Management of patients with non- ischemic heart diseases (myocarditis, pericarditis)

Management of patients with non- ischemic heart diseases 

 

Myocarditis

 

Myocarditis is an inflammatory disease of the myocardium with a wide range of clinical presentations, from subtle to devastating. More specifically, it is described as “an inflammatory infiltrate of the myocardium with necrosis and/or degeneration of adjacent myocytes.”  Myocarditis usually manifests in an otherwise healthy person and can result in rapidly progressive (and often fatal) heart failure and arrhythmia. In the clinical setting, myocarditis is synonymous with inflammatory cardiomyopathy. It is diagnosed by established histologic, immunologic, and immunochemical criteria.

Epidemiology

International occurrence

A population study in Finland found that, in a study of more than 670,000 healthy young male military recruits, 98 cases had myocarditis mimicking myocardial ischemia, 1 case presented as sudden death, and 9 cases presented as recent-onset dilated cardiomyopathy. Incidence of positive right ventricular biopsy findings in patients with suspected myocarditis is highly variable (ranging from 0-80%). According to estimates, as many as 1-5% of patients with acute viral infections may have involvement of the myocardium.

A Japanese 20-year series of 377,841 autopsies found idiopathic, nonspecific, interstitial, or viral myocarditis in only 0.11% of individuals.

Race-, sex-, and age-related demographics

No particular race predilection is noted for myocarditis except for peripartum cardiomyopathy (a specific form of myocarditis that appears to have a higher incidence in patients of African descent).

The incidence of myocarditis is similar between males and females, although young males are particularly susceptible.

Patients are usually fairly young. The median age of patients affected with lymphocytic myocarditis is 42 years. Patients with giant cell myocarditis may be older (mean age 58 years), but this condition usually does not discriminate with respect to age, sex, or presenting symptoms.

Other susceptible groups include immunocompromised individuals, pregnant women, and children (particularly neonates).

Etiology

In viral myocarditis, viral isolates differ in tissue tropism and virulence. For example, coxsackievirus A9 is a self-limiting myocarditis, whereas coxsackievirus B3 causes severe myocarditis resulting in a high mortality rate. The induction of the coxsackie-adenovirus receptor (CAR) and the complement deflecting protein decay accelerating factor (DAF, CD55) may allow efficient internationalization of the viral genome.

Viral replication may lead to further disruption of metabolism and to perturbation of inflammation and its response. Vasospasm induced by endothelial cell viral infection may also contribute to further damage.

New evidence of dystrophin disruption by expression of enteroviral protease 2A points to yet another unique pathogenic mechanism. In contrast, some viruses (such as parvovirus B19) may focus on pericapillary depositions, contributing to diastolic dysfunction rather than to direct myocyte destruction. Regardless, viral persistence provides the necessary stimuli for autoimmune or other inflammatory responses.

Approximately 50% of the time, myocarditis is classified as idiopathic, although a report by Klugman et al found that 82% of the pediatric cases studied were considered idiopathic. The investigators also determined that 3% of cases in the study had a known bacterial or viral etiology, and that 6% of cases were related to other diseases.

In idiopathic cases, a viral etiology is often suspected but unproved, even with sophisticated immunohistochemical and genomic studies. Studies on patients with idiopathic dilated cardiomyopathy found evidence of viral particles in endomyocardial biopsy specimens in up to two thirds of the patients.

Causes

Myocarditis can result from a wide spectrum of infectious pathogens, including viruses, bacteria, chlamydia, rickettsia, fungi, and protozoans, as well as toxic and hypersensitivity reactions. Viruses are the infectious pathogens most frequently implicated in reports of acute myocarditis. In the 1950s and 1960s, experimental and later seroepidemiological studies linked enteroviruses, particularly group B Coxsackie viruses, to myocarditis. In the 1980s, molecular techniques, including PCR, identified other viral genomes in the heart tissue of patients with acute myocarditis, broadening the spectrum of viruses associated with myocarditis. At present, the most frequently identified genomes are parvovirus B19 and human herpes virus 6, although enteroviruses are still an important cause is some regions. Because heart biopsy and viral genome analysis are rarely done in many regions of the world, the prevalence of viral myocarditis in much of Africa, Asia, the Middle East, and South America is unknown.

Corynebacterium diphtheriae can cause myocarditis associated with bradycardia ionimmunized children. Trypanosoma cruzi, the cause of Chagas disease, has been a leading cause of myocarditis in parts of rural South and Central America. The age-standardised incidence of myocarditis due to C diphtheriae has been estimated at nearly 50 cases per 100 million worldwide, with a much higher incidence in the former Soviet Union. T cruzi infection can occur in childhood after transcutaneous inoculation with excreta contaminated with the parasite from the haematophagous Reduviids. After an acute phase of mild febrile illness, a prolonged (10—30 year) asymptomatic latent phase follows. During this asymptomatic phase, subclinical cardiac involvement can be identified by Holter monitoring and echocardiography. Systolic and diastolic left ventricular dysfunction and ventricular arrhythmias have been documented in a high percentage of patients with chronic asymptomatic Chagas disease. Anti-heart antibodies directed against myosin heavy chain, mitochondrial antigens, the β1 adrenergic receptor, and muscarinic acetylcholine 2 receptors are increased in patients with T cruzi infection who develop myocarditis.  Ventricular aneurysms, biventricular systolic or diastolic heart failure, and cardiac autonomic dysfunction characterise chronic Chagas cardiomyopathy.

Myocarditis in patients with advanced HIV infections can result in chronic DCM and is associated with poor prognosis.  DCM in HIV can occur from cardiotoxicity induced by viral glycoprotein 120, opportunistic infections, autoimmune response, drug-related cardiac toxicity, and possibly nutritional deficiencies. HIV-1 and viral glycoprotein 120 both induce myocyte and endothelial apoptosis, whereas antiviral drugs can cause gap junction and mitochondrial dysfunction. Highly active antiviral therapy (HAART) significantly reduces the incidence of HIV-associated myocarditis and DCM. Before HAART was available, the prevalence of cardiomyopathy was as high as 30% and symptomatic heart failure was 5% in patients with HIV.  HAART regimens have reduced the incidence of HIV-associated cardiomyopathy by seven times, which has resulted in increased longevity and improved quality of life in HIV-infected patients.  However, HAART is only available to a small percentage of the global HIV-infected population. Therefore, programmes to increase the availability of HAART in regions of the world where HIV and other infectious diseases are endemic should reduce the rates of myocarditis and DCM.

 Causes of myocarditis include the following:

·                     Viral – Enterovirus,  coxsackie B, adenovirus, influenza, cytomegalovirus, poliomyelitis, Epstein-Barr virus, HIV-1, viral hepatitis, mumps, rubeola, varicella, variola/vaccinia, arbovirus, respiratory syncytial virus, herpes simplex virus, yellow fever virus, rabies, parvovirus

·                     Rickettsial – Scrub typhus, Rocky Mountain spotted fever, Q fever

·                     Bacterial – Diphtheria, tuberculosis, streptococci, meningococci, brucellosis, clostridia, staphylococci, melioidosis, Mycoplasma pneumoniae, psittacosis

·                     Spirochetal – Syphilis, leptospirosis/Weil disease, relapsing fever/Borrelia, Lyme disease

·                     Fungal – Candidiasis, aspergillosis, cryptococcosis, histoplasmosis, actinomycosis, blastomycosis, coccidioidomycosis, mucormycosis

·                     Protozoal – Chagas disease, toxoplasmosis, trypanosomiasis, malaria, leishmaniasis, balantidiasis, sarcosporidiosis

·                     Helminthic – Trichinosis, echinococcosis, schistosomiasis, heterophyiasis, cysticercosis, visceral larva migrans, filariasis

·                     Bites/stings – Scorpion venom, snake venom, black widow spider venom, wasp venom, tick paralysis

·                     Drugs (usually causing hypersensitivity myocarditis)

·                     Chemotherapeutic drugs – Doxorubicin and anthracyclines, streptomycin, cyclophosphamide, interleukin-2, anti-HER-2 receptor antibody/Herceptin

·                     Antibiotics – Penicillin, chloramphenicol, sulfonamides

·                     Antihypertensive drugs – Methyldopa, spironolactone

·                     Antiseizure drugs – Phenytoin, carbamazepine

·                     Amphetamines, cocaine, catecholamines

·                     Chemicals – Hydrocarbons, carbon monoxide, arsenic, lead, phosphorus, mercury, cobalt

·                     Physical agents (radiation, heatstroke, hypothermia)

·                     Acute rheumatic fever

·                     Systemic inflammatory disease – Giant cell myocarditis, sarcoidosis, Kawasaki disease, Crohn disease, systemic lupus erythematosus, ulcerative colitis, Wegener granulomatosis, thyrotoxicosis, scleroderma, rheumatoid arthritis

·                     Peripartum cardiomyopathy

·                     Posttransplant cellular rejection

Pathogenesis

Myocarditis refers to the clinical and histological manifestations of a broad range of pathological immune processes in the heart. Alterations in the number and function of lymphocyte subsets and macrophages and antibody-mediated injury are typically found in patients with acute and chronic myocarditis. The immune reaction in the heart causes structural and functional abnormalities in cardiomyocytes, which in turn leads to regional or global contractile impairment, chamber stiffening, or conduction system disease. Patients with acute myocarditis often present with non-specific symptoms of chest pain, dyspnoea, or palpitations; however, sometimes acute viral myocarditis can cause cardiac damage without symptoms, and the risk of chronic dilated cardiomyopathy (DCM) in this setting is uncertain. Immune-mediated cardiac injury and dysfunction can also occur in chronic myocarditis.

 Myocarditis results from the interaction of an external environmental trigger with the host’s immune system. The availability of murine enteroviral models of myocarditis has facilitated much of our understanding of the disorder. From the pathophysiological point of view, the disease can be conceptually divided into three phases:

·        acute viral,

·        subacute immune,

·        chronic myopathic.

 

http://www.sciencedirect.com/science/article/pii/S0171298511001422

 

Viral phase

Myocarditis is most commonly initiated by the introduction of a virus from a potentially pathogenic strain (eg, enteroviruses such as coxsackievirus), or reactivation of a dormant pathogen (eg, parvovirus B 19). The virus can proliferate in the permissive tissues of the susceptible host and ultimately reaches the myocardium or blood vessels through haematogenous or lymphangitic spread, or both. Clinically, the viral phase is typically short and often missed by clinicians. Once the virus reaches the target cells, it uses its specific receptor or receptor complex for targeted cell entry. Coxsackievirus uses the coxsackie-adenoviral receptor, which is a junctional protein that links one cell to another. The nature of the receptors might partially explain why coxsackieviruses and adenoviruses are common causative viruses for myocarditis.

Viral proliferation in myocytes can cause direct tissue injury. However, most tissue damage in myocarditis results from the interaction of the viral trigger with the immune system. Entry of the virus through its receptor also activates immune signalling systems, including tyrosine kinases p56lck, Fyn, and Abl. Activation of these signals modifies the host cell cytoskeleton to permit more viral entry. At the same time, these signals mediate the activation of immune cells, which are critically dependent on p56lck and Fyn.

Immune activation after viral entry

The balance of immune response by the host is a major determinant of patient outcome. On the one hand, the immune response is activated to eliminate as many virus-infected cells as possible to control the infection. On the other hand, it needs to be modulated and turned off when appropriate; otherwise there will be excessive tissue damage from the inflammatory response, which could lead to direct organ dysfunction.

 

http://www.sciencedirect.com/science/article/pii/S1471491412000810

 

 Protective and adverse cellular factors in viral myocarditis. Different leukocyte subsets have divergent effects on myocarditis severity in mice. Predominantly protective cell types include natural killer (NK) cells, alternatively activated (M2) macrophages, T helper 2 (Th2) cells, regulatory T cells, and B cells. NK cells are important for viral elimination and B cells through neutralizing antibody production. M2 macrophages, Th2 cells, and regulatory T cells have‘anti-inflammatory’ properties, which disfavor cellular immune responses leading to tissue injury. Leukocyte subsets with predominantly adverse effects include classically activated (M1) macrophages, Th1 cells, cytotoxic T cells, and γδ T cells. These cells contribute to proinflammatory signaling, cellular immune responses, and cardiac injury, which may outweigh their contribution to viral elimination.

 

 

Viral persistence can expose the host to prolonged antigenic trigger, chronic immune activation, and the potential for chronic myocarditis. Persistence of the viral genome, such as coxsackievirus, in the myocyte has been directly linked to the development of DCM through cytoskeleton remodelling.

