MYOCARDITIS, PERICARDITIS

Myocarditis is an underdiagnosed cause of acute heart failure, sudden death, and chronic dilated cardiomyopathy. In developed countries, viral infections commonly cause myocarditis; however, in the developing world, rheumatic carditis, Trypanosoma cruzi, and bacterial infections such as diphtheria still contribute to the global burden of the disease. The short-term prognosis of acute myocarditis is usually good, but varies widely by cause. Those patients who initially recover might develop recurrent dilated cardiomyopathy and heart failure, sometimes years later. Because myocarditis presents with non-specific symptoms including chest pain, dyspnoea, and palpitations, it often mimics more common disorders such as coronary artery disease. In some patients, cardiac MRI and endomyocardial biopsy can help identify myocarditis, predict risk of cardiovascular events, and guide treatment. Finding effective therapies has been challenging because the pathogenesis of chronic dilated cardiomyopathy after viral myocarditis is complex and determined by host and viral genetics as well as environmental factors. Findings from recent clinical trials suggest that some patients with chronic inflammatory cardiomyopathy have a progressive clinical course despite standard medical care and might improve with a short course of immunosuppression.

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 can be classified by cause, histology, immunohistology, and clinicopathological and clinical criteria (panel, figure 1). 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.

 

Panel

Selected classifications for myocarditis

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)

Clinicopathological

• Fulminant

• Acute

• Chronic active

• Chronic persistent

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.

Figure 1

Histological samples from patients with myocarditis!

(A) Endomyocardial biopsy showing an extensive interstitial lymphoplasmacytic infiltrate associated with myocardial necrosis in a patient with myocarditis. Presence of T lymphocytes (B) and macrophages (C) shown by antibody stains against CD3 and CD68. Image courtesy of Joesph J Maleszewski.

Although classifications on the basis of endomyocardial biopsy (EMB) results clearly have value, we have organised this Seminar around clinical classification for two reasons: (1) most clinical facilities have limited abilty to perform EMB and (2) the clinical value of EMB to provide prognosis and guide treatment is unproven for many clinical scenarios. We propose a three-tiered classification for acute myocarditis, which is primarily distinguished by increasing diagnostic certainty (table 1). An asymptomatic patient can be classified as having possible subclinical acute myocarditis if other causes of acute cardiac disease are excluded, and if they have a recent trigger for myocarditis, such as a recent viral illness, and one of the following findings: (1) an otherwise unexplained rise in troponin concentrations; (2) electrocardiographic changes suggestive of acute myocardial injury; or (3) abnormal cardiac function on echocardiogram or cardiac MRI. If a patient meets the criteria for possible subclinical myocarditis but also has one of four clinical syndromes consistent with acute myocarditis (acute heart failure, chest pain, presyncope or syncope, or myopericarditis), then they can be categorised as having probable acute myocarditis. If myocarditis is confirmed by histological studies, then the diagnosis is definite myocarditis, irrespective of the clinical syndrome.

Table 1

A three-tiered clinical classification for the diagnosis of myocarditis on the basis of level of diagnostic certainty

 

ECG=electrocardiogram.

In the course of chronic DCM, myocarditis can present as clinical deterioration without a clear cause. No clinically available serological or imaging tests can reliably identify inflammation or active cardiac viral infection in chronic DCM. Therefore, in patients with chronic DCM who deteriorate despite usual heart failure management, EMB might be considered to guide cause-specific treatment.

Common clinical scenarios associated with myocarditis

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,5 yet the incidence of clinical myocarditis is lower at 5·5 per 10 000.6 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.7 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 (figure 2). 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.

Figure 2

Lyme disease in a patient with myocarditis

(A) Erythema migrans (bull’s eye rash) in a patient with Lyme myocarditis. (B) Electrocardiogram from the patient revealed complete heart block.

Heart failure associated with progressive or chronic DCM

Myocarditis defined by immunohistological criteria is present in up to 40% of patients with chronic DCM who have symptoms of heart failure despite standard medical care. In patients with chronic DCM, imunohistological evidence of myocarditis is much more common than inflammation on routine histology. Kindermann and colleagues showed that the risk of death or need for cardiac transplantation in patients with myocarditis is worse in those with inflammation than in those without, as assessed by immunohistology. Findings from a case-control study suggested that patients with heart failure caused by chronic myocarditis and anti-cardiac antibodies but no viral genomes on EMB had a good response to immunosuppressive treatment. In a randomised, placebo-controlled trial, a course of prednisone and azathioprine improved left ventricular function in patients with chronic inflammatory cardiomyopathy and no active viral infection.

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.29, 30 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.31, 32 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.33, 34 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.35 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.36T 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.37, 38 Systolic and diastolic left ventricular dysfunction and ventricular arrhythmias have been documented in a high percentage of patients with chronic asymptomatic Chagas disease.39 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.40 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.41, 42 DCM in HIV can occur from cardiotoxicity induced by viral glycoprotein 120, opportunistic infections, autoimmune response, drug-related cardiac toxicity, and possibly nutritional deficiencies.43 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.44 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.44 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.

Non-infectious causes of myocarditis are uncommon but important because of the substantial morbidity associated with these conditions and the potential for specific treatments. For example, patients with systemic inflammatory diseases such as rheumatoid arthritis have an increased cardiovascular mortality rate compared with the general population. In patients with extra-articular manifestations of rheumatoid arthritis, the incidence of non-ischaemic cardiomyopathy, such as myocarditis, was estimated to be as high as 39% in the 1980s. This rate has decreased with the advent of disease-modifying anti-rheumatic drugs. The refinement of non-invasive diagnostic methods, such as cardiac MRI, to differentiate between ischaemic and non-ischaemic cardiac manifestation of rheumatoid arthritis are needed to further reduce the cardiac morbidity and mortality associated with rheumatoid arthritis and other systemic inflammatory disorders.

Eosinophilic myocarditis can be grouped by cause, including types associated with systemic disease (eg, hypereosinophilic syndrome, Churg-Strauss syndrome, and malignancies); those associated with drugs or vaccines (hypersensitivity eosinophilic myocarditis); and those associated with parasitic infections such as Toxocara canis49 and idiopathic acute necrotising eosinophilic myocarditis.50 Hypersensitivity myocarditis is particularly difficult to recognise because the clinical features characteristic of a drug hypersensitivity reaction—including non-specific skin rash, malaise, fever, and eosinophilia—are absent in most cases.51, 52Drugs associated with hypersensitivity myocarditis include clozapine, sulfonamide antibiotics, methyldopa, and some anti-seizure drugs. The rate of possible myocarditis after smallpox vaccination was 5·5 per 10 000 in the US civilian vaccination programme.6Fortunately, myocarditis after other vaccines is rare.

Acute necrotising eosinophilic myocarditis and giant-cell myocarditis are two rare idiopathic disorders that present with fulminant or acute heart failure, which is frequently associated with ventricular arrhythmias or heart block. These disorders share histological features of extensive myocyte necrosis, little fibrosis in the acute setting, and an eosinophil-rich infiltrate, suggesting that they might share a common pathogenesis. Both disorders might respond to multi-drug immunosuppression.54 In the case of giant-cell myocarditis, treatment with cyclosporine, high-dose steroids, and muromonab-CD3 was associated with a 91% 1-year survival.55

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.56, 57 From the pathophysiological point of view, the disease can be conceptually divided into three phases: (1) acute viral, (2) subacute immune, and (3) chronic myopathic.

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.58—60 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.

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.

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.64 A family of matrix metalloproteinases, including urokinase-type plasminogen activator, contribute to cardiac dilatation and inflammation.33 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.33 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.

When myocarditis is suspected, more common causes of cardiovascular disease, such as atherosclerotic and valvular heart disease, should be excluded according to present American Heart Association (AHA), American College of Cardiology Foundation (ACCF), European Society of Cardiology (ESC), and Heart Failure Society of America (HFSA) guidelines.

In patients with clinically suspected acute myocarditis, confirmatory testing usually begins with serum biomarkers. Troponin 1 was raised in 34% of patients with acute myocarditis who had up to 2 years of symptoms at the time of enrolment into the US Myocarditis Treatment Trial cohort.68 However, in sicker patients who were treated in hospital and who had acute or fulminant myocarditis, creatine kinase-MB concentrations of greater than 29·5 ng/mL predicted in-hospital mortality with a sensitivity of 83% and a specificity of 73%. In acute or fulminant myocarditis, higher interleukin-10 and soluble Fas concentrations are associated with an increased risk of death; however, tests for these markers are not commonly used clinically. In acute myocarditis, presence of anti-heart antibodies might predict risk of death or need for transplantation. Non-specific serum markers of inflammation, such as C-reactive protein, erythrocyte sedimentation rate, and leucocyte count, are frequently increased in patients with suspected myocarditis, but low specificity limits their diagnostic value.

There are non-specific changes on ECG in most patients with myocarditis. These changes include sinus tachycardia, ST-wave and T-wave abnormalities, and occasionally atrioventricular or bundle branch block. Electrocardiographic changes that are associated with poor prognosis in acute myocarditis include widened QRS and Q waves. Pericarditis with PR depression and diffuse ST segment elevation often accompanies epicardial inflammation.

New regional or global wall motion abnormalities that are not associated with a coronary distribution are a useful confirmatory and prognostic finding in acute myocarditis. In fulminant cases, there might be wall thickening due to oedema, and increased ventricular sphericity. Impaired right ventricular function is a strong predictor of death or need for transplantation. In one study, 14 of 23 patients, of those with right ventricular dysfunction died or needed a transplant compared with none of those with normal right ventricular function (p=0·03).76 Perhaps the greatest value of standard echocardiography in the assessment of acute myocarditis is for exclusion of primary valvular and congenital disease or pericardial constriction.

Cardiac MRI is becoming routine and is a sensitive non-invasive test for confirmation of acute myocarditis.77 In 82 patients with non-ischaemic DCM and myocarditis, all of whom had EMB, the correct diagnosis was obtained with cardiac MRI alone in 66 patients (80%). The sensitivity and specificity of cardiac MRI for the diagnosis of acute myocarditis varies with the sequences used (table 2). A combination of T2-weighted MRI and post-gadolinium early and late T1-weighted MRI provides the best sensitivity (67%) and specificity (91%) for diagnosis. However, T1 weighted imaging after gadolinium contrast might not distinguish acute myocarditis from chronic scarring.

