Sabine Pankuweit

Current state of knowledge on aetiology, diagnosis, management, and therapy of myocarditis: a position statement of the European Society of Cardiology Working Group on Myocardial and Pericardial Diseases

In this position statement of the ESC Working Group on Myocardial and Pericardial Diseases an expert consensus group reviews the current knowledge on clinical presentation, diagnosis and treatment of myocarditis, and proposes new diagnostic criteria for clinically suspected myocarditis and its distinct biopsy-proven pathogenetic forms. The aims are to bridge the gap between clinical and tissue-based diagnosis, to improve management and provide a common reference point for future registries and multicentre randomised controlled trials of aetiology-driven treatment in inflammatory heart muscle disease.

Current state of knowledge on aetiology, diagnosis, management, and therapy of peripartum cardiomyopathy: a position statement from the Heart Failure Association of the European Society of Cardiology Working Group on peripartum cardiomyopathy

Peripartum cardiomyopathy (PPCM) is a cause of pregnancy‐associated heart failure. It typically develops during the last month of, and up to 6 months after, pregnancy in women without known cardiovascular disease. The present position statement offers a state‐of‐the‐art summary of what is known about risk factors for potential pathophysiological mechanisms, clinical presentation of, and diagnosis and management of PPCM. A high index of suspicion is required for the diagnosis, as shortness of breath and ankle swelling are common in the peripartum period. Peripartum cardiomyopathy is a distinct form of cardiomyopathy, associated with a high morbidity and mortality, but also with the possibility of full recovery. Oxidative stress and the generation of a cardiotoxic subfragment of prolactin may play key roles in the pathophysiology of PPCM. In this regard, pharmacological blockade of prolactin offers the possibility of a disease‐specific therapy.

Genetic counselling and testing in cardiomyopathies: a position statement of the European Society of Cardiology Working Group on Myocardial and Pericardial Diseases

Advances in molecular genetics present new opportunities and challenges for cardiologists who manage patients and families with cardiomyopathies. The aims of this position statement of the European Society of Cardiology Working Group on Myocardial and Pericardial Diseases are to review the general issues related to genetic counselling, family screening and genetic testing in families with a cardiomyopathy, and to provide key messages and suggestions for clinicians involved in their management.

Risk Factors for Malignant Ventricular Arrhythmias in Lamin A/C Mutation Carriers A European Cohort Study

OBJECTIVES The purpose of this study was to determine risk factors that predict malignant ventricular arrhythmias (MVA) in Lamin A/C (LMNA) mutation carriers. BACKGROUND LMNA mutations cause a variety of clinical phenotypes, including dilated cardiomyopathy and conduction disease. Many LMNA mutation carriers have a poor prognosis, because of a high frequency of MVA and progression to end-stage heart failure. However, it is unclear how to identify mutation carriers that are at risk for MVA. METHODS In this multicenter cohort of 269 LMNA mutation carriers, we evaluated risk factors for MVA, defined as sudden cardiac death, resuscitation, and appropriate implantable cardioverter-defibrillator (ICD) treatment. RESULTS In a median follow-up period of 43 months (interquartile range: 17 to 101 months), 48 (18%) persons experienced a first episode of MVA: 11 persons received successful cardiopulmonary resuscitation, 25 received appropriate ICD treatment, and 12 persons died suddenly. Independent risk factors for MVA were nonsustained ventricular tachycardia, left ventricular ejection fraction <45% at the first clinical contact, male sex, and non-missense mutations (ins-del/truncating or mutations affecting splicing). MVA occurred only in persons with at least 2 of these risk factors. There was a cumulative risk for MVA per additional risk factor. CONCLUSIONS Carriers of LMNA mutations with a high risk of MVA can be identified using these risk factors. This facilitates selection of LMNA mutation carriers who are most likely to benefit from an ICD.