Innate immunity

The earliest host responses to the viral presence are members of the innate immune system. Innate immunity is an evolutionarily conserved host protective system that activates inflammatory responses through moieties such as toll-like receptors (TLRs). TLRs are present on all cell types, and TLR-3 and TLR-4 are particularly abundant in the cardiovascular system. These receptors recognise common antigenic patters from viruses, bacteria, foreigucleic acid sequences, or oxidised proteins. Once engaged, they transmit a cascade of signals to activate nuclear transcription factors, such as nuclear factor κB, and lead to inflammatory cytokine production and immune activation.

Acquired immunity

Signals from the innate immune system also sets in motion the activation and expansion of T cells and B cells that recognise specific peptide sequences as part of acquired immunity. This system is triggered by the recognition of a precise non-self molecular pattern by the variable region of the T-cell receptor, after a danger or stress signal by the host. The stimulated T cell will clonally expand to attack the source of the antigen, which could be the original viral coat protein or sometimes parts of the myocardium (such as myosin) that might resemble the molecular sequence of the virus (molecular mimicry), triggering autoimmunity.

Activation of acquired immunity can lead to the production of T-killer cells that can directly attack the virus and virally infected cells. The activation of T cells also leads to the activation of B cells and the production of specific antibodies to neutralise the antigen. This response results in subacute and chronic inflammation in myocarditis and contributes to the subsequent myocyte necrosis, fibrosis, and remodelling. The T-cell receptor activation sequence ultimately leads to the detrimental phenotype of the disease and supports the idea that decreasing inflammation from acquired immunity while finding ways to control the virus through innate immunity will lead to the most beneficial outcomes in myocarditis.

http://eurheartj.oxfordjournals.org/content/early/2011/06/22/eurheartj.ehr165/F1.expansion.html

Phases of myocardial injury in infectious and post-infectious myocarditis 

Myopathy phase

If the inflammatory response persists, the heart can undergo remodelling, with modification of the cardiac structure and function, which leads to the development of DCM. The inflammatory process from both innate and acquired immunity (described earlier) can also lead to release of cytokines, which are potent activators of matrix metalloproteinases that can digest the interstitial collagen and elastin framework of the heart and, in turn, participate in inflammation.  A family of matrix metalloproteinases, including urokinase-type plasminogen activator, contribute to cardiac dilatation and inflammation. Additionally, the activation of cytokines such as transforming growth factor can lead to activation of the SMAD signalling cascade, which causes production of profibrotic factors, leading to pathological fibrosis. The final result can be DCM, with its attendant systolic and diastolic dysfunction, and progressive heart failure. Studies in patients receiving interferon beta suggest that type 1 interferons might be able to modulate not only the viral load but also the remodelling of the affected hearts. Therapeutic drugs such as angiotensin modulators and β blockers modify the remodelling process and are equally effective for treatment of a dilated heart after myocarditis.

Classification

Myocarditis can be classified by cause, histology, immunohistology, and clinicopathological and clinical criteria. From each categorisation, the treating clinician should consider what information will provide unique prognostic and therapeutic information in a given clinical scenario. For example, assessment of left ventricular function in acute myocarditis is useful because more severe ventricular dysfunction is associated with greater risk of death or need for heart transplantation. An eosinophil-rich infiltrate with giant cells on heart biopsy can result from the uncommon but serious diagnosis of giant-cell myocarditis. Molecular studies on heart tissue, including viral genome amplification and transcriptome microarrays, can help identify specific pathogens or prognostically important inflammatory pathways.

Cause

·                     Viral, such as enteroviruses (eg, Coxsackie B), erythroviruses (eg, Parvovirus B19), adenoviruses, and herpes viruses

·                     Bacterial, such as Corynebacterium diphtheriae, Staphylococcus aureus, Borrelia burgdorferi, and Ehrlichia species

·                     Protozoal, such as Babesia

·                     Trypanosomal, such as Trypanosoma cruzi

·                     Toxic: alcohol, radiation, chemicals (hydrocarbons and arsenic), and drugs, including doxorubicin

·                     Hypersensitivity: sulphonamides and penicillins

Histology

·                     Eosinophilic

·                     Giant cell

·                     Granulomatous

·                     Lymphocytic

Immunohistology (not mutually exclusive)

·                     World Heart Federation: 14 or more CD3+ or CD68+ cells per high power field

·                     Increased expression of human leucocyte antigens (eg, HLA-DR)

·                     Increased expression of adhesion molecules (eg, intracellular adhesion molecule 1)

Clinical (not mutually exclusive)

·                     Acute heart failure

·                     Syncope

·                     Chest pain resembling an acute myocardial infarction

·                     Myopericarditis

This panel is a partial list of categories and criteria within common classification schemes.

Lieberman further classified myocarditis as follows :

·                     Fulminant myocarditis – Follows a viral prodrome; distinct onset of illness consisting of severe cardiovascular compromise with ventricular dysfunction and multiple foci of active myocarditis; either resolves spontaneously or results in death

·                     Acute myocarditis – Less distinct onset of illness, with established ventricular dysfunction; may progress to dilated cardiomyopathy

·                     Chronic active myocarditis – Less distinct onset of illness, with clinical and histologic relapses; development of ventricular dysfunction associated with chronic inflammatory changes (including giant cells)

·                     Chronic persistent myocarditis – Less distinct onset of illness; persistent histologic infiltrate with foci of myocyte necrosis but without ventricular dysfunction (despite symptoms, eg, chest pain, palpitations)

These terms are still used to describe the clinical presentation and progression of myocarditis, particularly in the absence of ongoing histologic evaluation.

Common clinical scenarios associated with myocarditis

Clinical manifestations range from asymptomatic ECG abnormalities to cardiogenic shock. Transient ECG abnormalities suggesting myocardial involvement commonly occur during community viral endemics; most patients remain entirely asymptomatic. In contrast, myocarditis can also result in fulminant heart failure presenting as new-onset cardiomyopathy. Patients may report a viral prodrome of fever, myalgias, respiratory symptoms, or gastroenteritis followed by an abrupt onset of hemodynamic collapse. The incidence of a reported infectious viral prodrome is highly variable, ranging from 10% to 80% of patients with documented myocarditis.

Acute dilated cardiomyopathy is one of the most dramatic and clinically relevant presentations of acute lymphocytic myocarditis. The link between clinical myocarditis and acute dilated cardiomyopathy is most convincingly provided by EMB findings. The 2 largest biopsy series have confirmed myocarditis in 9% to 16% of cases of new-onset dilated cardiomyopathy. The Giant Cell Myocarditis Study Group identified heart failure symptoms as the primary presentation in 75% of patients with giant cell myocarditis. Neither symptoms nor clinical course of myocarditis has been shown to correlate with histopathological features such as the extent of lymphocytic infiltrate or fibrosis.

The classification of Lieberman et al differentiates fulminant from active myocarditis. Fulminant myocarditis, manifested by severe hemodynamic compromise requiring high-dose vasopressor support or mechanical circulatory support, was identified in 15 of 147 patients (10.2%) in the largest prospective study to use this classification system. Fulminant cases were additionally characterized by a distinct viral prodrome, fever, and abrupt onset (generally <3 days) of advanced heart failure symptoms. These patients typically have severe global left ventricular dysfunction and minimally increased left ventricular end-diastolic dimensions. Of note, either borderline or active lymphocytic myocarditis can produce this dramatic clinical presentation.

Myocarditis masquerading as an acute coronary syndrome has also been well described. Elevated troponin levels have proven to be a more reliable predictor of myocardial injury than levels of creatine kinase. ECG changes suggestive of acute myocardial ischemia typically may include ST-segment elevation in ≥2 contiguous leads (54%), T-wave inversions (27%), widespread ST-segment depressions (18%), and pathological Q waves (18% to 27%). Segmental or global echocardiographic wall motion abnormalities are frequently evident despite angiographically normal coronary anatomy.

http://destinynet.org/27/acute-myocarditis

Acute myocarditis

Tachycardia and low voltage complexes throughout. In addition there is T wave inversion in V_1-6.

 

Clinicians should consider acute myocarditis in younger patients who present with acute coronary syndromes when coronary risk factors are absent, ECG abnormalities extend beyond a single coronary artery territory, or global rather than segmental left ventricular dysfunction is evident on echocardiography.

Myocarditis can produce variable effects on the cardiac conduction system. Ventricular tachycardia is an uncommon initial manifestation of myocarditis but often develops during long-term follow-up. The Giant Cell Myocarditis Study Group reported an initial incidence of ventricular tachycardia of <5% in a multicenter cohort. Ventricular tachycardia due to either lymphocytic or granulomatous myocarditis may infrequently result in sudden cardiac death.

Possible subclinical acute myocarditis

Possible subclinical acute myocarditis has been inferred from transient increases in troponin or electrocardiogram (ECG) abnormalities after an acute viral illness or vaccination. During the influenza A epidemic (H3N2) in Japan from 1998 to 1999, myosin light chain was raised in 11·4% of patients who did not have cardiac symptoms. 1 in 200 people had increased troponin 1 concentrations without symptoms of heart failure or chest pain after smallpox vaccination, yet the incidence of clinical myocarditis is lower at 5·5 per 10 000. The long-term risk of developing heart failure in patients with isolated laboratory evidence of cardiac injury is not known. Nonetheless, experimental and epidemiological data suggest that chronic DCM can result from acute myocarditis. Therefore, further research is needed to define the long-term clinical significance of possible subclinical acute myocarditis.

Acute heart failure with DCM

A clinical syndrome of dyspnoea, fatigue, and exercise intolerance, often with paroxysmal nocturnal dyspnoea and orthopnoea after an upper respiratory or gastrointestinal infection suggests post-viral myocarditis. Patients typically have a dilated ventricle, but occasionally the ventricular structure and function might suggest restrictive or even hypertrophic cardiomyopathy. Increased left ventricular wall thickness in fulminant myocarditis is a result of active inflammation and might regress over several weeks.  In this scenario, the risk of death or need for heart transplantation is closely linked to the amount of haemodynamic compromise, which is identified by assessment of left and right ventricular function and pressure. For most adult patients who have acute DCM in the setting of suspected myocarditis, both ventricular function and clinical status improve with standard heart failure treatment. The disease is often more fulminant in children than adults, but, in children, recovery of cardiac function is better than ion-inflammatory DCM, although supportive therapy can include mechanical circulatory support.

A small subset of adults who present with a sudden onset of severe heart failure within 2 weeks of a viral illness might need inotropic or mechanical circulatory support, but usually recover if they survive the initial illness. If patients with fulminant or acute DCM develop sustained or symptomatic ventricular tachycardia, high-degree heart block, or fail to respond to standard heart failure treatment, then prognosis is worse and a more serious form of myocarditis, such as giant-cell myocarditis, should be considered. EMB is indicated in patients with fulminant or acute heart failure who do not respond to usual care or who have sustained or symptomatic ventricular tachycardia or high-degree heart block because EMB can identify a specific histological cause and guide cause-specific treatment. Prognosis is poor if the biopsy reveals extensive fibrosis without inflammation.

Myopericarditis resembling an acute coronary syndrome

Myocarditis can mimic an acute coronary syndrome, often with globally preserved left ventricular function. When inflammation occurs in the pericardium, the presentation can mimic an acute myocardial infarction but without significant coronary artery disease on angiography. Yilmaz and colleagues noted coronary vasospasm with intracoronary acetylcholine testing in the absence of epicardial coronary disease in 70% of patients with clinical evidence of acute myocardial infarction and myocarditis proven on biopsy. In a series of patients with acute myocardial infarction-like syndrome and normal coronary arteries, 78% had evidence of myocarditis on scintigraphy. In a study by Kuhl and colleagues, 17 (71%) of 24 consecutive patients examined within 24 h after onset of chest pain without coronary artery disease had viral genomes detected in their myocardium (12 had parvovirus B19, three had enterovirus, and two had adenovirus). In most studies, such patients had good short-term prognosis, but the amount of ventricular compromise is still a borderline predictor of death risk. A minority of patients develop persistent or recurrent myopericarditis with normal ventricular function that might respond to colchicine or non-steroidal anti-inflammatory drugs.

Syncope from ventricular arrhythmias or heart block

Uemura and colleagues reported that three (6%) of 50 patients with unexplained atrioventricular heart block had myocarditis. Heart block or sustained or symptomatic ventricular arrhythmias in the setting of a cardiomyopathy should also raise suspicion for specific causes of myocarditis. For example, Lyme disease and Chagas diseases are associated with heart block, ventricular arrhythmias, and chronic myocarditis.  Diphtheria is associated with bradyarrhythmias and heart block. Patients who present with chronic DCM and have new ventricular arrhythmias or second-degree or third-degree heart block are at risk for cardiac sarcoidosis (idiopathic granulomatous myocarditis). Myocarditis associated with ventricular tachycardia can also mimic arrhythmogenic right ventricular dysplasia or cardiomyopathy.