 

Table 2

Accuracy of several combinations of cardiac MRI tissue criteria for the diagnosis of myocarditis

PPV=positive predictive value. T2=T2-weighted MRI. LGE=late gadolinium enhancement. Adapted with permission from Friedrich and colleagues.

Histological or immunohistological evidence of an inflammatory cell infiltrate with or without myocyte damage is the gold standard for the diagnosis of myocarditis. In clinical practice, EMB should be used when the incremental prognostic and therapeutic information gained from biopsy outweighs the risk and cost. An AHA/ACCF/ESC joint scientific statement3 recommended that EMB should be done (class 1 indication) in patients with heart failure and (1) a normal sized or dilated left ventricle, less than 2 weeks of symptoms, and haemodynamic compromise; or (2) a dilated ventricle, 2 weeks to 3 months of symptoms, new ventricular arrhythmias or Mobitz type 2 second-degree or third-degree heart block, or who fail to respond to usual care within 1—2 weeks. The scientific statement recommends that EMB be considered in several other clinical scenarios for which there is less robust evidence of incremental diagnostic, prognostic, or therapeutic value.

Since the publication of the joint scientific statement, the major complication rate of EMB has been shown to be less than one in 1000 when done by experienced operators.81 A strategy of early EMB in children with suspected acute myocarditis can be used to identify those who will respond to medical treatment and to decrease the need for heart transplantation.82 Left ventricular biopsy is as safe as right ventricular biopsy.83 Finally, EMB-based criteria (inflammation present on immunohistology and viral genomes absent on PCR) can identify patients with chronic DCM who respond to immunosuppression. The decrease in procedural risk and increase in diagnostic and therapeutic value is extending the role of EMB at medical referral centres that have the necessary technical expertise.

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.65—67

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.84, 85 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.86

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,87 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.88—90 However, in the Intervention for Myocarditis and Acute Cardiomyopathy trial,91 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.25 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 series33 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.13, 15 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.99

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.

The aim of this Seminar was to provide a clinical classification and guidelines for the assessment and treatment of suspected myocarditis in medical environments and epidemiological research where biopsy is unfeasible at present. We have emphasised the strengths and limitations of non-invasive methods such as echocardiography and cardiac MRI. Recently, several clinical scenarios in which EMB results added unique prognostic data or guide therapy have been defined. Therefore, we recommend that patients with a class 1 indication for EMB, who present to a medical centre without EMB capability, should be transferred to a centre where EMB can be done when feasible. Finally, ongoing translation of mechanistic insights from animal models to clinical care are permitting cause-specific treatment of viral and non-viral myocarditis and improving clinical outcomes in many forms of myocarditis.

 

PERICARDIAL DISEASE

The pericardium is composed of two distinct layers. The fibrous parietal pericardium provides a protective sac around the heart to prevent sudden cardiac dilation and to minimize bulk cardiac motion. The inner, visceral pericardium is intimately related to the surface of the heart. These two layers are normally separated by 10 to 50 mL of clear fluid, an ultrafiltrate of plasma that is produced by the visceral pericardium and functions as a lubricant to minimize frictional forces between the heart and the pericardium. In health, the intrapericardial pressure is slightly negative.

Although congenital total absence of the pericardium is not associated with clinical disease, partial or localized absence of pericardium, specifically around the left atrium, may be associated with focal herniation and subsequent strangulation. This condition, usually diagnosed by thoracic computed tomography (CT) or magnetic resonance imaging (MRI), has been associated with atypical chest pain or sudden death; surgical repair often is recommended when a partial pericardial defect is confirmed. Benign pericardial cysts are rare and often seen as rounded or lobulated structures adjacent to the usual cardiac silhouette on the chest radiograph or adjacent to the right atrium on transthoracic echocardiography.

Thoracic CT

and MRI (Fig. 1) are useful for the diagnosis of these cysts.

Acquired pericardial disease may have numerous causes, most of which produce responses that are pathophysiologically and clinically similar. These responses most frequently result in acute pericarditis, pericardial effusion, or constrictive pericarditis.

FIGURE 1  A, Transverse (axial) magnetic resonance image. Note the anterior pericardial cyst (straight white arrows) and the normal pericardium (curved white arrow). B, Transthoracic echocardiogram from the apical four-chamber view demonstrating a pericardial cyst (Cy) anterior to the right atrium (RA). The left atrium (LA) and descending thoracic aorta (DO) are also seen in this view. A, (Courtesy of Robert R. Edelman, MD).

ACUTE PERICARDITIS

Definition

The most common clinical pathologic process involving the pericardium is acute pericarditis. Although multiple causes are possible (Table 1), the most common are viral infection and unknown (idiopathic). Classically, this disorder is characterized by chest pain, pericardial friction rub, diffuse electrocardiographic changes, and pericardial effusion, although sometimes neither electrocardiographic changes nor a pericardial effusion is present. The clinical syndrome is often relatively brief (days to weeks) in duration and uncomplicated, although vigilance for progression to tamponade is always prudent.

TABLE 1   —  ETIOLOGY OF PERICARDITIS

INFECTIOUS PERICARDITIS

Viral (coxsackieviruses A and B, echovirus, mumps, adenovirus, Epstein–Barr, human immunodeficiency virus, influenza)      Mycobacterium tuberculosis      Bacterial (Pneumococcus, Streptococcus, Staphylococcus, Legionella)      Fungal (histoplasmosis, coccidioidomycosis, candidiasis, blastomycosis)      Other (syphilis, parasites, Q fever)

NONINFECTIOUS PERICARDITIS

Idiopathic      Neoplasm      Metastatic (lung cancer, breast cancer, melanoma, lymphoma)      Primary (mesothelioma)      Renal failure      Trauma      Irradiation (especially for breast cancer, Hodgkin’s disease)      Myocardial infarction      Hypothyroidism      Aortic dissection with hemopericardium      Chylopericardium (thoracic duct injury)      Trauma      Post pericardiotomy      Chest wall injury or trauma      Pneumonia

HYPERSENSITIVITY PERICARDITIS

Collagen vascular disease (systemic lupus erythematosus, rheumatoid arthritis, scleroderma, acute rheumatic fever,      Sjögren’s syndrome, Reiter’s syndrome, ankylosing spondylitis)      Drug induced (procainamide, hydralazine, isoniazid; smallpox vaccine)      Post myocardial infarction (Dressler’s syndrome)      Familial Mediterranean fever

 

Clinical Manifestations

Chest pain of acute infectious (viral) pericarditis typically develops in young adults (18 to 30 years) 1 to 2 weeks after a “viral illness.” The symptoms are sudden and severe in onset, characteristically with retrosternal or left precordial pain and referral to the back and trapezius ridge. Pain may be preceded by low-grade fever (in contrast to myocardial infarction, in which the pain precedes the fever). Although radiation to the arms in a manner similar to myocardial ischemia also may occur, it is less common. The pain is often pleuritic (e.g., accentuated by inspiration or coughing) and may be aggravated (supine or left lateral decubitus posture) or relieved (upright posture) by changes in posture.

The physical examination in patients with acute pericarditis is most notable for a pericardial friction rub. Although classically described as triphasic, with systolic and early (passive ventricular filling) and late (atrial systole) diastolic components, more commonly a biphasic (systole and diastole) or a monophasic rub may be heard. The rub may be transient and positional, often best appreciated in the supine or left lateral decubitus posture. Low-grade fever, resting tachycardia, and atrial ectopy are common, but atrial fibrillation is unusual.

Diagnosis

Diagnosis must proceed expeditiously to exclude emergent problems (Fig. 2). Electrocardiographic changes (Fig. 3) are common, particularly with an infectious etiology because of associated inflammation of the superficial epicardium. During the initial few days, diffuse (limb leads and precordial leads) ST segment elevations occur in the absence of reciprocal ST segment depression. PR segment depression also is common and reflects atrial involvement. After several days, the ST segments normalize and then the T waves become inverted (in contrast to the electrocardiographic changes seen with myocardial infarction, in which the temporal relationship of the T wave inversions is earlier and precedes normalization of the ST segment changes). In a large pericardial effusion, tachycardia, loss of R wave voltage (absolute R wave magnitude of 5 mm or less in all limb leads and 10 mm or less in all precordial leads), and electrical alternans (Fig. 4) also may be seen (see Pericardial Effusion). Blood tests reflect an inflammatory state, with an elevated sedimentation rate, C-reactive protein level, and usually, leukocyte count. A mildly increased creatine kinase MB fraction and elevated troponin level occur in up to half of patients and are thought to represent epicardial inflammation rather than myocardial necrosis. If the biomarker elevation persists for several weeks or is associated with ventricular dysfunction, myocarditis with or without concomitant pericarditis should be considered.

FIGURE 2  Initial management of patients with pericarditis. ASA, aspirin; CXR, chest radiograph; ECG, electrocardiogram; JVP, jugular venous pressure; NSAIDs, nonsteroidal anti-inflammatory drugs. (Modified from Malik F, Foster E: Pericardial disease. In Wachter RM, Goldman L, Hollander H [eds]: Hospital Medicine, 2nd ed. Philadelphia, Lippincott Williams & Wilkins, 2005, p 448.)

FIGURE 3  A 12-lead electrocardiogram from a patient with acute pericarditis. Note the diffuse ST-T wave changes and PR elevation in lead aVR and PR segment depression in leads II and aVF and in the precordial leads. (Courtesy of Ary L. Goldberger, MD.)

FIGURE 4  Lead II rhythm strip taken from a patient with acute pericarditis complicated by a large pericardial effusion and tamponade physiology. Note the resting sinus tachycardia with relatively low voltage and electrical alternans. (Courtesy of Ary L. Goldberger, MD.)

If the pericardial effusion is minimal, the chest radiograph is often unrevealing, although a small left pleural effusion may be seen. With larger effusions (see below Pericardial Effusion), there may be a loss of distinct cardiac contours and “water bottle” appearance to the cardiac silhouette (Fig. 5).

FIGURE 5  Posteroanterior chest radiograph in a patient with a large pericardial effusion. Note the loss of customary heart borders and a “water bottle” configuration. (Courtesy of Sven Paulin, MD.)

