 and 3) [4, 8, 10, 11]. A symptomatic treatment of acute pericarditis

(18)

is based on chest pain management and anti-inflammatory therapy. Non-steroidal anti-inflammatory agents (NSAIDs) are its mainstay. We prefer diclophenac (75 mg bid), ibuprofen (200–600 mg tid) or indomethacin (25–50 mg tid) as alternatives to aspirin [12]. Indomethacin should not be used in patients with or suspected of having coronary artery disease, since it reduces coronary flow. Colchicine (0.5 mg bid) as monotherapy or added to NSAIDs is also very effective for initial treatment and for the prevention of recurrences [13]. Systemic corticosteroids are indicated for connective tissue diseases, and autoreactive or uremic pericarditis. Ibuprofen or colchicine should be added early for tapering of corticosteroids [4, 12]. Intrapericar-dial application of corticosteroids (triamcinolone) is very efficient and mainly avoids systemic side effects in patients with a large autoreactive and uremic pericardial effusion [2].

Chronic pericarditis

Chronic (> 3 month) pericarditis comprises effusive, adhesive and constrictive forms [4, 5]. Symptoms include pericardial pain and fever and are related to pericardial inflammation. The diagnostic algorithm (Tab. 2) and symptomatic treatment are as in acute pericarditis.

Figure 1.

(19)

8

Table 2. Diagnostic algorithm in acute pericarditis [2–4, 8, 10, 11] (with permission from [12])

Diagnostic test Characteristic findings Step I – Tests obligatory in all patients

History and physical examination

- Identification of high-risk patients (should be hospitalized)a - Pericardial rub (mono-, bi-, or triphasic)

ECGb - Stage I: anterior and inferior concave ST segment elevation. PR segment deviations opposite to P waves

- Early stage II: all ST junctions return to the baseline. PR segments deviated

- Late stage II: T waves progressively flatten and invert

- Stage III: generalized T wave inversions in most leads

- Stage IV: ECG returns to prepericarditis state Echocardiography - Effusion types B-D (Horowitz)

- Signs of tamponade or concomitant heart or paracardial disease Laboratory analyses - ESR, CRP, LDH, leukocytes, parameters of renal and hepatic

function, urine analyses - Troponin Ic, CK-MB

Chest x-ray - Ranging from normal to “water bottle” shape. - To reveal pulmonary or mediastinal pathology

In self-limiting pericarditis (within 1 week) or known associated or systemic diseases no further diagnostic procedures are necessary. In patients symptomatic for > 1 week despite NSAID treatment, screening for systemic autoimmune disease (ANA, anti-ds-DNA, RF, C3, C4, immunoglobulins, immune complexes), thyroid disease, three sputum or gastric-aspirate cultures for mycobacteria, serological tests (mycoplasma, toxoplasma, borrelia, legionela), and lymph node biopsy, tumor markers, and additional imaging (abdominal sonography, CT, MR) should be done.

Step II – mandatory in tamponade, in large (> 20 mm) effusions and in suspected purulent, tuberculous or neoplastic etiology, or if previous tests were inconclusive in symptomatic patients resistant to conventional treatment

Pericardiocentesis/ drainage

- Analyses of pericardial effusion can establish the diagnosis of viral, bacterial, tuberculous, fungal, cholesterol, and malignant pericarditis:

- Analyses obligatory in all patients: - Cytology, cell counts

- Acid-fast bacilli staining

- Mycobacterium cultures (preferably with radiometric growth detection e.g., BACTEC-460) and PCR for M. tuberculosis - Biochemical analyses: specific gravity, protein level, glucose,

(20)

Recurrent (relapsing) pericarditis

Recurrent pericarditis encompasses two clinical forms: (1) the intermittent type with symptom-free intervals without therapy, and (2) the incessant type, in which the discontinuation of anti-inflammatory therapy causes the relapse [14]. The most common reasons of relapsing pericarditis are viral and “idiopathic” pericarditis, followed by postmyocardial infarction and postcardiotomy syndromes [14, 15]. Therapy aims at symptomatic treatment of acute episodes and the prevention of

Diagnostic test Characteristic findings Pericardiocentesis/

drainage (continued)