Clinical ResearchGenetic DisordersRisk Factors for Malignant Ventricular Arrhythmias in Lamin A/C Mutation Carriers: A European Cohort Study

OBJECTIVES The purpose of this study was to determine risk factors that predict malignant ventricular arrhythmias (MVA) in Lamin A/C (LMNA) mutation carriers. BACKGROUND LMNA mutations cause a variety of clinical phenotypes, including dilated cardiomyopathy and conduction disease. Many LMNA mutation carriers have a poor prognosis, because of a high frequency of MVA and progression to end-stage heart failure. However, it is unclear how to identify mutation carriers that are at risk for MVA. METHODS In this multicenter cohort of 269 LMNA mutation carriers, we evaluated risk factors for MVA, defined as sudden cardiac death, resuscitation, and appropriate implantable cardioverter-defibrillator (ICD) treatment. RESULTS In a median follow-up period of 43 months (interquartile range: 17 to 101 months), 48 (18%) persons experienced a first episode of MVA: 11 persons received successful cardiopulmonary resuscitation, 25 received appropriate ICD treatment, and 12 persons died suddenly. Independent risk factors for MVA were nonsustained ventricular tachycardia, left ventricular ejection fraction <45% at the first clinical contact, male sex, and non-missense mutations (ins-del/truncating or mutations affecting splicing). MVA occurred only in persons with at least 2 of these risk factors. There was a cumulative risk for MVA per additional risk factor. CONCLUSIONS Carriers of LMNA mutations with a high risk of MVA can be identified using these risk factors. This facilitates selection of LMNA mutation carriers who are most likely to benefit from an ICD.

The European Study of Epidemiology and Treatment of Cardiac Inflammatory Diseases (ESETCID) First Epidemiological Results

By including immunohistochemical parameters the WHF Task Force for the Definition of Acute and Chronic Myocarditis expanded the light microscopical Dalla criteria of myocarditis. The rapid development of new molecular biological techniques such as polymerase chain reaction (PCR) and in-situ hybridization has improved our understanding of the underlying etiological and pathophysiological mechanisms in inflammatory heart disease. Treatment of dilated cardiomyopathy with inflammation is still controversial, however. The American Myocarditis Treatment Trial could not demonstrate a significant difference in the improvement of ejection fraction between patients with active myocarditis in the cyclosporine/prednisolone treated group when compared to placebo.In the European Study of Epidemiology and Treatment of Inflammatory Heart Disease (ESETCID) patients with acute or chronic myocarditis are treated specifically according to the etiology of the disease. Patients are screened not only for infiltrating cells, but also for the presence of persisting viral genome (enterovirus, cytomegalovirus and adenovirus). By investigating endomyocardial biopsies of 3,055 patients ongoing inflammatory processes in the heart could be found in 17.2%. Only 182 showed a reduced ejection fraction below 45%, fulfilling the entrance criteria for the ESETCID trial. These data imply that in symptomatic patients inflammatory heart muscle disease has to be considered regardless of left ventricular function and that endomyocardial biopsy can be an important tool for diagnosis. Virus could be detected in 11.8% (enterovirus 2.2%, cytomegalovirus 5.4%, adenovirus 4.2%).These first epidemiological results of this prospective randomized study demonstrate that viral persistence may contribute to the pathogenesis of inflammatory heart muscle disease, and that in chronic myocarditis viral persistence occurs in a smaller percentage of patients compared to previously published studies which were performed on highly selected patients.ZusammenfassungDurch die Einbeziehung von immunhistochemischen Parametern in die Definition der akuten und chronischen Myokarditis hat die WHF Task Force die lichtmikroskopischen Dallas-Myokarditiskriterien erweitert. Die rasche Entwicklung der molekularbiologischen Techniken hat zahlreiche ätiologische und pathophysiologische Mechanismen der entzündlichen Herzmuskelerkrankungen geklärt. Die Therapie der dilatativen Kardiomyopathie mit Inflammation wird dagegen noch immer kontrovers diskutiert. Der American Myocarditis Treatment Trial konnte keinen signifikanten Unterschied in der Verbesserung der Ejektionsfraktion bei Patienten mit aktiver Myokarditis in der mit Cyclosporin/Azathioprin behandelten Gruppe im Vergleich zur Plazebogruppe zeigen.In der Europäischen Studie über Epidemiologie und Therapie von entzündlichen Herzmuskelerkrankungen (ESETCID) werden Patienten mit akuter oder chronischer Myokarditis entsprechend der Ätiologie der Erkrankung behandelt. Die Endomyokardbiopsien der Patienten werden nicht nur nach Entzündungszellen, sondern auch auf persistierendes Virusgenom (Enterovirus, Zytomegalievirus und Adenovirus) untersucht. Bei der Untersuchung der Endomyokardbiopsien von 3 055 Patienten konnten in 17,2% der Fälle entzündliche Prozesse im Herzmuskel diagnostiziert werden. Nur 182 Patienten hatten eine Ejektionsfraktion unter 45% und erfüllten die Eingangskriterien der ESETCID-Studie. Diese Daten zeigen, dass bei symptomatischen Patienten entzündliche Herzmuskelerkrankungen in die Differentialdiagnose einbezogen werden müssen, unabhängig von der linksventrikulären Funktion, und dass die Endomyokardbiopsie eine wichtige diagnostische Methode darstellt. Persistierendes virales Genom konnte in 11,8% der Patienten (Enterovirus 2,2%, Zytomegalievirus 5,4%, Adenovirus 4,2%) nachgewiesen werden.Diese ersten epidemiologischen Ergebnisse der pro-spektiven randomisierten Studie zeigen, dass die Viruspersis-tenz zur Pathogenese der entzündlichen Herzmuskelerkrankung beitragen kann. Eine Viruspersistenz im Myokard von Patienten mit chronischer Myokarditis konnte allerdings seltener nachgewiesen werden als in früheren Studien, die im Gegensatz zu unserer prospektiven Untersuchung an einem hoch selektierten Patientengut nur retrospektiv durchgeführt wurden.