Treatment

In the absence of significant pericardial effusion (see later), treatment that is directed primarily at relieving the patient’s symptoms can be successful in 85% or so of cases on an outpatient basis. Among nonsteroidal anti-inflammatory drugs, indomethacin (25 to 50 mg three times daily) is commonly prescribed, but ibuprofen (300 to 800 mg three or four times a day) or aspirin (325 to 650 mg three times daily) also may be used. Glucocorticoids (prednisone, 20 to 60 mg/day) may be useful for resistant situations. Anti-inflammatory drugs should be continued at a constant high dose until the patient is afebrile and asymptomatic for 5 to 7 days, followed by a gradual taper during the next several weeks. The use of warfarin or heparin should be avoided to minimize the risk of hemopericardium, but anticoagulation may be required in atrial fibrillation or in the presence of a coexistent prosthetic valve. Avoidance of vigorous physical activity is recommended during the acute and early convalescent periods. For patients with a first episode of viral or idiopathic pericarditis, colchicine (0.6 to 1.2 mg/day for 3 to 12 months) reduces the recurrence rate from about 32% to about 11%. Colchicine is also effective in patients with familial Mediterranean fever. Viral and idiopathic pericarditis usually is self-limited, but a quarter of patients may have recurrent pericarditis. For this group, prolonged treatment with nonsteroidal anti-inflammatory drugs (e.g., ibuprofen, 300 to 600 mg three times a day) plus colchicine (0.6 mg twice daily, declining to once daily after a year) should be considered.[2] For the 10 to 14% of patients who are intolerant of colchicine and have recurrent episodes despite high-dose nonsteroidal anti-inflammatory drugs (e.g., indomethacin, 50 mg three times a day, or ibuprofen, 800 mg four times a day), oral steroids (e.g., prednisone, 60 mg with a 2- to 4-week taper) and pericardiectomy should be considered. Patients with recurrent pericarditis are at increased risk for progression to constrictive pericarditis.

 

 

PERICARDIAL EFFUSION

Excess fluid may develop in the pericardial space in all forms of pericardial disease (Table 2). Most commonly, the fluid is exudative and reflects pericardial injury or inflammation. Serosanguineous effusions are typical of tuberculous and neoplastic disease but also may be seen in uremic and viral or idiopathic disease or in response to mediastinal irradiation. Hemopericardium is seen most commonly with trauma, myocardial rupture after myocardial infarction, catheter-induced myocardial or epicardial coronary artery rupture, aortic dissection with rupture into the pericardial space, or primary hemorrhage in patients receiving anticoagulant therapy (often after cardiac valve surgery). Chylopericardium is rare and results from leakage or injury to the thoracic duct.

TABLE 2   —  PRESENTATION AND TREATMENT OF THE MOST COMMON SPECIFIC CAUSES OF PERICARDITIS

Modified from Malik F, Foster E: Pericardial disease. In Wachter RM, Goldman L, Hollander H (eds): Hospital Medicine, 2nd ed. Philadelphia, Lippincott Williams & Wilkins, 2005, p 449.

CT = computed tomography; HIV = human immunodeficiency virus; MRI = magnetic resonance imaging; NSAIDs = nonsteroidal anti–inflammatory drugs.

 

 

 

Although the presence of pericardial effusion indicates underlying pericardial disease, the clinical relevance of the pericardial effusion is associated most closely with the rate of fluid collection, intrapericardial pressure, and subsequent development of tamponade physiology. A rapidly accumulating effusion, as in hemopericardium caused by trauma or aortic dissection, may result in tamponade physiology with collection of only 100 to 200 mL. By comparison, a more slowly developing effusion (hypothyroidism or chronic renal failure) may allow gradual stretching of the pericardium, with effusions exceeding 1500 mL in the absence of hemodynamic embarrassment.

Diagnosis

Pericardial effusion often is suspected clinically when the patient has symptoms and signs of tamponade physiology (see later), but it also may be suggested first by unsuspected cardiomegaly on the chest radiograph, especially if loss of the customary cardiac borders and a water bottle configuration are noted (Fig. 5). Fluoroscopy, which may display minimal or absent motion of cardiac borders, is performed commonly when myocardial or epicardial coronary artery perforation is suspected during a diagnostic or interventional percutaneous procedure.

In most situations, two-dimensional transthoracic (surface) echocardiography is the diagnostic imaging procedure of choice for the evaluation and qualitative assessment of suspected pericardial effusion (Fig. 6). In emergency situations, it can be performed at the bedside. The subcostal four-chamber view is the most informative imaging plane; it is particularly relevant because it allows the size and location of the effusion to be assessed from an orientation that determines whether the effusion can be drained percutaneously. Transudative effusions typically appear relatively echolucent (see Fig. 6), whereas organized-exudative and hemorrhagic effusions have an echo-filled or a ground-glass appearance (Fig. 7). Stranding, which may be appreciated in organized or chronic effusions, suggests loculation and an inability to drain the effusion fully by percutaneous approaches. In patients with large effusions, which are associated with electrical alternans (see Fig. 4), the heart may appear to swing freely within the pericardial sac.

FIGURE 6  Transthoracic echocardiogram from the subcostal approach. Note the large echolucent area/pericardial effusion (arrows) surrounding the heart. The right ventricle is compressed.

FIGURE 7  Transthoracic echocardiogram from the parasternal long-axis window in a different patient than the one in Figure 6. Note the large echo-filled pericardial effusion posterior (straight white arrows) to the left ventricle and anterior (curved white arrow) to the right ventricle. This patient had a hemorrhagic pericardial effusion that developed several weeks after aortic valve replacement and long-term warfarin treatment. A pleural effusion (black arrow) also is seen.

Cardiac Tamponade

Accumulation of fluid in the pericardium with a resultant increase in pericardial pressure and impairment of ventricular filling results in cardiac tamponade. Although progression to tamponade, which may be fatal if it is not recognized quickly and treated aggressively, occurs in 10 to 15% of patients with idiopathic pericarditis, it develops in more than 50% of patients with oncologic, tuberculous, or purulent pericarditis. The hallmarks of cardiac tamponade are increased intracardiac pressure and the resulting impaired ventricular filling and depressed cardiac output. In tamponade, ventricular filling is impaired throughout diastole; by comparison, early diastolic filling is relatively normal with pericardial constriction. Invasive hemodynamic assessment reveals equalization of right and left atrial and right and left ventricular diastolic pressures. Tamponade may not be an “all-or-none” phenomenon; mild or “low-pressure” tamponade can be seen when intrapericardial pressures are only modestly elevated, with resultant equalization of atrial pressures but not diastolic ventricular pressures.

Clinical Manifestations

The clinical features of cardiac tamponade may mimic those of heart failure, with dyspnea on exertion, orthopnea, and hepatic engorgement. Many clinical features help distinguish cardiac tamponade from constrictive pericarditis and restrictive cardiomyopathy (Table 3). The typical physical examination with tamponade includes jugular venous distention with a prominent x descent (Fig. 8), sinus tachycardia with hypotension, narrow pulse pressure, elevated (>10 mm Hg) pulsus paradoxus, and distant heart sounds. The pulsus paradoxus may be apparent with palpation, but more commonly it is measured with a sphygmomanometer during slow respiration; direct arterial monitoring is not generally necessary for quantification. A small (<10 mm Hg) pulsus is normal and is related to the ventricles being confined within the pericardium and sharing a common septum. With inspiration, right ventricular filling is enhanced, displacing the interventricular septum toward the left ventricle and exaggerating the reduction in left ventricular filling and resultant stroke volume. The exaggerated pulsus is not specific for tamponade; it also may be present with hypovolemic shock, chronic obstructive pulmonary disease, and bronchospasm.

TABLE 3   —  COMPARISON OF PHYSICAL EXAMINATION FINDINGS AND DIAGNOSTIC TEST RESULTS FOR CARDIAC TAMPONADE, CONSTRICTIVE PERICARDITIS, AND RESTRICTIVE CARDIOMYOPATHY

 

FIGURE 8  Simultaneous right atrial (RA), intrapericardial, and femoral artery (FA) pressure recordings in a patient with cardiac tamponade. Note the elevated and equilibrated intrapericardial and right atrial pressures with a prominent x descent and blunted y descent suggestive of impaired right atrial emptying in early diastole. The arterial pulse pressure is narrowed. (From Lorell BH: Profiles in constriction, restriction and tamponade. In Baim DS, Grossman W [eds]: Cardiac Catheterization, Angiography, and Intervention, 6th ed. Philadelphia, Williams & Wilkins, 2000, p 840.)

Diagnosis

For patients in whom the history or physical examination suggests tamponade, emergency transthoracic echocardiography is imperative and generally diagnostic. Echocardiographic evidence of tamponade physiology includes a compressed or small right ventricular chamber with late diastolic invagination of the right atrial and right ventricular free wall on two-dimensional imaging (Chapter 53). Because of the frequent coexistence of tachycardia, diastolic invagination sometimes is appreciated best with higher temporal resolution M-mode echocardiography. In addition to diastolic invagination, M-mode echocardiography also may show exaggerated inspiratory septal motion and variation in the duration of aortic valve opening. Localized right atrial, left atrial, and left ventricular diastolic collapse also may be seen and is particularly relevant for loculated effusions, such as effusions after trauma and cardiac surgery. Pseudoprolapse of the mitral valve may be seen because of the compressed left ventricular cavity. When surface echocardiography is inadequate, as in a post-thoracotomy patient or a patient with chest wall trauma, transesophageal echocardiography may be helpful.

Thoracic CT

and MRI may be particularly valuable for delineation of loculated pericardial effusions. Finally, Doppler echocardiography may be used to assess transtricuspid and transmitral flow profiles, with an exaggerated peak E wave respiratory variation seen in tamponade. Many of these typical echocardiographic findings may be absent in patients who have significant pulmonary artery hypertension or are on a ventilator.