Diagnostic criteria

Criteria for myocarditis (New York Heart Association 1964, 1973)

Significant indices:

The infection lasting for 10 days and resulting in:

1.                 signs of congestive cardiac failure

2.                 cardiogenic shock

3.                 complete AV block with Morgans – Adems – Stokes Syndrome

4.                 pathologic transpormations of  ESI

5.                 increased activity of myocardial enzymes in the serum

Insignificant Values

1.       laboratory Confirmation of a suffered viral infection

2.       tachycardia

3.       the first heart sound weakening on the apex of the heart

4.       gallop rhythm

5.       subendomiocardial biopsy findings

To diagnose mild myocardibis it is quite enough to take into consideration a suffered infection and 2 significant indices on 1 significant  and 2 insignificant ones.

The presences of one of 3 first significant values testify it an average severe or a severe course of the disease.

Bellow the typical features myocarditis forms are presented:

Infectious Allergic Myocarditis

V.A. Nasonova and I.A.Bronzov (1978) determined the following diagnostic criteria of infectious allergic myocarditis:

1.                   The conveetion of the disease with acute rhinopharyngeal infection, chronic tonsillitis exacerbations.

2.                   The absence of the latent period (less than 5-7 years) between clinical manifestations of rhinopharyngel infection and myocarditis onset.

3.                   The presence of the allergic syndrome accompanied by urticaria, vasomotor rhinitis, conjunctivitis, medicamental allergy.

4.                   Prevailing morbidity among middle aged people.

5.                   Slow progress of the disease, without evident progress, vnianifectations (taking into consideration lab. Finding)

6.                   Marked complaints of a cardiac nature (cardiac pain, palpitation, cardiac activity disorders, their resistance to antianginal pharmaceuticals, emotional colouring of the pain syndrome.

7.                   The absence of arthritis and rare cases of arthralgia.

8.                   Rare cases of pericarditis and the absence of valvulitis in all the cases.

9.                   Feebly marked laboratory findings activity or its lack in the presence of strongly pronounced signs of myocarditis.

10.              Quick development of asthenization which reaches the stage of adynamia, vegetative dystonia symptoms, thermoregulation disorders.

11.              Evident ECI transformations in all the patients.

Slow symptom dynamics due to antic – inflammatory therapy

The Dallas (1987) and the World Health Organization (WHO) Marburg criteria (1996) are commonly used based on the patterns in the following histologic characteristics:

·                     Cell types – Lymphocytic, eosinophilic, neutrophilic, giant cell, granulomatous, or mixed

·                     Amount – None (grade 0), mild (grade 1), moderate (grade 2), or severe (grade 3)

·                     Distribution – Focal (outside vessel lumen), confluent, diffuse, or reparative (in fibrotic areas)

The Dallas classification on initial biopsy is as follows:

·                     Myocarditis – Myocardial necrosis, degeneration, or both, in the absence of significant coronary artery disease with adjacent inflammatory infiltrate with or without fibrosis

·                     Borderline myocarditis – Inflammatory infiltrate too sparse or myocyte damage not apparent

·                     No myocarditis

The Dallas classification on subsequent biopsy is as follows:

·                     Ongoing (persistent) myocarditis with or without fibrosis

·                     Resolving (healing) myocarditis with or without fibrosis

·                     Resolved (healed) myocarditis with or without fibrosis

WHO Marburg criteria (1996) defines myocarditis as a minimum of 14 infiltrating leukocytes/mm², preferably T cells (CD45RO), with as many as 4 macrophages possibly included.

Diagnostics

 

 

 

http://cmapspublic3.ihmc.us/rid=1259597328252_1662306759_32869/myocarditis.cmap

 

Laboratory studies may include the following:

·                     Complete blood count (CBC) – Leukocytosis (may demonstrate eosinophilia)

·                     Elevated erythrocyte sedimentation rate (and other acute phase reactants, such as C-reactive protein)

·                     Rheumatologic screening – To rule out systemic inflammatory diseases

·                     Elevated cardiac enzymes – Creatine kinase or cardiac troponins

·                     Serum viral antibody titers – For viral myocarditis

Cardiac enzymes

Elevated cardiac enzymes are an indicator for cardiac myonecrosis. Cardiac troponin (troponin I or T), in particular, is elevated in at least 50% of patients with biopsy-proven myocarditis. Cardiac enzymes may also help to identify patients with resolution of viral myocarditis.

The test has 89% specificity and 34% sensitivity and increases more frequently than creatine kinase MB subunits (elevated in only 5.7% of patients with biopsy-proven myocarditis). However, these studies have been performed using standard clinical assays, and the sensitivity of newer-generation high-sensitivity cardiac troponin assays in diagnosing myocarditis may differ.

Viral antibody titers

Common viral antibody titers available for clinical evaluation include coxsackievirus group B, human immunodeficiency virus (HIV), cytomegalovirus, Ebstein-Barr virus, hepatitis virus family, and influenza viruses. Titers increase 4-fold or more, with a gradual fall during convalescence (nonspecific); hence, serial testing is required.

Antibody titer testing is rarely indicated in the diagnosis of viral myocarditis or any dilated cardiomyopathies, owing to its low specificity and the delayed rising of viral titers, which would have no impact on therapeutic decisions.

Viral genome

The presence of viral genome in endomyocardial biopsy samples is considered the criterion standard for viral persistence. However, the test lacks specificity, because the presence of viral genome can also be present in healthy controls. The most common viral genomes found include those of parvovirus and herpes simplex.

Histologic findings

Biopsy specimens from EMB should reveal the simultaneous findings of lymphocyte infiltration and myocyte necrosis.  Current American College of Cardiology/American Heart Association (ACC/AHA) guidelines for the treatment of heart failure describe EMB as a class IIb recommendation. Biopsy is generally reserved for patients with rapidly progressive cardiomyopathy refractory to conventional therapeutic management or an unexplained cardiomyopathy that is associated with progressive conduction system disease or life-threatening ventricular arrhythmias. It should also be considered when cardiovascular signs or symptoms develop in a patient with a systemic disease known to cause left ventricular dysfunction .

 

Indications for Endomyocardial Biopsy

 

http://emssolutionsinc.wordpress.com/2010/02/17/h1n1-swine-flu-myocarditis-associated/

Myocarditis is an inflammation of the myocardium (cardiac muscle).

 

Echocardiography

Echocardiography is performed to exclude other causes of heart failure (eg, amyloidosis or valvular or congenital causes) and to evaluate the degree of cardiac dysfunction (usually diffuse hypokinesis and diastolic dysfunction). It also may allow gross localization of the extent of inflammation (ie, wall motion abnormalities, wall thickening, pericardial effusion). In addition, echocardiography may distinguish between fulminant and acute myocarditis by identifying near-normal left ventricular diastolic dimensions and increased septal thickness in fulminant myocarditis (versus increased left ventricular diastolic dimensions and normal septal thickness in acute myocarditis), with marked improvement in systolic function in time.

Scintigraphy

Antimyosin scintigraphy (using antimyosin antibody injections) can identify myocardial inflammation with high sensitivity (91-100%) and negative predictive power (93-100%) but has low specificity (31-44%) and low positive predictive power (28-33%). In contrast, gallium scanning is used to reflect severe myocardial cellular infiltration and has a good negative predictive value, although specificity is low. Positron emission tomography (PET) scanning has been used in selected cases (eg, sarcoidosis) to assess the degree and location of inflammation.

Additional Imaging Techniques

Cardiac angiography is often indicated to rule out coronary ischemia as a cause of new-onset heart failure, especially when clinical presentation mimics acute myocardial infarction. It usually shows high filling pressures and reduced cardiac outputs.

Gadolinium-enhanced magnetic resonance imaging (MRI) is used for assessment of the extent of inflammation and cellular edema, although it is still nonspecific. Delayed-enhanced MRI has also been used to quantify the amount of scarring that occurred following acute myocarditis.

Monney et al suggested that cardiac magnetic resonance (CMR) scanning may be useful in patients with suspected acute coronary syndrome who are found not to have coronary artery disease. Despite preserved systolic function, a significant proportion of these patients were subsequently diagnosed with acute myocarditis on the basis of the CMR scan findings.

Electrocardiogram

Electrocardiograms are ofteonspecific (eg, sinus tachycardia, nonspecific ST- or T-wave changes). Occasionally, heart block (atrioventricular block or intraventricular conduction delay), ventricular arrhythmia, or injury patterns, with ST- or T-wave changes mimicking myocardial ischemia or pericarditis (pseudoinfarction pattern), may indicate poorer prognosis. Arrhythmia is common in Chagas heart disease. The following may be seen: right bundle-branch block with or without bifascicular block (50%), complete heart block (7-8%), atrial fibrillation (7-10%), and ventricular arrhythmia (39%).

Treatment according to clinical scenario

Possible subclinical acute myocarditis

The optimum management strategy for patients who have a rise in troponin concentrations or ECG changes suggestive of myocarditis or myopericarditis without cardiovascular symptoms is not known. These patients are often encountered during a medical assessment for non-cardiovascular disorders such as a flu-like illness. The short-term prognosis of possible subclinical acute myocarditis is good, but the long-term consequences are unknown. If ventricular function is normal, a reasonable therapeutic approach is to clinically reassess the patient after 1—2 weeks to ensure that troponin concentrations normalise and that symptoms of heart failure or arrhythmia do not develop. If the left ventricular ejection fraction is less than 40%, we recommend that an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker and possibly a β adrenergic blocker be given, as suggested in the present AHA/ACCF, HFSA, and ESC guidelines for the management of stage B heart failure.

Probable acute myocarditis

Treatment for probable acute myocarditis varies according to the presenting clinical scenario. In patients who present with an acute DCM and a syndrome of heart failure, supportive measures and pharmaceutical treatment with neurohormonal blockade is indicated, as is standard for chronic heart failure. Although clinical studies in myocarditis have not been done, captopril and candesartan improve myocarditis in murine myocarditis models. Most patients with acute myocarditis respond well to standard heart failure treatment. In addition to medical management, we recommend that patients with acute myocarditis refrain from competitive athletics for a period of up to 6 months after the acute infection or until ventricular recovery has been documented by non-invasive imaging.

Routine treatment of probable or definite acute viral or lymphocytic myocarditis with immunosuppressive drugs is not recommended for adults. In the US Myocarditis Treatment Trial, the placebo and immunosuppression (prednisone with either azathioprine or cyclosporin) arms had similar changes in left ventricular ejection fraction and transplant-free survival. In acute myocarditis, inflammation often has the beneficial effect of complete viral clearance. Exceptions include patients with uncommon, non-infectious, histological forms, including giant-cell myocarditis, cardiac sarcoidosis, and eosinophilic myocarditis; and those with myocarditis associated with inflammatory disorders such as systemic lupus erythematosus.

In small case series of acute paediatric myocarditis due to probable or definite lymphocytic myocarditis or Kawasaki disease, intravenous immunoglobulin has been effective. However, in the Intervention for Myocarditis and Acute Cardiomyopathy trial, there were no significant differences in transplant free survival between the intravenous immunoglobulin treatment group and placebo in adult patients who had DCM of less than 6 months duration. Therefore, in adults with probable acute myocarditis, there is insufficient evidence to recommend use of intravenous immunoglobulin.

Chronic DCM

Up to 40% of patients with chronic DCM who fail to respond to usual care have immunohistochemical evidence of myocardial inflammation.  In two randomised trials of patients with chronic inflammatory cardiomyopathy, immunosuppression with azathioprine and prednisone resulted in an improvement in quality of life and left ventricular ejection fraction as compared to placebo. In the Tailored Immunosuppression in Inflammatory Cardiomyopathy trial by Frustaci and colleagues, 85 patients with chronic inflammatory cardiomyopathy without persistent viral infection were enrolled and randomised to either prednisone and azathioprine or placebo. Prednisone and azathioprine treatment was associated with a mean left ventricular ejection fraction increase from 26% to 46%. Larger trials are needed to assess whether immunosuppression will affect the risk of death or admission to hospital in this population.

Although there are abundant data supporting the role of viral infection in the pathogenesis of myocarditis and DCM, there are no published randomised clinical trials of antiviral therapy in this population. In patients with chronic DCM and persistent viral genomes, one case series suggested that 6 mIU interferon beta three times per week for enteroviral or adenoviral infection can eliminate viral genomes and improve left ventricular function as compared with placebo. The applicability of these data to other common viruses, including parvovirus B19, is not known.