Prevalence of the parvovirus B19 genome in endomyocardial biopsy specimens

Although enteroviruses have long been considered the most common cause of inflammatory heart muscle diseases, parvovirus B19 (PVB19) is emerging as a new and important candidate for myocarditis and dilated cardiomyopathy with inflammation (DCMi) and without inflammation (DCM). We investigated left ventricular endomyocardial biopsy specimens from 110 patients with suspected inflammatory heart disease for the presence of PVB19, Coxsackie virus (CVB), and adenovirus (Ad2) genome by polymerase chain reaction. Diagnosis of myocarditis (36 patients), DCM (18 patients), DCMi (13 patients), and perimyocarditis (12 patients) was made by immunohistochemical and histopathological investigation of endomyocardial biopsy specimens. A control group consisting of patients with arterial hypertension was also investigated. Prevalence of the PVB19 genome in endomyocardial biopsy specimens was highest in patients with DCMi (3 of 13) and patients with myocarditis (7 of 36); in patients with DCM and perimyocarditis, prevalence was 3 of 13 and 2 of 12, respectively. In patients with resolved myocarditis, no PVB19 DNA was detected; in patients with no inflammation and controls, prevalence was only 4% and 7%, respectively. CVB-RNA was detected in endomyocardial biopsy specimens from 3 of 37 patients with myocarditis; Ad2-DNA was found in 1 patient with DCM and 1 patient with perimyocarditis. These findings suggest an association of the PVB19 genome in endomyocardial biopsy specimens of adults with the development of DCM, DCMi, and chronic myocarditis more frequently than previously expected. PVB19 should therefore be recognized as a potential cardiotropic pathogen in patients of all ages.

Definition of inflammatory cardiomyopathy (myocarditis): on the way to consensus. A status report.