Treatment

When tamponade is suggested clinically and confirmed on echocardiography, acute management includes maintenance of systolic blood pressure with volume resuscitation. In dire circumstances, immediate pericardiocentesis may be life-saving (Fig. 77-9). When time allows, right-sided heart catheterization should be performed to confirm elevated intrapericardial pressure and “equalization” of right atrial, left atrial, pulmonary capillary wedge, right ventricular diastolic, and left ventricular diastolic pressures. If echocardiography shows at least 1 cm of fluid anterior to the mid right ventricular free wall throughout diastole, percutaneous pericardiocentesis generally can be performed safely. During this procedure, a small catheter is advanced over a needle inserted into the pericardial cavity. Echocardiographic guidance is particularly useful for smaller effusions or if percutaneous pericardiocentesis is performed by less experienced operators. As much fluid as possible should be removed, with monitoring of filling pressures. Unless the cause already has been identified, pericardial fluid should be sent for evaluation (including pH, glucose, lactate dehydrogenase, protein, cell count, and cytology as well as staining and culture for bacteria, fungi, and tuberculosis). A flexible drainage catheter may be left in the pericardial space for several days to avoid early reaccumulation. Before the catheter is removed, serial echocardiography should be performed to confirm that the fluid has not reaccumulated. Hemodynamically significant effusions of less than 1 cm, organized or multiloculated effusions, and focal effusions confined to the posterior or lateral cardiac borders or around the atria should be approached surgically through a limited thoracotomy-mediastinoscopy and pericardial window. For all effusions related to a malignant neoplasm and for which aggressive chemotherapy is not being administered, reaccumulation in the ensuing weeks or months is the norm, and elective surgery (pericardial window) should be considered before hospital discharge. Hemorrhagic effusions related to cardiac trauma or aortic dissection also are managed best by emergency surgery (if it is available) or in combination with temporizing pericardiocentesis. If the patient is in extremis, emergency pericardiocentesis should be performed at the bedside.   FIGURE 9  Aspiration of pericardial fluid is indicated in cardiac tamponade or to obtain fluid for diagnostic purposes. A wide-bore needle is inserted in the epigastrium below the xiphoid process and advanced in the direction of the medial third of the right clavicle. The procedure is preferably performed in a catheterization laboratory under echocardiographic guidance, but it may need to be performed emergently for life-saving purposes in other settings. If the needle is connected to the V lead of an electrocardiographic monitor, ST elevation usually is seen if the needle touches the epicardium. This can be useful in distinguishing a bloody pericardial effusion from accidental puncture of the heart. Other complications of the procedure may include arrhythmias, vasovagal attack, and pneumothorax. (From Forbes CD, Jackson WF: Color Atlas and Text of Clinical Medicine, 3rd ed. London, Mosby, 2003, with permission.)

 

 Approach to Effusion without Tamponade

For patients with suspected pericardial effusion, transthoracic echocardiography is the initial test of choice and in most patients is definitive in confirming the presence or absence of a significant pericardial effusion (loculated effusions may be identified better by CT or MRI). If a small (0.5 to 1 cm) echolucent or “organized” pericardial effusion is seen, the patient generally can be observed with a follow-up echocardiogram in 1 to 2 weeks (sooner if clinical deterioration is evident). If the follow-up study shows a smaller effusion, subsequent echocardiograms are not necessary (unless the patient’s clinical condition changes). Assuming a clinical history of “viral” pericarditis, assessment of renal function and thyroid-stimulating hormone is reasonable, but the results probably will be normal. A tuberculin skin test should be performed routinely. One also should exclude a drug-induced etiology (e.g., cromolyn, hydralazine, isoniazid, phenytoin, procainamide, reserpine).

In a moderate (1 to 2 cm) or large (>2 cm) pericardial effusion, treatment and follow-up depend on the clinical scenario and echocardiographic findings. If the patient is clinically unstable and tamponade is suggested (see earlier), urgent cardiology consultation and diagnostic or therapeutic pericardiocentesis should be planned. If the patient is hemodynamically stable and tamponade is not suggested, the patient can be observed with a follow-up echocardiographic study performed in 1 to 7 days. The initial evaluation is the same as listed earlier for a small effusion. Follow-up echocardiographic studies should be continued until the size of the effusion is minimal, but echocardiograms need not be repeated until complete resolution. If bacterial or malignant pericarditis is suspected, diagnostic pericardiocentesis should be performed even in the absence of clinical instability or suggestion of tamponade; tuberculous pericarditis is diagnosed best by pericardial biopsy. A tuberculin skin test, complete blood count with differential, platelet count, and coagulation parameters also should be assessed. Anticoagulation with heparin or warfarin should be discontinued unless the patient has a mechanical heart valve or atrial fibrillation. Blood cultures are indicated if an infectious cause is suspected. Complement, antinuclear antibodies, and the sedimentation rate may be helpful if systemic lupus erythematosus is being considered, although isolated pericardial effusion is unlikely to be the first manifestation of this disorder. Pericarditis after myocardial infarction (Dressler’s syndrome) is now unusual; given experimental laboratory evidence that some of the nonsteroidal drugs promote left ventricular aneurysm formation in this setting, aspirin is the preferred agent to relieve pain in Dressler’s syndrome. The presence of an echo-filled effusion should raise concern for hemorrhagic or organized pericarditis, which may progress to constriction.

 Chronic or Recurrent Pericardial Effusions

With chronic or recurrent pericarditis from any cause, pericardial calcification develops and can be appreciated by thoracic CT (Fig. 10). Symptoms are those of a chronic systemic illness and include weight loss, fatigue, and dyspnea on exertion.

FIGURE 10  Transverse computed tomography of a 32-year-old patient with anterior and posterior pericardial calcification (arrows). (Courtesy of Noriko Oyama, MD.)

The evaluation of chronic pericarditis should exclude the possibility of tuberculosis; a tuberculin skin test, chest radiograph, and (when highly suspicious) analysis of gastric aspirates should be performed. Pericardial biopsy is more commonly diagnostic of tuberculous pericarditis than is pericardial fluid staining or culture. Aggressive drug treatment is indicated.

Hypothyroidism-myxedema is another common cause of large pericardial effusions, especially in the elderly. The effusion commonly is identified first on a chest radiograph and often is seen in the absence of resting tachycardia. Measurement of thyroid-stimulating hormone is diagnostic. The effusion and coexistent cardiomyopathy respond to hormone replacement, but sometimes slowly during several months. In the absence of hemodynamic compromise, pericardiocentesis often is not needed in this situation as the effusion has developed slowly and does not present hemodynamic compromise. Uremic pericardial effusions also are common and often respond to initiation of or more intensive dialysis.

Treatment of chronic or recurrent idiopathic effusions is similar to the treatment of recurrent pericarditis. If medical therapy is unsuccessful, creation of a pericardial window is indicated.

CONSTRICTIVE PERICARDITIS

Constrictive pericarditis is an uncommon condition with impairment of mid and late ventricular filling from a thickened or noncompliant pericardium. In the classic form, fibrous scarring and adhesions of both pericardial layers lead to obliteration of the pericardial cavity. Early ventricular filling is unimpeded, but diastolic filling subsequently is reduced abruptly as a result of the inability of the ventricles to fill because of physical constraints imposed by a rigid, thickened, and sometimes calcified pericardium. In less developed countries, tuberculosis is the most common cause of chronic constrictive pericarditis, whereas in the United States, tuberculosis is infrequently the culprit. Constriction may be associated with malignant disease (lung cancer, breast cancer, lymphoma), histoplasmosis, mediastinal irradiation, purulent or recurrent viral pericarditis, rheumatoid arthritis, uremia, chest trauma or hemopericardium, and cardiac surgery. Constriction may follow cardiac surgery by several weeks to months and may occur decades after chest wall irradiation. The “cause” may not be identified in many patients.

Pathobiology

The normal pericardium is 3 mm or less thick. With chronic constriction, especially from tuberculosis, the pericardium may thicken to 6 mm or more, calcify, and intimately involve the epicardium. In subacute constriction, calcification is less prominent, and the pericardium may be only minimally thickened. As with cardiac tamponade, the pathophysiologic process of constriction includes impaired diastolic ventricular filling, which leads to elevated venous pressure. Tamponade and constriction have many important differences (see Table 3), however. With constriction, the impairment in ventricular filling is minimal in early diastole, and a prominent y descent is present (Fig. 11). Subsequently, diastolic pressure rises abruptly when cardiac volume reaches the anatomic limit set by the noncompliant pericardium; by comparison, in tamponade, ventricular filling is impaired throughout diastole. Diastolic pressure remains elevated until the onset of systole. This prominent y descent with an elevated plateau of ventricular pressure has been termed the “dip and plateau” or “square root” sign (Fig. 12); by comparison, in tamponade, the y descent is absent. Stroke volume and cardiac output are reduced because of impaired filling, whereas intrinsic systolic function of the ventricles may be normal or only minimally impaired.

FIGURE 11  Right atrial (RA) pressure recording from a patient with constrictive pericarditis. Note the elevation in pressure and prominent y descent corresponding to rapid early diastolic right atrial emptying. (From Lorell BH: Profiles in constriction, restriction and tamponade. In Baim DS, Grossman W [eds]: Cardiac Catheterization, Angiography, and Intervention, 6th ed. Philadelphia, Williams & Wilkins, 2000, p 832.)

FIGURE 12  Simultaneous left ventricular (LV) and right ventricular (RV) pressure recordings in a patient with constrictive pericarditis. Note the equilibration of LV and RV diastolic pressures and the “dip and plateau” most apparent with the prolonged diastole. (From Lorell BH: Profiles in constriction, restriction and tamponade. In Baim DS, Grossman W [eds]: Grossman’s Cardiac Catheterization, Angiography, and Intervention, 6th ed. Philadelphia, Lippincott Williams & Wilkins, 2000, p 832.)

Clinical Manifestations

In constriction, the most prominent physical finding is an abnormal jugular venous pulse. Central venous pressure is elevated and displays prominent x and y descents. For patients in sinus rhythm, the x descent is coincident with the carotid pulse. The y descent, which is absent or diminished in tamponade, is most prominent and abbreviated because of a rapid rise in pressure in mid-diastole. A diagnosis of constriction always should be suspected in patients with a prominent y descent with dyspnea, weakness, anorexia, peripheral edema, hepatomegaly, splenomegaly, and ascites. The pulse pressure is oftearrowed, but pulsus paradoxus is usually absent. Pleural effusions are common. The clinical picture may mimic hepatic cirrhosis, but with distended neck veins. Venous pressure often fails to fall with inspiration (Kussmaul’s sign), and arterial pulse pressure is normal or reduced. The apical pulse is often poorly defined, and heart sounds may be distant. A loud S₃, the pericardial knock, may be audible early after aortic valve closure because of the sudden deceleration in ventricular filling.

