Arsen D. Ristić

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.

Recommendations on pre-hospital & early hospital management of acute heart failure: a consensus paper from the Heart Failure Association of the European Society of Cardiology, the European Society of Emergency Medicine and the Society of Academic Emergenc: Recommendations on pre-hospital & early hospital management of acute heart failure

Acute heart failure is a fatal syndrome. Emergency physicians, cardiologists, intensivists, nurses and other health care providers have to cooperate to provide optimal benefit. However, many treatment decisions are opinion‐based and few are evidenced‐based. This consensus paper provides guidance to practicing physicians and nurses to manage acute heart failure in the pre‐hospital and hospital setting. Criteria of hospitalization and of discharge are described. Gaps in knowledge and perspectives in the management of acute heart failure are also detailed. This consensus paper on acute heart failure might help enable contiguous practice.

Colchicine for Prevention of Postpericardiotomy Syndrome and Postoperative Atrial Fibrillation: The COPPS-2 Randomized Clinical Trial

IMPORTANCE Postpericardiotomy syndrome, postoperative atrial fibrillation (AF), and postoperative effusions may be responsible for increased morbidity and health care costs after cardiac surgery. Postoperative use of colchicine prevented these complications in a single trial. OBJECTIVE To determine the efficacy and safety of perioperative use of oral colchicine in reducing postpericardiotomy syndrome, postoperative AF, and postoperative pericardial or pleural effusions. DESIGN, SETTING, AND PARTICIPANTS Investigator-initiated, double-blind, placebo-controlled, randomized clinical trial among 360 consecutive candidates for cardiac surgery enrolled in 11 Italian centers between March 2012 and March 2014. At enrollment, mean age of the trial participants was 67.5 years (SD, 10.6 years), 69% were men, and 36% had planned valvular surgery. Main exclusion criteria were absence of sinus rhythm at enrollment, cardiac transplantation, and contraindications to colchicine. INTERVENTIONS Patients were randomized to receive placebo (n=180) or colchicine (0.5 mg twice daily in patients ≥70 kg or 0.5 mg once daily in patients <70 kg; n=180) starting between 48 and 72 hours before surgery and continued for 1 month after surgery. MAIN OUTCOMES AND MEASURES Occurrence of postpericardiotomy syndrome within 3 months; main secondary study end points were postoperative AF and pericardial or pleural effusion. RESULTS The primary end point of postpericardiotomy syndrome occurred in 35 patients (19.4%) assigned to colchicine and in 53 (29.4%) assigned to placebo (absolute difference, 10.0%; 95% CI, 1.1%-18.7%; number needed to treat = 10). There were no significant differences between the colchicine and placebo groups for the secondary end points of postoperative AF (colchicine, 61 patients [33.9%]; placebo, 75 patients [41.7%]; absolute difference, 7.8%; 95% CI, -2.2% to 17.6%) or postoperative pericardial/pleural effusion (colchicine, 103 patients [57.2%]; placebo, 106 patients [58.9%]; absolute difference, 1.7%; 95% CI, -8.5% to 11.7%), although there was a reduction in postoperative AF in the prespecified on-treatment analysis (placebo, 61/148 patients [41.2%]; colchicine, 38/141 patients [27.0%]; absolute difference, 14.2%; 95% CI, 3.3%-24.7%). Adverse events occurred in 21 patients (11.7%) in the placebo group vs 36 (20.0%) in the colchicine group (absolute difference, 8.3%; 95% CI; 0.76%-15.9%; number needed to harm = 12), but discontinuation rates were similar. No serious adverse events were observed. CONCLUSIONS AND RELEVANCE Among patients undergoing cardiac surgery, perioperative use of colchicine compared with placebo reduced the incidence of postpericardiotomy syndrome but not of postoperative AF or postoperative pericardial/pleural effusion. The increased risk of gastrointestinal adverse effects reduced the potential benefits of colchicine in this setting. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01552187.

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.