Mechanical circulatory support or extracorporeal membrane oxygenation can allow a bridge to transplantation or recovery in patients with cardiogenic shock despite optimum medical care. Time to recovery in acute myocarditis varies from a few days to a few months. Survival after transplantation for myocarditis in adults is similar to survival after cardiac transplantation for other reasons, however, survival after transplantation in children with myocarditis seems to be reduced. Patients with giant-cell myocarditis have a 20—25% risk of recurrence in the allograft heart.

Myopericarditis resembling an acute coronary syndrome

Patients who present with an acute myocardial infarction pattern usually recover with normal left ventricular ejection fraction; however, the likelihood of recovery is still dependent on left ventricular function.  Colchicine at an initial dose of 1—2 mg followed by reduced daily doses for up to 3 months can improve chest pain from associated pericarditis. Non-steroidal anti-inflammatory drugs such as indometacin should be used with caution and generally be reserved for patients with normal ventricular function because they worsen myocarditis in murine models.

Syncope from ventricular arrhythmias or heart block

Patients with ventricular arrhythmias or heart block due to acute myocarditis should be admitted to hospital for electrocardiographic monitoring. The 2006 ACC/AHA/ESC guidelines for the management of ventricular arrhythmias recommended that acute arrhythmia emergencies be managed conventionally in the setting of myocarditis. Generally, the indications for an implantable cardiac defibrillator are the same as for non-ischaemic DCM. However, because of the relatively high risk of death or need for transplantation, the presence of symptomatic ventricular arrhythmias or heart block in giant-cell myocarditis or cardiac sarcoidosis might warrant early consideration for an implantable cardiac defibrillator.

 

 

 

 

 

Pericarditis

 

 

 

Pericarditis describes the condition where the thin membrane lining the heart becomes inflamed. Most often, acute pericarditis is self-limiting and will resolve within a few weeks. However, it may recur and is considered chronic if the symptoms persist for more than 6-12 months. Some people that develop pericarditis can have complications such as fluid accumulation around the heart (pericardial effusion) or heart compression (pericardial constriction) that may require emergency or surgical interventions.

The pericardium is a thin membrane that encloses the heart and the base of the great vessels of the heart (aorta, vena cava, pulmonary artery and pulmonary vein). It is composed of to layers. The visceral layer is attached to the heart surface and then folds back on itself to form the parietal layer. This forms a small place that normally holds less than 50cc of fluid.

The pericardium holds the heart in its appropriate position in the chest and protects it from infection or tumors that might spread directly from other organs near the heart, such as the lung or esophagus. The pericardium also prevents the heart from dilating too much, which allows the heart muscle fibers to maintain their ideal length to contract or squeeze forcefully.

 

http://www.emedicinehealth.com/pericarditis/article_em.htm

 

Most often, pericarditis is self-limiting with medical care directed toward controlling the major symptom of pain. However, chronic inflammation of the pericardium can cause scarring that prevents the heart from beating appropriately and surgery may be required.

Inflammation can occur in many places in the heart. Pericarditis describes an inflammation of the membrane lining of the heart. It is different than  myocarditis (inflammation of the heart muscle) and endocarditis (inflammation of the heart valves).

Epidemiology

Epidemiologic data on the incidence of pericarditis are lacking, likely because this condition is frequently inapparent clinically, despite its presence iumerous disorders. Lorell noted a diagnosis of acute pericarditis in approximately 1 per 1000 hospital admissions.  In addition, acute pericarditis comprises 1% of emergency room visits in patients with ST-segment elevation.In fact, the reported incidence of acute pericardial tamponade is approximately 2% of penetrating trauma; however, this condition is rarely seen in blunt chest trauma.

Uremic pericarditis may occur in 6-10% of patients with advanced renal failure before initiation of dialysis. When patients with large effusions are studied, uremia may account for up to 20% of cases in some series. The widespread availability of dialysis has reduced the incidence of uremic pericarditis.

Malignant disease is the most common cause of pericardial effusion with tamponade in developed countries; However, tuberculosis should be considered in endemic areas.

Acute pericarditis is more common in men than in women. However, although this condition is more common in adults than in children, adolescents are more commonly affected than young adults. Nonetheless, Merce et al found no difference in etiology, clinical course, and prognosis between elderly and younger patients with moderate and large pericardial effusions.

Pericarditis Causes

The most common cause (up to about 80 %) of pericarditis is idiopathic, meaning the reason cannot be determined. However, listed below are some known causes of pericarditis.

Infection

Infections may cause inflammation of the pericardium and viruses such as the Coxsackie B, adenovirus and influenza A and B are most common.

Other viruses can be involved, examples include:

·                     Epstein-Barr virus that causes infectious mononucleosis, 

·                     herpes simplex type 1, 

·                     measles, 

·                     mumps, and 

·                     human immunodeficiency virus (HIV).

Even less commonly, bacterial infections such as tuberculosis may cause pericarditis and often bacterial infections are associated with the development of constrictive pericarditis (see below). Other infectious causes include parasites and fungi.

Inflammatory Diseases

Illnesses that can cause generalized inflammation in the body can also cause inflammation of the pericardium. Examples of these may include:

·                     rheumatoid arthritis, 

·                     systemic lupus erythematosus, 

·                     scleroderma, and

·                     sarcoidosis.

Other Illnesses

Other illnesses may contribute or cause pericarditis and examples include:

·                     Kidney disorders including patients on chronic dialysis.

·                     Patients having a heart attack can develop pericardial inflammation because of the underlying heart muscle damage. This may occur within days of the heart attack or may be delayed by 2-3 weeks. Dressler’s syndrome describes delayed pericarditis after heart attack or heart surgery. It may be associated with lung inflammation and effusion (fluid accumulation).

·                     Hypothyroidism or decreased thyroid function may be associated with pericardial inflammation.

·                     Cancers and other malignancies can be associated with pericarditis. The pericardium can be inflamed by direct extension of cancer cells from nearby structures or there can be hematogenous spread of abnormal cancer cells through the blood stream. Lung cancer, breast cancer, leukemia andlymphoma

, both Hodgkin’s and non-Hodgkin’s are the common cancer causes of pericarditis.

Other causes

·        Trauma that injures the heart can cause inflammation of the pericardium. The injury can be a direct blow to the chest causing a cardiac contusion or it can be a penetrating injury to the chest and heart.

·        Radiation cancer therapy can cause inflammation of the pericardium.

·        Pericarditis can be an uncommon side effect of some medications. Examples include some cancer chemotherapy medications, a few heart medications (for example, procainamide ,hydralazine , phenytoin and smallpox vaccine.

Pathophysiology

Pericardial physiology includes 3 main functions. First, through its mechanical function, the pericardium promotes cardiac efficiency by limiting acute dilation, maintaining ventricular compliance with preservation of the Starling curve, and distributing hydrostatic forces. The pericardium also creates a closed chamber with subatmospheric pressure that aids atrial filling and lowers transmural cardiac pressures. Second, through its membranous function, the pericardium shields the heart by reducing external friction and acting as a barrier against extension of infection and malignancy. Third, through its ligamentous function, the pericardium anatomically fixes the heart.

In most cases of acute pericarditis, the pericardium is acutely inflamed and has an infiltration of polymorphonuclear (PMN) leukocytes and pericardial vascularization. Often, the pericardium manifests a fibrinous reaction with exudates and adhesions. The pericardium may develop a serous or hemorrhagic effusion. A granulomatous pericarditis occurs with tuberculosis, fungal infections, rheumatoid arthritis (RA), and sarcoidosis.

Uremic pericarditis is thought to result from inflammation of the visceral and parietal layers of the pericardium by metabolic toxins that accumulate in the body owing to kidney failure. Other factors may be involved, however, because pericarditis also may occur in patients with chronic renal failure who are already receiving dialysis therapy.

The putative toxins suggested to precipitate uremic pericarditis when they accumulate are poorly characterized, but they may include urea, creatinine, methylguanidine, guanidinoacetate, parathyroid hormone, beta2-microglobulin, uric acid, and others. More than one toxin apparently may be involved, although considerable controversy surrounds this point.

The precise pathogenetic changes induced by these toxins when causing uremic pericarditis have not been elucidated, although a rough correlation with the degree and the duration of azotemia exists; the blood urea nitrogen (BUN) level is usually greater than 60 mg/dL (22 mmol/L). Uremic pericarditis may be associated with hemorrhagic or serous effusion, although considerable overlap exists. Hemorrhagic effusions are more common and result in part from uremia-induced platelet dysfunction.

Clinic

Congenital defects of the pericardium

Homolateral cardiac displacement and augmented heart mobility impose an increased risk for traumatic aortic dissection. Partial left side defects can be complicated by herniation and strangulation of the heart through the defect (chest pain, shortness of breath, syncope or sudden death). Surgical pericardioplasty (Dacron, Gore-tex, or bovine pericardium) is indicated for imminent strangulation.

Acute pericarditis

Acute pericarditis is dry, fibrinous or effusive, independent from its aetiology. The diagnostic algorithm can be derived from.  A prodrome of fever, malaise, and myalgia is common, but elderly patients may not be febrile. Major symptoms are retrosternal or left precordialchest pain (radiates to the trapezius ridge, can be pleuritic or simulate ischemia, and varies with posture) and shortness of breath. The pericardial friction rub can be transient, mono-, bi- or triphasic. Pleural effusion may be present. Heart rate is usually rapid and regular. Microvoltage and electrical alternans are reversible after effusion drainage. Echocardiography is essential to detect effusion, concomitant heart or paracardial disease.

          Perimyocarditis is evidenced by global or regional myocardial dysfunction, elevations of troponins I and T, MB creatine-kinase, myoglobin and tumour necrosis factor. Auscultation of a new S3 heart sound, convexly elevated J-ST segment in the ECG, fixation of Indium-111-labelled antimyosin antibodies, and structural changes in MRI are indicative, but only endomyocardial/epimyocardial biopsy is diagnostic.

Hospitalisation is warranted to determine the aetiology and observe for tamponade as well as the effect of treatment. Nonsteroidal anti-inflammatory drugs (NSAID) are the mainstay (level of evidence B, class I). Indomethacine should be avoided in elderly patients due to its flow reduction in the coronaries. Ibuprofen is preferred for its rare side-effects, favourable impact on the coronary flow, and the large dose range. Depending on severity and response, 300–800 mg every 6–8 hours may be initially required and can be continued for days or weeks, best until the effusion has disappeared. Gastrointestinal protection must be provided. Colchicine (0.5 mg bid) added to an NSAID or as monotherapy also appears to be effective for the initial attack and the prevention of recurrences (level of evidence B, class IIa indication). It is well tolerated with fewer side effects than NSAIDs. Systemic corticosteroid therapy should be restricted to connective tissue diseases, autoreactive or uremic pericarditis. Intrapericardial application avoids systemic side effects and is highly effective (level of evidence B, class IIa indication).  For tapering of prednisone, ibuprofen or colchicine should be introduced early

Chronic pericarditis

Chronic (3 months) pericarditis includes effusive (inflammatory or hydropericardium in heart failure), adhesive, and constrictive forms.⁷Symptoms are usually mild (chest pain, palpitations, fatigue), related to the degree of cardiac compression and pericardial inflammation. The diagnostic algorithm is similar as in acute pericarditis. The detection of the curable causes (e.g., tuberculosis, toxoplasmosis, myxedema, autoimmune, and systemic diseases) allows successful specific therapy. Symptomatic treatment and indications for pericardiocentesis are as in acute pericarditis. For frequent and symptomatic recurrences balloon pericardiotomy or pericardiectomy should be considered (level of evidence B, indication IIb).

Recurrent pericarditis

The term recurrent pericarditis encompasses:

·        the intermittent type (symptom free intervals without therapy)

·        the incessant type (discontinuation of anti-inflammatory therapy ensures a relapse).

Massive pericardial effusion, overt tamponade or constriction are rare. Evidence for an immunopathological process include: 

·        the latent period lasting for months;

·        the presence of anti-heart antibodies;

·        the quick response to steroid treatment and the similarity and co-existence of recurrent pericarditis with other autoimmune conditions (lupus, serum sickness, polyserositis, postpericardiotomy/postmyocardial infarction syndrome, celiac disease, dermatitis herpetiformis, frequent arthralgias, eosinophilia, allergic drug reaction, and history of allergy).

Potential underlying genetic disorders were also reported: autosomal dominant inheritance with incomplete penetrance and sex-linked inheritance (recurrent pericarditis associated with ocular hypertension).