Diagnosis

The electrocardiogram of patients with constriction is often abnormal and displays low QRS voltage (especially in the limb leads), P mitrale, and nonspecific ST-T wave changes. Atrial fibrillation may be present in one third of patients. The chest radiograph may show pericardial calcification in tuberculous constriction. Though suggestive, the finding of pericar-dial calcification is not diagnostic of constriction. Cardiac size may be small, normal, or enlarged. Transthoracic echocardiography is less helpful than with cardiac tamponade, but it may display pericardial thickening or calcification, abrupt posterior deflection of the interventricular septum at end diastole, and M-mode posterior wall “flat tiring.” Enhanced transmitral and transtricuspid Doppler E wave variation with respiration may be particularly helpful in establishing the diagnosis. The inferior vena cava and hepatic veins often are markedly dilated with blunted respiratory variability in caval diameter. Newer tissue Doppler imaging is also helpful to distinguish constrictive pericarditis from restrictive cardiomyopathy; constrictive pericarditis displays normal or enhanced early diastolic indexes.

Increased pericardial thickness is diagnosed most reliably by CT or MRI (see Fig. 10). CT is more helpful for the identification of pericardial calcification. Right atrial, inferior vena cava, and hepatic vein distention also are seen commonly with CT and MRI. Like chest radiography, CT and MRI do not indicate the physiologic significance of these anatomic findings and need to be interpreted in the context of the clinical findings.

At cardiac catheterization, patients with chronic constrictive pericarditis usually have elevation (>15 mm Hg) and equalization (within 5 mm Hg) of right atrial, right ventricular diastolic, pulmonary capillary wedge, and left ventricular diastolic pressures. Right ventricular end-diastolic pressure is often one third of systolic pressure, and pulmonary artery hypertension is mild. Cardiac output usually is depressed. Right atrial pressure is characterized by a preserved x descent with a prominent early diastolic y descent. The right atrial pressure fails to decrease appropriately or may rise during inspiration. Right and left ventricular diastolic pressures display an early diastolic dip followed by a plateau (see Fig. 12), although this finding may be difficult to appreciate if the patient is tachycardic or in atrial fibrillation.

Treatment

Constrictive pericarditis occasionally may reverse spontaneously when it develops in acute pericarditis. More commonly, the natural history of this disease is one of progression with declining cardiac output and progressive renal and hepatic failure. Surgical stripping or removal of both layers of the adherent pericardium is the definitive therapy. The benefits of pericardial stripping may be modest initially but continue to be manifested in the ensuing months. Operative mortality is generally low but may exceed 5 to 15% in the most advanced cases. The surgical risk is related to the extent of myocardial involvement and the severity of secondary hepatic or renal dysfunction. For patients with suspected tuberculous constriction, antituberculosis therapy should be administered before and after pericardial surgery. In addition to advanced age and systolic dysfunction, postirradiation constriction is a predictor of worse prognosis.

 

Effusive-Constrictive Pericarditis

Effusive-constrictive pericarditis is a rare disorder occurring in about 1% of patients who have pericarditis and approximately 7% of patients with tamponade. It is characterized by the combination of a tense pericardial effusion in the presence of visceral pericardial constriction and may represent an intermediate stage in the development of constrictive pericarditis. Causes of effusive-constrictive pericarditis are the same as those associated with constriction, and the clinical features resemble those of tamponade and constriction. Physical examination shows pulsus paradoxus and a prominent x descent in the absence of a y descent. The cardiac silhouette is generally enlarged because of the associated pericardial effusion, whereas the electrocardiogram displays low QRS voltage and nonspecific ST-T wave changes. Surface echocardiography may show an echo-filled pericardial effusion with thickened pericardium and fibrinous pericardial bands. Although this echocardiographic appearance should heighten suspicion, the diagnosis generally is made after successful pericardiocentesis. Rather thaormalizing after pericardiocentesis, intracardiac pressures remain elevated with a square root sign in the ventricular tracings and development of a prominent y descent in the atrial and jugular venous pressure pulses. Kussmaul’s sign also may be evident. Treatment by excision of visceral and parietal pericardium is usually effective. A transient, self-limited form of effusive-constrictive pericarditis has also been reported.

Overview of keypoints

Definition

 

Myocarditis is an inflammatory disease of the myocardium, caused by direct or indirect influence of infectious pathogens (viruses, bacteria, parasites), toxins, chemical or physical agents, allergic reactions and events in context of systemic/autoimmune diseases.

 

Terminology

 

According to clinical course myocarditis is described as “fulminant”, “acute”, or “chronic” (>14 days). Histological terminology has been standardized according to Dallas and WHO Marburg criteria (see Diagnosis section below). The World Heart Federation introduced the term “inflammatory cardiomyopathy” – a new entity among secondary (specific) cardiomyopathies defined as chronic myocarditis with impaired systolic function (1995). In 1997 the World Heart Federation panel reached consensus defining ‘chronic myocarditis’ interchangeably with “inflammatory cardiomyopathy” or “dilated inflammatory cardiomyopathy”.

 

Epidemiology

The true incidence of myocarditis in the community is unknown. Myocarditis is found in up to 20% of unexpected sudden deaths in young adults, and in around 40% of cases of new-onset heart failure in children. Up to 40% of patients with chronic dilated cardiomyopathy who fail to respond to standard medical care have immunohistochemical evidence of myocarditis. Approximately 1 % of population infected with cardiotropic viruses have clinical evidence of cardiac involvement (up to 5% in Coxsackie B viral infection). Most studies of acute myocarditis show a slight preponderance in males, which may be due to a protective effect of hormones in women.

Etiology

 

Infective myocarditis

– Viral myocarditis (50% of cases) is most frequently associated with cardiotropic strains of Coxsackie viruses (B1-B6) and to a lesser extent with Adenovirus. Other viruses that have also been associated less frequently with myocarditis include parvovirus B19, echovirus, cytomegalovirus, hepatitis C virus, Epstein-Barr virus, Human Immunodeficiency virus, and human herpesvirus 6.

– Bacteria: Brucella, Corynebacterium diphtheriae, Salmonella, Haemophilus influenzae, Mycoplasma pneumoniae, Neisseria meningitidis (meningococcus), Streptococcus pneumoniae, Staphylococcus, Mycobacterium, Neisseria gonorrhoeae (gonococcus), Vibrio cholerae.

– protozoa: trypanosoma cruzi (Chagas’ disease), toxoplasma gondii, leishmania. – spirochetes: Treponema pallidium, Borrelia burdgorferi (Lyme disease), Leptospira. – other (fungal, rickettsial, parasitic)   noninfective myocarditis – immune-mediated disorders: autoantigens – Churg-Strauss syndrome, celiac disease, Whipple’s disease, giant cell myocarditis, Kawasaki’s disease, systemic lupus erythematosus, systemic sclerosis, sarcoidosis, scleroderma, polymyositis, thrombocytopenic purpura; alloantigens – heart transplant rejection; drug-induced hypersensitivity reactions (penicillin, sulfonamides, tetracycline, methyldopa, streptomycin, tricyclic antidepressants, thiazide diuretics, dobutamine, indomethacin). – toxic causes: alcohol, drugs (anthracyclines, catecholamines, amphetamines, cocaine, cyclophosphamide, 5-fluorouracil, herceptin, interferon, interleukin-2), physical agents (electric shock, radiation, hyperpyrexia), heavy metals (copper, iron, lead), other (arsenic, snake bites, scorpion bites, wasp and spider stings, phosphorus, carbon monoxide). – cardiac sarcoidosis (idiopathic granulomatous Fiedler’s myocarditis)

 

Pathogenesis

 

Contributory factors of myocardial dysfunction include:

1) a direct cytototoxic of a viral, bacterial or other agent;

2) a secondary immune response triggered by any of the infective or non-infective agents;

3) cytokine expression in the myocardium;

4) induction of apoptosis.

 

Clinical presentation

 

The clinical manifestations of myocarditis are variable, ranging from subclinical disease to profound cardiogenic shock and sudden death. Some patients may be asymptomatic with abnormalities being detected incidentally on ECG or echocardiogram. Around 60% of patients have a viral prodrome with fever, myalgia, and respiratory or gastrointestinal symptoms, occurring 7 to 10 days prior to cardiac involvement. Around 70% of patients have dyspnea, 35% have chest pain, and 20% have arrhythmias. Children often have a more fulminant presentation. Chest pain in acute myocarditis may result from associated pericarditis or from coronary artery spasm. Syncope and sudden death can be the initial manifestations of myocarditis due to complete heart block or ventricular arrhythmias.

Physical examination findings include fever, tachycardia, and signs of congestive heart failure. The first heart sound may be soft, gallop rhythm may be present, an apical systolic murmur of mitral regurgitation and a pericardial friction rub may be present.

 

Diagnosis

 

A diagnosis of myocarditis most often results from patient’s history and the exclusion of other heart diseases, particularly coronary artery disease and valvulopathy (Table 1).

 

Table 1. Evaluation of suspected myocarditis

 

Clinical evaluation

Thorough history and physical examination to identify cardiac and noncardiac disorders      Assessment of ability to perform routine and desired activities      Assessment of volume status

Laboratory evaluation

Electrocardiogram      Chest radiograph      Two-dimensional and Doppler echocardiogram      Chemistry      Serum sodium, potassium, glucose, creatinine, blood urea nitrogen, calcium, magnesium      Albumin, total protein, liver function tests, serum iron, ferritin      Urinalysis      Creatine kinase      Thyroid-stimulating hormone      Hematology      Hemoglobin/hematocrit      White blood cell count with differential, including eosinophils      Erythrocyte sedimentation rate (ESR)

Initial evaluation in selected patients only

Titers for suspected infection      Acute viral (coxsackievirus, echovirus, influenza virus)      Human immunodeficiency virus, Epstein-Barr virus      Lyme disease, toxoplasmosis      Chagas’ disease      Catheterization with coronary angiography in patients with angina who are candidates for intervention      Serologic studies for active rheumatologic disease      Endomyocardial biopsy

From McKenna W. Diseases of the myocardium and endocardium. In: Goldman L. and Ausiello D.A., eds. Cecil Medicine . 23rd edition. Philadelphia, PA: Saunders Elsevier; 2007: chap. 59.