Recommendations on pre-hospital and early hospital management of acute heart failure : a consensus paper from the Heart Failure Association of the European Society of Cardiology, the European Society of Emergency Medicine and the Society of Academic Emergency Medicine - short version

Despite several critical steps forward in the management of chronic heart failure (CHF), the area of acute heart failure (AHF) has remained relatively stagnant. As stated in the updated ESC HF guidelines, clinicians responsible for managing patients with AHF must frequently make treatment decisions without adequate evidence, usually on the basis of expert opinion consensus.2 Specifically, the treatment of acute HF remains largely opinion-based with little good evidence to guide therapy. Acute heart failure is a syndrome in which emergency physicians, cardiologists, intensivists, nurses, and other healthcare providers have to cooperate to provide ‘rapid’ benefit to the patients. We hereby would like to underscore the wider experience grown in different settings of the area of intensive care on acute heart failure, actually larger and more composite than that got in specialized Care Units. The distillate of such different experiences is discussed and integrated in the present document. Hence, the authors of this consensus paper believe a common working definition of AHF covering all dimensions and modes of presentations has to be made, with the understanding that most AHF presentations are either acute decompensations of chronic underlying HF or the abrupt onset of dyspnoea associated with significantly elevated blood pressure. Secondly, recent data show that, much like acute coronary syndrome, AHF might have a ‘time to therapy’ concept. Accordingly, ‘pre-hospital’ management is considered a critical component of care. Thirdly, most patients with AHF have normal or high blood pressure at presentation, and are admitted with symptoms and/or signs of congestion. This is in contradiction to the presentation where low cardiac output leads to symptomatic hypotension and signs/symptoms of hypoperfusion, a circumstance that is relatively rare, present in coronary care unit/intensive care unit (CCU/ICU) but associated with a particularly poor outcome. Hence, it is important to note that appropriate therapy requires appropriate identification of the specific AHF phenotype.3 The aim of the current paper is not to replace guidelines, but, to provide contemporary perspective for early hospital management within the context of the most recent data and to provide guidance, based on expert opinions, to practicing physicians and other healthcare professionals (Figure 1). We believe that the experience accrued in the different settings from the emergency department through to the ICU/CCU is collectivel valuable in determining how best to manage the patients with AHF. Herein, a shortened version mainly including group recommendations is provided. Full version of the consensus paper is provided as Supplementary material online.

Contemporary management of acute right ventricular failure: a statement from the Heart Failure Association and the Working Group on Pulmonary Circulation and Right Ventricular Function of the European Society of Cardiology

Acute right ventricular (RV) failure is a complex clinical syndrome that results from many causes. Research efforts have disproportionately focused on the failing left ventricle, but recently the need has been recognized to achieve a more comprehensive understanding of RV anatomy, physiology, and pathophysiology, and of management approaches. Right ventricular mechanics and function are altered in the setting of either pressure overload or volume overload. Failure may also result from a primary reduction of myocardial contractility owing to ischaemia, cardiomyopathy, or arrhythmia. Dysfunction leads to impaired RV filling and increased right atrial pressures. As dysfunction progresses to overt RV failure, the RV chamber becomes more spherical and tricuspid regurgitation is aggravated, a cascade leading to increasing venous congestion. Ventricular interdependence results in impaired left ventricular filling, a decrease in left ventricular stroke volume, and ultimately low cardiac output and cardiogenic shock. Identification and treatment of the underlying cause of RV failure, such as acute pulmonary embolism, acute respiratory distress syndrome, acute decompensation of chronic pulmonary hypertension, RV infarction, or arrhythmia, is the primary management strategy. Judicious fluid management, use of inotropes and vasopressors, assist devices, and a strategy focusing on RV protection for mechanical ventilation if required all play a role in the clinical care of these patients. Future research should aim to address the remaining areas of uncertainty which result from the complexity of RV haemodynamics and lack of conclusive evidence regarding RV‐specific treatment approaches.

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.

Bacterial pericarditis: diagnosis and management.