Symptomatic management relies on exercise restriction and the regimen used in acute pericarditis. Colchicine was effective when NSAIDs and corticosteroids failed to prevent relapses. During 1004 months of colchicine treatment, only 13.7% new recurrences occurred. During the 2333 months of follow-up, 60.7% of the patients remained recurrence-free. The recommended dose is 2 mg/day for one or two days, followed by 1 mg/day (level of evidence B, indication I). Corticosteroids should be used only in patients with poor general condition or in frequent crises (level of evidence C, indication IIa). A common mistake is to use a dose too low to be effective or to taper the dose too rapidly. The recommended regimen is: prednisone 1–1.5 mg/kg, for at least one month. If patients do not respond adequately, azathioprine (75–100 mg/day) or cyclophosphamide can be added. Corticoids should be tapered over a three-month period. If symptoms still recur, return to the last dose that suppressed the manifestations, maintain that dose for 2–3 weeks and then recommence tapering. Towards the end of the taper, introduce anti-inflammatory treatment with colchicine or NSAID. Renewed treatment should continue for at least three months. Pericardiectomy is indicated only in frequent and highly symptomatic recurrences resistant to medical treatment (level of evidence B, indication IIa). Before pericardiectomy, the patient should be on a steroid-free regimen for several weeks. Post pericardiectomy recurrences were also demonstrated, possibly due to incomplete resection of the pericardium.

Pericardial effusion and cardiac tamponade

Pericardial effusion may appear as transudate (hydropericardium), exudate, pyopericardium or haemopericardium. Large effusions are common with neoplastic, tuberculous, cholesterol, uremic pericarditis, myxedema, and parasitoses. Effusions that develop slowly can be remarkably asymptomatic, while rapidly accumulating smaller effusions can present with tamponade. Loculated effusions are more common when scarring has supervened (e.g., postsurgical, posttrauma, purulent pericarditis). Massive chronic pericardial effusions are rare (2–3.5% of all large effusions). Cardiac tamponade is the decompensated phase of cardiac compression caused by effusion accumulation and the increased intrapericardial pressure. In “surgical” tamponade intrapericardial pressure is rising rapidly, in the matter of minutes to hours (i.e. haemorrhage), whereas a low-intensity inflammatory process is developing days to weeks before cardiac compression occurs (“medical” tamponade). Heart sounds are distant. Orthopnoea, cough and dysphagia, occasionally with episodes of unconsciousness can be observed. Insidiously developing tamponade may present with the signs of its complications (renal failure, abdominal plethora, shock liver and mesenteric ischemia). In 60% of the patients, the cause of pericardial effusion may be a known medical condition. Tamponade without two or more inflammatory signs (typical pain, pericardial friction rub, fever, diffuse ST segment elevation) is usually associated with a malignant effusion (likelihood ratio 2.9). Electrocardiography may demonstrate diminished QRS and T-wave voltages, PR-segment depression, ST-T changes, bundle branch block, and electrical alternans (rarely seen in the absence of tamponade). In chest radiography large effusions are depicted as globular cardiomegaly with sharp margins (“water bottle” silhouette). On well-penetrated lateral radiographies, or cine films, pericardial fluid is suggested by lucent lines within the cardiopericardial shadow (epicardial halo). This sign is useful for the fluoroscopic guidance of pericardiocentesis. The separation of pericardial layers can be detected in echocardiography, when the pericardial fluid exceeds 15–35 ml. The size of effusions can be graded as:

·        small (echo-free space in diastole 10 mm),

·        moderate (10–20 mm),

·        large (≥20 mm), 

·        very large (≥20 mm and compression of the heart).

In the parasternal long-axis view pericardial fluid reflects at the posterior atrioventricular groove, while pleural fluid continues under the left atrium, posterior to the descending aorta. In large pericardial effusions, the heart may move freely within the pericardial cavity (“swinging heart”) inducing pseudo-prolapse and pseudosystolic anterior motion of the mitral valve, paradoxical motion of the interventricular septum, and midsystolic aortic valve closure. Importantly, large effusions generally indicate more serious disease.

http://dic.academic.ru/dic.nsf/enc_medicine/23018/%D0%9F%D0%B5%D1%80%D0%B8%D0%BA%D0%B0%D1%80%D0%B4%D0%B8%D1%82

 

 

 Intrapericardial bands, combined with a thick visceral or parietal pericardium are often found after radiation of the chest. Rarely tumour masses, sometimes cauliflower-like, are found within or adjacent to the pericardium and may even masquerade tamponade. Other diagnostic pitfalls are: small loculated effusions, haematoma, cysts, foramen of Morgagni hernia, hiatus hernia, lipodystrophia with paracardial fat, inferior left pulmonary vein, left pleural effusion, mitral annulus calcification, giant left atrium, epicardial fat (best differentiated in CT), and left ventricular pseudoaneurysm. When bleeding into the pericardium occurs and thrombosis develops the typical echolucent areas may disappear, so that cardiac tamponade may be overlooked. Transesophageal echocardiography is here particularly useful  as well as in identifying metastases and pericardial thickening. CT, spin-echo and cine MRI can also be used to assess the size and extent of simple and complex pericardial effusions. Effusions measured by CT/MRI tend to be larger than in echocardiography. Up to one-third of patients with asymptomatic large pericardial chronic effusion develop unexpected cardiac tamponade. Triggers for tamponade include hypovolemia, paroxysmal tachyarrhythmia and intercurrent acute pericarditis.

 

Horowitz classification of pericardial effusions.

Type A: No effusion;

Type B: Separation of epicardium and pericardium (3–16 ml);

Type C 1: Systolic and diastolic separation of epicardium and pericardium (small effusion 16 ml);

Type C 2: Systolic and diastolic separation of epicardium and pericardium with attenuated pericardial motion;

Type D: Pronounced separation of epicardium and pericardium with large echo-free space;

Type E: Pericardial thickening (4 mm). 

 

Pericardiocentesis is not necessary when the diagnosis can be made otherwise or the effusions are small or resolving under anti-inflammatory treatment. Haemodynamic compromise and cardiac tamponade is an absolute indication for drainage. Patients with dehydration and hypovolemia may temporarily improve with intravenous fluids. Whenever possible, treatment should be aimed at the underlying aetiology. Even in idiopathic effusions extended pericardial catheter drainage (3±2 days, range 1–13 days) was associated with a lower recurrence rates (6% vs. 23%) than in those without catheter drainage during the follow-up of 3.8±4.3 years.Resistant neoplastic processes require intrapericardial treatment, percutaneous balloon pericardiotomy  or rarely pericardiectomy. Surgical approach is recommended only in patients with very large chronic effusion in whom repeated pericardiocentesis and/or intrapericardial therapy were not successful.

Constrictive pericarditis

Constrictive pericarditis is a rare but severely disabling consequence of the chronic inflammation of the pericardium, leading to an impaired filling of the ventricles and reduced ventricular function. Until recently, increased pericardial thickness has been considered an essential diagnostic feature of constrictive pericarditis. However, in the large surgical series from the Mayo clinic constriction was present in 18% of the patients with normal pericardial thickness. Tuberculosis, mediastinal irradiation, and previous cardiac surgical procedures are frequent causes of the disease, which can present in several pathoanatomical forms^. Constrictive pericarditis may rarely develop only in the epicardial layer in patients with previously removed parietal pericardium. Transient constrictive pericarditis is uncommon but important entity, since these patients are not indicated for pericardiectomy. Patients complain about fatigue, peripheral oedema, breathlessness, and abdominal swelling, which may be aggravated by a protein-loosing enteropathy. Typically, there is a long delay between the initial pericardial inflammation and the onset of constriction. In decompensated patients venous congestion, hepatomegaly, pleural effusions, and ascites may occur. Haemodynamic impairment of the patient can be additionally aggravated by a systolic dysfunction due to myocardial fibrosis or atrophy Differential diagnosis has to include acute dilatation of the heart, pulmonary embolism, right ventricular infarction, pleural effusion, chronic obstructive lung diseases and restrictive cardiomyopathy. The best way to distinguish constrictive pericarditis from restrictive cardiomyopathy is the analysis of respiratory changes with or without changes of preload by Doppler and/or tissue Doppler echocardiography, but physical findings, ECG, chest radiography, CT and MRI, haemodynamics, and endomyocardial biopsy may be helpful as well.

 

Pathoanatomical forms of constrictive pericarditis vs. restrictive cardiomyopathy. (a) Annular form of pericardial constriction with bilateral thickening of the pericardium along the atrial ventricular grooves with normal configuration of both ventricles and enlargement of both atria. (b) Left sided form of pericardial constriction with thickened pericardium along the left ventricle and right sided bending of the interventricular septum with tube-like configuration of mainly left ventricle and enlargement of both atria. (lateral sternotomy and partial pericardiectomy is indicated). (c) Right sided form of pericardial constriction with thickened pericardium along the right ventricle and left sided bending of the interventricular septum with tube-like configuration of mainly right ventricle and enlargement of both atria (median sternotomy and partial pericardiectomy is indicated). (d)Myocardial atrophy and global form of pericardial constriction with bilateral thickening of the pericardium along both ventricles separated from the right myocardial wall by a thin layer of subepicardial fat. Tube-like configuration of both ventricles and enlargement of both atria, however, thinning of the interventricular septum and posterolateral wall of the left ventricle below 1 cm is suggesting myocardial atrophy (pericardiectomy is contraindicated). (e) Perimyocardial fibrosis and global form of pericardial constriction with bilateral thickening of the pericardium along both ventricles, however, the right sided thickened pericardium cannot be separated from the wave-like thin form of right sided ventricular wall suggesting perimyocardial fibrosis (pericardiectomy is contraindicated). (f) Global form of pericardial constriction with bilateral thickening of the pericardium along both ventricles separated from the right myocardial wall by a thin layer of subepicardial fat. Tube-like configuration of both ventricles and enlargement of both atria (median sternotomy and pericardiectomy is indicated). (g) Restrictive cardiomyopathy with normal thin pericardium along both ventricles that show normal configuration and with enlargement of both atria.

          Pericardiectomy is the only treatment for permanent constriction. The indications are based upon clinical symptoms, echocardiography findings, CT/MRI, and heart catheterisation. There are two standard approaches, both aiming at resecting the diseased pericardium as far as possible:(1) The antero-lateral thoracotomy (fifth intercostal space) and (2) median sternotomy (faster access to the aorta and right atrium for extracorporeal circulation). A primary installation of cardiopulmonary bypass is not recommended (diffuse bleeding following systemic heparinisation). If severe calcified adhesions between peri- and epicardium or a general affection of the epicardium (“outer porcelain heart”) are present surgery carries a high risk of either incomplete success or severe myocardial damage. An alternative approach in such cases may be a “laser shaving” using an Excimer laser. Areas of strong calcification or dense scaring may be left as islands to avoid major bleeding. Pericardiectomy for constrictive pericarditis has a mortality rate of 6–12%.  The complete normalization of cardiac haemodynamics is reported in only 60% of the patients. The deceleration time (DT) may remain prolonged  and postoperative respiratory variations of mitral/tricuspid flow are found in 9–25%.  Left ventricular ejection fraction can increase due to a better ventricular filling. Major complications include acute perioperative cardiac insufficiency and ventricular wall rupture. Cardiac mortality and morbidity at pericardiectomy is mainly caused by the pre-surgically unrecognised presence of myocardial atrophy or myocardial fibrosis. Exclusion of patients with extensive myocardial fibrosis and/or atrophy reduced the mortality rate for pericardiectomy to 5%. Postoperative low cardiac output  should be treated by fluid substitution and catecholamines, high doses of digitalis, and intraaortic balloon pump in most severe cases. If indication for surgery was established early, long-term survival after pericardiectomy corresponds to that of the general population.  However, if severe clinical symptoms were present for a longer period before surgery, even a complete pericardiectomy may not achieve a total restitution.

Pericardial cysts

Congenital pericardial cysts are uncommon; they may be unilocular or multilocular, with the diameter from 1–5 cm. 

Inflammatory cysts comprise pseudocysts as well as encapsulated and loculated pericardial effusions, caused by rheumatic pericarditis, bacterial infection, particularly tuberculosis, trauma and cardiac surgery. 

Echinococcal cysts usually originate from ruptured hydatid cysts in the liver and lungs. Most patients are asymptomatic and cysts are detected incidentally on chest roentgenograms as an oval, homogeneous radiodense lesion, usually at the right cardiophrenic angle. However, the patients can also present with chest discomfort, dyspnoea, cough or palpitations, due to the compression of the heart. Echocardiography is useful, but additional imaging by computed tomography (density readings) or magnetic resonance is ofteeeded. The treatment for congenital and inflammatory cysts is percutaneous aspiration and ethanol sclerosis. If this is not feasible, video assisted thoracotomy or surgical resection may be necessary. The surgical excision of ecchinococcal cysts is not recommended. Percutanous aspiration and instillation of ethanol or silver nitrate after pre-treatment with Albendazole (800 mg/day 4 weeks) is safe and effective.