- In areas with high incidence of tuberculosis:

- Adenosine deaminase, interferon-gamma, pericardial lysozyme

- In suspected autoreactive or viral pericarditis - PCR analyses for cardiotropic viruses - In suspected bacterial or fungal pericarditis

- Cultures of pericardial fluid for aerobes, anaerobes and fungi (3x)

- Blood cultures (3x)

- In suspected chylopericardium - Cholesterol, triglycerides

Step III – Optional or if previous tests inconclusive in symptomatic patients resistant to conventional treatment

Pericardial/epicardial biopsy (preferably by pericardioscopy)

- Histology (neoplastic and tuberculous pericarditis) - PCR for cardiotropic viruses, borreliosis and tuberculosis - Immunohistochemistry (autoreactive forms)

a _{Indication for hospitalization: fever > 38°C, subacute onset, immunodepression, trauma,}

oral anticoagulant therapy, myopericarditis, severe pericardial effusion, or cardiac tampon-ade. Others can be treated as outpatients.

b _{Typical lead involvement: I, II, aVL, aVF, and V3-V6. If ECG is first recorded in stage III,}

pericarditis cannot be differentiated by ECG from diffuse myocardial injury, “biventricular strain”, or myocarditis. Early repolarization is similar to stage I, but does not acutely evolve and J-point elevations are usually accompanied by a slur, oscillation, or notch at the end of the QRS just before and including the J point (best seen with tall R and T waves – large in early repolarization). Pericarditis is likely if in V6 the J point is > 25% of the T wave height (using the PR segment as a baseline).

c_{A cTnI rise was detectable in 32.2%, but > 1.5 ng/ml in 7.6%. It was not a negative}

prognostic marker regarding the incidence of recurrences, constrictive pericarditis, cardiac tamponade or residual LV dysfunction.

(21)

10

recurrences. Symptomatic treatment includes exercise restriction and the manage-ment of acute episodes as in acute pericarditis with NSAIDs [4]. Colchicine has been demonstrated to prevent relapses [13, 15]. Corticosteroids should be restricted to patients with refractory symptoms and frequent crises. Viral infection should be excluded by analyses of pericardial fluid or epicardial tissue with polymerase chain reaction (PCR) prior to administering corticosteroids to prevent augmented viral replication leading to frequent recurrences [14]. Percutaneous balloon pericar-diotomy (Fig. 4) or surgical pericardiectomy is beneficial in patients with frequent and symptomatic recurrences refractory to any other treatment [12].

Pericardial effusion

Pericardial effusion can develop in any of the above-mentioned pericardial diseases. Large effusions are common with neoplastic, tuberculous, cholesterol or uremic pericarditis, with myxedema and parasitoses [16]. Large effusions develop slowly and therefore can be remarkably asymptomatic. Rapidly accumulating small

effu-Figure 2.

(22)

sions may result in symptomatic cardiac tamponade. The ECG may display low QRS and T-wave voltage, PR segment depression, ST-T changes, bundle branch block and electrical alternans [3]. In chest radiography large effusions resemble a water bottle heart (Fig. 5 left). Echocardiography classifies pericardial effusion and determines its hemodynamic significance. Effusions can be graded as small (sepa-ration of the pericardial layers in diastole < 10 mm), moderate (10–20 mm), large (> 20 mm) or very large (> 20 mm with compression of the heart) [4], or classified according to Horowitz into types B–F (Fig. 6) [17]. Hemodynamic compromise,

Figure 3.

Diagnostic algorithms in pericarditis. (1A) Pericardioscopy of fibrinous pericarditis with little changes on the epicardium. (1B) Pericardioscopy of exudative pericarditis with small pete-chiae. (1C) Pericardioscopy of exudative pericarditis with increase vascular injections. (2A) Pericardioscopy in lymphocytic pericarditis. (2B) Epicardial biopsy in lymphocytic pericarditis with CD45Rho-positive infiltrate. (2C) Cytology in lymphocytic pericarditis: numerous lym-phocytes are found in the pericardial fluid. (2D) Immunohistological staining of an epicardial biopsy in lymphocytic pericardial effusion.