 

Laboratory findings may demonstrate leukocytosis, eosinophilia, elevated ESR, C-reactive protein, and occasionally elevated titers to cardiotropic viruses. These findings are generally nondiagnostic due to low specificity. Biomarkers of cardiac injury are elevated in some patients with acute myocarditis. Troponin I may help to confirm the diagnosis of acute myocarditis with a high specificity (89%), but low sensitivity (34%). An increase in the myocardial band (MB) of creatine phosphokinase (CPK) may be observed in approximately 10% of patients.

Electrocardiogram most frequently shows sinus tachycardia, nonspecific ST-T changes, conduction delay, low voltage, prolonged QT interval, and occasionally acute infarct patterns (ST-segment elevation, ST-segment depression, and pathologic Q-waves). The sensitivily of the electrocardiogram for myocarditis is limited (47%).

Echocardiogram. There are no specific echocardiographic features of acute myocarditis. Ventricular contractility may be unaffected during an early stage, while diastolic dysfunction is observed more frequently. Regional and global wall motion abnormalities are seen in up to 60% of cases and may simulate myocardial infarction. However, wall motion abnormalities in myocarditis are not associated with a coronary distribution. Wall thickening (pseudohypertrophy due to inflammation) and increased ventricular sphericity may be present. Ventricular thrombi are seen in 15% of patients. Overall, echocardiographic patterns of dilated, hypertrophic, restrictive, and ischemic cardiomyopathies have been described in histologically proven myocarditis.

Chest roentgenography may show heart enlargement and signs of pulmonary congestion.

Cardiac MRI with delayed enhancement sequences may be used to visualize tissue edema and to characterize inflammatory changes as well as to localize the sites for endomyocardial biopsy. Myocardial inflammation leads to characteristic T2-weighted images and gadolinium-enhanced T1 images identifying areas of myocardial injury. Typical findings suggestive of myocarditis include diffuse or heterogeneous involvement of the lateral wall, subepicardial, or mid-myocardial regions sparing the subendocardium.

Endomyocardial biopsy (EMB) should be considered on the basis of the likelihood of finding specific treatable disorders. According to the joint scientific statement of the American Heart Association, the American College of Cardiology, and the European society of Cardiology (2007) should be performed in two clinical scenarios, describing the most common presentation of fulminant myocarditis and giant-cell myocarditis (class I recommendation). These scenarios include:

– unexplained, new-onset heart failure of less than 2 weeks’ duration in association with a normal or dilated left ventricle and hemodynamic compromise (for suspected fulminant myocarditis);

– unexplained new-onset heart failure of 2 weeks’ to 3 months’ duration in association with a dilated left ventricle and new ventricular arrhythmias or II-III degree heart block, and in patients with lack of response to usual care within 1 to 2 weeks (for suspected giant-cell myocarditis).

The standard Dallas pathological criteria (1987) separate initial biopsies into active myocarditis, borderline myocarditis, and no myocarditis. On subsequent biopsies myocarditis is classified as ongoing (persistent), resolving (healing) or resolved (healed). The WHO Marburg criteria (1996) define myocarditis as a minimum of 14 infiltrating leukocytes/mm², preferably activated T cells.

 

Dallas Criteria

– active myocarditis: the presence of an inflammatory infiltrate of the myocardium with necrosis and/or degeneration of adjacent myocytes not typical of the ischaemic damage associated with coronary artery disease;

– borderline myocarditis: the presence of an inflammatory infiltrate of the myocardium without necrosis or degeneration of adjacent myocytes.

The inflammatory infiltrate should be further described as lymphocytic, eosinophilic, neutrophilic, giant cell, granulomatous, or mixed. The amount of inflammation may be mild, moderate or severe, and its distribution may be focal, confluent or diffuse, respectively. Localization or formation of fibrosis should be outlined as endocardial, replacement, or interstitial.

 

The Dallas criteria, however, have considerable limitations, yielding diagnostic information in only 10 to 20% of cases. Sampling error remains a significant limitation leading to the low sensitivity of EMB. MRI-guided biopsy my improve the sensitivity of the technique. Furthermore, the incidence of myocarditis is underestimated when standard Dallas criteria are used. Myocyte-specific major histocampatibility (MCH) antigen expression detected by immunohistochemical staining or the presence of viral genome in the myocardium demonstrated by molecular techniques (such as in situ hybridization or polymerase chain reaction) have been found in a significant percentage of patients presenting with unexplained dilated cardiomyopathy. These newer approaches now permit more accurate identification of patients with dilated (inflammatory) cardiomyopathy due to unrecognized myocarditis, as well as further stratification of inflammatory cardiomyopathy into type with viral persistence or autoimmune type.

Although EMB still provides the most specific diagnosis for myocarditis, most clinical facilities still have limited ability to perform EMB and the clinical value of EMB remains unproven for many clinical scenarios. A combination of clinical, laboratory and cardiac MRI criteria may help to diagnose myocarditis without necessarily performing biopsy in all cases (Table 2).

 

Table 2 – Expanded Criteria for Diagnosis of Myocarditis

 

Suggestive of myocarditis:	2 positive categories
Compatible with myocarditis:	3 positive categories
High probability of being myocarditis:	all 4 categories positive
(Any matching feature in category = positive for category)
Category I: Clinical Symptoms
Clinical heart failure     Fever     Viral prodrome     Fatigue     Dyspnea on exertion     Chest pain     Palpitations     Presyncope or syncope
Category II: Evidence of Cardiac Structural or Functional Perturbation in the absence of Regional Coronary Ischemia
Echocardiography evidence     Regional wall motion abnormalities     Cardiac dilation     Regional cardiac hypertrophy     Troponin release     High sensitivity (>0.1 ng/mL)     Positive indium-111 antimyosin scintigraphy and     Normal coronary angiography or     Absence of reversible ischemia by coronary distribution on perfusion scan
Category III: Cardiac Magnetic Resonance Imaging
Increased myocardial T2 signal on inversion recovery sequence     Delayed contrast enhancement after gadolinium-DTPA* infusion
Category IV: Myocardial biopsy—Pathologic or Molecular Analysis
Pathology findings compatible with Dallas criteria     Presence of viral genome by polymerase chain reaction or in situ hybridization
* DPTA = diethylenetriamine penta-acetic acid
From Liu P., Baughman K.L. Myocarditis. In: Bonow R.O., Mann D.L., Zipes D.P., Libby P., eds. Braunwald’s Heart Disease: a textbook of cardiovascular medicine. 9th ed. Philadelphia, Pa: Saunders Elsevier; 2011:chap. 70.

 

Differential diagnosis

 

Acute myocarditis masquerading as acute coronary syndrome is occasionally seen and differential diagnosis may be challenging, since the affected patients complain of chest pain, the ECG changes are similar to those observed in acute coronary syndromes, and serum cardiac markers are increased. Normal coronary angiogram allows to exclude coronary artery disease. Clinically, acute myocarditis should be considered in young patients who present with chest pain when the coronary risk profile is low, ECG abnormalities extend beyond a single coronary artery territory, atypical ECG evolution, with slow ST segment normalization and no Q wave appearance, global rather than segmental left ventricular systolic dysfunction is seen on echocardiography. In such a clinical scenario coronary angiography is preferable to thrombolysis in order to avoid potential life-threatening side effects of thrombolysis, and EMB is not indicated.

 

Treatment

 

The treatment of myocarditis is supportive (class I, level C). Patients presenting with heart failure should be treated according to the current guidelines with a standard heart failure regimen, including angiotensin-converting-enzyme inhibitors or angiotensin-receptor blockers, beta-blockers, aldosterone antagonist, and diuretics, if needed. Rarely, a mechanical circulatory support, such as ventricular assist devices or extracorporeal membrane oxygenation may be needed, as a bridge to cardiac transplantation or recovery. Temporary pacemakers may be required for patients with symptomatic bradycardia or complete heart block. patients with aymptomatic or sustained ventricular tachycardia may need amiodarone or implantable cardioverter-defibrillator (ICD). The decision to prophylactically implant an ICD in patients with advanced left ventricular dysfunction should be postponed for several month to allow enough time for ventricular function recovery.

Antiviral therapy. Patients with viral genome expression may benefit from antiviral agents. Ribavirin, interferon-alpha, and interferon-beta have been shown hemodynamic and clinical benefits, however, data on their efficacy are currently limited to animal models and small case series. Interferon-beta has been shown to be the most effective in animal models. In patients treatment with interferon-beta also resulted in effective elimination of the viral genome and improvement of left ventricular function as well as of the clinical status. The clinical trial of interferon-beta in myocarditis is currently ongoing.

Intravenous immune globuline (IVIG). Antiviral and immunomodulatory effects of IVIG have been shown in experimental and uncontrolled studies. However, a study of IVIG within the Intervention in Myocarditis and Acute Cardiomyopathy trial (2001) did not demonstrate benefits of IVIG as compared with placebo. Therefore, the use of IVIG is not recommended for the treatment of acute myocarditis in adults, although IVIG may be used for the treatment of acute myocarditis in a pediatric population and in patients refractory to immunosuppressive therapy.

Immunosuppressive therapy. The results of immunosuppressive trials with prednisone and either cyclosporine or azathioprine did not show benefits of immunosupression in acute lymphocytic myocarditis. Unlike lymphocitic myocarditis, immunosuppression with a combination of cyclosporine and corticosteroids may prolong transplant-free survival in patients with giant-cell myocarditis. Immunosuppression can also benefit patients with myocarditis due to systemic autoimmune disease, particularly, systemic lupus erythematosus, scleroderma, and polymyositis. Patients with dilated cardiomyopathy and increased MHC expression on EMB are also more likely to respond to immunosuppression.

Immune adsorption therapy is a physical approach to remove circulating proinflammatory and cardiodepressant factors as well as cardiac autoantibodies thorough plasmapheresis of peripheral blood. This method has shown promising results in one randomized trial (demonstrating improvement of both left ventricular systolic function and symptomatic status), however objective endpoints, such as

death or hospitalization, have not been examined.

Overall, routine use of general or specific immunological therapies for myocarditis has not been recommended, as this has not been shown to alter outcomes, and may lead to side effects or complications (class III, level B). Immune therapy may be considered in those who have failed to improve spontaneously (Fig. 1).

 

 

 

 

 

 

Figure 1. Treatment algorithms for patients with myocarditis.