Specific forms of pericarditis:

Viral pericarditis

Viral pericarditis is the most common infection of the pericardium. Inflammatory abnormalities are due to direct viral attack, the immune response (antiviral or anticardiac), or both. Early viral replication in pericardial and epimyocardial tissue elicits cellular and humoral immune responses against the virus and/or cardiac tissue. Viral genomic fragments in pericardial tissue may not necessarily replicate, yet they serve as a source of antigen to stimulate immune responses. Deposits of IgM, IgG, and occasionally IgA, can be found in the pericardium and myocardium for years. Various viruses cause pericarditis (entero-, echo-, adeno-, cytomegalo-, Ebstein Barr-, herpes simplex-, influenza, parvo B19, hepatitis C, HIV, etc). Attacks of enteroviral pericarditis follow the seasonal epidemics of Coxsackie virus A+B and Echovirus infections. Cytomegalovirus pericarditis has an increased incidence in immunocompromised and HIV infected hosts. Infectious mononucleosis may also present with pericarditis. The diagnosis of viral pericarditis is not possible without the evaluation of pericardial effusion and/or pericardial/epicardial tissue, preferably by PCR or in-situ hybridisation (level of evidence B, class IIa indication) (Focus boxes 3–4). A four-fold rise in serum antibody levels is suggestive but not diagnostic for viral pericarditis (level of evidence B, class IIb indication).

Treatment of viral pericarditis is directed to resolve symptoms (see acute pericarditis), prevent complications, and eradicate the virus. In patients with chronic or recurrent symptomatic pericardial effusion and confirmed viral infection the following specific treatment is under investigation: (1) CMV pericarditis: hyperimmunoglobulin – 1 time per day 4 ml/kg on day 0, 4, and 8; 2 ml/kg on day 12 and 16; (2) Coxsackie B pericarditis: Interferon alpha or beta 2,5 Mio. IU/m² surface area s.c. 3×per week; (3) adenovirus and parvovirus B19 perimyocarditis: immunoglobulin treatment: 10 g intravenously at day 1 and 3 for 6–8 hours.

http://partnersah.vet.cornell.edu/avian-atlas/search/examfinding/742

 

Pericardial manifestation of human immunodeficiency virus (HIV) infectioncan be due to infective, non-infective and neoplastic diseases (Kaposi sarcoma and/or lymphoma). Infective (myo)pericarditis results from the local HIV infection and/or from the other viral (cytomegalovirus, herpes simplex), bacterial (S. aureus, K. pneumoniae, M. avium, and M. tuberculosis) and fungal coinfections (Cryptococcus neoformans). In progressive disease the incidence of echocardiographically detected pericardial effusion is up to 40%. Cardiac tamponade is rare.During the treatment with retroviral compounds, lipodystrophy can develop (best demonstrated by MRI) with intense paracardial fat deposition leading to heart failure. Treatment is symptomatic, while in large effusions and cardiac tamponade pericardiocentesis is necessary. The use of corticoid therapy is contraindicated except in patients with secondary tuberculous pericarditis, as an adjunct to tuberculostatic treatment (level of evidence A, indication I).

Bacterial pericarditis

Purulent pericarditis in adults is rare , but always fatal if untreated. Mortality rate in treated patients is 40%, mostly due to cardiac tamponade, toxicity, and constriction. It is usually a complication of an infection originating elsewhere in the body, arising by contiguous spread or haematogenous dissemination. Predisposing conditions are pericardial effusion, immunosuppression, chronic diseases (alcohol abuse, rheumatoid arthritis, etc), cardiac surgery and chest trauma. The disease appears as an acute, fulminant infectious illness with short duration. Percutaneous pericardiocentesis must be promptly performed. Obtained pericardial fluid should undergo urgent Gram, acid-fast and fungal staining, followed by cultures of the pericardial and body fluids (level of evidence B, indication I). Rinsing of the pericardial cavity, combined with effective systemic antibiotic therapy is mandatory (antistaphylococcal antibiotic plus aminoglycoside, followed by tailored antibiotic therapy according to pericardial fluid and blood cultures). Intrapericardial instillation of antibiotics (e.g., gentamycin) is useful but not sufficient. Frequent irrigation of the pericardial cavity with urokinase or streptokinase, using large catheters, may liquefy the purulent exudate, but open surgical drainage through subxiphoid pericardiotomy is preferable. Pericardiectomy is required in patients with dense adhesions, loculated and thick purulent effusion, recurrence of tamponade, persistent infection, and progression to constriction. Surgical mortality is up to 8%.

 

Differential diagnosis of the specific forms of pericarditis

 

	Viral	Bacterial	Tuberculous	Autoreactive
Cardiotropic microbial agents	Entero-, echo-, adeno-, cytomegalo, Ebstein Barr, herpes simplex, influenza, parvo B19, hepatitis A,B,C virus, HIV	Staphylococci, pneumococci, streptococci, Neisseria, proteus, gram negative rods, Legionella	Mycobacterium tuberculosis	Autoimmune process in the absence of viral and bacterial agents
Etiological evidence by	PCR or in situ hybridisation (evidence level B, indication IIa)	Gram-stain, bacterial culture, PCR for Borrelia and chlamydia pneumoniae (evidence level B, indication I)	Ziehl-Neelsen, auramin 0 stain, culture, PCR (evidence level B, indication I)	Ig-binding to peri- and epicardium, negative PCR for cardiotropic agents, epicarditis (evidence level B, indication IIa)
Incidence (%) Western countries	30	5–10 5 per 100,000 patients	4 (much more in Africa and South America)	20–30
Male: female ratio	3:1	1:1	1:1	1:1
Predisposition	Unknown	Chronic alcohol abuse, immuno-suppression,	Alcohol abuse, HIV infection	Association to autoimmune disorders
Clinical features	Identical to acute pericarditis, often subfebrile	Spiking fever, fulminant, tachycardia, pericardial rubs	Subfebrile, chronic	Subfebrile, chronic
Effusion size	Variable, mostly small	Variable	Variable, mostly large	Variable
Tamponade	Infrequent	80%	Frequent	Infrequent
Spontan. Remission	Frequent	None	None	Rare
Recurrence rate	30–50%	Rare	Frequent	Frequent; 25%
Aspect of PE	Serous/serosanginous	Purulent	Serosanginous	Serous
Protein content	3 g/dL	High	High/intermediate	Intermediate
Leukocyte count (PE)	5000/ml	≫10000/ml	Intermediate 8000	Intermediate <5000
Pericardial fluid analyses	Activated lymphocytes and macrophages (sparse) Adenosindeaminase (ADA)- negative	Granulocytes and macrophages (massive) ADA-negative	Granulocytes and macrophages (intermediate) ADA positive (40 U/ml)	Activated lymphocytes and macrophages (sparse) ADA-negative
Peri- and epicardial biopsy	Lymphocytic peri-/epicarditis, PCR positive for cardiotropic virus	Leukocytic epicarditis	Caseous granuloma, PCR	Lymphocytic peri-/epicarditis, PCR negative
Mortality if untreated	Depending on agent and tamponade	100%	85%	In untreated tamponade
Intrapericardial treatment	Drainage, if needed, no intrapercardial corticoids	Drainage and rinsing (saline) gentamycin 80 mg i.p.,	Drainage, if needed	Drainage, i.p. triamcinolon (evidence B, indication IIa)
Pericardiotomy/pericardiectomy	Rarely needed	Promptly needed (evidence level B, indication I)	Rarely needed	Rarely needed
Systemic treatment	I.V. immunoglobulins, IFN (in enteroviral pericarditis) s.c.	I.V. antibiotics	Tuberculostatic+prednisone	NSAIDs, Colchicine, prednisolone/azathioprin
Constriction	Rare	Frequent	Frequent (30–50%)	Rare

 

 

Tuberculous pericarditis

In the last decade TBC pericarditis in the developed countries has been primarily seen in immunocompromised patients (AIDS). The mortality rate in untreated acute effusive TBC pericarditis approaches 85%. Pericardial constriction occurs in 30–50%. The clinical presentation is variable: acute pericarditis with or without effusion; cardiac tamponade, silent, often large pericardial effusion with a relapsing course, toxic symptoms with persistent fever, acute constrictive pericarditis, subacute constriction, effusive-constrictive, or chronic constrictive pericarditis, and pericardial calcifications. The diagnosis is made by the identification of Mycobacterium tuberculosis in the pericardial fluid or tissue, and/or the presence of caseous granulomas in the pericardium. Importantly, PCR can identify DNA of Mycobacterium tuberculosis rapidly from only 1 μL of pericardial fluid. High adenosine deaminase activity and interferon gamma concentration in pericardial effusion are also diagnostic, with a high sensitivity and specificity (Focus box 3): Both pericardioscopy and pericardial biopsy have also improved the diagnostic accuracy for TBC pericarditis. Pericardial biopsy enables rapid diagnosis with better sensitivity than pericardiocentesis (100 vs. 33%).

http://www.vetmed.vt.edu/education/Curriculum/VM8304/vet%20pathology/CASES/INFPATT/PAGE2-4.htm

 

Pericarditis in a patient with proven extracardiac tuberculosis is strongly suggestive of TBC aetiology (several sputum cultures should be taken). The tuberculin skin test may be false negative in 25–33% of tests and false positive in 30–40% of patients. More accurate enzyme-linked immunospot (ELISPOT) test detects T-cells specific for Mycobacterium tuberculosis antigen. Perimyocardial TBC involvement is also associated with high serum titres of antimyolemmal and antimyosin antibodies. The diagnostic yield of pericardiocentesis in TBC pericarditis ranges from 30–76% according to the methods applied for the analyses of pericardial effusion. Pericardial fluid demonstrates high specific gravity, high protein levels, and high white-cell count (from 0.7–54×10⁹/l).

Various antituberculous drug combinations of different lengths (6, 9, 12 months) have been applied. However, only patients with proven or very likely TBC pericarditis should be treated. Prevention of constriction in chronic pericardial effusion of undetermined aetiology by “ex iuvantibus” antitubercular treatment was not successful. The use of steroids remains controversial. A meta analysis of patients with effusive and constrictive TBC pericarditis  suggested that tuberculostatic treatment combined with steroids might be associated with fewer deaths, less frequent need for pericardiocentesis or pericardiectomy (level of evidence A, indication IIb). If given, prednisone should be administered in relatively high doses (1–2 mg/kg per day) since rifampicin induces its liver metabolism. This dose is maintained for 5–7 days and is progressively reduced to discontinuation in 6–8 weeks. If, in spite of combination therapy, constriction develops pericardiectomy is indicated (level of evidence B, class I indication).

Pericarditis in renal failure

Renal failure is a common cause of pericardial disease, producing large pericardial effusions in up to 20% of patients. Two forms have been described:         Uremic pericarditis – in 6–10% of patients with advanced renal failure (acute or chronic) before dialysis has been instituted or shortly thereafter. It results from inflammation of the visceral and parietal pericardium and correlates with the degree of azotemia (BUN 60 mg/dl).

Dialysis-associated pericarditis – in up to 13% of patients on maintenance haemodialysis, and occasionally with chronic peritoneal dialysis due to inadequate dialysis and/or fluid overload. Pathologic examination of the pericardium shows adhesions between the thickened pericardial membranes (“bread and butter” appearance). The clinical features may include fever and pleuritic chest pain but many patients are asymptomatic. Pericardial rubs may persist even in large effusions or may be transient. Due to autonomic impairment in uremic patients, heart rate may remain slow (60–80 beats/min) during tamponade, despite fever and hypotension. Anaemia, due to induced resistance to erythropoetin may worsen the clinical picture. The ECG does not show the typical diffuse ST/T wave elevations observed with other causes of acute pericarditis due to the lack of the myocardial inflammation. 

If the ECG is typical of acute pericarditis, intercurrent infection must be suspected.Most patients with uremic pericarditis respond rapidly to haemo- or peritoneal dialysis with resolution of chest pain and pericardial effusion. To avoid haemopericardium heparin-free haemodialysis should be used. Hypokalemia and hypophosphatemia should be prevented by supplementing the dialysis solution when appropriate. Intensified dialysis usually leads to resolution of the pericarditis within 1–2 weeks. Peritoneal dialysis, which does not require heparinisation, may be therapeutic in pericarditis resistant to haemodialysis, or if heparin-free haemodialysis cannot be performed. NSAIDs and systemic corticosteroids have limited success when intensive dialysis is ineffective. Cardiac tamponade and large chronic effusions resistant to dialysis must be treated with pericardiocentesis. (level of evidence B, class IIa indication). Large, non-resolving symptomatic effusions should be treated with intrapericardial instillation of corticosteroids after pericardiocentesis or subxiphoid pericardiotomy (triamcinolone hexacetonide 50 mg every 6 h for 2–3 days).  Pericardiectomy is indicated only in refractory, severely symptomatic patients due to its potential morbidity and mortality. After renal transplantation, pericarditis has also been reported in 2.4% of patients, within two months. Uraemia or infection (CMV) may be the causes.