(23)

12

Figure 4.

Transcutaneous balloon pericardiotomy. Left: After insertion of the only partially inflated bal-loon, showing the original small entrance to the pericardial sac. Middle: Schematic drawing of the procedure. Right: Fully inflated balloon, demonstrating a new pericardial window.

Figure 5.

Left: Chest radiography with a large pericardial effusion (water bottle heart). In contrast to congestive heart failure, the pulmonary arteries are small and hardly visible. Right: Constric-tive pericarditis with pericardial calcifications (arrows).

(24)

cardiac tamponade or suspected purulent or tuberculous pericardial effusion are absolute indications for periocardiocentesis and drainage (Tab. 3, Figs 7 and 8). Pericardiocentesis is not necessary when the diagnosis can be established by other means, or if the effusions are small, or respond well to conventional anti-inflamma-tory treatment [4, 12].

Cardiac tamponade

Any pericardial disease can cause cardiac tamponade, but neoplastic effusion is the most frequent [3, 5]. Classical clinical findings include hypotension, elevated jugu-lar venous pressure apparent as jugujugu-lar venous distension, and pulsus paradoxus (inspiratory decline of systolic blood pressure greater than 10 mm Hg). The

treat-Figure 6.

Classification of pericardial effusion according to Horowitz. EN: Endocardial; EP: epicardial; P: pericardial. Type A is a normal motion of both layers of the pericardium in systole and diastole; type B is a systolic separation of the epicardial and pericardial layer; type C shows a clear cut systolic separation of the epicardial and pericardial layer; type D shows the separation of both layers in systole and diastole; type E displays thickened pericardial layers without fluid separation and type F demonstrates residual fluid between the thickened and concomitantly moving epicardial and pericardial layer.

(25)

14

Table 3. Indications for pericardiocentesis/pericardial drainage (with permission from the ESC Textbook on the Management on Pericardial Diseases [12])

Class I indications (Evidence and/or general agreement that the procedure is useful and effective)

- Cardiac tamponade

- Effusions > 20 mm in echocardiography (diastole). - Suspected purulent or tuberculous pericardial effusion

Class II indications (Conflicting evidence and/or a divergence of opinion about the usefulness/

efficacy of a procedure or treatment)

Class IIa indications (The weight of evidence or opinion is in favor of the procedure or treatment)

- Effusions 10–20 mm in echocardiography in diastole for diagnostic purposes other than purulent pericarditis or tuberculosis (pericardial fluid and tissue analyses, pericardioscopy, and epicardial/ pericardial biopsy)

- Suspected neoplastic pericardial effusion

Class IIb indications (Usefulness/efficacy is less well established by evidence or opinion)

- Effusions < 10 mm in echocardiography in diastole for diagnostic purposes other than purulent; neoplastic or tuberculous pericarditis (pericardial fluid and tissue analyses, pericardioscopy and epicardial/pericardial biopsy). In symptomatic patients diagnostic pericardial puncture should be reserved to dedicated centers

Contraindications (Class III)

- Aortic dissection

- Relative contraindications include uncorrected coagulopathy, anticoagulant therapy, thrombocytopenia < 50,000/mm3, small, posterior and loculated effusions

- Pericardiocentesis is not necessary when the diagnosis can be made otherwise or the effusions are small and resolving under anti-inflammatory treatment

LA: left atrium, LV: left ventricle, RA: right atrium, RV: right ventricle, VCI: inferior vena cava

How to perform pericardiocentesis

- Recent and reliable echocardiography, best immediately before the procedure. The operator has to perform the echocardiography or see the video himself.

- Pericardiocentesis guided by fluoroscopy should be performed in the cardiac catheterization laboratory in local anesthesia. The SUBXIPHOID APPROACH has been used most commonly, with a 8–17-cm, long blunt-tip needle (e.g., Tuohy-17) permitting the passage of the guide-wire, directed towards the left shoulder at a 30° angle to the frontal plane.