This article reviews the current state of consensus reached for the diagnosis of myocarditis and dilated cardiomyopathy on the basis of conventional histopathological and immunohistochemical methods for inflammatory infiltrates in addition to molecular biological methods for persistence of viral genome in endomyocardial biopsies.Additionally, a brief overview is presented stating the current knowledge on effector mechanisms of the immune system in myocarditis and dilated cardiomyopathy.ZusammenfassungDie Definition der Kardiomyopathie mit und ohne Entzündungsreaktion sowie die mögliche Beteiligung von Effektormechanismen des humoralen und zellulären Immunsystems an ihrer Pathogenese war in den letzten Jahren Gegenstand der Forschung.Um einen Konsens für die Diagnose dilatative Kardiomyopathie mit und ohne Entzündung zu erreichen, kamen in Marburg Experten auf den Gebieten Histopathologie und Virologie zusammen, um Kriterien zu erarbeiten, die die 1987 publizierten Dallas-Kriterien zur Diagnostik der Myokarditis erweitern und mit Hilfe neuer Technologien präzisieren.Histopathologie: Für die Diagnose “Myokarditis” wird ein Minimum von 14 Leukozyten/mm2, bestehend aus T-Lymphozyten (CD3) oder aktivierten T-Lymphozyten (zum Beispiel CD45RO), gefordert (allerdings dürfen bis zu vier Makrophagen eingeschlossen werden). Ein fokaler entzündlicher Prozess wird beschrieben, wenn sich mindestens drei Lymphozyten in einem Nest außerhalb von Gefäßen befinden. Wenn solche Foci vorhanden sind, kann eine Myokarditis diagnostiziert werden, auch wenn nicht die kritische Zahl von 14 Leukozyten/mm2 erreicht werden. Wenn Leukozyten, fokal oder diffus, in fibrotischen Arealen auftreten, kann man von einem reparativen Prozess sprechen.In Anlehnung an die Dallas-Kriterien (1987 von Aretz et al. publiziert, siehe Tabelle 1) unterscheidet man bei der ersten Biopsie die akute (mit Myozytolyse) von der “Borderline” (ohne Myozytolyse) bzw. keiner Myokarditis. Werden konsekutive Biopsien entnommen, kann eine persistierende (= akute) von einer abheilenden und abgeheilten Myokarditis unterschieden werden. Die neue modifizierte Klassifikation ist quantitativ:1. Akute Myokarditis: entzündliches Infiltrat (diffus, fokal oder konfluierend) mit ≥ 14 Leukozyten/mm2. Zur Unterstützung werden immunhistochemische Verfahren zur Subklassifizierung der Leukozyten herangezogen. Nekrose ist obligat, Fibrose kann vorhanden sein;2. chronische Myokarditis: entzündliches Infiltrat (diffus, fokal oder konfluierend) mit ≥ 14 Leukozyten/mm2. Keine Nekrose erforderlich, Fibrose ist möglich;3. keine Myokarditis: keine oder weniger als 14 Leukozyten/mm2;4. persistierende Myokarditis (zweite Biopsie): Kriterien wir in 1 oder 2;5. abheilende Myokarditis (zweite Biopsie): Kriterien wie in 1 oder 2, der immunologische Prozess ist aber spärlicher;6. abgeheilte Myokarditis (zweite Biopsie): entsprechend den Dallas-Kriterien.Virologie: Da beim Erwachsenen die Anzucht von Viren aus Biopsien meist erfolglos verläuft, werden sensitivere molekularbiologische Methoden, wie die PCR und/oder die Insitu-Hybridisierung eingesetzt. Im Falle von HIV, Hepatitis C und Zytomegalie und Borreliose wird die serologische Diagnostik zusätzlich verwendet. In Marburg wurde Konsens darüber erreicht, welche Methodik im Einzelnen im Hinblick auf die Sensitivität und Reproduzierbarkeit zu bevorzugen ist.Im zweiten Abschnitt der Arbeit werden Effektormechanismen des Immunsystems vorgestellt, für die in tierexperimentellen Studien bzw. Untersuchungen an Serum oder Endomyokardbiopsien vom Menschen ein möglicher Zusammenhang mit der Pathogenese der dilatativen Kardiomyopathie mit oder ohne Entzündungsreaktion gefunden wurde. In Tabelle 2 sind Autoantikörper sowie deren möglicher Pathomechanismus dargestellt. Im Anschluss werden neuere Untersuchungen zur möglichen Rolle von Zytokinen, Adhäsionsmolekülen und Immunkomplexen kurz zusammengefasst.