Bacterial pericarditis occurs by direct infection during trauma, thoracic surgery, or catheter drainage, by spread from an intrathoracic, myocardial, or subdiaphragmatic focus, and by hematogenous dissemination. The frequent causes are Staphylococcus and Streptococcus (rheumatic pancarditis), Haemophilus, and M. tuberculosis. In AIDS pericarditis, the incidence of bacterial infection is much higher than in the general population, with a high proportion of Mycobacterium avium-intracellulare infection. Purulent pericarditis is the most serious manifestation of bacterial pericarditis, characterized by gross pus in the pericardium or microscopically purulent effusion. It is an acute, fulminant illness with fever in virtually all patients. Chest pain is uncommon. Purulent pericarditis is always fatal if untreated. The mortality rate in treated patients is 40%, and death is mostly due to cardiac tamponade, systemic toxicity, cardiac decompensation, and constriction. Tuberculous infection may present as acute pericarditis, cardiac tamponade, silent (often large) relapsing pericardial effusion, effusive-constrictive pericarditis, toxic symptoms with persistent fever, and acute, subacute, or chronic constriction. The mortality in untreated patients approaches 85%. Urgent pericardial drainage, combined with intravenous antibacterial therapy (e. g. vancomycin 1g twice daily, ceftriaxone 1–2g twice daily, and ciprofloxacin 400 mg/ day) is mandatory in purulent pericarditis. Irrigation with urokinase or streptokinase, using large catheters, may liquify the purulent exudate, but open surgical drainage is preferable. The initial treatment of tuberculous pericarditis should include isoniazid 300 mg/day, rifampin 600 mg/day, pyrazinamide 15–30 mg/kg/day, and ethambutol 15–25 mg/kg/day. Prednisone 1–2 mg/kg/day is given for 5–7 days and progressively reduced to discontinuation in 6–8 weeks. Drug sensitivity testing is essential. Pericardiectomy is reserved for recurrent effusions or continued elevation of central venous pressure after 4–6 weeks of antituberculous and corticosteroid therapy.

European Association of Cardiovascular Imaging (EACVI) position paper: multimodality imaging in pericardial disease

Although pericardial diseases are common in the daily clinical practice and can result in a significant morbidity and mortality, imaging of patients with suspected or known pericardial disorders remain challenging. Multimodality imaging is part of the management of pericardial diseases. Echocardiography, cardiac computed tomography, and cardiovascular magnetic resonance are often used as complementary imaging modalities. The choice of one or multiple imaging modalities is driven by the clinical context or conditions of the patient. The scope of the present document is to highlight the respective role of each technique according to the clinical context in the diagnosis and management of pericardial diseases.

Renal effects of ularitide in patients with decompensated heart failure

BACKGROUND Renal function frequently deteriorates in decompensated heart failure (DHF) patients, and one determinant is reduced renal blood flow. This may, in part, result from low cardiac output (CO), reduced mean arterial pressure (MAP), and venous congestion. The combined impact of both venous congestion (elevated right atrial pressure [RAP]) and low MAP are reflected by a reduced pressure gradient MAP-RAP. This study investigated the renal effects of ularitide, a synthetic version of the renal natriuretic peptide urodilatin in DHF patients. METHODS In SIRIUS II, a double-blind phase II trial, 221 patients hospitalized for DHF (with dyspnea at rest or minimal activity, cardiac index <or=2.5 L/min per square meter, and pulmonary artery wedge pressure >or=18 mm Hg) were randomized to a single 24-hour infusion of ularitide (7.5, 15, or 30 ng/kg per minute) or placebo added to standard therapy. RESULTS Estimated glomerular filtration rate, serum creatinine, creatinine clearance, and blood urea nitrogen (BUN) were not impaired by ularitide throughout infusion and during a 2-day follow-up period. At 24 hours, 15 ng/kg per minute ularitide reduced BUN levels (-4.07 +/- 12.30 vs -0.20 +/- 7.50 for placebo, P < .05). Ularitide at 15 and 30 ng/kg per minute rapidly elevated CO with sustained effects. Although 15 ng/kg per minute ularitide preserved the pressure gradient MAP-RAP, 30 ng/kg per minute ularitide reduced MAP-RAP by -7.8 +/- 10.6 mm Hg vs -2.4 +/- 9.8 mm Hg for placebo (P < .01, at 6 hours). A strong inverse correlation between MAP-RAP and BUN levels (Corr = -0.50579, P = .00015) was observed with 15 ng/kg per minute ularitide. CONCLUSIONS Single 24-hour infusions of ularitide at 15 ng/kg per minute preserved short-term renal function in DHF patients possibly by both elevating CO and maintaining the MAP-RAP pressure gradient.