- Pericardiocentesis guided by echocardiography can be performed in the intensive care unit, or at bed-side. Echocardiography should identify the shortest route to enter the pericardium INTERCOSTALLY (usually in the sixth or seventh rib space in the anterior axillary line). The intercostal arteries should be avoided by puncturing close to the upper margin of the rip. - It is essential that the needle approach the pericardium slowly under steady manual aspiration

(negative pressure). As soon as the pericardial effusion is aspirated a soft J-tip guidewire should be inserted and after dilatation exchanged for a multi-holed pigtail catheter.

- Strict aseptic conditions, ECG and blood pressure monitoring have to be provided. - Direct ECG monitoring from the puncturing needle is not an adequate safeguard. - Right-heart catheterization can be performed simultaneously, allowing the assessment of

tamponade, hemodynamic monitoring of pericardiocentesis, and exclusion of constriction. - In large pericardial effusions it is prudent to drain < 1 l at the time of initial procedure to avoid the

acute right-ventricular dilatation.

Prolonged pericardial drainage is recommended after pericardiocentesis until the volume of effusion obtained by intermittent pericardial aspiration (every 4–6 h) fall to < 25 ml/day.

(26)

ment of choice is urgent pericardial drainage. Medical treatment is only a temporary measure until pericardiocentesis is performed [4].

Constrictive pericarditis

Constrictive pericarditis describes impaired expansion and cardiac filling by a chronically inflamed thickened pericardium. Rarely, constriction can exist in the absence of pericardial thickening with only ultrastructural changes [18]. The most frequent causes are tuberculosis, mediastinal irradiation and previous cardiac

sur-Figure 7.

Pericardial access and drainage. The subxyphoidal approach is performed under fluoroscopic guidance with a long blunt-tip needle with a mandrel (Tuohy) utilizing the epicardial halo phenomenon in the left lateral angiographic view. The needle is inserted in the subxiphoid region at a 30° angle to the skin and directed towards the left shoulder. As the needle approaches the pericardium the operator intermittently injects contrast medium and attempts to aspirate fluid. After penetration of the pericardial layer and aspiration of pericardial fluid, the needle must be replaced by a soft J-guidewire. After dilatation, the guidewire is exchanged for a multi-holed pigtail catheter to drain the pericardial fluid. The lateral approach (Mayo clinic) is particularly suited, if only echocardiography is available [35].

(27)

16

gery [4]. Patients complain about fatigue, breathlessness and abdominal swelling. In decompensated patients venous congestion, hepatomegaly, pleural effusions, ascites and a protein-loosing enteropathy can be observed [12]. The differential diagnosis between constrictive pericarditis and restrictive cardiomyopathy may create the most serious diagnostic problems [4, 12]. Physical findings, chest radiography (Fig. 5 right), echocardiography [19], CT, MRI, hemodynamics, and endomyocardial biopsy contribute to establishing the final diagnosis (Fig. 9). A recent report dem-onstrated that patients with constrictive pericarditis had only minimal elevated brain-natiuretic peptide (BNP) plasma levels, whereas in restrictive cardiomyopathy the BNP levels were significantly higher [20]. Pericardiectomy is the only treatment for permanent constriction (Tab. 4).

Specific forms of pericarditis

Figure 10 shows the incidence of the various specific forms of pericarditis in a popu-lation of 260 patients undergoing pericardiocentesis, pericardioscopy and epicar-dial biopsy (Marburg pericarditis registry 1988–2001), with neoplastic pericarditis being the leading cause [1] The corresponding etiologically differentiated treatment regimen is also represented.

Figure 8.

Pericardiocentesis under fluoroscopic guidance using the epicardial halo phenomenon (black vertical arrows) in the left lateral angiographic view. The left panel shows the puncturing needle approaching the pericardium (horizontal black arrow). The right panel displays con-trast medium in the pericardial sac after successful pericardial puncture.

(28)

Viral pericarditis

Viral pericarditis is the most common infectious disease of the pericardium, resulting from direct viral attack, the immune response (antiviral or anticardiac) or both [3]. The most frequent causative agents are enterovirus, echovirus, cytomegalovirus, ade-novirus, parvovirus B19, Epstein Barr virus, herpes humanus 6 virus, herpes simplex virus, influenza virus, hepatitis C virus and human immunodeficiency virus. A definite diagnosis can only be established through evaluation of pericardial fluid or epicardial/ pericardial tissue by PCR or in situ hybridization. However, in cases of suspected viral pericarditis responsive to conventional treatment with anti-inflammatory drugs, confirmation by molecular methods may not be necessary [4]. Symptomatic treatment is as in acute pericarditis. In chronic or recurrent confirmed viral pericarditis the fol-lowing treatment options are currently under investigation: hyperimmunoglobulin

Figure 9.