ACEi = angiotensin-converting enzyme inhibitors; AICD = automatic implantable cardioverter-defibrillator; ARB = angiotensin receptor blocker; CMR = cardiac magnetic resonance; EMB = endomyocardial biopsy; indiv = based on individual assessment of risk versus benefit; LVEF = left ventricular ejection fraction; VAD = ventricular assist device

From Liu P., Baughman K.L. Myocarditis. In: Bonow R.O., Mann D.L., Zipes D.P., Libby P., eds. Braunwald’s Heart Disease: a textbook of cardiovascular medicine. 9th ed. Philadelphia, Pa: Saunders Elsevier; 2011:chap. 70.

 

	Figure 1. Treatment algorithms for patients with myocarditis. ACEi = angiotensin-converting enzyme inhibitors; AICD = automatic implantable cardioverter-defibrillator; ARB = angiotensin receptor blocker; CMR = cardiac magnetic resonance; EMB = endomyocardial biopsy; indiv = based on individual assessment of risk versus benefit; LVEF = left ventricular ejection fraction; VAD = ventricular assist device From Liu P., Baughman K.L. Myocarditis. In: Bonow R.O., Mann D.L., Zipes D.P., Libby P., eds. Braunwald’s Heart Disease: a textbook of cardiovascular medicine. 9th ed. Philadelphia, Pa: Saunders Elsevier; 2011:chap. 70.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Physical activity recommendations

 

Patients recovering from acute myocarditis should refrain from aerobic exercise for a period of months after the clinical onset of the disease. This recommendation is based on animal studies of myocarditis, in which increased death rates were associated with sustained exercise. The reintroduction of aerobic exercises depends on the severity of myocardial dysfunction and the degree of recovery. In general, current heart failure guidelines should be applied to patients with heart failure recovering from myocarditis.

 

Prognosis

Predicting prognosis for the individual patient with myocarditis remains problematic. The prognosis is good in myocarditis mimicking acute myocardial infarction as usually a complete recovery is observed. Fulminant myocarditis (active lymphocytic myocarditis on EMB) has also been described as having a favourable long-term prognosis with >90% event-free survival, but acute care often requires inotropic or mechanical circulatory support as a bridge to recovery. Patients who present with heart failure and mildly decreased left ventricular systolic function (left ventricular ejection fraction [LVEF] 40 to 50%) would typically improve within weeks to months. Among patients presenting with severe left ventricular dysfunction (LVEF<35%, left ventricular end-diastolic dimension >60 mm), 50% will develop chronic ventricular dysfunction, 25% will progress to heart transplantation or death, while the remaining 25% will experience spontaneous improvement of their left ventricular function. Giant-cell myocarditis is associated with the worst prognosis: the median survival is 5.5 month from the onset of heart failure symptoms or arrhythmias, and the 5-year survival rate is <20%.

 

Specific forms of myocarditis

 

Fulminant myocarditis is characterized by abrupt onset. Patients present with severe hemodynamic compromise, often requiring pressors or mechanical support. Echocardiogram shows diffuse global hypokinesis, thickening of myocardial walls due to edema. Cardiac cavities are rarely dilated. Peripheral edema is often absent.  EMB reveals diffuse myocarditis in virtually each histologic section. The long-term prognosis, however, is good, reemphasizing the need of aggressive support of these patients in acute care.

Giant-cell myocarditis. It is a distinct clinicopathologic form of myocarditis with a high risk of death or need for cardiac transplantation. The pathogenesis of giant-cell myocarditis is suspected to be autoimmune iature because of its association with autoimmune disorders, thymoma, Crohn’s disease, and drug hypersensitivity.

It is more subtle in onset than fulminant myocarditis. Patients present with heart failure, arrhythmias, heart blocks which fail to improve despite optimal medical therapy. EMB reveals giant cells with active inflammation and scar tissue. The rate of death or transplantation is about 90%. Prolonged high-dose multiagent immunosuppression may improve the prognosis. After cardiac transplantation for giant-cell myocarditis patients have a 20-25% risk of recurrence in the allograft heart.

Chagas’ disease (or American Trypanosomiasis) is an infection caused by Trypanosoma cruzi. Although it is limited to Central and South America (particularly Brazil and Argentina), it is considered to be the most frequent non-viral myocardial infection. The disease is transmitted by hematophagous triatomine insects (reduvii bugs, commonly called the kissing bugs), however infection can also result from maternal-fetal transmission, from food contaminated with feces or urine from infected Triatominae, from laboratory accidents, and from blood transfusion, which can therefore lead to isolated cases outside the endemic area. Acute myocarditis is rarely symptomatic. Years or decades after initial infection 10-30% of infected persons evolve into chronic phase of Chagas’ myocarditis, leading to arrhythmias, heart failure, and sudden death. The most common ECG findings are right bundle-branch block, left anterior hemiblock, atrial fibrillation, and premature ventricular contractions. The pathological substrate for this is extensive myocardial fibrosis. Echocardiograpghy may reveal left ventricular apical aneurysm, regional wall motion abnormalities or diffuse myocardial involvement. The diagnosis of Chagas’ disease is based on the presence of parasites in the blood or tissues. Antitripanosomal drugs (benzidazole and nifurtimox) may be effective in the acute phase of the disease or congenital infection, but not in the chronic phase. Drug therapy has little influence on the chronic course of the disease. Implantation of an ICD is frequently required for prevention of sudden cardiac death. In patients with severe heart failure, cardiac transplantation is feasible.

Lyme disease is caused by a tick-borne spirochete Borrelia burgdorferi. Patients typically develop a skin rash (erythema chronicum migrans). Cardiac involvement develops in 4 to 10% of patients with Lyme disease weeks to months later. The demonstration of spirochetes in myocardial biopsy specimens of patients with Lyme carditis suggests a direct cardiac effect. Lyme carditis should be suspected in patients with a history of a tick bite or travel to endemic regions. Most often cardiac involvement is mild and self-limited. The most common manifestations are variable degrees of heart block. Nonspecific ST segment and T wave abnormalities may be seen on ECG. Temporary pacing may be needed in patients with high-grade AV-block. AV conduction usually improves and a permanent pacemaker is rarely needed. Corticosteroids may reduce myocardial inflammation and edema, and therefore shorten the duration of heart block. The efficacy of antibiotics for Lyme carditis has not been established, although they are routinely used. In a patient with suspected Lyme disease after a tick byte, the possibility of Ehrlichia (ehrlichiosis) or Babesia (babesiosis) should be also considered as both can also cause myocarditis. Serologic tests are available for both disorders.

Human immunodeficiency virus (HIV). Myocarditis in HIV-infected patients has been described in >50% of autopsy examinations. However, manifest cardiac disease occurs only in 2-8% of cases of HIV infection. Cardiomyopathy in patients with HIV infection may be induced by the HIV itself (inhibition of cardiac contractility by HIV type 1 glycoprotein 120), by opportunistic infection (including cytomegalovirus, enteroviruses and fungi),  by therapeutic drugs (antiviral medications, antibiotics, chemotherapeutic agents) or by malnutrition (e.g., selenium deficiency in the late stage). Heart failure occurs only in late stages of AIDS. Highly active antiviral therapy (HAART) regimens permit to reduce by seven times the incidence of HIV-related cardiomyopathy, however, HAART is only available to a small percentage of the global HIV-infected population. The average survival after the onset of HIV-related severe heart failure is 1-3 months.

Introduction

 

Pericardial diseases may have different presentations either as an isolated disease or as a manifestation of a systemic disorder. The main clinical presentations include (1) acute pericarditis without effusion, (2) pericardial effusion with or without tamponade, (3) constrictive pericarditis, (4) effusive-constrictive pericarditis, (5) calcific pericarditis without constriction.

 

Etiology

The causes of pericardial diseases are varied (Table 1). The most common causes are idiopathic, viral, uraemic, neoplastic, tuberculous pericarditis, and acute myocardial infarction. Tuberculosis is the most important cause of pericardial disease in the world and developing countries, where the disease is endemic. In this setting, tuberculosis is often associated with HIV infection, especially in sub-Saharan Africa. In North American and Western European population, most cases (>80%) are idiopathic with a conventional diagnostic approach and the cause is often presumed viral.

 

Table 1. Causes of pericardial disease

 

 

ACUTE PERICARDITIS WITHOUT EFFUSION

 

syn. “dry” pericarditis

 

Etiology: any of the causes listed in Table 1 may cause dry pericarditis.

Symptoms: sharp, stabbing, central pain is common with radiation to the shoulders and upper arm. It is relieved by sitting up and leaning forward, and aggravated by lying down, and may be accentuated by inspiration, cough, swallowing, or movement of the trunk. Fever, night sweats and other symptoms may be present, depending on the underlying cause.

Signs: a pericardial friction rub is frequently heard. Positioning the patient leaning forward and listening in held inspiration may bring it out. The rub is classically described as triphasic, its components are attributed to atrial systole, ventricular systole and rapid ventricular filling.

ECG: the patient is usually in sinus rhythm, but atrial fibrillation may occur. Four stages of ST-T abnormalities may be distinguished. In stage I there is widesread ST segment elevation with concavity directed upwards, and PR segment deviation opposite to the polarity of the P wave. After a few days, in stage II,  ST and PR segments return to baseline, accompanied by T wave flattening. Stage III is characterized by inversion of the T waves. This should be contrasted with the early inversion of T waves in acute ST elevation myocardial infarction, which occurs prior to the return of ST segments to baseline. Stage IV represents reversion of the T wave changes to normal and may occur weeks to months after the acute event.

Chest X-ray: the cardiac shadow is not enlarged in dry pericarditis.

Differential diagnosis: acute pericarditis must be differentiated from myocardial infarction, spontaneous pneumothorax and pleurisy.

Diagnosis: a diagnosis of acute pericarditis is based on typical symptoms of chest pain, pericardial rub, and/or characteristic ECG changes.

Treatment: treat the undrelying cause. Pain relief can be achieved by the use of non-steroidal anti-inflammatory agents (Table 2).