Inflammatory Dilated Cardiomyopathy (DCMI)

Cardiomyopathies are heart muscle diseases, which have been defined by their central hemodynamics and macropathology and divided in five major forms: dilated (DCM), hypertrophic (HCM), restrictive (RCM), right ventricular (RVCM), and nonclassifiable cardiomyopathies (NCCM). Furthermore, the most recent WHO/WHF definition also comprises, among the specific cardiomyopathies, inflammatory cardiomyopathy as a distinct entity, defined as myocarditis in association with cardiac dysfunction. Idiopathic, autoimmune, and infectious forms of inflammatory cardiomyopathy were recognized. Viral cardiomyopathy has been defined as viral persistence in a dilated heart. It may be accompanied by myocardial inflammation and then termed inflammatory viral cardiomyopathy (or viral myocarditis with cardiomegaly). If no inflammation is observed in the biopsy of a dilated heart (< 14 lymphocytes and macrophages/mm2), the term viral cardiomyopathy or viral persistence in DCM should be applied according to the WHF Task Force recommendations.Within the German heart failure net it is the authors’ working hypothesis, that DCM shares genetic risk factors with other diseases of presumed autoimmune etiology and, therefore, the same multiple genes in combination with environmental factors lead to numerous different autoimmune diseases including DCM. Therefore, the authors’ primary goal is to acquire epidemiologic data of patients with DCM regarding an infectious and inflammatory etiology of the disease. Circumstantial evidence points to a major role of viral myocarditis in the etiology of DCM. The common presence of viral genetic material in the myocardium of patients with DCM provides the most compelling evidence, but proof of causality is still lacking. In addition, autoimmune reactions have been described in many studies, indicating them as an important etiologic factor. Nevertheless, data on the proportion of patients, in whom both mechanisms play a role are still missing.A pivotal role for autoimmunity in a substantial proportion of patients with DCM is supported by the presence of organ-specific autoantibodies, inflammatory infiltrates and pro-inflammatory cytotoxic cytokines. Furthermore, familial occurrence of DCM has been described in about 20–30% of cases, with the presence of autoantibodies and abnormal cytokine profiles in first-degree relatives with asymptomatic left ventricular enlargement. This suggests the involvement of a disrupted humoral and cellular immunity early in the development of the disease. A similar pattern of humoral and cellular immune dysregulation has been described in other autoimmune diseases. There is considerable evidence that genetic factors play an important role in the pathogenesis of DCM, either as contributors to the susceptibility to environmental factors or as determinants of functional and structural changes that characterize the phenotypic expression of the disease.Yet, it is not known whether the susceptibility to immunologically mediated myocardial damage reflects the presence of genetic risk factors shared by other autoimmune diseases. Preliminary investigations suggest, that this is the case, because the frequency of autoimmune disorders other than DCM was higher in first-degree relatives of the subjects with DCM including juvenile diabetes, rheumatoid arthritis, thyroiditis, psoriasis, and asthma.The nature of the genetic risk is undetermined and probably involves genes in the major histocompatibility (MHC) locus as well as other susceptibility loci. Therefore, the authors started their investigation with the search for MHC class 2 DQ polymorphisms in the peripheral blood of patients with DCM in parallel to the search for new interesting susceptibility loci by the use of the microarray analysis regarding genes responsible for inflammatory and autoimmune diseases. By this approach a new insight in the familial clustering of other autoimmune diseases in patients with DCM and in genetic predisposition can be expected.ZusammenfassungKardiomyopathien werden nach der letzten Klassifikation der WHO/ISFC-(WHF-)Task Force nach ihren makropathologischen und hämodynamischen Kriterien in fünf Formen eingeteilt: dilatative (DCM), hypertrophische (HCM), restriktive (RCM), rechtsventrikuläre (RVCM) und nicht klassifizierbare Herzmuskelerkrankungen (NCCM). Unter den spezifischen Kardiomyopathien wurde die inflammatorische Kardiomyopathie als Myokarditis mit hämodynamischer Dysfunktion eingereiht. Eine virale Kardiomyopathie wurde als Persistenz viralen Genoms bei einer DCM definiert, die mit einer histologisch validierten Entzündung einhergehen kann. Inflammation liegt nach den Empfehlungen der WHF-Task Force vor, wenn sich ≥ 14 Lymphozyten und Makrophagen/mm2 in einer Myokardbiopsie finden. Dann liegt eine virale inflammatorische Kardiomyopathie oder Virusmyokarditis vor.Im Herzinsuffizienznetz geht das Projekt der Autoren von der Hypothese aus, dass die DCM ein genetisches Risikoprofil mit anderen Autoimmunkrankheiten teilt und deshalb verschiedene Gene (Polymorphismen) zusammen mit Umweltfaktoren zu autoimmunen Krankheitsbildern führen, zu denen auch die DCM zählt. Mit dieser Hypothese gut vereinbar sind der Nachweis von viraler DNA oder RNA im Myokard oder autoimmune Phänomene bei Patienten, z. T. auch ihren (noch) nicht betroffenen Angehörigen. Ungeklärt sind bisher allerdings die kausalen ätiopathogenetischen Verknüpfungen oder Trennlinien zwischen den beiden Befunden: So lassen sich bei einem Großteil der DCM-Patienten zirkulierende und biopsiegebundene organspezifische Autoantikörper, entzündliche Infiltrate und die Freisetzung proinflammatorischer Zytokine nachweisen. Andererseits ist anzunehmen, dass mindestens 20–30% der DCMs familiär gehäuft auftreten, allerdings ohne dass dabei in allen Fällen eine monogenetische Erkrankung vorliegen muss. Es ist anzunehmen, dass genetische Faktoren deshalb entweder als Suszeptibilitätsfaktoren für Umwelteinflüsse (wie eine Virusinfektion, Stress usw.) oder als direkte Determinanten des funktionellen und strukturellen Phänotyps Kardiomyopathie verantwortlich sind. Dabei ist es weiteren Untersuchungen vorbehalten zu klären, ob die Prädisposition für eine autoreaktive kardiale Schädigung sich derselben genetischen Mechanismen wie bei anderen Autoimmunerkrankungen bedient. Bemerkenswert ist die Prävalenz anderer autoimmuner Erkrankungen bei einem substantiellen Anteil von Indexpatienten mit DCM und Verwandten ersten Grades, wie z. B. juveniler Diabetes, Rheuma, Thyreoiditis, Psoriasis, Asthma usw., in eigenen bisherigen Untersuchungen.Die Autoren leiten daraus ab, dass für die Abschätzung des genetisch prädisponierenden Risikos auch Gene des MHC („major histocompatibility complex“) eine Rolle spielen, und haben sich in einem ersten Ansatz deren Untersuchung vorgenommen.