Autoreactive pericarditis and pericardial involvement in systemic autoimmune diseases

Intrapericardial treatment with triamcinolone is highly efficient with rare side effects.

Pericarditis occurs in systemic autoimmune diseases: rheumatoid arthritis, systemic lupus erythematosus, progressive systemic sclerosis, polymyositis/ dermatomyositis, mixed connective tissue disease, seronegative spondyloarthropathies, systemic and hypersensitivity vasculitides, Behçet syndrome, Wegener granulomatosis, and sarcoidosis. Intensified treatment of the underlying disease and symptomatic management are indicated (evidence level B, indication I).

The post-cardiac injury syndrome: postpericardiotomy syndrome

Post-cardiac injury syndrome develops within days to months after cardiac, pericardial injury or both. It resembles the post-myocardial infarction syndrome, both appearing to be variants of a common immunopathic process. Unlike post-myocardial infarction syndrome, post-cardiac injury syndrome acutely provokes a greater antiheart antibody response (antisarcolemmal and antifibrillary), probably related to more extensive release of antigenic material. Pericardial effusion also occurs after orthotopic heart transplantation (21%). It is more frequent in patients receiving aminocaproic acid during the operation. Cardiac tamponade after open heart surgery is more common following valve surgery than coronary artery bypass grafting (CABG) alone and may be related to the preoperative use of anticoagulants. 

Constrictive pericarditis may also occur after cardiac surgery. Warfarin administration in patients with early postoperative pericardial effusion imposes the greatest risk, particularly in those who did not undergo pericardiocentesis and drainage of the effusion.  Symptomatic treatment is as in acute pericarditis (NSAIDs or colchicine for several weeks or months, even after disappearance of effusion). Long term (3–6 months) oral corticoids or preferably pericardiocentesis and intrapericardial instillation of triamcinolone (300 mg/m2) are therapeutic options in refractory forms. Redo surgery and pericardiectomy are very rarely needed. Primary prevention of postperiocardiotomy syndrome using short-term perioperative steroid treatment or colchicine is under investigation.

Postinfarction pericarditis

Two forms of postinfarction pericarditis can be distinguished: an “early” form (pericarditis epistenocardica) and a “delayed” form (Dressler’s syndrome). 

Epistenocardiac pericarditis, caused by direct exudation, occurs in 5–20% of transmural myocardial infarctions but is clinically discovered rarely. 

Dressler’s syndrome occurs from one week to several months after clinical onset of myocardial infarction with symptoms and manifestations similar to the post-cardiac injury syndrome. It does not require transmural infarction  and can also appear as an extension of epistenocardiac pericarditis. Its incidence is 0.5–5%  and is still lower in patients treated with thrombolytics (0.5%),  but was more frequent in cases of pericardial bleeding after antithrombotic treatment.  Of note, ECG changes are often overshadowed by myocardial infarction changes. Stage I ECG changes are uncommon and suggest “early” post-myocardial infarction syndrome whereas failure to evolve or “resurrection” of previously inverted T waves strongly suggest myocardial infarction pericarditis.  Postinfarction pericardial effusion 10 mm is most frequently associated with haemopericardium, and two thirds of these patients may develop tamponade/free wall rupture. Urgent surgical treatment is life saving. However, if the immediate surgery is not available or contraindicated pericardiocentesis an intrapericardial fibrin-glue instillation could be an alternative in subacute tamponade.

Hospitalisation to observe for tamponade, differential diagnosis, and adjustments of treatment is needed. Ibuprofen, which increases coronary flow, is the agent of choice. Aspirin, up to 650 mg every 4 hours for 2 to 5 days has also been successfully applied. Other nonsteroidal agents risk thinning the infarction zone.  Corticosteroid therapy can be used for refractory symptoms only but could delay myocardial infarction healing (level of evidence B, class IIa indication).

Traumatic pericardial effusion and haemopericardium in aortic dissection

Direct pericardial injury can be induced by accidents or iatrogenic wounds. Blood loss, vasoconstriction, and haematothorax leading to severe hypotension and shock may mask pulses paradoxus. Thoracotomy and surgical repair should be performed.

Iatrogenic tamponade occurs most frequently in percutaneous mitralvalvuloplasty, during or after transseptal puncture, particularly, if no biplane catheterisation laboratory is available and a small left atrium is present. Whereas the puncture of the interatrial septum is asymptomatic, the passage of the free wall induces chest-pain immediately. If high-pressure containing structures are punctured, rapid deterioration occurs. However, if only the atrial wall is passed, the onset of symptoms and the tamponade may be delayed for 4 to 6 hours. Rescue pericardiocentesis is successful in 95–100% with a 1% mortality.

Traumatic pericardial effusion

 

Effusion due to	Incidence (%)	Mortality (%)	Management	Comment/Reference
Iatrogenic
Transseptal puncture	1–3	1%	Rescue pericardiocentesis, if needed	Use biplane angio-graphy171
Coronary artery perforation during PTCA (guidewire only)	Not infrequent	Not available	Watchful waiting by withdrawal of guidewire	Reverse anticoagulation
Coronary artery transsection during PTCA	0.3–3.2	Not available	Sealing by graft stents (best) or perfusion catheters with balloon occlusion of perforated vessel, if pericardial puncture is need reinfusion of recovered blood in vein avoids anaemia.	Surgery only if 30% of myocardium at stake or bleeding cannot be stopped172,173
Rotablation	0.1–3	Not available	See above	See above172,173
Transluminal extraction atherectomy (atherocath)	0–2 %	Not available	See above	See above
Excimer laser angioplasty	1.7–3%	Not available	See above	See above173
High pressure stenting	2% (?)	Not available	See above	See above173
Mitral valvuloplasty	1–3%	<1%		171,179
Left ventricular biopsy (LV-EMB)	0.1–3.3%	0%	Routine echocardiography post EMB, pericardiocentesis, if needed; reverse anticoagulation	180,181,194
Right ventricular biopsy (RV-EMB)	0.3–5%	0–0.05%	Routine echocardiography post EMB, pericardiocentesis, if needed; reverse anticoagulation	180,181,194
Pacemaker leads	0–3–3.1%	0.1%	Routine echocardiography post implantation, pericardiocentesis, if needed	Pericardial effusion with/without tamponade190,191, postpericardiotomy syndrome192, constrictive pericarditis193
Other causes
Injury (direct: e.g., stabbing indirect: compression, closed chest massage)	Not available	Often lethal	Direct: surgery (see text) Indirect: pericardiocentesis or surgery
Aortic dissection	48% post mortem, 17–45% in clinical series	Lethal if not operated	Transoesophageal echo, CT or MRI, immediate surgery	Particularly in De- Bakey I + II=Stanford type A184–189

 

Transsection of the coronary artery and acute or subacute cardiac tamponade may occur during percutaneous coronary interventions. A breakthrough in the treatment of coronary perforation is membrane-covered graft stents.Perforation of the coronary artery by a guidewire is not infrequent and causes very rarely a relevant pericardial haemorrhage.

During right ventricular endomyocardial biopsy, due to the low stiffness of the myocardium, the catheter may pass the myocardium, particularly, when the bioptome has not been opened before reaching the endocardial border. The rate of perforation is reported to be in the range of 0.3–5%, leading to tamponade and circulatory collapse in less than half of the cases. The incidence of pericardial haemorrhage in left ventricular endomyocardial biopsy is lower (0.1–3.3%). Frank cardiac perforations seem to be accompanied by sudden bradycardia and hypotension. Severe complications, leading to procedure related mortality were reported in only 0.05% in a worldwide survey of more than 6000 cases and ione of the 2537 patients from the registry of an experienced reference centre.

Pacemaker leads penetrating the right ventricle or epicardial electrodes may cause pericarditis with tamponade, adhesions, or constriction. A right bundle brand block instead of a usually induced left bundle branch block is a clue.

Blunt chest trauma is the major risk of car accidence. The deceleration force can lead to myocardial contusion with intrapericardial haemorrhage, cardiac rupture, pericardial rupture, or herniation. Transesophageal echocardiography in the emergency room or immediate computed tomography should be performed. Pericardial laceration and partial extrusion of the heart into the mediastinum and pleural space may also occur after injury.

In dissection of the ascending aorta (pericardial effusion can be found in 17–45% of the patients and in 48% of the autopsy cases. In a clinical series of aortic dissection, pericardial tamponade was found by CT, MRI,or echocardiography  in 17–33% of patients with type I dissection and 18–45% in type II dissection and 6% in type III dissection. Pericardiocentesis is contraindicated, due to the risk of intensified bleeding and extension of the dissection. Surgery should be performed immediately (evidence level B, indication I).

Neoplastic pericarditis

Primary tumours of the pericardium are 40 times less common than the metastatic ones.Mesothelioma, the most common of the primary tumours, is almost always incurable. The most common secondary malignant tumours are lung cancer, breast cancer, malignant melanoma, lymphomas, and leukemias. Effusions may be small or large with an imminent tamponade (frequent recurrences) or constriction. It even may be the initial sign of malignant disease. With small malignant effusions most patients are asymptomatic. The onset of dyspnoea, cough, chest pain, tachycardia, jugular venous distension is observed when the volume of fluid exceeds 500 ml. Pulsus paradoxus, hypotension, cardiogenic shock and paradoxical movement of the jugular venous pulse are important signs of cardiac tamponade.

The diagnosis is based on the confirmation of the malignant infiltration within the pericardium. Of note, in almost 2/3 of the patients with documented malignancy pericardial effusion is caused by non-malignant diseases, e.g., radiation pericarditis, or opportunistic infections. The chest roentgenogram, CT, and MRI may reveal mediastinal widening, hilar masses, and pleural effusion. The analyses of pericardial fluid, pericardial or epicardial biopsy are essential for the confirmation of malignant pericardial disease (level of evidence B, indication I) (Focus boxes 3–4).

Treatment of cardiac tamponade is a class I indication for pericardiocentesis. The following steps are recommended in suspected neoplastic pericardial effusion without tamponade:

1.     systemic antineoplastic treatment as baseline therapy which can prevent recurrences in up to 67% of cases (level of evidence B, class I indication);

2.     pericardiocentesis to relieve symptoms and establish diagnosis (level of evidence B, class IIa indication);

3.     intrapericardial instillation of cytostatic/sclerosing agent (level of evidence B, class IIa indication).

 Pericardial drainage is recommended, in all patients with large effusions because of the high recurrence rate (40–70%)(level of evidence B, indication I). Prevention of recurrences may be achieved by intrapericardial instillation of sclerosing, cytotoxic agents, or immunomodulators. Intrapericardial treatment tailored to the type of the tumour indicates that administration of cisplatin is most effective in secondary lung cancer and intrapericardial instillation of thiotepa was more effective in breast cancer pericardial metastases. No patient showed signs of constrictive pericarditis (for both agents level of evidence B, indication IIa). Tetracyclines as sclerosing agents also control the malignant pericardial effusion in around 85% of cases, but side effects and complications are quite frequent: fever (19%), chest pain (20%), and atrial arrhythmias (10%) (level of evidence B, indication IIb).Although classic sclerotherapy after intrapericardial instillation of tetracycline, doxycycline, minocycline and bleomycin is an effective procedure, constrictive pericarditis secondary to fibrosis remains a severe problem in long-term survivors.

Although intrapericardial administration of radionuclides has yielded very good results, it is not widely accepted because of the logistic problems connected with their radioactivity(level of evidence B, indication IIa). Radiation therapy is very effective (93%) in controlling malignant pericardial effusion (level of evidence B, indication IIa) in patients with radiosensitive tumours such as lymphomas and leukemias. However, radiotherapy of the heart can cause myocarditis and pericarditis by itself. Subxyphoid pericardiotomy is indicated when pericardiocentesis cannot be performed (level of evidence B, indication IIb). The procedure can be carried out in local anaesthesia, but complications include myocardial laceration, pneumothorax, and mortality.Pleuropericardiotomy allows drainage of malignant pericardial fluid into the pleural space (level of evidence C, indication IIb). It is associated with a higher complications rate and offers no advantage over pericardiocentesis or subxyphoid pericardiotomy. Pericardiectomy is rarely indicated, mainly for pericardial constriction or complications of previous procedures.