 

Table 2. Empirical anti-inflammatory therapy for pericarditis

 

Drug	Attack dose	Treatment length	Tapering
Acetylsalicylic acid	750-1000 mg t.i.d.	Till symptoms and CRP normalized	Each week when CRP is normalized (i.e., 1000 mg t.i.d. for 1 week, 750 mg t.i.d. for 1 week, 500 mg t.i.d. for 1 week)
Ibuprofen	600 mg t.i.d.	Till symptoms and CRP normalized	Each week when CRP is normalized (i.e., 600-400-600 mg/day for 1 week, 600-400-400 mg/day for 1 week, 400 mg t.i.d. for 1 week)
Indomethacin	50 mg t.i.d.	Till symptoms and CRP normalized	Each week when CRP is normalized (i.e., 50-25-50 mg/day for 1 week, 50-25-25 mg/day for 1 week, 25 mg t.i.d. for 1 week)
Prednisone	0.2-0.5 mg/kg per day	Till symptoms and CRP normalized	Slow tapering when CRP is normalized
Colchicine	Attack dose not necessary. 0.5 mg b.i.d. (0.5 mg/day if <70 kg)	First attack: 3 months; recurrence: 6-12 months	May be required in recurrent form
b.i.d. = twice a day, CRP = C-reactive protein, t.i.d.= three times a day, NSAID = non-steroidal anti-inflammatory drugs. Treatment length is empirical. Generally 1-2 weeks but an individualized approach till symptom resolution and CRP normalization may be useful to reduce the subsequent recurrence rate. With the same aim a very slow tapering is recommended only after stable remission with symptom resolution and normalization of C-reactive protein: 5-10 mg/day every 1-2 weeks (prednisone daily dose >25 mg), 2.5 mg/day every 2-4 weeks (prednisone daily dose 15-25 mg), 1/0-2.5 mg/day every 2-6 weeks (prednisone daily dose <15 mg). NSAID and colchicine may be necessary during tapering of corticosteroids.
From Imazio M. Curr Opin Cardiol 2012;27:308-17

 

PERICARDIAL EFFUSION WITH OR WITHOUT TAMPONADE

 

Etiology: any of the causes listed in Table 1 may cause pericardial effusion. Large effusions are common with neoplasia, tuberculosis, uraemic pericarditis, and myxoedema.

Of note, the pericardial space normally contains 10 to 50 mL of fluid (plasma ultrafiltrate) that lubricates the contact between the two serosal layers of the pericardium.

Symptoms: chest pain may be typically pericardial (as in dry pericarditis), or it may be dull and heavy due to distension of the pericardium. Dyspnea is common. Cough may be present due to compression of surrounding structures. Other symptoms may be present, depending on the underlying cause.

Signs: typically precordial dullness extends beyond the apex beat which may be impalpable. Cardiac tamponade should be considered in a patient with hypotension, distended neck veins, and distant (muffled) heart sounds (Beck’s triad). The other clinical features of cardiac tamponade are the presence of tachycardia, pulsus paradoxus (fall in systolic blood pressure on inspiration of >10 mmHg), elevated jugular venous pressure, rise in jugular venous pressure on inspiration (Kussmaul’s sign), dyspnea or tachypnea with clear lungs, and hepatomegaly.

ECG: sinus tachycardia, generalized low-voltage QRS complexes with non-specific ST segment and T wave changes. Electrical alternans, involving the QRS complex, suggests the presence of massive pericardial effusion.

Echocardiography: is diagnostic, showing an echo-free space surrounding the heart. The fluid may be not evenly distributed. For clinical purposes, semiquantitative evaluation of the amount of pericardial fluid is usually sufficient.

For circumferential pericardial effusions, a pericardial effusion with less than 5 mm of echo-free space in diastole is considered as minimal (corresponding to a fluid volume of 50 to 100 mL), 5 to 10 mm separation is considered as small (corresponding to a fluid volume of 100 to 250 mL), 10 to 20 mm separation is considered as moderate (corresponding to a fluid volume of 250 to 500 mL), and greater than 20 mm separation is considered as large (corresponding to a fluid volume greater than 500 mL). Diastolic collapse of the right ventricle and right atrium indicate cardiac tamponade.

Benign idiopathic effusion tends to be more clear, while malignancy, bacterial infection, tuberculous and hemorrhagic effusions are more likely to be associated with thickening of the visceral pericardium and to have solid components or fibrinous strands. However, precise characterization may be elusive is more accurate with CT or MRI.

Chest X-ray: shows a large globular heart, usually with clear lung fields.

MRI: is very effective at detecting loculated effusions and pericardial thickening.

CT: can provide information about the quality of fluid in the pericardial sac. It also relays information about any underlying thoracic pathology that may yield an effusion (e.g., malignancy).

Troponins: troponin elevations are observed in 30% of patients with viral or idiopathic pericarditis, and are mostly low levels. Levels above the acute MI threshold are seen in 7.5% of patients with acute pericarditis, and likely represent associated myocarditis. Elevated troponins are more likely in younger male patients with ST-segment elevation on ECG and an effusion on echocardiography. The prognosis is good and, unlike troponin elevation in acute coronary syndromes, is not a negative prognostic marker.

Differential diagnosis: myocardial infarction, pulmonary embolism.

Treatment: when effusion does not cause hemodynamic impairment and the cause is known (e.g., myxedema), theo further investigations are necessary: trat the underlying cause. Cardiac tamponade is a life-threatening condition and requires an urgent pericardial aspiration. Surgical drainage is indicated for hemopericardium or purulent pericarditis.

 

CONSTRICTIVE PERICARDITIS

 

Etiology: The risk of developing constrictive pericarditis after an episode of acute pericarditis is low (1.8%) and depends on the etiology. Chronic constrictive pericarditis is very rare after viral or idiopathic pericarditis (<0.5%), and is highest for infectious causes (tuberculosis, 20% and purulent pericarditis, 33%). Other causes may include mediastinal radiation, previous trauma (surgical or non-surgical) with infection of the pericardial space.

Symptoms: dyspnea, oedema and abdominal swelling due to ascites and hepatomegaly.

Signs: small volume pulse and pulsus paradoxus. Jugular venous pressure is always elevated. A diastolic knock may be felt at the left sternal border due to sudden halting of the ventricles during diastolic filling. heart sounds are usually soft, and an early third sound coincident with diastolic knock is usually heard. The liver is commonly grossly enlarged, ascites is marked, and peripheral edema is present.

ECG: is always abnormal, but changes are non-specific (i.e., generalized low-voltage QRS complexes, widespread flattening and inversion of T-waves). Atrial fibrillation is common.

Echocardiography: pericardial thickening may be present. there is a restrictive mitral filling pattern on Doppler, with respiratory variation >25% over the atrio-ventricular valves (i.e., reduction >25% in peak early left ventricular inflow [E-wave] velocity with inspiration compared with <5% iormal individuals).

Chest X-ray: shows a normal or near-normal cardiac size in the presence of marked venous distension or heart failure, suggestive of constrictive pericarditis or restrictive cardiomyopathy. Pericardial calcification is diagnostic, but its incidence varies from 5 to 70% of cases in different series.

CT and MRI: demonstrate pericardial thickening (> 5 mm). Cardiac MRI with pericardial late gadolinium enhancement (> 3 mm) may predict constriction reversibility.

Cardiac catheterization: at present is considered the gold standard for the diagnosis. It demonstrates elevation and equalization of ventricular filling pressures by showing a “square-root” sign or dip-and-plateau pattern. The role of cardiac catheterization in suspected constriction is now especially considered in case of discrepancy between clinical and other diagnostic data.

Differential diagnosis: restrictive cardiomyopathy, pulmonary embolism.

Treatment: surgical removal of the fibrous constrictive tissue (pericardiectomy).

Prognosis: prognosis may not be good, with high mortality (20%) and most patients (>60%) requiring surgery with pericardiectomy regardless of the cause.

 

EFFUSIVE-CONSTRICTIVE PERICARDITIS

 

Effusive-constrictive pericarditis is an uncommon condition characterized by both pericardial effusion and constrictive pericarditis.

Etiology: this is characteristically encounterd in active tuberculous pericarditis. It may also occur ieoplastic, radiation, and septic pericarditis.

Symptoms: are usually those of constriction.

Imaging: should look for elements of pericardial effusion, a thickened pericardium or thick intrapericardial material, and evidence of constrictive physiology. The hallmark of effusive-constrictive pericarditis is persistence of constrictive physiology after adequate pericardial drainage.

Treatment: treatment of the underlying cause. Pericardial drainage may be indicated. Pericardiectomy is indicated if hemodynamics does not improve.

 

CALCIFIC PERICARDITIS WITHOUT CONSTRICTION

 

This condition is usually discovered during routine radiological examination, which demonstrates pericardial calcification. There are no symptoms nor signs of constriction, and the cause is usually unknown.

 

 

Future Directions

Access to the pericardial space may provide a new means to deliver novel gene or pharmacologic therapies for myocardial (angiogenesis, antiarrhythmics) or pericardial disease.

References:

A – Basic:

1.     Davidson’s Principles and Practice of Medicine (1st Edition) / Edited by  N. R. Colledge,    B. R. Walker,   S. H. Ralston. – Philadelphia : Churchill Livingstone, 2010. – 1376 p.

2.     Harrison‘s Principles of Internal Medicine / Dan L. Longo, A. S. Fauci, D.L. Kasper [et al.]. – New York : McGraw-Hill, 2011. – 4012 p.

3.     Kumar and Clark’s Clinical Medicine (8th Revised edition) (With STUDENTCONSULT Online Access) / Edited by P. Kumar, M. L. Clark. – London : Elsevier Health Sciences, 2012. – 1304 p.

 

 B – Additional:

1. Braunwald’s Heart Disease Review and Assessment  / L. S. Lilly. – Philadelphia : Elsevier – Health Sciences Division, 2012. – 320 p.

2. Cleveland Clinic Cardiology Board Review / by Cho L., Griffin B.P., Topol E.J., eds. – Lippincott Williams & Wilkins, 2009. – 385 p.

3. Oxford Handbook of Cardiology (2nd Revised edition) / Edited by P. Ramrakha, J.Hill. – Oxford : Oxford University Press, 2012. – 880 p.

4. Clinical Echocardiography (2 revised edition) / Edited by M. Y. Henein. – England : Springer London Ltd., 2012. – 328 p.

5. Mayo Clinic Cardiology: Concise Textbook  (4^rd ed.) / by Murphy J.G., Lloyd M.A., eds. – New York : Oxford University Press Inc., 2012. – 1608p.

6. Web -sites:

http://emedicine.medscape.com/cardiology

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