Evaluation and Management of Pericardial Effusion in Patients with Neoplastic Disease

The incidence and extent of pericardial involvement in neoplastic disease varies. In a considerable number of patients with breast or lung cancer or with mediastinal lymphoma, in addition to direct involvement by the tumor, radiation therapy as well as systemic tumor treatment can also lead to pericardial effusion. In addition, in immunosuppressed tumor patients, pericardial effusion can also arise from viral, bacterial, and autoimmune causes. To distinguish between these 3 different conditions leading to pericardial effusion, the diagnosis should be based on pericardiocentesis followed by fluid analysis for cytology and biomarkers, on epicardial and pericardial biopsy facilitated by flexible pericardioscopy with analysis of specimens by conventional histology and molecular biology techniques for viral and microbial aetiology. We collected prospectively but analyzed retrospectively 357 patients undergoing pericardiocentesis from 1988 to 2008 and identified 68 patients who had cancer-related pericardial effusion. With these methods, 42 patients demonstrated malignant effusion, 15 patients had radiation-induced pericardial, effusion, and in 11 patients without radiation therapy, the effusion could be attributed to either viral infection in 5 cases or to an autoimmune process in the remaining 6 patients. Consequently, intrapericardial treatment could be tailored for each cohort: neoplastic effusion was treated with intrapericardial cisplatin (single instillation of 30 mg/m(2) per 24 hours); in addition to the tumor-specific systemic chemotherapy, intrapericardial triamcinolone acetate (Volon A) was given in a dose of 500 mg/m(2) in the patients with autoimmune and radiation-induced effusion. Saline rinsing and intrapericardial sclerosing treatment were the treatment of choice in viral pericardial effusion. Oral colchicine treatment (2-3 x 0.5 mg) was given in all patients for at least 3 months. Recurrence of pericardial effusion was prevented for at least 3 months in more than 85% of patients. This differential diagnostic approach and the results of treatment were compared with published series.