Percutaneous balloon pericardiotomy creates a pleuro-pericardial direct communication, which allows fluid drainage into the pleural space (level of evidence B, indication IIa). In large malignant pericardial effusions and recurrent tamponade, it seems to be effective (90–97%) and safe.

Rare forms of pericardial disease

Fungal pericarditis

Fungal pericarditis occurs mainly in immunocompromised patients or in the course of endemic-acquired fungal infections. The clinical picture comprises the full spectrum of pericardial diseases including fungal myocarditis.Fungal pericarditis is mainly due to endemic fungi (Histoplasma, Coccidioides), or nonendemic – opportunistic fungi (Candida, Aspergillus, Blastomyces) and semifungi (Nocardia, Actinomyces). Diagnosis is obtained by staining and culturing pericardial fluid or tissue. Antifungal antibodies in serum are also helpful in establishing the diagnosis of fungal infection. Antifungal treatment with fluconazole, ketoconasole, itraconasole, amphotericin B, liposomal amphotericin B or amphotericin B lipid complex is indicated (level of evidence B, indication I). Corticosteroids and NSAIDs can support the treatment with antifungal drugs (level of evidence C, indication IIa).

 Patients with pericarditis in the course of histoplasmosis do not need antifungal therapy, but respond to nonsteroidal anti-inflammatory drugs given during 2–12 weeks. Sulfonamides are the drugs of choice for a nocardiosis infection. Combination of three antibiotics including penicillin should be given for actinomycosis (level of evidence C, indication I). Pericardiocentesis or surgical treatment is indicated for haemodynamic impairment. Pericardiectomy is indicated in fungal constrictive pericarditis (evidence level C, indication I).

Radiation pericarditis

The probability to develop radiation-induced pericarditis is influenced by the applied source, dose, its fractionation, duration, radiation exposed volume, form of mantel field therapy, and the age of the patients. Radiation induced pericarditis may occur already during the therapy or months and years later – with latency of up to 15–20 years. The effusion may be serous or haemorrhagic, later on with fibrinous adhesions or constriction, typically without tissue calcification. The symptoms may be masked by the underlying disease or the applied chemotherapy. Imaging should start with echocardiography, followed by cardiac CT or MRI if necessary.

Pericarditis without tamponade may be treated conservatively or by pericardiocentesis for diagnostic purposes or if haemodynamic compromise/tamponade occurs. Pericardial constriction may happen in up to 20% of patients, requiring pericardiectomy. The operative mortality is high (21%) and the postoperative five years survival rate is very low (1%)  mostly due to myocardial fibrosis.

Chylopericardium

Chylopericardium refers to a communication between the pericardial sac and the thoracic duct, as a result of trauma, congenital anomalies, or as a complication of open-heart surgery, mediastinal lymphangiomas, lymphangiomatous hamartomas, lymphangiectasis, and obstruction or anomalies of the thoracic duct. Infection, tamponade or constriction may aggravate the prognosis.The pericardial fluid is sterile, odourless, and opalescent with a milky white appearance and the microscopic finding of fat droplets. The chylous nature of the fluid is confirmed by its alkaline reaction, specific gravity between 1010 and 1021, Sudan III stain for fat, the high concentrations of triglycerides (5–50 g/l) and protein (22–60 g/l).

Enhanced computed tomography, alone or combined with lymphography, can identify not only the location of the thoracic duct but also its lymphatic connection to the pericardium. Treatment depends on the aetiology and the amount of chylous accumulation. Chylopericardium after thoracic or cardiac operation is preferably treated by pericardiocentesis and diet (medium chain triglycerides). If further production of chylous effusion continues, surgical treatment is mandatory (level of evidence B, indication I). When conservative treatment and pericardiocentesis fail, pericardio-peritoneal window is a reasonable option. Alternatively, when the course of the thoracic duct was precisely identified, its ligation and resection just above the diaphragm is the most effective treatment. In secondary chylopericardium the underlying disease should be treated.

Drug- and toxin-related pericarditis

Pericardial reactions to drugs are rare. However, several medications and toxic substances can induce pericarditis, tamponade, adhesions, fibrosis, or constriction.  Mechanisms include drug induced lupus reactions, idiosyncrasy, “serum sickness”, foreign substance reactions, and immunopathy. Management is based on the discontinuation of the causative agent and symptomatic treatment.

 

Drug- and toxin-related pericardial disease

 

 

 

Pericardial effusion in thyroid disorders

Pericardial effusion occurs in 5–30% of patients with hypothyroidism. Fluid accumulates slowly and tamponade occurs rarely. In some cases cholesterol pericarditis may be observed. The diagnosis of hypothyroidism is based on serum levels of thyroxin and thyroid stimulating hormone. Bradycardia, low-voltage of the QRS and T wave inversion or flattening in the ECG, cardiomegaly in the roentgenogram and pericardial effusion in echocardiography, as well as a history of radiation induced thyroid dysfunction, myopathy, ascites, pleural effusion and uveal oedema may be observed. Therapy with thyroid hormone decreases pericardial effusion (level of evidence B, indication I).

Pericardial effusion in pregnancy

There is no evidence that pregnancy affects susceptibility to pericardial disease. However, many pregnant women develop a minimal to moderate clinically silent hydropericardium by the third trimester. Cardiac compression is rare. ECG changes of acute pericarditis in pregnancy should be distinguished from the slight ST-segment depressions and T-wave changes seen iormal pregnancy. Occult constriction becomes manifest in pregnancy due to the increased blood volume.Most pericardial disorders are managed as ionpregnant.Caution is necessary while high-dose aspirin may prematurely close the ductus arteriosus, and colchicine is contraindicated in pregnancy. Pericardiotomy and pericardiectomy can be safely performed if necessary and do not impose a risk for subsequent pregnancies. Foetal pericardial fluid can be detected by echocardiography after 20 weeks’ gestation and is normally 2 mm or less in depth. More fluid should raise questions of hydrops foetalis, Rh disease, hypoalbuminemia, and immunopathy or maternally transmitted mycoplasmal or other infections, and neoplasia.

Pericardiocentesis

Pericardiocentesis is life saving in cardiac tamponade (level of evidence B, class I indication) and indicated in effusions 20 mm in echocardiography (diastole) but also in smaller effusions for diagnostic purposes (pericardial fluid and tissue analyses, pericardioscopy, and epicardial/pericardial biopsy)(level of evidence B, class IIa indication). Aortic dissection is a major contraindication. Relative contraindications include uncorrected coagulopathy, anticoagulant therapy, thrombocytopenia 50000/mm³, small, posterior, and loculated effusions. Surgical drainage is preferred in traumatic haemopericardium and purulent pericarditis.

Pericardiocentesis guided by fluoroscopy is performed in the cardiac catheterisation laboratory with ECG monitoring. Direct ECG monitoring from the puncturing needle is not an adequate safeguard. Right-heart catheterisation can be performed simultaneously, allowing exclusion of constriction. It is prudent to drain the fluid in 1 l steps to avoid the acute right-ventricular dilatation. The subxiphoid approach has been used most commonly, with a long needle with a mandrel (Tuohy or thin-walled 18-gauge) directed towards the left shoulder at a 30° angle to the skin. This route is extrapleural and avoids the coronary, pericardial, and internal mammary arteries. The operator intermittently attempts to aspirate fluid and injects small amounts of contrast. If haemorrhagic fluid is freely aspirated a few millilitres of contrast medium may be injected under fluoroscopic observation (sluggish layering inferiorly indicates that the needle is correctly positioned). A soft J-tip guidewire is introduced and after dilatation exchanged for a multi-holed pigtail catheter. It is essential to check the position of the guidewire in at least two angiographic projections before insertion of the dilator and drainage catheter.

Echocardiographic guidance of pericardiocentesis is technically less demanding and can be performed at the bedside. Echocardiography should identify the shortest route where the pericardium can be entered intercostally (usually in the sixth or seventh rib space in the anterior axillary line). Prolonged pericardial drainage is performed until the volume of effusion obtained by intermittent pericardial aspiration (every 4–6 h) fall to 25 ml per day. The feasibility is high (93%) in patients with anterior effusion ≥10 mm while the rate of success is only 58% with small, posteriorly located effusions. Fluoroscopic and haemodynamic monitoring improve feasibility (93.1% vs. 73.3%) in comparison to emergency pericardial puncture with no imaging control. The tangential approach using the epicardial halo phenomenon in the lateral view significantly increased the feasibility of fluoroscopically guided pericardiocentesis in patients with small effusions (200–300 ml)(92.6% vs. 84.9%) and very small effusions (<200 ml)(89.3% vs. 76.7%). Pericardiocentesis with echocardiography guidance was feasible in 96% of loculated pericardial effusions. Rescue pericardiocentesis guided by echocardiography relieved tamponade after cardiac perforation in 99% of 88 patients, and was the definitive therapy in 82%.

The most serious complications of pericardiocentesis are laceration and perforation of the myocardium and the coronary vessels. In addition, patients can experience air embolism, pneumothorax, arrhythmias (usually vasovagal bradycardia), and puncture of the peritoneal cavity or abdominal viscera. Internal mammary artery fistulas, acute pulmonary oedema, and purulent pericarditis were rarely reported. The safety was improved with echocardiographic or fluoroscopic guidance. Recent large echocardiographic series reported an incidence of major complications of 1.3–1.6%. In fluoroscopy-guided percutaneous pericardiocenteses cardiac perforations occurred in 0.9%, serious arrhythmias in 0.6%, arterial bleeding in 1.1%, pneumothorax in 0.6%, infection in 0.3%, and a major vagal reaction in 0.3%. Incidence of major complications was further reduced by utilizing the epicardial halo phenomenon for fluoroscopic guidance.

Pericardioscopy and epicardial/pericardial biopsy

Introduction of pericardioscopy and contemporary pathology, virology, and molecular biology techniques have improved the diagnostic value of epicardial/pericardial biopsy. Pericardioscopy makes possible to inspect pericardial surface, select the biopsy site, and take numerous samples safely. Targeted pericardial/epicardial biopsy during pericardioscopy was particularly useful in the diagnosis of neoplastic pericarditis. No major complications occurred in any of the flexible pericardioscopy studies. Mortality reported in the studies with rigid endoscopes was 2.1%, and 3.5%due to induction of anaesthesia in patients with very large pericardial effusions.

Histology of epicardial/pericardial biopsies can establish the diagnosis in patients with neoplastic pericarditis and tuberculosis. Diagnosis of viral pericarditis can be established by PCR techniques with much higher sensitivity and specificity in comparison to viral isolation from fluid and tissue. Immunohistochemistry, especially IgG-, IgM- and IgA- and complement fixation contribute significantly to the diagnostic value of epicardial biopsy. Specificity of immunoglobulin fixation in autoreactive pericarditis is 100%. Complement fixation was found primarily in patients with the autoreactive form and rarely in patients with neoplastic pericarditis.Malignant mesotheliomas can be distinguished from pulmonary adenocarcinomas by immunohistochemical staining for CEA, surfactant apoprotein, Lewis a, and Tn antigen.

Summary treatment

Proposed management strategy for patients with moderate or severe pericardial effusion accompanying acute pericarditis. PE: Pericardial effusion; PP: Purulent pericarditis; AIP: Acute idiopathic pericarditis; P-centesis: Pericardiocentesis.

 

 

 References.

A – Main:

1.     Davidson’s Principles and practice of medicine (21^st revised ed.) / by Colledge N.R., Walker B.R., and Ralston S.H., eds. – Churchill Livingstone, 2010. – 1376 p.

2.     Harrison’s principles of internal medicine (18^th edition) / by Longo D.L., Kasper D.L., Jameson J.L. et al. (eds.). – McGraw-Hill Professional, 2012. – 4012 p.

3.     The Merck Manual of Diagnosis and Therapy (nineteenth Edition)/ Robert Berkow, Andrew J. Fletcher and others. – published by Merck Research Laboratories, 2011.

4.     Web -sites:

A.   http://intranet.tdmu.edu.ua/data/kafedra/internal/index.php?&path=vnutrmed2/classes_stud

B.   www.eular.org

C.   www.rheumatology.org

D.   http://emedicine.medscape.com/

E.    http://meded.ucsd.edu/clinicalmed/introduction.htm

 

B – Optional:

1.     Braunwald’s Heart Disease: a textbook of cardiovascular medicine (9^th ed.) / by Bonow R.O., Mann D.L., and Zipes D.P., and Libby P. eds. – Saunders, 2012. – 2048 p.

2.     Braunwald’s Heart Disease: review and assessment (9^th ed.) / Lilly L.S., editor. – Saunders, 2012. – 320 p.

3.     Oxford Handbook of Cardiology (2^nd ed.) / by Ramrakha P., Hill J., eds. – Oxford University Press, 2012. – 851 p.