Physical, ECG, CT/MRI, echocardiographic and cardiac catheterization findings in constric-tive pericarditis (modified from [12]). LV: left ventricle, RV: right ventricle, RA: right atrium, LA: left atrium, AV: atrioventricular, CVP: central venous pressure, VCI: vena cava inferior (modified from [12]).

(29)

18

Table 4. Indications for pericardiectomy for constrictive pericarditis [4]

Clinical findings supporting referal for pericardiectomy - Presence of increasing jugular venous pressure - Need for diuretic therapy

- Evidence of hepatic insufficiency - Reduced exercise tolerance

Contraindications for pericardiectomy

- Very early constriction (asymptomatic patients, occult and functional class I) unless otherwise shown by:

- Exercise testing (preferably with maximal O₂ consumption) - Jugular venous pressure

- Liver function tests - Transitory constriction

- Extensive myocardial fibrosis and/or atrophy in CT/MRI

- Severe, advanced disease (NYHA Class IV) (operative mortality 30–40% vs. 6–19%)

With permission from the ESC-Textbook on Cardiovascular Medicine, chapter on the Man-agement of Pericardial Disease (Maisch et al. [12])

Figure 10.

Incidence of specific forms of pericarditis and their specific treatment in a population of 260 patients (from the Marburg Registry [1]).

(30)

for cytomegalovirus pericarditis, interferon alpha or beta for Coxsackie B pericarditis and immunoglobulin for adeno- and parvovirus B19 perimyocarditis [4, 21].

Bacterial (purulent) pericarditis

Bacterial pericarditis is rare since the advent of antibiotic therapy, but it is always fatal if untreated. Despite treatment, mortality is about 40%, mostly due to severe com-plications (cardiac tamponade, toxicity and constriction) [22]. Purulent pericarditis is an absolute indication for pericardiocentesis (Tab. 3) with drainage and rinsing of the pericardial cavity, combined with high doses of systemic antibiotics [4]. Gram, acid-fast and fungal staining, as well as cultures of obtained pericardial and body fluids are mandatory. Intrapericardial instillation of antibiotics (gentamycin) is useful but not sufficient. Frequent irrigation of the pericardial cavity with fibrinolytics (urokinase or streptokinase) may liquefy the purulent exudates [23], but open surgical drainage by subxiphoid pericardiotomy is preferable [4]. Indications for pericardiectomy include dense adhesions, loculated and thick purulent effusions, recurrence of tamponade, persistent infection and progression to constriction [4, 22].

Tuberculous pericarditis

The presentation of tuberculous pericarditis is highly variable; mortality rates in untreated cases reaches 85% and pericardial constriction develops in 30–50% [24]. Pericarditis in a patient with proven extracardiac tuberculosis suggests tuberculous pericarditis [3]. The definite diagnosis requires the identification of Mycobacterium tuberculosis in the pericardial fluid or tissue and/or the presence of caseous granulo-mas in the pericardium [3, 4]. Increased adenosine deaminase activity and interferon gamma levels in pericardial fluid are also suggestive of a tuberculous etiology. The tuberculin test may show a false negative or false positive in about one third of patients [24]. Tuberculous pericarditis should be promptly treated with a combina-tion of anti-tuberculous drugs for 9–12 months [4, 25]. The use of corticosteroids in tuberculous pericarditis remains controversial [26]. If pericardial constriction develops, pericardectomy is the only treatment.

Pericarditis in renal failure

Pericardial involvement is frequent in patients with renal failure. Uremic pericarditis (occurring in 6–10% of patients) in advanced renal failure before dialysis has been instituted or shortly thereafter [3, 27] can be distinguished from dialysis-associated pericarditis, which occurs in about 13% of patients on maintenance dialysis, caused